Elsevier

Atherosclerosis

Volume 173, Issue 1, March 2004, Pages 55-68
Atherosclerosis

Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia

https://doi.org/10.1016/j.atherosclerosis.2003.11.010Get rights and content

Abstract

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). FH is a public health problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% of males and 50% of females with FH will suffer a coronary event before 65 years old if appropriate preventive efforts are not implemented. Early identification of persons with FH and their relatives, and the early start of treatment are essential issues in the prevention of premature cardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from their diagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention to answer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of these patients.

Introduction

Familial hypercholesterolemia (FH: MIM#143890) is an autosomal codominant inherited disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). Usually, clinically identified FH results from defects in the LDL receptor (LDLR) gene [1], [2]. The LDLR gene was cloned and mapped to 19p13.1–13.3, and more than 800 mutations have been reported to date to cause FH (http.//www.ucl.ac.uk/fh; http.//www.umd.necker.fr). The penetrance of FH is almost 100%, meaning that half of the offspring of an affected parent have a severely elevated plasma cholesterol level from birth onwards, with males and females equally affected.

More recently, other loci have been identified to be responsible for other forms of hereditary hypercholesterolemia with phenotypes very similar to FH (Table 1) [3], [4], [5], [6], [7], [8]. One of these, a defective apolipoprotein B (apoB) that displays low affinity for the LDLR, called “familial defective apo B” is as common as FH in some European populations [5], [6]. A less frequent cause of autosomal dominant hypercholesterolemia has been linked to chromosome 1p32 [7], [8]. The clinical management of these other hereditary hypercholesterolemias does not differ from FH, and therefore these recommendations can be applied to them all.

The large primary and secondary prevention trials with statins during the last decade have clearly demonstrated the benefit of reducing LDLc in subjects with high LDLc and/or high cardiovascular risk [9], [10], [11], [12], [13], [14]. As heterozygous FH (heFH) subjects have both high LDLc and high cardiovascular risk, statins would seem to be the initial treatment of choice, though evidence of a subsequent reduction in cardiovascular disease (CVD) remains indirect [15]. This new information and the availability of potent LDLc-lowering drugs should have an enormous impact on heFH morbidity and mortality [16].

International recommendations for the treatment of hypercholesterolemia have pointed out the importance of identifying and treating persons at high risk of CHD [17], [18]. However, recommendations for the general population do not apply to heFH for several reasons: first, global risk assessment for general population is not applicable to subjects with total cholesterol concentrations over 300 mg/dl (7.7 mmol/l), as almost invariably occurs in heFH, since the number of subjects with such high levels in the prospective studies on which the recommendations are based is not enough to allow prediction [17], [18]. Second, traditional risk factors for the general population do not necessarily play the same role in CHD of heFH or with the same intensity [19]. Third, the timing of CHD in heFH has a different pattern, with very precocious disease in many cases, which requires different detection strategies and specific criteria for the onset and the intensity of treatment. Last, most persons in prospective studies have not had a high cholesterol all their lives and the application of standard risk estimates for cholesterol seriously under-estimated CHD risk in heFH [20], [21], [22]. For these reasons, guidelines for the general population formally exclude heFH from their diagnostic and treatment recommendations [17], [18].

Due to the importance of LDLc lowering treatment in heHF and the absence of international recommendations on this topic, three Spanish Medical Societies (Sociedad Española de Arteriosclerosis, Sociedad Española de Cardiologı́a and Fundación Española Hipercolesterolemia Familiar) promoted, through a group of international experts, the elaboration of guidelines to answer the main questions about heFH that physicians worldwide face in the management of these patients. This document is the result of that initiative.

Section snippets

Familial hypercholesterolemia (FH) is an international health problem

FH is one of the most frequent monogenic hereditary disorders in the general population. The frequency of heterozygotes is approximately one per 500 individuals in most countries. However, some populations around the world such as French Canadians, Afrikaners in South Africa, Lebanese and Finns [23], [24], [25] have a much higher prevalence due to a founder effect. It has been estimated that there are 10,000,000 people with FH worldwide. Of these, less than 10% are diagnosed, and less than 25%

Intervention studies in familial hypercholesterolemia

Scientific evidence coming from large clinical trials have demonstrated the benefit of LDLc reduction in the prevention of CVD in a broad spectrum of populations, especially in subjects with symptomatic CHD or with absolute high risk [17], [35]. As mentioned previously, most heFH should be considered high risk subjects due to the prevalence of CHD, and they should benefit as a group at least as much as other high risk groups.

Although there is not an LDLc lowering intervention trial with CVD

Clinical diagnosis of FH

Clinical criteria used to identify patients with FH include: high plasma levels of total and LDL cholesterol, family history of hypercholesterolemia especially in children, deposition of cholesterol in extravascular tissues such as tendon xanthomas or corneal arcus, and personal and family history of premature CVD [1].

HeFH patients have LDLc levels approximately twice those of the normal population, ranging from 190 to 400 mg/dl (4.9–10.3 mmol/l). Triglyceride levels are usually in the normal

Detection of familial hypercholesterolemia. The family approach

It is mandatory to search for FH subjects to obtain as soon as possible an early diagnosis. The best approach in most populations at present is to determine LDLc in all first-degree family members of a heFH proband and it is recommended that all second-degree family members are also screened [49]. Children of heFH should be studied as soon as of 2–3 years of age.

The clinical diagnosis of heFH can be made if any of the following criteria are present in a first-degree relative of an heFH proband:

CVD risk factors in FH

Clinical expression of CVD in heFH patients is highly variable in terms of the age of onset and severity. CVD in heFH tends to cluster with higher frequency in certain families, although with marked differences among individuals [27]. This clinical variability also occurs among subjects coming from families sharing the same mutations in the LDLR gene, indicating that other genetic or environmental factors play an important role in the development of atherosclerosis in FH [50].

Different studies

Genetic analysis

Severe hereditary hypercholesterolemia due to high LDLc can be produced by several monogenic disorders (Table 1). The relative frequency of these disorders varies among populations, Familial defective apo-B100 is rare in Mediterranean countries but frequent (1/500 persons) in some central European regions [6]. The best known and most frequent monogenic disorder in most countries around the world is FH caused by mutations in the LDLR gene.

Although a positive genetic diagnosis is unequivocal, it

Biochemical analysis

Blood total cholesterol, triglycerides and HDLc measurements, and LDLc calculated by the Friedewald formula remain the basic biochemical parameters for clinical management of heFH. Blood glucose, liver enzymes, creatinine and TSH measurements are necessary to rule out secondary causes, and for global risk assessment. Some would include Lp(a) as a useful additional measure of risk. Other lipid and non-lipid parameters, such as apo B, C reactive protein or homocysteine, need additional studies

Detection of subclinical atherosclerosis

Subclinical atherosclerosis should be actively sought for in heFH for three reasons: (1) Its high prevalence in these subjects (Gidding et al. have demonstrated that 66% of adolescents and young adults (<24 years) have deposits of calcium in their coronary arteries, indicating the presence of established atherosclerotic plaques at these ages [65] and Mabuchi et al. detected significant atherosclerotic plaques by coronary angiography in males over 17 years and females over 25 years [66]). (2)

Risk categories

An internationally accepted concept is that intervention should be proportional to the individual’s absolute risk of developing a CVD event [17], and for that to be determined requires the assessment of the subject’s overall or global risk (Table 7).

According to the presence of major risk factors and/or clinical or subclinical atherosclerosis, three categories of risk for heFH are suggested:

  • 1.

    low 10-year risk: with no major risk factors;

  • 2.

    moderate 10-year risk: with 1 major risk factor;

  • 3.

    high 10-year

LDLc goals according to categories of risk

High risk of CVD in heFH is due to the increase in plasma LDL cholesterol resulting from defective internalization of LDL particles into the hepatic cells via the LDLR. Hence, the main objective of the treatment in heFH subjects is normalize LDLc in blood by upregulating LDLRs as much as possible. To reach this goal, potent LDL-lowering drugs are usually necessary. However, CVD, even in heFH, is a multifactorial disease in which different risk factors play important roles. For this reason, it

Lifestyle in heFH treatment

Healthy lifestyle is an important aspect of heFH treatment with many benefits beyond LDLc lowering. Lifestyle comprises a healthy diet, ideal body weight, no smoking and moderate physical activity. Although LDLc is the basic pathogenic CVD risk factor in FH, these subjects are very sensitive to other risk factors such as smoking or low plasma HDLc concentration (Table 7). In addition, a healthy diet can increase the LDLc lowering power of drugs, as occurred in the L-TAP study [76]. Recent

A healthy diet to prevent CVD in heFH

Fatty acid composition and cholesterol content are important aspects of the heFH diet. Saturated fat reduces hepatic LDLR expression and increases VLDL synthesis. The most potent saturated fatty acid in this regard is palmitic acid, one of the commonest saturated fatty acids in the diet, particularly rich in dairy fats. In contrast, unsaturated fatty acids, mainly linoleic acid and oleic acid, reduce total cholesterol and LDLc when they replace saturated fat. Since linoleic acid also reduces

LDLc lowering for heFH: old and new drugs

Most heFH patients need LDLc lowering drugs to reach LDLc goals. Indeed, almost all heFH patients will need to reduce their LDLc by over 40% to reach target levels (Table 11). Therefore, they will usually require potent lipid-lowering drugs in high doses or combined drug regimens, and, in some cases, LDL-apheresis.

There are three major LDLc lowering agents available for treatment of heFH: HMG CoA reductase inhibitors or statins, bile acid sequestrants or resins, and ezetimibe—a new selective

When to initiate LDLc treatment in heFH

Lifestyle treatment should be encouraged in all heFH subjects. It is imperative to be vigilant in promoting a no smoking policy for heFH patients and to apply all reasonable means of preventing or stopping the use of cigarettes. Dietary recommendations apply to children after the age of 2–3 years.

All men over 18 years and women over 30 years are recommended to be on LDLc lowering drug treatment to reach the LDLc goal appropriate to their basal CVD risk. It is advisable to avoid prolonged

LDL-apheresis for heFH

The use of LDL-apheresis has become the standard treatment for homozygous FH in recent years [111]. However, LDL-apheresis has not been widely used in heFH, mainly because substantial LDLc reductions can be obtained with diet and drug combination therapy in most patients. The new LDLc lowering drugs will probably reduce further the number of heFH patients meeting suggested criteria for LDL-apheresis.

LDL-apheresis is an invasive and expensive but safe procedure, with no important differences in

Acknowledgments

This work was supported by grants from the Fundación Española de Arteriosclerosis and the Fundación Española de Hipercolesterolemia Familial.

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    1

    Members of the panel: Fernando Civeira, M.D., Ph.D. (Spain) (Chair of the panel), Miguel Pocovı́, Ph.D. (Spain) (Vicechair), Eduardo Alegrı́a, M.D. (Spain), Rodrigo Alonso, M.D. (Spain), Rafael Carmena, M.D., Ph.D. (Spain), Jose A. Casasnovas, M.D., Ph.D. (Spain), Joep C. Defesche, Ph.D. (the Netherlands), Henrik K. Jensen, M.D., Ph.D. (Denmark), Paul N. Hopkins, M.D., M.S.P.H. (USA), D. Roger Illingworth, M.D., Ph.D. (USA), Emilio Luengo, M.D. (Spain), Luis Masana, M.D., Ph.D. (Spain), Pedro Mata, M.D., Ph.D. (Spain), Francisco Pérez-Jiménez, M.D., Ph.D. (Spain), Ernst J. Schaefer, M.D. (USA), Gilbert R. Thompson, M.D., F.R.C.P. (UK). Promoter Organizations: Sociedad Española de Arteriosclerosis, Sociedad Española de Cardiologı́a, Fundación Española Hipercolesterolemia Familiar. Organization support: The document was approved by the following organizational representatives: Sociedad Española de Arteriosclerosis (Spain), Sociedad Española de Cardiologı́a (Spain), Fundación Española Hipercolesterolemia Familiar (Spain), Bloodlink Foundation, Patients Network Inherited Cardiovascular Diseases (The Netherlands), HEART UK (UK).

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