Correlation Between Genotype and Phenotype in Hereditary Hemochromatosis: Analysis of 61 Cases

doi:10.1006/bcmd.1997.0148

Blood Cells, Molecules, and Diseases

Volume 23, Issue 2, August 1997, Pages 314-320

https://doi.org/10.1006/bcmd.1997.0148 Get rights and content

Abstract

ABSTRACT: This report assesses the degree of iron overload in a cohort of patients in relationship to the presence or absence of the recently described 845 G→A (C282Y) and 187 C→G (H63D) mutations in the HFE (HLA-H) gene. Sixty-one patients with hereditary hemochromatosis diagnosed either with liver biopsy or on clinical grounds were included in this analysis. Forty-one patients were homozygous for C282Y, the genotype considered to be characteristic of hereditary hemochromatosis. At the time of this analysis, 37 of these 41 patients had achieved a state of iron depletion and mobilizable iron was calculated; 19 had less than 4 grams. Twenty-Five of these 41 patients had liver biopsies; 4 of these patients had a hepatic iron index less than 1.9. Of the 4 patients with a normal hepatic iron index, 3 had a quantitative hepatic iron of greater than 50 μmol/g dry weight, and one had an inadequate biopsy sample. These findings support our suspicion that individuals may have hereditary hemochromatosis and homozygous C282Y despite relatively low body iron stores.

Five patients were compound heterozygotes for C282Y and H63D. Four of these patients underwent liver biopsy; two had a hepatic iron index greater than 1.9. A third patient had a hepatic iron index of 1.3 but a quantitative hepatic iron of 90.6 μmol/g dry weight. All patients were phlebotomized to a state of iron depletion and only one of these patients had a mobilizable iron greater than 4 grams. Three patients were homozygous for H63D; these patients had either a hepatic iron index >1.9 or greater than 4 grams of mobilizable iron. Patients with homozygous H63D and significant iron overload are not well described. Seven patients were heterozygous for either C282Y or H63D; 4 had significant iron overload but three did not. Five patients had no HFE mutations; one of these patients unequivocally has iron overload with a hepatic iron index of 4.4.

We conclude that: (1) Identification of HFE mutations will be clinically useful in identifying patients with hereditary hemochromatosis, (2) Patient genotyping will help confirm a diagnosis of hereditary hemochromatosis in some patients with relatively low body iron stores, (3) Significant iron loading can occur in the absence of homozygous C282Y, adding to the evidence that genes other than HFE may be involved in iron loading, and (4) Homozygous H63D can be associated with significant iron overload.

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Cited by (68)

HFE hemochromatosis in African Americans: Prevalence estimates of iron overload and iron overload-related disease
2023, American Journal of the Medical Sciences
Citation Excerpt :
We found no description of an AA with HFE p.H63D/p.H63D identified either in population screening or in a referral evaluation who had documented IO as defined herein. Proportions of referred EA and European patients in hemochromatosis case series with p.H63D/p.H63D are very low.3,20-23 The proportion of referred patients with p.H63D/p.H63D who have documented IO is also very low.21-23
Little is known about the prevalence of HFE (homeostatic iron regulator) hemochromatosis in African Americans (AA).
We defined AA as self-identified AA, blacks, or non-Hispanic blacks. We defined hemochromatosis-associated HFE genotypes as p.C282Y/p.C282Y and p.C282Y/p.H63D. We compiled prevalences of these genotypes in AA using published population and cohort data and numbers of men and women ≥18 y‬ in 2018 U.S. Census estimates. We defined iron overload (IO) and IO-related disease by genotype as previously reported in population and cohort studies of hemochromatosis in whites of European ancestry. We used these definitions to estimate prevalences and numbers of AA with IO and IO-related disease associated with hemochromatosis-associated HFE genotypes.
There were ∼16,287,599 men and ∼17,644,898 women. HFE genotypes and their respective prevalences were: p.C282Y/p.C282Y, 0.00017 (6/34,905) [95% confidence interval 0.000034, 0.00031] and p.C282Y/p.H63D, 0.0012 (41/33,596) [0.000084, 0.0016]. IO prevalences were: men 0.000076 [0.000072, 0.000081] and women 0.0000061 [0.0000050, 0.0000073]. IO-related disease prevalences were: men 0.000063 [0.000059, 0.000067] and women 0.0000021 [0.0000014, 0.0000027]. There were ∼1021 [961, 1091] men and ∼36 [25, 48] women with IO-related disease.
We conclude that ∼1/25,061 AA >18 y have a hemochromatosis-associated HFE genotype and IO and that ∼1/32,103 AA >18 y have a hemochromatosis-associated HFE genotype and IO-related disease.
Are Current Serum and Plasma Ferritin Cut-offs for Iron Deficiency and Overload Accurate and Reflecting Iron Status? A Systematic Review
2018, Archives of Medical Research
Citation Excerpt :
The number of studies analysing ferritin data and liver iron content in patients suspected of iron overload was 31. The pathologies associated with iron overload in the eligible studies included mainly haemochromatosis (20 studies) (15,79–97); 7 studies on alcoholism and liver cirrhosis (98–104), 3 studies on chronic hepatitis C (105–107) and 1 in non-alcoholic fatty liver disease (108). From selected studies, mean ferritin concentration was 496.3 μg/L (n = 764) when liver iron content was <3.2 mg/g dry liver weight or classified as not iron overload by trialist, while the concentration of ferritin in case of iron overload was 1052.0 μg/L (n = 595).
Serum or plasma ferritin concentration is recommended by WHO as a biomarker to assess iron status in individuals and populations.
A systematic review was undertaken to summarise the evidence for ferritin reflecting iron status and to assess the cut-off points in different populations. Electronic databases were searched for studies evaluating ferritin concentrations compared against bone marrow aspirates for iron deficiency and to liver biopsies for risk of iron overload.
From 18822 records, 298 studies were assessed in full-text, including 72 studies on iron deficiency and 36 on iron overload in the quantitative analysis. All studies were observational. For iron deficiency, the mean ferritin concentration in healthy individuals was 15.1 μg/L (9 studies, 390 participants) when bone marrow iron content was 0, and 70.4 μg/L (3 studies, 151 participants) when bone marrow iron was 1+ or higher. In non-healthy populations, mean ferritin concentrations were 82.43 μg/L for iron depletion (38 studies, 1023 participants) and 381.61 μg/L for iron sufficiency (38 studies, 1549 participants) with wide variations depending on the pathology. For iron overload the results point out to a cut-off close to 500 μg/L although the data was very limited.
Ferritin concentration is low in iron deficient individuals and high in iron-loaded individuals, regardless of confounding clinical conditions. Current WHO thresholds for healthy populations appear valid but the data is limited for different age groups or physiological conditions. For iron overload, ferritin concentration would only help in the presumptive diagnosis and guide the need for further assessment.
When and how should we screen for hereditary hemochromatosis?
2003, Joint Bone Spine
Hemochromatosis is the clinical expression of iron overload and occurs as hereditary and secondary variants. In hereditary hemochromatosis, an inborn error in iron metabolism results in excess absorption of dietary iron, which gradually accumulates in the liver, pancreas, and heart. The most common form of hereditary hemochromatosis is related to homozygosity for the C282Y mutation in the HFE gene. Early diagnosis is essential because hereditary hemochromatosis is common, severe, and treatable. Early manifestations consist of asthenia, arthralgia, and serum transferrin saturation elevation. The C282Y mutation should be looked for to confirm the diagnosis in the patient and family members. Measurement of serum transferrin saturation followed by genetic testing in individuals with values above 45% is a reasonable screening strategy.
When and how should we screen for hereditary hemochromatosis?
2003, Revue du Rhumatisme (Edition Francaise)
L’hémochromatose est l’expression clinique d’une surcharge en fer ; elle peut être génétique ou secondaire. L’hémochromatose génétique résulte d’une erreur innée du métabolisme du fer, responsable d’une hyperabsorption intestinale de fer, à l’origine d’une surcharge progressive des cellules parenchymateuses du foie, du pancréas et du cœur. La forme la plus fréquente de la maladie est due à l’homozygotie pour la mutation C282Y du gène HFE. Il est important de savoir comment faire le diagnostic précoce de l’hémochromatose génétique parce qu’il s’agit d’une maladie fréquente, sévère et traitable. Les symptômes biocliniques précoces sont l’asthénie, les arthralgies et l’augmentation de la saturation de la tranferrine sérique. La recherche de la mutation C282Y sera utilisée pour confirmer le diagnostic, chez le patient et dans les familles avec un membre déjà atteint. La stratégie de dépistage pourrait être fondée sur l’évaluation initiale de la saturation de la tranferrine sérique pour chaque individu. Puis, le test génétique serait limité aux sujets qui ont une saturation de la tranferrine supérieure à 45 %.
Hemochromatosis is the clinical expression of iron overload and occurs as hereditary and secondary variants. In hereditary hemochromatosis, an inborn error in iron metabolism results in excess absorption of dietary iron, which gradually accumulates in the liver, pancreas and heart. The most common form of hereditary hemochromatosis is related to homozygosity for the C282Y mutation in the HFE gene. Early diagnosis is essential because hereditary hemochromatosis is common, severe and treatable. Early manifestations consist of asthenia, arthralgia and serum transferrin elevation. The C282Y mutation should be looked for to confirm the diagnosis in the patient and family members. Measurement of serum transferrin saturation followed by genetic testing in individuals with values above 45% is a reasonable screening strategy.
The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease
2002, Gastroenterology
Background & Aims: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. Methods: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. Results: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. Conclusions: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.
GASTROENTEROLOGY 2002;123:444-449
Prevalence and penetrance of HFE mutations in 4865 unselected primary care patients
2002, Blood cells, molecules & diseases
ABSTRACT
Two HFE gene mutations, C282Y and H63D, underlie the vast majority of cases of hereditary hemochromatosis. We performed a cross-sectional primary care-based study to determine the allele frequency of the C282Y and H63D mutations and the penetrance of each of the affected genotypes defined by their presence. Patients had previously undergone transferrin saturation (TS) testing. A total of 4865 unselected frozen serum samples were analyzed to determine serum ferritin (SF) levels. Genomic DNA isolated from these samples was analyzed for the C282Y and H63D HFE mutations. Homozygotes for each mutation and compound heterozygotes were evaluated to determine clinical penetrance. The allele frequency of C282Y was 0.0507 among Caucasian and 0.0067 among African Americans; that of H63D was 0.1512 and 0.0263, respectively. TS was ≥55% in 83% of individuals with C282Y/C282Y, 14.5% of C282Y/H63D, and 5% of H63D/H63D; SF was ≥300 μG/L in 42, 9, and 5% of these genotypes, respectively. None of the 12 C282Y homozygotes had cardiac dysfunction or hepatic cirrhosis. Only 9/129 (7%) individuals with the genotypes C282Y/H63D or H63D/H63D had a SF ≥300μG/L; many had explanations other than iron overload that accounted for this increase. Thus, the prevalence of the common HFE mutations is the same in our population as previously described. TS screening would detect most C282Y homozygotes but not the other two genotypes. The penetrance of C282Y/C282Y is significant. The biochemical penetrance of H63D/H63D and C282Y/H63D is modest and the clinical penetrance is low.

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^☆: 08/26/97

^f1: Reprint request to: Ronald L Sham, M.D., Rochester General Hospital, 1425 Portland Ave. Rochester, NY 14621. phone (716)338-4081, fax (716)338-2347, email: [email protected]

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Regular ArticleCorrelation Between Genotype and Phenotype in Hereditary Hemochromatosis: Analysis of 61 Cases☆

Abstract

Am J Med

Gastroenterology

Clin Chim Acta

Blood Cells Mol Dis

Lancet

Blood Cells Mol Dis

Hemochromatosis: Current concepts and management

Hosp Pract

Prevalence of hereditary hemochromatosis in primary care: An interim analysis

Blood

Prevalence of hemochromatosis among 11,065 presumably healthy blood donors

N Engl J Med

Cost effectiveness of screening for hereditary hemochromatosis

Arch Int Med

Screening blood donors for hereditary hemochromatosis: Decision analysis model based on a 30-year database

Gastroenterology

Regular Article
Correlation Between Genotype and Phenotype in Hereditary Hemochromatosis: Analysis of 61 Cases☆