How is hemochromatosis diagnosed?
Most patients with hemochromatosis are diagnosed between the ages of 30 and 50; and about 75% have no symptoms. Hemochromatosis is discovered when elevated levels of iron in the blood are found as part of routine blood testing; or when blood iron levels are measured as in screening studies in family members of patients with hereditary hemochromatosis. Some patients are diagnosed as having hemochromatosis when their doctors perform blood iron levels as part of the evaluation for abnormal elevations in blood levels of liver enzymes, AST and ALT. However, symptoms of skin bronzing or hyperpigmentation (about 70% eventually develop this symptom), diabetes, liver disease, arthropathy, hypogonadism, cardiomyopathy, and impotence or no menstrual periods (amenorrhea) may be present and may suggest that additional screening tests such as transferrin saturation and other blood and liver tests be ordered.
Blood iron tests
There are several blood tests that reflect the amount of iron in the body; ferritin level, iron level, total iron binding capacity (TIBC), and transferrin saturation.
Ferritin is a blood protein whose levels correlate with the amount of iron stored in the body. Blood ferritin levels usually are low in patients with iron deficiency anemia, and are high in patients with hemochromatosis and other conditions that cause an increase in body iron levels. Since ferritin also can be elevated in certain infections like viral hepatitis and other inflammatory conditions in the body, an elevated ferritin level alone is not sufficient to accurately diagnose hemochromatosis.
Serum iron, TIBC, and transferrin saturation are often performed together. Serum iron is the measure of the amount of iron in serum (the liquid portion of the blood). TIBC is a measure of the total amount of iron that can be carried in serum by transferrin, a protein that carries iron in serum from one part of the body to another. Transferrin saturation is a number calculated by dividing serum iron by TIBC - it is a number that reflects what percentage of the transferrin that is being used to transport iron. In healthy individuals the transferrin saturation is between 20% and 45%. In patients with iron deficiency anemia, the serum iron and transferrin saturation are abnormally low; and in patients with hereditary hemochromatosis the serum iron and transferrin saturation may be abnormally high. Consequently, if transferrin saturation is about 45% or higher, the presence of mutations C282Y or H63D should be examined to confirm the diagnosis of hereditary hemochromatosis.
Since serum iron can be elevated by eating and can fluctuate during the day, serum iron measurements should be done fasting, usually in the morning before breakfast.
The most accurate test for diagnosing hemochromatosis used to be the measurement of the iron content of liver tissue obtained by a biopsy. A liver biopsy involves the removal of a sample of liver tissue for analysis and is usually performed with a needle under local anesthesia. After numbing the skin and the underlying tissues, the doctor inserts the needle into the liver through the right lower rib cage, sometimes under ultrasound guidance. The tissue obtained by the needle is studied under a microscope for signs of active liver disease, fibrosis and cirrhosis (permanent scarring), and iron content (usually significantly elevated in hemochromatosis).
The liver biopsy also has prognostic value because it determines whether the patient already has irreversible advanced cirrhosis. Patients with hemochromatosis who have a normal liver biopsy have longevity similar to other healthy adults if adequately treated, while patients with cirrhosis as a result of hemochromatosis have significantly reduced longevity. Furthermore, the risks of cirrhotic patients developing liver cancer (hepatocellular carcinoma) are substantially higher than normal subjects, even with adequate treatment of the iron overload with phlebotomy. However, with the newer genetic testing, this invasive technique should be used only under certain conditions and is used infrequently.
The gene for hereditary hemochromatosis was identified in 1996. The gene is referred to as the HFE gene. Hereditary hemochromatosis is associated in most patients with two mutations of the HFE gene; C282Y and H63D. Currently, most investigators consider detection of these genes as diagnosis of heriditary hemochromatosis.
A C282Y homozygote is a person who has inherited one mutated C282Y gene from each parent. A C282Y homozygote is considered at considerable risk for developing iron overload disease. However, not every C282Y homozygote develops iron overload.
A C282Y/H63D compound heterozygote is a person who has inherited one mutated C282Y gene from one parent and a second mutated H63D gene from the other parent. Most compound heterozygotes have normal iron levels though some can develop mild to moderate iron overload.
A C282Y heterozygote is a person who has inherited one mutated C282Y gene from one parent and a second normal HFE gene from the other parent. Children born of two C282Y heterozygotes have a 25% chance of being a C282Y homozygote and, therefore, will be at risk of developing hemochromatosis. A C282Y heterozygote does not develop iron overload.
An algorithm for diagnosing hereditary hemochromatosis is as follows:
- Adults suspected of having hereditary hemochromatosis (for example, adult, first-degree relatives of a patient with hereditary hemochromatosis) are evaluated by measurements of fasting serum iron, TIBC, transferrin saturation and ferritin.
- Patients with elevated serum iron, ferritin, and transferrin saturation of greater than 45% are evaluated by genetic testing
- Patients with transferrin saturation greater than 45% who are C282Y homozygotes have hemochromatosis and, therefore, should be treated with therapeutic phlebotomy (see below).
Who should undergo liver biopsy?
Not all patients with hemochromatosis need to undergo liver biopsy. The purpose of liver biopsy is to identify those patients with cirrhosis and to exclude other possible liver diseases. (Patients with hemochromatosis and cirrhosis are at increased risk of complications, especially liver cancer.)
Young patients (<40 years of age) who are C282Y homozygotes with normal liver blood tests and serum ferritin levels <1000 ng/ml have a very low risk of having cirrhosis of the liver. Therefore, these patients can be treated with therapeutic phlebotomy without a liver biopsy. Their prognosis is excellent with adequate treatment.
Older patients (>40 years of age) who have serum ferritin levels >1000 ng/ml, and have abnormally elevated liver blood tests may already have developed cirrhosis. Doctors may recommend liver biopsies in these patients provided that it is safe for them to undergo liver biopsy.