Hemochromatosis and Iron Overload Screening (HEIRS) Study Design for an Evaluation of 100,000 Primary Care-Based Adults

McLaren, Christine E.; Barton, James C.; Adams, Paul C.; Harris, Emily; Acton, Ronald T.; Press, Nancy; Reboussin, David M.; McLaren, Gordon D.; Sholinsky, Phyliss; Walker, Ann P.; Gordeuk, Victor R.; Leiendecker–Foster, Catherine; Dawkins, Fitzroy W.; Eckfeldt, John H.; Mellen, Beverly G.; Speechley, Mark; Thomson, Elizabeth J.

doi:10.1097/00000441-200302000-00001

Cited by 120 publications

(209 citation statements)

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“…The HEIRS Study is evaluating the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 101,168 adults over a 7-years period [5]. Participants were at least 25-years old and were recruited from five Field Centers in the United States and Canada.…”

Section: Methodsmentioning

confidence: 99%

“…The study protocol was approved by the Institutional Review Board of each Field Center and written informed consent was obtained from each participant. Details of study design, laboratory testing, data management, and analysis are described elsewhere [5].…”

Section: Methodsmentioning

confidence: 99%

“…These latter tests were performed at the MDS Laboratory Services, Canada, using a method identical to that used by the Central Laboratory. Blood samples were obtained from participants for HFE mutation analysis that was performed using DNA extracted from buffy coat and a modification of the Invader assay (Third Wave Technologies, Inc., Madison, WI) at the Central Laboratory, as described in detail elsewhere [5]. Participants without C282Y or H63D are designated as having HFE wild-type genotype (wt/wt).…”

Section: Laboratory Testing For Initial Screeningmentioning

confidence: 99%

“…The Hemochromatosis and Iron Overload Screening (HEIRS) Study used TfSat and SF measurements and HFE mutation analysis to detect the C282Y and H63D alleles as initial screening of a racially and ethnically diverse sample of more than 100,000 persons ages 25 years who attended primary care clinics associated with five HEIRS Study Field Centers in North America [5,6]. HEIRS Study participants who were found to have HFE C282Y homozygosity, regardless of iron phenotype, and participants with TfSat and SF values that exceeded study thresholds, were invited to undergo a postscreening physical and laboratory evaluation that included repeat measurement of TfSat and SF, and determination of complete blood counts (CBC) and serum concentrations of hepatic enzymes and other liver-related blood tests (Clinical Examination, CE) [5].…”

Section: Introductionmentioning

confidence: 99%

“…HEIRS Study participants who were found to have HFE C282Y homozygosity, regardless of iron phenotype, and participants with TfSat and SF values that exceeded study thresholds, were invited to undergo a postscreening physical and laboratory evaluation that included repeat measurement of TfSat and SF, and determination of complete blood counts (CBC) and serum concentrations of hepatic enzymes and other liver-related blood tests (Clinical Examination, CE) [5]. A cohort of participants found to have normal TfSat and SF and a wild-type HFE genotype (HFE wt/ wt) on initial screening were invited to be evaluated in a CE as control subjects [5]. Subjects were considered ''screen positive'' and hence eligible for a CE if their genotypes were C282Y/C282Y or if their TfSat and SF values exceeded study thresholds for elevated iron measures.…”

Section: Introductionmentioning

confidence: 99%

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Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

McLaren

Barton²,

et al. 2007

American J Hematol

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Elevated mean corpuscular volume (MCV) is common in persons with hemochromatosis associated with HFE C282Y homozygosity. We evaluated data from the subset of non-Hispanic white participants in the Hemochromatosis and Iron Overload Screening Study to determine if elevated MCV in C282Y homozygotes is related to this genotype or to serum iron measures. Regression analysis was used to model MCV and Hb from transferrin saturation (TfSat), serum ferritin (SF), mean corpuscular hemoglobin concentration, red blood cell count, age, HFE genotype, Field Center, and presence of liver-related abnormalities in C282Y homozygotes and control subjects without HFE mutations (wt/wt genotype). Mean MCV was higher in C282Y homozygotes than in HFE wt/wt controls (94.4 vs. 89.7 fL in women; 95.3 vs. 91.2 fL in men; P < 0.0001 for both). These differences were largely associated with increased mean TfSat and SF in C282Y homozygotes. Adjusted mean MCV was 92.0 fL (95% confidence interval, 91.1, 92.9) in female C282Y homozygotes and 90.9 fL (90.3, 91.5) in controls. Among women with SF in the reference range 20-200 lg/L, adjusted mean MCV was 92.9 fL, (91.7, 94.2) in C282Y homozygotes, 1.8 fL higher than in controls (P 5 0.013). The adjusted mean MCV of male C282Y homozygotes and controls was similar (P 5 0.30). Adjusted mean Hb was 0.2 g/dL higher in women with C282Y/C282Y than in controls. Greater mean MCV in C282Y homozygosity reflects increased mean TfSat and mean SF in men and women; an additional effect of genotype on MCV and Hb was detected in women. Am. J. Hematol. 82:898-905, 2007. V V C 2007 Wiley-Liss, Inc. IntroductionElevated values of mean corpuscular volume (MCV) are common in persons with hemochromatosis. In early series of hemochromatosis cases, this was attributed to hepatic cirrhosis [1], a then-current diagnostic criterion of hemochromatosis and a common sequel of severe iron overload [1,2]. In Alabama hemochromatosis probands diagnosed in medical care, mean MCV and hemoglobin concentration (Hb) were significantly greater in HFE C282Y homozygotes than in probands with other HFE genotypes or in control subjects, and 44% of all probands had prephlebotomy values of MCV greater than the upper reference limit [3]. Further, there was a significant positive association of MCV in HFE C282Y homozygotes with serum transferrin saturation (TfSat) at diagnosis and with quantities of iron removed by phlebotomy to achieve iron depletion, but not with the presence of human leukocyte antigen-A*03 [3]. In a southern California hemochromatosis screening program that evaluated persons who attended a health appraisal clinic, mean TfSat, mean serum ferritin concentration (SF), mean MCV, and mean Hb were higher than the corresponding measures in participants without common HFE mutations [4].

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Laboratory Testing For Initial Screeningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

McLaren

Barton²,

et al. 2007

American J Hematol

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Serum Ferritin and Transferrin Saturation in Asians and Pacific Islanders

et al. 2007

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Background: Asians and Pacific Islanders in the Hemochromatosis and Iron Overload Screening (HEIRS) Study had the highest prevalence of elevated serum ferritin (SF) and transferrin saturation (TS) levels, but to our knowledge, the reasons for this have not been investigated. Methods: Using multiple linear regression, we compared TS and SF distributions for 42 720 Asian, Pacific Islander, and white HEIRS Study participants recruited through 5 field centers in North America who did not have HFE C282Y or H63D alleles. Results: Compared with their white counterparts, Asian men had a 69-ng/mL (155-pmol/L) higher adjusted mean SF level and a 3% higher TS level (PϽ.001); Asian women had 23-ng/mL (52-pmol/L) higher adjusted mean SF level and a 3% higher TS level (PϽ.001). The mean TS level of Asian women was higher than that of Pacific Islander women, and the mean SF level of Pacific Islander men was significantly higher than that of white men. These differences remained significant after adjusting for self-reported history of diabetes or liver disease. Additional information for selected participants suggested that these differences are largely unrelated to mean corpuscular volume less than 80 fL, body mass index, or self-reported alcohol intake. Available liver biopsy and phlebotomy data indicated that iron overload is probably uncommon in Asian participants. Conclusion: Higher TS and SF levels in persons of Asian or Pacific Island heritage may need to be interpreted differently than for whites, although the biological basis and clinical significance of higher levels among Asians and Pacific Islanders are unclear.

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Prevalence of Iron Deficiency Using 3 Definitions Among Women in the US and Canada

Barton,

Wiener,

Barton

et al. 2024

JAMA Netw Open

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ImportanceThe prevalence of iron deficiency varies widely according to how it is defined.ObjectiveTo compare the prevalence of iron deficiency among women using 3 different definitions.Design, Setting, and ParticipantsThe cross-sectional Hemochromatosis and Iron Overload Screening Study (HEIRS; 2000-2006) evaluated the prevalence, determinants, and outcomes of hemochromatosis and other iron-related disorders. Multiethnic, primary care–based screening (2001-2003) was performed at 5 field centers (4 in the US and 1 in Canada). Volunteer women aged 25 years and older were recruited at primary care venues associated with the field centers. Data were analyzed from June to December 2023.Main Outcomes and MeasuresMeasures included transferrin saturation, serum ferritin level, and self-reported age, pregnancy, and race and ethnicity. Three iron deficiency definitions were studied: (1) combined transferrin saturation less than 10% and serum ferritin less than 15 ng/mL (HEIRS), (2) serum ferritin less than 15 ng/mL (World Health Organization [WHO]), and (3) serum ferritin less than 25 ng/mL (a threshold for iron-deficient erythropoiesis [IDE]).ResultsAmong 62 685 women (mean [SD] age, 49.58 [14.27] years), 1957 women (3.12%) had iron deficiency according to the HEIRS definition, 4659 women (7.43%) had iron deficiency according to the WHO definition, and 9611 women (15.33%) had iron deficiency according to the IDE definition. Among 40 381 women aged 25 to 54 years, 1801 women (4.46%) had iron deficiency according to HEIRS, 4267 women (10.57%) had iron deficiency according to WHO, and 8573 women (21.23%) had iron deficiency according to IDE. Prevalence rates of iron deficiency among 2039 women aged 25 to 44 years who reported pregnancy were 5.44% (111 women) according to HEIRS, 18.05% (368 women) according to WHO, and 36.10% (736 women) according to IDE. Iron deficiency prevalence by the 3 respective definitions increased significantly in each racial and ethnic group and was significantly higher among Black and Hispanic participants than Asian and White participants. The relative iron deficiency prevalence among the 62 685 women increased 2.4-fold (95% CI, 2.3-2.5; P &lt; .001) using the WHO definition and increased 4.9-fold (95% CI, 4.7-5.2; P &lt; .001) using the IDE definition.Conclusions and RelevanceThree definitions of iron deficiency were associated with significantly different prevalence of iron deficiency in women, regardless of self-reported age, pregnancy, or race and ethnicity. Using higher serum ferritin thresholds to define iron deficiency could lead to diagnosis and treatment of more women with iron deficiency and greater reduction of related morbidity.

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Hemochromatosis and Iron Overload Screening (HEIRS) Study Design for an Evaluation of 100,000 Primary Care-Based Adults

Cited by 120 publications

References 34 publications

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

Serum Ferritin and Transferrin Saturation in Asians and Pacific Islanders

Prevalence of Iron Deficiency Using 3 Definitions Among Women in the US and Canada

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