Hemochromatosis
Work in progress!
Hemochromatosis is a hereditary disorder that leads to an increased intestinal iron uptake from food. The excess iron is stored in the parenchymal cells of organs and tissues and thus disrupts their normal function. There are various genotypes that can lead to hemochromatosis. The most common form of the disease is caused by a point mutation in the HFE gene.
Contents
Phenotype
Clinical symptoms include:
- 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 (diabetes mellitus).
- Gonadal dysfunction, hypogonadism and decreased libido.
- heart failure, arrhythmias or pericarditisheart failure
- grey or dark cutaneous (skin) pigmentation
The hemocromatosis phenotype and its harmfulness varies in patients with the same disease causing mutation. Symptoms are caused by a high, toxic iron accumulation in parenchymal cells of important organs, like the heart, the liver or the endocrine glands.
The disease is usually diagnosed in middle aged patients, because the iron accumulates over time and severe symptoms are not immidiately apparent.
Depending on which organs are affected most by the increased iron uptake, the symptoms range from simple biochemical abnormalities to severe diseases such as heart failure and liver cirrhosis.
The individual phenotype varies that much, because the genetic background only gives a predisposition to hemochromatosis. Human and environmental factors play an important role as well.
In general, male indiviuals that have the genetic predisposition, have a higher probability of developing hemochromatosis, supposedly because females have an overall higher iron loss due to menstruation.
Cross references
see also the description in
http://en.wikipedia.org/wiki/Hereditary_haemochromatosis
http://omim.org/entry/235200
http://www.gastrojournal.org/article/S0016-5085%2810%2900872-3/fulltext
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.
Cross references
see also the description in
KEGG ?? TODO
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.
| 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
The HFE gene is located on chromosome 6 on the short arm (p) in region 21.3 (6p21.3) and consists of 7 exons spanning 12 kb. It encodes for the HFE protein, which is a membrane protein similar to the MHC class I proteins and HFE wthuw associates with beta2-microglobulin. HFE binds to the transferrin receptor 2 (TfR2) and is thought to play a role in the pathway that senses the serum iron level (transferrin-bound and un-unbound) and regulates the expression of hepcidin.
A guanin to adenine transition at position 845 in the HFE gene lead 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 normally forms a disolfide bond in the unmutated protein. The tyrosine in the mutated protein therefore disrupts the structure and aberogates the binding of HFE to beta-2-microglobulin.
Cross references
see also the description in
http://omim.org/entry/613609
http://omim.org/entry/235200
http://www.genecards.org/cgi-bin/carddisp.pl?gene=HFE&search=HFE&suff=txt
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
Reference sequence
protein sequence:
>gi|1890180|emb|CAB07442.1| HFE [Homo sapiens] MGPRARPALLLLMLLQTAVLQGRLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEP RTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQVILGCEMQEDNSTEGYWKYGY DGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLV KVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRY TCQVEHPGLDQPLIVIWEPSPSGTLVIGVISGIAVFVVILFIGILFIILRKRQGSRGAMGHYVLAERE
http://www.ncbi.nlm.nih.gov/protein/1890180?report=fasta
Diagnosis and Treatment
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
http://omim.org/entry/235200
http://en.wikipedia.org/wiki/Hereditary_haemochromatosis
http://www.genecards.org/cgi-bin/carddisp.pl?gene=HFE&search=HFE&suff=txt
