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Strategies for early diagnosis of haemochromatosis

Niederau, Clausa; Strohmeyer, Georgb

European Journal of Gastroenterology & Hepatology: March 2002 - Volume 14 - Issue 3 - p 217-221
Leading Articles
  •  Strategies to look for haemochromatosis in the presence of clinical complications such as liver disease will detect haemochromatosis in a high percentage of patients with Celtic origin. However, up to one-half of these patients will already have an irreversible complication, such as liver cirrhosis.
  •  Only patients with early non-cirrhotic haemochromatosis treated by phlebotomies have a normal life expectancy.
  •  Thus, the current clinical approach to detect haemochromatosis is unacceptable. Only a more general type of screening in asymptomatic subjects, including genetic testing, will increase the rate of early diagnosis and improve the clinical outcome further.

 Strategies to look for haemochromatosis in the presence of clinical complications such as liver disease will detect haemochromatosis in a high percentage of patients with Celtic origin. However, up to one-half of these patients will already have an irreversible complication, such as liver cirrhosis. Only patients with early non-cirrhotic haemochromatosis treated by phlebotomies have a normal life expectancy. Thus, the current clinical approach to detect haemochromatosis is unacceptable. Only a more general type of screening in asymptomatic subjects, including genetic testing, will increase the rate of early diagnosis and improve the clinical outcome further. Genetic haemochromatosis is one of the most frequent inborn errors of metabolism. Only patients with early non-cirrhotic haemochromatosis treated by phlebotomies have a normal life expectancy. The present review analyses strategies for early diagnosis of haemochromatosis by using the Medline database and own data from a large cohort of patients with haemochromatosis. The still widely used approach to look for haemochromatosis in the presence of clinical complications such as liver disease will detect haemochromatosis in a considerable percentage of patients with Celtic origin. However, up to one half of these patients will already have an irreversible complication such as liver cirrhosis, diabetes mellitus or cardiomyopathy. In contrast, screening approaches of non-selected asymptomatic subjects using either determination of transferrin saturation and serum ferritin (phenotypic screening) or using genetic testing will detect haemochromatosis in most subjects in a precirrhotic stage without irreversible complications. Both phenotypic and genetic screening are highly cost-effective for detection of iron-loaded individuals in the general population. The current clinical approach to look for haemochromatosis in the presence of clinical disease is unacceptable. Only a more general type of screening in asymptomatic subjects including genetic testing will increase the rate of early diagnosis and will further improve the clinical outcome.

aDepartment of Medicine, St Josef-Hospital Oberhausen, Academic Teaching Hospital of the University of Essen, Oberhausen, and bDivision of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany

Correspondence to Prof. Dr Claus Niederau, St Josef-Hospital, Academic Teaching Hospital of the University of Essen, Department of Internal Medicine, Mülheimer Str. 83, 46045 Oberhausen, Germany Tel: +49 208 837 301; fax: +49 208 837 309; e-mail: claus.niederau@st-josef.de or claus.niederau@uni-duesseldorf.de

Received 5 November 2001

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Prevalence of haemochromatosis

The prevalence of haemochromatosis is difficult to estimate because the literature describes various case definitions: clinical signs and symptoms, abnormal iron indices, and genetic mutations [1]. Each case definition has its strengths and weaknesses. Clinical case definition (e.g. liver disease, diabetes mellitus, cardiomyopathy) usually reflects symptoms due to late stages, which may not be reversible. In early haemochromatosis, there may be no symptoms at all, or symptoms and signs may be nonspecific, such as fatigue, abdominal pain, joint pain, or elevated liver enzymes.

Case definitions more specific to haemochromatosis, such as elevated transferrin saturation or ferritin concentration, allow diagnosis before symptoms and signs due to complications occur. However, the rate and degree of progression from an asymptomatic stage of abnormal iron indices to clinical disease was ill defined until recently.

The case definition due to genetic testing (in particular, by identifying C282Y homozygotes) has the advantage that it includes a maximal number of subjects without clinical disease. The weakness of this approach is the uncertainty about the progression from genetic susceptibility to clinical complications.

In 1996, Feder et al. described two mutations associated with haemochromatosis: C282Y and H63D [2]. Although further mutations of the HFE gene have since been detected, mainly C282Y homozygotes and, to a lesser degree, C282Y/H63D compound heterozygotes are at risk of developing iron overload. In white populations of mainly Celtic origin, 85–95% of all patients with haemochromatosis are C282Y homozygotes, while 5–10% are C282Y/H63D compound heterozygotes. Several recent studies have determined the frequency of C282Y and H63D mutations in the general population. The frequency of C282Y homozygosity ranged between 0.2 and 0.5% in white populations, most of whom were of Celtic ancestry [3]. The frequency of compound heterozygosity for the C282Y/H63D mutation ranged from 1.9 to 2.4%, and the prevalence for C282Y/wild-type genotype ranged from 9 to 13% in white populations [3]. The allele frequency of the C282Y mutation approaches 10% in most white populations, and may be as high as 30% in Irish and Basque populations with predominant Celtic origin [4]. In contrast to white populations, C282Y mutation and clinical haemochromatosis are less frequent in black American populations and in populations from Asia and Africa [3]. Therefore, most of the following considerations, in particular those dealing with genetic testing, are valid only in white populations with a predominant Celtic heritage.

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Natural history and progression of haemochromatosis

The progression from an asymptomatic genetic susceptibility to stages of abnormal iron indices and finally to clinical disease was studied only recently when genetic testing became available. All new phenotypic data show a rather high penetrance of iron overload for C282Y homozygous subjects, ranging from 75 to 96%. The various studies used different definitions of iron overload, including increased transferrin saturation, increased serum ferritin, biochemical or histological hepatic iron index values, and clinical signs and symptoms [5–8]. As expected, the penetrance in relatives of haemochromatosis patients is higher in males (85%) than in females (69%) [8]. The majority of asymptomatic C282Y homozygotes were premenopausal females [8]. Of the C282Y homozygotes biopsied because of increased transferrin saturation or ferritin, hepatic iron excess was seen in all samples. When stratified by age and gender, penetrance of C282Y homozygosity in men older than 40 years is 95% for iron overload [8]. Fifty per cent of these men have clinical signs or symptoms. In men younger than 40 years, 80% have iron overload but only 12% have symptoms. Iron overload is seen in 80% of C282Y homozygous women older than 40 years, while only 13% of these women have symptoms. C282Y homozygous women younger than 40 years less frequently have iron overload (39%), and these are usually asymptomatic [9]. The course of iron overload is less well defined in C282Y/H63D compound heterozygotes. Less than 2% of these heterozygotes may have symptoms, which are often mild and occur mainly in males. In some male C282Y/H63D compound heterozygotes, iron overload may develop and cause cirrhosis [10]. In any case, C282Y homozygotes have a high risk of developing iron overload; only premenopausal women have a low risk because of menstrual blood loss.

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Diagnosis in patients with clinical signs or symptoms

The study by Moodie et al. [11] shows that C282Y homozygous haemochromatosis was detected in 3% of a liver clinic population in London. However, none of the patients of African, African-Caribbean, Asian or Mediterranean origin was homozygous for the C282Y mutation, and none had iron indices suggesting haemochromatosis. Siderosis on liver biopsy was restricted to C282Y homozygotes and C282Y/H63D compound heterozygotes. In subjects with northern European but not Celtic origin, C282Y homozygosity was found in 1%. In contrast, 7% (9/119) of patients with Celtic origin were C282Y homozygotes and 15% (18/119) were C282Y heterozygotes, including three subjects with compound C282Y/H63D heterozygosity. Liver biopsy showed that almost one-half of the C282Y homozygotes had cirrhosis due to haemochromatosis. Thus, C282Y homozygosity-associated end-stage haemochromatosis is frequent in liver clinic populations of Celtic origin.

The present study underlines that haemochromatosis must be excluded in every patient with chronic liver disease, in particular when the patient has a Celtic ancestry. This conclusion is appropriate clinical practice supported by the EASL International Consensus Conference [12]. Haemochromatosis also needs to be considered in other conditions, including cardiomyopathy and arrhythmias, diabetes mellitus, impotence, amenorrhoea, anterior pituitary failure, arthralgia, abnormal skin pigmentation, and porphyria cutanea tarda [12] (Table 1). The present study demonstrates that the current clinical approach to detect haemochromatosis is unacceptable [12] because one-half of patients already had an irreversible complication at diagnosis. The strategy to look for haemochromatosis in the presence of suspicious clinical signs and symptoms will fail to detect the disease in early stages [11]. It is widely accepted that patients with early non-cirrhotic haemochromatosis have a normal life expectancy when they are treated properly by phlebotomies [13–16]. Due to the recent consensus statement [12], future efforts to improve the rate of early diagnosis will include educating physicians and patients about haemochromatosis, as well as research projects involving screening in populations at risk for this disease. Although we agree with these goals, it is obvious that only a more general type of screening is likely to increase the rate of early diagnosis.

Table 1

Table 1

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Population screening for early and asymptomatic haemochromatosis

For decades, the diagnosis of haemochromatosis was carried out in symptomatic patients with typical complications from iron overload and elevations of transferrin saturation and ferritin [1,11,17]. All future efforts have to concentrate on an earlier diagnosis to prevent irreversible complications. Our own studies have shown that there was more than a four-fold increase in early diagnoses from the period 1947–1969 to the period 1970–1981 [16]. This marked improvement is probably explained largely by advances in the understanding of and education about the disease [18–20]. Although there was a further increase in the percentage of patients with early disease during 1982–1991, this was much smaller than that during preceding decades [16]. Most patients without symptoms were diagnosed by screening in families with an already diagnosed patient. It is important to support diagnosis in subgroups of people who have suspicious symptoms and findings [11,21–23] many of which will, however, be due to late-stage disease. Further improvement in early diagnosis and thus better long-term outcome will be possible only when screening is carried out in asymptomatic populations.

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Screening strategies

Two types of population screening have been discussed recently: (a) phenotypic screening followed by genetic analysis and (b) genetic testing followed by analysis of iron markers. Both strategies have advantages and disadvantages (Table 2).

Table 2

Table 2

Phenotypic screening strategies used unbound iron-binding capacity, transferrin saturation, and ferritin for determination of iron overload. However, these tests indicate the disease only when iron stores have accumulated to a certain degree [24]. Similar to clinical practice, genetic testing was used to confirm the diagnosis suspected by abnormal iron indices. Phenotypic screening has been cost effective for detection of iron-loaded individuals in the general population [23,25–29], although it involved a complex sequential visit and testing algorithm. Furthermore, the sensitivity and specificity of screening tests such as transferrin saturation have been based on a case definition of iron overload, and there is still a debate about optimal threshold values for transferrin saturation. For individuals with phenotypic features of haemochromatosis, C282Y homozygosity and C282Y/H63D compound heterozygosity confirms the diagnosis. However, a negative gene test does not rule out iron overload due to other mutations in HFE and other genes.

Primary genotyping has some advantages over phenotyping screening, although the test itself is more costly. This approach will maximize the number of subjects diagnosed in early stages. The detection of C282Y homozygosity usually obviates the need for liver biopsy. Genotyping, however, has also led to the recognition that not all C282Y homozygotes progress to significant iron overload, and that some C282Y homozygotes do not have iron overload (incomplete penetrance) [30–32]. The identification of homozygotes without abnormal iron indices is, however, helpful to detect iron-loaded family members [33]. Asymptomatic C282Y homozygotes are good candidates for blood donations, which will prevent any potential progression. Blood from these subjects is now being accepted by American blood banks; unfortunately, blood banks in several European countries still do not accept such blood [34]. Family members of an affected individual should be screened primarily by genetic testing.

As yet, there is no general agreement regarding the age at which screening should be initiated. There is a consensus that screening is not recommended in children in whom the risk of complications may not be ameliorated by treatment at this time [12,35]. However, one study suggested that screening children of homozygous patients is cost effective above the age of 10 years [25]. Screening is probably more useful and cost effective at age 25–30 years. The selection of the occasion for screening will depend on circumstances, such as reimbursement and insurance issues, which differ between various countries.

Several studies have shown that screening for haemochromatosis in the general population is highly cost effective [26,33,36–39]. The costs per year of life saved compare favourably with other medical interventions, which are beyond any medical or public discussion, e.g. treatment of hypertension [39]. It is well documented that transferrin saturation is the more sensitive marker for haemochromatosis compared with ferritin [35,40]. It remains to be determined whether primary phenotypic screening or primary genetic testing is more cost effective. Both approaches are probably cost effective anyway.

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Criticisms against genetic testing and population screening

Population screening is not accepted universally because of several issues [12,41]. There is still some debate about the natural history and the burden of suffering from the disease [41], and further criticisms relate to problems of genetic privacy and psychological issues [41,42]. The authors believe that many of these concerns will prove to be invalid.

All recent phenotypic data show a high penetrance of iron overload for C282Y homozygotes, ranging from 75 to 96%. In particular, C282Y homozygous men have a high risk of also developing clinical disease [5–9]. Some participants of the EASL Consensus Conference [11] felt that there was a lack of evidence from inception cohort studies reporting the course of untreated and treated haemochromatosis, and some criticized the fact that there are no randomized, controlled trials of treatment. With the authors’ own clinical experience and knowledge of the literature, the latter criticisms appear academic: the clinical data about the benefit of iron removal are so overwhelming that randomized treatment studies appear unethical. Such criticisms should not hinder the introduction of screening programmes, which, of course, should be evaluated carefully by appropriate scientific methods.

Privacy of genetic information remains a concern because of the potential for insurance and job discrimination. Although anecdotal evidence of genetic discrimination exists, no studies are available to determine the extent to which such discrimination occurs. Since therapy is without significant side effects and costs, and will guarantee a normal life expectancy, neither insurance companies nor employers should have problems with accepting C282Y homozygous subjects who will never develop iron overload because they know their genotype. In contrast, the risk of disease is much higher in C282Y homozygotes who do not know their genotype.

Other criticisms of genetic testing refer to the potential stress that may arise from the knowledge of genetic susceptibility for a disease. Two recent studies analysed the psychological stress attributable to genetic testing in subjects at risk for Huntington's disease and inherited breast cancer. Similar to haemochromatosis, these diseases cause complications only in adulthood, but they carry a greater clinical risk and can be treated less well compared with haemochromatosis. Subjects who knew their genotypes (mutation carrier or mutation negative) showed either no increase or a decrease in stress compared with subjects who did not know their genotypes [42,43].

Several controversial screening issues are addressed by a large screening study sponsored by the National Institutes of Health (NIH). One aim of the study is to validate the association between common HFE gene mutations and development of haemochromatosis in more than 100 000 subjects. This study, which is the largest genotyping study ever sponsored by the NIH, also tries to identify other genes that may be involved in the development of iron overload.

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Keywords:

haemochromatosis; iron overload; liver cirrhosis; ferritin; transferrin; HFE gene; phlebotomty

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