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Updated 31 July 2014

Hypercholesterolaemia

High cholesterol, or hypercholesterolaemia, is a condition in which the amount of cholesterol in the blood exceeds normal values. This may be due to genetic or lifestyle factors.

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Summary

  • High cholesterol, or hypercholesterolaemia, is a condition in which the amount of cholesterol in the blood exceeds normal values. This may be due to genetic disorders, dietary/lifestyle factors or another disease (such as kidney disease). The condition itself causes no symptoms and may therefore go undetected until organ damage occurs. For this reason, screening and regular follow-up testing is recommended, especially for people with known associated risk factors.
  • Diagnosis is easy by means of a blood test, performed after an overnight fast.
  • Treatment always begins with diet and lifestyle modification, and medication may be added if you don’t react adequately to lifestyle changes.
  • If you stick to a healthy lifestyle and take your medicine regularly, your outcome will generally be good.
  • Prevention of the devastating complications of hypercholesterolaemia is possible through early diagnosis and aggressive treatment. In the case of inherited disorders such as familial hypercholesterolaemia (FH), complete control and prevention of complications may be more difficult.
  • Because of the silent nature of the condition, even people with no risk factors should be screened. Anyone with known risk factors should see their doctor for testing. They will probably be more aggressively treated, and at an earlier stage. If you have established vascular disease – such as peripheral vascular disease, coronary heart disease or stroke – you should also be tested, as treatment can significantly delay the progression of the disorder.

What is hypercholesterolaemia?

Cholesterol is a fatty substance which is essential to the human body. It forms part of the lining membrane of every cell, is the basic substance used for the production of hormones (e.g. oestrogen and testosterone) and is used in the production of bile for digestion.

Cholesterol is derived from two main sources.

It is manufactured in the liver of all humans and animals. It is therefore present in our own bodies as well as in foods derived from animals.

  • Cholesterol from the bile used in digestion is reabsorbed and recycled to the liver for re-use.

Cholesterol travels in the blood attached to proteins. These cholesterol-protein packages, called lipoproteins, can be divided into two major types, depending on their composition. The more protein they contain, the higher the density.

  • High-density lipoprotein (HDL) cholesterol – lipoproteins with more protein than fat
  • Low-density lipoprotein (LDL) cholesterol – lipoproteins with more fat than protein

LDL is the “bad” cholesterol. It consists of mostly fat and about a quarter is protein. LDL carries cholesterol from the liver to other parts of the body where it is needed for cell repair and other activities. This lipoprotein tends to deposit its cholesterol part into artery walls and other body tissues such as tendons.

Cholesterol deposited into the walls of arteries form oily collections called plaques. The plaques seldom become thick enough to protrude towards the inside of the artery, but they can tear, forming clots. This could impair or stop the blood supply, so that tissue or an organ could malfunction temporarily or permanently.

If this happens in the arteries of the heart, a partial blockage can cause angina, and a total blockage can cause a heart attack, which can be fatal. Problems in the arteries of the brain can cause a stroke, and problems in the leg arteries can cause gangrene.

HDL is the “good” cholesterol. It consists of mostly protein with only a small amount of fat. HDL cholesterol helps clear cholesterol from the body by picking up leftover cholesterol from cells and carrying it back to the liver for disposal.

Low levels of HDL cholesterol increase the risk of coronary artery disease (CAD) and other forms of atherosclerotic disease. High levels of HDL cholesterol appear to help protect against heart disease.

Abnormally high levels of cholesterol in the blood are associated with an increased risk of atherosclerosis (hardening of the arteries), coronary heart disease (leading to angina and heart attacks) and stroke.

Although high cholesterol is an important risk factor for these conditions, it is only one of many contributory factors. Other risk factors such as smoking, high blood pressure, obesity, diabetes and a family history of vascular disease may be as, or even more, important than your cholesterol level.

Causes and risk factors

Hereditary factors, diseases of organs and diet each have a significant influence on cholesterol levels.

Genetics – High cholesterol levels may be caused by an inherited (genetic) problem that changes the way the body handles cholesterol. Your genes can give you cells that don’t remove LDL cholesterol from your blood efficiently, or a liver that produces too much cholesterol. In such cases, your total cholesterol will usually be well over 6.5 mmol/L.

These conditions are called lipid disorders and they may be more difficult to treat. Even if your fat intake is only average, you will have elevated cholesterol simply because your body has been “programmed” to balance cholesterol differently.

Diet – Diets high in cholesterol and saturated fats can increase blood cholesterol levels. While consuming cholesterol will clearly add to the total present in the body, the amount of saturated fat eaten is also important, because this regulates how the liver to makes cholesterol. Fats are classified as saturated or unsaturated according to their chemical structure.

Saturated fats are derived primarily from the meat of mammals and from dairy products and can markedly raise blood cholesterol levels. Some vegetable oils made from coconut, palm and cocoa are also high in saturated fats.

On the other hand, most other vegetable oils are high in unsaturated fats. These, consumed in the recommended amounts, do not raise blood cholesterol and can sometimes lower it. Olive and canola oils are high in monounsaturated fats, which may protect against coronary heart disease by virtue of their resistance to oxidation.

It is important to note that some "good" vegetable fats are treated by a process called hydrogenation to make them harder at room temperature and more commercially viable, for instance the vegetable oils used to make margarine in block form. This process converts unsaturated fats into the trans form, which has adverse effects on one’s cholesterol profile.

Because raised cholesterol (hypercholesterolaemia or HC) is such an important risk factor in heart disease, it is important to note the various risk factors, which can influence cholesterol levels and one’s risk for heart disease. There are three main risk factor types:

1. Uncontrollable

  • Inherited genetic factors. These affect fat metabolism and cholesterol production, but their impact is still modified by diet and medication.
  • Age. Cholesterol levels tend to rise somewhat with age, especially in post-menopausal women.
  • Gender. Men generally have higher levels compared with women of the same age.

2. Partly controllable

This refers to underlying medical conditions known to influence cholesterol levels, such as thyroid disease, obesity and diabetes. Improved control of these conditions will normalise cholesterol levels and so reduce the risk of heart disease.

3. Controllable

These include factors known to influence cholesterol levels and which can easily be changed:

  • Dietary habits. Too much fat (especially animal or saturated/trans fats) and too little fibre in the diet can raise levels of LDL and make blood more prone to clot.
  • Exercise. This can help raise levels of the protective HDL.
  • Overweight. This lowers the protective HDL and may raise levels of the harmful LDL. It also promotes the development of hypertension and diabetes, which can cause further changes in cholesterol levels and profile.
  • Smoking. This can significantly lower HDL (up to 15%, according to some sources).

How is hypercholesterolaemia diagnosed?

Before discussing how to treat the condition and handle the risk factors, it is essential to know whether or not you have raised cholesterol levels and, if so, to what extent, and what type of hypercholesterolaemia (HC) you have.

1. Symptoms

The commonest symptom of high cholesterol is no symptoms at all. The vast majority of people with high cholesterol are therefore unaware of their condition until they suffer a heart attack, stroke or gangrene. Although HC itself rarely causes symptoms, its complications can be devastating.

High cholesterol may be detected during a routine blood test that measures cholesterol levels.

Conditions that may result from cholesterol (such as CAD and stroke) may be the first clue that you have high cholesterol.

The first symptom of CAD is often angina (chest pain). Angina usually occurs during activities that raise the heart rate, such as walking uphill. However, many people suffer from CAD for several years without having any symptoms.

Unless you have a transient ischaemic attack (temporary interference with blood supply to the brain), it is rare to have any warning signs of an oncoming stroke.

In people with several of the genetic causes of high cholesterol, other distinct features may be present and helpful in making a diagnosis. In people with familial hypercholesterolaemia (FH) deposits of cholesterol may collect in tendons, skin or eye tissue. Most commonly, cholesterol accumulates in the Achilles tendon and sometimes the tendons of the hands.

Yellowish deposits of cholesterol in the eyelids, termed xanthelasma, are also sometimes seen with moderate elevations of cholesterol. However, a white line or arc on the cornea of the eye is more specific to severe inherited disorders in young adults.

2. Measuring blood levels

There is only one way to find out if your blood lipids are within normal range: you must have them measured. It is important to know not only what your total cholesterol value is, but also how that value is made up. That’s because while the total reading is important, the readings of subtypes such as LDL and HDL cholesterol are also important, because each type has its own influence on your overall risk profile.

You can have your cholesterol checked via full screening or finger-prick tests, as offered at some pharmacies.

However, there is only one test sufficiently accurate and reliable for diagnosis and treatment plans: the fasting full lipogram. This is a blood test performed by a pathologist that provides accurate measurements of your total cholesterol, as well as the levels of LDL, HDL and triglycerides. Based on these readings, the laboratory also computes your risk ratio for cardiovascular disease.

Several issues are of importance here:

  1. You must fast for at least six hours (preferably overnight) before the blood sample is taken. The blood sample measures the circulating total cholesterol (TC) and other lipids (fats) such as triglycerides and lipoproteins present in your blood at that time. If the blood is taken too soon after a meal, the test will measure your own levels as well as the fat content of the meal just eaten. It therefore gives little idea of how the body handles fats and cholesterol. This "baseline" condition is especially important when LDL cholesterol is calculated and not directly measured.
  2. While the TC value is important, it is more meaningful to know your LDL and HDL cholesterol. The TC value may be "normal", but if the reading is composed almost entirely of LDL, and not enough protective HDL, then you are at higher risk for heart attack and/or stroke than what your TC suggests. If you are under the impression that the reading is normal, you may not receive the treatment necessary to prevent a disaster.
  3. There are international standards of what is regarded as a normal reading and a high reading requiring action.
  4. Interventions such as lifestyle changes and/or medication will not only be based on blood readings. For example, if you have a strong family history of heart disease or another risk factor such as hypertension or diabetes, you’ll be a candidate for early intervention at a TC level below that of someone who does not have other risk factors.
  5. Measurement of Lp(a) and homocysteine may be relevant (see below).

Who and when to test
Most experts agree that everyone older than twenty years and without risk factors should have cholesterol tests at least once and then probably every five years.

People who could benefit from cholesterol tests at least once a year include:

  • Men over the age of 35 years
  • Women over the age of 45, or who are menopausal
  • Anyone – including children – with risk factors for heart disease (e.g. hypertension or diabetes)

More frequent testing may be required to monitor the progress of those already on treatment for HC. Those with familial hypercholesterolaemia may need additional testing for specific lipid disorders. 

Know the numbers
Here are values accepted as normal or ideal:

  • Total cholesterol: lower than 5 mmol/L
  • LDL: lower than 3 mmol/L when there is no manifest arterial disease and lower than 2.5 mmol/L when arterial disease is present
  • HDL: higher than 1 mmol/L
  • Triglycerides: lower than 1.7 mmol/L
  • Risk ratio (TC/HDL): higher than 4 constitutes moderate risk, higher than 5 constitutes high risk

The values obtained from a blood test are used as guidelines for treatment, and follow-up testing is used to monitor progress.

If you have known risk factors such as diabetes, or a normal TC but very high Lp(a) levels (see below), then treatment would be considered despite a normal TC. You would also probably start receiving treatment even if your TC is lower than normal, just to make sure the risk of cardiovascular complications is reduced.

Lp(a) is a modified form of LDL and is considered a genetically determined marker for a high risk of cardiovascular disease (CVD) – the higher the blood level, the greater the risk – and therefore an indication for early treatment. While treating raised TC will not lower levels of Lp(a), it will lower your overall risk of CVD.

Lp(a) levels by themselves are not good predictors of CVD risk, but there is a strong association if raised Lp(a) occurs together with raised TC, and even more so if the HDL (the protective cholesterol) is too low. The blood levels of what is considered normal also vary widely according to population groups. Diet has little effect on Lp(a).

Homocysteine is an amino acid present in all of us: normal values are 5-15 µmol/L. Excessively high levels are found in a rare genetic disorder, but moderately raised levels are present in up to 7% of the population of the USA. Raised levels are associated with:

  • Cigarette smoking
  • Chronic kidney failure
  • Deficiency of vitamin B12 or folic acid
  • An occasional side effect of fibrates or nicotinic acid used in the treatment of hypercholesterolaemia

There is evidence that raised homocysteine levels are implicated in recurrent venous thrombosis, but there is no agreement among experts that homocysteine helps cause CVD. In several large studies, treatment which lowered homocysteine levels made no difference to the incidence of CVD events (e.g. heart attack or stroke) or to the number of CVD deaths.

Treatment and management

  1. The first step is to have your cholesterol checked so you "know your numbers".
  2. Next, your doctor should identify any underlying conditions or risk factors which may contribute to a high cholesterol count.
  3. Based on this, the doctor will choose a target total cholesterol level appropriate to you.
  4. You and your doctor can then decide on a treatment plan.

The point at which treatment becomes necessary will depend on the presence of associated risk factors as explained above.

Treatment plans

The aim of treatment is to lower your cholesterol levels and so minimise your risk of serious CVD and organ damage, which could be permanent (think heart attack, stroke or sudden death). Very high-risk patients (those with genetic disorders, manifest vascular disease or diabetes) will need treatment with medication regardless of other considerations. Those who have been identified as high risk by calculating their risk from multiple risk factors also need treatment. In most cases, you will be considered high risk if you have a higher than 20% risk of a heart attack, or a higher than 5% risk of death within 10 years.

Non-medical interventions
These include dealing with known risk factors and can consist of:

  • Smoking cessation. Smoking is an independent major risk factor for CHD, cerebrovascular disease and total atherosclerotic cardiovascular disease.
  • Exercising more. This normalises the composition of the TC, raising HDL, lowering triglycerides and possibly lowering LDL; improves body mass and lessens the risk of diabetes.
  • Losing weight. Obesity is associated with a number of risk factors for atherosclerosis, cardiovascular disease and cardiovascular mortality. These include hypertension, insulin resistance and glucose intolerance, hypertriglyceridaemia and reduced HDL-cholesterol.
  • Eating correctly (quantity and quality). Except for the inherited genetic forms of hypercholesterolaemia, cholesterol production is closely linked to fat intake and metabolism. Just by controlling intake, especially of fat, your total cholesterol can be lowered by 10-20%. The prudent diet advised here includes:
    • Eating enough kilojoules to reach and maintain your correct body weight, which is a BMI of 20-25 kg/m2.
    • Eating 55% or more of your total kilojoules (kJ) as complex carbohydrates.
    • Eating 12-15% of your total kilojoules as protein.
    • Eating generous amounts of fresh fruits, vegetables, grains, cereals, poultry, fish, lean meats and low-fat dairy products.
    • Limiting your total daily fat consumption to 30% or less of your total kilojoule intake.
    • Consuming less than 200 mg cholesterol daily.
  • Taking supplements. Omega-3 oils, soy, sterol-enriched margarines, some forms of fibre, garlic, nuts, green tea and calcium have individually been shown to have a small LDL-lowering effect, especially when combined with diet modification and the use of statins.

Medical interventions
These include:

  • Identifying and treating known contributory conditions, such as diabetes, hypertension, thyroid disorders, kidney disease and several others.
  • Medical treatment to lower your total cholesterol or its components.

As cholesterol is derived from two sources, there are two basic approaches to lowering total cholesterol: limiting the amount the body manufactures, and interrupting the recycling of used cholesterol. The best results are obtained when these two approaches are combined. 

Drugs that limit the production of cholesterol

1. Statins
The statins are a group of drugs which interfere with the production of cholesterol in the liver, in the process lowering the level of cholesterol in your blood. They are the most commonly used and most potent anti-cholesterol drugs, and can reduce your total cholesterol by 20 to 60%. They work by inhibiting one of the enzymes needed to produce cholesterol.

The effects of statins add to those of a controlled diet. Adverse reactions, such as muscle pain, occur in a minority of patients.

For patients with severe hypercholesterolaemia, statins alone may not be enough – even at high doses, which increase the risk of side effects. For every doubling of the dose of a statin, there is only a further 6% reduction in cholesterol. In such cases, the addition of a different type of medication is advised.

Examples of statins include pravastatin, simvastatin, atorvastatin and rosuvastatin. 

2. Fibrates
This group of drugs act mainly to lower triglycerides and may help to raise HDL. They act on several genes to alter the metabolism of lipids in many tissues. This includes lowering the export of triglyceride from the liver and raising the production of HDL.

Examples of fibrates are bezafibrate, gemfibrozil and fenofibrate.

3. Nicotinic acid
This is one of the B group of vitamins. It can help normalise cholesterol levels when given in very large doses. Its use, however, is often limited by its unpleasant side effects, such as severe flushing. Some more recent products claim to be flush-free and although there is anecdotal experience that this is the case, it has not been validated in published studies yet.

Nicotinamide is a different chemical form but is ineffective.

Drugs that interrupt the recycling of cholesterol

1. Bile acid sequestrants
The best known of these is cholestyramine. It binds to bile acids in the gut and so prevents reabsorption. As a result, the liver is stimulated into producing new bile. Because cholesterol is used in the production of bile, the total amount in circulation is gradually reduced.

Side effects are common and include abdominal discomfort and possible vitamin deficiencies, as it interferes with the absorption of fat-soluble vitamins.

2. Ezetimibe
This drug prevents the reabsorption of cholesterol by the small intestine and so the cholesterol recycling process. As a result there’s an increased clearance of cholesterol from the blood and a decrease in total cholesterol, LDL-cholesterol, ApoB (a low-density lipoprotein) and triglycerides.

Side effects are uncommon; most patients tolerate the drug well.

At present, ezetimibe plus a statin is the most effective drug combination to drastically lower LDL cholesterol, 

Caution
All of these medications must be used with care and under medical supervision. They can all potentially cause abnormalities in liver function, so liver function should be tested before the drugs are started and should afterwards be regularly monitored if necessary.

There are also known drug interactions which can affect the results and side effects of cholesterol drugs, such as when they’re used with warfarin, certain herbs and other anti-cholesterol medication. Cholesterol drugs should not be used in pregnancy.

Outcome

All patients with hypercholesterolaemia will benefit from lowering their total cholesterol, by whatever means. Regardless of the drugs used, permanent lifestyle changes remain necessary. If old habits are resumed, the risk of CVD will not be fully lowered.

Patients with familial or genetic HC will need individually tailored treatment plans and are best managed at a specialised lipid clinic. Treating these patients may be very difficult, and many of them may suffer heart attacks at an early age despite the best of treatments.

When to see your doctor

  1. If you have a family history of cholesterol problems or cardiovascular disease, regardless of your age, you have to see your doctor to have a full fasting lipogram done. You may have no symptoms at all and still have raised cholesterol levels, which can be treated before it causes permanent problems.
  2. If you have any symptoms such as angina or leg claudication (pain when walking, which subsides when you stop walking), consult your doctor for testing.
  3. Anyone with known risk factors for CVD, such as hypertension or diabetes, should have a fasting lipogram test performed.

Reviewed by Dr A.G. Hall (B.Soc.Sc.(SW), MB,Ch.B)
January 2008.

Updated by Prof David Marais, head of the Lipid Clinic at Groote Schuur Hospital and head of lipodology at the faculty of health sciences of the University of Cape Town, September 2010.

 
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