Michael Camilleri, MD¹, Henry P. Parkman, MD², Mehnaz A. Shafi, MD³, Thomas L. Abell, MD⁴ and Lauren Gerson, MD, MSc⁵

¹Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA; ²Temple University, Philadelphia, Pennsylvania, USA; ³University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; ⁴University of Mississippi, Jackson, Mississippi, USA; ⁵Stanford University, Palo Alto, California, USA.

This guideline presents recommendations for the evaluation and management of patients with gastroparesis. Gastroparesis is identified in clinical practice through the recognition of the clinical symptoms and documentation of delayed gastric emptying. Symptoms from gastroparesis include nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain. Management of gastroparesis should include assessment and correction of nutritional state, relief of symptoms, improvement of gastric emptying and, in diabetics, glycemic control. Patient nutritional state should be managed by oral dietary modifications. If oral intake is not adequate, then enteral nutrition via jejunostomy tube needs to be considered. Parenteral nutrition is rarely required when hydration and nutritional state cannot be maintained. Medical treatment entails use of prokinetic and antiemetic therapies. Current approved treatment options, including metoclopramide and gastric electrical stimulation (GES, approved on a humanitarian device exemption), do not adequately address clinical need. Antiemetics have not been specifically tested in gastroparesis, but they may relieve nausea and vomiting. Other medications aimed at symptom relief include unapproved medications or off-label indications, and include domperidone, erythromycin (primarily over a short term), and centrally acting antidepressants used as symptom modulators. GES may relieve symptoms, including weekly vomiting frequency, and the need for nutritional supplementation, based on open-label studies. Second-line approaches include venting gastrostomy or feeding jejunostomy; intrapyloric botulinum toxin injection was not effective in randomized controlled trials. Most of these treatments are based on open-label treatment trials and small numbers. Partial gastrectomy and pyloroplasty should be used rarely, only in carefully selected patients. Attention should be given to the development of new effective therapies for symptomatic control.

Am J Gastroenterol 2013; 108:18–37; doi: 10.1038/ajg.2012.373; published online 13 November 2012
Received 24 May 2012; accepted 5 October 2012

Correspondence: Michael Camilleri, Department of Gastroenterology, Mayo Clinic, 200 First Street SW, Charlton 8-110, Rochester, Minnesota 55905, USA.
E-mail: camilleri.michael@mayo.edu

This clinical guideline addresses the definition, diagnosis, differential diagnosis, and treatment of gastroparesis, including nutritional supplementation, glycemic control, pharmacological, endoscopic, device, and surgical therapy.

Each section of this document will present the key recommendations related to the section topic and a subsequent summary of the evidence supporting those recommendations. An overall summary will be presented in the first table. A search of OVID Medline, Pubmed, and ISI Web of Science was conducted for the years from 1960 to 2011 using the following major search terms and subheadings including “gastroparesis,” “electrical stimulation,” “botulinum toxin,” “drug therapy,” “glycemic control,” “dietary therapy,” and “alternative therapy”. We used systematic reviews and meta-analyses for each topic when available, followed by a review of clinical trials.

The GRADE system was used to evaluate the strength of the recommendations and the overall quality of evidence (1) (Table 1). The strength of a recommendation was graded as “strong” when the desirable effects of an intervention clearly outweigh the undesirable effects and as “conditional” when there is uncertainty about the trade-offs. The quality of evidence could range from “high” (implying that further research was unlikely to change the authors’ confidence in the estimate of the effect) to “moderate” (further research would be likely to have an impact on the confidence in the estimate of effect) or “low” (further research would be expected to have an important impact on the confidence in the estimate of the effect and would be likely to change the estimate).

Table 1. Criteria for assigning grade of evidence

Type of evidence

Randomized trial=high

Observational study=low

Any other evidence=very low

Decrease grade if:

Serious (−1) or very serious (−2) limitation to study quality

Important inconsistency (−1)

Some (−1) or major (−2) uncertainty about directness

Imprecise or sparse data (−1)

High probability of reporting bias (−1)

Increase grade if:

Strong evidence of association—significant relative risk of >2 (<0.5) based on consistent evidence from two or more observational studies, with no plausible confounders (+1)

Very strong evidence of association—significant relative risk of >5 (<0.2) based on direct evidence with no major threats to validity (+2)

Evidence of a dose response gradient (+1)

All plausible confounders would have reduced the effect (+1)

Definitions of grades of evidence

High= Further research is unlikely to change our confidence in the estimate of effect

Moderate=Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate

Low=Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate

Very low=Any estimate of effect is very uncertain

Recommendations

1. The diagnosis of gastroparesis is based on the combination of symptoms of gastroparesis, absence of gastric outlet obstruction or ulceration, and delay in gastric emptying. (Strong recommendation,
   high level of evidence)
2. Accelerated gastric emptying and functional dyspepsia can present with symptoms similar to those of gastroparesis; therefore, documentation of delayed gastric emptying is recommended before selecting therapy with prokinetics agents or gastric electrical stimulation (GES). (Strong recommendation, moderate level of evidence)

Summary of Evidence

Gastroparesis is defined as a syndrome of objectively delayed gastric emptying in the absence of mechanical obstruction and cardinal symptoms including early satiety, postprandial fullness, nausea, vomiting, bloating, and upper abdominal pain (2); the same constellation of complaints may be seen with other etiologies, including gastritis secondary to Helicobacter pylori infection, peptic ulcer, and functional dyspepsia. Symptoms have not been well correlated with gastric emptying. Nausea, vomiting, early satiety, and postprandial fullness correlate better with delayed gastric emptying than upper abdominal pain and bloating (3,4). The epidemiology and impact of gastroparesis are reviewed elsewhere (2). In summary, although a high prevalence of gastroparesis has been reported in type 1 diabetics (40%) and type 2 diabetics (10–20%), these studies were from tertiary academic medical centers where the prevalence is expected to be higher than the general population; the community prevalence was estimated to be ~5% among type 1 diabetics, 1% among type 2 diabetics, and 0.2% of controls in Olmsted County, Minnesota (5). More community-based data are required to confirm or enhance the published figures. Gastroparesis significantly impacts quality of life (6,7), increases direct health-care costs through hospitalizations, emergency room, or doctor visits, and is associated with morbidity and mortality (8,9).

The symptoms are often the same with the different etiologies of gastroparesis: nausea, vomiting, early satiety, and postprandial fullness (10). In 416 patients from the NIH Gastroparesis Registry, symptoms prompting evaluation more often included vomiting for diabetic gastroparesis (DG) and abdominal pain for idiopathic gastroparesis (IG). Patients with IG have more early satiety and abdominal pain compared with patients with DG who have more severe retching; all the patients included in these multicenter studies had documentation of delayed gastric emptying in their medical record (11,12).

Abdominal pain is an often under-appreciated symptom in gastroparesis. In a multicenter study from an NIH consortium on gastroparesis, 72% of patients with gastroparesis had abdominal pain, but was the dominant symptom in only 18% (13), reflecting the heterogeneous patient population in this cohort. A tertiary referral study showed that abdominal pain was reported in 90% of 68 patients with delayed gastric emptying (18 DG and 50 IG). Pain was induced by eating (72%), was nocturnal (74%), and interfered with sleep (66%). Severity ranking of abdominal pain was in the same range as other symptoms (e.g., fullness, bloating, and nausea) and was not correlated with gastric emptying rate, but was associated with impaired quality of life. The preponderance of the idiopathic group and large proportion of daily (43%) or even constant pain (38%) in this cohort of patients may reflect the type of referred patients often seen in tertiary academic centers (12). The presence of anxiety or depression has been associated with more severe symptoms (14,15).

The combination of symptoms and delayed gastric emptying is required to establish the diagnosis of gastroparesis as the epidemiology, natural history, pathophysiology, and treatment of gastroparesis (which are reviewed in detail elsewhere (2)) are typically based on combined criteria. Diabetes with evidence of gastroparesis on objective testing has been associated with increased health-care costs, including increased clinic visits, emergency room visits, hospitalizations, overall morbidity and mortality (8,9).

Since accelerated gastric emptying and functional dyspepsia can also present with symptoms similar to gastroparesis, documentation of delayed gastric emptying (3,16) is necessary before selecting therapy with prokinetics agents or GES.

Recommendations

1. Patients with gastroparesis should be screened for the presence of diabetes mellitus, thyroid dysfunction, neurological disease, prior gastric or bariatric surgery, and autoimmune disorders. Patients should undergo biochemical screen for diabetes and hypothyroidism; other tests are as indicated clinically. (Strong recommendation, high level of evidence)
2. A prodrome suggesting a viral illness may lead to gastroparesis (postviral gastroparesis). This condition may improve over time in some patients. Clinicians should inquire about the presence of a prior acute illness suggestive of a viral infection. (Conditional recommendation, low level of evidence)
3. Markedly uncontrolled ( > 200 mg/dl) glucose levels may aggravate symptoms of gastroparesis and delay gastric emptying. (Strong recommendation, high level of evidence.) Optimization of glycemic control should be a target for therapy; this may improve symptoms and the delayed gastric emptying. (Moderate recommendation, moderate level of evidence)
4. Medication-induced delay in gastric emptying, particularly from narcotic and anticholinergic agents and glucagon like peptide-1 (GLP-1) and amylin analogs among diabetics, should be considered in patients before assigning an etiological diagnosis. Narcotics and other medications that can delay gastric emptying should be stopped to establish the diagnosis with a gastric emptying test. (Strong recommendation, high level of evidence)
5. Gastroparesis can be associated with and may aggravate gastroesophageal reflux disease (GERD). Evaluation for the presence of gastroparesis should be considered in patients with GERD that is refractory to acid-suppressive treatment. (Conditional recommendation, moderate level of evidence)

Summary of Evidence

Diabetic (29%), postsurgical (13%), and idiopathic (36%) etiologies comprise the majority of cases in tertiary referral setting (8). Diabetes mellitus is the most commonly recognized systemic disease associated with gastroparesis. In the NIH consortium cohort, delayed gastric emptying was more pronounced in patients with type 1 DG (10). The 10-year incidence of gastroparesis has been reported to be 5.2% in type 1 diabetes, 1% in type 2 diabetes, and 0.2% in non-diabetic controls in a US community (5).

Idiopathic gastroparesis refers to a symptomatic patient from delayed gastric empting with no detectable primary underlying abnormality for the delayed gastric emptying. This may represent the most common form of gastroparesis (10,17). Most patients with IG are women; typically young or middle aged. Symptoms of IG overlap with those of functional dyspepsia; it may be difficult to provide a definitive distinction between the two based on symptoms, and many regard IG and functional dyspepsia with delayed gastric emptying as the same condition. Abdominal pain/discomfort typically is the predominant symptom in functional dyspepsia, whereas nausea, vomiting, early satiety, and bloating predominate in IG. Therefore, measurement of gastric emptying is important, as therapies differ if gastric emptying is delayed, normal, or rapid.

A subset of patients with gastroparesis report sudden onset of symptoms after a viral prodrome, suggesting a potential viral etiology for their symptoms, and the diagnosis of postviral gastroparesis (18,19). Previously, healthy subjects have developed the sudden onset of nausea, vomiting, diarrhea, fever, and cramps suggestive of a systemic viral infection. However, instead of experiencing resolution of symptoms, these individuals note persistent nausea, vomiting, and early satiety. Over a period of about a year, the gastroparesis often improves. In general, this course is typical of postviral gastroparesis that is not associated with autonomic neuropathy. On the other hand, a minority of patients with infections due to viruses such as cytomegalovirus, Epstein–Barr virus, and varicella zoster may develop a form of autonomic neuropathy (generalized or selective cholinergic dysautonomia) that includes gastroparesis. These patients with autonomic dysfunction may have slower resolution of their symptoms that may take several years and the prognosis is worse than in postviral gastroparesis without autonomic disorders (20,21).

Postsurgical gastroparesis (PSG), often with vagotomy or vagus nerve injury, represents the third most common etiology of gastroparesis. In the past, most cases resulted from vagotomy performed in combination with gastric drainage to correct medically refractory or complicated peptic ulcer disease. Since the advent of laparoscopic techniques for the treatment of GERD, gastroparesis has become a recognized complication of fundoplication (possibly from vagal injury during the surgery) or bariatric surgery that involves gastroplasty or bypass procedures. The combination of vagotomy, distal gastric resection, and Roux-en-Y gastrojejunostomy predisposes to slow emptying from the gastric remnant and delayed transit in the denervated Roux efferent limb. The Roux-en-Y stasis syndrome—characterized by postprandial abdominal pain, bloating, nausea, and vomiting—is particularly difficult to manage, and its severity may be proportional to the length of the Roux limb (generally, 25 cm is ideal to avoid stasis).

The precise role of the antireflux surgery itself is not clearly demonstrated in the published literature. Thus, while symptoms suggesting gastric stasis are extremely common in the first 3 months after fundoplication, they persist in a minority of patients at 1 year post surgery. In a series of 615 patients who underwent laparoscopic Nissen fundoplication, all had symptoms during the first 3 postoperative months (e.g., early satiety in 88% and bloating/flatulence in 64%); however, by 1 year these symptoms suggestive of gastroparesis like bloating/flatulence had resolved in >90% of patients (22). Moreover, among 81 patients with antireflux operations followed for >1 year, the finding of postoperative symptoms suggesting delayed gastric emptying was usually associated with delayed gastric emptying pre-operatively (23). The precise role of fundoplication is therefore difficult to determine unless the patient undergoes testing for abdominal vagal dysfunction, such as the plasma pancreatic polypeptide response to modified sham feeding; such tests are described elsewhere (24).

In patients with refractory symptoms of GERD, investigation for delayed gastric emptying should be considered, since delayed gastric emptying can be associated with GERD and possibly aggravate symptoms of heartburn, regurgitation, and other symptoms associated with GERD.

Known causes of iatrogenic gastroparesis include surgical vagal disruption, which may be due to vagal nerve injury (e.g., after fundoplication for GERD), or intentional vagotomy as part of peptic ulcer surgery. The second major category of iatrogenic gastroparesis is induced by pharmacological agents as may occur with narcotic opiate analgesics, anticholinergic agents, and some diabetic medications. Administration of μ-opiate receptor agonists results in delayed gastric emptying and also may cause nausea and vomiting. These include agents such as morphine (25), as well as oxycodone and tapentadol (26), but less with tramadol (27). Therefore, patients receiving such agents should first undergo withdrawal of the agent before assuming a diagnosis of gastroparesis. GLP-1 analogs, such as exenatide, used for treatment of type 2 diabetes mellitus (28) can delay gastric emptying. In contrast to GLP-1 analogs, which substantially increase plasma GLP-1 concentrations, dipeptidyl peptidase IV inhibitors, which increase plasma GLP-1 concentrations by inhibiting metabolism of GLP-1, do not delay gastric emptying (29). Nausea (43.5%) was the most commonly reported adverse event with exenatide treatment, and vomiting was also quite commonly encountered (12.8% (30)). The antirejection drug, cyclosporine, can delay gastric emptying. Thus, in patients with prior pancreatic transplantation treated with antirejection treatment with cyclosporine, there may be delay in gastric emptying (31). This does not apply to another calcineurin inhibitor, tacrolimus, which is derived from a macrolide molecule and retains prokinetic properties (32).

Other rarer causes of gastroparesis include diseases affecting the extrinsic neural control (such as Parkinsonism, amyloidosis, and paraneoplastic disease) or disorders that result in infiltration or degeneration of the muscle layer of the stomach (such as scleroderma). Mesenteric ischemia should also be considered as a rare cause of gastroparesis that is potentially reversible.

Recommendations

1. Documented delay in gastric emptying is required for the diagnosis of gastroparesis. Scintigraphic gastric emptying of solids is the standard for the evaluation of gastric emptying and the diagnosis of gastroparesis. The most reliable method and parameter for diagnosis of gastroparesis is gastric retention of solids at 4 h measured by scintigraphy. Studies of shorter duration or based on a liquid challenge result in decreased sensitivity in the diagnosis of gastroparesis. (Strong recommendation, high level of evidence)
2. Alternative approaches for assessment of gastric emptying include wireless capsule motility testing and 13 C breath testing using octanoate or spirulina incorporated into a solid meal; they require further validation before they can be considered as alternates to scintigraphy for the diagnosis of gastroparesis. (Conditional recommendation, moderate level of evidence)
3. Medications that affect gastric emptying should be stopped at least 48 h before diagnostic testing; depending on the pharmacokinetics of the medication, the drug may need to be stopped > 48 h before testing. (Strong recommendation, high level of evidence)
4. Patients with diabetes should have blood glucose measured before starting the gastric emptying test, and hyperglycemia treated with test started after blood glucose is < 275 mg/dl. (Strong recommendation, moderate-high level of evidence)

Summary of evidence

There are three tests to objectively demonstrate delayed gastric emptying: scintigraphy, wireless motility capsule (WMC), and breath testing.

For any type of gastric emptying test, patients should discontinue medications that may affect gastric emptying. For most medications, this will be 48–72 h. These include medications that can delay gastric emptying, such as narcotic opioid analgesics and anticholinergic agents. These agents may give a falsely delayed result. Medications that accelerate gastric emptying, such as metoclopramide, domperidone, and erythromycin, may give a falsely normal result. Hyperglycemia (glucose level >200 mg/dl) delays gastric emptying in diabetic patients. It is recommended to defer gastric emptying testing until relative euglycemia (blood glucose <275 mg/dl) is achieved in diabetics to obtain a reliable determination of emptying parameters in the absence of acute metabolic derangement.

The conventional test for measurement of gastric emptying is scintigraphy (33,34). Gastric emptying scintigraphy of a solid-phase meal is considered as the standard for diagnosis of gastroparesis, as it quantifies the emptying of a physiologic caloric meal. For solid-phase testing, most centers use a ^99mTc sulfur colloid-labeled egg sandwich as the test meal, with standard imaging at 0, 1, 2, and 4 h. A 4-h gastric emptying scintigraphy test using radiolabeled EggBeaters (ConAgra Foods Inc., Omaha, NE, USA) meal with jam, toast, and water is advocated by the Society of Nuclear Medicine and The American Neurogastroenterology and Motility Society (34). Assessment of gastric emptying over 4 h is necessary (35). Shorter duration solid emptying or sole liquid emptying by scintigraphy is associated with lower diagnostic sensitivity. Measurement of liquid gastric emptying, simultaneously or in addition to solid emptying, has been advocated as a means of increasing sensitivity (by an estimated 25–36% in non-diabetics) to detect the presence of gastroparesis in patients with upper gastrointestinal (GI) symptoms (36,37). On the other hand, the clinical significance of selectively delayed gastric emptying of liquids has not been assessed, for example, in terms of its value in predicting response of symptoms to treatment. There is evidence that the effect of hyperglycemia on gastric emptying in diabetics is more clearly demonstrated in the retardation of the gastric emptying of liquids (38).

The most reliable parameter to report gastric emptying is the gastric retention at 4 h. Gastric emptying T_1/2 is also acceptable if imaging has been performed for 4 h or at least to 50% emptying, as extrapolation to measure t_1/2 may be erroneous. However, it is also important to assess emptying at least 1 and 2 h after radiolabeled meal ingestion, since prolongation of the early phases of emptying may also be associated with symptoms of gastroparesis, even though the gastric retention at 4 h is normal or mildly delayed. Gastric emptying T_1/2 can be quite easily inferred from the linear interpolation of the data points at 1, 2, and 4 h, since the emptying phase of solids is generally linear after the initial lag phase and gastroparesis due to neuropathic or myopathic motility disorders retards gastric emptying T_1/2 (39,40,41).

A WMC that measures pH, pressure, and temperature can assess gastric emptying by the acidic gastric residence time of the capsule. Gastric emptying is determined when there is a rapid increase in the pH recorded indicating emptying from the acidic stomach to the alkaline duodenum. The gastric residence time of the WMC (e.g., SmartPill, Given Imaging, Yoqneam, Israel) had a high correlation 85% with the T-90% of gastric emptying scintigraphy (that is the time when there was only 10% of the meal remaining in the stomach), suggesting that the gastric residence time of the WMC represents a time near the end of the emptying of a solid meal (42). The overall correlation between gastric emptying time of the WMC and gastric emptying at 4 h by scintigraphy was 0.73. A 5-h gastric residence time of the WMC was best to differentiate subjects with delayed or normal gastric emptying based on scintigraphy conducted simultaneously with sensitivity of 83%and specificity of 83%.

Breath testing has been used in both clinical and clinical research studies for determining gastric emptying (43). These breath tests using ¹³C-octanoate or -spirulina (44) provide reproducible results that correlate with results on gastric emptying scintigraphy, including responsiveness to pharmacological therapy. The optimization of mathematical models for measurement of gastric emptying derived from breath excretion profiles has been thoroughly examined in the literature (45). Both WMC and breath testing require further validation before they can be considered as alternates to scintigraphy for diagnosis of gastroparesis.

Recommendations

1. The presence of rumination syndrome and/or eating disorders (including anorexia nervosa and bulimia) should be considered when evaluating a patient for gastroparesis. These disorders may be associated with delayed gastric emptying, and identification of these disorders may alter management. (Strong recommendation, moderate-high level of evidence)
2. Cyclic vomiting syndrome (CVS) defined as recurrent episodic episodes of nausea and vomiting, should also be considered during the patient history. These patients may require alternative
   therapy. (Conditional recommendation, moderate level of evidence)
3. Chronic usage of cannabinoid agents may cause a syndrome similar to CVS. Patients presenting with symptoms of gastroparesis should be advised to stop using these agents. (Conditional recommendation, low level of evidence)

Summary of Evidence

The vomiting symptom of a patient can be difficult to differentiate from the regurgitation seen in GERD or the regurgitation seen in rumination syndrome. Rumination syndrome is a condition characterized by the repetitive, effortless regurgitation of recently ingested food into the mouth followed by re-chewing and re-swallowing or expectorating of food. Although initially described in infants and the developmentally disabled, rumination syndrome is now widely recognized at all ages and cognitive abilities; the condition is more frequent in females, but it is recognized in adolescent and adult males (46,47). Rumination can become a habit, often initiated by a belch, a swallow, or by stimulation of the palate with the tongue. Abdominal muscle contraction with lower esophageal sphincter relaxation in the early postprandial period is responsible for regurgitation. Typically, the effortless repetitive regurgitation occurs within 15 min of starting a meal, in contrast to vomiting from gastroparesis, which occurs later in the postprandial period.

Eating disorders, such as anorexia and bulimia, can present with similar presentations. Anorexia nervosa is a psychiatric disorder occurring primarily in adolescent and young adult women characterized by distorted body image and fear of obesity with compulsive dieting and self-imposed starvation to maintain a profoundly low body weight. GI symptoms are common and include lack of appetite, early satiety, epigastric fullness, abdominal bloating, nausea, and vomiting. The loss of body weight seen in eating disorders can cause a compensatory delay in gastric emptying. Interestingly, re-alimentation and maintenance of normal body weight improve gastric emptying and GI symptoms, but do not totally normalize them (reviewed in ref. (48)).

Bulimia nervosa is characterized by recurrent episodes of binge eating with a feeling of lack of control over the eating behavior during the binges, often followed by self-induced vomiting, the use of laxatives or diuretics, strict dieting or fasting, or vigorous exercise to prevent weight gain. Gastric emptying studies in bulimia have yielded conflicting results (49,50,51).

CVS or episodic vomiting episodes are becoming more frequently diagnosed in adults (52). CVS refers to recurrent episodes of intense nausea and vomiting lasting hours to days separated by symptom-free periods of variable lengths. Typically, each episode is similar. Vomiting often starts abruptly, although a prodrome of nausea and abdominal pain can occur. In adults, as compared to children with CVS, the vomiting episodes are longer (3–5 days), less frequent (every 3–4 months), and triggering events are less evident; there is usually a long delay in diagnosis. Gastric emptying has been reported to be rapid in the symptom-free period. When the episodes of vomiting become closer together, differentiation of “coalescent” CVS from the more typical daily symptoms of gastroparesis in an adult can be challenging. New data on the prevalence of gastric stasis in migraine offer the potential for a better understanding of the mechanisms of CVS. Typically, gastric emptying in CVS is normal or rapid; however, 14% of a large series of patients had delayed gastric emptying (53).

Recommendations

1. The first line of management for gastroparesis patients should include restoration of fluids and electrolytes, nutritional support and in diabetics, optimization of glycemic control. (Strong recommendation, moderate level of evidence.)
2. Oral intake is preferable for nutrition and hydration. Patients should receive counseling from a dietician regarding consumption of frequent small volume nutrient meals that are low in fat and soluble fiber. If unable to tolerate solid food, then use of homogenized or liquid nutrient meals is recommended. (Conditional recommendation, low level of evidence)
3. Oral intake is the preferable route for nutrition and hydration. If oral intake is insufficient, then enteral alimentation by jejunostomy tube feeding should be pursued (after a trial of nasoenteric tube feeding). Indications for enteral nutrition include unintentional loss of 10% or more of the usual body weight during a period of 3–6 months, and/or repeated hospitalizations for refractory symptoms. (Strong recommendation, moderate level of evidence)
4. For enteral alimentation, postpyloric feeding is preferable to gastric feeding because gastric delivery can be associated with erratic nutritional support. (Conditional recommendation, low level of evidence)
5. Enteral feeding is preferable to parenteral nutrition. (Conditional recommendation, low level of evidence)

Summary of Evidence

Diet and Nutritional Support

Gastroparesis can lead to poor oral intake, a calorie-deficient diet, and deficiencies in vitamins and minerals (54,55). The choice of nutritional support depends on the severity of disease. In mild disease, maintaining oral nutrition is the goal of therapy. In severe gastroparesis, enteral or parenteral nutrition may be needed. For oral intake, dietary recommendations rely on measures that optimize gastric emptying such as incorporating a diet consisting of small meals that are low in fat and fiber. Since gastric emptying of liquids is often preserved in gastroparesis, blenderized solids or nutrient liquids may empty normally. The rationale of this approach is not validated by controlled studies, but mainly derived from an empirical approach.

Oral Nutrition

Meals with low-fat content and with low residue should be recommended for gastroparesis patients, since both fat and fiber tend to delay gastric emptying. Small meal size is advisable because the stomach may only empty an ~1–2 kcal/min. Therefore, small, low-fat, low-fiber meals, 4–5 times a day, are appropriate for patients with gastroparesis. Increasing the liquid nutrient component of a meal should be advocated, as gastric emptying of liquids is often normal in patients with delayed emptying for solids (56,57). Poor tolerance of a liquid diet is predictive of poor outcome with oral nutrition (57). High calorie liquids in small volumes can deliver energy and nutrients without exacerbating symptoms. The caloric requirement of a patient can be calculated by multiplying 25 kcal by their current body weight in kilograms (58).

In some patients, carbonated beverages, with release of carbon dioxide, can aggravate gastric distension; their intake should be minimized (56). Alcohol and tobacco smoking should be avoided because both can modify gastric emptying (59,60,61). In diabetics, near normal glycemic control with diet and hypoglycemic drugs should be aimed for, as improvement of hyperglycemia can accelerate gastric emptying.

Enteral Nutrition

For patients with gastroparesis who are unable to maintain nutrition with oral intake, a feeding jejunostomy tube, which bypasses the affected stomach, can improve symptoms and reduce hospitalizations (62). Placement of a jejunal feeding tube, if needed for alimentation, should be preceded by a successful trial of nasojejunal feeding. Occasionally, small bowel dysfunction may occur in patients with gastroparesis leading to intolerance to jejunal feeding.

Usefulness and disadvantages of different forms of intubation are summarized in Table 2. In appropriate patients with normal small bowel function, jejunal feeding maintains nutrition, relieves symptoms, and reduces the frequency of hospital admissions for acute exacerbation of symptoms (64). Small intestinal motility/transit can be assessed before placement of jejunostomy tube with antroduodenojejunal manometry, WMC, and small intestinal transit scintigraphy. Given the large coefficient of variation of small bowel transit time, and the difficulty in interpretation of orocecal transit measurements in the setting of gastroparesis, a practical way to assess small bowel function is by a trial of nasojejunal feeding. Nutrient feeds are started with diluted infusions and advanced gradually to iso-osmolar preparations at relatively low infusion rates (e.g., 20 ml/h) increasing to the target infusion rate to support nutrition and hydration typically to at least 60 ml/h over 12–15 h/day. Regulated enteral nutrition may improve glycemic control in diabetic patients with recurrent vomiting and unpredictable oral intake. Complications include infection, tube migration, and dislodgement (65). Such nutritional support may also be effective in patients with systemic sclerosis with significant malnutrition, and lead to restoration of adequate nutritional status, improved quality of life, and few metabolic or technical complications over a period of 12–86 months (66). There is a theoretical risk of increased pulmonary aspiration in patients with weak lower esophageal sphincter; hence, it is advisable that the feeding tube should be placed well beyond the angle of Treitz in such patients.

Enteral feeding should always be preferred over parenteral nutrition for a wide range of practical reasons, such as costs, potential for complications, and ease of delivery.

Table 2. Intubations for decompression and feeding in patients with gastroparesis

Type of evidence	Usefulness	Disadvantages
Nasogastric tube	Gastric decompression in acute management	Not meant for long-term use Large tube size often causes is comfort Is a poor choice for feeding due to delayed gastric emptying as significant gastroesophageal reflux can occur
Nasoduodenal/ nasojejunal tube	Used to give trial feedings to determine if jejunal feedings are tolerated. May be acceptable if there are no other options	Not for long-term use Vomiting may expel the tube into the stomach
Gastrostomy tubes	May be used for venting of secretions to decrease vomiting and fullness	Poor choice for feeding due to delayed gastric emptying May prevent proper electrode placement for gastric electrical stimulation
PEG-J or Jet-PEG	Allows the patient to vent gastric secretions to decrease/ prevent persistent emesis Provides jejunal feedings New PEG-Js have distal feeding ports to reduce duodenogastric reflux	Migration of the J-tube extension into stomach Pyloric obstruction from J-tube May prevent proper electrode placement for gastric electrical stimulation
Jejunostomy (surgical, endoscopic, radiographic)	Stable access for reliable jejunal nutrient delivery Avoids gastric penetration that would interfere with proper electrode placement for gastric electrical stimulation	Cannot vent stomach
Dual gastrostomy and jejunostomy	Two sites—one for venting and one for enteral nutrition	Increased risk of leakage, infection Cosmetic issues
PEG, percutaneous endoscopic gastrostomy; PEG-J, percutaneous endoscopic gastrostomy with jejunal extension tube. Table created from text of ref. (63).

Recommendations

1. Good glycemic control should be the goal. Since acute hyperglycemia inhibits gastric emptying, it is assumed that improved glycemic control may improve gastric emptying and reduce symptoms. (Conditional recommendation, moderate level of evidence)
2. Pramlintide and GLP-1 analogs may delay gastric emptying in diabetics. Cessation of these treatments and use of alternative approaches should be considered before initiation of therapy for gastroparesis. (Conditional recommendation, low level of evidence)

Summary of Evidence

The evidence that hyperglycemia is clinically relevant in delaying gastric emptying or in causing symptoms is controversial and is summarized in Table 3. Acute hyperglycemia induced in experimental clinical studies has been shown to worsen gastric emptying or inhibit antral contractility, though the relationship to symptoms is unclear. The efficacy of long-term improvement in glycemic control on normalization of gastric emptying and relief of symptoms in diabetic patients is controversial. Nevertheless, short- and long-term glycemic control is indicated for improved long-term outcome of diabetes. Attempts to normalize glycemic control using amylin analogs (e.g., pramlintide) or GLP-1 analogs (e.g., exenatide) may result in delayed gastric emptying (75,76). In contrast, dipeptidyl peptidase IV inhibitors (e.g., sitagliptin and vildagliptin (29)) do not delay gastric emptying.

Table 3. Relationship of glycemic control and gastrointestinal symptoms or gastric emptying

Reference #	Nature of evidence	Assessment of glycemic control	Outcome
(67)	Epidemiological	Patient report or HbA1c	Higher prevalence of upper GI symptoms
(68,69,70)	Experimental	Acute hyperglycemic clamp	Delayed GE or inhibition of antral motility index
(71)	Case series	Poor glucose control	Poor glycemic control in 36% of patients hospitalized with acute exacerbation of gastroparesis
(72)	Case series	HbA1c	Does not predict abnormal vs. normal GE
(73)	Case series	Long-term glucose control	No association with delayed GE in T2DM
(74)	Case series	Renal and pancreas transplant with normalized blood glucose	Positive impact on GE and associated GI symptoms
GE, gastric emptying; GI, gastrointestinal; T2DM, type 2 diabetics.

Recommendations

1. In addition to dietary therapy, prokinetic therapy should be considered to improve gastric emptying and gastroparesis symptoms, taking into account benefits and risks of treatment. (Strong recommendation, moderate level of evidence)
2. Metoclopramide is the first line of prokinetic therapy and should be administered at the lowest effective dose in a liquid formation to facilitate absorption. The risk of tardive dyskinesia has been estimated to be < 1%. Patients should be instructed to discontinue therapy if they develop side effects including involuntary movements. (Moderate
   recommendation, moderate level of evidence)
3. For patients unable to use metoclopramide, domperidone can be prescribed with investigational new drug clearance from the Food and Drug Administration (FDA) and has been shown to be as effective as metoclopramide in reducing symptoms without the propensity for causing central nervous system side effects; given the propensity of domperidone to prolong corrected QT interval on electrocardiogram, a baseline electrocardiogram is recommended and treatment withheld if the corrected QT is > 470 ms in male and 450 ms in female patients. Follow-up electrocardiogram on treatment with domperidone is also advised. (Moderate recommendation, moderate level of evidence)
4. Erythromycin improves gastric emptying and symptoms from delayed gastric emptying. Administration of intravenous (IV) erythromycin should be considered when IV prokinetic therapy is needed in hospitalized patients. Oral treatment with erythromycin improves gastric emptying also. However, the longterm effectiveness of oral therapy is limited by tachyphylaxis. (Strong recommendation, moderate level of evidence)
5. Treatment with antiemetic agents should occur for improvement of associated nausea and vomiting but will not result in improved gastric emptying. (Conditional recommendation, moderate level of evidence)
6. Tricyclic antidepressants (TCA) can be considered for refractory nausea and vomiting in gastroparesis but will not result in improved gastric emptying and may potentially retard gastric emptying. (Conditional recommendation, low level of evidence)

Summary of Evidence

The evidence for use of current prokinetics is based on trials performed two or three decades ago. Therefore, the level of evidence is not based on the currently suggested rigorous, large trials with validated patient response outcomes measured on a daily basis. Current trials include the daily diary Gastroparesis Cardinal Symptom Index (77) and a validated instrument to assess quality of life specific for upper GI disorders, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (78)); however, there are no full manuscripts published using such instruments and the recent institution of patient reported outcome requirements at the FDA may result in modification of this and other diaries.

Metoclopramide, a dopamine D2-receptor antagonist, is the only US FDA-approved medication for the treatment of gastroparesis for no longer than a 12-week period (79), unless patients have therapeutic benefit that outweighs the potential for risk. Metoclopramide is available in several formulations including oral dissolution tablet, oral tablet, liquid formulation, and parenteral formulation. The latter may be administered IV, by intramuscular injection, or subcutaneously (80). The FDA placed a black-box warning on metoclopramide because of the risk of side effects, including tardive dyskinesia. The most common adverse extrapyramidal side effects of metoclopramide are acute dystonias (incidence of 0.2% (81)). The incidence of acute dystonias in a UK series was higher in females, patients receiving higher doses, in children, and young adults. Whereas prolonged reactions were more common in elderly patients. About 95% of metoclopramide-induced involuntary movements reported over 15 years were dystonias, 4%parkinsonism type movements, and 1% tardive dyskinesia (82). Involuntary movements may be more likely with parenteral administration (83). The dystonic reactions may be reversed with antihistamines (e.g., diphenhydramine 25–50 mg IV administered over 2 min), benzodiazepines (e.g., diazepam 5–10 mg IV) or centrally acting anticholinergic agents (e.g., benztropine 1–4 mg IV up to 6 mg/day). Metoclopramide can also be associated with corrected QT interval prolongation.

The efficacy of metoclopramide in the treatment of DG has been assessed in four placebo-controlled trials, two active comparator-controlled and open-label studies that are summarized in Table 4. In summary, symptoms improved in five studies in which the primary objective was clinical; gastric emptying was accelerated in all studies in which it was appraised. None of the trials was conducted for >4 weeks, and longer term efficacy is unproven and limited to open-label experience in small numbers of patients (92). Recommendations on when and how to use metoclopramide for the treatment of gastroparesis in clinical practice have been published (93) and include careful monitoring of the patient for earliest signs of tardive dyskinesia (which may be reversible with early recognition and cessation of therapy), use of the lowest effective dose for each patient, starting at 5 mg t.i.d. before meals, use of the liquid formulation to improve absorption and facilitate dose titration to a maximum dose of 40 mg/day and use of “drug holidays” or dose reductions (e.g., 5 mg, before two main meals of the day) whenever clinically possible. Drug–drug interactions may occur with concomitant administration of drugs that alter cytochrome P450-2D6 (CYP2D6) function (94).

Table 4. Trials of metoclopramide for gastroparesis

Reference #	Design	#, Etiology	Dose	Duration	Results
(84)	DB, PC, XO, RCT	10 DG	10 mg q.i.d.	3 weeks/arm	Improved symptoms and vomiting; ~60% acceleration in GE liquid 150 kcal meal
(85)	DB, PC, PG, RCT	28: 5 DM, 4 PSG, 19 IG	10 mg q.i.d.	3 weeks	Improved symptoms by 29%
(86)	PC, RCT	18 DG	10 mg q.i.d.	3 weeks	Improved symptom score by 29%, improved GE by 25%
(87)	DB, PC, XO, RCT	13 DG with GE accelerated by metoclopramide	10 mg q.i.d.	3 weeks/arm	Improved symptoms with mean reduction of 52.6%
(88)	DB, RCT, domperidone-controlled, multicenter	45 DG	10 mg q.i.d.	4 weeks	Improved symptoms by 39%; similar efficacy with domperidone which had less AEs
(89)	DB, XO, erythromycin-controlled RCT	13 DG	10 mg t.i.d.	3 weeks/arm	Both treatments accelerated GE compared with baseline and improved symptoms score
(90)	Open	1 DG	15 mg q.i.d.	6 months	Improved symptoms, GE liquids, antral contraction frequency
(91)	Open	10 GI symptomatic (N, V) T1DM; 6 asymptomatic T1DM, 18 controls	10 mg once	Acute	Improved GE solids
AEs, adverse effects; DB, double blind; DG, diabetic gastroparesis; DM, diabetic; GE, gastric emptying; GI, gastrointestinal; IG, idiopathic gastroparesis; N, nausea; PC, placebo controlled; PG, parallel group; PSG, postsurgical gastroparesis; RCT, randomized-controlled trial; T1DM, type 1 diabetics; T2DM, type 2 diabetics; V, vomiting; XO, crossover.

Domperidone is a type II dopamine antagonist similar to metoclopramide, and is equally efficacious but with lower central side effects. It is available for use under a special program administered by the FDA and via other pathways. Table 5 summarizes the full articles of clinical trials with domperidone; this drug is generally as effective as metoclopramide with main efficacy on nausea and vomiting and lower risk of adverse effects than with metoclopramide. The starting dose is 10 mg t.i.d. increasing to 20 mg t.i.d. and at bedtime. Given the propensity of domperidone to prolong corrected QT interval on electrocardiogram and to rarely cause cardiac arrhythmias, a baseline electrocardiogram is recommended and treatment with this agent should be withheld if the corrected QT is >470 ms in male and over 450 ms in female patients. Follow-up electrocardiogram on domperidone is also advised to check for prolongation of the corrected QT interval. Domperidone may also cause increased prolactin levels and result in lactation; drug–drug interactions may occur with concomitant administration of drugs that alter CYP2D6 function (106). Drugs that influence CYP2D6 include antiemetics and antidepressants that are frequently co-administered in patients with gastroparesis.

Table 5. Trials of domperidone in gastroparesis

Reference #	Type of study	N, Etiology	Duration	Symptom improvement vs. baseline (OPEN) or vs. placebo (RCT)	Δ Gastric emptying	Adverse effects
(95)	Open, 10 mg q.i.d.	3 DG	1 week	Yes, not quantified	Improved, not quantified	NA
(96)	Open	12 IG; 3 DG, 2 PSG	48 months	68.3% (P<0.05)	34.5% (P<0.05)	↑ Prolactin (100%), symptoms (17.6%)
(97)	Retrospective	57 DM	377 days	70% Patients improved	NA	16%
(98)	Open	6 DG	6 months	79.2% (P<0.01)	26.9% (NS)	NA
(99)	Open	12 DG	Single oral dose	Chronic oral administration (35–51 days) reduced symptoms	↑ Solid and liquid emptying (P<0.005)	NA
(100)	RCT, PG, withdrawal study	208 DG: 105 DOM, 103 PLA	4 weeks	53.8% Lower overall score with DOM (P=0.025)	NA	2–3% ↑ Prolactin, similar to PLA
(101)	RCT, PC, XO	13 DG	8 weeks	↓ In symptom frequency and intensity vs. PLA (P<0.03)	NA	NA
(102)	RCT, PC, XO	6 DG	Single IV 10 mg	NA	↑ Homogenized solid emptying	NA
(103)	RCT, PC, XO	8 IG; 3 DG	4 weeks	No overall benefit over PLA; two of three DM improved	NA	Gas pains, skin rash
(104)	RCT, PG vs. cisapride, 14 per group	Total 31 pediatric DG; 3 excluded for poor compliance	8 weeks	DOM improved vs. baseline (P<0.001); DOM vs. cisapride (P<0.01)	DOM significantly more effective than PLA in reducing the gastric emptying time measured by ultrasound	None recorded
(105)	RCT, PG, vs. metoclopramide	95 DG	4 weeks	41.19% Improved vs. baseline (NA); NS vs. metoclopramide	ND	CNS effects more severe and common with metoclopramide: somnolence, mental acuity (49% M vs. 29% D)
CNS, central nervous system; DM, diabetic; DG, diabetic gastroparesis; IG, idiopathic gastroparesis; IV, intravenous; PSG, postsurgical gastroparesis; NA, not assessed; NS, not statistically; DOM, domperidone; PLA, placebo.

Erythromycin lactobionate is effective when given IV at a dose of 3 mg/kg every 8 h (by IV infusion over 45 min to avoid sclerosing veins), as was shown in hospitalized diabetics with gastroparesis (107). Many motilin agonists, including erythromycin, when given orally may also improve gastric emptying and symptoms for several weeks, but over longer periods are often associated with tachyphylaxis due to downregulation of the motilin receptor. Clinical responsiveness drops after 4 weeks of oral erythromycin (108); however, some patients may continue to experience benefit. Erythromycin is also subject to drug interactions with agents that alter or are metabolized by CYP3A4. Administration of erythromycin can also be associated with the development of corrected QT prolongation.

Metoclopramide and erythromycin are available in liquid form. In healthy volunteers, an orally disintegrating tablet was bioequivalent to a conventional tablet. In healthy volunteers, single administration of 10-mg metoclopramide orally disintegrating tablet (ODT) was well tolerated and bioequivalent to single administration of a conventional 10-mg metoclopramide tablet (109). It is possible that their pharmacokinetic profiles will be enhanced relative to tablet formulation in patients with gastroparesis; however, this has not been demonstrated in trials in patients. In patients with gastroparesis, liquid formulation is less likely to accumulate in the stomach in contrast to tablets, which may require more effective gastric motility to empty from the stomach; such erratic emptying may conceivably lead to several retained tablets being emptied together and lead to high plasma levels after absorption, potentially causing adverse events. Another potential advantage of the liquid formulation is that it allows for easier dose titration. For these reasons, a recent review recommended use of the liquid formula of metoclopramide in patients with severe gastroparesis (93).

Symptomatic Treatment of Nausea, Vomiting, and Pain in Gastroparesis Syndrome

Other than prokinetics, the symptomatic treatment of these symptoms remains empirical and off-label use of these drugs from the indications for non-specific nausea and vomiting, or chemotherapy-induced emesis and palliative care. The most commonly prescribed antiemetic drugs are the phenothiazines (including prochlorperazine and thiethylperazine) or antihistamine agents (including promethazine). Several US medical centers have recently placed several additional restrictions on promethazine, related to concerns about sedation, possible cardiac toxicity (corrected QT prolongation (110)), damage to peripheral veins, and lack of availability of the drug (111). There are no studies that compare efficacy of phenothiazines with newer antiemetics (such as serotonin 5-HT3-receptor antagonists) for gastroparesis. There is no evidence that ondansetron is superior to metoclopramide and promethazine in reducing nausea in adults attending an emergency department (112). 5-HT3-receptor antagonists are reasonable second-line medications; the neurokinin receptor-1 antagonist, aprepitant, was effective in treatment of severe vomiting and repeated episodes of ketoacidosis in a patient with diabetes (113).

The synthetic cannabinoid, dronabinol, is also used in practice, but there is risk of hyperemesis on withdrawal (114), and optimum treatment strategies are unclear. Transdermal scopolamine, which is effective for nausea associated with motion sickness, is used for nausea and vomiting of gastroparesis, albeit without peer-reviewed publications to support this practice. Among alternative medicine therapies, acupuncture is the method most studied in treatment of nausea and vomiting; one study reported impressive relief in 94% of patients (115) (see section on alternative medicine).

TCA can be considered for refractory nausea and vomiting in gastroparesis (116,117). The management of pain remains a challenge, which has not been addressed in clinical trials of patients with gastroparesis. Agents used in practice are not based on evidence of efficacy for pain. TCA and selective serotonin reuptake inhibitors are effective for depression in diabetes, and this is associated with improved glycemic control and physical symptoms (118,119). Open-label treatment studies have reported that TCA in low doses may decrease symptoms of nausea, vomiting, and abdominal pain in DG and IG (116,117). However, some tricyclic agents, such as amitriptyline, have anticholinergic effects and should be avoided in patients with gastroparesis, as they delay gastric emptying. Nortriptyline has lower incidence of anticholinergic side effects than amitriptyline. The 5-HT2 receptor antagonist, mirtazapine, has been reported efficacious in a single report in gastroparesis (120).

For patients taking narcotic opiate analgesics, these narcotics should be stopped, if possible, as these agents worsen gastric emptying and may themselves induce symptoms of nausea and vomiting. In addition, chronic use may be associated with increasing abdominal pain. Tramadol, tapentadol, gabapentin, pregabalin, and nortriptyline may be alternatives for pain; however, their effect on gastric emptying is still unclear. The μ-opioid receptor agonist, tramadol (which also releases serotonin and inhibits the reuptake of norepinephrine), is also used. In one study (27), it did not delay gastric emptying, though it significantly delayed colonic transit in healthy volunteers. No data are available in patients with gastroparesis. Both the related compound, tapentadol, and the more selective μ-opioid receptor agonist, oxycodone, are reported to retard gastric emptying in healthy subjects (26).

Recommendations

Intrapyloric injection of botulinum toxin is not recommended for patients with gastroparesis based on randomized controlled trials. (Strong recommendation, high level of evidence.)

Summary of Evidence

Manometric studies of patients with DG show prolonged periods of increased pyloric tone and phasic contractions, a phenomenon termed as “pylorospasm.” Botulinum toxin is a potent inhibitor of neuromuscular transmission. Several open-label studies in small numbers of patients with DG and IG observed mild improvements in gastric emptying and modest in symptoms for several months (see Table 6). Two double-blind, placebo-controlled studies have shown some improvement in gastric emptying, but no improvement in symptoms compared with placebo (131,135). Thus, botulinum toxin injection into the pylorus is not recommended as a treatment for gastroparesis (134), although there is a need for further study in patients with documented “pylorospasm.”

Table 6. Systematic review of studies on botulinum toxin injection into the pylori sphincter for treatment of gastroparesis

Reference #	Type of study	Dose of botulinum toxin	N, Etiology	Duration of follow-up	Outcome/Result	Δ Gastric emptying
(121)	Open label	80 U	1 DG	4 months	Symptoms improved	GE improved by 33%
(122)	Open label	200 U	3 DG	4–10 weeks	Symptoms improved
(123)	Open label	200 U	1 DG	4.5 months	Symptoms improved	GE improved by 43%
(124)	Open label	100 U	6 DG	6 weeks	Symptoms decreased by 55% at 2 and 6 weeks	GE improved by 43% at 2 and 6 weeks
(125)	Open label	200 U	8 DG	12 weeks	Symptoms improved by 58%	GE improved in 50% of patients
(126)	Open label	80–100 U	10 IG	4 weeks	Symptoms improved by 38% at 1 month	GE improved by 48% at 1 month
(127)	Open label	100 U	20 Total: 3 DG, 17 IG	1 month	Symptoms improved by 29% at 1 month	GE of solids improved by 35% at 1 month
(128)	Open label	200 U	8 DG	12 weeks	Symptoms improved in 50% of patients
(129)	Open label	100–200 U	63 Total: 26 DG, 35 IG	Mean 9.3 weeks	Symptoms improved in 42.9% of patients
(130)	Open label	100 U	20 Total: 3 DG, 17 IG	4 weeks	Symptoms improved	GE of solids improved
(131)	Randomized, double-blind, placebo-controlled	100 U	23 Total: 2 DG, 19 IG	4 weeks	Symptoms improved similar to placebo response	GE improved
(132)	Randomized, double-blind, placebo-controlled	200 U	32 Total: 18 DG, 13 IG	4 weeks	Symptoms improved similar to placebo response	GE improved
(133)	Open label	100–200 U	179 Total: 81 DG, 82 IG, 16 PSG	1–4 months	Symptoms improved in 51.4% of patients; responses depended on the dose
Updated from reports by refs. (64) and (134). DG, diabetic gastroparesis; IG, idiopathic gastroparesis; PSG, postsurgical gastroparesis; GE, gastric emptying.

Recommendations

1. GES may be considered for compassionate treatment in patients with refractory symptoms, particularly nausea and vomiting. Symptom severity and gastric emptying have been shown to improve in patients with DG, but not in patients with IG or PSG. (Conditional recommendation, moderate level of evidence.)

Summary of Evidence

GES delivers high frequency (Table 7) (several fold higher than the intrinsic gastric electrical frequency), lower energy electrical stimulation to the stomach. The device was approved by the FDA as a humanitarian device exemption in patients with refractory symptoms of gastroparesis of diabetic or idiopathic etiology in 2000 based on two studies (158). The first, an open-labeled study showed improvement in both specific and global gastroparesis symptoms and gastric emptying (137). The second, a double-blind, randomized, crossover study reported improvement of weekly vomiting frequency (WVF) and quality of life in DG and in the whole patient cohort, but not in the IG subgroup. The study sample size enrolled only about 50% of what had originally been planned and was underpowered (159). Most subsequent reports have been open-label studies, including long-term efficacy reports of several hundred patients, suggesting that GES enhances symptom control and quality of life and improves oral tolerance of feeding (155). An initial meta-analysis (157) suggested substantial benefits for gastroparesis, but identified that, among 13 included studies, 12 lacked controls and only 1 was blinded and randomized. A more recent meta-analysis on GES showed similar results and identified DG patients as the most responsive to GES, both subjectively and objectively, while the IG and PSG subgroups were less responsive (160). Both meta-analyses and review of the literature indicate that further controlled studies are required to confirm the clinical benefits of high-frequency GES.

Table 7. Summary of trials of gastric electrical stimulation in patients with gastroparesis

Reference #	Type of study	N, Etiology	Duration of follow-up	Outcome/Result	Δ Gastric emptying	Main adverse effects
(136)	Open label	25 Total: DM 19, idiopathic 3, PS 3	12 months	Severity and frequency of nausea and vomiting improved significantly at 3 months and sustained for 12 months	GE faster at 3 months, not at 6 or 12 months	Three devices removed; one death unrelated to device
(137)	Open label	Total 38	Median 12 (range 2.9–15.6) months	97% Experienced >80% reduction in vomiting and nausea; average weight gain 5.5%; 9/14 stopped enteral or parenteral nutrition support	GE improved in most patients at 12 months	Magnetic inactivation of earlier device; removal of device because of local infection; two underwent total gastrectomy
(138)	RCT crossover, and open prospective (10 months)	33 Total: DM 17, idiopathic 16	1 month; each crossover	ON vs. OFF period: self-reported vomiting frequency significantly reduced; efficacy in DM not in idiopathic group; open phase of trial: vomiting, other symptoms, and QOL improved	Improved GE at 12 months in open-label phase in DM	Five devices explanted or revised because of infection
(139)	Open label	48 DM	12 months	All 6 upper GI symptoms, total symptom score, physical and mental composite score on HRQOL significantly improved at 6 and 12 months; 8/13 stopped nutrition support and 9/9 stopped TPN; HbA1c improved by average 1%	No effect on GE overall; 5/48 had normalization of GE	Four device-pocket infections required removal of device; one immediate postsurgery death from pulmonary embolism; eight other deaths unrelated
(140)	Open label	9 Total, 7 studied with GES off/on	Not stated	Reduced total symptoms score ~40%	ND	None
(141)	Open label	17 DM	12 months	Weekly vomiting and nausea frequencies decreased significantly at 6 and 12 months; HbA1c reduced in all, average 2.3%	ND	None
(142)	Open label	29 Total: DM 24, idiopathic 5	Median 20 months	Symptom control excellent to good in 19/27; stopped nutrition support in 19/19; BMI mean increase of 2.2 kg/m2; poor outcome in 3	GE in 15/27: ~twice as fast	Additional procedures in four patients; postoperative morbidity in four
(143)	Open label	9 GES vs. 9 medical Rx	36 months	GI symptoms improved on GES relative to baseline and to medical Rx; lower health-care use lower at 12, 24, and 36 months; no difference in hospitalizations	ND	ND
(144)	Open label	16 PS	12 months	All 6 upper GI symptoms, total symptom score, physical and mental composite score on HRQOL significantly improved at 6 and 12 months; 4/7 stopped nutrition support; reduced hospitalizations compared with prior year	GE normalized in three	One device removed; one re-implantation
(145)	Open label	16 Total: DM 7, idiopathic 7, 1 PS, 1 brain injury	10 with >6 months f/up	improvement in QOL (RAND 36 Health Survey); decreased pyrosis, early satiety and pain; 6/10 stopped prokinetics; 75% jejunal feeding tubes removed	Normalized GE in 6/8 patients	Two repositioning of device for pain or skin erosion
(146)	Open label	15 Total: DM 5, idiopathic 6, PS 4	6 months	GI QOL Index and nausea/vomiting scores improved overall; bloating, regurgitations, abdo pain and appetite improved in eight with baseline delayed GE	4/8 With delayed GE normalized	Two epigastric pain
(147)	Open label	156 Total	Median 48 months	Reduced GI symptoms, and improved HRQOL; 90% had response in at least one of three main symptoms	Improved	Pocket infections, later re-implanted successfully; no deaths directly related to the device
(148)	Open label	42 Total: DM 24, idiopathic 17, PS 1	Median 12 (range 1–42) months	Relative to preoperative, 11/42 no response; others improved dyspepsia, and bowel dysfunction of GSRS and 2 domains on SF-36	ND	2% Immediate postoperative morbidity rate and 7% long-term morbidity rate (device extrusion)
(149)	Open label	28 Total: DM 12, idiopathic 16	Mean 5 months	14 Improved, 8 unchanged, and 6 worsened; on GCSI, improvements in N/V and postprandial subscores	ND	9 Hospitalized; 4 jejunostomy placed; 2 GES removed; 2 sepsis; 2 unrelated deaths
(150)	Open label	9 Pediatric	8–42 months	Improved combined symptoms score, nausea, vomiting; 7/ 9 patients sustained improvement in symptoms and QOL	No change	1/9 Required repeated surgery, jejunal tube placement, local infection, skin erosion
(151)	Open label	13 Total: 3 postlung transplant; 5 DM, 5 idiopathic	Mean 12 months	100% Reported improved QOL; all groups similar improvements in nausea, vomiting, and retching and postprandial symptoms	ND	Not reported
(152)	First open label;, second, crossover RCT; final open trial	55 DM	6-week open label; two 3-month crossover	Open phase: 57% reduction in weekly vomiting frequency; no difference in frequency or severity of individual or TSS between OFF and ON periods of crossover study; individual and TSS, and QOL all improved in 1-year open phase	Accelerated GE in 1-year open phase	94% Patient-related AEs ( such as hospitalizations for gastroparesis symptoms); 6% device related AEs (e.g. lead or device migration, infection) with minority requiring surgery
(153)	Temporary mucosal GES DB, PC, crossover RCT	Total 58: 13 DM, 38 idiopathic, 7 PS	crossover, two 3-day sessions with 1 day washout	Improved vomiting in both ON and OFF Rx arms; significantly better vomiting scores with stimulation on day 3 (particularly in DM group); overall treatment effect not significant	No effect on GE	Lead dislodgement of orally placed electrodes
(154)	Temporary, percutaneous GES; open label in 14; crossover RCT in 13	Total 27: 11 idiopathic (gastroparesis or CIP); 9 dyspepsia; 2 PS; 2 DM; 3 other	Crossover (n=13; ON for 12–14 days, OFF for 12–14 days)	22 of 27 Evaluable patients had a favorable symptom reduction; 6 had symptom reduction during ON compared with OFF	Baseline GE not predictive of outcome	Abdominal cramping, local infection with temporary GES; myocardial infarction unrelated to permanent GES
(155)	Open label	Total 221: 142 DM; 48 idiopathic; 31 PS	Follow-up 1–10 years	TSS, hospitalization, use of medical Rx all reduced; weight increased; 89%jejunal tubes removed; in 37 DG patients, HbA1c reduced 0.7%	ND	7% Devices removed because of infection at device site 1–43 months after implant
(156)	Open label	20/31 Available at follow-up	5 years	QOL 27% improvement; 15/20 had 50%improvement with global satisfaction	Baseline GE not predictive of outcome	6/31 Device explanted; 1 death;12/20 epigastric pain; 1 device-related infection
AEs, adverse effects; BMI, body mass index; CIP, chronic intestinal pseudo-obstruction; DG, diabetic gastroparesis; DM, diabetic; GCSI, gastroparesis cardinal symptom index; GE, gastric emptying; GES, gastric electrical stimulation; GI, gastrointestinal; GSRS, gastrointestinal symptom rating scale; HRQOL, health-related quality of life; N, nausea; ND, not done; PS, postsurgical; QOL, quality of life; TPN, total parenteral nutrition; TSS, total symptom score; V, vomiting. Reproduced in part from ref. (157). N reports patients recruited into each study; outcomes were often available on fewer patients.

A multicenter, randomized, controlled study involving 55 patients with DG (mean age 38 years, 66% female, average 5.9 years of gastroparesis), in which all patients had the devices on for several weeks before the randomization occurred, showed no significant difference in WVF between on vs. off periods during the subsequent crossover period (161). However, at 1 year post implant, when all patients had the device switched on, the WVF remained lower than baseline (median reduction of WVF of 67.8%, P<0.001), reflecting the previously reported open-label experience. Similar reports have been recorded in IG (162).

More recent data (153) have shown effects of GES on GI symptoms in as little as 72 h of stimulation, suggesting rapid effect of GES on gastric motor activity. In this study, after a temporary endoscopic lead was implanted for a trial of high-frequency/low-energy GES using an external device, patients were randomized to either on/off or off/on at baseline. Although temporary endoscopic placement of stimulation leads in the stomach may predict response to the permanent device (153), this proposal needs further studies to support this practice. In summary, the data presented in Table 7 show that open-label treatment is associated with symptomatic improvement, particularly WVF, and a propensity to cessation of special methods to provide nutrition (such as enteral or parenteral nutrition). Improvement in gastric emptying has been variable. Complications from the device such as local infection or lead migration, as well as complications related to the surgery may occur in up to 10% of patients implanted. In general, efficacy for symptomatic improvement appears to be greater for DG than for IG. There is no consensus or societal guideline on the selection of patients (e.g., failed therapeutic trials, or level of nutritional compromise) for the use of GES as compassionate treatment.

Recommendations

1. Gastrostomy for venting and/or jejunostomy for feeding may be performed for symptom relief. (Conditional recommendation, low level of evidence)
2. Completion gastrectomy could be considered in patients with PSG who remain markedly symptomatic and fail medical therapy. (Conditional recommendation, low level of evidence)
3. Surgical pyloroplasty or gastrojejunosotomy has been performed for treatment for refractory gastroparesis. However, further studies are needed before advocating this treatment. Partial gastrectomy and pyloroplasty should be used rarely, only in carefully selected patients. (Conditional recommendation, low level of evidence)

Summary of Evidence

In patients with significant upper GI motility disorders, surgically placed venting gastrostomy, with or without a venting enterostomy, reduced hospitalization rate by a factor of 5 during the year after placement (163,164). Results of endoscopic venting (percutaneous endoscopic gastrostomy and direct percutaneous endoscopic jejunostomy) on nutritional outcomes and gastroparesis symptoms have not been formally studied and remain unclear. In an open-label study, patients experienced marked symptomatic improvement, weight was maintained, and total symptom score was reduced up to 3 years post venting gastrostomy (165). It is assumed that the same beneficial outcome occurs with percutaneous endoscopic gastrostomy, though this is not proven.

Several types of surgical interventions have been tried for treatment of gastroparesis: gastrojejunostomy, pyloromyotomy, and completion or subtotal gastrectomy. A recent study reported on a series of 28 patients with gastroparesis in whom pyloroplasty resulted in symptom improvement, with significant improvement in gastric emptying and reduction in the need for prokinetic therapy when followed at 3 months post surgery (166). It is unclear whether the efficacy of pyloroplasty depends on the residual antral motor function; thus, in the few diabetics included in the series, there was no significant improvement in gastric emptying (166), and further studies with longer follow-up are needed to determine overall efficacy and optimal candidates for pyloroplasty to treat gastroparesis. Completion or subtotal gastrectomy was applied most often for gastroparesis that followed gastric surgery for peptic ulcer disease (167,168); experience from tertiary referral centers suggests that, in carefully selected patients, major gastric surgery can relieve distressing vomiting from severe gastroparesis and improve quality of life (169,170) in seriously affected patients where risk of subsequent renal failure is high and where life expectancy is poor. The risk of malnutrition and weight loss following gastrectomy has to be weighed relative to the symptom relief. The use of completion or subtotal gastrectomy in patients with intact gastroparetic stomachs has not been favorable. Pyloroplasty may relieve symptoms in gastroparesis and is often combined with operative jejunal tube placement to support nutrition (166,171). Subtotal gastrectomy with Roux-Y reconstruction may be needed for gastric atony secondary to PSG (167). In patients undergoing surgical treatment for gastroparesis, a full-thickness gastric biopsy may be helpful to assess the pathologic basis associated with the patient’s gastroparesis (172,173,174,175).

Recommendations

Acupuncture can be considered as an alternative therapy. This has been associated with improved rates of gastric emptying and reduction of symptoms. (Conditional recommendation, low level of evidence)

Summary of Evidence

As with many chronic conditions that are poorly understood, patients may search for alternative therapies. These can include: dietary manipulations, physical retraining modalities (autogenic retraining such as that developed by NASA for space motion sickness), and therapies such as acupuncture. Dietary manipulations have been discussed above. The use of autonomic retraining in the one series using NASA technology showed that patients with more intact autonomic nervous system activity responded better than patients whose autonomic function was more impaired (176).

Other therapies, such as acupuncture, have been tried in a more systematic way than other alternative therapies of gastroparesis. Several recent studies, including one single-blinded, randomized pilot study with sham treatment control, have demonstrated that acupuncture may be of benefit in gastroparesis (177). This study of 19 patients with type 2 diabetics was conducted for 2 weeks with 2 week follow-up: symptom severity (Gastroparesis Cardinal Symptom Index) and, particularly, the postprandial fullness and early satiety and bloating subscales were reduced at end of treatment and end of follow-up. Gastric emptying of solids was shortened with active electroacupuncture relative to baseline; however, gastric emptying times in the active and sham-controlled arms were not well matched at baseline (177). Further studies are needed to assess clinical benefit of acupuncture and other complementary and alternative treatments in patients with gastroparesis.

Summary of Recommendations

Figure 1 demonstrates a stepwise approach to management of gastroparesis based on these recommendations. An algorithm for management is shown in Figure 2, and suggestions for prokinetic dosing are outlined in Figure 3. Clearly, there are specific refinements to this approach based on individual differences: Degree of nutritional deficiency or weight loss, degree of impairment of gastric emptying (or gastric retention at 4 h), and response to earlier “steps” in the management.

Figure 1. Stepwise algorithm for gastroparesis diagnosis and management.

Figure 2. Treatment algorithm for gastroparesis.

Figure 3. Algorithm for prokinetic therapy in gastroparesis.

1. The diagnosis of gastroparesis is based on the combination of symptoms of gastroparesis, absence of gastric outlet obstruction or ulceration, and delay in gastric emptying. (Strong recommendation, high level of evidence)
2. Accelerated gastric emptying and functional dyspepsia can present with symptoms similar to those of gastroparesis; therefore, documentation of delayed gastric emptying is recommended before selecting therapy with prokinetics agents or GES. (Strong recommendation, moderate level of evidence)
3. Patients with gastroparesis should be screened for the presence of diabetes mellitus, thyroid dysfunction, neuro logical disease, prior gastric or bariatric surgery, and autoimmune disorders. Patients should undergo biochemical screen for diabetes and hypothyroidism; other tests are as indicated clinically. (Strong recommendation, high level of evidence)
4. A prodrome suggesting a viral illness may lead to gastroparesis (postviral gastroparesis). This condition may improve over time in some patients. Clinicians should inquire about the presence of a prior acute illness suggestive of a viral infection. (Conditional recommendation, low level of evidence)
5. Markedly uncontrolled ( > 200 mg/dl) glucose levels may aggravate symptoms of gastroparesis and delay gastric emptying. (Strong recommendation, high level of evidence.) Optimization of glycemic control should be a target for therapy; this may improve symptoms and the delayed gastric emptying. (Moderate recommendation, moderate level of evidence)
6. Medication-induced delay in gastric emptying, particularly from narcotic and anticholinergic agents and GLP-1 and amylin analogs among diabetics, should be considered in patients before assigning an etiological diagnosis. Narcotics and other medications that can delay gastric emptying should be stopped to establish the diagnosis with a gastric emptying test. (Strong recommendation, high level of evidence)
7. Gastroparesis can be associated with and may aggravate GERD. Evaluation for the presence of gastroparesis should be considered in patients with GERD that is refractory to acid-suppressive treatment. (Conditional recommendation, moderate level of evidence)
8. Documented delay in gastric emptying is required for the diagnosis of gastroparesis. Scintigraphic gastric emptying of solids is the standard for the evaluation of gastric emptying and the diagnosis of gastroparesis. The most reliable method and parameter for diagnosis of gastroparesis is gastric retention of solids at 4 h measured by scintigraphy. Studies of shorter duration or based on a liquid challenge result in decreased sensitivity in the diagnosis of gastroparesis. (Strong recommendation, high level of evidence)
9. Alternative approaches for assessment of gastric emptying include wireless capsule motility testing and ¹³C breath testing using octanoate or spirulina incorporated into a solid meal; they require further validation before they can be considered as alternates to scintigraphy for diagnosis of gastroparesis. (Conditional recommendation, moderate level of evidence)
10. Medications that affect gastric emptying should be stopped at least 48 h before diagnostic testing; depending on the pharmacokinetics of the medication, the drug may need to be stopped > 48 h before testing. (Strong recommendation, high level of evidence)
11. Patients with diabetes should have blood glucose measured before starting the gastric emptying test, and hyperglycemia treated with test started after blood glucose is < 275 mg/dl. (Strong recommendation, moderate-high level of evidence)
12. The presence of rumination syndrome and/or eating disorders (including anorexia nervosa and bulimia) should be considered when evaluating a patient for gastroparesis. These disorders may be associated with delayed gastric emptying, and identification of these disorders may alter management. (Strong recommendation, moderate-high level of evidence)
13. CVS defined as recurrent episodic episodes of nausea and vomiting should also be considered during the patient history. These patients may require alternative therapy. (Conditional recommendation, moderate level of evidence)
14. Chronic usage of cannabinoid agents may cause a syndrome similar to CVS. Patients presenting with symptoms of gastroparesis should be advised to stop usage of these agents. (Conditional recommendation, low level of evidence)
15. The first line of management for gastroparesis patients should include restoration of fluids and electrolytes, nutritional support and in diabetics, optimization of glycemic control. (Strong recommendation, moderate level of evidence)
16. Oral intake is preferable for nutrition and hydration. Patients should receive counseling from a dietician regarding consumption of frequent small volume nutrient meals that are low in fat and soluble fiber. If unable to tolerate solid food, then use of homogenized or liquid nutrient meals is recommended. (Conditional recommendation, low level of evidence)
17. Oral intake is the preferable route for nutrition and hydration. If oral intake is insufficient, then enteral alimentation by jejunostomy tube feeding should be pursued (after a trial of nasoenteric tube feeding). Indications for enteral nutrition include unintentional loss of 10% or more of the usual body weight during a period of 3–6 months, and/or repeated hospitalizations for refractory symptoms. (Strong recommendation, moderate level of evidence)
18. For enteral alimentation, postpyloric feeding is preferable to gastric feeding because gastric delivery can be associated with erratic nutritional support. (Conditional recommendation, low level of evidence)
19. Enteral feeding is preferable to parenteral nutrition. (Conditional recommendation, low level of evidence)
20. Good glycemic control should be the goal. Since acute hyperglycemia inhibits gastric emptying, it is assumed that improved glycemic control may improve gastric emptying and reduce symptoms. (Conditional recommendation, moderate level of evidence)
21. Pramlintide and GLP-1 analogs may delay gastric emptying in diabetics. Cessation of these treatments and use of alternative approaches should be considered before initiation of therapy for gastroparesis. (Conditional recommendation, low level of evidence)
22. In addition to dietary therapy, prokinetic therapy should be considered to improve gastric emptying and gastroparesis symptoms, taking into account benefits and risks of treatment. (Strong recommendation, moderate level of evidence)
23. Metoclopramide is the first line of prokinetic therapy and should be administered at the lowest effective dose. The risk of tardive dyskinesia has been estimated to be < 1%. Patients should be instructed to discontinue therapy if they develop side effects including involuntary movements. (Moderate recommendation, moderate level of evidence)
24. For patients unable to use metoclopramide, domperidone can be prescribed with investigational new drug clearance from the FDA and has been shown to be as effective as metoclopramide in reducing symptoms without the propensity for causing central nervous system side effects; given propensity of domperidone to prolong corrected QT interval on electrocardiogram, a baseline electrocardiogram is recommended and treatment withheld if the corrected QT is > 470 ms in male and 450 ms in female patients. Follow-up electrocardiogram on treatment with domperidone is also advised. (Moderate recommendation, moderate level of evidence)
25. Erythromycin improves gastric emptying and symptoms from delayed gastric emptying. Administration of IV erythromycin should be considered when IV prokinetic therapy is needed in hospitalized patients. Oral treatment with erythromycin improves gastric emptying also. However, the long-term effectiveness of oral therapy is limited by tachyphylaxis. (Strong recommendation, moderate level of evidence)
26. Treatment with antiemetic agents should occur for improvement of associated nausea and vomiting but will not result in improved gastric emptying. (Conditional recommendation, moderate level of evidence)
27. TCA can be considered for refractory nausea and vomiting in gastroparesis but will not result in improved gastric emptying and may potentially retard gastric emptying. (Conditional recommendation, low level of evidence)
28. Intrapyloric injection of botulinum toxin is not recommended for patients with gastroparesis based on randomized controlled trials. (Strong recommendation, high level of evidence)
29. GES may be considered for compassionate treatment in patients with refractory symptoms, particularly nausea and vomiting. Symptom severity and gastric emptying have been shown to improve in patients with DG, but not in patients with IG or PSG. (Conditional recommendation, moderate level of evidence)
30. Gastrostomy for venting and/or jejunostomy for feeding may be performed for symptom relief. (Conditional recommendation, low level of evidence)
31. Completion gastrectomy could be considered in patients with PSG who remain markedly symptomatic and fail medical therapy. (Conditional recommendation, low level of evidence)
32. Surgical pyloroplasty or gastrojejunosotomy has been performed for treatment for refractory gastroparesis. However, further studies are needed before advocating this treatment. Partial gastrectomy and pyloroplasty should be used rarely, only in carefully selected patients.
33. Acupuncture can be considered as an alternative therapy. This has been associated with improved rates of gastric emptying and reduction of symptoms. (Conditional recommendation, low level of evidence)

Guarantor of the article: Michael Camilleri, MD

Specific author contributions: All authors were involved in writing the manuscript and providing critical revision of the manuscript for important intellectual content.

Financial support: The authors are supported by National Institutes of Health PO1 DK68055-04 and DK67071 (M.C.), NIH 1 U01 DK073975-06 (H.P.P.), and U01 DK074007 (T.L.A.).

Potential competing interests: Dr Camilleri has received support from Shire (prucalopride), Theravance (velusetrag), Rhythm (RM-131, research grant), and Tranzyme (TZP-101, 102). Dr Parkman has received support from SmartPill, Tranzyme, GSK, Evoke, and Rhythm. Dr Abell NIH GPCRC is an investigator, consultant, and licensor for Medtronic; is a consultant and investigator for Rhythm. Dr Shafi has received support from Salix Pharmaceuticals. Dr Gerson is a consultant for Takeda, Santarus, and IntroMedic.

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David A. Lieberman,¹ Douglas K. Rex,² Sidney J. Winawer,³ Francis M. Giardiello,⁴ David A. Johnson,⁵ Theodore R. Levin⁶

¹Oregon Health and Science University, Portland, Oregon; ²Indiana University School of Medicine, Indianapolis, Indiana; ³Memorial Sloan-Kettering Cancer Center, New York, New York; ⁴Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁵Eastern Virginia Medical School, Norfolk, Virginia; and ⁶Kaiser Permanente Medical Center, Walnut Creek, California

Podcast interview: www.gastro.org/gastropodcast. Also available on iTunes.

Screening for colorectal cancer (CRC) in asymptomatic patients can reduce the incidence and mortality of CRC. In the United States, colonoscopy has become the most commonly used screening test. Adenomatous polyps are the most common neoplasm found during CRC screening. There is evidence that detection and removal of these cancer precursor lesions may prevent many cancers and reduce mortality. (1) However, patients who have adenomas are at increased risk for developing metachronous adenomas or cancer compared with patients without adenomas. There is new evidence that some patients may develop cancer within 3–5 years of colonoscopy and polypectomy—so-called interval cancers.

Ideally, screening and surveillance intervals should be based on evidence showing that interval examinations prevent interval cancers and cancer-related mortality. We have focused on the interval diagnosis of advanced adenomas as a surrogate marker for the more serious end point of cancer incidence or mortality. In 2006, the United States Multi-Society Task Force (MSTF) on CRC issued a guideline on postpolypectomy surveillance, (2) which updated a prior 1997 guideline. A key principle of the 2006 guideline was risk stratification of patients based on the findings at the baseline colonoscopy. The surveillance schema identified 2 major risk groups based on the likelihood of developing advanced neoplasia during surveillance: (1) low-risk adenomas (LRAs), defined as 1–2 tubular adenomas <10 mm, and (2) high-risk adenomas (HRAs), defined as adenoma with villous histology, high-grade dysplasia (HGD), ≥10 mm, or 3 or more adenomas. The task force also published recommendations for follow-up after resection of CRC. (3)

More recently, the British Society of Gastroenterology updated their 2002 surveillance guideline in 2010.(4) Their risk stratification differs from the US guideline, dividing patients into 3 groups: low risk (1–2 adenomas <10 mm), intermediate risk (3–4 small adenomas or one ≥10 mm), and high risk (>5 small adenomas or ≥3 with at least one ≥10 mm). They recommend that the high-risk group undergo surveillance at 1 year because of concerns about missed lesions at baseline. US guidelines place emphasis on performing a high-quality baseline examination. In 2008, the MSTF published screening guidelines for CRC, which included recommendations for the interval for repeat colonoscopy after negative findings on baseline examination. (5)

New issues have emerged since the 2006 guideline, including risk of interval CRC, proximal CRC, and the role of serrated polyps in colon carcinogenesis. New evidence suggests that adherence to prior guidelines is poor. The task force now issues an updated set of surveillance recommendations. During the past 6 years, new evidence has emerged that endorses and strengthens the 2006 recommendations. We believe that a stronger evidence base will improve adherence to the guidelines. The 2012 guidelines are summarized in Table 1 and are based on risk stratification principles used in the 2006 guideline. The ensuing discussion reviews the new evidence that supports these guidelines. This guideline does not address surveillance after colonoscopic or surgical resection of a malignant polyp.

Gastroenterology 2012;143:844–857; doi:10.1053/j.gastro.2012.06.001; published online 03 July 2012

Reprint requests: Address requests for reprints to: David A. Lieberman, MD, Division of Gastroenterology, Oregon Health and Science University, L-461, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. e-mail: lieberma@ohsu.edu; fax: (503) 220-3426.

Abbreviations used in this paper: CI, confidence interval; CIMP, CpG island methylator phenotype; CRC, colorectal cancer; CT, computed tomography; FDR, first-degree relative; FOBT, fecal occult blood test; HGD, high-grade dysplasia; HP, hyperplastic polyp; HR, hazard ratio; HRA, high-risk adenoma; LRA, low-risk adenoma; MSTF, Multi-Society Task Force; NCI, National Cancer Institute; OR, odds ratio; PPT, Polyp Prevention Trial; RR, relative risk; TVA, tubulovillous adenoma; USPSTF, United States Preventive Services Task Force.

Literature Review

We performed a MEDLINE search of the postpolypectomy literature under the subject headings of colonoscopy, adenoma, polypectomy surveillance, and adenoma surveillance, limited to English language articles from 2005 to 2011. Subsequently, additional articles were gleaned from references of the reviewed articles. Relevant studies include those in which outcomes addressed the relationship between baseline examination findings and the detection of CRC, advanced adenoma, or any adenoma during the follow-up period. Studies used in the final analysis are summarized in Table 2 by specific category. We also reviewed studies with results of more than one surveillance examination to determine the downstream risk that may be associated with the baseline findings. A key goal was to determine if the risk of subsequent neoplasia was reduced once a patient had negative findings on colonoscopy or had low-risk adenomas. We excluded studies that included patients with inflammatory bowel disease or prior history of CRC. This review applies to average-risk individuals and excluded patients with hereditary syndromes associated with CRC.

Table 1. 2012 Recommendations for Surveillance and Screening Intervals in Individuals With Baseline Average Risk

Baseline colonoscopy: most advanced finding(s)	Recommended surveillance interval (y)	Quality of evidence supporting the recommendation	New evidence stronger than 2006
No polyps	10	Moderate	Yes
Small (<10 mm) hyperplastic polyps in rectum or sigmoid	10	Moderate	No
1–2 small (<10 mm) tubular adenomas	5–10	Moderate	Yes
3–10 tubular adenomas	3	Moderate	Yes
>10 adenomas	<3	Moderate	No
One or more tubular adenomas ≥10 mm	3	High	Yes
One or more villous adenomas	3	Moderate	Yes
Adenoma with HGD	3	Moderate	No
Serrated lesions
Sessile serrated polyp(s) <10 mm with no dysplasia	5	Low	NA
Sessile serrated polyp(s) ≥10 mm	3	Low	NA
OR
Sessile serrated polyp with dysplasia
OR
Traditional serrated adenoma
Serrated polyposis syndromea	1	Moderate	NA
NOTE. The recommendations assume that the baseline colonoscopy was complete and adequate and that all visible polyps were completely removed. NA, not applicable. aBased on the World Health Organization definition of serrated polyposis syndrome, with one of the following criteria: (1) at least 5 serrated polyps proximal to sigmoid, with 2 or more ≥10 mm; (2) any serrated polyps proximal to sigmoid with family history of serrated polyposis syndrome; and (3) >20 serrated polyps of any size throughout the colon.

Table 2. New Papers Since 2005 With Surveillance Outcomes After Baseline Colonoscopy

Category: baseline colonoscopy finding	No. of papers meeting criteria (reference no.)
Exposure to colonoscopy:	6 (18–22, 52)
1. Risk of CRC
2. Risk of proximal vs distal CRC
Exposure to colonoscopy: rate of CRC within 10 y	4 (18, 20, 21, 52)
No polyps at baseline: rates of advanced neoplasia	6 (14, 47–51)
HPs	1 (61)
Small adenomas <10 mm	7 (7, 14, 51, 64–67)
Advanced adenomas	3 (7, 14, 66)
Adenoma with HGD	3 (7, 14, 71)
Serrated polyps	2 (72, 73)
Family history of CRC or polyps	1 (59)
Multiple rounds of surveillance	3 (67, 77, 78)
Poor bowel preparation	2 (68, 82)
Surveillance after FOBT	2 (84, 85)
Miscellaneous risk factors
Smoking	1 (58)
Aspirin/nonsteroidal anti-inflammatory drugs	4 (54–57)

Levels of Evidence

There are no high-quality randomized controlled trials of polyp surveillance performed in the past 6 years. All studies are either retrospective or prospective observational, cohort, population-based, or case-control studies. We have adopted a well-accepted rating of evidence (6) that relies on expert consensus about whether new research is likely to change the confidence level of the recommendation (Table 3).

Table 3. Rating Evidence

Rating of evidence	Impact of potential further research
High quality	Very unlikely to change confidence in the estimate of effect
Moderate quality	Likely to have an important impact on confidence and may change estimate of effect
Low quality	Very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate
Very low quality	Any estimate of effect is very uncertain

Process

The task force is composed of gastroenterology specialists with a special interest in CRC, representing the 3 major gastroenterology professional organizations: American College of Gastroenterology, American Gastroenterological Association Institute, and American Society for Gastrointestinal Endoscopy. We recognize that inherent bias can be introduced when a group of experts in the field review evidence and provide recommendations. In addition to the task force, the practice committees of the American Gastroenterological Association Institute and the American College of Gastroenterology and the governing board of the American Society for Gastrointestinal Endoscopy reviewed and approved this document.

Format of the Report 

The report includes statements that summarize new, relevant literature since 2005. This is followed by recommendations for surveillance based on the most advanced finding of the baseline colonoscopy examination. For each baseline finding (or lack of finding), there is a recommendation, background section, summary of new evidence since 2006, and discussion of unresolved issues and areas for further research.

Terms and Definitions 

Low-risk adenoma (LRA) refers to patients with 1–2 tubular adenomas <10 mm in diameter. High-risk adenoma (HRA) refers to patients with tubular adenoma ≥10 mm, 3 or more adenomas, adenoma with villous histology, or HGD. Advanced neoplasia is defined as adenoma with size ≥10 mm, villous histology, or HGD.

Throughout the document, statistical terms are used. The odds ratio (OR) is the ratio of the odds of an event occurring in one group to the odds of it occurring in another group. Generally there is a referent group (OR = 1.0) that is compared with another group. Relative risk (RR) is used frequently in the statistical analysis of binary outcomes where the outcome of interest has relatively low probability. The RR is different from the OR, although it asymptotically approaches it for small probabilities. The OR has much wider use in statistics, because logistic regression, often associated with clinical trials, works with the log of the OR, not RR. In survival analysis, the hazard ratio (HR) is the ratio of the hazard rates corresponding to the conditions described by 2 sets of explanatory variables in a defined period. For example, in a drug study, the treated population may die at twice the rate per unit time as the control population. The HR would be 2, indicating higher hazard of death from the treatment.

New Evidence on Limitations of Colonoscopic Surveillance

New evidence documents the risk of developing interval CRC after polypectomy or negative findings on baseline colonoscopy. New data have emerged on the risk of interval cancer after colonoscopy. Data from studies in which patients had adenomas detected and removed were analyzed in a pooling project funded by the National Cancer Institute (NCI) (hereafter referred to as the NCI Pooling Project).(7) These include randomized controlled trials to evaluate chemoprevention (8, 9, 10, 11, 12, 13) and cohort studies. (1, 14, 15) The overall rate of interval cancer was 1.1–2.7 per 1000 person-years of follow-up.

Interval cancers have also been reported in patients with baseline examinations negative for neoplasia. Studies from Ontario (16) and Manitoba (17) used cancer registries to identify patients with cancer and then linked these patients to claims data to determine if there had been a prior colonoscopy. These studies suggest that up to 9% of cancers in the registry were interval cancers, with the patients having had a colonoscopy in the 6 to 36 months before diagnosis of CRC. These studies did not include data on completion rates and quality of prior colonoscopy.

Several studies (18, 19, 20, 21, 22) have suggested that patients who develop cancer after colonoscopy are more likely to have proximal compared than distal cancers (Table 4). One hypothesis is that some endoscopists may be more likely to miss lesions in the proximal colon compared with the distal colon. This could be due to quality of bowel preparation, failure to fully examine the proximal colon, differences in proximal polyp/cancer morphology, the skill of the endoscopist, and variable quality of colonoscopy. Serrated polyps and some classic adenomatous polyps in the proximal colon may be challenging to detect if they are flat, covered with mucus, or behind folds. Most prior studies of colonoscopy have failed to report on the quality of the colonoscopy examinations. A second hypothesis is that neoplastic lesions of the proximal colon may biologically differ from distal lesions and progress to malignancy with a short dwell time. The serrated pathway has a predilection for the proximal colon. These lesions may be associated with BRAF or k-ras mutations, and CPG island methylation, which can lead to silencing of mismatch repair genes (MLH1), which could result in more rapid progression to malignancy in some individuals. (23)

Concerns about interval cancer may impact physician behavior with regard to surveillance intervals and may contribute to early repeat examinations in some cases.

Table 4. Risk of CRC After Colonoscopy: Case-Control or Observational Studies

Study	Location and type of study	n	Follow-up (y)	CRC risk	Risk over 10 ya	Notes: proximal vs distalb
Singh et al, 2006 (18)	Manitoba Cohort/claims data	35,975 with colonoscopy compared with expected rates of CRC in population	10	Incidence: SIR, 0.55 (0.41–0.73)	SIR: 1 y, 0.66 2 y, 0.59 5 y, 0.55 10 y, 0.28	Proximal CRC more common in patients with interval CRC (47%) vs those with prevalent CRC (28%)
Lakoff et al, 2008 (20)	Ontario Cohort/claims data	110,402 with negative colonoscopy compared with rates in population	Up to 14		Incidence RR: 2 y, 0.80 5 y, 0.56 10 y, 0.45 14 y, 0.25	No reduction in proximal CRC risk until year 8 of follow-up
Baxter et al, 2009 (21)	Ontario Case-control claims data	10,292 CRC cases vs 51,460 cancer-free controls; measured exposure to colonoscopy	Median, 7.8	Mortality: OR, 0.69 (0.63–0.74)		Proximal CRC: OR, 0.99 Distal CRC: OR, 0.33 (0.28–0.39)
Brenner et al, 2011 (22)	Germany Case-control	1688 CRC cases vs cancer-free controls; exposure to colonoscopy	10	Incidence: OR, 0.23 (0.19–0.27)		Proximal CRC: OR, 0.44 (0.35–0.55) Distal CRC OR, 0.16 (0.12–0.20)
Brenner et al, 2011 (52)	Germany Case-control	1945 CRC cases vs 2399 controls	Up to 20		Incidence OR: 1–2, 0.14 3–4, 0.12 5–9, 0.26c 10–19, 0.28
SIR, standardized incidence ratio. aBased on interval since prior colonoscopy. bPrevalent CRC, diagnosis of CRC at time of initial colonoscopy; interval CRC, diagnosis of CRC at time of follow-up colonoscopy, at some interval after baseline examination. cAt 5–9 years: OR of 0.61 in smoker, OR of 0.66 with positive family history.

Important lesions are missed at baseline colonoscopy. Considerable evidence suggests that important lesions may be missed at colonoscopy. Studies that have compared computed tomography (CT) colonography and optical colonoscopy use a method of segmental unblinding to assess the sensitivity of colonoscopy. As each segment is examined, the endoscopist is informed of findings at CT. If the CT revealed a polyp and colonoscopy did not, the region is reexamined; if a polyp(s) is found on the second look, it is considered a missed lesion by colonoscopy. These studies suggest that up to 17% of lesions ≥10 mm are missed with optical colonoscopy. (24,25, 26, 27, 28, 29) Recent studies suggest that most interval cancers are due to missed lesions at baseline colonoscopy. (30, 31) Missed lesions are directly related to the quality of the examination.

Adenomas may be incompletely removed at the time of baseline colonoscopy. If adenoma removal is not complete, residual neoplastic tissue could progress to malignancy. New studies have found that 19%–27% of interval cancers occur in the same portion of the colon as the site of prior polypectomy. In a study of patients with large sessile polyps (>2 cm), 17.6% had residual adenomatous tissue when reexamined. (30, 32, 33, 34, 35)

Interval CRC may biologically differ from prevalent CRC. When interval CRCs are compared with prevalent CRC, interval lesions are more likely located in the proximal colon, be microsatellite unstable, and have CpG island methylator phenotype (CIMP). It has been proposed that the mismatch repair defects associated with microsatellite unstable tumors can lead to a rapid accumulation of mutations and accelerated tumor growth. (36, 37)

Quality of baseline colonoscopy is associated with risk of interval cancer. An underlying premise of recommendations for surveillance is that the baseline colonoscopy was performed with high quality, which minimizes the risk of missed lesions. Since 2002, quality indicators for reporting and performance have been published. (38, 39, 40) There is now evidence of a clear relationship between specific quality indicators and the risk of interval cancer after colonoscopy. Variation in adenoma detection rate among endoscopists has been reported. (16, 41) A large Polish study found that if the adenoma detection rate in screening examinations was <20%, a significantly higher risk of interval cancer occurred in the next 5 years. (42) In Ontario, investigators compared endoscopists with high and low polyp detection rates, finding that interval cancers were less likely when the colonoscopy was performed by an endoscopist with high polyp detection rates. (16) The same investigators compared endoscopists with high (>95%) and low (<80%) cecal intubation rates and similarly found that interval cancers were less common among the patients who had colonoscopy performed by higher-performance endoscopists. These new data reinforce the importance of colonoscopy quality and its impact on surveillance.

There is growing interest in using adherence to polyp surveillance recommendations as an indicator of endoscopy quality. (40) There is evidence that guideline adherence is variable and overall far from consistent with national guideline recommendations. Surveys of primary care and specialty physicians revealed that many recommend frequent surveillance colonoscopy for low-risk patients, despite recommendations for lengthened surveillance intervals. (43, 44) A recent study reported on actual surveillance performance after colonoscopy. (45) Approximately 25% of patients with no adenomas at baseline had a repeat colonoscopy within 5 years, and more than 40% of patients with small adenomas had one or more examinations within 5 years. The study also revealed evidence for underutilization of surveillance in some higher-risk patients with advanced neoplasia at baseline. Roughly 40% of such patients did not have surveillance within 5 years. Overutilization exposes patients to the cost and risk of unnecessary procedures. Underutilization could result in higher-risk patients developing cancer.

Recommendations for Surveillance

Baseline examination: no adenomas or polyps

2008 recommendation for next examination	10 years
2012 recommendation for next examination	No change
Quality of evidence	Moderate – stronger than 2008

Background. The foundation of the 10-year interval is based on indirect, observational data discussed in prior guidelines. (5)

New information since 2008. The United Kingdom sigmoidoscopy randomized controlled trial demonstrated a reduction in CRC incidence and mortality at 10 years in patients who received one-time sigmoidoscopy compared with controls—a benefit limited to the distal colon. (46) This is the first randomized study to show the effectiveness of endoscopic screening, an effect that appears to have at least a 10-year duration.

Risk of advanced adenomas at follow-up colonoscopy. Several prospective observational studies (14, 47, 48, 49, 50, 51) in different populations have shown that the risk of advanced adenomas within 5 years after negative findings on colonoscopy is low (1.3%–2.4%) relative to the rate on initial screening examination (4%–10%). In these studies, interval cancers within 5 years were rare (Table 5).

Table 5. Prevalence of Advanced Neoplasia After Negative Findings on Colonoscopy

Study	N (type of cohort)	Interval after baseline (y)	Advanced neoplasia (%)
Lieberman et al, 2007 (14)	291 (veterans, male)	5	2.4
Imperiale et al, 2008 (47)	1256 (US, men and women)	5	1.3
Leung et al, 2009 (48)	370 (Chinese men and women)	5	1.4
Brenner et al, 2010 (49)	115 (men and women)	5	4.4
Miller et al, 2010 (50)	US veterans (99% male)	5–10
	5-y follow-up: n = 86 6- to 10-y follow-up: n = 111		7.0 3.6
Chung et al, 2011 (51)	1242 Korean men and women)	5	2.0

Risk of cancer during surveillance. Case-control and observational studies (18, 20, 21, 52) have suggested that patients with prior colonoscopy have either reduced CRC incidence or mortality, with a duration of effect of 10 years or more (Table 4). A large case-control study from Germany compared patients undergoing true screening colonoscopy with unscreened controls, finding a durable risk reduction with colonoscopy for at least 10 years. (53) Other studies that have included higher-risk patients (lower gastrointestinal symptoms or positive fecal occult blood test [FOBT] result) have reported higher rates of interval cancers, (18,53) which may be due to a higher likelihood of cancer at baseline compared with asymptomatic screening cohorts.

Other risk factors.
There are new data about the possible impact of nonsteroidal anti-inflammatory drugs (reduced risk) and smoking (no effect) on risk of adenomas during surveillance. (54, 55, 56, 57, 58) There is insufficient evidence to tailor recommendations based on these risk factors.

Recommendation. There is now stronger evidence to support the 10-year interval after negative findings on baseline colonoscopy for average-risk individuals, assuming that the baseline colon examination is complete with a good bowel preparation.

Individuals with a first-degree relative (FDR) with CRC or HRA have an increased lifetime risk of developing CRC, particularly if the FDR was younger than 60 years at the time of diagnosis. (59) If colonoscopy is performed and the finding is normal, the recommended interval for repeat screening should be 5 years if the FDR was younger than 60 years and 10 years if the FDR was 60 years or older.

Unresolved issues and areas for further research.
The reports of interval cancer after negative findings on colonoscopy have raised concerns about the 10-year interval recommendation. The new prospective studies are reassuring and show that the risk of advanced neoplasia is very low at 5 years. However, one Canadian population-based study suggests that the highest risk of interval CRC is within 1–5 years of the baseline examination, when it is most likely that missed lesions will progress and lead to diagnosis of CRC. (18) These data emphasize the importance of performing high-quality examinations to reduce the likelihood of missed lesions. Future studies should make every effort to document quality indicators.

Baseline examination: no adenomas; distal small (<10 mm) hyperplastic polyps

2006 recommendation for next examination	10 years
2012 recommendation for next examination	No change
Quality of evidence	Moderate

Background. There is considerable evidence that patients with only rectal or sigmoid hyperplastic polyps (HPs) appear to represent a low-risk cohort. Earlier literature focused on whether the finding in the distal colon was a marker of risk for advanced neoplasia elsewhere. Most studies show no such relationship. (2) Most evidence suggests that small lesions (<10 mm) limited to the rectum and sigmoid are benign.

New information since 2006. Distal HPs are a common finding at screening colonoscopy. (60) HPs accounted for 50% of polyps 1–5 mm, 27.9% of polyps 6–9 mm, and 13.7% of polyps >10 mm.

Laiyemo et al (61) followed up 437 participants of the Polyp Prevention Trial (PPT) who had baseline HPs coexisting with adenomas. Neither proximal nor distal HPs were associated with an increased risk of recurrent adenomas at 3 years after the baseline examination. There are no other new studies of follow-up colonoscopy in patients with baseline distal HPs.

Recommendation. Prior and current evidence suggests that distal HPs <10 mm are benign and nonneoplastic. If the most advanced lesions at baseline colonoscopy are distal HPs <10 mm, the interval for colonoscopic follow-up should be 10 years.

Unresolved issues and areas for further research. Future research should include patients with distal HPs in analyses of surveillance outcomes.

Baseline examination: 1–2 tubular adenomas <10 mm

2006 recommendation for next examination	5- to 10-year interval
2012 recommendation for next examination	No change
Quality of evidence	Moderate – evidence stronger than 2006

Background. Prior evidence suggested that patients with LRAs had a lower risk of developing advanced adenomas during follow-up compared with patients with HRAs. An independent meta-analysis and systematic review in 2006 confirmed the findings of the MSTF. (63) At that time, the consensus on the task force was that “observations of cohort studies supports an interval of at least 5 years in this low-risk group; however we reasoned that based on the data from Atkin et al (62)…that a 10 year interval, similar to that used in the average-risk population, also would be acceptable.”

New information since 2006. There are new studies (7, 14, 50, 51, 63, 64, 65, 66) confirming that individuals with LRAs represent a low-risk group (Table 6). Laiyemo et al (64) used the 2006 guideline to predict risk for advanced neoplasia during surveillance in the PPT, comparing high-risk with low-risk patients. The probability of recurrence of advanced adenoma was 0.09 among patients with HRAs at baseline and 0.05 among those with LRAs at baseline (RR, 1.68; 95% confidence interval [CI], 1.19–2.38).

Table 6. Follow-up of Patients With Adenomas at Baseline Colonoscopy

Reference	Type of study	Rate or risk of advanced adenoma during surveillance
Saini et al, 2006 (63)	Meta-analysis: 5 studies stratified by index findings	Baseline RR: ≥3 vs 1–2 adenomas, 2.52 Villous vs TA, 1.26 Adenoma >10 mm vs ≤10 mm, 1.39 HGD vs low-grade dysplasia, 1.84
Laiyemo et al, 2008 (64)	PPT N = 1905	Baseline RR: LRA, 1.00 (ref) HRA, 1.68 (1.19–2.38)
Lieberman et al, 2007 (14)	N = 895 with baseline neoplasia	Baseline rate of AA at 5 y: 1–2 TA <10 mm, 6.1% TA >10 mm, 15.5% ≥3 adenomas, 15.9% Villous adenoma/TVA, 16.1%
Martinez et al, 2009 (7)	Pooling 8 studies	Baseline OR: Size >10 mm, 1.56 ≥3 adenomas, 1.32 Proximal adenoma, 1.68 Villous adenoma/TVA, 1.40
Miller H et al, 2010 (50)	VA cohort	Baseline rate of AA at follow-up: LRA 5 y (n = 77), 5.2% LRA 6–10 y (n = 81), 6.2% HRA 5 y (n = 23), 26.1%
Miller J et al, 2010 (65)	Cohort N = 88	Baseline rate of AA at follow-up: 1–2 small tubular adenomas, 4.5%
Chung et al, 2011 (51)	Cohort	Baseline rate of AA at follow-up: LRA (n = 671), 2.4% HRA (n = 539), 12.2%
Cottet et al, 2011 (66)	Cohort, population-based registry, France; 7.7-y follow-up	Baseline rate of CRC at follow-up: LRA (n = 3236), 0.8%; SIR, 0.68 HRA (n = 1899), 2.8%; SIR, 2.23
AA, advanced adenoma; TA, tubular adenoma; SIR, standardized incidence ratio.

The NCI Pooling Project analyzed data from 8 prospective studies in which patients with baseline adenomas were followed up over 3–5 years and had repeat colonoscopy. (7) Compared with patients with LRAs, ORs were increased in patients with 3 or more adenomas, size ≥10 mm, and villous histology. The VA Cooperative Study 380 (14) compared risk of advanced neoplasia at 5 years in 298 patients with no baseline neoplasia (2.4%) and 496 patients with 1–2 tubular adenomas <10 mm (4.6%), with an adjusted RR of 1.92 (0.83–4.42) not reaching statistical significance.

Korean investigators followed up patients for 5 years after baseline colonoscopy. (51) HRAs were found in 2.0% of 1242 patients with no baseline neoplasia compared with 2.4% in 671 patients with LRAs (adjusted HR, 1.14 [0.61–2.17]). The Prostate Lung Colorectal Ovarian Cancer study (67) compared rates of advanced neoplasia during 6–7 years of follow-up after baseline colonoscopy. Among 318 patients with no adenoma at baseline, the risk of advanced neoplasia during surveillance was similar to those with LRAs (5.3%).

Recommendation. Data published since 2006 endorse the assessment that patients with 1–2 tubular adenomas with low-grade dysplasia <10 mm represent a low-risk group. Three new studies suggest that this group may have only a small, nonsignificant increase in risk of advanced neoplasia within 5 years compared with individuals with no baseline neoplasia.

The evidence supports a surveillance interval of longer than 5 years for most patients. We recognize that quality of the bowel preparation may result in a less than optimal examination in some portions of the colon. In a recent report, when the bowel preparation was inadequate, the miss rates for adenoma and advanced adenoma at 1 year were 35% and 36%, respectively. Factors associated with finding an adenoma on subsequent examination included lack of cecal intubation (OR, 3.62; 95% CI, 2.50–5.24) and finding a polyp at the baseline examination (OR, 1.55; 95% CI, 1.17–2.07). In these circumstances, a 5-year interval might still be prudent.

Unresolved issues and areas for further research. Most studies have not subclassified patients whose largest polyp is diminutive (1–5 mm) versus small (6–9 mm) on screening examinations. Improvements in colonoscopy have resulted in higher detection rates for diminutive polyps. Future study is needed to stratify risk for individuals with LRAs <6 mm and LRAs 6–9 mm in diameter.

Baseline examination: 3–10 adenomas 

2006 recommendation for next examination	3-year interval
2012 recommendation for next examination	No change
Quality of evidence	Moderate: if any polyp ≥6 mm Low: if all polyps <6 mm Evidence stronger than 2006

Background. Two independent meta-analyses in 2006 found that patients with 3 or more adenomas at baseline had an increased RR for adenomas during surveillance, ranging from 1.7 to 4.8. (3, 63) Other studies show that patients with multiple adenomas are more likely to have adenomas detected at 1 year, suggesting that lesions may be more likely to be missed on the baseline examination when multiple polyps are present. These data form the basis of the recommendation for a 3-year interval, similar to the recommendation for large polyps and those with advanced histology. The earlier studies did not stratify multiplicity based on size. Many of the studies of multiplicity include patients with larger polyps. It was not possible to determine if the risk level was different if all polyps were <6 mm versus >6 mm.

New information since 2006. Two new studies reported outcomes in patients with multiple adenomas. The NCI Pooling Project (7) analysis found that with each additional adenoma, there is a linear increase in risk for both advanced and nonadvanced neoplasia (Table 7).

The VA study (which contributed data to the pooling project) also provided a second referent group: patients with no baseline neoplasia. (14) The risk of advanced neoplasia at 5 years was 2.4% in the nonneoplasia referent group, 4.6% if patients had 1–2 tubular adenomas <10 mm (RR, 1.92; 95% CI, 0.83–4.42), and 11.9% if they had 3 or more tubular adenomas <10 mm (RR, 5.01; 95% CI, 2.10–11.96). The VA study shows that even if all of the adenomas are <10 mm, there is increased risk of advanced neoplasia with multiplicity of adenomas.

Table 7. NCI Pooling Project (8 Studies): Risk of Advanced Adenoma at 3–5 Years Based on Number of Polyps at Baseline Colonoscopy (7)

Baseline adenoma no.	% with advanced adenoma at follow-up (95% CI)	Adjusted OR (95% CI)
1	8.6 (7.8–9.3)	1.00 (referent)
2	12.7 (11.3–14.1)	1.39 (1.17–1.66)
3	15.3 (12.9–17.6)	1.85 (1.46–2.34)
4	19.6 (15.3–19.3)	2.23 (1.71–3.40)
5+	24.1(19.8–28.5)	3.87(2.76–5.42)
P trend		<.0001
From Martinez et al. (7)

Recommendation. The new information from the VA study and the NCI Pooling Project support the previous recommendation that patients with 3 or more adenomas have a level of risk for advanced neoplasia similar to other patients with advanced neoplasia (adenoma >10 mm, adenoma with HGD). There are insufficient new data to support a change in the prior recommendation.

Unresolved issues and areas for further research. Historically, some older studies had lower rates of adenoma detection compared with modern studies. In a recent review (69) of screening studies (n = 18), the prevalence of adenomas in average-risk cohorts was 30.2% (range, 22.2%–58.2%). In more recent screening studies using modern technology (such as high-definition white light), adenoma detection rates of 40% or more have been reported. (70) Therefore, it is very likely that there was misclassification of some patients in earlier studies; patients reported to have 1–2 adenomas may have had additional adenomas that were not detected.

There remains some doubt about whether patients who have 3–5 diminutive adenomas (all <6 mm) really have an increased risk of interval advanced neoplasia during surveillance. However, there is little doubt that if patients have 3 or more adenomas, and at least one is advanced, the risk of having advanced neoplasia during surveillance is high. In the VA study, these patients had a nearly 10-fold increased RR compared with patients with no neoplasia and a 5-fold increased RR compared with those with 1–2 small tubular adenomas. (14)

Further research is needed to determine the level of risk of advanced neoplasia if a patient has 3–5 adenomas all <6 mm at the baseline examination. These new studies should use modern colonoscopic technology to determine an accurate number of adenomas at baseline.

Baseline examination: >10 adenomas 

2006 recommendation for next examination	<3-year interval
2012 recommendation for next examination	No change
Quality of evidence	Moderate-high

Background. These patients represent a small proportion of patients undergoing screening examinations. The 2006 guideline noted that such patients should be considered for hereditary syndromes. The recommendation for early follow-up is based on clinical judgment because there is little evidence.

New evidence since 2006. There are no new studies that single out this small group of patients for analysis. The NCI Pooling Project notes a marked increased risk of advanced neoplasia among patients with 5 or more adenomas at baseline.

Recommendation. There is no basis for changing the recommendation to consider follow-up in less than 3 years after a baseline colonoscopy.

Baseline examination: one or more tubular adenomas ≥10 mm 

2006 recommendation for next examination	3-year interval
2012 recommendation for next examination	No change
Quality of evidence	High – evidence stronger than 2006

Background. The 2006 guideline reviewed data related to adenoma size, demonstrating that most studies showed a 2- to 5-fold increased risk of advanced neoplasia during follow-up if the baseline examination had one or more adenomas ≥10 mm.

New information since 2006. The NCI Pooling Project analyzed polyp size as a risk factor for development of interval advanced neoplasia (Table 6). (7) Compared with patients with adenomas <5 mm, those with baseline polyp(s) 10–19 mm had an increased risk of advanced neoplasia (15.9% vs 7.7%; OR, 2.27; 95% CI, 1.84–2.78). If the baseline polyp was 20 mm or more, the risk of advanced neoplasia at follow-up was 19.3% (OR, 2.99; 95% CI, 2.24–4.00). In the VA Cooperative Study 380, the referent group was patients with no neoplasia. (14) The risk of advanced neoplasia within 5.5 years was 2.4% in the no neoplasia group and 15.5% in patients with baseline adenomas >10 mm (RR, 5.01; 95% CI, 2.10–11.96).

Recommendation. The new information provides additional data showing that patients with one or more adenomas ≥10 mm have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (<10 mm) adenomas. There is no basis for changing the recommended 3-year surveillance interval. This recommendation assumes that the examination was of high quality and complete removal of neoplastic tissue occurred at baseline. This group represents a small proportion of all patients with adenomas. If there is question about complete removal (ie, piecemeal resection), early follow-up colonoscopy is warranted.

Baseline examination: one or more adenomas with villous features of any size 

2006 recommendation for next examination	3-year interval
2012 recommendation for next examination	No change
Quality of evidence	Moderate

Background. The 2006 guideline regarded adenomas with villous histology to be HRA.

New information since 2006. The NCI Pooling Project analyzed polyp histology as a risk factor for development of interval advanced neoplasia (Table 6). (7) Compared with patients with tubular adenomas, those with baseline polyp(s) showing adenomas with villous or tubulovillous histology (TVA) had increased risk of advanced neoplasia during follow-up (16.8% vs 9.7%; adjusted OR, 1.28; 95% CI, 1.07–1.52). The level of risk was lower than that associated with size or multiplicity. In the VA Cooperative Study 380, the referent group was patients with no neoplasia. (14) The risk of advanced neoplasia within 5.5 years was 2.4% in the no neoplasia group and 16.1% in patients with baseline adenomas >10 mm (RR, 6.05; 95% CI, 2.48–14.71).

Recommendation. The new information provides additional data showing that patients with one or more adenomas with villous histology have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (<10 mm) tubular adenomas. There is no basis for changing the recommended 3-year surveillance interval.

Unresolved issues and areas for further research. The available studies do not separately identify patients whose most advanced polyp is a TVA or villous adenoma <10 mm in size. Future studies should stratify risk based on both pathology and polyp size.

Baseline examination: one or more adenomas with HGD 

2006 recommendation for next examination	3-year interval
2012 recommendation for next examination	No change
Quality of evidence	Moderate

Background. The 2006 guideline concluded that the presence of HGD in an adenoma was associated with both villous histology and larger size, which are both risk factors for advanced neoplasia during surveillance.

New information since 2006. In a univariate analysis from the NCI Pooling Project, (7) HGD was strongly associated with risk of advanced neoplasia during surveillance (OR, 1.77; 95% CI, 1.41–2.22). The NCI Pooling Project did not find that HGD was independently associated with an increased risk of metachronous advanced neoplasia (OR, 1.05; 95% CI, 0.81–1.35) after adjustments for size and histology, which are known confounders. Toll et al (71) followed up 83 patients with HGD over a median of 4 years, during which 7% developed new HGD or CRC.

Recommendation. The presence of an adenoma with HGD is an important risk factor for development of advanced neoplasia and CRC during surveillance. There is no basis for changing the recommended 3-year surveillance interval.

Baseline examination: serrated polyps 

2006 recommendation for next examination	None
2012 recommendation for next examination	See Table 1
Quality of evidence	Low

Background. A total of 20%–30% of CRCs arise through a molecular pathway characterized by hypermethylation of genes, known as CIMP. (23) Precursors are believed to be serrated polyps (Table 8). Tumors in this pathway have a high frequency of BRAF mutation, and up to 50% are microsatellite unstable. CIMP-positive tumors are overrepresented in interval cancers, particularly in the proximal colon. The principal precursor of hypermethylated cancers is probably the sessile serrate polyp (synonymous with sessile serrated adenoma; Table 8). Sessile serrated polyps sometimes have foci of cytological dysplasia, which indicates a more advanced lesion in the polyp-cancer sequence.

These polyps are difficult to detect at endoscopy. They may be the same color as surrounding colonic mucosa, have indiscrete edges, are nearly always flat or sessile, and may have a layer of adherent mucus and obscure the vascular pattern.

Table 8. Clinical Features of Serrated Lesions of the Colorectum

World Health Organization classification	Prevalence	Shape	Distribution	Malignant potential
Hyperplastic polyp	Very common	Sessile/flat	Mostly distal	Very low
Sessile serrated adenoma/polyp	Common	Sessile/flat	80% proximal
No dysplasia				Low
Dysplastic				Significant
Traditional serrated adenoma	Uncommon	Sessile or pedunculated	Mostly distal	Significant

New information since 2006. The clinical implications of serrated polyps are uncertain. Recent studies show that proximal colon location or size >10 mm may be markers of risk for synchronous advanced adenomas elsewhere in the colon. (72, 73) Surveillance after colonoscopy was evaluated in one study, which found that coexisting serrated polyps and HRA is associated with a higher risk of advanced neoplasia at surveillance. (72) This study also found that if small proximal serrated polyps are the only finding at baseline, the risk of adenomas during surveillance is similar to that of patients with LRA.

Recommendation. Prior surveillance guidelines did not comment on surveillance intervals if proximal serrated polyps are found at baseline colonoscopy. There are no longitudinal studies available on which to base surveillance intervals after resection. Our recommendation is based on low-quality evidence and will require updating when new data are available. The current evidence suggests that size (>10 mm), histology (a sessile serrated polyp is a more significant lesion than an HP; a sessile serrated polyp with cytological dysplasia is more advanced than a sessile serrated polyp without dysplasia), and location (proximal to the sigmoid colon) are risk factors that might be associated with higher risk of CRC. A sessile serrated polyp ≥10 mm and a sessile serrated polyp with cytological dysplasia should be managed like HRA (Table 1). Serrated polyps that are <10 mm and do not have cytological dysplasia may have lower risk and can be managed like LRA.

Unresolved issues and areas for further study. There is considerable variation in detection rate by different endoscopists (74, 75) and histologic interpretation by pathologists (76) that makes it challenging to evaluate the natural history of serrated polyps. It is likely that many patients are misclassified because of one or both of these factors. Because of this interobserver variation in pathologic interpretation, some experts endorse a position that all proximal colon serrated lesions ≥10 mm should be considered sessile serrated polyps, even if the pathologic interpretation is HP. Further study is needed to reduce interobserver variability in diagnosis and determine natural history.

Other Issues Related to Colon Surveillance 

Surveillance after the first follow-up colonoscopy. The follow-up of patients after they undergo surveillance has been uncertain. It is not clear if risk continues to be increased if surveillance colonoscopy reveals an LRA or no neoplasia. There are 3 new cohort studies that have followed up patients over several surveillance cycles to determine the risk of advanced neoplasia over time. (67, 77, 78) These studies all have important limitations, because many patients did not receive a second surveillance, which could lead to selection bias, and intervals were irregular. Data from these studies are summarized in Table 9. These data suggest that the detection of an advanced adenoma is an important risk factor for finding advanced adenoma at the next examination. Once patients have a low-risk lesion or no adenoma, the risk of advanced neoplasia at the next examination is lower. Patients with LRA at baseline and no adenomas at first surveillance have a very low risk (2.8%–4.9%) of having advanced adenomas at the second surveillance examination 3–5 years later. Although the evidence is weak due to incomplete follow-up of the cohorts, it is consistent across 3 longitudinal studies.

Table 9. Multiple Rounds of Colonoscopy Surveillance

Baseline colonoscopy	First surveillance	Advanced neoplasia at second surveillance (%)
		Pinsky et al, 2009, Prostate Lung Colorectal Ovarian Cancer study (67)	Laiyemo et al, 2009, PPT (77)	Robertson et al, 2009 (78)
HRA	HRA	19.3	30.6	18.2
	LRA	6.7	8.9	13.6
	No adenoma	5.9	4.8	12.3
LRA	HRA	15.6	6.9	20.0
	LRA	5.7	4.7	9.5
	No adenoma	3.9	2.8	4.9
No adenoma	HRA	11.5
	LRA	4.7
	No adenoma	3.1
NOTE. HRA is defined as 3 or more adenomas, tubular adenoma ≥10 mm, adenoma with villous histology, or HGD. LRA is defined as 1–2 tubular adenomas <10 mm.

Recommendation. We believe that patients with LRA at baseline and negative findings at first surveillance can have their next surveillance examination at 10 years. Patients who have HRA at any examination appear to remain at high risk and should have shorter follow-up intervals for surveillance. A summary of these recommendations is outlined in Table 10.

Table 10. Recommendations for Polyp Surveillance After First Surveillance Colonoscopy

Baseline colonoscopy	First surveillance	Interval for second surveillance (y)
LRA	HRA	3
	LRA	5
	No adenoma	10
HRA	HRA	3
	LRA	5
	No adenoma	5a
aIf the findings on the second surveillance are negative, there is insufficient evidence to make a recommendation.

When should surveillance stop?

There is considerable new evidence that the risk of colonoscopy increases with advancing age. (79, 80) Both surveillance and screening should not be continued when risk may outweigh benefit. The United States Preventive Services Task Force (USPSTF) determined that screening should not be continued after age 85 years (81) because risk could exceed potential benefit. Patients with HRA are at higher risk for developing advanced neoplasia compared with average-risk screenees. Therefore, the potential benefit of surveillance could be higher than for screening in these individuals. For patients aged 75–85 years, the USPSTF recommends against continued routine screening but argues for individualization based on comorbidities and findings of any prior colonoscopy. This age group may be more likely to benefit from surveillance, depending on life expectancy.

It is the opinion of the MSTF that the decision to continue surveillance should be individualized, based on an assessment of benefit, risk, and comorbidities.

When should colonoscopy be repeated if there is a poor bowel preparation at baseline colonoscopy? 

Poor-quality bowel preparations that obscure visualization of the colon may be associated with missed lesions at the baseline colonoscopy. (68, 82) Current quality indicators for colonoscopy call for monitoring the quality of bowel preparation, (39) with the goal of achieving preparations adequate for detection of lesions >5 mm. There is now substantial evidence (83) that splitting the dose of bowel preparation results in better quality, and this practice is strongly encouraged by the MSTF.

If the bowel preparation is poor, the MSTF recommends that in most cases the examination should be repeated within 1 year. Alternative methods of imaging, such as CT colonography, also require excellent bowel preparation for an adequate examination. If the bowel preparation is fair but adequate (to detect lesions >5 mm) and if small (<10 mm) tubular adenomas are detected, follow-up at 5 years should be considered.

Positive FOBT (guaiac FOBT or fecal immunochemical test) result before scheduled surveillance 

If patients have an adequate baseline colonoscopy, surveillance colonoscopy should be based on the current guidelines. Patients should not have interval fecal blood testing if colonoscopy is planned. The role of interval fecal testing is uncertain. (84) A recent study from Australia found that interval fecal immunochemical test led to diagnosis of cancers before the scheduled surveillance. (85) However, this study included patients with baseline cancer and did not provide information about the findings or quality of the baseline examination, which may have been important risk factors for interval pathology.

In clinical practice, patients may have had an interval FOBT performed. A decision to perform an early colonoscopy due to positive fecal test result could be based on careful review of the baseline examination. If this examination was not complete or somewhat compromised by fair bowel preparation, it may be quite reasonable to perform an early examination. There are no data to support the practice of a routine early examination and no evidence that these patients have a higher than expected risk of cancer or advanced adenoma.

Interval fecal testing should not be a substitute for high-quality performance of colonoscopy. The task force recommends that interval fecal testing not be performed within the first 5 years after colonoscopy. There is currently insufficient evidence to support this practice. The likelihood of false-positive test results is high, which would result in unnecessary early colonoscopies.

If fecal blood test is performed in the first 5 years after colonoscopy, there is insufficient evidence to make a recommendation. If the patient does have an interval-positive FOBT result, the clinician’s judgment to repeat colonoscopy could consider the prior colonoscopy findings, completeness of examination and bowel preparation, and family history. Despite the low likelihood of significant pathology if the baseline examination was high quality, we recognize that there may be concerns about missed lesions at the baseline examination. Potential medical-legal issues often lead to repeat examination. Future studies of this subject should carefully document the quality of the baseline examination and determine rates of significant pathology.

Development of new symptoms during the surveillance interval (minor rectal bleeding, diarrhea, constipation)

Patients may develop new problems within 3–5 years after colonoscopy that might otherwise be indications for colonoscopy. If patients develop significant lower gastrointestinal bleeding as defined by clinical judgment, they may need further evaluation.

Change in bowel habits, abdominal pain, or minor rectal bleeding are common symptoms that may occur after completion of a colonoscopy. This creates a clinical dilemma: should colonoscopy be repeated before the scheduled surveillance examination? The likelihood of finding significant pathology after a prior complete and adequate colonoscopy is uncertain but likely to be low. However, if the colonoscopy will answer an important clinical question, it may be valuable to repeat.

The consensus of the task force is that there is insufficient evidence to make a recommendation.

Should surveillance be modified based on lifestyle risk factors for CRC?

There is considerable new evidence that risk of recurrent adenomas may be reduced by taking aspirin or nonsteroidal anti-inflammatory drugs. (11, 54, 55, 56, 57) We believe there is insufficient evidence to recommend any change in surveillance intervals in patients who are taking these medications.

Should surveillance be modified based on patient race, ethnicity, or sex?

CRC age-adjusted risk varies based on patient demographic characteristics. However, there is no new evidence that that the surveillance interval should be altered once patients have had colonoscopy and polypectomy based on these factors.

The 2006 MSTF guideline provided a valuable framework for polyp surveillance based on the histology and number of polyps detected at the baseline examination. We find that new data since 2006 support these recommendations.

The current guideline recommendations apply only to high-quality baseline examinations.

Quality indicators (37, 38, 39) for reporting and performance have been well documented and should become part of routine endoscopic practice. Several key performance indicators, such as cecal intubation rate and adenoma detection rate, are associated with rates of interval cancer. (16, 42) The task force believes that quality indicators must be measured as an essential part of a colonoscopy screening and surveillance program.

The 2006 guideline posed several important questions, some of which are now addressed:

What are the reasons that guidelines are not followed more closely? The utilization of colonoscopy for surveillance has an important impact on resource utilization and health care costs. New evidence suggests that surveillance is often overutilized, which increases cost and risk to patients and the health care system. Reasons for poor adherence to guidelines are unclear. We speculate that concerns about interval cancer after colonoscopy may result in some overutilization during surveillance. Incorporation of the guidelines as quality indicators of colonoscopy may improve adherence.

Will emerging studies with longer colonoscopy follow-up times support the safety of lengthening surveillance intervals? New evidence from 3 longitudinal studies in which patients have undergone multiple surveillance examinations has identified a low-risk group that may require little or no surveillance after 2 examinations. (65, 77, 78)

What is the role of family history in predicting advanced adenomas and CRC? There is some new evidence that individuals with an FDR with CRC or HRA have an increased risk of developing HRA or CRC. (59)

What roles will chromoendoscopy, magnification endoscopy, narrow band imaging, and CT colonography play in postpolypectomy surveillance? The role of new endoscopic technologies has not been studied in surveillance cohorts, although there are ongoing studies of CT colonography. The technical endoscopic enhancements may increase the likelihood of detecting small polyps. Chromoendoscopy and narrow band imaging may enable endoscopists to accurately determine if lesions are neoplastic, and if there is a need to remove them and send material to pathology. At this point, these technologies do not have an impact on surveillance intervals.

What is the usefulness of FOBT in postpolypectomy surveillance? A new study (85) found that a positive fecal immunochemical test performed at some interval before scheduled surveillance colonoscopy, may help identify patients who may benefit from early surveillance. This study did not evaluate baseline findings or examination quality to determine their relationship to development of interval CRC. The question of interval testing to detect interval CRC is important and merits further study.

What is the importance of the serrated polyp pathway and detection of serrated adenomas and proximal HPs? The current guideline reviews new information about serrated polyps and makes recommendations for follow-up.

What is the appropriate surveillance of patients who had an adenoma removed in piecemeal resection? Flat and sessile adenomatous and serrated polyps >15 mm are increasingly removed using injection-assisted polypectomy and piecemeal resection technique. There are insufficient data upon which to base a recommendation. However, the MSTF recommends consideration of a short interval for repeat colonoscopy (<1 year) if there is any question about completeness of resection of neoplastic tissue.

The MSTF believes that the evidence supporting these recommendations for screening and surveillance intervals has become stronger in the past 6 years. We have highlighted areas of uncertainty that require further research. The guidelines are dynamic and will be revised in the future based on new evidence. This new evidence should include information about the quality of the baseline examinations. The task force recommends that all endoscopists monitor key quality indicators as part of a colonoscopy screening and surveillance program.

The authors disclose the following: D.A.L. is an advisory board member for Given Imaging and Exact Sciences. D.K.R. is an advisory board member for Given Imaging and has received research funding from Olympus Corp. D.A.J. is a clinical investigator for Exact Sciences and an advisory board member for Given Imaging. The remaining authors disclose no conflicts.

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Loren Laine, MD^1,2 and Dennis M. Jensen, MD^3–5

¹Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA; ²VA Connecticut Healthcare System, New Haven, Connecticut, USA; ³David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; ⁴CURE Digestive Diseases Research Center, Los Angeles, California, USA; ⁵VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.

This guideline presents recommendations for the step-wise management of patients with overt upper gastrointestinal bleeding. Hemodynamic status is first assessed, and resuscitation initiated as needed. Patients are risk-stratified based on features such as hemodynamic status, comorbidities, age, and laboratory tests. Pre-endoscopic erythromycin is considered to increase diagnostic yield at first endoscopy. Pre-endoscopic proton pump inhibitor (PPI) may be considered to decrease the need for endoscopic therapy but does not improve clinical outcomes. Upper endoscopy is generally performed within 24 h. The endoscopic features of ulcers direct further management. Patients with active bleeding or non-bleeding visible vessels receive endoscopic therapy (e.g., bipolar electrocoagulation, heater probe, sclerosant, clips) and those with an adherent clot may receive endoscopic therapy; these patients then receive intravenous PPI with a bolus followed by continuous infusion. Patients with flat spots or clean-based ulcers do not require endoscopic therapy or intensive PPI therapy. Recurrent bleeding after endoscopic therapy is treated with a second endoscopic treatment; if bleeding persists or recurs, treatment with surgery or interventional radiology is undertaken. Prevention of recurrent bleeding is based on the etiology of the bleeding ulcer. H. pylori is eradicated and after cure is documented anti-ulcer therapy is generally not given. Nonsteroidal anti-inflammatory drugs (NSAIDs) are stopped; if they must be resumed low-dose COX-2-selective NSAID plus PPI is used. Patients with established cardiovascular disease who require aspirin should start PPI and generally re-institute aspirin soon after bleeding ceases (within 7 days and ideally 1–3 days). Patients with idiopathic ulcers receive long-term anti-ulcer therapy.

Am J Gastroenterol 2012; 107:345–360; doi: 10.1038/ajg.2011.480; published online 7 February 2012
Received 31 July 2011; accepted 21 December 2011.

Correspondence: Loren Laine, MD, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street/1080 LMP, New Haven, Connecticut 06520-8019, USA. E-mail: loren.laine@yale.edu

Ulcers are the most common cause of hospitalization for upper gastrointestinal bleeding (UGIB), and the vast majority of clinical trials of therapy for nonvariceal UGIB focus on ulcer disease. This guideline provides recommendations for the management of patients with overt UGIB due to gastric or duodenal ulcers. "Overt" indicates that patients present with symptoms of hematemesis, melena, and/or hematochezia. We first discuss the initial management of UGIB in patients without known portal hypertension, including initial assessment and risk stratification, pre-endoscopic use of medications and gastric lavage, and timing of endoscopy. We then focus on the endoscopic and medical management of ulcer disease, including endoscopic findings and their prognostic implications, endoscopic hemostatic therapy, post-endoscopic medical therapy and disposition, and prevention of recurrent ulcer bleeding.

Each section of the document presents the key recommendations related to the section topic, followed by a summary of the supporting evidence. A summary of recommendations is provided in Table 1.

A search of MEDLINE via the OVID interface using the MeSH term "gastrointestinal hemorrhage" limited to "all clinical trials " and " meta-analysis " for years 1966–2010 without language restriction as well as review of clinical trials and reviews known to the authors were performed for preparation of this document. The GRADE system was used to grade the strength of recommendations and the quality of evidence (1). The quality of evidence, which influences the strength of recommendation, ranges from "high" (further research is very unlikely to change our confidence in the estimate of effect) to "moderate" (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) to "low" (further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate), and "very low" (any estimate of effect is very uncertain). The strength of a recommendation is graded as strong when the desirable effects of an intervention clearly outweigh the undesirable effects and is graded as conditional when uncertainty exists about the trade-offs (1). In addition to quality of evidence and balance between desirable and undesirable effects, other factors affecting the strength of recommendation include variability in values and preferences of patients, and whether an intervention represents a wise use of resources (1).

Table 1. Summary and strength of recommendations

Initial assessment and risk stratification

1. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed (Strong recommendation).

2. Blood transfusions should target hemoglobin >= 7 g/dl, with higher hemoglobins targeted in patients with clinical evidence of intravascular volume depletion or comorbidities, such as coronary artery disease (Conditional recommendation).

3. Risk assessment should be performed to stratify patients into higher and lower risk categories and may assist in initial decisions such as timing of endoscopy, time of discharge, and level of care (Conditional recommendation).

4. Discharge from the emergency department without inpatient endoscopy may be considered in patients with urea nitrogen < 18.2 mg/dl; hemoglobin >= 13.0 g/dl for men (12.0 g/dl for women), systolic blood pressure >= 110 mm Hg; pulse < 100 beats / min; and absence of melena, syncope, cardiac failure, and liver disease, as they have < 1% chance of requiring intervention (Conditional recommendation).

Pre-endoscopic medical therapy

5. Intravenous infusion of erythromycin (250 mg ~30 min before endoscopy) should be considered to improve diagnostic yield and decrease the need for repeat endoscopy. However, erythromycin has not consistently been shown to improve clinical outcomes (Conditional recommendation).

6. Pre-endoscopic intravenous PPI (e.g., 80 mg bolus followed by 8 mg/h infusion) may be considered to decrease the proportion of patients who have higher risk stigmata of hemorrhage at endoscopy and who receive endoscopic therapy. However, PPIs do not improve clinical outcomes such as further bleeding, surgery, or death (Conditional recommendation).

7. If endoscopy will be delayed or cannot be performed, intravenous PPI is recommended to reduce further bleeding (Conditional recommendation).

Gastric lavage

8. Nasogastric or orogastric lavage is not required in patients with UGIB for diagnosis, prognosis, visualization, or therapeutic effect (Conditional recommendation).

Timing of endoscopy

9. Patients with UGIB should generally undergo endoscopy within 24 h of admission, following resuscitative efforts to optimize hemodynamic parameters and other medical problems (Conditional recommendation).

10. In patients who are hemodynamically stable and without serious comorbidities endoscopy should be performed as soon as possible in a non-emergent setting to identify the substantial proportion of patients with low-risk endoscopic findings who can be safely discharged (Conditional recommendation).

11. In patients with higher risk clinical features (e.g., tachycardia, hypotension, bloody emesis or nasogastric aspirate in hospital) endoscopy within 12 h may be considered to potentially improve clinical outcomes (Conditional recommendation).

Endoscopic diagnosis

12. Stigmata of recent hemorrhage should be recorded as they predict risk of further bleeding and guide management decisions. The stigmata, in descending risk of further bleeding, are active spurting, non-bleeding visible vessel, active oozing, adherent clot, flat pigmented spot, and clean base (Strong recommendation).

Endoscopic therapy

13. Endoscopic therapy should be provided to patients with active spurting or oozing bleeding or a non-bleeding visible vessel (Strong recommendation).

14. Endoscopic therapy may be considered for patients with an adherent clot resistant to vigorous irrigation. Benefit may be greater in patients with clinical features potentially associated with a higher risk of rebleeding (e.g., older age, concurrent illness, inpatient at time bleeding began) (Conditional recommendation).

15. Endoscopic therapy should not be provided to patients who have an ulcer with a clean base or a flat pigmented spot (Strong recommendation).

16. Epinephrine therapy should not be used alone. If used, it should be combined with a second modality (Strong recommendation).

17. Thermal therapy with bipolar electrocoagulation or heater probe and injection of sclerosant (e.g., absolute alcohol) are recommended because they reduce further bleeding, need for surgery, and mortality (Strong recommendation).

18. Clips are recommended because they appear to decrease further bleeding and need for surgery. However, comparisons of clips vs. other therapies yield variable results and currently used clips have not been well studied (Conditional recommendation).

19. For the subset of patients with actively bleeding ulcers, thermal therapy or epinephrine plus a second modality may be preferred over clips or sclerosant alone to achieve initial hemostasis (Conditional recommendation).

Medical therapy after endoscopy

20. After successful endoscopic hemostasis, intravenous PPI therapy with 80 mg bolus followed by 8 mg/h continuous infusion for 72 h should be given to patients who have an ulcer with active bleeding, a non-bleeding visible vessel, or an adherent clot (Strong recommendation).

21. Patients with ulcers that have flat pigmented spots or clean bases can receive standard PPI therapy (e.g., oral PPI once daily) (Strong recommendation).

Repeat endoscopy

22. Routine second-look endoscopy, in which repeat endoscopy is performed 24 h after initial endoscopic hemostatic therapy, is not recommended (Conditional recommendation).

23. Repeat endoscopy should be performed in patients with clinical evidence of recurrent bleeding and hemostatic therapy should be applied in those with higher risk stigmata of hemorrhage (Strong recommendation).

24. If further bleeding occurs after a second endoscopic therapeutic session, surgery or interventional radiology with transcathether arterial embolization is generally employed (Conditional recommendation).

Hospitalization

25. Patients with high-risk stigmata (active bleeding, visible vessels, clots) should generally be hospitalized for 3 days assuming no rebleeding and no other reason for hospitalization. They may be fed clear liquids soon after endoscopy (Conditional recommendation).

26. Patients with clean-based ulcers may receive a regular diet and be discharged after endoscopy assuming they are hemodynamically stable, their hemoglobin is stable, they have no other medical problems, and they have a residence where they can be observed by a responsible adult (Strong recommendation).

Long-term prevention of recurrent bleeding ulcers

27. Patients with H. pylori-associated bleeding ulcers should receive H. pylori therapy. After documentation of eradication, maintenance antisecretory therapy is not needed unless the patient also requires NSAIDs or antithrombotics (Strong recommendation).

28. In patients with NSAID-associated bleeding ulcers, the need for NSAIDs should be carefully assessed and NSAIDs should not be resumed if possible. In patients who must resume NSAIDs, a COX-2 selective NSAID at the lowest effective dose plus daily PPI is recommended (Strong recommendation).

29. In patients with low-dose aspirin-associated bleeding ulcers, the need for aspirin should be assessed. If given for secondary prevention (i.e., established cardiovascular disease) then aspirin should be resumed as soon as possible after bleeding ceases in most patients: ideally within 1–3 days and certainly within 7 days. Long-term daily PPI therapy should also be provided. If given for primary prevention (i.e., no established cardiovascular disease), anti-platelet therapy likely should not be resumed in most patients (Conditional recommendation).

30. In patients with idiopathic (non-H. pylori, non-NSAID) ulcers, long-term antiulcer therapy (e.g., daily PPI) is recommended (Conditional recommendation).

PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; UGIB, upper gastrointestinal bleeding.

Recommendations.

1. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed (Strong recommendation, low-quality evidence).
2. Blood transfusions should target hemoglobin >= 7 g/dl, with higher hemoglobins targeted in patients with clinical evidence of intravascular volume depletion or comorbidities such as coronary artery disease (Conditional recommendation, low-to-moderate-quality evidence).
3. Risk assessment should be performed to stratify patients into higher and lower risk categories, and may assist in initial decisions such as timing of endoscopy, time of discharge, and level of care (Conditional recommendation, low-quality evidence).
4. Discharge from the emergency department without inpatient endoscopy may be considered in patients with urea nitrogen < 18.2 mg/dl; hemoglobin >= 13.0 g/dl for men (12.0 g/dl for women), systolic blood pressure >= 110 mm Hg; pulse < 100 beats/min; and absence of melena, syncope, cardiac failure, and liver disease, as they have < 1% chance of requiring intervention (Conditional recommendation, low-quality evidence).

Summary of evidence. Based on other models of hemorrhage (2), the first step in management of patients presenting with overt upper gastrointestinal bleeding (UGIB) is assessment of hemodynamic status and initiation of resuscitative measures as needed. In addition to intravenous fluids, transfusion of red blood cells may be required. Randomized trials in euvolemic patients without current bleeding (3) and in cirrhotics with UGIB (4) indicate that transfusions should be given to maintain hemoglobin >=7 g/dl. A restrictive transfusion policy is also supported by an older randomized trial of 50 patients without known varices in which patients transfused >= 2 units within 24 h of admission had significantly more rebleeding than those not transfused unless Hgb was < 8 g/dl (5). Higher hemoglobin levels may need to be targeted in patients with other illnesses (e.g., coronary artery disease) (6) and in those with intravascular volume depletion (i.e., hypotension and tachycardia) in whom the hemoglobin is "artificially " elevated before repletion with intravascular fluid. Intubation may be considered to protect the airway and prevent aspiration in patients with severe ongoing hematemesis and/or altered mental status; it may also be necessary in some patients (e.g., those with comorbidities) to safely and effectively provide sedation for endoscopy.

Risk assessment of patients is clinically useful to determine which patients are at higher risk of further bleeding or death, and may inform management decisions such as timing of endoscopy, time of discharge, and level of care (e.g., ward vs. step-down vs. intensive care).

Instruments used to assess risk include the pre-endoscopic Rockall score (7) and the Blatchford score (8). The pre-endoscopic Rockall score (range, 0–7) uses only clinical data available immediately at presentation, which are related to the severity of the bleeding episode (systolic blood pressure and pulse) and to the patient (age and comorbidities). It has been shown to predict the risk of further bleeding and death in a population of patients hospitalized with UGIB (7). The Blatchford score (range, 0–23) uses clinical data (systolic blood pressure, pulse, melena, syncope, hepatic disease, and heart failure) and laboratory data (hemoglobin and blood urea nitrogen) available early after admission. It has been shown to predict the risk of intervention (transfusion and endoscopic or surgical therapy) and death in a population of patients presenting to hospital with UGIB (8).

In general, risk assessment with scoring systems such as Blatchford or Rockall is not able to unequivocally identify individual patients who will require intervention, with one exception. Patients with a Blatchford score of 0 (urea nitrogen < 18.2 mg/dl; hemoglobin >= 13.0 g/dl for men (12.0 g/dl for women), systolic blood pressure >= 110 mm Hg; pulse < 100 beats/min; absence of melena, syncope, cardiac failure, and liver disease), which may occur in up to ~5–20% of those presenting with UGIB, have < 1% chance of requiring intervention (8–11).

In a prospective series, Stanley et al. (9) did not admit patients presenting to emergency departments with UGIB who had Blatchford scores of 0 unless necessary for other reasons. Of 123 patients with scores of 0, 84 were not admitted. Among the 23 patients receiving outpatient endoscopy no ulcers, varices, or malignancies were found and no interventions were needed. Among the remainder, none were readmitted with UGIB or died during >= 6 months of follow-up. Thus, discharge from the emergency department without inpatient endoscopy may be considered in very low-risk patients with Blatchford scores of 0.

Prokinetic therapy

Recommendations.

5. Intravenous infusion of erythromycin (250 mg ~30 min before endoscopy) should be considered to improve diagnostic yield and decrease the need for repeat endoscopy. However, erythromycin has not consistently been shown to improve clinical outcomes (Conditional recommendation, moderate-quality evidence).

Summary of evidence. Prokinetic agents given before endoscopy have been proposed to improve visualization at endoscopy. Three fully published randomized trials of erythromycin given intravenously before endoscopy were identified in a recent systematic review (12). Infusions of erythromycin 250 mg or 3 mg/kg were given over 5 or 30 min and endoscopy was performed 20–60 min after the infusion finished (13–15). All trials showed significant improvement in their primary end point related to visualization of mucosa.
However, a more clinically appropriate question is whether use of erythromycin translates into more diagnoses made at initial endoscopy or better clinical outcomes. Meta-analysis of these three trials (13–15) reveals a very modest but significant benefit (relative risk (RR) = 1.13, 1.02–1.26; number needed to treat (NNT) = 9) in diagnosis at first endoscopy. Erythromycin did not significantly reduce clinical outcomes such as blood transfusions, hospital stay, or surgery, but did decrease the proportion of patients undergoing a second endoscopy (12). Only two abstracts assessing metoclopramide were identified in this meta-analysis, and no significant benefits were found in this small sample (12).

Since this meta-analysis, a study reporting on the non-randomized cohort of patients with variceal bleeding from within a randomized trial found better visualization and shorter hospital stay with erythromycin, but no significant decreases in transfusions or repeat endoscopy (16). A randomized comparison of erythromycin, standard-bore nasogastric (NG) tube, or erythromycin plus NG tube in 253 patients with UGIB revealed no significant differences in visualization, diagnosis at first endoscopy, second-look endoscopy, further bleeding, or transfusions (17).

Proton pump inhibitor therapy

Recommendations.

6. Pre-endoscopic intravenous proton pump inhibitor (PPI) (e.g., 80 mg bolus followed by 8 mg/h infusion) may be considered to decrease the proportion of patients who have higher risk stigmata of hemorrhage at endoscopy and who receive endoscopic therapy. However, PPIs do not improve clinical outcomes such as further bleeding, surgery, or death (Conditional recommendation, high-quality evidence).
7. If endoscopy will be delayed or cannot be performed, intravenous PPI is recommended to reduce further bleeding (Conditional recommendation, moderate-quality evidence).

Summary of evidence. A Cochrane meta-analysis of six randomized trials (N = 2,223) of pre-endoscopic PPI therapy found no significant differences between PPI and control in mortality (6.1 vs. 5.5%; odds ratio (OR) = 1.12, 0.72–1.73), rebleeding (13.9 vs. 16.6%; OR = 0.81, 0.61–1.09), or surgery (9.9 vs. 10.2% , OR = 0.96, 0.68–1.35) (18). PPI therapy significantly reduced the proportion of participants with higher risk stigmata of hemorrhage (active bleeding, non-bleeding visible vessel, and adherent clot) at index endoscopy (37.2 vs. 46.5%; OR = 0.67, 0.54–0.84) and undergoing endoscopic therapy at index endoscopy (8.6 vs. 11.7%; OR = 0.68, 0.50–0.93). Similar results were seen in the highest quality study, which also was the only study employing high-dose bolus and continuous infusion intravenous PPI (19). Endoscopic therapy was performed in 19.1 vs. 28.4% (P = 0.007), and, among those with ulcers, active bleeding was significantly less common (6.4 vs. 14.7%; P = 0.01) and clean-based ulcers more common (64.2 vs. 47.4%; P = 0.001) with PPI therapy. PPI therapy should be discontinued after endoscopy unless the patient has a source for which PPIs may be beneficial (e.g., ulcers and erosions).

A Cochrane meta-analysis of randomized trials of patients with UGIB who did not consistently receive endoscopic hemostatic therapy reported that PPI therapy was associated with reduced rebleeding (OR = 0.38, 0.18–0.81 (with significant heterogeneity); NNT = 10) and surgery (OR = 0.62, 0.44–0.88; NNT = 17), but not mortality (20). This suggests that if endoscopy will be delayed or cannot be performed, PPI therapy may improve clinical outcomes.

Gastric lavage

Recommendations.

8. NG or orogastric lavage is not required in patients with UGIB for diagnosis, prognosis, visualization, or therapeutic effect (Conditional recommendation, low-quality evidence).

Summary of evidence. A variety of reasons have been advanced to perform NG lavage in patients with gastrointestinal (GI) bleeding: to determine if the source of bleeding is in the upper GI tract, to provide prognostic information, to clear blood and clots and allow better visualization at endoscopy, and to treat UGIB.

Documentation of a UGI source. NG aspirates with blood or coffee-ground material clearly document UGIB, and a bloody NG aspirate increases the likelihood of finding active bleeding or a non-bleeding visible vessel as compared with coffee-grounds or a clear NG aspirate (21,22). However, a clear or bile-stained NG aspirate may be seen in up to 18% of patients with an upper GI source (22–27). For example, in a Canadian UGIB registry, 13% of patients with UGIB had a clear or bile-stained aspirate; 15% of patients with a clear / bile-stained aspirate had active bleeding or non-bleeding visible vessel compared with 23% with coffee-grounds and 45% with bloody aspirates (22). In a prospective study of patients presenting with hematochezia plus hypotension, tachycardia, dropping hemoglobin, or transfusion, and a negative NG aspirate, 15% had an upper GI source (27). Although some suggest that a non-bloody bile-stained aspirate indicates duodenal contents were sampled and rules out a UGI source, physicians are incorrect about 50% of the time when they report bile in the aspirate (25). In addition, testing NG aspirates for occult blood is not documented to be useful.

Prognostic value. Intuitively, a persistently bloody NG aspirate would seem likely to indicate a more severe UGIB episode. An NG aspirate with red blood is reported to be associated with more severe bleeding (proportion requiring > 5 units of blood and surgery) (21,22), and increases the chance of identifying high-risk stigmata at the time of endoscopy (21,22). However, whether a bloody aspirate provides better prognostic information than other readily available data such as blood pressure and pulse is not known. In a prospective trial in 325 patients, the proportion with "shock" (systolic blood pressure < 100 mm Hg and pulse > 100 beats/minute) correlated with the NG aspirate finding: 11% with a clear aspirate, 36% with coffee-grounds, and 60% with bloody aspirate (28).

Improvement of visualization. The standard small-bore NG tube typically used for aspiration is not likely to effectively clear clots from the stomach. A large-bore orogastric tube is more likely to be successful in clearing the stomach with major UGIB. A small randomized comparison of a 40 French orogastric tube (with sedation) vs. no lavage in 38 patients showed a significantly higher proportion with excellent visualization in the fundus (the primary end point) and a trend in the antrum (P = 0.06) (29). There was no significant difference in the proportion with the bleeding source defined (95 vs. 83%). The use of a large-bore orogastric tube is difficult and uncomfortable for patients and cannot be recommended routinely.

Endoscopic methods of aspiration designed to improve visualization, including use of a jumbo channel (6 mm) or an external auxiliary device, have been assessed in case series (30,31). Further study is needed to determine their potential role as compared with prokinetic therapy and NG aspiration.

Therapeutic effect. Older textbooks reported that NG lavage could stop bleeding in a majority of cases and recommended use of iced saline. However, UGIB stops spontaneously in a majority of patients without specific therapy, and studies in dogs with experimentally induced ulcers indicated that results with lavage are no better and may even be worse at temperatures of 0–4° C (32).

Timing of endoscopy

Recommendations.

9. Patients with UGIB should generally undergo endoscopy within 24 h of admission, following resuscitative efforts to optimize hemodynamic parameters and other medical problems (Conditional recommendation, low-quality evidence).
10. In patients who are hemodynamically stable and without serious comorbidities endoscopy should be performed as soon as possible in a non-emergent setting to identify the substantial proportion of patients with low-risk endoscopic findings who can be safely discharged (Conditional recommendation, moderate-quality evidence).
11. In patients with higher risk clinical features (e.g., tachycardia, hypotension, bloody emesis or NG aspirate in hospital) endoscopy within 12 h may be considered to potentially improve clinical outcomes (Conditional recommendation, low-quality evidence).

Summary of evidence. Early endoscopy has been variably defined as endoscopy performed within 2–24 h of presentation. A variety of observational studies and a few randomized trials have assessed this issue, but marked variations in study design, definitions, end points, and methodologic rigor make synthesis of the results difficult. Two systematic reviews summarize these studies (33,34). Studies of early endoscopy consistently show that patients undergoing endoscopy within 8 h of presentation have more high-risk stigmata (active bleeding, visible vessels, or adherent clots) than those with later endoscopies (34), thereby increasing the proportion who requires endoscopic therapy. However, observational studies do not document a benefit in clinical outcomes of endoscopy performed within 2–12 h of presentation (33,34). Observational studies do suggest a benefit of endoscopy within 24 h after admission in terms of decreased length of stay (35,36) and surgical intervention (35). Thus, endoscopy within 24 h appears appropriate in a population hospitalized with UGIB. However, risk stratification also may have a role in considerations regarding timing of endoscopy.

Low-risk patients. Lee et al. (37) performed a randomized trial comparing endoscopy within 2 h vs. endoscopy within 48 h in 110 patients who were hemodynamically stable, had no serious comorbidity, and had no reason to suspect variceal bleeding. No significant improvements in end points such as bleeding, surgery, or mortality were identified. However, the length of hospital stay, post-discharge unplanned physician visits, and costs were significantly decreased in the early endoscopy group. Forty-six percent of patients in the early endoscopy group could be discharged home immediately and had no rebleeding or repeat endoscopy during the next month.

In a second randomized trial comparing early endoscopy within 6 h vs. within 48 h in 93 patients with hemodynamic stabilization and absence of severe comorbidity, no significant benefits were seen in clinical end points or in resource utilization (38). Although discharge without hospitalization was recommended in the 40% of early endoscopy patients who met criteria for early discharge, this advice was followed in only 9% , suggesting that the financial benefit of early endoscopy can only be realized if physicians use the results of endoscopy in making management decisions.

Thus, both studies suggest that early endoscopy in patients who are hemodynamically stable and have no serious comorbidities can potentially result in lower costs by allowing early discharge in up to ~40–45% of patients, supporting performance of endoscopy as soon as possible in patients with low-risk clinical features. However, the lack of clinical benefit argues against the need for endoscopy in an emergent setting (e.g., "middle of the night") for low-risk patients. Furthermore, as mentioned earlier, patients with very low risk based on pre-endoscopic assessment (e.g., Blatchford score of 0) may be considered for discharge from the emergency department without undergoing endoscopy (9).

High-risk patients. In a randomized trial comparing endoscopy within 12 h with endoscopy > 12 h after presentation, without exclusion of higher risk patients, no significant benefit was identified in bleeding, surgery, or mortality. In subgroup analyses, patients who had a bloody NG aspirate pre-endoscopy (but not those with clear or coffee-grounds aspirates) had significantly fewer units of blood transfused and hospital days (28). As mentioned above, a majority of these patients with a bloody aspirate had systolic blood pressure < 100 mm Hg and pulse > 100 beats/minute. A recent observational study also found a significantly higher mortality in high-risk UGIB patients (Blatchford score >= 12) having endoscopy > 13 h after presentation (44%) than in those having earlier endoscopy (0% , P < 0.001) (39). Multivariate analysis found that presentation-to-endoscopy time was the only variable significantly associated with mortality.

Thus, limited data, from subgroup analysis of a randomized trial and an observational study, raise the possibility that patients with high-risk clinical features may have improved clinical outcomes if endoscopy is performed within 12 h of presentation.

Risk of early endoscopy. The potential risk of endoscopy, often performed during off hours in sick patients, must be considered. A prospective, non-randomized study indicated an increased risk of oxygen desaturation in patients undergoing endoscopy within 2 h as compared with endoscopy at 2–24 h (40). This study highlights the fact that early endoscopy has the potential to further increase complications if performed too early, before appropriate resuscitation and stabilization.

Endoscopic diagnosis of ulcer and stigmata of recent hemorrhage

Recommendations.

12. Stigmata of recent hemorrhage (SRH) should be recorded as they predict risk of further bleeding and guide management decisions. The stigmata, in descending risk of further bleeding, are active spurting, non-bleeding visible vessel, active oozing, adherent clot, flat pigmented spot, and clean base (Strong recommendation, high-quality evidence).

Summary of evidence. The definition of an ulcer is a histological one, requiring extension into the submucosa or deeper. In contrast, erosions are breaks that remain confined to the mucosa. This is clinically relevant because serious bleeding does not occur from an erosion due to the absence of veins and arteries in the mucosa. Rather serious bleeding occurs when an ulcer erodes into vessels in the submucosa or deeper. Swain et al. (41) assessed the histological characteristics of gastric ulcers with visible vessels in 27 patients who required surgery for further bleeding, and identified arteries in the ulcer base in 26 (96%) of the 27 specimens.

Although the definition of an ulcer relates to histological depth, in practice no objective measure of the depth of an ulcer is performed. Currently, the endoscopic diagnosis of an ulcer is based on the interpretation of the endoscopist that unequivocal depth is present at endoscopic visualization.

Ulcer surface area dimensions or diameter can be estimated with the use of a device of known dimension, such as an open biopsy forceps. Ulcers larger than 1–2 cm are associated with increased rates of further bleeding with conservative therapy and after endoscopic therapy (42–44).

SRH are terms that describe the appearance of an ulcer base at endoscopy in patients with ulcer bleeding. SRH provide prognostic information regarding the risk of rebleeding, need for therapeutic intervention, and death (45,46). SRH are therefore used to stratify patients with ulcer bleeding and guide management decisions including endoscopic and medical therapy, admission vs. discharge, and level of care in hospital. In the absence of clinical evidence of bleeding, however, the presence of SRH does not appear to be associated with a risk of sub sequent bleeding (47).

Descriptive terms for SRH are generally used in North America whereas the Forrest classification is common in Europe and Asia. The descriptive terms for SRH and corresponding Forrest classifications are shown in Table 2 with US prevalences. Most patients with ulcer bleeding have low risk characteristics of clean bases or flat spots identified at endoscopy (48). Active bleeding may be broken down into arterial spurting and oozing, although most studies of prevalence have combined these categories. A recent large prospective trial found that only 68 (17%) of 397 patients enrolled with actively bleeding ulcers had arterial spurting (49). Table 3 shows pooled rates of further bleeding, surgery, and death without endoscopic therapy stratified by SRH.

Table 2. Classification and prevalences of stigmata of recent hemorrhage in 2,401 patients hospitalized with bleeding ulcers at 72 US endoscopy centers (48)

Stigmata of hemorrhage	Forrest classification	Prevalence
Active spurting bleeding	IA	12% (spurting+oozing)
Active oozing bleeding	IB
Non-bleeding visible vessel	IIA	8%
Adherent clot	IIB	8%
Flat pigmented spot	IIC	16%
Clean base	III	55%

Most studies and meta-analyses of ulcer hemorrhage outcomes combine both spurting and oozing bleeding into an "active ulcer bleeding" category. However, results from prospective trials suggest they should be viewed separately because the risk of further bleeding with spurting probably is substantially higher than the risk with oozing. In non-randomized cohorts of patients receiving only conservative therapy (without endoscopic therapy) in two studies, the rate of further bleeding requiring surgery was higher in those with spurting than those with oozing (7/10 (70%) vs. 7/24 (29%) and 5/8 (63%) vs. 7/35 (20%)) (50,51). In a study restricted to UGIB patients requiring intensive care unit admission, transfusion-requiring further bleeding occurred in 23/24 (88%) with spurting and 3/28 (11%) of those with oozing (52). Data from eight prospective trials including UGIB patients with oozing treated conservatively without endoscopic therapy reveal a pooled rate of further bleeding of 39% (range, 10–100%) (50,51,53–58) and further bleeding requiring emergency surgery in 26% (range, 20–38%) (50,51,55,56).

Table 3. Stigmata of recent hemorrhage and average rates (with ranges) of further bleeding, surgery, and mortality in prospective trials without endoscopic therapy (45)

Stigmata	Further bleeding (N =2,994)	Surgery for bleeding (N =1,499)	Mortality (N=1,387)
Active bleeding	55% (17–100%)	35% (20–69%)	11% (0–23%)
Non-bleeding visible vessel	43% (0–81%)	34% (0–56%)	11% (0–21%)
Adherent clot	22% (14–36%)	10% (5–12%)	7% (0–10%)
Flat pigmented spot	10% (0–13%)	6% (0–10%)	3% (0–10%)
Clean ulcer base	5% (0–10%)	0.5% (0–3%)	2% (0–3%)

Marked differences can be seen across different reports in the relative proportions of SRH and may relate to several factors. One potential explanation is the timing of the endoscopy, as discussed above, with more high-risk SRH identified with earlier endoscopy. Another potential explanation is inter-observer disagreement among endoscopists. Considerable variability has been reported among endoscopists in classifying SRH from photographs or video clips (59,60). Improvements in agreement may be achieved with training (e.g., instruction with review of photographs or videos, atlases) (49,59,61). It is also possible that differing patient characteristics (e.g., severity of comorbidities) may influence the prevalence of SRH.

Another potential difference in reported proportions of SRH may relate to variability in irrigation of clots. Vigorous irrigation with a water pump device will wash away overlying clot and reveal underlying SRH in a substantial portion of patients. Syringe irrigation followed by only 10 s of water pump irrigation removed clots in 33% of patients in one study (62). In another study water pump irrigation for up to 5 min removed clots in 43% of patients, revealing high-risk stigmata mandating endoscopic therapy in 30% and low-risk stigmata in 13%; no therapy was provided to the 57% with adherent clots and the rebleeding rate was only 8% (63). Thus, vigorous irrigation of clots on an ulcer base is recommended to more accurately determine underlying SRH and more accurately assess the risk of rebleeding.

Who should receive endoscopic therapy?

Recommendations.

13. Endoscopic therapy should be provided to patients with active spurting or oozing bleeding or a non-bleeding visible vessel (Strong recommendation, high-quality evidence) (Figure 1).
14. Endoscopic therapy may be considered for patients with an adherent clot resistant to vigorous irrigation. Benefit may be greater in patients with clinical features potentially associated with a higher risk of rebleeding (e.g., older age, concurrent illness, inpatient at time bleeding began) (Conditional recommendation, moderate-quality evidence).
15. Endoscopic therapy should not be provided to patients who have an ulcer with a clean base or a flat pigmented spot (Strong recommendation, high-quality evidence).

Figure 1. Recommended endoscopic and medical management based on stigmata of hemorrhage in ulcer base. IV, intravenous; PPI, proton pump inhibitor.

Summary of evidence. Meta-analysis of trials of endoscopic therapy vs. no endoscopic therapy for patients with an actively bleeding ulcer (spurting and oozing combined) shows a significant decrease in further bleeding (RR = 0.29, 0.20–0.43) with an NNT of only 2 (64). The need for urgent intervention and surgery is also significantly decreased. Meta-analysis of patients with a non-bleeding visible vessel in an ulcer reveals a significant decrease in further bleeding (RR = 0.49, 0.40–0.59; NNT = 5) as well as urgent intervention and surgery (64).

Although spurting and oozing bleeding are combined in most randomized trials and meta-analyses, as discussed above the rate of further bleeding appears to be substantially lower with oozing. Nevertheless, the 39% pooled rate of rebleeding in patients who were treated conservatively does support performing endoscopic therapy for oozing. Better efficacy may be expected after endoscopic therapy in patients with oozing than in those with other high-risk stigmata. In a cohort of patients within the placebo arm of a randomized trial of high-dose PPI vs. placebo after endoscopic therapy, the rates of further bleeding at 72 h were lower with oozing (4.9%) than with spurting (22.5%), clots (17.7%), or non-bleeding visible vessels (11.3%) (65).

Meta-analysis of randomized trials in patients with an adherent clot does not show a significant benefit (RR = 0.31, 0.06–1.77) (64). However, significant heterogeneity is present among the studies. Two US trials reported significant benefit of endoscopic hemostasis, with pooled rebleeding rates for endoscopic vs. medical therapy of 3 vs. 35% (61,66). The other studies, from Europe and Asia, showed no suggestion of any benefit. The one study using therapy matching current recommendations (vigorous irrigation; bolus and continuous infusion of PPI following endoscopy) reported no rebleeding in the 24 control patients with clots receiving only medical therapy (67). The reasons for the marked variation in results are uncertain but potential explanations might include differences in severity of comorbidities (US studies done primarily in tertiary care centers), etiology of the ulcer disease (H. pylori ulcers may be more common outside the US), and response to PPIs (greater in H. pylori-positive patients and in Asia).
Patients with clean-based ulcers or flat pigmented spots rarely have serious recurrent bleeding (45) and therefore would not derive significant benefit from endoscopic therapy.

What endoscopic therapies should be used?

Recommendations.

16. Epinephrine therapy should not be used alone. If used, it should be combined with a second modality (Strong recommendation, high-quality evidence).
17. Thermal therapy with bipolar electrocoagulation or heater probe and injection of sclerosant (e.g., absolute alcohol) are recommended because they decrease further bleeding, need for surgery, and mortality (Strong recommendation, high-quality evidence).
18. Clips are recommended because they appear to decrease further bleeding and need for surgery. However, comparisons of clips vs. other therapies yield variable results and currently used clips have not been well studied (Conditional recommendation, low-to-moderate quality evidence).
19. For the subset of patients with actively bleeding ulcers, thermal therapy or epinephrine plus a second modality may be preferred over clips or sclerosant alone to achieve initial hemostasis (Conditional recommendation, low-to-moderate-quality evidence).

Summary of evidence. The primary end point recommended in trials of UGIB is prevention of further bleeding, which includes initial hemostasis in actively bleeding patients plus prevention of rebleeding in those with initial hemostasis and in those without active bleeding at presentation (68). Endoscopic therapies that have shown efficacy in randomized trials include thermal therapy (e.g., bipolar electrocoagulation, heater probe, monopolar electrocoagulation, argon plasma coagulation, and laser), injection (epinephrine, sclerosants (e.g., absolute ethanol, polidocanol, and ethanolamine), thrombin or fibrin glue (thrombin plus fibrinogen)),
and clips (64).

Randomized trials indicate epinephrine injection is effective at achieving initial hemostasis in patients with active bleeding, with results not significantly different from other therapies (64). However, epinephrine monotherapy is less effective than other monotherapies in preventing further bleeding (RR = 1.72, 1.08–2.78; NNT = 9) and surgery based on meta-analysis of three trials employing bipolar electrocoagulation, clips, or fibrin glue as comparators (64). Furthermore, epinephrine plus a second modality (e.g., bipolar electrocoagulation, sclerosant, and clip) is significantly more effective than epinephrine alone in reducing further bleeding (RR = 0.34, 0.23– 0.50; NNT = 5) and surgery (64). However, if a second-look endoscopy is performed and higher risk lesions are retreated, the benefit of combined therapy vs. epinephrine alone is not seen (64).

Thermal contact therapy with bipolar electrocoagulation or heater probe is significantly more effective than no endoscopic therapy in achieving initial hemostasis (RR = 11.70, 5.15–26.56), reducing further bleeding (RR = 0.44, 0.36–0.54; NNT = 4), surgery, and mortality (RR = 0.58, 0.34–0.98; NNT = 33) in a meta-analysis of 15 randomized trials (64). No significant differences were seen in randomized trials comparing these two thermal modalities. The term “multipolar electrocoagulation” is used in some studies. The multipolar probe and other bipolar probes all deliver bipolar electrocoagulation; the difference in terms relates only to the configuration of the electrodes on the probe tip. Thus, meta-analyses combine multipolar and bipolar electrocoagulation trials.

Results of two small studies suggested benefit of epinephrine plus bipolar electrocoagulation vs. bipolar electrocoagulation alone, but results with thermal monotherapy were poorer in these trials than most other studies (69,70). A larger high-quality study found that injection of thrombin plus heater probe was not better than heater probe alone (71). Thus, although limited information suggests that epinephrine followed by thermal contact therapy may be more efficacious than thermal therapy alone, data are insufficient to recommend that thermal contact devices should not be used alone as monotherapy.

However, there may be practical reasons to pre-inject epinephrine before other therapies for specific SRH. Anecdotally, for active bleeding, injection of epinephrine may slow or stop bleeding allowing improved visualization for application of subsequent therapy. In addition, if clot removal is planned for adherent clots resistant to irrigation, pre-injection of epinephrine may reduce the rate of severe bleeding induced by clot removal.

Sclerosant injection also significantly reduces further bleeding (RR = 0.56, 0.38–0.83; NNT = 5) as well as surgery and mortality as compared with no endoscopic therapy based on meta-analysis of three randomized trials of absolute alcohol (64). Because the volume of sclerosants must be limited due to concern for tissue necrosis, sclerosant therapy alone may not be optimal for actively bleeding ulcers. Among actively bleeding patients in a randomized trial comparing absolute alcohol vs. no therapy, initial hemostasis was achieved in only 46% with alcohol vs. 8% in controls (64). Epinephrine injection before sclerosant therapy for actively bleeding ulcers seems reasonable although this has not been compared with sclerosant alone in randomized trials.

Trials comparing thermal therapy with sclerosant therapy show no significant difference in further bleeding, surgery, or mortality, although thermal therapy showed significantly fewer urgent interventions (surgery, repeat endoscopic therapy, or interventional radiology) and a trend to less further bleeding (RR = 0.69, 0.47–1.01) (64).

Clips have not been compared with no endoscopic therapy but are more effective than injection of epinephrine or water in reducing further bleeding and surgery (64). On comparison with other standard therapies (thermal or sclerosant, with or without epinephrine), clips were less effective at initial hemostasis than thermal therapy (heater probe) (64), but not significantly different in other outcomes such as further bleeding. However, these studies were heterogeneous with one showing clips to be significantly better and two others indicating clips were significantly worse than the comparators in their effect on further bleeding. Thus, more data are needed on the role of clips alone in the acute management of UGIB. Variables to consider in assessing the heterogeneous study results include variation among different endoscopists and among different types of clips. Newer clips in current use are easier to apply and vary in size, rigidity, depth of attachment, and duration of retention (72,73); however, they have not been well studied in randomized trials. Clips also have the theoretical benefit of not inducing tissue injury, unlike thermal therapies and sclerosants — and therefore may be preferred in patients on antithrombotic therapy and those undergoing retreatment for rebleeding.

Despite showing efficacy in randomized trials, laser, monopolar electrocoagulation, argon plasma coagulation, and injection of thrombin or fibrin glue are not recommended as first-line therapies due to less robust evidence, potential for slightly higher risk of adverse effects, availability, ease of use, and/or cost (64).

Techniques for endoscopic hemostatic therapy. Endoscopic hemostatic modalities are generally applied to the bleeding site to halt bleeding and in the immediate area of the SRH in the ulcer base with the intent to close or obliterate the underlying vessel and prevent rebleeding. The technique used to treat adherent clots in the two studies reporting benefit of endoscopic therapy was epinephrine injection into all four quadrants of the ulcer followed by mechanical clot removal (e.g., snare; manipulation with forceps, probe, or tip of endoscope) and application of thermal therapy (61,66). Dilute (1:10,000 or 1:20,000 in saline) epinephrine is generally injected in 0.5–2 ml aliquots in and around the stigmata of hemorrhage in the ulcer base. Although large volumes of epinephrine (e.g., 30–45 ml) are reported to be more effective as monotherapy (74–76), no studies have documented the optimal volume when used in combination with other modalities. We recommend injection until active bleeding slows or stops or, for non-bleeding stigmata, in all four quadrants next to the SRH in the ulcer base.

Absolute alcohol is generally administered in 0.1–0.2 ml aliquots with a limitation of 1–2 ml (77) due to the concern for tissue injury with higher volumes. Five percent ethanolamine is administered in 0.5–1.0 ml aliquots; widely variable total volumes of 0.5–14 ml have been reported in randomized trials for ulcer bleeding (78–80).

Bipolar electrocoagulation should be performed with the endoscope tip as close as possible to the bleeding ulcer; the large (3.2 mm) probe should be applied en face or at the least possible angulation with firm/maximal pressure (81,82). A setting of ~15 W and 8–10 s applications are recommended (81,83,84). Multiple applications should be applied in the ulcer base on and around the SRH, until bleeding has stopped, the vessel is flattened, and the base is whitened. Recommendations for the heater probe are identical with a setting of 30 J being used.

Clips should be placed over the bleeding site and on either side of the SRH in an attempt to seal the underlying artery.

Recommendations.

20. After successful endoscopic hemostasis, intravenous PPI therapy with 80 mg bolus followed by 8 mg/h continuous infusion for 72 h should be given to patients who have an ulcer with active bleeding, a non-bleeding visible vessel, or an adherent clot (Strong recommendation, high-quality evidence) (Figure 1).
21. Patients with ulcers that have flat pigmented spots or clean bases can receive standard PPI therapy (e.g., oral PPI once-daily) (Strong recommendation, moderate-quality evidence).

Summary of evidence. Meta-analysis of randomized trials of intravenous PPI therapy (80 mg bolus followed by 8 mg/h continuous infusion) vs. placebo/no treatment for 72 h after endoscopic therapy of high-risk stigmata reveals a significant reduction in further bleeding (RR = 0.40, 0.28–0.59; NNT = 12), surgery (RR = 0.43, 0.24– 0.76; NNT = 28), and mortality (RR = 0.41, 0.20–0.84; NNT = 45) (64).

In a recent large randomized trial of bolus followed by continuous infusion PPI vs. placebo after successful endoscopic hemostasis, subgroup analysis of patients with oozing bleeding showed a very low rebleeding rate with placebo (8/163 (4.9%)) (65). The results of this subgroup analysis suggest that intensive PPI therapy may not be needed for oozing bleeding without other SRH.

Meta-analysis of trials of intermittent oral or intravenous PPI vs. placebo/no therapy reveals a significant reduction in further bleeding (RR = 0.53, 0.35–0.78), but no significant difference in surgery, urgent intervention, or mortality. Meta-analysis of five fully published randomized trials that compare bolus followed by continuous infusion PPI vs. intermittent PPI therapy after endoscopic therapy for high-risk stigmata reveals an absolute risk reduction in further bleeding with intermittent PPI of 1% (95% CI − 3 to 5%) (85–89). Most of these trials were relatively small, methodologic concerns have been raised about the single large trial, and rates of rebleeding were very low in all arms of the studies (3–14%). For these reasons, it is difficult to conclude that the two treatments are “equivalent”. Nevertheless, these data do suggest that intermittent PPI therapy may suffice after endoscopic therapy for high-risk stigmata.

Rates of serious rebleeding with lower risk stigmata (clean base, flat pigmented spot) are low (45) and thus standard antisecretory therapy to heal the ulcer is all that is recommended in patients with these findings.

Recommendations.

22. Routine second-look endoscopy, in which repeat endoscopy is performed 24 h after initial endoscopic hemostatic therapy, is not recommended (Conditional recommendation, moderate-quality evidence).
23. Repeat endoscopy should be performed in patients with clinical evidence of recurrent bleeding and hemostatic therapy should be applied in those with higher risk stigmata of hemorrhage (Strong recommendation, high-quality evidence).
24. If further bleeding occurs after a second endoscopic therapeutic session, surgery or interventional radiology with transcathether arterial embolization is generally employed (Conditional recommendation, low-quality evidence).

Summary of evidence. Second-look endoscopy is generally defined as routine repeat endoscopy within 24 h after initial endoscopy and hemostatic therapy. Repeat endoscopic hemostatic therapy is typically given to patients with higher risk SRH. A meta-analysis of randomized trials assessing second-look endoscopy reported a small but significant reduction in rebleeding in patients undergoing second-look endoscopy (absolute risk reduction = 6.2% (1.3–11.1%; NNT = 16)) with no significant benefit in reducing surgery or death (90). A subsequent metaanalysis found no significant benefit when hemostatic therapy was epinephrine injection or fibrin glue injection, but did identify a significant difference in rebleeding for the two randomized trials employing thermal therapy (RR = 0.29, 0.11–0.73) (91).

However, these studies were done before the currently accepted practice of adding intensive PPI therapy after endoscopic therapy, which has been shown to reduce further bleeding. In a randomized trial of single endoscopy plus high-dose intravenous PPI vs. routine second-look endoscopy without PPI, rebleeding occurred in 8.2 vs. 8.7% (RR = 1.1, 0.4–2.7) (91).

The expense of second-look endoscopy also must be considered. A large number of unnecessary endoscopies will be performed since most patients do not have recurrent bleeding. In addition, second-look endoscopies do not prevent further bleeding in all patients, and repeat endoscopic therapy is successful in most patients with rebleeding (92). An economic analysis suggests that intravenous PPI therapy would be the dominant strategy as compared with second-look endoscopy if the PPI therapy reduced rebleeding to 9% or if it cost $10 per day (93). Recent randomized trials report rebleeding rates < 9% (49,91) in patients with high-risk ulcer bleeding treated with endoscopic and PPI therapy. Furthermore, intensive PPI therapy is considered as standard therapy after endoscopic therapy of high-risk SRH (as discussed above) and would be employed even if second-look endoscopy is done.

If a population at very high risk of recurrent bleeding after endoscopic hemostasis could be identified, this group potentially could derive benefit from second-look endoscopy. Although several characteristics are reported to be associated with an increased risk of bleeding after hemostatic therapy, no grading system has been validated to reliably identify a very high-risk population (44).

Repeat endoscopy with endoscopic therapy is appropriate in patients with clinical evidence of rebleeding. A randomized trial comparing endoscopic therapy vs. surgery for recurrent bleeding after endoscopic hemostatic therapy revealed that 73% of patients with recurrent bleeding can be successfully treated with repeat endoscopic therapy and avoid the need for surgery, with a lower rate of complications than those treated with surgery (92). If further bleeding occurs after the second endoscopic treatment, surgery or interventional radiology (transcatheter arterial embolization) is reported to be successful in achieving hemostasis. A recent review of case series of angiographic embolization in patients with UGIB failing endoscopic and medical therapy revealed a technical success rate > 90% and a rebleeding rate of 33%, which was widely variable across studies (9–66%) (94).

Recommendations.

25. Patients with high-risk stigmata (active bleeding, visible vessels, clots) should generally be hospitalized for 3 days assuming no rebleeding and no other reason for hospitalization. They may be fed clear liquids soon after endoscopy (Conditional recommendation, low-quality evidence).
26. Patients with clean-based ulcers may receive a regular diet and be discharged after endoscopy assuming they are hemodynamically stable, their hemoglobin is stable, they have no other medical problems, and they have a residence where they can be observed by a responsible adult (Strong recommendation, moderate-quality evidence).

Summary of evidence. Clear liquid diet can be provided after endoscopic therapy. This recommendation is based on the fact that patients with recurrent bleeding may have to undergo urgent interventions such as endoscopy, interventional radiology, or surgery. Clear liquids allow sedation or anesthesia to be administered within 2 h after the last ingestion (95). Thus, we suggest clear liquid diet for ~2 days in patients who are at higher risk for rebleeding. However, given the excellent results obtained with current endoscopic and medical therapy some investigators have raised the possibility of early refeeding in higher risk patients. A randomized trial of normal diet vs. nothing by mouth for 24 h after endoscopic therapy for oozing or non-bleeding visible vessels found no significant difference in rebleeding (2 vs. 6%) (96). This trial may not simulate standard practice; however, because second-look endoscopy with retreatment was performed at 24 h.

With a low risk of recurrent bleeding, regular diet may be instituted. A randomized trial of patients with lower risk lesions (e.g.,
Mallory-Weiss tears, ulcers with clean base or flat pigmented spots) revealed no significant differences in outcomes with immediate refeeding of regular diet vs. delayed refeeding (clear liquids at 36 h and regular diet at 48 h) (97). Although patients with flat spots in this trial had similar outcomes with immediate refeeding, the 8% rebleeding rate and 5% rate of urgent intervention may argue for clear liquid diet in these patients for 1–2 days. Data to guide the duration of hospitalization for patients with flat pigmented spots are lacking.

Several trials have demonstrated that patients with UGIB who have low-risk features may be discharged on the first hospital day (or worked up and discharged as an outpatient) without negative consequences (9,33,98). Criteria vary across studies but generally include low-risk clinical features (e.g., stable vital signs and hemoglobin, no serious comorbidities), low-risk endoscopic features (e.g., clean-based ulcer, erosive disease, Mallory-Weiss tear), and satisfactory home/social support.

Other patients with higher risk stigmata (active bleeding, visible vessel, and clot) generally remain in the hospital for 3 days assuming no rebleeding or other medical issues. This is based primarily on older studies suggesting that recurrent bleeding almost always (~>=95%) occurred within 3 days (43,99–101). More recent results of randomized trials suggest that a substantial minority of patients may have recurrent bleeding after 3 days — most often occurring within 7 days (49,102,103). For example, in a recent large randomized trial of patients with higher risk bleeding ulcers treated with endoscopic therapy, 24% of the 82 patients with rebleeding in the 30-day study rebled beyond 3 days, with equal proportions in the group receiving continuous infusion PPI and those receiving placebo after endoscopic therapy (49). Six percent of rebleeding occurred after 7 days (49).

Although patients should be educated about symptoms of UGIB and the need to return to hospital if these symptoms develop, we do not recommend hospital stays be routinely extended beyond 3 days in patients without further bleeding or other medical problems.

Recommendations.

27. Patients with H. pylori-associated bleeding ulcers should receive H. pylori therapy. After documentation of eradication, maintenance antisecretory therapy is not needed unless the patient also requires non-steroidal anti-inflammatory drugs (NSAIDs) or antithrombotics (Strong recommendation, high-quality evidence) (Figure 2).
28. In patients with NSAID-associated bleeding ulcers, the need for NSAIDs should be carefully assessed and NSAIDs should not be resumed if possible. In patients who must resume NSAIDs, a COX-2-selective NSAID at the lowest effective dose plus daily PPI is recommended (Strong recommendation, high-quality evidence).
29. In patients with low-dose aspirin-associated bleeding ulcers, the need for aspirin should be assessed. If given for secondary prevention (i.e., established cardiovascular disease) then aspirin should be resumed as soon as possible after bleeding ceases in most patients: ideally within 1–3 days and certainly within 7 days. Long-term daily PPI therapy should also be provided. If given for primary prevention (i.e., no established cardiovascular disease), antiplatelet therapy likely should not be resumed in most patients (Conditional recommendation, moderate-quality evidence).
30. In patients with idiopathic (non-H. pylori, non-NSAID) ulcers, long-term antiulcer therapy (e.g., daily PPI) is recommended (Conditional recommendation, low-quality evidence).

Summary of evidence. Patients with bleeding ulcers have an unacceptably high rate of recurrent bleeding if no strategy is employed to reduce this risk. For example, in patients with duodenal ulcer bleeding (H. pylori not assessed, no NSAID use) followed in a double-blind trial after ulcer healing, bleeding recurred within 1 year in nearly 40% (104). In a systematic review of randomized trials of patients with H. pylori-associated bleeding ulcers (105), the rate of recurrent bleeding in studies with 12-month follow-up was 26% (106–109). In H. pylori-positive NSAID users with bleeding ulcers followed for 6 months after ulcer healing, recurrent bleeding ulcers occurred with resumption of NSAIDs in 19% of those given only H. pylori therapy (110), while in H. pylori-positive low-dose aspirin users who presented with ulcer complications and were followed for a median of 12 months after ulcer healing and H. pylori eradication, recurrent bleeding ulcers occurred with resumption of low-dose aspirin in 15% (111). Finally, in a prospective cohort of patients with idiopathic bleeding ulcers (H. pylori negative, no NSAID use) followed for 7 years, the incidence of recurrent ulcer bleeding was 42% (112).

H. pylori ulcers

Biopsy-based H. pylori testing is recommended by ACG H. pylori guidelines in patients presenting with a bleeding ulcer (113). Because some studies suggest sensitivity may be decreased with acute UGIB, confirmation of a negative test with a subsequent nonendoscopic test has also been recommended (113,114). However, if histological examination of the biopsy specimens shows no mucosal mononuclear cell infiltrate, the predictive value for absence of H. pylori approaches 100%, while a neutrophilic infiltrate has > 95% positive predictive value for H. pylori infection (115).

A meta-analysis of randomized trials showed that H. pylori eradication therapy for prevention of recurrent ulcer bleeding is significantly more effective than short-term antisecretory therapy alone (rebleeding 4.5 vs. 23.7%; OR = 0.18, 0.10–0.35) (105). Furthermore, H. pylori eradication was also more effective than long-term maintenance antisecretory therapy with PPI or histamine-2 receptor antagonist (H2RA) (although most patients received H2RA: 1.6 vs. 5.6%; OR = 0.24, 0.09–0.67) (105). A systematic review of studies assessing rebleeding in patients with documented H. pylori eradication revealed a 1.3% incidence of rebleeding over mean follow-up periods of 11–53 months (105).

Figure 2. Recommended management to prevent recurrent ulcer bleeding based on etiology of ulcer bleeding. CV, cardiovascular; H2RA, histamine-2 receptor antagonist; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor.

Because patients with H. pylori ulcers have such low rebleeding rates if they have eradication of the infection, it is important to document cure of the infection at >= 1 month following the end of H. pylori therapy. Endoscopic biopsy can be done if patients are undergoing repeat endoscopy for another reason (e.g., to document gastric ulcer healing), but a urea breath test or stool antigen test should be done if endoscopy is not needed (113). Antibody testing should not be employed since it remains positive in most patients after successful therapy (116). PPIs can cause falsely negative H. pylori testing in approximately one third of cases (117,118) so PPIs should be discontinued 2 weeks before testing to ensure optimal sensitivity (118). Some practitioners may use an H2RA during this period to decrease risk of recurrent ulcers in case H. pylori therapy was not successful.

NSAID ulcers

Randomized trials in NSAID users show that co-therapy with misoprostol, PPIs, and double-dose H2RAs or use of COX-2-selective inhibitors decrease endoscopic ulcers in patients taking NSAIDs (119,120) and that misoprostol and COX-2-selective NSAIDs also decrease complicated ulcers in arthritis patients (120,121). Although these trials suggest that the agents studied may be beneficial in patients who presented with a bleeding ulcer, they do not specifically address management of these high-risk patients.

Several randomized trials from Hong Kong have studied prevention of recurrent bleeding in NSAID users who presented with bleeding ulcers. In patients who were restarted on NSAID after ulcer healing, maintenance PPI therapy had a significantly lower risk of recurrent ulcer bleeding at 6 months as compared with H. pylori therapy only (4.4 vs. 18.8%; NNT=7) (110). In a follow-up study, celecoxib was compared with diclofenac plus PPI after ulcer healing in patients who were H. pylori negative or had successful H. pylori therapy (122). The rates of recurrent ulcer bleeding at 6 months were 4.9% with celecoxib and 6.4% for diclofenac plus PPI; recurrent ulcers were seen at 6-month endoscopy in 19 and 26% of patients (123). Because rates of recurrent ulcer bleeding were relatively high with either protective strategy, a subsequent 12-month double-blind study of similar design compared celecoxib plus twice-daily PPI vs. celecoxib plus placebo (124). Recurrent ulcer bleeding occurred in 0 vs. 8.9% (NNT = 12). Thus, patients with a bleeding ulcer while on NSAIDs who must remain on NSAIDs should receive a COX-2-selective NSAID at the lowest effective dose plus PPI therapy.

Low-dose aspirin ulcers

Randomized trials in low-dose aspirin users show that PPIs and standard dose H2RAs reduce endoscopic ulcers (125–127) and that PPIs reduce UGIB in patients taking low-dose aspirin plus clopidogrel (128).

In a study of H. pylori-positive low-dose aspirin users with bleeding ulcers, the rates of recurrent ulcer bleeding at 6 months after resuming low-dose aspirin were 0.9% with PPI and 1.9% with H. pylori therapy (110). Although no placebo group was included, this trial raised the possibility that H. pylori eradication alone may reduce recurrent ulcer bleeding with low-dose aspirin. A subsequent trial performed in H. pylori-positive low-dose aspirin users with ulcer complications showed that after H. pylori eradication and ulcer healing, PPI therapy had significantly less recurrent ulcer bleeding than placebo at a median of 12 months (1.6 vs. 14.8%; NNT = 8) (111). Thus, in patients with bleeding ulcers who require continued antiplatelet therapy, once-daily PPI should be given.

The need for antiplatelet therapy should be reviewed in patients who have ulcer bleeding while taking low-dose aspirin. In patients taking aspirin for primary prophylaxis (no overt cardiovascular disease), the benefit of low-dose aspirin is relatively small: meta-analysis of randomized trials reveals an annual absolute risk reduction of 0.07% (NNT = 1,429) (129). Primary prevention is recommended only in patients at higher risk for cardiovascular events, based on risk assessment tools. In patients hospitalized with ulcer bleeding, the risk of subsequent bleeding likely outweighs the cardiovascular benefit in many or most patients on primary prophylaxis. In contrast, the benefit of low-dose aspirin for secondary prophylaxis in patients with established cardiovascular disease is much larger (annual absolute risk reduction of 1.49% (NNT = 68)) (129) and failure to resume low-dose aspirin after ulcer bleeding is associated with an increased mortality (130). A randomized trial in low-dose aspirin users with established cardiovascular disease who presented with a bleeding ulcer showed that resumption of low-dose aspirin vs. placebo after endoscopic hemostasis and initiation of PPI therapy was associated with no significant increase in recurrent ulcer bleeding at 1 month (10.3 vs. 5.4%), but a significant decrease in mortality at 1 month and 2 months (1.3 vs. 12.9%) (130). Thus, it is important to resume antiplatelet therapy, along with PPI co-therapy, as early as possible in patients with established cardiovascular disease.

The timing of resumption of aspirin is not clear and data are primarily based on observational studies. A systematic review found that thrombotic events in patients with established cardiovascular disease occurred at a mean of 10.7 days after aspirin withdrawal (131), while another review of patients on secondary prevention stopping aspirin perioperatively reported the mean interval after discontinuation for acute cerebral events was 14.3 days and for acute coronary syndrome was 8.5 days (132). Recent joint consensus recommendations from US cardiology and GI organizations stated that “reintroduction of antiplatelet therapy in high-cardiovascular-risk patients is reasonable in those who remain free of rebleeding after 3–7 days” (133), while the study from Sung et al. (130) indicated a benefit of resumption of low-dose aspirin immediately after endoscopic hemostasis in patients with high-risk stigmata. Thus, the benefit-risk ratio of aspirin resumption must be carefully considered jointly by gastroenterologists, cardiologists, neurologists, and patients on a case-by-case basis. However, early resumption of antiplatelet therapy within 1–3 days after hemostasis, and certainly within 7 days, will be appropriate in most patients with established cardiovascular disease.

Idiopathic (non- H. pylori, non-NSAID) ulcers

Patients with idiopathic bleeding ulcers have a high rate of recurrence when followed without protective co-therapy (112). Surreptitious NSAID use undoubtedly accounts for some of these ulcers. Although no randomized trials have assessed the benefit of medical co-therapy in this population, antiulcer therapy seems likely to reduce recurrent idiopathic ulcers and will also be effective at reducing recurrent ulcers in those surreptitiously using NSAIDs.

Management of the patient presenting with overt bleeding proceeds in a step-wise manner. The first step is assessment of hemodynamic status and initiation of resuscitative measures as needed. Patients are risk stratified based on clinical features such as hemodynamic status, comorbidities, age, and initial laboratory tests. Most patients should receive an upper endoscopy within 24 h or less, and endoscopic features of the ulcer assist in directing further management. Those with high-risk findings of active bleeding or non-bleeding visible vessel should receive endoscopic therapy and those with an adherent clot may receive endoscopic therapy; these patients should then receive intravenous PPI therapy with a bolus followed by continuous infusion. Those with fl at spots or clean-based ulcers do not require endoscopic therapy or intensive intravenous PPI therapy. Recurrent ulcer bleeding after endoscopic therapy should be treated with a second endoscopic treatment, but if bleeding still persists or recurs treatment with surgery or interventional radiology is undertaken.

Prevention of recurrent bleeding is based on the presumed etiology of the bleeding ulcer. H. pylori should be eradicated if present and after cure is documented, no further therapy is needed. NSAIDs should be stopped; if they must be continued a low-dose of a COX-2-selective NSAID plus a PPI should be used. Patients with established cardiovascular disease who require aspirin or other antiplatelet agents should start PPI therapy and generally have antiplatelet therapy reinstituted as soon as possible after bleeding ceases (ideally within 1–3 days and certainly within 7 days). Those with idiopathic ulcers should receive long-term antiulcer therapy.

Guarantor of the article: Loren Laine, MD.
Specific author contributions: L. Laine: planning and conducting review; analysis/interpretation of data; drafting and revision of the manuscript. He approved final draft submitted. D. Jensen: planning and conducting review; analysis/interpretation of data; critical review and revision of the manuscript. He approved final draft submitted.
Financial support: None.
Potential competing interests: L. Laine has served as a consultant for AstraZeneca, Eisai, Pfizer, Horizon, and Logical Therapeutics, and has served on Data Safety Monitoring Boards for Bayer, BMS, and Merck. D. Jensen is a consultant for AstraZeneca, Boston Scientific, Merck, and US Endoscopy. D. Jensen has received research grants from Boston Scientific, Pentax, Olympus, US Endoscopy, and Vascular Technology Inc.

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Marc G. Ghany,¹ David R. Nelson,² Doris B. Strader,³ David L. Thomas,⁴ and Leonard B. Seeff⁵

This practice guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and endorsed by the Infectious Diseases Society of America, the American College of Gastroenterology and the National Viral Hepatitis Roundtable.

These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: 1) a formal review and analysis of the recently published world literature on the topic (MEDLINE search up to June 2011); 2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (1) 3) guideline policies, including the AASLD Policy on the Development and
Use of Practice Guidelines and the American Gastroenterological Association’s Policy Statement on the Use of Medical Practice Guidelines; (2) and 4) the experience of the authors in regard to hepatitis C.

Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines). (3,4)

Hepatology 2011;54:1433–1444

All AASLD Practice Guidelines are updated annually. If you are viewing a Practice Guideline that is more than 12 months old, please visit www.aasld.org for an update in the material.

Abbreviations: AKR, aldoketoreductase; BOC, boceprevir; CYP, cytochrome P450; DAA, direct-acting antivirals; eRVR, extended rapid virological response; FDA, Food and Drug Administration; HCV, hepatitis C virus; IL28B, interleukin-28B; NS3/4A, HCV nonstructural protein 3/4A; PegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; RGT, response-guided therapy; RVR, rapid virological response; SOC, standard of care; SVR, sustained virological response; TVR, telaprevir.

From the ¹Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; ²Section of Hepatobiliary Disease, University of Florida, Gainesville, FL; ³Gastroenterology and Hepatology Division, Fletcher Allen Health Care, University of Vermont College of Medicine, Burlington, VT; ⁴Johns Hopkins Medical Institution, Baltimore, MD; and ⁵The Hill Group, Bethesda, MD.

Received August 29, 2011; accepted August 29, 2011.

*Consultant in Hepatology for the U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20943.

The views expressed in the document are those of the authos and not of the Food and Drug Administration.

Address reprint requests to: Marc G. Ghany, M.D., Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B-16, 10 Center Drive, MSC 1800, Bethesda, MD 20892-1800. E-mail: marcg@intra.niddk.nih.gov; fax: 301-402-0491.

Copyright © 2011 by the American Association for the Study of Liver Diseases.

View this article online at wileyonlinelibrary.com.

DOI 10.1002/hep.24641

Potential conflict of interest: Dr. Nelson receives research support from Vertex, Merck, Phamassett, Genentech/Roche, Gilead, Bristol-Myers Squibb, Tibotec, Bayer/Onyx and serves on advisory boards of Merck, Pharmassett, Genentech/Roche, Gilead, Tibotec, and Bayer/Onyx, and is a consultant for Vertex.

Dr. Thomas receives research support from Merck, Gilead and serves on a Merck advisory board.

Dr. Ghany, Dr. Seeff, and Dr. Strader have nothing to report.

The standard of care (SOC) therapy for patients with chronic hepatitis C virus (HCV) infection has been the use of both peginterferon (PegIFN) and ribavirin (RBV). These drugs are administered for either 48 weeks (HCV genotypes 1, 4, 5, and 6) or for 24 weeks (HCV genotypes 2 and 3), inducing sustained virologic response (SVR) rates of 40%-50% in those with genotype 1 and of 80% or more in those with genotypes 2 and 3 infections. (5-7) Once achieved, an SVR is associated with long-term clearance of HCV infection, which is regarded as a virologic "cure," as well as with improved morbidity and mortality. (8-10) Two major advances have occurred since the last update of treatment guidelines for chronic hepatitis C (CHC) that have changed the optimal treatment regimen of genotype 1 chronic HCV infection: the development of direct-acting antiviral (DAA) agents (11-17) and the identification of several single-nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection. (18,19) Although PegIFN and RBV remain vital components of therapy, the emergence of DAAs has led to a substantial improvement in SVR rates and the option of abbreviated therapy in many patients with genotype 1 chronic HCV infection. A revision of the prior treatment guidelines is therefore necessary, but is based on data that are presently limited. Accordingly, there may be need to reconsider some of the recommendations as additional data become available. These guidelines review what treatment for genotype 1 chronic HCV infection is now regarded as optimal, but they do not address the issue of prioritization of patient selection for treatment or of treatment of special patient populations.

Table 1. Grading System for Recommendations

Class 1	Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Class 2	Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment
Class 2a	Weight of evidence/opinion is in favor of usefulness/efficacy
Class 2b	Usefulness/efficacy is less well established by evidence/opinion
Class 3	Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful
Level of Evidence	Description
Level A	Data derived from multiple randomized clinical trials or meta-analyses
Level B	Data derived from a single randomized trial, or nonrandomized studies
Level C	Only consensus opinion of experts, case studies, or standard-of-care

There are multiple steps in the viral lifecycle that represent potential pharmacologic targets. A number of compounds encompassing at least five distinct drug classes are currently under development for the treatment of CHC. Presently, only inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease have been approved by the Food and Drug Administration (FDA).

The NS3/4A serine protease is required for RNA replication and virion assembly. Two inhibitors of the NS3/4A serine protease, boceprevir (BOC) and telaprevir (TVR), have demonstrated potent inhibition of HCV genotype 1 replication and markedly improved SVR rates in treatment-naïve and treatment-experienced patients. (12, 13, 16, 17) Limited phase 2 testing has shown that TVR also has activity against HCV genotype 2 infection but not against genotype 3. (20) With regard to BOC, there are limited data indicating that it too, has activity against genotype 2 but also against genotype 3 HCV infection. (21) However, at this time, neither drug should be used to treat patients with genotype 2 or 3 HCV infections, and when administered as monotherapy, each PI rapidly selects for resistance variants, leading to virological failure. Combining either PI with PegIFN and RBV limits selection of resistant variants and improves antiviral response. (15)

Boceprevir. The SPRINT-2 trial evaluated BOC in two cohorts of treatment-naïve patients: Caucasian and black patients. (12) The number of patients in the black cohort was small in comparison to that of the Caucasian cohort and may have been insufficient to provide an adequate assessment of true response in this population. All patients were first treated with PegIFN alfa2b and weight-based RBV as lead-in therapy for a period of 4 weeks, followed by one of three regimens:

1) BOC, PegIFN, and RBV that was administered for 24 weeks if, at study week 8 (week 4 of triple therapy), the HCV RNA level became undetectable (as defined in the package insert as <10-15 IU/mL), referred to as response-guided therapy (RGT); if, however, HCV RNA remained detectable at any visit from week 8 up to but not including week 24 (i.e., a slow virological response), BOC was discontinued and the patient received SOC treatment for an additional 20 weeks 2) BOC, PegIFN, and RBV administered for a fixed duration of 44 weeks; and 3) PegIFN alfa-2b and weight-based RBV alone continued for an additional 44 weeks, representing SOC therapy.12 The BOC dose was 800 mg, given by mouth three times per day with food. The overall SVR rates were higher in the BOC arms, (63% and 66% respectively) than in the SOC arm (38%), but differed according to race (Fig. 1). The SVR rates among Caucasian patients were 67% in the RGT, 69% in the fixed duration, and 41% in the SOC arms, respectively. (12) In black patients, the SVR rates were 42% in the RGT, 53% in the fixed duration, and 23% in the SOC arms, respectively (Fig. 1). (12) A total of 54% of Caucasian recipients of BOC experienced a rapid virological response (RVR; HCV RNA undetectable, <10-15 IU/mL at week 8, this interval selected because of the 4 week lead-in). By contrast, only 20% of black recipients of BOC experienced an RVR. Regardless of race, among those patients who became HCV RNA negative at week 8 (~57% in both BOC arms and 17% in SOC arm), the SVR rates were 88% in the RGT arm, 90% in the fixed duration arm and 85% in the arm treated by SOC, compared to SVR rates of 36%, 40%, and 30%, respectively, if HCV RNA remained detectable at week 8 (Fig. 2). (12)

Fig. 1. Sustained virological response (SVR) rates, overall and according to race, in treatment-naïve patients with genotype 1 chronic HCV infection: Boceprevir (BOC) plus peginterferon (PegIFN) and ribavirin (RBV) versus standard of care (SOC). All patients were first treated with PegIFN + RBV for 4 weeks as lead-in therapy followed by one of three regiments: 1) BOC/PegIFN/RBV RGT – triple therapy for 24 weeks provided HCV RNA levels were negative weeks 8 thorugh 24 – response guided therapy; those with a detectable HCV RNA level
between weeks 8 and 24 received SOC for an additional 20 weeks; 2) BOC/PegIFN/RBV fixed duration – triple therapy for a fixed duration of 44 weeks; and 3) SOC – consisted of PegIFN and weight based RBV administered for 48 weeks. (12)

In subgroup analysis, SVR rates were higher in BOC-containing regimens across all the pretreatment variables that had been identified in previous studies to influence response to SOC therapy, including advanced fibrosis, race, and high pretreatment HCV viral load. Moreover, the SVR rate in subgroups was similar in both the RGT and fixed duration arms and therefore, the AASLD and the FDA support the use of RGT for treatment-naïve patients without cirrhosis. The FDA recommends that patients with compensated cirrhosis should not receive RGT, however, this is based on limited data and requires further study. Of note, if the virological response did not meet criteria for RGT, i.e., a slow virological response, the FDA recommends (based on modeling) triple therapy for 32 weeks preceded by the 4 weeks of SOC treatment), followed by 12 weeks of PegIFN and RBV alone; a strategy that differs from the phase 3 trial design. All therapy should be discontinued if the HCV RNA level is >=100 IU/mL at week 12 or >=10 to 15 IU/ mL at week 24.

Fig. 2. Sustained virological response (SVR) rates, overall and based on a rapid virological response (RVR, undetectable HCV RNA at week 8 [week 4 of triple therapy]) in treatment-naïve patients with genotype 1 chronic HCV infection: Boceprevir (BOC) plus peginterferon (PegIFN) versus standard of care (SOC). All patients were first treated with PegIFN + RBV for 4 weeks as lead-in therapy followed by one of three regiments: 1) BOC/PegIFN/RBV RGT – patients who achieved an RVR (undetable HCV RNA at week 8 [week 4 of triple therapy]) continued treatment for an additional 24 weeks (RGT – response guided therapy); if an RVR did not develop, treatment with triple therapy continued to week 28 followed by SOC treatment for 20 weeks. SOC treatment consisted of PegIFN and RBV administered for 48 weeks. (12) Note that the combined numbers of RVR-positive and RVR-negative patients are not equivalent to the total number of patients enrolled, presumably because of missing HCV RNA values at the week 8 time point.

Telaprevir. Two phase 3 trials evaluated the efficacy of TVR in combination with PegIFN alfa-2a and RBV in treatment-naïve patients with genotype 1 chronic HCV infection. (16,22) Black patients were included but not as a separate cohort and were insufficient in number to provide an adequate assessment of true response in this population. In the ADVANCE trial, patients received TVR together with PegIFN and RBV for either 8 (T8PR) or 12 (T12PR) weeks followed by PegIFN and RBV alone in a response-guided paradigm. (16) The TVR dose was 750 mg given by mouth every 8 hours with food (in particular, a fatty meal). Patients in the T8PR and T12PR groups who achieved an "extended RVR" (eRVR)—which for this drug was defined as undetectable (<10-15 IU/mL) HCV RNA levels at weeks 4 and 12—stopped therapy at week 24, whereas those in whom an eRVR did not occur received a total of 48 weeks of PegIFN and RBV. All patients in the control group received PegIFN and RBV therapy for 48 weeks. The overall SVR rates among patients in the T8PR and T12PR groups were 69% and 75%, respectively, (16) compared with a rate of 44% in the control group (Table 2 and Fig. 3). Using the RGT approach, 58% and 57% of patients in the T12PR and T8PR groups, respectively, attained an eRVR, 89% and 83% of whom ultimately achieved an SVR. (16) Thus, developing an eRVR appears to be the strongest predictor that an SVR will occur.

Table 2. Comparison of Protease Inhibitors in Combination with Peginterferon Alfa (PegIFN) and Ribavirin (RBV) in Treatment-Naive Subjects

Variable	Boceprevir (BOC) (12)	Telaprevir (TVR) (16)
Study design	RCT	RCT
4-Week lead-in PegIFN/RBV	Yes	No
Duration of triple therapy	24 or 44 weeks in combination with PegIFN/RBV*	12 weeks followed by 12 or 36 weeks PegIFN/RBV†
Response-guided therapy (RGT)	Yes	Yes
Eligible for response-guided therapy (%)	44	58
SVR (%)	BOC44/PR: 66	T8PR: 69
	BOC/PR/RGT: 63	T12PR: 75
	SOC: 38	SOC: 44
End of treatment response (%)	BOC44/PR: 76	T8PR: 81
	BOC/PR/RGT: 71	T12PR: 87
	SOC: 53	SOC: 63
Relapse (%)	BOC44/PR: 9	T8PR: 9
	BOC/PR/RGT: 9	T12PR: 9
	SOC: 22	SOC: 28
Treatment emergent resistance (%)	16	12
Adverse event more frequent in triple therapy arm compared to SOC	Anemia, dysgeusia	Rash, anemia, pruritus, nausea, diarrhea
Adverse events leading to treatment discontinuation (%)	NA	12
Serious adverse events study drug vs SOC (%)	11 vs 9	9 vs 7

NA, not available; PR, peginterferon plus ribavirin; RCT, randomized, controlled trial; SOC, standard of care; SVR, sustained virological response.

*All patients were first treated with PegIFN alfa-2b and weight-based RBV as lead-in therapy for a period of 4 weeks, followed by one of three regimens: 1) BOC/PR/RGT: BOC, PegIFN, and RBV that was administered for 24 weeks if, at study week 8 (week 4 of triple therapy), the HCV RNA level became undetectable (as defined in the package insert as <10-15 IU/mL), referred to as response-guided therapy (RGT); if, however, HCV RNA remained detectable at any visit from week 8 up to but not including week 24 (i.e., a slow virological response), BOC was discontinued and the patient received SOC treatment for an additional 20 weeks; 2) BOC44/PR: BOC, PegIFN, and RBV administered for a fixed duration of 44 weeks; and 3) SOC: PegIFN alfa-2b and weight-based RBV alone continued for an additional 44 weeks.

†Telaprevir (TVR) plus peginterferon and ribavirin (PR) treatment for 8 (T8PR) or 12 (T12PR) weeks versus standard of care (SOC). Patients in the T8PR and T12PR groups who achieved an "extended RVR" (eRVR), which for this drug was defined as undetectable (<10-15 IU/mL) HCV RNA levels at weeks 4 and 12, stopped therapy at week 24, whereas those in whom an eRVR did not occur received a total of 48 weeks of PegIFN and RBV. All patients in the control group received PegIFN and RBV therapy for 48 weeks.

SVR rates were higher in TVR-containing regimens compared to SOC treatment among patients with disease characteristics found previously to be associated with a poorer response to SOC treatment. Although few black patients and other difficult-to-treat patient populations were included in the TVR phase 3 trials, an improved SVR rate was observed regardless of race, ethnicity, or level of hepatic fibrosis. With regard to race, treatment with a TVR-based regimen significantly improved SVR rates in black patients (T8PR, 58% and T12PR, 62%) compared to the SVR rates achieved in those treated with the SOC regimen (25%) (Fig. 3). Moreover, the SVR rate was >80% among black patients who achieved an eRVR on a TVR-based regimen. A total of 62% of patients in the T12PR group and 53% in the T8PR group with advanced fibrosis achieved an SVR, the rate improving to >80% among those with an eRVR. In the T12PR group, the impact of high versus low viral load (>800,000 or <800,000 IU/mL) on SVR rates was minimal; the SVR rate was 74% in patients with a high viral load and 78% in those with a low viral load.

Fig. 3. Sustained virological response (SVR) rates, overall and according to race, in treatment naïve patients with genotype 1 chronic HCV infection: Telaprevir (TVR) plus peginterferon and ribavirin (PR) treatment for 8 (T8PR) or 12 (T12PR) weeks versus standard of care (SOC). Patients in the triple therapy arms who developed an eRVR (extended rapid virological response; defined as undetectable HCV RNA at weeks 4 and 12) stopped treatment at week 24 (response-guided therapy, RGT); if eRVR did not develop, treatment continued to 48 weeks. SOC treatment consisted of PegIFN and RBV administered for 48 weeks. (16)

The ILLUMINATE trial focused on defining the utility of RGT in patients with an eRVR. All patients received an initial 12 weeks of TVR-based triple therapy followed by PegIFN and RBV therapy alone. (22) Those who achieved an eRVR were randomized at week 20 to receive either an additional 4 or an additional 28 weeks of PegIFN and RBV whereas those who failed to achieve an eRVR were not randomized and received an additional 28 weeks of PegIFN and RBV. The overall SVR rate for all patients was 72% (Fig. 4), similar to the 75% rate found in the ADVANCE trial. (22) Among the 65% of patients who achieved an eRVR and received either an additional 4 or 28 weeks of PegIFN and RBV, SVR rates were 92% and 88%, respectively (Fig. 4). By contrast, the SVR rate was only 64% among patients who did not achieve an eRVR. (22) These data suggest that a response-guided strategy based on eRVR permits a shortened duration of therapy without jeopardizing the SVR response rate and may be appropriate for up to two-thirds of patients with genotype 1 chronic HCV infection. The use of RGT may, however, be unsuitable for patients with cirrhosis, but at present the data are insufficient to guide management in this difficult-to-treat population. Therapy should be discontinued in all patients if HCV RNA levels are >=1,000 IU/mL at weeks 4 or 12 and/or >10-15 IU/mL at week 24.

Fig. 4. Sustained virological response (SVR) rates in treatment naïve patients with genotype 1 chronic HCV infection: Telaprevir (TVR) plus peginterferon and ribavirin (PR) results overall and among those who did or did not achieve an eRVR (extended rapid virological response; undetectable HCV RNA at weeks 4 and 12). Patients who achieved an eRVR were randomized at week 20 to receive an additional 4 or an additional 28 weeks of SOC therapy; those who did not develop an eRVR were not randomized and all received an additional 24 weeks of SOC therapy. (22)

Recommendations:

1. The optimal therapy for genotype 1, chronic HCV infection is the use of boceprevir or telaprevir in combination with peginterferon alfa and ribavirin (Class 1, Level A).
2. Boceprevir and telaprevir should not be used without peginterferon alfa and weight-based ribavirin (Class 1, Level A).

For Treatment-Naïve Patients:

3. The recommended dose of boceprevir is 800 mg administered with food three times per day (every 79 hours) together with peginterferon alfa and weight-based ribavirin for 24-44 weeks preceded by 4 weeks of lead-in treatment with peginterferon alfa and ribavirin alone (Class 1, Level A).
4. Patients without cirrhosis treated with boceprevir, peginterferon, and ribavirin, preceded by 4 weeks of lead-in peginterferon and ribavirin, whose HCV RNA level at weeks 8 and 24 is undetectable, may be considered for a shortened duration of treatment of 28 weeks in total (4 weeks lead-in with peginterferon and ribavirin followed by 24 weeks of triple therapy) (Class 2a, Level B).
5. Treatment with all three drugs (boceprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or detectable at treatment week 24 (Class 2a, Level B).
6. The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 12 weeks followed by an additional 12-36 weeks of peginterferon alfa and ribavirin (Class 1, Level A).
7. Patients without cirrhosis treated with telaprevir, peginterferon, and ribavirin, whose HCV RNA level at weeks 4 and 12 is undetectable should be considered for a shortened duration of therapy of 24 weeks (Class 2a, Level A).
8. Patients with cirrhosis treated with either boceprevir or telaprevir in combination with peginterferon and ribavirin should receive therapy for a duration of 48 weeks (Class 2b, Level B).
9. Treatment with all three drugs (telaprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24 (Class 2a, Level B).

Three categories have been defined for persons who had received previous therapy for CHC but who had failed the treatment. Null responders are persons whose HCV RNA level did not decline by at least 2 log IU/mL at treatment week 12; partial responders are persons whose HCV RNA level dropped by at least 2 log IU/mL at treatment week 12 but in whom HCV RNA was still detected at treatment week 24; and relapsers are persons whose HCV RNA became undetectable during treatment, but then reappeared after treatment ended. Taking these categories into account, phase 3 trials have been performed also in treatment-experienced patients with genotype 1 chronic HCV infection using BOC and TVR in combination with PegIFN and RBV. The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy (BOC plus PegIFN and RBV for 32 weeks; patients with a detectable HCV RNA level at week 8 received SOC for an additional 12 weeks) and a fixed duration of triple therapy given for 44 weeks (total 48 weeks of therapy), to SOC therapy. (13) The TVR trial design consisted of three arms: in the first arm, patients received triple therapy for 12 weeks followed by SOC treatment for 36 weeks; in the second arm, patients received lead-in treatment with SOC for 4 weeks, followed by triple therapy for 12 weeks, ending with SOC treatment for 32 weeks; the third arm consisted of SOC treatment for 48 weeks. (17) In both trials, an SVR occurred significantly more frequently in those who received the triple therapy regimens than in those who received the SOC therapy. In the BOC trial (RESPOND-2 Trial), the SVR rates were 66% and 59% in the two triple therapy arms compared to 21% in the control arm, prior relapsers achieving higher SVR rates (75% and 69%, respectively) than prior partial responders (52% and 40%, respectively) compared to the rates attained in the SOC arm (29% and 7%, respectively); null responders were excluded from this trial (Table 3 and Fig. 5). (13) Similarly, the SVR rates in the TVR trial (REALIZE Study) were 64% and 66% in the TVR-containing arms (83% and 88% in relapsers, 59% and 54% in partial responders, and 29% and 33% in null responders) and 17% in the control arm (24% in relapsers, 15% in partial responders and 5% in null responders) (Fig. 6). (17) Thus, the response to the triple therapy regimen in both the BOC and TVR trials was influenced by the outcome of the previous treatment with PegIFN and RBV which highlights the importance of reviewing old treatment records to document previous treatment response. In the BOC trial, the SVR rate was higher in those who were relapsers than in those who were partial responders. In the TVR trial also, the highest SVR rate occurred in prior relapsers, a lower rate in partial responders, and the lowest rate in null responders (defined as patients who had <2 log₁₀ decline in HCV RNA at week 12 of prior treatment) (Table 3 and Fig. 6). (17)

Table 3. Comparison of Protease Inhibitors in Combination with Peginterferon Alfa (PegIFN) and Ribavirin (RBV) in Treatment-Experienced Patients

Variable	Boceprevir (BOC) (13)	Telaprevir (TVR) (17)
Study design	RCT	RCT
4-Week lead-in PegIFN/RBV	Yes	Yes/No*
Duration of triple therapy	32 or 44 weeks in combination with PegIFN and RBV**	12 weeks followed by 36 weeks of PegIFN and RBV***
Response-guided therapy (RGT)	Yes	No
Eligible for RGT (%)	46	NA
Prior response to PegIFN/RBV (%)
Relapser	64	53
Partial responder	36	19
Null responder	NA	28
Efficacy, SVR (%)
Relapser	BOC/PR48: 75	T12/PR48: 83
	BOC/RGT: 69	LI-T12/PR48: 88
	PR48: 29	PR48: 24
Partial responder	BOC/PR48: 52	T12/PR48: 59
	BOC/RGT: 40	LI-T12/PR48: 54
	PR48: 7	PR48: 15
Null responder	NA	T12/PR48: 29
		LI-T12/PR48: 33
		PR48: 5
Overall relapse (%)	12-15	NA
Relapser	NA	T12/PR48: 7
		LI-T12/PR48: 7
		PR48: 65
Partial responder	NA	T12/PR48: 21
		LI-T12/PR48: 25
		PR48: 0
Null responder	NA	T12/PR48: 27
		LI-T12/PR48: 25
		PR48: 60
Adverse events
Discontinuation (%)	8-12	NA
SAE (%)	10-14	11-15
Adverse event more frequent in triple therapy arm	Anemia, dysgeusia	Rash, anemia, pruritus, nausea, diarrhea

NA, not available; PR, peginterferon plus ribavirin; RCT, randomized, controlled trial; SAE, serious adverse event; SVR, sustained virological response.

*A lead-in arm was included in the telaprevir retreatment trial but the FDA approved regimen did not include a lead-in strategy.

†The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy and a fixed duration triple therapy given for 44 weeks to peginterferon and ribavirin therapy. BOC/RGT response-guided therapy patients who achieved an eRVR (undetectable HCV RNA at week 8 [week 4 of triple therapy]) received an additional 24 weeks (total 32 weeks of therapy). If an eRVR was not achieved but HCV RNA became undetectable at week 12, BOC was stopped at week 32, and patients received an additional 12 weeks of SOC treatment (total 48 weeks of therapy). BOC/PR48: 4-week lead-in with peginterferon and ribavirin followed by a fixed duration of triple therapy for 44 weeks; PR48: PegIFN and RBV administered for 48 weeks.

‡Telaprevir (TVR) plus peginterferon and ribavirin (PR) administered with and without a 4 week SOC treatment lead in versus standard of care (SOC). T12PR48: TVR administered for 12 weeks followed by 36 weeks of peginterferon and ribavirin; LI-T12/PR48: peginterferon and ribavirin for 4 weeks followed by TVR plus peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin for 32 weeks; PR48: peginterferon and ribavirin administered for 48 weeks.

Thus, the decision to re-treat patients should depend on their prior response to PegIFN and RBV, as well as on the reasons for why they may have failed, such as inadequate drug dosing or side effect management. Relapsers and partial responder patients can expect relatively high SVR rates to re-treatment with a PI-containing triple regimen and should be considered candidates for re-treatment. The decision to re-treat a null responder should be individualized, particularly in patients with cirrhosis, because fewer than one-third of null responder patients in the TVR trial achieved an SVR; there are no comparable data for BOC because null responders were excluded from treatment. In addition, a majority of null responders developed antiviral resistance. The FDA label, however, indicates that BOC can be used in null responders but, given the lack of definitive information from phase 3 data, caution is advised in the use of BOC in null responders until further supportive evidence becomes available. Accordingly, any potential for benefit from treating nonresponders must be weighed against the risk of development of antiviral resistance and of serious side effects, and the high cost of therapy.

Fig. 5. Sustained virological response (SVR) rates, overall and among relapsers and partial responders, in treatment experienced patients with genotype 1 chronic HCV infection: Boceprevir (BOC) plus peginterferon and ribavirin (PR) versus standard of care (SOC). All patients were first treated with PegIFN and RBV for 4 weeks as lead-in therapy followed by one of 3 regimens: 1) BOC/PR48 triple therapy for 44 weeks. 2) BOC RGT triple therapy for 32 weeks if an eRVR was achieved (undetecatble HCV RNA at week 8 and 12). If an eRVR was not achieved, but HCV RNA became undetectable at week 12, BOC was stopped at week 32 and patients received an additional 12 weeks of SOC treatment (total 48 weeks of therapy). 3) SOC treatment consisted of PegIFN and RBV administered for 48 weeks. (13)

There is uncertainty about the benefit of a lead-in phase. Theoretically, a PegIFN and RBV lead-in phase may serve to improve treatment efficacy by lowering HCV RNA levels which would allow for steady-state PegIFN and RBV levels at the time the PI is dosed, thereby reducing the risk of viral breakthrough or resistance. In addition, a lead-in strategy does allow for determination of interferon responsiveness and on-treatment assessment of SVR in patients receiving either BOC or TVR. Patients whose interferon response is suboptimal, defined as a reduction of the HCV RNA level of less than 1 log during the 4-week lead-in, have lower SVR rates than do patients with a good IFN response during lead-in treatment. (12) Nevertheless, the addition of BOC to poor responders during lead-in still leads to significantly improved SVR rates (28% to 38% compared with 4% if a PI is not added) and thus a poor response during the lead-in phase should not be used to deny patients access to PI therapy.

Fig. 6. Sustained virological response (SVR) rates, overall and among relapsers, partial responders, and null responders, in treatment-experienced
patients with genotype 1 chronic HCV infection. T12PR48: Telaprevir (TVR) plus peginterferon and ribavirin (PR) administered for 12 weeks followed by 36 PR for 12 weeks followed by PR for 32 weeks; SOC consisted of PegIFN and RBV administered for 48 weeks. (17)

A direct comparison of the lead-in and non-lead-in groups in the BOC phase 2 study, however, did not show a significant difference in SVR rates for either the 28 week regimen, 56% and 54%, or the 48 week regimen, 75% and 67%, treated with and without lead-in, respectively. (11) Combining data across all treatment groups in the phase 2 trial demonstrated a trend for a higher rate of virological breakthrough in the BOC-treated patients without a lead-in, 9%, than in those who received lead-in treatment, 4%, (P = 0.06). However, because all the phase 3 data were based on the lead-in strategy, until there is evidence to the contrary, BOC should be used with a 4-week lead-in. A lead-in strategy was not evaluated in the phase 3 TVR treatment-naïve trial, and therefore no recommendation can be made for this drug.

Recommendations:

For treatment-experienced patients:

10. Re-treatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, can be recommended for patients who had virological relapse or were partial responders after a prior course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin (Class 1, Level A).
11. Re-treatment with telaprevir, together with peginterferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of standard interferon alfa or peginterferon alfa and/or weight-based ribavirin (Class 2b, Level B.)
12. Response-guided therapy of treatment-experienced patients using either a boceprevir- or telaprevir-based regimen can be considered for relapsers (Class 2a, Level B for boceprevir; Class 2b, Level C for telaprevir), may be considered for partial responders (Class 2b, Level B for boceprevir; Class 3, Level C for telaprevir), but cannot be recommended for null responders (Class 3, Level C).
13. Patients re-treated with boceprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).
14. Patients re-treated with telaprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 1,000 IU at weeks 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).

Adverse events occurred more frequently in patients treated with PIs than in those treated with PegIFN and RBV therapy alone. In the BOC trials, anemia and dysgeusia were the most common adverse events, whereas in the TVR trials, rash, anemia, pruritus, nausea, and diarrhea developed more commonly among those who received TVR than who received SOC therapy. (12,16) In the phase 3 TVR trials, a rash of any severity was noted in 56% of patients who received a TVR-based regimen compared to 32% of those who received a PegIFN and RBV regimen. (16) The rash was typically eczematous and maculopapular in character, consistent with a drug-induced eruption. In most patients, the rash was mild to moderate in severity but was severe (involving >50% of the body surface area) in 4% of cases. The development of rash necessitated discontinuation of TVR in 6% and of the entire regimen in 1% of the cases. The Stevens Johnson Syndrome or Drug-Related Eruption with Systemic Symptoms (DRESS) occurred in <1% of subjects but at a higher frequency than generally observed for other drugs. The response of the rash to local or systemic treatment with corticosteroids and oral antihistamines is uncertain. Pruritus, commonly but not always associated with rash, was noted in 50% of patients who received TVR therapy. (16)

Anemia developed among recipients of both PIs. Hemoglobin decreases below 10 g/dL (grade 2 toxicity) occurred in 49% of patients who received a BOC regimen compared to 29% of those who received the SOC regimen, whereas 9% had a hemoglobin decline of <8.5 g/dL (grade 3 toxicity). (12) Among patients treated with T12PR, hemoglobin levels of <10 g/dL were observed in 36% of patients compared to in 14% of patients who received SOC, and 9% had hemoglobin decreases to <8.5 g/dL. (16) Because hematopoietic growth factors were not permitted during the TVR trials, there was a 5%-6% higher rate of treatment discontinuation among those who developed anemia than among those who did not. However, neither anemia nor RBV dose reduction adversely affected the SVR rate. Of note is that in the BOC trial, SVR rates in patients managed by RBV dose reduction alone were comparable to those in patients managed with erythropoietin therapy. (23) Similarly, in the TVR trials, dose reduction of RBV had no effect on SVR rates, and therefore dose reduction should be the initial response to management of anemia. (24) Because the duration of BOC therapy (24 to 44 weeks) is longer than the duration of TVR therapy (12 weeks), the frequency of anemia is likely to be greater in BOC-containing regimens, leading to more RBV dose reductions and consideration of erythropoietin use. However, the potential benefits of erythropoietin must be weighed against its potential side effects, the fact that its use in HCV therapy is not approved by the FDA, and its considerable cost. If a PI treatment–limiting adverse event occurs, PegIFN and RBV can be continued provided that an on-treatment response had occurred. There are no data to help guide substitution of one for the other HCV PI. If a patient has a serious adverse reaction related to PegIFN and/or RBV, the PegIFN and/or RBV dose should be reduced or discontinued. If either PegIFN and/or RBV are discontinued, the HCV PI should be stopped. Additional information on management of other adverse events can be found in the package insert.

Because patients with CHC frequently receive medications in addition to those used to treat HCV infection, and because the PIs can inhibit hepatic drug-metabolizing enzymes such as cytochrome P450 2C (CYP2C), CYP3A4, or CYP1A, both BOC and TVR were studied for potential interactions with a number of drugs likely to be coadministered. These included statins, immune suppressants, drugs used to treat HIV coinfection, opportunistic infections, mood disorders, and drug addiction support medications. Both BOC and TVR, were noted to cause interactions with several of the drugs examined, either increasing or decreasing pharmacokinetic parameters. It is particularly important, therefore, that the medical provider review this information as listed in the package insert for each of the drugs before starting treatment for CHC. This information can be obtained at the FDA Web site: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Other helpful sites are: http//:222.drug-interactions.com and www.hep-druginteractions.org

Emergence of antiviral-resistant variants during PI-based therapy has been observed during all trials and is associated with virological failure and relapse (Tables 2 and 3). Mutations that confer either high or low level resistance to BOC and TVR cluster around the catalytic site of the NS3/4A serine protease. Similar variants were detected in both BOC and TVR-treated subjects, suggesting that some degree of cross-resistance exists between the two PIs. In both phase 3 studies, sequence analysis of the NS3/4A region was performed in all subjects at baseline and for all subjects who failed to achieve an SVR. Antiviral resistant variants were detected in a small proportion of patients at baseline, 7% in the BOC studies and 5% in the TVR trials, but did not appear to impact response to either PI. (25,26) Therefore, there is currently no clinical indication for baseline resistance testing.

Among treatment-naïve patients receiving a BOC regimen, antiviral resistant variants developing during treatment were observed overall in 16% of patients (Table 2). (12) During treatment, TVR-associated antiviral variants occurred in 12% of treatment-naïve patients and 22% of treatment-experienced patients (Tables 2 and 3). (16,17) A majority (80%-90%) of patients who experienced virological breakthrough or incomplete virological suppression on therapy, or virological relapse after discontinuation of PI therapy, were found to have antiviral resistant variants. In the BOC studies, poor response to interferon (<1 log decline in HCV RNA during the lead-in phase) was associated with a higher rate of development of resistance. (12) Among TVR-treated patients, population sequencing has suggested that high-level resistance develops more commonly when virological failure occurs during the initial 12 weeks of treatment, whereas low-level resistance variants are more likely when virological failure occurs later, during treatment with PegIFN and RBV alone. These observations highlight the importance of response to interferon for the prevention of emergence of antiviral resistance.

The clinical significance of antiviral resistant variants that emerge during PI therapy is uncertain. In longitudinal follow-up of patients enrolled in phase 2 trials, BOC-resistant variants were detected in 43% of subjects after 2 years of follow-up. Similarly, among patients with documented TVR-resistant variants who were enrolled in the TVR phase 3 trials, 40% still had detectable resistant variants after a median follow-up period of 45 weeks. (27) In general, the decline or loss of variants appears to be related to their level of fitness.

Further data are needed to determine whether selection of these variants during and after PI therapy affects subsequent treatment choices. In phase 3 studies, the emergence of resistant variants and virological breakthrough was more common in patients infected with HCV subtype 1a than 1b, a result of a higher genetic barrier required for selection of resistant variants in HCV subtype 1b compared to 1a. (28) Thus, HCV subtyping may play a role in helping to select future treatment regimens and predict the development of resistance. Finally, minimizing development of compensatory mutations would involve early discontinuation of PI therapy when antiviral therapy is unlikely to succeed. Although viral stop rules varied widely in the phase 2 and 3 trials, week 4 and 12 time points on triple therapy are still key decision points for stopping therapy based on HCV RNA levels. Current data suggest that for patients receiving BOC, therapy should be stopped at week 12 if the viral level is >100 IU/mL or >10-15 IU/mL at treatment week 24 and, for TVR, therapy should be stopped at either week 4 or 12 if the viral level is >1,000 IU/mL or if week 24 HCV RNA is detectable.

Recommendations:

15. Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose (Class 2a, Level A).
16. Patients on protease inhibitor-based therapy should undergo close monitoring of HCV RNA levels and the protease inhibitors should be discontinued if virological breakthrough (>1 log increase in serum HCV RNA above nadir) is observed (Class 1, Level A).
17. Patients who fail to have a virological response, who experience virological breakthrough, or who relapse on one protease inhibitor should not be re-treated with the other protease inhibitor (Class 2a, Level C).

The likelihood of achieving an SVR with PegIFN and RBV and of spontaneous resolution of HCV infection differ depending on the nucleotide sequence near the gene for IL28B or lambda interferon 3 on chromosome 19. (18,19) One single-nucleotide polymorphism that is highly predictive is detection of the C or T allele at position rs12979860. (18) The CC genotype is found more than twice as frequently in persons who have spontaneously cleared HCV infection than in those who had progressed to CHC. Among persons with genotype 1 chronic HCV infection who are treated with PegIFN and RBV, SVR is achieved in 69%, 33%, and 27% of Caucasians who have the CC, CT, and TT genotypes, respectively; among black patients, SVR rates were 48%, 15%, and 13% for CC, CT, and TT genotypes, respectively. (29) The predictive value of IL28B genotype testing for SVR is superior to that of the pretreatment HCV RNA level, fibrosis stage, age, and sex, and is higher for HCV genotype 1 virus than for genotypes 2 and 3 viruses. (29,30) There are other polymorphisms near the gene for IL28B that also predict SVR, including detection of the G or T allele at position rs8099917, where T is the favorable genotype, and essentially provides the same information in Caucasians as C at rs12979860. (31,32)

In one study, as well as in preliminary analyses of the phase 3 registration data, IL28B genotype remained predictive of SVR even in persons taking BOC or TVR. (33) In Caucasian patients randomized in the SPRINT 2 trial to take BOC for 48 weeks, SVR was achieved by 80%, 71%, and 59% of patients with CC, CT, and TT genotypes, respectively. (34) In Caucasian patients randomized in the ADVANCE trial to take TVR for 12 weeks, SVR was achieved by 90%, 71%, and 73% of patients with CC, CT, and TT genotypes, respectively. (35) IL28B genotype also predicts the likelihood of qualifying for RGT. In treatment-naïve Caucasian patients randomized in SPRINT 2 to BOC, the week 8 HCV RNA threshold was achieved in 89% and 52% of patients with CC and CT/TT genotypes, respectively. (34( In treatment-naïve Caucasian patients randomized in the ADVANCE study to TVR, eRVR was achieved in 78%, 57%, and 45% of patients with CC, CT, and TT genotypes, respectively. (35) Although the IL28B genotype provides information regarding the probability of SVR and abbreviated therapy that may be important to provider and patient, there are insufficient data to support withholding PIs from persons with the favorable CC genotype because of the potential to abbreviate therapy and the trend for higher SVR rates observed in the TVR study. In addition, the negative predictive value of the T allele with PI-inclusive therapy is not suffciently high to restrict therapy for all patients, because SVR was achieved by more than half of Caucasians with the TT genotype. (34,35)

In summary, these data indicate that IL28B genotype is a significant pretreatment predictor of response to therapy. Consideration should be given to ordering the test when it is likely to influence either the physician’s or patient’s decision to initiate therapy. There are insufficient data to determine whether IL28B testing can be used to recommend selection of SOC over a PI-based regimen with a favorable genotype (CC) and in deciding upon the duration of therapy with either regimen.

Recommendation:

18. IL28B genotype is a robust pretreatment predictor of SVR to peginterferon alfa and ribavirin as well as to protease inhibitor triple therapy in patients with genotype 1 chronic hepatitis C virus infection. Testing may be considered when the patient or provider wish additional information on the probability of treatment response or on the probable treatment duration needed (Class 2a, Level B).

There is a paucity of information for many of the subgroups with the greatest unmet need for treatment (e.g., patients coinfected with HIV and HCV, those with decompensated cirrhosis, and those after liver transplantation). Data from phase 1 and 2 trials have provided interim information that may guide related treatment issues. BOC and TVR undergo extensive hepatic metabolism, BOC primarily by way of the aldoketoreductase (AKR) system but also by the cytochrome P450 enzyme system, whereas TVR is metabolized only by the cytochrome P450 enzyme system, and the main route of elimination is via the feces with minimal urinary excretion. Thus, no dose adjustment of BOC or TVR is required in patients with renal insufficiency. No clinically significant differences in pharmacokinetic parameters were observed with varying degrees of chronic liver impairment in patients treated with BOC and therefore, no dosage adjustment of this drug is required in patients with cirrhosis and liver impairment. Although TVR may be used to treat patients with mild hepatic impairment (Child-Turcotte-Pugh class A, score 5 or 6), it should not be used in HCV-infected patients with moderate to severe hepatic impairment, because no pharmacokinetic or safety data are available regarding its use in such patients. As noted above, BOC and TVR are both inhibitors of CYP3A4, and concomitant administration of medications known to be CYP3A4 substrates should be done with caution and under close clinical monitoring. Pharmacokinetic interactions have particular implications in HIV-coinfected and transplant populations, where drug–drug interactions will complicate treatment paradigms, so that any use of BOC or TVR in transplant or HIVcoinfected populations of patients with HCV should be done with caution and under close clinical monitoring. TVR and BOC are not recommended for use in children and adolescents younger than 18 years of age, because the safety and efficacy has not been established in this population. Thus, whereas BOC and TVR have great promise for improved SVR in special populations, many complex treatment issues remain to be evaluated in further phase 2 and 3 testing.

This practice guideline was produced in collaboration with the Practice Guidelines Committee of the AASLD. This committee provided extensive peer review of the manuscript. Members of the Practice Guidelines Committee include Jayant A. Talwalkar, M.D., M.P.H. (Chair), Adrian M. Di Bisceglie, M.D. (Board Liaison), Jeffrey H. Albrecht, M.D., Hari S. Conjeevaram, M.D., M.S., Amanda DeVoss, M.M.S., PA-C, Hashem B. El-Serag, M.D., M.P.H., David A. Gerber, M.D., Christopher Koh, M.D., Kevin Korenblat, M.D., Raphael B. Merriman, M.D., M.R.C.P.I., Gerald Y. Minuk, M.D., Robert S. O’shea, M.D., Michael K. Porayko, M.D., Adnan Said, M.D., Benjamin L. Shneider, M.D., and Tram T. Tran, M.D. External review was provided by Gary Davis, M.D., Chair, AASLD HCV Special Interest Group, and the American College of Gastroenterology, the Infectious Diseases Society of America, and the National Viral Hepatitis Roundtable. Senior officials at the Division of Viral Hepatitis of the Centers for Disease Control and Prevention, the Office of HIV/AIDS Policy, U.S. Department of Health and Human Services, and the Public Health Strategic Health Care Group, U.S. Department of Veterans Affairs were provided an opportunity to review and comment on the manuscript.

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Asher Kornbluth, David B Sachar and The Practice Parameters Committee of the American College of Gastroenterology

Am J Gastroenterol 2010;105:500; doi:10.1038 / ajg.2010.52; published online 23 February 2010

Correction to: Am J Gastroenterol 2010;105:501 – 523; doi:10.1038 / ajg.2009.727

In the Conflict of Interest section of the article, the Financial Support subsection should have stated that “No support was provided for this work.” The publisher regrets any confusion this misstatement may have caused.

The corrected Potential Competing Interests subsection for Dr Kornbluth is as follows: “Asher Kornbluth is a consultant for Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, and Prometheus Laboratory and has received research support from Salix Pharmaceutical, Procter and Gamble Pharmaceuticals, and Centocor Inc. He is also on the Speaker’s Bureau of Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, Prometheus, and Axcan Pharmaceutical.”

Also in the Conflict of Interest section, Dr Sacher’s Potential Competing Interests statement was not included. It is as follows: “David Sachar serves as expert witness for the plaintiffs in litigation claiming that isotretinoin was a cause of their inflammatory bowel disease. He has no other conflicts of interest to report.”

Asher Kornbluth, MD¹, David B. Sachar, MD, MACG¹ and The Practice Parameters Committee of the American College of Gastroenterology

¹Dr. Henry D. Janowitz Division of Gastroenterology, Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

Guidelines for clinical practice are aimed to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind placebo controlled studies are preferable, but compassionate-use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject regardless of specialty training or interests and are aimed to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the board of trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision analysis. The recommendations of each guideline are therefore considered valid at the time of composition based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at a time established and indicated at publication to assure continued validity. The recommendations made are based on the level of evidence found. Grade A recommendations imply that there is consistent level 1 evidence (randomized controlled trials), grade B indicates that the evidence would be level 2 or 3, which are cohort studies or case–control studies. Grade C recommendations are based on level 4 studies, meaning case series or poor-quality cohort studies, and grade D recommendations are based on level 5 evidence, meaning expert opinion.

Am J Gastroenterol 2010; 105:501–523; doi: 10.1038/ajg.2009.727; published online 12 January 2010
Received 2 February 2009; accepted 19 February 2009.

Correspondence: Asher Kornbluth, MD, The Dr. Henry D. Janowitz Division of Gastroenterology, Samuel Bronfman Department of Medicine, Mount Sinai Medical Center, 1751 York Avenue, New York, New York 10128, USA. E-mail: asher.kornbluth@mssm.edu

Ulcerative colitis (UC) is a chronic disease characterized by diffuse mucosal inflammation limited to the colon. It involves the rectum in about 95% of cases and may extend proximally in a symmetrical, circumferential, and uninterrupted pattern to involve parts or all of the large intestine. The hallmark clinical symptom is bloody diarrhea often with prominent symptoms of rectal urgency and tenesmus. The clinical course is marked by exacerbations and remissions, which may occur spontaneously or in response to treatment changes or intercurrent illnesses (1, 2). UC affects approximately 500,000 individuals in the United States with an incidence of 8–12 per 100,000 population per year; the incidence has remained relatively constant over the last five decades (3–8).

The disease accounts for a quarter million physician visits annually, 30,000 hospitalizations, and loss of over a million workdays per year (9). The direct medical costs alone exceed four billion dollars annually, comprising estimated hospital costs of over US$960 million (10, 11) and drug costs of $680 million (11).

In a patient presenting with persistent bloody diarrhea, rectal urgency, or tenesmus, stool examinations and sigmoidoscopy or colonoscopy and biopsy should be performed to confirm the presence of colitis and to exclude the presence of infectious and noninfectious etiologies. Characteristic endoscopic and histologic findings with negative evaluation for infectious causes will suggest the diagnosis of UC.

The diagnosis of UC is suspected on clinical grounds and supported by the appropriate findings on proctosigmoidoscopy or colonoscopy, biopsy, and by negative stool examination for infectious causes (12). Inquiries should be made regarding factors that may potentially exacerbate symptoms of UC; e.g., smoking cessation or nonsteroidal anti-inflammatory drug use or possibly isotretinoin (13–16). Infections can also produce clinical findings indistinguishable from idiopathic UC, so microbiologic studies for bacterial infection (including specific assays for Escherichia coli 0157:H7) and parasitic infestation, as well as serologic testing for ameba when clinical suspicion is high, should be performed in each new patient (17), and should be considered in patients in remission or with mild stable symptoms who unexpectedly develop a severe or atypical exacerbation (18, 19). Similarly, patients who have recently been admitted to hospital or treated with antibiotics should have stools examined for Clostridium difficile, although antibiotic-associated diarrhea may be present even with a negative assay for C. difficile toxin. The incidence of C. difficile is increasing in UC (20–23), and in inflammatory bowel disease (IBD) patients it is associated with a more severe course, greater length of hospital stay, higher financial costs, greater likelihood of colectomy, and increased mortality (22, 24). Multiple stool assays may be required for diagnosis because of frequent false-negative results (22, 24, 25).

Proctosigmoidoscopy or colonoscopy will reveal the mucosal changes characteristic of UC, consisting of loss of the typical vascular pattern, granularity, friability, and ulceration (26–28). These changes typically involve the distal rectum, both endoscopically and histologically (29) and proceed proximally in a symmetric, continuous, and circumferential pattern to involve all or part of the colon. However, isolated patchy cecal inflammation is often seen in UC patients with otherwise only distal disease (30). These endoscopic features may not present in a typical manner in UC patients who have already received treatment, in which case-selective healing may have resulted in skip areas and rectal sparing. Because none of these endoscopic findings is specific for UC, histologic findings obtained from biopsies may be helpful in the differential diagnosis (31). Imaging of the small bowel may also be helpful when the diagnosis of Crohn’s disease (CD) is being considered (32, 33).

In the patient with acute onset of bloody diarrhea, the mucosal biopsy may help distinguish UC from infectious colitis. In UC, more commonly than in infectious colitis, the mucosa shows separation, distortion, and atrophy of crypts; chronic inflammatory cells in the lamina propria; preferential homing of neutrophils to the crypt epithelium; increased number of lymphocytes and plasma cells at the crypt bases; “shortfall” of crypts not reaching to the muscularis mucosae; and basal lymphoid aggregates (12, 34–36). Villous mucosal architecture and Paneth cell metaplasia on rectal biopsy are other features favoring the diagnosis of UC (37). Crypt abscesses, on the other hand, are a nonspecific indication of inflammation and do not indicate a particular diagnosis (38). However, a large, bulging, cystic dilation with a small “necklace” of flat or cuboidal cells around the crypt abscess is more common in infectious, or acute self-limited colitis, than it is in UC (12). CD may be suggested by certain histologic findings such as noncaseating granulomas or microscopic focality, but their absence does not rule out the diagnosis. Furthermore, even in UC or in acute self-limited colitis, muciphage (or “cryptolytic”) granulomas may form in response to ruptured crypts and are therefore not pathognomonic for CD (37). “Backwash ileitis” may occur in UC and appears as mild ileal inflammation endoscopically; it is almost always associated with cecal inflammation and has characteristic histologic findings of mild villous atrophy and only scattered crypt abscesses (39).

Other histologic findings that may suggest an infectious etiology include caseating or confluent granulomas in tuberculosis (TB) (or less commonly in schistosomiasis, syphilis, and Chlamydia trachomatis), trophozoites in amebiasis, pseudomembranes in C. difficile colitis (although in UC, most cases of C. difficile infection occur in the absence of pseudomembranes) (22), ova in schistosomiasis, and viral inclusions in herpetic or cytomegaloviral colitis, although the latter appears almost exclusively in immunocompromised patients (see “Recommendations for management of severe colitis”). In the appropriate clinical settings, sigmoidoscopy or colonoscopy and biopsy may also distinguish the various noninfectious colitides from UC. These conditions include ischemia, radiation, collagenous and microscopic colitis, drug-induced colitis, and the solitary rectal ulcer syndrome (38, 40, 41). Segmental colitis associated with diverticulosis, which usually presents with painless hematochezia in patients older than 60, is distinguished from UC by its segmental location in an area of divericula, typically in the sigmoid colon and with rectal sparing (42–44).

Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been identified in 60–70% of UC patients, but are also found in up to 40% of patients with CD. These pANCA-positive CD patients typically have a clinical phenotype resembling left-sided UC, so pANCA detection alone is of little value in distinguishing between UC and Crohn’s colitis (45). However, reactivity to CBir 1, an anti-flagellin antibody, is preferentially present in pANCA-positive CD patients as compared with pANCA-positive UC patients, 44% vs. 4%, respectively (46). A meta-analysis of 60 studies analyzing performance characteristics of pANCA and anti-saccharomyces cerevisiae antibodies in 3,841 UC patients and 4,019 CD patients found a specificity of 89% pANCA for UC, but a sensitivity of only 59%. For patients with CD, a positive anti-saccharomyces cerevisiae antibodies with a negative ANCA had a specificity of 93% for CD, but again with a sensitivity of only 55% (47). The low sensitivity of pANCA for the diagnosis of UC prevents it from serving as a useful diagnostic tool. However, their specificities may make these assays useful in the occasional patient in whom no other clinical or pathologic features allow a differential diagnosis between UC and Crohn’s colitis (48, 49). Although this distinction is not always crucial, it may have important consequences in terms of counseling, prognosis, and the choice of medical and surgical therapies (50).

Goals of treatment are induction and maintenance of remission of symptoms to provide an improved quality of life, reduction in need for long-term corticosteroids, and minimization of cancer risk.

After the diagnosis of UC is confirmed, the anatomic extent is assessed endoscopically. The key question to be addressed at this point is whether the inflammation is “distal” (i.e., limited to below the descending colon and hence within reach of topical therapy) or extends proximal to the descending colon, requiring systemic medication. Therefore, a delineation of the proximal margin of inflammation, if not achieved on initial evaluation, is desirable at some point once the patient’s condition permits. From a practical standpoint, the endoscopic extent and clinical severity of an acute attack determine the approach to therapy. Importantly, a flare-up during which distal disease extends proximally is often a severe episode with the need for early aggressive therapy (51). Although therapeutic decisions are rarely based on histologic severity of inflammation, histology may well be taken into account when planning a surveillance regimen (see below). Based on clinical and endoscopic findings, the severity and extent of the disease are characterized. Severity may be classified as mild, moderate, severe, or fulminant (52, 53). Patients with mild disease have less than four stools daily, with or without blood, no systemic signs of toxicity, and a normal erythrocyte sedimentation rate. Moderate disease is characterized by more than four stools daily but with minimal signs of toxicity. Severe disease is manifested by more than six bloody stools daily, and evidence of toxicity as showed by fever, tachycardia, anemia, or an elevated erythrocyte sedimentation rate (52). Patients with fulminant disease may have more than 10 bowel movement daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement, and colonic dilation on abdominal plain films (53). Although this classification of mild, moderate, and severe disease is based on the original Truelove–Witts criteria of 1,955 (52), more recent clinical trials, especially with ambulatory patients, have relied more frequently on composite scores based on the number of loose or soft stools, frequency of rectal bleeding, sigmoidoscopic appearance, and a physician global assessment. These scores are variably termed the Mayo Clinic index, Sutherland index, or the UC Disease Activity Index (54, 55). Despite the widespread adoption of these indices in clinical trials, they do not take into account symptoms of abdominal pain, nocturnal bowel movements, urgency, or the dreadful fear of episodes of incontinence, which are often the patients’ greatest concerns. Furthermore, in assessing patients’ own perception of clinical response, the sigmoidoscopic score may not yield additional information beyond the patients’ simple reports of stool frequency and rectal bleeding (56, 57). As a practical therapeutic end point, endoscopic demonstration of mucosal healing is not usually necessary for a patient who achieves clinical remission. Conversely, long-term mucosal healing may reduce the risk of dysplasia (58, 59) and perhaps predicts a better long-term outcome (60, 61). In addition to the evaluation of colitis extent and activity, a global assessment of the patient should include attention to general health concerns, and quality of life issues that may be influenced by colitis activity as well as by extraintestinal manifestations (EIMs) of the disease. Some EIMs are associated with the colitis disease activity, and include the ocular complications of episcleritis, scleritis, and uveitis (which may require urgent consultation), peripheral arthropathies of small and large joints, and dermatologic findings of erythema nodosum and pyoderma gangrenosum. Other EIMs present with a course independent of the colitis activity and include the axial arthropathies, sacroilitis and ankylosing spondylitis, and the chief hepatic EIM associated with UC, primary sclerosing cholangitis (PSC). Although recognition of these EIMs is usually apparent, their management will often require consultation with the appropriate specialist.

Routine vaccination status should be reviewed (62). In patients on immunosuppresants, live vaccines are contraindicated, so if these are required they should be administered at the time of UC diagnosis. However, patients on immunosuppressant drugs can and should be vaccinated routinely for influenza and pneumococcal infection, and for tetanus and meningococcus in the appropriate settings (63–65). Patients being started on infliximab should be screened for hepatitis B before initiating infliximab therapy (63).

Referral-based series (66, 67) have found an increase in abnormal Pap smears in women with IBD, whereas a population-based series found increased risk only in those patients on corticosteroids and immunosuppressants (68). IBD patients have been reported to undergo routine Pap smear testing with suboptimal frequency (69) and should be advised to adhere to guidelines for cervical dysplasia screening (70). Furthermore, current guidelines recommend consideration of administering the human papilloma virus vaccine to all females between the ages of 9 and 26 (71).

Concerns regarding quality of life should be addressed: impairment of function at school, work, or in personal relationships; social and emotional support; financial resources; and adequacy of patient education regarding their disease (13). Anxiety and major depression are more prevalent in patients with IBD than in the general population, and these conditions are more pronounced in patients with greater ongoing disease activity (72, 73). Besides providing indication for specific therapies, these psychiatric diagnoses may also predict the likelihood for medication noncompliance, a frequent contributing factor to poorer clinical outcomes and greater health-care costs (74–76).

Patients with mild to moderate distal colitis may be treated with oral aminosalicylates, topical mesalamine, or topical steroids (Evidence A). Topical mesalamine agents are superior to topical steroids or oral aminosalicylates (Evidence A). The combination of oral and topical aminosalicylates is more effective than either alone (Evidence A). In patients refractory to oral aminosalicylates or topical corticosteroids, mesalamine enemas or suppositories may still be effective (Evidence A). The unusual patient who is refractory to all of the above agents in maximal doses, or who is systemically ill, may require treatment with oral prednisone in doses up to 40–60 mg per day, or infliximab with an induction regimen of 5 mg/kg at weeks 0, 2, and 6, although the latter two agents have not been studied specifically in patients with distal disease (Evidence C).

The therapeutic plan in these cases is determined largely by the patient’s preferences, because both oral and topical therapies are effective. However, a meta-analysis of controlled trials indicates that topical mesalamine is superior to oral aminosalicylates alone in achieving clinical improvement in patients with mild – moderate distal colitis (77–79). Oral therapy with the aminosalicylates (sulfasalazine, olsalazine, mesalamine, or balsalazide) is beneficial in achieving and maintaining remission (1,80–84). Effective doses of sulfasalazine range between 4 and 6 g a day in four divided doses (85, 86); for mesalamine 2 and 4.8 g per day in three divided doses (54, 87); for balsalazide 6.75 g per day in three divided doses (82, 88, 89); and for olsalazine 1.5–3 g per day in two divided doses (90–93), although efficacy of olsalazine in active UC is not conclusively established, perhaps in part because of a confounding dose-related diarrhea. A newer mesalamine formulated with a multimatrix formulation allows comparable efficacy with once daily dosing in doses of 2.4–4.8 g per day (94, 95). These drugs generally exert their effect within 2–4 weeks (80) and are effective in 40–80% patients (77, 80). Intolerance to the sulfapyridine moiety of sulfasalazine is fairly common and may result in nausea, vomiting, dyspepsia, anorexia, and headache. More severe but less common adverse effects include allergic reactions, pancreatitis, hepatotoxicity, drug-induced connective tissue disease, bone marrow suppression, interstitial nephritis, and hemolytic anemia or megaloblastic anemia. Abnormal sperm counts, motility, and morphology are also related to the sulfapyridine moiety of sulfasalazine and are not seen with the mesalamine preparations. Approximately 80% of patients intolerant to sulfasalazine are able to tolerate olsalazine, mesalamine, and balsalazide (80, 92, 96–98). However, several of the allergic reactions previously thought to be due to the sulfa moiety have occasionally been seen with newer aminosalicylates as well (80).

The occurrence of nephrotoxicity with either sulfasalazine or any of the mesalamine compounds is rare. In a review of 30 series in which serum creatinine or creatinine clearance was measured regularly in 2,671 patients for 3,070 years of follow-up, the mean annual nephrotoxicity rate per patient-year was 0.26% (99). Nephrotoxicity usually presents as interstitial nephritis; it occurs most frequently during the first year of treatment, but can occur unpredictably with a delayed presentation. There is no clear relationship between dose and the risk of nephrotoxicity, raising the possibility that this reaction might be idiosyncratic (100). In addition, patients with active IBD may develop an increase in microalbuminuria in the presence of active disease (101). Furthermore in an epidemiologic study of over 20,000 IBD patients from the UK, there was not an increased incidence of nephrotoxicity in IBD patients taking mesalamine compounds, compared with IBD patients without mesalamine use (102). It is recommended that serum creatinine should be measured before initiating treatment with mesalamine or its prodrugs, and periodically while on treatment. Although it may be reasonable to monitor serum creatinine at 3–6 months intervals during the first year of mesalamine treatment, and then annually thereafter, at present the optimal monitoring schedule of serum creatinine in patients treated with mesalamine remains to be determined, as there is no evidence currently to suggest that the frequency of testing improves patient outcomes (99).

An alternative to oral aminosalicylates is topical therapy with either mesalamine suppositories or enemas, or hydrocortisone foam or enemas. Mesalamine suppositories in a dose of 500 mg twice daily or 1,000 mg once daily are effective in the treatment of proctitis (103), and maintenance of remission (104), whereas mesalamine enemas in doses of 1–4 g may be able to reach as proximal as the splenic flexure and are effective in inducing (105, 106) and maintaining (107–109) remission in distal colitis. Topical corticosteroids, available in the United States as a 100 mg hydrocortisone enema, or as a 10% hydrocortisone foam, are effective in acute therapy of distal colitis (110–112) but have not proven effective in maintaining remission (77). Foam is often better tolerated by patients who have difficulty retaining enemas. Mesalamine enemas in a dose of 4 g have been more successful than corticosteroid enemas in inducing remission in two double-blind controlled studies (113–115). One-gram mesalamine enemas may prove as effective as the standard 4 g formulation for induction of remission in patients with left-sided colitis (77). Budesonide, a second-generation corticosteroid that undergoes first-pass hepatic metabolism, has also been evaluated; the optimal budesonide enema dose, 2 mg, not yet available in the United States, seems to be at least as effective as the standard hydrocortisone preparation with fewer side effects (116, 117). Advantages of topical therapy include a generally quicker response time and a less frequent dosing schedule than oral therapy, as well as less systemic absorption. The choice of topical vehicle is also guided by patient preference as well as by the proximal extent of disease. Suppositories have been showed to reach approximately 10 cm, hydrocortisone foam to approximately 15 – 20 cm, and enemas as far as the splenic flexure (118–122), although of course in individual patients the actual proximal extent of distribution may vary.

Some patients may achieve maximum benefit from combination of oral and topical therapy; a combination of oral mesalamine 2.4 and 4 g per day mesalamine enema was more effective in achieving clinical improvement, as well as an earlier response, than either agent alone (123).

Mesalamine suppositories are effective in the maintenance of remission in patients with proctitis, whereas mesalamine enemas are effective in patients with distal colitis when dosed even as infrequently as every third night (Evidence A). Sulfasalazine, mesalamine compounds, and balsalazide are also effective in maintaining remission; the combination of oral and topical mesalamine is more effective than either one alone (Evidence A). Topical corticosteroids including budesonide, however, have not proven effective for maintaining remission in distal colitis (Evidence A). When all of these measures fail to maintain remission in distal disease, thiopurines (6-mercaptopurine (6-MP) or azathioprine) and infliximab (Evidence A), but not corticosteroids, may prove effective (Evidence B).

Mesalamine suppositories in doses of 500 mg daily or twice daily are effective in maintaining remission with an apparent dose–response relationship; only 10% of patients treated with 500 mg twice daily relapsed at 1 year, compared with a relapse rate of 36% with once daily dosing (124, 125). Mesalamine enemas in doses of 2–4 g maintained remission when administered daily (78% effective), every other day (72% effective), or even as infrequently as every third day (65% effective) (77, 78). Sulfasalazine in a dose of 2 g per day, olsalazine 1 g per day, Eudragit-S-coated mesalamine 3.2 g per day, balsalazide 3–6 g per day (126, 127), and granulated extended release mesalamine capsules 1.5 g per day (128) were all effective in maintaining remission in distal disease. The combination of oral mesalamine 1.6 g per day and mesalamine enema 4 g twice weekly was more effective than the oral mesalamine alone (129). Topical corticosteroids, whether hydrocortisone or budesonide, have not proven effective for maintaining remission in distal colitis (77, 78, 130).

The indications for the use of thiopurines and infliximab are identical to those described in the section on maintenance in extensive colitis although they have not been studied in trials limited to patients with distal disease (79).

Patients with mild to moderate extensive colitis should begin therapy with oral sulfasalazine in daily doses titrated up to 4–6 g per day, or an alternate aminosalicylate in doses up to 4.8 g per day of the active 5-aminosalicylate acid (5-ASA) moiety (Evidence A). Oral steroids are generally reserved for patients who are refractory to oral aminosalicylates in combination with topical therapy, or for patients whose symptoms are so troubling as to demand rapid improvement (Evidence B). 6-MP and azathioprine are effective for patients who do not respond to oral steroids, and continue to have moderate disease, and are not so acutely ill as to require intravenous therapy (Evidence A). Infliximab is an effective treatment for patients who are steroid refractory or steroid dependent despite adequate doses of a thiopurine, or who are intolerant of these medications. The infliximab induction dose is 5 mg/kg intravenously at weeks 0, 2, and 6 weeks (Evidence A). Infliximab is contraindicated in patients with active infection, untreated latent TB, preexisting demyelinating disorder or optic neuritis, moderate to severe congestive heart failure, or current or recent malignancies.

Aminosalicylates

When inflammation extends proximal to the reach of topical therapy (i.e., descending colon), oral therapy is required, either solely or in combination with topical therapy. For clinically mild to moderate but anatomically extensive disease, the first-line therapy traditionally has been sulfasalazine. Responses are dose related, with up to 80% of patients who receive daily doses of 4–6 g manifesting complete clinical remission or significant clinical improvement within 4 weeks (85, 86) and approximately half achieving sigmoidoscopic remission (85). However, the benefits of greater efficacy with the higher dose are somewhat offset by an increase in side effects. The strongest advantage of sulfasalazine compared with the “newer” aminosalicylates is its considerably lower cost. However, the most recent Cochrane Systematic Review found a trend in favor of a slight benefit for the newer 5-ASA preparations over sulfasalazine in the induction of global/clinical and endoscopic improvement including remission, when equivalent amounts of the active 5-ASA moiety were compared. There was a modest dose–response relationship of mesalamine when compared to placebo; the trend was significant in terms of global/clinical improvement or remission. This trend was only marginally significant when the rate of complete global/clinical remission was evaluated (80).

If these higher doses of sulfasalazine are not well tolerated, or if there is concern regarding potential sulfonamide toxicity, then one of the other nonsulfonamide 5-ASA-containing compounds should be used at doses of at least 2 g per day, titrating up to 4.8 g per day of the active 5-ASA moiety (54).

The “newer” aminosalicylates—balsalazide (82, 88, 89), olsalazine (90–93), Eudragit-S-coated, pH-dependent mesalamine (54, 87), ethylcellulose-coated mesalamine (131), and multimatrix-release mesalamine (83, 132)—are all superior to placebo and equivalent to sulfasalazine in acute therapy (80). As with sulfasalazine, therapeutic benefit requires a threshold dose, with daily doses less than 2 g being ineffective (54, 80, 87, 133). Two dose-ranging studies of Eudragit-S-coated pH-dependent release mesalamine show a dose–response relationship, comparing 2.4 g daily with 4.8 g daily, with a greater clinical response to the higher dose seen in patients with moderate but not mild disease. No differences were seen, however, in complete remission rates between the two dosages (134, 135). Similarly, there were no significant differences in clinical responses or remissions in patients with mild or moderate disease when treated with multimatrix-mesalamine with 2.4 g daily compared to 4.8 g daily (83, 132). The combination of oral mesalamine and topical mesalamine was more successful than oral mesalamine alone in achieving clinical remission at 8 (but not 4) weeks (136).

Nicotine

A Cochrane systematic review of transdermal nicotine in active UC identified five relevant studies (137). Nicotine was more effective than placebo in achieving remission and improvement. However, comparative trials to mesalamine did not show any clinical advantage for nicotine. At present therefore, the place of nicotine in the therapy of UC remains limited.

Corticosteroids

Oral prednisone shows a dose–response effect between 20 and 60 mg per day (52, 138, 139), with 60 mg per day modestly more effective than 40 mg per day but at the expense of greater side effects (139). No randomized trials have studied steroid taper schedules; most recommendations (140) have advised 40–60 mg per day until significant clinical improvement occurs and then a dose taper of 5–10 mg weekly until a daily dose of 20 mg is reached. At this point tapering generally proceeds at 2.5 mg per week. The frequency and severity of steroid toxicity are substantial and may involve many metabolic activities in virtually every organ system. These adverse effects include cushingoid features, emotional and psychiatric disturbances, infections, glaucoma, and cataracts. Annual ophthalmologic examinations for patients on chronic steroids are recommended (140). Additional steroid-induced complications include gastroduodenal mucosal injury, skin striae, impaired wound healing, and metabolic bone disease. The latter can present insidiously with osteopenia and osteoporosis, or with the more dramatic bone fracture or unpredictable osteonecrosis. When osteonecrosis occurs, it is almost always after high cumulative doses of steroids. This complication is not prevented by calcium and vitamin D supplementation and is not detected by dual energy X-ray absorptiometry scanning. The diagnosis is generally not suspected until a patient complains of specific joint pain, and it is then established by magnetic resonance imaging. The distribution of affected joints in IBD is similar to other conditions associated with osteonecrosis, with the hips being the most frequently involved (141).

Steroid-induced metabolic disturbances include hyperglycemia, sodium and fluid retention, hypokalemia, metabolic alkalosis, hyperlipidemia, and accelerated atherogenesis. Patients on chronic steroids are at risk of adrenal insufficiency if steroids are discontinued or tapered too rapidly, and therefore require steroid replacement at periods of increased stress, such as surgery (142).

Dual-energy X-ray absorptiometry bone testing should be considered in IBD patients with risk factors for osteoporosis such as smoking, low body mass, sedentary lifestyle, hypogonadism, family history, and nutritional deficiencies (143, 144). IBD patients at greatest risk for fracture are over age 60 and all these subjects should be considered for dual-energy X-ray absorptiometry testing. Patients using corticosteroids beyond 3 months consecutively or who are recurrent users should likewise be considered for dual-energy X-ray absorptiometry testing and even prevention with bisphosphonate therapy (143, 145, 146). Prospective implementation of these guidelines in IBD patients identified 44% of IBD patients with osteopenia and 12% with osteoporosis (147). Calcium supplementation 1,000–1,500 mg per day and vitamin D 800 U per day should be considered as well as estrogen replacement in the postmenopausal woman (148). In non-IBD populations, controlled trials have shown efficacy for alendronate (149), risedronate (150), etidronate (151), and teriparatide (152) in the prevention of glucocorticoid-induced osteoporosis. In IBD patients, clodronate (not yet available in the United States) has shown efficacy in preventing glucocorticoid-induced bone loss (153).

Modifiable risk factors, such as cigarette smoking, alcohol use, and a sedentary lifestyle, should be addressed. It is advisable to prescribe a bisphosphonate for IBD patients at a T score below − 2.5. For patients on long-term corticosteroids, or with other important risk factors such as previous fractures, it may be reasonable to prescribe a bisphosphonate at T scores below − 1.0 (146). However, referral to a specialist should be considered in view of the multiple variables to be assessed in patients with different risk factors, the choices of treatments available, and their potential adverse effects.

The use of steroids in IBD increases the risk of opportunistic infections about threefold: the risk is dose related and more common in those over the age of 50 (154). The risk for opportunistic infections is synergistically increased when steroids are used concomitantly with either the thiopurines or infliximab (154).

Infliximab

Infliximab, an intravenously administered monoclonal antibody to tumor necrosis factor-α, is effective in inducing response and remission and improving quality of life in patients with moderate to severe UC. The two largest randomized controlled trials of infliximab in UC, ACT 1 and ACT 2, studied 728 patients. In ACT 1, patients were enrolled if they had failed corticosteroids and/or thiopurines within the previous 18 months; whereas in ACT 2, patients could be enrolled if they had failed aminosalicylates without having failed previous corticosteroids and/or thiopurines (155).

Doses of 5 vs. 10 mg/ kg vs. placebo were studied for induction (and maintenance, see below) of response and remission, and were infused at weeks 0, 2, and 6 and then every 8 weeks through week 46 in ACT 1, and through week 22 in ACT 2. Both infliximab doses were more effective than placebo in inducing and maintaining response and remission. There was no difference in efficacy between the two doses. All of the patients in these trials were outpatients (for results of infliximab in severe UC, see below). Patients who fail to respond after the initial two doses are very unlikely to respond to a third dose. For patients who initially respond, but then begin to lose their response after a number of infusions, increasing the dose to 10 mg/kg, or shortening the interval between doses, may improve the likelihood of success (although this strategy was not studied in a controlled manner in the ACT 1 and 2 studies). Patients who do not respond to a dose as high as 10 mg/ kg as oft en as every 4 weeks should not be continued on the drug (156).

At present it is unknown whether the concomitant administration of a thiopurine enhances the efficacy of infliximab in UC. In CD, for which infliximab was approved by the US Food and Drug Administration 8 years earlier than for UC, concomitant use of thiopurines reduced the formation of antibodies to infliximab. In CD, regular dosing at 8-week (or shorter) intervals, as opposed to episodic dosing does, reduces the incidence of antibodies to infliximab, and has been associated with higher likelihood of response (157), and a lower incidence of infusion reactions (157, 158).

The infliximab infusion is administered over a 2 h period in a monitored setting, with personnel trained to treat severe infusion reactions (see next paragraph). Besides infusion reactions, the most common or troubling adverse effects of infliximab include autoimmunity and increased risks of infection, lymphoma, and possibly other malignancies; these concerns are described in more detail below. Other rare but serious adverse effects of infliximab include hepatotoxicity, development or exacerbation of multiple sclerosis or optic neuritis, and worsening of congestive heart failure in patients with preexisting cardiac disease (159).

Infusion reactions

As described above, the incidence of infusion reactions is decreased by regular 8-week dosing intervals and concomitant immunosuppressive treatment. In the ACT 1 and 2 studies, these reactions occurred in approximately 10% of patients, and were more frequent in patients with antibodies to infliximab (155). Even though adverse reactions to infliximab after a treatment hiatus are the exception rather than the rule, premedication with a corticosteroid and an antihistamine may still be prudent. Similarly, patients with previous mild–moderate infusion reactions should be premedicated with corticosteroids and an antihistamine (160). Most infusion reactions are mild–moderate and consist of flushing, headaches, dizziness, chest pain, cough, dyspnea, fevers, chills, and pruritus. For mild–moderate infusion reactions, slowing the infusion rate, or temporarily halting the infusion often relieves the reaction. Delayed hypersensitivity-like or serum sickness-like reactions occur in 1–2% of patients with CD (161, 162), most commonly in patients who have had a long hiatus between infusions. The clinical presentations may include myalgias, arthralgias, fevers, or rashes similar to the symptoms of a serum sickness-like disorder. These symptoms generally respond to a brief course of corticosteroids. Autoantibodies may occur in response to infliximab use. In the ACT 1 and 2 studies, antinuclear antibodies and anti-double-stranded DNA antibodies occurred in approximately 30% and 10% patients, respectively. Fortunately, the development of a lupus-like illness occurs in fewer than 1% of patients (163).

Infections

Infliximab increases the risk of infection of intracellular pathogens, most notably TB (164–167). Furthermore, extrapulmonary involvement may occur in more than 50% of cases, and disseminated disease in approximately one-third of patients. A detailed history should be taken with attention to potential risk factors for TB, and a careful physical examination for any evidence of pulmonary or extrapulmonary evidence of TB. Patients should be screened for latent TB with a skin test of standard purified protein derivative, and chest radiograph. Interpretation of the purified protein derivative may be confounded either because of previous vaccination with BCG or because many patients may have anergy due to concomitant immunosuppressive treatment. In these patients, especially those at high risk of latent TB, testing with QuantiFERON (Cellestis International, Melbourne, Victoria, Australia), a more sensitive and specific TB assay, should be considered (156). Patients with evidence of latent TB should be treated according to the recommendations of the American Thoracic Society (168, 169).

Patients treated with infliximab are also at increased risk for other opportunistic infections that require macrophages for intracellular killing. Serious infection occurred in approximately 3% of infliximab-treated patients in the ACT 1 and 2 trials. Additional information regarding risk of infection is available from the Therapy, Resource, Evaluation, and Assessment Tool registry, an ongoing observational infliximab safety registry in patients with CD, which contains approximately 6,000 patients with 16,000 years of patient follow-up, half of whom are treated with infliximab, and compared with an uncontrolled group treated without infliximab (170). Multivariate analysis of this registry indicates that increased rate of serious infection was not associated with infliximab use, but was associated with steroid use, narcotic use, and more severe disease activity. However, a meta-analysis of randomized controlled trials of antitumor necrosis factor treatment in rheumatoid arthritis found a twofold increased risk of serious infection, compared with rheumatoid arthritis patients treated with placebo (171). Furthermore, a case–control series from the Mayo Clinic found that IBD patients treated with infliximab had a significantly increased risk for opportunistic infections, especially when used in conjunction with either steroids or thiopurines or both (154). Similarly, analysis of post-marketing adverse event reported to the Food and Drug Administration indicated that serious infections occurred three times more often than expected (167, 172–174). Use of infliximab is also associated with reactivation of hepatitis B infection, so screening for hepatitis B should be undertaken before initiation with infliximab therapy (175) and vaccination should be considered in those patients at risk for hepatitis B infection (63).

The risk of malignancy in IBD patients treated with tumor necrosis factor-inhibitors remains unclear. An analysis of the Therapy, Resource, Evaluation, and Assessment Tool registry has not found an increased risk of malignancy, though the mean follow-up to date is only 2 years (170). However, multiple analyses indicate an increased risk of lymphoma (176). In rheumatoid arthritis, a meta-analysis found 10 patients with lymphoma in 3,500 infliximab-treated patients, compared to none in 1,500 control patients (171). Review of the Food and Drug Administration adverse event registry found that lymphomas were reported seven times more likely than would have been expected (172). Furthermore, a cluster of cases of a rare, particularly aggressive lymphoma, hepatosplenic T-cell lymphoma, has been reported in CD patients treated with concomitant azathioprine and infliximab (177–179). This particular lymphoma has only rarely been reported and some cases were associated with azathioprine monotherapy (180). It usually presents in younger male patients and has an almost universally fatal outcome.

Patients with decompensated heart failure should not be treated with infliximab because of the risk of further decline in cardiac function (181, 182). Rare reports of the development of optic neuritis and multiple sclerosis have led to the recommendation that infliximab is relatively contraindicated in patients with a history of these disorders (156).

Thiopurines

Randomized controlled trials with a relatively small number of enrolled patients (183, 184) as well as uncontrolled trials (185, 186) of azathioprine in doses up to 1.5–2.5 mg/kg per day have shown its effectiveness in patients who do not respond to, or cannot be weaned from steroids (187). Their primary benefit is in the steroid-sparing effect, rather than as an agent to be used as monotherapy to induce remission. Its use in this setting is somewhat limited by its slow onset of action; up to 3–6 months of treatment may be necessary to appreciate an optimal effect (188, 189). However, its long-term use results in steroid sparing (190), fewer admissions to hospital, and fewer operations (191). In a prospective 2-year trial, the addition of olsalazine did not enhance the efficacy of azathioprine (192).

Azathioprine and 6-MP toxicities include bone marrow suppression, particularly leukopenia, which is usually dose dependent. Leukopenia most often occurs within the first weeks to months of use, so complete blood counts should be measured more frequently during this period, though late bone marrow suppression may occur (193). The risk of opportunistic infections is increased approximately threefold, and there is a further synergistic risk when thiopurines are used concomitantly with either steroids or infliximab (154). There is a greater tendency for serious infections in patients with lower absolute lymphocyte counts or leukopenia (154). The frequency of liver abnormalities varies between 2% and 17% of patients and depends largely on the definitions of liver abnormalities reported (194). The liver test abnormalities are usually reversible and generally occur soon after the initiation of thiopurine treatment. Although the thiopurine metabolite 6-methylmercaptopurine (6-MMP) has been associated with elevated transaminases (195), the sensitivity and specificity of 6­MMP for hepatotoxicity are poor (196). Allergic reactions occur in approximately 2–5% of patients and usually present as some combination of fever, rash, myalgias, or arthralgias. Pancreatitis occurs as a hypersensitivity reaction in approximately 2% of patients (197), and will invariably reoccur if treatment with the alternative thiopurine is attempted. Conversely, patients with gastrointestinal intolerance to azathioprine not related to pancreatitis may tolerate 6-MP (198, 199). Long-term use of thiopurines has not been associated with increased risk of solid tumors (200–202).

6-Mercaptopurine, after it is generated from its prodrug, azathioprine, is metabolized by thiopurine methyltransferase (TPMT), an enzyme that exhibits variation as a result of a genetic polymorphism of its alleles and that can be measured by commercial laboratories. Approximately 0.3% (1 in 300) of the general population has low to absent enzyme activity, 11% have intermediate, and 89% have normal to high levels of activity (203). However, only about a quarter of cases of leukopenia in practice are associated with one of these genetic polymorphisms (204). Although TPMT testing cannot substitute for complete blood count monitoring in patients being started on thiopurines, TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Because the phenotype assay reports a quantitative level of the TPMT enzyme activity, it is preferred to the genotype assay. A TPMT assay is therefore recommended by many authorities before initiating thiopurine therapy, to identify the rare patient who is at risk of developing severe myelotoxicity (140).

A meta-analysis of the association between levels of the thiopurine metabolite 6-thioguanine nucleotide (6-TGN) and clinical remission rates (mostly in patients with CD) strongly suggested that higher levels of 6-TGN are associated with clinical remission rates (205). In addition, a retrospective study found that a subset of patients with 6-TGN levels of less than 235 pmol per 8×10⁸ erythrocytes but with high 6-MMP levels may remain refractory to dose escalations of 6-MP/AZA, as they may preferentially metabolize 6-MP/AZA to 6-MMP and thus achieve suboptimal 6-TGN levels (206). Given the conflicting data, the retrospective nature of these studies, and the limited positive and negative predictive values for these particular uses, the utility of measuring metabolite levels needs prospective controlled evaluation before their routine use can be recommended as providing much incremental benefit to the traditional routine of monitoring the complete blood count, liver tests, and clinical response. However, these metabolite markers can be of value in assessing whether a patient is noncompliant or preferentially metabolizes the drug to 6-MMP instead of 6-TGN (206). Leukopenia was observed in only 8% of responders, indicating that it is not a necessary condition for effective dosing (195), though it may still be useful as an indication that maximal dosage has been achieved before abandoning the drug as a failure.

Methotrexate has not been proven to be effective in UC when administered in a weekly dose of 12.5 mg per day (207); neither higher doses nor administration by a parenteral route has been studied in controlled trials.

Once the acute attack is controlled, a maintenance regimen is usually required, especially in patients with extensive or relapsing disease. Sulfasalazine, olsalazine, mesalamine, and balsalazide are all effective in reducing relapses (Evidence A). Patients should not be treated chronically with steroids. Azathioprine or 6-MP may be useful as steroid-sparing agents for steroid-dependent patients and for maintenance of remission not adequately sustained by aminosalicylates, and occasionally for patients who are steroid dependent but not acutely ill (Evidence A). Infliximab is effective in maintaining improvement and remission in the patients responding to the infliximab induction regimen (Evidence A).

Sulfasalazine reduces relapse rates in UC in a dose-related manner, with benefits showed at 2–4 g per day (85, 208, 209). Although the 4 g per day regimen is the most effective in preventing relapse, up to one quarter of patients cannot tolerate the side effects at this dose, which limits its overall utility (208). The newer aminosalicylate preparations—including olsalazine (210, 211), mesalamine (212–218), balsalazide (98), granulated extended release mesalamine capsules (128), and multimatrix-mesalamine (though the latter has not yet been studied in a placebo-controlled trial) (95, 219) have relapse-prevention properties virtually the same as, but not greater than, those of equivalent doses of sulfasalazine (80, 220). Because of the well-documented efficacy of sulfasalazine in the prevention of relapse, most (212, 214–218, 221–225 ) but not all (226) 5-ASA relapse-prevention trials have used sulfasalazine as the control. As with sulfasalazine, most (225, 227, 228) but not all (229, 230) comparison studies of mesalamine have shown increased efficacy with higher doses up to 4 g per day of 5-ASA. However, unlike sulfasalazine, larger doses of 5-ASA in the newer preparations are generally well tolerated, lending these analogues an advantage over sulfasalazine for the prevention of relapse. However, the cost of sulfasalazine, especially when considered for long-term use, is considerably lower. Although the maximum length of remission-maintenance benefit has not been established, most experts recommend permanent maintenance; however, the patient with a mild first episode, or with very infrequent mild relapses that are easily controlled, may opt for being followed without long-term medical maintenance therapy.

The immunomodulators, azathioprine and 6-MP, have been studied for the prevention of relapse prevention. Azathioprine has been found effective in maintaining remission in controlled and uncontrolled drug withdrawal studies (231, 232) and in a meta-analysis of seven placebo-controlled maintenance trials (233). Retrospective studies have shown the value of 6-MP and azathioprine in maintaining long-term remission (200, 234), and it is generally well tolerated during long-term use (197, 200, 201, 234). As with induction of remission in UC, there have been no studies comparing 6-MP with azathioprine. A systematic review (235) and meta-analysis (236) concluded that azathioprine is a modestly effective (236) maintenance therapy for patients who have failed or cannot tolerate mesalamine or sulfasalazine, and for patients who require repeated courses of steroids and this benefit should be considered in the context of the potential for adverse events from the thiopurines (235). Similarly, uncontrolled retrospective data from 105 patients treated with continued long-term 6-MP (234), from 351 patients treated with long-term azathioprine (200) in the United States, and from 298 patients treated with azathioprine in multiple centers in Europe (186) appear to confirm the efficacy of these agents continued long-term in maintaining remissions of UC (237).

The risk-benefit ratio of indefinite azathioprine or 6-MP use for the maintenance of remission, especially when compared with colectomy, is not known. However, experience with the thiopurines over the last four decades indicates that there is not an increased risk of the development of solid tumors (as discussed above) (201) or overall mortality (200, 238). Conversely, a recent meta-analysis of six cohort studies calculated a fourfold increased risk of lymphoma among IBD patients treated with thiopurines, but it remains unclear whether this risk was due to the medications themselves or due to the underlying disease (176, 180, 239).

In the double-blind, placebo-controlled ACT 1 and ACT 2 studies (155), infliximab administered every 8 weeks was effective in maintaining response and remission at week 30 (53% and 32%, respectively), and week 54 (45% and 42%, respectively) in those patients with an initial response or remission at week 8 (after three infusions of 5 or 10 mg/kg at weeks 0, 2, and 6). There was no benefit to initial treatment with the higher dose. Although not studied in a controlled manner in these trials, some patients with an initial response to 5 mg/kg in whom the benefit is attenuated after multiple doses may benefit from dose escalation, or shortening dosing intervals, or both. Similar response and remission rates were seen whether patients had been steroid refractory or steroid naive. However, the success rate in maintaining a steroid-free remission at week 54 was only 21%. These studies did not prospectively address whether concomitant thiopurine therapy would inflence clinical success rates.

The patient with severe colitis refractory to maximal oral treatment with prednisone, oral aminosalicylate drugs, and topical medications may be treated with infliximab 5 mg/kg if urgent hospitalization is not necessary (Evidence A). The patient who presents with toxicity should be admitted to hospital for a course of intravenous steroids (Evidence C). Failure to show significant improvement within 3–5 days is an indication for either colectomy (Evidence B) or treatment with intravenous cyclosporine (CSA; Evidence A) in the patient with severe colitis. Long-term remission in these patients is significantly enhanced with the addition of maintenance 6-MP (Evidence B). Infliximab may also be effective in avoiding colectomy in patients failing intravenous steroids but its long-term efficacy is unknown in this setting (Evidence A).

Infliximab 5 mg/kg is indicated for the patient who may not require immediate hospitalization but who continues to have severe symptoms despite optimal doses of oral steroids (40–60 mg daily of prednisone), oral aminosalicylates (4–6 g sulfasalazine, 4.8 g mesalamine or 6.75 g balsalazide), and topical medications (155). The mainstay of therapy for those patients requiring hospitalization at this point is an intravenous steroid in a daily dose equivalent to 300 mg hydrocortisone or 60 mg methylprednisolone if the patient has received steroids in the previous month. There is no benefit to treatment with a much higher daily dose of steroids, which exposes the patient to a higher potential rate of side effects (240).

In the absence of any proven infection, controlled trials of antibiotics have showed no therapeutic benefit from the use of oral vancomycin (241), intravenous metronidazole (242), or ciprofloxacin (243), when added to intravenous steroids. However, protocols outlining treatment regimens for severe colitis generally include broad-spectrum antibiotics for patients with signs of toxicity, or with worsening symptoms despite maximal medical therapy (244–246).

Controlled studies of the impact of total parenteral nutrition show no benefit from this maneuver as a primary therapy for UC (247, 248). In fact, it may even be detrimental by depriving the colonic enterocytes of the short-chain fatty acids vital to their metabolism and repair (249). However, total parenteral nutrition may be useful as a nutritional adjunct in patients with significant nutritional depletion (250).

There are no studies to show that an oral aminosalicylate is of clinical benefit in this setting, so it is generally withheld if the patient is nil per os, but it may be continued if the patient is eating and has been tolerating this drug. Likewise, no controlled studies have confirmed any incremental benefit of topical medications in this setting, but they are still often prescribed if they can be retained and tolerated. Because the failure rate of medical therapy with intravenous steroids in patients admitted to hospital for severe colitis is approximately 20–40% (251), these patients should be followed closely in conjunction with a surgeon experienced in the management of patients with IBD.

Superimposed infection with enteric pathogens and C. difficile should be ruled out. The incidence of C. difficile in hospitalized patients with UC is rising dramatically. This infection results in higher costs, longer length of stay, and increased morbidity and mortality (20–22, 24, 252), and it is more refractory to treatment in patients on immunosuppressive drugs (253). A recent prospective study of hospitalized patients (without IBD) showed a high failure rate with metronidazole treatment for C. difficile in patients who had been recently treated with cephalosporins, in those who were positive for C. difficile on admission, and in those transferred from another hospital. In such cases, therefore, vancomycin should be considered as the preferred initial antibiotic (254).

Cytomegalovirus superinfection may also occur in the setting of severe colitis and should therefore be considered in any patient who is not responding to maximal immunosuppressive therapy. Cytomegalovirus superinfection can be diagnosed with sigmoidoscopic biopsy and viral culture; treatment with gancyclovir may lead to clinical improvement (255, 256). The frequency with which cytomegalovirus has been reported in the setting of severe colitis depends in large part on the sensitivity of the method chosen to detect cytomegalovirus (19, 257–259).

Patients may present with a megacolon with or without toxicity. The absolute dimension to define a “megacolon” has been variably defined and may be considered as total or segmental nonobstructive dilation to >=6 cm. Hypokalemia or hypomagnesemia, which can exacerbate dilation, should be aggressively corrected (260, 261). In patients with either toxic signs (fever, leukocytosis, or worsening symptoms) or megacolon, medications with anticholinergic or narcotic properties should be avoided for possibility of worsening colonic atony or dilatation, as increased colonic and small intestinal gas is a predictor of a poor outcome to medical therapy (262–265).

Enhanced vigilance must be maintained for an additional, potentially lethal complication; namely, venous thromboembolism, which occurs approximately twice as frequently in hospitalized UC patients compared with hospitalized controls. Although heparin no longer warrants consideration as primary therapy for UC (266), it has an important role in prophylaxis against thromboembolism in patients admitted to hospital with severe colitis ( 267 ). For the patient with a series of thrombotic or embolic events during a course of severe colitis, emergent colectomy may be life­saving in preventing additional, potentially fatal thrombi.

Patients with severe colitis who do not improve significantly after 3–5 days (268, 269) of maximal medical therapy are unlikely to benefit from prolongation of this medical treatment (246, 270) and should either be referred for surgery (see below) or considered for treatment with intravenous CSA or perhaps infliximab. In one placebo-controlled double-blind trial, 82% of patients with steroid-refractory severe colitis treated with intravenous CSA with a dose of 4 mg/kg per day experienced improvement and were able to avoid colectomy in the acute stage (271). These results in the acute phase are consistent with multiple open-label series (272–274). Additional randomized controlled trials showed similar efficacy with an intravenous CSA dose of 2 mg/ kg per day (275), and CSA 2 mg/kg per day was as effective as hydrocortisone intravenously (276). Predictive factors for failure to respond to CSA include persistent fevers, tachycardia, elevated C-reactive protein, hypoalbuminemia, and deep colonic ulcerations (277, 278).

Patients with fulminant colitis are treated similarly but decisions regarding surgery vs. CSA or infliximab should be taken within a few days of initiating intravenous steroid therapy (279). No randomized controlled trials have been performed studying the addition of azathioprine or 6-MP to CSA. Retrospective series with long-term follow-up of up to 14 years (274, 280) indicate a significantly higher long-term success rate when azathioprine or 6-MP was used during the oral CSA phase (272, 275, 276, 280, 281) although the ideal dose or time to add 6-MP or azathioprine has not been studied. However, even in those patients in whom CSA is effective in combination with a thiopurine, the long-term success rate in avoiding relapse and colectomy is substantially lower in those patients who had already been treated (ineffectively) before initiating cyclosporin use. In the largest series to date, 83% of 113 patients had an initial response to CSA and avoided colectomy during the hospital stay. However, during continued follow-up, 54% of the initial patients initially responding to CSA required a future colectomy with the mean time to colectomy at 5 years. The rate of colectomy in those already on azathioprine compared with those starting azathioprine concurrently with CSA was 59% vs. 31%, respectively. Life-table analysis showed that although only 33% of patients required colectomy at 1 year, 88% required colectomy at 7 years (274).

Significant toxicity may occur with CSA use in UC. Severe adverse events include nephrotoxicity, infection, and seizures (particularly in patients with associated hypocholesterolemia or hypomagnesemia). More common but less severe side effects include paresthesias, hypertension, hypertrichosis, headache, abnormal liver function tests, hyperkalemia, and gingival hyperplasia (282). During intervals of triple immunosuppression with steroids, CSA, and a thiopurine, many experts treat patients with prophylaxis against Pneumocystis jiroveci (carinii), such as trimethoprim/sulfamethoxazole or dapsone. Most authors have found that CSA does not increase the rate of postoperative complications in patients undergoing proctocolectomy (281, 283), in contrast to the preoperative use of corticosteroids in patients with IBD that substantially increases the risk of postoperative infections (284).

Tacrolimus, like CSA, is a calcineurin inhibitor, and has been studied in a single randomized controlled trial (285) as well as in several open-label series (286–288). In a 2-week placebo-controlled trial in moderate–severe UC, patients treated with tacrolimus doses targeted to trough levels of 5–15 ng/ml were more likely than placebo-treated patients to achieve clinical response, though not remission (285). However, at present the available data for tacrolimus are insufficient to guide optimal dosing, duration of acute and maintenance treatment, or follow-up intervals. Furthermore, the need for concomitant thiopurine therapy and benefits in achieving long-term, steroid-free remission and avoiding colectomy are not well defined for tacrolimus (289).

There are limited controlled trial data regarding the role of infliximab in patients with severe or fulminant UC refractory to intravenous steroids. In one double-blind series of 45 patients, patients with either fulminant colitis at day 3, or severe colitis at days 6–8, despite continued intravenous steroids, were randomized to either a single dose of infliximab 5 mg/kg or placebo (290). At day 90, 29% of infliximab-treated patients had undergone colectomy, compared to 67% of placebo-treated patients. In patients with fulminant colitis, 47% of infliximab-treated patients underwent colectomy, compared to 69% of placebo-treated patients. In a smaller randomized controlled trial of patients failing intravenous steroids, four of eight patients treated with infliximab responded clinically 2 weeks after a single dose of infliximab, whereas none of three placebo-treated patients responded (291). Comparable results were achieved in open-label series (292) in the short term but at 5 years approximately half of infliximab-treated patients required colectomy (293–295).

There are no controlled or uncontrolled trials directly comparing CSA to infliximab in patients with severe steroid-refractory UC. However, in a series of 19 patients who failed one therapy, and were then treated with the alternative drug within 30 days, only approximately 30% of patients had avoided colectomy and remained in a steroid-free remission at 12 months; 2 patients developed septicemia, and 1 died during the 30-day interval of receiving both the drugs (296). There is conflicting evidence as to whether infliximab increases the risk of postoperative complications. Most (297–300), but not all (301) series found no increased risk of postoperative complications after infliximab treatment: in the latter series, although there was no increased risk of overall surgical morbidity in patients treated with perioperative infliximab, a multivariate analysis found that these patients did have a higher incidence of postoperative infectious complications albeit without correction for concomitant medications or immediate preoperative duration or severity of the attack (301).

Patients with fulminant colitis or toxic megacolon should be treated as above; in addition they should be kept nil per os, have a small bowel decompression tube if a small bowel ileus is present, and instructed to rotate frequently into the prone or knee-elbow (302 position to aid in evacuation of bowel gas. Broad-spectrum antibiotics are usually used empirically in these patients. The duration of medical treatment of megacolon is controversial; some experts advocate surgery within 72 h if no significant improvement is noted (303, 304), whereas others take a more watchful stance if no toxic symptoms are present (302). All agree, however, that any clinical, laboratory, or radiologic deterioration on medical therapy mandates immediate colectomy.

Absolute indications for surgery are exsanguinating hemorrhage, perforation, and documented or strongly suspected carcinoma (Evidence C). Other indications for surgery are severe colitis with or without toxic megacolon unresponsive to conventional maximal medical therapy, and less severe but medically intractable symptoms or intolerable medication side effects (Evidence C).

There are no prospective randomized trials comparing medical treatment to surgery for any indication in UC, but three situations are absolute indications for surgery because continued medical therapy is doomed to failure and potentially fatal: exsanguinating hemorrhage, frank perforation, and documented or strongly suspected carcinoma; i.e., high-grade dysplasia (HGD) or perhaps low-grade dysplasia (LGD) in flat mucosa (see section “Recommendations for Cancer Surveillance”).

Massive hemorrhage in UC is due to diffuse mucosal ulceration. If the hemorrhage is exsanguinating or even persisting despite maximal medical therapy (see above), it is an indication for emergency surgery. Subtotal colectomy with preservation of the rectum for a future restorative procedure is recommended in this situation (305–307) so long as the small risk of further hemorrhage is appreciated and appropriately monitored. Another indication for emergency surgery is severe colitis or toxic megacolon unresponsive to maximal intravenous medical therapy (see above). It is essential to recognize, however, that perforation can occur without being preceded by megacolon.

Although the clinical scenarios described above provide absolute indications for surgery, the most common indication is persistence of chronic refractory symptoms despite maximal medical therapy, resulting in physical debility, psychosocial dysfunction, or intolerable medication side effects.

Only rarely is surgery necessary to control the EIMs of UC (308, 309). Previously, patients with severe progressive pyoderma gangrenosum, in whom the pyoderma activity paralleled the activity of the colitis, required surgery (310); however, infliximab (311–313) has been found effective in healing pyoderma gangrenosum, and should therefore be tried before resorting to surgery for this indication. By contrast, the course of PSC is independent of the activity of the colitis and is not affected by colectomy (314–317).

Whatever the indication for surgery, patients should be informed of the different options available. These include a total proctocolectomy with permanent ileostomy, or the ileal pouch-anal anastomosis (IPAA) procedure. The patient should be aware of the risks and benefits of these operations within different clinical settings. The option of a total proctocolectomy with a continent ileostomy (Koch pouch) is rarely used because of the frequency of pouch outlet obstruction over time. A subtotal colectomy with an ileorectal anstomosis is rarely advisable as it leaves the potential for disease recurrence and/or cancer risk in the retained rectal segment. IPAA has become the most commonly performed operation for UC, and is performed in 1, 2, or 3 stages, depending on the patient’s clinical status at the time of surgery and the judgment and experience of the surgeon. In general, most series report an improvement in quality of life compared to the patients’ preoperative status (318). Nevertheless, there is increasing recognition of the potential complications following IPAA (319). Besides pouchitis (see below), which may occur in up to 50% of patients during long-term follow-up, a variety of surgical complications may ensue (320). A meta-analysis of 17 series of nearly 1,500 patients undergoing IPAA found that when this surgery was performed without a diverting ileostomy, functional outcomes were similar to those of surgery with proximal diversion but there was an increased risk of anastomotic leak. Notably, 30% of these patients undergoing IPAA required reoperation for postoperative complications including anastomotic leak, pelvic sepsis/abscess, anastomotic stricture, and bowel obstruction; the time intervals during which reoperations for complications were performed were not specified (321). A large database analysis of privately insured UC patients undergoing IPAA found a 20% rate of postoperative complications resulting in an unexpected reoperation. The most frequent early complications (defined as within 30 days of surgery) were abscess (12%), sepsis (8%), and fistula (4%). An additional 11% of IPAA patients required reoperation for complications of abscess and stricture, respectively, between 30 and 180 days after surgery (322). An additional sobering observation was that a 10-year (1995 – 2005) survey of 7,100 patients undergoing surgery for UC found a mortality and morbidity of 2% and 31%, respectively. Furthermore, there were higher mortality rates in hospitals with low-volume experience with IBD patients (323). For patients undergoing colectomy, mortality in hospitals performing low volumes of colectomies was increased twofold compared with high-volume hospitals. Increased mortality was also found in patients who were admitted emergently, aged over 60 years, or insured by Medicaid (324).

In addition to the risks described above, patients should be counseled regarding the effects of the IPAA on fertility and sexual function. A meta-analysis of eight series found a threefold increase in infertility in women after IPAA, compared with women with UC treated medically (though there was no control for the extent of disease severity in patients treated medically) (325). Fecundity among women with UC before surgery is comparable to a control population of women without UC, but is only 20% of fecundity rates of controls after IPAA (326). Approximately 20% of women will have dyspareunia or fecal incontinence during intercourse during a 3-year follow-up after IPAA (320). A meta-analysis of 43 observational studies found a 4% risk of sexual dysfunction in men postoperatively (320). However, most men note improvement in overall sexual quality of life after IPAA, likely due to improvement in general health (327).

Patients who develop typical symptoms and signs of pouchitis after the IPAA should be treated with a short course of antibiotics (Evidence A). Controlled trial studies show efficacy for metronidazole in a dose of 400 mg three times daily, or 20 mg/kg daily, or ciprofloxacin 500 mg twice daily (Evidence A). Other etiologies mimicking pouchitis include irritable pouch syndrome, cuffitis, CD of the pouch, and postoperative complications such as anastomotic leak or stricture. Inadequate evidence exists to recommend routine surveillance of the pouch for dysplasia or adenocarcinoma (Evidence C).

Patients who undergo the IPAA procedure may develop an idiopathic inflammation termed “pouchitis,” which typically presents with variable symptoms of increased stool frequency, rectal bleeding, abdominal cramping, rectal urgency, tenesmus, incontinence, fevers, and the appearance of EIMs (328, 329). The diagnosis is suggested based on clinical symptoms but needs to be confirmed with the characteristic endoscopic and histologic features (330, 331). Symptoms do not always correlate with endoscopic and histologic findings (332). Demonstrating the diagnosis with pouchoscopy as opposed to empiric treatment with metronidazole may be the more cost-effective strategy (333). Pouchitis occurs in up to 60% of patients after a mean follow-up of 40 months (334, 335) and occurs more frequently in patients with PSC, preoperative EIMs (336–338), and in patients who had never smoked (339). Chronic pouchitis may be more likely to occur in those patients with early postoperative anastomotic complications (340).

Only rarely does refractory or recurrent pouchitis occur because of the missed diagnosis of CD (341), which may occur more commonly in patients with a family history of CD or preoperative antisaccharomyces cerevisiae antibody seropositivity (342). CD of the pouch should be suspected if a de novo fistula develops 6–12 months after ileostomy takedown in the absence of postoperative leak, abscess, or sepsis. Endoscopically, CD of the pouch shows ulcers and/or strictures in the afferent limb or in other areas of the small bowel, in the absence of nonsteroidal anti-inflammatory drug use. In CD of the pouch, pelvic magnetic resonance imaging may reveal sinus tracts, fistulae, and leaks and abscesses outside the cuff (343). Pouch excision, or revision in expert hands (344), is required as a result of intractable pouch complications in fewer than 5% of patients in most series.

Some patients with episodes of increased stool frequency and cramping, but with normal endoscopic and histologic findings in the pouch may be experiencing “irritable pouch” symptoms and may respond to anticholinergics, antidepressants, and antidiarrheals (343, 345). Other patients may have inflammation limited to a short cuff of retained rectal mucosa (“cuffitis”) and may respond to topical hydrocortisone or mesalamine (346). C. difficile infection should be considered in cases of recurrent or refractory pouchitis, as it may occur in as many as 20% of these patients, who may then benefit from eradication of C. difficile. In patients using chronic nonsteroidal anti-inflammatory drugs, chronic pouchitis may resolve on cessation of the nonsteroidal anti-inflammatory drugs (343).

Controlled drug trials for the treatment of pouchitis are very limited (329, 347–350). Metronidazole in a dose of 400 mg three times daily (349) or 20 mg/kg per day (347) is effective in the treatment of chronic active pouchitis; in clinical practice, metronidazole in a dose of 250 mg three times daily is often used (329, 349). Controlled trials showed at least similar efficacy with ciprofloxacin 500 mg twice daily (347), or with budesonide enema 2 g daily (not available in the United States) (350). Many uncontrolled trials show similar results with metronidazole and other antibiotics (334, 351, 352) as well as with oral and topical mesalamine and steroids. An oral probiotic formulation VSL-3 (containing lactobacilli, bifidobacteria, and Streptococcus salivarius) was effective in the prevention of pouchitis for up to 1 year after surgery (353) and in the prevention of pouchitis relapse (354), although benefit has not been as consistently seen in open-label use in other centers (355).

In a surveillance program of 106 high-risk patients, only 1 patient had multifocal LGD, and no adenocarcinoma was found (356). Nonetheless, adenocarcinoma remains a risk after IPAA as the duration of follow-up increases. A recent review of 26 cases of adenocarcinoma developing after IPAA found that carcinoma can occur after either mucosectomy or stapled anastomosis, even in patients without dysplasia or cancer before colectomy, as well as in patients whose preoperative dysplasia was not located in or near the rectum (360).

After 8–10 years of colitis, annual or biannual surveillance colonoscopy with multiple biopsies at regular intervals should be performed (Evidence B). The finding of HGD in flat mucosa, confirmed by expert pathologists’ review, is an indication for colectomy, whereas the finding of LGD in flat mucosa may also be an indication for colectomy to prevent progression to a higher grade of neoplasia (Evidence B).

Patients with UC are at increased risk for colorectal cancer (CRC); the degree of risk is related to the duration and anatomic extent of colitis and also to the degree of microscopic inflammation over time (58, 59, 361–368). After 10 years of universal disease, the cancer risk has been widely reported in the range of 0.5–1% per year (361, 363–367). However, a recent nationwide population-based analysis from the Netherlands found that 20% of all UC-related cancers were detected before 8 years of disease had elapsed (369). Even patients with left-sided colitis reach similar levels of cumulative cancer risk after 3–4 decades of disease (361, 363, 370, 371); patients with proctitis or proctosigmoiditis do not appear to be at increased cancer risk. Although some data suggest a later onset of cancer risk in left -sided than in more extensive colitis (361), this evidence is not sufficiently strong to justify different guidelines for surveillance in the two groups (372).

Compared with noncolitis-associated CRC, colitis-associated cancers are more often multiple, broadly infiltrating, anaplastic, and uniformly distributed throughout the colon, and seem to arise from flat mucosa instead of following the usual adenoma–cancer sequence (363). However, lesions that may previously have been interpreted as “flat” may now may be more readily visible with newer, widely available colonoscopes with improved optics, or with the use of chromoendoscopy (described below). Furthermore, colitis-associated CRC often occurs in a much younger patient population than does CRC in the general population (361, 363–367, 369, 371, 372).

Determination of anatomic extent in assessing cancer risk has historically been based on macroscopic rather than histologic inflammation. On the other hand, both macroscopic and microscopic healing may occur, but once extensive colitis is documented, the cancer risk should be assumed to correlate with the greatest previously determined extent. Furthermore, areas of microscopic inflammation, without history of macroscopic inflammation may also harbor the risk of neoplasia proximal to known macroscopic disease (58, 367, 373).

Most groups have found that patients with PSC complicating UC have an increased risk of CRC (362, 374–377). Whether this observation reflects a true biologic phenomenon or a statistical artifact of longer than appreciated colitis duration, it is prudent to start colonoscopic surveillance as soon as the coexisting diagnoses of UC and PSC are established. In addition, ursodeoxycholic acid in daily divided doses of 13–15 mg/kg should be considered, because a prospective randomized, placebo-controlled trial found that this strategy significantly reduced the risk for developing colorectal neoplasia in these patients (378). UC patients with a family history of CRC have a fivefold risk of cancer compared with matched controls (379).

However, the risk of CRC and dysplasia may be reduced with the use of mesalamine. A meta-analysis of six case–control (58, 380–384) and three cohort studies (385–387) that included 334 cases of CRC and 140 cases of dysplasia among 1,932 patients suggested a chemopreventive effect of mesalamine with a 50% risk reduction of CRC and dysplasia (388). Additional series reported since this meta-analysis (362, 389) have not shown the same chemopreventive effect of mesalamine. However comparison of the different series is confounded by failure to control consistently for risk factors including disease duration, family history of CRC, presence of PSC, patient adherence, daily and cumulative mesalamine dose, and degree and duration of colonic inflammation.

The degree of histologic inflammation is an important variable to consider and control risk reduction of dysplasia and CRC in UC. In a case–control series from a surveillance database of 600 patients, Rutter et al. (58) found in a univariate analysis that both increased microscopic and macroscopic inflammation increased CRC and dysplasia risk, whereas in a multivariate analysis microscopic inflammation increased CRC and dysplasia risk fivefold. Similarly, a cohort study from a surveillance database of 400 patients found that an increase in microscopic inflammation increased the risk of CRC threefold (59). Several studies have shown that most dysplasia is visible at colonoscopy: in approximately three quarters of cases of confirmed dysplasia, the endoscopist had noted an abnormality during the procedure (390–392). Endoscopic features that have been predictive of greater likelihood of presence of dysplasia include the presence of pseudopolyps (393, 394) and colonic strictures (393, 395, 396). Although pseudopolyps per se are not premalignant, they indicate a higher degree of previous colonic inflammation. In the presence of countless pseudopolyps, which are too numerous to biopsy or which obscure substantial areas of mucosa, an adequate surveillance examination may be impossible. Patients should be informed of the reduced reliability of colonoscopic surveillance in this situation.

Simply stated, the goals of any cancer surveillance program in UC are to prevent cancer and to save lives. There are no randomized prospective studies comparing different surveillance protocols or, for that matter, even surveillance vs. no surveillance. Nonetheless, at present, the best practical recommendation for patients who are candidates for surgery, based on review of dysplasia surveillance series, calls for annual or biannual colonoscopy. A recent Cochrane analysis concluded that for patients undergoing surveillance, cancers tend to be detected at an earlier stage and hence have a better prognosis. However, lead-time bias could contribute substantially to this apparent benefit. In addition, there appears to be indirect evidence that surveillance is likely to be effective in reducing the risk of death from IBD-associated CRC and that it may be acceptably cost-effective (404).

Examination every second year as opposed to annually would reduce costs, particularly in patients with longer disease duration, but at the expense of reducing likelihood of early cancer detection (405), as in some (365, 406), but not all (367) series annual hazard rates increased with longer disease duration. Whatever schedule might be theoretically most advisable, being both frankly informative and programmatically flexible with patients is important in gaining adherence. The cost of such a surveillance program for each successful detection of precancer or cancer compares favorably with the cost of population-wide screening by flexible sigmoidoscopy for all subjects at average risk for CRC (407–409) as well as with the cost of other widely accepted screening programs such as mammography (410) and Pap smears (411). Patients with long-standing UC may also be offered the option of a prophylactic total proctocolectomy, but patients in remission rarely opt for this approach.

The standardization of “high-grade” and “low-grade” dysplasia published by the Inflammatory Bowel Disease—Dysplasia Morphology Group (IBD-DMG) has been widely adopted and has served to make the diagnosis of dysplasia more stringent and more consistent (412). When colon cancer is identified, the need for surgery is obvious; similarly, the colonoscopic biopsy diagnosis of dysplasia in flat mucosa is often indicative of a concurrent or future cancer. Such findings are an absolute indication for colectomy in patients with HGD (413, 414), and should prompt consideration of colectomy in patients with LGD as well. LGD in a mass lesion (415) that does not resemble a typical sporadic adenoma and cannot be resected endoscopically (see below), or a stricture that is symptomatic or not passable during colonoscopy (393, 395, 396), especially in long-standing disease, is often indicative of coexistent colon cancer; hence, colectomy is advisable. LGD in fl at mucosa (i.e., when no raised lesion is visible endoscopically) may also be an indication for colectomy, as the 5-year predictive value of LGD for either cancer or HGD has been reported as high as 54% (416–418). In fact, a meta-analysis of 20 surveillance series found that among patients with LGD who underwent colectomy within 6 months, 26% of patients had a concurrent cancer, and an additional 12% of patients were found to have HGD. Furthermore, the detection of LGD on surveillance was associated with a 9-fold risk of developing cancer and a 12-fold risk of developing any advanced lesion (cancer or HGD) over a mean of 5.2 years (419). Patients not undergoing colectomy should be counseled regarding these risks, and undergo surveillance at a more frequent surveillance schedule.

A number of series have addressed an approach to management of patients with long-standing UC who are found to have a polypoid or adenomatous mass within a colitic area (420–425). If the lesion is resected in its entirety by colonoscopic polypectomy and if no dysplasia is found in the adjacent flat mucosa or anywhere else in the colon, long-term follow-up has not found an increased risk of cancer in these cases, suggesting that vigilant follow-up surveillance colonoscopy may suffice (420–425). Polyps with a plaque or carpet-like morphology that could not be endoscopically resected in their entirety were excluded from these studies; such cases should be referred for surgery. From a practical perspective, therefore, it matters little whether a mass lesion is called an adenoma­like mass, or a dysplasia-associated lesion or mass; the important issue is to determine whether the lesion is completely resectable endoscopically and the rest of the colon is free of dysplasia.

Guidelines for the patient found to have LGD or HGD are discussed above. It is essential to obtain corroborating pathologic review to confirm the unequivocal distinction between definite neoplastic dysplasia and regenerative atypia due to inflammation and repair (426). However, attempts to repeatedly show dysplasia on subsequent examinations before recommending colectomy should not be undertaken without the awareness of the high risk of concomitant or subsequent advanced neoplasia by both patient and physician. Conversely, the patient whose biopsies are interpreted as “indefinite” for dysplasia should have the slides reviewed by an expert gastrointestinal pathologist and should undergo repeat surveillance colonoscopy at a briefer interval (412), because these patients may have an elevated risk of subsequent progression to definite dysplasia (389).

We acknowledge the invaluable assistance of Seamus J Murphy in the preparation of this paper, particularly his help in assembling, collating, and editing the extensive bibliography.

Guarantor of the article: Asher Kornbluth, MD.
Specific author contributions: Primary research and analysis, authorship, and final editing of the paper: Asher Kornbluth.
Financial support: This work was supported by Salix Pharmaceutical, Proctor and Gamble Pharmaceutical, and Centocor Inc.
Potential competing interests: Asher Kornbluth is a consultant for Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, and Prometheus Laboratory. He is also on the Speaker’s Bureau of Salix Pharmaceutical, Shire Pharmaceutical, Proctor and Gamble Pharmaceutical, Centocor, Prometheus, and Axcan Pharmaceutical.

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Young-Mee Lee, M.D., Marshall M. Kaplan, M.D., and the Practice Guideline Committee of the ACG

Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts

Members of the Practice Guideline Committee of the ACG: Nimish Vakil, M.D., F.A.C.G., Chair; Freda L. Arlow, M.D., F.A.C.G.; William D. Carey, M.D., M.A.C.G.; Christopher P. Cheney, M.D., F.A.C.G.; Sita S. Chokhavatia, M.D.; Francis A. Farraye, M.D., F.A.C.G.; Stephen B. Hanauer, M.D., F.A.C.G.; Kent C. Holtzmuller, M.D.; Kris V. Kowdley, M.D.; Gary R. Lichtenstein, M.D., F.A.C.G.; George W. Meyer, M.D., F.A.C.G.; Daniel S. Pratt, M.D.; Dawn Provenzale, M.D., F.A.C.G.; Amy M. Tsuchida, M.D., F.A.C.G.; J. Patrick Waring, M.D., F.A.C.G.; Maurits J. Wiersema, M.D., F.A.C.G.; John M. Wo, M.D.; and Marc J. Zuckerman, M.D., F.A.C.G.

Guidelines for clinical practice are intended to indicate preferred approaches to medical problems as established by scientifically valid research. Double blind, placebo-controlled studies are preferable, but reports and expert review articles are also utilized in a thorough review of the literature conducted through the National Library of Medicine’s MEDLINE. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject, without regard to specialty training or interests, and are intended to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of specifics in any health care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision.

Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision of analysis. The recommendations of each guideline are therefore considered valid at the time of their production based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at an established time and indicated at publication to assure continued validity.

Am J Gastroenterol 2002;97:528–534
Received Nov. 8, 2001; accepted Nov. 20, 2001.

Reprint requests and correspondence: Young-Mee Lee, M.D., Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, 750 Washington Street, Box 002, Boston, MA 02111.

Primary sclerosing cholangitis (PSC) is a chronic progressive liver disorder that is characterized by ongoing inflammation, obliteration, and fibrosis of both intrahepatic and extrahepatic bile ducts. Diffuse strictures with short intervening segments of normal or dilated bile ducts produce the characteristic beaded appearance on cholangiography.

The pathogenesis of PSC is unknown, but available data suggest that both immunological and nonimmunological host defenses may be impaired (1). Hence, the normal intestinal flora or their metabolic products may play a pathogenic role (1). The disease is usually progressive and may lead to cirrhosis and portal hypertension. PSC is an uncommon disorder for which there are few extensive prevalence data. The estimated prevalence of PSC in the United States, based on studies of inflammatory bowel disease, is 6.3/100,000 (2). A true population-based study has only been done in Norway, where incidence and point prevalence were 1.3 and 8.5 per 100,000 inhabitants, respectively. This compares to incidence and point prevalence of 1.6 and 14.6 for primary biliary cirrhosis. These values seem to be higher than in the rest of Europe or the United States. The recognition of PSC as a distinct liver disease is relatively recent. Until 1970, fewer than 100 patients with PSC had been reported. However, the introduction of endoscopic retrograde cholangiography has changed our perception of this disease. It is now recognized more frequently and is the fourth leading indication for liver transplantation in adults (3). Here we will review the clinical features of PSC, and then propose recommendations regarding appropriate diagnostic and therapeutic strategies. There is no proven medical treatment short of liver transplantation. However, there is effective treatment of many of the symptoms associated with PSC.

Approximately 70% of patients with PSC are men, with a mean age at diagnosis of 40 yr (4). There is a strong association between PSC and inflammatory bowel disease, particularly ulcerative colitis (2, 5). PSC may occur alone and, rarely, in association with retroperitoneal or mediastinal fibrosis. Patients with PSC and without inflammatory bowel disease were more likely to be female (6). Of the approximately 75–90% of patients who have inflammatory bowel disease, about 87% have ulcerative colitis, and 13% have Crohn’s colitis. Approximately 4% of patients with inflammatory bowel disease will either have or develop PSC (7).

There are variations in the clinical course of patients with PSC. The majority of patients are initially asymptomatic but can usually be identified on the basis of a cholestatic pattern of liver tests—specifically, elevation of serum alkaline that is proportionately greater than elevations of the aminotransferases. Some asymptomatic patients may have surprisingly advanced disease. This can be demonstrated histologically and radiologically. Some patients may remain asymptomatic for many years. When symptoms of fatigue, pruritus, jaundice, and weight loss develop, these patients usually have advanced disease. Other patients with histologically and radiologically early disease may be symptomatic and have recurrent episodes of fever, chills, jaundice, right upper quadrant pain, or itching. Intermittent episodes of bacterial cholangitis may be present in 10 –15% of patients with PSC. Complications of PSC include dominant strictures with pruritus and/or jaundice, cholelithiasis, cholangiocarcinoma, malabsorption of fat-soluble vitamins, bleeding from stomal varices, and osteopenia.

Although the majority of patients are asymptomatic at the time of diagnosis, most eventually develop fatigue, pruritus, and jaundice. Cirrhosis, portal hypertension, and liver failure usually follow. Patients who were symptomatic at diagnosis had shortened survival relative to those who were asymptomatic. The survival of asymptomatic patients is significantly shorter than that of a healthy control population. The estimated median survival time from diagnosis to liver transplantation or death is 10 –15 yr (8, 9). There is no relationship between the course of PSC and that of the accompanying inflammatory bowel disease.

The most accurate means to diagnose PSC is cholangiography. Serum liver tests usually show a cholestatic profile, particularly elevation of the serum ALP level. Although liver biopsy is usually consistent with PSC, it is rarely diagnostic. Liver biopsy is useful in staging and aids in prognosis. Neither liver histology nor cholangiography alone will reliably reflect the severity of the disease. They must be used together with symptoms, physical findings, blood tests, and imaging or upper endoscopy tests that indicate the presence and severity of portal hypertension.

General

PSC must be distinguished from secondary sclerosing cholangitis due to other types of biliary disorders. These include chronic bacterial cholangitis in patients with bile duct stricture or choledocholithiasis, ischemic bile duct damage due to treatment with floxuridine, infectious cholangiopathy associated with AIDS, prior biliary surgery, congenital biliary tree abnormalities, and bile duct neoplasms.

Blood Tests

Serum liver tests usually demonstrate a cholestatic pattern. The initial laboratory evaluation of cholestatic liver disease includes serum ALP, aminotransferases, bilirubin, albumin levels, and the antimitochondrial antibody test. The serum ALP level is usually elevated, although a small number of patients may have normal levels. Most patients have slight increases in serum aminotransferase levels. Serum albumin levels are normal early in the disease. In early stages of PSC, serum bilirubin values are usually normal, but they gradually increase as the disease progresses. Occasionally, striking fluctuations in bilirubin levels may occur, even at early stages.

Hypergammaglobulinemia is found in about 30% of patients, and increased IgM levels in 50% (10). Autoantibodies occur less frequently than in autoimmune chronic active hepatitis and primary biliary cirrhosis. Anti–smooth muscle antibodies and antinuclear antibodies are detectable in less than 10 –20% of patients with PSC (11). Antimitochondrial antibodies are rarely, if ever, found in patients with PSC. About 30 –80% of PSC patients have perinuclear antineutrophil cytoplasmic antibodies (12), and 52% have the human leukocyte antigen DRw52a (13). There is still no consensus as to whether specific alleles in the human leukocyte antigen loci, such as DRB1 0301 or DRB1 1301, are directly associated with PSC (14). As in primary biliary cirrhosis, levels of hepatic and urine copper levels are increased, as is the serum ceruloplasmin. Because copper is excreted primarily in bile, the amount of copper in the body increases as cholestasis worsens.

Cholangiography

Cholangiography is the usual way to diagnose PSC. Endoscopic retrograde cholangiography is the test of choice. Transhepatic cholangiography is performed only if endoscopic retrograde cholangiography is unsuccessful. Magnetic resonance cholangiography is increasingly available but does not yet visualize the intrahepatic bile ducts sufficiently to replace direct cholangiography. The radiological findings of PSC are characteristic and include multifocal strictures and dilations, usually involving both the intrahepatic and the extrahepatic biliary trees. Diffuse strictures with short intervening segments of normal or dilated bile duct produce the classic beaded appearance. Some patients may have ulcerations in the larger bile ducts that resemble those seen in Crohn’s disease. The gallbladder and cystic duct are involved in up to 15% of cases (15). Abnormalities of the pancreatic ducts resembling those of chronic pancreatitis have been reported (16, 17). Dominant strictures of the larger bile ducts were seen in only 7% of 1000 patients seen at the Mayo Clinic in the last 10 yr. Dilation of these dominant strictures improved symptoms and blood tests (18).

There is one putative variant, called small duct PSC, in which the affected bile ducts are too small to be seen by cholangiography (19). The prevalence of small duct PSC is uncertain but was reported to be less than 5% of PSC patients at the Mayo Clinic (19). It is diagnosed in patients with inflammatory bowel disease who have cholestatic liver tests, and characteristic liver biopsies but normal endoscopic retrograde cholangiography and negative antimitochondrial antibody tests.

Histological Features

PSC has been divided into four histological stages (20). Stage 1 represents the initial lesion, and the other stages presumably develop with time and the progression of disease. Stage 1 is characterized by the degeneration of bile duct epithelial cells and infiltration of the bile ducts by inflammatory cells, predominantly lymphocytes but occasionally neutrophils. There is inflammation, scarring and enlargement of portal triads, and, at times, portal edema. There may be proliferation of bile ducts in some portal triads, vacuolization of ductular epithelial cells, and concentric layers of connective tissue surrounding bile ducts (onionskin lesion). There is typically less inflammation in the portal triads than in primary biliary cirrhosis. In stage 2, the lesion is more widespread. The fibrosis and inflammation infiltrate the periportal parenchyma, and the periportal hepatocytes may be destroyed. Portal triads are often enlarged. Bile ductopenia is a prominent feature; concentric periductal fibrosis is less obvious. As the disease progresses to stage 3, there is formation of portal-to-portal bridging fibrous septa. Bile ducts are absent or have undergone severe degenerative changes. Cholestasis may be prominent, primarily in periportal and paraseptal hepatocytes. Stage 4, the end stage, is characterized by frank cirrhosis; the histological features are similar to those seen in other forms of that disease. In PSC, however, there may also be changes associated with large duct obstruction, the proliferation and dilation of interlobular bile ducts, and increased numbers of periportal neutrophils.

The most characteristic sign of PSC, the onionskin lesion, is rarely seen on a percutaneous liver biopsy (21). It is more common to see only a paucity of normal bile ducts with nonspecific fibrosis and inflammation in the portal triads. Therefore, a definite diagnosis must be established by cholangiography. Liver histology is used for confirmation and to determine the stage and the prognosis of disease. As sampling variation may occur with liver biopsy, histological staging requires the examination of a sufficiently large specimen that has at least 10 portal triads.

There is no proven medical therapy for PSC. The goal of management should be treatment of symptoms and complications of cholestasis, as well as attempts at treating the underlying disease process. In addition, efforts should be made to recognize and treat or prevent the known complications of PSC such as fat-soluble vitamin deficiency, osteopenia, dominant biliary strictures, and cholangiocarcinoma. Liver transplantation is the only effective treatment and is recommended for patients with end-stage liver disease and symptomatic portal hypertension, liver failure, and recurrent or intractable bacterial cholangitis.

Management of Chronic Cholestasis and Its Complications

Symptoms of chronic cholestasis in PSC are similar to those of primary biliary cirrhosis. They include fatigue, pruritus, steatorrhea, and metabolic bone disease. However, unique problems result from mechanical bile duct obstruction, including bacterial cholangitis, sepsis, and the formation of pigment stones within the obstructed bile ducts. In addition, patients with PSC are at risk of developing cholangiocarcinoma. Cholangiocarcinoma may be difficult to distinguish from the bile duct strictures typical of PSC.

Pruritus. Pruritus is a common symptom of PSC and may be disabling. The precise cause of pruritus remains uncertain. Recent evidence suggests that pruritus may be mediated by an upregulation of central opioidergic receptors (22). It is not caused by the retention of bile acids in skin (23). A variety of agents have been evaluated in the management of pruritus. Cholestyramine, a nonabsorbed resin, is effective in most patients as long as there is adequate bile flow (24). The usual starting dose of cholestyramine is 4 g t.i.d. p.o. The dose must be adjusted in individual patients. There is usually a 2-to 4-day interval between the time that cholestyramine is begun and pruritus remits. Colestipol hydrochloride, another ammonium resin, is as effective as cholestyramine and may be used in those patients who cannot tolerate cholestyramine. Patients must be cautioned to take these resins 2.5 to 3 h before or after they take other medications. Many drugs will bind tightly to these resins in the intestinal tract, particularly ursodeoxycholic acid (UDCA), and will not be absorbed. Rifampin (150 mg b.i.d.) is effective in many patients whose pruritus does not respond to cholestyramine or colestipol (25). Phenobarbital (60–100 mg at bedtime) may also be helpful in this setting (26). Antihistamines are occasionally helpful in patients with mild pruritus if taken at bedtime. Naloxone (27) and naltrexone (28), opioid antagonists, may be helpful in patients who do not respond to any of the above. Large volume plasmapheresis is almost always effective if there is intractable pruritus that fails to respond to all of the above (29). However, it is expensive and time consuming and usually reserved for those awaiting liver transplantation. Methyl-testosterone (30), ursodiol (31), S-adenosylmethionine (32), ondansetron (33), prednisone, and ultraviolet light (34) have been used to control pruritus in individual patients but are tried only if all else fails. Although ursodiol is commonly used for the management of pruritus, there are no controlled data supporting its use.

Steatorrhea and Vitamin Deficiency. Steatorrhea and malabsorption of fat-soluble vitamins may occur late in the course of PSC. Fat malabsorption in jaundiced patients is usually related to decreased secretion of conjugated bile acids into the small intestine. Other causes are pancreatic insufficiency and celiac disease, both of which may be associated with PSC (35, 36). Vitamin A deficiency has been reported in up to 82% of patients with advanced PSC (37). Vitamin D and E occur in approximately 40 –50% of patients with advanced PSC (37). Clinically important vitamin K deficiency rarely occurs unless the patient is chronically jaundiced and takes cholestyramine regularly. In PSC patients with chronic jaundice, fat-soluble vitamin levels should be monitored, and deficiencies treated with supplements.

Metabolic Bone Disease. Osteoporosis is a more common complication of patients with chronic cholestasis than osteomalacia (38). The pathogenesis of osteoporosis in PSC or other chronic cholestatic liver diseases is unknown. Osteoporosis is not related to vitamin D deficiency. The serum concentrations of 25-hydroxyvitamin D and 1,25­dihydroxyvitamin D, the physiologically active metabolites of vitamin D, are usually normal. The osteoporosis may be related to osteoblast inhibitors in cholestatic serum (39). There is no proven medical treatment for osteoporosis in PSC. Treatment with 25-hydroxyvitamin D with calcium, ursodiol, calcitonin, and biphosphonates has been suggested, but there are no controlled data that demonstrate efficacy (40). Alendronate is more effective than etiodronate in osteopenic patients with PBC (41). However, there have been no published controlled trials of bisphosphonates in the osteoporosis associated with PSC.

Bacterial Cholangitis. Bacterial cholangitis may occur after endoscopic procedures or in patients with bile duct stones or tight strictures. Antibiotics are effective in treating recurrent episodes of ascending cholangitis but have not been shown to slow the progression of PSC. Anecdotal reports suggest that such drugs reduce the frequency and severity of attacks of recurrent bacterial cholangitis. Ciprofloxacin has been recommended for treatment and prophylaxis of bacterial cholangitis because of its high biliary tract penetration. Alternative agents are amoxicillin or trimethoprim-sulfamethoxazole. Tetracycline was ineffective in one small study in PSC (42). However, there have been no randomized prospective trials that have critically evaluated antibiotics in PSC. Additional controlled trials are needed to evaluate the efficacy of antibiotics.

Dominant Biliary Strictures. Dominant strictures of the extrahepatic bile duct occur in 7–20% of patients with PSC (18, 43). Several studies reported successful management with endoscopic balloon dilation or biliary stenting of the dominant strictures (44 –47). Endoscopic dilation was associated with fewer episodes of cholangitis and improvement of cholangiographic appearance and biochemical tests. There are no randomized controlled trials that have evaluated the efficacy of endoscopic therapy. There appears to be little risk and some potential benefit in this approach. In one uncontrolled trial, endoscopic dilation plus ursodiol appeared to prolong survival without liver transplantation when compared to the expected survival in untreated patients (47). Another approach to the dominant stricture is surgical dilation or choledochojejunostomy. Surgical resection of hilar and extrahepatic strictures in noncirrhotic patients may postpone the need for transplantation and the development of cholangiocarcinoma in carefully selected patients (48). However, surgical resection carries the risk of postoperative infection and increases scarring in the portahepatis, potentially complicating future liver transplantation.

Cholangiocarcinoma. There is an increased incidence of cholangiocarcinoma in patients with PSC. The reported frequencies of cholangiocarcinomas associated with PSC range from 6% to 30% (49). Patients with long-standing chronic ulcerative colitis and cirrhosis are at highest risk. Most cholangiocarcinomas occur at or near the junction of the right and left hepatic bile ducts. The lack of sensitive and specific serological tumor markers as well as the insensitivity of biliary brush cytology have hampered early diagnosis of cholangiocarcinoma. The serological tumor markers, such as carcinoembryonic antigen and cancer antigen 19-9, have not been useful in diagnosing early, potentially treatable cholangiocarcinomas (50). In addition, it is difficult to distinguish PSC from PSC complicated by cholangiocarcinoma. Often an unsuspected cholangiocarcinoma is found after liver transplantation when the resected liver is examined in the pathology laboratory. Treatment of clinically apparent cholangiocarcinoma by resection, chemotherapy, and radiation has been discouraging, as have been the results with liver transplantation (51). Some experts have suggested surgical extirpation of the biliary tree or liver transplantation before the development of cholangiocarcinoma. The value of screening for cholangiocarcinoma has not been proven.

Specific Therapy of PSC

A variety of choleretic, immunosuppressive, and antifibrotic agents have been used to treat PSC. However, no drug has been shown to alter its natural history.

The evaluation of treatment of PSC has been limited by the uncertainty about its cause and the unpredictable course of the disease. The course of PSC is indolent in most patients but may be rapidly progressive in some and associated with spontaneous exacerbations and remissions in others. Hence, even if a drug is effective, it will probably be years before its efficacy can be proven.

UDCA. UDCA, a hydrophilic bile acid, has been widely used to treat PSC. Therapy with the drug leads to a 2-to 3-fold increase in serum bile acid concentration. There is an increase in the biliary and urinary excretion of bile acids and an increase in bile flow. In vitro, UDCA stabilizes liver cell membranes exposed to toxic concentrations of the naturally occurring bile acid chenodeoxycholic acid.

There have been several small studies and one large controlled trial that reported improvements in symptoms and liver tests with UDCA (52–55) (Table 1). The long term beneficial effects of UDCA on the natural history were unclear because these trials were of relatively short duration and included few patients. A prospective randomized double-blind placebo-controlled trial of 105 patients continued for 2 yr confirmed earlier reports that UDCA (13–15 mg/kg of body weight/day) significantly improved liver tests (56). However, UDCA had no beneficial effect on time to treatment failure or liver transplantation. Furthermore, UDCA did not improve symptoms, cholangiographic appearance, and liver histology.

Table 1. Controlled Trials of UDCA in PSC*

Reference	No. of Patients	UDCA Dose	Treatment Duration	Symptoms	Liver Function Tests	Histology
Beuers (54)	14	13–15 mg/kg/day	12 mo	Unchanged	Improved	Improved
Stiehl (47, 52)	20	750 mg/day	Mean = 45 mo	Unchanged	Improved, except bilirubin	Improved
Lindor (56)	105	13–15 mg/kg/day	Mean = 0.5–72 mo	Unchanged	Improved	Unchanged
Mitchell (57)	24	20 mg/kg/day	24 mo	Unchanged	Improved	Improved
* No study has shown improvement in the natural history of PSC.

A nonrandomized study of UDCA with endoscopic dilation of dominant stricture indicates that this combination may be more effective than UDCA alone (47).

Higher dose UDCA in a pilot study appears to be promising. A double-blind placebo-controlled pilot study of higher dose (20 mg/kg) UDCA in patients observed for 2 yr showed that UDCA was associated with improvement of ALP and liver histology (57). The higher dose UDCA was well tolerated and had no significant side effects. In addition, there is a trial that employs a still higher dose of UDCA, 25–30 mg/kg/day (58). It is as well tolerated as lower doses of UDCA. Because there are no long term data on higher doses of UDCA, their ability to improve the natural history of PSC is still unproven.

Immunosuppressive and Antifibrotic Agents. Despite anecdotal reports of improvement with glucocorticoids and azathioprine in patients with PSC, there is little enthusiasm for their use (59). In addition, glucocorticoids may accelerate the onset and progression of osteoporosis and increase the likelihood of spontaneous bone fractures. Colchicine was not effective in a double blind study of 85 patients with PSC (60), and neither was the combination of colchicine and prednisone (61). In a randomized trial of 34 patients, cyclosporine had no beneficial effect on pruritus, fatigue, liver tests, or survival free of liver transplantation (62). Tacrolimus (FK 506) appeared to improve liver tests in a small, uncontrolled pilot study of 1 yr duration. However, its short duration and lack of histological and cholangiographic data limited its value (63). Methotrexate improved liver tests and liver histology in an uncontrolled trial of 10 patients (64). However, in a double blind, controlled trial of 24 patients, methotrexate was not effective in prolonging survival free of liver transplantation when compared to a placebo (65). Pentoxifylline prevents the production of tumor necrosis factor, which has been postulated to have a role in hepatic injury in PSC. In a pilot study of 20 patients, pentoxifylline was not beneficial in improvement of symptoms or liver tests (66). D-Penicillamine, a cupruretic and antifibrotic agent, was evaluated in a double-blind prospective trial in 70 patients observed during 36 months (67). D-Penicillamine produced the expected cupriuresis, but had no beneficial effect on symptoms, liver tests, liver histology, or survival.

Other Agents. Several other agents have been used to treat PSC, including cholestyramine and nicotine (68). The rationale for nicotine is based on the observation that PSC is less common in smokers and nicotine has a beneficial effect in some patients with ulcerative colitis. However, neither agent was effective.

For patients with advanced PSC, liver transplantation is the only effective therapeutic option.

Indications for liver transplantation include bleeding from varices or portal gastropathy, intractable ascites with or without spontaneous bacterial peritonitis, recurrent episodes of bacterial cholangitis, progressive muscle wasting, and hepatic encephalopathy. A number of transplant centers now report a 3-yr survival rate of 85–90% for patients with PSC (69). However, stricturing of the transplanted bile ducts is a post–liver transplantation problem that is more common in PSC patients than in other diseases that lead to liver transplantation. The pattern of the strictures is similar to that seen in PSC. Possible causes include recurrence of PSC, ischemia, chronic rejection, or infectious cholangitis related to the Roux-en-Y biliary anastomosis and immunosuppression. How often and when PSC recurs after liver transplantation is uncertain. Data from one center suggest that PSC recurs in 10 –20% of PSC patients (70), whereas others report lower rates of recurrence (71).

In PSC patients with inflammatory bowel disease who undergo liver transplantation, inflammatory bowel syndrome symptoms are generally improved. On the other hand, there is a continuing and perhaps increased risk of colon cancer in inflammatory bowel disease patients. Thus, it is important to continue annual surveillance colonoscopies in PSC patients who have chronic ulcerative colitis.

There are many unresolved questions regarding practice guidelines for PSC because of insufficient data. Some of the unresolved issues are:

1. What is the role of UDCA in PSC? Are larger doses truly efficacious? Should standard doses (13–15 mg/kg of body weight/day) be offered given the lack of proven efficacy?
   
2. What is the optimal endoscopic method for treating dominant strictures, balloon dilation or stenting? If dilation is effective, how often should it be done? Should dilation be done in the asymptomatic nonjaundiced patient?
   
3. What can be done to detect cholangiocarcinoma early? Despite the relatively high incidence of cholangiocarcinoma in PSC, surveillance guidelines have yet to be defined.
4. What is the appropriate treatment for osteoporosis associated with PSC? Is there any short of liver transplantation?
5. What is the role of immunosuppressive therapy and antibiotics in PSC? Should combination therapy be tried? If so, what drugs should be used?
6. Is there any way to diagnose PSC before there are characteristic cholangiographic abnormalities? Because these are caused by scarring that could be irreversible, it is possible that all patients with PSC have medically untreatable disease at the time of diagnosis.
7. Is PSC one disease or is it a syndrome, similar to chronic hepatitis?

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Peter A. Banks, M.D., M.A.C.G.,¹ Martin L. Freeman, M.D., F.A.C.G.,² and the Practice Parameters Committee* of the American College of Gastroenterology

¹Division of Gastroenterology, Center for Pancreatic Disease, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; ²Division of Gastroenterology, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota

*The members of the Practice Parameters Committee of the American College of Gastroenterology are listed in the Appendix.

Guidelines for the diagnosis and treatment of acute pancreatitis were published by the American College of Gastroenterology in 1997 (1). These and subsequent guidelines (2–7) have undergone periodic review (6, 8–13) in accordance with advances that have been made in the diagnosis and treatment of acute pancreatitis. Guidelines for clinical practice are intended to apply to all health-care providers who take care of patients with acute pancreatitis and are intended to be flexible, and to suggest preferable (but not the only) approaches. Because there is a wide range of choices in any health-care situation, the physician should select the course best suited to the individual patient and the clinical situation.

These guidelines have been developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee, and approved by the Board of Trustees. The world literature in English was reviewed using a MEDLINE search and also using the Cochrane Library. The ratings of levels of evidence for these guidelines are indicated in Table 1. The final recommendations are based on the data available at the time of the publication of this document and may be updated with appropriate scientific development at a later time. The following guidelines are intended for adult and not pediatric patients. The main diagnostic guidelines include an assessment of risk factors of severity at admission and determination of severity. The major treatment guidelines include supportive care, fluid resuscitation, transfer to intensive care unit, enteral feeding, use of antibiotics, treatment of infected pancreatic necrosis, treatment of sterile pancreatic necrosis, treatment of associated pancreatic duct disruptions, and role of magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), and endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy for detection and treatment of choledocholithiasis in biliary pancreatitis.

Table 1. Ratings of Evidence Used for This Guideline

I.	Strong evidence from at least one published systematic review of multiple well-designed randomized controlled trials
II.	Strong evidence from at least one published properly designed randomized controlled trial of appropriate size and in an appropriate clinical setting
III.	Evidence from published well-designed trials without randomization, single group prepost, cohort, time series, or matched case-controlled studies
IV.	Evidence from well-designed nonexperimental studies from more than one center or research group or opinion of respected authorities, based on clinical evidence, descriptive studies, or reports of expert consensus committees

Am J Gastroenterol 2006;101:2379–2400
Received April 14, 2006; accepted July 5, 2006.

Reprint requests and correspondence: Peter A. Banks, M.D., M.A.C.G., Division of Gastroenterology, Center for Pancreatic Disease, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

The pathophysiology of acute pancreatitis is generally considered in three phases. In the first phase, there is premature activation of trypsin within pancreatic acinar cells. A variety of mechanisms have been proposed including disruption of calcium signaling in acinar cells (14–18), cleavage of trypsinogen to trypsin by the lysosomal hydrolase cathepsin-B, and decreased activity of the intracellular pancreatic trypsin inhibitor (17, 18). Once trypsin is activated, it activates a variety of injurious pancreatic digestive enzymes.

In the second phase, there is intrapancreatic inflammation through a variety of mechanisms and pathways (16, 18–28). In the third phase, there is extrapancreatic inflammation including acute respiratory syndrome (ARDS) (16, 19–21, 29). In both phases, there are four important steps mediated by cytokines and other inflammatory mediators: 1) activation of inflammatory cells, 2) chemoattraction of activated inflammatory cells to the microcirculation, 3) activation of adhesion molecules allowing the binding of inflammatory cells to the endothelium, and 4) migration of activated inflammatory cells into areas of inflammation.

In the majority of patients, acute pancreatitis is mild. In 10–20%, the various pathways that contribute to increased intrapancreatic and extrapancreatic inflammation result in what is generally termed systemic inflammatory response syndrome (SIRS) (Table 2). In some instances, SIRS predisposes to multiple organ dysfunction and/or pancreatic necrosis. The factors that determine severity are not clearly understood, but appear to involve a balance between proinflammatory and anti-inflammatory factors. Recent evidence suggests that the balance may be tipped in favor of proinflammatory factors by genetic polymorphisms of inflammatory mediators that increase severity of acute pancreatitis (27, 30, 31).

Table 2. Systemic Inflammatory Response Syndrome (SIRS)

Defined by Two or More of the Following Criteria: Pulse >90 beats/min Respiratory rate >20/min or PCO2 <32 mmHg Rectal temperature <36°C or >38°C White blood count <4,000 or >12,000/mm3

Clinical Diagnosis

It has been estimated that in the United States there are 210,000 admissions for acute pancreatitis each year (13). Most patients with acute pancreatitis experience abdominal pain that is located generally in the epigastrium and radiates to the back in approximately half of cases. The onset may be swift with pain reaching maximum intensity within 30 min, is frequently unbearable, and characteristically persists for more than 24 h without relief. The pain is often associated with nausea and vomiting. Physical examination usually reveals severe upper abdominal tenderness at times associated with guarding (32).

There is general acceptance that a diagnosis of acute pancreatitis requires two of the following three features: 1) abdominal pain characteristic of acute pancreatitis, 2) serum amylase and/or lipase >=3 times the upper limit of normal, and 3) characteristic findings of acute pancreatitis on CT scan. This definition allows for the possibility that an amylase and/or lipase might be <3 times the upper limit of normal in acute pancreatitis. In a patient with abdominal pain characteristic of acute pancreatitis and serum enzyme levels that are lower than 3 times the upper limit of normal, a CT scan must be performed to confirm a diagnosis of acute pancreatitis. In addition, this definition allows for the possibility that presence of abdominal pain cannot be assessed in some patients with severely altered mental status due to acute or chronic illness.

In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum lipase may remain elevated slightly longer than amylase. The height of the serum amylase and/or lipase does not correlate with the severity of acute pancreatitis. It is usually not necessary to measure both serum amylase and lipase. Serum lipase may be preferable because it remains normal in some nonpancreatic conditions that increase serum amylase including macroamylasemia, parotitis, and some carcinomas. In general, serum lipase is thought to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis. Daily measurement of serum amylase or lipase after the diagnosis of acute pancreatitis has limited value in assessing the clinical progress of the illness or ultimate prognosis (32). If serum amylase and/or lipase remain elevated for several weeks, possibilities include persisting pancreatic/peripancreatic inflammation, blockage of the pancreatic duct, or development of a pseudocyst.

The differential diagnosis of acute pancreatitis is broad and includes mesenteric ischemia or infarction, perforated gastric or duodenal ulcer, biliary colic, dissecting aortic aneurysm, intestinal obstruction, and possibly inferior wall myocardial infarction. In severe pancreatitis, the patients appear toxic and quite ill. In mild pancreatitis, the patients generally appear uncomfortable but not as ill (32).

A detailed discussion of the approach to determining the etiology of acute pancreatitis is beyond the scope of this paper. During the initial hospitalization for acute pancreatitis, reasonable attempts to determine etiology are appropriate, and in particular those causes that may affect acute management. Relevant historical clues include any previous diagnosis of biliary tract disease or gallstones, cholecystectomy, other biliary or pancreatic surgery, acute or chronic pancreatitis or their complications, use of ethanol, medications and the timing of their initiation, recent abdominal trauma, weight loss or other symptoms suggesting a malignancy, or a family history of pancreatitis. Blood tests within the first 24 h should include liver chemistries, calcium, and triglycerides.

Abdominal ultrasound is usually performed at the time of admission to assess for gallstones as the etiology rather than to establish the diagnosis of acute pancreatitis. Detection of common bile duct stones by ultrasound is limited by poor sensitivity, although specificity is quite high if they are identified. Dilation of the common bile duct alone is neither sensitive nor specific for the detection of common bile duct stones. Occasionally, the pancreas is well enough seen by abdominal ultrasound to reveal features that are consistent with the diagnosis of acute pancreatitis including diffuse glandular enlargement, hypoechoic texture of the pancreas reflective of edema, and ascites. Contrast-enhanced CT scan (and in particular a contrast-enhanced thin-section multidetector-row CT scan) is the best imaging technique to exclude conditions that masquerade as acute pancreatitis, to diagnose the severity of acute pancreatitis, and to identify complications of pancreatitis (33–35). Findings on CT scan that confirm the diagnosis of acute pancreatitis include enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections. With the use of IV contrast, a diagnosis of pancreatic necrosis can be established. In addition, contrast-enhanced CT scan may give clues as to the etiology of acute pancreatitis: for example, a common bile duct stone may occasionally be directly visualized, pancreatic calcifications may indicate underlying chronic pancreatitis due to alcohol or other causes, a pancreatic mass may suggest malignancy, and diffuse dilation of the pancreatic duct or a cystic lesion may suggest intraductal papillary mucinous neoplasia or cystic neoplasm. The role of magnetic resonance imaging (MRI) and MRCP in the diagnosis of acute pancreatitis and establishment of severity is undergoing evaluation. These techniques are superior to CT scan in delineating pancreatic ductal anatomy (36–38) and detecting choledocholithiasis (39).

Definitions

The International Symposium, held in Atlanta, GA, in 1992, established a clinically based classification system for acute pancreatitis (40, 41). The goal was to establish international standards of definitions of acute pancreatitis and its complications to make possible valid comparisons of severity of illness and results of therapy and also to establish criteria for patient selection in randomized prospective trials. According to the Atlanta Symposium, acute pancreatitis was defined as an acute inflammatory process of the pancreas that may also involve peripancreatic tissues and/or remote organ systems. Criteria for severity included organ failure (particularly shock, pulmonary insufficiency, and renal failure) and/or local complications (especially pancreatic necrosis but also including abscess and pseudocyst). Early predictors of severity within 48 h of initial hospitalization included Ranson signs and APACHE-II points (Table 3).

Table 3. Severe Acute Pancreatitis as Defined by Atlanta Symposium

Early Prognostic Signs    Ranson signs >=3    APACHE-II score >=8 Organ Failure    and/or Local Complications    Necrosis    Abscess    Pseudocyst

Interstitial pancreatitis was defined as focal or diffuse enlargement of the pancreas with enhancement of the parenchyma that is either homogeneous or slightly heterogeneous in response to IV contrast. There may be inflammatory changes in peripancreatic fatty tissue characterized by a hazy appearance.

Pancreatic necrosis was defined as diffuse or focal areas of nonviable pancreatic parenchyma that was typically associated with peripancreatic fat necrosis. The criteria for the CT diagnosis of necrosis included focal or diffuse well-marginated zones of nonenhanced pancreatic parenchyma greater than 3 cm in size or greater than 30% of the pancreas. It was recognized that pancreatic necrosis could be either sterile or infected and that infected necrosis was characterized by the presence of bacteria (and/or fungi) within the necrotic tissue.

An extrapancreatic fluid collection was defined as pancreatic fluid that extravasates out of the pancreas during acute pancreatitis into the anterior pararenal spaces and other areas as well. Fluid collections may occur both with interstitial and necrotizing pancreatitis. Most fluid collections remain sterile and disappear during the recovery period.

A pancreatic pseudocyst was defined as a collection of pancreatic juice enclosed by a nonepithelialized wall that occurs as a result of acute pancreatitis, pancreatic trauma, or chronic pancreatitis. It is generally believed that a period of at least 4 wk is required from the onset of acute pancreatitis to form a well-defined wall composed of granulation and fibrous tissue. Pancreatic pseudocysts contain considerable pancreatic enzymes and are usually sterile. According to the Atlanta Symposium, an infected pancreatic pseudocyst should be termed a pancreatic abscess. A pancreatic abscess may also occur when an area of pancreatic necrosis undergoes secondary liquefaction and then becomes infected.

Mild acute pancreatitis was defined as pancreatitis associated with minimal organ dysfunction and an uneventful recovery. Severe pancreatitis was defined as pancreatitis associated with organ failure and/or local complications (necrosis, abscess, or pseudocyst).

Organ failure was defined as shock, pulmonary insufficiency, renal failure, or gastrointestinal bleeding (Table 4). There were a number of additional systemic complications that were identified as characteristic of severe acute pancreatitis including disseminated intravascular coagulation (platelets <=100,000/mm3, fibrinogen <=100 mg/dL, fibrin split products >80 μg/mL), or a severe metabolic disturbance (serum calcium <=7.5 mg/dL).

Table 4. Organ Failure as Defined by Atlanta Symposium

Shock–systolic pressure <90 mmHg PaO2 <=60 mmHg Creatinine >2.0 mg/L after rehydration Gastrointestinal bleeding >500 cc/24 h

The Atlanta Symposium was an important initiative in establishing a clinically based classification system. However, it is now clear some of the information included in the classification was subject to different interpretations, and that criteria of severity as defined by the Atlanta Symposium have not been used in a uniform fashion in recent publications (3, 10, 13, 25, 27, 31, 42–165). In addition, there is new scientific information that should be included in a revised classification. Areas of major concern are as follows:

1. In the Atlanta Symposium, a uniform threshold was not established for serum amylase and/or lipase for the diagnosis of acute pancreatitis. In recently published articles, the threshold varied from >=2 times to >=4 times the upper limit of normal.
2. In the Atlanta Symposium, criteria for severe pancreatitis included organ failure and/or local complications (Table 3). This broad definition describes a heterogeneous group of patients with varying levels of severity. For example, the prognosis of pancreatic necrosis is more serious than a pseudocyst or pancreatic abscess. Also, almost all patients with necrotizing pancreatitis without organ failure survive, whereas those with multisystem organ failure  have a median mortality of 47% (48, 66, 68, 83, 120, 163, 164).
3. There was no distinction between transient and persistent organ failure. Patients with persistent organ failure have a more serious prognosis than those with transient organ failure (71, 72, 151).
4. Criteria for organ failure that were established have not been used in a uniform fashion. Some reports have restricted organ failure to shock, hypotension, renal failure, and gastrointestinal bleeding (10, 13, 44, 46, 50–52, 57, 73, 74, 83, 84, 89, 140, 145, 148). Other reports have altered thresholds for organ failure, or have included additional criteria, or have used alternative or nonspecified scoring systems (3, 25, 31, 43, 45, 47, 48, 53, 54, 56, 58– 61, 64, 66–69, 77–80, 82, 86–88, 90–95, 97–100, 102, 103, 105–112, 114, 119–123, 125–129, 134–136, 138, 139, 142, 143, 146, 147, 149–153, 155, 156, 159–161, 165). A revision of the Atlanta criteria will undoubtedly delete gastrointestinal bleeding (which is rarely encountered in acute pancreatitis) and will retain shock, hypotension, and renal failure as the important components of organ failure. In addition, a revision will likely include one of the formal scoring systems for organ failure that are currently available.
5. In the Atlanta Symposium, pancreatic necrosis was considered as either greater than 30% of the pancreas or greater than 3 cm in size. These are, in effect, two different definitions. Because of the variability in the minimum criteria used for the presence of necrosis, it is difficult to compare studies from different institutions (10, 13, 25, 27, 31, 44–60, 62–64, 66–74, 77–92, 98, 100–102, 104–107, 113, 115, 116, 119–121, 126–129, 131, 133–135, 137, 138, 140, 142–148, 150, 153, 154, 156, 157, 159, 161). A revision of the Atlanta criteria will undoubtedly provide a uniform threshold for the diagnosis of pancreatic necrosis.
6. Regarding the term pancreatic pseudocyst, a distinction was not made between two relatively distinctive entities. The first is a collection of pancreatic juice enclosed by a nonepithelialized wall that occurs mostly near the pancreas. While the contents may also include peripancreatic necrotic material, the contents are usually mostly fluid. The second type of pancreatic pseudocyst is that which takes place within the confines of the pancreas and involves pancreatic necrotic tissue with variable amounts of pancreatic fluid. This entity, frequently termed “organized necrosis” (166), is a distinct clinical entity that poses substantially greater management challenges (167). Additional terminology will be needed to separate these two conditions.

Overview of Acute Pancreatitis

Overall, 85% of patients have interstitial pancreatitis; 15% (range 4–47%) have necrotizing pancreatitis (25, 44, 46, 50, 68, 83, 86, 128, 140, 169). Among patients with necrotizing pancreatitis, 33% (range 16–47%) have infected necrosis (62, 66, 68, 83, 91, 111, 113, 117, 118, 120, 121, 147, 159, 169, 170).

Approximately 10% of patients with interstitial pancreatitis experience organ failure, but in the majority it is transient with a very low mortality. Median prevalence of organ failure in necrotizing pancreatitis is 54% (range 29–78%) (31, 50, 54, 82, 83, 120, 147, 148). Prevalence of organ failure is the same or somewhat higher in infected necrosis (34–89%) than in sterile necrosis (45–73%) (66, 83, 138, 161).

The overall mortality in acute pancreatitis is approximately 5%: 3% in interstitial pancreatitis, 17% in necrotizing pancreatitis (30% in infected necrosis, 12% in sterile necrosis) (Table 5).

Table 5. Mortality in Acute Pancreatitis

	Median (%)	Range (%)	References
All cases	5	2–9	2, 25, 44, 46, 50, 56, 59, 61, 73, 75, 76, 86, 109, 140, 168
Interstitial pancreatitis	3	1–7	46, 50, 82, 133, 145, 153, 168
Necrotizing pancreatitis	17	8–39	46, 50, 54, 55, 59, 60, 66, 67, 75, 83, 86, 91, 92, 109, 111, 113, 114, 120, 121, 128, 133, 145, 147, 148, 153, 168, 169
Infected necrosis	30	14–62	45, 62–64, 68, 69, 83, 109–111, 113, 118, 120, 121, 126, 128, 134, 138, 148, 161, 164, 170
Sterile necrosis	12	2–44	68, 83, 109–111, 113, 118, 120, 121, 128, 134, 138, 148, 161, 170

The mortality in the absence of organ failure is 0 (50, 66, 68, 83), with single organ failure is 3% (range 0–8%) (66, 83, 163), with multisystem organ failure 47% (range 28–69%) (48, 66, 68, 83, 120, 163, 164).

Although older literature suggested that 80% of deaths occur after several weeks of illness as a result of infected necrosis, more recent surveys have shown considerable variation with several reports showing a reasonably even distribution of early deaths (within 1–2 wk) versus later deaths (46, 72, 76, 150, 151, 163), a few showing the majority of deaths within the first 2 wk (67, 75), and others showing the majority of deaths after the first 2 wk (59, 89, 135). These variations reflect a variety of influences including percentage of very ill patients referred to a reporting hospital compared to patients admitted directly. Deaths within the first 2 wk are generally attributed to organ failure; deaths after this interval are generally caused by infected necrosis or complications of sterile necrosis.

Older age (>55), obesity (BMI >30), organ failure at admission, and pleural effusion and/or infiltrates are risk factors for severity that should be noted at admission. Patients with these characteristics may require treatment in a highly supervised area, such as a step-down unit or an intensive care unit.

Level of evidence: III

The importance of establishing risk factors of severity of acute pancreatitis at admission is several-fold: to transfer those patients who are most likely to have a severe episode to a step-down unit or an intensive care unit for closer supervision, to allow physicians to compare results of optimal therapy, and to facilitate the identification of seriously ill patients for inclusion in randomized prospective trials. A variety of potential risk factors have been investigated as follows.

There have been a variety of studies that have sought to determine whether obesity is a risk factor for severity in acute pancreatitis (56–60, 75, 87, 88). A recent meta-analysis concluded that obese patients (defined as those with a BMI >30) had more systemic and local complications but not greater mortality (57). In one recent report, the combination of APACHE-II and obesity (a classification termed APACHE­O) measured within the first 24 h of admission improved the prediction of severity in patients with acute pancreatitis (58).

Several reports have pointed out that patients with organ failure at admission have a higher mortality than those who do not experience organ failure at admission (50, 61, 69, 71, 72, 83, 163). The progression of single organ failure to multisystem organ failure is a major determinant in the high mortality associated with organ failure at admission (83). Survival among patients with organ failure at admission has also been shown to correlate with the duration of organ failure (71, 72, 151). When organ failure is corrected within 48 h, mortality was close to 0. When organ failure persisted for more than 48 h, mortality was 36% (72).

Several reports have pointed out that a pleural effusion obtained on chest X-ray within the first 24 h of admission correlates with greater severity in terms of necrosis or organ failure (84) or greater mortality (75, 86). Additionally, the presence of infiltrates on chest X-ray within 24 h has been associated with greater mortality (75, 85, 86).

Several reports have indicated that gender has no prognostic significance (31, 46, 73, 83, 87, 91, 165). Furthermore, etiology has also been shown to have no prognostic significance (46, 53, 60, 61, 75, 83, 87, 91, 168) other than one report that indicated that patients with alcoholic pancreatitis in their first episode of pancreatitis have a greater need for intubation and greater prevalence of pancreatic necrosis (74).

In three reports (82, 83, 171), almost all deaths in acute pancreatitis occurred during the first two episodes, fewer in the third episode. Studies in the future should stratify patients on the basis of number of prior episodes to confirm this observation. In one report (172), but not in another (83), a short interval between onset of symptoms and hospitalization correlated with more severe disease, presumably because abdominal pain was particularly intense among patients with early spread of inflammatory changes in the retroperitoneum and elsewhere that would cause early third space losses.

The two tests that are most helpful at admission in distinguishing mild from severe acute pancreatitis are APACHE-II score and serum hematocrit. It is recommended that APACHE-II scores be generated during the first 3 days of hospitalization and thereafter as needed to help in this distinction. It is also recommended that serum hematocrit be obtained at admission, 12 h after admission, and 24 h after admission to help gauge adequacy of fluid resuscitation.

Level of evidence: III

The APACHE-II severity of disease classification system includes a variety of physiologic variables, age points, and chronic health points, which can be measured at admission and daily as needed to help identify patients with severe pancreatitis (1, 7, Table 6). A variety of reports have correlated a higher APACHE-II at admission and during the first 72 h with a higher mortality (<4% with an APACHE-II <8 and 11–18% with an APACHE-II >8) (31, 46, 52, 72, 83, 128, 147). There are some limitations in the ability of the APACHE-II score to stratify patients for disease severity. For example, in one report, there was no sharp cutoff between interstitial and necrotizing pancreatitis (52). In three reports, APACHE-II scores were not statistically different among patients with sterile and infected necrosis (66, 83, 134). In one recent report, APACHE-II generated within the first 24 h had a positive predictive value of only 43% and negative predictive value of 86% for severe acute pancreatitis as compared to the 48-h Ranson score of 48% and 93%, respectively (53). The advantage of the APACHE-II score was the availability of this information within the first 24 h and daily (53). In general, an APACHE-II score that increases during the first 48 h is strongly suggestive of the development of severe pancreatitis, whereas an APACHE-II that decreases within the first 48 h strongly suggests mild pancreatitis.

Ranson signs have been used for many years to assess severity of acute pancreatitis but have the disadvantage of requiring a full 48 h for a complete evaluation. In general, when Ranson signs are <3, mortality is 0–3% (46, 86, 145); when >=3, 11–15% (46, 86, 145); when >=6, 40% (46). However, a more recent comprehensive evaluation of 110 studies concluded that Ranson signs provided very poor predictive power of severity of acute pancreatitis (173). In two studies, the Ranson score was the same in sterile and infected necrosis (66, 134).

Table 6. APACHE II Score APACHE II score = (acute physiology score) + (age points) + (chronic health points) Acute Physiology Score

		+4	+3	+2	+1	0	+1	+2	+3	+4
1	Rectal temp (°C)	>41	39–40.9		38–38.9	36–38.4	34–35.9	32–33.9	30–31.9	<29.9
2	Mean arterial pressure (mmHg)	>160	130–159	110–129		70–109		50–69		<49
3	Heart rate (bpm)	>180	140–179	110–139		70–109		55–69	40–54	<39
4	Respiratory rate (bpm)	>50	35–49		25–34	12–24	10–11	6–9		<5
5	Oxygen delivery (mL/min)	>500	350–499	200–349		<200
6	PO2 (mmHg)					>70	61–70		55–60	<55
7	Arterial pH	>7.7	7.6–7.69		7.5–7.59	7.3–7.49		7.25–7.3	7.15–7.2	<7.15
8	Serum sodium (mmol/L)	>180	160–179	155–159	150–154	130–149		120–129	111–119	<110
9	Serum potassium (mmol/L)	>7	6–6.9		5.5–5.9	3.5–5.4	3–3.4	2.5–2.9		<2.5
10	Serum creatinine (mg/dL)	>3.5	2–3.4	1.5–1.9		0.6–1.4		<0.6
11	Hematocrit (%)	>60		50–59.9	46–49.9	30–45.9		20–29.9		<20
12	White cell count (103/mL)	>40		20–39.9	15–19.9	3–14.9		1–2.9		<1
				Age Points
Age										Points
<44										0
45–54										2
55–64										3
65–74										5
>75										6
			Chronic Health Points
History of Severe Organ Insufficiency										Points
Nonoperative patients										5
Emergency postoperative patients										5
Elective postoperative patients										2

There have been studies that have attempted to correlate severity of pancreatitis with one or more serum measurements that are available at admission. In one study, creatinine at admission >2.0 mg/dL and a blood glucose >250 mg/dL were associated with a greater mortality (39% and 16%, respectively) (46). In two additional studies, serum creatinine >2.0 mg/dL within 24 h of admission was also associated with a greater mortality (75, 86). In another study, serum glucose >125 mg/dL at admission correlated with a variety of parameters including longer hospital stay but not organ failure, length of intensive care, or mortality (140).

The addition of an obesity score to the standard APACHE­II (so-called APACHE-O score) appears to increase accuracy of APACHE-II for severity. In this scoring system, a point is added to the APACHE-II score when the BMI is 26–30 and 2 points are added when the BMI is greater than 30 (58).

In severe acute pancreatitis, there is considerable extravasation of intravascular fluid into third spaces as a result of inflammatory mediators as well as local inflammation caused by widespread enzymerich pancreatic exudate. The reduction in intravascular volume, which can be detected by an increased serum hematocrit, can lead to decrease in the perfusion of the microcirculation of the pancreas and result in pancreatic necrosis. As such, hemoconcentration has been proposed as a reliable predictor of necrotizing pancreatitis (82). In this report, hematocrit >=44 at admission and failure of admission hematocrit to decrease at 24 h were the best predictors of necrotizing pancreatitis. In another study, patients who presented with hemoconcentration and then had a further increase in hematocrit at 24 h were at particularly high risk of pancreatic necrosis, whereas 41% of patients whose hematocrit decreased by 24 h did not develop pancreatic necrosis (172). Other reports have not confirmed that hemoconcentration at admission or at 24 h is a risk factor for severe acute pancreatitis (44, 75). However, there is agreement that the likelihood of necrotizing pancreatitis is very low in the absence of hemoconcentration at admission (44, 82). Hence, the absence of hemoconcentration at admission or during the first 24 h is strongly suggestive of a benign clinical course.

C-reactive protein (CRP) is an acute phase reactant. Plasma levels greater than 150 mg/L within the first 72 h of disease correlate with the presence of necrosis with a sensitivity and specificity that are both >80%. Because the peak is generally 36–72 h after admission, this test is not helpful at admission in assessing severity (16, 77, 79).

A variety of additional tests, including urinary trypsinogen activation peptide, serum trypsinogen-2, serum amyloid A, and calcitonin precursors, have shown promise at admission in distinguishing mild from severe pancreatitis in many (77–80, 159) but not all (165) reports. None of these tests is available commercially.

Pancreatic necrosis and organ failure are the two most important markers of severity in acute pancreatitis. The distinction between interstitial and necrotizing pancreatitis can be reliably made after 2–3 days of hospitalization by contrast-enhanced CT scan.

Level of evidence: III

A. Imaging Studies

CONTRAST-ENHANCED CT SCAN. Many patients with acute pancreatitis do not require a CT scan at admission or at any time during the hospitalization. For example, a CT scan is usually not essential in patients with recurrent mild pancreatitis caused by alcohol. A reasonable indication for a CT scan at admission (but not necessarily a CT with IV contrast) is to distinguish acute pancreatitis from another serious intra-abdominal condition, such as a perforated ulcer.

A reasonable indication for a contrast-enhanced CT scan a few days after admission is to distinguish interstitial from necrotizing pancreatitis when there is clinical evidence of increased severity. The distinction between interstitial and necrotizing pancreatitis can be made much more readily when a contrast-enhanced CT scan is obtained on the second or third day after admission rather than at the time of admission (34). Additional contrast-enhanced CT scans may be required at intervals during the hospitalization to detect and monitor the course of intra-abdominal complications of acute pancreatitis, such as the development of organized necrosis, pseudocysts, and vascular complications including pseudoaneurysms.

Contrast-enhanced CT scan (and in particular contrast enhanced thin-section multidetector-row CT scan) is the best available test to distinguish interstitial from necrotizing pancreatitis. Interstitial pancreatitis is characterized by an intact microcirculation and uniform enhancement of the gland. Necrotizing pancreatitis is characterized by disruption of the microcirculation such that devitalized areas do not enhance. Whereas small areas of nonenhancement could represent intrapancreatic fluid rather than necrosis, large areas of nonenhancement clearly indicate a disruption of microcirculation and pancreatic necrosis (33, 34, 38).

When there is significant renal impairment (generally a creatinine greater than 1.5 mg/dL) or history of significant allergy to contrast dye, CT scan should be performed without the use of IV contrast. Although the distinction between interstitial and necrotizing pancreatitis cannot be made in the absence of contrast enhancement, a nonenhanced CT scan provides some important information in accordance with Balthazar–Ranson criteria for severity (Table 7). In general, the most severe acute pancreatitis, both in terms of organ failure and in the development of pancreatic necrosis, occurs in grade E pancreatitis. When IV contrast is used, a CT severity index can be used. This index assigns points on the basis of the CT grade (A–E) and the amount of necrosis (none, less than 30%, 30–50%, greater than 50%). Patients with necrotizing pancreatitis have a higher morbidity and mortality than patients with interstitial disease (33, 34).

There have been concerns in some animal studies that the use of IV contrast might accentuate the severity of acute pancreatitis. While there have been very few studies that have addressed this issue, two recent reports found no evidence that IV contrast resulted in extension of necrosis as visualized on subsequent CT scans (143, 174).

The determination that a patient has pancreatic necrosis has clinical implications because the morbidity and mortality of necrotizing pancreatitis is higher than that of interstitial pancreatitis. Furthermore, the determination that a patient has necrotizing pancreatitis may lead to treatment that is not necessary in interstitial pancreatitis. However, the extent of necrosis may not be as important in the morbidity and mortality of necrotizing pancreatitis as was once thought. While some series have shown a correlation between extent of necrosis and prevalence of organ failure (66, 69, 148, 161), others have not (50, 83, 111); similarly, while some series have shown a correlation between the extent of necrosis and the prevalence of infected necrosis (117, 161, 175), others have not (83, 91, 111); while one recent study has shown a correlation of extent of necrosis with mortality (161), others have not (83, 128, 138).

In one recent study among patients with greater than 50% necrosis, mortality was the same in sterile necrosis as compared to infected necrosis (142). It is difficult to explain these differences among hospitals with similar expertise in the care of patients with acute pancreatitis. One possible explanation is that there is considerable variation in the number of patients with severe necrotizing pancreatitis who are referred to individual hospitals for specialized care. In recent series, among the total number of patients with severe pancreatitis who were cared for in referral hospitals, the median percentage of referred patients was 63% (range 32–73%) (55, 60, 62, 64, 68, 83, 106, 110, 138, 156, 161, 164). In some series (60, 62, 68), but not all (83, 138), patients who were transferred were more seriously ill than those who were admitted directly to the reporting hospital. The clinician should keep in mind that organ failure (and particularly multisystem organ failure) rather than the extent of necrosis appears to be a more important factor in the morbidity and mortality of acute pancreatitis.

Complications in acute pancreatitis that can be recognized on abdominal CT scan include pancreatic fluid collections, gastrointestinal and biliary complications (such as obstruction of duodenum or stomach, inflammation of the transverse colon, and biliary obstruction), solid organ involvement (such as splenic infarct), vascular complications (such as pseudoaneurysms, splenic vein thrombosis with varices, portal vein thrombosis), and pancreatic ascites (33, 35, 90).

MAGNETIC RESONANCE IMAGING. Thus far, magnetic resonance imaging (MRI) has not been widely used in the care of patients with acute pancreatitis. While CT scan remains the primary imaging technique to evaluate patients with acute pancreatitis, recent reports have indicated that MRI has some advantages: the lack of nephrotoxicity of gadolinium as compared to an iodinated preparation used for contrast-enhanced CT scan, potential concerns regarding radiation exposure, the greater ability of MRI as compared to CT to distinguish necrosis from fluid, and the overall reliability of MRI as compared to CT scan in staging the severity of acute pancreatitis and its complications (36–38). In one study, secretin-MRCP provided accurate identification of retained bile duct stones and pancreatic duct leaks (38). Disadvantages of MRI include lack of availability when urgently needed, variation in quality among centers, and the difficulty of supervising a critically ill patient undergoing MRI.

B. Organ Failure

It has already been noted that patients with organ failure at admission have a higher mortality than those who do not have organ failure at admission (50, 61, 69, 71, 72, 83, 163). It has also been determined that for patients who develop organ failure for the first time after admission, mortality may be as high when organ failure is experienced at admission (71, 72, 83, 163). Hence, the development of organ failure, whether at admission or thereafter, implies a high mortality. The highest mortalities (>=36%) are among patients with multisystem organ failure (83) and sustained organ failure (that is, organ failure lasting more than 48 h) (72). Because it is not clear at the onset of organ failure whether it is likely to be transient or sustained, patients who demonstrate signs of organ failure in accordance with the Atlanta Symposium (Table 4) require more diligent care in a specialized unit, such as an intensive care unit or step-down unit, until there is resolution or improvement.

It is recommended that a standardized organ failure score that stratifies for severity (including need for pressor agents for shock, assisted ventilation for refractory hypoxemia, and dialysis for renal failure) be used to grade the severity of organ failure and results of therapy among institutions.

It is recommended that a standardized organ failure score that stratifies for severity (including need for pressor agents for shock, assisted ventilation for refractory hypoxemia, and dialysis for renal failure) be used to grade the severity of organ failure and results of therapy among institutions.

Level of evidence: III

Proper supportive care is invaluable in the treatment of acute pancreatitis. It is important to obtain vital signs at frequent intervals (such as every 4 h) and to obtain measurement of bedside oxygen saturation whenever vital signs are recorded. These measurements are of utmost importance during the first 24 h of admission when the care of the patient can be fragmented. For example, in many hospitals it is not unusual for patients to be maintained in an emergency ward setting for prolonged intervals of time until a hospital bed becomes available. Under these circumstances, caregivers are usually attending to obviously critically ill patients, and supervision may be less focused on patients with acute pancreatitis who appear to be resting comfortably while receiving a parenterally administered narcotic agent every 2–4 h. The clinician should realize that hypoxemia and inadequate fluid resuscitation may be unrecognized for prolonged periods of time unless vital signs, oxygen saturation, and fluid balance are carefully monitored during the first 24 h and each day thereafter as indicated. It is recommended that supplemental oxygen be administered during the first 24–48 h, especially if narcotic agents are used to control pain. Supplemental oxygen should be continued until the clinician is fully satisfied that there is no further threat of hypoxemia. Blood gas analysis should be performed when oxygen saturation is <=95% or when other clinical manifestations suggest the possibility of hypoxemia (including labored respiration or hypotension refractory to a bolus of IV fluids). There is no specific value of bedside oxygen saturation that correlates accurately with aPO2 <=60 mmHg.

Aggressive IV fluid replacement is of critical importance to counteract hypovolemia caused by third space losses, vomiting, diaphoresis, and greater vascular permeability caused by inflammatory mediators. Hypovolemia compromises the microcirculation of the pancreas and is a major contributor to the development of necrotizing pancreatitis. Intravascular volume depletion leads to hemoconcentration (hematocrit >=44), tachycardia, hypotension, scanty urine output, and prerenal azotemia. There is abundant experimental evidence that early aggressive fluid resuscitation and improved delivery of oxygen prevent or minimize pancreatic necrosis and improve survival (176–178). Although comparable studies have not been carried out in clinical practice, there is widespread acceptance of the importance of aggressive fluid resuscitation in acute pancreatitis. In one study, all patients who exhibited hemoconcentration at admission and whose hematocrit increased further after the first 24 h (as a result of inadequate fluid resuscitation) developed pancreatic necrosis (172). Clinically, the adequacy of fluid resuscitation should be monitored by vital signs, urinary output, and decrease of hematocrit at 12 and 24 h after admission (particularly for patients with hemoconcentration at admission). Monitoring of central venous pressure is generally not required.

A second important consequence of hypovolemia is intestinal ischemia. There is evidence that ischemia increases intestinal permeability to bacteria, products of bacteria, and endotoxins. Translocation of bacteria is an important cause of secondary pancreatic infection. Translocation of bacterial products and endotoxins are also potent stimulants of cytokine release and increases in nitric oxide that contribute both to ongoing pancreatic injury and also to organ failure (particularly respiratory failure) (98–100, 179).

It is important to relieve abdominal pain with a parenterally administered narcotic medication. There is no evidence to suggest an advantage of any particular type of medication. The amount of narcotic agent and the frequency of administration should be monitored closely by experienced physicians. Many hospitals have a dedicated pain service staffed by experienced physicians. When abdominal pain is particularly severe, patient-controlled analgesia can be used. It is particularly important to obtain measurements of bedside oxygen saturation frequently whenever narcotic agents are administered to relieve pain.

Prompt transfer to an intensive care unit should take place for sustained organ failure. Transfer to an intensive care unit (or possibly a step-down care unit) should be considered if there are signs that suggest that the pancreatitis is severe or is likely to be severe.

Level of evidence: III

Evidence of organ dysfunction is the most important reason for prompt transfer to an intensive care unit. In particular, sustained hypoxemia, hypotension refractory to a bolus of IV fluids, and possibly renal insufficiency that does not respond to a fluid bolus (such as a serum creatinine >2.0 mg/dL) warrant prompt transfer to an intensive care unit.

There are indications other than organ failure that should prompt consideration of transfer to an intensive care unit. One indication is the need for very aggressive fluid resuscitation to overcome hemoconcentration, especially in an older person who may have underlying cardiovascular disease such that meticulous care will be required to gauge the amount of IV fluids. Also, if a patient does not have hypoxemia but is showing signs of labored respiration, transfer should be considered to monitor pulmonary status carefully in anticipation of a need for intubation with assisted ventilation.

Additional danger signals that warrant close supervision by physicians and nursing staff in a step down unit but not necessarily urgent transfer to an intensive care unit include obesity (BMI >30), oliguria with urine output <50 mL/h, tachycardia with pulse >120 beats/min, evidence of encephalopathy, and increasing need of narcotic agents to counteract pain. The advantage of a specialized unit such as an intensive care unit is the opportunity of coordinated care under the direction of a multidisciplinary team with representation from pulmonary/critical care, gastroenterology, surgery, and radiology services. While an intensive care unit offers the best supportive treatment, including optimal fluid resuscitation, monitoring for early signs of organ dysfunction, pressor agents for sustained hypotension, intubation and assisted ventilation for respiratory failure, and renal dialysis for intractable renal failure, there is currently no specific treatment to counteract progressive organ failure.

Whenever possible, enteral feeding rather than total parenteral nutrition (TPN) is suggested for patients who require nutritional support.

Level of evidence: II

In mild pancreatitis, oral intake is usually restored within 3–7 days of hospitalization, and nutritional support is not required. The exact timing of oral nutrition and the content of oral nutrition have not as yet been subjected to randomized prospective trials. In general, oral intake of limited amounts of calories is usually initiated when abdominal pain has subsided such that parenteral narcotics are no longer required, abdominal tenderness has markedly decreased, nausea and vomiting have ceased, bowel sounds are present, and the overall assessment of the physician is that the patient has improved. It has not been ascertained whether patients recovering from mild pancreatitis can safely receive a low-fat diet at the onset of oral nutrition rather than a diet of clear or full liquids prior to a low-fat diet. The need for dietary restriction of fat at the onset of nutrition has also not been evaluated. In interstitial pancreatitis, there is no role for pancreatic enzymes when the patient resumes an oral diet. However, in severe necrotizing pancreatitis (especially when most or all of the pancreas is necrotic but also when the body of the pancreas is totally necrotic such that enzymes from a remnant viable tail of the pancreas cannot gain access to the duodenum), it is prudent to provide potent oral pancreatic enzymes and then make an evaluation later in the recovery period whether or not the patient has pancreatic steatorrhea. Also, in subtotal or total pancreatic necrosis, it is prudent to use a proton pump inhibitor on a daily basis because of the likelihood that bicarbonate secretion by the pancreas is severely diminished rendering the patient susceptible to a duodenal ulcer.

In severe pancreatitis, nutritional support should be initiated when it becomes clear that the patient will not be able to consume nourishment by mouth for several weeks. This assessment can usually be made within the first 3–4 days of illness. There is reason to believe that enteral feeding is preferable to TPN. First, there is compelling evidence that in severe acute pancreatitis gut barrier function is compromised resulting in greater intestinal permeability to bacteria (which may lead to infected necrosis) and endotoxins (which stimulate nitric oxide and cytokine production that contribute to organ failure) (98–100, 179). There is also evidence that there is a higher incidence of gastric colonization with potentially pathogenic enteric bacteria in severe disease that may also contribute to septic complications (130). Because enteral feeding stabilizes gut barrier function, there has been considerable interest in the ability of enteral feeding not only to provide appropriate nutritional support, but also to prevent systemic complications and improve morbidity and mortality. Finally, there are numerous complications associated with the use of TPN (including line sepsis) that can be avoided by use of enteral feeding.

There have been a number of randomized prospective, but not double-blind, trials that have compared enteral feeding with TPN (92, 93, 95–97). All have included relatively few patients (median 33, range 17–53) that have differed considerably in entry criteria. There have been other methodologic concerns that have been well outlined in two meta-analyses (180, 181). In general, it is reasonable to conclude that enteral feeding is safer and less expensive than TPN, but there is not yet convincing findings that there are major improvements in morbidity and mortality of acute pancreatitis.

The conclusions of the two meta-analyses, one of which reported on six studies (181) and the other on two of the six studies (180), were contradictory. In one, enteral nutrition was favored versus TPN (180); in the other, the interpretation was that there were insufficient data to provide firm conclusions about the safety and efficacy of enteral nutrition when compared to TPN (181). Additional studies will be required to determine the advantages of nasojejunal feeding versus TPN.

In one study, nasogastric feeding was found to be comparable to nasojejunal feeding in terms of safety, morbidity, and mortality (42). Additional studies will be required to determine the role of nasogastric feeding rather nasojejunal feeding for nutritional support. A major concern relates to stimulation of pancreatic secretion when feeding is introduced into the stomach or duodenum. There is evidence that intraduodenal feedings increase pancreatic enzyme synthesis (182) and secretion (183). The result may be an exacerbation of abdominal pain associated with a greater serum amylase (182).

A practical limitation of enteral feeding is that some patients do not tolerate the mechanical discomfort of a nasojejunal or nasogastric tube over extended periods of time. Thus the route of nutritional support must be tailored to the individual patient, and modified depending on the patient’s response and tolerance.

The use of prophylactic antibiotics to prevent pancreatic infection is not recommended at this time among patients with necrotizing pancreatitis.

Level of evidence: III

In recent years, there have been six randomized, prospective, but not double-blind, studies that have evaluated the role of antibiotics in preventing pancreatic infection (112– 114, 120–122). The number of patients randomized in each study was small (median 60, range 23–102). Five of these studies used IV antibiotics (112–114, 120, 122) and one used selective decontamination of the digestive tract (121). Among these studies, three (113, 120, 121) demonstrated a decrease in infected necrosis with the use of prophylactic antibiotics, and two did not (112, 122). None showed a convincing decrease in mortality. There have been two meta-analyses: one (184) evaluated three of these studies (112, 114, 120) and a fourth that was published in German; the other (185) evaluated two studies (112, 120) and the same article published in German. The conclusion reached in one (185) was that antibiotic prophylaxis significantly reduced mortality, and in the other that antibiotics reduced pancreatic infection (184).

More recently, a multicenter, double-blind, placebo-controlled study on the effectiveness of ciprofloxacin and metronidazole in reducing morbidity and mortality concluded that there was no difference in the rate of infected necrosis, systemic complications, or mortality in the two groups (111). While the numbers in this study were also relatively small (76 patients in all), this remains the only placebo-controlled, double-blind trial that has evaluated this important problem.

A recent editorial concluded that a definitive answer would require larger studies with improvement in study design pertaining to the standardization of feedings, length of antibiotic therapy, and improved stratification based on predictors of severity (186). The editorial also pointed out an increasing concern that the use of potent antibiotics may lead to a superimposed fungal infection. This risk appears to correlate with prolonged use of antibiotic therapy (62–64). While the prevalence of fungal infection among patients with necrotizing pancreatitis in recent studies has been 9% (range 8–35%) (62, 64, 65, 91, 110, 119, 187), it remains unclear whether mortality is significantly higher when there is superimposed fungal infection. Some reports indicate a greater mortality (63, 65, 91, 116), whereas others do not (62, 64, 115, 119, 187). It also remains unclear which patients should receive prophylaxis with antifungal agents.

Until further evidence is available, prophylactic antibiotics are not recommended in necrotizing pancreatitis. There is no indication for routine antibiotics in patients with interstitial pancreatitis.

It should be understood that during the first 7–10 days, patients with pancreatic necrosis may appear septic with leukocytosis, fever, and/or organ failure. During this interval, antibiotic therapy is appropriate while an evaluation for a source of infection is undertaken. Once blood and other cultures (including culture of CT-guided fine needle aspiration) are found to be negative and no source of infection is identified, our recommendation is to discontinue antibiotic therapy. It should also be understood that patients with necrotizing pancreatitis may appear clinically septic at various intervals during a prolonged hospitalization. Antibiotic therapy is appropriate for these patients while a thorough investigation for a source of infection takes place. If appropriate cultures, including imaging-guided fine needle aspiration of pancreatic necrosis, are found to be negative, antibiotic therapy should be discontinued.

CT-guided percutaneous aspiration with Gram’s stain and culture is recommended when infected necrosis is suspected. Treatment of choice in infected necrosis is surgical debridement. Alternative minimally invasive approaches may be used in selected circumstances.

Level of evidence: III

Approximately 33% of patients with necrotizing pancreatitis develop infected necrosis, usually after 10 days of illness (62, 66, 68, 83, 91, 111, 113, 117, 118, 120, 121, 147, 159, 169, 170). Most patients with infected necrosis have systemic toxicity (including fever and leukocytosis) that is either documented from the time of admission or develops at some time after admission. As many as 48% of patients with infected necrosis have persistent organ failure, either documented initially at admission or sometime after admission (83). Because the elevations in white blood count and temperature may be identical in sterile and infected necrosis (188), and because organ failure may occur in a substantial percentage of patients with both sterile and infected necrosis (45% vs 62% in one series) (83), it is impossible to distinguish these conditions clinically unless CT scan shows evidence of air bubbles in the retroperitoneum. The distinction between sterile and infected necrosis is an important concern throughout the course of necrotizing pancreatitis, but particularly during the second and third weeks, when at least one-half of cases of infected necrosis are documented (47, 117, 126, 159, 170).

The technique of percutaneous aspiration (usually by CT guidance) has proven to be safe and accurate in distinguishing sterile from infected necrosis (47, 89, 117, 120, 126, 170, 188) except possibly during the first week of illness (117). For this reason, when infected necrosis is suspected on the basis of systemic toxicity and/or organ failure, CT-guided percutaneous aspiration for Gram’s stain and culture is recommended (2–4, 6–13). The initial aspiration is usually performed during the second or third week of illness. If this aspiration is negative for bacteria or fungi, it is generally recommended that patients with persistence of systemic toxicity undergo CT-guided percutaneous aspiration every 5–7 days to identify instances of infected necrosis that develop at a later time (or conceivably may have already developed but were not diagnosed at the time of a prior aspiration).

If CT-guided percutaneous aspiration reveals the presence of Gram-negative organisms, choices for antibiotic treatment include a carbipenem, a fluoroquinolone plus metronidazole, or a third generation cephalosporin plus metronidazole pending results of culture and sensitivity. If Gram’s stain reveals the presence of Gram-positive bacteria, a reasonable choice is vancomycin until results of culture and sensitivity are determined.

The standard of care for infected pancreatic necrosis is surgical debridement unless patients are too ill to undergo surgical intervention (47, 55, 89, 111–113, 116, 120, 121, 156, 164, 169, 189). Guidelines (2, 4, 6, 7) and review articles (9–12) have generally suggested that surgery be performed promptly or have left unsaid the exact timing of surgery. However, one recent guideline specified that surgical debridement be performed for patients with infected necrosis who are “septic” (3). In addition, a review article suggested that the initial treatment for infected necrosis for patients who were clinically stable should be a 3-wk course of antibiotics prior to surgery to allow the inflammatory reaction to subside and the infected process to become better organized (10). The role of prolonged antibiotic therapy prior to surgical debridement in infected necrosis requires further study. The timing of surgical debridement (whether promptly after initiation of antibiotic therapy or after a delay of several weeks) is generally determined by the pancreatic surgeon.

The concept that infected pancreatic necrosis requires prompt surgical debridement has also been challenged by anecdotal reports of patients who have been treated by antibiotic therapy alone (131, 132) and by one report (126) of 28 patients with infected necrosis treated prospectively with antibiotics rather than urgent surgical debridement. In this report, there were two deaths among 12 patients who eventually required elective surgical intervention, and also two deaths among 16 patients who were treated with long-term antibiotic therapy without eventual surgical debridement. It is also noteworthy that in one prior study (131), two of six patients treated with prolonged antibiotics without surgery died. Additional studies will be required to determine the benefit of prolonged antibiotic therapy without surgery.

The types of surgery that have generally been recommended have included necrosectomy with closed continuous irrigation via indwelling catheters (47, 55, 89, 104, 110, 112, 119, 156, 164, 169), necrosectomy and open packing (89, 104, 116, 119, 156, 164, 169), or necrosectomy with closed drainage without irrigation (89, 106). There have not been randomized prospective trials comparing these procedures. All are generally considered to provide equal benefit in skilled surgical centers.

More recently, several additional procedures have been introduced that are less invasive than standard open surgical debridement of infected necrosis. These techniques have generally been reserved for patients with infected pancreatic necrosis who are too ill to undergo prompt surgical debridement (such as those with organ failure and/or serious comorbid disease). The first technique is minimally invasive retroperitoneal necrosectomy (55, 101, 102, 116, 156), which uses a percutaneous technique to gain access to the necrotic area, dilatation of the tract to a 30-French size, an operating nephroscope for piecemeal retrieval of solid material, irrigation with high volume lavage, and placement of catheters for long-term continuous irrigation. This technique requires general anesthesia and has not been compared in a prospective fashion to more traditional surgical debridement. Another technique is laparoscopic necrosectomy with placement of large caliber drains under direct surgical inspection. This technique presumably has less physiologic stress and may have fewer complications than open surgical debridement (190–194). This technique has not been compared in a prospective fashion to open surgical debridement.

A third technique is percutaneous catheter drainage of infected necrosis (89, 103, 124, 131, 132, 137, 169, 195). The results from this technique have been encouraging, either as a temporizing measure until the patient has stabilized sufficiently to undergo surgical necrosectomy or as definitive therapy that completely eradicates infected necrosis after several weeks or months. This technique has not been compared to surgical debridement and requires a dedicated team of skilled radiologists who are willing to place at least one or more large bore drains, be available at all times for supervision of irrigation of catheters, exchange or upsizing of catheters because of inadequate drainage of infected material, and placement of new catheters as indicated. Finally, endoscopic drainage, as applied to sterile necrosis, may occasionally be applicable to selected patients with infected necrosis, but should be approached with caution (166, 195) (see Treatment Guideline VI).

A pancreatic abscess (whether in the form of an infected peripancreatic pseudocyst or late liquefaction of an area of pancreatic necrosis) generally takes place after 5 wk in a patient who is in the recovery phase of acute pancreatitis. Mortality of a properly treated pancreatic abscess is very low. Appropriate treatments include surgical drainage, percutaneous catheter drainage, or possibly endoscopic drainage (196).

Sterile necrosis is best managed medically during the first 2–3 wk. After this interval, if abdominal pain persists and prevents oral intake, debridement should be considered. This is usually accomplished surgically, but percutaneous or endoscopic debridement is a reasonable choice in selected circumstances with the appropriate expertise. Pancreatic duct leaks and fistulas are common and may require endoscopic or surgical therapy.

Level of evidence: III

Organ failure occurs in at least 48% of patients with sterile necrosis (66, 83). Until the past 10–15 yr, surgical debridement was favored in patients with sterile necrosis with persistent organ failure with the view that removal of the necrotic material would improve chances of survival. There is now an increasing consensus that patients with sterile necrosis should continue to be managed medically during the first 2–3 wk for the following reasons. First, there have been several retrospective reports suggesting that a delay in surgical necrosectomy and at times a total avoidance of surgery results in less morbidity and mortality than early surgical debridement (55, 60, 68, 107–109, 138). Secondly, when sterile necrosis is debrided surgically, a common sequela is the development of infected necrosis and the need for additional surgery (55, 91, 112, 138, 160). In at least one report, patients so treated had a very high mortality (138). Finally, in one randomized prospective trial that compared early to late surgery in a small number of patients with sterile necrosis, there was a trend to greater mortality among those operated on within 4 days (105).

The concept of removing necrotic tissue in severe sterile necrosis in an effort to overcome organ failure may still be valid when a less invasive technique is used. Such a technique is minimally invasive retroperitoneal surgery, which has been used in sterile necrosis as well as infected necrosis (55, 102, 156). Minimally invasive surgery within the first 2–3 wk of severe sterile necrosis has not been compared prospectively with the continuation of medical therapy and thus far is an evolving technology that has been restricted to research centers.

If surgery is delayed for at least 2–3 wk, the diffuse inflammatory process in the retroperitoneum resolves considerably, and gives rise to an encapsulated structure that envelops the necrotic pancreas and peripancreatic area (166). This structure has frequently been called organized necrosis. By this time, organ failure has usually subsided, and many patients are now asymptomatic and do not require additional therapy. Those that are symptomatic generally have persistence in temperature and leukocytosis suggesting the possibility of infected necrosis, nausea or vomiting indicating compression of stomach or duodenum, or abdominal pain especially after eating as a result of greater pressure within organized necrosis caused by extravasation of fluid from residual normal pancreatic parenchyma in the remnant tail of the pancreas. Patients who remain symptomatic require decompression of organized necrosis, either by surgical, percutaneous, or endoscopic techniques. More than one technique is often necessary in an individual patient. Management of patients with pancreatic necrosis is complex and is optimally provided by a multidisciplinary team at a center with expertise in all specialties dealing with pancreatic disease.

Surgical management involves debridement of the necrotic material, evacuation of the fluid within the organized necrosis, and if a suitable capsule is present, creation of an anastomosis to the posterior wall of the stomach or to a Roux-en-Y loop of jejunum. This can be done by traditional open or by a newer laparoscopic approach. Percutaneous management of organized necrosis can be performed but requires aggressive management including placement of one or more large bore drains, aggressive lavage, and repositioning of catheters as necessary, and in some cases sinus-tract endoscopy (89, 103, 124, 131, 132, 137, 169, 195). Endoscopic debridement can be considered when the organized necrosis is firmly adherent to the wall of the stomach (or duodenum) and when endoscopic ultrasound reveals no intervening vessels (197). The technique includes puncture of the intervening gastric (or duodenal) wall with an instrument introduced through a duodenoscope or echo-endoscope, followed by endoscopic balloon dilation to enlarge the opening, retrieval of necrotic material and evacuation of fluid, often requiring direct endoscopic entry into the cavity and mechanical evacuation of solid contents, and insertion of double pigtail catheters between the stomach (or duodenum) and the cavity to maintain drainage. Repeated endoscopic debridements and/or prolonged nasocystic lavage of the cavity are often required (166, 196). While this technique appears to have a high success rate in limited reports, complications including infection and need for surgery have been noted in up to 37% of cases (166, 196). Endoscopic debridement should be performed at medical centers with extensive expertise in pancreatic therapeutic endoscopy. The major concern with any nonoperative technique is the potential for incomplete evacuation and secondary infection of residual necrotic material.

On very rare occasions, sterile pancreatic necrosis requires urgent surgical treatment even during the first several weeks of illness (2, 4). One indication is the development of an abdominal compartment syndrome. This is manifested by marked abdominal distention with increase of intra­abdominal pressure. Laparotomy with decompression can be life saving. The second is the development of severe abdominal pain suggestive of intestinal perforation or infarction caused by extension of the inflammatory exudate to either the colon or small bowel. A third indication is the development of severe bleeding from a pseudoaneurysm. An appropriate way to document the presence of a pseudoaneurysm is contrast-enhanced CT scan. If a pseudoaneurysm is discovered, the treatment of choice is angiographic insertion of a coil to embolize the pseudoaneurysm. Surgery is required if this technique fails (35, 198).

Pancreatic duct leaks and/or main pancreatic duct disconnection (“disconnected duct syndrome”) may occur in one-third or more of patients with pancreatic necrosis, either spontaneously or as a result of debridement procedures (195, 199, 200). Duct leaks may be associated with worse outcomes (199), and present substantial acute and long-term management problems including recurrent fluid collections, pancreatic ascites, pleural effusions, or pancreatic-cutaneous fistulas. Management of pancreatic duct leaks requires expertise and cooperation of endoscopy, surgery, and radiology. Medical treatment is aimed at minimizing pancreatic secretion, including nasojejunal tube feeding or total parenteral nutrition, antisecretory therapy with octreotide, or repeated or chronic drainage procedures. Duct leaks can be identified by ERCP or by MRCP with secretin stimulation (38). ERCP should be performed for patients with evidence of persistent or symptomatic pancreatic duct leaks, and at centers with experience in pancreatic endotherapy.

Endoscopic treatment of a pancreatic duct leak includes placement of a pancreatic stent, preferably bridging the leak when the main pancreatic duct is in continuity (200–202). Endoscopic pancreatic duct stent placement in the setting of organized necrosis or larger or debris-filled pseudocysts should generally be accompanied by direct drainage of the necrotic cavity by another route as already described; placement of pancreatic stents alone during acutely evolving pancreatic necrosis is considered experimental at the current time, with concern about colonization with bacteria and infection of otherwise sterile necrosis (203). Closure of duct leaks with stents is successful in about two-thirds to three-quarters of cases, depending on a number of factors including site and size of duct disruption, superinfection, downstream obstruction as a consequence of pancreatic stricture or stone, whether the leak can be bridged, and the presence of the “disconnected duct syndrome” (200–202). Closure of refractory pancreatic fistulas by injection of cyanoacrylate glue by endoscopic or percutaneous routes has been reported (196). “Disconnected duct syndrome” occurs when there is a wide gap in the main pancreatic duct, usually due to necrosis that cannot be bridged by a stent. In such cases, eventual surgical resection of the upstream remnant tail of the pancreas or internal drainage via Roux-en-Y anastamosis is often required (204).

ERCP is indicated for clearance of bile duct stones in patients with severe pancreatitis, in those with cholangitis, in those who are poor candidates for cholecystectomy, in those who are postcholecystectomy, and in those with strong evidence of persistent biliary obstruction. ERCP should be performed primarily in patients with high suspicion of bile duct stones when therapy is indicated. Routine ERCP should be avoided in patients with low to intermediate suspicion of retained bile duct stones, who are planned to have cholecystectomy. EUS or MRCP can be used to identify common bile duct stones and determine need for ERCP in clinically ambiguous situations.  

Level of evidence: I

Gallstones are suspected as a cause of acute pancreatitis when there are elevations of liver chemistries (particularly ALT >=3 times the upper limit of normal) (205, 206), when gallstones are visualized, and to a lesser extent when the common bile duct is found to be dilated on the basis of ultrasound or computerized axial tomography (39, 207). Gallstones can be documented within the common bile duct with accuracy similar to ERCP by EUS (39, 205, 207–226), with somewhat lower accuracy by MRCP (227–233), and by intraoperative cholangiography at the time of laparoscopic cholecystectomy (234–237). identification of a biliary etiology of acute pancreatitis is important because recurrent episodes will occur in one-third to two-thirds of these patients in follow-up periods of as short as 3 months unless gallstones are eliminated (238, 239).

The role of urgent ERCP and biliary sphincterotomy in gallstone pancreatitis has been the subject of three published randomized controlled studies. These studies have compared early ERCP with biliary sphincterotomy with delayed or selective ERCP (240–242). Inclusion criteria and presence of bile duct stones vary considerably among these trials. Two of the trials (240, 242), but not the third (241), showed a significant benefit for early sphincterotomy and stone extraction, primarily in patients with severe acute pancreatitis and those with ascending cholangitis. Meta-analysis of randomized controlled trials including an additional unpublished abstract suggested that early intervention with ERCP in acute biliary pancreatitis resulted in a significant reduction in complication rate and nonsignificant reduction in mortality (243). Subsequent meta-analysis limited to the three published trials concluded that endoscopic sphincterotomy significantly reduced complications in severe but not mild gallstone-associated pancreatitis but did not reduce mortality in mild or severe disease (244). There is insufficient evidence to draw any conclusions about hospital stay and cost. One interpretation is that there is a strong correlation between persistent biliary obstruction and more severe disease (245). Hence, common bile duct stones were seen more often in the two positive studies (240, 242) than in the negative study (241). Retained common bile duct stones could lead to organ failure by causing ascending cholangitis or by causing intensification of the pancreatitis if a gallstone is blocking the pancreatic duct. Overall, these studies suggest that ERCP and biliary sphincterotomy is indicated (preferably within 24 h of admission) for patients with severe biliary pancreatitis with retained common bile duct stones and for those with cholangitis.

In the majority of patients with mild biliary pancreatitis, bile duct stones have passed by the time cholangiography is considered, such that routine ERCP prior to cholecystectomy is unnecessary and adds avoidable risk (246–250). For example, in a randomized trial in patients with mild gallstone pancreatitis with high suspicion of persisting common bile duct stones (elevated serum bilirubin, dilated common bile duct, or persistent hyperamylasemia) but without cholangitis, selective postoperative ERCP and CBD stone extraction was necessary in only approximately one in four such patients, and was associated with a shorter hospital stay, less cost, no increase in combined treatment failure rate, and significant reduction in ERCP use compared with routine preoperative ERCP (251). Thus, patients with resolving mild acute pancreatitis can undergo laparoscopic cholecystectomy with intraoperative cholangiography, and any remaining bile duct stones can be dealt with by postoperative or intraoperative ERCP, or by laparoscopic or open common bile duct exploration, depending on local expertise and access to referral centers in cases of unsuccessful ERCP.

During the course of biliary pancreatitis, progressive increases in serum bilirubin and other liver function tests and persistent dilatation of the common bile duct are strongly suggestive of common bile duct obstruction by gallstones (251–254). In this circumstance, it is reasonable to proceed directly to ERCP. In clinical practice, if there is intermediate concern regarding the possibility of a retained common bile duct stone, and the patient is not felt to be a good candidate for cholecystectomy with cholangiogram within the near future, EUS or MRCP can be performed to assess for presence of bile duct stones and determine need for ERCP. EUS is generally considered to be the most accurate method to detect bile duct stones; sensitivity of MRCP for small bile duct stones is lower, especially for those that are impacted at the ampulla (229, 230). EUS or MRCP are also useful to determine need for ERCP in patients who are pregnant, or in whom ERCP would be high risk or technically difficult due to reasons such as severe coagulopathy or altered surgical anatomy. In critically ill patients, EUS can be performed at the bedside. The limitations of this technique include availability and operator-dependency. The limitations of MRCP include variable quality, difficulty in performing this procedure in critically ill or uncooperative patients, and contraindications such as presence of pacemakers or cerebral aneurysm clips.

Biliary sphincterotomy rather than cholecystectomy may be appropriate for proven mild biliary pancreatitis, especially in elderly patients who are poor candidates for surgery because of severe medical comorbidity, patients in whom cholecystectomy must be delayed because of local or systemic complications of pancreatitis, or because of pregnancy (255– 258). The role of biliary sphincterotomy when biliary pancreatitis is strongly suspected but not proven has not been fully characterized. Some studies have suggested the effectiveness of endoscopic biliary sphincterotomy in these circumstances in preventing further episodes of acute biliary pancreatitis. These uncontrolled case series mostly suggest a reduction in the frequency of attacks of pancreatitis, although recurrent bile duct stones or acute cholecystitis may still be a problem in the future (255–264). Before considering an empiric biliary sphincterotomy for recurrent pancreatitis with or without abnormal liver function tests, the clinician must be aware of the possibility of an alternative etiology, such as sphincter of Oddi dysfunction, especially in women, young or middle-aged patients, and patients who are postcholecystectomy, or do not have clearly documented gallstone disease. Empiric biliary sphincterotomy and even diagnostic ERCP in patients with recurrent pancreatitis, and especially those with suspected sphincter of Oddi dysfunction, are associated with significantly greater risk of post-ERCP pancreatitis, and are less likely to be of therapeutic benefit than for patients with biliary pancreatitis (246–250). ERCP in such patients may be best approached in the context of a more comprehensive evaluation using other imaging techniques including MRCP and EUS, and risk of post-ERCP pancreatitis may be reduced by placement of a temporary small-caliber pancreatic stent (207, 265).

A summary of the recommendations for use of ERCP, EUS, and MRCP in patients with acute biliary pancreatitis is shown in Table 8.

Table 8. Suggested Indications for ERCP, EUS, and MRCP in Patients with Acute Biliary Pancreatitis

Urgent ERCP (Preferably Within 24 h of Admission):    Severe pancreatitis (organ failure)    Suspicion of cholangitis Elective ERCP with Sphincterotomy:    Imaging study demonstrating persistent common bile duct stone    Evolving evidence of biliary obstruction (such as rising liver chemistries)    Poor surgical candidate for laparoscopic cholecystectomy    Strong suspicion of bile duct stones postcholecystectomy Endoscopic Ultrasound or MRCP to Determine Need for ERCP:    Clinical course not improving sufficiently to allow timely laparoscopic cholecystectomy and intraoperative cholangiogram    Pregnant patient    High-risk or difficult ERCP (e.g., coagulopathy, altered surgical anatomy)    Uncertainty regarding biliary etiology of pancreatitis

The diagnosis of acute pancreatitis requires two of the following three features: 1) characteristic abdominal pain, 2) serum amylase and/or lipase >=3 times the upper limit of normal, and 3) characteristic findings of acute pancreatitis on CT scan.

Risk factors of severity of acute pancreatitis at admission include older age, obesity, and organ failure. Tests at admission that are also helpful in distinguishing mild from severe acute pancreatitis include APACHE-II score >=8 and serum hematocrit (a value <44 strongly suggests mild acute pancreatitis). An APACHE-II score that continues to increase for the first 48 h strongly suggests the development of severe acute pancreatitis. A CRP >150 mg/L within the first 72 h strongly correlates with the presence of pancreatic necrosis.

The two most important markers of severity in acute pancreatitis are organ failure (particularly multisystem organ failure) and pancreatic necrosis. Contrast-enhanced CT scan is the best available test to distinguish interstitial from necrotizing pancreatitis, particularly after 2–3 days of illness. Mortality of sustained multisystem organ failure in association with necrotizing pancreatitis is generally >36%.

Supportive care includes vigorous fluid resuscitation that can be monitored in a variety of ways including a progressive decrease in serum hematocrit at 12 and 24 h. Supplemental oxygen should be administered during the first 24–48 h, bedside oxygen saturation monitored at frequent intervals, and blood gases obtained when clinically indicated, particularly when oxygen saturation is <=95%.

Transfer to an intensive care unit is recommended if there is sustained organ failure or if there are other indications that the pancreatitis is severe including oliguria, persistent tachycardia, and labored respiration.

Patients who are unlikely to resume oral nutrition within 5 days because of sustained organ failure or other indications require nutritional support. Nutiritional support can be provided by TPN or by enteral feeding. There appear to be some advantages to enteral feeding.

Patients with acute pancreatitis caused by gallstones, who are strongly suspected of harboring common bile duct stones on the basis of organ failure or other signs of severe systemic toxicity (marked leukocytosis and/or fever), require evaluation for the presence of choledocholithiasis, preferably within the first 24 h of admission. ERCP with endosocopic biliary sphincterotomy and stone removal are indicated for patients with cholangitis, severe acute pancreatitis, or high clinical suspicion or definitive demonstration of persistent bile duct stones by other imaging techniques. Expectant management with interval cholecystectomy including intraoperative cholangiogram is appropriate for most patients with mild to moderate pancreatitis and an improving clinical course. Routine precholecystectomy ERCP is not recommended in patients with biliary pancreatitis. In ambiguous cases, where available, evaluation for bile duct stones can be performed by endoscopic ultrasound or MRCP.

The use of prophylactic antibiotics in necrotizing pancreatitis is not recommended in view of a recent prospective randomized double-blind trial that showed no benefit and in view of the concern that the prolonged use of potent antibiotic agents may lead to the emergence of resistant Gram-positive organisms and fungal infections in the necrotic pancreas. It is reasonable to administer appropriate antibiotics in necrotizing pancreatitis associated with fever, leukocytosis, and/or organ failure while appropriate cultures (including culture of CT-guided percutaneous aspiration of the pancreas) are obtained. Antibiotics should then be discontinued if no source of infection is found.

CT-guided percutaneous aspiration with Gram’s stain and culture is recommended when infected pancreatic necrosis is suspected. Treatment of choice of infected necrosis is surgical debridement. The timing of surgery is left to the discretion of the pancreatic surgeon. Patients who are medically unfit for open surgical debridement can be treated with less invasive surgical techniques, radiologic techniques, and, at times, endoscopic techniques in medical centers with these capabilities.

Treatment of sterile pancreatic necrosis is generally medical during the first several weeks even in the presence of multisystem organ failure. Eventually, after the acute inflammatory process has subsided and coalesced into an encapsulated structure that is frequently called organized necrosis, debridement may be required for intractable abdominal pain, intractable nausea or vomiting caused by extrinsic compression of stomach or duodenum, or systemic toxicity (fever and/or intractable malaise). Debridement can be performed by surgical, endoscopic, or radiologic techniques.

ACG Practice Parameters Committee

Committee Chair: Ronnie Fass, M.D., F.A.C.G.
Darren S. Baroni, M.D.
Ece A. Mutlu, M.D.
David E. Bernstein, M.D., F.A.C.G.
Henry P. Parkman, M.D., F.A.C.G.
Adil E. Bharucha, M.D.
Charlene Prather, M.D.
William R. Brugge, M.D., F.A.C.G.
Daniel S. Pratt, M.D.
Lin Chang, M.D.
Albert C. Roach, PharmD, F.A.C.G.
William Chey, M.D., F.A.C.G.
Richard E. Sampliner, M.D.
Matthew E. Cohen, M.D.
Subbaramiah Sridhar, M.D.
John T. Cunningham, M.D., F.A.C.G.
Nimish Vakil, M.D.
Steven A. Edmundowicz, M.D.
Miguel A. Valdovinos, M.D.
John M. Inadomi, M.D., F.A.C.G.
Benjamin C.Y. Wong, M.D., F.A.C.G.
Timothy R. Koch, M.D., F.A.C.G.
Alvin M. Zfass, M.D., M.A.C.G.

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Asif Khalid, M.D., F.A.C.G.,¹ and William Brugge, M.D., F.A.C.G.²

¹VA Pittsburgh Health Care System & Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania; and ²GI Unit, Massachusetts General Hospital, Boston, Massachusetts

The diagnosis and management of pancreatic cystic lesions is a common problem. At least 1% of hospitalized patients at major medical centers will have a pancreatic cystic lesion on cross sectional imaging. Up to a quarter of all pancreata examined in an autopsy series contained a pancreatic cyst, 16% of which were lined by an “atypical” epithelium and 3% of which had progressed to carcinoma-in-situ (high grade dysplasia). in the past, it was thought these cystic lesions were benign, but increasing evidence points to the cystic lesions as being the origin of some pancreatic malignancies.

The most important clinical tools in the diagnosis and management of pancreatic cystic lesions are cross sectional imaging, endoscopic ultrasound, and cyst fluid analysis. The most important differential diagnosis is distinguishing mucinous (pre-malignant) and non-mucinous cystic lesions. The findings of a macrocystic lesion containing viscous fluid rich in CEA are supportive of a diagnosis of a mucinous lesion. Serous lesion are the most common non-mucinous cyst and are characterized by a microcystic morphology, non-viscous fluid and a low concentration of CEA in the cyst fluid.

The following document includes a description of neoplastic pancreatic cysts, a critical review of relevant diagnostic tests, and a discussion of treatment options. We have proposed a set of guidelines for the diagnonis and management of patients with neoplastic pancreatic cysts. The guidelines are based on published data backed by an analysis of the quality of the data and are designed to address the most frequent and important clinical scenarios. In addition to providing a summary of the diagnostic data, we offer diagnostic and management suggestions based on 13 common clinical problems. Although the field is rapidly evolving, a set of core principles is provided based on a balance between the risk of malignancy and the benefit of pancreatic resection.

Am J Gastroenterol 2007;102:2339–2349
Received November 28, 2006; accepted June 21, 2007.

Reprint requests and correspondence: William Brugge, M.D., F.A.C.G., GI Unit, Massachusetts General Hospital, Boston, Massachusetts.

Pancreatic cysts are receiving increased attention due to widespread use of high-resolution noninvasive abdominal imaging. While there has been increased awareness of these lesions, their natural history and optimal management is unclear. To address some of these issues, guidelines for the diagnosis and management of pancreatic cysts have been developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. These guidelines have been developed to assist clinicians in managing patients with pancreatic cysts. Alternative strategies to those described may be best for select patients, based on their unique circumstances.

The following guidelines are based on a critical review of the world’s available scientific literature identified in a PubMed search on February 1, 2006. These guidelines are intended to apply to adult and not pediatric patients. They are focused on differentiating (a) premalignant and malignant pancreatic cysts, and (b) pancreatic cysts with malignant potential from those without.

Most pancreatic cysts are detected incidentally when non­invasive abdominal imaging is performed for unrelated indications. At least 1% of inpatients in a major medical center at any one time are likely to have a pancreatic cyst detectable by CT or MRI, of which more than half are neoplastic (1). Up to a quarter of all pancreata examined in an autopsy series contained a pancreatic cyst, 16% of which were lined by an “atypical” epithelium and 3% of which had progressed to carcinoma in situ (high-grade dysplasia) (2).

Among pancreatic cysts, pseudocysts are most likely to be symptomatic, while intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) are the most prevalent (and usually asymptomatic) pancreatic cysts (3).

A patient with a pancreatic cyst strongly suspected to be benign without malignant potential may be managed expectantly. A patient with a pancreatic cyst strongly suspected to be malignant may be managed surgically. A patient with a pancreatic cyst strongly suspected to be benign with malignant potential (precancerous) may be managed expectantly or surgically. Emerging data support observation as the preferred approach to managing patients with small incidental cysts (4), but comprehensive data are lacking on the natural history of such lesions, which prevents confident calculations of the risk and benefit of competing management strategies.

The following document includes a description of neoplastic pancreatic cysts, a critical review of relevant diagnostic tests, and a discussion of treatment options, followed by guidelines for the diagnosis and management of patients with neoplastic pancreatic cysts. A discussion of the management of pancreatic pseudocysts is beyond the scope of this guideline, but is included in the ACG’s guideline on the management of acute pancreatitis.

Data regarding the natural history and clinical impact of diagnostic and therapeutic interventions in patients with pancreatic cysts remain limited. Therefore, preferred strategies for evaluating and managing patients with pancreatic cysts remain in evolution. These guidelines are based on published data and an analysis of its quality, plus expert opinion and the authors’ experience when data were lacking. They are designed to address in a practical fashion the most frequent and most important clinical scenarios encountered when caring for patients with pancreatic cysts.

The WHO histological classification of neoplastic pancreatic cysts is provided in Table 1. Table 2 summarizes the salient features of these lesions followed by a discussion of individual categories.

Table 1. WHO Histological Classification of Neoplastic Pancreatic Cysts

Serous cystic tumors    Serous cystadenoma    Serous cystadenocarcinoma Mucinous cystic tumors    Mucinous cystadenoma    Mucinous cystadenoma with moderate dysplasia    Mucinous cystadenocarcinoma       Noninfiltrating       Infiltrating    Intraductal papillary mucinous adenoma    Intraductal papillary mucinous neoplasm with moderate dysplasia    Intraductal papillary mucinous carcinoma       Noninfiltrating       Infiltrating Solid pseudopapillary tumors

Adapted from Kloppel G SE, Longnecker DS, Capella C, Sobin LH. Histological typing of tumors of the exocrine pancreas. World Health Organization International Histological Classification of Tumors. Berlin: Springer-Verlag, 1996.

 

Table 2. Key Features of Neoplastic Pancreatic Cysts

	Intraductal Papillary Mucinous Neoplasms	Mucinous Cystic Neoplasms	Serous Cystadenomas	Solid and Pseudopapillary Tumors
Sex distribution	M = F	F > M	F > M	F > M
Historical age of presentation	7th decade	5th to 7th decade	7th decade	2nd and 3rd decade
Clinical presentation	Incidental, abdominal pain, pancreatitis, symptoms or signs of malabsorption	Incidental, abdominal pain, or palpable mass	Usually incidental, rarely abdominal pain or palpable mass	Usually incidental, rarely abdominal pain or palpable mass
Morphology/imaging characteristics	Dilated main pancreatic duct or pancreatic duct branches; solid component, if present may suggest malignancy	Unilocular cyst. Septations and wall calcifications may be present. Solid component, if present may suggest malignancy	Microcystic/honeycomb appearance typical. Oligocystic appearance less common	Solid and cystic mass
Fluid characteristics	Usually thick	Usually viscous	Thin, if sufficient fluid aspirated from a dominant cyst	Often bloody
Cytology	Stains positive for mucin. Columnar cells with variable atypia; yield <50%	Stains positive for mucin. Columnar cells with variable atypia; yield <50%	Cuboidal cells stain positive for glycogen; yield <50%	Characteristic branching papillae with myxoid stroma; yield very high from solid component.
Accuracy of cyst CEA (ng/mL)	>192, 0.79 area under curve on receiver operator characteristic*<5, 67%
Malignant potential	Yes	Yes	No	Yes
Treatment	Resection for main duct IPMN and resection or surveillance for branch duct IPMN depending upon the clinical situation	Resection is generally recommended in appropriate candidates	No surveillance or treatment unless symptomatic	Resection
*The performance characteristics of fluid CEA level in IPMN and mucinous cystadenoma have not been studied separately. M = male; F = female; CEA = carcinoembryonic antigen.

Intraductal papillary mucinous neoplasm (IPMN) is an intraductal papillary neoplasm affecting men and women equally, which exhibits variable cellular atypia, secretes mucin, and causes dilation of the pancreatic ducts (5). IPMN is usually located in the head of the pancreas, may involve the main pancreatic duct or side branches of the pancreatic duct, is often multifocal or diffuse, and can extend microscopically from the recognized lesion. IPMN is classified histologically as adenoma, borderline, or carcinoma. The natural history of IPMN is not clear, but an interval of 5 yr has been observed between adenoma and transformation to invasive carcinoma (6). Historically, IPMN was usually not diagnosed until the seventh decade of life (6), but is now being discovered at younger ages. The risk of malignancy being present at the time of diagnosis increases with older age, presence of symptoms, involvement of the main pancreatic duct, dilation of the main pancreatic duct over 10 mm, the presence of mural nodules, and size over 3 cm for side-branch IPMN. However, a measurable risk of malignant IPMN exists even in the absence of symptoms (3). Risk of recurrence following resection with curative intent is high in IPMN with invasive cancer (60–70%) but low in noninvasive disease (<10%) (7).

Historically, IPMN was diagnosed by endoscopic retrograde pancreatography (ERP). However, contrast-enhanced multidetector thin-cut computed tomography (CT) is the diagnostic test of choice (Fig. 1). When uncertainty persists, EUS may discriminate between diagnostic possibilities. EUS can identify focal or diffuse dilation of the pancreatic duct in the absence of chronic pancreatitis or obstructing mass, or multiple dilated pancreatic duct side branches (referred to as a “cluster of grapes”). Endoscopic visualization of mucus extruding from a patulous ampulla (referred to as a “fish mouth”) supports the diagnosis. Compared with abdominal ultrasonography, CT, and ERP, EUS provides higher resolution imaging of the pancreatic duct and is more sensitive in detecting mural nodules (8). In addition, cytological analysis, determination of tumor marker concentrations, and molecular diagnostic evaluations from samples obtained by EUS-guided fine-needle aspiration (EUS-FNA) may further guide management (9, 10). In IPMN of the main pancreatic duct, intraductal ultrasound can help to determine its extent and identify parenchymal invasion. Pancreatoscopy, like ERCP, can distinguish main duct from side-branch IPMN, but in addition may identify papillary projections associated with malignant transformation, and determine the longitudinal extent of tumor (11). Secretin-stimulated magnetic resonance cholangiopancreatogram (MRCP) also provides excellent imaging of the pancreatic duct, including identification of communication between a cystic lesion and the main pancreatic duct, e.g., in the case of branch-duct IPMN (12).

Figure 1. Contrast-enhanced CT scan shows a markedly dilated main pancreatic duct with pancreatic parenchymal atrophy. Multiple areas of soft tissue growth are seen within the pancreatic duct consistent with multifocal cancer arising in main duct IPMN.

Given the challenges of excluding malignancy with confidence, combined with uncertainty regarding the natural history of IPMN, resection is recommended for patients considered to be at acceptable risk for perioperative complications, especially in the main-duct variety. Firm recommendations as to the management of branch-duct IPMN cannot be made at this time and the evidence is still evolving. The approach will probably encompass a combination of surveillance and resection depending upon factors like the presence of symptoms, cyst distribution and size, and patient-related factors. IPMN can extend microscopically from the recognized lesion, so submission of frozen sections from the resection margin is appropriate when anticipating partial pancreatectomy.

Like IPMN, mucinous cystic neoplasm (MCN) is a neoplasm which exhibits variable cellular atypia and secretes mucin (13, 14). In contrast to IPMN, MCN does not extend along the pancreatic ducts, demonstrates ovarian-like stroma (15), typically involves the tail or body of the pancreas, and affects women more often than men. MCN is classified as either mucinous cystadenoma or mucinous cystadenocarcinoma. Historically, MCN was discovered in the fifth to seventh decades of life, often in the evaluation of symptoms which heralded malignancy. As with IPMN, the natural history of MCN is not clear. However, the risk of malignancy appears to be less than that associated with IPMN of the main pancreatic duct (15).

Contrast-enhanced multidetector thin-cut CT is the test of choice to diagnose MCN, followed by EUS for further characterization or fluid analysis if the diagnosis remains in doubt. In contrast to IPMN, MCN do not communicate with the pancreatic duct. This feature may be useful in differentiating these lesions, e.g., on ERCP or less invasively by secretin-stimulated MRCP. MCN appear as septated cysts with a wall (16). The wall lining may contain eccentric calcifications in about 15% of patients (13) (Fig. 2). Malignant transformation is suggested by greater size (>2 cm), cyst wall irregularity and thickening, intracystic solid regions, an adjacent solid mass, and perhaps calcification of the cyst wall (14, 16).

Figure 2. Contrast-enhanced CT scan of the abdomen reveals a hypodense well-circumscribed lesion in the body of the pancreas. Internal septations are seen as are calcifications in the wall-suggestive of a mucinous cystic neoplasm.

EUS-FNA can be used to aspirate cyst fluid, to support the diagnosis of MCN (or IPMN, which possesses indistinguishable cyst fluid characteristics). CEA concentration in cyst fluid is elevated above 200 in approximately 80% of MCN (9), and cytological analysis reveals cuboidal or columnar epithelial cells in approximately 50% (17). Detection of malignant cells is diagnostic of a mucinous cystadenocarcinoma or malignant IPMN. Unfortunately, the sensitivity of cytology is suboptimal (<50%) (17).

Resection is recommended for patients with MCN considered to be at acceptable risk for perioperative complications, for the same reasons used to support this recommendation in IPMN. The prognosis is good in those that have not undergone malignant degeneration (18, 19).

Serous cystadenomas (SCA) are considered to be benign neoplasms originating from centro-acinar cells. SCA are usually comprised of multiple small fluid-filled cysts, and can arise in any region of the pancreas. Historically, SCA was diagnosed in women during their seventh decade of life, in evaluation of symptoms caused by continued enlargement of the neoplasm (20–22). Small, incidental SCA are now being identified more frequently. Occasionally, SCA manifests as an oligocystic lesion, which can be difficult to distinguish from MCN if it appears in the pancreas tail or body (23–25). On imaging, SCA appears as a focal, well-demarcated lesion. A central scar or “sunburst” calcification will be visible in 20% of SCA. EUS often demonstrates a honeycomb appearance (23) (Fig. 3). FNA of fluid within SCA microcysts can be challenging. When obtained, the fluid is usually thin, and cytological analysis reveals cuboidal glycogen-staining cells in 50% of cases (26–28). Given their benign nature, SCA should be resected only if symptomatic, or if the diagnosis remains in doubt.

Figure 3. Convex linear array endoscopic ultrasound exam reveals a lobular multimacro and microcystic lesion in the pancreas with posterior acoustic enhancement reminiscent of a honeycomb. This imaging is classic for a serous cystadenoma/microcystic adenoma.

Solid pseudopapillary tumors (SPT) of the pancreas are rare neoplasms with malignant potential diagnosed in young women. Historically, SPT were diagnosed in the evaluation of signs or symptoms of an abdominal mass, as the growth rate of SPT can be dramatic (29, 30). SPT often contain both solid and cystic components and occasionally calcifications (31, 32). Though not yet reported, SPT are now being discovered with increasing frequency at an asymptomatic stage. EUS-guided FNA cytological analysis reveals characteristic branching papillae with myxoid stroma, best seen in cell-block material (33). When identified, regardless of the stage, resection should be considered. Malignant SPT can be cured when completely excised, and prolonged survival can be seen even in the presence of metastatic disease (29, 30).

Lymphoepithelial cysts (LEC) are rare cystic neoplasms lined by mature keratinizing squamous epithelium surrounded by a distinct layer of lymphoid tissue (34). LEC can be present in all age groups and are usually asymptomatic. Unlike the previously described cystic neoplasms, LEC occur most often in men (35). LEC display characteristic intracystic heterogeneous hyperechogenicity on ultrasound, hyperdensity on precontrast CT, and granular hypointensity on T2-weighted MRI due to abundant intracystic keratinaceous material, which can usually be differentiating from other pancreatic cysts (36). If the diagnosis remains in doubt, FNA will usually reveal characteristic epithelial cells and small, mature lymphocytes in a background of keratinaceous debris, anucleate squamous cells, and multinucleated histiocytes (35).

Non-neoplastic pancreatic cystic lesions are reactive lesions without malignant potential, including pseudocysts and inclusion cysts. Diagnostic efforts focus on distinguishing these pancreatic lesions without malignant potential from those that with malignant potential.

Varying degrees of cystic degeneration may be seen in solid pancreatic tumors including islet cell tumors, ductal carcinoma, and acinar cell cancer. Cystic islet cell tumors may be indistinguishable from a MCN or side-branch IPMN. In the authors’ experience EUS-FNA cytology evaluation is almost always diagnostic in cystic islet cell tumors; however, this has not been rigorously studied.

Imaging (Level 2–3)

The data available on the accuracy of preoperative imaging of pancreatic cysts is not encouraging especially when it comes to differentiating the various types of pancreatic cystic lesions at an incidental stage. This is primarily due to the morphologic overlap between the early MCN and IPMN, and benign neoplastic cysts and reactive cystic lesions (37). However, certain imaging characteristics have very good predictive value, e.g., an asymptomatic microcystic lesion with honeycomb appearance and a central scar on cross-sectional imaging is very predictive of an SCA. Likewise, the infrequently seen peripheral eggshell calcification on CT is specific to a mucinous cystic neoplasm and may predict malignancy (38). On the other hand a unilocular cyst that communicates with the pancreatic duct and is found in the setting of acute pancreatitis may represent a pseudocyst or an IPMN.

A CT scan typically identifies the pancreatic cyst or is the first test ordered to evaluate it. The primary advantage of cross-sectional imaging such as CT scan and magnetic resonance (MR) of pancreatic cystic lesions over endoscopic techniques lies in determining the extent of malignant spread (39, 40). Features predictive of invasive carcinoma in IPMN by CT and other imaging studies include involvement of the main pancreatic duct, marked dilatation of the main pancreatic duct, diffuse or multifocal involvement, the presence of a large mural nodule or solid mass, large size of the mass, and obstruction of the common bile duct. The presence of intracystic mural nodules >3 mm in size on CT also suggests malignancy (39–41). MRP is more sensitive than ERCP in differentiating mural nodules from mucin globules (40–44). It also consistently demonstrates the internal architecture of the main duct and the extent of IPMN better than ERP.

ERP affords inspection of the duodenal papillae, pancreatography, and pancreatoscopy in the evaluation of pancreatic cysts. In IPMN, mucus is seen extruding from a patulous ampulla in 20–50% of patients and may be seen more frequently in malignant disease (45–48). A variety of findings are seen during pancreatography, unfortunately, most of which are nonspecific. Conflicting values are reported for the accuracy of tissue sampling (mucus aspiration, brush cytology, and biopsies) during ERP in IPMN (45, 48, 49). Pancreatoscopy in IPMN may be facilitated by an enlarged papilla and provides an assessment of disease extent and direct biopsies. The combination of pancreatoscopy and intraductal US in IPMN may detect malignancy with high accuracy (11).

The role of EUS lies in improved visualization of the cyst or pancreatic duct wall (looking for a small mass or mural nodules), or FNA.

A variety of studies have assessed the role of EUS imaging in discriminating benign pancreatic cysts from the mucinous varieties. For example, pseudocysts are more likely to be unilocular and exhibit internal echogenic debris and surrounding pancreatic parenchymal abnormalities suggestive of pancreatitis, whereas cyst septations, solid component, and mural nodules occur more frequently in cystic tumors (50). SCA on the other hand are more likely to have a honeycomb appearance or multiple small (<3 mm) cysts (50), although an oligocystic variety with fewer and larger cysts is less frequently encountered. Predicting malignancy in MCN and IPMN based on EUS imaging, however, remains impossible in the absence of advanced disease (9). EUS is also confounded by the apparent subjectivity of its interpretation. For example, a study evaluating the degree of agreement among experienced endosonographers for EUS diagnosis of neoplastic versus non-neoplastic pancreatic cystic lesions and the specific type of cystic lesion found fair interobserver agreement between endosonographers for diagnosis of SCA (kappa = 0.46) and presence or absence of a solid component (kappa = 0.43). Agreement among experienced endosonographers for diagnosis of neoplastic versus non-neoplastic, specific cyst type, and other EUS characteristics (presence of septations, parenchymal and ductal abnormalities, etc.) was poor (51). In summary, while EUS findings may add some diagnostic information, its greatest utility in the evaluation of pancreatic cystic lesions may be from data obtained via FNA.

One study (52) compared the accuracy of preoperative CT (25 patients), ERP (29 patients), and EUS (21 patients) to detect malignancy in 47 patients who were ultimately found to have IPMN and MCN (43% of whom had invasive carcinoma and 21% with carcinoma in situ). The overall accuracy of CT, ERP, and EUS in distinguishing between invasive and noninvasive tumors was less than 80% for each of the imaging studies evaluated. Differentiating cysts with malignant potential from benign cystic lesions by imaging techniques is suboptimal.

Table 3. Ratings of Evidence Used for This Guideline

Ratings of the Quality of Evidence
Level 1	Strong evidence from at least one published systematic review of multiple well-designed randomized controlled trials
Level 2	Strong evidence from at least one published well-designed randomized controlled trial
Level 3	Evidence from published well-designed single group, cohort, time series or matched case-controlled studies
Level 4	Evidence from well-designed nonexperimental studies from more than one center or research group or opinion of respected authorities, based on clinical evidence, descriptive studies, or reports of expert consensus committees

EUS-FNA (Level 2)

EUS-FNA of pancreatic cysts is performed using a method similar to that used for solid masses. One distinction, however, is that usually a single pass is performed with a needle to aspirate fluid and attempt to sample the cyst wall. A variety of needles are available and their use should be tailored to the lesion and clinical situation. Principles of FNA for suspected malignant cytology evaluation are similar to other cancers; targeting the highest stage lesion, e.g., liver metastasis, nonregional and regional lymph nodes near the gastroduodenal lumen, solid component/mural nodule, and fluid aspiration, in that order. In addition, fluid aspiration for tumor markers, chemical analysis, and molecular analysis, may be performed. Typically a single pass is made into the cyst cavity with intent to aspirate all the fluid for analysis; this is often not feasible if the fluid is thick. It is accepted practice to administer IV antibiotics (e.g., ciprofloxacin 400 mg) prior to cyst aspiration followed by oral antibiotics for 3 days to prevent infection. Controlled studies to support this practice are lacking. Subjecting pseudocysts with internal debris, organized necrosis, etc., to FNA in particular should be avoided to prevent introducing an infection.

Cytology (Level 2)

A number of studies have reported varying accuracy of pancreatic cyst EUS-FNA cytology, but the overall accuracy is around 50% (9, 26, 45, 53–55). The yield in smaller pancreatic cysts may be lower still (26). Findings suggestive of a pseudocyst include macrophages, histiocytes, and neutrophils. The presence of mucin indicates a mucinous pancreatic cyst and is seen in around a third of cases (26, 55). FNA from a minority of SCA may reveal the presence of glycogen-rich cuboidal cells (26). The cytologic diagnosis of a malignant cyst has a high specificity (approaching 100%), although the sensitivity is low (26, 45, 54, 55). The role of trucut biopsy to obtain a larger sample of the cyst wall has been evaluated in a small sample of patients and appears to be safe (56). Its impact on the diagnostic yield cannot be assessed at this time and requires further studies.

Chemistries and Tumor Marker Analysis (Level 2)

Cyst fluid may be analyzed for levels of pancreatic enzymes and tumor marker analysis. Cyst fluid amylase, CEA, and CA 19-9 have been reported in a number of studies and the results of a recent meta-analysis have been summarized in Table 4. A broad range of sensitivities and specificities has been reported for these markers, making interpretation difficult. However, using certain cutoffs provides a high specificity, e.g., an amylase <250 and CEA >800 essentially excludes a pseudocyst. Likewise, a CEA <5 and CA19-9 <37 virtually excludes a mucinous cyst (Table 5) (17, 26, 57).

A recent prospective, multicenter study of 112 cysts diagnosed by surgical resection or positive FNA found a CEA level of 192 ng/mL to be accurate in differentiating mucinous from nonmucinous pancreatic cysts (sensitivity 75% and specificity 84%) (9). This finding is also supported by a recent meta-analysis (17) and a cost-benefit analysis (58). The CEA level is not predictive of malignancy, however. The accuracy of fluid CEA level in predicting mucinous cystadenomas and IPMN separately instead of as a group (bunched together) has not been rigorously studied, and may be divergent.

The threshold values identified as possessing the best discrimination between types of lesions may not be applicable to other institutions based on unappreciated differences between patient populations, methods of sampling, or techniques used to assay the samples.

Table 4. Pancreatic Cyst Fluid Tumor Markers

	Cyst Types	Cytology	CEA	CA 19-9	CA 72-4	CA 15-3	Mucin Antigens
Hammel 1995 (57), prospective, non-EUS aspirate	50; 12 mucinous cysts, 7 SCA, 31 pseudocysts		<5 ng/mL, 100% sensitive and 86% specific for SCA	>50,000 U/mL, 75% sensitive and 90% specific for mucinous cysts
Sperti 1996 (59), retrospective, non-EUS aspirate	48; 14 mucinous cysts, 7 SCA, 21 pseudocysts, 6 ductal cancers	48% sensitive and 100% specific			80% sensitive and 95% specific for mucinous cysts
Hammel 1997 (60), retrospective, non-EUS aspirate	65; 9 MCA, 8 MCAC, 6 IPMN, 12 SCA, 30 pseudocysts		>20 ng/mL, 82% sensitive and 100% specific for differentiating mucinous cysts from SCA >300 ng/mL, 56% sensitive and 100% specific for differentiating mucinous cysts from pseudocysts				Gastric mucins >50 U M1/mL, 78% sensitive and 100% specific for differentiating mucinous cysts from SCA > 1,200 U M1/mL, 30% sensitive and 100% specific for differentiating mucinous cysts from pseudocysts
Sperti 1997 (61), retrospective, non-EUS aspirate	24; 8 mucinous cysts, 6 SCA, 10 pseudocysts	50% sensitive and 100% specific for mucinous cysts	87% sensitive and 44% specific for mucinous cysts		87% sensitive and 94% specific for mucinous cysts	50% sensitive and 94% specific for mucinous cysts	Carcinoma associated; 87% sensitive and 100% specific for mucinous cysts
Hammel 1998 (62), prospective, non-EUS aspirate	91; 16 MCA, 14 MCAC, 16 SCA, 45 pseudocysts		>400 ng/mL, 57% sensitive and 100% specific for mucinous cysts <4 ng/mL, 100% sensitive and 93% specific for SCA		>40 U/mL, 63% sensitive and 98% specific for mucinous cysts
Frossard 2003 (26), prospective, EUS aspirate	67; 17 mucinous cysts, 9 MCAC, 14 SCA, 6 pseudocysts			>50,000 U/mL, 15% sensitive and 81% specific for mucinous cysts and 86% sensitive and 85% specific for MCAC
Brugge 2004 (9), prospective, multicenter, EUS aspirate	112; 68 mucinous cysts, 7 SCA, 27 pseudocysts, 5 endocrine, 5 others	34% sensitive and 83% specific for mucinous cyst, 22% sensitivity for malignancy in mucinous cysts	>192 ng/mL, 73% sensitive and 84% specific for mucinous cysts	>2,900 ng/mL; 68% sensitive and 62% specific for mucinous cysts	>7 ng/mL 80% sensitive and 61% specific for mucinous cysts	>121 ng/mL, 19% sensitive and 94% specific for mucinous cysts
IPMN = intraductal papillary mucinous neoplasia; SCA = serous cystadenoma; MCA = mucinous cystadenoma; MCAC = Mucinous cystadenocarcinoma.

 

Table 5. Cyst Fluid Amylase, CEA, and CA 19-9 Levels in Pancreatic Cysts

Cyst Fluid Marker	Total Patients	Cystic Lesion	# of Cases	Median Value	Performance Characteristics
Amylase U/L	155	Pseudocyst	60	11,000	<250, 44% sensitive & 98% specific for SCA/ MCA/MCAC
		SCA	32	250
		MCA	32	8,000
		MCAC	31	150
CEA ng/mL	332	Pseudocyst	125	10	<5, 50% sensitive & 95% specific for SCA/pseudocyst
		SCA	79	3
		MCA	64	400	>800, 48% sensitive & 98% specific for MCA/MCAC
		MCAC	64	2,000
CA 19-9 U/L	136	Pseudocyst	66	4,000	<37, 19% sensitive & 98% specific for SCA/pseudocyst
		SCA	24	500
		MCA	24	15,000
		MCAC	22	20,000
CEA = carcinoembryonic antigen; SCA = serous cystadenoma; MCA = mucinous cystadenoma; MCAC = mucinous cystadenocarcinoma. A variety of other markers have also been evaluated in pancreatic cyst fluid with reported yield that varies significantly. Some of the salient studies have been summarized in Table 4. In situations in which duplication of the patient populations may have occurred across reports, only the most recent reports have been included.

DNA Analysis (Level 3)

A detailed molecular analysis of pancreatic cyst aspirated fluid may be helpful in predicting malignancy. The presence of higher amounts (based on optical density at a 260–280 wavelength) of good quality (based on amount of amplifiable DNA on quantitative PCR) DNA and key tumor suppressor gene allelic loss along with k-ras point mutation correlates with the presence of malignancy in pancreatic cysts. An initial k-ras mutation followed by allelic loss is most predictive (~90%) of a malignant pancreatic cyst (10). A 2-yr multicenter study is underway to verify these results and a report is expected in 2007.

Complication of Pancreatic Cyst EUS-FNA (Level 3)

EUS-FNA of pancreatic cysts appears to have an overall complication rate of 2%. The most common complication is pancreatitis and most complications are mild (63). Infection is rare and data supporting the use of antibiotics to prevent FNA-related infection are lacking (level 4). Overall, consensus among experts supports this practice.

Intracystic hemorrhage may occur more frequently than recognized, but the clinical significance may not amount to more than transient abdominal pain (up to 6%) (64).

Endoscopic Therapy of Neoplastic Pancreatic Cysts (Level 4)

Ablation of the epithelial lining of a pancreatic cystic neoplasm may decrease or eliminate malignant or metastatic potential in benign and malignant lesions, respectively. Ethanol lavage of MCN and IPMN cystic lesions appears to be safe, but its efficacy has not yet been determined (65).

Pancreatic cystic lesions can be differentiated into mucinous and non-mucinous types through the use of cross sectional imaging, EUS, and cyst fluid analysis. Management is based upon a balance of malignant potential and risk of surgical resection.

Table 6. Common Clinical Scenarios and Frequently Asked Questions About Neoplastic Pancreatic Cysts

1.	What are the initial imaging tests to evaluate a pancreatic cyst? A contrast-enhanced triphasic multidetector CT scan is the first test, which may be followed by an EUS depending on the clinical situation, e.g., if FNA is desired for CEA level to differentiate a mucinous from nonmucinous cyst or to target a solid component.
2.	Do incidental/asymptomatic pancreatic cysts need to be evaluated? Yes, most cysts detected today are asymptomatic and more than half of these are premalignant (MCN and IPMN). Furthermore, 1/6 asymptomatic cysts may be malignant. The absence of symptoms and size less than 2 cm supports indolence, especially in a unilocular cyst; however, the decision regarding surgery versus surveillance versus "no further follow-up" depends upon whether the cyst is mucinous (premalignant) or not. The most accurate test to make this diagnosis is the cyst aspirate CEA level.
3.	But what if the asymptomatic cyst is very small, say 5 mm? A reasonable approach may be to repeat cross-sectional imaging in a year to assess for change. There are no firm guidelines for this situation but the chances of a very small incidental cyst (<1 cm) becoming malignant in a year are likely small. This is being supported by more recent studies (12, 66) and will likely be true especially in the case of side-branch IPMN. Hopefully, as we learn more about the natural history of these lesions a surveillance strategy will evolve. Increasing size or the development of symptoms should lead to further investigation.
4.	Do all cystic neoplasms have to be evaluated with EUS? No, in some cases, the clinical and CT findings are sufficient to diagnose the type of cystic lesion with confidence. For example, a 50-yr-old healthy woman without a history of pancreatitis with a 3-cm thick-walled, septated cyst in the tail of the pancreas should not necessarily undergo an EUS. The clinical picture is sufficiently compelling for an MCN and she should undergo a distal pancreatectomy.
5.	5. Is EUS imaging alone all we need for the evaluation of a pancreatic cystic lesion? No, determination of morphology based on EUS imaging is not specific enough. Cyst fluid needs to be evaluated with cytology and tumor markers.
6.	Should all cysts be aspirated? No, in some situations aspiration is not indicated or may even be contraindicated. For example, the classic imaging of a lobulated microcystic lesion is diagnostic of a serous cystadenoma, and FNA will not add any information. Another example is an immature pseudocyst with internal debris. EUS-FNA will pose a risk of introducing an infection and is therefore contraindicated.
7.	How many passes should be made to sample a cyst? Typically one pass is made to acquire fluid from a pancreatic cyst. During this pass the cyst wall may be targeted to increase the cytologic yield, but the data to support this practice are lacking. If there is an associated solid component then additional passes may be made for cytology evaluation.
8.	Are all cysts occurring in the setting of pancreatitis pseudocysts? No, IPMN may present with pancreatitis. Only half of the cysts associated with pancreatitis may be pseudocysts (3). If a pancreatic cyst cannot be confirmed to have developed coincident with acute pancreatitis, then further evaluation is indicated. Following recovery from the attack of pancreatitis, the cyst should be evaluated with EUS, and in the absence of intracystic debris, should be aspirated for CEA, amylase, and cytology.
9.	If minimal fluid is acquired during aspiration, for what analysis should it be sent? Frequently, pancreatic cyst aspiration may yield very little fluid due to either a small cyst or thick mucinous fluid. For thick fluid a larger bore needle may yield a bigger sample. Since cyst fluid CEA is the most sensitive indicator of a mucinous cyst, priority should be given to this test. The minimum fluid required for cyst fluid CEA analysis may vary between laboratories and should be confirmed. The remaining fluid can be divided for cytology exam and DNA analysis (0.4 mL required). In the setting of minimal fluid, some experts may opt to centrifuge the sample, submitting the supernatant for CEA analysis and the sediment for cytology. However, the affect of centrifugation on pancreatic cyst fluid CEA measurements has not been studied.
10.	Can fluid analysis differentiate between MCN and IPMN? No, cyst aspirate cytology exam and CEA (or other tumor markers) are not helpful in differentiating between MCN and IPMN. In theory, cyst fluid amylase should be higher in IPMN, but this has not been rigorously examined.
11.	Can cyst fluid analysis detect malignancy in a mucinous cyst? In the absence of a solid component with directed FNA, the yield of cytology for malignant cysts is low. Although very high CEA levels are sometimes seen in malignant cysts, in general, the CEA level does not differentiate between malignant and premalignant cysts. Cyst fluid DNA analysis has been shown to be an accurate marker of malignancy in mucinous cysts, but there is only one published study.
12.	Should antibiotics be administered at the time of cyst FNA? It is accepted practice to administer a broad spectrum IV antibiotic (e.g., a quinolone) at the time of cyst aspiration. For large or incompletely aspirated cysts or cysts with internal debris, oral antibiotics may be given for 3 days following the EUS-FNA. Data to support this practice are lacking.
13.	If surgery is not undertaken, how should these lesions be followed? It depends on the lesion and the reason why resection is not performed. If the patient is not a good operative candidate (presumably with time the candidacy will not improve) then interval cross-sectional imaging may suffice, as long as the patient would be considered for resection if the imaging looked more concerning. On the other hand, in high-risk situations (main duct IPMN) or a healthy patient opting for surveillance there are no firm recommendations. Interval cross-sectional imaging, EUS with FNA, pancreatoscopy with sampling, and DNA analysis may be a part of this "surveillance." At the University of Pittsburgh, we perform interval EUS (every 6–12 months) and perform FNA for cytology evaluation and DNA analysis for MCN and side-branch IPMN. Main duct IPMN surveillance also may include pancreatic protocol CT scan and MRCP.

The authors have no potential conflicts of interest.

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