BIOIRON classification of hemochromatosis
| . | Gene/mutations . | Molecular diagnosis . | Clinical features . | Pathophysiology . |
|---|---|---|---|---|
| HFE-H | HFE (High Fe) | First-level genetic test for C282Y (widely available) | Common In populations of Northern European descent Low penetrance, often requiring cofactors. Adults, typically after the fourth-sixth decades, predominantly in males | Mild hepcidin deficiency, with blunted feedback response to increasing plasma Fe. Hepcidin level mildly reduced or inappropriately normal for iron stores. |
| Non–HFE-H | HJV (hemojuvelin) HAMP (hepcidin) TFR2 (transferrin receptor 2) SLC40A1 (ferroportin)a Digenic inheritance possible (PIG-A)b (other still unknown) | Second-level genetic test (NGS panel looking for “private” mutations in iron genes) available at referral centers and requiring expert interpretation | Rare or ultrarare Any population High penetrance (negligible role for cofactors) Juvenile onset (esp. HJV and HAMP) Both sexes equally affected Heart and endocrine complications often predominant (esp. HJV and HAMP) | Severe hepcidin deficiency (or, rarely, hepcidin resistance in gain-of-function SLC40A1 mutations). Hepcidin levels very low to undetectable (increased in hepcidin resistance). |
| . | Gene/mutations . | Molecular diagnosis . | Clinical features . | Pathophysiology . |
|---|---|---|---|---|
| HFE-H | HFE (High Fe) | First-level genetic test for C282Y (widely available) | Common In populations of Northern European descent Low penetrance, often requiring cofactors. Adults, typically after the fourth-sixth decades, predominantly in males | Mild hepcidin deficiency, with blunted feedback response to increasing plasma Fe. Hepcidin level mildly reduced or inappropriately normal for iron stores. |
| Non–HFE-H | HJV (hemojuvelin) HAMP (hepcidin) TFR2 (transferrin receptor 2) SLC40A1 (ferroportin)a Digenic inheritance possible (PIG-A)b (other still unknown) | Second-level genetic test (NGS panel looking for “private” mutations in iron genes) available at referral centers and requiring expert interpretation | Rare or ultrarare Any population High penetrance (negligible role for cofactors) Juvenile onset (esp. HJV and HAMP) Both sexes equally affected Heart and endocrine complications often predominant (esp. HJV and HAMP) | Severe hepcidin deficiency (or, rarely, hepcidin resistance in gain-of-function SLC40A1 mutations). Hepcidin levels very low to undetectable (increased in hepcidin resistance). |
The main features of HFE—and non-HFE-H—are illustrated. Decreased production of hepcidin is the common pathophysiological background.
Rare gain-of-function mutations in the gene encoding ferroportin (SLC40A1) give rise to a decreased hepcidin effect because of ferroportin resistance. Loss-of-function SLC40A1 mutations lead to ferroportin disease, a distinct disorder.3
Recently, a new pediatric form of iron overload due to constitutional PIGA (phosphatidylinositol glycan anchor biosynthesis class A) mutations affecting membrane binding of hemojuvelin has been described.40At variance with hemochromatosis, it is mainly characterized by neurologic dysfunction.40 In rare cases of hemochromatosis no mutation is found in the listed genes, indicating the role of still unknown gene(s).
Fe, iron.
Adapted from Girelli et al.3