• 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 dietary/lifestyle factors. The condition itself causes no symptoms, and may thus go undetected until organ damage occurs. For this reason, screening and regular follow-up testing is recommended, especially for persons with known associated risk factors.

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  Diagnosis is easy by means of a blood test done after an overnight fast.
• Treatment always begins with diet and lifestyle modification, and medication may need to be added if the response is inadequate.
• The outcome of treatment, with good patient compliance, is generally good.
• Prevention of the devastating complications of hypercholesterolaemia is possible through early diagnosis and aggressive treatment. In the case of genetic or familial hypercholesterolaemia, prevention of the condition and its complications may be more difficult.
• Because of the silent nature of the condition, even those persons with no risk factors should be screened at regular intervals. Anyone with known risk factors should see their doctor for testing. These persons will most likely be more aggressively treated, and at an earlier stage. Patients with established vascular disease, e.g. peripheral vascular disease, coronary heart disease or stroke, must also be tested as treatment can significantly delay the progression of the disorder.

What is hypercholesterolaemia?

Cholesterol is derived from two main sources:

• It is manufactured in the liver from the fats contained in the food we eat.
• Cholesterol from the bile used in digestion is reabsorbed and recycled to the liver for re-use.

Cholesterol travels in the blood attached to a protein along with other lipids (triglycerides and phospholipids). These cholesterol-protein packages, called lipoproteins, can be divided into two major types, depending on their composition. The more protein, 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 is 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 package is unstable, and, if present in high amounts, tends to deposit the cholesterol part into body tissues.

The most commonly affected tissue for this is the wall of arteries, where the deposits of cholesterol form clumps, called plaques. The plaque can become large enough to protrude towards the inside of the artery, obstructing the blood flow, and thus reducing the blood supply to the organ normally fed by that artery.

In addition, the tip of the bulging plaque can rupture, which causes a clot to form on top of the plaque. This plaque-and-clot combination may be enough to partially or totally block off the artery. 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 is 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

Genetics – High cholesterol levels may be caused by an inherited (genetic) problem that changes the way the body handles cholesterol (lipid disorders). 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, a person's total cholesterol will usually be well over 6.5 mmol/L.

These lipid disorders may be more difficult to treat. In these persons, even with a diet of only average fat intake, there will be elevated blood cholesterol levels, simply because their body is "programmed" to manufacture more cholesterol than normal.

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 fat eaten is much more important, because this is the building block used by the liver to make cholesterol. Fats are classified as saturated or unsaturated according to their chemical structure.

Saturated fats are derived primarily from meat and 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, e.g. the vegetable oils used to make margarine in block form. This process converts unsaturated fats into the trans form, which has adverse effects on the 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, thereby, one’s risk for heart disease. There are three main types of risk factors:

1. Uncontrollable

• Inherited genetic factors. These affect fat metabolism and cholesterol production.
• Age. Cholesterol levels tend to rise somewhat with age, especially in post-menopausal females.
• Gender. Males generally have higher levels compared to females of the same age.

2. Partly controllable

3. Controllable

• 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 then cause further changes in cholesterol levels and profile.
• Smoking. This can significantly lower HDL (up to 15% according to some sources).

How is it diagnosed?

1. Symptoms

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 a person has 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 have CAD for several years without having any symptoms.

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

Yellowish deposits of cholesterol in the eyelids are also frequently seen with moderate elevations of cholesterol. However, a white area on the cornea of the eye is more specific to severe inherited disorders.

2. Measuring blood levels

There are different ways of obtaining a value for total cholesterol, e.g. full screening or fingerprick tests (as offered at some pharmacies).

However, there is only one test used as the gold standard, which is sufficiently accurate and reliable for diagnosis and treatment plans: the fasting full lipogram. This is a blood test done by a pathologist, which gives accurate measurements of the total cholesterol, as well as the levels of LDL, HDL and triglycerides. The laboratory also computes the risk ratio for cardiovascular disease for the patient, based on these readings.

Several points are important to know here:

1. The patient must have fasted for at least 6 hours (preferably overnight) before the blood sample is taken. The blood sample measures the circulating total cholesterol (TC) and fats present in the blood at that time: if the blood is taken too soon after a meal, then the test will measure the patient's own levels PLUS the TC and fat content of the meal just eaten. It thus gives no idea of how the body handles fats and cholesterol under "baseline" conditions, which is the important time. As much of cholesterol production is thought to occur at night, this "baseline" measurement is very important.
2. While the TC value is important, it is meaningless without knowing the values of the subtypes LDL and HDL. The TC value may be "normal", but if the reading is composed of all LDL, and not enough protective HDL, then the patient is at high risk for heart attack and/or stroke. If s/he is under the impression that the reading is normal, then s/he may not receive the necessary treatment to prevent these disasters.
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, a person with a strong family history of heart disease or who has another risk factor such as hypertension or diabetes will be a candidate for early intervention at a TC level below that for a person who does not have these other risk factors.
5. Measurement of Lp(a) and homocysteine may be relevant (see below).

Who and when to test
Most experts agree that persons over the age of twenty who have no risk factors should have cholesterol tests every five years.

Persons who should have cholesterol tests at least once a year include:

• Men over the age of 35
• Women over the age of 45, or who are menopausal
• Anyone – including children – with a family history of heart disease
• 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 persons already on treatment for HC. Those with familial HC may need additional testing for specific lipid disorders.

Know the numbers
The accepted normal, or ideal, values are:

• Total cholesterol: <5mmol/l
• LDL: <3mmol/l
• HDL: >1mmol/l
• Triglycerides: <1.7mmol/l
• Risk ratio (TC/HDL): >4 = moderate risk, >5 = high risk

The values obtained from a blood test are used as guidelines for treatment, and follow-up testing is used to monitor progress. However, it is important to note that these normal values are for persons without other risk factors.

If a person has known risk factors, e.g. diabetes, or normal TC but very high Lp(a) levels, then treatment would be considered despite a normal TC. Also, for these persons, treatment might be started at a TC value somewhat lower than normal to reduce the risk of cardiovascular complication.

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 thus an indication for early treatment. (While treating raised TC will not lower levels of Lp(a), it will lower the overall risk of CVD in that patient.)

Lp(a) levels by themselves are not a good predictor 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 varies 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΅mol/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 of 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 plays a causal role in CVD. In several large studies, treatment which lowered homocysteine levels made no difference to the incidence of CVD events (e.g. heart attack, stroke) or to the number of CVD deaths.

Treatment/management

1. The first step is to "know your numbers".
2. Next, identify any underlying conditions or risk factors which may contribute to the HC.
3. Based on this, choose a target level of TC appropriate to that patient.
4. Decide on a treatment plan.

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

Treatment plans

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

• 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, by lowering LDL and raising HDL.
• 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 HC, cholesterol production is closely linked to fat intake and metabolism. Just by controlling intake, especially of fat, TC can be lowered by 10-20%. The Prudent Diet advised here includes:
  • Eating enough kilojoules to reach and maintain your correct body weight = BMI 20-25.
  • Eating 55% or more of your total kilojoules (kJ) as complex carbohydrates.
  • Eating 12-15% of total kJ as protein.
  • Eating generous amounts of fresh fruits, vegetables, grains, cereals, poultry, fish, lean meats and low-fat dairy products.
  • Limiting total daily fat consumption to 30% or less of total kJ.
  • Eating less than 200mg 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.

[Also read our article on the Top 10 foods to control cholesterol.]

Medical interventions
These include:

• Identifying and treating known contributory conditions, e.g. diabetes, hypertension, thyroid disorders.
• Medical treatment to lower TC or its components.

As cholesterol is derived from two sources, there are two basic approaches to lowering TC: one approach is to limit the amount that the body manufactures, and the other interrupts the recycling of used cholesterol. The best results are obtained when these two approaches are combined.

Drugs limiting the production of cholesterol

1. Statins
The statins are a group of drugs which interfere with the production of cholesterol in the liver, thereby lowering the blood levels. They are the most commonly used and most potent anti-cholesterol drugs, with TC reductions possible between 20 and 60%.

The effects of statins are additive to those of a controlled diet. Adverse reactions, such as muscle cramps, occur in a minority of patients. Statins work by inhibiting the enzymes needed to produce cholesterol.

For patients with severe HC, 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. How they work has not been definitely established, but there is some indication that they increase the breakdown of some types of cholesterol and triglycerides, and at the same time help prevent further production of both.

Examples of fibrates are bezafibrate and gemfibrozil.

3. Nicotinic acid
This is one of the B group of vitamins. It can help to normalise cholesterol levels when given in adequate doses. Its use, however, is often limited by its unpleasant side effects, such as severe flushing. Nicotinamide in high doses can limit the production of some types of LDL.

Drugs interrupting the recycling of cholesterol

1. Bile acid sequestrants
The best known of these is cholestyramine. This acts by binding to bile in the gut, preventing reabsorption. The liver is thus stimulated to produce new bile. As 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 (interferes with absorption of fat-soluble vitamins).

2. Ezetimibe
This drug prevents the reabsorption of cholesterol by the small intestine, thus lowering the total amount of cholesterol by interrupting the recycling process. The result is an increased clearance of cholesterol from the blood, a decrease in TC, LDL-cholesterol (LDL-C), ApoB and triglycerides (TG), and an increase in HDL-cholesterol.

Side effects may include headache, but most patients tolerate the drug well.

At present, ezetimibe plus low-dose rosuvastatin, is the most effective drug combination, giving a drastic and quick reduction in cholesterol, especially LDL.

A trial is currently underway to confirm this in practice, and measure the actual benefits obtained. Results are expected to be made public around March 2008.

CAUTION:
All of these medications must be used with care and under strict medical supervision. They can all potentially cause abnormalities in liver function, thus blood tests of liver function should be done before starting these drugs, and regular monitoring of liver function thereafter is necessary. There are also known drug interactions which can affect the results and side effects, e.g. when used with warfarin, certain herbs, combined with other anti-cholesterol medication, and in pregnancy.

Outcome

Patients with familial genetic HC will need individually tailored treatment plans and are best managed by 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, please see your doctor for a full fasting lipogram. 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. Any person with known risk factors for CVD, such as hypertension or diabetes, should have a fasting lipogram.

Reviewed by Dr A.G. Hall (B.Soc.Sc.(SW), MB,Ch.B)
Last updated: 2008/01/11
 

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