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HuGE Review
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by E. H. Hanson1, G. Imperatore2, W. Burke3 March 12, 2001 (Updated October 22, 2004) Authors’
affiliations: Abbreviations: AF, attributable fraction; CI, confidence interval; HLA, human leukocyte antigen; HHC, hereditary hemochromatosis; OR, odds ratio; PCR, polymerase chain reaction; PPV, positive predictive value; TS, transferrin saturation; SF, serum ferritin Key Words: epidemiology, genetics, hereditary hemochromatosis, hereditary haemochromatosis, HLA-H gene, HFE gene, iron overload Acknowledgement:
HuGE Review Internet
Sites Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and deposition in the liver, pancreas, heart, joints, and pituitary gland. Without treatment, death may occur from cirrhosis, primary liver cancer, diabetes, or cardiomyopathy. In 1996, HFE, the gene for HHC, was mapped on the short arm of chromosome 6 (6p21.3). Two of the 37 allelic variants of the HFE gene described to date (C282Y and H63D) are significantly correlated with HHC. Homozygosity for the C282Y mutation is present in 52-100% of clinically diagnosed probands. Five percent of HHC probands are compound heterozygotes (C282Y/H63D), and 1.5% are homozygous for the H63D mutation; 3.6% are C282Y heterozygotes, and 5.2% are H63D heterozygotes. In 7% of cases, C282Y and H63D mutations are not present. In the general population, the frequency of the C282Y/C282Y genotype is 0.4%. C282Y heterozygosity ranges from 9.2% in Europeans to nil in the Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations. The H63D carrier frequency is 22% in European populations. Accurate data on the penetrance of the different HFE genotypes are not available. Extrapolating from limited clinical observations in screening studies, an estimated 40-70% of persons with the C282Y homozygous genotype will develop biochemical evidence of iron overload. A smaller proportion will die from complications of iron overload. To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible individuals, laboratory standardization and the potential for possible stigmatization or discrimination. After two decades of intensive research the genetic complexity of hereditary hemochromatosis (HHC) is still unfolding. More than 20 years ago, HHC was described as an autosomal recessive disorder associated with the human leukocyte antigen (HLA)-A3 complex (1) . Subsequently, HHC was linked to HLA-A on the short arm of chromosome 6 (2, 3) . In 1996, Feder et al. (4) identified a 250-kilobase region located more than 3 megabases telomeric from the major histocompatibility complex on chromosome 6 that was identical by descent in 85 percent of HHC patients. In this region, they identified a gene related to the major histocompatibility complex class I family that they called HLA-H, but was subsequently named HFE (5) . Feder et al. (4) described two missense mutations of this gene (C282Y and H63D) that accounted for 88 percent of the 178 HHC probands in their study. The HFE gene is located at 6p21.3- approximately 4.6 megabases telomeric from HLA-A, and covers approximately 10 kilobases(6) . The HFE protein is a 343 residue type I transmembrane protein that associates with class I light chain beta2-microglobulin (4) . The HFE protein product binds to the transferrin receptor and reduces its affinity for iron-loaded transferrin by 5- to 10-fold (7) . The C282Y mutation alters the HFE protein structure and beta2-microglobulin association, disrupting its transport to and presentation on the cell surface (8) . The H63D mutation, in contrast, does not appear to prevent beta2-microglobulin association or cell surface expression (9) , indicating that the C282Y mutation results in a greater loss of protein function than does H63D (10) . The localization of the HFE protein in the crypt cells of the duodenum (the site of dietary iron absorption) and its association with transferrin receptor in those cells are consistent with a role in regulating iron absorption (9, 11) . The observation that HFE-deficient mice (HFE gene knockout model) develop iron overload similar to that seen in human HHC provides evidence that the HFE protein is involved in regulating iron homeostasis (12). To date, 37 allelic variants of the HFE gene have been reported (13), but this review will focus on the C282Y and H63D mutations (4). The C282Y mutation results from a G-to-A transition at nucleotide 845 of the HFE gene (845GŕA) that produces a substitution of cysteine for a tyrosine at amino acid position 282 in the protein product. In the H63D mutation, a G replaces C at nucleotide 187 of the gene (187CŕG), causing aspartate to substitute for histidine at amino acid position 63 in the HFE protein. In addition to C282Y and H63D, nine other missense mutations causing amino acid substitutions have been documented. In one, a substitution of a cysteine for serine at amino acid position 65 (S65C) has been implicated in a mild form of HHC (14). A number of intronic polymorphisms have also been found (13). One polymorphism occurs within the intron 4 (5569G-A) of the HFE gene in the binding region of the primer originally described by Feder et al. (4). One laboratory reported that when a polymerase chain reaction (PCR)-based restriction endonuclease digestion assay is used, the presence of this polymorphism might cause C282Y heterozygosity to be misdiagnosed as C282Y homozygosity (15, 16). However, three groups could not replicate this finding (17-19). In these studies, previously identified homozygotes for the C282Y mutation were confirmed by sequencing or using a primer external to the 5569G-A polymorphism, suggesting that genotyping errors due to this polymorphism are likely to be rare. Population Frequencies A computerized search of the PubMed database (National Library of Medicine) using the terms "hemochromatosis", "haemochromatosis", “HLA-H”, and "HFE" for papers published in English through February 2000 was performed. Of the studies identified, we included only those with sample sizes greater than 50 persons and where genotyping was performed for both the C282Y and H63D mutations in all individuals. In table 1 the frequency of the HFE genotypes in clinically diagnosed probands is reported by geographic location. Except for two studies (14, 20), case definitions of HHC included diagnostic evidence of iron overload by liver biopsy or quantitative phlebotomy. In European countries, the estimated prevalence of homozygosity for the C282Y mutation in 2,229 HHC probands ranged from 52 percent (21) to 96 percent (22). In North America, C282Y homozygosity was present in 81 percent of 588 probands (range: 67 to 95 percent). Worldwide, among 2,929 probands 6.9 percent (95 percent CI: 6.0, 7.9) were homozygous for the wild allele. This finding suggests that nongenetic influence; additional HFE mutations; genetic redundancy, which is known to occur within the HLA region (23); or variation in additional genes affecting iron metabolism, as a recent twin study has suggested (24) may also cause iron overload. Heterozygosity for the H63D mutation and compound heterozygosity each accounted for 6 percent of European cases and 4 percent of cases in North America. Globally, 3.6 percent (95 percent CI: 2.9, 4.3) of proband patients had the C282Y/wild genotype, and 1.5 percent (95 percent CI: 1.1, 2.1) had the H63D/H63D genotype. The estimated frequency of the HFE genotype in the general population is shown in table 2; 27 studies were evaluated. A total of 6,203 samples from European countries revealed on average a C282Y homozygous and heterozygous prevalence of 0.4 percent and 9.2 percent, respectively. However, C282Y homozygosity has not been reported in the general population of Southern or Eastern Europe. The frequency of the C282Y heterozygosity is 1 to 3 percent in Southern and Eastern Europe and as high as 24.8 percent in Ireland. In North America (3,752 samples) these percentages were 0.5 percent (C282Y homozygous) and 9.0 percent (C282Y heterozygous). In the Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations, C282Y homozygotes were not found and the frequency of C282Y heterozygosity was very low (range: 0 to 0.5 percent). C282Y/H63D compound and H63D homozygosity each accounted for 2 percent of the European general population and 2.5 percent and 2.1 percent in the American populations, respectively. The carrier frequency of the H63D mutation was 22 percent in Europe and 23 percent in North America. Assuming that the proband studies correctly indicate that 78 percent of affected individuals are homozygous for C282Y, the estimated prevalence of HHC ranges from 51 to 64/10,000. In population-based intervention trials, the estimated prevalence of homozygosity based on phenotype, defined as biochemical evidence of iron overload, is 50 per 10,000 (25). In primary care settings among whites, the estimated prevalence of clinically proven or biopsy proven HHC is 54 per 10,000 (26). Higher prevalence (80/10,000) was obtained in one study when elevated transferrin saturation (TS) alone was used for a case definition (27) . This may simply reflect the fact that a significant proportion of unaffected or heterozygous individuals have TS levels above the cutoff, especially when TS thresholds of 50% are used (25). HHC is a disorder of iron metabolism characterized by increased iron absorption. Iron is progressively deposited in various tissues, particularly the liver, pancreas, heart, joints, and pituitary gland. Beside HHC, there are other genetic causes of iron overload. For example, families have been identified with a clinical syndrome indistinguishable from HHC but without linkage to chromosome 6 (28, 29). Recently, linkage to the Tfr2 gene was described in two such families (30). In addition, a rare autosomal condition, juvenile hemochromatosis that results in rapid accumulation of iron, has recently been mapped to chromosome 1 (31). Two other syndromes, neonatal hemochromatosis and African iron overload syndrome, have been described, but genetic influences or other contributing factors are not well understood. Many studies have evaluated the occurrence of clinical symptoms in persons with HHC, but differences in sample selection, population characteristics, and case definition make it difficult to characterize attributable morbidity. Studies in clinical settings may overestimate the disease burden because patients with advanced disease are more likely to be included. Conversely, studies including "healthy people" (e.g., blood donors, asymptomatic adults in a screening program) may, by excluding sick persons, underestimate the disease burden. These limitations highlight the need for controlled, population-based studies that allow unbiased ascertainment of HHC's impact, including the extent to which its common manifestations are etiologically related. In the absence of such studies, current knowledge about clinical manifestations is based largely on observation of patients seen in referral centers. Phenotypic expression of HHC, which is variable, appears to depend on a complex interplay of the severity of the genetic defect, age, sex, and such environmental influences as dietary iron, the extent of iron losses from other processes, and the presence of other diseases or toxins (e.g., alcohol) (32). The rate of iron accumulation and the frequency and severity of clinical symptoms vary markedly; early complaints may include fatigue, weakness, joint pain, palpitations, and abdominal pain (33). Because these symptoms are relatively nonspecific, HHC is often not diagnosed at this stage. The disease can ultimately lead to hyperpigmentation of the skin, arthritis, cirrhosis, diabetes mellitus, chronic abdominal pain, severe fatigue, hypopituitarism, hypogonadism, cardiomyopathy, primary liver cancer, or an increased risk of certain bacterial infections (34). Most of these advanced complications are also common primary disorders, and iron overload can be missed at this stage unless looked for specifically. The liver is usually the first organ to be affected and hepatomegaly is one of the most frequent findings at clinical presentation (35). In one study, noncirrhotic probands at clinical presentation reported weakness, lethargy, and loss of libido more frequently than probands with cirrhosis, but symptoms of abdominal pain were markedly more frequent in the cirrhotic patients (34). The proportion of patients with cirrhosis at clinical presentation has varied from 22 to 60 percent (34, 36, 37). Primary hepatocellular carcinoma is 200 times more common in HHC patients (34) but it rarely occurs without cirrhosis. Hepatocellular carcinoma has been reported to account for 30 to 45 percent of deaths among the HHC patients seen in referral centers (38, 39). In patients with this kind of cancer, the prevalence of HHC ranges from 11 to 15 percent (40). Diabetes mellitus is the major endocrine disorder associated with HHC. The mechanisms responsible are still obscure, but iron deposition that damages the pancreatic beta cells and insulin resistance (38) have been postulated. Hypogonadism also occurs and is caused primarily by a gonadotropin deficiency resulting from iron deposition at the pituitary or hypothalamic levels. Other endocrine disorders involving an effect of HHC on the thyroid, parathyroid, or adrenal glands are rarely seen. Cardiac manifestations include cardiomyopathy and arrhythmias. Congestive heart failure has been seen in 2 to 35 percent and arrhythmias are present in 7 to 36 percent of HHC patients (41). Increases in melanin (42) lead to hyperpigmentation in 27 to 85 percent of patients (41). Loss of body hair, atrophy of the skin and koilonychia (dystrophy of the fingernails) may also occur. Arthropathies are found in 40 to75 percent of patients (38) and may affect the second and third metacarpal phalanges (43), wrist, shoulder, knees, or feet. Symptoms of HHC usually appear between ages 40 and 60 years with the onset normally later in women (44). This difference may relate to loss of iron with menstruation, pregnancy and lactation and to their lower iron intake relative to their iron needs (45). Men are more likely to develop clinical disease. Presenting signs and symptoms of HHC also vary by sex, with women more likely to present with fatigue, arthralgia, and pigmentation changes and men presenting more often with symptoms of liver disease (37). Symptoms and disease complications increase with age; in one study, 73 percent of men and 44 percent of women HHC homozygotes over age 40 had at least one clinical finding consistent with HHC (25). A smaller proportion, not yet well defined, is likely to develop potentially life-threatening complications (21, 46-48). Treatment Periodic phlebotomy or venesection to remove iron is a safe, inexpensive, and effective treatment for HHC. Venesection is usually initiated when serum ferritin (SF) concentrations indicate excess accumulation of iron stores. For example, the College of American Pathologists recommends initiation of venesection when SF reaches 300µg/L in men and 200µg/L in women (41); however, the appropriate SF cutoff for women may vary with their reproductive status (49). There have been no controlled trials of phlebotomy treatment, but observational studies in referral centers suggest that iron removal markedly increases survival (34, 38, 50, 51). Dietary management includes avoidance of iron supplements, excess vitamin C, and uncooked seafood, which is known to increase the risk of Vibrio vulnificus and Salmonella enteritidis infections in HHC patients (49). If treated early in the course of the illness, complications improve in some patients after iron depletion. In patients with established iron overload, liver function, weakness and lethargy (or fatigue), right upper quadrant abdominal pain, abnormal skin pigmentation, and cardiomyopathy usually improve, but hypogonadotropic hypogonadism does not (49). Response to treatment for patients with arthralgias is highly variable. Removal of excess iron does not reverse diabetes but can reduce insulin requirements (34, 50). Chelation therapy, which increases iron excretion, is less efficient and more expensive than phlebotomy. In general, management of HHC complications including liver failure, cardiac failure, and diabetes, differs little from the conventional management of these diseases. Mortality The prognosis of untreated HHC relates to the duration and amount of excess iron present at diagnosis. The severity of overload can be estimated from the number of venesections required to deplete iron stores (34, 36). As liver iron concentration increases, the prevalence of diabetes, cirrhosis, and cardiac disease is higher (33) which has implications for mortality rates. In general, persons with symptomatic HHC have lower survival than age- and sex-matched normal populations (34, 36) with the presence of cirrhosis being the primary factor affecting survival. However, studies from three referral centers indicate that if phlebotomy is initiated before cirrhosis develops, survival does not differ from that of the general population after adjustment for age and sex (34, 36, 39). Whether diabetes mellitus affects survival is controversial. Niederau et al. found reduced survival in HHC patients presenting with diabetes at the diagnosis (34), but 64 percent of those with diabetes also had cirrhosis, and thus their increased mortality might have been due to that complication. Even so, in a multivariate analysis with diabetes, cirrhosis, arthritis, age, and sex as covariates, the presence of diabetes significantly increased mortality (relative risk of 4.3) (34). In contrast, in an analysis of a Canadian HHC cohort that controlled for cirrhosis, diabetes did not increase risk of death (36). In evaluating these observations, the fact that data on the efficacy of treatment were derived from observational studies in referral centers rather than from population-based intervention trials should be considered, as should the limited availability of data on the efficacy of treating asymptomatic persons. The most widely quoted studies on the benefit of early treatment have been on the clinical outcome of a cohort of patients diagnosed at two clinical centers in Germany over a 40-year period (34, 38). In the most recent report, data were presented on 251 patients (89 percent male) followed for a mean of 14 years; 109 patients (43 percent) were noncirrhotic at diagnosis, 68 had other clinical findings and 41 were asymptomatic. The life expectancy of these patients as measured over the follow-up period, was indistinguishable from that of the general population, corrected for age and sex. Adams et al. reported similar data (36). While such reports are consistent with a significant benefit from phlebotomy treatment, they do not constitute proof that treatment of asymptomatic persons with HHC improves outcome, because the numbers are small and there was no untreated control group. An alternative explanation is that disease progression is minimal in many people with HHC genotypes who are asymptomatic or in the early stages of iron overload. Available data on survival are based on clinical cohorts diagnosed primarily on the basis of symptoms, and thus they reflect outcome in relatively late manifestations of the disease rather than in people diagnosed early. Historically, HHC survival has been poor. Before the introduction of insulin in 1921 and then phlebotomy treatment in 1935, the time from symptomatic presentation to death was 18 months (52). In recent times, HHC patients had more deaths from hepatocellular carcinoma, cardiomyopathy, liver cirrhosis, and diabetes mellitus than would be expected in the general population (34). In 1992, the HHC-associated mortality rate in the American population was reported at 1.8 deaths per million (0.0002 percent) (53), far lower than the estimated prevalence of HHC, suggesting that HHC is underdiagnosed, that the penetrance of the disease is low, or both. Disease Associations Genotype-phenotype correlation Factors that limit the comparability of studies and estimates of disease risk include the heterogeneity of clinical presentations, limited population characteristics studied and the lack of a uniform case definition. A pooled analysis on 14 studies in whites, including 2,205 cases and 5,604 controls, showed the highest risk for iron overload was associated with homozygosity for the C282Y mutation (odds ratio (OR)= 4,383, 95 percent CI: 1,374 to > 10,000; attributable fraction (AF) = 0.73) (54). The pooled OR for iron overload among persons with compound heterozygosity for C282Y and H63D mutations was 32 (95 percent CI: 18.5 to 55.4; AF = 0.06). H63D homozygosity carried a lower risk (pooled OR = 5.7, 95 percent CI: 3.2 to 10.1; AF = 0.01). Heterozygosity for the C282Y mutation was associated with a four-fold risk of iron overload (OR = 4.1, 95 percent CI: 2.9 to 5.8; AF = 0.03), but for this genotype significant differences in the OR were detected across the studies, making this result of uncertain significance. A small association also existed between iron overload and heterozygosity for H63D mutation (OR = 1.6, 95 percent CI: 1.0 to 2.6; AF = 0.03). Potential biases, however, might have influenced the magnitude of these associations. First, investigators used a variety of diagnostic criteria. Second, ascertainment of both cases and controls varied markedly and often was not clearly defined. Lastly, inappropriate control populations and the lack of consideration of modifiers such as age, sex, dietary iron intake, and alcohol consumption may have decreased the accuracy of estimates. The clinical expression of HHC is influenced by a variety of factors, both genetic and environmental. In HFE knockout mice, mutations of other genes involved in iron metabolism, such as beta2-microglobulin, transferrin receptor, and DTM1 (transmembrane iron import molecule), strongly modify the amount of liver iron (55), suggesting that modifier genes may influence the course of HHC in humans. There is also evidence that sex plays a primary role in the clinical manifestation of HHC. Family studies based on HLA linkage report an equal frequency of affected brothers and sisters, as expected for an autosomal recessive disorder, but the proportion of females among probands diagnosed on the basis of clinical symptoms is 11 to 35 percent lower than in males (33, 34, 39). And in a large screening trial, the prevalence of iron overload as determined by liver biopsy or phlebotomy was twice as frequent in males as females (47). This sex difference has been attributed to the lower degree of iron overload in women because of menstruation, pregnancy and lactation. The environment has also been reported to modify the expressivity, or penetrance, of the HHC genotype. Possible positive (beneficial) modifiers of disease phenotype include pregnancy and menstruation in females and chronic blood loss (gastrointestinal bleeding, regular hematuria, helminthic or other parasitic infections) and regular blood donation in both men and females. Detrimental factors include alcohol abuse, excessive iron intake, or other factors that increase iron stores (e.g., vitamin C). Tannates, phytates, oxalates, calcium and phosphates also modify HHC because they are known to bind iron and inhibit iron absorption (49). Chronic viral hepatitis B and C and metals such as zinc and cobalt may also influence expression of HHC (49, 56). Iron modulates the course of hepatitis B (57), and iron reduction has been shown to decrease the severity of chronic hepatitis C while increasing the likelihood of response to antiviral therapy. Hepatitis C virus infection and HFE mutations have also been identified as risk factors for porphyria cutanea tarda (57). Conte et al. (58), who studied 894 diabetic patients from Northern Italy, calculated an OR for HHC of 6.3 and a 1.34 percent prevalence of HHC in type II patients. The authors suggested that screening diabetic patients for HHC might be beneficial (58). However, Frayling et al. found a type II C282Y homozygosity prevalence of 0.42 percent, similar to an age-matched normoglycemic control group (59). Larger, population-based studies are needed to reach definitive conclusions. Iron overload can be a complication of certain disorders that are characterized by increased erythropoietic activity. Studies evaluating the impact of HHC on hereditary spherocytosis and acquired anemia have been inconsistent (60). Transferrin saturation and serum ferritin The most widely used biochemical markers of body iron status are transferrin saturation percent (TS = serum iron/total iron binding capacity x 100) and SF values. Elevated TS is usually present before symptoms occur or other studies indicate iron overload. The cutoff TS values recommended for screening have varied from 45 to 70 percent (26, 41, 61, 62). If the TS is above the threshold and no other explanations exist for iron overload (e.g., chronic anemias, liver diseases due to alcohol or viral infection) the test should be repeated after an overnight fast (41). Subjects should avoid iron and vitamin C supplements for at least 24 hours before testing. Simultaneously, tests of liver function, and a complete blood count should be performed. A second elevated TS indicates that the person may have HHC. If SF levels are also elevated then additional diagnostic testing (quantitative phlebotomy or liver biopsy) is recommended to confirm the presence of iron overload (17). In persons identified as having iron overload related to HHC by this screening and diagnostic process, the probability of developing clinical complications is uncertain. Family and screening trials suggest that 50 to 70 percent of males and 40 to 50 percent of females will develop symptoms or complications of HHC (25, 63), but most complications recorded in such studies were common and nonspecific clinical manifestations such as joint pain and diabetes. In the absence of control groups, the proportion of complications attributable to HHC is difficult to determine; as a result, the probability of developing clinical complications may be considerably lower. The analytical validity of the TS test can be evaluated by its sensitivity, specificity, and predictive value for the genotype, which depend in turn on the characteristics of the test and the underlying gene frequency. Using data from family studies and screening trials, Bradley et al. (25) found that screening at a TS cutoff value of 50 percent would identify approximately 94 percent of homozygote men and 82 percent of homozygote women and approximately 6 percent of men and 3 percent of women would be false positive results. Assuming an HHC genotype prevalence of 50 in 10,000, the odds of being affected given a positive result would be about 1:12 for males and 1:8 for females, corresponding to a positive predictive value (PPV) of 8 percent and 11 percent, respectively. PPVs using HLA typing as the standard increase when an initial elevated TS is followed by fasting TS higher than the first TS (64). The lack of a standard case definition makes it difficult to assess the clinical validity of the TS test. In a large, population-based screening study, the sensitivity of a single elevated TS for HHC (defined as the presence of iron overload with SF ł 95th percentile and mobilizable iron >99th percentile) was 100 percent, with a specificity of 97 percent and a PPV of 8 percent (27). The PPV rises with increasing prevalence of HHC. In a screening study of patients with liver disease, who presumably are more likely to have HHC, the PPV of a single elevated TS test was 41 percent (65). In patients with diabetes, the PPV of repeated elevated TS tests ranged from 63 to 83 percent when HHC was defined as increased liver iron stores (58, 66, 67). Ferritin is an intracellular iron storage protein and SF concentration significantly correlates with body iron stores (1ng/mL = 10 mg of stored iron) (68). SF values, but not TS values, are associated with HHC clinical signs, and SF is higher for those with clinical manifestations (25) . SF has been used as a second screening test in many trials, and it can be very effective in reducing the number of false positives (47), if cutoffs appropriate for age and sex are used. Elevation of the SF concentration in HHC must be differentiated, however, from other liver disorders such as alcoholic liver disease, chronic viral hepatitis, and nonalcoholic steatohepatitis. Serum ferritin is also an acute phase reactant and can be elevated during infection, chronic inflammation, or when the subject has a histiocytic neoplasm (41). HFE gene mutation analysis Methodologies used for identifying the C282Y and H63D allelic variants of the HFE gene should be sensitive and specific; however, data on technical performance are pending. The accuracy of the mutation analysis in predicting the HHC phenotype is uncertain because of genetic heterogeneity, reduced penetrance, and the lack of a standardized HHC case definition. As C282Y and H63D account for most but not all clinically diagnosed cases of HHC in whites (table 1), it is plausible that other mutations or other genes yet to be identified (30, 31) may also cause HHC. In addition, even in persons with detectable mutations the penetrance of the HFE genotype is not complete. In the general population, the C282Y/H63D and H63D/H63D genotypes occur more frequently than the C282Y/C282Y genotype (table 2), but among clinically diagnosed probands the C282Y/H63D and H63D/H63D account for only a small proportion of cases, suggesting low penetrance of the H63D allele (table 1). Studies on the HFE protein showing a lower loss of protein function with the H63D mutation corroborate this observation (7, 41). Reduced penetrance is likely for the C282Y/C282Y genotype, as indicated by case reports of elderly persons with this genotype and no evidence of significant disease (69, 70). That death from HHC complications does not lead to underrepresentation of this genotype in the elderly is suggested by a study of 600 patients over age 70 years that reported a prevalence of C2828Y homozygosity of 1 in 150 (71). Taken as a whole, this data indicates that mutation analysis alone cannot provide a simple positive or negative screening test for HHC. In populations of European descent, the prevalence estimates for C282Y homozygosity is 4 per 1,000 and for C282Y heterozygosity is 90 per 1,000 (table 2). The estimated U.S. population in November 1999 was 273,866,000, with 196,409,000 (71.7 percent) white persons (non-Hispanic) (72). Using these figures, at least 1,095,464 white (non-Hispanic) persons are C282Y homozygous and another 24,647,940 are C282Y heterozygous carriers. This estimate of the potential HHC public health burden would be enlarged if other ethnic groups and other etiologies of primary and secondary iron overload disorders were included. Although HHC meets most of the World Health Organization criteria for population screening, crucial questions remain to be answered before recommending population screening (17, 40, 73, 74). In particular, more information is needed about penetrance of clinical expression among persons with elevated TS or HFE mutations. Data about the disease burden associated with HHC is inadequate in the general population, and studies conducted in cohorts of patients with diseases associated with HHC are inconclusive in this regard (31, 58, 59, 75). Questions on screening accuracy, available diagnostic tests and the efficacy of early treatment need to be answered. Evidence on the efficacy of treatment is only available from retrospective studies and case series (34, 36, 50), and indicates that therapeutic phlebotomy improves survival among subjects with HHC who have clinical disease. For ethical reasons, randomized, controlled trials comparing therapeutic phlebotomy with no treatment cannot be undertaken and the effect of early phlebotomy treatment on life expectancy and quality of life cannot be objectively determined. Genetic testing for HHC raises general concerns of stigmatization, discrimination, diminished self-worth, and as a result, concerns about possible breaches of privacy and confidentiality. In particular, there is concern about the possible loss of insurance coverage and employment, which has been reported in anecdotal cases (76). Efforts to pass laws prohibiting discrimination in health insurance and employment have not yet ensured full protection from such discrimination. The cost-effectiveness of population-based TS screening has been assessed in numerous favorable but conservative studies (49, 62, 77, 78). Each study had important limitations however. First, they all assumed that people will fully follow the recommendations and that there will be no dropouts during the screening, diagnostic, and treatment process. Second, none included costs to individuals. More generally, cost-effectiveness analysis is very sensitive to variation in the proportion of individuals who test positive and would eventually develop clinical manifestations of the disease in question (49, 62, 77, 78). It may be that for low levels of penetrance, screening for HHC is not cost-effective. This hypothesis, however, has not yet been tested. Another area that requires further study is consideration of the relative cost and efficacy of genetic testing versus phenotypic screening tests. An efficient method of screening after identification of a proband is testing spouses of probands with the results of the spouse’s test guiding further testing of children (79, 80). Additional issues in population-based testing for HHC include the need for a centralized management and coordination mechanism for outreach and information services. The Centers for Disease Control and Prevention and the National Human Genome Research Institute have started a process that facilitates organization, education of health care providers and patients, and cooperation of individuals with expertise in this unique disorder. Explorations of the contributions of the gene-gene and gene-environment interactions in HHC offer unique opportunities to create valuable models to guide future programs in genetic medicine and genetic epidemiology. Genetic Databases Educational Resources Support Groups |
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