Familial hypercholestrolaemia

We learn more about familial hypercholestrolaemia (FH) (inherited high cholesterol).

What is FH?

It is one of the most common inherited diseases worldwide, affecting a total of about 10 million people. The disease causes a very high blood cholesterol concentration which in most cases will result in relatively unimpressive physical changes. It imparts a very high risk of heart disease in middle adulthood.

How serious is FH?

Severe hypercholesterlaemia is taken as a cholesterol concentration of more than 7,5mmol/L in adults. Though, in children more than 5,5mmol/L should alert one to the possibility of FH.

It is usually accepted that the age of more than 55 years brings about a high risk of heart disease. But in FH, the average age of death from heart attack is between 40 and 50 years in men and about 10 years later in women. The heart attacks may sometimes occur during the decade from 20 to 30 years of age but in some lucky individuals this may be much later. The variation in outcome is poorly understood although the usual risk factors, such as smoking, clearly play a role.

Experience in South Africa indicates that the average age of death, heart attack, onset of angina or bypass operation is about 45 years.

Since more than 85% of people with FH will get heart disease before the age of 60 years, and because survivors beyond 60 years still have a much higher risk than their peers, the disease must be taken seriously at all ages.

How common is FH?

It is sufficiently common to prompt every person to ascertain whether he or she has or has not inherited it. It has been found in 1 out of 500 unrelated persons in most populations studied.

In some populations that were founded by migration and isolation, the frequency may be higher. The best-known example of this founder effect is in the Afrikaner population of South Africa. Though this country also has a higher prevalence of FH in Jews, and Indians from Gujurat. On average about 1 in 100 people in these communities will have FH.

Why should people with FH be identified?

Diagnosis of FH is imperative as the risk of heart disease is so high. Furthermore, the onset of heart disease is usually much younger than expected. The most convincing reason for identifying this condition is that there is now very effective treatment available.

Does a person with FH have visible signs of it?

Most adults with FH will display some sign of it but often the signs are not noticed. There are usually no complaints until heart disease sets in, but in a small number of subjects there may be pain in the Achilles tendons. The Achilles tendon is thick (wider than 10mm) and irregular in most adults with FH. A nodule of the tendon is called a xanthoma.

Another but less common sign is a white arc on the cornea of the eye, typically on the bottom. This is due to cholesterol deposition but these may be apparent in older persons for other reasons.

Premature heart disease in a person or family member should also trigger the suspicion of FH. This is especially likely if heart attack, angina or death occurs before the age of 55 to 60 years.

Why is the blood cholesterol so high in FH?

There are several particles (lipoproteins) carrying cholesterol in the blood. The particle called low-density lipoprotein (LDL) carries the bulk of the blood cholesterol. LDL serves as a store of cholesterol in the blood and is removed by a special protein called LDL-receptor.

The LDL-receptor imports LDL into organs that needs cholesterol: the liver being the most active, as it requires cholesterol for making bile acids and bile.

The LDL-receptor is defective in FH and, occasionally, the protein (apolipoprotien B) on LDL that should bind the LDL-receptor is defective.

Rarely, the LDL-receptor may be digested by an enzyme (PCSK9) that has become overactive due to an inherited error. The failure to remove LDL effectively in FH results in a high concentration of this lipoprotein in the blood. The concentration can be made higher as a result of eating a fatty diet. A very low-fat diet improves LDL levels and the outcome of the disease, but will never correct the genetic error.

There are now more than 1000 different genetic errors (mutations) known that render the LDL-receptor defective. In the founder populations mentioned, one or a few mutations may account for almost all the FH.

How is FH inherited?

There are two genes for every protein, one coming from the mother and one from the father. FH is inherited by the passing of a LDL-receptor gene with a mutation. The person with one copy of the defective gene (called heterozygote) will display the features of the disease as described.

Because there is a 50% chance of passing on the abnormal gene from a heterozygote parent, about half of the offspring will be affected. The transmission of the genetic defect can best be determined by measuring the cholesterol, or by testing for the gene defect if this is known.

When two heterozygotes for FH have offspring, there is a 1 in 4 chance that a child could inherit both abnormal genes. In this instance, the condition is called heterozygous FH and the impact is far more severe since neither gene makes a functional LDL-receptor. The LDL cholesterol is extremely high and the total cholesterol is usually more than 15mmol/L. Skin and tendon deposits occur in childhood and heart disease may already set in during the teenage years, if treatment is not begun early.

If FH is diagnosed in your family, it is imperative that cholesterol screening is done with all your immediate family to detect other members who are affected. Although the condition is easy to manage it needs to be correctly treated.

How does FH cause heart disease?

The disease process in arteries, called atherosclerosis (plaque build-up inside arteries), progresses slowly and painlessly until the final complicating event, such as a heart attack.

Atherosclerosis is influenced by the gender (males are more susceptible), age, smoking, LDL cholesterol, HDL cholesterol (a lipoprotein that can remove cholesterol and return it to the liver), repair processes and other factors that are yet poorly understood.

In FH, the severely increased LDL concentrations is a powerful driving force for atherosclerosis. The accumulations of cholesterol (in plaques) may cause arteries to function inappropriately and produce angina.

Later, the plaques may rupture and expose the blood to the fatty material. Nature’s way of responding to this breach is to seal it with a clot. Though, such a clot could impair blood flow and cause a heart attack if flow is not restored

It can thus be understood that factors that reduce the extent of clotting can be beneficial: being lean, abstaining from smoking, eating more fatty fish (omega-3 fatty acids) and taking a small dose of aspirin.

What tests should be done to confirm FH?

If you suspect that you or someone in your family has FH, it is best to consult your doctor. The doctor will assess the current status of your health and will examine you for the arcus, and tendon thickening. Having detailed information about family is very useful as well. Other diseases that can influence cholesterol need also to be considered.

The evaluation by the doctor should be followed by some laboratory tests. The most important starting point is a blood test for total cholesterol. Initially, a finger prick screening test is acceptable. If the total cholesterol concentration is undesirably high, then a test describing cholesterol in different lipoproteins should follow. An LDL cholesterol concentration of 5mmol/L and the presence of the Achilles tendon deposits will clinch the diagnosis. The cholesterol tests are also used to judge if treatment is achieving the target (total cholesterol less than 4,5mmol/L or LDL cholesterol less than 2,5mmol/L).

Genetic testing

Research has made it possible to determine the inherited error in the LDL-receptor. In founder populations, a small number of tests on the person’s DNA can identify the presence of specific genetic faults. These tests, however, cannot rule out the presence of other mutations and do not especially influence treatment.

Genetic tests for LDL-receptor mutations are helpful when cholesterol concentrations are on the border between moderate and severe FH, and where other diseases may influence cholesterol concentration. This information may also be useful in deciding whether an unborn child is a homozygote, if the mutations are known in both parents.

How is FH treated?

FH should be treated holistically by controlling all lifestyle risk factors for heart disease from a young age – a healthy lifestyle involving a low-fat diet that emphasises vegetables, fruit, grains and fish, sustaining an ideal body weight, doing regular exercises and avoiding smoking.

The use of plant sterol containing margarines also lowers cholesterol. Lifestyle adjustment is for the whole family as unaffected members will also have better health. However, persons with FH still need drugs to control the high cholesterol concentrations.

  • Drug therapy

Statins are the drugs most commonly prescribed to reduce cholesterol levels. They reduce LDL-cholesterol by blocking a key step in the process of manufacturing cholesterol in the liver.

Your doctor may use other drugs that lower cholesterol by different means if a statin does not work sufficiently. These drugs include:

  • Ezetimibe: a cholesterol absorption inhibitor
  • Fibrates
  • PCSK9-inhibitors (which will hopefully be available in SA soon).

These drugs may be used alone or in combination to achieve the cholesterol goal applicable for you.

  • Compliance

If you suffer from elevated cholesterol and your doctor prescribes a drug, it is important that you take your medication every day over all the years that cholesterol control is desired.

This medication will probably be for life. If you stop taking your medication your cholesterol levels will increase and you will be more at risk of a heart attack, stroke or any other vascular event.

Once on medication, you should have your cholesterol levels checked every six months to make sure your levels are at acceptable goals of your condition.

When should people with FH be treated with drugs?

Conventional risk calculations that are used for the usual members of the population do not apply to people with FH. Owing to the high risk of heart disease, all person with FH will require medication. The decisions about medications needs to be individualised because some factors may place an individual at highest than average risk.

In absence of additional risk factors, men should be treated from the age of 18 and women from the age of 30. In special high-risk settings, treatment may begin earlier than the ages indicated.

It is important to avoid conception and pregnancy while on cholesterol-lowering medication as there is always risk of harming the baby.

The most cost-effective drugs are the statins which should be used in conjunction with other risk reduction strategies.

The information was provided courtesy of LASSA (The Lipid & Atherosclerosis Society of Southern Africa).


Professor Frederick J. Raal (Derick) MBBCh, FRCP, FRCPC, FCP(SA), Cert Endo, MMED, PhD – Director, Carbohydrate & Lipid Metabolism Research Unit; Professor & Head, Division of Endocrinology & Metabolism, University of the Witwatersrand | email: [email protected]

Professor Derick Raal is Professor and Head of the Division of Endocrinology and Metabolism at the University of the Witwatersrand, Johannesburg. After obtaining his MBBCh degree cum laude in 1981, he obtained his Master of Medicine and then his PhD in 2000. Professor Raal has received numerous postgraduate awards including the TH Bothwell Research Prize, the FJ Milne award, and most recently, the University of the Witwatersrand Vice Chancellor’s Research Award. He has authored over 230 original articles and book chapters and has reviewed for several international journals including the New England Journal of Medicineand the Lancet. He is also on the Editorial Board of Atherosclerosis. Professor Raal is particularly interested in lipid disorders, especially familial or inherited hypercholesterolaemia (FH). His Unit has one of the largest cohorts of homozygous FH patients in the world and is involved in research with novel medication for the management of these patients.