Posted on April 1, 2022

Hepatic Decompensation Rate Is 0.05 per 100 person-years in NAFLD with Stage F0-F2 Fibrosis, but Rises to 1 per 100 person-years with Stage F3

  Philip Schoenfeld, MD, MSED, MSc (Epi)1 and Sonali Paul, MD, MS2

1Chief (Emeritus)-Gastroenterology Section, John D. Dingell VA Medical Center, Detroit, Michigan
2Assistant Professor of Medicine, Center for Liver Disease, Division of  Gastroenterology, Hepatology & Nutrition, University of Chicago School of Medicine, Chicago, Illinois

This article reviews Sanyal AJ, Van Natta ML, Clark J, et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N Engl J Med 2021; 385: 1559-69. DOI: 10.1056/NEJMoa2029349. PMID: 34670043

Access the article in PubMed

Correspondence to Philip Schoenfeld, MD, MSED, MSc (Epi), Editor-in-Chief, Associate Editor. Email:

Question:Whatis the risk of hepatic decompensation, hepatocellular carcinoma (HCC), liver-related mortality and all-cause mortality among patients diagnosed with non-alcoholic fatty liver disease (NAFLD) after stratification by fibrosis score?
Design: Prospective, nonintervention registry.
Setting: Nonalcoholic Steatohepatitis (NASH) Clinical Research Network which consists of multiple US academic medical centers.
Patients: Overall, 1,773 adults (mean age 52; 64% women; 85% White and European ancestry; 42% diabetic) with biopsy-proven NAFLD and at least 1 follow-up visit 48 weeks after liver biopsy. Fibrosis score was determined from liver biopsy: F0-no fibrosis; F1-sinusoidal fibrosis; F2-sinusoidal and
portal fibrosis; F3-bridging fibrosis; F4-cirrhosis, and 30% had F3/F4 fibrosis score. Study patients had minimal or no alcohol consumption based on answers to the Alcohol Use Disorders Identification Test questionnaire. Patients received standard of care at their NASH Clinical Research Network center.
Interventions/ExposureAll  patients completed -protocol-mandated laboratory data and specific case-record forms at baseline (after liver-biopsy) and at 48-week intervals.
Outcome: Rate of hepatic decompensation (defined as clinically apparent ascites, overt encephalopathy, or variceal hemorrhage), HCC, mortality from any cause, non-hepatic cancer, cardiovascular event, cerebrovascular event, and development of Model for End-Stage Liver Disease (MELD) score of 15 or higher. Outcomes were adjudicated centrally.
Data Analysis: Rates of new-onset events per 100 person-years were calculated using only the first decompensating event. These events were then stratified by fibrosis score. Hazard ratios with 95% confidence intervals were derived from regression models that were further stratified for age, race, sex, diabetes status, and length of biopsy specimen. Investigators noted that the widths of the confidence intervals have not been adjusted for multiplicity, so the intervals should not be used to infer definitive associations.
Funding: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Results: Among 1,773 studypatients,median follow-up was 4.0 years (interquartile range: 2.1-7.4) and total follow-up was 8,210 person-years. Among NAFLD patients with stage F0-F2 fibrosis, the rate of hepatic decompensation is 0.05 per 100 person-years of follow-up (Table 1). This rises to 0.99 among patients with stage F3 (bridging fibrosis) with crude hazard ratio = 18.3; 95% confidence interval (CI): 5.4-62.6. This suggests that one-stage regression from stage F3 to stage F2 may be a beneficial target for NAFLD treatments. In a multivariate regression model adjusted for multiple factors, new hepatic decompensation was the only factor associated with higher mortality: hazard ratio = 6.8; 95% CI: 2.2-21.3. Rate of HCC was numerically higher in stage F3 vs stage F4: 0.34 vs 0.14 per 100 person-years.

Table 1. Rates of hepatic and non-hepatic outcomes in NASH patients (per 100 person-years of follow-up)  *Hepatic decompensation: clinically apparent ascites, overt encephalopathy, or variceal hemorrhag



Why Is This Important?

NAFLD, which is a complex metabolic disorder closely linked to obesity and type 2 diabetes mellitus, is present in more than a quarter of the adult population.1 NASH, the progressive form of NAFLD, has surpassed hepatitis C as the primary cause of cirrhosis and is present in 5% of the US population.2 With the ongoing epidemic of obesity in the US, the prevalence of NASH will continue to grow. Management of patients with NAFLD includes education about the incidence of hepatic decompensation and HCC. Previously, these estimates came from retrospective analyses. Data from the NASH Clinical Research Network and this specific study are prospective, utilize liver histology to determine fibrosis score, and adhere to STROBE guidelines for optimal design and reporting about prospective cohort studies.3 Thus, this study provides precise data about prognosis and supplements the most recent guidelines about NAFLD management.4

Key Study Findings
In multivariate logistic regression models, new hepatic decompensation was the only factor associated with increased risk of all-cause mortality. Rates of hepatic decompensation are very small among patients with stage F0-F2 fibrosis (0.05 per 100 person-years), but increase significantly with stage F3 fibrosis (0.99 per 100 person-years, crude hazard ratio = 18.6; 95% CI: 5.4-62.6).

Study patients were primarily White and of European descent (85%), so it’s unclear if outcomes are different in African-Americans. Fibrosis stage was determined by liver biopsy in study patients while non-invasive tools are more commonly used to define fibrosis stage. Ultimately, there were only 37 hepatic decompensation events and 9 cases of HCC during the 8,210 person-years of follow-up, so confidence intervals around study estimates are quite wide.

My Practice
When I (SP) see a new patient for nonalcoholic fatty liver disease (usually seen on some imaging tests), one of my priorities as a hepatologist is to risk stratify their liver disease, i.e do they have fibrosis. I do this with the use of transient elastography (TE), which is commonly referred to as FibroScan, and which uses shear wave imaging to estimate liver stiffness.

TE can accurately diagnose cirrhosis and is useful in determining advanced fibrosis (F3/F4) from  minimal or no fibrosis.5 If TE is unavailable, a FIB-4 index (that uses platelet count, ALT, AST, and age; online calculator that has good predictive
accuracy for advanced fibrosis.6 Should the TE or FIB-4 index be elevated or indeterminate, then MR elastography can be used, which examines the entire liver and can determine both fibrosis and fat fractions. However, it is not available everywhere and in those cases a liver biopsy may be warranted. Liver biopsy may also be done if the patient’s liver tests are elevated to help differentiate nonalcoholic steatohepatitis (NASH) from other liver diseases (such as autoimmune hepatitis, depending on serological markers).

If the patient is at low risk (TE < 8 kPa or FIB-4 index < 1.3), it is reasonable to continue to encourage dietary changes and weight loss with repeat testing in 2-3 years (if everything has remained stable). Those at indeterminate (TE 8-12 kPa, Fib-4 1.3-2.67) or high risk (TE > 12 kPa, FIB-4 > 2.67, or liver biopsy with F2-F4) would benefit from more intensive and structured weight loss programs, weight management medications, or bariatric surgery with close hepatology follow up.4

For Future Research
Larger cohorts followed for longer durations are still neededto provide precise prognostic data. Future studies of NAFLD therapies will need to demonstrate that regression from stage F3 fibrosis to stage F1-F2 translates into reduced risk of hepatic decompensation events.

Conflicts of Interest

The authors have no potential conflicts of interest.


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