Your Health A-Z

Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an inherited genetic condition that results in markedly elevated low-density lipoprotein cholesterol levels, beginning at birth.


FH is an inherited disorder that markedly increases the “bad” LDL cholesterol in the blood and, in most cases, causes deposits of cholesterol in tendons and causes premature heart disease.

People have suffered from FH for thousands of years – in fact, FH may even have been responsible for the premature death of Leonardo da Vinci’s famous Mona Lisa (in real life Madonna Lisa Maria de Gherardini) at the age of 37 years.

What causes FH?

Most people with FH have mutations of the gene which encodes the LDL receptor. The receptor removes LDL from the blood by binding with apolipoprotein B, a component of LDL. Since 1973, when problems with the LDL receptor were first identified as a cause of FH, more than 1 000 mutations have been found in the LDL receptor, and other genes have also been implicated.

A very rare other cause of FH is excessive digestion of the LDL receptor by a protein called PCSK9.

Both these causes have been identified in SA patients.

There are two forms of FH:

  • Severely affected (homozygous). This occurs when the patient has two abnormal copies of the gene, having inherited an abnormal gene from each parent. This form is rare and has more prominent deposits of cholesterol at a younger age. Heart disease can occur by the teenage years.
  • Less severely affected (heterozygous). This happens when the patient carries only one abnormal copy of the gene, having inherited it from only one parent. It is the common and less severe form. There is a mortality rate of 85% before 60 years of age, almost always from coronary atherosclerosis.

What is the prevalence of FH?

FH occurs in about 1 in 500 people in most populations studied.

In South Africa the condition is more prevalent in communities where the originator(s) of the disease joined a small community, a phenomenon known as the “founder effect”. FH occurs in about one in 75 people in the white Afrikaans-speaking community and in about one in 100 in South Africa’s Lithuanian Jewish and Gujarati Indian communities. The incidence in the indigenous African population is not known, but is estimated at about one in 500.

The more severe homozygous form is found mainly in white Afrikaans speakers, where it may occur in one in 40 000 births. The estimate for the number of heterozygous FH patients is about 150 000, whereas the number of homozygotes is estimated at about 200.

The course and symptoms of FH

In people with FH, the blood cholesterol concentration is raised from birth. Arteries may be harmed during childhood and adolescence, but atherosclerosis usually causes heart attacks in men in their forties and women in their fifties.

In adults with the less severe form of FH, LDL levels usually range between 5 and 12 mmol/L.

In patients with the severe form of FH, LDL exceeds 15 mmol/L.

The symptoms and complications take time to develop. Untreated, about 10% of FH patients develop Achilles tendon pain in their teens. Arcus cornealis, a fine white line of cholesterol deposited in the cornea of the eyes, is common in younger people with FH. Nodules forming in the tendon are called tendon xanthomata and also develop in young adulthood to middle age.

Xanthelasma is a deposit of fat in the skin of the eyelids with a yellowish colour. While it is found more commonly in FH than in normal people, it is not a reliable indicator of a significant cholesterol problem. Nevertheless, when present, cholesterol should be tested.

The homozygous form of FH may be overlooked in children, because cholesterol deposits under the skin and in the tendons may not be recognised.

Angina, which could interfere with play or sport, is also not expected in young people and is therefore easily missed.

Who gets it?

Everyone with a family history of heart disease before the age of 55 years should be considered to have an inherited hyperlipidaemia such as FH.

Children are also at risk. Research shows that the average age of the first heart attack for people with FH is 45 years, their ethnic group notwithstanding. But among Afrikaans people, children tend to also be affected and researchers are concerned because kids as young as six and seven have had to undergo heart bypass surgery as a result of the condition.

FH is inherited in a dominant fashion, which means that even if you inherit only one FH gene, you will be born with FH. There is a 50% chance of a boy or girl inheriting the gene from an affected parent.


The diagnosis of FH is certain when the following three criteria are met:

(1) An LDL cholesterol count of more than 5 mmol/L

(2) Xanthomata in tendons

(3) A personal or family history of heart disease before the age of 55 years in men

     or 65 years in women

If you have an LDL of more than 5 mmol/L and meet one of the other two criteria, “probable FH” is diagnosed. Because one in 500 South Africans has FH, the condition should be diagnosed at primary healthcare level. Young adults should have at least one cholesterol test done. If you test positive, your family should also be tested.

 A diagnosis can often be made clinically with routine laboratory measurements.

Blood tests. The gold standard for determining the nature of an error in lipoprotein metabolism remains the fasting lipogram, measuring the total cholesterol, LDL cholesterol, HDL (“good”) cholesterol and triglyceride levels. An LDL cholesterol concentration higher than 5 mmol/L in adults could point to FH. In children, the concentration may be lower so the doctor will compare a child’s result with that of siblings, to ensure the higher count is not the result of diet or caused by other genes.

Genetic testing. The results of genetic testing don’t influence the management of heterozygous FH. Because a large number of different inherited errors can cause FH, genetic testing of the actual error is impractical, unless the problem has already been identified in the family, or if the patient comes from a population with a few known defects. However, a genetic diagnosis is useful in unusual circumstances, such as a concern that the patient may suffer from the more severe form of FH, homozygous FH. Timeous testing for homozygous FH has improved the outlook of patients enormously.

Other tests. Additional tests may assist in the management of FH. When the condition is first considered, the doctor will test for thyroid and kidney function, as their disorders may affect cholesterol concentration. An electrocardiograph (EGC) is useful for later comparison when the patient may develop heart disease. If heart complaints need clarification, intensive cardiologic investigation is needed. Before medication is prescribed, it is useful to do liver and muscle function tests.

An ultrasound examination will accurately measure the thickness of the artery wall of the carotid artery in the neck, which reflects the state of other arteries in the body. This can be used to monitor progression or regression of atherosclerosis and may help the doctor decide on treatment of children and young adults.

Another risk factor that modifies the heart disease risk in FH is lipoprotein(a) (Lp(a)), which is also strongly inherited and does not respond to medication, with the exception of nicotinic acid (niacin).


Basic management consists of lifestyle interventions and medication. Special treatments such as plasmapheresis may be required in unusual situations, for instance when FH patients don’t respond well to other treatments.

1. Lifestyle

We know that lifestyle is important in the management of FH because Japanese FH patients on average live 10 years longer than their European counterparts with the same diagnosis. The Japanese low-fat diet with its emphasis on marine products could be the reason why the Japanese develop coronary disease at a later stage.

Lifestyle management is advised for pregnant and nursing women and for children from the time solid foods are first introduced. The whole family should follow this eating plan.

Other lifestyle habits to follow:

  • keep an eye on kilojoules so that you maintain your ideal body weight
  • exercise regularly
  • you should not smoke at all and should also avoid passive smoking
  • In small amounts, alcohol is not unhealthy.

2. Medication: statins

There is no doubt that medication can decrease the risk of a heart attack dramatically. Statins don’t cure FH but in combination with lifestyle interventions, they powerfully reduce the risk of heart disease, the main cause of death in FH. Within a decade of introducing statins in Britain, vascular events in people with FH decreased by 75%. Medication is required for everyone with FH.

In the absence of detailed studies of timing and intensity of cholesterol treatment, the following are regarded as the minimal requirements in treatment:

  • statins which have a short duration of action are normally taken in the evenings for best results as the bulk of the manufacturing of cholesterol in the body occurs at night
  • atorva and rosuvastatin are long-acting statins that may be taken any time of the day
  • all adult men over 25 years should be treated
  • in women the use of statins could be delayed until the family is complete. This is because of the later onset of cardiovascular-disease complications and the possibility of pregnancy. Treatment can also be stopped for planned pregnancies.
  • the aim is to achieve an LDL cholesterol concentration of less than 3 mmol/L in all FH patients, and even lower in patients who have suffered vascular events.
  • the treatment of children has not been fully researched. Previously it was thought not to be necessary to place heterozygous FH children on statins, but studies have shown that statins are safe for them to take and lower their cholesterol. Boys and girls at a much higher risk than average should therefore probably be treated. The doctor will make the decision to treat children with statins, based on multiple risk factors. It is best to have these decisions made by specialists at specialised centres such as lipid clinics.
  • all other risk factors such as blood pressure and diabetes should also be treated.

If your targeted LDL concentration is not achieved by statins alone, you may have to take additional drugs with different mechanisms of action. Your doctor may prescribe ezetimibe, a drug that is convenient to use and significantly lowers LDL cholesterol by lowering cholesterol absorption.

Cholestyramine, a powder that’s not absorbed, is less convenient but also significantly reduces LDL cholesterol. It wastes bile acids so that cholesterol has to be used to replace these losses.

The B vitamin niacin lowers LDL and has favourable effects on HDL, triglycerides and Lp(a), but may not be easy to take because it has flushing as a side effect. Flush-free preparations should be available in South Africa soon. A recent development is the combination of a flush inhibitor (laropiprant) with niacin.

Fibrates are other drugs that could be useful if there is an additional problem with high triglycerides or low HDL, but they don’t have a powerful effect on LDL. 

3. Plasmapheresis

In a small proportion of heterozygous FH patients and in almost all cases of homozygous FH, plasmapheresis is required to achieve control.

Plasmapheresis is an expensive procedure, requiring a special machine and nursing staff to cleanse the blood of cholesterol over about four hours. The cholesterol concentration decreases dramatically but rebounds over the next fortnight, so that repeat procedures are required every 14 days. Plasmapheresis is life-saving but is available to only a few South African patients. Newer treatments are under investigation at specialised centres in South Africa.

Compiled with the help of and reviewed by Prof David Marais, head of the Lipid Clinic at Groote Schuur Hospital and the University of Cape Town, September 2010.

The information provided in this article was correct at the time of publishing. At Mediclinic we endeavour to provide our patients and readers with accurate and reliable information, which is why we continually review and update our content. However, due to the dynamic nature of clinical information and medicine, some information may from time to time become outdated prior to revision.