Associations between metabolic hyperferritinaemia, fibrosis-promoting alleles and clinical outcomes in steatotic liver disease.

BACKGROUND & AIMS: Ferritin has been investigated as a biomarker for liver fibrosis and iron in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether metabolic hyperferritinaemia predicts progression of liver disease remains unknown. In this study, we sought to understand associations between hyperferritinaemia and (1) adverse clinical outcomes and (2) common genetic variants related to iron metabolism and liver fibrosis. METHODS: This was a retrospective analysis of adults with MASLD seen at the University of Michigan Health System, where MASLD was defined by hepatic steatosis on imaging, biopsy or vibration-controlled transient elastography, plus metabolic risk factors in the absence of chronic liver diseases other than hemochromatosis. The primary predictor was serum ferritin level, which was dichotomized based on a cut-off of 300 or 450 mcg/L for women or men. Primary outcomes included (1) incident cirrhosis, liver-related events, congestive heart failure (CHF), and mortality and (2) distribution of common genetic variants associated with hepatic fibrosis and hereditary hemochromatosis. RESULTS: Of 7333 patients with MASLD, 1468 (20%) had elevated ferritin. In multivariate analysis, ferritinaemia was associated with increased mortality (HR 1.68 [1.35-2.09], p < .001) and incident liver-related events (HR 1.92 [1.11-3.32], p = .019). Furthermore, elevated ferritin was associated with carriage of cirrhosis-promoting alleles including PNPLA3-rs738409-G allele (p = .0068) and TM6SF2-rs58542926-T allele (p = 0.0083) but not with common HFE mutations. CONCLUSIONS: In MASLD patients, metabolic hyperferritinaemia was associated with increased mortality and higher incidence of liver-related events, and cirrhosis-promoting alleles but not with iron overload-promoting HFE mutations.

Higher mortality among lean patients with non-alcoholic fatty liver disease despite fewer metabolic comorbidities.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can develop in individuals who are not overweight. Whether lean persons with NAFLD have lower mortality and lower incidence of cirrhosis, cardiovascular diseases (CVD), diabetes mellitus (DM) and cancer than overweight/obese persons with NAFLD remains inconclusive. We compared mortality and incidence of cirrhosis, CVD, DM and cancer between lean versus non-lean persons with NAFLD. METHODS: This is a retrospective study of adults with NAFLD in a single centre from 2012 to 2021. Primary outcomes were mortality and new diagnosis of cirrhosis, CVD, DM and cancer. Outcomes were modelled using competing risk analysis and Cox proportional hazards regression analysis. RESULTS: A total of 18,594 and 13,420 patients were identified for cross-sectional and longitudinal analysis respectively: approximately 11% lean, 25% overweight, 28% class 1 obesity and 35% class 2-3 obesity. The median age was 51.0 years, 54.6% were women. The median follow-up was 49.3 months. Lean patients had lower prevalence of metabolic diseases at baseline and lower incidence of cirrhosis and DM than non-lean patients and no difference in CVD, any cancer or obesity-related cancer during follow-up. However, lean patients had significantly higher mortality with incidence per 1000 person-years of 16.67, 10.11, 7.37 and 8.99, respectively, in lean, overweight, obesity class 1 and obesity class 2-3 groups respectively. CONCLUSIONS: Lean patients with NAFLD had higher mortality despite lower incidence of cirrhosis and DM, and similar incidence of CVD and cancer and merit similar if not more attention as non-lean patients with NAFLD.