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AJM online Clinical research study| Volume 120, ISSUE 8, P734.e1-734.e9, August 01, 2007

African Americans at Risk for Increased Iron Stores or Liver Disease

Published:March 16, 2007DOI:https://doi.org/10.1016/j.amjmed.2006.05.049
African Americans at Risk for Increased Iron Stores or Liver Disease
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      Abstract

      Purpose

      We sought to determine the prevalence of elevated measures of iron status in African Americans and whether the combination of serum ferritin concentration >200 μg/L for women or >300 μg/L for men and transferrin saturation in the highest quartile represents increased likelihood of mutation of HFE, self-reported iron overload or self-reported liver disease.

      Subjects and Methods

      A cross-sectional observational study of 27,224 African Americans ≥25 years of age recruited in a primary care setting was conducted as part of the multi-center, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study. Measurements included serum ferritin concentration, transferrin saturation, testing for HFE C282Y and H63D, and self-reported iron overload and liver disease.

      Results

      Serum ferritin concentration >200 μg/L for women or >300 μg/L for men occurred in 5263 (19.3%) of African Americans, while serum ferritin concentration in this range with highest-quartile transferrin saturation (>29% women; >35% men) occurred in 1837 (6.7%). Adjusted odds of HFE mutation (1.76 women, 1.67 men), self-reported iron overload (1.97 women, 2.88 men), or self-reported liver disease (5.18 women, 3.73 men) were greater with elevated serum ferritin concentration and highest-quartile transferrin saturation than with nonelevated serum ferritin concentration (each P <.05).

      Conclusions

      Serum ferritin concentration >200 μg/L for women or >300 μg/L for men in combination with transferrin saturation >29% for women or >35% for men occurs in approximately 7% of adult African American primary care patients. Patients with this combination of iron test results should be evaluated for increased body iron stores or liver disease.

      Keywords

      Increased iron stores attributable to dietary and possibly heritable factors occur in approximately 10% of rural adults in sub-Saharan Africa,
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      • Hasstedt S.J.
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      Iron overload in Africa: interaction between a gene and dietary iron content.
      N Engl J Med. 1992; 326: 95-100
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      • Hasstedt S.J.
      • et al.
      Evidence of genetic transmission in African iron overload.
      Blood. 1998; 91: 1076-1082
      but few cases of primary increases in body iron stores have been reported in African Americans.
      • Dawkins F.W.
      • Gordeuk V.R.
      Other disorders of increased iron absorption: iron overload in Africans and African Americans.
      in: Templeton D.M. Molecular and Cellular Iron Transport. Marcel Dekker, Inc, New York, New York2002: 775-785
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      • Barton J.C.
      • Edwards C.Q.
      • Bertoli L.F.
      • et al.
      Iron overload in African Americans.
      Am J Med. 1995; 99: 616-623
      Nonetheless, autopsy studies suggest that an increase in hepatic iron is a fairly common finding in African Americans.
      • Wurapa R.K.
      • Gordeuk V.R.
      • Brittenham G.M.
      • et al.
      Primary iron overload in African Americans.
      Am J Med. 1996; 101: 9-18
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      • Brown K.E.
      • Khan C.M.
      • Zimmerman M.B.
      • Brunt E.M.
      Hepatic iron overload in blacks and whites; a comparative autopsy study.
      Am J Gastroenterol. 2003; 98: 1594-1598
      Most Africans and African Americans with increased iron stores do not have HFE mutations that are common in whites with hemochromatosis,
      • Wurapa R.K.
      • Gordeuk V.R.
      • Brittenham G.M.
      • et al.
      Primary iron overload in African Americans.
      Am J Med. 1996; 101: 9-18
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      • McNamara L.
      • MacPhail A.P.
      • Gordeuk V.R.
      • et al.
      Is there a link between African iron overload and the described mutations of the hereditary haemochromatosis gene?.
      Br J Haematol. 1998; 102: 1176-1178
      , 
      • Monaghan K.G.
      • Rybicki B.A.
      • Shurafa M.
      • Feldman G.L.
      Mutation analysis of the HFE gene association with hereditary hemochromatosis in African Americans.
      Am J Hematol. 1998; 58: 213-217
      , 
      • Barton J.C.
      • Acton R.T.
      • Rivers C.A.
      • et al.
      Genotypic and phenotypic heterogeneity of African Americans with primary iron overload.
      Blood Cells Mol Dis. 2003; 31: 310-319
      and the prevalence of HFE C282Y homozygosity is approximately 14 per 100,000 among African American primary care patients.
      • Adams P.C.
      • Reboussin D.M.
      • Barton J.C.
      • et al.
      Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators
      Hemochromatosis and iron-overload screening in a racially diverse population.
      N Engl J Med. 2005; 352: 1769-1778
      • •
        Elevated serum ferritin (>200 μg/L women, >300 μg/L men) in combination with highest quartile transferrin saturation (>29% women, >35% men) occurred in 7% of 27,224 African American primary care patients.
      • •
        This combination was associated with significantly increased odds of HFE mutation, self-reported iron overload, and self-reported liver disease.
      • •
        African American patients with elevated ferritin and highest quartile transferrin saturation should be screened for increased iron stores and liver disease.
      Increased iron stores may lead to multisystem organ dysfunction, contribute to the severity of viral hepatitis, or increase the risk for certain infections and malignancies.
      • Dawkins F.W.
      • Gordeuk V.R.
      Other disorders of increased iron absorption: iron overload in Africans and African Americans.
      in: Templeton D.M. Molecular and Cellular Iron Transport. Marcel Dekker, Inc, New York, New York2002: 775-785
      , 
      • Gordeuk V.R.
      • McLaren G.D.
      • Samowitz W.
      Etiologies, consequences, and treatment of iron overload.
      Crit Rev Clin Lab Sci. 1994; 31: 89-133
      Increased iron stores are often suspected when there is an unexplained elevation in serum ferritin concentration and transferrin saturation. Elevations in these measures of iron status are not in themselves sufficient to confirm a diagnosis of increased iron stores, for this combination is frequently seen in liver disease without iron overload. In the multicenter HEmochromatosis and IRon Overload Screening (HEIRS) Study in the US and Canada, more than 100,000 participants, of whom more than 27,000 were self-identified as African Americans, were tested for serum ferritin concentration, transferrin saturation, and HFE mutations, and questioned regarding health conditions including iron overload and liver disease.
      Infectious and other inflammatory processes, hepatic disorders such as alcoholic and viral hepatitis and nonalcoholic steatohepatitis (NASH), and increased body iron stores resulting from multiple blood transfusions, HFE mutations, or other primary processes are all potential causes of increases in serum ferritin concentrations.
      • Reissmann K.R.
      • Diedrich M.R.
      On the presence of ferritin in the peripheral blood of patients with hepatocellular disease.
      J Clin Invest. 1956; 35: 588
      , 
      • Aungst C.W.
      Ferritin in body fluids.
      J Lab Clin Med. 1968; 71: 517
      , 
      • Lipschitz D.A.
      • Cook J.D.
      • Finch C.A.
      A clinical evaluation of serum ferritin as an index of iron stores.
      N Engl J Med. 1975; 290: 1213
      , 
      • Prieto J.
      • Barry M.
      • Sherlock S.
      Serum ferritin in patients with chronic liver disease.
      Gastroenterology. 1975; 68: 525
      , 
      • Meyer T.E.
      • Kassianides C.
      • Bothwell T.H.
      • Green A.
      Effects of heavy alcohol consumption on serum ferritin concentrations.
      S Afr Med J. 1984; 66: 573
      , 
      • Leggett B.A.
      • Brown N.N.
      • Bryant S.J.
      • et al.
      Factors affecting the concentrations of ferritin in serum in a healthy Australian population.
      Clin Chem. 1990; 36: 1350
      , 
      • Cartwright G.E.
      • Wintrobe M.M.
      Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXXIX. The anemia of infection. Studies on the iron-binding capacity of serum.
      J Clin Invest. 1949; 28: 86
      , 
      • Di Bisceglie A.M.
      • Axiotis C.A.
      • Hoofnagle J.H.
      • Bacon B.R.
      Measurements of iron status in patients with chronic hepatitis.
      Gastroenterology. 1992; 102: 2108-2113
      Inflammatory processes are typically characterized by reduced serum iron concentration and transferrin saturation in association with increased serum ferritin concentration.
      • Cartwright G.E.
      • Wintrobe M.M.
      Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXXIX. The anemia of infection. Studies on the iron-binding capacity of serum.
      J Clin Invest. 1949; 28: 86
      On the other hand, patients with elevated iron stores or hepatic disorders tend to have transferrin saturations above the population mean in association with increased serum ferritin concentration.
      • Di Bisceglie A.M.
      • Axiotis C.A.
      • Hoofnagle J.H.
      • Bacon B.R.
      Measurements of iron status in patients with chronic hepatitis.
      Gastroenterology. 1992; 102: 2108-2113
      , 
      • Gordeuk V.R.
      • Boyd R.D.
      • Brittenham G.M.
      Dietary iron overload persists in rural sub-Saharan Africa.
      Lancet. 1986; 1: 1310-1313
      We therefore reasoned that assessing serum ferritin concentration in the context of the accompanying transferrin saturation would be useful in developing certain broad categories of potential causes for serum ferritin elevation. Specifically, we hypothesized that serum ferritin concentration above the upper limit of the reference range in association with transferrin saturation in the upper population quartile would represent increased likelihood of HFE mutation, self-reported iron overload, or self-reported liver disease. We also hypothesized that serum ferritin concentration above the upper limit of the reference range in association with transferrin saturation in the lower population quartile would represent increased likelihood of self-reported inflammatory processes.

      Study Participants and Methods

      Study Approval

      The local Institutional Review Board of each field center approved the study protocol, which is described in detail elsewhere,
      • McLaren C.E.
      • Barton J.C.
      • Adams P.C.
      • et al.
      Hemochromatosis and iron overload screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.
      Am J Med Sci. 2003; 325: 53-62
      and written informed consent was obtained from each participant.

      Selection of Study Subjects

      Participants 25 years of age or older were recruited during the interval of February 2001 to March 2003 from public and private primary care offices and ambulatory clinics (Howard University, Washington, DC; University of Alabama at Birmingham; and University of California, Irvine), from a health maintenance organization (Kaiser Permanente Northwest in Portland, Oregon and Kaiser Permanente Hawaii), and from diagnostic blood collection centers (MDS Laboratories, London, Ontario, and Dynacare Laboratories, Richmond Hill, Ontario, Canada) associated with the 5 HEIRS Study field centers. These facilities serve ethnically and socioeconomically diverse primary care patients. Other adult volunteers, such as family members or friends accompanying a patient, were also eligible to participate.
      • McLaren C.E.
      • Barton J.C.
      • Adams P.C.
      • et al.
      Hemochromatosis and iron overload screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.
      Am J Med Sci. 2003; 325: 53-62
      At the screening visit, HEIRS Study participants completed a questionnaire that included questions about race/ethnicity.
      • McLaren C.E.
      • Barton J.C.
      • Adams P.C.
      • et al.
      Hemochromatosis and iron overload screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.
      Am J Med Sci. 2003; 325: 53-62
      Of the 101,168 participants with complete transferrin saturation, serum ferritin concentration, and HFE mutation results, those who identified themselves only as African American or black, hereafter referred to as African Americans, were selected for this analysis. Participants who also reported Hispanic race/ethnicity or 2 or more race/ethnicity groups were not included in this analysis. The questionnaire also asked whether participants had ever been diagnosed with any or all of the following conditions: iron overload or hemochromatosis, arthritis, diabetes mellitus, liver disease or liver cancer, heart failure, and fertility problems or impotence. The options for each category were “yes,” “no,” or “not sure.” Blood samples were obtained from participants to measure transferrin saturation and serum ferritin concentration and to analyze for HFE C282Y and H63D mutations. Participants who were negative for C282Y and H63D were designated as having a wild type (wt) genotype.

      Laboratory Methods

      The Central Laboratory (located at University of Minnesota Medical Center, Minneapolis) performed all laboratory screening tests, except transferrin saturation testing of London Health Sciences Centre participants (performed by MDS Laboratory Services, Canada, using an identical method). Measurements included spectrophotometric serum iron and unsaturated iron-binding capacity, turbidometric immunoassay of serum ferritin concentration (Roche Diagnostics/Hitachi 911, Indianapolis, Indiana), and calculated total iron-binding capacity and transferrin saturation. Method biases were assessed 3 times a year using external proficiency testing samples provided by the College of American Pathologists Surveys (Northfield, Illinois). Internal quality control pools were included with each analytical batch at both normal and elevated transferrin saturation and serum ferritin values to assess assay drift. To monitor overall reproducibility, blind replicate samples collected from 2% of participants at each field center were analyzed at the Central Laboratory or the MDS Laboratory, as appropriate. Analytical variability was determined for transferrin saturation and serum ferritin concentration by analysis of routine internal laboratory quality control pools in each analytical batch. For transferrin saturation measurements, the batch-to-batch coefficient of variation was 3.0%, and the correlation coefficient between original and blind replicate values was 0.98. For serum ferritin measurements, the batch-to-batch coefficient of variation was 4.7%, and the correlation coefficient between original and blind replicate values was 0.99.
      HFE C282Y and H63D were detected by a modification of the Invader assay (Third Wave Technologies, Inc., Madison, Wisconsin), which increases the allele-specific fluorescent signal by including 12 cycles of locus-specific polymerase chain reaction before the cleavase reaction. Buffy coats from whole-blood EDTA samples were spotted onto FTA paper (Fitzco, Inc., Maple Plain, Minnesota), and a 1.5-mm punch was used for testing. Analyses of blind replicate participant samples to detect C282Y and H63D were concordant in 99.8% and 99.2% of participants, respectively. In 2% of samples selected randomly, repetition of analyses using a different genotyping method (PCR-RFLP) yielded concordant results in 99.8% of C282Y determinations and 99.9% of H63D determinations. Specimens for which inconsistent results were obtained were analyzed further, as indicated, to resolve uncertainty about respective HFE genotypes before the corresponding participant data were subjected to final analysis.

      Statistical Analysis

      The HEIRS Study prospectively defined elevated serum ferritin concentration as >300 ug/L for men and >200 ug/L for women.
      • McLaren C.E.
      • Barton J.C.
      • Adams P.C.
      • et al.
      Hemochromatosis and iron overload screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.
      Am J Med Sci. 2003; 325: 53-62
      The hypothesis that categorizing iron status further by transferrin saturation quartiles would identify subgroups at greater risk for HFE mutations, self-reported iron overload, or self-reported liver disease versus self-reported inflammatory conditions was developed after collection of the screening data. Differences in self-reported disease and the presence of HFE mutations with respect to subgroups for serum ferritin concentrations were assessed using multiple logistic regression models adjusting for sex and age. Each subgroup with elevated serum ferritin concentration based on transferrin saturation quartile was compared with the nonelevated serum ferritin concentration group using a separate model. P <.05 was considered statistically significant. Means are reported ± SD; medians are reported with interquartile ranges. Odds ratio estimates (adjusted for sex and age) are reported with corresponding 95% confidence intervals (CIs). To estimate the population risk (percent) of elevated measures of iron status not attributable to mutation of HFE, self-reported iron overload or self-reported liver disease, we divided the proportion with the elevated measure in those with none of the 3 conditions by the proportion with the elevated measure among all participants
      • Kahn H.A.
      • Sempos C.T.
      Statistical Methods in Epidemiology. Oxford University Press, New York, New York1989
      ; the estimates were calculated in those participants with complete self-report information. SAS statistical software (version 8.2, SAS Institute Inc., Cary, NC) was used for all regression analyses.

      Results

      Study Participants

      Of the 101,168 participants >25 years of age screened in the HEIRS Study, 27,224 were African Americans. Demographic and clinical characteristics are summarized in Table 1. Participants were recruited from 5 field centers in the United States and Canada. Two field centers, Howard University in Washington, DC and the University of Alabama at Birmingham, Birmingham, AL enrolled 97% of the African American participants. Self-reported arthritis was noted in 30.0% of participants (95% CI, 29.5-30.6), diabetes mellitus in 17.5% (95% CI, 17.0-18.0), heart failure in 5.3% (95% CI, 5.0-5.5), sexual dysfunction or fertility problems in 3.3% (95% CI, 3.1-3.5), liver disease in 2.0% (95% CI, 1.8-2.1), and iron overload or hemochromatosis in 1.1% (95% CI, 1.0-1.3). Ninety-two percent (95% CI, 91.6-92.2) of the participants were negative for HFE mutations.
      Table 1Demographic and Clinical Features of 27,224 African American Study Participants
      The sample size is 27,224 except where noted.
      Women (n = 17,341)Men (n = 9883)
      Age in years (mean ± SD) (n = 9881 men, 17,334 women)49 ± 1449 ± 14
      Field Center at which recruited (no. and %)
       Howard University, Washington, DC10,576 (61.0%)6054 (61.3%)
       Kaiser Permanente, Portland, Oregon188 (1.1%)139 (1.4%)
       University of Alabama, Birmingham6273 (36.2%)3453 (34.9%)
       University of California, Irvine192 (1.1%)155 (1.6%)
       University of Western Ontario, London112 (0.7%)82 (0.8%)
      Self-reported disease (no. and %)
       Arthritis (n = 9234 men, 16,161 women)5506 (34.1%)2116 (22.9%)
       Diabetes mellitus (9267 men, 16,168 women)2857 (17.7%)1590 (17.2%)
       Heart disease (9218 men, 16,134 women)784 (4.9%)549 (6.0%)
       Sexual dysfunction or infertility (9105 men, 16,016 women)467 (2.9%)361 (4.0%)
       Liver disease (9209 men, 16,112 women)270 (1.7%)229 (2.5%)
       Iron overload/hemochromatosis (9039 men, 15,864 women)182 (1.1%)95 (1.1%)
      HFE mutations (no. and %)
       Wild type/wild type15,934 (91.89%)9084 (91.92%)
       H63D/wild type970 (5.59%)560 (5.67%)
       C282Y/wild type394 (2.27%)212 (2.12%)
       C282Y/H53D21 (0.12%)15 (0.15%)
       H63D/H63D21 (0.12%)9 (0.09%)
       C282Y/C282Y1 (0.01%)3 (0.03%)
      low asterisk The sample size is 27,224 except where noted.

      Serum Biochemical Measures of Iron Status

      Results for serum ferritin concentration and transferrin saturation values are summarized in Table 2, Table 3. The median serum ferritin concentration was 2.5-fold higher in men than in women, and the median transferrin saturation was 1.3-fold higher. Overall, 5263 (19.3%) of African Americans had serum ferritin levels above 200 μg/L for women and 300 μg/L for men, with 1837 (6.7%; 95% CI, 6.5%-7.1%) having serum ferritin concentration in this range in combination with transferrin saturation in the highest quartile (>29% in women and >35% in men). In contrast, the combination of serum ferritin concentration above 200 μg/L for women and 300 μg/L for men and transferrin saturation in the lowest quartile (<17% in women and <23% in men) occurred in 792 (2.9%). There was a tendency to higher serum ferritin concentrations and transferrin saturations in the participants with HFE mutations compared with the wild type participants (Table 3).
      Table 2Measures of Iron Status in 27,224 African American Study Participants
      Women (n = 17,341)Men (n = 9883)
      Serum ferritin in μg/L (median and IQ range)75 (35-146)186 (110-309)
      Serum ferritin >200 μg/L women, >300 μg/L men (no. and %)2688 (15.5%)2575 (26.1%)
      Transferrin saturation in % (median and IQ range)22 (16-29)28 (22-35)
      Transferrin saturation in % by approximate quartile
       1st Quartile<3-16<3-22
       2nd Quartile17-2223-28
       3rd Quartile23-2929-35
       4th Quartile30-10036-100
      Serum ferritin >200 μg/L women, >300 μg/L men by Approximate transferrin saturation quartile (no. and column %)
       1st TS quartile258 (9.6%)534 (20.7%)
       2nd TS quartile554 (20.6%)634 (24.6%)
       3rd TS quartile842 (31.3%)604 (23.5%)
       4th TS quartile1034 (38.5%)803 (31.2%)
      Table 3Indirect Measures of Iron Status by Sex and HFE C282Y and H63D Genotype in African Americans
      HFE C282Y and H63D GenotypenAge (Years) Mean ± SDSerum Ferritin (μg/L)Transferrin Saturation (%)
      Mean ± SDMedian (Interquartile Range)Mean ± SDMedian (Interquartile Range)
      All participants27,224
       All Women17,34149 ± 14118 ± 17875 (35-146)23 ± 1122 (16-29)
       All Men988349 ± 14249 ± 280186 (110-309)29 ± 1228 (22-35)
      Wild type/wild type25,018
       Women15,93449 ± 14117 ± 18074 (35-144)23 ± 1122 (16-29)
       Men908449 ± 14244 ± 282184 (110-306)29 ± 1127 (22-35)
      H63D/wild type1530
       Women97050 ± 15113 ± 13575 (38-46)25 ± 1125 (18-31)
       Men56050 ± 15266 ± 257198 (113-339)32 ± 1230 (24-38)
      C282Y/wild type606
       Women39450 ± 15145 ± 18597 (39-191)28 ± 1327 (19-34)
       Men21251 ± 14280 ± 255204 (126-357)35 ± 1333 (25-42)
      H63D/H63D30
       Women2160 ± 16146 ± 12485 (52-241)33 ± 1328 (23-38)
       Men954 ± 15194 ± 101173 (159-193)30 ± 1228 (21-37)
      C282Y/H63D36
       Women2152 ± 17155 ± 194103 (50-168)36 ± 1235 (30-45)
       Men1550 ± 19233 ± 129211 (131-363)45 ± 1544 (31-55)
      C282Y/C282Y4
       Women1653033033030
       Men345 ± 25397 ± 400297 (57-838)95 ± 799 (87-99)
      “Wild type” indicates the absence of an HFE C282Y or H63D mutation.

      Prevalence of HFE Mutations in Serum Ferritin Subgroups Based on Transferrin Saturation Quartiles

      Mutations of HFE (C282Y/C282Y, C282Y/H63D, H63D/H63D, C282Y/wild type or H63D/wild type) were found in 13.7% of women with elevated serum ferritin concentration in combination with highest-quartile transferrin saturation compared with 7.9% of women and 7.6% of men without serum ferritin concentration elevation (Table 4). The adjusted odds ratio for having mutation of HFE in patients with elevated serum ferritin concentration and highest-quartile transferrin saturation compared to those with nonelevated serum ferritin concentration was 1.76 (95% CI, 1.45-2.13) for women and 1.67 (95% CI, 1.32-2.10) for men.
      Table 4Prevalence of HFE Mutations in Subgroups of Patients Based on Serum Ferritin Concentration and Transferrin Saturation (The Comparison Group Consists of Patients with Serum Ferritin Concentration ≤200 μg/L for Women and ≤300 μg/L for Men)
      PhenotypeWomen (n = 17,341)Men (n = 9883)
      Serum Ferritin Concentration
      P <.0001.
      		Transferrin Saturation in % (Quartile)nPrevalence of HFE Mutations
      All HFE mutations (C282Y/C282Y, C282Y/H63D, C282Y/+, H63D/H63D, H63D/+).
      (No. and %)      		Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      		nPrevalence of HFE Mutations
      All HFE mutations (C282Y/C282Y, C282Y/H63D, C282Y/+, H63D/H63D, H63D/+).
      (No. and %)      		Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      >200 μg/L women; >300 μg/L men<3-16 F, <3-22 M (Q1)25812 (4.7%)0.54
      .0001<P<.05.
       (0.30-0.98)      		52438 (7.1%)0.93 (0.66-1.30)
      17-29 F, 23-35 M (Q2 & Q3)139695 (6.8%)0.79
      .0001<P<.05.
       (0.64-0.99)      		1238110 (8.9%)1.18 (0.96-1.47)
      30-100 F, 36-100 M (Q4)1034142 (13.7%)1.76
      P <.0001.
       (1.45-2.13)      		80397 (12.1%)1.67
      P <.0001.
       (1.32-2.10)
      Below above cutoffsAll14,6531158 (7.9%)17308554 (7.6%)1
      CI = confidence interval.
      low asterisk P <.0001.
      † All HFE mutations (C282Y/C282Y, C282Y/H63D, C282Y/+, H63D/H63D, H63D/+).
      ‡ The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      § .0001 < P < .05.

      Prevalence of Self-Reported Disease in Serum Ferritin Subgroups Based on Transferrin Saturation Quartiles

      Among both women and men, the adjusted odds of having self reported arthritis (1.36, 95% CI, 1.03, 1.80 for women; 1.32, 95% CI, 1.07, 1.64 for men) or diabetes mellitus (2.34, 95% CI, 1.77, 3.09 for women; 1.99, 95% CI, 1.61, 2.46 for men) were significantly higher with the combination of elevated serum ferritin concentration and transferrin saturation in the lowest quartile when compared to the group with nonelevated serum ferritin concentration (Table 5, Table 6). In contrast, the adjusted odds of self-reported liver disease (5.18, 95% CI, 3.80-7.08 for women; 3.73, 95% CI, 2.66-5.24 for men) or iron overload (1.97, 95% CI, 1.20-3.23 for women; 2.88, 95% CI, 1.71-4.86 for men) were significantly higher with the combination of elevated serum ferritin concentration and transferrin saturation in the highest quartile when compared to the group with nonelevated serum ferritin concentration. Among women, but not men, the adjusted odds of having self-reported heart failure were significantly higher with elevated serum ferritin concentration and transferrin saturation in the lowest quartile than with nonelevated serum ferritin concentration. Among both women and men, the odds of having self-reported arthritis, diabetes mellitus, or liver disease also were significantly higher with elevated serum ferritin concentration and transferrin saturation in the middle quartiles (17%-29% for women and 23%-35% for men) than with nonelevated serum ferritin concentration.
      Table 5 Prevalence of Self-Reported Condition in Subgroups of 17,341 African American Women Based on Serum Ferritin Concentration and Transferrin Saturation (The Comparison Group Consists of Patients with Serum Ferritin Concentration ≤200 μg/L)
      Phenotypen%Self-Reported ArthritisSelf-Reported Diabetes MellitusSelf-Reported Heart FailureSelf-Reported InfertilitySelf-Reported Liver DiseaseSelf-Reported Iron Overload or Hemochromatosis
      Serum ferritinTransferrin Saturation in % (Quartile)Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      ≤200 μg/L<3-16 (Q1)2581.5113/240 (47.1%)1.36
      .0001<P<.05.
       (1.03-1.80)      		85/239 (35.6%)2.34
      P <.0001.
       (1.77-3.09)      		29/239 (12.1%)2.21
      P <.0001.
       (1.47-3.31)      		6/235 (2.6%)1.00 (0.44-2.28)3/238 (1.3%)0.99 (0.31-3.12)4/231 (1.7%)1.62 (0.59-4.42)
      17-29 (Q2 & Q3)13968.1660/1306 (50.5%)1.35
      P <.0001.
       (1.19-1.52)      		414/1315 (31.5%)1.78
      P <.0001.
      (1.56-2.03)      		91/1302 (7.0%)1.03 (0.81-1.30)39/1297 (3.0%)1.25 (0.89-1.76)32/1310 (2.4%)1.95
      .0001<P<.05.
       (1.32-2.87)      		18/1284 (1.4%)1.26 (0.76-2.09)
      30-100 (Q4)10346.0442/965 (45.8%)1.10 (0.95-1.27)221/960 (23.0%)1.13 (0.96-1.33)57/960 (5.9%)0.89 (0.66-1.18)18/951 (1.9%)0.80 (0.49-1.29)58/960 (6.0%)5.18
      P <.0001.
       (3.80-7.08)      		19/930 (2.0%)1.97
      .0001<P<.05.
      (1.20-3.23)
      ≤200 μg/LAll14,65384.54291/13,650 (31.4%)12137/13,654 (15.7%)1607/13,633 (4.5%)1404/13,533 (3.0%)1177/13,604 (1.3%)1141/13419(1.1%)1
      CI = confidence interval.
      For self-reported conditions, the denominators for prevalence estimates are different from the n for the transferrin saturation quartiles because not all participants completed this part of the questionnaire.
      low asterisk P <.0001.
      † The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age.
      ‡ .0001 < P < .05.
      Table 6Prevalence of Self-Reported Condition in Subgroups of 9883 African American Men Based on Serum Ferritin Concentration and Transferrin Saturation (The Comparison Group Consists of Patients with Serum Ferritin Concentration ≤300 μg/L)
      Phenotypen%Self-Reported ArthritisSelf-Reported DiabetesSelf-Reported Heart FailureSelf-Reported Infertility/ ImpotenceSelf-Reported Liver DiseaseSelf-Reported Iron Overload or Hemochromatosis
      Serum ferritin Concentration
      P <.0001.
      		Transferrin Saturation in % (Quartile)Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age. CI denotes confidence interval.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age. CI denotes confidence interval.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age. CI denotes confidence interval.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age. CI denotes confidence interval.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age. CI denotes confidence interval.
      		Prevalence (%)Adjusted Odds Ratio (95% CI)
      The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age. CI denotes confidence interval.
      >300 μg/L<3-22 (Q1)5245.4147/504 (29.2%)1.32
      .0001<P <.05.
       (1.07-1.64)      		140/509 (27.5%)1.99
      P <.0001.
       (1.61-2.46)      		38/504 (7.5%)1.18 (0.83-1.67)21/496 (4.2%)0.95 (0.60-1.51)15/506 (3.0%)1.60 (0.93-2.75)2/490 (0.4%)0.43 (0.11-1.78)
      23-35 (Q2 & Q3)123812.5304/1174 (25.9%)1.17
      .0001<P <.05.
       (1.01-1.36)      		277/1178 (23.5%)1.66
      P <.0001.
       (1.42-1.93)      		67/1166 (5.8%)0.92 (0.70-1.20)49/1156 (4.2%)1.00 (0.73-1.37)39/1165 (3.4%)1.82
      .0001<P <.05.
       (1.26-2.62)      		14/1151 (1.2%)1.32 (0.74-2.38)
      36-100 (Q4)8038.1172/747 (23.0%)0.99 (0.82-1.20)133/749 (17.8%)1.14 (0.93-1.40)42/743 (5.7%)0.90 (0.65-1.25)23/729 (3.2%)0.74 (0.48-1.14)49/739 (6.6%)3.73
      P <.0001.
       (2.66-5.24)      		19/733 (2.6%)2.88
      P <.0001.
       (1.71–4.86)
      ≤300 μg/LAll730874.01493/6809 (21.9%)11040/6831 (15.2%)1402/6805 (5.9%)1268/6724 (4.0%)1126/6799 (1.9%)160/6665 (0.9%)1
      For self-reported conditions, the denominators for prevalence estimates are different from the n for the transferrin saturation quartiles because not all participants completed this part of the questionnaire.
      low asterisk P <.0001.
      † The effect of each subgroup for elevated serum ferritin concentration was compared with the nonelevated serum ferritin concentration group using multiple logistic regression models adjusted for age. CI denotes confidence interval.
      ‡ .0001 < P <.05.

      Attributable Risk for Combinations of Serum Ferritin Concentration and Transferrin Saturation above Certain Cutoff Levels

      The combination of serum ferritin concentration above 200 μg/L in women or 300 μg/L in men and transferrin saturation above 29% in women or 35% in men, which applied to 6.7% of our population, could be attributed to mutation of HFE, self-reported iron overload, or self-reported liver disease in 10.6% (95% CI, 8.5-12.7) of patients with the combination. The combination of serum ferritin concentration above 500 μg/L in women or 600 μg/L in men and transferrin saturation above 29% in women or 35% in men, which applied to 1.7% of our population, could be attributed to mutation of HFE, self-reported iron overload or self-reported liver disease in 18.4% (95% CI, 13.6-23.2) of patients with the combination.

      Discussion

      Based on the prospective definition of the HEIRS Study, we found serum ferritin concentration above 200 μg/L for women or 300 μg/L for men in 19.3% of more than 27,000 African Americans investigated in a multicenter primary care setting. Although the definition of what constitutes an elevated serum ferritin concentration in African Americans is open to discussion, participants with the combination of elevated serum ferritin concentration as defined by the HEIRS Study and transferrin saturations in the highest quartile to a significant extent more often had HFE mutations and self-reported histories of iron overload or liver disease than those with nonelevated serum ferritin concentrations. Conversely, African American participants with the combination of elevated serum ferritin concentration and transferrin saturation in the lowest quartile gave histories of arthritis, diabetes mellitus and, for women only, heart failure significantly more often than those with nonelevated serum ferritin concentration. Although arthritis, diabetes mellitus, and heart failure are sometimes associated with certain iron overload conditions or increased indirect measures of iron status,
      • Niederau C.
      • Fischer R.
      • Sonnenberg A.
      • et al.
      Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.
      N Engl J Med. 1985; 313: 1256-1262
      , 
      • Jiang R.
      • Manson J.E.
      • Meigs J.B.
      • et al.
      Body iron stores in relation to risk of type 2 diabetes in apparently healthy women.
      JAMA. 2004; 291: 711-717
      , 
      • Thomas M.C.
      • MacIssac R.J.
      • Tsalamadris C.
      • Jerums G.
      Elevated iron iondices in patients with diabetes.
      Diabet Med. 2004; 21: 798-802
      , 
      • Porter J.
      • Cary N.
      • Schofield P.
      Haemochromatosis presenting as congestive cardiac failure.
      Br Heart J. 1995; 73: 73-75
      considerable research points to strong associations of these conditions with inflammation.
      • Nielen M.M.
      • van Schaardenburg D.
      • Reesink H.W.
      • et al.
      Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis.
      Arthritis Rheum. 2004; 50: 2423-2427
      , 
      • Barzilay J.
      • Freedland E.
      Inflammation and its association with glucose disorders and cardiovascular disease.
      Treat Endocrinol. 2003; 2: 85-94
      , 
      • Dandona P.
      • Aljada A.
      • Bandyopadhyay A.
      Inflammation: the link between insulin resistance, obesity and diabetes.
      Trends Immunol. 2004; 25: 4-7
      , 
      • Cesari M.
      • Penninx B.W.
      • Newman A.B.
      • et al.
      Inflammatory markers and onset of cardiovascular events: results from the Health ABC study.
      Circulation. 2003; 108: 2317-2322
      The combination of elevated serum ferritin concentration and transferrin saturation in the highest quartile occurred in 6.7% of the participants, while the combination of elevated serum ferritin concentration and transferrin saturation in the lowest quartile occurred in 2.9%. This observation suggests that more participants with serum ferritin elevation had abnormalities related to increased iron stores or liver disease than to inflammation. Based on population risk estimates, approximately 11% of the cases of elevated serum ferritin concentration in combination with highest quartile transferrin saturation could be attributed to mutation of HFE, self-reported iron overload, or self-reported liver disease. Because self-reporting may considerably underestimate true prevalence of disease,
      • Tormo M.J.
      • Navarro C.
      • Chirlaque M.D.
      • Barber X.
      EPIC Group of Spain
      Validation of self diagnosis of high blood pressure in a sample of the Spanish EPIC cohort: overall agreement and predictive values.
      J Epidemiol Community Health. 2000; 54: 221-226
      , 
      • Browning J.D.
      • Szczepaniak L.S.
      • Dobbins R.
      • et al.
      Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
      Hepatology. 2004; 40: 1387-1395
      , 
      • St. Sauver J.L.
      • Hagen P.T.
      • Cha S.S.
      • et al.
      Agreement between patient reports of cardiovascular disease and patient medical records.
      Mayo Clin Proc. 2005; 80: 203-210
      it seems likely that 11% is a conservative estimate. In addition to HFE mutations, potential causes for increased body iron stores in African Americans include multiple blood transfusions in patients with sickle cell disease and other hematologic disorders
      • Ballas S.K.
      Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease.
      Semin Hematol. 2001; 38: 30-36
      , 
      • Olivieri N.
      Progression of iron overload in sickle cell disease.
      Semin Hematol. 2001; 38: 57-62
      and non-HFE primary iron-loading conditions,
      • Adams P.C.
      • Reboussin D.M.
      • Barton J.C.
      • et al.
      Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators
      Hemochromatosis and iron-overload screening in a racially diverse population.
      N Engl J Med. 2005; 352: 1769-1778
      , 
      • Beutler E.
      • Barton J.C.
      • Felitti V.J.
      • et al.
      Ferroportin 1 (SCL40A1) variant associated with iron overload in African Americans.
      Blood Cells Mol Dis. 2003; 31: 305-309
      some perhaps not yet identified. Potential causes of hepatic dysfunction in African Americans include hepatitis C infection,
      • Alter M.J.
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      • Nainan O.V.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
      N Engl J Med. 1999; 341: 556-562
      nonalcoholic steatosis and hepatitis (NASH),
      • Browning J.D.
      • Szczepaniak L.S.
      • Dobbins R.
      • et al.
      Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
      Hepatology. 2004; 40: 1387-1395
      , 
      • Weston S.R.
      • Leyden W.
      • Murphy R.
      • et al.
      Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease.
      Hepatology. 2005; 41: 372-379
      and heavy alcohol consumption.
      • Caetano R.
      • Kaskutas L.A.
      Changes in drinking patterns among whites, blacks, and Hispanics, 1984-1992.
      J Stud Alcohol. 1995; 56: 558-565
      , 
      • Moirand R.
      • Lescoat G.
      • Delamaire D.
      • et al.
      Increase in glycosylated and nonglycosylated serum ferritin in chronic alcoholism and their evolution during alcohol withdrawal.
      Alcohol Clin Exp Res. 1991; 15: 963-969
      Limitations to our study include these considerations: The values for serum biochemical measures of iron status reported here represent single random determinations not confirmed by repeat testing. Other than testing for HFE mutations and concomitant transferrin saturation and interviewing patients for histories of certain diseases, possible explanations for an elevated serum ferritin concentration were not investigated in this screening cohort in the HEIRS Study.
      We conclude that approximately 7% of African American primary care patients have the combination of serum ferritin concentration above 200 μg/L in women or 300 μg/L in men, and transferrin saturation above 29% in women or 35% in men, and that such individuals should be evaluated for increased body iron stores or liver disease.

      Acknowledgments

      Participating “HEIRS Study” Investigators and Institutions:
      Field Centers
      Birmingham, AL—University of Alabama at Birmingham:
      Dr. Ronald T. Acton (Principal Investigator), Dr. James C. Barton (Co-Principal Investigator), Ms. Deborah Dixon, Dr. Susan Ferguson, Dr. Richard Jones, Dr. Jerry McKnight, Dr. Charles A. Rivers, Dr. Diane Tucker and Ms. Janice C. Ware.
      Irvine, CA—University of California, Irvine:
      Dr. Christine E. McLaren (Principal Investigator), Dr. Gordon D. McLaren (Co-Principal Investigator), Dr. Hoda Anton-Culver, Ms. Jo Ann A. Baca, Dr. Thomas C. Bent, Dr. Lance C. Brunner, Dr. Michael M. Dao, Dr. Korey S. Jorgensen, Dr. Julie Kuniyoshi, Dr. Huan D. Le, Dr. Miles K. Masatsugu, Dr. Frank L. Meyskens, Dr. David Morohashi, Dr. Huan P. Nguyen, Dr. Sophocles N. Panagon, Dr. Chi Phung, Dr. Virgil Raymundo, Dr. Thomas Ton, Professor Ann P. Walker, Dr. Lari B. Wenzel and Dr. Argyrios Ziogas.
      London, Ontario, Canada—London Health Sciences Center:
      Dr. Paul C. Adams (Principal Investigator), Ms. Erin Bloch, Dr. Subrata Chakrabarti, Ms. Arlene Fleischhauer, Ms. Helen Harrison, Ms. Kelly Jia, Ms. Sheila Larson, Dr. Edward Lin, Ms. Melissa Lopez, Ms. Lien Nguyen, Ms. Corry Pepper, Dr. Tara Power, Dr. Mark Speechley, Dr. Donald Sun and Ms. Diane Woelfle.
      Portland, OR and Honolulu, HI—Kaiser Permanente Center for Health Research, Northwest and Hawaii, and Oregon Health and Science University:
      Dr. Emily L. Harris (Principal Investigator), Dr. Mikel Aickin, Dr. Elaine Baker, Ms. Marjorie Erwin, Ms. Joan Holup, Ms. Carol Lloyd, Dr. Nancy Press, Dr. Richard D. Press, Dr. Jacob Reiss, Dr. Cheryl Ritenbaugh, Ms. Aileen Uchida, Dr. Thomas Vogt and Dr. Dwight Yim.
      Washington, DC—Howard University:
      Dr. Victor R. Gordeuk (Principal Investigator), Dr. Fitzroy W. Dawkins (Co-Principal Investigator), Ms. Margaret Fadojutimi-Akinsiku, Dr. Oswaldo Castro, Dr. Debra White-Coleman, Dr. Melvin Gerald, Ms. Barbara W. Harrison, Dr. Ometha Lewis-Jack, Dr. Robert F. Murray, Dr. Shelley McDonald-Pinkett, Ms. Angela Rock, Dr. Juan Romagoza and Dr. Robert Williams.
      Central Laboratory
      Minneapolis, MN—University of Minnesota Medical Center, Minneapolis, Minnesota:
      Dr. John H. Eckfeldt (Principal Investigator and Steering Committee Chair), Ms. Catherine Leiendecker-Foster, Dr. Ronald C. McGlennen, Mr. Greg Rynders and Dr. Michael Y. Tsai.
      Coordinating Center
      Winston-Salem, NC—Wake Forest University:
      Dr. David M. Reboussin (Principal Investigator), Dr. Beverly M. Snively (Co-Principal Investigator), Dr. Roger Anderson, Ms. Elease Bostic, Ms. Brenda L. Craven, Ms. Shellie Ellis, Dr. Curt Furberg, Mr. Jason Griffin, Dr. Mark Hall, Mr. Darrin Harris, Ms. Leora Henkin, Dr. Sharon Jackson, Dr. Tamison Jewett, Mr. Mark D. King, Mr. Kurt Lohman, Ms. Laura Lovato, Dr. Joe Michaleckyj, Ms. Shana Palla, Ms. Tina Parks, Ms. Leah Passmore, Dr. Pradyumna D. Phatak, Dr. Stephen Rich, Ms. Andrea Ruggiero, Dr. Mara Vitolins, Mr. Gary Wolgast and Mr. Daniel Zaccaro.
      NHLBI Project Office
      Bethesda, MD—Ms. Phyliss Sholinsky (Project Officer), Dr. Ebony Bookman, Dr. Henry Chang, Dr. Richard Fabsitz, Dr. Cashell Jaquish, Dr. Teri Manolio and Ms. Lisa O’Neill.
      NHGRI Project Office
      Bethesda, MD—Ms. Elizabeth Thomson.
      Dr. Jean MacCluer, Southwest Foundation for Biomedical Research, also contributed to the design of this study.

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      Article Info

      Publication History

      Published online: March 16, 2007

      Footnotes

      The HEIRS Study was initiated and funded by NHLBI, in conjunction with NHGRI. The study is supported by contracts N01-HC-05185 (University of Minnesota), N01-HC-05186 (Howard University), N01-HC-05188 (University of Alabama at Birmingham), N01-HC-05189 (Kaiser Permanente Center for Health Research), N01-HC-05190 (University of California, Irvine), N01-HC-05191 (London Health Sciences Centre), and N01-HC-05192 (Wake Forest University). Additional support was provided by grant UH1-HL03679-07 from NHLBI and the Office of Minority Health, and by General Clinical Research Center (GCRC) grants to Howard University (M01-RR10284), University of California, Irvine (5M01RR 00827-29) and University of Alabama at Birmingham (M01-RR00032), sponsored by the National Center for Research Resources, National Institutes of Health (NCRR/NIH).

      Identification

      DOI: https://doi.org/10.1016/j.amjmed.2006.05.049

      Copyright

      © 2007 Elsevier Inc. Published by Elsevier Inc. All rights reserved.

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