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Persons with Screening-detected Haemochromatosis: as Healthy as the General Population?
Abstract
Hereditary haemochromatosis (HH) is a common genetic disease leading to iron deposition in the liver and other organs. Early treatment will prevent clinical disease and population-based screening for HH has been advocated. However, the benefit of screening depends on the morbidity of HH. We have compared the morbidity in HH persons detected by screening with the morbidity in the rest of the population.
All inhabitants 20 years or older in a Norwegian county (94,191 persons) were invited to participate in a health survey programme. Of 65,717 participating persons, a blood specimen for transferrin saturation was obtained from 65,238. After repeated laboratory testing and clinical examination, 269 persons were found to have phenotypic HH, while 297 had genotypic HH (the C282/C282Y mutation). Using self-reported data, clinical examinations and analysis of non-fasting blood samples, the morbidity in phenotypic and genotypic HH persons was compared with the morbidity in the rest of the population. All data were collected before subjects were diagnosed with HH, and all comparisons were corrected for age and gender.
Compared to control persons, phenotypic and genotypic HH men and women had a higher score on 1 of 17 questions dealing with joint complaints. Phenotypic and genotypic HH women below 50 years of age had a higher prevalence of hypothyroidism (15.2% and 12.5%, respectively, compared to 3.0% in the control population). Phenotypic HH women below 50 years of age had higher diastolic blood pressure than control women. Phenotypic HH men above 50 years of age and genotypic HH men scored lower than control men on a compound myocardial infarction risk score variable, in part due to lower serum cholesterol concentration. Fewer phenotypic HH men above 50 years of age reported having angina pectoris. Otherwise, the health of phenotypic and genotypic HH persons was not different from the health of control persons.
When corrected for age and gender, the morbidity in persons with screening-detected HH was not very different from the morbidity in the control group, indicating that population-based screening may not be as beneficial as anticipated.
... Pathological iron overload may result in severe organ damage which can be efficiently prevented by iron-depleting therapy 5,6 . Only a small proportion of patients, however, develop such organ damage 1,7 and, as a result of screening, most affected individuals are diagnosed before the onset of clinical disease [7][8][9] . The preclinical phase can be divided into a pure genetic disposition with normal iron stores and biochemical haemochromatosis with a genetic disposition and increased iron stores, but no organ damage 6 . ...
... Pathological iron overload may result in severe organ damage which can be efficiently prevented by iron-depleting therapy 5,6 . Only a small proportion of patients, however, develop such organ damage 1,7 and, as a result of screening, most affected individuals are diagnosed before the onset of clinical disease [7][8][9] . The preclinical phase can be divided into a pure genetic disposition with normal iron stores and biochemical haemochromatosis with a genetic disposition and increased iron stores, but no organ damage 6 . ...
... The preclinical phase can be divided into a pure genetic disposition with normal iron stores and biochemical haemochromatosis with a genetic disposition and increased iron stores, but no organ damage 6 . Clinical benefit from treatment has not been documented in individuals with pure genetic disposition or slight biochemical haemochromatosis 1,7 . ...
Hereditary haemochromatosis may result in severe organ damage which can be prevented by therapy. We studied the possible advantages and disadvantages of erythrocytapheresis as compared with phlebotomy in patients with hereditary haemochromatosis.
In a prospective, randomised, open-label study, patients with hereditary haemochromatosis were randomised to bi-weekly apheresis or weekly whole blood phlebotomy. Primary end-points were decrease in ferritin levels and transferrin saturation. Secondary endpoints were decrease in haemoglobin levels, discomfort during the therapeutic procedure, costs and technicians' working time.
Sixty-two patients were included. Thirty patients were randomised to apheresis and 32 to whole blood phlebotomy. Initially, ferritin levels declined more rapidly in the apheresis group, and the difference became statistically highly significant at 11 weeks; however, time to normalisation of ferritin level was equal in the two groups. We observed no significant differences in decline of transferrin saturation, haemoglobin levels or discomfort. The mean cumulative technician time consumption until the ferritin level reached 50 μg/L was longer in the apheresis group, but the difference was not statistically significant. The cumulative costs for materials until achievement of the desired ferritin levels were three-fold higher in the apheresis group.
Treatment of hereditary haemochromatosis with erythrocytapheresis instead of whole blood phlebotomy results in a more rapid initial decline in ferritin levels and a reduced number of procedures per patient, but not in earlier achievement of target ferritin level. The frequency of discomfort was equally low with the two methods. The costs and, probably, technician time consumption were higher in the apheresis group.
... This group of patients is designated as Nord-Trøndelag patients. Most of the clinical and laboratory information about all patients were already available and described elsewhere [8,18,[24][25][26][27][28]. Previously available information included, in all patients, the iron parameters at diagnosis: transferrin saturation (TfSat) and serum ferritin (SF); HFE genotype (all homozygous for the C282Y mutation); and HLA class I alleles (A and B) as determined by low-resolution DNAbased techniques (PCR/sequence-specific oligonucleotide probes, Dynal RELI TM SSO, Dynal Biotech Ltd, UK). ...
... The HH cohort from Nord-Trøndelag was the only one in which patients were identified in screening programs. Moreover, previous studies in the same population showed that, in general, Nord-Trøndelag patients have a low prevalence of clinical symptoms and less severe iron overload [27,28]. ...
... supporting the different founder effects or distinct recombination histories in the respective populations. The highest haplotype diversity observed in the Nord-Trøndelag population is also consistent with the high frequency of HFE C282Y in Norwegians [27,28,38], possibly related with characteristics of rapid population growth that has occurred in northwestern Europe since the Celtic period [14]. On the contrary, patients from Alabama showed the lowest haplotype diversity, reflecting a more recent founder effect. ...
Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8(+)T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182), the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8(+) T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021), but significant differences were not confirmed in the 3 separate populations. Low CD8(+) T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8(+) T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01-B*08 or A*03-B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci associated with the genetic transmission of CD8(+) T-lymphocyte numbers.
... Among 391 patients with hemochromatosis diagnosed in medical care combined from five stud-ies, 4.1% had primary hypothyroidism and 0.3% had hyperthyroidism (5)(6)(7)(8)(9). To date, there is no report of thyroid-related laboratory measures in participants of large population or workplace hemochromatosis screening programs (2,(10)(11)(12). ...
... In a large population hemochromatosis screening program in Norway, 12.5% of women aged 20-49 years with C282Y homozygosity reported having hypothyroidism, whereas only 3.0% of the control participants reported having hypothyroidism (11). Thyroid-related laboratory measures were not quantified in participants in this study (11). ...
... In a large population hemochromatosis screening program in Norway, 12.5% of women aged 20-49 years with C282Y homozygosity reported having hypothyroidism, whereas only 3.0% of the control participants reported having hypothyroidism (11). Thyroid-related laboratory measures were not quantified in participants in this study (11). By design, only study participants with elevated TS at initial screening underwent HFE genotyping, and therefore C282Y homozygotes without elevated TS would have been excluded from the Norway screening study (11). ...
Relationships of thyroid and iron measures in large cohorts are unreported. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (T4) in white participants of the primary care-based Hemochromatosis and Iron Overload Screening (HEIRS) Study.
We measured serum TSH and free T4 in 176 HFE C282Y homozygotes without previous hemochromatosis diagnoses and in 312 controls without HFE C282Y or H63D who had normal serum iron measures and were matched to C282Y homozygotes for Field Center, age group, and initial screening date. We defined hypothyroidism as having TSH >5.00 mIU/L and free T4 <0.70 ng/dL, and hyperthyroidism as having TSH <0.400 mIU/L and free T4 >1.85 ng/dL. Multivariate analyses were performed using age, sex, Field Center, log(10) serum ferritin (SF), HFE genotype, log(10) TSH, and log(10) free T4.
Prevalences of hypothyroidism in C282Y homozygotes and controls were 1.7% and 1.3%, respectively, and of hyperthyroidism 0% and 1.0%, respectively. Corresponding prevalences did not differ significantly. Correlations of log(10) SF with log(10) free T4 were positive (p = 0.2368, C282Y homozygotes; p = 0.0492, controls). Independent predictors of log(10) free T4 were log(10) TSH (negative association) and age (positive association); positive predictors of log(10) SF were age, male sex, and C282Y homozygosity. Proportions of C282Y homozygotes and controls who took medications to supplement or suppress thyroid function did not differ significantly.
Prevalences of hypothyroidism and hyperthyroidism are similar in C282Y homozygotes without previous hemochromatosis diagnoses and controls. In controls, there is a significant positive association of SF with free T4. We conclude that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs.
... Sykeligheten blant homozygote, sammenliknet med en relevant kontrollgruppe, er også undersøkt i Norge (3,21). Denne undersøkelsen var et ledd i den såkalte HUNT-studien, der alle personer over 20 år, bosatt i Nord-Trøndelag i 1995-1997 ble invitert til å delta i en stor helseundersøkelse, omfattende minst 70 delprosjekter. ...
... Homozygoti for C282Y-mutasjonen ble påvist hos 171 menn og 126 kvinner, noe som gir et minimumsestimat for C282Yhomozygoti på 0,68% i Nord-Trøndelag. Selvrapportert sykelighet hos homozygote var generelt lav og omtrent på samme nivå som i befolkningen ellers (21). Imidlertid fant vi 4 tilfeller av skrumplever blant 107 (3,7%) homozygote menn som ble undersøkt med leverbiopsi. ...
... Buffone & Beck (28) Før vi går videre i rekken av spørsmål, må vi ta stilling til hvilke screeningtiltak som er aktuelle. Selv har vi bare analysert nytten av å screene menn (24), fordi vi ikke fant alvorlig sykdom hos screenede kvinner (3,21). Dermed er det ikke sagt at screening av kvinner er nytteløst, bare at vi manglet data for å kunne analysere problemstillingen formelt. ...
p>Arvelig hemokromatose fører til jernopphopning i kroppen, men gir sjelden alvorlig helseskade. Nesten alle hemokromatosepasienter i vårt land er homozygote for C282Y-mutasjonen i HFE-genet. Omtrent 7 per 1000 innbyggere har denne genotypen. Alvorlig syke blir bare omkring 5-15% av homozygote menn og nesten ingen kvinner. Likevel er det holdepunkter for at screening for hemokromatose blant friske, yngre menn kan være kostnadseffektivt. Det er relativt lett å påvise om en person er disponert for sykdommen, i god tid før den bryter ut, og forebyggende behandling er billig og effektiv. Imidlertid kan vi ikke forutsi hvilke screeningpositive personer som ubehandlet får alvorlig sykdom. Et kontrollert forsøk med screening bør gjennomføres
Hereditary hemochromatosis – benefits of screening. Hereditary hemochromatosis leads to iron accumulation in the body; however, serious illness due to hemochromatosis is rare. In Norway, almost all patients with hemochromatosis are homozygous for the C282Ymutation in the HFE-gene, a genotype carried by about 7 per 1000 inhabitants. Serious complications are seen in only about 5-15% of homozygous men and in very few women. Nevertheless, screening young men for hemochromatosis may be cost-effective. Detecting predisposed men is relatively straightforward, and prophylactic treatment is cheap and effective. However, we can not predict, among screen-positive men, the few who untreated will become seriously ill. A controlled screening trial should be conducted.</p
... We followed participants to identify a series of outcomes previously linked to hemochromatosis (1,4,7,8,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19): hepatocellular carcinoma, chronic liver disease, cirrhosis, knee or hip replacement, osteoarthritis, diabetes, and all-cause death. We also looked back for evidence of these outcomes in the patient's health history. ...
... Since the discovery of the HFE gene in 1996 (26), there have been conflicting opinions about the clinical expression of the C282Y mutation of the HFE gene1 (4,(12)(13)(14)(15)(16)(17)(18)(19) and the efficacy of phlebotomy therapy in preventing long-term medical complications. Population studies using genetic testing have identified many non-expressing C282Y homozygotes, most commonly in young women (1). ...
Background:
We report long-term survival and development of selected health conditions in Ontario-based referred and screened C282Y homozygotes for hemochromatosis treated by phlebotomy compared with an untreated control group known to be without HFE mutations.
Methods:
Patient characteristics and outcomes (all-cause mortality, liver cancer, diabetes, cirrhosis, hip or knee joint replacement, and osteoarthritis) were ascertained using a linked health administrative database held at ICES. Outcomes were assessed between groups without the outcome at baseline using Cox proportional hazards regression adjusted for age and sex. All C282Y homozygotes with elevated serum ferritin were treated by phlebotomy to reach serum ferritin of 50 µg/L. Our cohort included 527 C282Y homozygotes (311 men, 216 women, mean age 48 years) and 12,879 control participants (5,667 men and 7,212 women).
Results:
C282Y homozygotes had an increased risk of all-cause mortality (aHR 1.44 [1.19-1.75], p <0.001); hepatocellular carcinoma (aHR 8.30 [3.97-17.34], p <0.001); hip or knee joint replacement (aHR 3.06 [2.46-3.81], p <0.001); osteoarthritis (aHR 1.72 [1.47-2.01], p <0.001); and cirrhosis (aHR 3.87 [3.05-4.92], p <0.001). C282Y homozygotes did not have an increased risk for diagnosis of diabetes) (aHR 0.84 [0.67-1.07], p = 0.16) during follow-up (median 17.7 y).
Conclusions:
C282Y homozygotes experience higher death and complication rates than individuals without HFE mutations, despite treatment by phlebotomy. Diabetes did not increase after phlebotomy therapy.
... HFE mutation genotyping was a diagnostic adjunct in three studies [1,2,10]. Percentages of participants in population-based screening studies discovered to have HFE p.C282Y homozygosity who reported that they had previous diagnoses of diabetes [115,[170][171][172]. There were two such reports from 2002 and two others from 2008. ...
... Greater proportions of men than women had cirrhosis. See cirrhosis prevalence in screening hemochromatosis cases in Figure 4. [3,172,179,180] and in an archived liver biopsy collection (second 2000 publication) [181] discovered to have HFE p.C282Y homozygosity who were previously diagnosed or were subsequently demonstrated to have advanced hepatic fibrosis or cirrhosis by biopsy [3,170,172,180,181]. Greater proportions of men than women had cirrhosis. ...
Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis.
... [13][14][15] The prevalence of HFE C282Y homozygosity is relatively high in Alabama, 16 like it is in Iceland, Norway, and the British Isles. [17][18][19][20][21][22][23] The HFE genotype C282Y/H63D occurs in ∼0.021 of white Americans, of whom 10.8% of men and 7.8% of women have elevated serum transferrin saturation and ferritin levels. 12 Persons with HFE hemochromatosis may have increased risk to develop DC because at-risk populations and some co-morbid conditions in HFE hemochromatosis and DC cohorts are similar, but we were unable to identify a report of the occurrence of these two disorders in the same patient. ...
... 37 These modern estimates agree with historic accounts of DC in Europe. [38][39][40] The prevalence of HFE C282Y homozygosity is relatively high in Alabama, 16,26 like it is in Iceland, 17,18 Norway, 19,20 Northeast Scotland, 21 England, 22 and Ireland. 23 Hemochromatosis probands from Alabama with C282Y homozygosity indicated that they are predominantly from the British Isles and proportional British Isles ancestry was significantly higher in hemochromatosis probands than in Caucasian Alabama control subjects. ...
Dupuytren's contracture (DC) and HFE hemochromatosis occur in some of the same at-risk populations and present with similar comorbid conditions.
We estimated DC prevalence in two cohorts of white Alabama hemochromatosis probands (294 C282Y homozygotes, 67 C282Y/H63D compound heterozygotes) in a retrospective study. We performed logistic regressions on DC using the following independent variables: age, body mass index, heavy ethanol consumption, serum ferritin, elevated serum AST/ALT, non-alcoholic fatty liver disease, viral hepatitis, cirrhosis, and diabetes.
One man and two women with C282Y homozygosity had DC (prevalence 1.02%; 95% CI 0.35%-2.96%). A man with C282Y/H63D had DC (prevalence 1.49%; 95% CI 0.26%-7.98%). DC occurred as an autosomal dominant trait in his kinship. In regression analyses, no single variable predicted DC. We observed no new DC cases after the diagnosis of hemochromatosis (mean follow-up 12.9 ± 7.5 years (1 SD), and 9.0 ± 5.1 years, respectively).
Our prevalence estimates of DC in white Alabama hemochromatosis probands are similar to those found in the white US population cohorts. DC risk was unrelated to the variables we studied.
... The major complications of iron overload in hemochromatosis patients can be prevented by phlebotomy therapy to remove excess iron, and patients treated before the onset of organ damage have a normal life expectancy. 20 Although it is not known how many such patients will go on to develop organ damage if untreated, this observation has stimulated interest in early detection, 3,21,22 and several screening studies recently have been conducted, [23][24][25][26][27] including the Hemochromatosis and Iron Overload Screening (HEIRS) Study. 28 The HEIRS Study evaluated the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multi-ethnic, primary care-based sample of 101,168 adults enrolled over a 2-year period at four field centers in the US and one in Canada. ...
... This prevalence is consistent with other primary careand population-based studies. 25,26 Quantitative phlebotomy was conducted in 122 of 1102 non-homozygotes with non-transfusional SF elevation at clinical evaluation. All of these non-homozygous participants had elevated SF and TfS at initial screening. ...
Hemochromatosis comprises a group of inherited disorders resulting from mutations of genes involved in regulating iron metabolism. The multicenter, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study screened approximately 100,000 participants in the US and Canada, testing for HFE mutations, serum ferritin and transferrin saturation. As in other studies, HFE C282Y homozygosity was common in Caucasians but rare in other ethnic groups, and there was a marked heterogeneity of disease expression in C282Y homozygotes. Nevertheless, this genotype was often associated with elevations of serum ferritin and transferrin saturation and with iron stores of more than four grams in men but not in women. If liver biopsy was performed, in some cases because of evidence of hepatic dysfunction, fibrosis or cirrhosis was often found. Combined elevations of serum ferritin and transferrin saturation were observed in non-C282Y homozygotes of all ethnic groups, most prominently Asians, but not often with iron stores of more than four grams. Future studies to discover modifier genes that affect phenotypic expression in C282Y hemochromatosis should help identify patients who are at greatest risk of developing iron overload and who may benefit from continued monitoring of iron status to detect progressive iron loading.
... In contrast, participants in the large multicentre HEIRS Study were enrolled without regard to any clinical conditions. Our findings are consistent with the results of several single-centre and regional population-and primary care-based studies (15)(16)(17)(18). A recent study of first-degree relatives of patients with known C282Y hemochromatosis also found a low prevalence of clinical manifestations in family members who were C282Y homozygotes or C282Y/H63D compound heterozygotes, despite evidence of iron overload in most cases (31). ...
... A possible interpretation of the relative lack of an increased prevalence of symptoms and signs among C282Y homozygotes in the current study may be that most homozygotes do not develop sufficient iron overload to cause symptoms and clinical manifestations (15)(16)(17)(18), even though the majority have evidence of excess iron accumulation (46). Previous studies of hemochromatosis patients (47) in referral practice settings have shown that the risk of hepatic cirrhosis in C282Y homozygotes begins to increase when SF levels rise above 1000 µg/L, but this SF level was exceeded in only 29 of 131 newly diagnosed C282Y homozygotes with elevated SF in the current study (24). ...
Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences.
To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening.
Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364).
Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects.
Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.
... What this phenotype is, is difficult to assess from recent population studies which were designed to assess screening programmes in undiagnosed 'healthy' populations, rather than a population-based 'disease' cohort. 5,6 We know that the genotype alone is not associated with the classical haemochromatosis disease associations of arthritis, 7 cardiac involvement 8,9 and diabetes 10 and that the phenotype of cases identified through screening studies has a low proportion of cirrhosis (3-9%), 1, 6, 11 diabetes (4%), 11 and arthritis (14-16%). 5,11 In contrast, previous studies based on a clinical diagnosis have shown stronger associations with diabetes (14-48%), 12-17 cirrhosis (22-70%), 12, 14-16, 18, 19 arthritis (12-66%), 13,16,17,20 and cardiomyopathy. ...
... 5,6 We know that the genotype alone is not associated with the classical haemochromatosis disease associations of arthritis, 7 cardiac involvement 8,9 and diabetes 10 and that the phenotype of cases identified through screening studies has a low proportion of cirrhosis (3-9%), 1, 6, 11 diabetes (4%), 11 and arthritis (14-16%). 5,11 In contrast, previous studies based on a clinical diagnosis have shown stronger associations with diabetes (14-48%), 12-17 cirrhosis (22-70%), 12, 14-16, 18, 19 arthritis (12-66%), 13,16,17,20 and cardiomyopathy. 15,21 If then we are to understand the current incidence, mortality rates and associations of haemochromatosis and thereby gain some inkling of the effect of recent diagnostic trends, a contemporary population-based cohort study based on a clinical diagnosis of haemochromatosis is needed. ...
The discovery of the HFE genotype has revolutionized the diagnosis of haemochromatosis, changing the associated mortality and morbidity.
To investigate the clinical significance of a diagnosis of haemochromatosis.
In a cohort study, we identified 501 people with haemochromatosis and 4950 age- and gender-matched controls from the UK General Practice Research Database between 1987 and 2002.
The incidence of a diagnosis of haemochromatosis increased approximately 2-fold over the study period and was associated with a 2.2-fold increase in mortality [hazard ratio, 95% confidence interval (95% CI), 1.6-3.0]. There was no increase in extra hepatic malignancy, but an absolute risk excess of liver cancer of 0.89% per year. Diabetes, impotence, osteoarthritis and crystal arthritis were associated with haemochromatosis with odds ratios of 5.4 (95% CI, 4.1-7.0), 2.7(95% CI, 1.8-4.0), 1.9(95% CI, 1.5-2.4) and 2.1(95% CI, 1.4-3.1) respectively.
Increasing numbers of people are being diagnosed with haemochromatosis, and the mortality associated with this disease remains high. However, people are living with considerably lower levels of morbidity than previously reported. This encouragingly suggests earlier diagnoses are being made, prior to the development of complications.
... One simple explanation for the survival and multiplication of the HFE mutation is its often mild phenotypic expression in homozygotes [49]. Even in those with a severe phenotype this comes late and does not interfere with reproduction. ...
Background
Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p.C282Y mutation is inherited with other recessive disorders such as Wilson´s disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation (KCNQ1/p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL).Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. MethodsLQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. ResultsOf nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder ( b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjällsjö river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of the late 16th century. One was of Swedish origin carrying the WHRN, c.1977delC, (p.S660Afs*30) mutation, the other was a TMC1(NM_138691),c.1814T>C,(p.L605P) mutation, possibly of Finnish origin. Conclusions
Deep human HFE genealogies show HFE to be associated with other genetic disorders like Wilson´s disease, LQTS, JLNS, and autosomal recessive hearing loss. Two new homozygous HL mutations in WHRN/p.S660Afs*30 and TMC1/p.L605P were identified,none of them previously reported from Scandinavia. The rarity of JLNS was possibly caused by miscarriage or intrauterine death. Most hearing loss (81.7%) was seen after 1844 when first cousin marriages were permitted. However, only 10 (10.3%) came from 1st cousin unions and only 2 (2.0 %) was born out of wedlock.
... The natural progression of hemochromatosis is largely unknown. However, from the relatively few studies addressing this issue it appears that the penetrance of clinical manifestations is low [51][52][53][54]. On the other hand, some patients do develop overt clinical hemochromatosis, but the factors determining this are largely unknown. ...
Iron loading in p.C282Y homozygous HFE hemochromatosis subjects is highly variable, and it is unclear what factors cause this variability. Finding such factors could aid in predicting which patients are at highest risk and require closest follow-up. The degree of iron loading has previously been associated with certain HLA-types and with abnormally low CD8 + cell counts in peripheral blood. In 183 Norwegian, p.C282Y homozygotes (104 men, 79 women) originally found through population screening we determined HLA type and measured total T-lymphocytes, CD4 + and CD8 + cells, and compared this with data on iron loading. In p.C282Y homozygous men, but not in homozygous women, we found that the presence of two HLA-A*03 alleles increased the iron load on average by approximately 2-fold compared to p.C282Y homozygous men carrying zero or one A*03 allele. On the other hand, the presence of two HLA-A*01 alleles, in male subjects, apparently reduced the iron loading. In p.C282Y homozygous individuals, the iron loading was increased if the CD8 + cell number was below the 25 percentile or if the CD4 + cell number was above the 75 percentile. This effect appeared to be additive to the effect of the number of HLA-A*03 alleles. Our data indicate that homozygosity for the HLA-A*03 allele significantly increases the risk of excessive iron loading in Norwegian p.C282Y homozygous male patients. In addition, low CD8 + cell number or high CD4 + cell number further increases the risk of excessive iron loading.
... type 2 diabetes in p.C282Y homozygotes and persons without common HFE mutations is similar. [11][12][13][14] Today, increased type 2 diabetes risk in persons with HFE hemochromatosis is associated with one or more factors, including severe iron overload, 7 8 15 decreased insulin secretion, 15 16 cirrhosis, 6 history of diabetes in firstdegree relatives, [17][18][19] increased body mass index, [19][20][21][22] insulin resistance, 21 and metabolic syndrome. 22 In the US National Health and Nutrition Examination Survey (NHANES) 1999-2002, approximately one-third of participants with diabetes had previously undiagnosed diabetes mellitus (UDM). ...
Objective
To determine prevalences and predictors of undiagnosed diabetes mellitus (UDM) and impaired fasting glucose (IFG) in non-Hispanic whites with HFE p.C282Y homozygosity and controls without common HFE mutations identified in population screening.
Research design and methods
We analyzed these observations in a postscreening examination: age; sex; body mass index; systolic/diastolic blood pressure; metacarpophalangeal joint hypertrophy; hepatomegaly; blood neutrophils; alanine and aspartate aminotransferase; elevated C reactive protein; transferrin saturation; serum ferritin; and Field Center.
Results
There were 223 p.C282Y homozygotes and 449 controls without diagnosed diabetes (43.9% men). Mean age of p.C282Y homozygotes was 52±13 years (controls 57±14 years; p<0.0001). Mean transferrin saturation in p.C282Y homozygotes was 67±26% (controls 34±14%; p<0.0001). Mean serum ferritin in p.C282Y homozygotes was 607 pmol/L (95% CI 497 to 517; controls 274 pmol/L (247 to 301); p<0.0001). Overall prevalences of UDM (4.0% vs 4.2%) and IFG (23.8% vs 25.6%) did not differ significantly between p.C282Y homozygotes and wt/wt controls, respectively. In logistic regressions, male sex, body mass index, and alanine aminotransferase were significantly associated with UDM. ORs were 2.7 (1.2 to 2.8); 1.0 (1.0 to 1.1); and 1.0 (1.0 to 1.0), respectively. Age, male sex, and body mass index were significantly associated with IFG. ORs were 1.0 (1.0 to 1.1); 2.8 (1.9 to 4.2); and 1.0 (1.0 to 1.1), respectively.
Conclusions
Prevalences of UDM and IFG were similar in p.C282Y homozygotes and controls in a postpopulation screening examination. Male sex was the strongest predictor of UDM and IFG.
... The prevalence of HT in the present probands was 8.1% (5.1, 12.5). In women aged 20-49 y in a large population hemochromatosis screening program in Norway, 12.5% of HFE C282Y homozygotes and 3.0% of control participants reported having hypothyroidism [51]. In the Hemochromatosis and Iron Overload Screening Study of adult primary care participants in North America, 8.5% of 176 HFE C282Y homozygotes and 10.9% of 312 HFE wt/wt controls reported taking thyroid supplements ( = 0.4019) [52]. ...
We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes
A
∗
01
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B
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08
;
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∗
02
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44
;
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∗
03
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07
;
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∗
03
,
B
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; and
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29
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. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto’s thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.
... Det er ikke klarlagt hvorfor ca. 10 % av pasientene med arvelig hemokromatose, vurdert ut fra kliniske funn og påviselig jernoverskudd, ikke har de aktuelle mutasjoner, eller hvorfor noen personer har C282Y-mutasjonen uten at det kan påvises jernoverskudd (15). Dette viser imidlertid at det må finnes andre genetiske faktorer som også påvirker utviklingen av arvelig hemokromatose. ...
... There is no significant difference between any of the groups: homozygotes for hemochromatosis were no more likely to enjoy less than good health than were controls (f). From data of Asberg et al 14 the data reported by groups claiming high penetrance and those who consider penetrance to be low. The difference is largely a philosophic one. ...
Drs Richard S. Ajioka and James P. Kushner provide an able review of the studies that have led them to conclude that the penetrance of hereditary hemochromatosis is much higher than our study of Kaiser-Permanente patients has shown it to be. They suggest that the cause of the discrepancy is
... Neben der diskutierten Studie aus Kalifornien liegen derzeit nur begrenzt Daten zur Morbidita Èt bei HH-Anlagetra Ègern vor, die im Rahmen eines Populationsscreening identifiziert wurden. Eine Untersuchung aus Norwegen zeigt ebenfalls, dass sich der Gesundheitszustand der in einem Screeningprogramm identifizierten HH-Anlagetra Èger nur in wenigen Punkten (Gelenkbeschwerden, Hypothyreoidismus) von einer Kontrollpopulation unterscheidet, was die Sinnfa Èlligkeit eines unselektierten Screenings weiter in Frage stellt [119]. ...
Zusammenfassung: Die hereditäre Hämochromatose (HH) ist eine autosomal-rezessiv vererbte Erkrankung des Eisenstoffwechsels, die durch eine verstärkte intestinale Eisenresorption mit nachfolgender Ablagerung von Eisen in Geweben charakterisiert ist. Die molekulare Ursache liegt in den Mutationen C282Y und H63D im HFE-Gen. Einer außergewöhnlich häufigen genetischen Anlage in der europiden Bevölkerung (Homozygotenfrequenz für HFE C282Y von bis zu 1 : 200) steht eine niedrige klinische Penetranz gegenüber, deren Ausmaß im Zentrum aktueller Kontroversen steht. Laboratoriumsdiagnostisch kann die phänotypische Ausprägung der Eisenüberladung durch Analysen der Transferrinsättigung und/oder Ferritinkonzentration erfaßt werden. Der Mutationsnachweis im HFE-Gen sichert die Diagnose HH. Ein Populationsscreening für die HH ist bei einer niedrigen Penetranz der Erkrankung aus Kosten- und medizinischen Gründen nicht vertretbar. Gezielte Screeningprogramme bei vorliegender Symptomatik und/oder auffälligen klinisch-chemischen Befunden sollten die molekulargenetische Abklärung einschließen.
... The variant is virtually absent in populations of non-European origin. The clinical penetrance of homozygosity for C282Y is highly variable and the majority of people with this genotype never become ill as a result of iron overload313233. The H63D variant is more widespread worldwide and has a less defined role in predisposing towards iron loading. Most compound heterozygotes do not develop iron overload [34]. ...
This article is a summary of the publication "Iron and Health" by the Scientific Advisory Committee on Nutrition (SACN) to the U.K. Government (2010), which reviews the dietary intake of iron and the impact of different dietary patterns on the nutritional and health status of the U.K. population. It concludes that several uncertainties make it difficult to determine dose-response relationships or to confidently characterize the risks associated with iron deficiency or excess. The publication makes several recommendations concerning iron intakes from food, including meat, and from supplements, as well as recommendations for further research.
... In population-based studies, these complications occur in approximately 5% of male and less than 1% of female C282Y homozygotes. 21,22 The presence of symptoms related to iron overload in C282Y homozygotes found in a population screening study was 28.4% in men and 1.2% in women. 21 Several studies in which the authors evaluated liver biopsies before and after phlebotomy therapy demonstrated that hepatic fibrosis can be reversed by phlebotomy therapy. ...
Hemochromatosis is a common genetic disorder in which iron may progressively accumulate in the liver, heart, and other organs. The primary goal of therapy is iron depletion to normalize body iron stores and to prevent or decrease organ dysfunction. The primary therapy to normalize iron stores is phlebotomy. In this opinion article, we discuss the indications for and monitoring of phlebotomy therapy to achieve iron depletion, maintenance therapy, dietary and pharmacologic maneuvers that could reduce iron absorption, and the role of voluntary blood donation.
... 3 Symptoms correlate poorly with the presence of iron overload in HH, and morbidity in screening-detected HH does not differ from that in controls. 4 However, once diagnosed, HH is readily treatable, and, provided complications have not arisen, life expectancy is not reduced. 5 Continued effort should be made to educate all physicians in an attempt to increase awareness of HH and lead to earlier diagnosis. ...
... There were no differences in age distribution except a small shift toward younger ages in C282Y homozygote males. Despite demonstration of low penetrance of these mutations in regard to symptom or effects on age distribution by this large study, and those of several others (11, 16, 19, 20) this remains an area of controversy (2, 5, 21–23). There are several important differences between our studies and other studies reporting a higher penetrance of the C282Y homozygous state. ...
We undertook a three-year screening program for mutations of the HFE gene among 41,000 subjects attending the Kaiser Permanente Health Appraisal Center in San Diego, California. Our results show that the C282Y and H63D mutations of the HFE gene associated with hemochromatosis have measurable and consistent effects on iron indicators and are associated with liver disorders, but have no measurable effect on other iron overload-related symptoms and life-expectancy. The very low clinical penetrance of the HFE mutations must be taken into account in calculating cost/benefit and risk/benefit ratios in screening for hemochromatosis.
A practical, clinically-oriented handbook of iron overload disorders giving a compact guide to normal iron metabolism, iron-related pathobiology, and the diagnosis and management of heritable and acquired iron overload disorders. Many of these disorders were discovered and characterized only in the last decade, and are unmentioned or inadequately described in most texts. Written by clinicians for clinicians, this handbook summarizes information on diverse iron overload conditions, including their history, signs, symptoms, physical examination findings, genetics, genotype-phenotype correlations, pathophysiology, differential diagnosis and treatment. Most physicians, regardless of specialty, encounter patients with systemic or organ-specific iron overload conditions. This book contains essential information for practising adult and pediatric medical specialists in the fields of hematology, gastroenterology, hepatology, rheumatology, endocrinology, diabetology, neurology, oncology, dermatology and internal medicine. Pathologists, pharmacologists, geneticists, genetic counselors and epidemiologists will also find substantial, up-to-date sections in this handbook that are pertinent to their respective fields of interest.
A practical, clinically-oriented handbook of iron overload disorders giving a compact guide to normal iron metabolism, iron-related pathobiology, and the diagnosis and management of heritable and acquired iron overload disorders. Many of these disorders were discovered and characterized only in the last decade, and are unmentioned or inadequately described in most texts. Written by clinicians for clinicians, this handbook summarizes information on diverse iron overload conditions, including their history, signs, symptoms, physical examination findings, genetics, genotype-phenotype correlations, pathophysiology, differential diagnosis and treatment. Most physicians, regardless of specialty, encounter patients with systemic or organ-specific iron overload conditions. This book contains essential information for practising adult and pediatric medical specialists in the fields of hematology, gastroenterology, hepatology, rheumatology, endocrinology, diabetology, neurology, oncology, dermatology and internal medicine. Pathologists, pharmacologists, geneticists, genetic counselors and epidemiologists will also find substantial, up-to-date sections in this handbook that are pertinent to their respective fields of interest.
Hemochromatosis is the most common genetic disease in populations of European ancestry. Despite estimates based on genetic testing in Caucasian populations of 1 in 227, many physicians consider hemochromatosis to be a rare disease. The diagnosis can be elusive because of the non-specific nature of the symptoms. The discovery of the HFE gene in 1996 has provided new insights into the pathogenesis of the disease and resulted in new diagnostic strategies
Haemochromatosis is now known to be an iron-storage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to increase in intestinal absorption and deposition of excessive amounts of iron in parenchymal cells which in turn results in eventual tissue damage and organ failure. A clinical enigma has been the variable clinical expression with some patients presenting with hepatic cirrhosis at a young age and others almost asymptomatic for life. Research is unravelling this puzzle by identifying environmental factors—especially alcohol consumption—and associated modifying genes that modulate phenotypic expression. A high index of suspicion is required for early diagnosis but this can lead to presymptomatic therapy and a normal life expectancy. Venesection (phlebotomy) therapy remains the mainstay of therapy, but alternative therapies are the subject of current research.
This chapter discusses hemochromatosis. The term hemochromatosis was originally defined as a disease state caused by excess iron storage. Hemosiderosis was a designation that was sometimes applied to states in which iron stores were increased but in which there might or might not be pathologic consequences. Hemochromatosis is a clinical syndrome in which the accumulation of excess amounts of iron produces abnormalities that may include cirrhosis, diabetes, cardiomyopathy, and hypogonadism. Although the clinical syndrome is rare, two mutations of the HFE gene are present at polymorphic frequencies in the European population. The detection of these mutations in DNA samples can be readily accomplished by a number of different methods. These are rare in frequency and heterogeneous in the mutations that have been identified. Mutations of these genes may be detected by direct sequencing of amplified DNA and by dHPLC. The genetic basis of some forms of hemochromatosis remains unknown, and the diagnosis cannot be established by molecular analysis in every case. The report of the results of molecular analysis of iron regulatory genes should clearly state not only what was found, but also what was examined.
In the past seven years numerous genes that influence iron homeostasis have been discovered. Dr. Beutler provides a brief overview of these genes, genes that encode HFE, DMT-1, ferroportin, transferrin receptor 2, hephaestin, and hepcidin to lay the groundwork for a discussion of the various clinical forms of iron storage disease and how they differ from one another.
In Section I, Dr. Beutler also discusses the types of hemochromatosis that exist as acquired and as hereditary forms. Acquired hemochromatosis occurs in patients with marrow failure, particularly when there is active ineffective erythropoiesis. Hereditary hemochromatosis is most commonly due to mutations in the HLA-linked HFE gene, and hemochromatosis clinically indistinguishable from HFE hemochromatosis is the consequence of mutations in three transferrin receptor-2 gene. A more severe, juvenile form of iron storage disease results from mutations of the gene encoding hepcidin or of a not-yet-identified gene on chromosome 1q. Autosomal dominant iron storage disease is a consequence of ferroportin mutations, and a polymorphism in the ferroportin gene appears to be involved in the African iron overload syndrome.
Evidence regarding the biochemical and clinical penetrance of hemochromatosis due to mutations of the HFE gene is rapidly accumulating. These studies, emanating from several centers in Europe and the United States, all agree that the penetrance of hemochromatosis is much lower than had previously been thought. Probably only 1% of homozygotes develop clinical findings. The implications of these new findings for the management of hemochromatosis will be discussed.
In Section II, Dr. Victor Hoffbrand discusses the management of iron storage disease by chelation therapy, treatment that is usually reserved for patients with secondary hemochromatosis such as occurs in the thalassemias and in patients with transfusion requirements due to myelodysplasia and other marrow failure states. Tissue iron can be estimated by determining serum ferritin levels, measuring liver iron, and by measuring cardiac iron using the MRI-T2* technique. The standard form of chelation therapy is the slow intravenous or subcutaneous infusion of desferoxamine. An orally active bidentate iron chelator, deferiprone, is now licensed in 25 countries for treatment of patients with thalassemia major. Possibly because of the ability of this compound to cross membranes, it appears to have superior cardioprotective properties. Agranulocytosis is the most serious complication of deferiprone therapy and occurs in about 1% of treated patients. Deferiprone and desferoxamine can be given together or on alternating schedules. A new orally active chelating agent ICL 670 seems promising in early clinical studies.
In Section III, Dr. James Cook discusses the most common disorder of iron homeostasis, iron deficiency. He will compare some of the standard methods for identifying iron deficiency, the hemoglobin level, transferrin saturation, and mean corpuscular hemoglobin and compare these with some of the newer methods that have been introduced, specifically the percentage of hypochromic erythrocytes and reticulocyte hemoglobin content. The measurement of storage iron is achieved by measuring serum ferritin levels. The soluble transferrin receptor is a truncated form of the cellular transferrin receptor and the possible value of this measurement in the diagnosis of iron deficiency will be discussed. Until recently iron dextran was the only parental iron preparation available in the US. Sodium ferric gluconate, which has been used extensively in Europe for many years, is now available in the United States. It seems to have a distinct advantage over iron dextran in that anaphylactic reactions are much less common with the latter preparation.
In the last decades, a large number of epidemiological studies in gastroenterology and hepatology have originated from the Scandinavian countries. With the help of large health databases, with good validity and other registries related to patient outcomes, researchers from the Scandinavian countries have been able to make some very important contributions to the field. These countries, Sweden, Norway, Finland, Denmark and Iceland, have all universal access to health care and have shown to be ideal for epidemiological research. Population-based studies have been frequent and follow-up studies have been able to describe the temporal trends and changes in phenotypes. Our ability in Scandinavia to follow up defined groups of patients over time has been crucial to learn the natural history of many gastrointestinal and liver diseases and often in a population-based setting. Patient-related outcomes measures will probably gain increasing importance in the future, but Scandinavian gastroenterologists and surgeons are likely to have a better infrastructure for such endeavors compared to most other populations. Thus, there is a bright future for international competitive research within the field of gastrointestinal and liver diseases in Scandinavia.
Background
Hemochromatosis is a disease of hereditary (HFE) or acquired origin and has been related to cardiovascular disease (CVD) development.
Aim
To compare alellic frequencies of different HFE mutations in patients with ischemic diseases versus control population and to study possible associations between these mutations, CVD and iron and lipid metabolisms.
Results
No difference was observed in the HFE genotypic distribution between patients with CVD and controls, regardless of gender and menstrual status. Allelic variant frequencies in HFE gene were around 21% in the analyzed population for the H63D phenotype and 2,5% for the C282Y phenotype both in patients and controls. Statistically-significant differences between total and HDL cholesterol and Apo AI and enzymatic hepatic damage markers were observed between controls and patients. However, these differences were not related to allelic variants of HFE gene. Metabolic iron parameters such as serum iron, ferritin and iron-binding capacity were not altered or related to HFE mutations in analyzed patients.
Conclusion
Current data suggest a lack of association between HFE genotype variations and CVD. However, the elevated proportion of HFE mutations detected suggests that these mutations could be associated with diseases of variable penetrance, including those related to vascular pathology.
Background/aims:
Hereditary hemochromatosis is an autosomal recessive disorder associated with the HFE genes. Early identification and diagnosis is important as end stage organ damage may occur if treatment is delayed.. This study aimed to identify the prevalence of hereditary hemochromatosis in Kayseri and surroundings known as Central Anatolia.
Materials and methods:
2304 participants (1220 males, 1084 females) who were older then the age of 17 were included in the study conducted between December 2005 and December 2006 in Kayseri, Turkey. Transferin saturation was measured from overnight fasting blood samples. Serum iron, total iron binding capacity, and transferin saturation were measured. Serum ferritin levels and hereditary hemochromatosis genetic analysis were also performed after an overnight fasting blood samples from participants whose transferin saturation results were more than 50% in man and more than 45% in women.
Results:
The homozygote C282Y mutation and heterozygote C282Y mutation prevalences were found as 0.08% (1/1220) and 0.08% (1/1220) in male participants, respectively. The heterozygote H63D mutation prevalence was found in 0.09% (1/1084) of female participants. Calculated prevalences in general population are as follows; The homozygote C282Y mutation prevalence is 0.043% (1/2304), the heterozygote C282Y mutation prevalence is 0.043% (1/2304) and the heterozygote H63D mutation prevalence is 0.043% (1/2304).
Conclusions:
The prevalence of hereditary hemochromatosis in Central Anatolia is 0.043% (1/2304). Because of the relatively low frequency, population screening studies are not cost-effective.
Objective:
In addition to hepatocellular cancer, HFE C282Y homozygotes are reported to have increased risk of colorectal cancer and breast cancer. This study was done to further explore the cancer risk in C282Y homozygotes.
Material and methods:
We studied cancer incidence in 292 homozygotes and 62,568 others that participated in the HUNT 2 population screening in 1995-1997. Using Cox proportional hazard models, we estimated cancer hazard ratio as a function of C282Y homozygosity and several screening variables including serum transferrin saturation, alcohol consumption and daily smoking.
Results:
Cancer was diagnosed in 36 homozygotes, five of which had two cancer diagnoses. The overall cancer incidence was not increased in C282Y homozygotes (hazard ratio 1.10 [95% CI 0.60-2.03] in women and 0.94 [95% CI 0.53-1.66] in men). However, homozygous men had increased risk of colorectal cancer (hazard ratio 3.03 [95% CI 1.17-7.82], p = 0.022) and primary liver cancer (hazard ratio 54.0 [95% CI 2.68-1089], p = 0.009). The risk of breast cancer in homozygous women was not increased (hazard ratio 1.13 [95% CI 0.35-3.72]). Adjusted for other variables including C282Y homozygosity, very low and very high serum transferrin saturation were associated with increased overall cancer incidence.
Conclusions:
C282Y homozygosity is associated with increased risk of colorectal cancer and hepatocellular cancer in men. In the general population, individuals with a very low or a very high serum transferrin saturation may have increased cancer risk.
Zusammenfassung: Die hereditre Hmochromatose (HH) ist eine autosomal-rezessiv vererbte Erkrankung des Eisenstoffwechsels, die durch eine verstrkte intestinale Eisenresorption mit nachfolgender Ablagerung von Eisen in Geweben charakterisiert ist. Die molekulare Ursache liegt in den Mutationen C282Y und H63D im HFE-Gen. Einer außergewöhnlich hufigen genetischen Anlage in der europiden Bevölkerung (Homozygotenfrequenz für HFE C282Y von bis zu 1 : 200) steht eine niedrige klinische Penetranz gegenüber, deren Ausmaß im Zentrum aktueller Kontroversen steht. Laboratoriumsdiagnostisch kann die phnotypische Ausprgung der Eisenüberladung durch Analysen der Transferrinsttigung und/oder Ferritinkonzentration erfaßt werden. Der Mutationsnachweis im HFE-Gen sichert die Diagnose HH. Ein Populationsscreening für die HH ist bei einer niedrigen Penetranz der Erkrankung aus Kosten- und medizinischen Gründen nicht vertretbar. Gezielte Screeningprogramme bei vorliegender Symptomatik und/oder aufflligen klinisch-chemischen Befunden sollten die molekulargenetische Abklrung einschließen.Summary: Hereditary haemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism characterised by increased intestinal iron resorption and subsequent deposition in parenchymatous organs. The molecular defect underlying HH consists of two point mutations (C282Y, H63D) in the HFE gene. Recent studies have demonstrated a high frequency of the homozygous HFE mutation status, approaching up to 1 in 200 among the general population, as opposed to a low clinical penetrance of the disease. This is the subject of ongoing studies and scientific debate. In the clinical laboratory, iron overload is phenotypically assessed by the transferrin saturation rate and/or ferritin concentration. The demonstration of the HFE gene mutations confirms the diagnosis at the genetic level. At the present time, a population screening of HH cannot be recommended due to the low penetrance of the disease. In contrast, a targeted genetic screening in patients presenting with laboratory evidence of iron overload and/or signs and symptoms known to be overrepresented in HH seems to be a promising approach. This review article attempts to present new data related to HH and to evaluate ongoing scientific controversy.
IntroductionPathogenesis of hemochromatosisDiagnosis of hemochromatosisPopulation screeningTreatment of hemochromatosisWilson disease
Schätzungen zufolge beruhen 82-90% der Erkrankungen an Hämochromatose auf einer homozygoten C282Y-Mutation im HFE-Gen. Weitere bekannte HFE-Gen Mutationen sind die H63D- und die S65C-Mutation. Ziel der Studie war die Ermittlung der Korrelation zwischen Parametern des Eisenstoffwechsels, Prävalenz von HFE-Gen-Mutationen und die Korrelation einer erhöhten Transferrinsättigung mti verschiedenen Parametern. Zudem sollte mittels MRT die Eisenüberladung der Leber bei an Hämochromatose-Erkrankten gezeigt werden.
Hemochromatosis has generally been considered to be a genetic disease in which progressive iron accumulation over many years can lead to cirrhosis of the liver, hepatocellular carcinoma, diabetes, cardiomyopathy, and arthropathy. Iron depletion by phlebotomy has been the recommended therapy although a randomized trial of phlebotomy versus no treatment has never been reported. Since the discovery of the HFE gene in 1996, it has been possible to predict the risk of developing iron overload by a simple blood test to detect C282Y homozygotes of the HFE gene. The application of the hemochromatosis genetic test in large population studies often initiated to investigate other diseases has provided a fascinating glimpse into the natural history of untreated C282Y homozygotes followed for over 20 years without phlebotomy treatment. These observations are summarized in this review article which raises questions about the need for phlebotomy in all C282Y homozygous patients.
An up to date review of our knowledge of human iron metabolism is given including problems of iron balance, internal transport, and intracellular mechanisms. Current knowledge of the iron proteins is summarized and this background is used in discussing the pathophysiology of iron deficiency and overload, together with the internal derangements such as sideroblastic anemia which form much of the clinical practice associated with disorders of iron metabolism. The therapeutic approach to these problems will be described.
Hereditary hemochromatosis (HH) is a common genetic disease leading to accumulation of iron in the body, most notably in the liver. More men than women become clinically ill. The prognosis is excellent if phlebotomy treatment is started before liver cirrhosis develops. Screening has been recommended, but the benefit of population-based screening has never been shown in a randomized clinical trial. In this article, we estimate the benefit of screening young men, using a theoretical model.
A phenotypic screening scenario was modelled using a decision tree. Gain of quality-adjusted life-years was used as a measure of benefit, and estimated using Markov processes. Data on the accuracy of the screening tests, the prevalence of HH and the risk of liver cirrhosis were mainly derived from a cross-sectional study on the prevalence and morbidity of HH in 30509 men. Data on the excess mortality of cirrhosis were taken from relevant literature. Sensitivity analysis was done for important variables.
Assuming basal case values for variables, screening a cohort of 1000 men aged 30 years for phenotypic HH would gain about 8 quality-adjusted life-years, compared to awaiting symptomatic disease. Based on actual costs of our cross-sectional study, the screening cost was US$250 per quality-adjusted life-year gained. The prevalence of phenotypic HH, the excess mortality of liver cirrhosis, the quality of life in non-cirrhotic HH patients, and the fractions of patients compliant with treatment were the most important variables in the sensitivity analysis.
Incorporating screening for phenotypic HH in health survey programmes for young men may be worthwhile.
Hereditary hemochromatosis is characterized by marked variation of expression of the defect: very few homozygotes with the C282Y/C282Y HFE genotype have full-blown clinical disease, a larger number show biochemical stigmata of iron overload, and some seem normal biochemically. The following candidate genes have been examined in detail to determine whether polymorphisms in them may be responsible for this variation: transferrin, transferrin receptor 1, transferrin receptor 2, ferritin-L, ferritin-H, IRP1, IRP2, HFE, beta(2) microglobulin, mobilferrin/calreticulin, ceruloplasmin, ferroportin, NRAMP1, NRAMP2 (DMT1), haptoglobin, heme oxygenase-1, heme oxygenase-2, hepcidin, USF2, ZIRTL, duodenal cytochrome b ferric reductase (DCYTB), TNFalpha, keratin 8, and keratin 18. The coding sequence, exon-intron junctions, and promoters of each of these genes was sequenced in DNA from 20 subjects: 5 HFE C282Y/C282Y with clinical disease, 5 HFE C282Y/C282Y with normal/low ferritin levels and no disease, 5 wt/wt with high ferritin and transferrin saturation, and 5 wt/wt normal controls. When coding or promoter polymorphisms were encountered, DNA from large numbers of ethnically defined subjects was examined for these polymorphisms and a relationship between their existence and abnormalities of iron homeostasis was sought. Only in the case of one transferrin mutation did we find a strong relationship between the polymorphism and iron deficiency anemia. The putative genes that affect the expression of HFE mutations remain elusive.
Ryan and colleagues ( Gut 2002; 51 :108–12) note that the expected homozygote frequency of 1 in 83 for the HFE C282Y mutation is not reflected in the number of patients with haemochromatosis seen in a clinical setting. Accordingly, they have studied family members of patients with haemochromatosis as a surrogate for population screening. As they point out, there are probably genes other than HFE that affect the expression of hereditary haemochromatosis, and such genes are likely to be overrepresented in the families …
The progression rate of iron overload in hereditary hemochromatosis in individuals in the general population is unknown. We therefore examined in the general population iron overload progression rate in C282Y homozygotes. Using a cohort study of the Danish general population, The Copenhagen City Heart Study, we genotyped 9174 individuals. The 23 C282Y homozygotes identified were matched to 2 subjects each of 5 other HFE genotypes with respect to sex, age, and alcohol consumption. As a function of biologic age, transferrin saturation increased from 50% to 70% from 25 to 85 years of age and from 70% to 80% from 35 to 80 years of age in female and male C282Y homozygotes, respectively. Equivalently, ferritin levels increased from 100 to 500 microg/L and decreased from 800 to 400 microg/L in female and male C282Y homozygotes. As a function of 25 years follow-up irrespective of age, transferrin saturation and ferritin levels increased slightly in male and female C282Y homozygotes. None of the C282Y homozygotes developed clinically overt hemochromatosis. In conclusion, individuals in the general population with C282Y homozygosity at most demonstrate modest increases in transferrin saturation and ferritin levels, and clinically overt hemochromatosis is rare. Therefore, C282Y homozygotes identified during population screening, and not because of clinically overt hemochromatosis, at most need to be screened for manifestations of hemochromatosis every 10 to 20 years.
Haemochromatosis continues to be considered an uncommon disease despite large scale population screening studies demonstrating a high prevalence of C282Y homozygotes of approximately 1 in 200. Since many of the C282Y homozygotes that are discovered through screening are asymptomatic, or have non-specific symptoms commonly found in the ageing population, the attribution of any symptoms to haemochromatosis has become increasingly difficult. The demonstration of significant liver disease in family members is a strong reminder of the vital importance of pedigree studies when a typical haemochromatosis patient is identified.
Elucidation of the molecular pathways of iron transport through cells and its control is leading to an understanding of genetic iron loading conditions. The general phenotype of haemochromatosis is iron accumulation in liver parenchymal cells, a raised serum transferrin saturation and ferritin concentration. Four types have been identified: type 1 is the common form and is an autosomal recessive disorder of low penetrance strongly associated with mutations in the HFE gene on chromosome 6(p21.3); type 2 (juvenile haemochromatosis) is autosomal recessive, of high penetrance with causative mutations identified in the HFE2 gene on chromosome 1 (q21) and the HAMP gene on chromosome 19 (q13); type 3 is also autosomal recessive with mutations in the TfR2 gene on chromosome 3 (7q22); type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene. In type 4, iron accumulates in both parenchymal and reticuloendothelial cells and the transferrin saturation may be normal. There are also inherited neurodegenerative conditions associated with iron accumulation. The current research challenges include understanding the central role of the HAMP gene (hepcidin) in controlling iron absorption and the reasons for the variable penetrance in HFE type 1.
To evaluate the efficacy of identifying presymptomatic hereditary haemochromatosis through population based screening.
Review the hereditary pattern, prevalence, and clinical manifestations of haemochromatosis. Estimate the detection and false positive rates associated with available screening and diagnostic tests. Develop examples of screening protocols and other components that would be necessary for proper implementation. Identify potential barriers and objections.
Hereditary haemochromatosis, an autosomal recessive disorder with a prevalence of three to five per thousand in the general population, is associated with a wide variety of clinical manifestations, usually beginning in mid to late adult years. Identifying and treating this disorder after symptoms appear can arrest its progress but usually cannot reverse existing damage to joints, liver, pancreas, pituitary gland, and other organs. Measuring transferrin saturation in serum is now known to be a reliable screening test for haemochromatosis when applied to a general population of healthy adults, detecting about 80% of cases, with a 0.3% false positive rate. Liver biopsy with iron staining and total iron concentration is the recommended diagnostic test for subjects with positive screening tests. Treatment with phlebotomy can then prevent manifestations. Effective systematic identification and management of presymptomatic haemochromatosis in the general population is best accomplished within the framework of an organised screening programme. Potential barriers include accessibility of young adult populations and attitudes in the health community that severe clinical manifestations are relatively uncommon. It is recommended that pilot programmes be undertaken to determine the feasibility of introducing screening for haemochromatosis as part of routine health care.
Haemochromatosis is a genetic disease associated with progressive iron overload, and is common among populations of northern European origin. HLA-H is a recently reported candidate gene for this condition. Two mutations have been identified, a substitution of cysteine for tyrosine at amino acid 282 (C282Y, nucleotide 845) and of histidine for aspartate at amino acid 63 (H63D, nucleotide 187). Over 90% of UK haemochromatosis patients are homozygous for the C282Y mutation. We have examined 5956 chromosomes (2978 people) for the presence of HLA-H C282Y and H63D by PCR followed by restriction enzyme analysis. We have found world wide allele frequencies of 1.9% for C282Y and 8.1% for H63D. The highest frequencies were 10% for C282Y in 90 Irish chromosomes and 30.4% for H63D in 56 Basque chromosomes. C282Y was most frequent in northern European populations and absent from 1042 African chromosomes, 484 Asian chromosomes, and 644 Australasian chromosomes. The distribution of the C282Y mutation coincides with that of populations in which haemochromatosis has been reported and is consistent with the theory of a north European origin for the mutation. The H63D polymorphism is more widely distributed and its connection with haemochromatosis remains unclear.
To review the epidemiological and experimental data concerning iron and the development of atherosclerosis and ischemic heart disease.
The English-language literature was searched from 1981 through 1998 manually and using MEDLINE and Current Contents. Important references in the articles that were found were also included in this review.
There is growing epidemiological evidence for a relationship between iron levels and cardiovascular disease. Some experimental data support the role of iron in the process of lipid peroxidation, the first step in the formation of atherosclerotic lesions. Macrophages and endothelial cells are involved in this process, but the exact mechanism and the sites of the interactions between these cells, iron, and low-density lipoprotein are still unknown.
Strong epidemiological evidence is available that iron is an important factor in the process of atherosclerosis. Epidemiological studies, eg, prospective follow-up studies in blood donors, may clarify the cardiovascular benefits of iron depletion. Knowledge of the molecular mechanism of iron-related cardiovascular disease is still limited. We speculate that catalytically active iron species modify low-density lipoprotein levels to interact with the macrophage oxidized low-density lipoprotein receptor. Both nontransferrin-bound plasma iron and hemoglobin are candidates for such interactions.
The gene that causes most cases of hereditary hemochromatosis is designated HFE. Three mutations exist at this locus at a relatively high gene frequency.
To determine the gene frequency of the three HFE mutations and to relate genotypes to various clinical and laboratory variables.
Observational study.
Health appraisal clinic.
10,198 adults who registered for health appraisal and consented to DNA examination for hemochromatosis. Consenting patients were slightly older and had attained a slightly higher educational level than nonconsenting patients.
Extensive medical history and laboratory tests, including complete blood count, transferrin saturation, and other chemistries; serum ferritin levels; and HFE genotype.
In white participants, the gene frequencies were 0.063 for the C282Y mutation, 0.152 for the H63D mutation, and 0.016 for the S65C mutation. Gene frequencies were lower in other ethnic groups. In participants with HFE mutations, the average serum transferrin saturation and ferritin levels were slightly increased, as were mean hemoglobin levels and mean corpuscular volume. A transferrin saturation of 50% had a sensitivity of only 0.52 (95% CI, 0.345 to 0.686) and a specificity of 0.908 (CI, 0.902 to 0.914) for detection of homozygosity. A ferritin level of 200 microg/L in women and 250 microg/L in men had a sensitivity of 0.70 (CI, 0.540 to 0.854) and a specificity of 0.803 (CI, 0.796 to 0.811). The prevalence of iron deficiency anemia was lower in women who carried HFE mutations.
Screening for transferrin saturation and ferritin levels does not detect all homozygotes for the major hemochromatosis mutation. Heterozygotes for HFE mutations had a lower prevalence of iron deficiency anemia.
Hereditary hemochromatosis (HH) is a common genetic disease leading to accumulation of iron in several organs, most notably the liver. The C282Y/C282Y mutation in the HFE gene is found in most cases. In order to prevent clinical disease and to study the cost and feasibility of screening, a large population was screened.
In a Norwegian county, all inhabitants 20 years or older were invited to participate in a population-based health survey programme. Screening for HH was one of several subprojects. Blood samples were obtained from 65,238 persons. Subjects with high serum transferrin saturation in two tests and high serum ferritin were clinically evaluated for HH. All subjects with high serum transferrin saturation in two tests were offered genotyping.
HH was newly diagnosed in 92 women and 177 men. Phlebotomy treatment was performed in 64 women and 152 men. Severe organ damage (liver cirrhosis) was ascertained in only 4 men. We found no correlation between serum ferritin and age. The estimated cost was US$ 1.6 per subject screened and US$ 390 per newly discovered HH subject. The estimated prevalence of phenotypical HH not previously known was 0.34% in women and 0.68% in men. The prevalence of the C282Y/C282Y mutation was at least 0.68%.
Large-scale screening for HH can be performed at a relatively low cost if combined with a health survey programme. The yield in terms of newly discovered cases is considerable, but few cases were found seriously ill. Better knowledge of the natural course of HH is necessary if we are to be able to estimate the cost-effectiveness of large-scale screening.
Background: The gene that causes most cases of hereditary hemochromatosis is designated HFE. Three mutations exist at this locus at a relatively high gene frequency. Objective: To determine the gene frequency of the three HFE mutations and to relate genotypes to various clinical and laboratory variables. Design: Observational study. Setting: Health appraisal clinic. Patients: 10198 adults who registered for health appraisal and consented to DNA examination for hemochromatosis. Consenting patients were slightly older and had attained a slightly higher educational level than nonconsenting patients. Measurements: Extensive medical history and laboratory tests, including complete blood count, transferrin saturation, and other chemistries; serum ferritin levels; and HFE genotype. Results: In white participants, the gene frequencies were 0.063 for the C282Y mutation, 0.152 for the H63D mutation, and 0.016 for the S65C mutation. Gene frequencies were lower in other ethnic groups. In participants with HFE mutations, the average serum transferrin saturation and ferritin levels were slightly increased, as were mean hemoglobin levels and mean corpuscular volume. A transferrin saturation of 50% had a sensitivity of only 0.52 (95% Cl, 0.345 to 0.686) and a specificity of 0.908 (Cl, 0.902 to 0.914) for detection of homozygosity. A ferritin level of 200 μg/L in women and 250 μg/L in men had a sensitivity of 0.70 (Cl, 0.540 to 0.854) and a specificity of 0.803 (Cl, 0.796 to 0.811). The prevalence of iron deficiency anemia was lower in women who carried HFE mutations. Conclusions: Screening for transferrin saturation and ferritin levels does not detect all homozygotes for the major hemochromatosis mutation. Heterozygotes for HFE mutations had a lower prevalence of iron deficiency anemia.
Context: The discovery of the HFE gene in 1996 has introduced DNA testing as a possible tool for screening and diagnosis of hemochromatosis and increased interest in the disorder. Population screening using transferrin saturation has been advocated by experts to permit early detection and treatment with phlebotomy before the onset of clinical disease. Methods: Based on a literature review, we consider the relative risks and merits of two screening tests as part of a broader look at the evidence required for the recommendation of universal screening for hemochromatosis. Results: Several questions must be answered before universal screening can be recommended. Uncertainties remain about the penetrance and preventable disease burden, laboratory standardization, and optimal strategies to minimize potential risks of screening for hemochromatosis. Conclusions: As a common genetic disorder with simple, effective therapy, hemochromatosis offers a model for other genetically influenced chronic diseases that some day may have interventions to improve prognosis. Resolution of questions related to prevention of chronic diseases from hemochromatosis, therefore, will have broad usefulness in the future.
Hereditary haemochromatosis (HHC) is a common inherited disorder of iron metabolism characterised by progressive iron loading of parenchymal cells of the liver, pancreas, heart and other organs ultimately leading to cirrhosis and organ failure. Despite HLA studies which localised the defective gene to the short arm of chromosome 6, the haemochromatosis gene remained elusive until 1996, when the gene was identified by a massive positional cloning effort. The haemochromatosis gene (HFE) encodes a novel non-classical MHC class-1-like molecule. Two missense mutations have been identified in patients with HHC, a G to A at nucleotide 845, resulting in a substitution of tyrosine for cysteine at amino acid 282 (referred to as the C282Y mutation) and a C to G at nucleotide 187, resulting in a substitution of aspartate for histidine at amino acid 63 (H63D). An average of 85–90% of patients with typical clinical features of HHC are homozygous for the C282Y mutation. H63D is not associated with the same degree of iron loading as C282Y. Clinical expression is variable depending on environmental (dietary) iron, physiological and pathological blood loss and as yet unidentified modifying genetic factors. One recent Australian study indicates that only about 50% of homozygous subjects are fully expressing and symptomatic and that about 30% show no clinical or biochemical expression. Genetic tests for identifying mutations in the HFE gene provide precise means for diagnosis, family testing and population screening and have led to re-evaluation of the indications for liver biopsy in this disease. At the present time, however, the most practical and cost-effective method of screening is for phenotypic expression by transferrin saturation or unsaturated iron binding capacity measurement. In the future, population screening by genotype should be feasible once the relevant technical, legal and ethical issues are resolved.
During the past several years hereditary haemochromatosis has risen from relative obscurity to become a topic of intense interest in the health community. Traditionally, hereditary haemochromatosis has been viewed as a rare inherited disorder, primarily of older men, that presents with life threatening complications such as “bronzed diabetes” (skin pigmentation, diabetes, and cirrhosis), primary liver cancer, or heart failure. Knowledge gained in the past 30 years, however, has shown that hereditary haemochromatosis occurs in as many as 5 in every 1000 white people of northern European heritage.1 The classic “bronzed diabetes” presentation is actually rare because it represents only a small proportion of affected individuals, usually those in whom the diagnosis has been missed for many years.2 This disorder more often presents in both men and women with non-specific medical complaints, such as abdominal pain, fatigue, sexual dysfunction, or joint pain, and hereditary haemochromatosis is often overlooked as a potential explanation.1 2 As iron loading progresses many organs and tissues can be damaged, leading to hepatic fibrosis and cirrhosis, primary liver cancer, endocrine dysfunction, cardiomyopathy, or arthropathy.1 2For over 10 years laboratory tests for assessing iron burden (transferrin saturation, serum ferritin) have been widely used in population screening, in conjunction with diagnostic …
Hereditary hemochromatosis is an autosomal recessive disorder, the gene for which occurs in approximately 10% of Americans, most of whom are unaffected heterozygotes. Approximately white Americans are homozygous and at risk of developing severe and potentially lethal hemochromatosis. The disorder affects numerous organ systems, but the most common symptoms are fatigue, palpitations, joint pains, and impotence; the most common signs are those that relate to hypothalamic, cardiac, hepatic or pancreatic dysfunction, including poor cold tolerance, impotence in males, amenorrhea in females, cardiac arrhythmias, dyspnea, edema, hepatosplenomegaly, spider telangiectases, ascites, deformity, swelling or limitation of motion of joints, weight loss, hyperpigmentation. Characteristic abnormalities of laboratory tests include elevated serum iron concentration, high transferrin saturation, elevated serum ferritin concentration, elevated serum transaminases, hyperglycemia and low values for thyroid-stimulating hormone (TSH) and gonadotropins. Death may be the result of cardiac arrhythmia, congestive heart failure, liver failure or liver cancer. Since many of these complications cannot be reversed once they have developed, early diagnosis and treatment are essential. In view of the high prevalence in the American population (prevalence varies with ethnic background), the low cost of diagnosis and treatment, the efficacy of treatment if begun early, and, on the other hand, high costs and low success rate of late diagnosis and treatment, systematic screening for hemochromatosis is warranted for all persons over the age of 20 years. The initial screening should be by measurement of serum iron concentration and transferrin saturation. The practice guideline provides a diagnostic algorithm for cases in which the serum transferrin saturation is 60% or greater. It also provides guidelines for clinical management.
Purpose:
To investigate the changing modes of clinical presentation and diagnosis in 93 patients with familial hemochromatosis and to compare the results with other reports from 1935 to the present.
Patients and methods:
The presenting features and the frequency of signs and symptoms were analyzed in 93 homozygotes from 56 families.
Results:
Hemochromatosis was detected by chance in 40% of the 56 probands. Abdominal pain (16%), joint pains (11%), and weakness (9%) were prominent features that brought the patient to the physician. Although 38% of the male patients had loss of libido and impotence, these were not identified as presenting features. Features of liver disease (84%), arthritis (11%), and diabetes (2%) led the physician to the diagnosis. Impotence and testicular atrophy were notable, by their absence, in alerting physicians to the presence of hemochromatosis. Screening of family members led to the detection of 37 homozygotes, of whom 46% were asymptomatic. Among this group, arthropathy and gonadal failure were the most common symptoms. The classic triad of hepatomegaly, diabetes, and pigmentation was present in only 8% of patients. Clinical features were rare in patients with less than 5 g of exchangeable body iron and invariably present in those with more than 16 g.
Conclusion:
The presenting clinical features of hemochromatosis have changed since the original description of the disease in 1935. Family studies have led to the earlier discovery of more homozygous women and earlier detection with less iron loading and, as a result, fewer signs and symptoms.
Summary of a conference sponsored by the Division of Digestive Diseases and Nutrition and the Division of Kidney, Urology and Hematology of the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MarylandGASTROENTEROLOGY 1999;116:193-207
In 1974-76 a cardiovascular disease study was started in three Norwegian counties, Finnmark, Sogn or Fjordane and Oppland. This report presents the background and organization of the study. Particular emphasis is laid on execution of field work and methodology, as well as on size and profile of the study population. Results will be presented in further reports.
Twenty-three probands with idiopathic hemochromatosis were assigned the status of homozygotes: 132 of their relatives were classified as homozygotes, heterozygotes or normal individuals using the HLA haplotypes of the probands as markers of the hemochromatosis allele. Only half of the probands sought help because of symptoms or signs of iron overload. Clinical manifestations of iron loading were present, however, 95% of the probands and 67% of the discovered homozygotes. The commonest symptom was joint pain and stiffness. None of the heterozygotes had any clinical symptoms of excess body iron. High transferrin saturation and serum ferritin levels were prevalent in homozygotes: only 1 of 38 homozygotes had values for both of these measurements that were within normal limits. The level of transferrin saturation was increased in 6% of heterozygotes but only 1% had serum ferritin concns greater than 350 ng ml-1. The mean radioiron absorption levels of 27 homozygotes and 28 heterozygotes were similar to those in 44 controls. Radioiron absorption in relation to the respective serum ferritin concn was above the 95% confidence interval of controls in 65% of the homozygotes and 7% of the heterozygotes. The inverse relation between radioiron absorption and the respective serum ferritin concn observed in controls was absent in homozygotes but remained strong in the heterozygotes. Absence of the inverse relation indicates a deregulation of the iron absorptive mechanism in homozygotes which results in the size of body iron stores having no effect on the level of iron absorption.(ABSTRACT TRUNCATED AT 250 WORDS)
Haemochromatosis is one of the most common inborn errors of metabolism. In prospective epidemiological studies the frequency of haemochromatosis is 0.0037 (76/20333 subjects) for homozygotes which corresponds to a gene frequency of 0.061 and a frequency of heterozygotes of 0.115. Abnormality in liver function tests, weakness and lethargy, skin hyperpigmentation, diabetes mellitus, arthralgia, impotence and ECG abnormalities are the most frequent findings and symptoms at diagnosis. In recent years about 50% of patients were detected without having liver cirrhosis and 20% of patients did not have any symptoms and pathology except iron overload. Survival analyses in long-term studies showed that in the absence of cirrhosis and diabetes, iron removal by phlebotomy therapy prevents further tissue damage and guarantees a normal life expectancy. Patients with massive and long-lasting iron overload had a worse prognosis than those with less severe iron excess. Iron removal in general ameliorated liver disease, weakness and cardiac abnormalities, and also prevented the progression of endocrine alterations. Therapy, however, did not influence insulin-dependent diabetes. Most deaths in patients with hereditary haemochromatosis were caused by liver cancers which often occurred many years after complete iron removal. In patients with haemochromatosis, liver cirrhosis, cardiomyopathy, and diabetes mellitus are also significantly more frequent causes of deaths when compared with the general population. Further strategies have to evaluate the design of screening programmes in order to diagnose more patients in the precirrhotic and asymptomatic stage.
Hemochromatosis is an autosomal recessive disorder that often results in accumulation of excessive amounts of storage iron in parenchymal organs. 1-14 The end-stage of the disease in individuals who are homozygous for the HLA-linked hemochromatosis allele is characterized by massive iron overload associated with organ damage. The frequency of homozygosity for hemochromatosis in some populations, including the U.S. Caucasian population, is estimated to be about 5 per 1000. 15 Massive iron overload, however, with multiple organ failure occurs less frequently. 15-21 The disparity between the frequency of the homozygous genotype and the observed frequency of massive iron over-load is due in part to physiologic iron loss in women, and may be due to variable penetrance of the clinical phenotype in homozygotes of both sexes. 15,20
Epidemiology:
Eleven prospective epidemiological studies from various countries have as yet evaluated the gene prevalence of HLA-linked hemochromatosis. The estimated frequency ranged from 0.027-0.107, the frequency of homozygotes from 0.00074-0.0116, and the frequency of heterozygotes from 0.052-0.191. In a meta-analysis of the eleven surveys the frequency is 0.0016 (106/64758 subjects) for homozygotes which corresponds to a gene frequency of 0.041 and a frequency of heterozygotes of 0.078. Further analyses showed that some of these studies have probably underestimated the prevalence which in reality is probably two- to threefold higher than estimated by the meta-analysis.
Clinical spectrum:
In the total group of 251 patients diagnosed with hemochromatosis in the University of Düsseldorf from 1959-1992, abnormality in liver function tests (75%), weakness and lethargy (74%), skin hyperpigmentation (70%), diabetes mellitus (48%), arthralgia (44%), impotence (45% in males), and ECG abnormalities (31%) were the most frequent findings and symptoms at diagnosis. In recent years about 50% of patients were detected without having liver cirrhosis and 20% of patients did not have any symptoms and pathology except iron overload.
Prognosis:
Survival analysis in the 251 patients showed that in the absence of cirrhosis and diabetes iron removal by phlebotomy therapy prevents further tissue damage and guarantees a normal life expectancy. Sex and presence of arthropathy did not predict prognosis. However, patients with massive and long-lasting iron overload had a worse prognosis than patients with less severe iron excess. Iron removal in general ameliorated liver disease, weakness and cardiac abnormalities, and also prevented the progression of endocrine alterations. Therapy, however, did not influence arthropathy which even got worse in several patients. Iron removal also failed to reverse insulin-dependent diabetes. During a mean followup of 13.4 years 69 deaths occurred in the 251 patients. In 19 patients death was due to liver cancer, in 14 due to liver cirrhosis, in 5 due to cardiomyopathy, and in 3 due to diabetes mellitus (all causes significantly more frequent than expected for the general population). The other causes of death were as frequent as expected including extrahepatic malignancies. All liver cancers were seen in cirrhotic livers, but often occurred many years or even decades after complete iron removal. Further strategies have to evaluate the design of screening programs in order to diagnose more patients in the precirrhotic and asymptomatic stage.
Hereditary hemochromatosis is an autosomal recessive disorder, the gene for which occurs in approximately 10% of Americans, most of whom are unaffected heterozygotes. Approximately 5/1000 white Americans are homozygous and at risk of developing severe and potentially lethal hemochromatosis. The disorder affects numerous organ systems, but the most common symptoms are fatigue, palpitations, joint pains, and impotence; the most common signs are those that relate to hypothalamic, cardiac, hepatic or pancreatic dysfunction, including poor cold tolerance, impotence in males, amenorrhea in females, cardiac arrhythmias, dyspnea, edema, hepatosplenomegaly, spider telangiectases, ascites, deformity, swelling or limitation of motion of joints, weight loss, hyperpigmentation. Characteristic abnormalities of laboratory tests include elevated serum iron concentration, high transferrin saturation, elevated serum ferritin concentration, elevated serum transaminases, hyperglycemia and low values for thyroid-stimulating hormone (TSH) and gonadotropins. Death may be the result of cardiac arrhythmia, congestive heart failure, liver failure or liver cancer. Since many of these complications cannot be reversed once they have developed, early diagnosis and treatment are essential. In view of the high prevalence in the American population (prevalence varies with ethnic background), the low cost of diagnosis and treatment, the efficacy of treatment if begun early, and, on the other hand, high costs and low success rate of late diagnosis and treatment, systematic screening for hemochromatosis is warranted for all persons over the age of 20 years. The initial screening should be by measurement of serum iron concentration and transferrin saturation. The practice guideline provides a diagnostic algorithm for cases in which the serum transferrin saturation is 60% or greater. It also provides guidelines for clinical management.
In the past, patients with hereditary hemochromatosis have been identified predominantly from symptomatic presentation or from family studies. In the 1990s, iron studies on routine screening chemistry panels have become more commonplace. The purpose of this paper is to describe the clinical, laboratory, and presenting features of a series of patients with hereditary hemochromatosis, diagnosed from 1990 to 1995.
Clinical information, serum and liver iron studies, liver histology, and phlebotomy requirements were evaluated in 40 patients with newly diagnosed hereditary hemochromatosis prospectively referred to a tertiary university-based hepatology clinic.
Eighty-three percent of patients came to medical attention as a result of screening blood work: 73% were asymptomatic and 78% had normal physical examinations. Only three patients had cirrhosis from hemochromatosis alone, only two were diabetic, and only two had increased skin pigmentation. These findings are in contrast to previous reports of hemochromatosis probands in which patients with symptoms and more advanced disease were identified. The hepatic iron concentration, hepatic iron index, and age at diagnosis were similar for men and women.
With the use of screening iron studies on routine serum chemistry panels, patients with hemochromatosis can be identified and subsequently treated before they have symptoms or organ damage.
Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease. The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing. Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes. Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures a family history of hemochromatosis, or consistent early signs and symptoms of the disease.
Hemochromatosis, which can lead to serious chronic diseases resulting from iron overload, has an estimated prevalence of 50 to 80 cases per 10000 persons. However, little population-based information is available on the impact of hemochromatosis on morbidity and mortality.
To evaluate trends over 14 years in deaths and medical conditions associated with hemochromatosis in the United States.
We searched Multiple-Cause Mortality Files compiled by the National Center for Health Statistics for the years 1979 to 1992 for all records listing hemochromatosis. We used these data to calculate age-adjusted and age-specific mortality rates, identify medical conditions associated with a known diagnosis of hemochromatosis at death, and calculate proportionate mortality ratios for these medical conditions.
The listing of hemochromatosis on death certificates increased 60% from 1979 to 1992. Decedents with hemochromatosis were 23, 13, and 5 times more likely to have liver neoplasms, liver disease, and cardiomyopathy, respectively, than were decedents without hemochromatosis. Conversely, decedents with liver neoplasms, liver disease, and cardiomyopathy were 26, 14, and 5 times more likely, respectively, to have hemochromatosis than were decedents without these conditions. Hemochromatosis was 82 times more likely in persons with the combination of liver neoplasms and diabetes and 43 times more likely in those with the combination of liver disease and diabetes than in those without these conditions.
Comparison of the reported prevalence of hemochromatosis among decedents with estimates of prevalence in the general U.S. population suggests that either the penetrance or the recognition of hemochromatosis, or both, is low. Nevertheless, substantial mortality resulting from liver disease, liver neoplasms, cardiomyopathy, and a combination of liver disease and diabetes in patients with hemochromatosis argues for the improved diagnosis and treatment of hemochromatosis in persons with these conditions.
The discovery of the HFE gene in 1996 has introduced DNA testing as a possible tool for screening and diagnosis of hemochromatosis and increased interest in the disorder. Population screening using transferrin saturation has been advocated by experts to permit early detection and treatment with phlebotomy before the onset of clinical disease.
Based on a literature review, we consider the relative risks and merits of two screening tests as part of a broader look at the evidence required for the recommendation of universal screening for hemochromatosis.
Several questions must be answered before universal screening can be recommended. Uncertainties remain about the penetrance and preventable disease burden, laboratory standardization, and optimal strategies to minimize potential risks of screening for hemochromatosis.
As a common genetic disorder with simple, effective therapy, hemochromatosis offers a model for other genetically influenced chronic diseases that some day may have interventions to improve prognosis. Resolution of questions related to prevention of chronic diseases from hemochromatosis, therefore, will have broad usefulness in the future.
Background —Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated ( HFE ) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study.
Methods and Results —Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1.1 to 4.8; P =0.03) risk of acute myocardial infarction compared with noncarriers.
Conclusions —Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.
Background —The genetic background of hereditary hemochromatosis ( HH ) is homozygosity for a cysteine-to-tyrosine transition at position 282 in the HFE gene. Heterozygosity for HH is associated with moderately increased iron levels and could be a risk factor for cardiovascular death.
Methods and Results —We studied the relation between HH heterozygosity and cardiovascular death in a cohort study among 12 239 women 51 to 69 years of age residing in Utrecht, the Netherlands. Women were followed for 16 to 18 years (182 976 follow-up years). The allele prevalence of the HH gene in the reference group was 4.0 (95% CI 2.9 to 5.4). The mortality rate ratios for HH heterozygotes compared with wild types was 1.5 (95% CI 0.9 to 2.5) for myocardial infarction (n=242), 2.4 (95% CI 1.3 to 3.5) for cerebrovascular disease (n=118), and 1.6 (95% CI 1.1 to 2.4) for total cardiovascular disease (n=530). The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3.3%, 8.8%, and 4.0%, respectively. In addition, we found evidence for effect modification by hypertension and smoking.
Conclusions —We found important evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors.
Results of many studies from around the world have revealed that haemochromatosis is the most prevalent genetic disease in people of European descent. However, it continues to be regarded as an uncommon disease by many physicians and is not listed as a common cause of death. The gene for haemochromatosis was discovered in 1996 and most typical patients are homozygous for the C282Y mutation of the HFE gene.1 Studies using genetic testing have estimated the prevalence to be in the 1:188 to 1:327 range (table1).2-5 The two most likely explanations for the apparent discrepancy between prevalence studies of haemochromatosis and the clinical impression are: ( a ) the failure to consider the diagnosis and to order the appropriate diagnostic tests (underdiagnosis) and ( b ) absence of iron overload and clinical disease in patients homozygous for the haemochromatosis gene (incomplete penetrance).
View this table:
Table 1
Prevalence of haemochromatosis in screening studies using genotyping and phenotyping
The percentage of C282Y homozygotes with iron overload as defined by an increased serum ferritin in population screening studies has ranged from 19% (blood donors) to 75% in the general population (table 1). However, an elevated serum ferritin is not synonymous with the inevitable progression of the disease to cirrhosis, diabetes, heart disease, and other haemochromatosis related morbidity. In a study of patients with haemochromatosis from our hospital, treated at the time of diagnosis and followed over a 30 year period, 43% of men and 28% of women developed life threatening complications.6 This is likely to be an overestimate of the morbidity of haemochromatosis because of a referral bias. A major impediment in the implementation of population screening for haemochromatosis has been this uncertainty about the burden of disease and the natural history of disease in an asymptomatic C282Y homozygote detected by screening. The unique design of the …
Iron, atherosclerosis, and ischemie heart disease [see comments]
- B De Vaik
- Marx
- B De Vaik
- Marx
Descriptive studies In: Mayrent SL, editor. Epidemiology in medicine
- Ch Hennekens
- Buring
- Ch Hennekens
- Buring
After the acceptanc e of this manuscript, the following related publication has come to our attention Penetrance of 845 G ® A (C282Y) HFE hereditary haemochromatosi s mutation in the USA
- E Beutler
- Vj Felitti
- Ja Koziol
- Ho Nj
- Gelbart
NOTE: After the acceptanc e of this manuscript, the following related publication has come to our attention : Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845 G ® A (C282Y) HFE hereditary haemochromatosi s mutation in the USA. Lancet 2002; 359:211–18.
Screening for hemochromatosi s [see comments]
- Edwards Cq Kushner
- Jp
Edwards CQ, Kushner JP. Screening for hemochromatosi s [see comments]. N Engl J Med 1993;328:1616 –20.
Descriptive studies Epidemiology in medicine
- Hennekens Ch Buring
- Je
Hennekens CH, Buring JE. Descriptive studies. In: Mayrent SL, editor. Epidemiology in medicine. Boston: Little Brown; 1987. p. 101–31.
Screening-detecte d Haemochromatosi s spectrum and prognosi s of hemochromatosis
- C Niederau
- G Strohmeyer
- Stremmel
Niederau C, Strohmeyer G, Stremmel W. Epidemiology, clinical Scand J Gastroenterol 2002 (6) Screening-detecte d Haemochromatosi s spectrum and prognosi s of hemochromatosis. Adv Exp Med Biol 1994;356:293 –302.
Genetic and phenotypi c expressio n of hemochromatosi s in Canadians
- Borwein
- St
- Cn Ghent
- Pr Flanagan
- Chamberlain Mj
- Valberg
- Ls
Borwein ST, Ghent CN, Flanagan PR, Chamberlain MJ, Valberg LS. Genetic and phenotypi c expressio n of hemochromatosi s in Canadians. Clin Invest Med 1983;6:171 –9.
Haemochromatosi s in the new millennium
- Powell Lw Subramaniam Vn
- Yapp
- Tr
Powell LW, Subramaniam VN, Yapp TR. Haemochromatosi s in the new millennium. J Hepatol 2000;32:48 –62.
Heterozygosit y for a hereditar y hemochromatosi s gene is associated with cardiovascula r death in women [see comments]
- Roest M Van
- Yt Schouw
- Marx B Jj Valk
- Mj Tempelman
- De
- Pg
Roest M, van der Schouw YT, de Valk B, Marx JJ, Tempelman MJ, de Groot PG, et al. Heterozygosit y for a hereditar y hemochromatosi s gene is associated with cardiovascula r death in women [see comments]. Circulation 1999;100:1268 –73.
Wintrobe's clinical hematology. Baltimore: Williams & Wilkins
- Cq Hemochromatosis Edwards
- Gr Lee
- F Paraskevas
- J Foerster
- Jp Greer
- J Lukem
- Gm Rodgers
Global prevalence of putative haemochromatosi s mutations [see comments]
- At Merryweather-Clarke
- Jj Pointon
- Jd Shearman
- Kj Robson