Hyperferritinemia: Pathophysiology, Etiologies, and Diagnostic Approach

Area of Science:

• Internal Medicine
• Hematology
• Endocrinology

Background:

• Hyperferritinemia is common in adults but frequently misdiagnosed.
• Confusion arises from metabolic, inflammatory, genetic, and reactive causes.
• Medications like SGLT2 inhibitors and GLP-1 receptor agonists complicate ferritin interpretation.

Purpose of the Study:

• To synthesize the hepcidin-ferroportin axis as a unifying mechanism for hyperferritinemia.
• To establish a transferrin saturation (TSAT)-guided pathway for diagnostic workup.
• To clarify the impact of specific medications on ferritin levels.

Main Methods:

• Narrative review of literature.
• Structured searches of PubMed, Embase, and Cochrane databases.
• Evaluation of diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) in adults.

Main Results:

• Ferritin >10,000 μg/L suggests HLH, with adult criteria (HLH-2004, HScore) showing variable sensitivity/specificity.
• A TSAT-guided pathway directs evaluation towards HFE genotyping, hepatic MRI, or metabolic assessment.
• Soluble transferrin receptor (sTfR) aids in differentiating iron deficiency from anemia of inflammation.

Conclusions:

• The hepcidin-ferroportin axis unifies hyperferritinemia evaluation under TSAT guidance.
• The diagnostic algorithm requires consideration of medication effects, particularly SGLT2 inhibitors.
• Further research is needed on GLP-1 receptor agonists' impact on ferritin.