Wrought Iron Thresholds: How Magnetic Resonance Liver Iron Concentration Can Guide Decision-Making in Hyperferritinemic Patients

Excerpt

Hemochromatosis is a common genetic cause of iron overload, most prevalent among people of Northern European ancestry, associated in > 80% of cases with homozygosity for the p.C282Y missense mutation on the High Fe⁺⁺ (HFE) gene [1]. Though HFE p.C282Y:p.H63D and p.H63D:p.H63D mutations contribute to hyperferritinemia, they rarely cause clinically significant iron overload in the absence of additional risk factors [2]. Although elevated serum ferritin is a sensitive biomarker for diagnosing hemochromatosis and iron overload, its specificity is low. Though risk factors, including other hepatopathies, metabolic syndrome, systemic inflammation, and excessive alcohol intake can confound the serum ferritin, hyperferritinemia is also present in a wide variety of other diseases. This lack of specificity due to a spurious elevation of serum ferritin may complicate the diagnosis of iron overload and its treatment with venesection. Despite a low risk of hemochromatosis-related morbidity and the unclear benefits of venesection, 14–30% of venesection referrals are for compound heterozygotes [3], an observation not enhanced by the scarcity of clinical trials specifically investigating management of these genetic mutations. The EASL guidelines published in 2022 recommend further investigation for iron overload and management according to phenotypic presentation, leaving considerable scope for clinical judgement [1]. …