Review
A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia

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Abstract

Background: Familial hypercholesterolaemia (FH) affects approximately 1 in 500 people (10 million world-wide) and the elevated serum cholesterol concentrations lead to a more than 50% risk of fatal or non-fatal coronary heart disease by age 50 years in men and at least 30% in women aged 60 years. Based on a systematic literature search, we review the natural history of FH, describe the diagnostic criteria, and consider the effectiveness of treatment. Methods: A comprehensive review was conducted of the literature on the diagnosis of FH, the morbidity and mortality related to treated and untreated FH, and the evidence on the effectiveness of treatment of FH in adults and children. Treatment options have changed since statin treatment became available, and we have not considered pre-statin therapy studies of treatment effectiveness. Findings and discussion: A clinical diagnosis of FH is widely used, but a definitive diagnosis can be made by genetic screening, although mutations are currently only detected in 30–50% of patients with a clinical diagnosis. Under-diagnosis of FH has been reported world-wide ranging from less than 1% to 44%. The relative risk of death of FH patients not treated with statins is between three and fourfold but treatment is effective, and delays or prevents the onset of coronary heart disease. Early detection and treatment is important. Aggressive LDL therapy is more effective in the regression of the carotid intima media thickness than conventional LDL therapy. Diagnosis at birth is problematic, and should be delayed until at least 2 years of age. Statins are not generally recommended for the treatment of children up to adolescence. Resins may be used but poor adherence is a problem. Technical advances in mutation detection, and the identification of other genes that cause FH, are likely to have important implications for the cost effectiveness of genetic diagnosis of FH.

Introduction

Familial hypercholesterolaemia (FH) is characterised by substantially elevated serum cholesterol concentrations [1] with a more than 50% cumulative risk of fatal or non-fatal coronary heart disease by age 50 years in men and at least 30% in women aged 60 years [2], [3]. Most people with FH are undiagnosed or only diagnosed after their first coronary event, but treatment with statins is effective in FH [4], [5] and it delays or prevents the onset of coronary heart disease [6], [7], [8], [9], [10]. Early identification of affected individuals is important because early treatment with statins can substantially reduce the cardiovascular risk.

In this paper we review what is known about the natural history of the condition, describe the options for making the diagnosis, and discuss the evidence for the effectiveness of treatment. Options for screening for FH are discussed elsewhere [11].

Section snippets

Methods

We conducted a systematic review of the literature on the diagnosis of FH, the morbidity and mortality related to treated and untreated FH patients, and the evidence regarding treatment of FH in adults and children. The literature search included a systematic search of electronic databases including Medline, Ovid (Embase), BIDS, Psychlit, Healthstar and Health Management, the Cochrane Library and the NHS Centre for Reviews and Dissemination databases. An Internet search was also conducted. We

Diagnostic criteria for FH

The primary clinical diagnostic criteria for FH are an elevated cholesterol level, presence of tendon xanthomata in the patient or first degree relative, and a dominant pattern of inheritance of premature coronary heart disease or elevated cholesterol.

Prevalence of diagnosed and undiagnosed FH

The prevalence of FH in most populations is believed to be 1/500 [1], and thus world-wide, there are estimated to be 10 million FH patients [22]. This estimate is imprecise, and is based on calculations using the Hardy-Weinberg equation p2+2pq+q2=1, with q2 being the observed frequency of FH homozygotes in a country and p and q being the frequency of the normal and FH causing alleles, respectively. The prevalence is known to be higher in certain regions. In countries where a founder gene effect

Morbidity and mortality associated with untreated FH

Several early studies examined the risk of CHD associated with a diagnosis of FH before statins became available (Table 2). Before the availability of statins, treatment with resins and dietary advice had only small effects on plasma lipid levels, and the risk of CHD remained high. For this reason, although some of the subjects in the early studies were being treated for their hypercholesterolaemia, the event rates reported are likely to be indicative of the natural history of the disease.

Mortality and morbidity of FH treated with statins

The safety and efficacy of statin use has been tested in large double-blind placebo controlled randomised trials which are well reported elsewhere [6], [7], [8], [9], [10]. These trials demonstrate the effectiveness of statin therapy in populations with elevated cholesterol levels, but not in patients with FH. No such trial has been conducted in FH subjects, and is unlikely ever to be conducted for ethical reasons, since the effectiveness of statins in preventing coronary morbidity and

Diagnosis

A study conducted in the US in 1973 tested 29 children at birth (from 23 FH families) of which 16 had elevated cholesterol levels compatible with the diagnosis of FH. However, three had levels below the 95th percentile of total cholesterol in healthy control children indicating that up to 20% of FH children would be wrongly diagnosed if only tested for total cholesterol [75]. At follow up between one and two and a half years later, all but one child were still hypercholesterolaemic, and the one

Summary and future trends

It is clear from this review that there are still many gaps in knowledge. There are few longitudinal studies of people with FH and there are very few data on the effects of treatment. With the data available from trials of statins in people at only moderate risk of CHD, trials in people with FH would be unethical. However, consideration should be given to undertaking observational studies, particularly longitudinal cohort studies of people with FH.

Statins are not normally prescribed in children

Acknowledgements

This project was funded by the HTA programme (project number 95/29/04). The opinions expressed therein are those of the authors and not necessarily those of the NHS Executive. DM was supported in the preparation of this paper by an unconditional grant from Merck Sharpe and Dohme. SEH and HAWN would like to acknowledge grants RG2000025, RG93008 from the British Heart Foundation.

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