Original Article
Disease-Related Conditions in Relatives of Patients with Hemochromatosis
N Engl J Med 2000; 343:1529-1535November 23, 2000
- Abstract
Background
Hemochromatosis occurs in approximately 5 white people per 1000 and is usually due to homozygosity for mutations in the HLA-linked HFE gene. Although screening has been proposed, the proportion of homozygotes with conditions related to hemochromatosis is uncertain.
Methods
We studied the prevalence of disease-related conditions among relatives of probands with hemochromatosis. We identified probands who presented to a clinic with signs or symptoms of hemochromatosis or who had elevated transferrin-saturation values. We identified homozygous relatives, mainly siblings, on the basis of HLA identity with the proband and by HFE genotyping. Disease-related conditions were cirrhosis, hepatic fibrosis, elevated aminotransferase values, and hemochromatotic arthropathy.
Results
We identified 214 homozygous relatives of 291 homozygous probands. Of the 113 men in this group (mean age, 41 years), 96 (85 percent) had iron overload, and 43 (38 percent) had at least one disease-related condition. Of the 52 men over 40 years of age, 27 (52 percent) had at least one disease-related condition. Of the 101 female homozygous relatives (mean age, 44 years), 69 (68 percent) had iron overload, and 10 (10 percent) had at least one disease-related condition. Of the 43 women over 50 years of age, 7 (16 percent) had at least one disease-related condition. If the proband had a disease-related condition, relatives who were men were more likely to have morbidity than if the proband had no disease-related condition.
Conclusions
A substantial number of homozygous relatives of patients with hemochromatosis — more commonly men than women — have conditions related to hemochromatosis that have yet to be detected clinically.
Media in This Article
Table 1
Demographic Characteristics and Iron Phenotypes of Probands and Their Clinically Unselected Homozygous Relatives.Table 2
Disease-Related Conditions and Other Clinical Findings in Three Groups of Subjects Who Were Homozygous for Hemochromatosis.Article Activity
- Article
Hemochromatosis occurs in approximately 5 white people per 10001,2 and is usually due to a mutation in the HLA-linked hemochromatosis gene (HFE) that causes a change from cysteine to tyrosine at position 282 in the HFE protein (C282Y).3 The phenotypic expression may vary from that of a fully penetrant clinical syndrome (with bronze pigmentation, cirrhosis, arthritis, endocrinopathy, and cardiomyopathy) to a simple laboratory abnormality — namely, elevated transferrin-saturation values.1,4
Screening for hemochromatosis has been proposed but is difficult to justify, because the proportion of homozygotes in whom disease-related conditions are destined to develop is unknown. Homozygotes identified because of clinical sequelae of iron overload all have disease-related conditions,4-6 whereas screening of healthy subjects generally uncovers few clinically affected homozygotes.7,8 The incidence of disease-related conditions might be best estimated by studying homozygotes who have not been preselected for illness or good health; such a study would thus be free of ascertainment bias.9
We report the frequency of conditions related to hemochromatosis in 214 clinically unselected homozygous relatives of 291 homozygous probands.
Methods
All study procedures were approved by the institutional review board of the University of Utah. Written informed consent was obtained from all participants.
Probands
The probands were identified between 1975 and 1998. One hundred eighty-four probands were identified because they presented with signs or symptoms of hemochromatosis. These probands were considered to be clinically affected. One hundred seven pro-bands were identified on the basis of findings of elevated transferrin-saturation values during hemochromatosis-screening programs7 or at routine health maintenance examinations.
Families
The available first-degree relatives and many additional relatives of the probands were evaluated. Genotypic assignments within a family were based on the proband's HLA haplotype.10,11 Siblings who were HLA-identical to the proband were considered homozygotes.10 Persons who married into affected families and who had unexplained, persistent transferrin-saturation values of more than 62 percent were also considered homozygotes.12
HFE Mutations
Genotypic assignments based on HLA haplotypes were verified by HFE genotyping of available specimens. The C282Y mutation and the change from histidine to aspartic acid at position 63 (H63D) were detected by previously described methods.3
Iron Studies
The serum iron concentration, transferrin saturation, and ferritin concentration were measured in all subjects. Liver-biopsy samples were assessed for iron content by histologic staining and atomic-absorption spectrophotometry.13 Iron overload was considered to be present when the hepatic-parenchymal-cell stainable iron grade was 2 to 414 and the hepatic iron concentration was greater than 25 μmol per gram.11 If liver biopsy was not performed, iron overload was considered to be present when the ferritin concentration was greater than 325 μg per liter in men and 125 μg per liter in women.1
Determination of Disease-Related Conditions
All probands and their homozygous relatives were evaluated by means of a history taking and physical examination. Alcohol consumption was estimated by previously described methods.15 Methods for measuring aminotransferases varied over the 23-year period during which subjects were identified. To normalize results, we defined an elevated aminotransferase value to be at least 1.2 times the upper limit of the reference range at the time. Porphyria cutanea tarda was documented by measuring urinary porphyrin excretion.15 Histologic grading of fibrosis and cirrhosis was performed as previously described.16 Fibrosis was considered to be present if grade 2 (periportal) or more severe fibrosis was noted. Only cirrhosis, fibrosis, elevated aminotransferase values in the absence of any identifiable cause other than iron overload, and radiographically confirmed hemochromatotic arthropathy of the metacarpal–phalangeal joints were considered conditions related to hemochromatosis. Diabetes, other endocrine abnormalities, and cardiac arrhythmias were noted but were not considered to be related to hemochromatosis, since it was difficult to establish that these abnormalities were due solely to iron overload. Antibodies against hepatitis C virus were detected with an enzyme-linked immunosorbent assay (ELISA 2.0, Chiron, Emeryville, Calif.). Although symptoms were not considered criteria for conditions related to hemochromatosis, all subjects were asked about arthralgias, abdominal pain, and weakness.
Classification of Homozygous Relatives of the Probands
The clinically unselected homozygous relatives of the probands were classified into three groups: those with iron overload and disease-related conditions, those with iron overload and no disease-related conditions, and those without iron overload.
Statistical Analysis
Statistical analyses used the Prophet software package.17 Age and transferrin-saturation values were compared between groups by Student's t-test. Comparisons with respect to ferritin concentration (and age, when values were not normally distributed) were performed with the Kruskal–Wallis and Mann–Whitney nonparametric tests.18 All reported P values are two-sided. The frequency of morbidity was compared by chi-square analysis.18 Logistic regression was used to test for concordance with respect to morbidity.18 Morbidity in this analysis was defined as present if either cirrhosis or fibrosis was present, and as absent if neither of these conditions was present. In the regression analysis, morbidity or absence of morbidity in the relative was entered as the dependent variable, and morbidity in the proband was entered as the independent variable. The relative's age was entered as a covariate.
Results
Probands
Probands were classified according to how they were identified and according to sex (Table 1Table 1
Demographic Characteristics and Iron Phenotypes of Probands and Their Clinically Unselected Homozygous Relatives.). Clinically affected probands were identified on the basis of signs or symptoms. Other probands were identified because they had elevated transferrin-saturation values. Among men, the clinically affected probands were older than the probands identified because of elevated transferrin-saturation values and homozygous relatives of the probands (P<0.001). The latter two groups did not differ significantly in age from one another (P=0.16). Among women, there was no significant difference in age between the probands and their homozygous relatives.Clinically Unselected Homozygous Relatives of the Probands
Two hundred fourteen homozygous relatives of 291 homozygous probands were identified from 103 families. HLA identity between probands and their homozygous siblings was present in 94 families. In nine families, the parents of the proband represented a homozygote–heterozygote pairing, resulting in three HLA-linked haplotypes among their offspring and HLA nonidentity in some homozygous siblings. HFE genotypes were determined in 158 clinically unselected homozygotes; the genotype was C282Y/C282Y in 140 (88.6 percent), C282Y/H63D in 10 (6.3 percent), C282Y/wild type in 5 (3.2 percent), H63D/wild type in 2 (1.3 percent), and wild type/wild type in 1 (0.6 percent). The 158 genotyped subjects have a total of 316 HFE alleles. The allelic frequency of C282Y in this population is 0.930. In contrast, the frequency of C282Y in the white population of Utah is 0.062.3,15
Iron Phenotype
There were no significant differences in transferrin-saturation values among clinically affected male probands, male probands detected because of elevated transferrin-saturation values, and homozygous male relatives of probands (Table 1). Among women, the mean transferrin saturation in homozygous relatives was lower than that in either clinically affected pro-bands or probands detected because of elevated transferrin-saturation values (P=0.002 and P=0.03, respectively). The ferritin concentrations were highest in clinically affected probands of either sex.
Ninety-one percent of clinically affected probands and 81 percent of those identified because of elevated transferrin-saturation values underwent liver biopsy (Table 2Table 2
Disease-Related Conditions and Other Clinical Findings in Three Groups of Subjects Who Were Homozygous for Hemochromatosis.). Sixty-nine percent of male homozygous relatives of probands, but only 40 percent of female relatives, agreed to undergo liver biopsy. Female relatives who underwent biopsy did not differ significantly in age or ferritin concentration from those who did not. Among both male and female subjects, the mean hepatic iron grade and the median iron concentration were highest in clinically affected probands (3.5 and 181 μmol per gram, respectively), next highest in homozygous relatives of probands (3.1 and 126 μmol per gram), and lowest in probands identified because of elevated transferrin-saturation values (2.7 and 69 μmol per gram).Classification of Homozygous Relatives of Probands
The homozygous relatives of probands were classified into three groups: those with iron overload and disease-related conditions, those with iron overload and no disease-related conditions, and those without iron overload (Table 3Table 3
Disease-Related Conditions and Iron Overload in 214 Clinically Unselected Homozygous Relatives of Probands, According to Sex and Age.). There were no differences in estimated alcohol consumption among these groups. No relative with iron overload and a disease-related condition (the first group) had evidence of hepatitis C. A relative was assigned to this group if he or she had cirrhosis, fibrosis, elevated aminotransferase values, or arthropathy (Table 2). If the relative had more than one of these conditions, he or she was classified as having only the condition named earliest in the list. Forty-three men (38 percent) were assigned to this group, and 40 of them underwent liver biopsy.Ninety percent of the men in the group had the C282Y/C282Y genotype. The age, ferritin concentration, hepatic iron grade, and iron concentration were all higher for men in this group than for men who had iron overload and no disease-related conditions (mean age, 48 vs. 38 years [P=0.007]; median ferritin concentration, 1000 vs. 500 μg per liter [P= 0.01]; mean hepatic iron grade, 3.8 vs. 3.2 [P< 0.001]; median iron concentration, 283 vs. 126 μmol per gram [P=0.002]).
Cirrhosis or fibrosis was found in 27 men (Table 2). Fourteen of these men had elevated aminotransferase values, and nine had arthropathy. Hepatocellular carcinoma developed in one of the men who had cirrhosis, and porphyria cutanea tarda in another. Among those without cirrhosis or fibrosis, arthropathy was found in eight (either alone or in combination with elevated aminotransferase values). There was no significant difference between men with and without liver damage in the frequency of arthropathy.
Seventeen of the 43 men with iron overload and disease-related conditions (40 percent) had arthropathy. Sixteen men in the group had no symptoms. Among the 27 who had symptoms, arthralgias were the most common, being reported by 22 men. Four men in the group with iron overload and no disease-related conditions had cardiac arrhythmias, but all other manifestations shown in Table 2 were found only in men in the group with iron overload and disease-related conditions.
Ten women (10 percent) were assigned to the group with iron overload and disease-related conditions (Table 3), and nine of these women underwent biopsy. In seven of the women the genotype was determined; all had the C282Y/C282Y genotype. Among women with iron overload, those with and without disease-related conditions did not differ significantly in age, ferritin concentration, hepatic iron grade, or iron concentration. Cirrhosis or fibrosis was found in six women (Table 2), of whom three had elevated aminotransferase values and three had arthropathy. One woman with fibrosis and elevated aminotransferase values also had porphyria cutanea tarda. Three of the four women without histologic evidence of liver damage had arthropathy. As with men, the frequency of arthropathy did not differ between women with and without liver damage. Three women in the group with iron overload and disease-related conditions were asymptomatic. Arthralgias occurred in five of the remaining seven. Two women in the group with iron overload and no disease-related conditions had diabetes and cardiac arrhythmias, but all other manifestations listed in Table 2 were found only in women in the group with iron overload and disease-related conditions.
Effects of Age and Sex on Disease-Related Conditions in Homozygous Relatives of Probands
Iron overload in male homozygous relatives of probands became prominent after the age of 20 years (Table 3). Among female homozygous relatives of probands, iron overload was most common after the age of 50 years. Among men over 40 years old, 90 percent had iron overload and 52 percent had disease-related conditions. Among women over 50 years old, 88 percent had iron overload and 16 percent had disease-related conditions.
Disease-Related Conditions in Probands
All clinically affected probands had iron overload. Arthralgias and weakness were the most common symptoms. Only 10 percent of men and 6 percent of women were asymptomatic. Arthralgias were reported by 65 of 122 symptomatic men, weakness by 63, and abdominal pain by 48. One hundred eight clinically affected male probands (79 percent) had one or more disease-related conditions. Other findings in clinically affected male probands are shown in Table 2. Arthralgias were reported by 23 of 45 symptomatic women, weakness by 22, and abdominal pain by 10. The criteria used to assign relatives of probands to the group with iron overload and disease-related conditions were found in 29 clinically affected female probands (60 percent). Other findings in clinically affected female probands are shown in Table 2.
Among probands identified because of elevated transferrin-saturation values, 52 percent of the men and 34 percent of the women had iron overload, and 97 percent of the men and 90 percent of the women were asymptomatic. Among probands identified because of elevated transferrin-saturation values, disease-related conditions were present in 19 men (29 percent) and 14 women (34 percent). Other disease-related manifestations of hemochromatosis in pro-bands identified because of elevated transferrin-saturation values are shown in Table 2.
Effect of Type of Proband on the Frequency of Iron Overload and Disease-Related Conditions among Clinically Unselected Homozygous Relatives
The frequency of disease-related conditions among homozygous relatives of clinically affected probands was compared with that among relatives of probands identified because of elevated transferrin-saturation values (Table 4Table 4
Effect of the Method of Identifying the Proband on Frequency of Iron Overload and Disease-Related Conditions in Clinically Unselected Homozygous Relatives of Clinically Affected Probands and of Probands Identified Because of Elevated Transferrin-Saturation Values.). The mean age of clinically affected probands was greater than that of probands identified because of elevated transferrin-saturation values (P<0.001) (Table 1). The homozygous relatives of clinically affected probands and those of probands selected by screening did not differ significantly in age (Table 4), median ferritin concentration, hepatic iron grade, hepatic iron concentration, or estimated alcohol consumption. There was, however, a higher incidence of disease-related conditions in male relatives of clinically affected probands than in male relatives of probands identified because of elevated transferrin-saturation values (Table 4).Among men with iron overload and disease-related conditions, relatives of affected probands and relatives of probands identified because of elevated transferrin-saturation values did not differ significantly in age. The proportion of homozygous female relatives with disease-related conditions was also higher among relatives of clinically affected probands than among relatives of probands identified by elevated transferrin-saturation values, but this difference was not significant (Table 4). A minimal estimate of the age-related incidence of morbidity in homozygotes was derived from the homozygous relatives of probands identified because of elevated transferrin-saturation values. Twenty-nine percent of male relatives over 40 years of age and 11 percent of female relatives over 50 years of age met our criteria for morbidity.
Concordance with respect to morbidity was analyzed in pairs of siblings from 34 pedigrees in which a male proband and one or more male siblings had undergone liver biopsy. Of 19 proband–sibling pairs in which the proband had cirrhosis or fibrosis, 10 were concordant and 9 were not. Of 23 pairs in which the proband had neither fibrosis nor cirrhosis, 18 were concordant and 5 were not. The ferritin concentration was higher when fibrosis or cirrhosis was present than when both these findings were absent. Logistic-regression analysis indicated that siblings of probands with liver-biopsy abnormalities were approximately three times as likely to have liver-biopsy abnormalities themselves as siblings of probands with normal biopsy results (odds ratio, 3.42; 95 percent confidence interval, 0.85 to 13.70). This effect was independent of age. Although these data suggest an increased risk of morbidity among siblings of probands with morbidity, the sample size was not sufficient to generate a significant result. In families with female probands, too few proband–sibling pairs underwent liver biopsy for us to perform valid analyses.
Discussion
We identified homozygous relatives of persons with hemochromatosis by using HLA typing and HFE genotyping. The homozygous relatives were identified without regard to health status and were therefore considered to be clinically unselected. We obtained complete clinical information on all homozygous relatives, and most also underwent liver biopsy (Table 2). This process enabled us to define disease-related conditions by objective criteria. Even with our conservative definition, we found at least one disease-related condition in 38 percent of homozygous male relatives and 10 percent of homozygous female relatives. Age and sex influenced the incidence of disease-related conditions (Table 3). Cirrhosis and fibrosis were associated with the highest ferritin values, as previously reported,19 but arthropathy often occurred with only moderate iron overload.
Homozygous relatives were identified without bias related to health status, but the incidence of disease-related conditions among male relatives of clinically affected probands was higher than that among male relatives of probands identified because of elevated transferrin-saturation values (Table 4), even though the two groups of male relatives did not differ in any relevant feature. For probands identified because of elevated transferrin-saturation values, a transferrin saturation of 62 percent or greater was used as the threshold. This value is probably appropriate for men, since our first screening program, involving over 11,000 healthy young blood donors,7 identified 4.5 homozygotes per 1000 men, a figure approximating the known frequency of hemochromatosis. A population-screening study in which HFE genotyping was used as the screening probe identified 16 C282Y homozygotes in a population of 3011 Australians (5.3 per 1000).8 The observed frequency of homozygosity was within the range predicted by the Hardy–Weinberg principle, given the observed frequency of C282Y HFE alleles in the normal white population of 0.032 to 0.062.3,15
Transferrin saturation was measured twice in all newly discovered homozygotes, and at least one value of 62 percent or greater was recorded for all. Using lower threshold values for the transferrin saturation in men might slightly increase the sensitivity of the test but would sacrifice specificity.20,21 These data suggest that the male probands we identified because they had elevated transferrin-saturation values are representative of the overall population of men who are homozygous for hemochromatosis and that our estimate of a 24 percent minimal frequency of disease-related conditions among homozygous men over 40 years of age is reasonable. We applied our criteria for disease-related conditions to male probands identified because of elevated transferrin-saturation values (Table 2) and found that the frequency of disease-related conditions did not differ from that among clinically unselected male relatives (Table 4).
There was also a difference in the incidence of disease-related conditions among homozygous female relatives of probands identified by the two different methods (Table 4). Identification of female probands on the basis of elevated transferrin-saturation values probably underestimated the number of homozygotes, since the threshold value for the transferrin saturation was set at 62 percent before 1993,7 rather than the more appropriate 50 percent.22 By using the 62 percent threshold, we may have identified a subgroup of homozygous female probands with a more highly penetrant phenotype,7,22 since the median ferritin concentration among female probands identified because of elevated transferrin-saturation values was higher than that among clinically unselected homozygous female relatives identified by HLA typing and HFE genotyping (Table 1). The frequency of disease-related conditions among female probands identified because they had elevated transferrin-saturation values was also higher than that among clinically unselected female relatives (Table 2).
The most frequently recognized disease-related conditions among both affected probands and their homozygous relatives were hepatic fibrosis and cirrhosis, which were related to the ferritin concentration. Our data suggest that familial factors influence the degree of iron loading in hemochromatosis and hence the frequency of disease-related conditions. Strain-specific modifier loci affecting hepatic iron loading have been described both in mice with targeted disruptions of the HFE locus and in mice with wild-type HFE alleles.23,24 Differences in modifier loci in humans may explain the broad range of phenotypic expression noted in persons who are homozygous for hemochromatosis.
In conclusion, our data emphasize the importance of screening relatives of persons with hemochromatosis. Disease-related conditions were found in 52 percent of clinically unselected homozygous men over 40 years of age and 16 percent of women over 50 years of age. Our minimal estimate of the incidence of disease-related conditions among homozygous relatives of probands with elevated transferrin-saturation values is 29 percent for men over 40 years of age and 11 percent for women over 50 years of age. This estimate is most likely applicable to homozygotes in the white population.
Supported in part by grants (DK-20630, DK-20503, CA-42014, T32-DK07115, RR-00064, and GM-59290) from the National Institutes of Health.
We are indebted to Dr. Ernest Beutler for his insight and advice and to the staff of the Huntsman General Clinical Research Center for their assistance.
Source Information
From the Departments of Medicine (Z.J.B., R.S.A., J.D.P., C.Q.E., J.P.K.) and Human Genetics (L.B.J.) and the General Clinical Research Center (B.A.L., L.M.G.), University of Utah School of Medicine; and the LDS Hospital (C.Q.E.) — all in Salt Lake City.
Address reprint requests to Dr. Kushner at the Division of Hematology, 4C-416, University of Utah School of Medicine, 50 North Medical Dr., Salt Lake City, UT 84132, or at james.kushner@hsc.utah.edu.
- References
References
1
Edwards CQ. Hemochromatosis. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe's clinical hematology. 10th ed. Vol. 1. Baltimore: Lippincott Williams & Wilkins, 1999:1056-70.
2
Bothwell TH, Charlton RW, Motulsky AG. Hemochromatosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 2. New York: McGraw-Hill, 1995:2237-69.
3
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 | Web of Science | Medline4
Edwards CQ ,Dadone MM ,Skolnick MH ,Kushner JP . Hereditary haemochromatosis. Clin Haematol 1982;11:411-435
Medline5
Moirand R ,Adams PC ,Bicheler V ,Brissot P ,Deugnier Y . Clinical features of genetic hemochromatosis in women compared with men. Ann Intern Med 1997;127:105-110
Web of Science | Medline6
McDonnell SM ,Preston BL ,Jewell SA , et al. A survey of 2,851 patients with hemochromatosis: symptoms and response to treatment. Am J Med 1999;106:619-624
CrossRef | Web of Science | Medline7
Edwards CQ ,Griffen LM ,Goldgar D ,Drummond C ,Skolnick MH ,Kushner JP . Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 1988;318:1355-1362
Full Text | Web of Science | Medline8
Olynyk JK ,Cullen DJ ,Aquilia S ,Rossi E ,Summerville L ,Powell LW . A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-724
Full Text | Web of Science | Medline9
Adams PC ,Kertesz AE ,Valberg LS . Clinical presentation of hemochromatosis: a changing scene. Am J Med 1991;90:445-449
Web of Science | Medline10
Edwards CQ ,Skolnick MH ,Kushner JP . Hereditary hemochromatosis: contributions of genetic analyses. Prog Hematol 1981;12:43-71
Medline11
Bulaj ZJ ,Griffen LM ,Jorde LB ,Edwards CQ ,Kushner JP . Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med 1996;335:1799-1805
Full Text | Web of Science | Medline12
Dadone MM ,Kushner JP ,Edwards CQ ,Bishop DT ,Skolnick MH . Hereditary hemochromatosis: analysis of laboratory expression of the disease by genotype in 18 pedigrees. Am J Clin Pathol 1982;78:196-207
Web of Science | Medline13
Edwards CQ ,Carroll M ,Bray P ,Cartwright GE . Hereditary hemochromatosis: diagnosis in siblings and children. N Engl J Med 1977;297:7-13
Full Text | Web of Science | Medline14
Scheuer PJ ,Williams R ,Muir AR . Hepatic pathology in relatives of patients with haemochromatosis. J Pathol Bacteriol 1962;84:53-64
CrossRef | Web of Science | Medline15
Bulaj ZJ ,Phillips JD ,Ajioka RS , et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 2000;95:1565-1571
Web of Science | Medline16
Batts KP ,Ludwig J . Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol 1995;19:1409-1417
CrossRef | Web of Science | Medline17
PROPHET. Cambridge, Mass.: Bolt Beranek and Newman, 1997 (software).
18
Daniel WW. Biostatistics: a foundation for analysis in the health sciences. 7th ed. New York: John Wiley, 1999.
19
Guyader D ,Jacquelinet C ,Moirand R , et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998;115:929-936
CrossRef | Web of Science | Medline20
Witte D. Screening for hemochromatosis. In: Barton J, Edwards C, eds. Hemochromatosis: genetics, pathophysiology, diagnosis and treatment. Cambridge, England: Cambridge University Press, 2000:519-24.
21
Adams PC ,Kertesz AE ,McLaren CE ,Barr R ,Bamford A ,Chakrabarti S . Population screening for hemochromatosis: a comparison of unbound iron-binding capacity, transferrin saturation, and C282Y genotyping in 5,211 voluntary blood donors. Hepatology 2000;31:1160-1164
CrossRef | Web of Science | Medline22
Edwards CQ ,Kushner JP . Screening for hemochromatosis. N Engl J Med 1993;328:1616-1620
Full Text | Web of Science | Medline23
Leboeuf RC ,Tolson D ,Heinecke JW . Dissociation between tissue iron concentrations and transferrin saturation among inbred mouse strains. J Lab Clin Med 1995;126:128-136
Medline24
Levy JE ,Montross LK ,Cohen DE ,Fleming MD ,Andrews NC . The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 1999;94:9-11
Web of Science | Medline
- Citing Articles (73)
Citing Articles
1
Soo Aleman, Sanam Endalib, Per Stål, Lars Lööf, Stefan Lindgren, Hanna Sandberg-Gertzén, Sven Almer, Sigvard Olsson, Åke Danielsson, Sven Wallerstedt, Rolf Hultcrantz. (2011) Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population. Scandinavian Journal of Gastroenterology 46:9, 1118-1126
CrossRef2
Bruce R. Bacon, Paul C. Adams, Kris V. Kowdley, Lawrie W. Powell, Anthony S. Tavill. (2011) Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology 54:1, 328-343
CrossRef3
Richard W. Lambrecht, Richard K. Sterling, Deepa Naishadham, Anne M. Stoddard, Thomas Rogers, Chihiro Morishima, Timothy R. Morgan, Herbert L. Bonkovsky. (2011) Iron Levels in Hepatocytes and Portal Tract Cells Predict Progression and Outcomes of Patients With Advanced Chronic Hepatitis C. Gastroenterology 140:5, 1490-1500.e3
CrossRef4
Federica Giambattistelli, Serena Bucossi, Carlo Salustri, Valentina Panetta, Stefania Mariani, Mariacristina Siotto, Mariacarla Ventriglia, Fabrizio Vernieri, Maria Luisa Dell'Acqua, Emanuele Cassetta, Paolo Maria Rossini, Rosanna Squitti. (2011) Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease. Neurobiology of Aging
CrossRef5
Frauke Becker, Carla G van El, Dolores Ibarreta, Eleni Zika, Stuart Hogarth, Pascal Borry, Anne Cambon-Thomsen, Jean Jacques Cassiman, Gerry Evers-Kiebooms, Shirley Hodgson, A Cécile J W Janssens, Helena Kaariainen, Michael Krawczak, Ulf Kristoffersson, Jan Lubinski, Christine Patch, Victor B Penchaszadeh, Andrew Read, Wolf Rogowski, Jorge Sequeiros, Lisbeth Tranebjaerg, Irene M van Langen, Helen Wallace, Ron Zimmern, Jörg Schmidtke, Martina C Cornel. (2011) Genetic testing and common disorders in a public health framework: how to assess relevance and possibilities. European Journal of Human Genetics 19, S6-S44
CrossRef6
G. J. Carroll, W. H. Breidahl, M. K. Bulsara, J. K. Olynyk. (2011) Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load. Arthritis & Rheumatism 63:1, 286-294
CrossRef7
G. J. Carroll, W. H. Breidahl, J. K. Olynyk. (2011) Characteristics of the arthropathy described in hereditary haemochromatosis. Arthritis Care & Researchn/a-n/a
CrossRef8
T. Weber, S. Theurich, M. Christopeit, T. Klapperstueck, G. Behre. (2010) Human herpesvirus-6 as an inducer of porphyria cutanea tarda: implications from a case. Transplant Infectious Disease 12:5, 432-436
CrossRef9
Katrina J. Allen, Nadine A. Bertalli, Nicholas J. Osborne, Clare C. Constantine, Martin B. Delatycki, Amy E. Nisselle, Amanda J. Nicoll, Dorota M. Gertig, Christine E. McLaren, Graham G. Giles, John L. Hopper, Gregory J. Anderson, John K. Olynyk, Lawrie W. Powell, Lyle C. Gurrin, . (2010) HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 μg/L are at low risk of hemochromatosis. Hepatology 52:3, 925-933
CrossRef10
Antonello Pietrangelo. (2010) Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment. Gastroenterology 139:2, 393-408.e2
CrossRef11
Pierre-Alexandre Krayenbuehl, Martin Hersberger, Kaspar Truninger, Beat Müllhaupt, Friedrich E. Maly, Mario Bargetzi, Georg Schulthess. (2010) Toll-like receptor 4 gene polymorphism modulates phenotypic expression in patients with hereditary hemochromatosis. European Journal of Gastroenterology & Hepatology 22:7, 835-841
CrossRef12
Mensud Hatunic, Francis M. Finucane, Aoife M. Brennan, Suzanne Norris, Giovanni Pacini, John J. Nolan. (2010) Effect of iron overload on glucose metabolism in patients with hereditary hemochromatosis. Metabolism 59:3, 380-384
CrossRef13
Kristina M. Utzschneider, Kris V. Kowdley. (2010) Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice. Nature Reviews Endocrinology 6:1, 26-33
CrossRef14
Clare C. Constantine, Greg J. Anderson, Chris D. Vulpe, Christine E. McLaren, Melanie Bahlo, Heng Lin Yeap, Dorota M. Gertig, Nicholas J. Osborne, Nadine A. Bertalli, Kenneth B. Beckman, Victoria Chen, Pavel Matak, Andrew T. McKie, Martin B. Delatycki, John K. Olynyk, Dallas R. English, Melissa C. Southey, Graham G. Giles, John L. Hopper, Katrina J. Allen, Lyle C. Gurrin. (2009) A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis. British Journal of Haematology 147:1, 140-149
CrossRef15
Lana Kaiser, John M. Davis, Jon Patterson, Abby L. Johnson, George Bohart, N. Bari Olivier, Kenneth A. Schwartz. (2009) Iron sufficient to cause hepatic fibrosis and ascites does not cause cardiac arrhythmias in the gerbil. Translational Research 154:4, 202-213
CrossRef16
Min Tao, David L Pelletier. (2009) The effect of dietary iron intake on the development of iron overload among homozygotes for haemochromatosis. Public Health Nutrition 12:10, 1823
CrossRef17
Daniel F. Wallace, V. Nathan Subramaniam. (2009) Co-factors in liver disease: The role of HFE-related hereditary hemochromatosis and iron. Biochimica et Biophysica Acta (BBA) - General Subjects 1790:7, 663-670
CrossRef18
Eng K Gan, Debbie Trinder, Oyekoya T Ayonrinde, John K Olynyk. (2009) Genetics of hereditary hemochromatosis: a clinical perspective. Expert Review of Endocrinology & Metabolism 4:3, 225-239
CrossRef19
Joanna Picot, Jackie Bryant, Keith Cooper, Andy Clegg, Paul Roderick, William Rosenberg, Christine Patch. (2009) Psychosocial Aspects of DNA Testing for Hereditary Hemochromatosis in At-Risk Individuals: A Systematic Review. Genetic Testing and Molecular Biomarkers 13:1, 7-14
CrossRef20
Beatriz Porto, Raquel Vieira, Graça Porto. (2009) Increased capacity of lymphocytes from hereditary hemochromatosis patients homozygous for the C282Y HFE mutation to respond to the genotoxic effect of diepoxybutane. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 673:1, 37-42
CrossRef21
Joanna Picot, Jackie Bryant, Keith Cooper, Andy Clegg, Paul Roderick, William Rosenberg, Christine Patch. (2009) Psychosocial Aspects of DNA Testing for Hereditary Hemochromatosis in At-Risk Individuals: A Systematic Review. Genetic Testing 0:0, 090108090224061
CrossRef22
Esther M.G. Jacobs, Jan C.M. Hendriks, Cees Th.B.M. van Deursen, Herman G. Kreeftenberg, Richard A. de Vries, Joannes J.M. Marx, Anton F.H. Stalenhoef, André L.M. Verbeek, Dorine W. Swinkels. (2009) Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: The HEmochromatosis FAmily Study. Journal of Hepatology 50:1, 174-183
CrossRef23
Kristin D. Helm, Ralf M. Nass, William S. Evans. 2009. Physiologic and Pathophysiologic Alterations of the Neuroendocrine Components of the Reproductive Axis. , 441-488.
CrossRef24
Enrico Rossi, John K Olynyk, Gary P Jeffrey. (2008) Clinical penetrance of C282Y homozygous HFE hemochromatosis. Expert Review of Hematology 1:2, 205-216
CrossRef25
R. S. Ajioka, J. D. Phillips, R. B. Weiss, D. M. Dunn, M. W. Smit, S. C. Proll, M. G. Katze, J. P. Kushner. (2008) Down-regulation of hepcidin in porphyria cutanea tarda. Blood 112:12, 4723-4728
CrossRef26
John K. Olynyk, Debbie Trinder, Grant A. Ramm, Robert S. Britton, Bruce R. Bacon. (2008) Hereditary hemochromatosis in the post- HFE era. Hepatology 48:3, 991-1001
CrossRef27
Yves Deugnier, Jean Mosser. (2008) Modifying factors of the HFE hemochromatosis phenotype. Expert Review of Gastroenterology & Hepatology 2:4, 531-540
CrossRef28
F. Morisco, L. Pagliaro, N. Caporaso, E. Bianco, L. Sagliocca, S. Fargion, A. Smedile, M. Salvagnini, A. Mele. (2008) Consensus recommendations for managing asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels. Digestive and Liver Disease 40:7, 585-598
CrossRef29
Bacon, Bruce R., Britton, Robert S., . (2008) Clinical Penetrance of Hereditary Hemochromatosis. New England Journal of Medicine 358:3, 291-292
Full Text30
Allen, Katrina J., Gurrin, Lyle C., Constantine, Clare C., Osborne, Nicholas J., Delatycki, Martin B., Nicoll, Amanda J., McLaren, Christine E., Bahlo, Melanie, Nisselle, Amy E., Vulpe, Chris D., Anderson, Gregory J., Southey, Melissa C., Giles, Graham G., English, Dallas R., Hopper, John L., Olynyk, John K., Powell, Lawrie W., Gertig, Dorota M., . (2008) Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis. New England Journal of Medicine 358:3, 221-230
Full Text31
Ivana De Domenico, Diane McVey Ward, Jerry Kaplan. (2008) Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nature Reviews Molecular Cell Biology 9:1, 72-81
CrossRef32
Ann P. Walker, Diane C. Tucker, Mark A. Hall, Kurt Lohman, Helen Harrison, Barbara W. Harrison, Jacob Reiss, Ronald T. Acton, Paul C. Adams, Sharmin Diaz, Joan Holup, Elizabeth Thomson, Shellie D. Ellis, Christine E. McLaren. (2007) Results communication and patient education after screening for possible hemochromatosis and iron overload: experience from the HEIRS Study of a large ethnically and linguistically diverse group. Genetics in Medicine 9:11, 778-791
CrossRef33
Jacqueline Milet, Valérie Déhais, Catherine Bourgain, Anne Marie Jouanolle, Annick Mosser, Michèle Perrin, Jeff Morcet, Pierre Brissot, Véronique David, Yves Deugnier, Jean Mosser. (2007) Common Variants in the BMP2, BMP4, and HJV Genes of the Hepcidin Regulation Pathway Modulate HFE Hemochromatosis Penetrance. The American Journal of Human Genetics 81:4, 799-807
CrossRef34
Silvia Mandel, Tamar Amit, Orit Bar-Am, Moussa B.H. Youdim. (2007) Iron dysregulation in Alzheimer's disease: Multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents. Progress in Neurobiology 82:6, 348-360
CrossRef35
Tahereh Ghaziani, Seyed-Moayed Alavian, Mohammad R. Zali, Saeid Shahraz, Mohammdreza Agah, Kevin P. Jensen, Shahin Ansari, Hossein Sendi, Richard W. Lambrecht, Jonathan Covault, Herbert L. Bonkovsky. (2007) Serum measures of iron status and HFE gene mutations in patients with hepatitis B virus infection. Hepatology Research 37:3, 172-178
CrossRef36
John D. Phillips, Frank G. Whitby, Beth M. Stadtmueller, Corwin Q. Edwards, Christopher P. Hill, James P. Kushner. (2007) Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Translational Research 149:2, 85-91
CrossRef37
Herbert L. Bonkovsky, Deepa Naishadham, Richard W. Lambrecht, Raymond T. Chung, John C. Hoefs, S. Russell Nash, Thomas E. Rogers, Barbara F. Banner, Richard K. Sterling, John A. Donovan, Robert J. Fontana, Adrian M. Di Bisceglie, Marc G. Ghany, Chihiro Morishima. (2006) Roles of Iron and HFE Mutations on Severity and Response to Therapy During Retreatment of Advanced Chronic Hepatitis C. Gastroenterology 131:5, 1440-1451
CrossRef38
Cabot, Richard C.Harris, Nancy Lee, Shepard, Jo-Anne O., Rosenberg, Eric S., Cort, Alice M., Ebeling, Sally H.Peters, Christine C., Chung, Raymond T., Misdraji, Joseph, Sahani, Dushyant V., . (2006) Case 33-2006. New England Journal of Medicine 355:17, 1812-1819
Full Text39
Antonello Pietrangelo. (2006) Hereditary Hemochromatosis. Annual Review of Nutrition 26:1, 251-270
CrossRef40
D. A. McClain, D. Abraham, J. Rogers, R. Brady, P. Gault, R. Ajioka, J. P. Kushner. (2006) High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia 49:7, 1661-1669
CrossRef41
Gavin Y. Oudit, Maria G. Trivieri, Neelam Khaper, Peter P. Liu, Peter H. Backx. (2006) Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. Journal of Molecular Medicine 84:5, 349-364
CrossRef42
Ernest Beutler. (2006) Hemochromatosis: Genetics and Pathophysiology. Annual Review of Medicine 57:1, 331-347
CrossRef43
Nancy C Andrews. 2006. Iron Metabolism: Disorders. .
CrossRef44
Chiang W. Siah, Debbie Trinder, John K. Olynyk. (2005) Iron overload. Clinica Chimica Acta 358:1-2, 24-36
CrossRef45
Paul C Adams. (2005) Screening for haemochromatosis—producing or preventing illness?. The Lancet 366:9482, 269-271
CrossRef46
Albert Altés. (2005) Cribado genético de la hemocromatosis hereditaria en España. Situación actual. Medicina Clínica 125:5, 184-186
CrossRef47
Sang Y. Lee, James R. Connor. (2005) Regulation of Hfe by stress factors in BV-2 cells. Neurobiology of Aging 26:6, 803-812
CrossRef48
H BAPTISTAGONZALEZ, F ROSENFELDMANN, R TRUEBAGOMEZ, N MENDEZSANCHEZ, M URIBE. (2005) Evaluation of Iron Overload in Healthy Adult Residents of Mexico City. Archives of Medical Research 36:2, 142-147
CrossRef49
LAWRIE W POWELL. (2004) Recent concepts in iron metabolism and HFE mutations. Journal of Gastroenterology and Hepatology 19:s7, S258-S263
CrossRef50
F Gleeson, E Ryan, S Barrett, J Crowe. (2004) Clinical expression of haemochromatosis in Irish C282Y homozygotes identified through family screening. European Journal of Gastroenterology & Hepatology 16:9, 859-863
CrossRef51
S. DuBois, K. V. Kowdley. (2004) Targeted screening for hereditary haemochromatosis in high-risk groups. Alimentary Pharmacology and Therapeutics 20:1, 1-14
CrossRef52
Pietrangelo, Antonello, . (2004) Hereditary Hemochromatosis — A New Look at an Old Disease. New England Journal of Medicine 350:23, 2383-2397
Full Text53
Mounia Bensaid, Séverine Fruchon, Christine Mazères, Seiamak Bahram, Marie-paule Roth, Hélène Coppin. (2004) Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology 126:5, 1400-1408
CrossRef54
AE Nisselle, MB Delatycki, V Collins, S Metcalfe, MA Aitken, D Du Sart, J Halliday, I Macciocca, A Wakefield, V Hill, A Gason, B Warner, V Calabro, R Williamson, KJ Allen. (2004) Implementation of HaemScreen, a workplace-based genetic screening program for hemochromatosis. Clinical Genetics 65:5, 358-367
CrossRef55
Sumedha P. Galhenage, Charlie H. Viiala, John K. Olynyk. (2004) Screening for hemochromatosis: Patients with liver disease, families, and populations. Current Gastroenterology Reports 6:1, 44-51
CrossRef56
Susan F. Leitman, Janet N. Browning, Yu Ying Yau, Glorice Mason, Harvey G. Klein, Cathy Conry-Cantilena, Charles D. Bolan. (2003) Hemochromatosis subjects as allogeneic blood donors: a prospective study. Transfusion 43:11, 1538-1544
CrossRef57
Gérard Chalès, Pascal Guggenbuhl. (2003) When and how should we screen for hereditary hemochromatosis?. Joint Bone Spine 70:4, 263-270
CrossRef58
Linda M Fletcher, Kim R Bridle, Darrell H.G Crawford. (2003) Effect of alcohol on iron storage diseases of the liver. Best Practice & Research Clinical Gastroenterology 17:4, 663-677
CrossRef59
George N. Ioannou, Kris V. Kowdley. (2003) Iron, HFE mutations, and hepatocellular carcinoma: is hepatic iron a carcinogen?. Clinical Gastroenterology and Hepatology 1:4, 246-248
CrossRef60
Antonello Pietrangelo. (2003) Hemochromatosis gene modifies course of hepatitis C viral infection. Gastroenterology 124:5, 1509-1523
CrossRef61
Giuseppina Imperatore, Linda E. Pinsky, Arno Motulsky, Michele Reyes, Linda A. Bradley, Wylie Burke. (2003) Hereditary hemochromatosis: Perspectives of public health, medical genetics, and primary care. Genetics in Medicine 5:1, 1-8
CrossRef62
Ian McCrossin. (2002) Porphyria cutanea tarda in south-east New South Wales. Australasian Journal of Dermatology 43:4, 285-288
CrossRef63
Jill Waalen, Vincent Felitti, Terri Gelbart, Ngoc J. Ho, Ernest Beutler. (2002) Penetrance of Hemochromatosis. Blood Cells, Molecules, and Diseases 29:3, 418-432
CrossRef64
Prem Ponka. (2002) Rare causes of hereditary iron overload. Seminars in Hematology 39:4, 249-262
CrossRef65
Richard S Ajioka, James P Kushner. (2002) Hereditary hemochromatosis. Seminars in Hematology 39:4, 235-241
CrossRef66
Nancy C Andrews. (2002) A genetic view of iron homeostasis. Seminars in Hematology 39:4, 227-234
CrossRef67
Yves Deugnier, Anne-Marie Jouanolle, Jacques Chaperon, Romain Moirand, Catherine Pithois, Jean-Francois Meyer, Michel Pouchard, Bernard Lafraise, Alain Brigand, Celine Caserio-Schoenemann, Jean Mosser, Paul Adams, Jean-Yves Le Gall, Veronique David. (2002) Gender-specific phenotypic expression and screening strategies in C282Y-linked haemochromatosis: a study of 9396 French people. British Journal of Haematology 118:4, 1170-1178
CrossRef68
Celso Bianco, Gary Brittenham, Ronald O. Gilcher, Victor R. Gordeuk, James P. Kushner, Merlyn Sayers, Linda Chambers, Richard B. Counts, Cheryl Aylesworth, George Nemo, Barbara Alving. (2002) Maintaining iron balance in women blood donors of childbearing age: summary of a workshop. Transfusion 42:6, 798-805
CrossRef69
J. Waalen, V. Felitti, T. Gelbart, N. J. Ho, E. Beutler. (2002) Prevalence of Hemochromatosis-Related Symptoms Among Individuals With Mutations in the HFE Gene. Mayo Clinic Proceedings 77:6, 522-530
CrossRef70
Claus Niederau, Georg Strohmeyer. (2002) Strategies for early diagnosis of haemochromatosis. European Journal of Gastroenterology & Hepatology 14:3, 217-221
CrossRef71
Mark A McCullen, Darrell H.G Crawford, Peter E Hickman. (2002) Screening for hemochromatosis. Clinica Chimica Acta 315:1-2, 169-186
CrossRef72
Ernest Beutler, Vincent J Felitti, James A Koziol, Ngoc J Ho, Terri Gelbart. (2002) Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. The Lancet 359:9302, 211-218
CrossRef73
(2001) Disease-Related Conditions in Relatives of Patients with Hemochromatosis. New England Journal of Medicine 344:19, 1477-1478
Full Text
