Elsevier

Atherosclerosis

Volume 170, Issue 1, September 2003, Pages 73-78
Atherosclerosis

Comparison of the risk of fatal coronary heart disease in treated xanthomatous and non-xanthomatous heterozygous familial hypercholesterolaemia: a prospective registry study

https://doi.org/10.1016/S0021-9150(03)00233-8Get rights and content

Abstract

Background: A clinical diagnosis of familial hypercholesterolaemia (FH) is often made in the absence of tendon xanthomata (TX), which are not usually present before the fourth decade of life. The prognosis of treated non-xanthomatous (TX−) FH is uncertain and the objective of this study was to compare mortality from coronary heart disease (CHD) in patients with treated TX+ (definite) and TX− (possible) heterozygous FH. Methods: A diagnosis of definite or possible FH was based on raised cholesterol levels (>7.5 mmol/l) and a family history of premature CHD or hypercholesterolaemia. Patients were recruited from 21 outpatient lipid clinics in the UK from 1980 to 1998. The cohort of 1569 patients with TX+ FH were followed for 12 754 person years and the cohort of 1302 patients with TX− FH for 10 238 person years. The standardised mortality ratio (SMR) was calculated from the ratio of the number of deaths observed to the number expected in the general population of England and Wales (SMR=100 for reference population). Findings and discussion: CHD accounted for 64 (63%) of the 102 deaths in the TX+ cohort and 38 (57%) of the 67 deaths in the TX− cohort with the SMR for a fatal coronary event being, respectively, 294 (95% confidence interval 228, 380, P<0.00001) and 205 (95% CI 145, 282, P=0.0001). The similarly elevated CHD mortality risk suggests that, in adulthood, both groups of patients should be treated equally aggressively with HMG Co A reductase inhibitors (statins).

Introduction

Heterozygous familial hypercholesterolaemia (FH) is an autosomal dominant disorder of lipoprotein metabolism that affects about 1 in 500 of the UK population [1]. It is characterised by mutations of the low-density lipoprotein receptor (LDLR) resulting in an accumulation of low density lipoprotein (LDL) in the plasma [1]. Deposition of cholesterol in the tendons leads to the development of tendon xanthomata (TX), which are usually not evident before the fourth decade of life [2]. TX are, however, becoming a less common diagnostic feature since increased awareness of the importance of screening relatives of index patients has resulted in the earlier diagnosis and treatment of secondary cases.

TX positive (TX+) or “definite” heterozygous FH results in a substantial excess mortality from CHD [1]. The cumulative risk of a fatal or non-fatal coronary event by the age of 60 without effective treatment is at least 50% in men and about 30% in women [3], [4], with about a 100-fold increase in relative risk for fatal CHD in young adults aged 20–39 years [5]. The prognosis has improved since the introduction and widespread use of HMG Co-A reductase inhibitors (statins) and more effective treatment for secondary prevention of CHD [6]. Furthermore, treated patients do not appear to be at increased risk of fatal stroke [7]. To date, the prognostic implications of a clinical diagnosis of non-xanthomatous (TX−) “possible” FH are not clear, although in most clinics these patients are more numerous than those with TX+ FH [8]. The aim of our study was to compare coronary mortality in patients with treated TX+ “definite” and TX− “possible” FH.

Section snippets

Patients and methods

The methods have been described in detail previously [5], [6]. The 21 participating clinics registered patients referred to them by either general practitioners or hospital specialists. A diagnosis of definite FH [8] was made if (a) total cholesterol concentration (either pre-treatment or highest on treatment) was above 7.5 mmol/l in adults over 16 years or the LDL-cholesterol concentration was above 4.9 mmol/l, plus (b) tendon xanthomas in the patient or a first or second degree relative. A

Registration and follow-up

The demographic and clinical characteristics of patients were recorded on a standard registration form [5]. A fasting venous blood specimen was taken at the registration visit and serum total cholesterol, triglycerides, and high density lipoprotein were measured by the laboratories routinely used by the participating clinics. Serum low-density lipoprotein concentrations were calculated using the Friedewald formula [9]. The names of registered patients were flagged by the NHS Central Registry

Statistical methods

The mortality analysis was undertaken using a computer programme for cohort studies [10] that applies standard methods [11]. Person years of risk were accumulated within 5-year age groups and 5-year calendar periods to estimate the expected number of deaths from specified causes. Thirty-two subjects were censored on reaching the age 80 years and six patients who had emigrated were censored at the date of embarkation. The expected number of deaths from coronary heart disease (CHD) (ICD codes

Results

After excluding 22 patients whose vital status was unknown, the cohort of patients consisted of 2871 patients registered between 1 January 1980 and 31 December 1998. A total of 1569 patients (774 men) with definite (TX+) FH were followed for 12 754 person years and 1302 patients (631 men) with possible (TX−) FH were followed for 10 238 person years. Of the 22 992 person years prospective observation, 7435 were accumulated before 1992.

Table 1 compares the clinical characteristics by gender of

Discussion

In comparison with the general population, the study found a similar 2–3-fold higher coronary mortality both in patients with treated definite FH diagnosed on the basis of elevated cholesterol concentrations and the presence of TX, and in patients with a presumptive diagnosis of FH based on elevated cholesterol concentrations and a dominant pattern of transmission of premature CHD or hypercholesterolaemia within the kindred. As far as we are aware this has not been demonstrated previously.

Acknowledgements

The Simon Broome FH register is currently supported by an unrestricted educational grant from Astra Zeneca, and has also received support from Pfizer Ltd and Schering-Plough Ltd. SEH and HAWN would like to acknowledge grants RG93008 and PG2000015 from the British Heart Foundation.

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    Members of the Scientific Steering Committee of the Simon Broome Registry Group of the Hyperlipidaemia Education and Research Trust (HEART UK): D.J. Betteridge, N. Capps (Chairman), P.N. Durrington, S.E. Humphries, J.I. Mann, R. Naoumova, H.A.W. Neil, M. Seed (Honorary Secretary). Participating physicians and clinics: K. Arnsten, S. Flemming (Royal Cornwall Hospital, Truro), D.J. Betteridge (University College Hospital, London), P.N. Durrington (Manchester Royal Infirmary), R.S. Elkeles (St Mary's Hospital, London), R.M. Finnie (St John's Hospital, Livingston), D.J. Galton (St Bartholomew's Hospital, London), R. Hillson (Hillingdon Hospital, Uxbridge, and Mount Vernon Hospital, Northwood), E.A. Hughes (Sandwell District Hospital, West Bromwich), M.F. Laker (Royal Victoria Infirmary, Newcastle-Upon-Tyne), B. Lewis, A.S. Wierzbicki (St Thomas's Hospital, London), R. Lorimor (Glasgow Royal Infirmary), J.I. Mann (John Radcliffe Hospital, Oxford), D.R. Matthews, H.A.W. Neil (Radcliffe Infirmary, Oxford), J.P. Miller (University Hospital of South Manchester, J.P.D. Reckless (Royal United Hospital, Bath), L.N. Sandle (Trafford General Hospital, Manchester), M. Seed (Charing Cross Hospital, London, and King Edward VII Hospital), K.G. Taylor (City Hospital, Birmingham), G.R. Thompson, R. Naoumova (Hammersmith Hospital, London), R. West (St George's Hospital, London).

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