Background and Methods Hereditary hemochromatosis is associatedwith homozygosity for the C282Y mutation in the hemochromatosis(HFE) gene on chromosome 6, elevated serum transferrin saturation,and excess iron deposits throughout the body. To assess theprevalence and clinical expression of the HFE gene, we conducteda population-based study in Busselton, Australia. In 1994, weobtained blood samples for the determination of serum transferrinsaturation and ferritin levels and the presence or absence ofthe C282Y mutation and the H63D mutation (which may contributeto increased hepatic iron levels) in 3011 unrelated white adults.We evaluated all subjects who had persistently elevated transferrin-saturationvalues (45 percent or higher) or were homozygous for the C282Ymutation. We recommended liver biopsy for subjects with serumferritin levels of 300 ng per milliliter or higher. The subjectswere followed for up to four years.
Results Sixteen of the subjects (0.5 percent) were homozygousfor the C282Y mutation, and 424 (14.1 percent) were heterozygous.The serum transferrin saturation was 45 percent or higher in15 of the 16 who were homozygous; in 1 subject it was 43 percent.Four of the homozygous subjects had previously been given adiagnosis of hemochromatosis, and 12 had not. Seven of these12 patients had elevated serum ferritin levels in 1994; 6 ofthe 7 had further increases in 1998, and 1 had a decrease, althoughthe value remained elevated. The serum ferritin levels in thefour other homozygous patients remained in the normal range.Eleven of the 16 homozygous subjects underwent liver biopsy;3 had hepatic fibrosis, and 1, who had a history of excessivealcohol consumption, had cirrhosis and mild microvesicular steatosis.Eight of the 16 homozygous subjects had clinical findings thatwere consistent with the presence of hereditary hemochromatosis,such as hepatomegaly, skin pigmentation, and arthritis.
Conclusions In a population of white adults of northern Europeanancestry, 0.5 percent were homozygous for the C282Y mutationin the HFE gene. However, only half of those who were homozygoushad clinical features of hemochromatosis, and one quarter hadserum ferritin levels that remained normal over a four-yearperiod.
Hereditary hemochromatosis is a common inherited disorder ofiron metabolism.1,2,3,4 Recently, a new major-histocompatibility-complexclass I–like candidate gene (HFE) for hereditary hemochromatosiscontaining two missense mutations was identified on chromosome6.5 A single mutation (G to A at nucleotide 845) in the HFEgene results in the substitution of tyrosine for cysteine atamino acid 282 and is termed the C282Y mutation. A second mutation(C to G at nucleotide 187) in the HFE gene results in the substitutionof aspartate for histidine at amino acid 63 and is termed theH63D mutation. These mutations are usually detected by restriction-enzymedigestion after amplification of DNA with the polymerase chainreaction (PCR). The C282Y mutation results in the formationof a unique SnaBI restriction site, whereas the H63D mutationresults in the loss of a DpnII site.
Homozygosity for the C282Y mutation is found in 85 to 90 percentof patients of northern European origin who have typical hereditaryhemochromatosis.3,5,6,7,8,9,10,11,12,13,14 Fifteen to 20 percentof the patient population is heterozygous for the H63D mutation.This mutation may contribute to increased hepatic iron levelsbut does not result in iron overload in the absence of the C282Ymutation.3,15,16 The diagnosis of overt hereditary hemochromatosisis usually based on clinical features, elevated serum transferrinsaturation, elevated ferritin levels, characteristic findingson liver biopsy, and elevated hepatic iron levels.17 Measurementof transferrin saturation is the single best screening test.2,18,19,20
The degree to which the hemochromatosis mutation affects thedevelopment of iron overload and clinical disease is unknown.21Recent family studies of subjects of known genotype with hereditaryhemochromatosis have shown that in up to 26 percent of subjectswho are homozygous for the C282Y mutation, iron overload maynot develop.22,23 These studies suggest that rates of expressionof the disease may be variable and lower than previously believed.We conducted a population-based study to determine the prevalenceof the C282Y mutation, the frequency of the clinical expressionof iron overload, and genotype–phenotype correlationsover a four-year period.
Methods
Subjects
Busselton is a town in the southwestern region of Western Australia,with a population of 10,888 in 1994. The residents are predominantlyof Anglo-Celtic descent. They have been prospectively studiedsince 1966 and, in many respects, are similar to the populationof Framingham, Massachusetts.24,25 The most recent follow-upstudy of this population was performed in 1994. At this evaluationof approximately 5000 white subjects, clinical assessment wasperformed and whole-blood and serum samples were obtained whilethe subjects were fasting. From this group, we randomly selecteda sample of 3011 unrelated subjects, 20 to 79 years old. Thepredicted rates of prevalence of heterozygosity and homozygosityfor the C282Y mutation in this sample were 8 percent (95 percentconfidence interval, 7 to 9 percent) and 0.3 percent (95 percentconfidence interval, 0.1 to 0.6 percent), respectively.1
Clinical, biochemical, and genotypic information was collectedfor all the subjects. Only in cases in which the serum transferrinsaturation was elevated (45 percent) were the data on the subjectsreviewed by one of the investigators and the serum iron studiesrepeated while the subjects were fasting. All subjects withpersistently elevated transferrin-saturation values and thosewho were homozygous for the C282Y mutation underwent clinicalevaluation. Liver biopsy was recommended if the serum ferritinlevel was 300 ng per milliliter or higher.
Informed consent was obtained before the biopsies were performed.The Busselton Population Medical Research Foundation and theCommittee for Human Rights at the University of Western Australiagranted us permission to conduct the study.
Measurement of Serum Iron, Transferrin, and Ferritin
Serum iron levels were measured by a standard colorimetric method,and serum transferrin levels were determined by rate immunoturbidimetryon an automated analyzer (model 917, Hitachi, Tokyo, Japan).Serum transferrin-saturation values were calculated as follows:([serum iron÷2] x serum transferrin) x 100. Serum ferritinlevels were measured by chemiluminescence immunoassay (ACS-180,Chiron Diagnostics, Norwood, Mass.). Hepatic iron levels weremeasured as previously described.26
Identification of the C282Y and H63D Mutations in the Hfe Gene
DNA was extracted from spots of whole blood collected on neonatal-typescreening cards, as described by Singer-Sam and Tanguay.27 PCRamplification of the regions containing the missense mutationswas performed with the primer sequences of Feder et al.5 (GenBankaccession number U60319) and the cycling conditions describedby Cullen et al.28 The C282Y and H63D mutations were identifiedwith use of restriction-enzyme digestion, followed by analysison a 3 percent agarose gel. The status of all subjects homozygousfor the C282Y mutation was confirmed with the use of the primersequence of Jeffrey et al.29 Only subjects with a single C282Ymutation or persistently elevated serum iron levels underwentgenotyping for the H63D mutation.
Statistical Analysis
All values are presented as means ±SD unless otherwisespecified. Comparisons between groups were made with the Mann–WhitneyU test.30 All P values are two-tailed.
Results
Characteristics of the Subjects
The age and sex of the subjects are shown in Table 1. Therewere 1491 women and 1520 men, with an age range of 20 to 79years. Four subjects (two men and two women) were being treatedfor hemochromatosis at the time of the study.
The frequency distributions of the serum transferrin-saturationvalues and serum ferritin levels are shown in Figure 1. Theserum transferrin saturation had a normal distribution in bothmen and women, whereas the serum ferritin levels had a skeweddistribution. One hundred thirty-five men and 57 women had transferrin-saturationvalues of 45 percent or higher; 343 men and 62 women had ferritinlevels of 300 ng per milliliter or higher. Forty men and sixwomen had both serum transferrin-saturation values of 45 percentor higher and serum ferritin levels of 300 ng per milliliteror higher.
Figure 1. Frequency Distributions of Transferrin-Saturation (Panel A) and Ferritin Levels (Panel B) in Blood Samples Obtained from the Busselton, Australia, Population in 1994.
Each bar represents cumulative data for the preceding 10-percent range for transferrin saturation or the preceding 50-ng-per-milliliter range for ferritin.
Hemochromatosis Genotypes
The prevalence rates for the C282Y and H63D mutations are shownin Table 2 and Table 3. Subjects were grouped according to whetheror not they had serum transferrin-saturation values of 45 percentor higher (Table 2) and whether or not they had serum ferritinlevels of 300 ng per milliliter or higher (Table 3). There were16 subjects with the C282Y/C282Y genotype (0.5 percent), 359with the C282Y/wild-type genotype (11.9 percent), and 65 withthe C282Y/H63D genotype (2.2 percent). The remaining 2571 subjectsdid not have the C282Y mutation (those with the wild-type/wild-typegenotype).
Table 3. Prevalence of Elevated Serum Ferritin Level (300 ng per milliliter) in 1994, According to the Hemochromatosis Genotype.
Of the 192 subjects with transferrin-saturation values of 45percent or higher in 1994, 15 had the C282Y/C282Y genotype,38 had the C282Y/wild-type genotype, 14 had the C282Y/H63D genotype,and 125 had the wild-type/wild-type genotype (Table 2). In 1994,one 53-year-old homozygous man had a serum transferrin-saturationvalue of 43 percent and a serum ferritin level of 647 ng permilliliter; in 1998, he had a serum transferrin-saturation valueof 102 percent and a serum ferritin level of 731 ng per milliliter(Subject 1, Table 4). He had no history of blood donation orblood loss at the time of the initial testing.
Table 4. Clinical Characteristics of the Subjects Who Were Homozygous for the C282Y Mutation.
Only 35 of the 192 subjects with elevated transferrin-saturationvalues in 1994 had persistently elevated transferrin-saturationvalues. Of these 35, 15 had the C282Y/C282Y genotype (Subjects2 through 16 in Table 4), 5 had the C282Y/wild-type genotype,1 had the C282Y/H63D genotype, and 14 had the wild-type/wild-typegenotype. Thus, the sensitivity, specificity, and positive predictivevalue of a single serum transferrin-saturation value of 45 percentor higher (measured while the subject was fasting) for the detectionof C282Y homozygosity were 94 percent, 94 percent, and 6 percent,respectively.
Of the 405 subjects who had serum ferritin levels of 300 ngper milliliter or higher in 1994, 8 had the C282Y/C282Y genotype,47 had the C282Y/wild-type genotype, 22 had the C282Y/H63D genotype,and 328 did not have the C282Y mutation (Table 3). Thus, thesensitivity, specificity, and positive predictive value of aserum ferritin level of 300 ng per milliliter or higher forthe detection of C282Y homozygosity were 50 percent, 87 percent,and 2 percent, respectively. When the four subjects who wereundergoing treatment for hemochromatosis at the time of thestudy were excluded from the analysis of serum ferritin levels,the sensitivity, specificity, and positive predictive valuewere 75 percent, 87 percent, and 2 percent, respectively. Ninesubjects had a persistently elevated serum ferritin level (300ng per milliliter or higher) and a serum transferrin-saturationvalue of 45 percent or less.
Serum Iron Levels, Sex, and Genotype
Men and women with the C282Y/H63D genotype had significantlyhigher serum transferrin-saturation values (41±15 percentand 36±11 percent, respectively) than men and women witheither the C282Y/wild-type genotype (32±11 percent and28±12 percent, respectively) or the wild-type/wild-typegenotype (30±11 percent and 26±14 percent, respectively;P<0.001). Men with the C282Y/H63D genotype had significantlyhigher serum ferritin levels (351±191 ng per milliliter)than men with the C282Y/wild-type genotype (217±173 ngper milliliter) or the wild-type/wild-type genotype (221±263 ng per milliliter, P<0.001). There was a trend towardhigher serum ferritin levels in women with the C282Y/H63D genotypethan in those with the C282Y/wild-type or wild-type/wild-typegenotype (P=0.07). Men and women who were homozygous for theC282Y mutation had similar serum transferrin-saturation values(80±24 percent and 70±16 percent, respectively);the serum ferritin levels in the men were higher than thosein the women but were not significantly different (609±55ng per milliliter and 334±387 ng per milliliter, respectively).
Clinical Characteristics of the Subjects Who Were Homozygous for the C282Y Mutation
Of the 16 subjects with the C282Y/C282Y genotype, 12 had notpreviously received a diagnosis of hemochromatosis (Table 4).In 1994, 7 of these 12 subjects had elevated serum ferritinlevels (300 ng per milliliter or higher); 6 of these 7 (Subjects1, 2, 7, 8, 9, and 10) had further increases during the four-yearfollow-up period, and 1 (Subject 4) had a decrease althoughthe value remained elevated. Four subjects (Subjects 3, 5, 11,and 12) had normal serum ferritin levels that did not increasesubstantially during the four-year follow-up period; none hada history of blood donation, gastrointestinal bleeding, or malabsorptionof food. Two subjects without an increase in serum ferritinlevels over the four-year period (Subjects 4 and 5) had hepaticiron levels above the normal range (reference range in our laboratory,20 µmol per gram of liver, dry weight).
Clinical features that are consistent with the diagnosis ofhereditary hemochromatosis were present at the time of diagnosisin 8 of the 16 subjects. Eleven of the 16 underwent liver biopsy.Three of the five who did not (Subjects 3, 11, and 12) did notmeet the criteria for liver biopsy and had serum ferritin levelsof 100 ng per milliliter or less. Two subjects (Subjects 6 and9) met the criteria for liver biopsy but declined to undergothe procedure. All subjects who underwent liver biopsy had ahepatic iron level above the upper limit of the normal range.Three subjects had a hepatic iron index of 1.9 or less (Subjects1, 4, and 5). Three subjects had hepatic fibrosis, and one hadcirrhosis; the patient with cirrhosis also had mild microvascularsteatosis and a history of excessive alcohol consumption (>60g per day). None of the other homozygous subjects had a historyof chronic viral hepatitis or excessive alcohol consumption.
Clinical Characteristics of the Subjects with Elevated Iron Levels Who Were Not Homozygous for the C282Y Mutation
Eleven subjects who were not homozygous for the C282Y mutationhad serum transferrin-saturation values of 45 percent or higherand serum ferritin levels of 300 ng per milliliter or higher.Two of these subjects had recognizable clinical conditions resultingin elevated iron levels: one subject, who was 69 years old andhad the C282Y/wild-type genotype, had myelofibrosis, and one,who was 66 years old and had the wild-type/wild-type genotype,had chronic lymphocytic leukemia. Of the other nine subjects,three between the ages of 38 and 54 years (one with the C282Y/H63Dgenotype, one with the C282Y/wild-type genotype, and one withthe wild-type/wild-type genotype) had grade 3 hepatic iron deposition(defined as 75 to 100 percent of hepatocytes with stainableiron deposits31) without fibrosis and are currently undergoingphlebotomy therapy. Two subjects who were 66 and 71 years ofage (one with the C282Y/wild-type genotype and one with thewild-type/wild-type genotype) had no stainable iron or evidenceof liver injury. One 77-year-old subject with the wild-type/wild-typegenotype declined to undergo liver biopsy and is undergoingphlebotomy therapy. Six of the nine subjects with elevated ironlevels had the wild-type/wild-type genotype, and all had historiesof excessive alcohol consumption. Thus, the overall prevalenceof clinically significant iron overload among the subjects whowere not homozygous for the C282Y mutation and who did not haveother conditions causing iron overload was 4 in 2995 (0.13 percent).In nine subjects (seven with the wild-type/wild-type genotypeand two with the C282Y/wild-type genotype) the serum transferrin-saturationvalues were 45 percent or higher and the serum ferritin levelswere normal. There was no identifiable cause of the overloadin eight of these subjects; one had chronic lymphocytic leukemiaand consumed an excessive amount of alcohol. In nine subjects(five with the wild-type/wild-type genotype and four with theC282Y/wild-type genotype) the serum ferritin levels were 300ng per milliliter or higher and the serum transferrin-saturationvalues were 45 percent or less. Three had histories of excessivealcohol consumption, and one had chronic lymphocytic leukemia.
Discussion
We evaluated the penetrance of the C282Y mutation in the HFEgene in a population study that was not based on blood-bankdata. In our sample of 3011 white Australians, 0.5 percent ofthe subjects were homozygous for the mutation. Twelve percenthad the C282Y/wild-type genotype, and 2 percent had the C282Y/H63Dgenotype. The frequency of heterozygosity for the C282Y mutationin our sample (0.141) was consistent with the frequency thatwould be predicted with the Hardy–Weinberg equation (0.135),on the basis of an allelic frequency of 0.076 for the C282Ymutation. These prevalence rates for the C282Y mutation areamong the highest that have been reported.2,28,32 There is noevidence of consanguinity in this population, and it has beenstable, with minimal migration in or out of the region overa period of 30 years.
All 16 subjects with the C282Y/C282Y genotype had elevated serumtransferrin-saturation values or serum ferritin levels, andall the subjects with this mutation who underwent liver biopsyhad hepatic iron levels above the upper limit of the normalrange. However, only 8 of the 16 subjects had clinical featuresof hemochromatosis, and 4 had hepatic fibrosis or cirrhosis.Four subjects had no clinical symptoms or signs of disease,and their serum ferritin levels were normal over the four-yearfollow-up period.
Sixty percent of the subjects with newly diagnosed hemochromatosishad an increase in iron stores over the four-year follow-upperiod, as demonstrated by the changes in their serum ferritinlevels. Four women (between the ages of 30 and 45 years) didnot have elevated ferritin levels. These data are consistentwith the findings reported by Crawford et al.22; up to 30 percentof the women in their study who were homozygous for the C282Ymutation did not have iron overload.
Eleven subjects in our study had elevated serum transferrin-saturationand ferritin levels but were not homozygous for the C282Y mutation;4 of the 11 had evidence of hepatic iron overload and are undergoingphlebotomy treatment. An additional nine subjects had elevatedferritin levels but normal serum transferrin-saturation values.These subjects may have disordered iron metabolism, which hasbeen termed the "dysmetabolic iron overload syndrome,"33 ortheir high ferritin levels may be due to an acute-phase reactant.
The C282Y/H63D genotype (compound heterozygosity) was associatedwith higher serum iron levels than the C282Y/wild-type or thewild-type/wild-type genotype. These data provide further supportfor a synergistic interaction between the two mutations.3,15,16
Our data confirm and extend the recent reports of McLaren etal.20 and Burt et al.2 and indicate that serum transferrin saturationis a more sensitive biochemical marker than the serum ferritinlevel for the detection of the C282Y mutation. The sensitivity,specificity, and positive predictive value of serum transferrinsaturation for the detection of the homozygous C282Y mutationwere 94 percent, 94 percent, and 6 percent, respectively. Ifthe threshold level for serum transferrin saturation had beenset at 50 percent, the sensitivity, specificity, and positivepredictive value would have been 94 percent, 96 percent, and16 percent, respectively. Since the serum ferritin level closelyreflects total-body iron stores, however, and since one subjectwho was homozygous for the C282Y mutation would not have beenidentified if we had relied only on serum transferrin saturationas a screening test, we recommend that the initial screeningalso include measurement of the serum ferritin level.34
McLaren et al.20 predicted that a serum transferrin-saturationvalue of 45 percent or higher, obtained while the subject wasfasting, would identify 98 percent of subjects with homozygoushemochromatosis but no normal subjects. In their control population,none of the subjects had a serum transferrin-saturation valueof 45 percent or higher. In contrast, we found that 0.5 percentof subjects with the wild-type/wild-type genotype had serumtransferrin-saturation values above 45 percent. The cause ofthis discrepancy is not clear but could be related to differencesin the populations studied. The population studied by McLarenet al. was composed of employees of banks and insurance companies,whereas our sample was drawn from the general population andhad a wider age range.
Five of the 12 subjects with newly diagnosed homozygous hemochromatosishad no significant changes in serum transferrin-saturation valuesor serum ferritin levels over the four-year study period (Subjects3, 4, 5, 11, and 12). Two of these subjects (a woman who was45 years old and a man who was 74) underwent liver biopsy, andboth were found to have a hepatic iron index below the thresholdof 1.9. The man had hepatic fibrosis. The other three subjectshad no symptoms or signs of disease and had serum ferritin levelsof 100 ng per milliliter or lower; none of them underwent liverbiopsy. Although all the women in this group had normal menstrualcycles, two had excessive postpartum bleeding. Iron overloaddevelops at a slower rate in women with hereditary hemochromatosisthan in men with the disorder, because in women iron storesare reduced during menstruation and pregnancy.34
A cross-sectional study is limited to the evaluation of dataat specific times. Since hemochromatosis is a disease that changesphenotypically with time, we used initial screening informationfrom 1994; the subjects with abnormal test results were evaluatedfour years later. This study design eliminated ethical issuesthat would have arisen if this had been a prospective study.Although a four-year follow-up period is likely to be adequatefor the assessment of a progressive increase in iron stores,as determined by measurements of serum ferritin levels,33 itis possible that in some subjects iron overload progressed ata rate that was too slow to be detected after four years becauseof physiologic or pathologic blood loss or other factors.
Our findings have implications for population screening forhereditary hemochromatosis and for identifying the most appropriateinitial test. In our view, the high prevalence of the disorderand the opportunity to detect early phenotypic expression andto intervene and prevent subsequent disease justify routinescreening of asymptomatic white people of northern Europeanancestry. The findings of our study demonstrate that biochemicalscreening for hereditary hemochromatosis identifies virtuallyall adults who are homozygous for the C282Y mutation and whohave iron overload. Alternatively, genetic screening could beperformed at birth, with biochemical follow-up of persons withthe homozygous mutation and those with the compound heterozygousmutation, in order to identify those who would require treatment.If hemochromatosis is detected before the age of 40 years andif the serum ferritin level is less than 1000 ng per milliliter,then hepatic fibrosis is very likely to be absent and treatmentcan be initiated without the need for liver biopsy.3,15,35,36
Supported by grants from the Gastroenterology Research TrustFund at Fremantle Hospital and the National Health and MedicalResearch Council of Australia.
We are indebted to Tina Glassick, Anna Zounarzi, Heidi Marshall,Lara Cullen, and Fran Busfield for their assistance in performingthe genotyping; to the Busselton Population Medical ResearchFoundation for their invaluable cooperation; and to Drs. GeorgePapadopolous, Brendan Murphy, Alison Ross, and Luca Crostellafor their assistance.
Source Information
From the Department of Medicine, University of Western Australia, Fremantle (J.K.O.); the Department of Gastroenterology, Fremantle Hospital, Fremantle (J.K.O., D.J.C., S.A.); the Busselton Population Medical Research Foundation, Perth (D.J.C.); the Pathcentre, Queen Elizabeth II Medical Centre, Nedlands (E.R.); and the Queensland Institute of Medical Research and the University of Queensland, Brisbane (L.S., L.W.P.) — all in Australia.
Address reprint requests to Dr. Olynyk at the University Department of Medicine, P.O. Box 480, Fremantle 6959, Western Australia, Australia, or at jolynyk{at}cyllene.uwa.edu.au.
Burt MJ, George PM, Upton JD, et al. The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut 1998;43:830-836. [Free Full Text]
Bacon BR, Powell LW, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and hemochromatosis: at the crossroads. Gastroenterology 1999;116:193-207. [CrossRef][Medline]
Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-1119. [CrossRef][Medline]
Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408. [CrossRef][Medline]
Beutler E, Gelbart T, West C, et al. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 1996;22:187-194. [CrossRef][Medline]
Barton JC, Shih WW, Sawada-Hirai R, et al. Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis. Blood Cells Mol Dis 1997;23:135-145. [CrossRef][Medline]
Adams PC, Campion ML, Gandon G, LeGall JY, David V, Jouanolle AM. Clinical and family studies in genetic hemochromatosis: microsatellite and HFE studies in five atypical families. Hepatology 1997;26:986-990. [CrossRef][Medline]
The UK Haemochromatosis Consortium. A simple genetic test identifies 90% of UK patients with haemochromatosis. Gut 1997;41:841-844. [Free Full Text]
Borot N, Roth M-P, Malfroy L, et al. Mutations in the MHC class I-like candidate gene for hemochromatosis in French patients. Immunogenetics 1997;45:320-324. [CrossRef][Medline]
Carella M, D'Ambrosio L, Totaro A, et al. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet 1997;60:828-832. [Medline]
Cardoso EMP, Stal P, Hagen K, et al. HFE mutations in patients with hereditary hemochromatosis in Sweden. J Intern Med 1998;243:203-208. [CrossRef][Medline]
Rossi E, Henderson S, Chin CY, et al. Genotyping as a diagnostic aid in genetic haemochromatosis. J Gastroenterol Hepatol 1999;14:427-430. [CrossRef][Medline]
Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK. HFE genotype in patients with hemochromatosis and in patients with liver disease. Ann Intern Med 1999;130:953-962. [Free Full Text]
Moirand R, Jouanolle AM, Brissot P, Le Gall JY, David V, Deugnier Y. Phenotypic expression of HFE mutations: a French study of 1110 unrelated iron-overloaded patients and relatives. Gastroenterology 1999;116:372-377. [CrossRef][Medline]
Olynyk JK, Bacon BR. Hereditary hemochromatosis: detecting and correcting iron overload. Postgrad Med 1994;96:151-8, 161, 165.
Bassett ML, Halliday JW, Bryant S, Dent O, Powell LW. Screening for hemochromatosis. Ann N Y Acad Sci 1988;526:274-289. [Medline]
Beilby J, Olynyk J, Ching S, et al. Transferrin index: an alternative method for calculating the iron saturation of transferrin. Clin Chem 1992;38:2078-2081. [Abstract]
McLaren CE, McLachlan GJ, Halliday JW, et al. Distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of hemochromatosis. Gastroenterology 1998;114:543-549. [CrossRef][Medline]
Powell LW, Summers KM, Board PG, Axelsen E, Webb S, Halliday JW. Expression of hemochromatosis in homozygous subjects: implications for early diagnosis and prevention. Gastroenterology 1990;98:1625-1632. [Medline]
Crawford DH, Jazwinska EC, Cullen LM, Powell LW. Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation. Gastroenterology 1998;114:1003-1008. [CrossRef][Medline]
Adams PC, Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology 1998;114:319-323. [CrossRef][Medline]
Welborn TA, Curnow DH, Wearne JT, Cullen KJ, McCall MG, Stenhouse NS. Diabetes detected by blood-sugar measurement after a glucose load: report from the Busselton survey, 1966. Med J Aust 1968;2:778-783. [Medline]
Knuiman MW, Vu HT. Prediction of coronary heart disease mortality in Busselton, Western Australia: an evaluation of the Framingham, national health epidemiologic follow up study, and WHO ERICA risk scores. J Epidemiol Community Health 1997;51:515-519. [Free Full Text]
Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 1986;6:24-29. [Medline]
Use of chelex to improve the PCR signal from a small number of cells. In: Singer-Sam J, Tanguay R. Amplifications, a forum for PCR users. Issue 3. 1989.
Cullen LM, Summerville L, Glassick TV, Crawford DH, Powell LW, Jazwinska EC. Neonatal screening for the hemochromatosis defect. Blood 1997;90:4236-4237. [Free Full Text]
Jeffrey GP, Chakrabarti S, Megele RA, Adams PC. Polymorphism in intron 4 of HFE may cause overestimation of C282Y homozygote prevalence in haemochromatosis. Nat Genet (in press).
Snedecor GW, Cochran WG. Statistical methods. 6th ed. Ames: Iowa State University Press, 1967.
Searle J, Kerr JRF, Halliday JW, Powell LW. Iron storage disease. In: MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portmann BC, eds. Pathology of the liver. London: Churchill Livingstone, 1994:224.
Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet 1997;34:275-278. [Free Full Text]
Mendler MH, Moirand R, Turlin B, et al. Study of HFE mutations in the "dysmetabolic iron overload syndrome." Hepatology 1998;28:Suppl:419A-419A.abstract
Powell LW, Jazwinska E, Halliday JW. Primary iron overload. In: Brock JH, Halliday JW, Pippard MJ, Powell LW, eds. Iron metabolism in health and disease. London: Saunders, 1994:227-70.
Burke W, Thomson E, Khoury MJ, et al. Hereditary hemochromatosis: gene discovery and its implications for population-based screening. JAMA 1998;280:172-178. [Free Full Text]
Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998;115:929-936. [CrossRef][Medline]
Rogowski, W. H.
(2009). The Cost-Effectiveness of Screening for Hereditary Hemochromatosis in Germany: A Remodeling Study. Med Decis Making
29: 224-238
[Abstract]
Ajioka, R. S., Phillips, J. D., Weiss, R. B., Dunn, D. M., Smit, M. W., Proll, S. C., Katze, M. G., Kushner, J. P.
(2008). Down-regulation of hepcidin in porphyria cutanea tarda. Blood
112: 4723-4728
[Abstract][Full Text]
Nagayoshi, Y., Nakayama, M., Suzuki, S., Hokamaki, J., Shimomura, H., Tsujita, K., Fukuda, M., Yamashita, T., Nakamura, Y., Sugiyama, S., Ogawa, H.
(2008). A Q312X mutation in the hemojuvelin gene is associated with cardiomyopathy due to juvenile haemochromatosis. Eur J Heart Fail
10: 1001-1006
[Abstract][Full Text]
Davis, T. M.E., Beilby, J., Davis, W. A., Olynyk, J. K., Jeffrey, G. P., Rossi, E., Boyder, C., Bruce, D. G.
(2008). Prevalence, Characteristics, and Prognostic Significance of HFE Gene Mutations in Type 2 Diabetes: The Fremantle Diabetes Study. Diabetes Care
31: 1795-1801
[Abstract][Full Text]
Cooper, K., Bryant, J., Picot, J., Clegg, A., Roderick, P.R., Rosenberg, W.M., Patch, C.
(2008). A decision analysis model for diagnostic strategies using DNA testing for hereditary haemochromatosis in at risk populations. QJM
101: 631-641
[Abstract][Full Text]
Milward, E. A., Baines, S. K., Knuiman, M. W., Bartholomew, H. C., Divitini, M. L., Ravine, D. G., Bruce, D. G., Olynyk, J. K.
(2008). Noncitrus Fruits as Novel Dietary Environmental Modifiers of Iron Stores in People With or Without HFE Gene Mutations. Mayo Clin Proc.
83: 543-549
[Abstract][Full Text]
Wood, M. J., Powell, L. W., Ramm, G. A.
(2008). Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood
111: 4456-4462
[Abstract][Full Text]
Allen, K. J., Gurrin, L. C., Constantine, C. C., Osborne, N. J., Delatycki, M. B., Nicoll, A. J., McLaren, C. E., Bahlo, M., Nisselle, A. E., Vulpe, C. D., Anderson, G. J., Southey, M. C., Giles, G. G., English, D. R., Hopper, J. L., Olynyk, J. K., Powell, L. W., Gertig, D. M.
(2008). Iron-Overload-Related Disease in HFE Hereditary Hemochromatosis. NEJM
358: 221-230
[Abstract][Full Text]
Bacon, B. R., Britton, R. S.
(2008). Clinical Penetrance of Hereditary Hemochromatosis. NEJM
358: 291-292
[Full Text]
Piperno, A., Girelli, D., Nemeth, E., Trombini, P., Bozzini, C., Poggiali, E., Phung, Y., Ganz, T., Camaschella, C.
(2007). Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood
110: 4096-4100
[Abstract][Full Text]
(2007). Brown and Black Scaly Patches on the Lower Leg Diagnosis. Arch Dermatol
143: 1441-1446
[Full Text]
Alizadeh, B Z, Njajou, O T, Hazes, J M W, Hofman, A, Slagboom, P E, Pols, H A P, van Duijn, C M
(2007). The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis. Ann Rheum Dis
66: 1436-1442
[Abstract][Full Text]
Thursz, M.
(2007). Iron, haemochromatosis and thalassaemia as risk factors for fibrosis in hepatitis C virus infection. Gut
56: 613-614
[Full Text]
McCullough, K. D., Bartfay, W. J.
(2007). The Dose-Dependent Effects of Chronic Iron Overload on the Production of Oxygen Free Radicals and Vitamin E Concentrations in the Liver of a Murine Model. Biol Res Nurs
8: 300-304
[Abstract]
Sutedja, N. A., Sinke, R. J., Van Vught, P. W. J., Van der Linden, M. W., Wokke, J. H. J., Van Duijn, C. M., Njajou, O. T., Van der Schouw, Y. T., Veldink, J. H., Van den Berg, L. H.
(2007). The Association Between H63D Mutations in HFE and Amyotrophic Lateral Sclerosis in a Dutch Population. Arch Neurol
64: 63-67
[Abstract][Full Text]
Ma, A. D., Udden, M. M.
(2007). Iron metabolism, iron overload, and the porphyrias. ASH-SAP
2007: 61-77
[Full Text]
Chung, R. T., Misdraji, J., Sahani, D. V.
(2006). Case 33-2006 -- A 43-Year-Old Man with Diabetes, Hypogonadism, Cirrhosis, Arthralgias, and Fatigue. NEJM
355: 1812-1819
[Full Text]
Whitlock, E. P., Garlitz, B. A., Harris, E. L., Beil, T. L., Smith, P. R.
(2006). Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force.. ANN INTERN MED
145: 209-223
[Abstract][Full Text]
Krayenbuehl, P.-A., Maly, F. E., Hersberger, M., Wiesli, P., Himmelmann, A., Eid, K., Greminger, P., Vetter, W., Schulthess, G.
(2006). Tumor Necrosis Factor-{alpha} -308G>A Allelic Variant Modulates Iron Accumulation in Patients with Hereditary Hemochromatosis. Clin. Chem.
52: 1552-1558
[Abstract][Full Text]
Vantyghem, M.-C., Fajardy, I., Dhondt, F., Girardot, C., D'Herbomez, M., Danze, P.-M., Rousseaux, J., Wemeau, J.-L.
(2006). Phenotype and HFE genotype in a population with abnormal iron markers recruited from an Endocrinology Department.. Eur J Endocrinol
154: 835-841
[Abstract][Full Text]
Lecube, A., Hernandez, C., Genesca, J., Simo, R.
(2006). Proinflammatory Cytokines, Insulin Resistance, and Insulin Secretion in Chronic Hepatitis C patients: A case-control study. Diabetes Care
29: 1096-1101
[Abstract][Full Text]
Powell, L. W., Dixon, J. L., Ramm, G. A., Purdie, D. M., Lincoln, D. J., Anderson, G. J., Subramaniam, V. N., Hewett, D. G., Searle, J. W., Fletcher, L. M., Crawford, D. H., Rodgers, H., Allen, K. J., Cavanaugh, J. A., Bassett, M. L.
(2006). Screening for hemochromatosis in asymptomatic subjects with or without a family history.. Arch Intern Med
166: 294-301
[Abstract][Full Text]
Goland, S., Malnick, S. D., Ellervik, C., Nordestgaard, B. G., Tybjaerg-Hansen, A., Grande, P., Tybjaerg-Hansen, A., Appleyard, M., Nordestgaard, B. G.
(2006). Letter Regarding Article by Ellervik et al, "Hereditary Hemochromatosis and Risk of Ischemic Heart Disease: A Prospective Study and a Case-Control Study" * Response. Circulation
113: e10-e10
[Full Text]
Camaschella, C.
(2005). Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood
106: 3710-3717
[Abstract][Full Text]
Qaseem, A., Aronson, M., Fitterman, N., Snow, V., Weiss, K. B., Owens, D. K., for the Clinical Efficacy Assessment Subcommittee,
(2005). Screening for Hereditary Hemochromatosis: A Clinical Practice Guideline from the American College of Physicians. ANN INTERN MED
143: 517-521
[Abstract][Full Text]
Schmitt, B., Golub, R. M., Green, R.
(2005). Screening Primary Care Patients for Hereditary Hemochromatosis with Transferrin Saturation and Serum Ferritin Level: Systematic Review for the American College of Physicians. ANN INTERN MED
143: 522-536
[Abstract][Full Text]
Stickel, F., Osterreicher, C. H., Datz, C., Ferenci, P., Wolfel, M., Norgauer, W., Kraus, M. R., Wrba, F., Hellerbrand, C., Schuppan, D.
(2005). Prediction of Progression to Cirrhosis by a Glutathione S-Transferase P1 Polymorphism in Subjects With Hereditary Hemochromatosis. Arch Intern Med
165: 1835-1840
[Abstract][Full Text]
Chan, A. T., Ma, J., Tranah, G. J., Giovannucci, E. L., Rifai, N., Hunter, D. J., Fuchs, C. S.
(2005). Hemochromatosis Gene Mutations, Body Iron Stores, Dietary Iron, and Risk of Colorectal Adenoma in Women. JNCI J Natl Cancer Inst
97: 917-926
[Abstract][Full Text]
Robinson, J. P., Johnson, V. L., Rogers, P. A., Houlston, R. S., Maher, E. R., Bishop, D.T., Evans, D.G. R., Thomas, H. J.W., Tomlinson, I. P.M., Silver, A. R.J., Colorectal Cancer Gene Identification (CORGI) cons,
(2005). Evidence for an Association between Compound Heterozygosity for Germ Line Mutations in the Hemochromatosis (HFE) Gene and Increased Risk of Colorectal Cancer. Cancer Epidemiol. Biomarkers Prev.
14: 1460-1463
[Abstract][Full Text]
Krayenbuehl, P.-A., Walczyk, T., Schoenberg, R., von Blanckenburg, F., Schulthess, G.
(2005). Hereditary hemochromatosis is reflected in the iron isotope composition of blood. Blood
105: 3812-3816
[Abstract][Full Text]
Cadet, E, Capron, D, Gallet, M, Omanga-Leke, M-L, Boutignon, H, Julier, C, Robson, K J H, Rochette, J
(2005). Reverse cascade screening of newborns for hereditary haemochromatosis: a model for other late onset diseases?. J. Med. Genet.
42: 390-395
[Abstract][Full Text]
Adams, P. C., Reboussin, D. M., Barton, J. C., McLaren, C. E., Eckfeldt, J. H., McLaren, G. D., Dawkins, F. W., Acton, R. T., Harris, E. L., Gordeuk, V. R., Leiendecker-Foster, C., Speechley, M., Snively, B. M., Holup, J. L., Thomson, E., Sholinsky, P., the Hemochromatosis and Iron Overload Screening (H,
(2005). Hemochromatosis and Iron-Overload Screening in a Racially Diverse Population. NEJM
352: 1769-1778
[Abstract][Full Text]
Valenti, L, Conte, D, Piperno, A, Dongiovanni, P, Fracanzani, A L, Fraquelli, M, Vergani, A, Gianni, C, Carmagnola, L, Fargion, S
(2004). The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis. J. Med. Genet.
41: 946-950
[Abstract][Full Text]
Lecube, A., Hernandez, C., Genesca, J., Esteban, J. I., Jardi, R., Garcia, L., Simo, R.
(2004). Diabetes Is the Main Factor Accounting for the High Ferritin Levels Detected in Chronic Hepatitis C Virus Infection. Diabetes Care
27: 2669-2675
[Abstract][Full Text]
Hunt, J. R, Zeng, H.
(2004). Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis. Am. J. Clin. Nutr.
80: 924-931
[Abstract][Full Text]
Palka, P., Lange, A., Atherton, J., Stafford, W. J., Burstow, D. J.
(2004). Biventricular diastolic behaviour in patients with hypertrophic and hereditary hemochromatosis cardiomyopathies. Eur J Echocardiogr
5: 356-366
[Abstract][Full Text]
Chua, A. C. G., Olynyk, J. K., Leedman, P. J., Trinder, D.
(2004). Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis. Blood
104: 1519-1525
[Abstract][Full Text]
Davis, M. T., Bartfay, W. J.
(2004). Ebselen Decreases Oxygen Free Radical Production and Iron Concentrations in the Hearts of Chronically Iron-Overloaded Mice. Biol Res Nurs
6: 37-45
[Abstract]
Pietrangelo, A.
(2004). Hereditary Hemochromatosis -- A New Look at an Old Disease. NEJM
350: 2383-2397
[Full Text]
Lanzara, C., Roetto, A., Daraio, F., Rivard, S., Ficarella, R., Simard, H., Cox, T. M., Cazzola, M., Piperno, A., Gimenez-Roqueplo, A.-P., Grammatico, P., Volinia, S., Gasparini, P., Camaschella, C.
(2004). Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood
103: 4317-4321
[Abstract][Full Text]
Andersen, R. V., Tybjaerg-Hansen, A., Appleyard, M., Birgens, H., Nordestgaard, B. G.
(2004). Hemochromatosis mutations in the general population: iron overload progression rate. Blood
103: 2914-2919
[Abstract][Full Text]
Miranda, C. J., Makui, H., Andrews, N. C., Santos, M. M.
(2004). Contributions of {beta}2-microglobulin-dependent molecules and lymphocytes to iron regulation: insights from HfeRag1-/- and {beta}2mRag1-/- double knock-out mice. Blood
103: 2847-2849
[Abstract][Full Text]
Olynyk, J. K., Hagan, S. E., Cullen, D. J., Beilby, J., Whittall, D. E.
(2004). Evolution of Untreated Hereditary Hemochromatosis in the Busselton Population: A 17-Year Study. Mayo Clin Proc.
79: 309-313
[Abstract]
McDonnell, S. M., Parrish, R. G.
(2003). Hereditary Hemochromatosis and Its Elusive Natural History. Arch Intern Med
163: 2421-2423
[Full Text]
Dubois, S., Kowdley, K. V.
(2003). The Importance of Screening for Hemochromatosis. Arch Intern Med
163: 2424-2426
[Full Text]
Scotet, V., Merour, M.-C., Mercier, A.-Y., Chanu, B., Le Faou, T., Raguenes, O., Le Gac, G., Mura, C., Nousbaum, J.-B., Ferec, C.
(2003). Hereditary Hemochromatosis: Effect of Excessive Alcohol Consumption on Disease Expression in Patients Homozygous for the C282Y Mutation. Am J Epidemiol
158: 129-134
[Abstract][Full Text]
Stuart, K A, Anderson, G J, Frazer, D M, Powell, L W, McCullen, M, Fletcher, L M, Crawford, D H G
(2003). Duodenal expression of iron transport molecules in untreated haemochromatosis subjects. Gut
52: 953-959
[Abstract][Full Text]
Fruchon, S., Bensaid, M., Borot, N., Roth, M.-P., Coppin, H.
(2003). Use of Denaturing HPLC and a Heteroduplex Generator to Detect the HFE C282Y Mutation Associated with Genetic Hemochromatosis. Clin. Chem.
49: 822-824
[Full Text]
Surber, R, Sigusch, H H, Kuehnert, H, Figulla, H R
(2003). Haemochromatosis (HFE) gene C282Y mutation and the risk of coronary artery disease and myocardial infarction: a study in 1279 patients undergoing coronary angiography. J. Med. Genet.
40: e58-58
[Full Text]
Ferenci, P
(2003). How to identify the genetic basis of gastrointestinal and liver diseases?. Gut
52: ii6-9
[Abstract][Full Text]
Beutler, E.
(2003). The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis. Blood
101: 3347-3350
[Full Text]
Ajioka, R. S., Kushner, J. P.
(2003). Clinical consequences of iron overload in hemochromatosis homozygotes. Blood
101: 3351-3353
[Full Text]
Beutler, E.
(2003). Rebuttal to Ajioka and Kushner. Blood
101: 3354-3357
[Full Text]
Shaheen, N. J., Silverman, L. M., Keku, T., Lawrence, L. B., Rohlfs, E. M., Martin, C. F., Galanko, J., Sandler, R. S.
(2003). Association Between Hemochromatosis (HFE) Gene Mutation Carrier Status and the Risk of Colon Cancer. JNCI J Natl Cancer Inst
95: 154-159
[Abstract][Full Text]
Beutler, E., Hoffbrand, A. V., Cook, J. D.
(2003). Iron Deficiency and Overload. ASH Education Book
2003: 40-61
[Abstract][Full Text]
Ramakrishnan, U., Kuklina, E., Stein, A. D
(2002). Iron stores and cardiovascular disease risk factors in women of reproductive age in the United States. Am. J. Clin. Nutr.
76: 1256-1260
[Abstract][Full Text]
Holmstrom, P, Marmur, J, Eggertsen, G, Gafvels, M, Stal, P
(2002). Mild iron overload in patients carrying the HFE S65C gene mutation: a retrospective study in patients with suspected iron overload and healthy controls. Gut
51: 723-730
[Abstract][Full Text]
Trinder, D, Fox, C, Vautier, G, Olynyk, J K
(2002). Molecular pathogenesis of iron overload. Gut
51: 290-295
[Abstract][Full Text]
Timms, A E, Sathananthan, R, Bradbury, L, Athanasou, N A, Brown, M A
(2002). Genetic testing for haemochromatosis in patients with chondrocalcinosis. Ann Rheum Dis
61: 745-747
[Abstract][Full Text]
Waalen, J., Felitti, V., Gelbart, T., Ho, N. J., Beutler, E.
(2002). Prevalence of Hemochromatosis-Related Symptoms Among Individuals With Mutations in the HFE Gene. Mayo Clin Proc.
77: 522-530
[Abstract]
Trinder, D., Olynyk, J. K., Sly, W. S., Morgan, E. H.
(2002). Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse. Proc. Natl. Acad. Sci. USA
99: 5622-5626
[Abstract][Full Text]
Willis, G., Scott, D. G. I., Jennings, B. A., Smith, K., Bukhari, M., Wimperis, J. Z.
(2002). HFE mutations in an inflammatory arthritis population. Rheumatology (Oxford)
41: 176-179
[Abstract][Full Text]
Girouard, J., Giguere, Y., Delage, R., Rousseau, F.
(2002). Prevalence of HFE gene C282Y and H63D mutations in a French-Canadian population of neonates and in referred patients. Hum Mol Genet
11: 185-189
[Abstract][Full Text]
Anderson, L.J., Holden, S., Davis, B., Prescott, E., Charrier, C.C., Bunce, N.H., Firmin, D.N., Wonke, B., Porter, J., Walker, J.M., Pennell, D.J.
(2001). Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J
22: 2171-2179
[Abstract]
Beutler, E.
(2001). Discrepancies between genotype and phenotype in hematology: an important frontier. Blood
98: 2597-2602
[Abstract][Full Text]
Lyon, E., Frank, E. L.
(2001). Hereditary Hemochromatosis Since Discovery of the HFE Gene. Clin. Chem.
47: 1147-1156
[Abstract][Full Text]
Fargion, S., Valenti, L., Dongiovanni, P., Scaccabarozzi, A., Fracanzani, A. L., Taioli, E., Mattioli, M., Sampietro, M., Fiorelli, G.
(2001). Tumor necrosis factor {alpha} promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis. Blood
97: 3707-3712
[Abstract][Full Text]
ADAMS, P C
(2001). Iron overload in Montpelier. Gut
48: 755-756
[Full Text]
Aguilar-Martinez, P, Bismuth, M, Picot, M C, Thelcide, C, Pageaux, G-P, Blanc, F, Blanc, P, Schved, J-F, Larrey, D
(2001). Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause?. Gut
48: 836-842
[Abstract][Full Text]
Steinberg, K. K., Cogswell, M. E., Chang, J. C., Caudill, S. P., McQuillan, G. M., Bowman, B. A., Grummer-Strawn, L. M., Sampson, E. J., Khoury, M. J., Gallagher, M. L.
(2001). Prevalence of C282Y and H63D Mutations in the Hemochromatosis (HFE) Gene in the United States. JAMA
285: 2216-2222
[Abstract][Full Text]
Fleming, R. E., Holden, C. C., Tomatsu, S., Waheed, A., Brunt, E. M., Britton, R. S., Bacon, B. R., Roopenian, D. C., Sly, W. S.
(2001). Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Proc. Natl. Acad. Sci. USA
98: 2707-2711
[Abstract][Full Text]
Rossi, E., Bulsara, M. K., Olynyk, J. K., Cullen, D. J., Summerville, L., Powell, L. W.
(2001). Effect of Hemochromatosis Genotype and Lifestyle Factors on Iron and Red Cell Indices in a Community Population. Clin. Chem.
47: 202-208
[Abstract][Full Text]
Brittenham, G. M., Klein, H. G., Kushner, J. P., Ajioka, R. S.
(2001). Preserving the National Blood Supply. ASH Education Book
2001: 422-432
[Abstract][Full Text]
Dufour, D. R., Lott, J. A., Nolte, F. S., Gretch, D. R., Koff, R. S., Seeff, L. B.
(2000). Diagnosis and Monitoring of Hepatic Injury. II. Recommendations for Use of Laboratory Tests in Screening, Diagnosis, and Monitoring. Clin. Chem.
46: 2050-2068
[Abstract][Full Text]
Rossi, E., McQuillan, B. M., Hung, J., Thompson, P. L., Kuek, C., Beilby, J. P.
(2000). Serum Ferritin and C282Y Mutation of the Hemochromatosis Gene as Predictors of Asymptomatic Carotid Atherosclerosis in a Community Population. Stroke
31: 3015-3020
[Abstract][Full Text]
Sham, R. L., Raubertas, R. F., Braggins, C., Cappuccio, J., Gallagher, M., Phatak, P. D.
(2000). Asymptomatic hemochromatosis subjects: genotypic and phenotypic profiles. Blood
96: 3707-3711
[Abstract][Full Text]
Bulaj, Z. J., Ajioka, R. S., Phillips, J. D., LaSalle, B. A., Jorde, L. B., Griffen, L. M., Edwards, C. Q., Kushner, J. P.
(2000). Disease-Related Conditions in Relatives of Patients with Hemochromatosis. NEJM
343: 1529-1535
[Abstract][Full Text]
Griffiths, W., Cox, T.
(2000). Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. Hum Mol Genet
9: 2377-2382
[Abstract][Full Text]
Beutler, E., Felitti, V., Gelbart, T., Ho, N.
(2000). The Effect of HFE Genotypes on Measurements of Iron Overload in Patients Attending a Health Appraisal Clinic. ANN INTERN MED
133: 329-337
[Abstract][Full Text]
Seamark, C. J, Hutchinson, M., Heath, I., McMullin, M F
(2000). Controversy in primary care: Should asymptomatic haemochromatosis be treated? Treatment can be onerous for patient and doctor Commentary: False certainty of clinical guidance Commentary: Early treatment is essential. BMJ
320: 1314-1317
[Full Text]
ADAMS, P C
(2000). Population screening for haemochromatosis. Gut
46: 301-303
[Full Text]
Bulaj, Z. J., Phillips, J. D., Ajioka, R. S., Franklin, M. R., Griffen, L. M., Guinee, D. J., Edwards, C. Q., Kushner, J. P.
(2000). Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood
95: 1565-1571
[Abstract][Full Text]
El-Serag, H. B., Inadomi, J. M., Kowdley, K. V.
(2000). Screening for Hereditary Hemochromatosis in Siblings and Children of Affected Patients: A Cost-Effectiveness Analysis. ANN INTERN MED
132: 261-269
[Abstract][Full Text]
Rossi, E., Olynyk, J. K., Cullen, D. J., Papadopoulos, G., Bulsara, M., Summerville, L., Powell, L. W.
(2000). Compound Heterozygous Hemochromatosis Genotype Predicts Increased Iron and Erythrocyte Indices in Women. Clin. Chem.
46: 162-166
[Abstract][Full Text]
Brittenham, G. M., Weiss, G., Brissot, P., Laine, F., Guillygomarc'h, A., Guyader, D., Moirand, R., Deugnier, Y.
(2000). Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism. ASH Education Book
2000: 39-50
[Abstract][Full Text]
Andrews, N. C.
(1999). Disorders of Iron Metabolism. NEJM
341: 1986-1995
[Full Text]
Tavill, A. S.
(1999). Clinical Implications of the Hemochromatosis Gene. NEJM
341: 755-757
[Full Text]
Trinder, D., Olynyk, J. K., Sly, W. S., Morgan, E. H.
(2002). Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse. Proc. Natl. Acad. Sci. USA
99: 5622-5626
[Abstract][Full Text]
Sproule, T. J., Jazwinska, E. C., Britton, R. S., Bacon, B. R., Fleming, R. E., Sly, W. S., Roopenian, D. C.
(2001). Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice. Proc. Natl. Acad. Sci. USA
98: 5170-5174
[Abstract][Full Text]
A correction has been published: N Engl J Med 1999;341(22):1708.
45 percent) were the data on the subjects reviewed by one of the investigators and the serum iron studies repeated while the subjects were fasting. All subjects with persistently elevated transferrin-saturation values and those who were homozygous for the C282Y mutation underwent clinical evaluation. Liver biopsy was recommended if the serum ferritin level was 300 ng per milliliter or higher. 
20 µmol per gram of liver, dry weight). 
Previous
