Which Test, on Whom, and When?
An outline of which test, on whom and when to perform the test is shown in Table 1. The first indication of possible systemic iron overload in people screened for HH is documentation of raised fasting serum iron indices that includes transferrin saturation and ferritin. Raised transferrin saturation (≥ 45%) is usually the earliest phenotypic biochemical indication to HH.[65–67] Iron is accumulated in the transferrin pool well ahead of progressive iron loading of end organs, which in turn, is reflected by increased serum ferritin. Iron indices are usually raised in symptomatic patients and are seen in 61–82% of HFE C282Y homozygotes. False-positive elevations of serum ferritin can be seen in the setting of inflammatory conditions such as rheumatoid arthritis, infection, and various neoplastic diseases, as ferritin is an acute-phase reactant. Importantly, transferrin saturation is usually normal in these clinical settings. If in doubt, serum ferritin levels should be repeated once potential confounding situations have abated. Combination of serum transferrin saturation or unsaturated iron binding capacity and ferritin provide a simple and reliable test to identify most adults with significant iron overload resulting from HFE C282Y homozygous HH.[65,69] Serum ferritin levels >1000 μg/L increase the risk of fibrosis or cirrhosis. If either serum iron indices are abnormal, genetic testing for hemochromatosis is warranted.
HFE Mutation Testing
Testing for HFE gene mutations is generally indicated in those with the iron-loaded phenotype outlined above and those with a family history of HFE-related HH. These tests are generally widely acceptable with minimal adverse psychological or economic sequelae of discrimination following genetic testing.[24,42,71,72] Second-line mutation testing of the HJV, HAMP, and TFR2 of ferroportin gene in young adults with suspected iron overload is also possible, but not widely available. This may be overcome by the emergence of new diagnostic tests such as the measurement of serum hepcidin-25 levels. Because HFE-, TFR2-, and HJV-related hemochromatosis are all associated with low levels of serum hepcidin, this serum marker may prove in the future to be a useful surrogate marker of the presence of mutations that cannot readily be evaluated by routine laboratory testing.
How Do I Determine the Total Iron Body Burden?
Once HH is diagnosed, knowledge of the degree of iron burden is attained by measuring the hepatic iron concentration (HIC). There is compelling evidence that the severity of many clinical features and the risk of hepatic fibrosis and cirrhosis are tightly related to the level of HIC. This is achieved prospectively either by liver biopsy or noninvasively by using hepatic magnetic resonance imaging (MRI). Magnetic resonance imaging has emerged as a rapid, reliable, and noninvasive method that is more accurate than liver biopsy in measuring HIC. Quantitative phlebotomy requirements can be used retrospectively to estimate the total body iron burden.
Liver biopsy is used as a prognostic indicator to establish or exclude the presence of cirrhosis. The current indications for liver biopsy include those aged >45 years, serum ferritin level >1000 μg/L, or abnormal liver function tests. Given the invasive nature of liver biopsy, efforts are being directed to establishing noninvasive approaches to guide assessment of the severity of liver fibrosis. Serum hyaluronic acid has been reported as a useful predictor of significant fibrosis or cirrhosis. Other noninvasive technologies include transient elastography, which has been applied in a wide variety of chronic liver disease such as viral hepatitis and nonalcoholic fatty liver disease. FibroScan™ may be useful in monitoring the response of liver fibrosis to phlebotomy therapy.
Semin Liver Dis. 2011;31(3):293-301. © 2011 Thieme Medical Publishers