Incidence
High serum cholesterol levels are common in adults in much of Europe, the USA, Australia and New Zealand. In the UK, for example, 25-30% of middle-aged individuals have levels exceeding 6.5 mmol/L (250 mg/dL), while the equivalent proportion in the USA is at least 10%.

Familial hypercholesterolaemia
For a review of familial hypercholesterolaemia see references [Durrington, 1995a; Goldstein, 1995].

Heterozygous familial hypercholesterolaemia

What is the incidence?
Familial hypercholesterolaemia is dominantly inherited. The heterozygous form of the condition affects about one in 500 people in Europe and the USA, making it the most common genetic disorder in these countries. In some populations (eg, Lebanese Christians, Afrikaners and Cape-coloured peoples of South Africa and French Canadians) it is considerably more common. This is because such people have descended from a relatively small number of early settlers, a few of whom, by chance, had familial hypercholesterolaemia. This is known as a founder effect. In other populations, such as Africans who have not intermingled with Europeans, familial hypercholesterolaemia is rare.

What is the lipoprotein phenotype?
Typically, the serum cholesterol in adult heterozygotes is 9-12 mmol/L (350-450 mg/dL). The condition is expressed regardless of diet or age, and elevated cholesterol levels are already present in cord blood and throughout childhood. The lipoprotein phenotype is usually IIa, but occasionally there is a moderate increase in fasting serum triglycerides to produce a IIb pattern. There is a tendency for HDL-C to be at the lower end of the range, particularly if triglycerides are elevated.

Features of familial hypercholesterolaemia

Tendon xanthomata The clinical hallmark of familial hypercholesterolaemia is the presence of tendon xanthomata. These appear in heterozygotes from the age of 20 years onwards. The most common sites for tendon xanthomata are in the tendons overlying the knuckles and in the Achilles tendons (see Figure 6). Less commonly, they may also be found in other tendons. It is also common to find subperiosteal xanthomata on the upper tibia where the patellar tendon inserts. The skin overlying tendon xanthomata is of normal colour and they do not appear yellow. The cholesteryl ester deposits are deep within the tendons. Tendon xanthomata feel hard because they are fibrotic. Indeed, it is not uncommon for those in the Achilles tendons to become inflamed from time to time, sometimes presenting as chronic Achilles tenosynovitis. More generalised tendinitis may follow rapid therapeutic reductions in serum cholesterol levels. Other occurrences of tendon xanthomata Tendon xanthomata occur in only two disorders apart from familial hypercholesterolaemia and these are so rare as not to pose any diagnostic difficulty. The conditions are cerebrotendinous xanthomatosis, in which plasma cholestanol is elevated and deposited in tendons, and phytosterolaemia (beta-sitosterolaemia), in which there is abnormal intestinal absorption of plant sterols, which are then deposited in tendons. Corneal arcus Corneal arcus is also a frequent occurrence in familial hypercholesterolaemia. When it occurs in adolescence or early adulthood, it is more likely to be associated with familial hypercholesterolaemia than when the condition occurs in middle age or later. It is, however, not uncommon to encounter patients with familial hypercholesterolaemia who have florid tendon xanthomata, but no arcus. It is, therefore, not a very valuable physical sign. Xanthelasmata palpebrarum Xanthelasmata palpebrarum, although occurring with greater frequency and at a younger age in familial hypercholesterolaemia affect only a minority of heterozygous individuals and: are not specific for any particular type of hypercholesterolaemia; occur in polygenic hypercholesterolaemia, pregnancy, primary biliary cirrhosis and hypothyroidism; are common in middle-aged women, often overweight, with no very marked increase in serum cholesterol, if any; and may run in families, apparently independently of hypercholesterolaemia.

Figure 6. Types of xanthoma in familial hypercholesterolaemia

Identification of patients
Identifying familial hypercholesterolaemia heterozygotes as early as possible is important, because of their risk of CHD. Over 50% of affected men die before the age of 60 years if untreated. It is not uncommon for men to have their first myocardial infarction or develop angina in their thirties (occasionally even earlier). Some 15% of women with familial hypercholesterolaemia die of CHD before the age of 60 years, and the majority have symptomatic coronary disease by that age. Some evidence of cardiac ischaemia may be seen in perhaps as many as 10% of women before their menopause. However, whereas it is exceptional for a man with familial hypercholesterolaemia to live to 70 years of age without symptomatic CHD, almost 25% of women do so.

 

Why are not all patients detected?

The above accounts largely for the reason why a family history of premature CHD is absent in as many as 25% of patients discovered to have familial hypercholesterolaemia on screening, or in men who are discovered to have familial hypercholesterolaemia when they present with a heart attack in early life. The latter occurs because the condition has been inherited from their mother, who has not yet developed coronary symptoms. Most people with familial hypercholesterolaemia are not overweight and do not have risk factors for CHD, such as obesity, hypertension, diabetes or a history of smoking, other than hypercholesterolaemia and a family history of premature coronary disease. Those without a family history of premature CHD (approximately 25%) will be missed in screening programmes for risk factors for CHD, in which cholesterol is only measured selectively.

CHD risk calculations
Methods of CHD risk calculation based on epidemiological studies (which do not include significant numbers of people with familial hypercholesterolaemia) will underestimate risk [Bhatnagar, 2000] (see later). Thus, screening for high cholesterol in the relatives of patients with known familial hypercholesterolaemia is important if new cases are to be detected [Durrington, 2001].

Early development of CHD
Those patients with familial hypercholesterolaemia who develop CHD particularly early, often come from families in which the affected members have also developed the condition early. This may be because other genetic factors in the family predispose to CHD. Thus, low serum HDL-C and increased fasting triglycerides are associated with a worse prognosis. Serum Lp(a) is increased in familial hypercholesterolaemia and any familial tendency to run a high level of Lp(a) is exacerbated in those members who also have familial hypercholesterolaemia. The apo E4 genotype is also associated with more aggressive atheroma in familial hypercholesterolaemia. A knowledge of the average age at which affected members of a family developed CHD may be helpful in planning how actively to treat boys and young adult women.

Occurrence of atheroma
There is an increased risk of atheroma in other parts of the arterial tree in heterozygous familial hypercholesterolaemia, but this is strikingly less so than in the coronary arteries. Some heterozygotes have aortic systolic cardiac murmurs caused by deposits of atheroma in the aortic root, sometimes involving the aortic cusps.

What is the incidence?
Most cases of homozygous familial hypercholesterolaemia occur in societies in which consanguineous marriages and heterozygous familial hypercholesterolaemia are frequent. The chance of marriage between unrelated heterozygotes, meeting by chance in countries such as the UK or the USA is one in 500², and each of their children would stand a one in four chance of being homozygotes. Assuming no adverse effect on the survival of the conceptus, an incidence of homozygous familial hypercholesterolaemia of one in 10⁶ births would be predicted. It is, thus, a rare condition under these circumstances.

What is the lipoprotein phenotype?
Serum cholesterol is typically greater than 15 mmol/L (600 mg/dL).

 

Features of homozygous familial hypercholesterolaemia

Cutaneous xanthomata Clinically, homozygous familial hypercholesterolaemia is characterised by the development of cutaneous xanthomata in childhood. Cutaneous xanthomata may be present in the first year of life or may not develop until later childhood. They are typically orange-yellow, subcutaneous, planar xanthomata, occurring on the buttocks, antecubital fossae and the hands, frequently in the webs between the fingers (see Figure 6c). Tuberose subcutaneous xanthomata on the knees, elbows and knuckles are also a feature.

Clinical course of the disease
Myocardial infarction and angina frequently occur in childhood, sometimes even in infancy. Atheromatous deposits at the aortic root, invariably present by puberty, are so marked as to produce significant aortic stenosis, which contributes to the risk of sudden death. Death before the age of 30 years, and often considerably younger, was the rule before the advent of plasmapheresis and similar techniques for the extracorporeal removal of LDL.

Polyarthritis
Polyarthritis, predominantly affecting the ankles, knees, wrists and proximal interphalangeal joints is common in homozygotes for familial hypercholesterolaemia.

Decreased catabolism of LDL
In familial hypercholesterolaemia decreased catabolism of LDL means that it remains for longer in the circulation. Normally the plasma half-life of LDL is between two-and-a-half and three days, whereas in familial hypercholesterolaemia heterozygotes it is between four-and-a-half and five days (and even longer in homozygotes).

What causes the defect?
The molecular defect that causes this has been elucidated following the discovery of the LDL receptor (see above) by Goldstein and Brown in 1973, for which they received the Nobel Prize for Medicine in 1985. The gene encoding the LDL receptor is located on chromosome 19. Heterozygotes express only about half the quantity of LDL receptors that a person without familial hypercholesterolaemia expresses, while homozygotes have between none and 25% of normal receptor activity.

What are the effects of mutations?
Mutations in the LDL receptor gene have two general effects. They either:

• produce receptors with no binding activity (receptor negative), which causes problems because the receptor is not synthesised, is not transported to the cell surface, or, if it gets there, cannot be internalised after binding to LDL; or
• produce receptors with an abnormal binding site (receptor defective), which allows some LDL to be bound and to enter the cell, but this occurs only slowly because of the abnormal binding.

CHD mortality
Table 2 gives estimates of the extent to which different levels of cholesterol contribute to the overall cumulative male mortality from CHD by the age of 60 years, and shows that the majority of such premature deaths come from the mid range of cholesterol distribution. It has been argued that if a significant reduction in the incidence of CHD is to be achieved in countries such as the UK, efforts to lower cholesterol cannot simply be confined to those individuals whose plasma cholesterol lies at the upper end of the distribution.

Table 2. Estimates of UK mortality from CHD in men

How can the incidence be decreased?
Nevertheless, because the number of people with values in the mid range is so huge (the vast majority of whom are not at increased risk of premature CHD), a different strategy from that applied to those in the upper part of the cholesterol distribution must be applied to reducing their cholesterol. This is the 'low-risk' or 'population' strategy, which aims to lower serum cholesterol by public health measures directed at encouraging the adoption of a lower fat diet and the avoidance of obesity.

Who will develop CHD?
Some patients from the mid range of cholesterol are, however, at much greater individual risk from their cholesterol level than the majority, because they have other risk factors for CHD, which combine to increase their susceptibility. Probably the most potent of these is that the individual already has CHD. In middle-aged people with existing CHD, serum cholesterol is an important indicator of cardiac prognosis (see Figure 7) [Pekkanen, 1990], which ranks after left ventricular function, but ahead of most of the other risk factors for CHD. Lipoproteins are also the most important risk factors for occlusion of coronary artery bypass grafts after the initial postoperative period. In people, who have not yet developed CHD, the effect of risk factors, such as cigarette smoking, hypertension and diabetes, is also to increase the risk from any given level of cholesterol (see Figure 4). A family history of CHD at an early age in a first-degree relative also increases the likelihood of CHD, and part of this effect is independent of other risk factors.

 

When is intervention appropriate?

The combination of all of these factors, with a relatively modestly increased serum cholesterol level, can increase individual risk substantially to a level where clinical intervention is as justified, as it is with more marked elevations in serum cholesterol. This is the 'high-risk' or 'clinical' approach to prevention of CHD.

Figure 7. Age-adjusted deaths from CHD

Measuring CHD risk
The equations derived from the results of the Framingham study permit an assessment of CHD and stroke risk, and can assist clinical judgement in assessing the likelihood that a patient can benefit from antihypertensive or lipid-lowering therapy. These equations are reproduced in the Cardiac Risk Assessor Programme of the Joint British Societies (available from the British Heart Foundation and on the websites of the British Hypertension Society and the British National Formulary and in the recent American Treatment Panel third report (ATP III). Several attempts have been made to portray these risk equations as charts, tables or scoring systems [Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001; British Cardiac Society, 2000; Wood, 1998]. In one study, the Joint British Coronary Risk Charts (see Figure 8) [British Cardiac Society, 1998] were the closest to the original equation [Jones, 2001].

Figure 8a. CHD risk prediction charts: no diabetes

Figure 8b. CHD risk prediction charts: diabetes

Metabolic defect in polygenic hypercholesterolaemia
In polygenic hypercholesterolaemia, there is generally overproduction of VLDL by the liver. If this is converted rapidly to LDL, there is no increase in serum triglyceride levels. The LDL-receptor mechanism is probably overloaded in many individuals, and in any case, appears to catabolise only about one-third of LDL. The build-up of cholesterol in most patients is, therefore, not caused by any defect in the LDL receptor, but to the inability of non-receptor-mediated catabolism to cope without a rise in the serum cholesterol concentration.

What are the factors that affect polygenic hypercholesterolaemia?
Obesity and a high-fat diet (particularly one high in saturated fat) are probably the major reasons for the enormous differences in the prevalence of polygenic hypercholesterolaemia in different parts of the world. Undoubtedly, however, individual responses to diet vary tremendously, and there is probably a complex interplay between dietetic and genetic factors in the genesis of polygenic hypercholesterolaemia. The rise in cholesterol with age, which occurs in both men before and women after the climacteric, seems less evident in societies where the cholesterol level is, for dietetic reasons, lower.

Dietary modification
There is an impression that dietary modification, aimed at lowering cholesterol in middle age in societies where serum cholesterol is high, does not reduce it to the extent that might be anticipated from populations habitually consuming such a diet. Whether this is simply a matter of non-compliance with diet or represents some permanent change in metabolism caused by a high-fat diet in early life, is at present uncertain.