Hemochromatosis, type 1 is caused by homozygous or compound heterozygous mutation in the HFE gene (OMIM).
Hemochromatosis type 1 (also called classic hemochromatosis) is not a rare disease. Hemochromatosis type 1 (classic, homozygous HFE C282Y/C282Y) is exclusively and commonly found in Caucasian populations with a prevalence of the genetic predisposition of 1/200-1/1,000 but, due to its low penetrance and variable phenotypic expression, severe forms of the disease are rare. Men are clinically more affected than women (Orphanet).
The homozygous HFEC282Y/C282Y hemochromatosis is no rare disease in Northern Europeans, but it is a rare disease in African Americans, Asians, and Hispanics.
The HFE H63D variant rarely causes clinical problems in the homozygous or compound heterozygous (C282Y + H63D) state and is relatively common in the heterozygous state in most populations (northern Europeans: 25%; Hispanics: 18%; African Americans: 6%; Asians: 8.5%) (GeneReviews).
Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism wherein the body accumulates excess iron (summary by Feder et al., 1996). Excess iron is deposited in a variety of organs leading to their failure, and resulting in ... Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism wherein the body accumulates excess iron (summary by Feder et al., 1996). Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. Removal of excess iron by therapeutic phlebotomy decreases morbidity and mortality if instituted early in the course of the disease. Classic hemochromatosis (HFE) is most often caused by mutation in a gene designated HFE on chromosome 6p21.3. Adams and Barton (2007) reviewed the clinical features, pathophysiology, and management of hemochromatosis. - Genetic Heterogeneity of Hemochromatosis At least 4 additional iron overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Juvenile hemochromatosis, or hemochromatosis type 2 (HFE2), is autosomal recessive and is divided into 2 forms: HFE2A (602390), caused by mutation in the HJV gene (608374) on chromosome 1q21, and HFE2B (613313), caused by mutation in the HAMP gene (606464) on chromosome 19q13. Hemochromatosis type 3 (HFE3; 604250), an autosomal recessive disorder, is caused by mutation in the TFR2 gene (604720) on chromosome 7q22. Hemochromatosis type 4 (HFE4; 606069), an autosomal dominant disorder, is caused by mutation in the SLC40A1 gene (604653) on chromosome 2q32. Hemochromatosis type 5 (HFE5; 615517) is caused by mutation in the FTH1 gene (134770) on chromosome 11q12.
Muir et al. (1984) recognized 4 different types of hereditary hemochromatosis which 'bred true' in families, suggesting that more than one genetic lesion in iron metabolism can lead to hereditary hemochromatosis. Group I was termed the classic form ... Muir et al. (1984) recognized 4 different types of hereditary hemochromatosis which 'bred true' in families, suggesting that more than one genetic lesion in iron metabolism can lead to hereditary hemochromatosis. Group I was termed the classic form with elevated transferrin (190000) saturation, serum ferritin levels, and liver iron content; group II was characterized by severe iron overload and accelerated disease manifesting at an early age; group III was characterized by elevated total body iron stores, normal transferrin saturation and serum ferritin levels; and group IV was characterized by markedly elevated findings on serum biochemical tests, i.e., transferrin saturation and serum ferritin, with minimal elevation in total body iron stores. Milman et al. (1992) found no relationship between genetic subtypes of transferrin and the expression of disease in hemochromatosis patients. Edwards et al. (1980) identified 35 hemochromatosis homozygotes through pedigree studies, using the close linkage to HLA-A (142800) in the identification. Thirteen were asymptomatic. Arthropathy was present in 20, hepatomegaly in 19, transaminasemia in 16, skin pigmentation in 15, splenomegaly in 14, cirrhosis in 14, hypogonadism in 6, and diabetes in 2. None had congestive heart failure. Only 1 had the triad of hepatomegaly, hyperpigmentation, and diabetes. Serum iron was increased in 30 of 35, transferrin saturation was increased in all 35, serum ferritin in 23 of 32, urinary iron excretion after deferoxamine in 28 of 33, hepatic parenchymal cell stainable iron in 32 of 33, and hepatic iron in 27 of 27. Iron loading was 2.7 times greater in men than in women. No female had hepatic cirrhosis. By studying 1,058 individuals who were heterozygous for the HLA-linked hemochromatosis mutation, Bulaj et al. (1996) found that the mean serum iron concentrations and transferrin-saturation values were higher in heterozygotes than in normal subjects and did not increase with age. Initial transferrin-saturation levels exceeding the threshold associated with the homozygous genotype were found in 4% of males and 8% of female heterozygotes. The geometric mean serum ferritin concentration was higher in heterozygotes than in normal subjects and increased with age. Higher-than-normal values were found in 20% of males and 8% of female heterozygotes. The clinical and biochemical expression of hemochromatosis was more marked in heterozygotes with paternally transmitted mutations than in those with maternally transmitted mutations. Liver biopsy abnormalities were generally associated with alcohol abuse, hepatitis, or porphyria cutanea tarda. Bulaj et al. (1996) concluded that complications due to iron overload alone in hemochromatosis heterozygotes are 'extremely rare.' This was the first description of parent-of-origin effects in hemochromatosis. Escobar et al. (1987) established the diagnosis of hemochromatosis in a 7-year-old boy and his 29-month-old brother. These were said to be the youngest children with primary hemochromatosis reported to that time. They were members of a family in which 3 generations had affected individuals. Data from the literature on values of serum iron, serum ferritin, transferrin saturation, and hepatic iron were reviewed. Kaikov et al. (1992) described hemochromatosis in asymptomatic sibs in whom the diagnosis was made after an unexpected finding of elevated serum iron concentrations. The sibs were 7, 6, and 4 years of age. Elevated red cell mean corpuscular volume (MCV) was elevated in all 3, at 90 to 92 fL. In their review of the literature, they found 16 cases of symptomatic homozygous children at ages ranging from 4 to 19 years at the time of diagnosis. They suggested that normalization of the MCV may be an indirect index of adequate phlebotomy. The cases of Escobar et al. (1987) and Kaikov et al. (1992) may have been juvenile hemochromatosis (602390). Roldan et al. (1998) described acute liver failure after iron supplementation in a 29-year-old woman with unrecognized hemochromatosis. Roy and Andrews (2001) reviewed disorders of iron metabolism, with emphasis on aberrations in hemochromatosis, Friedreich ataxia (FRDA; 229300), aceruloplasminemia (604290), and other inherited disorders. McDermott and Walsh (2005) assessed the prevalence of hypogonadism in a large group of patients with hemochromatosis diagnosed in a single center over a 20-year period. Abnormally low plasma testosterone levels, with low luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) levels, were found in 9 of 141 (6.4%) male patients tested. Eight of nine (89%) had associated hepatic cirrhosis; 3 of 9 (33%) had diabetes. Inappropriately low LH and FSH levels were found in 2 of 38 females (5.2%) in whom the pituitary-gonadal axis could be assessed. McDermott and Walsh (2005) concluded that patients with lesser degrees of hepatic siderosis at diagnosis are unlikely to develop hypogonadism. - Liver Cirrhosis and Liver Cancer Deugnier et al. (1993) analyzed the occurrence of primary liver cancer in hemochromatosis; there was 1 instance of cholangiocarcinoma and 53 instances of hepatocellular carcinoma (HCC; 114550). Of the 54 patients, 32 were untreated and 22 had been 'de-ironed.' Three of the patients had hepatocellular carcinoma in noncirrhotic but only fibrotic liver. Chronic alcoholism and tobacco smoking was higher in patients with hepatocellular carcinoma than in matched hemochromatosis patients without carcinoma. A common manifestation of tissue damage caused by iron accumulation in hereditary hemochromatosis is hepatic cirrhosis that may lead to hepatocellular carcinoma. Willis et al. (2000) determined the risk of developing such disease manifestations in individuals with HFE mutations in Norfolk, UK. The frequency of mutant HFE alleles in archived liver tissue blocks from patients with cirrhosis or liver cancer was compared with that in 1,000 control blood samples. This control group was derived from a number of sources; no sample was from an individual with diagnosed HH. Of 34 cases of liver cancer, 3 (8.8%) were homozygous for the C282Y (613609.0001) mutation (2 hepatocellular carcinomas, 1 undifferentiated liver carcinoma). None of these patients had been given a diagnosis of HH prior to the diagnosis of liver cancer. None were C282Y/H63D (613609.0002) compound heterozygotes. Five of 190 cirrhosis samples (2.6%) were homozygous for C282Y; 4 of these patients had been given a clinical diagnosis of HH at the time of biopsy, and the remaining case fell also into the liver cancer group. Six cirrhosis samples were from C282Y/H63D compound heterozygotes; none had been given a clinical diagnosis of HH. The frequency of C282Y homozygotes in the control group was 1 in 230, and of C282Y/H63D compound heterozygotes was 1 in 108. HFE mutations were significantly more common in disease than in control specimens. Willis et al. (2000) calculated that, in their population, 2.7% of C282Y homozygotes and 1% of C282Y/H63D compound heterozygotes develop liver disease at some point in their lives. Both Wilson disease (WND; 277900) and hemochromatosis, characterized by excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles (191170) in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, Hussain et al. (2000) determined the frequency of p53 mutated alleles in nontumorous liver tissue from WND and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249, and C:G to A:T transversions and C:G to T:A transitions at codon 250 were found in liver tissue from WND cases, and a higher frequency of G:C to T:A transversions at codon 249 was also found in liver tissue from hemochromatosis cases. Sixty percent of WND and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggested nitric oxide as a source of increased oxidative stress. The results were consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WND causes mutation in the p53 tumor suppressor gene.
Dadone et al. (1982) found saturation of transferrin above 62% to be the best simply measured indicator of genotype: homozygosity was accurately predicted in 92% of cases. The logarithmic scale of serum ferritin concentration was only 71% accurate. ... Dadone et al. (1982) found saturation of transferrin above 62% to be the best simply measured indicator of genotype: homozygosity was accurately predicted in 92% of cases. The logarithmic scale of serum ferritin concentration was only 71% accurate. The frequency of the hemochromatosis gene was estimated at 0.069 +/- 0.020, corresponding to a heterozygote frequency of 0.13 and a homozygote frequency of 0.005. Barton et al. (1999) studied the phenotype-genotype correlation in 150 family members (72 males and 78 females) of 61 Caucasian American probands. Thirty-four of the family members had an HFE phenotype. Genotyping was limited to the 2 major alleles, C282Y and H63D. Among the family members, 92% of C282Y homozygotes, 34.5% of C282Y/H63D compound heterozygotes, and none of the H63D homozygotes had the HFE phenotype. In contrast, a few individuals heterozygous for one or the other allele had iron overload. Pseudodominant patterns of inheritance were not infrequently observed. Hence, phenotyping and genotyping are complementary in screening for hemochromatosis among family members of probands. Mura et al. (2001) studied 545 probands who were homozygous for the C282Y mutation (613609.0001), showed various signs of clinical hemochromatosis, and had been referred for treatment by phlebotomy. Iron loading was found to be significantly lower in females than in males and to be correlated with increasing age in both males and females. A study of 18 same-sex sib pairs showed no correlation of iron marker status between HH sibs and other sibs, indicating a variable phenotypic expression of iron loading independent of the HFE genotype. Mura et al. (2001) also found that transferrin saturation percentage was the best indicator of the hereditary hemochromatosis phenotype in young subjects, and serum ferritin concentration was the best marker of iron overload in these patients. The superoxide dismutase-2 (SOD2; 147460) val16 allele (147460.0001) has 30 to 40% lower enzyme activity and increases susceptibility to oxidative stress. Valenti et al. (2004) found a significantly increased frequency of the val16 allele among 217 unrelated patients with hereditary hemochromatosis who developed dilated or nondilated cardiomyopathy compared to HH patients without cardiomyopathy and controls (frequencies of 0.67, 0.45, and 0.52, respectively). The val/val genotype conferred a 10.1-fold increased risk for cardiomyopathy in the HH patients. The association was independent of cirrhosis, diabetes, arthropathy, and hypogonadism, and did not apply to ischemic heart disease. Valenti et al. (2004) concluded that the val16 allele increased the risk of cardiomyopathy due to iron overload toxicity and oxidation in HH patients as a result of decreased activity of the SOD2 enzyme. To test whether common HFE mutations that associate with this condition and predispose to increases in serum iron indices are overrepresented in diabetic populations, Halsall et al. (2003) determined the allele frequencies of the C282Y (613609.0001) and H63D (613609.0002) HFE mutations among a cohort of 552 patients with typical type 2 diabetes mellitus. There was no evidence for overrepresentation of iron-loading HFE alleles in type 2 diabetes mellitus, suggesting that screening for HFE mutations in this population is of no value.
In patients with hereditary hemochromatosis, Feder et al. (1996) identified 2 mutations in the HFE gene (C282Y; 613609.0001 and 613609.0002). The C282Y mutation was detected in 85% of all HFE chromosomes, indicating that in their population 83% of ... In patients with hereditary hemochromatosis, Feder et al. (1996) identified 2 mutations in the HFE gene (C282Y; 613609.0001 and 613609.0002). The C282Y mutation was detected in 85% of all HFE chromosomes, indicating that in their population 83% of hemochromatosis cases are related to C282Y homozygosity. Beutler et al. (1997) pointed out that calreticulin (CALR; 109091), like beta-2-microglobulin (B2M; 109700), associates with class I HLA proteins and appears to be identical to mobilferrin, a putative iron transport protein. Thus these 2 proteins were considered candidates for mutations in patients with hemochromatosis. The investigators sequenced the coding region and parts of introns of the HFE gene (called by them HLA-H), the B2M gene, and the CALR gene in 10, 7, and 5 hemochromatosis patients, respectively, selecting those who were not homozygous for the common C282Y mutation. No additional mutations were found in the HLA-H gene and no disease related mutations in the other 2 genes. The authors noted that the basis for hemochromatosis in more than 10% of European patients and in most Asian patients awaits explanation. Beutler et al. (1997) speculated that the finding of some effects in heterozygotes (Bulaj et al., 1996) and the rarity of mutations other than C282Y and his63 to asp (H63D; 613609.0002) may point to a gain-of-function consequence of these mutations, similar, they suggested, to sickle cell anemia, which is caused by only 1 type of mutation (see 141900.0038) and represents in effect a gain-of-function mutation. The unique mutation causing achondroplasia, gly380 to arg (G380R; 134934.0001), might also be cited. By sequence analysis of exons 2, 3, 4, and 5, and portions of introns 2, 4, and 5 of the HFE gene, Barton et al. (1999) identified novel mutations in 4 of 20 hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity. Probands 1 and 2 were heterozygous for the previously undescribed mutations ile105 to thr (I105T; 613609.0009) and gly93 to arg (G93R; 613609.0010). Probands 3 and 4 were heterozygous for the previously described but uncommon HFE mutation ser65 to cys (S65C; 613609.0003). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda (see 176100), and proband 4 had hereditary stomatocytosis (185000). Each of these 4 probands had iron overload. In each proband with an uncommon HFE coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C occurred as spontaneous mutations in these probands. In 176 normal control subjects, 2 were heterozygous for S65C, but I105T and G93R were not detected. Griffiths and Cox (2000) reviewed the molecular pathophysiology of iron metabolism. Pietrangelo (2004) reviewed the various forms of hemochromatosis. In a useful diagram, he illustrated the polygenic nature and phenotypic continuum of hereditary hemochromatosis. The continuum involves age at onset, clinical severity, and contribution of host or environmental factors to expressivity. Intermediate phenotypes can result from combined heterozygous mutations (compound heterozygosity) or homozygous mutations of more than 1 hemochromatosis gene. For instance, the relatively mild phenotype associated with homozygous mutation of HFE can be aggravated and accelerated by a coexisting heterozygous mutation in a gene associated with a juvenile form of the disease, such as HAMP. The latter mutation, combined with a normally silent heterozygous HFE mutation, can also result in unexpected expression of disease. Lee et al. (2004) identified a patient with adult-onset hemochromatosis who was compound heterozygous for mutations in the HJV gene (G320V, 608374.0001; 608374.0007). - Genetic Modifiers In patients with 'atypical' hemochromatosis, defined as having a discordant iron phenotype despite having the same HFE genotype, Hofmann et al. (2002) performed mutation analysis of the transferrin receptor-2 gene (TFR2), which is mutated in HFE3. Sib pairs homozygous for HFE C282T had a discordant phenotype in serum transferrin concentration and/or significant differences in liver fibrosis and liver enzyme levels. Also included were individuals who were not homozygous for C282Y, but who had evidence of iron excess. In a pair of brothers homozygous for the C282Y mutation, Hofmann et al. (2002) found a mutation in the TFR2 only in the brother with liver fibrosis, suggesting that TFR2 functions as a modifier for penetrance of the hemochromatosis phenotype when present with homozygosity for C282Y. The screening for mutations in all 18 exons indicated that mutations of the TFR2 gene are rare. Merryweather-Clarke et al. (2003) described 2 families who exhibited digenic inheritance of hemochromatosis. In family A, the proband had a JH phenotype and was heterozygous for the C282Y mutation in the HFE gene as well as a frameshift mutation in the HAMP gene (606464.0003). The proband's unaffected mother was also heterozygous for the HAMP frameshift mutation, but lacked the HFE C282Y mutation and was heterozygous for the HFE H63D mutation (613609.0002). In family B, there was a correlation between severity of iron overload, heterozygosity for a HAMP G71D mutation (606464.0004), and heterozygosity or homozygosity for the HFE C282Y mutation. The authors proposed that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation. Among 310 C282Y homozygous HFE patients, Le Gac et al. (2004) found 9 patients with an additional heterozygous HJV mutation, including the L101P (608374.0006) and G320V mutations. Iron indices of 8 of these patients appeared to be more severe than those observed in sex- and age-matched C282Y homozygotes without an HJV mutation. Mean serum ferritin concentrations of the 6 males with an HJV mutation were significantly higher than those of C282Y homozygous males without an HJV mutation. Using pretherapeutic serum ferritin levels in C282Y homozygotes as a marker of penetrance, Milet et al. (2007) found an association between a common T/C SNP in the 3-prime region of the BMP2 gene (112261), dbSNP rs235756, and hemochromatosis penetrance. Mean ferritin level, adjusted for age and sex, was 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. The subjects studied were all homozygous for the common C282Y mutation. The results further suggested an interactive effect on serum ferritin level of dbSNP rs235756 in BMP2 and a SNP in HJV (608374), with a small additive effect of a SNP in BMP4 (112262). Le Gac et al. (2008) reported a 47-year-old woman of Sardinian descent who presented with mild hemochromatosis. Genetic analysis showed that she was homozygous for a deletion involving the entire HFE gene; however, her phenotype was relatively mild and similar to that of women homozygous for the common lower-penetrance C282Y mutation. The report indicated that additional genetic and environmental factors must play a role in the pathogenesis of the disease.
The frequency of the hemochromatosis gene in Utah was placed at 5.6% (Cartwright et al., 1979). Homozygotes had a frequency of 0.3% and heterozygotes a frequency of 10.6%. A similar gene frequency was estimated for Brittany (Beaumont et ... The frequency of the hemochromatosis gene in Utah was placed at 5.6% (Cartwright et al., 1979). Homozygotes had a frequency of 0.3% and heterozygotes a frequency of 10.6%. A similar gene frequency was estimated for Brittany (Beaumont et al., 1979). Krikker (1982) described the newly established Hemochromatosis Research Foundation, Inc. As justification for its existence, Krikker wrote as follows: 'The incidence of heterozygosity for the hemochromatosis allele in the white population is approximately 10%. The expected incidence of homozygosity is about 2 to 3 per 1000, an estimate supported by the finding of homozygosity in 1 in 333 residents of Utah (Cartwright et al., 1979), 1 in 400 Bretons (Beaumont et al., 1979), and in an autopsy study 1 in 500 Scots (MacSween and Scott, 1973).' In an extensive study of hemochromatosis in Brittany, Lalouel et al. (1985) confirmed the Salt Lake City data (Cartwright et al., 1979; Kravitz et al., 1979). In the county of Jamtland in central Sweden, an area known in the past for a high prevalence of iron deficiency, Olsson et al. (1983, 1984) screened for iron overload by a laboratory routine that automatically included determination of serum iron and transferrin saturation. They found a prevalence of 0.5% for genetic iron overload, which suggested that 12.8% of the population are gene carriers. Meyer et al. (1987) used serum ferritin concentration as a screening test for iron overload in 599 Afrikaners living in the South Western Cape, South Africa. Sixteen subjects, all males from different families, had concentrations greater than 400 micrograms/L. Reevaluations 3 and 5 years later included remeasurement of serum ferritin, assessment of alcohol intake, measurements of serum gamma-glutamyltransferase, percentage saturation of transferrin, and HLA typing. The serum ferritin concentration is significantly raised after excessive alcohol consumption; however, the measurement of serum gamma-glutamyltransferase helps resolve the confusion because a serum ferritin concentration above 300 micrograms/L is very unlikely to be the result of alcohol-induced hepatic damage if the gamma-glutamyltransferase is less than 50 units per liter. Of the 16 index persons, 4 were diagnosed as homozygous for the HLA-linked iron-loading gene. Six appeared to be heterozygotes, 3 were heterozygotes who were also abusing alcohol, and 2 did not fit into any of the diagnostic groups. The calculated gene frequency was 0.082, with an expected heterozygote frequency of 0.148. The fact that no females were identified in the study suggested to the authors that their criteria for homozygosity were set too high. When the data were recalculated for the 300 males, the gene frequency became 0.115 and the heterozygote frequency became 0.204. Simon et al. (1987) presented findings they interpreted as fitting well with the hypothesis that 'the hemochromatosis mutation was a rare if not unique event that produced an ancestral HLA marking that was subsequently modified by recombinations and geographical scattering due to migrations.' Among 11,065 presumably healthy blood donors (5,840 men and 5,225 women), Edwards et al. (1988) found that transferrin saturation of 62% or more after an overnight fast had a frequency of 0.008 in men and 0.003 in women. Detailed studies were performed in 38 persons with values higher than 62%; 35 underwent liver biopsy. Liver iron stores ranged from normal to markedly increased. Twelve sibs with an identical HLA match to a proband underwent liver biopsy, and 11 had increased liver iron stores. Analysis of pedigrees led to the conclusion that 26 of the 38 probands were homozygotes and 12 were heterozygotes. Basing the estimate of the frequency of homozygosity on the data in men, Edwards et al. (1988) arrived at an estimate of 0.0045, corresponding to a gene frequency of 0.067. By means of a screening using transferrin saturation followed by repeat transferrin saturation and serum ferritin, clinical examination, and laparoscopy, Karlsson et al. (1988) concluded that the prevalence of hemochromatosis in Finland is about 5 per 10,000. Milman et al. (1990) studied 1 Faroese and 4 Danish kindreds with hemochromatosis. Milman (1991) analyzed 179 patients ascertained in Denmark between 1950 and 1985, as well as 13 preclinical subjects ascertained through family studies or high serum transferrin-saturation values. The high frequency of the HFE gene may account, through the mechanism of pseudodominance, for the simulation of dominant inheritance and the consequent debates in the past as to the mode of inheritance of hemochromatosis. Dokal et al. (1991) reported on a family with affected members in 2 generations in a pseudodominant pedigree pattern. The affected father was deceased. The heterozygous mother and all 6 children (3 homozygotes, 3 heterozygotes) were HLA identical (A1B8/A3B14). Affected sibs were recognized in the precirrhotic stage of hemochromatosis by analysis of serum parameters of iron status in combination with magnetic resonance imaging. In the Saguenay-Lac-Saint-Jean region of northeastern Quebec, De Braekeleer (1993) estimated the prevalence of hereditary hemochromatosis to be 0.014, giving a heterozygote frequency of 0.21. These were among the highest frequencies found in white populations. Fertility studies showed that carriers of the gene tended to have more children than noncarriers. However, since the differences were not statistically significant, genetic drift could not be excluded. In an analysis of 82 unrelated HFE patients and 82 unrelated healthy controls, Jazwinska et al. (1993) found that allele 8 at the D6S105 locus was present in 93% of patients and only 21% of controls, giving an approximate relative risk for this allele of 48.4. HLA-A3 was present in 62% of patients and 26% of controls, giving an approximate relative risk for A3 of 4.8. They concluded that the microsatellite marker D6105 was the closest marker to HFE reported to that date. Jazwinska et al. (1995) found that hemochromatosis shows a very strong founder effect in Australia, with the majority of patients being of Celtic (Scottish/Irish) origin. By analyzing chromosomes from 26 multiply affected hemochromatosis pedigrees for linkage disequilibrium and genetic heterogeneity, they were able to assign hemochromatosis status unambiguously to 107 chromosomes: 64 as affected and 43 as unaffected. With the serologic marker HLA-A and 4 microsatellite markers, highly significant allelic association with hemochromatosis was found. One predominant ancestral haplotype was present in 33% of 64 affected chromosomes and was associated exclusively with hemochromatosis (haplotype relative risk 903). No other common haplotype was significantly associated with hemochromatosis. Thus, the common mutation probably underlies hemochromatosis in Australian patients, having been introduced into this population on an ancestral haplotype. Furthermore, the candidate HFE region extends between and includes D6S248 and D6S105. Pozzato et al. (2001) found a high prevalence of HFE gene mutations in the Cimbri population of the Asiago plateau, situated in the Italian region of Veneto. The Cimbri population descends from an ancient tribe of Celtic ancestry who settled on the plateau around the 2nd century B.C. and who preserved their independence and ethnic integrity. In 103 unrelated blood donors with parents and grandparents born in the Asiago plateau, the allele frequencies of the C282Y and H63D mutations were 0.048 and 0.174, respectively. The study confirmed the high prevalence of HFE gene mutations in Celtic populations, and the authors speculated that these mutations gave them selective advantages because of their iron-poor diet. They theorized that a larger amount of iron can be transferred from the mother through the placenta, reducing perinatal mortality and morbidity. Using a relative risk of 1.0 for the C282Y homozygote, Risch (1997) calculated the risk of the C282Y/H63D compound heterozygote to be 0.00525 and the relative risk of other genotypes to be 0.00015. There appeared to be a modestly increased risk (about 4-fold) associated with homozygosity for H63D. Great haplotype diversity on non-C282Y chromosomes had been observed in patients. This was not surprising, as the disequilibrium on H63D chromosomes spans a much shorter distance (700 kb) than on C828Y chromosomes (more than 7 Mb), consistent with the higher frequency and likely older origin for H63D. Indeed, the disequilibrium analysis of H63D chromosomes provided compelling evidence both for the implication of H63D in hemochromatosis and that HFE is the hemochromatosis gene. Beckman et al. (1997) found that the C282Y mutation is rare or absent in Asiatic (Indian, Chinese) populations. The highest allele frequency they found was in Swedes (7.5%). Parkkila et al. (1997) suggested a selective advantage of the C282Y mutation on the basis of improved survival during infancy, childhood, and pregnancy in times past, by leading to increased iron absorption and accumulation of larger body iron stores. Although this selection could operate at the level of increased dietary iron absorption, such mutations might also lead to enhanced maternal/fetal iron transport. Such an effect might confer a selective advantage on the fetus under conditions of maternal iron deprivation. Burt et al. (1998) determined the frequency of the C282Y and H63D HFE mutations in randomly selected adults from Christchurch, New Zealand. Heterozygote frequencies were 13.2% for C282Y and 24.3% for H63D. Heterozygotes for both alleles had significantly higher serum iron concentrations and transferrin saturations; only C282Y heterozygotes had significantly higher serum ferritin concentrations. Five individuals were homozygous for the C282Y mutation; 3 (2 females aged 38, and 1 male aged 71) had persistently elevated serum ferritin levels and liver biopsy findings consistent with hemochromatosis. The remaining 2 C282Y homozygotes (2 females aged 20 and 31) did not have elevated ferritin levels and were not biopsied. The authors commented that the population frequency of C282Y homozygosity was approximately 1 in 200 and that population screening programs should restrict genotyping to individuals with an elevated transferrin saturation. Steinberg et al. (2001) estimated the prevalence of the C282Y and H63D mutations in the U.S. population as 5.4% and 13.5%, respectively. The prevalence estimates of homozygosity for the C282Y and H63D mutations were 0.26% and 1.89%, respectively, and 1.97% for compound heterozygosity for these 2 alleles. The prevalence estimate for C282Y heterozygosity was 9.54% among non-Hispanic whites, 2.33% among non-Hispanic blacks, and 2.75% among Mexican Americans. The prevalence estimates for HFE mutations were within the expected range for non-Hispanic whites and blacks, but were less than expected for the C282Y mutation among Mexican Americans. Merryweather-Clarke et al. (1999) retrospectively analyzed 837 random dried blood spot samples from neonatal screening programs in Scandinavia for mutations in the HFE gene. They found that the C282Y allele had a frequency of 2.3% in Greenland, 4.5% in Iceland, 5.1% in the Faroe Islands, and 8.2% in Denmark. The high prevalence of HFE mutations in Denmark suggested that population screening for C282Y could be highly advantageous in terms of preventive health care. Furthermore, long-term follow-up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes would provide an indication of the penetrance of the mutations. Rochette et al. (1999) stated that over 80% of hemochromatosis patients are homozygous for the C282Y mutation in the unprocessed protein. In a proportion of these patients, compound heterozygosity is found for C282Y and H63D. The clinical significance of the second mutation is such that it appears to predispose 1 to 2% of compound heterozygotes to expression of the disease. The distribution of the 2 mutations differs, C282Y being limited to those of northwestern European ancestry, and H63D being found at allele frequencies of more than 5% in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends 6 Mb or less, suggesting that this mutation arose during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending 700 kb or less. Rochette et al. (1999) found the H63D and C282Y mutations on new haplotypes. In Sri Lanka, they found H63D on 3 new haplotypes and found C282Y on 1 new haplotype, demonstrating that these mutations have arisen independently on this island. The results suggested that the HFE gene has been subject to selection pressure. In a population of white adults of northern European ancestry in Busselton, Australia, Olynyk et al. (1999) found that 0.5% were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one-quarter had serum ferritin levels that remained normal over a 4-year period. Brown et al. (2001) used National Hospital Discharge Survey and census data to estimate hemochromatosis-associated hospitalization rates for persons 18 years of age and over. From 1979 to 1997, the rate of hemochromatosis-associated hospitalizations was 2.3 per 100,000 persons in the U.S. The rate among persons 60 years of age and over increased more than 60% during this time. Barton and Acton (2001) screened 1,373 African American controls in 5 regions of the U.S. for the C282Y and H63D mutations in the HFE gene. The frequency of the C282Y/C282Y genotype was 0.00011; that of C282Y/H63D, 0.00067; and that of H63D/H63D, 0.0101. Penetrance-adjusted estimates indicated that approximately 9 per 100,000 African Americans have a hemochromatosis phenotype and 2 common HFE mutations. Hemochromatosis-associated genotype frequencies varied 11.7-fold across regions. De Juan et al. (2001) analyzed the frequency of the C282Y, H63D, and S65C (613609.0003) HFE gene mutations in 35 unrelated HH patients from the Basque population. Only 20 (57.1%) of the patients were homozygous for the C282Y mutation, while 5 patients were compound heterozygous for C282Y/H63D or H63D/S65C. Eight patients were heterozygous for 1 of the 3 mutations, and 2 patients lacked any of the mutations studied. In a control group of 116 healthy blood donors of Basque origin, de Juan et al. (2001) found allele frequencies of 29.7%, 5.2%, and 3.0% for the H63D, C282Y, and S65C mutations, respectively. The authors suggested that the peculiar genetic characteristics of the Basques could explain the heterogeneity of HH genotypes found in this study, and the presence of other genetic and external factors could explain the severe iron overload and HH in some of the H63D heterozygotes and no mutated genotypes. The C282Y mutation probably occurred on a single chromosome carrying the ancestral hemochromatosis haplotype, which subsequently was spread by emigration and founder effect. The C282Y mutation is thought to have appeared 60 to 70 generations ago. Milman and Pedersen (2003) hypothesized that the distribution of the C282Y mutation in Europe is consistent with an origin among the Germanic Iron Age population in southern Scandinavia. From this area, the mutation could later be spread by the migratory activities of the Vikings. Milman and Pedersen (2003) found several arguments in favor of the 'Viking hypothesis': first, the highest frequencies (5.1 to 9.7%) of the C282Y mutation are observed in populations in the northern part of Europe, i.e., Denmark, Norway, Sweden, Faroe Islands, Iceland, eastern part of England and the Dublin area, all Viking homelands and settlements. Second, the highest allele frequencies are reported among populations living along the coastlines. Third, the frequencies of the C282Y mutation decline from northern to southern Europe. Intermediate allele frequencies (3.1 to 4.8%) are seen in populations in central Europe. Low allele frequencies (0 to 3.1%) are recognized in populations in southern Europe and the Mediterranean. Distante et al. (2004) reviewed the evidence on C282Y frequencies, extended haplotypes involving HLA-A and HLA-B alleles, calculations of mutation age, selective advantage, and the relative importance of population migration and cultural change in the neolithic transition in Europe. They concluded that the C282Y mutation occurred in mainland Europe before 4000 B.C. In a study of 645 Native Americans compared with 43,453 white participants in a hemochromatosis and iron overload screening study, Barton et al. (2006) found that the allele frequencies of HFE C282Y and H63D were significantly lower in Native Americans than in whites. Matas et al. (2006) studied the prevalence of the C282Y and H63D mutations in 255 non-Ashkenazi Jewish individuals. Analysis of 24 patients who were H63D homozygotes revealed that 12 had secondary causes of iron overload; of those who did not, 2 had symptomatic hemochromatosis, whereas the remaining 10 had only altered iron metabolism, particularly elevated ferritin, without clinical symptoms. Matas et al. (2006) concluded that homozygosity for the H63D mutation confers an increased risk of iron overload and therefore genetic susceptibility to developing hereditary hemochromatosis. - HLA Association In 50 unselected and unrelated patients with hemochromatosis, Ritter et al. (1984) found a high association with the HLA haplotype A3B14 (relative risk 23.4). One family with this haplotype was traced back to the end of the seventeenth century. Ritter et al. (1984) suggested that the high frequency of the hemochromatosis gene might be the result of a selective advantage of increased iron sequestration under conditions of iron deficiency: homozygous males would not lose reproductive capacity from effects of iron deficiency on testicular function, and females, homozygous and perhaps heterozygous as well, would be better prepared to meet the increased iron demands of pregnancy. Simon et al. (1988) suggested that a single ancient mutation of a gene involved in iron homeostasis resulted in the present-day hemochromatosis allele. This mutation was thought to have occurred on a chromosome 6 carrying HLA-A3 and HLA-B7. Over the years recombination events between the HLA-A and HLA-B loci presumably led to the observed association with other HLA-B alleles on haplotypes carrying HLA-A3, and recombinations between HLA-A and the hemochromatosis locus produced associations with other HLA-A alleles and haplotypes. The original mutation should be progressing toward equilibrium with the HLA alleles, with the residual association resulting either because there has been insufficient time to reach equilibrium or because the association confers a selective advantage (Kushner et al., 1988). A recent recombination event or perhaps a new mutation has placed a hemochromatosis allele on an HLA-A2,B12 chromosome in a population that made a major contribution to the present-day Australian gene pool. Because of the predominant origin of the present-day Australian population, Summers et al. (1989) suggested that this chromosome originated in England or perhaps, in view of the family names of many of the patients, Ireland. Jouanolle et al. (1990) studied RFLPs from the HLA-A region and identified a significantly high frequency of a particular EcoRI fragment among the hemochromatosis patients who were HLA-A3 in tissue type. In Denmark, Milman et al. (1988) found the pattern of HLA antigens associated with hemochromatosis to be similar to those reported both in Germany, where HLA-A3,B7 dominated, and in Brittany, Great Britain, and central Sweden, where HLA-A3,B14 dominated. In 74 Danish patients with hemochromatosis and 21 homozygous relatives, Milman et al. (1992) found atypical frequencies of HLA type: A3 was present in 53.6% as compared to 15.1% in the general population. B7 was present in 33.1% as compared with 15.6% in the general population. The 2 most frequent haplotypes were A3,B5 (10.3% vs 0.3%) and A3,B7 (25.6% vs 6.6%). In South Wales, Cragg et al. (1988) found that 80% of 15 unrelated patients had HLA-A3 compared with 24% of 600 unrelated and unaffected persons. The most common haplotype was HLA-A3,B7. They found no evidence in support of the possibility that either the ferritin heavy chain gene (134770) or HLA class I genes are candidates for the gene mutant in hemochromatosis. In studies of 24 Australian families, Summers et al. (1989) found linkage to HLA in at least 23. The evidence was interpreted as indicating the involvement of a single genetic locus in most (probably all) cases of familial hemochromatosis in Australia. As in all other populations reported, an association of HLA-A3 and HLA-B7 with the disease was found in the Australian cases. In addition, HLA-A2 and HLA-B12 were in significant linkage disequilibrium in patients but not in controls, which might indicate a new mutation or recent recombination between HLA-A and hemochromatosis either in the Australian patient population or in the founding population. In a review of 57 families with hereditary hemochromatosis, Adams (1992) found 3 pairs of HLA-identical, sex-matched sibs in which the younger sib demonstrated considerably more iron loading than the older sib. In 19 pairs of HLA-identical, sex-matched sibs homozygous for hemochromatosis, the iron loading was more marked in the older sib. There was no evidence of blood loss, difference in alcohol consumption, or dietary iron loading to explain the increased iron loading in the younger sibs. Yaouanq et al. (1992) used 5 biallelic polymorphisms located in the HLA class I region to test 198 HLA-typed subjects from the families of 22 hemochromatosis patients. The 5 polymorphisms provided sufficient information to identify unequivocally extended restriction haplotypes in all families. The restriction haplotypes cosegregated with the HFE allele and enabled identification of genotypically identical sibs in all families studied. The method avoids the disadvantages of HLA serologic typing and should be useful for genetic counseling in HFE families.
The American Association for the Study of Liver Disease (AASLD) has recently published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011; click for full text]. ...
DiagnosisThe American Association for the Study of Liver Disease (AASLD) has recently published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011; click for full text]. Clinical DiagnosisIt is increasingly unusual for individuals with HFE-associated hereditary hemochromatosis (HFE-HH) to present with advanced "clinical" HFE-HH (i.e., with end-organ damage secondary to iron storage). More typically, individuals with HFE-HH are determined to have "biochemical" HFE-HH (i.e., elevated serum TS and elevated serum ferritin concentration) after evaluation of transferrin-iron saturation and serum ferritin concentration reveals evidence of iron overload (see Testing). Occasionally, individuals with HFE-HH present either with early clinical findings of hereditary hemochromatosis such as elevated serum liver enzymes or vague nonspecific symptoms such as abdominal pain, fatigue, arthralgia, and/or decreased libido.HFE-HH should be suspected in any individual with clinical signs of advanced iron overload, including:HepatomegalyHepatic cirrhosisHepatocellular carcinomaDiabetes mellitusCardiomyopathyHypogonadismArthritis (especially involving the metacarpophalangeal joints)Progressive increase in skin pigmentationTestingBiochemical TestingTransferrin-iron saturation (TS) is an early and reliable indicator of risk for iron overload in HFE-HH; the TS is not age-related in adults and does not correlate with the presence or absence of clinical findings.Approximately 80% of individuals with HFE-HH have had a fasting serum transferrin-iron saturation of at least 60% (men) or at least 50% (women) on two or more occasions in the absence of other known causes of elevated transferrin-iron saturation.A screening study from Denmark of over 6,000 men showed that 89% of p.Cys282Tyr homozygotes had a serum TS higher than 50% [Pedersen & Milman 2009]. The Hemochromatosis and Iron-Overload Screening (HEIRS) study screened more than 100,000 persons in the US and Canada and found that 84% of male p.Cys282Tyr homozygotes had a serum TS higher than 50% and 73% of female p.Cys282Tyr homozygotes had a TS higher than 45% [Adams et al 2005].Although homozygotes for p.Cys282Tyr may have a serum TS below 45% in early adulthood, they commonly develop an elevated serum TS over time [Olynyk et al 2004]. Serum ferritin concentration generally increases progressively over time in individuals with untreated clinical HFE-HH; however, an elevated serum ferritin concentration alone is not specific for iron overload as it is an acute phase reactant and may be caused by inflammatory or neoplastic disorders (especially when the serum TS is normal). Commonly accepted ferritin values for the upper limit of normal (from the HEIRS study) are lower than 300 ng/mL in males and lower than 200 ng/mL in females [Adams et al 2005.No “typical” range for ferritin values for persons with HFE-HH has been defined: it may range from normal to several thousand.Note: McGrath et al [2002] developed a nomogram that allows prediction of genotype based on the pattern of serum iron studies. Select PDF (see Fig 1).FigureFigure 1. Testing strategy to establish the diagnosis of HFE-HH Quantitative phlebotomy can be used to determine the quantity of iron that can be mobilized, thus confirming the diagnosis of HFE-HH in an individual with evidence of iron overload who is not a p.Cys282Tyr homozygote or a p.Cys282Tyr/p.His63Asp compound heterozygote and who is unable or unwilling to undergo liver biopsy. Note: The quantity of iron (in grams) mobilized is calculated by multiplying the number of phlebotomies times 0.25; most individuals fully expressing the phenotype have more than four grams of iron that can be mobilized.Heterozygotes vs HomozygotesAlthough a threshold serum TS of 45% may be more sensitive than the higher values used in the past for detecting HFE-HH, it may identify heterozygotes who are not at risk of developing clinical findings [McLaren et al 1998]. In the large study in Danish men, Pedersen & Milman [2009] showed that:Among p.Cys282Tyr/wild type (wt) heterozygotes, 9% had elevated serum TS (≥50%), 9% had elevated ferritin (≥300 ng/mL), and 1.2% had elevation of both serum TS and ferritin. Among p.His63Asp/wt heterozygotes, 8% had elevated serum TS, 12% had elevated ferritin, and 2% had elevation of both serum TS and ferritin. No individuals with the p.Ser65Cys variant had elevation of both serum TS and ferritin.Note: The abnormalities in iron studies observed in p.Cys282Tyr heterozygotes do not necessarily reflect a hemochromatosis-associated phenotype.Histologic examination of liver tissue. Liver biopsy is useful to confirm hepatic iron overload, particularly in an individual with presumed HFE-HH who is not a p.Cys282Tyr homozygote or a p.Cys282Tyr/p.His63Asp compound heterozygote. Testing on liver tissue should include measurement of hepatic iron concentration, calculation of hepatic iron index, and stains to assess pattern and severity of iron overload, as well as stains to determine the presence or absence of hepatitis and fibrosis.The hepatic iron concentration (HIC) is determined in µmol/g of dry weight.The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Among individuals with HFE-HH who fully express the phenotype, 85%-90% have an HII of greater than 1.9. Note: (1) The HIC and HII were primarily used to differentiate presumed homozygotes from presumed heterozygotes prior to the era of HFE molecular genetic testing. (2) These histochemical tests are currently useful for diagnostic purposes when the diagnosis cannot be established by molecular genetic testing. The degree of hepatic iron loading can also be semi-quantitatively assessed by histochemical techniques using Perls' Prussian blue stain (grade: 0-4; normal: 0-1; 3-4: typical for HFE-HH) [Scheuer 1973]. In HFE-HH, the greatest density of iron staining is in the periportal hepatocytes, with minimal or no iron staining in reticuloendothelial cells.Note: Liver biopsy is usually not otherwise indicated for diagnostic purposes in HFE-HH but can be critical in establishing the presence or absence of cirrhosis, which influences prognosis (see Management, Evaluations Following Initial Diagnosis). Magnetic resonance imaging (MRI) has the potential to estimate liver iron content by utilizing the paramagnetic properties of iron. In the past, routine MRI scanning lacked sensitivity to differentiate between various degrees of iron overload; however, a specialized MRI technique with excellent sensitivity for estimation of hepatic iron concentration has been approved by the FDA for clinical use [St Pierre et al 2005]. Molecular Genetic TestingGene. All individuals with HFE-HH have biallelic mutations in HFE.Clinical testingTargeted mutation analysis identifies the two most common disease-causing alleles in HFE (p.Cys282Tyr and p.His63Asp) [Feder et al 1996]. Approximately 87% of individuals of European origin with HFE-HH are either homozygous for the p.Cys282Tyr mutation or compound heterozygous for the p.Cys282Tyr and p.His63Asp mutations. Note: Most clinical laboratories do not routinely test for the p.Ser65Cys allele because it appears to account for only 1% of individuals affected clinically [Mura et al 1999] and its clinical significance is currently unclear. Sequence analysis is used to identify other mutant alleles associated with HFE-HH [Barton et al 1999].Table 1. Summary of Molecular Genetic Testing Used in HFE-HHView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test Availability% of Individuals with HH 2, 3GenotypeHFETargeted mutation analysisp.Cys282Tyr, p.His63Asp~60%-90%p.[Cys282Tyr]+[Cys282Tyr]Clinical3%-8%p.[Cys282Tyr]+[His63Asp]~1%p.[His63Asp]+[His63Asp] 4Sequence analysisSequence variants 5, 6UnknownUnknown 7Deletion/duplication analysis 8Exonic and whole-gene deletionsUnknownUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. In populations of European origin [Ramrakhiani & Bacon 1998]3. Morrison et al [2003]4. There is no evidence that p.[ His63Asp]+[ His63Asp] is associated with a hemochromatosis phenotype in the absence of another cause of iron overload. 5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.6. Includes the three variants included in targeted mutation analysis7. A few individuals who are compound heterozygous for the p.Cys282Tyr allele and one of a small number of rare HFE mutations have the hemochromatosis phenotype.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in an adult with transferrin-iron saturation higher than 45% (see Figure 1):First, perform targeted mutation analysis. Those homozygous for the p.Cys282Tyr mutation or compound heterozygous for the p.Cys282Tyr and p.His63Asp mutations have the genotype to develop HFE-HH. For those individuals in whom only one p.Cys282Tyr mutation is identified, perform HFE sequence analysis and possibly deletion/duplication analysis. Those with a second disease-causing HFE allele have the genotype to develop HFE-HH. Those who do not have a second identifiable disease-causing HFE allele AND who are suspected of having HH (i.e., have elevated ferritin concentration and/or clinical manifestations of iron storage) warrant the following:Liver biopsy with assessment of histology and measurement of hepatic iron concentration [Morrison & Kowdley 2000, Whittington & Kowdley 2002, Nelson & Kowdley 2005] Consideration of testing for mutations in other genes that give rise to iron-overload (see Differential Diagnosis) Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersAlthough numerous studies have examined the relationship between HFE mutations and other diseases, no other phenotypes are known to be associated with mutations in HFE [DuBois & Kowdley 2004].
Three phenotypes of HFE-associated hereditary hemochromatosis (HFE-HH) are now recognized:...
Natural HistoryThree phenotypes of HFE-associated hereditary hemochromatosis (HFE-HH) are now recognized:Clinical HFE-HH (individuals with end-organ damage [e.g., advanced cirrhosis, cardiac failure, skin pigment changes, or diabetes] secondary to iron storage)Biochemical HFE-HH (individuals with evidence of iron overload as determined by transferrin-iron saturation and serum ferritin concentration only)Non-expressing p.Cys282Tyr homozygotes (p.Cys282Tyr homozygotes without clinical or biochemical evidence of iron overload [i.e., normal serum ferritin concentration]) Individuals with HFE-HH may be identified because of signs and symptoms related to iron overload (i.e., clinical HFE-HH); however, most frequently they are identified before symptoms develop, either through detection of abnormal iron-related studies (i.e., biochemical HFE-HH) or by molecular genetic testing used in the evaluation as family members at risk for HFE-HH (non-expressing p.Cys282Tyr homozygotes).The difference between clinical HFE-HH and biochemical HFE-HH must be understood in the interpretation of population studies evaluating morbidity related to HH. Several large-scale screening studies in the general population have demonstrated that most individuals homozygous for the p.Cys282Tyr mutation do not have clinical HFE-HH; however, a significant proportion of individuals with this genotype (especially males) have biochemical HFE-HH. Although early reports have suggested that males are ten times more likely than females to have symptoms of organ failure resulting from HFE-HH, subsequent studies showed that among individuals with HFE-HH males are twice as likely as women to develop complications of end-stage organ failure [Moirand et al 1997]. When identified through iron studies or screening of at-risk family members, 75%-90% of individuals with HFE-HH are asymptomatic. Normal serum ferritin concentration at diagnosis is usually associated with lack of symptom development [Yamashita & Adams 2003]. Clinical disease appears to be more common among at-risk sibs of clinically affected individuals.Clinical HFE-HH Individuals with clinical HFE-HH have inappropriately high absorption of iron from a normal diet by the gastrointestinal mucosa, resulting in excessive parenchymal storage of iron, which may result in damage in a number of end-organs and, potentially, organ failure. Symptoms related to iron overload usually appear between age 40 and 60 years in males and after menopause in females. Occasionally, HFE-HH manifests at an earlier age, but hepatic fibrosis or cirrhosis is rare before age 40 years. Often the first signs of clinical HFE-HH are arthropathy (joint stiffness and pain) involving the metacarpophalangeal joints, progressive increase in skin pigmentation resulting from deposits of melanin and iron, diabetes mellitus resulting from pancreatic iron deposits, and cardiomyopathy resulting from cardiac parenchymal iron stores. Hepatomegaly may or may not be present early in the disease; however, asymptomatic individuals can occasionally have hepatomegaly on physical examination. Males may have impotence from pituitary dysfunction. Abdominal pain, weakness, lethargy, and weight loss are common, but nonspecific, findings.Alcohol consumption worsens the symptoms in HFE-HH [Scotet et al 2003].With progression of the disease, liver cirrhosis may develop and be complicated by portal hypertension, hepatocellular carcinoma, and end-stage liver disease [Kowdley et al 2005]. The HEIRS study found an odds ratio of 3.3 for liver disease among p.Cys282Tyr homozygous men [Adams et al 2005]. In addition, cirrhosis is much more common among p.Cys282Tyr homozygotes who consume more than 60 g of alcohol per day compared to those who drink less [Fletcher et al 2002].By the time cirrhosis or liver failure is recognized, approximately 50% of individuals have diabetes mellitus and 15% have congestive heart failure or arrhythmias.Individuals diagnosed and treated prior to the development of cirrhosis appear to have normal life expectancy; those identified after the development of cirrhosis have a decreased life expectancy even with iron depletion therapy [Adams et al 2005]. Individuals with cirrhosis who are treated have a better outcome than those who are not; however, treatment does not eliminate the 10%-30% risk for hepatocellular carcinoma (HCC) and cholangiocarcinoma years after successful iron depletion.Failure to deplete iron stores after 18 months of treatment is a poor prognostic sign. With iron depletion, dysfunction of some affected organs (liver and heart) can improve; however, endocrine abnormalities and arthropathy improve in only 20% of those treated. Death in individuals with clinical HFE-HH is usually caused by liver failure, cancer, congestive heart failure, or arrhythmia. Biochemical HFE-HH Controversy exists among experts as to whether individuals who have biochemical HFE-HH in the absence of clinical HFE-HH are at increased risk for development of complications of iron overload and whether they are candidates for phlebotomy treatment (see Management). Prospective follow-up of a few individuals in some of these studies has been inconclusive as to whether iron overload is progressive. The evidence at present suggests that although serum ferritin concentration may rise in these individuals over time, end-organ damage is uncommon but is more frequently observed in male p.Cys282Tyr homozygotes than female p.Cys282Tyr homozygotes [see Yamashita & Adams 2003, Andersen et al 2004, Olynyk et al 2004, Allen et al 2008, Gurrin et al 2008]. Non-Expressing p.Cys282Tyr Homozygotes Three recent longitudinal population-based screening studies showed that 38%-50% of p.Cys282Tyr homozygotes may develop iron overload (i.e., elevated serum ferritin concentration) and 10%-33% may eventually develop hemochromatosis-related symptoms (i.e., nonspecific symptoms that may include fatigue and arthralgia) or end-organ damage (e.g., diabetes mellitus, cirrhosis, and/or cardiomyopathy); the vast majority developing end-organ damage are male [European Association for the Study of the Liver 2010]. It is estimated that 38%-50% of p.Cys282Tyr homozygotes may develop iron overload, and 10%-33% may develop clinical features [Whitlock et al 2006]. The proportion of p.Cys282Tyr homozygotes with iron overload-related disease is substantially higher for men than for women (28% vs. 1%) [Allen et al 2008].Therefore, although “non-expressing homozygotes” are unlikely to develop end-organ damage over time, a substantial proportion of male p.Cys282Tyr homozygotes may develop progressive iron overload or symptoms of iron overload [Yamashita & Adams 2003, Gurrin et al 2008, Gurrin et al 2009, Allen et al 2010, Gan et al 2011]. HeterozygotesAlthough some individuals who are heterozygous for an HFE mutation tend to have elevated serum TS and ferritin concentrations that exceed normal, they do not develop complications of iron overload [Bulaj et al 1996, Allen et al 2008]. See Diagnosis, Heterozygotes vs Homozygotes.
HFE-associated hereditary hemochromatosis (HFE-HH) (sometimes called type 1 HH) needs to be distinguished from several much rarer primary iron overload disorders as well as from secondary iron overload disorders....
Differential DiagnosisHFE-associated hereditary hemochromatosis (HFE-HH) (sometimes called type 1 HH) needs to be distinguished from several much rarer primary iron overload disorders as well as from secondary iron overload disorders.Primary overload disorders are characterized by increased absorption of iron from a normal diet:Juvenile hereditary hemochromatosis (sometimes called type 2 HH) has an earlier age of onset and more severe clinical manifestations than type 1 HH. Hepatocellular cancer has not been reported, possibly because of the short life span in this disorder. Causative mutations have been identified in two genes, giving rise to two clinically indistinguishable "subtypes": Type 2A, caused by mutations in HJV encoding hemojuvelin; and Type 2B, caused by mutations in HAMP. Inheritance is autosomal recessive [Roetto et al 1999, Camaschella et al 2000, De Gobbi et al 2002].TFR2-related hereditary hemochromatosis (sometimes called type 3 HH) has a similar presentation to HFE-HH. Age of onset is earlier and progression is slower than in juvenile HH. It is caused by mutations in TFR2, which encodes transferrin receptor 2. TFR2-related hereditary hemochromatosis is rare; it has primarily been reported in Italy. Inheritance is autosomal recessive [Mattman et al 2002].Ferroportin (SLC40A1)-related iron overload (ferroportin disease, type 4 hemochromatosis, HFE4) is also a disorder of iron overload, but unlike juvenile and HFE-HH, macrophages are iron laden. Onset is late and, in contrast to all other varieties of hemochromatosis, iron storage affects reticuloendothelial rather than parenchymal cells [Montosi et al 2001, Njajou et al 2001]. HFE4 presents in adulthood. It is caused by mutations in SLC40A1, which encodes ferroportin. Inheritance is autosomal dominant.African iron overload results from a predisposition to iron overload that is exacerbated by excessive intake of dietary iron. It is particularly prevalent among Africans who drink a traditional beer brewed in non-galvanized steel drums. Mutation of other yet-to-be-defined iron-related genes predisposes to this condition. A specific mutation (p.Gln248His) in SLC40A1 [NM_014585.5] encoding ferroportin has been associated with tendency to iron overload in Africans and African Americans [McNamara et al 2005, Rivers et al 2007]. Neonatal hemochromatosis is a severe, often fatal iron overload syndrome that usually presents at birth. Iron overload occurs in utero. Inheritance is unknown, but autosomal recessive and mitochondrial inheritance have been postulated. No locus has been identified. A recent paper suggests that mutations in DGUOK, the gene which encodes deoxyguanosine kinase, may lead to a phenotype resembling this condition [Pronicka et al 2011]. See DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form.Secondary iron overload disordersLiver diseases associated with parenchymal liver disease include conditions such as alcoholic liver disease, acute viral hepatitis or chronic hepatitis C, neoplasms, porphyria cutanea tarda, and inflammatory disorders, such as rheumatoid arthritis.A very common liver disease, nonalcoholic fatty liver disease (NAFLD) may frequently lead to elevated serum ferritin level and may be associated with increased hepatic iron deposition [Nelson et al 2011, Kowdley et al 2012].Iron overload can result from ingested iron in foods, cooking ware, and medicines, as well as parenteral iron from iron injections or transfusions for a chronic anemia such as beta-thalassemia or sickle cell disease.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).HFE-HHHFE-HH (heterozygotes)
The American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011; click for full text]. The European Association for the Study of the Liver (EASL) published Clinical Practice Guidelines on the Management of hemochromatosis [European Association for the Study of the Liver 2010; click for full text]. ...
ManagementThe American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011; click for full text]. The European Association for the Study of the Liver (EASL) published Clinical Practice Guidelines on the Management of hemochromatosis [European Association for the Study of the Liver 2010; click for full text]. Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with HFE-associated hereditary hemochromatosis (HFE-HH), the following evaluations are recommended at initial diagnosis:Serum ferritin concentration to establish disease status and prognosis (see Figure 2).For p.Cys282Tyr homozygotes:Liver biopsy is recommended for those with serum ferritin higher than 1,000 ng/mL or elevated AST and ALT to evaluate for advanced hepatic fibrosis [Morrison et al 2003, Bacon et al 2011]. Liver biopsy is not recommended for those with serum ferritin concentration lower than 1,000 ng/mL and normal ALT and AST because their risk for advanced hepatic fibrosis is low [Bacon et al 2011].MRI to estimate parenchymal iron content by utilizing the paramagnetic properties of iron: A specialized MRI technique with excellent sensitivity for estimation of hepatic iron concentration was approved by the FDA for clinical use [St Pierre et al 2005]. In addition, T2* MRI measurement of liver iron is now widely available [Brittenham et al 2003, Cheong et al 2005, Ptaszek et al 2005].Cardiac iron concentration can also be monitored using similar techniques and may be of prognostic value [Fischer & Harmatz 2009, Ramazzotti et al 2009].FigureFigure 2. (LFT = Liver function tests) Use of serum ferritin concentration to help direct management Treatment of ManifestationsThe American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011; click for full text). The European Association for the Study of the Liver (EASL) published Clinical Practice Guidelines on the Management of hemochromatosis [European Association for the Study of the Liver 2010; click for full text]. Clinical HFE-HHTherapeutic phlebotomy is indicated in the presence of symptoms of iron overload or evidence of end-organ damage (e.g., advanced cirrhosis, cardiac failure, skin pigment changes, or diabetes): Periodic phlebotomy is a simple, inexpensive, safe, and effective treatment. Each unit of blood (400-500 mL) with a hematocrit of 40% contains approximately 160-200 mg of iron. Each mL of packed red blood cells contains 1 mg of iron.The usual therapy is removal of the excess iron by weekly phlebotomy (i.e., removal of a unit of blood) until the serum ferritin concentration is 50 ng/mL or lower. Twice-weekly phlebotomy may be occasionally useful to accelerate iron depletion.Weekly phlebotomy is carried out until the hematocrit is 75% of the baseline hematocrit.At this point, if the serum ferritin concentration is 50 ng/mL or higher despite a significant reduction in hematocrit, the interval at which phlebotomy is performed needs to be spaced further apart. Once the serum ferritin concentration is 100 ng/mL or lower, serum ferritin concentration should be quantified in all affected individuals after each additional one or two treatments [Barton et al 1998].The serum ferritin concentration is the most reliable and inexpensive way to monitor therapeutic phlebotomy.Maintenance therapy is aimed at maintaining serum ferritin concentration below 50 ng/mL and transferrin-iron saturation below 50%. On average, men require removal of twice as many units of blood as women. Subsequent phlebotomies to prevent reaccumulation of iron can be carried out approximately every three to four months for men and once or twice a year for women.Iron chelation therapy is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia that makes therapeutic phlebotomy impossible. However, this is uncommon in individuals with HFE-HH.Orthotopic liver transplantation is the only treatment for end-stage liver disease from decompensated cirrhosis. However, the post-transplant survival among untreated individuals with HFE-HH is poor [Crawford et al 2004, Kowdley et al 2005]. Although a recent study suggested that outcomes may have improved, this report did not enroll persons with documented HFE-HH but rather used a database [Yu & Ioannou 2007].Biochemical HFE-HHBoth the EASL and AASLD guidelines now recommend therapeutic phlebotomy for persons with biochemical HFE-HH (i.e., those who have increased body iron stores in the absence of clinical evidence of iron overload) [European Association for the Study of the Liver 2010 (full text: ), Bacon et al 2011 (full text: )]. The exact serum ferritin concentration at which therapeutic phlebotomy should be initiated is not clear, the European Association for Study of Liver suggests performing phlebotomy once serum ferritin concentration is higher than 500 ng/mL.Non-Expressing p.Cys282Tyr HomozygotesThese individuals do not have iron overload and thus do not need phlebotomy.Prevention of Primary ManifestationsSee Treatment of Manifestations.Prevention of Secondary ComplicationsIndividuals with iron overload should be advised against ingestion of shellfish or raw fish.Vaccination against hepatitis A and B is advised [Tavill 2001].SurveillanceClinical HFE-HHOnce the serum ferritin concentration is lower than 50 ng/mL, monitor serum ferritin concentration every three to four months.It is reasonable to perform follow-up T2* MRI for assessment of cardiac iron among persons with a history of cardiac involvement or known cardiac iron deposition.Individuals who have cirrhosis should undergo routine screening for hepatocellular cancer (HCC) [Tavill 2001]. The AASLD Practice Guidelines on hepatocellular carcinoma advocate biannual abdominal imaging [Sherman 2010]. Note: The AASLD Guidelines recommend that individuals with cirrhosis undergo surveillance regardless of whether or not they have been iron depleted [Bacon et al 2011; full text: ]. Biochemical HFE-HH Begin annual measurement of serum ferritin concentration when ferritin concentration exceeds normal levels [European Association for the Study of the Liver 2010; full text: ].Non-Expressing p.Cys282Tyr Homozygotes Begin annual measurement of serum ferritin concentration when ferritin concentration exceeds normal levels [European Association for the Study of the Liver 2010].Agents/Circumstances to AvoidAvoid the following:Medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoodAlcohol consumption in those with hepatic involvementEvaluation of Relatives at RiskIn adults. The following strategy is appropriate:1.Offer molecular genetic testing to the adult sibs of an individual homozygous for p.Cys282Tyr.2.Perform iron studies (i.e., transferrin iron saturation and serum concentration of ferritin) on those sibs who are homozygous for p.Cys282Tyr.3.Begin phlebotomy therapy if serum ferritin concentration is elevated above the upper limits of normal and if the proband has clinical HFE-HH. Note: Sibs of probands with clinical HFE-HH appear to have a higher prevalence of clinical HFE-HH than asymptomatic individuals detected through screening programs.During childhood. No guidelines exist; however, screening in this age group is not advised because expression of symptomatic disease is rare.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationThe oral iron chelator, deferasirox (Exjade®) has been studied in a Phase I/II study in patients with hemochromatosis [Phatak et al 2010]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. HFE-Associated Hereditary Hemochromatosis: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHFE6p22.2Hereditary hemochromatosis proteinalsod/HFE genetic mutations ALS mutation database HFE homepage - Mendelian genesHFEData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for HFE-Associated Hereditary Hemochromatosis (View All in OMIM) View in own window 235200HEMOCHROMATOSIS; HFE 613609HFE GENE; HFENormal allelic variants. HFE is approximately 13 kb in size and comprises seven exons [Feder et al 1996, Albig et al 1998]; HFE gives rise to at least eleven alternative transcripts encoding four to seven exons.Pathologic allelic variants. At least 28 distinct mutations have been reported; most are missense or nonsense. Two missense mutations account for the vast majority of disease-causing alleles in the population:p.Cys282Tyr removes a highly conserved cysteine residue that normally forms an intermolecular disulfide bond with beta-2-microglobulin, and thereby prevents the protein from being expressed on the cell surface.p.His63Asp may alter a pH-dependent intramolecular salt bridge, possibly affecting interaction of the HFE protein with the transferrin receptor.Table 2. Selected HFE Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.187C>Gp.His63AspNM_000410.3 NP_000401.1c.193A>Tp.Ser65Cysc.845G>Ap.Cys282TyrSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. The largest predicted primary translation product is 348 amino acids, which gives rise to a mature protein of approximately 321 amino acids after cleavage of the signal sequence. The HFE protein is similar to HLA Class I molecules at the level of the primary structure [Feder et al 1996] and tertiary structure [Lebron et al 1998]. The mature protein is expressed on the cell surface as a heterodimer with beta-2-microglobulin, and this interaction is necessary for normal presentation on the cell surface. The normal HFE protein binds to transferrin receptor 1 on the cell surface and may reduce cellular iron uptake; however, the exact means by which the HFE protein regulates iron uptake is as yet unclear [Fleming et al 2004].Abnormal gene product. The p.Cys282Tyr mutation destroys a key cysteine residue that is required for disulfide bonding with beta-2-microglobulin. As a result, the HFE protein does not mature properly and becomes trapped in the endoplasmic reticulum and Golgi apparatus, leading to decreased cell-surface expression. The mechanistic basis for the phenotypic effect of other HFE mutations is not clear at present.
for full text]. ...