Atherosclerosis 173 (2004) 5568

Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia

Fernando Civeira International Panel on Management of Familial Hypercholesterolemia1
Lipid Unit, Hospital Universitario Miguel Servet, Avda Isabel La Catlica 1-3, 50009 Zaragoza, Spain Received 7 May 2003; received in revised form 8 September 2003; accepted 5 November 2003

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 identication 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. 2003 Elsevier Ireland Ltd. All rights reserved.
Keywords: Familial hypercholesterolemia; Management; Treatment; Guidelines

1. Introduction Familial hypercholesterolemia (FH: MIM#143890) is an autosomal codominant inherited disorder of lipoprotein

Fax: +34-97-6566569. E-mail address: civeira@unizar.es (F. Civeira). 1 Members of the panel: Fernando Civeira, M.D., Ph.D. (Spain) (Chair of the panel), Miguel Pocov , Ph.D. (Spain) (Vicechair), Eduardo Alegr a, 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 P erez-Jim enez, M.D., Ph.D. (Spain), Ernst J. Schaefer, M.D. (USA), Gilbert R. Thompson, M.D., F.R.C.P. (UK). Promoter Organizations: Sociedad Espaola de Arteriosclerosis, Sociedad Espaola de Cardiolog a, Fundaci on Espaola Hipercolesterolemia Familiar. Organization support: The document was approved by the following organizational representatives: Sociedad Espaola de Arteriosclerosis (Spain), Sociedad Espaola de Cardiolog a (Spain), Fundaci on Espaola Hipercolesterolemia Familiar (Spain), Bloodlink Foundation, Patients Network Inherited Cardiovascular Diseases (The Netherlands), HEART UK (UK).

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 identied FH results from defects in the LDL receptor (LDLR) gene [1,2]. The LDLR gene was cloned and mapped to 19p13.113.3, 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 identied to be responsible for other forms of hereditary hypercholesterolemia with phenotypes very similar to FH (Table 1) [38]. One of these, a defective apolipoprotein B (apoB) that displays low afnity 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

0021-9150/$ see front matter 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2003.11.010

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F. Civeira / Atherosclerosis 173 (2004) 5568 Table 2 Familial hypercholesterolemia as a worldwide health problem Ten million people worldwide are affected by familial hypercholesterolemia Two hundred thousand patients will die prematurely of coronary heart disease 80% of heFH patients remain undiagnosed 84% of heFH patients do not take any lipid-lowering drug

Table 1 Monogenic disorders and related genes associated with hypercholesterolemia Familial hypercholesterolemia (LDLR) Familial defective apo B-100 (FDB) (apo B) Autosomal dominant hypercholesterolemia (FH3) (linked to 1p32) Autosomal recessive hypercholesterolemia (ARH) (recessive) Cholesterol 7 alpha-hydroxylase deciency (CYP7A1) (recessive) Familial sitosterolemia (ABCG 5 and ABCG 8) (recessive) Hypercholesterolemia associated with rare apo E (apo E)

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 benet of reducing LDLc in subjects with high LDLc and/or high cardiovascular risk [914]. 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: rst, 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 specic 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 [2022]. For these reasons, guidelines for the general popTable 3 Premature coronary artery disease in familial hypercholesterolemiaa Study Hirobe et al. [26] Mabuchi et al. [33] Hill et al. [27] Hopkins et al. [51] Alonso et al. [29] Diagnosis criteria TC > 300; XTM (+) TC > 230; XTM (+) LDLc > 95th P; XTM (+) LDLc; clinical criteria MEDPED score

ulation 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 Espaola de Arteriosclerosis, Sociedad Espaola de Cardiolog a and Fundacin Espaola 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.

2. 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 [2325] 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% are treated with LDL-lowering drugs (Table 2) [16]. FH is a world public health problem due to the high incidence of premature (<55 years in men and <65 years in women) cardiovascular disease, mainly CHD, and to the reduction in the life expectancy observed in many families with FH [21]. Approximately, 85% of males and 50% of females will suffer a coronary event before 65 years old if they are not treated (Table 3) [1,21,2629]. Up to 9% of the total premature CHD in eastern Finland [30] and Germany [31,32] is associated with FH.

Patients 52 692 364 262 819

Females (%) 27 10 13 14.6 12

Males (%) 57 22 31 41 27.3

a TC, total cholesterol in mg/dl (to covert cholesterol to mmol/l, divide values by 38.7); XTM, tendon xanthomas; LDLc, low-density lipoprotein cholesterol; 95th P, 95th percentile; MEDPED, Make Early Diagnosis to Prevent Early Death Program.

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Long-term follow-up studies have shown that the main cause of death in FH patients is CHD [33,34] and that about 200,000 persons in the world die each year of preventable early heart attacks due to FH (Table 2). With adequate long-term pharmacological treatment, many FH patients could achieve substancial reductions in LDL cholesterol levels, and probably increase their life expectancy by 1030 years [16]. For the above reasons, early identication of persons with FH and their relatives, and the early start of treatment are very important issues in the prevention of premature cardiovascular disease and death in this population.

3. Intervention studies in familial hypercholesterolemia Scientic evidence coming from large clinical trials have demonstrated the benet 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 benet as a group at least as much as other high risk groups. Although there is not an LDLc lowering intervention trial with CVD disease as end point in heFH patients, in the last 15 years different groups have used well established surrogates of CVD to study the effects of aggressive LDL reduction in heFH. Major trials are presented in Table 4. All these studies, without exception, demonstrate that: coronary lesions measured by coronary angiography in SCOR [36], LARS [37], L-CAPS [38], LAARS [39] and FHRS [40], or by intracoronary ultrasonography in LACMART [41]; aortic lesions evaluated by transesophageal echocardiography [42]; carotid intimae-media thickness measured by quantitative B-mode ultrasound in ASAP [43]; endothelial dysfunction measured by ow mediated dilatation [44] and E-selectin [44]; myocardial ischemia detected by exercise test in LAARS [39]; and myocardial perfusion abnormalities assessed by digital angiography in LAARS [45], all improve with aggressive LDLc reduction obtained with LDL-apheresis and/or lipid-lowering drugs. Consistent with these ndings, the increased use of lipid-lowering drugs, especially HMG CoA reductase inhibitors, has been shown to be associated with improved cardiovascular prognosis without any change in non-cardiovascular mortality in heFH subjects on the Simon Broome Register in the United Kingdom [15].

tion 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 (4.910.3 mmol/l). Triglyceride levels are usually in the normal range. However, some patients with FH have elevated triglyceride levels, explained in part by the interaction with other genes (i.e. E2/E2 genotype) or environmental factors (i.e. alcohol, overweight and diabetes mellitus). Tendon xanthomas are pathognomonic of FH; however, their identication is not always easy and they are considered insensitive diagnostic markers. Recently, it has been reported that 29% of genetically diagnosed FH patients have Achilles tendon xanthomas diagnosed by ultrasound [46]. Probably, the variability in the frequency observed in different studies depends in part on the clinical criteria used for FH (some of them included the presence of xanthomas), and in the methods used for the identication of xanthomas. There are not absolutely predictive clinical criteria for the diagnosis of FH, and arbitrary criteria must be used. For the USA Make Early Diagnosis to Prevent Early Death (MEDPED) program [47], the diagnostic criteria focus principally on high LDLc levels in the individual, and in family history of hypercholesterolemia with evidence for a dominant transmission [16]. The presence of children with hypercholesterolemia increases the diagnostic probability. Using the proposed LDL cholesterol criteria shown in Table 5, the sensitivity is 91% while specicity is 98%. Recently, the Dutch MEDPED group described a clinical scoring system for the diagnosis of heFH [48]. These criteria include personal and familial LDLc levels, history of CVD (coronary, carotid and peripheral arteries), presence of corneal arcus before the age of 45 years and xanthomas. By weighing the occurrence of these clinical signs, alone or in combination with others, a diagnostic scoring table has been constructed in The Netherlands (Table 6). These criteria seem to be easy to use in clinical practice and consider all the criteria for the diagnosis of FH. However, even then the diagnosis is not always unequivocal.

5. 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 rst-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 23 years of age. The clinical diagnosis of heFH can be made if any of the following criteria are present in a rst-degree relative of an heFH proband:

4. 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, deposi-

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Table 4 Intervention studies in familial hypercholesterolemia Study, author (reference) Intervention Subjects (n) 32 40 30 20 19 21 21 21 21 16 25 11 25 160 165 11 7 Duration (years) 2.3 2.3 1 2.1 2.1 2 2 2 2 2 2.3 2.3 1 2 2 1 1 Baseline LDLc (mg/dl) 275 283 311 263 236 301 303 301 303 290 246 258 355 308 321 213 174 Follow-up LDLc (mg/dl) 243 172 156 114 121 114 160 114 160 193 140 170 194 149 185 140 181 Change (%) 11.6 39.2 49.8 56.7 48.7 62.1 47.2 62.1 47.2 33.5 43 33 43 50.5 41.2 34.3 +4 Effect Relation with LDLc change Yes No NR Yes Level of LDLc to avoid progression (mg/dl) <200 NR NR 110 F. Civeira / Atherosclerosis 173 (2004) 5568

SCOR, Kane et al. [36] LARS, Tatami et al. [37] FHRS, Thompson et al. [40] LAARS, Kroon et al. [39]

Diet Diet + LL drugs Aph + LL drugs Aph + simva 40 Simva40 + Co20 Aph + simva40 Simva40 + resin Aph + simva40 Simva40 + resin

No change or regr: 32%a No change or regr: 40%a No change or regr: 83.3%a No change or regr: 90%a No change or regr: 79%a No change or regr: 55%a No change or regr: 45%a +39%b 9.1%b No change or regr: 81.2%c No change or regr: No change or regr: 36%a +106.4%d +0.036 mme +0.12 mmf 0.08 mmf 0.031 mme 92%a

Pitsavos et al. [42] L-CAPS, Nishimura et al. [38] Alonso et al. [44] ASAP, Smilde et al. [43] LACMART, Matsuzaki et al. [41]

Prava40 Aph + LL drugs LL drugs Simva40-80 Atorva80 Simva40 Aph + LL drugs LL drugs

Yes Yes No Yes NR

NR 150

NR NR

LL drugs: lipid-lowering drugs; Regr: regression; Aph: LDL-apheresis; Simva: simvastatin; Co: colestipol; Prava: pravastatin; Atorva: atorvastatin; MLD: minimal lumen diameter. To cholesterol to mmol/l, divide values by 38.7. a Coronary angiography. b Exercise test (ST-time for 1 mm depression). c Thoracic aortic atherosclerosis. d Flow mediated dilatation. e Carotid intima media thickness. f Intracoronary ultrasound MLD.

F. Civeira / Atherosclerosis 173 (2004) 5568 Table 5 Total and LDL cholesterol (in parentheses) in mg/dla cut points for diagnosis FH in USA MEDPED Program [47] Age group (years) Degree of relationship to closer FH relative First <20 2029 3039 40 220 240 270 290 (155) (170) (190) (205) Second 230 250 280 300 (165) (180) (200) (215) Third 240 260 290 310 (170) (185) (210) (225) 270 290 340 360 (200) (220) (240) (260) 240 260 280 300 General population

59

100% probability

Expected to diagnose FH with 98% specicity. First: parents, offspring, brother and sister. Second: aunts, uncles, grandparents, nieces, nephews. Third: rst cousins, siblings of grandparents. MEDPED Program: Make Early Diagnosis to Prevent Early Death Program. a To covert cholesterol to mmol/l, divide values by 38.7.

tendon xanthomas; corneal arcus before 45 years of age with LDLc 190 mg/dl (4.9 mmol/l); LDLc 250 mg/dl (6.5 mmol/l) in subjects of 18 years or more or 190 mg/dl (4.9 mmol/l) if <18 years; LDLc between 190 and 249 mg/dl (4.96.5 mmol/l) on at least two occasions. In all rst-degree relatives of a heFH with LDLc > 160 mg/dl (4.1 mmol/l) or >135 mg/dl (3.5 mmol/l) if <18 years it is recommended that LDLc should be determined at least every 2 years. To detect the rare family at risk of having children with homozygous FH, it is also appropriate to screen the anc, husband or wife of all young patients with known heterozygous FH.

6. 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 in the last 10 years have analyzed the main risk factors associated with CHD or CVD in heFH in different populations [15,21,24,26,27,29,33,5058]. These are casecontrol studies where traditional risk factors, such as age or gender, or FH specic clinical or molecular features, as tendon xanthomas or LDLR defects, are analyzed. A common pattern of most studies is that traditional risk factors also play an important role in heFH, however, with a different predictive value in many cases. For example, premature CHD and cumulative CHD are two to ve times more frequent in heFH men than in heFH women, with an attributable excess risk much higher than in the general population [50]. The presence of tendon xanthomas [55] or receptor-negative mutations in the LDLR gene [55] have also been reported to increase risk of CHD in heFH. Major risk factors for CVD in heFH are presented in Table 7. The presence or absence of these factors
Table 7 Major CVD risk factors in heFH 1 Age Men: 30 years Women: 45 or postmenopausal Cigarette smoking: active smokers Family history of premature CHD (CHD in male rst-degree relative <55 years or in female rst-degree relative <65 years) Very high LDLc: >330 mg/dl (8.5 mmol/l) HDLc: <40 mg/dl (1.0 mmol/l) High blood pressure (>140/90 mmHg) Diabetes mellitus Lp(a): >60 mg/dl

Table 6 Clinical diagnosis of heterozygous familial hypercholesterolemia used by Dutch MEDPED group [48] Family history I. First-degree relative with premature coronary or vascular disease II. First-degree relative with LDL-c levels >95th percentile, and/or I. First-degree relative with tendon xanthomas and/or arcus cornealis II. Children <18 years old with LDL-c levels >95th percentile Personal history I. Coronary heart disease II. Premature peripheral or cerebrovascular disease Physical signs I. Tendon xanthomas II. Arcus cornealis (<45 years old) Score 1 1 2 2 2 1 6 4

Blood analysis (with triglyceride levels <200 mg/dl, <2.3 mmol/l) I. LDL-c >330 mg/dl (8.5 mmol/l) 8 II. LDL-c 250329 mg/dl (6.58.5 mmol/l) 5 III. LDL-c 190249 mg/dl (4.96.5 mmol/l) 3 IV. LDL-c 155189 mg/dl (4.04.9 mmol/l) 1 DNA analysis Functional mutation in LDL receptor gene present Diagnostic total score: certain: 8; probable: 67; possible: 35. 8

2 3

4 5 6 7 8

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F. Civeira / Atherosclerosis 173 (2004) 5568

modies absolute risk and helps to stratify heFH for LDLc goals.

7. 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 is frequently not possible to identify a causal LDLR mutation due to technical limitations of current DNA testing. This panel encourages investigators in different countries to improve genetic knowledge in their populations so as to simplify genetic diagnosis in the future. Allelic variants in candidate genes other than the LDLR have been related to clinical expression of heFH in association studies [56,5963]. However, the results of these studies, at the present time, are not consistent enough to recommend their use for clinical decisions [64]. Currently, we recommend genetic diagnosis in the following situations: Populations where only a few LDLR mutations are responsible for most FH cases. Populations where most of the causative mutations are known and rapid genetic diagnostic tools have been developed. Subjects in whom the clinical diagnosis is uncertain coming from families with known mutations.

lescents 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 signicant atherosclerotic plaques by coronary angiography in males over 17 years and females over 25 years [66]). (2) The usefulness of this information in risk stratication [67]. (3) The fact that treatment of silent vascular disease may prevent future clinical events. 9.1. Procedures for atherosclerosis detection Subclinical CHD detection is based on the demonstration of myocardial ischemia through a stress test [68] (exercise electrocardiogram test, stress echocardiography or radio nucleide test) or demonstration of coronary atherosclerotic plaques through myocardial perfusion imaging or detection of coronary calcium by electron beam computed tomography (EBCT) or multi-slice (spiral) CT [69]. Subclinical detection tests in other locations are: ankle-brachial blood pressure index (ABI) [70], carotid intimal medial thickening by sonography [71] and abdominal sonography for the detection of aortic aneurysms [72]. To detect disease in the general population, a reasonable protocol should include a test with high sensitivity (with few false negatives), followed by a high specicity test (with few false positives). However, due to the high prevalence of atherosclerotic disease in heFH the initial test can be avoided, and therefore subclinical atherosclerosis detection in heFH should be based on high specicity, non-invasive, simple and cost-effective tests [73]. 9.2. Guidelines for subclinical atherosclerosis detection in heFH Every heFH subject should be seen at least twice a year by a trained physician who will actively search for symptoms of CVD. High risk subjects over 20 years, all subjects with non-coronary atherosclerotic disease and all males over 30 years and females over 45 years are recommended to undergo a test for myocardial ischemia (Fig. 1) every 35 years. Other screening tests may also be considered (Table 8).
Table 8 Recommended tests for detection of subclinical non-coronary atherosclerosis in heFH Test Carotid sonography ABI Subjects to apply Men >40 years Women >50 years Men >40 years Women >50 years Men >40 years Women >50 years Frequency Every 3 years Annually

8. 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 before they can be recommended in heFH.

9. 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 ado-

Other possible tests CT for coronary calcication

Every 3 years

ABI: ankle-brachial blood pressure index; CT: electron beam or multi-slice computed tomography.

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Fig. 1. Guidelines for myocardial ischemia detection.

10. Risk categories An internationally accepted concept is that intervention should be proportional to the individuals absolute risk of developing a CVD event [17], and for that to be determined requires the assessment of the subjects 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 risk: (a) with 2 major risk factors; (b) subclinical atherosclerosis: (i) carotid intima media thickness >0.10 cm; (ii) ABI <0.9; (c) clinical CVD.

11. 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 is imperative to control all risk factors, specially smoking, in heFH to obtain maximum benet. LDLc in untreated heFH subjects is typically in the range of 190400 mg/dl (4.910.3 mmol/l). Considering that <100 mg/dl (2.6 mmol/l) is the optimal LDLc concentration as dened by the Third Report of the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATPIII) guidelines [17], it would be necessary to achieve mean reductions between 50 and 75% to reach

62 Table 9 LDLc treatment goals according to categories of risk Categories

F. Civeira / Atherosclerosis 173 (2004) 5568

13. 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 HDLc and oleic acid does not, oleic acid may be the better choice [79]. Other important fats in the heFH diet are n 3 polyunsaturated fatty acids. Although their contribution to the total caloric intake need not be very high, their biological effects are important in cardiovascular prevention. For this reason, foods with a high content of -linolenic acid from vegetables and eicosapentaenoic and docosaexaenoic acids from sh should be included in the diet of heFH subjects. Recently, other lipid components of the diet, plant sterols and stanols, have been demonstrated to exert a benecial effect on LDLc concentrations through inhibition of intestinal cholesterol absorption, even in the presence of diets with low cholesterol content [80]. Plant sterols, such as sitosterol and campesterol, are not synthesized by animals but by plant cells. They are poorly absorbed, less than 10%, and their serum levels are regulated by their intestinal absorption and their biliary secretion [81,82]. Plant stanols, such as sitostanol and campestanol, are saturated forms of sterols and are not absorbed [83]. The administration of plant sterols and stanols to heFH children reduced LDLc by 10 and 15%, respectively [84,85]. Hence, the incorporation of plant sterols/stanols enriched foods in the diet of heFH can be an useful tool for LDLc lowering. Serum plant sterols levels are higher in heFH patients than in controls [86] and they increase further during long-term statin treatment [87]. A recent report have suggested that slightly raised serum plant sterols might be a risk factor for CHD [88]. If conrmed, then dietary use of plant stanols, which lower rather than raise plasma levels of plant sterols, would be preferable. More studies are clearly warranted to conrm these preliminary results. Other foods with evidence for protective effects that can be recommended to high risk patients such as heFH include soy protein, oats, other whole grains, psylium, grapes, linseed, tea, guar gum, garlic, nuts and a variety of fruits and vegetables [89]. The NCEP-ATPIII diet, supplemented with plant stanols/sterols (Table 10) has a very appropriate nutrient composition and can be recommended for all heFH subjects, including children over 23 years old. 14. 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

Optimal goala mg/dl mmol/l 4.1 3.4 2.6

Low 10-year risk Moderate-10 year risk High 10-year risk

160 130 100

a If these optimal goals are not reached, the minimum reductions in LDLc to be achieved are: 40, 50 and 60%, respectively.

that goal. At the present time, such a stringent goal is not practical for most patients due to the limited efcacy of current LDLc-lowering drugs, their cost and side effects. However, an LDLc < 100 mg/dl (2.6 mmol/l) remains the optimal level and goal for those subjects with symptomatic CVD. For other heFH subjects, the LDLc target should be adjusted to the basal CVD risk. Patients with high short term risk will require more aggressive treatment than patients with lower risk. Recent intervention studies in heFH (Table 4) point out that to prevent progression of preexisting asymptomatic CVD LDLc should be maintained <150 mg/dl (<3.9 mmol/l) for a prolonged period. The percentage reduction in LDLc also provides a good index of outcome in coronary angiographic trials [74,75]. Reductions in the range of 2540% slow the progression of coronary atherosclerosis but reductions of >45% are needed to arrest progression [74,75]. For this reason, minimum percentage reductions can be used as secondary goals if optimal levels of LDLc are not reached. Based on published data from both heFH and other high risk populations, three different LDLc goals can recommended for heFH (Table 9).

12. Lifestyle in heFH treatment Healthy lifestyle is an important aspect of heFH treatment with many benets 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 intervention studies have clearly demonstrated that a healthy lifestyle, especially a healthy diet, reduce cardiovascular risk independently of the classic risk factors [77]. This benecial effect is probably mediated by a variety of mechanisms including improved carbohydrate metabolism, lower blood pressure, greater antioxidant protection, and regulating inammatory and thrombogenic processes [78,79].

F. Civeira / Atherosclerosis 173 (2004) 5568 Table 10 Nutrient composition of the recommended heFH diet Nutrient Saturated fat Polyunsaturated fat Monounsaturated fat Total fat Carbohydrate Fiber Protein Cholesterol Total calories Plant stanols/sterols Recommended intake <7% of total calories Up to 10% of total calories Up to 20% of total calories 2535% of total calories 5060% of total calories 2030 g per day 15% of total calories <200 mg per day To maintain desirable body weight 1.52 g per day

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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 ezetimibea new selective cholesterol intestinal absorption inhibitor [90]. Nicotinic acid and bric acids are especially effective in mixed hyperlipidemia and may be used in combination with the rst-line agents in selected cases. A statin is the drug of rst choice. The safety and efcacy of statins as LDLc lowering drugs and their demonstrated performance in preventing CVD morbidity and mortality in primary and secondary prevention trials have been amply demonstrated [35]. In addition, statins can be safely combined with either resins or ezetimibe, and their LDLc lowering effect is not modied by the concomitant use of plant sterols/stanols. Rosuvastatin is a new member of the statin class that has been marketed recently in several countries at doses ranging from 10 to 40 mg. The percent reduction of LDLc with rosuvastatin in recent trials ranged from 40.6 to 58.1% for 5 and 80 mg per day (approved dose range 540 mg per day), with signicantly greater decreases compared with other statins [9193]. Another new statin, pitavastatin, are currently undergoing clinical trials and will probably be available in the near future. Bile acid sequestrants are effective LDLc lowering drugs with large clinical experience. They decrease LDLc from 10 to 30% in a dose-dependent manner [9496], but with frequent side effects that limit their use in many cases. Colesevelam is a new, more potent bile acid sequestrant that is available in 625 mg tablets; the recommended dose in adults

is 3.8 g per day (three tablets twice daily with meals) and is better tolerated than the less potent bile acid sequestrants, colestyramine and colestipol [97]. Because of their good safety prole, resins, especially new resins, remain as alternative to statins in monotherapy, especially in children or young women. Ezetimibe is a new lipid-lowering drug that inhibits the intestinal absorption of cholesterol from dietary and biliary sources by impeding the transport of cholesterol across the intestinal wall [90]. Used as monotherapy, ezetimibe decreases LDLc by a mean of 17.3% [98]. The addition of ezetimibe 10 mg per day to ongoing statin therapy provides further reduction in LDLc levels (14 to 25%) and in triglycerides (11%) compared to placebo [99,100]. This regimen is generally well tolerated across a wide dose range of different statins, and offers a new approach to LDLc reduction, avoiding high doses of statins, or allowing reductions over 60% in LDLc when used with a potent statin to reach LDLc goals in high risk patients. Ezetimibe also inhibits intestinal absorption of the plant sterols sitosterol and campesterol and reduces their concentrations in plasma [90]. Because ezetimibe is better tolerated than older resins, it may become the rst choice for heFH patients who do not tolerate high doses of statins. To reach LDLc targets many heFH subjects will require combination treatment. Effective lipid-lowering combinations are currently under-utilized in heFH. In Table 12, the expected reductions in LDLc with the rst-line drugs as monotherapy and in combination are given [91106]. Moderate doses of statins in combination with ezetimibe or resins are the rst choice combination when over 50% LDLc reductions are required or when high doses of statins are not well tolerated [107]. The combination of a low dose of statin with ezetimibe or resin, preferably colesevelam, is a useful way of reaching less aggressive LDLc goals, especially in young patients. In some heFH patients, triple therapy may be required including combinations of statins, ezetimibe and resins, or statins, resins and niacin, or statins, resins and fenobrate [108]. A drug treatment practical approach is presented in Table 13. 15. 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

Table 11 Average percent reduction in LDLc to achieve treatment goals depending on baseline LDLc Target LDLc Baseline LDLc, mg/dl (mmol/l) 190 (4.9) <100 mg/dl (2.6 mmol/l) <130 mg/dl (3.4 mmol/l) <160 mg/dl (4.1 mmol/l) 47 32 16 220 (5.7) 55 41 27 250 (6.5) 60 48 36 280 (7.2) 64 54 43 310 (8.0) 68 58 48 340 (8.8) 71 62 53

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F. Civeira / Atherosclerosis 173 (2004) 5568

Table 12 Comparative efcacy of different LDLc lowering treatments Rosuvastatin (mg per day) Statin monotherapy 5 10 20 40 Ezetimibe monotherapy 10 mg per day Bile acid sequestrants monotherapy Colestyramine: 416 g per day Colestipol: 520 g per day Colesevelam: 2.34.5 g per day Statin (any statin, any dose) plus Ezetimibe 10 mg per day Statin (any statin, low-medium dose) plus bile acid sequestrants (low dose)
a

Atorvastatin (mg per day) 10 20 40 80

Simvastatin (mg per day) 10 20 40 80

Lovastatin (mg per day) 20 40 80

Pravastatin (mg per day) 20 40

Fluvastatin (mg per day) 40 80

% LDLc reduction 27 34 41 48 52 55 18 1030 1030 918 1425a 1020a

Additional reduction to that obtained with statin alone.

Table 13 Drug treatment approach 1 2a 2b 3 4 Start with moderate dose of high efcacy statin Increase to full dose if target level not reached or Add resins or ezetimibe if not at target or if maximal dose is not tolerated Increase to full dose of statin if with 2b still not at target Consider adding immediate release niacin or Niaspan

among countries, and for these reasons individual clinical judgement should always apply.

16. 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 efcacy between the various commercially available methods for selective removal of LDL [112,113]. In the United States, the FDA approved the use of LDL-apheresis for heFH patients without CHD having LDLc greater than 300 mg/dl (7.7 mmol/l) on maximal tolerated medical treatment or greater than 200 mg/dl (5.2 mmol/l) if CHD is present [114]. However, there is evidence that to obtain atherosclerosis regression, a lower LDLc concentration must be reached [74,75], and therefore, LDL-apheresis could be offered to symptomatic CHD heFH whose LDLc remains high (>160 mg/dl, 4.2 mmol/l) or decreases by <40% on maximal medical treatment [115,116]. It has been shown that LDL-apheresis can be used safely in pregnant heFH women with CVD [117].

means of preventing or stopping the use of cigarettes. Dietary recommendations apply to children after the age of 23 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 periods of titration, especially in high risk patients. In young women without major risk factors, drug treatment should be postponed if pregnancy is expected in the near future. Although drug treatment seems safe in children [109,110] and can be considered in the presence of major risk factors, statins should not normally be used before the age of 10 years in boys and until after puberty in girls (Table 14). The onset of drug treatment in childhood has potential difculties including long-term safety, poor compliance, cost effectiveness or different medical practices
Table 14 When to initiate treatment? Lifestyle modication from 2 to 3 years onwards Consider drug therapy 1. In presence of major risk factors a. Males >10 years of age b. Females after puberty 2. Low 10 year risk subjects a. Males >18 years of age b. Females >30 years of age

Acknowledgements This work was supported by grants from the Fundacin Espaola de Arteriosclerosis and the Fundacin Espaola de Hipercolesterolemia Familial.

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