guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia.pdf

Atherosclerosis 173 (2004) 55–68

Guidelines for the diagnosis and management of heterozygousfamilial hypercholesterolemia

Fernando Civeira∗International Panel on Management of Familial Hypercholesterolemia1

Lipid Unit, Hospital Universitario Miguel Servet, Avda Isabel La Católica 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 oflow density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). FH is a publichealth problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% ofmales 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 prematurecardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from theirdiagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention toanswer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of thesepatients.© 2003 Elsevier Ireland Ltd. All rights reserved.

Keywords: Familial hypercholesterolemia; Management; Treatment; Guidelines

1. Introduction

Familial hypercholesterolemia (FH: MIM#143890) isan autosomal codominant inherited disorder of lipoprotein

∗ Fax: +34-97-6566569.E-mail address: [email protected] (F. Civeira).1 Members of the panel: Fernando Civeira, M.D., Ph.D. (Spain) (Chair

of the panel), Miguel Pocovı, Ph.D. (Spain) (Vicechair), Eduardo Alegrıa,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. De-fesche, Ph.D. (the Netherlands), Henrik K. Jensen, M.D., Ph.D. (Den-mark), 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 Perez-Jimenez,M.D., Ph.D. (Spain), Ernst J. Schaefer, M.D. (USA), Gilbert R. Thomp-son, M.D., F.R.C.P. (UK).Promoter Organizations: Sociedad Española deArteriosclerosis, Sociedad Española de Cardiologıa, Fundacion EspañolaHipercolesterolemia Familiar.Organization support: The document wasapproved by the following organizational representatives: Sociedad Es-pañola de Arteriosclerosis (Spain), Sociedad Española de Cardiologıa(Spain), Fundacion Española Hipercolesterolemia Familiar (Spain), Blood-link Foundation, Patients Network Inherited Cardiovascular Diseases (TheNetherlands), HEART UK (UK).

metabolism characterized by very high plasma concentra-tions of low density lipoprotein cholesterol (LDLc), tendonxanthomas and increased risk of premature coronary heartdisease (CHD). Usually, clinically identified FH resultsfrom defects in the LDL receptor (LDLR) gene[1,2]. TheLDLR gene was cloned and mapped to 19p13.1–13.3, andmore than 800 mutations have been reported to date to causeFH (http.//www.ucl.ac.uk/fh; http.//www.umd.necker.fr).The penetrance of FH is almost 100%, meaning that half ofthe offspring of an affected parent have a severely elevatedplasma cholesterol level from birth onwards, with malesand females equally affected.

More recently, other loci have been identified to beresponsible for other forms of hereditary hypercholes-terolemia with phenotypes very similar to FH (Table 1)[3–8]. One of these, a defective apolipoprotein B (apoB)that displays low affinity for the LDLR, called “familialdefective apo B” is as common as FH in some Europeanpopulations[5,6]. A less frequent cause of autosomal dom-inant hypercholesterolemia has been linked to chromosome1p32[7,8]. The clinical management of these other hered-itary 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

http://http.//www.ucl.ac.uk/fh

http://http.//www.umd.necker.fr

Ameen

Highlight

Ameen

Highlight

56 F. Civeira / Atherosclerosis 173 (2004) 55–68

Table 1Monogenic disorders and related genes associated with hypercholes-terolemia

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 deficiency (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 themall.

The large primary and secondary prevention trials withstatins during the last decade have clearly demonstrated thebenefit of reducing LDLc in subjects with high LDLc and/orhigh cardiovascular risk[9–14]. 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 cardiovasculardisease (CVD) remains indirect[15]. This new informationand the availability of potent LDLc-lowering drugs shouldhave an enormous impact on heFH morbidity and mortality[16].

International recommendations for the treatment of hy-percholesterolemia have pointed out the importance ofidentifying and treating persons at high risk of CHD[17,18].However, recommendations for the general population donot apply to heFH for several reasons: first, global riskassessment for general population is not applicable to sub-jects with total cholesterol concentrations over 300 mg/dl(7.7 mmol/l), as almost invariably occurs in heFH, since thenumber of subjects with such high levels in the prospectivestudies on which the recommendations are based is notenough to allow prediction[17,18]. Second, traditional riskfactors for the general population do not necessarily playthe same role in CHD of heFH or with the same intensity[19]. Third, the timing of CHD in heFH has a differentpattern, with very precocious disease in many cases, whichrequires different detection strategies and specific criteriafor the onset and the intensity of treatment. Last, most per-sons in prospective studies have not had a high cholesterolall their lives and the application of standard risk estimatesfor cholesterol seriously under-estimated CHD risk in heFH[20–22]. For these reasons, guidelines for the general pop-

Table 3Premature coronary artery disease in familial hypercholesterolemiaa

Study Diagnosis criteria Patients Females (%) Males (%)

Hirobe et al.[26] TC > 300; XTM (+) 52 27 57Mabuchi et al.[33] TC > 230; XTM (+) 692 10 22Hill et al. [27] LDLc > 95th P; XTM (+) 364 13 31Hopkins et al.[51] LDLc; clinical criteria 262 14.6 41Alonso et al.[29] MEDPED score 819 12 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 lipoproteincholesterol; 95th P, 95th percentile; MEDPED, Make Early Diagnosis to Prevent Early Death Program.

Table 2Familial hypercholesterolemia as a worldwide health problem

Ten million people worldwide are affected by familialhypercholesterolemia

Two hundred thousand patients will die prematurely of coronary heartdisease

80% of heFH patients remain undiagnosed84% of heFH patients do not take any lipid-lowering drug

ulation formally exclude heFH from their diagnostic andtreatment recommendations[17,18].

Due to the importance of LDLc lowering treatment inheHF and the absence of international recommendationson this topic, three Spanish Medical Societies (SociedadEspañola de Arteriosclerosis, Sociedad Española de Car-diologıa and Fundación Española Hipercolesterolemia Fa-miliar) promoted, through a group of international experts,the elaboration of guidelines to answer the main questionsabout heFH that physicians worldwide face in the manage-ment of these patients. This document is the result of thatinitiative.

2. Familial hypercholesterolemia (FH) is aninternational health problem

FH is one of the most frequent monogenic hereditarydisorders in the general population. The frequency of het-erozygotes is approximately one per 500 individuals in mostcountries. However, some populations around the worldsuch as French Canadians, Afrikaners in South Africa,Lebanese and Finns[23–25]have a much higher prevalencedue to a founder effect. It has been estimated that thereare 10,000,000 people with FH worldwide. Of these, lessthan 10% are diagnosed, and less than 25% are treated withLDL-lowering drugs (Table 2) [16].

FH is a world public health problem due to the high in-cidence of premature (<55 years in men and<65 years inwomen) cardiovascular disease, mainly CHD, and to the re-duction in the life expectancy observed in many familieswith FH [21]. Approximately, 85% of males and 50% offemales will suffer a coronary event before 65 years old ifthey are not treated (Table 3) [1,21,26–29]. Up to 9% of thetotal premature CHD in eastern Finland[30] and Germany[31,32] is associated with FH.

Ameen

Highlight

Ameen

Highlight

Ameen

Highlight

F. Civeira / Atherosclerosis 173 (2004) 55–68 57

Long-term follow-up studies have shown that the maincause of death in FH patients is CHD[33,34]and that about200,000 persons in the world die each year of preventableearly heart attacks due to FH (Table 2). With adequatelong-term pharmacological treatment, many FH patientscould achieve substancial reductions in LDL cholesterollevels, and probably increase their life expectancy by 10–30years[16].

For the above reasons, early identification of persons withFH and their relatives, and the early start of treatment arevery important issues in the prevention of premature cardio-vascular disease and death in this population.

3. Intervention studies in familial hypercholesterolemia

Scientific evidence coming from large clinical trials havedemonstrated the benefit of LDLc reduction in the preven-tion of CVD in a broad spectrum of populations, especiallyin subjects with symptomatic CHD or with absolute highrisk [17,35]. As mentioned previously, most heFH should beconsidered high risk subjects due to the prevalence of CHD,and they should benefit as a group at least as much as otherhigh risk groups.

Although there is not an LDLc lowering interventiontrial with CVD disease as end point in heFH patients, in thelast 15 years different groups have used well establishedsurrogates of CVD to study the effects of aggressive LDLreduction in heFH. Major trials are presented inTable 4.All these studies, without exception, demonstrate that:coronary lesions measured by coronary angiography inSCOR[36], LARS [37], L-CAPS [38], LAARS [39] andFHRS [40], or by intracoronary ultrasonography in LAC-MART [41]; aortic lesions evaluated by transesophagealechocardiography[42]; carotid intimae-media thicknessmeasured by quantitative B-mode ultrasound in ASAP[43]; endothelial dysfunction measured by flow mediateddilatation [44] and E-selectin[44]; myocardial ischemiadetected by exercise test in LAARS[39]; and myocardialperfusion abnormalities assessed by digital angiography inLAARS [45], all improve with aggressive LDLc reduc-tion obtained with LDL-apheresis and/or lipid-loweringdrugs.

Consistent with these findings, the increased use oflipid-lowering drugs, especially HMG CoA reductaseinhibitors, has been shown to be associated with im-proved cardiovascular prognosis without any change innon-cardiovascular mortality in heFH subjects on the SimonBroome Register in the United Kingdom[15].

4. Clinical diagnosis of FH

Clinical criteria used to identify patients with FH include:high plasma levels of total and LDL cholesterol, family his-tory of hypercholesterolemia especially in children, deposi-

tion of cholesterol in extravascular tissues such as tendonxanthomas or corneal arcus, and personal and family historyof premature CVD[1].

HeFH patients have LDLc levels approximately twicethose of the normal population, ranging from 190 to400 mg/dl (4.9–10.3 mmol/l). Triglyceride levels are usuallyin the normal range. However, some patients with FH haveelevated triglyceride levels, explained in part by the interac-tion with other genes (i.e. E2/E2 genotype) or environmentalfactors (i.e. alcohol, overweight and diabetes mellitus).

Tendon xanthomas are pathognomonic of FH; however,their identification is not always easy and they are consid-ered insensitive diagnostic markers. Recently, it has beenreported that 29% of genetically diagnosed FH patientshave Achilles tendon xanthomas diagnosed by ultrasound[46]. Probably, the variability in the frequency observedin different studies depends in part on the clinical criteriaused for FH (some of them included the presence of xan-thomas), and in the methods used for the identification ofxanthomas.

There are not absolutely predictive clinical criteria forthe 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 focusprincipally on high LDLc levels in the individual, and infamily history of hypercholesterolemia with evidence fora dominant transmission[16]. The presence of childrenwith hypercholesterolemia increases the diagnostic proba-bility. Using the proposed LDL cholesterol criteria shownin Table 5, the sensitivity is 91% while specificity is 98%.Recently, the Dutch MEDPED group described a clinicalscoring system for the diagnosis of heFH[48]. These cri-teria include personal and familial LDLc levels, history ofCVD (coronary, carotid and peripheral arteries), presenceof corneal arcus before the age of 45 years and xanthomas.By weighing the occurrence of these clinical signs, alone orin combination with others, a diagnostic scoring table hasbeen constructed in The Netherlands (Table 6). These crite-ria seem to be easy to use in clinical practice and considerall the criteria for the diagnosis of FH. However, even thenthe diagnosis is not always unequivocal.

5. Detection of familial hypercholesterolemia. Thefamily approach

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

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

Ameen

Highlight

58F.

Civeira

/Atherosclerosis

173(2004)

55–68

Table 4Intervention studies in familial hypercholesterolemia

Study, author (reference) Intervention Subjects(n)

Duration(years)

BaselineLDLc(mg/dl)

Follow-upLDLc(mg/dl)

Change(%)

Effect Relation withLDLc change

Level of LDLc toavoid progression(mg/dl)

SCOR, Kane et al.[36] Diet 32 2.3 275 243 −11.6 No change or regr: 32%a Yes <200Diet + LL drugs 40 2.3 283 172 −39.2 No change or regr: 40%a

LARS, Tatami et al.[37] Aph + LL drugs 30 1 311 156 −49.8 No change or regr: 83.3%a No NR

FHRS, Thompson et al.[40] Aph + simva 40 20 2.1 263 114 −56.7 No change or regr: 90%a NR NRSimva40+ Co20 19 2.1 236 121 −48.7 No change or regr: 79%a

LAARS, Kroon et al.[39] Aph + simva40 21 2 301 114 −62.1 No change or regr: 55%a Yes 110Simva40+ resin 21 2 303 160 −47.2 No change or regr: 45%a

Aph + simva40 21 2 301 114 −62.1 +39%b

Simva40+ resin 21 2 303 160 −47.2 −9.1%b

Pitsavos et al.[42] Prava40 16 2 290 193 −33.5 No change or regr: 81.2%c Yes NR

L-CAPS, Nishimura et al.[38] Aph + LL drugs 25 2.3 246 140 −43 No change or regr: 92%a Yes 150LL drugs 11 2.3 258 170 −33 No change or regr: 36%a

Alonso et al.[44] Simva40-80 25 1 355 194 −43 +106.4%d No

ASAP, Smilde et al.[43] Atorva80 160 2 308 149 −50.5 −0.031 mme Yes NRSimva40 165 2 321 185 −41.2 +0.036 mme

LACMART, Matsuzaki et al.[41] Aph + LL drugs 11 1 213 140 −34.3 +0.12 mmf NR NRLL drugs 7 1 174 181 +4 −0.08 mmf

LL drugs: lipid-lowering drugs; Regr: regression; Aph: LDL-apheresis; Simva: simvastatin; Co: colestipol; Prava: pravastatin; Atorva: atorvastatin; MLD: minimal lumen diameter. To cholesterol tommol/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.


Table 5Total 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 General population “100%” probability

First Second Third

<20 220 (155) 230 (165) 240 (170) 270 (200) 24020–29 240 (170) 250 (180) 260 (185) 290 (220) 26030–39 270 (190) 280 (200) 290 (210) 340 (240) 280

≥40 290 (205) 300 (215) 310 (225) 360 (260) 300

Expected to diagnose FH with 98% specificity. First: parents, offspring, brother and sister. Second: aunts, uncles, grandparents, nieces, nephews.Third:first 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 (4.9–6.5 mmol/l) on at

least two occasions.

In all first-degree relatives of a heFH with LDLc>160 mg/dl (4.1 mmol/l) or >135 mg/dl (3.5 mmol/l) if<18years it is recommended that LDLc should be determinedat least every 2 years.

To detect the rare family at risk of having children withhomozygous FH, it is also appropriate to screen the fiancé,husband or wife of all young patients with known heterozy-gous FH.

Table 6Clinical diagnosis of heterozygous familial hypercholesterolemia used byDutch MEDPED group[48]

Family history Score

I. First-degree relative with premature coronary orvascular disease

1

II. First-degree relative with LDL-c levels >95thpercentile, and/or

1

I. First-degree relative with tendon xanthomas and/orarcus cornealis

2

II. Children <18 years old with LDL-c levels >95th percentile 2

Personal historyI. Coronary heart disease 2II. Premature peripheral or cerebrovascular disease 1

Physical signsI. Tendon xanthomas 6II. Arcus cornealis (<45 years old) 4

Blood analysis (with triglyceride levels<200 mg/dl,<2.3 mmol/l)I. LDL-c >330 mg/dl (8.5 mmol/l) 8II. LDL-c 250–329 mg/dl (6.5–8.5 mmol/l) 5III. LDL-c 190–249 mg/dl (4.9–6.5 mmol/l) 3IV. LDL-c 155–189 mg/dl (4.0–4.9 mmol/l) 1

DNA analysisFunctional mutation in LDL receptor gene present 8

Diagnostic total score: certain:≥8; probable: 6–7; possible: 3–5.

6. CVD risk factors in FH

Clinical expression of CVD in heFH patients is highlyvariable in terms of the age of onset and severity. CVDin heFH tends to cluster with higher frequency in certainfamilies, although with marked differences among individ-uals [27]. This clinical variability also occurs among sub-jects coming from families sharing the same mutations inthe LDLR gene, indicating that other genetic or environ-mental factors play an important role in the development ofatherosclerosis in FH[50].

Different studies in the last 10 years have analyzed themain risk factors associated with CHD or CVD in heFH indifferent populations[15,21,24,26,27,29,33,50–58]. Theseare case–control studies where traditional risk factors, suchas age or gender, or FH specific clinical or molecular fea-tures, as tendon xanthomas or LDLR defects, are analyzed.A common pattern of most studies is that traditional riskfactors also play an important role in heFH, however, with adifferent predictive value in many cases. For example, pre-mature CHD and cumulative CHD are two to five timesmore frequent in heFH men than in heFH women, withan attributable excess risk much higher than in the generalpopulation[50]. The presence of tendon xanthomas[55] orreceptor-negative mutations in the LDLR gene[55] havealso been reported to increase risk of CHD in heFH.

Major risk factors for CVD in heFH are presentedin Table 7. The presence or absence of these factors

Table 7Major CVD risk factors in heFH

1 AgeMen: ≥30 yearsWomen:≥45 or postmenopausal

2 Cigarette smoking: active smokers3 Family history of premature CHD (CHD in male

first-degree relative<55 years or in female first-degreerelative<65 years)

4 Very high LDLc: >330 mg/dl (8.5 mmol/l)5 HDLc: <40 mg/dl (1.0 mmol/l)6 High blood pressure (>140/90 mmHg)7 Diabetes mellitus8 Lp(a): >60 mg/dl

Ameen

Highlight


modifies absolute risk and helps to stratify heFH for LDLcgoals.

7. Genetic analysis

Severe hereditary hypercholesterolemia due to high LDLccan be produced by several monogenic disorders (Table 1).The relative frequency of these disorders varies among popu-lations, Familial defective apo-B100 is rare in Mediterraneancountries but frequent (1/500 persons) in some central Euro-pean regions[6]. The best known and most frequent mono-genic disorder in most countries around the world is FHcaused by mutations in the LDLR gene.

Although a positive genetic diagnosis is unequivocal, it isfrequently not possible to identify a causal LDLR mutationdue to technical limitations of current DNA testing.

This panel encourages investigators in different countriesto improve genetic knowledge in their populations so as tosimplify genetic diagnosis in the future.

Allelic variants in candidate genes other than the LDLRhave been related to clinical expression of heFH in associa-tion studies[56,59–63]. However, the results of these studies,at the present time, are not consistent enough to recommendtheir use for clinical decisions[64].

Currently, we recommend genetic diagnosis in the follow-ing situations:

• Populations where only a few LDLR mutations are re-sponsible for most FH cases.

• Populations where most of the causative mutations areknown and rapid genetic diagnostic tools have been de-veloped.

• Subjects in whom the clinical diagnosis is uncertain com-ing from families with known mutations.

8. Biochemical analysis

Blood total cholesterol, triglycerides and HDLc mea-surements, and LDLc calculated by the Friedewald for-mula remain the basic biochemical parameters for clinicalmanagement of heFH. Blood glucose, liver enzymes, cre-atinine and TSH measurements are necessary to rule outsecondary causes, and for global risk assessment. Somewould include Lp(a) as a useful additional measure of risk.Other lipid and non-lipid parameters, such as apo B, Creactive protein or homocysteine, need additional studiesbefore they can be recommended in heFH.

9. Detection of subclinical atherosclerosis

Subclinical atherosclerosis should be actively sought forin heFH for three reasons: (1) Its high prevalence in thesesubjects (Gidding et al. have demonstrated that 66% of ado-

lescents and young adults (<24 years) have deposits of cal-cium in their coronary arteries, indicating the presence ofestablished atherosclerotic plaques at these ages[65] andMabuchi et al. detected significant atherosclerotic plaquesby coronary angiography in males over 17 years and femalesover 25 years[66]). (2) The usefulness of this informationin risk stratification[67]. (3) The fact that treatment of silentvascular disease may prevent future clinical events.

9.1. Procedures for atherosclerosis detection

Subclinical CHD detection is based on the demonstra-tion of myocardial ischemia through a stress test[68] (exer-cise electrocardiogram test, stress echocardiography or radionucleide test) or demonstration of coronary atheroscleroticplaques through myocardial perfusion imaging or detectionof coronary calcium by electron beam computed tomogra-phy (EBCT) or multi-slice (spiral) CT[69].

Subclinical detection tests in other locations are:ankle-brachial blood pressure index (ABI)[70], carotid in-timal medial thickening by sonography[71] and abdominalsonography for the detection of aortic aneurysms[72].

To detect disease in the general population, a reasonableprotocol should include a test with high sensitivity (with fewfalse negatives), followed by a high specificity test (withfew false positives). However, due to the high prevalenceof atherosclerotic disease in heFH the initial test can beavoided, and therefore subclinical atherosclerosis detectionin heFH should be based on high specificity, non-invasive,simple and cost-effective tests[73].

9.2. Guidelines for subclinical atherosclerosis detection inheFH

Every heFH subject should be seen at least twice a yearby a trained physician who will actively search for symp-toms of CVD. High risk subjects over 20 years, all subjectswith non-coronary atherosclerotic disease and all males over30 years and females over 45 years are recommended to un-dergo a test for myocardial ischemia (Fig. 1) every 3–5 years.Other screening tests may also be considered (Table 8).

Table 8Recommended tests for detection of subclinical non-coronary atheroscle-rosis in heFH

Test Subjects to apply Frequency

Carotid sonography Men >40 years Every 3 yearsWomen >50 years

ABI Men >40 years AnnuallyWomen >50 years

Other possible testsCT for coronary calcification Men >40 years Every 3 years

Women >50 years

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


Fig. 1. Guidelines for myocardial ischemia detection.

10. Risk categories

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

According to the presence of major risk factors and/orclinical or subclinical atherosclerosis, three categories of riskfor 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 plasmaLDL cholesterol resulting from defective internalization ofLDL particles into the hepatic cells via the LDLR. Hence,the main objective of the treatment in heFH subjects is nor-malize LDLc in blood by upregulating LDLRs as much aspossible. To reach this goal, potent LDL-lowering drugs areusually necessary. However, CVD, even in heFH, is a mul-tifactorial disease in which different risk factors play im-portant roles. For this reason, it is imperative to control allrisk factors, specially smoking, in heFH to obtain maximumbenefit.

LDLc in untreated heFH subjects is typically in therange of 190–400 mg/dl (4.9–10.3 mmol/l). Consideringthat <100 mg/dl (2.6 mmol/l) is the optimal LDLc con-centration as defined by the Third Report of the NationalCholesterol Education Program Adult Treatment Panel(NCEP-ATPIII) guidelines[17], it would be necessary toachieve mean reductions between 50 and 75% to reach


Table 9LDLc treatment goals according to categories of risk

Categories Optimal goala

mg/dl mmol/l

Low 10-year risk 160 4.1Moderate-10 year risk 130 3.4High 10-year risk 100 2.6

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

that goal. At the present time, such a stringent goal is notpractical for most patients due to the limited efficacy ofcurrent LDLc-lowering drugs, their cost and side effects.However, an LDLc< 100 mg/dl (2.6 mmol/l) remains theoptimal level and goal for those subjects with symptomaticCVD.

For other heFH subjects, the LDLc target should beadjusted to the basal CVD risk. Patients with high shortterm risk will require more aggressive treatment than pa-tients with lower risk. Recent intervention studies in heFH(Table 4) point out that to prevent progression of preex-isting asymptomatic CVD LDLc should be maintained<150 mg/dl (<3.9 mmol/l) for a prolonged period. The per-centage reduction in LDLc also provides a good index ofoutcome in coronary angiographic trials[74,75]. Reductionsin the range of 25–40% slow the progression of coronaryatherosclerosis but reductions of >45% are needed to arrestprogression[74,75]. For this reason, minimum percentagereductions can be used as secondary goals if optimal levelsof LDLc are not reached.

Based on published data from both heFH and other highrisk populations, three different LDLc goals can recom-mended for heFH (Table 9).

12. Lifestyle in heFH treatment

Healthy lifestyle is an important aspect of heFH treat-ment with many benefits beyond LDLc lowering. Lifestylecomprises a healthy diet, ideal body weight, no smokingand moderate physical activity. Although LDLc is the ba-sic pathogenic CVD risk factor in FH, these subjects arevery sensitive to other risk factors such as smoking orlow plasma HDLc concentration (Table 7). In addition,a healthy diet can increase the LDLc lowering power ofdrugs, as occurred in the L-TAP study[76]. Recent inter-vention studies have clearly demonstrated that a healthylifestyle, especially a healthy diet, reduce cardiovascularrisk independently of the classic risk factors[77]. Thisbeneficial effect is probably mediated by a variety ofmechanisms including improved carbohydrate metabolism,lower blood pressure, greater antioxidant protection, andregulating inflammatory and thrombogenic processes[78,79].

13. A healthy diet to prevent CVD in heFH

Fatty acid composition and cholesterol content are impor-tant aspects of the heFH diet. Saturated fat reduces hepaticLDLR expression and increases VLDL synthesis. The mostpotent saturated fatty acid in this regard is palmitic acid, oneof the commonest saturated fatty acids in the diet, particu-larly rich in dairy fats. In contrast, unsaturated fatty acids,mainly linoleic acid and oleic acid, reduce total cholesteroland LDLc when they replace saturated fat. Since linoleicacid also reduces HDLc and oleic acid does not, oleic acidmay be the better choice[79].

Other important fats in the heFH diet aren − 3 polyun-saturated fatty acids. Although their contribution to the totalcaloric intake need not be very high, their biological effectsare important in cardiovascular prevention. For this reason,foods with a high content of�-linolenic acid from vegeta-bles and eicosapentaenoic and docosaexaenoic acids fromfish should be included in the diet of heFH subjects.

Recently, other lipid components of the diet, plant sterolsand stanols, have been demonstrated to exert a beneficial ef-fect on LDLc concentrations through inhibition of intestinalcholesterol absorption, even in the presence of diets withlow cholesterol content[80]. Plant sterols, such as sitos-terol and campesterol, are not synthesized by animals butby plant cells. They are poorly absorbed, less than 10%,and their serum levels are regulated by their intestinal ab-sorption and their biliary secretion[81,82]. Plant stanols,such as sitostanol and campestanol, are saturated forms ofsterols and are not absorbed[83]. The administration of plantsterols and stanols to heFH children reduced LDLc by 10and 15%, respectively[84,85]. Hence, the incorporation ofplant sterols/stanols enriched foods in the diet of heFH canbe an useful tool for LDLc lowering. Serum plant sterolslevels are higher in heFH patients than in controls[86] andthey increase further during long-term statin treatment[87].A recent report have suggested that slightly raised serumplant sterols might be a risk factor for CHD[88]. If con-firmed, then dietary use of plant stanols, which lower ratherthan raise plasma levels of plant sterols, would be prefer-able. More studies are clearly warranted to confirm thesepreliminary results.

Other foods with evidence for protective effects that canbe recommended to high risk patients such as heFH includesoy protein, oats, other whole grains, psylium, grapes, lin-seed, tea, guar gum, garlic, nuts and a variety of fruits andvegetables[89].

The NCEP-ATPIII diet, supplemented with plantstanols/sterols (Table 10) has a very appropriate nutrientcomposition and can be recommended for all heFH subjects,including children over 2–3 years old.

14. LDLc lowering for heFH: old and new drugs

Most heFH patients need LDLc lowering drugs to reachLDLc goals. Indeed, almost all heFH patients will need


Table 10Nutrient composition of the recommended heFH diet

Nutrient Recommended intake

Saturated fat <7% of total caloriesPolyunsaturated fat Up to 10% of total caloriesMonounsaturated fat Up to 20% of total caloriesTotal fat 25–35% of total caloriesCarbohydrate 50–60% of total caloriesFiber 20–30 g per dayProtein 15% of total caloriesCholesterol <200 mg per dayTotal calories To maintain desirable body weightPlant stanols/sterols 1.5–2 g per day

to reduce their LDLc by over 40% to reach target lev-els (Table 11). Therefore, they will usually require potentlipid-lowering drugs in high doses or combined drug regi-mens, and, in some cases, LDL-apheresis.

There are three major LDLc lowering agents availablefor treatment of heFH: HMG CoA reductase inhibitors orstatins, bile acid sequestrants or resins, and ezetimibe—anew selective cholesterol intestinal absorption inhibitor[90].Nicotinic acid and fibric acids are especially effective inmixed hyperlipidemia and may be used in combination withthe first-line agents in selected cases.

A statin is the drug of first choice. The safety and efficacyof statins as LDLc lowering drugs and their demonstratedperformance in preventing CVD morbidity and mortalityin primary and secondary prevention trials have been am-ply demonstrated[35]. In addition, statins can be safelycombined with either resins or ezetimibe, and their LDLclowering effect is not modified by the concomitant use ofplant sterols/stanols. Rosuvastatin is a new member of thestatin class that has been marketed recently in several coun-tries at doses ranging from 10 to 40 mg. The percent reduc-tion of LDLc with rosuvastatin in recent trials ranged from−40.6 to−58.1% for 5 and 80 mg per day (approved doserange 5–40 mg per day), with significantly greater decreasescompared with other statins[91–93]. Another new statin,pitavastatin, are currently undergoing clinical trials and willprobably be available in the near future.

Bile acid sequestrants are effective LDLc lowering drugswith large clinical experience. They decrease LDLc from 10to 30% in a dose-dependent manner[94–96], but with fre-quent side effects that limit their use in many cases. Cole-sevelam is a new, more potent bile acid sequestrant that isavailable in 625 mg tablets; the recommended dose in adults

Table 11Average percent reduction in LDLc to achieve treatment goals depending on baseline LDLc

Target LDLc Baseline LDLc, mg/dl (mmol/l)

190 (4.9) 220 (5.7) 250 (6.5) 280 (7.2) 310 (8.0) 340 (8.8)

<100 mg/dl (2.6 mmol/l) 47 55 60 64 68 71<130 mg/dl (3.4 mmol/l) 32 41 48 54 58 62<160 mg/dl (4.1 mmol/l) 16 27 36 43 48 53

is 3.8 g per day (three tablets twice daily with meals) and isbetter tolerated than the less potent bile acid sequestrants,colestyramine and colestipol[97]. Because of their goodsafety profile, resins, especially new resins, remain as alter-native to statins in monotherapy, especially in children oryoung women.

Ezetimibe is a new lipid-lowering drug that inhibits theintestinal absorption of cholesterol from dietary and biliarysources by impeding the transport of cholesterol across theintestinal wall [90]. Used as monotherapy, ezetimibe de-creases LDLc by a mean of 17.3%[98]. The addition ofezetimibe 10 mg per day to ongoing statin therapy providesfurther reduction in LDLc levels (−14 to −25%) and intriglycerides (−11%) compared to placebo[99,100]. Thisregimen is generally well tolerated across a wide dose rangeof different statins, and offers a new approach to LDLc re-duction, avoiding high doses of statins, or allowing reduc-tions over 60% in LDLc when used with a potent statin toreach LDLc goals in high risk patients. Ezetimibe also in-hibits intestinal absorption of the plant sterols sitosterol andcampesterol and reduces their concentrations in plasma[90].Because ezetimibe is better tolerated than older resins, itmay become the first choice for heFH patients who do nottolerate high doses of statins.

To reach LDLc targets many heFH subjects will requirecombination treatment. Effective lipid-lowering combina-tions are currently under-utilized in heFH. InTable 12, theexpected reductions in LDLc with the first-line drugs asmonotherapy and in combination are given[91–106]. Mod-erate doses of statins in combination with ezetimibe or resinsare the first choice combination when over 50% LDLc re-ductions are required or when high doses of statins are notwell tolerated[107]. The combination of a low dose of statinwith ezetimibe or resin, preferably colesevelam, is a usefulway of reaching less aggressive LDLc goals, especially inyoung patients. In some heFH patients, triple therapy maybe required including combinations of statins, ezetimibe andresins, or statins, resins and niacin, or statins, resins andfenofibrate[108]. A drug treatment practical approach ispresented inTable 13.

15. When to initiate LDLc treatment in heFH

Lifestyle treatment should be encouraged in all heFH sub-jects. It is imperative to be vigilant in promoting a no smok-ing policy for heFH patients and to apply all reasonable


Table 12Comparative efficacy of different LDLc lowering treatments

Rosuvastatin (mg per day) Atorvastatin(mg per day)

Simvastatin(mg per day)

Lovastatin(mg per day)

Pravastatin(mg per day)

Fluvastatin(mg per day)

% LDLcreduction

Statin monotherapy– – 10 20 20 40 27– 10 20 40 40 80 345 20 40 80 – – 4110 40 80 – – – 4820 80 – – – – 5240 – – – – – 55

Ezetimibe monotherapy10 mg per day 18

Bile acid sequestrants monotherapyColestyramine: 4–16 g per day 10–30Colestipol: 5–20 g per day 10–30Colesevelam: 2.3–4.5 g per day 9–18

Statin (any statin, any dose) plus Ezetimibe 10 mg per day 14–25a

Statin (any statin, low-medium dose) plus bile acid sequestrants (low dose) 10–20a

a Additional reduction to that obtained with statin alone.

Table 13Drug treatment approach

1 Start with moderate dose of high efficacy statin

2a Increase to full dose if target level not reached or2b Add resins or ezetimibe if not at target or if maximal

dose is not tolerated

3 Increase to full dose of statin if with 2b still not at target4 Consider adding immediate release niacin or Niaspan

means of preventing or stopping the use of cigarettes. Di-etary recommendations apply to children after the age of2–3 years.

All men over 18 years and women over 30 years are rec-ommended to be on LDLc lowering drug treatment to reachthe LDLc goal appropriate to their basal CVD risk. It isadvisable to avoid prolonged periods of titration, especiallyin high risk patients. In young women without major riskfactors, drug treatment should be postponed if pregnancy isexpected in the near future. Although drug treatment seemssafe in children[109,110]and can be considered in the pres-ence of major risk factors, statins should not normally beused before the age of 10 years in boys and until after pubertyin girls (Table 14). The onset of drug treatment in childhoodhas potential difficulties including long-term safety, poorcompliance, cost effectiveness or different medical practices

Table 14When to initiate treatment?

Lifestyle modification from 2 to 3 years onwards

Consider drug therapy1. In presence of major risk factors

a. Males >10 years of ageb. Females after puberty

2. Low 10 year risk subjectsa. Males >18 years of ageb. Females >30 years of age

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

16. LDL-apheresis for heFH

The use of LDL-apheresis has become the standard treat-ment for homozygous FH in recent years[111]. However,LDL-apheresis has not been widely used in heFH, mainlybecause substantial LDLc reductions can be obtained withdiet and drug combination therapy in most patients. Thenew LDLc lowering drugs will probably reduce further thenumber of heFH patients meeting suggested criteria forLDL-apheresis.

LDL-apheresis is an invasive and expensive but safe pro-cedure, with no important differences in efficacy betweenthe various commercially available methods for selectiveremoval of LDL [112,113]. In the United States, the FDAapproved the use of LDL-apheresis for heFH patients with-out CHD having LDLc greater than 300 mg/dl (7.7 mmol/l)on maximal tolerated medical treatment or greater than200 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 symp-tomatic CHD heFH whose LDLc remains high (>160 mg/dl,4.2 mmol/l) or decreases by<40% on maximal medicaltreatment[115,116]. It has been shown that LDL-apheresiscan be used safely in pregnant heFH women with CVD[117].

Acknowledgements

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


References

[1] Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia.In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolicbasis of inherited disease, vol. 120. New York: McGraw-Hill; 2001.p. 2863–913.

[2] Brown MS, Goldstein JL. A receptor-mediated pathway for choles-terol homeostasis. Science 1986;232:34–47.

[3] Goldstein JL, Brown MS. The cholesterol quartet. Science2001;292:1310–2.

[4] Pullinger CR, Eng C, Salen G, et al. Human cholesterol 7 alphahydroxylase (CYP7A1) deficiency has a hypercholesterolemic phe-notype. J Clin Invest 2002;110:109–17.

[5] Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM,Vega GL, et al. Familial defective apolipoprotein B-100: a mutationof apolipoprotein B that causes hypercholesterolemia. J Lipid Res1990;31:1337–49.

[6] Myant NB. Familial defective apolipoprotein B-100: a review,including some comparisons with familial hypercholesterolaemia.Atherosclerosis 1993;104:1–18.

[7] Varret M, Rabes JP, Saint-Jore B, Cenarro A, Marinoni JC, CiveiraF, et al. A third major locus for autosomal dominant hypercholes-terolemia maps to 1p34.1-p32. Am J Hum Genet 1999;64:1378–87.

[8] Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL, WardellBB, et al. Genetic localization to chromosome 1p32 of the third locusfor familial hypercholesterolemia in a Utah kindred. ArteriosclerThromb Vasc Biol 2000;20:1089–93.

[9] Scandinavian Simvastatin Survival Study Group. Randomized trialof cholesterol lowering in 4444 patients with coronary heart dis-ease: The Scandinavian Simvastatin Survival Study (4S). Lancet1994;344:1383–9.

[10] Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heartdisease with pravastatin in men with hypercholesterolemia. N EnglJ Med 1995;333:1301–7.

[11] Sacks FM, Pfeffer MA, Moye SA, Rouleau JL, Rutherford JD,Cole TG, et al. The effect of pravastatin on coronary events aftermyocardial infarction in patients with average cholesterol levels. NEngl J Med 1996;335:1001–9.

[12] Long-Term Intervention with Pravastatin in Ischaemic Disease(LIPID) Study Group. Prevention of cardiovascular events and deathwith pravastatin in patients with coronary Heart disease and a broadrange of initial cholesterol levels. N Engl J Med 1998;339:1349–57.

[13] Downs JR, Clearfield M, Weis S, et al. Primary Prevention of acutecoronary events with lovastatin in men and women with averagecholesterol levels. JAMA 1998;279:1615–22.

[14] MRC/BHF Heart Protection Study of cholesterol loweringwith simvastatin in 20,536 high-risk individuals: a randomizedplacebo-controlled trial. Lancet 2002;360:7–22.

[15] Mortality in treated heterozygous familial hypercholesterolaemia:implications for clinical management. Scientific Steering Committeeon behalf of the Simon Broome Register Group. Atherosclerosis1999;142:105–12.

[16] WHO. Human Genetic Program. Familial Hypercholesterolemia, re-port of a WHO consultation. WHO/HGN/FH/CONS/98.7 Paris; Oc-tober 1997.

[17] Executive Summary of The Third Report of The National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation,and Treatment of High Blood Cholesterol In Adults (Adult TreatmentPanel III). JAMA 2001;285:2486–97.

[18] Prevention of coronary heart disease in clinical practice. Recom-mendations of the Second Joint Task Force of European and otherSocieties on coronary prevention. Eur Heart J 1998;19:1434–503.

[19] Wilson PW, D’Agostino RB, Levy D, Belanger AM, SilbershatzH, Kannel WB. Prediction of coronary heart disease using riskcategories. Circulation 1998;97:1837–47.

[20] Assmann G, Cullen P, Schulte H. The Munster Heart Study (PRO-CAM). Results of follow-up at 8 years. Eur Heart J 1998;19(SupplA):A2–A11.

[21] Scientific Steering Committee (SSC) on behalf of the Simon Broomeregister Group. Risk of fatal coronary heart disease in familial hy-percholesterolemia. BMJ 1991;303:893–6.

[22] Goldman L, Goldman PA, Williams LW, Weinstein MC. Cost ef-fectiveness considerations in the treatment of heterozygous familialhypercholesterolemia with medications. Am J Cardiol 1993;72:75D–9D.

[23] Moorjani S, Roy M, Gagné C, Davignon J, Brun D, ToussaintM, et al. Homozygous familial hypercholesterolemia among FrenchCanadians in Québec Province. Arteriosclerosis 1989;9:211–6.

[24] Kotze MJ, De Villiers WJS, Steyn K, Kriek JA, Marais AD, Lan-genhoven E, et al. Phenotypic variation among familial hypercholes-terolemics heterozygous for either one of two Afrikaner founderLDL receptor mutations. Arterioscler Thromb 1993;13:1460–8.

[25] Gylling H, Aalto-Setälä K, Kontula K, Miettinen TA. Serumlow-density lipoprotein cholesterol level and cholesterol absorptionefficiency are influenced by apolipoprotein B and E polymorphismand by the FH-Helsinki mutation of the low-density lipoprotein re-ceptor gene in familial hypercholesterolemia. Arterioscler Thromb1991;11:1368–75.

[26] Hirobe K, Matsuzawa Y, Ishikawa K, et al. Coronary artery dis-ease in heterozygous familial hypercholesterolemia. Atherosclerosis1982;44:201–10.

[27] Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and envi-romental factors affecting the incidence of coronary artery diseasein heterozygous familial hypercholesterolemia. Arterioscler Thromb1991;11:290–7.

[28] Gagné C, Moorjani S, Brun D, Toussaint M, Lupien PJ. Heterozygousfamilial hypercholesterolemia. Atherosclerosis 1979;34:13–24.

[29] Alonso R, Castillo S, Civeira F, Puzo J, La Cruz JJ, Pocovi M, et al.Heterozygous familial hypercholesterolemia in Spain. Description of819 non related cases. Med Clin (Barc) 2002;118:487–92.

[30] Koivisto UM, Hamalainen L, Taskinen MR, Kettunen K, KontulaK. Prevalence of familial hypercholesterolemia among young northKarelian patients with coronary heart disease: a study based ondiagnosis by polymerase chain reaction. J Lipid Res 1993;34:269–77.

[31] Baron H, Fung S, Aydin A, Bahring S, Luft FC, Schuster H. Oligonu-cleotide ligation assay (OLA) for the diagnosis of familial hyperc-holesterolemia. Nat Biotechnol 1996;14:1279–82.

[32] Schuster H. High risk/high priority: familial hypercholesterolemia—aparadigm for molecular medicine. Atherosclerosis 2002;(Suppl2):27–32.

[33] Mabuchi H, Koizumi J, Shimuzu M, Takeda R, Hokuriku FH, CHDStudy Group. Development of coronary heart disease in familialhypercholesterolemia. Circulation 1989;79:225–32.

[34] Miettinen T, Gylling H. Mortality and cholesterol metabolism infamilial hypercholesterolemia. Arteriosclerosis 1988;8:163–7.

[35] Gotto Jr AM. Management of dyslipidemia. Am J Med2002;112(Suppl 8A):10S–8S.

[36] Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, HavelRJ. Regression of coronary atherosclerosis during treatment of fa-milial hypercholesterolemia with combined drug regimens. JAMA1990;264:3007–12.

[37] Tatami R, Inoue N, Itoh H, Kishino B, Koga N, Nakashima Y, et al.Regression of coronary atherosclerosis by combined LDL-apheresisand lipid-lowering drug therapy in patients with familial hypercholes-terolemia: a multicenter study. The LARS Investigators. Atheroscle-rosis 1992;95:1–13.

[38] Nishimura S, Sekiguchi M, Kano T, Ishiwata S, Nagasaki F, NishideT, et al. Effects of intensive lipid lowering by low-density lipopro-tein apheresis on regression of coronary atherosclerosis in patientswith familial hypercholesterolemia: Japan Low-density LipoproteinApheresis Coronary Atherosclerosis Prospective Study (L-CAPS).Atherosclerosis 1999;144:409–17.


[39] Kroon AA, Aengevaeren WR, van der Werf T, Uijen GJ, Reiber JH,Bruschke AV, et al. LDL-Apheresis Atherosclerosis Regression Study(LAARS). Effect of aggressive versus conventional lipid loweringtreatment on coronary atherosclerosis. Circulation 1996;93:1826–35.

[40] Thompson GR, Maher VM, Matthews S, Kitano Y, NeuwirthC, Shortt MB, et al. Familial Hypercholesterolaemia RegressionStudy: a randomised trial of low-density-lipoprotein apheresis. Lancet1995;345:811–6.

[41] Matsuzaki M, Hiramori K, Imaizumi T, Kitabatake A, Hishida H,Nomura M, et al. Intravascular ultrasound evaluation of coronaryplaque regression by low density lipoprotein-apheresis in familialhypercholesterolemia: the Low Density Lipoprotein-Apheresis Coro-nary Morphology and Reserve Trial (LACMART). J Am Coll Cardiol2002;40:220–7.

[42] Pitsavos CE, Aggeli KI, Barbetseas JD, Skoumas IN, LambrouSG, Frogoudaki AA, et al. Effects of pravastatin on thoracic aorticatherosclerosis in patients with heterozygous familial hypercholes-terolemia. Am J Cardiol 1998;82:1484–8.

[43] Smilde TJ, van Wissen S, Wollersheim H, Trip MD, KasteleinJJ, Stalenhoef AF. Effect of aggressive versus conventional lipidlowering on atherosclerosis progression in familial hypercholestero-laemia (ASAP): a prospective, randomised, double-blind trial. Lancet2001;357:577–81.

[44] Alonso R, Mata P, De Andres R, Villacastin BP, Martinez-GonzalezJ, Badimon L. Sustained long-term improvement of arterial endothe-lial function in heterozygous familial hypercholesterolemia patientstreated with simvastatin. Atherosclerosis 2001;157:423–9.

[45] Aengevaeren WR, Kroon AA, Stalenhoef AF, Uijen GJ, van derWerf T. Low density lipoprotein apheresis improves regional myocar-dial perfusion in patients with hypercholesterolemia and extensivecoronary artery disease. LDL-Apheresis Atherosclerosis RegressionStudy (LAARS). J Am Coll Cardiol 1996;28:1696–704.

[46] Descamps O, Leysen X, Van Leuven F, et al. The use of Achillestendon ultrasonography for the diagnosis of familial hypercholes-terolemia. Atherosclerosis 2001;157:514–8.

[47] Williams R, Hunt S, Schumacher C, et al. Diagnosing heterozygousfamilial hypercholesterolemia using new practical criteria validatedby molecular genetics. Am J Cardiol 1993;72:171–6.

[48] Defesche J. Familial hypercholesterolemia. In: Betteridge J, editor.Lipids and vascular disease, vol. 6. London: Martin Dunitz; 2000.p. 65–76.

[49] Marks D, Wonderling D, Thorogood M, Lambert H, HumphriesE, Neil AW. Cost effectiveness analysis of different approachesof screening for familial hypercholesterolemia. BMJ 2002;324:1303–8.

[50] Ferrieres J, Lambert J, Lussier-Cacan S, Davignon J. Coronary arterydisease in heterozygous familial hypercholesterolemia patients withthe same LDL receptor gene mutation. Circulation 1995;92:290–5.

[51] Hopkins P, Stephenson S, Wu L, Riley WA, Xin Y, Hunt SC.Evaluation of coronary risk factors in patients with heterozygousfamilial hypercholesterolemia. Am J Cardiol 2001;87:547–53.

[52] Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson GR,Boerwinkle E, et al. Relation of serum lipoprotein(a) concentrationand apolipoprotein(a) phenotype to coronary heart disease in patientswith familial hypercholesterolemia. N Engl J Med 1990;322:1494–9.

[53] Tonstad S, Joakimsen O, Stensland-Bugge E, Leren TP, Ose L,Russell D, et al. Risk factors related to carotid intima-media thicknessand plaque in children with familial hypercholesterolemia and controlsubjects. Arterioscler Thromb Vasc Biol 1996;16:984–91.

[54] Wittekoek ME, de Groot E, Prins MH, Trip MD, Büller HR, KasteleinJJ. Differences in intima-media thickness in the carotid and femoralarteries in familial hypercholesterolemic heterozygotes with and with-out clinical manifestations of cardiovascular disease. Atherosclerosis1999;146:271–9.

[55] Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S,et al. Clinical expression of familial hypercholesterolemia in clustersof mutations of the LDL receptor gene that cause a receptor-defective

or receptor-negative phenotype. Arterioscler Thromb Vasc Biol2000;20:E41–52.

[56] Smilde TJ, van Wissen S, Wollersheim H, Kastelein JJ, StalenhoefAF. Genetic and metabolic factors predicting risk of cardiovasculardisease in familial hypercholesterolemia. Neth J Med 2001;59:184–95.

[57] Taira K, Bujo H, Kobayashi J, Takahashi K, Miyazaki A, SaitoY. Positive family history for coronary heart disease and ’midbandlipoproteins’ are potential risk factors of carotid atherosclerosis infamilial hypercholesterolemia. Atherosclerosis 2002;160:391–7.

[58] Real JT, Chaves FJ, Ascaso JF, Carmena R. Importance of HDLcholesterol levels and total to HDL cholesterol ratio as risk factor forcoronary heart disease in molecularly defined heterozygous familialhypercholesterolemia. Eur Heart J 2001;22:465–71.

[59] Lundahl B, Leren TP, Ose L, Hamsten A, Karpe F. A functionalpolymorphism in the promoter region of the microsomal triglyc-eride transfer protein (MTP-493G/T) influences lipoprotein pheno-type in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol2000;20:1784–8.

[60] Wittekoek ME, Moll E, Pimstone SN, Trip MD, Lansberg PJ, De-fesche JC, et al. A frequent mutation in the lipoprotein lipase gene(D9N) deteriorates the biochemical and clinical phenotype of famil-ial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1999;19:2708–13.

[61] Wittekoek ME, Pimstone SN, Reymer PW, Feuth L, Botma GJ,Defesche JC, et al. A common mutation in the lipoprotein lipase gene(N291S) alters the lipoprotein phenotype and risk for cardiovasculardisease in patients with familial hypercholesterolemia. Circulation1998;97:729–35.

[62] Carmena-Ramon R, Ascaso JF, Real JT, Najera G, Ordovas JM,Carmena R. Association between the TaqIB polymorphism in theCETP gene locus and plasma lipoprotein levels in familial hyperc-holesterolemia. Metabolism 2001;50:651–6.

[63] Cenarro A, Artieda M, Castillo S, Mozas P, Reyes G, Tejedor D,et al. A common variant in the ABCA1 gene is associated with alower risk for premature coronary heart disease in familial hyperc-holesterolaemia. J Med Genet 2003;40:163–8.

[64] Jansen AC, van Wissen S, Defesche JC, Kastelein JJ. Phenotypicvariability in familial hypercholesterolemia: an update. Curr OpinLipidol 2002;13:165171.

[65] Gidding SS, Bookstein LC, Chomka EV. Usefulness of electronbeam tomography in adolescents and young adults with heterozygousfamilial hypercholesterolemia. Circulation 1998;98:2580–3.

[66] Mabuchi H, Koizumi J, Shimizu M, et al. Development of coro-nary heart disease in familial hypercholesterolemia. Circulation1989;79:225–32.

[67] Grundy SM, Pasternack R, Greenland P, Smith S, Fuster V. Assess-ment of cardiovascular risk by use of multiple risk factor assessmentequations. Circulation 1999;100:1.481–92.

[68] Arruda AM, Das MK, Roger VL, Klarich KW, Mahoney DW, Pel-likka PA. Prognostic value of exercise echocardiography in 2.632patients > or = 65 years of age. J Am Coll Cardiol 2001;37:1.036–41.

[69] O’Rourke RA, Brundage BH, Froelicher VF, Greenland P, GrundySM, Hachamovitch R, et al. American College of Cardiol-ogy/American Heart Association expert consensus document onelectron-beam computed tomography for the diagnosis and prognosisof coronary artery disease. Circulation 2000;102:126–40.

[70] Sacks D, Bakal CW, Beatty PT, Becker GJ, Cardella JF. Positionstatement of the use of the ankle-brachial index in the evaluationof patients with peripheral vascular disease: a consensus statementdeveloped by the standards division of the Society of Cardiovascular,Position statement of the use of the ankle-brachial index in theevaluation of patients with peripheral vascular disease: a consensusstatement developed by the standards division of the Society ofCardiovascular & Interventional Radiology. J Vasc Interv Radiol2002;13:353.


[71] Barth JD. An update on carotid ultrasound measurement ofintima-media thickness. Am J Cardiol 2002;89(Suppl 4A):32B–9B.

[72] Wilmink AB, Hubbard CS, Day NE, Quick CR. The incidenceof small abdominal aortic aneurysms and the change in normalinfrarenal aortic diameter: implications for screening. Eur J VascEndovasc Surg 2001;21:165–70.

[73] Feinstein SB, Voci P, Pizzuto F. Noninvasive surrogate markers ofatherosclerosis. Am J Cardiol 2002;89(Suppl 5A):31C–44C.

[74] Thompson GR, Hollyer J, Waters DD. Percentage change rather thanplasma level of LDL-cholesterol determines therapeutic response incoronary heart disease. Curr Opin Lipidol 1995;6:386–8.

[75] Thompson GR. What targets should lipid-modulating therapy achieveto optimize the prevention of coronary heart disease? Atherosclerosis1997;131:1–5.

[76] Pearson T, Laurora I, Chu H, Kafonek S. The lipid treatment as-sessment project. Arch Intern Med 2000;160:459–67.

[77] de Lorgeril M, Renaud S, Mamelle N, Salen P, Martın JL, MonjaudI, et al. Mediterranean alpha-linolenic acid-rich diet in secondaryprevention of coronary heart disease. Lancet 1994;343:1454–9.

[78] Mensink M, Katan M. Effect of dietary fatty acids on serum lipidsand lipoproteins. Arterioscler Thromb 1992;12:911–9.

[79] Perez-Jimenez F, Lopez-Miranda J, Mata P. Protective effect ofdietary monosaturated fat on arteriosclerosis: beyond cholesterol.Atherosclerosis 2002;163:385–98.

[80] Cleghorn CL, Skeaff CM, Mann J, Chisholm A. Plant sterol-enrichedspread enhances the cholesterol-lowering potencial of a fat-reduceddiet. Eur J Clin Nutr 2003;57:170–6.

[81] Ling WH, Jones PJ. Dietary phytosterol: a review of metabolism,benefits, and side effects. Life Sci 1995;57:195–206.

[82] Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, BinkoskiAE, Hilpert KF, et al. Bioactive compounds in foods: their rolein the prevention of cardiovascular dosease and cancer. Am J Med2002;113(9B):71S–88S.

[83] Sugano M, Morioka H, Ikeda I. A comparison of hypocholes-terolemic activity of beta-sitosterol and beta-sitostanol in rats. J Nutr1977;107:2011–9.

[84] Amundsen AL, Ose L, Nenseter MS, Ntanios F. Plant sterolester-enriched spread lowers plasma total and LDL cholesterolin children with familial hypercholesterolemia. Am J Clin Nutr2002;76:338–44.

[85] Gylling H, Siimes MA, Miettinen TA. Sitostanol ester margarine indietary treatment of children with familial hypercholesterolemia. JLipid Res 1995;36:1807–12.

[86] Ketomaki A, Gylling H, Siimes MA, Vuorio A, Miettinen TA. Squa-lene and noncholesterol sterols in serum and lipoproteins of chil-dren with and without familial hypercholesterolemia. Pediatr Res2003;53:1–6.

[87] Miettinen TA, Gylling H, Lindbohm N, Miettinen TE, RajaratnanRA, Relas H. Serum noncholesterol sterols during inhibition ofcholesterol synthesis by statins. J Lab Clin Med 2003;141:131–7.

[88] Sudhop T, Gottwald BM, von Bergmann K. Serum plant sterols as apotential risk factor for coronary disease. Metabolism 2002;51:1519–21.

[89] Mustaad V, Kris-Etherton PM. Beyond cholesterol lowering: deci-phering the benefits of dietary intervention on cardiovascular dis-eases. Curr Atherocler Rep 2000;2:461–6.

[90] Sudhop T, Lütjohann D, Kodal A, Igel M, Tribble DL, Shah S, et al.Inhibition of intestinal cholesterol absortion by ezetimibe in humans.Circulation 2002;106:1943–8.

[91] Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR,Simonson SG. Comparative effects of rosuvastatin and atorvastatinacross their dose ranges in patients with hypercholesterolemia andwithout active arterial disease. Am J Cardiol 2003;91:33–41.

[92] Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, MillerE, et al. Comparison of the efficacy and safety of rosuvastatin versusatorvastatin, simvastatin and pravastatin across doses (STELLARTrial). Am J Cardiol 2003;93:152–60.

[93] Blasetto JW, Stein EA, Brown WV, Chitra R, Raza A. Efficacy ofrosuvastatin compared with other statins at selected starting doses inhypercholesterolemic patients and in special population groups. AmJ Cardiol 2003;91(suppl):3C–10C.

[94] Insull Jr W, Marquis NR, Tsianco MC. Comparison of the efficacyof questran light, a new formulation of colestyramine powder, toregular questran in maintaining lowered plasma cholesterol levels.Am J Cardiol 1991;67:501–5.

[95] Hunninghake DB, Stein EA, Bremner WF, Greenland P, DemkeDM, Oliphant TH. Dose–response study of colestipol tablets inpatients with moderate hypercholesterolemia. Am J Ther 1995;2:180–9.

[96] Pravastatin Multicenter Study Group II. Comparative efficacy andsafety of pravastatin and cholestyramine alone and combined inpatients with hypercholesterolemia. Arch Intern Med 1993;153:1321–9.

[97] Insull Jr W, Toth P, Mullican W, Hunninghake D, Burke S, DonovanJM, et al. Effectiveness of colesevelam hydrochloride in decreas-ing LDL colesterol in patients with primary hypercholesterolemia:a 24-week randomized controlled trail. Mayo Clin Proc 2001;76:971–82.

[98] Dujovne CA, Ettinger MP, McNeer JF, Lipka LJ, LeBeaut AP, SureshR, et al., Esetimibe Study Group. Efficacy and safety of a potentnew selective cholesterol absortion inhibitor, ezetimibe, in patientswith primary hypercholesterolemia. Am J Cardiol 2002;90:1092–7.

[99] Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeautAP, et al. Ezetimibe coadministered with simvastatin inpatients withprimary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–34.

[100] Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, ChoM, et al., Ezetimibe Study Group. Efficacy and safety of eztimibeadded to ongoing statin therapy for treatment of patients with primaryhypercholesterolemia. Am J Cardiol 2002;90:1084–91.

[101] Mata P, Alonso R, Badimon JJ. Risk-benefit assessment of sim-vastatin in patients with familial hypercholesterolemia. Drug Saf2003;26:769–86.

[102] Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering bystatin drugs. Am J Cardiol 1997;82:106–7.

[103] Maron DJ, Fazio S, Linton MF. Current perspectives on statins.Circulation 2000;101:207–13.

[104] Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative doseefficacy study of atorvastatin versus simvastatin, lovastatin, and flu-vastatin in patients with hypercholesterolemia (the CURVES study).Am J Cardiol 1998;81:582–7.

[105] McCrindle BW, Helden E, Cullen-Dean G, Conner WT. A ran-domized crossover trial of combination pharmacologic therapy inchildren with familial hyperlipidemia. Pedriatr Res 2002;51:715–21.

[106] Hagen E, Istad H, Ose L, Bodd E, Eriksen HM, Selvig V, et al.Fluvastatin efficacy and tolerability in comparison and in combinationwith colestyramine. Eur J Clin Pharmacol 1994;46:445–9.

[107] Davidson MH. Combination therapy for dyslipidemia: safety andregulatory considerations. Am J Cardiol 2002;90(suppl):50K–60K.

[108] Leiteredorf E, Muratti EN, Eliav O, Peters TK. Effciacy and saftyof triple therapy (Fluvastatin-bezafibrate-cholestyramine) for severefamilial hypercholesterolaemia. Am J Cardiol 1995;76:84A–8A.

[109] Stein EA, Illingworth DR, Kwiterovich Jr PO, Liacouras CA,Siimes MA, Jacobson MS, et al. Efficacy and safety of lovastatin inadolescent males with heterozygous familial hypercholesterolemia:a randomized controlled trial. JAMA 1999;281:137–44.

[110] De Jongh S, Ose L, Szamosi T, Gagne C, Lambert M, Scott R, etal. Efficacy and safety of statin therapy in children with familial hy-percholesterolemia: a randomized, double-blind, placebo-controlledtrial with simvastatin. Circulation 2002;106:2231–7.

[111] Gordon BR, Saal SD. Current status of low density lipoprotein-apheresis for the therapy of severe hyperlipidemia. Curr Opin Lipidol1996;7:381–.

[112] Schmaldienst S, Banyai S, Stulnig ThM, Heinz G, Jansen M, HörlWH, et al. Prospective randomised cross-over comparison of three


LDL-apheresis systems in statin pretreated patients with familialhypercholesterolemia. Atherosclerosis 2000;151:493–9.

[113] Bambauer R. Low-density lipoprotein apheresis: clinical results withdifferent methods. Artif Organs 2002;26:133–9.

[114] Hudgins LC, Gordon BR, Parker TS, Saal SD, Levine DM, RubinAL. LDL apheresis: an effective and safe treatment for refractoryhypercholesterolemia. Cardiovasc Drug Rec 2002;20:271–80.

[115] Barter PJ. Coronary plaque regression: role of low densitylipoprotein-apheresis. J Am Coll Cardiol 2002;40:228–30.

[116] Thompson GR. LDL apheresis. Atherosclerosis 2003;167:1–13.

[117] Cashin-Hemphill L, Noone M, Abbott JF, Waksmonski CA, LeesRS. Low-density lipoprotein apheresis therapy during pregnancy. AmJ Cardiol 2000;86:1160, A10.

guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia.pdf

Documents