Letter: Iron Metabolism in SLD—A Complex Puzzle That Requires Further Evaluation

Abstract

We read with great interest the studies by Song, Amangurbanova et al. [1, 2]. Both of these studies present valuable insights into the relationship between serum ferritin levels and liver-related events (LREs) in patients with steatotic liver disease (SLD) or type 2 diabetes. However, we wish to highlight a few key considerations to enhance the interpretation of the findings and propose avenues for future research.

First, these studies solely rely on baseline serum ferritin levels as the primary indicator of iron storage but fails to adequately consider ferritin's role as an acute-phase reactant. Serum ferritin levels can increase during both acute and chronic inflammatory conditions, which does not necessarily reflect actual iron storage [3]. For instance, in patients with non-alcoholic steatohepatitis, elevated ferritin levels may more accurately indicate liver cell damage due to inflammation, rather than a simple increase in iron stores [3]. This suggests that using a baseline ferritin threshold alone may lead to misclassification of patients with active inflammation as having ‘high iron stores’. Future research should use multivariate models that account for inflammatory markers like CRP and include the sTfR-to-ferritin ratio for a more accurate assessment of iron status.

Second, these studies employ gender-specific ferritin thresholds (≥ 300 μg/L for males and ≥ 200 μg/L for females) based on the standards of hereditary haemochromatosis developed for western populations [4]. However, these thresholds do not account for racial differences in ferritin levels. Serum ferritin concentrations are observed to be 15%–20% elevated in individuals of Asian descent compared to those of Pacific Islander descent, which can be partially attributed to variations in single nucleotide polymorphisms [5, 6]. Additionally, eating habits like red meat consumption have a dose-dependent relationship with ferritin levels [7]. In future studies, considering the potential role of race and dietary factors may help deepen our understanding of iron homeostasis and subsequent health implications.

Third, the exclusion of patients with iron deficiency introduces a potential ‘healthy iron status bias’. Iron deficiency anaemia is prevalent in patients with SLD, with an incidence rate of approximately 30% [8]. Furthermore, low iron status may exacerbate liver fibrosis in NASH patients by impairing energy metabolism [8, 9]. Excluding these patients could lead to an underestimation of liver-related risks in those with low ferritin levels, potentially masking the impact of iron deficiency on LRE. The effect of iron supplementation was also not assessed, which could conceal the therapeutic potential of iron in patients with SLD. Future studies targeting iron-deficient populations, particularly anaemic cohorts, may clarify iron supplementation's effects on progression of SLD and type 2 diabetes.

Finally, these studies do not adequately address the potential impact of antidiabetic medications used by patients with diabetes on iron metabolism. Metformin, by activating the AMPK pathway, inhibits hepcidin expression, thereby promoting intestinal iron absorption [10]. This medication could introduce “noise bias” in ferritin levels. Future research might consider conducting stratified analyses based on medication usage, with a particular focus on patients exhibiting elevated ferritin levels.