Disease-rel Ated Conditions in Rel Atives of Patients With Hemochromatosis

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    Volume 343Number 21  ·  1529  DISEASE-RELATED CONDITIONS IN RELATIVES OF PATIENTS WITH HEMOCHROMATOSIS  DISEASE-RELATED CONDITIONS IN RELATIVES OF PATIENTS WITH HEMOCHROMATOSIS  Z   ANETA  J. B   ULAJ  , M.D., R   ICHARD  S. A   JIOKA  , P   H  .D., J   OHN  D. P   HILLIPS  , P   H  .D., B   ERNARD  A. L   A  S   ALLE  , B.S.,L   YNN  B. J   ORDE  , P   H  .D., L   INDA  M. G   RIFFEN  , B.A., C   ORWIN  Q. E   DWARDS  , M.D., AND  J   AMES  P. K   USHNER  , M.D.  A   BSTRACT  Background   Hemochromatosis occurs in approx-imately 5 white people per 1000 and is usually dueto homozygosity for mutations in the HLA-linked HFE   gene. Although screening has been proposed, theproportion of homozygotes with conditions relatedto hemochromatosis is uncertain.  Methods   We studied the prevalence of disease-related conditions among relatives of probands withhemochromatosis. We identified probands who pre-sented to a clinic with signs or symptoms of hemo-chromatosis or who had elevated transferrin-satu-ration values. We identified homozygous relatives,mainly siblings, on the basis of HLA identity with theproband and by HFE   genotyping. Disease-related con-ditions were cirrhosis, hepatic fibrosis, elevated amino-transferase values, and hemochromatotic arthropathy.  Results   We identified 214 homozygous relativesof 291 homozygous probands. Of the 113 men in thisgroup (mean age, 41 years), 96 (85 percent) had ironoverload, and 43 (38 percent) had at least one dis-ease-related condition. Of the 52 men over 40 yearsof age, 27 (52 percent) had at least one disease-relatedcondition. Of the 101 female homozygous relatives(mean age, 44 years), 69 (68 percent) had iron over-load, and 10 (10 percent) had at least one disease-related condition. Of the 43 women over 50 years ofage, 7 (16 percent) had at least one disease-relatedcondition. If the proband had a disease-related con-dition, relatives who were men were more likely tohave morbidity than if the proband had no disease-related condition.  Conclusions   A substantial number of homozy-gous relatives of patients with hemochromatosis —more commonly men than women — have condi-tions related to hemochromatosis that have yet to bedetected clinically. (N Engl J Med 2000;343:1529-35.)  ©2000, Massachusetts Medical Society.  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 ResearchCenter (B.A.L., L.M.G.), University of Utah School of Medicine; and theLDS Hospital (C.Q.E.) — all in Salt Lake City. Address reprint requests toDr. Kushner at the Division of Hematology, 4C-416, University of UtahSchool of Medicine, 50 North Medical Dr., Salt Lake City, UT 84132, orat james.kushner@hsc.utah.edu.  EMOCHROMATOSIS occurs in approx-imately 5 white people per 1000  1,2  and isusually due to a mutation in the HLA-linked hemochromatosis gene (  HFE   ) thatcauses a change from cysteine to tyrosine at position282 in the HFE protein (C282Y).  3  The phenotypicexpression may vary from that of a fully penetrantclinical syndrome (with bronze pigmentation, cirrho-sis, arthritis, endocrinopathy, and cardiomyopathy) toa simple laboratory abnormality — namely, elevatedtransferrin-saturation values.  1,4  Screening for hemochromatosis has been proposed H  but is difficult to justify, because the proportion of homozygotes in whom disease-related conditions aredestined to develop is unknown. Homozygotes iden-tified because of clinical sequelae of iron overload allhave disease-related conditions,  4-6   whereas screeningof healthy subjects generally uncovers few clinically affected homozygotes.  7,8  The incidence of disease-related conditions might be best estimated by study-ing homozygotes who have not been preselected forillness or good health; such a study would thus befree of ascertainment bias.  9   We report the frequency of conditions related tohemochromatosis in 214 clinically unselected ho-mozygous relatives of 291 homozygous probands.  METHODS   All study procedures were approved by the institutional review board of the University of Utah. Written informed consent wasobtained from all participants.  Probands  The probands were identified between 1975 and 1998. Onehundred eighty-four probands were identified because they present-ed 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 transfer-rin-saturation values during hemochromatosis-screening programs   7  or at routine health maintenance examinations.  Families  The available first-degree relatives and many additional relativesof the probands were evaluated. Genotypic assignments within afamily were based on the proband’s HLA haplotype.   10,11  Siblings who were HLA-identical to the proband were considered ho-mozygotes.   10  Persons who married into affected families and whohad unexplained, persistent transferrin-saturation values of morethan 62 percent were also considered homozygotes.   12  HFE   Mutations  Genotypic assignments based on HLA haplotypes were verifiedby  HFE   genotyping of available specimens. The C282Y mutationand 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 ferritinconcentration were measured in all subjects. Liver-biopsy samples Copyright © 2000 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 28, 2009 . For personal use only. No other uses without permission.   1530  ·  November 23, 2000  The New England Journal of Medicine   were assessed for iron content by histologic staining and atomic-absorption spectrophotometry.   13  Iron overload was considered tobe present when the hepatic-parenchymal-cell stainable iron grade was 2 to 4   14  and the hepatic iron concentration was greater than25 µmol per gram.   11  If liver biopsy was not performed, iron over-load 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 con-sumption was estimated by previously described methods.   15  Meth-ods for measuring aminotransferases varied over the 23-year pe-riod during which subjects were identified. To normalize results, we defined an elevated aminotransferase value to be at least 1.2 timesthe upper limit of the reference range at the time. Porphyria cu-tanea tarda was documented by measuring urinary porphyrin ex-cretion.   15  Histologic grading of fibrosis and cirrhosis was per-formed as previously described.   16  Fibrosis was considered to bepresent if grade 2 (periportal) or more severe fibrosis was noted.Only cirrhosis, fibrosis, elevated aminotransferase values in the ab-sence of any identifiable cause other than iron overload, and radio-graphically confirmed hemochromatotic arthropathy of the meta-carpal–phalangeal joints were considered conditions related tohemochromatosis. Diabetes, other endocrine abnormalities, and car-diac arrhythmias were noted but were not considered to be relatedto hemochromatosis, since it was difficult to establish that theseabnormalities were due solely to iron overload. Antibodies againsthepatitis C virus were detected with an enzyme-linked immuno-sorbent assay (ELISA 2.0, Chiron, Emeryville, Calif.). Althoughsymptoms were not considered criteria for conditions related tohemochromatosis, all subjects were asked about arthralgias, ab-dominal 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 dis-ease-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 andtransferrin-saturation values were compared between groups by Student’s t-test. Comparisons with respect to ferritin concentra-tion (and age, when values were not normally distributed) wereperformed with the Kruskal–Wallis and Mann–Whitney nonpara-metric tests.   18   All reported P values are two-sided. The frequency of morbidity was compared by chi-square analysis.   18  Logistic re-gression was used to test for concordance with respect to mor-bidity.   18  Morbidity in this analysis was defined as present if eithercirrhosis or fibrosis was present, and as absent if neither of theseconditions was present. In the regression analysis, morbidity orabsence of morbidity in the relative was entered as the dependent variable, and morbidity in the proband was entered as the inde-pendent 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 1). Clin-ically affected probands were identified on the basisof signs or symptoms. Other probands were identi-fied 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 homozy-gous relatives of the probands (P<0.001). The lattertwo groups did not differ significantly in age fromone another (P=0.16). Among women, there was nosignificant difference in age between the probandsand their homozygous relatives.  Clinically Unselected Homozygous Relativesof the Probands  Two hundred fourteen homozygous relatives of 291 homozygous probands were identified from 103  *Plus–minus values are means ±SD.†The homozygous relatives were 164 siblings, 10 parents, 19 offspring, 7 nieces, 6 nephews, 1 aunt, 2 uncles, 1 grand-mother, and 4 persons who married into an affected family and had transferrin-saturation values similar to those of ho-mozygotes.‡The P values calculated by the Kruskal–Wallis nonparametric test for the comparison of ferritin concentrations wereas follows: clinically affected probands as compared with probands identified because of elevated transferrin-saturation values: <0.001 for men, 0.002 for women; clinically affected probands as compared with clinically unselected homozy-gous relatives: <0.001 for men, <0.001 for women; probands identified because of elevated transferrin-saturation valuesas compared with clinically unselected homozygous relatives: 0.37 for men, 0.004 for women.  T  ABLE  1.  D  EMOGRAPHIC  C  HARACTERISTICS    AND  I  RON  P  HENOTYPES   OF  P  ROBANDS    AND  T  HEIR   C  LINICALLY   U  NSELECTED  H  OMOZYGOUS  R   ELATIVES  .*   V   ARIABLE   C   LINICALLY   A   FFECTED   P   ROBANDS   (N=184)P   ROBANDS   I   DENTIFIED   BY   E   LEVATED   T   RANSFERRIN   S   ATURATION   (N=107)C   LINICALLY   U   NSELECTED   H   OMOZYGOUS   R   ELATIVES   OF   P   ROBANDS   †(N=214)   MENWOMENMENWOMENMENWOMEN  No.136486641113101 Age (yr)51±1351±1437±1545±1941±1744±19Transferrin saturation (%)87±1081±1382±1379±1282±1469±16Ferritin concentration (µg/liter)‡Median10th and 90th percentiles1300518, 3164657242, 268242199, 127431969, 1023552147, 149517028, 580 Copyright © 2000 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 28, 2009 . For personal use only. No other uses without permission.   DISEASE-RELATED CONDITIONS IN RELATIVES OF PATIENTS WITH HEMOCHROMATOSIS   Volume 343Number 21  ·  1531  families. HLA identity between probands and theirhomozygous siblings was present in 94 families. Innine families, the parents of the proband representeda homozygote–heterozygote pairing, resulting in threeHLA-linked haplotypes among their offspring andHLA nonidentity in some homozygous siblings. HFE   genotypes were determined in 158 clinically unselect-ed homozygotes; the genotype was C282Y/C282Y in 140 (88.6 percent), C282Y/H63D in 10 (6.3 per-cent), C282Y/wild type in 5 (3.2 percent), H63D/ wild type in 2 (1.3 percent), and wild type/wild typein 1 (0.6 percent). The 158 genotyped subjects havea total of 316 HFE   alleles. The allelic frequency of C282Y in this population is 0.930. In contrast, thefrequency of C282Y in the white population of Utahis 0.062.  3,15  Iron Phenotype  There were no significant differences in transfer-rin-saturation values among clinically affected maleprobands, male probands detected because of elevatedtransferrin-saturation values, and homozygous malerelatives of probands (Table 1). Among women, themean transferrin saturation in homozygous relatives was lower than that in either clinically affected pro-bands or probands detected because of elevated trans-ferrin-saturation values (P=0.002 and P=0.03, re-spectively). The ferritin concentrations were highestin clinically affected probands of either sex.Ninety-one percent of clinically affected probandsand 81 percent of those identified because of elevat-ed transferrin-saturation values underwent liver biop-sy (Table 2). Sixty-nine percent of male homozygousrelatives of probands, but only 40 percent of femalerelatives, agreed to undergo liver biopsy. Female rel-atives who underwent biopsy did not differ signifi-cantly in age or ferritin concentration from those whodid not. Among both male and female subjects, themean hepatic iron grade and the median iron concen-tration were highest in clinically affected probands(3.5 and 181 µmol per gram, respectively), next high-est in homozygous relatives of probands (3.1 and126 µmol per gram), and lowest in probands iden-tified because of elevated transferrin-saturation val-ues (2.7 and 69 µmol per gram).  Classification of Homozygous Relatives of Probands  The homozygous relatives of probands were clas-sified into three groups: those with iron overload anddisease-related conditions, those with iron overloadand no disease-related conditions, and those withoutiron overload (Table 3). There were no differences inestimated alcohol consumption among these groups.No relative with iron overload and a disease-relatedcondition (the first group) had evidence of hepatitisC. A relative was assigned to this group if he or shehad cirrhosis, fibrosis, elevated aminotransferase val-ues, or arthropathy (Table 2). If the relative had morethan one of these conditions, he or she was classifiedas having only the condition named earliest in thelist. Forty-three men (38 percent) were assigned tothis group, and 40 of them underwent liver biopsy.  *If a subject had more than one of the four conditions listed, he or she was classified as having only the conditionlisted first.†Arrhythmia was documented by electrocardiography.  T  ABLE  2.  D  ISEASE  -R   ELATED  C  ONDITIONS    AND  O  THER   C  LINICAL   F  INDINGS   IN  T  HREE  G  ROUPS   OF  S  UBJECTS   W   HO   W   ERE  H  OMOZYGOUS   FOR   H  EMOCHROMATOSIS  .   V   ARIABLE   C   LINICALLY   A   FFECTED   P   ROBANDS   (N=184)P   ROBANDS   I   DENTIFIED   BY   E   LEVATED   T   RANSFERRIN   S   ATURATION   (N=107)C   LINICALLY   U   NSELECTED   H   OMOZYGOUS   R ELATIVES   OF P ROBANDS (N=214) MENWOMENMENWOMENMENWOMEN No. of subjects136486641113101Liver biopsies — no. of subjects1234454337840Disease-related conditions —no. of subjects*CirrhosisFibrosis Aminotransferase elevation Arthropathy 5532165109733691227314131152422Subjects with at least 1 disease-relatedcondition — no. (%)108 (79)29 (60)19 (29)14 (34)43 (38)10 (10)Other clinical findings — no. of subjectsDiabetesHypogonadotrophic hypogonadismCardiac arrhythmia†Portal hypertension with splenomegaly Hepatocellular carcinomaPorphyria cutanea tarda3216212514106354092020000110003410921503201 Copyright © 2000 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 28, 2009 . For personal use only. No other uses without permission.  1532 · November 23, 2000 The New England Journal of Medicine Ninety percent of the men in the group had theC282Y/C282Y genotype. The age, ferritin concen-tration, 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 condi-tions (mean age, 48 vs. 38 years [P=0.007]; medianferritin 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 µmolper gram [P=0.002]).Cirrhosis or fibrosis was found in 27 men (Table2). Fourteen of these men had elevated aminotrans-ferase values, and nine had arthropathy. Hepatocel-lular carcinoma developed in one of the men whohad cirrhosis, and porphyria cutanea tarda in another. Among those without cirrhosis or fibrosis, arthrop-athy was found in eight (either alone or in combina-tion 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 anddisease-related conditions (40 percent) had arthrop-athy. Sixteen men in the group had no symptoms. Among the 27 who had symptoms, arthralgias werethe most common, being reported by 22 men. Fourmen in the group with iron overload and no disease-related conditions had cardiac arrhythmias, but allother manifestations shown in Table 2 were foundonly in men in the group with iron overload and dis-ease-related conditions.Ten women (10 percent) were assigned to thegroup with iron overload and disease-related condi-tions (Table 3), and nine of these women underwentbiopsy. In seven of the women the genotype wasdetermined; all had the C282Y/C282Y genotype. Among women with iron overload, those with and without disease-related conditions did not differ sig-nificantly in age, ferritin concentration, hepatic irongrade, or iron concentration. Cirrhosis or fibrosis wasfound in six women (Table 2), of whom three hadelevated aminotransferase values and three had ar-thropathy. One woman with fibrosis and elevatedaminotransferase values also had porphyria cutaneatarda. Three of the four women without histologicevidence of liver damage had arthropathy. As withmen, the frequency of arthropathy did not differ be-tween women with and without liver damage. Three women in the group with iron overload and disease-related conditions were asymptomatic. Arthralgiasoccurred in five of the remaining seven. Two womenin the group with iron overload and no disease-related conditions had diabetes and cardiac arrhyth-mias, but all other manifestations listed in Table 2 were found only in women in the group with ironoverload and disease-related conditions. Effects of Age and Sex on Disease-Related Conditionsin Homozygous Relatives of Probands Iron overload in male homozygous relatives of pro-bands became prominent after the age of 20 years(Table 3). Among female homozygous relatives of probands, iron overload was most common after theage of 50 years. Among men over 40 years old, 90percent had iron overload and 52 percent had dis-ease-related conditions. Among women over 50 yearsold, 88 percent had iron overload and 16 percenthad disease-related conditions. Disease-Related Conditions in Probands  All clinically affected probands had iron overload. Arthralgias and weakness were the most commonsymptoms. Only 10 percent of men and 6 percent of  women were asymptomatic. Arthralgias were report-ed by 65 of 122 symptomatic men, weakness by 63,and abdominal pain by 48. One hundred eight clin-ically affected male probands (79 percent) had oneor more disease-related conditions. Other findingsin clinically affected male probands are shown in Ta-ble 2. Arthralgias were reported by 23 of 45 symp-tomatic women, weakness by 22, and abdominal painby 10. The criteria used to assign relatives of pro-bands to the group with iron overload and disease-related conditions were found in 29 clinically affectedfemale probands (60 percent). Other findings in clin-ically affected female probands are shown in Table 2. Among probands identified because of elevatedtransferrin-saturation values, 52 percent of the menand 34 percent of the women had iron overload, and97 percent of the men and 90 percent of the women were asymptomatic. Among probands identified be-cause of elevated transferrin-saturation values, dis-ease-related conditions were present in 19 men (29percent) and 14 women (34 percent). Other disease-related manifestations of hemochromatosis in pro- T ABLE 3. D ISEASE -R  ELATED C ONDITIONS    AND I RON O  VERLOAD   IN 214 C LINICALLY  U NSELECTED H OMOZYGOUS R  ELATIVES   OF P ROBANDS , A  CCORDING   TO S EX     AND A  GE . S EX   AND A GE T OTAL I RON O VERLOAD N O I RON  O VERLOAD DISEASE - RELATED   CONDITIONSNO   DISEASE - RELATED   CONDITIONS no. of subjects Male1–20 yr21–40 yr>40 yr1150521152742920665Female1–20 yr21–50 yr>50 yr85043127325314235 Copyright © 2000 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 28, 2009 . For personal use only. No other uses without permission.
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