Considering how commonly the above signs and symptoms occur in typical primary care practice, a low-cost method to evaluate for hereditary hemochromatosis is essential. Screening for hemochromatosis has resulted in earlier diagnosis. In some studies 75% of new cases are diagnosed during the clinically asymptomatic stage of the disease. Figure 4 displays an algorithm for the evaluation of patients with suspected hereditary hemochromatosis.

When clinical findings warrant evaluation, the best phenotypic screening tool is the serum transferrin saturation. A newer test, the unsaturated iron-binding capacity, shows promise as a more cost-effective screening test for the general population, but it is not yet widely available. Elevated transferrin saturation is usually the earliest phenotypic expression of the disease; its sensitivity for iron overload is 94% to 98%, with a specificity of 70% to 98%. In the white population, the sensitivity and specificity yield a positive predictive value of approximately 20%, and a negative predictive value of 99.9%. The test costs approximately $20.

Transferrin saturation is a calculated value (serum iron divided by total iron-binding capacity) that can be affected by other factors. If a screening transferrin saturation is high, the test should be obtained after an overnight fast, as serum iron levels can vary considerably after an oral dose. The iron-binding capacity is affected by acute and chronic disease states, oral contraceptives, and acute hepatitis. Normal transferrin saturation is less than 45%, and elevations above this level warrant further evaluation. In men and postmenopausal women, transferrin saturations of 45% to 54% should be monitored at 1- to 2-year intervals. If the transferrin saturation exceeds 45% in premenopausal women or 55% in men and postmenopausal women, the workup should proceed with determination of serum ferritin and hepatic enzyme levels.

Serum ferritin concentration is linearly related to total body iron stores. Serum ferritin levels are normally less than 300 µg/L in men and postmenopausal women, and less than 200 µg/L in premenopausal women. In patients with an elevated transferrin saturation but normal serum ferritin levels and normal liver enzyme levels, it is prudent to monitor these values yearly. An elevated serum ferritin level defines the point at which treatment should be initiated in patients with a confirmed diagnosis. Serum ferritin is an acute phase reactant and can be elevated in the absence of iron overload. Elevated levels of the serum ferritin generally occur later in the course of iron overload than elevated transferrin saturation. For these reasons, serum ferritin is less useful as an initial screening test for hereditary hemochromatosis.

Hepatic enzymes are useful to gauge the likelihood of hepatic iron toxicity, but they are not useful as a screening tool. Studies have shown, however, that up to 3.4% of patients with elevated hepatic enzymes might have hereditary hemochromatosis. Also, because concurrent hepatic toxins accelerate the hepatic toxicity of iron overload, it is recommended to screen for iron overload in patients with evidence of liver disease.

Elevated serum ferritin or elevated hepatic enzyme levels in patients with an elevated fasting transferrin saturation indicate the need for further evaluation with HFE gene testing or liver biopsy.

HFE gene testing is readily available in the United States. The test is performed on a whole blood specimen, and the cost to the patients is about $180. A much less costly method for identifying both mutations has recently been described. This lower cost test might eventually affect the role of genetic testing in both suspected persons and for general population screening. Currently, the appropriate use of HFE gene testing is being debated and refined. HFE gene testing will not distinguish the 10% to 40% (depending on the population) of whites with non-HFE iron overload, nor will it determine the cause of iron overload in most African-Americans or Asians. Thus, the HFE gene test is not recommended as a screening test for iron overload. At present, one well-defined use of HFE gene testing is to diagnose hereditary hemochromatosis in relatives of patients who have a confirmed diagnosis. First-degree relatives should be screened with HFE gene testing to determine risk and need for further evaluation and treatment.

In the pre-HFE testing era, liver biopsy was considered the reference standard for diagnosis of hereditary hemochromatosis, but this concept has recently been challenged. Liver biopsy has a low complication rate in properly selected patients. Mortality ranges from 0.01% to 0.1%, and the risk of hemorrhage is 0.3%. The traditional criteria for diagnosis based on hepatic iron stores are listed in Table 3. These criteria are not exclusive for hereditary hemochromatosis, as these levels of iron can be found in end-stage liver disease of other causes. Periportal iron deposition is usually seen in hereditary hemochromatosis as opposed to other patterns of iron deposition in other disease states. Liver biopsy establishes the presence and severity of iron overload as well as the presence or absence of hepatic fibrosis, which has important implications for future evaluation. Some authorities state that liver biopsy is not necessary in selected patients aged 30 to 40 years or younger with homozygous C282Y defect and no laboratory or physical evidence of liver disease. A serum ferritin level of less than 1,000 µg/L has also been shown to predict the absence of liver fibrosis and is included in the decision process by some authorities.

Because liver disease itself can cause elevated serum transferrin saturation and ferritin levels, biopsy combined with HFE gene testing is often necessary in patients with evidence of iron overload and suspected coexistent liver disease (such as viral hepatitis or ethanol-induced disease) to establish a definitive diagnosis. In these cases HFE gene testing can confirm hereditary hemochromatosis as the cause of the iron overload and can help in the risk stratification of family members.

For patients who cannot or will not receive liver biopsy, HFE gene testing should definitely be performed. In these patients, serum markers of iron overload, in combination with homozygous C282Y mutation, are sufficient for the diagnosis and to initiate treatment. For patients 30 to 40 years or younger with no evidence of liver involvement and serum ferritin levels of less than 1,000 µg/L, a similar strategy is recommended.

The diagnostic criteria for hereditary hemochromatosis listed in Table 3 were developed in the pre-HFE gene testing era and thus do not include HFE gene status. The availability of this technology will likely result in changes in these criteria in the foreseeable future.

One potential diagnostic criterion for hereditary hemochromatosis (Table 3) is the finding of 4 g or more of mobilizable iron (approximately 16 U of blood) through a weekly or biweekly phlebotomy schedule. Scheduled phlebotomy without inducing iron-limited erythropoiesis is considered diagnostic for parenchymal iron overload in lieu of tissue biopsy.

For patients showing evidence of iron overload with heterozygous C282Y results, isolated H63D homozygous mutations, or concurrent liver disease, liver biopsy and consultation with an expert can be helpful in defining the cause of the problem.

The role and method of population screening are currently being debated. At present, the most cost-effective general population screening test might be the an unbound iron-binding capacity or transferrin saturation at age 20 to 30 years.

Table 3. Traditional Diagnostic Criteria for Hereditary Hemochromatosis.