Non-HFE haemochromatosis

Table 1 Genetic, clinical and laboratory features of the various types of Hereditary Haemochromatosis

HHType	Gene	Inheritance	Clinical features	Laboratoryfindings	Liver pathology	Functional consequences ofmutations
1	HFE	Autosomal recessive	May include: fatigue, lethargy, arthropathy, skin pigmentation, liver damage, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadotropic hypogonadism	↑ serum ferritin, ↑ transferrin saturation	Hepatocyte iron loading, fibrosis, cirrhosis	Impaired hepcidin regulation by iron, leading to increased intestinal iron absorption and release of iron from reticuloendothelial cells
2A	Hemojuvelin(HJV)	Autosomal recessive	As for HFE. Earlier onset (< 30 yr). Cardiomyopathy and hypogonadism more prevalent.	↑ serum ferritin, ↑ transferrin saturation	Hepatocyte iron loading, fibrosis, cirrhosis	Loss of hepcidin regulation, leading to increased intestinal iron absorption and release of iron from reticuloendothelial cells
2B	Hepcidin(HAMP)	Autosomal recessive	As for HFE. Earlier onset (< 30 yr). Cardiomyopathy and hypogonadism more prevalent.	↑ serum ferritin, ↑ transferrin saturation	Hepatocyte iron loading, fibrosis, cirrhosis	No/inactive hepcidin, leading to maximal iron absorption and release of iron from reticuloendothelial cells
3	TransferrinReceptor 2(TfR2)	Autosomal recessive	As for HFE.	↑ serum ferritin, ↑ transferrin saturation	Hepatocyte iron loading, fibrosis, cirrhosis	Impaired hepcidin regulation by iron, leading to increased intestinal iron absorption and release of iron from reticuloendothelial cells
4	Ferroportin(Fpn), SLC40A1, IREG1, MTP1	Autosomal dominant	Typical presentation: as for HFE, except generally milder. May have mild anaemia and lower tolerance to venesection.	↑↑ serum ferritin, normal transferrin saturation	Predominant Kupffer cell iron loading, fibrosis	Reduced ferroportin iron transport ability, leading to accumulation of iron in reticuloendothelial cells
			Atypical: as for HFE	↑ serum ferritin, ↑ transferrin saturation	Predominant hepatocyte iron loading, fibrosis, cirrhosis	Loss of ferroportin regulation by hepcidin, leading to increased intestinal iron absorption and release of iron from reticuloendothelial cells