Hemochromatosis
From Iusmgenetics
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===General background information=== | ===General background information=== | ||
| + | *Toxic overload of iron buildup | ||
| + | *Pleotrophic: affects liver, heart, pancreas, endocrine system, and joints | ||
| + | *2-5 / 1000 '''Caucasians''' | ||
| + | *May be surprisingly prevalent for it's benefit during stressful times (war, famine, pregnancy). | ||
===Mode of inheritance=== | ===Mode of inheritance=== | ||
| + | *Hemochromatosis demonstrates '''variable expressivity''' and '''incomplete penetrance''' | ||
| + | **As "incomplete dominance" suggests, heterozygotes generally have no symptoms | ||
| + | **In face ''even some '''homozygotes''' have no symptoms''; these are usually premenopausal women and the very young. | ||
| + | *'''Sex-influenced''': 5-10 times more common in males | ||
| + | **Note that premenopausal women are detected less often because of menstrual blood loss. | ||
===Single important gene=== | ===Single important gene=== | ||
| + | *HFE | ||
| + | **Found by "positional cloning": "Positional cloning is a method of gene identification in which a gene for a specific phenotype is identified, with only its approximate chromosomal location (but not the function) known, also known as the candidate region." (per wikipedia) | ||
| + | *Most common mutation is '''Cys282Tyr''' (C282Y) in 85% of patients | ||
| + | **Perhaps there is a founder effect? | ||
| + | **Recall that hemochromatosis is especially common in Caucasians | ||
| + | *A second common mutation is '''His63Asp''' | ||
===Etiology=== | ===Etiology=== | ||
| + | *Increased iron uptake (in the duodenum) | ||
| + | *Increased deposition / accumulation in tissues | ||
| + | *Note that humans have no significant mechanism for excreting iron other than cell loss | ||
| + | |||
| + | |||
| + | *Normally, Fe is absorbed in the duodenum via villus enterocytes | ||
| + | *Normally, the liver produces: | ||
| + | **HFE (human hemochromatosis protein): inhibits transferrin from binding the transferrin receptors (TFRC and TFR2); regulates the production of hepciderin | ||
| + | **Transferrin: a glycoprotein carries Fe in serum | ||
| + | **Transferrin receptor (TFRC): facilitates moving transferrin (and therefore Fe) ''into cells'' | ||
| + | **Transferrin receptor 2 (TFR2): facilitates moving transferrin (and therefore Fe) ''into cells'' | ||
| + | **HJV: expressed in liver and bone, signals (through SMADs) to express HAMP (hepcidin) | ||
| + | **HAMP (hepcidin): a regulating amino acid protein that inhibits ferroprotein (which releases Fe from cells). | ||
| + | ***Ferroprotein moves Fe from enterocytes into the blood stream at the gut where Fe is being absorbed from the diet. | ||
| + | ***Ferroprotein moves Fe from macrophages into the ECF, too. | ||
| + | |||
| + | |||
| + | *Mutant forms of HFE inhibit hepcidin (an absorption inhibitor) and thus increase Fe absorption and release. | ||
| + | *Mutant hepcidin, itself, causes uncontrolled release of Fe and therefore '''juvenile hemochromatosis'''. | ||
| + | |||
| + | |||
| + | *Other genes have been implicated in hemochromatosis, also: | ||
| + | **TFR2 (transferrin receptor 2): similar onset to HFE mutations | ||
| + | ***Required for movement of Fe ''into cells'' via the transferrin / transferrin receptor mechanism | ||
| + | **HAMP (hepcidin): causes juvenile hemochromatosis | ||
| + | **HJV (RGMc / HFE2, hemojuvelin): causes juvenile hemochromatosis | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
| + | *Age of onset is variable; '''most common onset is in the 4th decade for males''' | ||
===Phenotypic information=== | ===Phenotypic information=== | ||
| + | *Often a vague clinical vignette | ||
| + | **Hemochromatosis demonstrates '''variable expressivity''' and '''incomplete penetrance''' | ||
| + | *Weakness, lethargy | ||
| + | *Abdominal pain | ||
| + | *Loss of libido | ||
| + | *Amenorrhea | ||
| + | *Loss of body hair | ||
| + | *Hepatomegaly | ||
| + | *Increased skin pigmentation (bronzing) | ||
| + | *Splenomegaly | ||
| + | *Diabetes | ||
| + | *Hypogonadism | ||
| + | |||
| + | |||
| + | *http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/Projects04/Transferrin/hemochromatosis.jpeg | ||
| + | *http://www.pathologieutrecht.nl/images/geknipt_subpagina/Diagnostics/histopathology/liver_with_hemochromatosis.gif | ||
| + | *http://www.pathguy.com/lectures/iron_overload.jpg | ||
===Diagnosis=== | ===Diagnosis=== | ||
| + | *Elevated serum transferrin iron saturation | ||
| + | *Elevated serum ferritin | ||
| + | *Hemochromatosis and the HFE gene is a candidate for genetic screening. | ||
===Treatment=== | ===Treatment=== | ||
| + | *Treat with phebotomy (blood letting). | ||
===Recent research=== | ===Recent research=== | ||
Revision as of 00:49, 14 October 2011
Contents |
Hemochromatosis
General background information
- Toxic overload of iron buildup
- Pleotrophic: affects liver, heart, pancreas, endocrine system, and joints
- 2-5 / 1000 Caucasians
- May be surprisingly prevalent for it's benefit during stressful times (war, famine, pregnancy).
Mode of inheritance
- Hemochromatosis demonstrates variable expressivity and incomplete penetrance
- As "incomplete dominance" suggests, heterozygotes generally have no symptoms
- In face even some homozygotes have no symptoms; these are usually premenopausal women and the very young.
- Sex-influenced: 5-10 times more common in males
- Note that premenopausal women are detected less often because of menstrual blood loss.
Single important gene
- HFE
- Found by "positional cloning": "Positional cloning is a method of gene identification in which a gene for a specific phenotype is identified, with only its approximate chromosomal location (but not the function) known, also known as the candidate region." (per wikipedia)
- Most common mutation is Cys282Tyr (C282Y) in 85% of patients
- Perhaps there is a founder effect?
- Recall that hemochromatosis is especially common in Caucasians
- A second common mutation is His63Asp
Etiology
- Increased iron uptake (in the duodenum)
- Increased deposition / accumulation in tissues
- Note that humans have no significant mechanism for excreting iron other than cell loss
- Normally, Fe is absorbed in the duodenum via villus enterocytes
- Normally, the liver produces:
- HFE (human hemochromatosis protein): inhibits transferrin from binding the transferrin receptors (TFRC and TFR2); regulates the production of hepciderin
- Transferrin: a glycoprotein carries Fe in serum
- Transferrin receptor (TFRC): facilitates moving transferrin (and therefore Fe) into cells
- Transferrin receptor 2 (TFR2): facilitates moving transferrin (and therefore Fe) into cells
- HJV: expressed in liver and bone, signals (through SMADs) to express HAMP (hepcidin)
- HAMP (hepcidin): a regulating amino acid protein that inhibits ferroprotein (which releases Fe from cells).
- Ferroprotein moves Fe from enterocytes into the blood stream at the gut where Fe is being absorbed from the diet.
- Ferroprotein moves Fe from macrophages into the ECF, too.
- Mutant forms of HFE inhibit hepcidin (an absorption inhibitor) and thus increase Fe absorption and release.
- Mutant hepcidin, itself, causes uncontrolled release of Fe and therefore juvenile hemochromatosis.
- Other genes have been implicated in hemochromatosis, also:
- TFR2 (transferrin receptor 2): similar onset to HFE mutations
- Required for movement of Fe into cells via the transferrin / transferrin receptor mechanism
- HAMP (hepcidin): causes juvenile hemochromatosis
- HJV (RGMc / HFE2, hemojuvelin): causes juvenile hemochromatosis
- TFR2 (transferrin receptor 2): similar onset to HFE mutations
Pathogenesis
- Age of onset is variable; most common onset is in the 4th decade for males
Phenotypic information
- Often a vague clinical vignette
- Hemochromatosis demonstrates variable expressivity and incomplete penetrance
- Weakness, lethargy
- Abdominal pain
- Loss of libido
- Amenorrhea
- Loss of body hair
- Hepatomegaly
- Increased skin pigmentation (bronzing)
- Splenomegaly
- Diabetes
- Hypogonadism
Diagnosis
- Elevated serum transferrin iron saturation
- Elevated serum ferritin
- Hemochromatosis and the HFE gene is a candidate for genetic screening.
Treatment
- Treat with phebotomy (blood letting).
