Hemochromatosis 2011
Contents
Summary
Iron is conserved by all living cells because it is necessary for aerobic respiration. But an excessive amount of iron stored in the body is toxic. Hemochromatosis is the generally used term if the body stores too much iron. There are two different forms with subtypes of hemochromatosis possible: primary and secondary.
Primary hemochromatosis is usually caused by a genetic problem or mutation, resulting in storing too much iron due malfunction at the regulation of the the iron absorption.
Secondary hemochromatosis can be temporarily acquired if a person is affected by chronic alcoholism or received many blood transfusion in a short time.
This entry is about the primary form and especially type 1 of it. It is a hereditary autosomal recessiv genetic disorder caused by a mutation of the HFE-Gene and the breakdown of the regulation of the iron absorption. It was first described by Armand Trousseau in 1865 in a report about diabetes.
Phenotype
| Symptoms |
|---|
| decoloration/darkening of skin (also known as bronzening) |
| weakness |
| fatigue |
| heart failure |
| diabetes |
| arthritis (iron in joints) |
| loss of weight |
| loss of body hair |
| loss of sexual energy |
| liver cirrhosis |
| liver swelling |
Primary Hemochromatosis occurs at different subtypes, each of them caused by a mutation of a important protein. But all of these have in common that an excess of iron is deposited in different organs leading to their malfunction. The symptoms occur mostly between the fourth to fifth decade of lifetime. Women show symptoms typically later than males because of the menstruation and the resulting loss of blood.
Type 1: HFE OMIM: #235200 classical haemochromatosis also called hereditary hemochromatosis
Mutation at the HFE gene on the short arm of the chromosome 6 position 6p21.3 encoding the protein hereditary hemochromatosis.
Type 2A: HFE2A OMIM: #602390 juvenile haemochromatosis (autosomal recessive)
Mutation at the HJV gene on the long arm of the chromosome 1 position 1q21 encoding the protein hemojuvelin.
Type 2B: HFE2B OMIM: #606464 juvenile haemochromatosis (autosomal recessive)
Mutation at the HAMP gene on the long arm of the chromosome 19 position 1q13 enconding the protein hepcidin
Type 3: HFE3 OMIM: #604250 (autosomal recessive)
Mutation at the TFR2 gene on the long arm of the chromosome 7 position 7q22 enconding the protein transferrin receptor 2.
Type 4: HFE4 OMIM: #604653 African iron overload (autosomal dominant)
Mutation at the SLC40A1 gene on the long arm of the chromosome 2 position 2q32.30 encoding the protein ferroportin.
There are some more subtypes, but their frequency in population is too rare, to go in detail.
Diagnosis
It can be diagnosed by a simple blood test or a liver biopsy. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/000327.htm</ref>
- Blood test: The concentrations of serum ferritin (SF, amount of stored iron) and serum iron (SI, amount of free or unboud iron) and the percentage of transferrin saturation (TS, effencieny of binding iron) are measured. It's likely to be affected hemochromatosis if these values are all higher than the average/recommend ones. Other blood elements can also be used for diagnosing like the level of blood sugar (glucose) or the concentration of alpha fetoprotein.
- Liver biopsy: A tiny part of the tissue of the liver is extracted during a local anesthetic and afterwards examined. If the level of the stored iron at the liver is higher than average/recommend values, it is recommend to do a blood test of the protein concentrations. This is a reliable testing because of the breakdown of the regulation the body stores agumented iron at the liver.
Treatment
There are two treatments which can but must not be combined to remove iron from the body.
- Phlebotomy: Around .5 liter of blood are extracted once a week, until iron level begin to even out to normal level. This prodecure is repeated as long it needs to maintain the iron level. After the initial loss the frequency of the action can be slightly lowered to once a month but have to kept on during the whole life.
- Diet: A special diet which includes only food with a low iron level is also good and necessary. This diet prohibits every food or drinks, which directly affect the liver like alcohol. If used together with frequent phlebotomy the iron level will lower even faster to normal level. Therefore it compensates the need for phlebotomy and lowers the frequency significant. The diet has to be kept during the whole life, too.
Cross-references
The disesase is also described in detail at
Biochemical disease mechanism
The HFE-Gene alleviates the binding of transferrin which is the carrier protein for iron in the blood cyclus. With a mutated HFE-Gen, the intestines interpret a strong transferrin signal as an deficient in iron. Therefore the cells start to import iron, which leads to an iron overload.
Gene
The HFE (High Iron FE) gene is located on the short arm (p) of the chromosome 6 at position 6p22, it is between base pair 26,087,447 to 26,097,058. It contains 7 exons spanning around 12 kb and maps to the MHC region 6p21.3 in telomeric position. Therefore the position is almost everywhere defined as 6p21.3. There are homologs in almost all other vertebrate but the position of gene differs greatly.
TODO! resize chromosome picture to thumbnail! (why does it not work? o.O)
Protein
A MHC-related 6 domain membrane protein<ref>http://www.pdb.org/pdb/explore/explore.do?structureId=1A6Z</ref>. It is located in all tissues except for the brain<ref>http://www.uniprot.org/uniprot/Q30201</ref>. HFE forms a complex with the transferrin receptor to lower the affinity for iron-loaded transferrin<ref>http://www.ncbi.nlm.nih.gov/pubmed/9465039</ref>. If the Protein has a disfunction due to a mutation, the repression of the iron import become disturbed because the affinity of the receptor for transferrin is not reduced. The exact mechanisms are not yet clear. Some mutations have a direct influence of the affinity, other decrase the ability to form complexes with beta2-microglobulin but have no effect on the affinity to bind iron-loaded transferrin.
Function
HFE is a regulator protein which forms a stable complex with the transferrin receptor in the cell membrane. By complexing with the receptor, it reduces the affinity for iron-loaded transferrin. If this function is disturbed, the cell starts an uncontroled iron import.
Cross-references
Links to proteins that are involved in causing the disease
- KEGG at Hemochromatosis
- UniProt at Hemochromatosis Protein (HLA-H)
- UniProt at Hepcidin (HAMP)
- UniProt at (Sero)transferrin (TF)
- UniProt at Transferrin receptor protein 1 (TFR)
- UniProt at Transferrin receptor protein 2 (TF2)
- PDB at HFE (HUMAN) HEMOCHROMATOSIS PROTEIN
Mutations
There are 11 disease causing allelic variants of the HFE-gene available at the OMIM database.
- HFE, CYS282TYR
- HFE, HIS63ASP
- HFE, SER65CYS
- HFE, 5569G-A
- HFE, VAL53MET
- HFE, VAL59MET
- HFE, GLN127HIS
- HFE, ARG330MET
- HFE, ILE105THR
- HFE, GLY93ARG
- HFE, GLN283PRO
Reference sequence
Which sequence does not cause the disease and is most often found in the population.
Neutral mutations
Disease causing mutations
References
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