Hemochromatosis
From Iusmgenetics
(Difference between revisions)
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===General background information=== | ===General background information=== | ||
*Toxic overload of iron buildup | *Toxic overload of iron buildup | ||
+ | **Humans don't have a good way to excrete Fe. | ||
*Pleotrophic: affects liver, heart, pancreas, endocrine system, and joints | *Pleotrophic: affects liver, heart, pancreas, endocrine system, and joints | ||
- | *2-5 / 1000 '''Caucasians''' | + | **Classic example of an amorphous presentation |
+ | *Common: 2-5 / 1000 '''Caucasians''' | ||
*May be surprisingly prevalent for it's benefit during stressful times (war, famine, pregnancy). | *May be surprisingly prevalent for it's benefit during stressful times (war, famine, pregnancy). | ||
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*HFE | *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) | **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) | ||
+ | **Found it by mapping human genome, then looked more specifically in that area associated with the disease. | ||
*Most common mutation is '''Cys282Tyr''' (C282Y) in 85% of patients | *Most common mutation is '''Cys282Tyr''' (C282Y) in 85% of patients | ||
**Perhaps there is a founder effect? | **Perhaps there is a founder effect? | ||
Line 76: | Line 79: | ||
*Elevated serum ferritin | *Elevated serum ferritin | ||
*Hemochromatosis and the HFE gene is a candidate for genetic screening. | *Hemochromatosis and the HFE gene is a candidate for genetic screening. | ||
+ | |||
+ | |||
+ | *Considered for screening | ||
+ | **However, there is low penetrance so there is debate because there would likely be many false positives. | ||
===Treatment=== | ===Treatment=== |
Revision as of 22:56, 18 October 2011
Contents |
Hemochromatosis
General background information
- Toxic overload of iron buildup
- Humans don't have a good way to excrete Fe.
- Pleotrophic: affects liver, heart, pancreas, endocrine system, and joints
- Classic example of an amorphous presentation
- Common: 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)
- Found it by mapping human genome, then looked more specifically in that area associated with the disease.
- 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.
- Considered for screening
- However, there is low penetrance so there is debate because there would likely be many false positives.
Treatment
- Treat with phebotomy (blood letting).