08 March 2018

Familial hypercholesterolaemia

This disorder is where high cholesterol is the result of specific genetic defects with a similar pattern.


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 into the liver 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. 

Uncommonly, there is an error in apolipoprotein B that confers poor binding to the LDL receptor. 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:

• Less severely affected (heterozygous form). This happens when the patient carries only one abnormal copy of the gene, having inherited it from only one parent. It is the commoner and less severe form. This pattern is seen with the 3 genes mentioned for the proteins involved in removing LDL: the LDL receptor, apolipoprotein B and PCSK9 that degrades the LDL receptor.

There is a mortality rate of 85% before 60 years of age, almost always from coronary atherosclerosis.  Inheriting the gene results in the high cholesterol in everybody.  In and adult with FH the total cholesterol is usually more than 7.5mmol/L and the LDL cholesterol is more than 5 mmol/L.  

• Severely affected (homozygous form). This occurs when the patient has two abnormal copies of the genes involving cholesterol metabolism. This means an abnormal gene was inherited from each parent. By far the majority of the homozygous form results from parents with heterozygous FH due to the 3 genes mentioned. 

A very small proportion of persons who display the homozygous pattern, are due to extremely rare disorders involving plant sterols or an adaptor protein for the LDLR. In these cases, having one abnormal does not affect the function of LDL removal but having both genes abnormal is serious. The parents in these cases have normal cholesterol values. 

The homozygous pattern is rare but very serious. It is usually noticed in children as they develop deposits of cholesterol in the skin: between the fingers, at the elbows and places with creases of the skin, including the eyelids Heart disease can occur by the teenage years The cholesterol concentration is more than 15mmol/L and the LDL cholesterol more than 13 mmol/L. 

What is the prevalence of FH?

Originally it was estimated that FH occurs in about 1 in 500 people in most populations  but more recent studies in Europe suggest about 1 in 250 are affected. 

In South Africa the condition is more prevalent in communities where the originator(s) of the disease migrated to this country to create a small community in which the gene is then commoner. This phenomenon is 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.

Who gets it?

Although FH is commoner in some communities, it is possible that anyone can inherit this disorder. Hopefully it will be diagnosed early by a cholesterol test (and ideally a confirmation by a genetic test) so that the heart disease can be prevented. 

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. FH is inherited in a dominant fashion, which means that even if your FH gene; you will have the high cholesterol from birth.

There is a 50% chance of a boy or girl inheriting the gene from an affected parent.

Research shows that the average age of the first heart attack for people with FH is 45 years, their ethnic group notwithstanding. When both parents have such a family history or have cholesterol levels suggestive of FH, it is important to test the offspring as soon as possible after birth as the homozygous form may be present.

This is particularly important amongst Afrikaans people where FH s commoner than in other populations. , Children may develop because heart disease by the age of 5 years 


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 at least 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.


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. Recently, alternative treatment has become available that makes treatment of FH even more effective. 

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

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 but it is not entirely clear at what age it should be introduced. Since the medication has proven safe and effective, there is an increasing trend to treat younger persons. 

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 have not been studied as well and may not be as effective.

The combination of a flush inhibitor (laropiprant) with niacin was effective during development studies but was not marketed.

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. The outlook for patients with the homozygous pattern has improved enormously: earlier diagnosis is essential to ensure that the patient benefits from treatment.