Doc Talk

High cholesterol from a genetic disorder

FH affects the way the liver clears cholesterol from the blood; it occurs in 1 in 500 people

When Andrew (not his real name) discovered he had high cholesterol several years ago, at the age of 38, he dismissed it.

Some time later, his older brother, who had high cholesterol but did not take his medication regularly, suffered a mild stroke.

His four sisters are also on medications for high cholesterol.

His mother, too, had a stroke several years back, when she found out she had a very high cholesterol level of more than 500 mg/dl. The normal rate is 200mg/dl.

That was when Andrew realised he had to take his condition seriously. He started going for regular check-ups and now takes his medication regularly. His cholesterol readings are now near healthy levels.

Recently, Andrew's 26-year-old nephew and 27-year-old niece came for cholesterol screening and were found to have high cholesterol levels of more than 300 mg/dl.

Andrew's family is not afflicted with the typical garden variety type of high cholesterol. What the members have is familial hypercholesterolaemia (FH), a genetic disorder that affects the way the liver clears cholesterol from the blood.

It is estimated to occur at a frequency of 1 in 500 people. Individuals with this condition have high cholesterol because they lack LDL (bad) cholesterol receptors which are needed to mop up cholesterol from the blood. They are at high risk of heart attacks.


The link between high cholesterol and heart disease is no longer a hypothesis but proven by many studies anchored by established academic institutions.

Yet, there are still many untruths circulating on the Internet that challenge this relationship.

Statins, which are drugs that lower cholesterol, have been conclusively proven to be effective and safe. However, many patients choose to believe the myths about the dangers of statin treatment.

The Prosper study, a large study done in the United Kingdom, has proven that statin use does not prevent nor does it cause dementia.

Statin use is associated with a slight increase in the risk of getting diabetes but there is no evidence that it causes kidney failure.

Statins, which are the most frequently used drugs for lowering cholesterol, work by inhibiting an important step in the synthesis of cholesterol. This reduces the cholesterol in the body.

Another class of drugs known as Ezetimibe disrupts the re-absorption of cholesterol secreted in the bile acids from the intestines, complementing the action of the statins.

Only 20 per cent of our blood cholesterol comes from the food we eat. The remaining 80 per cent is produced predominantly by the liver and a smaller proportion by the intestines.

The liver takes the sugar, fats and protein we eat to create cholesterol, which is needed for hormone production, aids in digestion and is an important structural component of cells in our body.

Our level of blood cholesterol is regulated by LDL receptors found in cells throughout the body but mainly in the liver, whose main function is to facilitate the transfer of cholesterol into cells throughout the body. Excess cholesterol is transported by LDL receptors to the liver for recycling or excretion from the gut via the bile acids.

The magnitude of cholesterol reduction with statins is dependent on the availability of LDL receptors.

Those with FH have insufficient LDL receptors and thus a poorer response to statins.

It is not possible to determine the number of LDL receptors in FH individuals. But in those with a severe form, called homozygote FH, the LDL receptors can be almost non-existent.

Such patients can have high cholesterol levels even from the time they are infants. Some may even have extremely high levels exceeding 800 mg/dl.

Most patients with homozygote FH will die from coronary heart disease by their 20s if their condition is not treated aggressively.


Recently, a new class of cholesterol lowering drug known as PCSK 9 inhibitors became available.

The drug reduces the breakdown of LDL receptors in the liver and thus increases the number of LDL receptors available to mop up cholesterol from the circulation.

It is given via injection once every two weeks but it is not meant for every single person with high cholesterol.

There are two PCSK 9 inhibitors available in Singapore. Most individuals with high cholesterol that is not due to FH would be able to attain their cholesterol targets with statins alone or in combination with Ezetimibe.

However, for those with FH, many of whom are already on high dosages of statins with Ezetimibe, the use of PCSK 9 inhibitors will reduce cholesterol levels substantially and thus lower their chances of heart attacks.

Another group who can benefit from PCSK 9 inhibitors is those who cannot tolerate the side effects of statins, such as abnormal liver function.

Individuals with FH are unlikely to reduce their cholesterol levels adequately just by dietary measures alone.

Also, men with untreated FH are likely to get heart attacks by the time they are in their fourth decade while women with FH may suffer heart attacks when they are between 50 and 60 years of age.

Aggressive reduction of cholesterol is mandatory regardless of any other risk factors the patient may have.

That is also why screening of families with FH is vital in picking up individuals affected early and for intervention to be initiated.

•Dr Tan Chee Eng is a consultant endocrinologist at Gleneagles Medical Centre.

A version of this article appeared in the print edition of The Straits Times on December 05, 2017, with the headline 'High cholesterol from a genetic disorder'. Print Edition | Subscribe