Andrea Cortese Hassett, Ph.D., Scientific Director, Coagulation Laboratory
Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism wherein the body accumulates excessive amounts of iron. This disorder was first described more than 100 years ago and has been much underdiagnosed and misdiagnosed. There is now convincing evidence that homozygosity for hemochromatosis occurs in 3 to 5 persons per thousand of Northern European descent, with a carrier frequency ranging from 1 in 10 to 1 in 15. With as many as one million affected people, it is the most common recessively inherited disease in the US population.
CLINICAL MANIFESTATIONS and TREATMENT
Hemochromatosis is manifested by increased intestinal absorption of dietary iron, resulting in excess iron deposition initially in the parenchymal cells of the liver, and later in the skin, heart, and certain endocrine organs. The presenting symptoms may appear to be nonspecific, particularly in the early stages before the typical pattern of multiorgan involvement becomes evident. Weakness, weight loss, arthralgias, abdominal pain, and palpitations are frequently reported. Over a period of many years, progressive iron deposition leads to organ failure, resulting in serious complications including cirrhosis, hepatoma, diabetes, cardiomyopathy, gonadal insufficiency, arthropathy, and bronze skin pigmentation, a characteristic finding of the disease. By the time signs of parenchymal organ damage appear, the total body burden of iron has usually reached 15 - 20 grams (compared with about 2 - 4 grams normally present). Men typically have two and a half times more storage iron than women and are diagnosed five times more frequently. Heterozygotes with HH are generally spared severe consequences because iron accumulation is limited.
Until the advent of genetic testing, the diagnosis of HH was based on the combination of measurements of plasma iron and transferrin saturation, and ferritin, followed by liver biopsy to confirm elevated tissue iron levels. Increased plasma iron (normally < 170 ug/dl) and transferrin saturation > 50% suggest the diagnosis in the absence of another disorder known to cause elevation of these tests (see table). The presence of increased storage iron is suggested by finding a serum ferritin level > 325 ug/L in men, and >125 ug/L in women. It is important to consider that iron overload may not be present in all patients with HH (e.g., during screening studies in children and in young women); in addition, measurement of transferrin saturation may be unreliable and ferritin levels may be nonspecifically increased by coexistent liver disease, inflammation, or malignancy.
Removal of excess iron by therapeutic phlebotomy decreases morbidity and mortality in patients with HH if instituted early in the course of the disease. Even in advanced disease, clinical improvement has been noted in hepatic function, cardiac failure, skin pigmentation, and gonadal function. The goal of therapy is the reduction of body iron levels and maintenance at normal levels indefinitely. Depending on the clinical urgency, phlebotomy is usually carried out at weekly intervals. For the patient with a high iron burden (>20 grams), more than 2 years may be required. After normalization of iron levels, maintenance phlebotomy is usually needed every 3 - 4 months to maintain ferritin levels under 50 ug/L.
In 1975, hereditary hemochromatosis was shown to be associated with HLA-A3 on the short arm of chromosome 6. The linkage of HH to HLA-A has been utilized clinically to track affected pedigrees. Recently, a gene related to the MHC class I family and quite distinct, termed HLA-H, has been identified as a strong candidate gene for this disorder. A point mutation (single nucleotide change from G to A) in the HLA-H gene is responsible for the amino acid substitution of cysteine to tyrosine at position 282. This substitution is associated with hereditary hemochromatosis.
Transmission of the mutant HLA-H gene is consistent with an autosomal recessive pattern of inheritance. The mutation has been reported to be present in more than 85% of affected individuals. Although most affected individuals are homozygous carriers of the mutation, a few may be heterozygous with variable phenotypic expression, complicating their clinical presentation. The absence of the mutation in some affected individuals may indicate the presence of another, as yet unidentified mutation, or may indicate iron loading caused by acquired clinical conditions, rather than genetic causes.
A major advantage of the noninvasive identification of the HLA-H mutation is a precise molecular diagnosis of the disorder in the preclinical stage, thereby leading to early diagnosis and improved patient management. Furthermore, the ability to detect the mutation should be of considerable practical assistance in distinguishing hemochromatosis from other liver diseases in which increased iron stores may be found, such as alcoholic cirrhosis, viral hepatitis, steatohepatitis, and porphyria cutanea tarda.
Hereditary hemochromatosis is associated with a mutation in the HLA-H gene. Molecular detection in patients and their first degree relatives (parents, siblings, and children) may lead to early diagnosis and treatment to prevent the serious sequelae of iron overload seen in this common genetic disease.
Copyright © 1997, Institute For Transfusion Medicine
For questions regarding the ITxM assay that is available for the diagnosis of hemochromatosis, contact
Andrea Cortese Hassett, Ph.D. at (412) 209-7345
Joseph E. Kiss, M.D. at (412) 209-7326;
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