Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease

Abstract

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD). The minimal pathologic criteria for NASH include hepatic steatosis, ballooning degeneration, and lobular inflammation. The resolution of NASH, which relies on the loss of ballooning degeneration, is subject to sampling and observer variability in pathologic interpretation. Ballooning is associated with advanced hepatic fibrosis in cross‐sectional studies but is not a predictor of mortality in NAFLD. Fibrosis staging, while still subject to some sampling variability, has less observer variability and is a robust predictor of liver‐related mortality in NAFLD. In this study, we hypothesize that, regardless of the diagnosis of NASH, the presence of steatofibrosis (steatosis accompanied by fibrosis) regardless of other pathologic features can also be a robust predictor of mortality in NAFLD. We used our previously reported cohort of patients with NAFLD with liver biopsies and long‐term mortality follow‐up. Cox proportional hazard models were used to determine the predictors of overall and liver‐related mortality. Of 209 enrolled NAFLD subjects, 97 can be classified as having steatofibrosis. During follow‐up (median 150 months), 64 (30.6%) patients died, with 18 (8.6%) from liver‐related causes. Adjusted for age, both diagnostic categories of NASH and steatofibrosis were significantly and similarly associated with liver‐related mortality (adjusted hazard ratio [aHR], 9.9; 95% confidence interval (CI), 1.3‐74.9; P = 0.027; aHR, 6.7; 95% CI, 1.5‐29.8; P = 0.013, respectively). However, only steatofibrosis showed independent association with overall mortality (aHR, 1.76; 95% CI, 1.02‐3.05; P = 0.043). Conclusion: Steatofibrosis and NASH are similarly associated with liver‐related mortality, but only steatofibrosis is associated with overall mortality in patients with NAFLD. Given the inherent observer variability in ballooning degeneration, a key diagnostic component of NASH, we suggest that steatofibrosis should be considered a viable diagnostic classification for NAFLD subjects at risk or adverse outcomes and provides a simpler endpoint for clinical trials of therapeutic agents. (Hepatology Communications 2017;1:421–428)

Burden of Illness and Economic Model for Patients With Nonalcoholic Steatohepatitis in the United States

“…The annual transition probabilities for the all NASH model are shown in Table . Transition probabilities were derived for each health state from clinical trials, systematic literature reviews, meta‐analyses, and our previously published model . The transition probabilities for F1, F2, F3, and CC to later stages of liver disease were obtained from a recent meta‐analysis .…”

“…In this context, there are a number of studies that have suggested that subjects with histologic NASH are at risk for progressive liver disease and that those with significant fibrosis are at the greatest risk . In fact, the stage of fibrosis has been shown to be the only and most reliable predictor of liver‐related mortality . Therefore, one can argue that these are the patients with the most urgent need for treatment.…”

Patient‐Reported Outcomes and the Economic Effects of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: The Value Proposition

“…In a separate Markov model focusing on NASH and advanced NASH in the United States, investigators determined that in 2017 there were 5,527,812 adult subjects with NASH (18‐79 years old) in the United States. The lifetime cost burden of all NASH patients in the United States was estimated to be enormous and expected to increase by approximately 400% in the next 5 years …”

“…On the other hand, aggressive lifestyle modifications that target components of metabolic syndrome could be beneficial. Patients with NASH at greatest risk for death can be identified based on the presence of metabolic conditions such as type 2 diabetes and significant fibrosis . Patients with significant fibrosis also have larger reductions in quality of life .…”

“…Although mortality is the ultimate clinical outcome, it is not a practical endpoint for clinical trials . Improvement of fibrosis and possibly NASH can be assessed to determine efficacy . Clinical trials of therapeutic agents must include PROs, and these agents must be found to improve quality outcomes, such as quality of life .…”