German Haemapheresis Centre

and

German Apheresis Research Centre

What is cholesterol ?

Cholesterol is a component of the body, which is mainly needed in the central nervous system but is also a component of cell walls. It is partly is supplied via nutrition but it is also produced by the human body (mainly during the night from the liver) to ensure a sufficient amount of cholesterol. The chemical structure is different from that of fat. Quite often cholesterol and fat are mixed up as both of them occur in the same type of food. This is the reason why diseases of the cholesterol metabolism are often called diseases of the fat metabolism.

As cholesterol is not soluble in water, it has to be bound to proteins (the so-called apolipoproteins) for better transport conditions. Large amounts of these molecule complexes can have a negative influence on the rheology of the blood due to their size.

Over the years biochemists have recognised the existance of different types of cholesterol carriers, which can be divided into the (if levels are elevated) harmful LDL-cholesterol and into the protective HDL-cholesterol after separation in special centrifuges (ultracentrifuges). The terms were first used in the USA: LDL stands for "low density lipoprotein" and HDL for "high density lipoprotein". The density of these particles is responsible for the different separation behavior.

Is cholesterol dangerous ?

Cholesterol is not dangerous, if only present at concentrations needed from the body. In higher concentrations LDL-cholesterol is stored in the vessel walls and leads to premature arteriosclerosis. If LDL-cholesterol concentrations are elevated or if the LDL- / HDL-cholesterol ratio is unfavourable, an attempt of normalisation of cholesterol levels or the LDL-/HDL-cholesterol ratio is mandatory.

What is the meaning of arteriosclerosis ?

Arteriosclerosis (or atherosclerosis) describes a process in blood vessel walls which usually leads to a decrease of elasticity with increasing age. The process is enhanced by elevated cholesterol levels in the blood and is present at an elderly age where the results of the disease can cause multiple problems for the patient himself and his or her family also. Perfusion problems especially in the heart, carotid arteries, brain and different organs often lead to a premature decrease of the quality of life or a reduced life expectancy due to myocardial infarction, stroke or other deteriorations of the circulation. At this stage the reduction in quality of life is most important as it is associated with dependance on the environment, suffering and invalidism.

Is there a negative effect of fat ?

For the chemist fat (triglycerides) is a substance different from cholesterol. Unfortunately, both terms a frequently mixed up due to ignorance. Thus the fat metabolism has to be considered differently from the cholesterol metabolism.

Low or normal fat levels in the blood are not dangerous. If both blood fat and cholesterol levels are elevated, the process of arteriosclerosis can be accelerated.

Elevated blood cholesterol is now recognized generally as the most important risk factor for the development of arteriosclerosis.

Several other risk factors for the development of arteriosclerosis are also known. First of all smoking has to be named. Like elevated cholesterol levels smoking is generally accepted as a major risk factor for arteriosclerosis. Also hypertension, diabetes mellitus, overweight and lack of exercise are recognized as risk factors.

To what extent is prophylaxis of arteriosclerosis possible ?

On the one hand arteriosclerosis is part of the normal process of aging. On the other hand the timing of manifestation can be influenced. Physicians recommend a healthy lifestyle with a reduced consumption of cholesterol- and fat-containing food but a high consume of fruit and vegetables providing also for an appropriate amount of vitamins. Also, exercise is of major importance.

There are classes of arteriosclerosis where the treatment with dietary regimen and exercise is insufficient. They belong to the group of genetic disorders of the cholesterol metabolism, the so-called familial hypercholesterolaemias.

Which are the various types of genetic disorders of the cholesterol metabolism (familial hypercholesterolaemia) ?

A common classification for hypercholesterolaemia is named after Frederickson, a scientist for metabolic disorders. The most common form is called type II and is characterized by an elevation of LDL-cholesterol due to a defect of reduction capacity of the liver.

The two forms of type II hypercholesterolaemia differ in their blood cholesterol level. The more severe form is called homocygous. These patients present with remarkably elevated LDL-cholesterol levels between 450 and 1.500 mg/dl without treatment. A less severe form is called heterocygous. Untreated patients present with levels just under 450 mg/dl. Patients suffering from the homocygous form are very rare (1:1.000.000), whereas the heterocygous form is less rare (0,2% of the population).

Another type with mainly elevated blood fats but less distincted elevation of cholesterol is called type IV.

Which are the treatment options for genetic hypercholesterolaemia ?

First, all patients are adviced to favour a fat- and cholesterolpoor diet. Likewise patients should exercise on an individually established level. Patients with an advanced disease should exercise carefully, possibly under medical observation within a coronary exercise group. Within the group of non-genetically elevated fat or cholesterol levels or in heterocygous patients a reduction of LDL/HDL-ratio can be achieved already by the changes in lifestyle.

Most patients with genetically elevated cholesterol need cholesterol-lowering drugs. They are classified into earlier drugs like the group of fibrates (e.g. Cedur®, Lipanthyl®), adsorbants (e.g. Lipocol®, Quantalan®, Vasosan®) and the modern cholesterol synthesis inhibitors named statins (e.g. Sortis®, Zocor®). Due to medical knowledge and experience a single drug or the combination of drug can be prescribed to achieve the target values. For the prescription compliance, oeconomic aspects and the clinical condition of the patient have to be considered. Patients at high-risk need a more intense treatment as compared to those with limited clinical symptoms. Patients with homocygous familial hypercholesterolaemia are not expected to have a remarkable effect of any cholesterol lowering medication, while heterocygous patients usually reach the target values with an appropriate medication. Also patients with type IV hypercholesterolaemia demonstrate a very mild effect of drug treatment alone, thus a radical dietary regime is regarded as a basis for the treatment in familial hypercholesterolaemia.

In cases where neither a dietary regime nor a drug therapy is sufficient to lower cholesterol levels towards the normal range of serum cholesterol further therapeutical options like e.g. haemapheresis can be considered, especially if the clinical condition e.g. advanced coronary heart disease of the patient requires such a procedure.

Which blood purification procedures are available ?

The oldest procedure for elimination of LDL-cholesterol out of the blood is called therapeutic plasma exchange (TPE). First experience was made in France and TPE was further investigated in Britain. Studies then showed that regular fortnightly treatments can improve the quality of life and extend life expectancy.

In 1981 LDL-apheresis was performed on the first patients in Cologne. It is still the only procedure available eliminating specifically Apoprotein B associated cholesterol. In fact no other proteins are removed from the blood by the procedure. Furthermore patients profit from a high cholesterol-binding capacity due to a technique of repeated loading and unloading of adsorption columns during the treatment. This method has been modified in Japan and marketed in a similar form some years later.

The filtration of separated plasma represents another technical principle just as the heparin-induced LDL-precipitation. Both methods have rheological advantages, but are less efficient in LDL-cholesterol removal as compared to the adsorption therapy.

While in a first step all named procedures (excluding TPE) separate plasma from the blood cells, more recently whole blood perfusion using adsorption columns has been established. It appears that this method seems to be very easy. The use of only one column demonstrates that the capacity is limited to an extent that medical targets are only achieved in patients with a mild disease. For patients with a moderate or severe disease the disadvantage of this procedure is obvious.

A decision for the selection of the correct procedure is determined from the target value. LDL-cholesterol levels of less than 50 mg/dl by the end of treatment should be reached.

While all procedures mentioned above can be used in hypercholesterolaemia, elevated blood fats usually are treated with TPE because blood fat occludes the separation devices.

Nowadays the availability of different treatment options is important. The selection of an optimal treatment procedure for the patient is experience related indeed. The DHZ is active since 1987 however the experience of the directing physicians dates back to 1981.

Are optional cholesterol-lowering treatments available ?

Likewise in other untreatable diseases several therapeutical options have been investigated in the past (e.g. the surgical removal of bowel parts). Since the availability of the LDL-apheresis this treatment are outdated.

Looking into the future leaves us with unrealistic expectations presently. Neither liver transplantation nor genetic therapy have fulfilled our expectations approximately.

Probably, further development is a development of small steps like e.g. availability of drug therapy with an improved profile of activity. Unfortunately it is not expected, that patients with severe forms of the disease profit from this development.

Which are the targets of a cholesterol-lowering treatment ?

The goals of a cholesterol-lowering therapy are dependent on the pre-treatment level of the patient.
A juvenile homocygous patient who presents with highly elevated cholesterol levels (e.g. above 1.000 mg/dl) but with no alteration of vessels cannot be treated effectively by drug therapy only. He will need LDL-apheresis early for primary prevention.

Another patient with the same cholesterol values can already present with an alteration of his blood vessels. This patient will profit from LDL-apheresis by a total reduction of his cholesterol plaques called regression.
Heterocygous patients are frequently diagnosed later, when cholesterol deposits are also calcified. At this stage a regression of the disease is less probable, but a stabilisation of the disease is likely. Especially cholesterol depots in the vessels which contain cholesterol and calcium (so-called plaques) frequently burst and may be dangerous and lead to the development of thrombosis. Due to regular haemapheresis these plaques can be turned into less dangerous alterations in the vessel walls (secondary prevention).
According to our 25 years of experience the adjustment of post-treatment cholesterol levels in hypercholesterolaemic patients has to be optimal by achieving the lowest possible levels of cholesterol.

Two targets are most important for the patient. Knowing that the approximate life expectancy increases year by year (in Germany the average age of females is 81,1 years at present) reasons for a reduced life expectancy of patients suffering from familial hypercholesterolaemia as the only risk factor appear not to exist any more, if this risk factor is completely eliminated.

It is also accepted now that the quality of life of elderly patients is not only dependant on their genotype but also on their life style. Everybody can influence his or her quality of life as a pensioneer due to his or her lifestyle over the years. The physician`s task is to advice patients about the state-of-the-art knowledge. According to the current medical knowledge patients themselves are responsible for their well-being while taking an active part in preservation of health.

Which is the mandatory reduction of cholesterol levels to achieve the medical targets ?

The minimum targets in each cholesterol-lowering treatment are commited unequivocally. These target values are based on national and international groups of specialists with relation to consensus conferences (e.g. American Heart Association) and not on the opinion of individuals. Therefore experienced scientists on the topic "cholesterol metabolism" meet in regular intervals and separate reliable from unreliable information.

Accordingly, it is accepted that persons without any cardiovascular diseases should have total cholesterol levels below 250 mg/dl and LDL-cholesterol levels below 160 mg/dl regardless of their age. HDL-cholesterol should be above 40 mg/dl and triglycerides below 200 mg/dl.

In patients without cardiovascular disease but presenting with risk factors the target values should be kept below the above mentioned (e.g. cholesterol below 200 mg/dl).

Patients with cardiovascular diseases (e.g. coronary heart disease) need a strict adjustment with cholesterol levels below 100 mg/dl and LDL-cholesterol levels below 70 mg/dl. The concentration of triglycerides in the blood is not allowed to exceed 200 mg/dl and the LDL-/ HDL-ratio should be kept below 2.

The target values of the DHZ have always been more demanding than those of the international consensus conferences. This is due to the fact that the DHZ already operated at times where no comparable centre existed worldwide. Thus the DHZ was forced to set up standards without waiting for other institutions entering into the field. Furthermore the number of patients with initially very high values is larger than elsewhere. This strategy has obviously payed out as the DHZ can present with the worldwide best long-term survival rates. While the target values defined by the consensus conferences are referring to drug treatment of most patients, tighter values have to be set up for high-risk patients and patients with familial hypercholesterolaemia. Therefore the target values at the DHZ are below those defined by the consensus conference. Also technical options are available in contrast to other therapeutic institutions to achieve our tight target values. A reduction of cholesterol levels to underneath 50 - 100 mg/dl by the end of apheresis is considered as standard.

Is it possible to combine blood purification with drug therapy ?

Since 1981 numerous treatments not only at the university hospital Cologne have shown that LDL-apheresis alone can be sufficient. An additional medication can be useful, if tolerated by the patient. Due to a relevant reduction of cholesterol shorter treatment times can be achieved. The elevation of cholesterol levels after combined haemapheresis / drug treatment can be delayed. The interval of low cholesterol levels can be extended, which is important for regression of disease. This is valid for patients with hypercholesterolaemia type II.

Drug therapy for patients with elevated fat levels is available although the effect of a diet is much stronger.

Whom can I talk to, if I have more questions, would like to know more about my disease or the treatment or if I need advice ?

All physicians and nurses at the DHZ are trained to answer your questions. For special information and further questions Prof. Borberg is willing to provide you with the relevant information.