Haemochromatosis

Abstract

Haemochromatosis is defined as systemic iron overload of genetic origin, caused by a reduction in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin-ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified cellular iron exporter. The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein. Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer. Mutations in SLC40A1 (also known as FPN1; encoding ferroportin) that prevent hepcidin-ferroportin binding also cause haemochromatosis. Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive and includes clinical examination, assessment of plasma iron parameters, imaging and genetic testing. The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. Hepcidin supplementation might be an innovative future approach.

Ablation of Hepatocyte Smad1, Smad5, and Smad8 Causes Severe Tissue Iron Loading and Liver Fibrosis in Mice

“…The Smad158;Alb‐Cre + mice provide a model to study the mechanisms of liver injury and fibrosis in hemochromatosis. In contrast to humans, liver injury and fibrosis are not reported in most mouse hemochromatosis models . For example, no liver injury or fibrosis was reported in mice lacking Hfe or Hjv , even after a high‐iron diet .…”

“…Tissue iron accumulation in human hemochromatosis patients leads to injury and organ dysfunction . Although mouse models of hemochromatosis phenocopy the iron overload seen in humans, most mouse models do not develop tissue injury and fibrosis .…”

“…Tissue iron accumulation in human hemochromatosis patients leads to injury and organ dysfunction. (3) Although mouse models of hemochromatosis phenocopy the iron overload seen in humans, most mouse models do not develop tissue injury and fibrosis. (31)(32)(33)(34) The severity of liver iron accumulation in Smad158;Alb-Cre + mice led us to examine for evidence of liver damage and fibrosis.…”

“…The importance of hepcidin was recognized when mutations were linked to juvenile hemochromatosis, characterized by early‐onset tissue iron loading that leads to organ dysfunction including cirrhosis, hypogonadism, cardiomyopathy, and diabetes mellitus . Subsequently, the inability of iron to appropriately induce hepcidin was recognized as the common pathogenic mechanism for other genetic causes of hemochromatosis, including homeostatic iron regulator ( HFE ), transferrin receptor 2 ( TFR2 ), and hemojuvelin ( HJV ) mutations …”

“…(2) Subsequently, the inability of iron to appropriately induce hepcidin was recognized as the common pathogenic mechanism for other genetic causes of hemochromatosis, including homeostatic iron regulator (HFE), transferrin receptor 2 (TFR2), and hemojuvelin (HJV) mutations. (3) Bone morphogenetic protein (BMP)-SMAD signaling is a central pathway for hepcidin regulation by iron. (4) Tissue iron stores induce BMP6 and BMP2 ligand expression in liver endothelial cells.…”