Introduction:

Haemochromatosis is an autosomal recessive disorder characterized by abnormal absorption of dietary iron in the small intestine, and excess iron deposits in various joints and organs of the body, particularly the liver (McKenzie, 2004.) It has been found to be caused by mutations of the HFE gene on chromosome 6, which is a gene associated with the body's regulation of iron absorption (Hash, 2001.)

Prevalence:

Haemochromatosis is the most common genetic disorder in people with northern European ancestry (McKenzie, 2004.) It is thought to have originated as a chance defect in a single celtic or viking ancestor approximately 2,000 years ago (O'Neil, 2005.) It is estimated that 1 in 200 caucasions in the United States are homozygous for the mutated gene, but there may be as many as 1 in 150 cases in some populations (Hash, 2001.)

Genetic Background:

Primary haemochromatosis is caused by mutations of the HFE gene located on chromosome 6 (6q21,3), which was first identified in 1996. HFE is a transmembrane protein located in crypt cells of the duodenum, as well as in other cells. It is associated with B2-microglobulin and Transferrin Receptor (TfR). HFE binds to B2-microglobulin and TfR on cells, and regulates the receptor's interaction with transferrin. It acts by decreasing the affinity of the TfR for the iron bound transferrin (Tf-Fe), thus regulating iron absorption and uptake (McKenzie, 2004.) The production of HFE protein is thought to be regulated by a number of iron regulating proteins, but the exact mechanisms are unknown (Hash, 2001.)

The most common mutation of the HFE gene in haemochromatosis cases is found on position 282 of the protein. The mutation is a single missense in which cystein is replaced by tyrosine: cys282 -> C282Y. If only one gene is inherited, the patient is heterozygous, but if two mutated genes are inherited, the patient is homozygous for the C282Y mutation. More than 90% of patients homozygous for the C282Y gene mutation exhibit phenotypic expressions of the disease, ie. significant iron overload. Heterozygous C282Y cases rarely present phenotypic expressions (O'Neil, 2005.)

A second, less common mutation of the HFE gene is found on position 63 of the protein, in which histidine is replaced by aspartate: his63 -> asp: H63D. Patients who inherit two mutated H63D genes are homozygous to the mutation, and when one C282Y gene is accompanied by a H63D gene, this combination is referred to as "compound heterozygous." Compund heterozygous rarely present with phenotypic expression.

Another mutation which has been identified, but is a very rare occurance, is ser65 -> cys: S65C (McKenzie, 2004.)

Symptoms and Clinical Features:

Only a small proportion of patients homozygous for a HFE gene mutation present with clinical features of the disease (Hoffbrand, 2006.) The lack of specific symptoms of iron overload disorders make it difficult to diagnose haemochromatosis. Symptoms which due appear are due to high serrum ferretin levels in the body. Haemochromatosis is more commonly expressed in males rather than females, as it is believed that natural iron loss through menstruation and childbirth may compensate for the excessive iron absorption (O'Neil, 2005.) By the age of 40, normal total body iron stores are approximately 4g. In cases of haemochromatosis, these body iron stores may reach as high as 40-60g (Underwood, 2004.)