Haemochromatosis

Haemochromatosis is a hereditary disease characterized by excessive absorption of dietary iron resulting in a pathological increase in total body iron stores.Excess iron accumulates in tissues and organs disrupting their normal function.The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of British or Irish descent.

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Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon and for most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they suffer premature morbidity. The more common clinical manifestations include:

* Malaise
* Liver cirrhosis (with an increased risk of hepatocellular carcinoma Liver disease is always preceded by evidence of liver dysfunction including elevated serum enzymes specific to the liver.
* Insulin resistance (often patients have already been diagnosed with diabetes mellitus type 2) due to pancreatic damage from iron deposition
* Erectile dysfunction and hypogonadism
* Decreased libido secondary to the above
* Congestive heart failure, arrhythmias or pericarditis
* Arthritis of the hands (especially the first and second MCP joints), but also the knee and shoulder joints
o Adrenal gland (leading to adrenal insufficiency)

Less common findings including:

* Deafness
* Dyskinesias, including Parkinsonian symptoms
* Dysfunction of certain endocrine organs:
o Parathyroid gland (leading to hypocalcaemia)
o Pituitary gland
* A darkish colour to the skin (see pigmentation, hence its name Diabetes bronze when it was first described by Armand Trousseau in 1865)
* An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms:
o Vibrio vulnificus infections from eating seafood
o Listeria monocytogenes
o Yersinia enterocolica
o Salmonella enterica (serotype Typhymurium)
o Klebsiella pneumoniae
o Escherichia coli
o Rhizopus arrhizus
o Mucor species

Males are usually diagnosed after their forties and fifties, and women several decades later, owing to regular iron loss through menstruation (which ceases in menopause). The severity of clinical disease in the hereditary form varies considerably. There is evidence suggesting that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease suffer worse liver disease than those with either condition alone. There are also juvenile forms of hereditary haemochromatosis that present in childhood with the same consequences of iron overload.

Genetics:

The regulation of dietary iron absorption is complex and our understanding is incomplete. One of the better characterized genes responsible for hereditary haemochromatosis is HFE on chromosome 6 which codes for a protein that participates in the regulation of iron absorption. The HFE gene has two common alleles, C282Y and H63D. Heterozygotes for either allele do not manifest clinical iron overload but may display an increased iron uptake. Mutations of the HFE gene account for 90% of the cases of non-transfusional iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, results in clinically evident iron overload. There is considerable debate regarding the penetrance -- the probability of clinical expression of the trait given the genotype -- is for clinical disease in HHC homozygotes. Most, if not all, males homozygous for HFE C282Y will show manifestations of liver dysfunction such as elevated liver-specific enzymes such as serum gamma glutamyltransferase (GGT) by late middle age. Homozygous females can delay the onset of iron accumulation because of iron loss through menstruation. Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the mutation and the presence of other insults to the liver such as alcohol and viral disease. As such the degree to which the liver and other organs is affected, expressivity, is highly variable and is dependent on such these other factors and co-morbidities as well as age at which they are studied for manifestations of disease. Penetrance differs between different populations.