Mutations in transferrin receptor 2 (TFR2) gene that codes for a protein that appears to control saturation of transferrin, can cause a rare autosomal recessive form of hemochromatosis.
Type 4 hereditary hemochromatosis (ferroportin disease) occurs largely in people of southern European ancestry. It results from an autosomal dominant mutation in the SLC40A1 gene and affects the ability of ferroportin to bind hepcidin.
In transferrin deficiency (hypotransferrinemia or atransferrinemia), absorbed iron that enters the portal system not bound to transferrin is deposited in the liver. Subsequent iron transfer to sites of red blood cell production is reduced because of transferrin deficiency.
In ceruloplasmin deficiency (aceruloplasminemia), lack of ferroxidase causes defective conversion of Fe2+ to Fe3+; such conversion is necessary for binding to transferrin. Defective transferrin binding impairs the movement of iron from intracellular stores to plasma transport, resulting in accumulation of iron in tissues.
Hereditary hemochromatosis is characterized by excessive iron (Fe) accumulation that results in tissue damage.
Manifestations can include systemic symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy. Diagnosis is by elevated serum ferritin, iron, and transferrin saturation levels and confirmed by a gene assay. Treatment is usually with serial phlebotomies.