Hemochromatosis: More Common Than You Think?

Rowen K. Zetterman, MD


October 22, 2012

In This Article

Screening and Diagnosis of Hemochromatosis

At the present time, screening of all patients for hemochromatosis is not recommended. However, patients with liver disease and those who have a positive family history, suggestive symptoms, or abnormal iron studies should be tested for the disease.[14]

Elevated transferrin saturation and ferritin levels should prompt further evaluation. Transferrin saturation is elevated in 40%-60% of women and 75%-100% of men with hemochromatosis. Ferritin levels are high in approximately 70% of patients with the disease; levels > 250 µg/L are seen in 75%-88% of men, and 55% of women will have levels >200 µg/L.[11,15] Elevated ferritin levels are associated with a higher likelihood of hepatic fibrosis or cirrhosis.[1,23] Patients with ferritin levels > 1000 µg/L are more likely to have symptoms of their disease.[1] Because ferritin is also a reactive protein, it may be elevated in other inflammatory disorders. In patients with suspected iron overload of the liver, an MRI can be obtained to estimate hepatic iron content.[24]

How do I make the diagnosis of HFE hemochromatosis? Patients suspected of having iron overload should undergo HFE mutation analysis[14] because C282Y homozygotes and C282Y/H63D compound heterozygotes (but not C282Y heterozygotes) are at increased risk for iron overload. H63D homozygotes can develop mild iron overload.[25] In patients with iron overload who are not C282Y homozygotes, the following should be considered:

  • If heterozygous for C282Y, a possible association with one of the other rare HFE mutations or with a form of non-HFE hemochromatosis (eg, transferrin receptor 2 disease);

  • A homozygous deletion of HFE, which will result in disease similar to homozygous C282Y disease; or

  • A form of non-HFE hemochromatosis.

Should family members be screened? Family members of patients with hemochromatosis should be evaluated with the goal of preventing development of disease.[26] Therefore, patients should be screened before age 40 years, if possible.[27] Transferrin saturation levels, ferritin levels, and HFE analysis should be obtained from all first-degree relatives (eg, brothers, sisters, parents).[14] Family members who are C282Y homozygotes or compound heterozygotes with normal ferritin levels can be observed and periodically re-evaluated, whereas those with elevated ferritin levels should be treated.

The child of a parent with homozygous C282Y disease is a carrier of C282Y. The issue is whether the child might have inherited a second HFE mutation from the other parent. Absence of C282Y or H63D in the second parent indicates that the child is not at increased risk for iron overload.

Should every patient with hemochromatosis have a liver biopsy? Liver biopsy is performed less frequently today given the availability of other tests for hemochromatosis.[14] Assessing liver histology can be useful to determine the degree of fibrosis or cirrhosis and to assist in determining the need for future hepatocellular carcinoma screening.[28] Histology also can be useful if other causes of liver injury, such as alcoholism or nonalcoholic steatohepatitis, are still in the differential diagnosis. Determination of the hepatic iron index (hepatic iron content in µg/g dry weight divided by the patient's age) can be helpful. An index > 1.9 supports a diagnosis of hemochromatosis.[14]

The probability of cirrhosis is higher in patients with high ferritin levels.[29] In a patient with a ferritin level > 1000 µg/L, a platelet count < 200,000/mL, and an elevated aspartate aminotransferase level, the risk for cirrhosis is > 75%.[23]

The AASLD guidelines recommend that a liver biopsy be performed in homozygotes or compound heterozygotes if liver tests are elevated or the ferritin level is > 1000 µg/L.[14] They also recommend obtaining a liver biopsy to assess hepatic iron content in patients with evidence of iron overload who are not homozygotes or compound heterozygotes.

Liver histology will demonstrate intracytoplasmic deposition of iron predominately within the periportal hepatocytes with extension towards the pericentral region of the lobules.[30] Iron deposition within biliary epithelium, Kupffer cells, and endothelium; periportal fibrosis; and micronodular cirrhosis may be observed.