Hyperferritinemia: Pathophysiology, Etiologies, and Diagnostic Approach.

OBJECTIVES: Hyperferritinemia is common in adults, yet most lack true iron overload. Confusion among metabolic, inflammatory, genetic, and reactive causes drives under-investigation and over-treatment, compounded by SGLT2 inhibitors and, less certainly, GLP-1 receptor agonists. We synthesize the hepcidin-ferroportin axis as the unifying mechanism and a transferrin saturation (TSAT)-guided pathway for workup. METHODS: Narrative review with structured PubMed, Embase, and Cochrane searches through April 2026, written to address the SANRA quality domains. RESULTS: Ferritin above 10 000 μg/L flags hemophagocytic lymphohistiocytosis (HLH), although the often-cited 90%/96% performance is pediatric; adult HLH-2004 or HScore ≥ 169 reach 82%-95% sensitivity and 60%-94% specificity, lower in ICU populations. The Valenti consensus on metabolic hyperferritinemia is partially validated against clinical outcomes in cohorts applying its grading. A TSAT-guided pathway directs workup toward HFE genotyping, hepatic MRI, or metabolic evaluation; soluble transferrin receptor (sTfR) and the sTfR/log-ferritin index complement ferritin in distinguishing iron deficiency from anemia of inflammation, though sTfR is itself influenced by inflammation. CONCLUSIONS: The hepcidin-ferroportin axis unifies adult hyperferritinemia under TSAT-guided evaluation, though the algorithm does not capture diabetes risk in C282Y homozygosity. SGLT2 inhibitors alter ferritin interpretation; GLP-1 receptor agonists may do so, though dedicated human evidence remains insufficient. Both warrant documentation at review.