Hereditary Hemochromatosis
The following material contains information for the evaluation, diagnosis and treatment of hereditary hemochromatosis patients and their first-degree relatives. This information should be modified according to the needs of each individual patient. This material has been compiled with the assistance of Robert Gish, M.D. of California Pacific Medical Center and Bruce Bacon, M.D. of St. Louis, Mo. It is anticipated that as we gain more knowledge about hereditary hemochromatosis, changes to this protocol will be made. Any suggestions for improvement to this protocol are most welcome.
Diagnosis and Treatment | Genetic Testing | Genetic Diagnosis | Liver Biopsy | Treatment | Test CodesDiagnosis and Treatment
Factors of Importance in the Diagnosis and Treatment of Hereditary Hemochromatosis
1) The diagnosis of iron overload and potentially hereditary hemochromatosis should be suspected in men whose transferrin saturation is greater than 55% and in women whose transferrin saturation is greater than 50%. A medical history that includes frequent blood donations or unusual blood loss may lower these percentages by an additional 10%.
Serum ferritin has many false positives (because it is an acute phase reactant) and too many false negatives to be of any significant value as a screening test. However, if a patient is found to have an elevated ferritin, a transferrin saturation study should be performed. It is important to note that all patients with iron overload may not have hereditary hemochromatosis; indeed some patients may have secondary iron overload due to excess iron, hemoglobinopathies or a dysmetabolic iron overload state. Each is a serious disorder and may lead to cirrhosis, liver failure or liver cancer. Excess liver iron may modulate viral hepatitis, response to antiviral treatment or disease progression in other liver conditions such as fatty liver.
2) Hemochromatosis can also be diagnosed by any of the following:
- Hepatic Iron Index >1.9
- Hepatic Iron Concentration > 40 Umol/Gm dry weight
- 3+ to 4+ stainable iron in liver hepatocytes
- Greater than 3 grams of iron removed by quantitative phlebotomy (each 500 ml of blood contains approximately 250 mg of iron)
- Hereditary hemochromatosis by one or more of the factors above and genetic testing
3) Hepatic iron concentration: Determined by actually measuring the amount of iron in a liver biopsy. Presently, you can send all of these liver biopsies for iron concentration to the Mayo Clinic or Dr. Bacon's laboratory.
4) Hepatic Iron Index: Calculated by hepatic iron concentration Umol/Gm dry weight/56/Patient's age in years.
5) Patients who are diagnosed with hemochromatosis by the criteria described above should then be tested for the two known gene mutations by PCR testing.
6) First-degree relatives can be tested for the gene abnormality and undergo phlebotomy and/or monitoring if positive by genetic analysis for the CYS282 tyrosine or H63D mutation.
7) If a patient is heterozygous or is a compound heterozygote for the hemochromatosis gene(s), one can consider having their blood analyzed for iron parameters now and every five or ten years, depending on whether or not there is a significant rise in the percent saturation of the transferrin to a level greater than 50%. If any first-degree relative refuses genetic or HLA testing, do iron studies every three years.
Algorithm for first degree relatives of patients with hereditary hemochromatosis in proband*
Perform genetic testing on the following:
- Proband
- All Siblings
- Both Parents
- All Children (if partner + for one or both genes)
* Diagnosed by Liver Biopsy or Hepatic Iron Index**
**Hepatic Iron Index = Hepatic Iron Concentration Umol/Gm Dry Weight divided by patient's age in years; (Umol Iron=Ugm Iron/56)
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Genetic Testing
Genetic Testing for Hemochromatosis
The discovery of the gene for the hemochromatosis has changed our algorithm for the evaluation of patients and family members. The gene defect as described in the literature is found in >85% of patients of Northern European descent who have evidence of iron overload by liver tissue assessment (iron index >2.0). This genetic test can be ordered through many labs including Smith Kline Beecham.
Genetic Testing for Hemochromatosis DNA by PCR: This genetic test may be useful for the following clinical situations:
- Patients with an iron index between 1.5 and 2.0
- First-stage screening of family members if the proband has been proven to have the genetic defect by PCR testing
- Patients with iron overload (index > 2.0) but no other evidence of hemochromatosis and other reasons for iron excess
If the patient does not have the genetic defect by PCR testing, then family screening may need to take place by HLA typing of the proband and relatives.
Relatives are homozygous for HFE gene mutations: If any first-degree relative is homozygous for one of the two mutations, especially C282Y, then the first-degree relative is presumed to have hemochromatosis and should be treated according to the protocol.
No mutation is identified: If a first-degree relative of the proband is not identical for either of the gene mutations, then the first-degree relative is presumed to not have hemochromatosis. A transferrin saturation can be performed now and every five years. See below for decisions to be made on the basis of the transferrin saturation.
The patient tested is heterozygote for the HFE gene mutation: Since there are numerous allelic combinations that are associated with hemochromatosis, it is possible (although rare) that first-degree relatives may have hemochromatosis due to a different combination of alleles. A transferrin saturation could be performed now and every five years, and acted upon in accordance with the recommendations below.
It remains controversial whether patients who are heterozygotes can develop pathological iron overload, yet some cases have clearly been documented in the literature. There may be undiscovered genes other factors that lead or contribute to iron overload or a condition called compound heterozygote.
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Genetic Diagnosis
Although virtually all first-degree relatives who are heterozygous for hemochromatosis by HFE testing will not develop any clinical manifestations of hemochromatosis, an occasional "heterozygous" first-degree relative may in fact develop clinical manifestations of hemochromatosis. This is most likely caused by a homozygous/heterozygous mating of the parents with three of the four haplotypes linked to the disease.
Therefore, first-degree relatives of hemochromatotic probands who are determined to be heterozygous for hemochromatosis by HFE testing should still have their blood tested to determine their iron parameters and should be subject to the evaluation protocol. These heterozygous individuals should be encouraged to minimize alcohol consumption and avoid iron supplementation.
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Liver Biopsy
Who Needs a Liver Biopsy?
Indicators for patients who need a liver biopsy include:
- Elevated AST/ALT
- Low platelets or other suggestions of portal hypertension
- Abnormal iron saturation and negative for HFE gene mutations
- Also consider heterozygotes or compound heterozygotes if iron saturation >50%
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Treatment
Following Diagnosis of Hereditary Hemochromatosis
Once the diagnosis of hereditary hemochromatosis has been established by the criteria described above, treatment should be instituted even though there is no clinical evidence of disease. The treatment regimen is as follows:
1) The patient should be instructed on the rudiments of iron metabolism so that he/she can understand the basis of phlebotomy therapy. He/she should also understand the reason for the need of a screening of all blood relatives.
2) Phlebotomies of 500 ml of blood (equivalent to approximately 250 mg of iron) should be performed at a rate sufficient to maintain a mild anemia (i.e. a hematocrit of 34%). Most patients can tolerate the removal of two 500 ml units per week. Folate at 2 mg per day should be prescribed. Any patient over age 35 should have an electrocardiogram. A cardiologist consultation may be advisable in those patients who have angina or other cardiac abnormalities. The hematocrit should be measured before each phlebotomy.
3) When the patient's iron stores have been depleted as determined by a hematocrit that does not return to 40% or higher after the last phlebotomy or by an MCV that is less than 75FL, iron studies can be performed to establish that the iron stores have been depleted. It is probably unnecessary to perform iron studies as a means of controlling the frequency of phlebotomies.
4) Phlebotomy therapy should be maintained for life. After he/she has become iron deficient, four to six phlebotomies per year should be sufficient to prevent re-acummulation of iron stores.
5) Iron chelating agents are not often useful in the treatment of hemochromatosis except in acute cardiac iron toxicity. The parental injections are uncomfortable and should only be considered when no veins are available for phlebotomy or the patient is anemic. An iron poor diet is not recommended. Avoid vitamin C supplements and vitamin preparations containing iron at any dose. It is unappetizing and an unpleasant nuisance and only reduces the amount of iron accumulation by a few milligrams a day. Patients should avoid iron supplements that are often present in vitamin pills.
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Test Codes
1) Transferrin saturation
APL test code #359,
specimen required: one red top tube
2) Hepatic iron concentration
APL test code #1489 (Mayo Clinic test code # 8350)
Specimen required: 0.5 x 5.0 mm portion of liver submitted in formalin
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