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

Abstract

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.

Keywords: biomarkers; fatty liver disease; ferritin; genetics.

Figure 1.

Consort Diagram. Note that patients could have multiple exclusion criteria.

Figure 2.

Incidence of Mortality, Cirrhosis, and Congestive Heart Failure based on Ferritin Level. Graphs depict incidence of (A) mortality, (2) incident cirrhosis, and (3) incident congestive heart failure. Ferritin levels were stratified as high (≥300/450 ng/mL for women/men) or normal (<450/300 ng/mL for women/men). Mortality was modeled using a Cox proportional hazards model whereas the cirrhosis and congestive heart failure outcomes were modeled using a Fine-Gray competing risk model. All analyses used a 365 day landmark.

Figure 3.

Frequency of Liver Fibrosis-Associated Genetic Alleles Based on Ferritin Level. Allele frequencies of the fibrosis-associated (A) PNPLA3-rs738409, (B) TM6SF2-rs58542926, and (C) HSD17B13-rs6834314. High ferritin was defined as ≥300 ng/mL for females and ≥450 ng/mL for males.