Hemochromatosis

From Iusmgenetics

Contents 1 Hemochromatosis 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

[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

[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

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[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).

[edit] Recent research

[edit] 5 important facts

[edit] Not to be confused with

[edit] Questions and answers