Iron Overload (cont.)
Dennis Lee, MD
Dennis Lee, MD
Dr. Lee was born in Shanghai, China, and received his college and medical training in the United States. He is fluent in English and three Chinese dialects. He graduated with chemistry departmental honors from Harvey Mudd College. He was appointed president of AOA society at UCLA School of Medicine. He underwent internal medicine residency and gastroenterology fellowship training at Cedars Sinai Medical Center.
In this Article
What are the symptoms and signs of hemochromatosis?
Patients with early hemochromatosis have no symptoms and are unaware of their condition. The disease may then be discovered when elevated iron blood levels are noted by routine blood testing. In men, symptoms may not appear until 40-50 years of age. Iron deposits in the skin cause darkening of the skin. Since females lose iron through menstrual blood loss, they develop organ damage from iron accumulation 15 to 20 years later than men on average.
Iron deposits in the pituitary gland and testicles cause shrinkage of the testicles and impotence. Iron deposits in the pancreas cause a decrease in insulin production resulting in diabetes mellitus (please read the Diabetes Mellitus article). Iron deposits in the heart muscle can cause heart failure as well as abnormal heart rhythms. Iron accumulation in the liver causes scarring of the liver (cirrhosis) and an increased risk of developing liver cancer. For further information on the consequences of cirrhosis, please read the Cirrhosis article.
How is hemochromatosis diagnosed?
Most patients with hemochromatosis are diagnosed early and have no symptoms. Their 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.
Blood iron tests
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 such as 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 50 percent. 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 are abnormally high.
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 is 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 but an otherwise 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 (see below).
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.
A C282Y homozygote is a person who has inherited one mutated C282Y gene from each parent. A C282Y homozygote is considered at risk of developing iron overload. In fact, C282Y homozygotes account for 95% of all hereditary hemochromatosis. Conversely, not every C282Y homozygote develops iron overload. Studies have shown that an estimated 50% of C282Y homozygotes may not develop iron overload or its complications.
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 but 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:
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 levels 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 levels may already have developed cirrhosis. Doctors may recommend liver biopsies in these patients provided that it is safe for them to undergo liver biopsy.