Historia

Metabolic liver disease

Haemochromatosis
William rosenberg

What’s new?
• Hepcidin has been identified as the key regulator of iron absorption and macrophage iron release • at least five different types of hereditary haemochromatosis are now recognized • there is greater awareness that the common genotype of haemochromatosis has a relatively low penetrance

Abstract
Hereditaryhaemochromatosis is the syndrome of end-organ damage due to progressive iron accumulation caused by genetic disorders. it is the commonest genetic disorder of northern europeans. in over 90% of cases the disease is associated with mutations in the HFE gene. identification of the genetic basis of rare causes of hereditary haemochromatosis has greatly increased understanding of iron metabolism. symptoms ofhaemochromatosis are frequently non-specific and include abdominal pain, arthralgia and general malaise. iron accumulates predominantly in the liver, leading to liver dysfunction, and ultimately to cirrhosis and hepatocellular cancer. iron accumulation in the pancreas and joints result in diabetes and degenerative arthritis. diagnosis of the common form of haemochromatosis can be made in themajority of cases using biochemical tests of iron, transferrin and ferritin combined with genetic tests for mutations in HFE. liver biopsy may reveal a characteristic pattern of iron deposition in periportal hepatocytes, with relative Kupffer cell sparing and liver fibrosis that may progress to cirrhosis. treatment with phlebotomy removes iron in haemoglobin, drawing iron out of other tissues. this caneffectively reduce the morbidity and mortality of the disease if diagnosed in the pre-cirrhotic state. due to the poor specificity of symptoms, late diagnosis remains a problem and is associated with significant morbidity and mortality. screening with biochemical and genetic tests, particularly in families, may prevent disease.

• the recognition that penetrance of HFE mutations is variable hasled to a search for other genes that modify patterns of iron loading • transferrin receptor-2, ferroportin, haemojuvelin and hepcidin have been identified as proteins implicated in rare forms of hereditary haemochromatosis

cells that absorb iron (duodenal enterocytes), utilize iron (erythroid precursors) and store iron (hepatocytes and tissue resident macrophages). A newly identifiedβ-defensin-like antimicrobial peptide, hepcidin,1,2 is thought to be the molecule that controls iron absorption and macrophage iron release. The genetic and metabolic defects that cause HHC have recently been defined, increasing knowledge of the condition and making screening, testing and early diagnosis and treatment feasible.

Causes of iron overload
Primary iron overload • Hereditary haemochromatosis(c282Y, transferrin receptor-1, ferroportin) • congenital aceruloplasminaemia • congenital atransferrinaemia Secondary iron overload • Parenteral iron loading (blood transfusion, iron dextran infusions, chronic haemodialysis) • iron-loading anaemia (thalassaemia, sideroblastic anaemia, pyruvate kinase deficiency) • liver disease (post-portacaval anastomosis) • dietary iron overload (prolonged oraliron therapy) Complex iron overload • Juvenile haemochromatosis • Neonatal haemochromatosis • alcoholic liver disease • Porphyria cutanea tarda • african iron overload (bantu siderosis) Table 1

Keywords biochemistry; cirrhosis; genetics; haemochromatosis; iron;
liver; macrophages; phlebotomy

Iron is vital for many basic cellular processes, including the transport of oxygen and electrons. Inexcess, these potent oxidative processes can lead to tissue damage and fibrosis, resulting in organ failure. Iron overload may occur as a genetic condition termed ‘hereditary haemochromatosis’ (HHC) or as a secondary event (Table 1). Tight regulation of iron metabolism is vitally important. Maintenance of iron homeostasis is effected through communication between the

William Rosenberg MA...