Professor Freiberger: "The sooner we start treating high cholesterol, the better. Especially if we have a genetic predisposition to it."
Up to forty thousand Czechs live with a genetic disorder that can shorten their lives by decades. We are talking about familial hypercholesterolaemia, a serious inherited disease that causes a dramatic increase in the level of harmful LDL cholesterol in the blood. The disease occurs in one in two to three hundred people, making it one of the most prevalent genetic metabolic disorders. Without treatment, patients are at risk of a heart attack in their third or fourth decade of life. Although modern medicine can effectively reduce high blood cholesterol levels, most patients are unaware of their diagnosis. The international FH-EARLY project, which also involves Masaryk University's Faculty of Medicine, should bring about a change. Professor Tomas Freiberger, who is also the principal investigator for MU at the National Institute for Metabolic and Cardiovascular Diseases CarDia, has long been working on the genetic basis of the disease. He sees it as his ambition to move the diagnosis of patients at high risk of heart attack to younger age groups so that they can be treated early and live to the same age as those who do not have this genetic burden.
There are countless texts about cholesterol in the media space, often working with terms such as ‘good’ and ‘bad’ cholesterol, and I even noticed recently that it was the subject of a chain e-mail. How big a topic and bogeyman is cholesterol today?
It is a big topic in the professional community. Cholesterol cannot simply be divided into “good” and “bad” cholesterol, because even the so-called “good” HDL cholesterol is controversial and it cannot be clearly stated that it is beneficial to have a lot of it. That is not how it works. It is true, however, that it is the LDL cholesterol, the so-called bad cholesterol, that does the most damage. It can already be said quite clearly, on the basis of many studies and evidence, that it is a proven causal factor in the development of atherosclerosis, which leads to premature heart attacks and death, and that hypolipidaemic treatment works and leads to a reduction in these events. Unfortunately, there is still a certain misunderstanding of the importance of lowering cholesterol in the general public, although we are trying to dispel it within the Czech Atherosclerosis Society, for example, and some time ago we published a booklet called Ten Myths about Statins. Moreover, statins are no longer the only option for lowering cholesterol levels and, with it, the risk of atherosclerotic and ischaemic events. Biological treatments are now available.
You are researching familial hypercholesterolaemia, a genetic disease that causes excessive accumulation of LDL cholesterol in the body, which increases the risk of heart attack many times over at a young age. Around 40 000 people in the Czech Republic have this diagnosis, but most of them do not know about it. Is this underdiagnosis the main reason for the disease's insidiousness?
The problem is that high cholesterol levels do not hurt. So you don't find out about it until you have a heart attack, or until someone measures it and tells you it's high. But even so, people tend to underestimate such information. Cholesterol is then gradually deposited in the walls of blood vessels, leading to the development of so-called atherosclerotic plaques, or fatty deposits, which narrow the arteries and contribute to further damage, which can result in blood clots and blockages. This leads to a heart attack or stroke.
Can you explain what happens in the body when familial hypercholesterolaemia develops?
If we go down to the molecular level, most often there is a defect in the LDL receptor gene. This is found, among other things, on liver cells and its purpose is to pick up LDL cholesterol from the bloodstream. However, if this receptor is defective, cholesterol is not taken up - or not enough - and its level in the blood increases, it is deposited in the walls of blood vessels and the processes described above occur.
Are these processes the same in the case of familial hypercholesterolaemia as when cholesterol levels increase naturally with age or when we contribute to it through poor lifestyle?
In principle, yes. The big difference, however, is that this genetic disposition manifests itself from birth. So from birth we have high LDL cholesterol levels, which increase over the years, and the critical level is exceeded at a much younger age. And, of course, if a person with familial hypercholesterolaemia has a poorer lifestyle on top of that, the effects add up. The bottom line is also that the genetic component is so strong that while in otherwise healthy people cholesterol levels can be lowered by twenty percent or more by changing the lifestyle, in patients with familial hypercholesterolemia it is at most up to ten percent and one cannot do without medication.
“In Europe, about eight children with homozygous familial hypercholesterolaemia have been reported to have died as a result of a heart attack before the age of six since 2010.”
Tomáš Freiberger
How much higher is the risk of early heart attack in patients with familial hypercholesterolaemia compared to the general population?
Familial hypercholesterolaemia affects one person in two hundred and fifty to three hundred, and the risk of heart attack is several times higher in these patients, especially in the age group of twenty to forty years. Later in life, lifestyle factors become more prevalent, so that the difference gradually becomes blurred. However, we are talking about the so-called heterozygous form of the disease, where a person inherits a defective gene from only one parent. When two parents with a given diagnosis meet, the children have a 25 percent chance of inheriting the defective gene from both of them, which is then the so-called homozygous form of the disease, which is much rarer, but also much more severe. Children with this diagnosis can then have a heart attack before the age of ten, and in Europe, since 2010, around eight children with homozygous familial hypercholesterolaemia have been recorded as dying as a result of a heart attack before the age of six.
Four years ago, you were the expert guarantor of the pilot project Early Detection of Familial Hypercholesterolaemia, which aimed to catch the diagnosis in newborns. Can you give us an overview?
Of course, the earlier the diagnosis is detected, the better. When comparing patients with familial hypercholesterolaemia who were treated from around the age of ten with their parents who started treatment in early adulthood, it was found that those treated earlier had a significantly reduced incidence of health complications by the age of forty. Thus, treatment started in childhood has a clear benefit. In addition, if we find a diagnosis in a child through early screening, we also find it in a parent, who also benefits. Because if the parents do not know about their diagnosis and we confirm it later in the children, this additional confirmation may come too late for the parents.
It is reported that globally up to 90% of people with familial hypercholesterolaemia are unaware of their diagnosis, while in the Czech Republic it is 75%. Why is it that we are so much better off?
In our country, the MedPed project (Make early diagnosis to prevent early death) has been running since the end of the 1990s and we have built up a nationwide database of patients whose detection we are among the best in the world. There are about sixty-five centres across the country that have these patients under their care and continue to follow them up. The way it works in practice is that when we find a patient, we offer to screen other family members.
So what stage is the implementation of newborn screening at?
Most patients enter the MedPed project through what is called opportunistic screening, i.e. screening that is done when there is an opportunity. However, we have also enacted what is called selective screening, where children should be screened for cholesterol levels at the age of five and thirteen at a preventive check-up if they have a confirmed family history of their parents or grandparents having suffered a premature heart attack. However, our goal, which is, after all, what the Europe-wide initiatives are aiming for, is the introduction of nationwide screening. The Czech Republic is even the first country to have the implementation of nationwide screening for familial hypercholesterolaemia in its National Cardiovascular Plan, which was recently approved by the government. Our project has shown that cholesterol screening from umbilical cord blood is already effective, so this would be one of the possible ways to implement it, perhaps the most cost-effective one. It would speed up the cascade of testing and in a certain number of years we would get virtually over a generation to the point where everyone would be screened and in the future it would be sufficient to screen only the offspring of existing patients and there would be no further need for full screening. Discussions are currently underway to determine whether such a procedure will be approved and whether cord blood screening will be implemented.
“In a relatively large proportion of patients who meet the clinical criteria for a diagnosis of familial hypercholesterolaemia, a genetic cause is not found, although it seems clear that some genetic factors play a role.”
Tomáš Freiberger
Fifteen European institutions are involved in the current FH-EARLY project. How will your institution participate in it?
The project has several objectives. We will be involved in the search for new mechanisms and possibly new genes responsible for the disease. A relatively large proportion of patients who meet the clinical criteria for a diagnosis of familial hypercholesterolaemia are not found to have a genetic cause, although it seems clear that some genetic factors play a role. We will therefore investigate them more closely and perform more detailed genetic tests in these patients. And we will also look for factors responsible for a worse or better course of the disease, because it happens that patients who have the same genetic mutation have different courses, even within the same family. Some people have a heart attack in their thirties, others live to be sixty-five without being affected by this type of complication.
One of your proclaimed outcomes of the project is the establishment of a so-called genetic risk score. How should it work in practice?
If we can delve deeper into the genetic basis of disease, we can better determine the individual risk for each patient, which is a step towards personalised medicine and better targeting of treatment and regimens. In fact, in addition to the so-called “big effect genes”, or the main ones in which we know that a defect leads to disease, there are a number of other genes and various relatively common gene variants, each of which may contribute to a small extent to, for example, higher LDL cholesterol levels or other complications. And when these variants come together, the polygenic risk - or the risk from multiple variants in so-called small effect genes - can rise to the level of the monogenic risk from a large effect gene defect. Not to mention that both of these types of risk can occur simultaneously. We will therefore try to find a composition of these other gene variants that most accurately determines the polygenic risk and thus the genetic risk score for each patient.
How can the announced artificial intelligence be applied in research?
This will be the main focus of colleagues from the Netherlands. We would like to make use of an international database of patients from centres in the Czech Republic, Portugal, France and Turkey, which have hundreds of patients in their registries. We will collect as much clinical and genetic data as possible and we will have information on the lipid levels of these patients, what complications they have and at what age. With the help of artificial intelligence, we would then like to find some patterns and ways to use this knowledge specifically to predict individual risk.
If the diagnosis is made early - and it may not be just familial hypercholesterolaemia, but high LDL cholesterol in general - what are the treatment options and how effective can they be?
The doctor should look at the patient holistically and take into account all of his or her risk factors. However, LDL cholesterol is one of the key ones and lowering it is essential. Generally speaking, the more we can lower it, the better off we are; however, different target levels are recommended for different categories of patients. There are already plenty of ways to achieve them and thus substantially reduce the risk of atherosclerosis-related complications, from statins to the aforementioned biological treatments. But if we are talking about patients with high cholesterol in general, lifestyle management is of course essential. That should be the basis. That is: be physically active, eat a rational diet and, above all, do not smoke! If we get this right, we can say that at least our condition will not get worse. However, if we manage to lower our cholesterol levels to target levels, it has been shown that the atherosclerotic plaques that have already formed will gradually start to shrink again.
