Fibrosis Stages F3 and F4 Associated With Higher Mortality Rate in NAFLD

Liver Cirrhosis
Liver with cirrhosis, computer illustration. Cirrhosis is a consequence of chronic liver disease characterized by fibrosis and scarring of tissue.
Investigators assessed the incidence of mortality and other clinical outcomes among patients with various histologic stages of nonalcoholic fatty liver disease.

Among patients with nonalcoholic fatty liver disease (NAFLD), fibrosis stages F3 and F4 are associated with an increased risk for liver-related complications and death, according to a study in the New England Journal of Medicine.

The findings are based on data from the NAFLD Database Study Phase 2, a prospective, noninterventional registry of the nonalcoholic steatohepatitis (NASH) Clinical Research Network. Participants were adults with liver biopsies that confirmed NAFLD and who had at least 1 follow-up visit after 48 weeks.

A total of 1773 patients (64% women) were included, and the median duration of follow-up was 4.0 (IQR, 2.1 to 7.4) years. The mean patient age was 52±12 years, and 85% were White and of European ancestry.

All-cause mortality was associated with fibrosis stage at baseline and increased from 0.32 deaths per 100 person-years at stages F0 to F2 to 0.89 deaths per 100 person-years at stage F3, and to 1.76 deaths per 100 person-years at stage F4. A higher all-cause mortality was found in patients with stage F4 disease (hazard ratio [HR], 3.9; 95% CI, 1.8-8.4), as well as higher liver-related mortality (HR, 12.7; 95% CI, 1.8-88.6), than in patients with stages F0 to F2 fibrosis.

The HR for death from any cause in patients who had stage F2 fibrosis vs patients with stage F0 or F1 disease was 2.3 (95% CI, 0.8-7.0), and for stage F3 fibrosis vs stages F0 to F2 fibrosis the HR was 1.9 (95% CI, 0.9-3.7).

The incidence of new-onset hepatic decompensation was 0.05 per 100 person-years in patients with stages F0 to F2 fibrosis at baseline and increased at stage 3 to 0.99 per 100 person-years (HR, 18.7; 95% CI, 4.8-73.1) and again at stage 4 to 2.69 per 100 person-years (HR, 36.1; 95% CI, 8.9-146.3).

All hepatic decompensation events were greater among patients with stage F4 disease than in those at lower stages. The incidence of type 2 diabetes, hypertension, and a decrease in estimated glomerular filtration rate were also greater in stage F4 fibrosis vs stages F0 to F2.

A multivariable model adjusted for age, sex, race, type 2 diabetes, NASH or NAFLD, and fibrosis stage at baseline showed that any new hepatic decompensation event was associated with death from any cause (HR, 6.8; 95% CI, 2.2-21.3).

Study limitations include the predominantly White population. Additionally, the widths of the confidence intervals around the hazard ratios were not adjusted for multiplicity and did not allow statistical inferences regarding the associations. Finally, the majority of deaths occurred outside the study sites, and the quality of the data was mixed regarding the cause of death.

“These data may be helpful in the assessment of prognoses and in the use of treatments for NASH,” the investigators concluded.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


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(17):1559-1569. doi: 10.1056/NEJMoa2029349

This article originally appeared on Gastroenterology Advisor