Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri

doi:10.1016/S0002-9343(99)00163-1

The American Journal of Medicine

Volume 107, Issue 1, July 1999, Pages 30-37

https://doi.org/10.1016/S0002-9343(99)00163-1 Get rights and content

Abstract

BACKGROUND: Hemochromatosis reportedly affects 3 to 8 persons per 1,000 and is associated with an elevated risk of morbidity and mortality. We sought to ascertain its prevalence in a community and to assess the association between phenotype and genotype.

METHODS: All health maintenance organization employees were invited to participate in hemochromatosis screening using a repeated elevation of the transferrin saturation test as the case definition (≥50% in women and ≥60% in men with no other cause). Iron overload from hemochromatosis was defined as serum ferritin concentration ≥95th percentile and mobilizable iron ≥99th percentile for age and sex, or hepatic iron index ≥1.9. The HFE gene was analyzed for mutations.

RESULTS: Participation among employees was 28% (1,653 of 6,000); 83% were women. The prevalence of hemochromatosis was 8 per 1,000 (13 of 1,653), and the prevalence of iron overload from hemochromatosis was 4 per 1,000 (5 of 1,653). Compared with those who had no HFE mutation, the relative risk (RR) for hemochromatosis was greatest for C282Y homozygotes (RR = 147), compound heterozygotes (RR = 19), and H63D homozygotes (RR = 9). Overall, 38% of participants had at least one HFE mutation. Screening based on an initial elevated transferrin saturation test had the best sensitivity, whereas DNA testing offered the best specificity and predictive value positive for iron overload disease.

CONCLUSIONS: In this population, we found a greater than expected prevalence of hemochromatosis and demonstrated a clear association with the HFE genotype. Promotion of screening is complicated by controversies in case definition and the large number of persons who will be detected before they have clinically significant iron loading, in whom the risk of clinical disease is unknown. Larger screening studies in more diverse populations are necessary to characterize the burden of disease and to follow those at risk (based on HFE or iron status measures) to establish the natural history of hemochromatosis.

Section snippets

Methods

After approval of the study by institutional review boards at all participating institutions, all employees of St. John’s Health System were invited by mail and at work to participate in a hemochromatosis screening program. There are 6,000 employees in the St. John’s Health System within 200 miles of Springfield, Missouri. The employees are 80% women (80% of whom are <50 years of age); 97% are white.

The first step in recruitment was physician education concerning hemochromatosis, followed by

Results

The participation rate for the transferrin saturation screening was 28% (1,653 of 6,000) of whom 88% (1,450 of 1,653) also participated in the genetic screening. The sample included 1,365 women (83%) and 288 men (17%); 1,620 (98%) participants were white. The mean age (±SD) was 41 ± 11 years.

Discussion and conclusions

This study provides information on population screening for hemochromatosis using conventional measurements of transferrin saturation and newer DNA testing, as well as on the association between genotype and phenotype. The findings corroborate recent population-based studies that have reported a much greater prevalence of hemochromatosis than previously estimated 26, 28. They underscore the importance of the case definition in estimating the prevalence of hemochromatosis and illustrate the

Acknowledgements

The authors gratefully acknowledge the assistance of Jim Blaine, MD, Ed Barber, MPA, John Heywood, PhD, Harold Bensch, MPH, James Barton, MD, Vince Felliti, MD, Bruce Bacon, MD, Elaine Gunter, MS, and Muin Khoury, MD, PhD.

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Transferrin Saturation: A Body Iron Biomarker
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Iron is an essential element for several metabolic pathways and physiological processes. The maintenance of iron homeostasis within the human body requires a dynamic and highly sophisticated interplay of several proteins, as states of iron deficiency or excess are both potentially deleterious to health. Among these is plasma transferrin, which is central to iron metabolism not only through iron transport between body tissues in a soluble nontoxic form but also through its protective scavenger role in sequestering free toxic iron. The transferrin saturation (TSAT), an index that takes into account both plasma iron and its main transport protein, is considered an important biochemical marker of body iron status. Its increasing use in many health systems is due to the increased availability of measurement methods, such as calorimetry, turbidimetry, nephelometry, and immunochemistry to estimate its value. However, despite its frequent use in clinical practice to detect states of iron deficiency or iron overload, careful attention should be paid to the inherent limitations of the test especially in certain settings such as inflammation in order to avoid misinterpretation and erroneous conclusions. Beyond its usual clinical use, an emerging body of evidence has linked TSAT levels to major clinical outcomes such as cardiovascular mortality. This has the potential to extend the utility of TSAT index to risk stratification and prognostication. However, most of the current evidence is mainly driven by observational studies where the risk of residual confounding cannot be fully eliminated. Indeed, future efforts are required to fully explore this capability in well-designed clinical trials or prospective large-scale cohorts.
Hemochromatosis Genotypes and Risk of Iron Overload-A Meta-Analysis
2011, Annals of Epidemiology
Citation Excerpt :
The studies varied in their geographical setting, with 79.1% being of European origin (8, 19–21, 24–38, 41–45, 47–50, 52–55). One study was prospective (25), 33 studies were case-control studies (8, 20, 26–34, 35–55), seven studies were cross-sectional (18, 19, 23, 24), and two studies had combined design, cross-sectional, and case-control (21, 22). Homozygosity for the C282Y mutation conferred the highest risk for both provisional and documented iron overload (Figure 2 and Supplementary Table 2) and accounted for the majority of iron overload cases in all studies (37.2%) (Supplementary Table 1).
The incomplete phenotypic penetrance of high iron Fe genotypes in relation to hemochromatosis poses a practical problem in the interpretation of the genotyping results by clinicians. We carried out meta-analyses of the associations between hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, C282Y/wild-type, H63D/H63D, H63D/wild-type, versus wild-type/wild-type and iron overload, both provisional (elevated serum iron markers) and documented (elevated serum iron markers associated with evidence of iron excess based on liver biopsy and/or quantitative phlebotomy).
After reviewing 3572 article titles and evaluating 92 articles in detail, odds ratios were pooled from 43 study populations (9986 cases and 25,492 controls) using a random-effects model.
Homozygosity for either variant or compound heterozygosity was associated with both provisional and documented iron overload. Single heterozygosity conferred no risk for elevated hepatic iron index and/or mobilizable iron by quantitative phlebotomy. In patients with clinical hereditary hemochromatosis, no evidence of provisional and documented iron overload with transferrin saturation (TS) values greater than 55% was evidenced for C282Y and H63D single heterozygotes whereas documented iron overload including TS of 45% to 50% was weakly associated with C282Y/wild-type genotype; H63D/H63D genotype was not associated with documented iron overload in patients with TS values of 45% to 50%.
The results, mainly from case-control studies, cannot necessarily be extrapolated to the general population.
EASL clinical practice guidelines for HFE hemochromatosis
2010, Journal of Hepatology
Iron overload in humans is associated with a variety of genetic and acquired conditions. Of these, HFE hemochromatosis (HFE-HC) is by far the most frequent and most well-defined inherited cause when considering epidemiological aspects and risks for iron-related morbidity and mortality. The majority of patients with HFE-HC are homozygotes for the C282Y polymorphism [1]. Without therapeutic intervention, there is a risk that iron overload will occur, with the potential for tissue damage and disease. While a specific genetic test now allows for the diagnosis of HFE-HC, the uncertainty in defining cases and disease burden, as well as the low phenotypic penetrance of C282Y homozygosity poses a number of clinical problems in the management of patients with HC. This Clinical Practice Guideline will therefore, focus on HFE-HC, while rarer forms of genetic iron overload recently attributed to pathogenic mutations of transferrin receptor 2, (TFR2), hepcidin (HAMP), hemojuvelin (HJV), or to a sub-type of ferroportin (FPN) mutations, on which limited and sparse clinical and epidemiologic data are available, will not be discussed. We have developed recommendations for the screening, diagnosis, and management of HFE-HC.
HFE mutations in α-1-antitrypsin deficiency: An examination of cirrhotic explants
2010, Modern Pathology
Increased iron deposition is often seen in liver explants with α-1-antitrypsin deficiency, but it remains unclear if this is a nonspecific effect of end-stage liver disease or if individuals with α-1-antitrypsin deficiency and excess iron are at increased risk for HFE mutations. To further examine this question, 45 liver explants with α-1-antitrypsin deficiency and 33 control livers with chronic hepatitis C were examined for histological iron accumulation, graded on a scale of 0 to 4+, and HFE mutations. Interestingly, the α-1-antitrypsin cirrhotic livers showed a bimodal distribution of iron accumulation, with peaks at grades 1 and 3. In contrast, hepatitis C cirrhotic livers showed a unimodal distribution with a peak at grade 2. HFE mutations in livers with α-1-antitrypsin deficiency were as follows: C282Y=2%, H63D=42%. H63D mutations were more frequent in α-1-antitrypsin deficiency cases than in controls (42 vs 27%), but was not statistically significant, P=0.17. However, there was a significant association with HFE mutations in α-1-antitrypsin deficiency livers with grade 3+ or 4+ iron, P=0.02. In contrast, livers with hepatitis C showed a similar frequency of HFE mutations as the general population: C282Y=15%, H63D=27%. A rare S65C mutation and a novel A271S mutation were also found in this study; the latter patient had 4+ iron in the liver and later developed heart failure with cardiac iron. In conclusion, total H63D mutations were high (42%) in cirrhotics with α-1-antitrypsin deficiency and there was a significant association between HFE mutations and high levels of iron accumulation.
Genes for gestational iron loading? [1] (multiple letters)
2004, Gastroenterology
$Background & Aims$ : Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. To circumvent these difficulties, we used 2 strains of mice made deficient for the Hfe gene that strongly differ in their propensity to develop hepatic iron loading. $Methods$ : To localize the loci controlling hepatic iron loading in this murine model of hemochromatosis, we produced 1028 mice by an F2 intercross between the C57BL/6 and DBA/2 Hfe-deficient strains. We selected the 276 mice that contributed the most to the total linkage information for genotyping with 145 microsatellite markers. $Results$ : We mapped 4 modifier loci on chromosomes 7, 8, 11, and 12, with logarithm of odds scores of 14.47, 12.96, 6.04, and 6.72, respectively, in regions containing several genes recently shown to exert important roles in the regulation of iron metabolism. $Conclusions$ : Our data provide a clear demonstration of the polygenic pattern of hepatic iron loading inheritance in Hfe-deficient mice. Examination of candidate genes residing at the loci identified in this study and genetic analysis of the syntenic chromosomal regions in humans may provide important insight into the heterogeneous disease presentation observed among HFE C282Y homozygotes.
Pathogenesis of hereditary hemochromatosis
2004, Clinics in Liver Disease

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^☆: Supported by the Centers for Disease Control and Prevention Grant number 1700.

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Clinical StudiesPopulation-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri☆

Abstract

Section snippets

Methods

Results

Discussion and conclusions

Acknowledgements

Clin Chem Acta

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Mayo Clin Proc

Blood

Gastroenterology

Gastroenterology

Blood Cells, Mol Dis

Blood Cells Mol Dis

Lancet

Gastroenterology

Blood

Am J Clin Nutr

Blood

Gastroenterology

The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding

Proc Natl Acad Sci

Evolving expression of hereditary hemochromatosis

Sem liver dis

Population screening for haemochromatosisa unifying analysis of published intervention trials

J Med Screen

Hepatocellular carcinoma in the United States

Cancer

Surgical treatment of hepatocarcinoma in cirrhosis

Ann Gastroenterol Hepatol

Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver diseases

J Intern Med

Liver iron concentration in chronic viral hepatitisa study of 98 patients

Eur J Gastroenterol Hepatol

Testing for haemochromatosis in the diabetic clinic

Ann Clin Biochem

Screening for idiopathic haemochromatosis among diabetic patients

Diabetes Care

Prevalence of haemochromatosis amongst patients with diabetes mellitus

Diabet Med

Usefulness of biochemical screening of diabetic patients for hemochromatosis

Diabetes Care

Hemochromatosis and diabetes

Mayo Clin Proc

Non-insulin-dependent diabetes mellitus and elevated serum ferritin level

J Diabet Complications

Clinical Studies
Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri☆