Ferroportin disease

Ferroportin disease, also known as hemochromatosis type 4 or SLC40A1-related hemochromatosis, is a rare inherited iron overload disorder caused by mutations in the SLC40A1 gene, which encodes ferroportin — the only known cellular iron exporter in humans. Unlike classical hereditary hemochromatosis (HFE-related), ferroportin disease follows an autosomal dominant inheritance pattern. There are two recognized subtypes: Type A (loss-of-function mutations) is characterized by iron accumulation predominantly in macrophages of the reticuloendothelial system (liver Kupffer cells, spleen), leading to elevated serum ferritin with low-to-normal transferrin saturation, and patients may have poor tolerance to phlebotomy. Type B (gain-of-function mutations) more closely resembles classical hemochromatosis, with iron loading in hepatocytes, elevated transferrin saturation, and better tolerance to phlebotomy. The disease primarily affects the liver, spleen, and other organs of the reticuloendothelial system. Key clinical features include hyperferritinemia, which is often the earliest laboratory finding, and progressive iron overload that can lead to hepatic fibrosis, cirrhosis, and organ damage if untreated. Some patients may also develop fatigue, joint pain, and abdominal discomfort. Compared to other forms of hemochromatosis, ferroportin disease tends to have a milder clinical course, though significant variability exists between individuals and between the two subtypes. Treatment depends on the subtype. For Type B ferroportin disease, therapeutic phlebotomy is the mainstay of treatment, similar to classical hemochromatosis. For Type A, phlebotomy must be approached cautiously because patients may develop anemia due to impaired iron recycling from macrophages, despite elevated ferritin levels. In such cases, low-volume or less frequent phlebotomy may be used, and serum ferritin and hemoglobin levels must be closely monitored. Iron chelation therapy may be considered in select cases. Genetic counseling is recommended for affected families given the autosomal dominant inheritance pattern.

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