Transferrin Saturation
Hereditary hemochromatosis is the most common genetic disorder in the US white population and is transmitted as an autosomal recessive trait. One in every 250 to 300 persons is homozygous for the hemochromatosis mutation and at least 1 in every 10 persons is a carrier for the mutation. The most common genetic abnormality is the C282Y mutation of the HFE gene, which is believed to have originally occurred in a Celtic ancestor. Most persons diagnosed with hereditary hemochromatosis are C282Y homozygotes (60-100%), while a small proportion (0–4%) is homozygous for a second mutation, H63D. Approximately 0–7% of patients are found to be compound heterozygotes (C282Y/H63D).
Hereditary hemochromatosis is associated with increased small intestinal iron absorption and progressive tissue deposition. Between the ages of 40 and 60, excessive iron accumulation may result in cirrhosis, heart failure, arrhythmia, diabetes, impotence, arthropathy, and skin bronzing. However, if hemochromatosis is detected in the pre-cirrhotic stage and treated with phlebotomy, affected individuals can have a normal life expectancy.
The College of American Pathologists has advocated screening for hereditary hemochromatosis with transferrin saturation. Transferrin saturation is the ratio of serum iron to total iron binding capacity and reflects the iron in transit from the reticuloendothelial system to the bone marrow. Elevated transferrin saturation is the earliest phenotypic abnormality in hemochromatosis. Although transferrin saturation is recommended as the best initial screening test, it has several limitations. Test results may be normal early in the course of the disease. Serum iron values exhibit diurnal variation and measurements may be affected by recent food ingestion. Therefore, an elevated transferrin saturation value should be repeated as a fasting early morning determination. In addition to hemochromatosis, transferrin saturation is often elevated in patients with acute or chronic viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, hemolytic anemia, iron therapy, recent red cell transfusions, and African iron overload. Debate exists about the appropriate transferrin saturation cutoff for screening. Generally, a cutoff of 50% for women and 60% for men is recommended.
Recently, we compared the results of transferrin saturation with the HFE genotype in 37 patients to determine the efficacy of this screening strategy. Six patients were homozygous for the C282Y mutation and all of these patients had elevated transferrin saturation ranging between 59 and 111%. As expected, transferrin saturation did not detect heterozygous carriers of the C282Y gene. Four female patients had transferrin saturation values between 22 and 41% and four male patients had values between 21 and 58%.
Genotype
|
% Sat |
Homo |
Hetero |
Normal |
Total |
|
Normal |
0 |
8 |
19 |
27 |
|
Elevated |
6 |
0 |
4 |
10 |
|
Total |
6 |
8 |
23 |
37 |
A total of 23 patients with normal genotypes were also reviewed. Two female and two male patients had elevated transferrin saturation values, ranging between 63 and 99%. The two women had other laboratory abnormalities consistent with hepatitis C infection and alcoholic liver disease. The latter patient had a liver biopsy that demonstrated increased iron deposition. The two men had very low transferrin levels secondary to malnutrition. One of the men also had ineffective erythropoiesis secondary to myelodysplastic syndrome. Both men had been transfused shortly before measuring transferrin saturation.
Our data suggests that screening for hereditary hemochromatosis with transferrin saturation, using cutoff values of 50% for women and 60% for men, is an effective diagnostic tool. In this limited sample, the sensitivity and specificity of elevated transferrin saturation for hemochromatosis were 100% and 83% respectively. Larger series have published sensitivities of 67 to 94% and specificities of 93 to 99%, depending on the cutoff used. False positive diagnosis can be avoided by ordering confirmatory HFE genotype testing. Genotype testing is also helpful in working up patients with inconsistently normal or abnormal iron studies. Direct genotype testing may be useful in evaluating asymptomatic individuals with a family history of hereditary hemochromatosis and in confirming a clinical diagnosis of hereditary hemochromatosis.
