OBSOLETE: Hemochromatosis type 4

Hemochromatosis type 4, also known as ferroportin disease, is a hereditary iron overload disorder caused by mutations in the SLC40A1 gene, which encodes ferroportin — the only known cellular iron exporter in humans. This Orphanet entry (139491) is marked as OBSOLETE, meaning it has been reclassified or merged into other entries. Hemochromatosis type 4 has been subdivided into two distinct subtypes: ferroportin disease type A (loss-of-function mutations) and ferroportin disease type B (gain-of-function mutations), which differ in their clinical presentation and iron loading patterns. In ferroportin disease type A, iron accumulates predominantly in macrophages (reticuloendothelial cells) of the liver and spleen, leading to elevated serum ferritin with low-to-normal transferrin saturation. Patients may tolerate phlebotomy poorly. In type B, the phenotype more closely resembles classic hereditary hemochromatosis, with parenchymal iron loading in hepatocytes, elevated transferrin saturation, and potential complications including liver fibrosis, cirrhosis, diabetes mellitus, cardiomyopathy, skin hyperpigmentation, and arthropathy. Unlike the more common HFE-related hemochromatosis (type 1), hemochromatosis type 4 follows an autosomal dominant inheritance pattern, meaning only one copy of the mutated gene is sufficient to cause disease. Management depends on the subtype: type B generally responds well to phlebotomy therapy, while type A patients may develop anemia with aggressive phlebotomy and require a more cautious approach. Monitoring of serum ferritin, transferrin saturation, and organ iron stores via MRI is recommended. Patients should be referred to a hepatologist or hematologist experienced in iron overload disorders for individualized treatment planning.

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