Diagnosis Of Hemochromatosis

Hereditary hemochromatosis (HH) is the most prevalent mono-allelic genetic disorder in whites. It should be considered in persons with hepatomegaly, abnormal liver tests, increased skin pigmentation, diabetes, heart disease (arrhythmias e.g. atrial fibrillation, PVC's), arthritis, and hypogonadism. That being said, the diagnosis in the preclinical phase is ideal and persons who are relatives of those already diagnosed should be tested.

Testing can be done by a combination of the following tests: serum ferritin, serum iron and TIBC, genetic testing, and liver biopsy.

Serum ferritin reflects the total body iron content and will be normal early in the disease. An elevated level may suggest hemochromatosis but is non-specific. Ferritin may be elevated in inflammatory states and in other liver diseases, commonly alcoholic liver disease. The serum ferritin is a useful value to follow during treatment with phlebotomy.

Estimation of serum iron concentration and TIBC is a good screening test and will be abnormal early in the disease. If the percent saturation (serum iron X 100 divided by TIBC) is greater than 50 percent, HH should be strongly considered. Serum iron should be measured fasting, while the patient is off any supplementary oral iron, and in females several days off oral contraceptive agents.

Specific genetic testing is now available. There are two common genetic mutations of the hemochromatosis gene (HFE), which is present on chromosome 6. The most significant mutation, C282Y, has been traced back to a common Celtic ancestor who lived sixty to seventy generations ago. It is present commonly in people of Scottish, Irish, English, and French ancestry, which makes it very important in the Atlantic Canada population. About 9 percent of this population is heterozygous and will be carriers, whereas 0.4 percent, or 1:200 individuals, are homozygous, and are diagnosed with HH. The second less serious mutation, involving the same HFE protein, is H63D, also predisposing to HH. It is not as serious as the C282Y mutation but is even a little more common.

HH is a recessive condition. Interpretation of the gene analysis is as follows:

The C282Y homozygous state diagnoses HH and all of these individuals are at high risk for serious iron load and clinical disease.

Liver biopsy is not necessary in all individuals. If the gene study is positive, and ferritin is less than 300 micrograms per litre, and liver function tests (LFT) are normal, observe and re-test in one to two years.

If the gene study is positive, and the ferritin is 300 - 1000 micrograms per litre, and LFT's are normal, proceed to phlebotomy.

If the gene study is positive and the ferritin is greater than 1000 micrograms per litre and/or LFT's are abnormal, liver biopsy should should be done to confirm iron overload and assess for cirrhosis.

1. Hereditary hemochromatosis is likely under diagnosed in our population.
    
2. Relatives of affected individuals should be screened.
    
3. The diagnosis is usually not difficult using iron studies, genetic testing, and liver biopsy.

Michael O'Brien, MD, FRCPC

Thanks to Dr. Sue Robinson, Consultant Hematologist at the Queen Elizabeth 2 Health Sciences Centre in Halifax, Nova Scotia, for reviewing the draft of this article.

1. Andrews, N.C. Disorders of Iron Metabolism. NEJM, Dec 23, 1999, Volume 341:1986-1995. (Level 4 Evidence)
    
2. Tefferi, A. Primary Hematology, HUMNA Press 2001, 351- 364. (Level 4 Evidence)
    
3. Harrison's Principles of Internal Medicine, 15th ED, 2257-2261 (Level 4 Evidence)

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