From the AGA Journals

Mortality increases substantially with fibrosis stage in NAFLD

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Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases globally. This meta-analysis shows that all-cause mortality and liver-related mortality increase significantly and exponentially from fibrosis stage F2 onward. The findings have important implications for patients, care providers, health policy, and the NAFLD research agenda.

Achita P. Desai, MD is a NIH-funded Clinician Scientist, Transplant Hepatologist and Assistant Professor at Indiana University School of Medicine, Division of Gastroenterology and Hepatology, Indianapolis

Dr. Achita P. Desai

As gastroenterologists and hepatologists, we see individuals at varying stages of NAFLD. While treatment for all stages of NAFLD remains focused on weight loss, this goal can be achieved by interventions of varying cost and intensity, ranging from lifestyle modifications to medication-assisted weight loss to bariatric surgery. Furthermore, ongoing clinical trials are another treatment option. Guided by prognosis provided by this meta-analysis using an internationally representative cohort, patients and providers can participate in more accurate shared decision-making as they consider their weight loss and treatment options.

At the policy level, the significant increase in all-cause mortality even at early stages of NAFLD also highlights gaps in the need for coverage of well-established weight-loss treatments. While provisions of the Affordable Care Act have tried to reduce health disparities and improve access to weight-loss treatment, many health plans continue to limit or deny coverage for medications and bariatric surgery. Finally, the study emphasizes the urgency of conducting more research to establish successful treatments for individuals with advanced fibrosis, specifically those with cirrhosis.

Overall, the study provides valuable insights into mortality risks associated with different stages of fibrosis in NAFLD for all stakeholders in the NAFLD community.

Achita P. Desai, MD is an National Institutes of Health–funded clinician scientist, transplant hepatologist, and assistant professor in the division of gastroenterology and hepatology at Indiana University, Indianapolis. She reported no conflicts of interest.



The risks of all-cause and liver-related mortality increase substantially based on fibrosis stage in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), according to a study published in Clinical Gastroenterology and Hepatology.

In particular, patients with NAFLD and advanced fibrosis have a threefold higher risk of all-cause mortality and 10-fold higher risk of liver-related mortality, as compared with patients with NAFLD but not advanced fibrosis, Cheng Han Ng, with the National University of Singapore, and colleagues wrote.

“These data provide high-level evidence that provides prognostication for each stage of fibrosis to inform care providers and patients,” they wrote. “In addition, these findings have important implications for clinical trial design and highlight the importance of developing therapeutics.”

Although previous studies have found higher risks of all-cause and liver-related mortality in patients with NAFLD with increasing fibrosis stages, they examined the risk of mortality in reference to stage 0 fibrosis and didn’t include comparisons across different stages of fibrosis. In addition, the studies typically used pooled risk ratios, didn’t account for time-to-event analysis, or incorporate the most recent data.

The study investigators conducted an updated time-to-event meta-analysis to understand the impact of fibrosis stage on all-cause and liver-related mortality in biopsy-confirmed NAFLD. In addition, they pooled the survival estimates of individual fibrosis stages based on reconstructed individual patient data and compared mortality between fibrosis stages.

In 14 included studies, 17,301 patients had biopsy-proven NAFLD, including 6,069 assessed for overall mortality and 3,421 for liver-related mortality. The studies were conducted in the United States, Canada, Sweden, Israel, Japan, and Hong Kong, with four multicenter studies across multiple regions. The median follow-up duration was 7.7 years, and the average age of patients was 50.5.

For nonadvanced fibrosis (F0-F2), the 1-, 3-, 5-, 8-, and 10-year all-cause mortality were 0.1%, 1.9%, 3.3%, 6%, and 7.7%, respectively. For clinically significant fibrosis (F2-F4), the rates were 0.3%, 8.4%, 14%, 23.7%, and 29.3%, respectively. For advanced fibrosis (F3-F4), the rates were 0.3%, 8.8%, 14.9%, 25.5%, and 32.2%, respectively. For cirrhosis (F4), the rates were 0.3%, 13%, 20.6%, 33.3%, and 41.5%, respectively.

Compared with F0 as a reference, there were no statistically significant differences in all-cause mortality for F1. However, the risk significantly increased for F2 (HR, 1.46; 95% confidence interval, 1.08-1.98; P 1⁄4 .01), F3 (HR, 1.96; 95% CI, 1.41-2.72; P < .01), and F4 (HR, 3.66; 95% CI, 2.65-5.05; P < .01). In addition, early fibrosis (F1-F2) resulted in a statistically significant increase in all-cause mortality, as did the presence of clinically significant fibrosis or advanced fibrosis.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in a statistically significant increase in mortality (HR, 2.06; 95% CI, 1.52-2.81; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a significantly increased risk of mortality (HR, 3.32; 95% CI, 2.38-4.65; P < .01).

In a comparison between F3 and F4, F4 resulted in a statistically significant increase in mortality (HR, 2.67; 95% CI, 1.47-4.83; P < .01). In a sensitivity analysis with three studies including nonalcoholic steatohepatitis, patients with NASH had a significantly increased risk of mortality in F4 (HR, 5.08; 95% CI, 2.70-9.55; P < .01).

For liver-related mortality, F1 didn’t result in a statistically significant increase, as compared with F0. However, increased risks were found for F2 (HR, 4.07; 95% CI, 1.44-11.5; P < .01), F3 (HR, 7.59; 95% CI, 2.80-20.5; P < .01), and F4 (HR, 15.1; 95% CI, 5.27-43.4; P < .01). In addition, any fibrosis (F1-F4) resulted in an increased risk of mortality, early fibrosis resulted in a borderline nonsignificant increase, and clinically significant or advanced fibrosis led to an increased risk.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in an increase in liver-related mortality (HR, 6.49; 95% CI, 3.30-12.8; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a statistically significant increase in liver-related mortality (HR, 10.4; 95% CI, 6.18-17.5; P < .01).

In a comparison between F3 and F4, F4 resulted in a significant increase in liver-related mortality (HR, 2.57; 95% CI, 1.22-5.42; P < .01).

Although the presence of F4 leads to the greatest risk of mortality, selection criteria in NASH clinical trials have predominately targeted patients with F0-F3, the authors wrote.

“NASH is currently the fastest growing cause for liver transplant and [transplant] remains the only known curative treatment for cirrhosis,” they wrote. “However, with the global shortage of suitable grafts for transplant and lack of viable treatment, our results highlight that there is an urgent need for an efficacious treatment for patients with NASH and F4.”

The researchers outlined several limitations of their study. The development of hepatocellular carcinoma and its effects on survival were outside the scope of the study, they wrote. Analysis of liver-related mortality by proportion was not conducted because of insufficient studies. Data were insufficient to perform subgroup analyses by gender, age, study design, medication use, and diagnostic modality for fibrosis stage.

The authors reported funding support from several national U.S. grants and disclosed consultant and advisory rules for numerous pharmaceutical companies.

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