Overview
The diagnosis of hemochromatosis is made by patient history, physical examination, blood tests and liver biopsy. Patients who present with symptoms suggestive of hereditary hemochromatosis, such as hepatomegaly, arrhythmias, cardiac insufficiency, diabetes mellitus, abnormal liver function tests (LFTs), hyperpigmentation or hypergonadism should be evaluated for hemochromatosis.
The demonstration of a high serum iron, transferrin-saturation (serum iron/total iron binding capacity) greater than 60% in men and post-menopausal women or 50% in premenopausal women, and an elevated serum ferritin value suggests hereditary hemochromatosis. The combination of elevated transferrin saturation and an elevated serum ferritin is associated with a sensitivity of 0.94 and a specificity of 0.86 in the detection of early hemochromatosis. A liver biopsy is recommended in patients with elevations of both serum transferrin saturation and serum ferritin to evaluate the extent of iron overload and hepatic damage. Biopsy remains the gold standard for quantifying iron and estimating prognosis (Figure 11). The liver biopsy specimen is stained with Prussian blue for iron. The pattern and amount of iron deposition are then evaluated. Iron deposits in the liver consist of ferritin and hemosiderin. In the early stages, iron is found in periportal hepatocytes, especially in lysosomes. In more advanced disease, there is perilobular fibrosis and deposition of iron in the bile duct epithelium, Kupffer cells, and fibrous septa and eventually the development of cirrhosis (Figure 12). Measurement of hepatic iron concentration with determination of the hepatic iron index (hepatic iron concentration in pmoles/gm dry weight/age in years) is useful in diagnosis. Patients with genetic hemochromatosis have an index greater than 2.0. Computed tomography (CT) or magnetic resonance imaging (MRI) can also detect hepatic iron overload, but their sensitivity is low and they do not provide information on the degree of associated liver damage.  | | Figure 12. Natural history of iron overload in liver disease. Gross liver and histological section. (Click on the blue letters to view the consecutive images) |
Finding a homozygous genotype C282Y/C282Y in a patient with iron overload confirms the diagnosis of hemochromatosis, but does not diagnose cirrhosis or suggest prognosis. A small group of homozygotes have no clinical or biochemical evidence of iron overload, so the test is not predictive of disease state. Compound heterozygous C282Y/H63D have a four-fold increased risk of hemochromatosis as compared with the general population. Homozygous genotype H63D/H63D is not associated with increased iron deposition.
Screening
First-degree relatives of patients with HH should be screened for the disease. However, a definitive screening strategy has not been established. Screening should start between the ages of 18-30 (when iron studies are abnormal but serious organ damage has not occurred). Initial testing should include a fasting transferrin saturation and ferritin concentration. Incorporation of genetic testing has been controversial. Cost analysis suggests that screening for homozygosity for the C282Y mutation in first-degree relatives is cost-effective. The patient should be gene tested and if positive the spouse should be tested. If the spouse is heterozygous the children should be tested. Siblings of a homozygous patient should also be tested. Individuals identified as C282Y/C282Y or C282Y/H63D should undergo biochemical screening (iron studies) (Figure 13).
 | | Figure 13. Family tree. |
Population screening is more controversial. Cost-effectiveness studies suggest that screening asymptomatic white men with iron studies is comparable to other common medical interventions. Arguments against genetic screening, however, suggest that homozygous individuals could face discrimination from health and life insurers if identified, and point out that the test is not always predictive.
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