What causes high blood cholesterol levels?

What is hypercholesterolaemia?

The term ‘hypercholesterolaemia’ means high blood cholesterol levels. ‘Hyperlipidaemia’ is a less specific term that refers to an increase in one or more blood fat levels. As both cholesterol and triglycerides are fats, hyperlipidaemia could be used to indicate raised blood levels of either.

High blood cholesterol levels are caused by two main types of condition: primary and secondary hypercholesterolaemia:

• Primary hypercholesterolaemia results from inherited genetic abnormalities that lead to increased blood cholesterol levels.
• Secondary hypercholesterolaemia is found when a disease produces high blood cholesterol levels as a complication.

It is important for doctors to make this distinction because it affects the treatment. Primary hypercholesterolaemia may require direct treatment, whereas secondary hypercholesterolaemia usually improves on its own if the underlying disease is treated.

Primary genetic (inherited) causes of hyperlipidaemia

Familial hypercholesterolaemia

The way in which lipids are transported in the blood and taken up by cells is controlled by a number of proteins, two of which, apoB and the low-density lipoprotein (LDL) receptor, were discussed on pages 27–30. A common genetic cause of hypercholesterol­aemia is a defect in the LDL receptors (the ‘locks’ that allow LDL particles to enter cells), which results in familial hypercholesterolaemia.

A single gene controls LDL receptors in our bodies. We inherit one copy of this gene from our mother and one copy from our father, and both of these copies operate.

How common is it?

In the UK, about 1 in 500 people has a fault in one of these genes. In some parts of the world it is more common – for example, one per cent (1 in 100) of the Afrikaner population in South Africa have the condition. There is often a strong family history of early coronary heart disease (CHD) in relatives of patients with familial hypercholesterolaemia, sometimes affecting several generations of the family.

Causes of hypercholesterolaemia

Primary (genetic) hypercholesterolaemia

• Single abnormal gene, for example, familial hypercholesterolaemia
• Minor variations in several genes combined with a high-fat diet (polygenic hypercholesterolaemia)
• Familial combined hyperlipidaemia (raised cholesterol and triglyceride levels)
• Rare genetic disorders

Secondary hypercholesterolaemia

• Diabetes mellitus
• Obesity
• Alcohol abuse
• Hypothyroidism (underactive thyroid gland)
• Liver disease
• Kidney disease
• Drugs, for example, Roaccutane used to treat severe acne, thiazide diuretics used to treat fluid retention or high blood pressure, some beta-blocking drugs used to treat high blood pressure or angina

Why are blood cholesterol levels raised?

People with familial hypercholesterolaemia have only half the usual number of normal LDL receptors. As a result, fewer LDL particles are taken up by body cells, so there are more in the blood than normal. These excess LDL particles, together with the cholesterol that they contain, are taken up by scavenger cells and find their way into the walls of arteries where they build up to produce fatty streaks and atherosclerosis.

The risk of CHD developing in people with familial hypercholesterolaemia is significantly higher than in those without the condition. About 50 per cent of men with this condition will die before the age of 60 years unless their high blood cholesterol levels are treated effectively with cholesterol-lowering drugs, together with dietary and lifestyle changes. But before you can be treated, the condition must be diagnosed.

Diagnosing hypercholesterolaemia

Sometimes there are signs that suggest that hypercholesterolaemia may be present. These include tendon xanthomas, xanthelasmas and corneal arcus.

Tendon xanthomas

These are swellings on the tendons of muscles, typically the Achilles’ heel, on the backs of the hands or on the elbows. They are caused by deposits of cholesterol and strongly suggest that familial hypercholesterolaemia may be present. They may weaken the tendons, which can then snap when they are being strained – for example, during vigorous physical exercise.

Xanthelasmas

These are cholesterol deposits in the skin around the eye.

Corneal arcus

This is a white ring found in the outer part of the cornea of the eye. It can appear as we grow older and, under these circumstances, has little significance. However, it is found at a younger age (in the 30s and 40s) in patients with familial hypercholesterolaemia and may be picked up by an optician during a routine eye test.

Although xanthelasmas and corneal arcus occur with increased frequency in familial hypercholesterolaemia, they also occur in patients with normal blood cholesterol levels and in those with hypercholesterolaemia from other causes. If found, they indicate that the blood cholesterol levels should be measured (see page 60), although these levels will often be normal.

Sometimes there are no clues that familial hypercholesterolaemia may be present before a heart attack occurs.

The diagnosis of familial hypercholesterolaemia depends on a number of criteria (see the box below).

Criteria for the diagnosis of familial hypercholesterolaemia

Definite familial hypercholesterolaemia

• Blood cholesterol level above 6.7 millimoles per litre (mmol/l) in children or 7.5 mmol/l in adults
plus
• Tendon xanthomas in the patient or in a close relative
 

Possible familial hypercholesterolaemia

• Blood cholesterol level above 6.7 mmol/l in children or 7.5 mmol/l in adults
plus
• Family history of a heart attack below the age of 50 in a grandparent, uncle, aunt or cousin, or below the age of 60 years in a parent, brother or sister
or
• Family history of blood cholesterol levels above 7.5 mmol/l in a close relative

Inheriting familial hypercholesterolaemia

If you have familial hypercholesterolaemia, you have a 50:50 chance of passing it on to any children that you may have. This is because each child will hopefully inherit a normal gene from your partner and has a 50 per cent chance of inheriting the abnormal gene from you.

Very rarely, both parents have the condition. As the incidence of familial hypercholesterolaemia is 1 in 500 in the UK, the chances of this happening are 1 in 5002 – that is, 1 in 250,000. In this case, each parent has one normal and one abnormal gene. Therefore, if they have four children the chances are that one child will be normal, two children will have one abnormal gene (and will therefore have the more common form of familial hypercholesterolaemia) and one child will inherit two abnormal genes.

Two abnormal genes cause a much more severe form of familial hypercholesterolaemia than inheriting just one abnormal gene, and CHD is more severe and occurs earlier, often in the early teens.
There is little chance of someone with two abnormal genes reaching middle age without very extensive treatment, such as a type of dialysis treatment (to remove excess fats from the blood) or a liver transplantation to provide normal LDL receptors. It is fortunate that this very severe form of the disease is very rare.

Polygenic hypercholesterolaemia

Polygenic hypercholesterolaemia is more common than familial hypercholesterolaemia, affecting around one in five people. Rather than an abnormality of a single gene, small variations occur in several genes that regulate how the body deals with cholesterol. This results in hypercholesterolaemia if people with the condition eat food that is relatively high in fat, particularly saturated fat – typical behaviour in this country, other northern European countries and the USA.

This type of hypercholesterolaemia usually responds to reducing saturated fat intake, and people with this condition usually show a more satisfactory response to diet and lifestyle changes than those with familial hypercholesterolaemia.

The risk of CHD is increased two- to threefold in polygenic hypercholesterolaemia, although the increased risk is not as high as in familial hypercholesterolaemia. The pattern of inheritance is less clear and there may be no history of early CHD in relatives. Xanthelasmas and premature corneal arcus may occur, but not tendon xanthomas.

Familial combined hyperlipidaemia

When blood levels of both cholesterol and triglycerides are increased it is known as combined hyperlipidaemia or, if it is hereditary, familial combined hyperlipidaemia. Raised blood triglyceride levels may also occur in both polygenic and familial hypercholesterolaemia, but is usually a minor finding in these conditions, increases in triglycerides being modest.

Combined hyperlipidaemia occurs when LDL particles contain some triglyceride, or when the number of very­low-density lipoprotein (VLDL) particles (which contain more triglyceride than LDL) is increased.

In familial combined hyperlipidaemia, the pattern of blood fat levels may vary between family members, or even in the same patient at different times. Thus, both blood cholesterol and triglyceride levels may be raised or just blood cholesterol. The features are similar to those seen in polygenic hypercholesterolaemia.

Other inherited forms of hyperlipidaemia

There are other inherited causes of hyperlipidaemia, some of which affect blood triglyceride levels more than cholesterol, and so hypertriglyceridaemia can be the predominant abnormality.

Secondary hyperlipidaemia

Raised blood cholesterol and/or triglyceride levels may be found in a number of conditions outlined in the box above. The abnormal blood lipids occur as a result of the disease or behaviour, rather than an underlying abnormality in body fats.

Diabetes mellitus

Diabetes mellitus is often thought of as a disease affecting just the way that the body handles glucose. However, disturbances of other body processes are extremely common in diabetes, and hyperlipidaemia is frequently present, particularly in the adult form of the disease (type 2 diabetes mellitus).

The most characteristic lipid changes are high blood triglyceride levels and low levels of cholesterol in HDL particles (HDL-cholesterol). Occasionally, total cholesterol is elevated. Rarely, more significant changes in blood triglyceride levels occur, particularly if diabetes is poorly controlled (see page 106).

The blood lipid levels usually improve with effective management of blood glucose levels, but the risk of CHD and other forms of arterial disease is very high in this condition, being similar to that in patients with existing CHD. For this reason, abnormalities of blood lipid levels are often treated with drugs if they don’t respond to diet and medication to control the diabetes. Many people with type 2 diabetes are overweight, and both the diabetes and blood lipid abnormalities can improve if they lose weight.

Obesity

Two patterns of obesity are recognised, one mostly affecting the shoulders and buttocks (gynaecoid pattern, more common in women), and the other producing an enlarged waist (android pattern, more common in men).

The risk of CHD is doubled in those who are 50 per cent overweight, this increased risk resulting mainly from the android pattern of obesity. The reason is poorly understood but thought to relate to two factors: a greater incidence of high blood pressure and an abnormality in the way that the body handles dietary fats. Abnormalities of blood fats occur in the android pattern, for example, with changes resembling those seen in diabetes mellitus (raised triglyceride and low HDL-cholesterol levels). Blood fats are usually normal in the gynaecoid pattern, and it has a lesser effect on the risk of CHD.

Abnormal blood fat levels respond to weight reduction, similar to the situation in diabetes. However, many obese patients find this very difficult to achieve.

Alcohol abuse

Moderate alcohol intake seems to protect against CHD and has beneficial effects on blood lipids (see page 78). However, excess alcohol intake can lead to large increases in blood lipids, particularly triglycerides, because liver cells stop their normal processing of dietary fats in order to detoxify the alcohol, which is a powerful cell poison.

Very rarely, triglyceride levels may increase by 80 to 100 times. Total cholesterol levels may also be raised (see page 106).

The hyperlipidaemia of excess alcohol intake responds to reduced consumption of alcohol.

Hypothyroidism

Hypercholesterolaemia is common when the thyroid gland is underactive (hypothyroidism), to such an extent that, before reliable measurements of thyroid hormone levels became available, blood cholesterol concentrations were used as a test of how well the thyroid gland was working.

If hypothyroidism is treated with thyroid hormone replacement, abnormal cholesterol levels usually improve, although doctors often check the levels again once the thyroid condition has been controlled. This is because both thyroid problems and hypercholesterolaemia are relatively common and the two conditions are not always related.

Liver and kidney disease

Both liver and kidney (renal) disease can produce abnormal blood fat levels. Hypercholesterolaemia is common if the outflow of bile from the liver is impaired as a result of a blockage in the bile duct. This is because excess cholesterol is removed from the body in the bile.

In some types of renal disease the production of LDL particles is increased, whereas in others the removal of triglycerides from the blood is reduced. These changes may partly explain the increased risk of CHD that occurs in people with kidney failure.

Drugs

Some drugs can raise blood lipids, usually affecting triglycerides more than cholesterol. These increases are often quite high, such as the hypertriglyceridaemia seen occasionally with Roaccutane, a drug used to treat acne.

Interestingly, some drugs used to treat heart disease can also lead to hyperlipidaemia, such as thiazide diuretics (‘water tablets’, also used to treat high blood pressure) and beta-blocking agents (used mainly in the treatment of high blood pressure or angina). This doesn’t mean that the use of these drugs is inappropriate – the benefit may be greater than any increased risk from lipids. An example of this is the use of thiazide diuretics in the treatment of high blood pressure. Such drugs can cause slight increases in blood lipid levels, but the advantage resulting from the lowering of blood pressure, leading to a lower incidence of stroke, outweighs the negative effect on lipids.

KEY POINTS

• Hypercholesterolaemia may be caused by an inherited abnormality

• Raised blood triglyceride levels may accompany hypercholesterolaemia

• Hyperlipidaemia may result from other diseases such as diabetes or an underactive thyroid gland