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E-Case

October 15-22, 2001

Melissa Chen R-2

A 23 year old woman tells you in clinic that her father was just diagnosed with hemachromatosis, and she was told that she should see her doctor.  She is otherwise feeling healthy and has no complaints.  PE is benign.

What workup will you do?

Hemochromatosis is the most common inherited disease in those of Nordic/Celtic ancestry - about 10% are heterozygous for the C282Y mutation.  Mutations in this gene cause increased iron absorption, which results in buildup of iron in tissues such as the liver, pancreas, heart, pituitary, and thyroid.

  • Genetic testing for C282Y and H63D mutations:  Patients develop hemochromatosis if they are homozygous for the C282Y mutation, or have a C282Y mutation on one chromosome and an H63D mutation on another (the compound heterozygous state).
  • Baseline LFTs, CBC, and iron studies (Iron, TIBC) and fasting ferritin.
  • Criteria for being able to nix the liver biopsy:
    • Homozygous for C282Y, ferritin <1000, normal AST, and no hepatomegaly.

When do you decide to initiate therapeutic phlebotomy?

  • When ferritin >200 in nonpregnant women;  >300 in men;  >500 in pregnant women.
  • Initially, schedule phlebotomy weekly.  Don't allow Hct to fall by more than 20% of the prior level.  Check ferritin every 10-20 phlebotomies.  Goal:  ferritin <50.

What are the clinical manifestations?

Iron accumulates at a rate of about 1gram/year.  End organ damage won't happen until > 20 grams accumulates, so patients usually won't get symptoms until they're over 40 years old.  If therapeutic phlebotomy is initiated before cirrhosis or diabetes develops, survival returns to normal.  Many symptoms can be prevented or improved with therapeutic phlebotomy.

  1. Liver disease:  hepatomegaly, elevated LFTs, cirrhosis.
    Hepatocellular carcinoma risk greatly increased in those who have developed cirrhosis.
  2. Diabetes from pancreatic iron deposition. Patients on insulin may require less after iron removal.
  3. Arthropathy:  Typically 2nd and 3rd MCP joint, wrist.  Often looks like CPPD.  Unaffected by extent of iron accumulation or iron removal.
  4. Dilated cardiomyopathy.  Most common EKG abnormality is ventricular ectopy.
  5. Decreased libido / secondary hypogonadism from iron deposition in pituitary cells
  6. Osteoporosis (especially if hypogonadal)
  7. Hypothyroidism from iron deposition in thyroid.
  8. Susceptibility to certain infections:  Hemochromatosis patients shouldn't eat uncooked seafood - they're particularly susceptible to listeria, yersinia, and vibrio infections.

When would you screen a person without a family history?

  • Increased LFTs
  • Decreased libido at a younger age than you might expect
  • Characteristic arthropathy (2nd and 3rd MCPs).

When screening, note that getting a fasting level of the ferritin eliminates 80% of false positive results.

References:

Edwards, Corwin and James Kushner.  "Current Concepts:  Screening for Hemochromatosis."  NEJM 328 (22), 3 June 1993:  1616-1620. 

Powell, Lawrie and Thomas Yapp.  "Hemochromatosis."  Clinics in Liver Disease 4(1) Feb 2000: 211-228.  (Next to UpToDate, this was the most helpful source for general info.)

UpToDate.