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HFE-type Genetic Hemochromatosis

Summary from "Laboratory Medicine", Oct. 1999, vol. 10, p. 639, David L. Witte, M. D.

"Hemochromatosis is inherited with an autosomal recessive pattern. The presence of two abnormal genes creates a metabolic abnormality that allows too much transfer of iron across the gastrointestinal mucosal cell barrier. If this absorption continues in the absence of any excessive loss, storage iron accumulates and causes damage to the liver, heart, joints, pancreas, and other tissues. The rate of accumulation is highly variable, and patient age ranges from teen to geriatric, the metabolic abnormality can be detected by testing serum transferrin saturation; accumulation is measured by testing serum ferritin.

"The most common genetic abnormality is the G845A genetic mutation (producing the C282Y amino acid change on gel electrophoresis) of the HFE gene. A second HFE mutation, C187G (producing the H63D amino acid change) is less clearly linked to Hemochromatosis. The C282Y mutation is thought to have occurred in a Celtic ancestor and is therefore most frequently associated with Hemochromatosis in Celtic populations. Its penetrance is less than 1%. The C282Y mutation occurs in 80 to 90% of cases of Hemochromatosis world-wide. The frequency of C282Y varies among patients with Hemochromatosis, from 100% in Irish and Australians to 69% in Northern Italians and 35% is Southern Italians. Other unknown genetic and environmental factors modify the severity of the manifestation of iron overload.

"Diagnosis in screening programs for asymptomatic individuals is best accomplished with phenotype identification using serum transferrin saturation and ferritin measurement. Phenotypic testing identifies those likely to benefit from intervention. Persons with transferrin saturation greater than 55 to 60% following an overnight fast can be considered phenotypic-screening-test positive and should be tested for serum ferritin to access iron accumulation. Genotype testing is screening programs should be limited to identifying individuals heterozygous for the abnormal gene and other persons with inconsistently normal or abnormal test results.

"Confirming the diagnosis in phenotypic screening-test-positive individuals are those with suspicious clinical symptoms rests on three possible strategies. First a therapeutic trial of phlebotomy could be considered. Removal of three g of iron from females or 5 g from males through weekly phlebotomy both confirms the diagnosis and initiates therapy. A second option is liver biopsy. Hepatic iron content (HIC) with a Perls' positive 3 or 4 plus pattern or chemical content in excess of 80 micromols/g of liver dry weight suggests hemochromatosis. If the HIC divided by age is greater than 1.9, this result adds [further] evidence of hemochromatosis (HIC/age is the hepatic iron index, or HII). Third, testing for mutations of HFE can be helpful. However, not all patients with hemochromatosis have abnormal HFE, and not all patients with abnormal HFE will develop symptoms [ or signs/findings] of hemochromatosis. Interpretation of HFE results must consider signs, symptoms, plus transferrin saturation and ferritin measurements. HFE abnormality may be the only confirmatory abnormality in those with high transferrin saturation but no iron accumulation. " [end of article; bibliography not included]

My Attempt AT Layman Explanation

Hemochromatosis is a constitutional condition in which there is a fundamental increase in the absorption of iron from the intestine at rates well above the general population. The actual biochemical defect is as yet uncertain. Over 90% of cases are related to genetic mutations, most being in the HFE gene. That defect being recessively inherited (the "disease" mostly shows up when both of your from momma and one from daddy), "carriers" (persons with only one of their genes mutated...heterozygotes) tend not to develop the "disease". Persons with both genes mutated...homozygotes...have a high risk (but are not absolutely obligated) of developing the "disease". A person "expresses" anger with a facial frown; gene defects "express" themselves recessively (when a person has the gene defect on both of his/her chromosomes) or dominantly (when only one gene is defective). A person can have the genetic defect but without any detectable evidence of the disease: his/her genotype is in place for the "disease" but the "disease" has not begun to "express" itself...there is not yet any phenotype manifestation..."expression"...of the disease. The earliest dependable phenotypic expression of hemochromatosis is the blood...revealed in the hemochromatosis screening test elevation of the "% transferrin saturation" above 45-55%...or, maybe in some of African ancestry, by elevated serum ferritin levels. The "disease" does its dirty work by way of excessive iron deposits in organ tissues, over the long run, being toxic to vital organs. In the United States general population, about 3-5 per 1000 are homozygotes and about 100 per 1000 are carriers. For uncertain reasons, the ability of the genetic defect to "penetrate" defenses and manifest as "disease"...genetic penetrance...varies among both carriers and homozygotes. AND, if a genetically defective person compounds their situation with habits/behaviors or intake of stuff which also increases iron absorption, their situation is worsened.

The Genetic Stuff

The HFE gene is linked to the major histocompatibility complex (MHC) allele HLA-H (formerly HLA-A3) locus of the short arm of chromosome 6p. The major (most common and most certainly relevant) mutation is C282Y (Cys282Tyr; B45A), and it is homozygously paired in 80-85% of Caucasians with a doctor's diagnosis of hemochromatosis.

Another mutation (near the HFE?) is H63D (His63Asp; 187G) which is found in 200 per 1000 of the general population. Alone, carriers or heterozygotes for this mutation only rarely...if ever...get the "disease" of hemochromatosis & tend not get iron overload. Homozygotes can get a mild & easily treatable form of iron overload.

When C282Y and H63D combine in an individual (creating a "double heterozygote"), only 1.5% of them develop hemochromatosis. Of all patients with hemochromatosis associated with a documented genetic mutation, 5-7% are this C282Y/H63D double heterozygote.

Persons having no-doubt-about-it hemochromatosis...and not secondary iron an apparently inherited pattern but with normal genetic tests are referred to as a genotypic "wild type" (WT) [sort of like a "wild card" in card games].

Male homozygotes of C282Y/C282Y genotype have 95% phenotypic penetrance when over age 40 years of age; 50% of the 95% are symptomatic of organ damage. Female homozygotes of C282Y/C282Y genotype have 70% phenotypic penetrance when over age 40 years of age; 13% of the 70% are symptomatic of organ damage. Of all cases of no-doubt-about-it hemochromatosis, the C282Y/C282Y homozygote accounts for 80.9% (some say 90%). On the other hand, some homozygotes are negative for either direct or indirect evidence of iron overload.


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(posted 16 October 1999; latest addition 18 July 2009)