Editorial: Hyperferritinaemia—An Ironclad Biomarker for the Prognostication of MASLD?

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global liver disease linked to obesity and adverse clinical outcomes [1]. Given its ubiquity and diverse clinical phenotypes, coupled with long periods of asymptomatic metabolic dysfunction-associated steatohepatitis (MASH) prior to cirrhotic decompensation, effective screening for progressive fibrosis and adverse liver-related outcomes is crucial.

Hyperferritinaemia is closely associated with MASLD, type 2 diabetes mellitus (T2DM) and metabolic syndrome [2]. Excessive iron accumulation within hepatic Kupffer cells induces liver injury and exacerbates insulin resistance through increased oxidative stress and dysregulation of lipid metabolism [3]. Thus, hyperferritinaemia may indicate ongoing MASH activity contributing to progressive metabolic dysfunction and hepatic fibrosis.

There is growing interest in the role of hyperferritinaemia for prognosticating MASLD. A multicenter study of 1400 MASLD patients demonstrated a 50% increased risk of liver-related events (LREs) and a 27% increased risk of all-cause mortality in those with hyperferritinaemia [4]. Similarly, a retrospective cohort of 7333 patients linked hyperferritinaemia with increased mortality, LREs, and cirrhosis-promoting alleles (PNPLA3 and TM6SF2) [5]. In another cohort of T2DM patients, 80% with hyperferritinaemia had MASLD, with one-third exhibiting significant liver fibrosis [6].

In this journal, Song et al. evaluated 17,560 patients with ultrasonic steatotic liver disease (SLD) (15,744 MASLD, 1103 metabolic alcoholic liver disease (MetALD) and 713 cryptogenic), followed up for a total of 211,425 person-years [7]. Regardless of SLD subtype, patients with hyperferritinaemia (> 300 μg/L for males, > 200 μg/L for females) had an increased risk of LRE (ascites, variceal bleeding, hepatic encephalopathy or hepatocellular carcinoma) and severity of liver disease as assessed by FIB-4. However, there were only 74 LREs despite the huge cohort and long follow-up period. This is likely because the study population is a health screening cohort with participants having better overall health compared to the general population. Thus, the generalizability of the findings is limited. The study is also limited by the lack of accounting for other possible causes of hyperferritinaemia. Nevertheless, the study is significant as one of the largest published cohorts and adds insight for hyperferritinaemia as prognosticative not only for MASLD but for other subtypes of SLD as well.

Although serum ferritin may be attractive as a prognostic biomarker due to its widespread availability and low cost, there are inherent limitations. Hyperferritinaemia is not disease-specific and may result from any chronic inflammatory state. In addition, hyperferritinaemia may also be contributed to by cardiac or renal failure, which are not uncommon complications of patients with metabolic syndrome. In Western cohorts, HFE gene mutations are common [8], limiting the utility of hyperferritinaemia as a population screening tool for MASLD patients. Finally, current evidence is largely retrospective, using baseline hyperferritinaemia for risk stratification. There is limited data on longitudinal changes in ferritin levels with disease progression in MASLD or, indeed, whether an elevated serum ferritin level that is improving is a surrogate indicator of MASH regression.

In conclusion, as MASLD enters the therapeutic era, we need biomarkers to guide treatment efficacy and predict non-response. Perhaps further research may even derive scoring systems for disease staging and treatment guidance with serum ferritin as one of the algorithm parameters.

Mark C. C. Cheah: conceptualization, writing – original draft, resources. Chee-Kiat Tan: conceptualization, writing – review and editing.

The authors declare no conflicts of interest.

This article is linked to Song et al. papers. To view these articles, visit https://doi.org/10.1111/apt.18402 and https://doi.org/10.1111/apt.70036.