Hemochromatosis

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Hemochromatosis is a hereditary disorder that leads to an iron overload in organs due to an increased iron absorption from food. It is caused by a point mutation in one of several genes.

Phenotype

The hemocromatosis phenotype and its harmfulness varies in patients. Symptoms are caused by a high toxic iron accumulation in parenchymal cells of important organs, e.g. heart, liver, endocrine glands. The disease is usually diagnosed in middle aged patients. Based on the affected organs, the symptoms range from simple biochemical abnormalities to severe diseases such as heart failure and liver cirhosis.

The individual phenotype varies that much, because the genetic background only gived a predisposition to hemochromatosis. Human and environmental factors play an important role as well. For example, C282Y HFE homozygous individuals that drink extensive alcohol have a much higher penetrance to develop a hemachromatosis-related liver cirhosis. In general, male have a higher probability of developping hemochromatosis, supposedly because of female menstruation.

Clinical representation includes:

• tiredness
• joint and bone pain
• destructive arthritis

• liver fibrosis and cirrhosis, increased risk to develop hepatocellular carcinoma
• Glucose intolerance and insulin resistance due to damages in the pancreas (many patients have diabetes mellitus).

• Gonadal dysfunction, hypogonadism and decreased libido.

• heart failure, arrhythmias or pericarditisheart failure

• grey or dark cutaneous (skin) pigmentation

Biochemical disease mechanism

The basis for hemocromatosis is a hepcidin deficiency. Hepcidin is a protein that is responsible for the downregulation of iron entry into the bloodstream. Patients do not suffer from a perturbance of the iron metabolism, which works normal, but from an increased iron uptake into the blood.

Iron Metabolism

Iron is only able to enter the human body in the small intestines.

Genetics and Inheritance

There are several different types of hemochromatosis. Each type is connected to defects in the iron uptake regulation through hepcdin. The most common and less severe type is caused by a mutation in the HFE gene on chromosome 6. The other types are rare and based on a mutations in the TfR2 gene or, in the case of juvenile hemochromatisis, mutations in the HJV or HAMP (Hepcidin) gene. Mutations in the FPN(Ferroportin) gene can also result in hemachromatosis like symptoms, but it is often termed ferroportin disease. The mutations leads to a hepcidin resistance and thus to an iron hyperabsorbtion from the diet, although the hepcidin production is not impaired in this patients.

Homozygosity for one of the above mentioned mutations only results in a certain predisposition to hemochromatosis, but not all persons with this genetic background develop the disease. It depends on other influences on the iron metabolism, such as abusive drinking.

Characterisation of the various forms of hemochromatosis

form	male/female	age	non-/caucasian
HFE	male	40-50 years	caucasian
TfR2	male or female	30-40 years	caucasian or non-caucasian
HJV, HAMP	male or female	15-20 years	caucasian or non-caucasian
Ferroportin disease	male or female	10-80 years	caucasian or non-caucasian

Hemochromatosis is an autosomal recessive inherited disorder with reduced penetrance in female. The HFE C282Y mutation is a very common one with a homozygozity prevalence of 1:200 to 1:300 in white persons, why it is a polymorphism rather than a disease mutation. But among Asians, Hispanics or black persons it is much less common. Roughly 80% of northern European hemachromatosis patients are homozygous for HFE C282Y. A Celtic or Vikin ancester was probably the first person having the mutation. Since hemochromatisis does not infect reproduction, the mutation spread through populations. The C282Y allel has a frequency of 12.5% in Ireland and 0% in southern Europe, but the mean frequency among white individuals is 6%.

H63D is anothe HFE polymorphism with less geographic distribution and a higher prevalence of 14%, but it has nearly no penetrance. The S65C polymorphism is associated with high iron levels when it is inherited together with C282Y on one allele.

All the other non-HFE hemochromatosis types are spread throughout the world, independent of any race, but they are much rarer. In 50% of families with a case of juvenile hemachromatose has the G320V mutation in the HJV gene been detected.

This wiki entry focuses on the HFE C282Y mutation, because it is the most common reason for hemachromatosis in northern Europe.

HFE C282Y

[[File:Hfe c282y.png|frame|HFE dimer with cystein at position 282 highlited in red. Source: PDB]

The HFE gene is located on chromosome 6 at 6p21.3 and consists of 7 exons spanning 12 kb.

A guanin to adenine transition at position 845 in the HFE gene leas to the C282Y substitiution in the protein sequence. This missense mutation affects a highly conserved cystein in the alpha-3 loop of the HFE protein that forms a disolfide bond in the functional protein. The tyrosine in the mutated protein therefore disrupte the structure and aberogates the binding of HFE to beta-2-microglobulin.

Mutations

Each of the above mentioned different types of hemochromatosis is caused by a different mutation.

HFE: C282Y, H63D
TfR2: Y250X (nonsense mutation, it truncates TfR2 at amoino acid 250)
HJV: G320V
HAMP: several, no specific
FPN: C326S and C326Y

Diagnosis and Treatment

Algorithm for the diagnosis of hemochromatosis. Source: http://www.gastrojournal.org/article/S0016-5085%2810%2900872-3/fulltext

Hemochromatosis is diagnosed in patients with an unnormal high transferrin saturation (TS) and, in later stages, increased serum ferritin levels. The transferrin saturation denotes the concentration of free iron in proportion to the concentration of transferin in the blood serum. However, the diagnosis should always be supported by a gene test for HFE C282Y homyozygocity. Inflammation, metabolic disorders, diabetes mellitus, alcohol abuse and liver cell necrosis can also lead to an increased serum ferritin level. On the other hand, a finding of normal serum ferritin level alsways excludes hemochromatosis.

Since iron can only be removed from the system by blood loss, the only possible treatment is phlebotomy (bloodletting). It is aimed to reduce the iron content in the body. The first step of the iron-depletion treatment is to induce a slightly iron-deficient state in the body. Therfore, 400-500 ml blood are removed weekly. After 1 to 2 years a serum ferrition level of 20-50 μg/l is reached. In the long term, a maintenance therapy with two to four phlebotomies a year is then enough to keep the serum ferritin level between 50-100 μg/l.

A low iron diet can help. The life expectancy of dignosed and treated hemochromatosis patients withour complications is comparable to that of the normal population. But early diagnosis and initation of therapy increase survival time.

Resources

The entry is based on several resources:

http://www.gastrojournal.org/article/S0016-5085%2810%2900872-3/fulltext

http://omim.org/entry/613609