Hemochromatosis
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Hemochromatosis is defined as a disorder in iron metabolism that is characterized by excess iron absorption, saturation of iron-binding proteins and deposition of hemosiderin (amorphous iron deposits) in the tissues. The primary affected tissues are the liver, pancreas, and skin. Iron deposition in the liver leads to cirrhosis and in the pancreas causes diabetes. The excess iron deposition leads to bronze pigmentation of the organs and skin. In fact, the bronze skin pigmentation seen in hemochromatosis, coupled with the resultant diabetes lead to the designation of this condition as bronze diabetes.
Primary hemochromatosis is referred to as type 1 hemochromatosis. The cause of type 1 hemochromatosis is the inheritance of an autosomal recessive allele. The locus causing type 1 hemochromatosis has been designated the HFE1 locus and is a major histocompatibility complex (MHC) class-1 gene located on chromosome 6p21.3. Hemochromatosis, that is associated with the HFE1 locus, is one of the most commonly inherited genetic defects. Manifestation of the symptoms of the disease is modified by several environmental influences. Dietary iron intake and alcohol consumption are especially significant to hemochromatosis. Menstruation and pregnancy can also influence symptoms. Hemochromatosis occurs about 5 to 10 times more frequently in men than in women. Symptoms usually appear between the ages of 40 and 60 in about 70% of individuals.
The HFE1 gene encodes an α-chain protein with three immunoglobulin-like domains. This α chain protein associates with β2-microglobulin, typical of MHC class 1 encoded proteins. Normal HFE1 has been shown to form a complex with the transferrin receptor and in so doing is thought to regulate the rate of iron transfer into cells. A mutation in HFE1 will therefore, lead to increased iron uptake and storage. The majority of hereditary hemochromatosis patients have inherited a mutation in HFE1 that results in the substitution of Cys 282 for a Tyr. This mutation causes loss of conformation of one of the immunoglobulin domains in HFE1. Another mutation found in certain forms of hereditary hemochromatosis also affects the HFE1 locus and causes a change of His 68 to Asp. This latter mutation is found along with the more common C282Y mutations resulting in a compound heterozygosity. Of note, homozygosity for the H63D mutation is not itself associated with clinically significant iron overload.
As a result of the C282Y mutation the HFE1 protein remains trapped in the intracellular compartment. Because it cannot associate with the transferin receptor there is a reduced uptake of iron by intestinal crypt cells. It is thought that this defect in intestinal iron-uptake results in an increase in the expression of the divalent metal transporter (DMT-1) on the brush border of the intestinal villus cells (for more information on iron uptake and transport see the Iron, Heme and Porphyrin page). Excess DMT-1 expression leads to an inappropriate increase in intestinal iron absorption.
In hemochromatosis the liver is usually the first organ to be affected. Hepatomegaly will be present in >95% of patients manifesting symptoms. Initial symptoms include weakness, abdominal pain, change in skin color and the onset of symptoms of diabetes mellitus. In advanced cases of hemochromatosis there will likely be cardiac arrhythmias, congestive heart failure, testicular atrophy, jaundice, increased pigmentation, spider angiomas and splenomegaly. Diagnosis of the disease is usually suggested when there is the presence of hepatomegaly, skin pigmentation, diabetes mellitus, heart disease, arthritis and hypogonadism. The degree of increase in total body iron stores in patients suspected of having hemochromatosis should focus primarily on parenchymal iron concentration. It is also important to ascertain whether other circumstances could be the cause of the symptoms of iron overload. These would include alcohol consumption, iron intake and excessive vitamin C ingestion as the latter promotes iron absorption.
Treatment of hemochromatosis before there is permanent organ damage can restore life expectancy to normal. Treatment involves removal of the excess body iron. This is accomplished by twice-weekly phlebotomy at the beginning of treatment. Alcohol consumption should be curtailed and preferably eliminated in hemochromatosis patients. Iron chelating agents, such as deferoxamine, can be used to remove around 10 to 20 mg of iron per day. However, these agents are expensive and phlebotomy is more convenient and safer for most patients.
There are several additional causes of hemochromatosis, although none are as common as classic hemochromatosis. There are four additional forms of hemochromatosis, two of which are juvenile forms. The juvenile forms are the result of defects in the HFE2 gene on chromosome 1q21 which encodes hemojuvelin and HFE2B on chromosome 19q13 which encodes hepcidin. The HFE3 locus encodes the transferrin receptor-2 gene on chromosome 7q22 and the HFE4 locus encodes the Ireg1 (ferroportin) gene on chromosome 2q32.
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Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu>