DOI: 10.1111/ejh.70285 ISSN: 0902-4441
Hyperferritinemia: Pathophysiology, Etiologies, and Diagnostic Approach
Youjin Kim, Thomas C. Landry, Lukas Seifer, Corinne LaVasseur, Kylee Martens, Joseph Shatzel ABSTRACT
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.