Serum Ferritin Concentration in Haematologic, Infectious and Metabolic Disorders: A Critical Appraisal of Interpretive Thresholds, Mechanistic Assumptions and Clinical Utility

Vollständiger Abstract

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Serum ferritin is among the most frequently requested laboratory investigations in general medicine, yet its interpretation rests on assumptions that the accumulated evidence supports only in part. The analyte is used simultaneously as a surrogate for body iron stores, as an acute-phase reactant and as a prognostic marker of hyperinflammation, and these roles impose mutually incompatible interpretive rules on a single measurement. This critical narrative review evaluates how serum ferritin performs across haematologic, infectious and metabolic disease, and examines whether the decision thresholds in routine use are supported by the evidence from which they are derived. Literature was identified through searches of open scholarly databases and indexes covering the period from January 2010 to 14 June 2026, supplemented by citation searching and by an authoritative institutional guideline. Sources were appraised for design adequacy, reference-standard quality, treatment of confounding by inflammation and external validity, and were synthesised thematically rather than sequentially. Three findings recur across the disease domains examined. First, the widely used lower thresholds for iron deficiency were derived largely from bone-marrow-referenced observational studies in apparently healthy populations, and functional studies based on the upregulation of iron absorption identify substantially higher inflection points, which implies that current cut-offs define late rather than incipient deficiency. Second, the upper thresholds are weaker still. Marked hyperferritinaemia is aetiologically non-specific in adults, and its prognostic associations in sepsis, coronavirus disease 2019 and clonal marrow disorders are consistent but heavily confounded by illness severity, renal function and hepatocellular injury. Third, in metabolic disease the association between ferritin and adverse outcomes is robust and reproducible, while the inference that iron accumulation causes those outcomes is not, since genetic and interventional evidence diverge. The recurring interpretive failure is the treatment of ferritin as a quantity of iron rather than as a composite signal whose iron-derived component varies with inflammatory state, hepatocellular integrity and renal clearance. Priorities for research include reference-standard-anchored threshold derivation in populations with inflammation, prospective evaluation of ferritin-guided intervention rather than ferritin-associated risk, and adequately powered assessment of iron depletion in metabolic hyperferritinaemia.