Hemochromatosis
From Iusmgenetics
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===General background information=== | ===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=== | ===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) | ||
+ | **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=== | ===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. | ||
+ | |||
+ | http://www.scielo.cl/fbpe/img/bres/v39n1/fig32.gif | ||
+ | http://courses.washington.edu/conj/bess/iron/ironfig.png | ||
+ | http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/iron.gif | ||
+ | |||
+ | |||
+ | *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. | ||
+ | |||
+ | |||
+ | *Considered for screening | ||
+ | **However, there is low penetrance so there is debate because there would likely be many false positives. | ||
===Treatment=== | ===Treatment=== | ||
+ | *Treat with phebotomy (blood letting). | ||
===Recent research=== | ===Recent research=== |
Current revision as of 15:11, 13 December 2011
Contents |
[edit] Hemochromatosis
[edit] 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).
[edit] 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.
[edit] 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
[edit] 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
[edit] Pathogenesis
- Age of onset is variable; most common onset is in the 4th decade for males
[edit] 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
[edit] 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.
[edit] Treatment
- Treat with phebotomy (blood letting).