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Patients with nonalcoholic steatohepatitis (NASH)-related advanced fibrosis and cirrhosis who experienced significant fatigue had a greater risk of adverse clinical events, a post hoc analysis of two phase III trials suggested.

Cox proportional hazard models showed that lower baseline scores indicating worse fatigue on the chronic liver disease questionnaire (CLDQ)-NASH were significantly associated with risks of liver-related or decompensation events for those with:

• Bridging fibrosis (F3): HR 0.85 per 1 point in fatigue score (95% CI 0.75-0.96, P=0.0088)
• Compensated cirrhosis (F4): HR 0.67 per 1 point (95% CI 0.53-0.85, P=0.0014)

These associations remained significant even after adjusting for clinical and demographic confounders, reported Zobair M. Younossi, MD, MPH, of Inova Fairfax Hospital in Falls Church, Virginia, and colleagues in .

"The lower the fatigue score, the more likely patients with advanced NASH were to experience a worsening of their liver disease within the next year or two," they concluded. "These findings may also help identify patients who would most benefit when new drug therapy becomes available."

NASH, the progressive form of non-alcoholic fatty liver disease (NAFLD), can lead to hepatocellular carcinoma (HCC), cirrhosis, liver transplantation, or even death, Younossi's group noted. About half of all NASH patients present with clinically significant fatigue. Prior studies have shown that the stage of hepatic fibrosis was the primary .

For this post-hoc retrospective study, Younossi and colleagues used data from two phase III trials (), which were conducted across 27 countries from 2017 to 2019. These studies were terminated due to a lack of efficacy in the study drug, selonsertib, at week 48, but follow-up for event-free survival continued for up to 26 months for patients who were enrolled in the open-label analyses.

The authors looked at 1,679 patients with NASH, of whom 802 had F3 and 877 had F4 disease. A majority of the patients were women (60%), mean age was 58 years, and about three-fourths also had type 2 diabetes.

Mean baseline CLDQ-NASH fatigue scores were 4.8 (range 1-7) for F3 and 4.6 for F4. Scores were slightly lower among F3 patients with liver-related events (4.5) and for those with F4 who were decompensated by follow-up (3.7).

Over a median follow-up of 16 months, 15% of NASH patients with F3 had liver-related events, of which 95% had progression to cirrhosis indicated by their biopsy at week 48, and the remaining experienced hepatic decompensation. Among patients with NASH F4, 3.5% had an event related to hepatic decompensation. Of these patients, 42% had ascites, 23% had hepatic encephalopathy, 13% developed HCC, 13% developed portal hypertension-related upper GI bleeding, and 3% underwent liver transplant.

Patients with worse liver function tests at baseline and liver-related clinical events at follow-up showed more baseline hepatic impairment with lower platelet counts, higher aspartate aminotransferase levels, and higher fibrosis scores on non-invasive tests (NITs). Moreover, those who experienced liver-related clinical events had NAFLD activity scores that were no different than those of stable patients, regardless of their baseline fibrosis stage.

"This suggests that it may be fibrosis rather than NASH activity that is driving liver disease progression," Younossi and team wrote. "On the other hand, semi-quantitative pathologic scoring of liver fibrosis may be not granular enough to risk-stratify patients with advanced fibrosis. Indeed, all NITs that were included in the study ... of progressed F3 patients were similar to those of stable F4 patients suggesting minimal clinically relevant difference between these groups despite different fibrosis stage classification at baseline."

"One of the major issues in NASH is in identifying patients at highest risk of liver-related events who are in most need of treatment," said Michelle Long, MD, of Boston Medical Center in Massachusetts. "Several tools, including non-invasive tests, have been developed to identify patients at risk for progressive disease, but it is still burdensome for providers to put these tools to use in practice."

"Identifying symptoms, such as fatigue, which may help identify patients at risk for progressive disease, is useful and may help guide providers on which patients require additional evaluation with non-invasive tests to risk stratify for disease progression risk," added Long, who was not involved in this study.

The authors noted that the patients included in their analysis had been enrolled in clinical trials and may not be representative of those in the general population. Additionally, the length of follow-up was limited, which may have curbed the number of adverse events that could have occurred.

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