Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an inherited disorder that markedly increases the “bad” LDL cholesterol in the blood. In most cases, it causes deposits of cholesterol in the tendons and 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.

Most people with FH have mutations of the gene that encodes the LDL receptor. This 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’s an error in apolipoprotein B that confers poor binding to the LDL receptor. And 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 South Africans.

There are two forms of FH:

• The heterozygous form (less severe). This occurs when a person carries only one abnormal copy of the gene, having inherited it from only one parent. It’s the commoner and less severe form. It comes with a mortality rate of 85% before 60 years of age – almost always from coronary atherosclerosis. Inheriting the gene results in high cholesterol in everybody who has it. In and adult with FH, the total cholesterol is usually more than 7.5mmol/L, and the LDL cholesterol more than 5mmol/L.
  
• The homozygous form (severe). This occurs when a person has two abnormal copies of the genes involving cholesterol metabolism. This means an abnormal gene was inherited from each parent. In the vast majority of cases, the homozygous form results from parents with heterozygous FH.

A very small proportion of people’s FH arises from mutations in the gene encoding an adaptor protein involved in the internalisation of the LDLR gene (the gene that provides instructions for making low-density lipoprotein receptor, LDLR).

Having one abnormal gene doesn’t affect the function of LDL removal, but having two abnormal genes is serious. In these instances, the parents have normal cholesterol values.

It’s usually noticed in children as they develop deposits of cholesterol in the skin: between the fingers, at the elbows and in places with creases of the skin, including the eyelids. Heart disease can occur by the teenage years. The cholesterol concentration is usually more than 15mmol/L, and the LDL cholesterol more than 13mmol/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 that about 1 in 250 people are affected.

In South Africa, the condition is more prevalent in communities where the originator(s) of the disease migrated to in previous centuries. 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 people who form part of South Africa’s Lithuanian Jewish and Gujarati Indian communities. The incidence in the indigenous African population isn’t known, but is estimated at about one in 500.

Although FH occurs more commonly in some communities, it’s possible that anyone can inherit this disorder. The best scenario is that it’s diagnosed early with the help of a cholesterol test and confirmed by a genetic test, so that steps can be taken to prevent heart disease.

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, and there’s 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 a family history, or have cholesterol levels suggestive of FH, it’s important to test children as soon as possible after birth as the homozygous form may be present. This is particularly important among Afrikaans people, where FH is quite common. Children may develop heart disease by the age of 5 years.

How is FH diagnosed?

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

• An LDL cholesterol count of more than 5mmol/L
• Xanthomata (yellow deposits) in tendons
• 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 level of more than 5mmol/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.

How is familial hypercholesterolaemia treated?

Basic management consists of lifestyle interventions and medication to prevent the complications of atherosclerosis.

Over the past two decades, effective and safe medication has become available to treat FH. The result has been a dramatic decrease in risk for most people who have this disorder.

In rare instances, special treatments such as plasmapheresis (where blood plasma is removed from the body, separated into plasma and cells, and the cells are placed back into the bloodstream) may be required in unusual situations, for instance when a person with FH doesn’t respond well to other treatments.

There’s hope that this disorder may be corrected by gene treatment in future. In the meantime, the following treatment is followed:

1. Lifestyle
We know that lifestyle is important in the management of FH because, on average, Japanese people with the condition live 10 years longer than Europeans with the same diagnosis. The Japanese low-fat diet, with its emphasis on seafood, could be the reason why this population develops coronary artery 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. In fact, the entire family should strive to keep their saturated and trans fat intake in check. Avoid processed foods, eat lean cuts of meat, and try to eat fresh, wholesome meals made from scratch.

Other lifestyle habits include:

• Keeping an eye on your kilojoule intake so that you maintain your ideal body weight.
• Exercising regularly.
• Not smoking at all and avoiding passive smoking.

2. Medication: statins
There’s no doubt that medication can decrease the risk of a heart attack dramatically if you have FH.

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. The time at which this should be introduced isn’t clear, but the safety of the medication has resulted in it being prescribed in children who come from families associated with very-early-onset heart disease.

If your targeted low density lipoprotein (LDL) concentration isn’t achieved by statins alone, you may have to take additional drugs with different mechanisms of action. Your doctor may prescribe ezetimibe, a drug that’s convenient to use and which significantly lowers LDL cholesterol by lowering cholesterol absorption.

The B vitamin niacin lowers LDL and has favourable effects on “good” high-density lipoprotein (HDL), triglycerides and Lp(a), but may not be easy to take because it has flushing as a side effect. Flush-free preparations are available without prescription, but there’s little scientific information about them.

Fibrates are other drugs that could be useful if there’s 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 people with heterozygous, and in almost all cases of homozygous FH, plasmapheresis is required to achieve control. If you inherit the FH gene from one parent, you have heterozygous FH. If both of your parents have FH, and you inherit the FH gene from each of them, you have homozygous FH.

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. Recently, drugs have been developed that work more effectively in people with severe FH, but they’re not yet available and will likely be costly. These newer treatments are under investigation at specialised centres in South Africa.

Reviewed by Prof David Marais, FCP(SA), Head of Lipidology at Groote Schuur Hospital and the University of Cape Town. January 2018.