Hereditary Hemochromatosis

1
HereditaryHemochromatosis

• James Foxhall
• UCSF-FCM Noon Conference
• August 24, 2005

2
Case Presentation

• 56 yo white male, previously healthy, with
  gradual onset of fatigue, insomnia, and myalgias
  over the past few years.
• CBC and Chemistries normal.
• Alkaline phosphatase elevated (140s)
• Minimally elevated AST ALT

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Case Presentation (cont.)

• Hep serologies normal
• Alpha-1 antitrypsin normal
• Trial of antidepressants yielded no reduction in
  symptoms of fatigue.
• Lyme titers ordered along with iron studies.
• Lyme titers cancelled when results of Fe studies
  were known

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Case Presentation (cont.)

• Ferritin 6,920
• Transferrin Saturation 100
• Total Iron Binding Capacity 238

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HereditaryHemochromatosis

• Autosomal recessive disorder
• Harrisons
• A common disorder of iron storage in which
  anincrease in intestinal iron absorption results
  in deposition of excessive amounts of iron in
  parenchymal cells with eventual tissue damage and
  impaired function of organs, especially the
  liver, pancreas, heart, joints, and pituitary.

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Prevalence of Hereditary Hemochromatosis

• Varies by race
• Most common single gene disorder in whites
  Approximately 1/200 are homozygous and 1/10 are
  carriers.
• Latinos 1/3,700
• Blacks 1/7,100
• Pacific Islanders 1/8,300
• Asians 1/2.5 million

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A Bit of History

• An ancient disease, but first described in the
  19th century.
• 1935 Characterized as a hereditary disorder
  associated with excess iron deposition in
  tissues.
• 1970s and 80s Autosomal recessive mode of
  inheritence linked to Chrom 6
• 1996 HFE, the hemochromatosis gene is isolated.

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The Investigation Continues

• While the mutant gene has been identified, our
  understanding of the disease remains clouded.
• We know that the iron homeostasis cascade is
  altered, but specifically how is not known.
• There are, however, some theories.
• To understand it well have to

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Flashback to Medical School
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Iron Homeostasis
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The HFE Defect

• Single base change which results in the
  substitution of tyrosine for cysteine at position
  282 of the protein.
• Role of HFE is not clear
• MHC-I-like protein that interacts with the
  transferrin receptor.
• Mutants have altered interaction with the
  transferrin receptor.

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Some Observations

• Decreased Fe levels are found in the cells of the
  intestinal lumen and in macrophages of patients
  with hemochromatosis
• After an insult such as phlebotomy, nl pts
  increase their iron intake from 1.5 mg per day to
  5 mg per day. Pts with hemochr. Increase their
  iron intake to 8-10 mg/day, and it remains
  elevated.

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HFEs Possible Effect on Iron Homeostasis
Crypt-Programming Model
Hepcidin Model
14
Is the Gut to Blame?
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Or is it the Macrophages?
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Clinical Manifestations
Adapted from Riely CA, Vera SR, Burrell MI, Koff
RS. Inherited liver diseases. AGA clinical
teaching project unit 8. Bethesda, Md. American
Gastroenterological Association, 1993.
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Liver Pathology

• Usually the first organ affected.
• Hepatomegaly present in 95 of symptomatic pts.
• HCC occurs in 30 of pts who develop cirrhosis
  and is the most common cause of death in treated
  pts.
• Portal HTN and varices are rare.

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Cardiac Pathology

• Presenting problem in 15 of pts.
• Mostly CHF and arrhythmias

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Pancreatic Pathology

• Causes diabetes in 65 of pts.
• Affected pts tend to have a family history of
  diabetes, indicating that iron deposition along
  with genetic susceptibility is likely necessary.

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Skin Pathology

• Excessive skin pigmentation is present in 90 of
  symptomatic pts.
• Metallic or slate grey hue is characteristic and
  due to increased iron and melanin in the dermis.

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Pituitary Pathology

• Hypogonadism can develop in men and women.
• Decreased libido, impotence, amenorrhea,
  testicular atrophy, and gynecomastia.

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Joint Pathology

• Arthritic changes in 25-50 of symptomatic pts.
• Often starts in the hands (MCP joints of index
  and middle finger).
• Pseudogout can occur.

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Diagnosis

• Symptoms are often non-specific and include
  weakness, weight loss, skin color changes,
  abdominal pain, and decreased libido.

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Diagnosis (cont.)

• Transferrin saturation gt50
• TS100 x (serum Fe / TIBC)
• Ferritin elevated (gt1000 usually associated with
  cirrhosis).
• N.B. SFGH labs reports iron studies uniquely.
  Percent sat tranferrin sat. TIBC Transferrin
  x 1.25.

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Diagnosis

• Symptomatic patients with abnormal iron studies
  should undergo DNA testing.
• If the mutation is found, first degree relatives
  should be tested.

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Treatment

• Phlebotomy!
• 500 mL of blood lowers the iron content by
  200-250mg.
• May take one to two years of 1/wk to 2/wk blood
  draws to achieve normal ferritin and transferrin
  saturation.

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Should we Screen?

• Initial lab tests are cheap, and could
  potentially identify pts with a prevalent disease
  prior to symptoms.
• DNA test for HFE as screen less attractive b/c of
  cost and unknown penetrance.

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Case Presentation (cont.)

• More than 2 yrs after diagnosis, ferritin levels
  are now lt100.
• Phlebotomy now every 2mo.
• Pt has cirrhosis which is stable and follows with
  the liver clinic.
• Unfortunately, the pts fatigue persists.

29
References

• Brandhagen, DJ, Fairbanks VF, Baldus W.
  Recognition and management of hereditary
  hemochromatosis. AFP. Vol 655, March 1, 2002
  853-60.
• Pietrangelo, A. Hereditary hemochromatosisA new
  look at an old disease. NEJM. Vol 35023, June
  3, 2004 2383-97.
• Powell, LW and Isselbacher, KJ. Hemochromatosis.
  Harrisons Principles of Internal Medicine.
  15th Edition, 2001 2257-61.
• Adams, PC, et al. Hemochromatosis and
  iron-overload screening in a racially diverse
  population. NEJM. Vol 35217, April 28, 2005
  1769-78.