Researchers Say Results Argue for “Progression to Cirrhosis” Outcomes for Studies of NAFLD Treatments

Findings from a longitudinal study of mortality among nonalcoholic fatty liver disease (NAFLD) argues for using “progression to cirrhosis” as a surrogate outcome for approval of therapeutic agents for the disease, say the researchers who conducted the study.

Results of the study, which were reported in the Oct. 21, 2021, issue of the New England Journal of Medicine, showed that all-cause mortality among 1,773 NAFLD patients who were followed for a median of four years climbed with increasing fibrosis. There were 0.32 deaths per 100 person-years for stages F0 to F2, which means no, mild, or moderate fibrosis; .89 deaths per 100 persons-years for stage F3, which includes bridging fibrosis, and 1.76 deaths per 100 person-years for stage F4 (cirrhosis).

The research team, which was led by Virginia Commonwealth University researcher Arun Sanyal, M.D., also said that their results provide a rationale for testing whether treatments that move NAFLD patients from stage F3 to stage 2 fibrosis would result in fewer “hepatic decompensation events,” includes ascites, variceal bleeding and encephalopathy.

In an accompanying editorial, Guadalupe Garcia-Tsao, M.D., a professor at the Yale University School of Medicine and chief of digestive diseases at the VA-Connecticut Healthcare System, noted that unlike findings from other studies, the results reported by Sanyal did not show higher mortality among those with F2 fibrosis. Garcia-Tsao also commented that the occurrence of a hepatic decompensation event “was the only factor significantly associated with death, while nonhepatic new events (cardiac, declining kidney function, or extrahepatic cancer) were not significantly associated with death.” Incident decompensation occurred mainly among those with stage F4 fibrosis, she pointed out.

Garcia-Tsao echoed some of what Sanyal and his colleagues said about regression to F3, but she sounded a note of caution about using liver biopsies to enroll patients in studies.

“A more feasible strategy — and one that would facilitate patient recruitment — would be to forgo liver biopsy and include only patients at high risk for decompensation. A combination of noninvasive markers that are currently used in clinical practice, including liver stiffness and routine laboratory tests (e.g., platelet count and albumin level), can identify patients who have clinically significant portal hypertension and thereby a higher likelihood of decompensation,” she wrote.

Virginia Commonwealth put out a press release about the study that said the findings argue for testing for liver disease, particularly among patients with type 2 diabetes.

The press release quoted Sanyal as saying that many primary care physicians and diabetes specialists “have felt that, because the roots of the disease lie in insulin resistance, then if we treat the diabetes, we've already taken care of the problem.” In the press release, Sanyal adds that even within an especially obese, diabetic population, those who have advanced fibrosis are dying of liver disease. Just treating diabetes doesn't get the job done.”