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European Journal of Heart Failure 2004 6(5):547-550; doi:10.1016/j.ejheart.2003.11.003
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© 2004 European Society of Cardiology

Hemochromatosis mutations are not linked to dilated cardiomyopathy in Israeli patients

Sorel Goland*, Nick Beilinson, Avinoam Kaftouri, Sara Shimoni, Abraham Caspi and Stephen D.H. Malnick

Heart Institute, Kaplan Medical Center Rehovot 76100, Israel

* Corresponding author. Fax: +972-8-9441852. E-mail address: stevash{at}trendline.co.il


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims.: Hemochromatosis is a condition in which iron loading impairs the function of many organs, including the heart. Congestive heart failure with left ventricular dilatation is commonly found in patients with hemochromatosis. Two missense mutations (C282Y and H63D) have been shown to be responsible for the majority of cases of hemochromatosis.

Methods and results.: We examined 156 patients with congestive heart failure due to dilated cardiomyopathy. Details were recorded of clinical and echocardiographic parameters. DNA was extracted from peripheral blood and checked for the presence of the C282Y and H63D mutations by a commercially available single nucleotide primer extension assay. A control group of 98 healthy blood donors was also checked for the presence of these mutations. Of the 157 patients, 42 (26.75%) had at least one mutation. Five (3.65%) were homozygotic for the H63D mutation and 37 (23.6%) were heterozygotic for the H63D mutation. The C282Y mutation was not present. In a control population of 98 healthy blood donors, 27 (27.6%) were heterozygous for the H63D population and none had the C282Y mutation (no significant difference between the patients with cardiomyopathy and the healthy blood donors, {chi}2 test 0.754). There was a non-significant trend to a difference in the prevalence of homozygotic H63D between the cardiomyopathy patients and the healthy blood donors (3.18% vs. 0%, P=0.076, {chi}2 test). There was no statistically significant difference between the cardiomyopathy patients with and without the mutations in terms of age, gender, hemoglobin, iron, transferrin, ferritin, presence of diabetes mellitus, hypertension and previous coronary artery bypass grafting.

Conclusion.: In our population of patients with dilated cardiomyopathy, there was no evidence for hemochromatosis being an important etiology.

Key Words: Hemochromatosis • Mutations • Heart failure • Cardiomyopathy

Received August 8, 2003; Revised September 17, 2003; Accepted November 13, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Hereditary hemochromatosis (HC) is a disorder due to an inappropriately increased iron absorption in which iron loading of parenchymal cells in the liver, pancreas, heart and other organs impairs the function and damages the structure of these organs [1]. This condition is caused by inborn errors of iron metabolism. In 1996, the gene for HC, designated HFE was discovered by Feder et al. [2]. Two missense mutations have been found that are responsible for the majority of the cases of HC. The first is a cysteine/tyrosine substitution at position 282 (C282Y) and the second is a histidine/aspartate substitution at position 63 (H53D). The proportion of HC due to known HFE mutations varies in different parts of the world, and is highest in countries with a predominantly Northern European population. The C282Y genotype is the most penetrant leading to iron overload in more than 60% of individuals. Other HFE mutations, such as H63D are less common causes. HC is defined in terms of phenotype, not genotype (reviewed in [3]).

The clinical spectrum of hemochromatosis may be wider than the classical presentation. For example, an increased detection of hemochromatosis has been found by examining patients in diabetic out-patient clinics [4].

There are cardiac manifestations of hemochromatosis. Congestive heart failure has been observed in 2–35% and arrhythmias are present in 7–36% of hemochromatosis patients [5]. It has been suggested that hemochromatosis is related to atherosclerosis [6], although other reports have not found a relationship between hemochromatosis mutations and the risk of coronary artery disease [7].

Since hemochromatosis can result in left ventricular dilatation and heart failure, and there are marked geographical variations in the incidence of hemochromatosis, we decided to investigate the incidence of both the C282Y and the H63D mutations in a cohort of Israeli patients with dilated cardiomyopathy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
One hundred and fifty-seven consecutive patients with congestive heart failure (CHF) due to dilated cardiomyopathy of diverse etiology were included in this study. All patients had been admitted during the previous year for either treatment or evaluation of heart failure.

The patient evaluation included a complete history and physical examination, electrocardiogram and echocardiogram. Coronary angiography was performed when clinically indicated. The diagnosis of dilated cardiomyopathy was based on accepted international criteria [8]. Patients were classified into either ischemic or non-ischemic cardiomyopathy. The diagnosis of ischemic cardiomyopathy was based on the basis of angiographically-proven coronary artery disease or previous coronary artery revascularization. Transthoracic echocardiography measurements were obtained using standard guidelines [9]. Patients with ejection fraction less than 35% by two-dimensional echocardiography were included in the study. Venous blood was obtained for FBC, renal and hepatic function, electrolytes, iron, transferrin and ferritin. DNA was extracted and amplified by standard techniques and the ProntoTM Hemochromatosis kit (Savyon Diagnostics Ltd) which is a single nucleotide primer extension assay, determined by ELISA, was employed for the detection of the C282Y and H63D mutations in the HFE gene.

2.1. Statistical analysis
Allele and genotype frequencies among the patients were analyzed by the {chi}2 test and multi-variate analysis using the SPSS software program (version 9). A P value <0.05 was considered significant. The Student t test was performed for parametric variables and the {chi}2 test for non-parametric variables.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
One hundred and fifty-six patients were included in the study. All patient data are presented in Table 1. There were 128 males and 28 females. The average age was 66.91+12.41 years. Data regarding diabetes mellitus were available in 147 patients, of these there were 62 patients with diabetes mellitus and there were 70 patients with hypertension. In addition, the etiology could be determined in 155 cases and was ischemic in 117 (75.5%) and non-ischemic in 38 (24.5%) cases.


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  		Table 1 Characteristics of the patients (n=156)

 
The distribution of the mutations is shown in Table 2. 42 (26.75%) had at least one of the hemochromatosis mutations. Five (3.65%) were homozygotic for the H63D mutation and 37 (23.6%) were heterozygotic for the H63D mutation. The C282Y mutation was not present. In a control population of 98 healthy blood donors, 27 (27.6%) were heterozygous for the H63D population and none had the C282Y mutation (no significant difference between the patients with cardiomyopathy and the healthy blood donors, P=0.754 {chi}2 test). There was a non-significant trend to a difference in the prevalence of homozygotic H63D between the cardiomyopathy patients and the healthy blood donors (3.18% vs. 0%, P=0.076, {chi}2 test). The genotype and allele frequencies of the H63D mutation are shown in Table 3.


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  		Table 2 Distribution of the C282Y and H63D mutation among subjects with dilated cardiomyopathy (DCM) and controls

 


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  		Table 3 Allele and genotype frequencies of H63 in the control and cardiomyopathy patients

 
There was no statistically significant difference between the cardiomyopathy patients with and without the mutations in terms of age, LV systolic and diastolic diameter, ejection fraction, NY heart association class, ischemic or non-ischemic origin, cardiac rhythm, presence of diabetes or hypertension (Table 4). In addition there was no difference between the patients with or without HFE mutations and haemoglobin, serum iron, transferring, ferritin, urea, creatinine, and serum ALT. The serum albumin was significantly lower in the patients without mutations compared to those with mutations, 3.6 g/dl vs. 3.9 g/dl, P=0.029 (Table 5).


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  		Table 4 Comparison between patients with and without a HFE mutation

 


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  		Table 5 Biochemical indices and iron concentrations according to genotype

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Hemochromatosis is a genetically determined disorder in which mutations in the HFE gene cause increased intestinal iron absorption. The clinical manifestations of iron overload include liver disease, skin pigmentation, diabetes mellitus, arthropathy, impotence in males and cardiac enlargement with or without conduction defects [1].

Diabetes is present in up to 30% of hemochromatosis patients [1]. It is unclear, however, whether all diabetic patients should be screened for hemochromatosis. In one report of 716 Danish patients who developed type 1 diabetes after the age of 30, 1.26% were homozygous for the C282Y mutation compared to 0.25% of the control group [9]. Results from other studies have been inconclusive [10–12].

Hemochromatosis can cause a dilated cardiomyopathy with heart failure and conduction disturbances, such as the sick sinus syndrome [13–15], due to excess deposition of iron within the myocardium [16]. In the past, cardiac disease was the presenting feature in up to 15% of cases of hemochromatosis. Treatment with phlebotomy [13–15] or chelation [17] has been reported to improve left ventricular dysfunction but irreversible cardiac dysfunction may be associated with advanced disease.

It is unclear if there is an effect of hemochromatosis on coronary artery disease. The C282Y mutation has been shown to be associated with an increased risk of coronary heart disease in the ARIC study after adjusting for other confounding risk factors [18]. In addition, in patients with hemochromatosis arterial wall thickness is increased before the onset of cardiovascular complications and is reversed by iron depletion therapy [19]. However, in the ECTIM and GENIC studies, there was no difference in the prevalence of C282Y and H63D mutations [20]. Also, in this report, the prevalence of C282Y carriers was not found more frequently in patients with atherosclerotic plaques in the carotid or femoral arteries but the H63D mutation was more prevalent. Other reports have also not found a relationship between hemochromatosis mutations and the risk of coronary artery disease [21–25]. Recently, a population-based study of 30 916 white adults did not find a consistent association between HFE mutations and the prevalence of coronary artery disease [26]. Taken together, these studies suggest that iron plays a small role, if any in the pathogenesis of coronary artery disease.

There are two previous reports on the incidence of hemochromatosis mutations in patients with cardiomyopathy and they have differing results. In a report from the UK of 207 white patients with idiopathic dilated cardiomyopathy, there was an increased rate of H63D mutations but not of C282Y in the cardiomyopathy patients compared to a group of healthy control patients [27]. There was, however, a trend to increased survival in the C282Y heterozygotes. The pathogenetic lesson is unclear since the effect of H63D mutations on the iron status is much less than the C282Y mutation. The other report is from Brazil of 319 patients with cardiomyopathy of different etiologies [28]. A higher incidence of C282Y mutations was found in the group of patients with ischemic cardiomyopathy (58 patients) than in patients with non-ischemic cardiomyopathy. There was no difference in the incidence of the H63D mutations in this group. The difference in the findings of these two groups is also compounded by marked geographical differences in the incidence of hemochromatosis.

We did not find the presence of the C282Y mutations in either our control population of healthy blood donors or the patients with cardiomyopathy. Although we do not have any clinical details of the blood donors, we assume that the gene frequency is representative of the general population. However, it is possible that there was undiagnosed cardiomyopathy with relatively asymptonatic left ventricular dysfunction in our healthy blood donors. This absence of the C282Y mutation may explain the low incidence of hemochromatosis found in Israel (Reznizki, personal communication) and is consistent with a previous report that the C282Y mutation and hereditary hemochromatosis are both uncommon in Jews [29]. We did find a similar presence of the H63D mutation in both our control and cardiomyopathy patients, although there was a non-significant trend towards a higher incidence of homozygotes for the H63D mutation in the patients with cardiomyopathy. There was, however, no effect of the presence of the homozygous H63D mutation on transferrin saturation or serum ferritin levels.

In this report the majority of the patients with cardiomyopathy had an ischemic origin. 97 had a previous myocardial infarction and seven had coronary artery bypass graft surgery in the absence of an infarction. This number of ischemic cardiomyopathy patients is much higher than in the report from Brazil [28], in which only 58 patients had an ischemic origin. Since in our population there were no patients with the C282Y mutation we cannot comment on the link between ischemic cardiomyopathy and this mutation in the Brazilian report.

In summary, we find no evidence for an effect of the hemochromatosis mutations on the clinical or laboratory parameters of our patients with cardiomyopathy. Thus, in Israel we suggest that it is not necessary to check for the presence of hemochromatosis in patients with cardiomyopathy. In view of the difference in the prevalence of this disease amongst different populations, the effectiveness of examining for the presence of hemochromatosis amongst patients with cardiomyopathy, should be investigated.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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S. Goland, S. D. Malnick, C. Ellervik, B. G. Nordestgaard, A. Tybjaerg-Hansen, P. Grande, A. Tybjaerg-Hansen, M. Appleyard, and B. G. Nordestgaard
Letter Regarding Article by Ellervik et al, "Hereditary Hemochromatosis and Risk of Ischemic Heart Disease: A Prospective Study and a Case-Control Study" * Response
Circulation, January 3, 2006; 113(1): e10 - e10.
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