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Familial hypercholesterolaemia 

Familial hypercholesterolaemia
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Familial hypercholesterolaemia
Author(s):

Gilbert R. Thompson

DOI:
10.1093/med/9780199235292.003.1240
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Introduction

Familial hypercholesterolaemia (OMIM 143890) is characterized by hypercholesterolaemia from birth, with the subsequent development of cutaneous and tendon xanthomas and premature onset of atherosclerosis, as first described by Müller over 70 years ago (1). Myant (2) noted that the monogenically determined increase in plasma cholesterol was largely confined to low-density lipoprotein (LDL) cholesterol and Goldstein and Brown (3) showed that the increase in LDL was due to mutations of the gene encoding the formation of LDL receptors, leading to defective catabolism of LDL.

Over 1000 variations in the LDL receptor gene have now been described, most of which can cause familial hypercholesterolaemia (4). Usually only one mutant gene is inherited, which gives rise to the heterozygous form of the disease. Rarely, inheritance of two identical mutant alleles occurs, giving rise to homozygous familial hypercholesterolaemia. Inheritance of two mutations results in compound heterozygosity, which is clinically indistinguishable from genetically homozygous familial hypercholesterolaemia.

The frequency of familial hypercholesterolaemia in the populations of Europe and North America averages 0.2%, but in some parts of the world it is much higher. Regions with an increased prevalence of familial hypercholesterolaemia include Lebanon, South Africa, and the Canadian province of Quebec. In each instance this is attributable to an unusually high frequency of one or two mutations within the population, such as the Lebanese allele, the Afrikaner 1 and 2 mutations, and the French Canadian allele. In South Africa and Canada the increased prevalence of familial hypercholesterolaemia represents a founder gene effect traceable to immigrant settlers from Europe, whereas in Muslim communities it reflects the frequency of first-cousin marriages. In notable contrast is the multiplicity of mutations found among familial hypercholesterolaemia patients in the UK, as shown in Fig. 12.2.2.1.


Fig. 12.2.2.1 Schematic diagram of the LDL receptor, illustrating the nature and site of mutations identified in patients referred to Hammersmith Hospital (compiled from Sun X-M, Webb JC, Gudnason V, Humphries S, Seed M, Thompson GR, et al. Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom. Arterioscler Thromb, 1992; 12: 762–70; Webb JC, Sun XM, McCarthy SN, Neuwirth C, Thompson GR, Knight BL, et al. Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom. J Lipid Res, 1996; 37: 368–81; Sun X-M, Patel DD, Knight BL, Soutar AK. Comparison of the genetic defect with LDL-receptor activity in cultured cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolemia. The Familial Hypercholesterolaemia Regression Study Group. Arterioscler Thromb Vasc Biol, 1997; 17: 3092–101; and Bourbon M, Sun X-M, Soutar AK. A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing. Atherosclerosis, 2007; 195: e17–20). (Modified with permission from Thompson GR, Abnormalities of plasma lipoprotein transport. In: Barter P, Rye K, eds. Plasma Lipids and Their Role in Disease. Harwood Academic Publishers, Australia, 1999.)

Fig. 12.2.2.1
Schematic diagram of the LDL receptor, illustrating the nature and site of mutations identified in patients referred to Hammersmith Hospital (compiled from Sun X-M, Webb JC, Gudnason V, Humphries S, Seed M, Thompson GR, et al. Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom. Arterioscler Thromb, 1992; 12: 762–70; Webb JC, Sun XM, McCarthy SN, Neuwirth C, Thompson GR, Knight BL, et al. Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom. J Lipid Res, 1996; 37: 368–81; Sun X-M, Patel DD, Knight BL, Soutar AK. Comparison of the genetic defect with LDL-receptor activity in cultured cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolemia. The Familial Hypercholesterolaemia Regression Study Group. Arterioscler Thromb Vasc Biol, 1997; 17: 3092–101; and Bourbon M, Sun X-M, Soutar AK. A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing. Atherosclerosis, 2007; 195: e17–20). (Modified with permission from Thompson GR, Abnormalities of plasma lipoprotein transport. In: Barter P, Rye K, eds. Plasma Lipids and Their Role in Disease. Harwood Academic Publishers, Australia, 1999.)

An identical clinical syndrome to familial hypercholesterolaemia can occur as a result of inheritance of a mutation at the apoB locus, which results in a functionally defective form of LDL (5). This disorder, familial defective apoB-100 or FDB (OMIM 144010), has a frequency of 0.1% in people of European descent but has never been described in Japan. Rarely, familial hypercholesterolaemia is caused by dominantly inherited gain of function mutations of a gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) (OMIM 603776), which results in increased degradation of LDL receptors and an unusually severe clinical phenotype (6). It can also be caused by recessively inherited loss of function mutations of a gene encoding a protein involved in the clathrin-mediated internalization of the LDL receptor (6), which results in a milder phenotype than dominantly inherited forms of the condition and is known as autosomal recessive hypercholesterolaemia (OMIM 603813).

A recent survey detected mutations of the LDL receptor, apoB, and PCSK9 genes in only 62% of patients with clinically definite familial hypercholesterolaemia (7), raising the likelihood that mutations of genes encoding other proteins involved in LDL metabolism remain to be discovered.

Plasma lipoprotein abnormalities

Plasma or serum total cholesterol levels usually range from 18 to greater than 20 mmol/l in homozygotes and from 9 to 11 mmol/l in heterozygotes. The increase in total cholesterol in homozygotes is largely due to an increase in LDL cholesterol, which is accompanied by a decrease in high-density lipoprotein (HDL) cholesterol, resulting in very high total:HDL cholesterol ratios. Triglycerides are usually normal but may be raised, especially in pregnancy. Analogous, but less marked, increases in LDL cholesterol characterize heterozygous familial hypercholesterolaemia. The lipoprotein phenotype of heterozygotes is age-dependent, with 10% of children and 40% of adults exhibiting a IIb phenotype, the remainder a IIa phenotype. HDL cholesterol is reduced but to a less marked extent than in homozygotes. Another lipoprotein abnormality found in familial hypercholesterolaemia is an increased concentration of lipoprotein (a) (Lp(a)), which appears to be mediated via increased secretion rather than by decreased catabolism, as occurs with LDL. Levels above 30 mg/dl (1.07 mmol/L)are associated with an increased risk of coronary heart disease (8).

Laboratory diagnosis

Antenatal diagnosis of homozygous familial hypercholesterolaemia involves analysing fetal DNA obtained from chorionic villi (9). Diagnosis of heterozygous familial hypercholesterolaemia in infants of a parent with familial hypercholesterolaemia can be attempted at birth by estimating the concentration of LDL cholesterol in cord blood, values in excess of the 95th percentile (1.1 mmol/l) being suggestive. However, LDL cholesterol should always be re-estimated in serum or plasma after the age of 6 months, by which time an increase in LDL is usually apparent if the child is affected. Between the ages of 1 and 16 years serum total cholesterol levels are nearly twice as high in heterozygotes as in their unaffected siblings, but the diagnosis cannot be made with confidence when the value is in the range 6.5–7.0 mmol/l. The UK’s National Institute for Health and Clinical Excellence (NICE) recommends that in children of an affected parent with a known mutation the DNA should be analysed before the age of 10 years or have their LDL cholesterol measured if the family mutation is unknown. Serum total and LDL cholesterol levels higher than 6.7 and 4.0 mmol/l, respectively, are considered to be diagnostic of heterozygous familial hypercholesterolaemia in children and adolescents below the age of 16 (10).

In adults the diagnosis is usually based on the Simon Broome criteria. Definite familial hypercholesterolaemia consists of having total and LDL cholesterol above 7.5 and 4.9 mmol/l, respectively, plus tendon xanthomas in the person concerned or in a first or second degree relative, or DNA evidence of a causal mutation. However, these signs are often absent in parts of the world where the diet is low in fat (11). A diagnosis of possible familial hypercholesterolaemia involves having a raised cholesterol as defined above, and either a family history of hypercholesterolaemia or of myocardial infarction before age 60 in a first degree relative or before the age of 50 in a second degree relative. NICE advocates the use of cascade screening of relatives of index cases to identify affected family members, using a combination of DNA testing and gender- and age-related LDL cholesterol cut-offs, the latter being lower than the Simon Broome criteria used to diagnose index cases (10). Currently it is estimated that 75% of subjects with familial hypercholesterolaemia in the UK remain undiagnosed until middle age (12). When measuring serum lipids, it is important to exclude causes of secondary hyperlipidaemia such as hypothyroidism, which can masquerade as, or coexist with, familial hypercholesterolaemia.

Clinicopathological features of homozygous familial hypercholesterolaemia

Clinically, homozygous familial hypercholesterolaemia is characterized by extreme hypercholesterolaemia and the onset in childhood of cutaneous xanthomas, typically planar or tuberose, plus tendon xanthomas and corneal arcus. Levels of plasma cholesterol correlate inversely with the severity of the LDL receptor deficit, which is more marked with mutations that impair the ability to produce receptors (receptor-negative) than with mutations leading to the formation of functionally abnormal receptors (receptor-defective).

Atheromatous involvement of the aortic root in homozygotes is always evident by puberty, as manifested by an aortic systolic murmur, a gradient across the aortic valve, and angiographic narrowing of the aortic root together with coronary ostial stenosis. Sudden death from myocardial infarction or acute coronary insufficiency before 30 was the rule before the introduction of plasmapheresis.

Post-mortem examination of homozygotes reveals that the aortic valve, sinuses of Valsalva, and ascending arch of the aorta are grossly infiltrated with atheroma, with similar but less severe changes in the abdominal aorta, pulmonary and carotid arteries, and circle of Willis. Coronary ostia are sometimes narrowed down to pinhole size but the distal coronary arteries often seem to be relatively spared, especially in young subjects. Typical advanced atherosclerotic plaques are found in the aorta, together with fibrous thickening of the aortic valve cusps (Fig. 12.2.2.2). Many of the cells in advanced plaques are macrophages, containing large amounts of esterified cholesterol, whereas free cholesterol crystals are extracellular.


Fig. 12.2.2.2 Thickened aortic valve cusps (arrowed) in a familial hypercholesterolaemia homozygote individual who died aged 23 years.

Fig. 12.2.2.2
Thickened aortic valve cusps (arrowed) in a familial hypercholesterolaemia homozygote individual who died aged 23 years.

Clinicopathological features of heterozygous familial hypercholesterolaemia

Heterozygotes often remain undiagnosed until the onset of cardiovascular symptoms in adult life. In addition to hypercholesterolaemia there may be visible signs of cholesterol deposition, such as corneal arcus, xanthelasma, and tendon xanthomas, characteristic sites for the latter being the extensor tendons on the back of the hands and elbows, Achilles’ tendons, and the patellar tendon insertion into the pretibial tuberosity. The development of tendon xanthomas, a more specific hallmark of familial hypercholesterolaemia than corneal arcus or xanthelasma, is age dependent. An analysis of patients with familial hypercholesterolaemia in the UK showed that the overall frequency of tendon xanthomas was 75% in males and 72% in females, but these were never detected before the age of 10 years.

LDL levels in familial hypercholesterolaemia are determined by both genetic and environmental influences. For example, in heterozygous children in Quebec the LDL cholesterol was significantly lower in those with a receptor-defective missense mutation than in those with the receptor-negative French-Canadian deletion (13). Similarly, mutations in exon 4 of the gene for the LDL receptor, which encodes its apoB/E- binding domain, are associated with a higher LDL cholesterol than mutations in other exons (14). In Norwegian children with familial hypercholesterolaemia, the degree of obesity has been shown to be an important determinant of variations in LDL level among those with any given mutation of the LDL receptor (15).

The high frequency and premature onset of coronary heart disease in heterozygous familial hypercholesterolaemia has been well documented, and it has been estimated that coronary heart disease occurs about 20 years earlier in carriers than in the rest of the population. The incidence of coronary heart disease is lower in females than in males, although their relative risk of fatal coronary heart disease is higher (16). On coronary angiography the majority of male heterozygotes have triple vessel disease, including almost a third with disease of the left main stem. In addition to a raised Lp(a), other risk factors for coronary heart disease in heterozygotes are smoking and a low HDL cholesterol (17).

Extracoronary atherosclerosis is also common, asymptomatic carotid disease being present in 75% of heterozygotes on ultrasonography (18). Abnormalities ranged from intimal−medial thickening to the presence of heterogeneous plaques, the latter finding being strongly correlated with the presence of coronary heart disease and with a Lp(a) level above 30 mg/dl (1.07 mmol/L). Independent predictors of carotid artery disease in this study were age, serum triglycerides, and the cholesterol-years score.

Post-mortem examination of heterozygotes usually shows severe atherosclerosis of the aorta, especially of the abdominal portion. The aortic root is involved to a much lesser extent than in homozygotes and the aortic valve usually remains normal. In contrast, the coronary arteries are extensively involved with atheroma, which causes both stenotic and ectatic lesions.

Contrasting features of atherosclerosis in homozygotes and heterozygotes

As mentioned above, familial hypercholesterolaemia homozygotes evince severe atherosclerosis of the aortic root and sinuses of Valsalva, as well as marked valvular fibrosis, which is sometimes very severe and accompanied by calcification. Frequently this leads to haemodynamically significant aortic stenosis, often despite radical lipid-lowering therapy. Aortic stenosis is rare in heterozygotes and is confined to those with an unusually marked degree of hypercholesterolaemia (19).

A possible explanation for this contrast emerged from an echocardiographic study of the aortic root in six homozygotes and 78 heterozygotes attending Hammersmith Hospital (20). The homozygotes were younger and their pretreatment LDL cholesterol levels were higher. The mean aortic gradient was also much higher in homozygotes than in heterozygotes, despite the latter having a greater cholesterol-years score, an index of the lifelong exposure of the vasculature to cholesterol. These findings suggest that long exposure to moderately raised levels of cholesterol has different effects from shorter exposure to very high levels. One explanation for this apparent anomaly is that concentrated solutions of LDL aggregate in vitro when subjected to vigorous agitation and it is possible that subjection of the high concentration of LDL in the plasma of untreated homozygotes to the haemodynamic forces accompanying systolic ejection of blood into the aorta results in aggregation of LDL particles in vivo. These aggregates might then be deposited during diastole in the sinuses of Valsalva and on the surface of the aortic valve, and subsequently get taken up by scavenger receptors on macrophages (21). Presumably the concentration of LDL in heterozygotes is usually below the critical level above which aggregation of LDL occurs and treatment of homozygotes would exert a similar protective effect.

Treatment

The treatment of familial hypercholesterolaemia starts in childhood and is a lifelong endeavour. The vigour with which it is pursued will depend on individual circumstances, most notably on whether the patient is homozygous or heterozygous, male or female. Control of additional risk factors, such as smoking, hypertension, and diabetes is vital.

Treatment of homozygous familial hypercholesterolaemia

The management of homozygous familial hypercholesterolaemia presents a major therapeutic challenge. Diet has little impact on the hypercholesterolaemia, and the same applies for drug therapy except for maximum doses of the most potent statins, as discussed below. Partial ileal bypass is ineffective, and although portacaval shunt occasionally has a remarkable effect, its outcome is unpredictable. Liver transplantation remedies the hepatic deficiency of LDL receptors and can result in normal lipid levels, including Lp(a) (22), but has the disadvantage of requiring long-term immunosuppression. Gene therapy offers a possible means of treating this disorder but so far has proved disappointing. Currently the safest and most reliable means of reducing cholesterol levels is to undertake plasma exchange or LDL apheresis at 1–2-weekly intervals. This has been performed over durations of 15 years or more without side effects, and leads to resolution of xanthomas and slows progression of atherosclerosis (23).

Recent data on the effect in homozygotes of long-term plasma exchange or LDL apheresis, usually combined with high-dose atorvastatin plus ezetimibe, are shown in Table 12.2.2.1 (2426). Apheresis was commonly initiated between the ages of 7 and 9 years and maintained for 6–12 years. Baseline levels of total or LDL cholesterol off all treatment exceeded 20 mmol/l and were reduced by 45–55%. Other studies in homozygotes undergoing apheresis have shown reductions in LDL cholesterol of approximately 20% after adding atorvastatin 80 mg or rosuvastatin 40 mg daily (27) and a further reduction of 20% when ezetimibe 10 mg daily was added to high-dose statin therapy (28). This combined approach should enable a mean total cholesterol of less than 7 mmol/l or LDL cholesterol lower than 6.5 mmol/l (or decreases of >60% or >65%, respectively, from baseline values off all treatment) to be achieved in most instances (29).

Table 12.2.2.1 Combined use of LDL apheresis and drug therapy in homozygous familial hypercholesterolaemia

Kolansky et al. (26)

Palcoux et al. (24)

Hudgins et al. (25)

On apheresis; n

17

27a

20b

Age started, Years

7

8.5

9

Duration, Years

6.6

12.6

6

Baseline cholesterol, mmol/l

20.5(TC)

23(TC)

21(LDLC)

∆ Baseline chol with apheresis/drugs

–45%

–51%

–55%

a All aged <15 years

b All aged <18 years

LDLC, low-density lipoprotein cholesterol; n, number; TC, total cholesterol. Adapted from Thompson GR et al. Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis, 2009 (29).

Despite the improved prognosis resulting from medical treatment, the combination of severe aortic stenosis and coronary artery disease often necessitates aortic valve replacement and coronary artery bypass grafting. Reconstruction of the aortic root is the main operative risk and carries a high mortality. However, it is possible that introduction of effective control of hypercholesterolaemia in early childhood will reduce the need for surgery. LDL apheresis should be started as soon as feasible and not later than the age of 7 years. There have been no randomized trials of the effects of treatment on clinical endpoints, but plasma exchange has been shown to increase significantly the life expectancy of homozygotes compared with their untreated siblings (30).

Treatment of heterozygous familial hypercholesterolaemia

A lipid-lowering diet alone seldom suffices to maintain desirable levels of LDL cholesterol in adults, but should always be used as an adjunct to drug therapy. The National Cholesterol Education Program Step 2 diet is appropriate for this purpose, limiting fat intake to less than 30% of total calories, of which less than 7% is saturated, up to 10% polyunsaturated, and 10–15% monounsaturated fatty acid in origin. Dietary cholesterol is restricted to 200 mg/day and total calories are limited so as to achieve ideal body weight. Consumption of foods containing plant sterol or stanol esters 2 g daily decreases LDL cholesterol by 10–15%, an effect which is additive to that of statins.

Bile acid sequestrants (cholestyramine and colestipol) were for many years the drug of choice for familial hypercholesterolaemia, achieving reductions in LDL cholesterol of up to 30% when given in doses of 24–30 g/day. However, most people are unable to tolerate more than 16 g/day because of gastrointestinal side effects and except where safety is an overriding concern, as in pregnancy, they have largely been replaced by 3-hydroxy-3-methylglutaryl (HMG) CoA reductase (EC 1.1.1.34) inhibitors (statins). The latter class of drug has revolutionized the outlook for familial hypercholesterolaemia patients and provides a safe and effective means of lowering LDL cholesterol, although not Lp(a). Rosuvastatin and atorvastatin are the most potent in their ability to lower LDL cholesterol, the latter drug reducing it by 57% when given in a dose of 80 mg/day (31).

Despite the efficacy of statins, there is considerable interindividual variation in the extent to which they lower LDL cholesterol in familial hypercholesterolaemia. Subjects whose LDL response is below average have lower rates of cholesterol synthesis than those whose response is above average (32). A possible mechanism for this is that genetic influences cause poor responders to absorb cholesterol more efficiently than good responders, resulting in greater down-regulation of hepatic HMG CoA reductase and thus a decreased responsiveness to statins.

NICE recommends that the objective of statin therapy is to lower LDL cholesterol by 50% (10) and that ezetimibe should be used as an adjuvant in patients failing to achieve that target or as monotherapy for those intolerant of statins (33). Combining a high dose of statin with ezetimibe 10 mg daily has been shown to decrease LDL cholesterol by more than 60% (34). Given the fact that ezetimibe blocks cholesterol absorption it is noteworthy that patients who responded least well to statin monotherapy showed a greater additional reduction in LDL when ezetimibe was added than did those who responded best to statin monotherapy, as shown in Fig. 12.2.2.3. When administered alone ezetimibe decreased LDL cholesterol by 27% in statin-intolerant patients. The risk of coronary heart disease is less in pre-menopausal female heterozygotes than in males, unless they are smokers or have unusually severe hypercholesterolaemia or a family history of premature coronary heart disease or a raised level of lipoprotein (a). However, before embarking on treatment with a statin, steps should be taken to ensure effective contraception.


Fig. 12.2.2.3 Correlation between percentage change in low-density lipoprotein cholesterol (LDL-C) on statins and further change after addition of ezetimibe, as compared with baseline, in patients with and without familial hypercholesterolaemia (FH). Reproduced from British Journal of Cardiology (Sarwar R et al. 2008; 15: 205–9).

Fig. 12.2.2.3
Correlation between percentage change in low-density lipoprotein cholesterol (LDL-C) on statins and further change after addition of ezetimibe, as compared with baseline, in patients with and without familial hypercholesterolaemia (FH). Reproduced from British Journal of Cardiology (Sarwar R et al. 2008; 15: 205–9).

The treatment of heterozygous familial hypercholesterolaemia in childhood initially involves dietary intervention. The US National Cholesterol Education Program guidelines (35) advocate that all children with familial hypercholesterolaemia should be treated from the age of 2 years onwards with a Step 1 diet, i.e. not more than 30% of calories from fat, with less than 10% from saturated fat, and cholesterol intake less than 300 mg/day. High-risk children are treated with a Step 2 diet, i.e. calories from saturated fat less than 7% and cholesterol intake less than 200 mg/day. As in adults, plant stanol esters are a useful addition to the diet, lowering LDL cholesterol by 15% (36). NICE recommendations are that lipid-modifying drug therapy, specifically a statin licensed for paediatric use, should be considered by the age of 10 years, the decision to treat being influenced by the age of the child and by the presence of other risk factors (10). Children regarded as being at high risk are boys with total cholesterol above 9 mmol/l or those of either sex with a total cholesterol above 7 mmol/l and a history of coronary heart disease occurring before the age of 40 in a male first or second degree relative or before 50 in a female relative (37). The efficacy and short-term safety of statins has been confirmed by a meta-analysis of trials in children and adolescents but their duration was insufficient to establish long-term safety (38).

Nonpharmacological approaches

The resistance or intolerance to drug therapy of a minority of heterozygotes has led to various nonpharmacological modes of therapy being developed. These include surgical manoeuvres, such as partial ileal bypass, and medical procedures, such as repetitive plasma exchange and LDL apheresis.

Partial ileal bypass

This procedure involves bypassing the terminal third of the ileum and anastomosing the distal end of the remaining ileum with the caecum. The main result is a fourfold increase in bile acid excretion, which leads to an increased rate of turnover of cholesterol to bile acids and a compensatory increase in cholesterol synthesis, the net effect being a 38% reduction in LDL cholesterol. Even greater decreases can be achieved by concomitant administration of an HMG CoA reductase inhibitor. However, in a significant minority of patients, the operation needs to be reversed because of persistent diarrhoea or recurrent abdominal pain.

Extracorporeal removal of cholesterol

In view of their success in homozygotes, plasma exchange and LDL apheresis have also been used to treat heterozygotes. The results of such an approach have been assessed by a meta-analysis of data from six trials of LDL apheresis and two diet-controlled drug trials conducted in patients with heterozygous familial hypercholesterolaemia (39). Reductions in LDL cholesterol on diet, drugs, and on apheresis (usually plus drugs) averaged 7.5%, 35%, and 53%, respectively. The corresponding proportion of patients showing regression/no change in lesions within 2 years on quantitative coronary angiography was 54%, 67%, and 82%. These findings suggest that LDL apheresis is just as effective as drug therapy in arresting progression of coronary disease and should be considered as a therapeutic option in patients who cannot tolerate or are unresponsive to drug therapy.

Effect of treatment on outcome

There have been no randomized trials of the effects of treatment on clinical endpoints, but a survey of over 3300 British heterozygotes suggested that coronary heart disease mortality has markedly decreased since 1992, probably reflecting the widespread use of statins during the past 15 years (40). The reduction in coronary deaths was greater for primary prevention than for secondary prevention (–48% vs –25%) and was more marked in women than in men. These findings were amplified by those from a study of more than 2000 Dutch patients treated with statins, which showed a 76% reduction in the risk of coronary heart disease in the context of primary prevention (41). As a result, the risk of coronary disease in these statin-treated patients with familial hypercholesterolaemia was no greater than that of the population at large. Future advances in lipid-lowering drug therapy, reviewed by Stein (42), may result in even better control of this disorder in the years ahead.

Summary

Familial hypercholesterolaemia affects 1:500 of the population of much of the world and provides a unique model for the causal role of LDL cholesterol in human atherosclerosis. The disorder is usually due to monogenically inherited mutations of the LDL receptor, a large number of which have been described. Homozygotes manifest extreme hypercholesterolaemia from birth and cardiovascular involvement by puberty, with a particular predilection to develop atheroma of the aortic root and valve. Early treatment of homozygotes is essential to prevent the onset of aortic stenosis, a frequent and potentially fatal complication. LDL cholesterol is elevated to a lesser extent in heterozygotes in whom premature coronary artery disease is common but aortic stenosis rare. LDL-lowering therapy can lead to regression of atheromatous lesions in heterozygotes and a decreased incidence of fatal coronary events. Long-term follow-up studies show a marked reduction in the risk of coronary heart disease during the past 15 years, reflecting the increasingly widespread use of statins.

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