Hypercholesterolemia

A high level of cholesterol in the blood--hypercholesterolemia--is a major risk factor for atherosclerosis and subsequently, coronary heart disease (CHD). Atherosclerosis comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It's the name of the process in which deposits of fatty substances, cholesterol, calcium and other substances build up in the inner lining of an artery (plaque formation). Plaques can grow large enough to significantly reduce the blood flow in an artery, but most of the damage occurs when they become fragile and rupture. Plaques that rupture cause blood clots to form that can block blood flow or break off, causing a heart attack or stroke.

Cholesterol is transported in blood by carriers called lipoproteins. Low-density lipoprotein (LDL) is the "bad cholesterol" associated with CHD. High-density lipoprotein (HDL) is the "good cholesterol", which helps protect against CHD. LDL-cholesterol is cleared from the bloodstream by a receptors on the surface of liver cells. The LDL-cholesterol particle binds to the receptor like a key fitting a lock.

Cholesterol is not only associated with atherosclerosis but it is also a major constituent of our body's cells. We need cholesterol to build certain essential compounds such as sex and growth hormones. In familial hypercholesterolemia, the balance between the cholesterol we need for our body and the cholesterol that is cleared from the bloodstream is disturbed.

Familial hypercholesterolemia (FH) is one of the most common inherited metabolic diseases. The frequency of FH in Western European populations is about one in 500. FH patients have high LDL-cholesterol levels from birth onwards leading to atherosclerosis at a young age. Typically, approximately 45% of male and 20% of female people with FH suffer from CHD by the age of 50.

LDL-cholesterol levels are increased in the blood of these patients due to malfunctioning liver cell receptors. In FH patients, half of the LDL-receptors are absent or do not work properly and the other half are normal. This means their livers can't clear the LDL as effectively as normal people. The receptors are defective because of inheritance of an abnormal gene which is inherited from one's mother or father.

The diagnosis of FH is based on a patient's family history, physical examination, laboratory findings and DNA analysis. In FH patients, xanthomas and an arcus lipoides are often seen upon physical examination. Xanthomas are deposits of cholesterol in the skin, on the Achilles tendons, knuckles of the hand, elbows and knees. An arcus lipoides is a deposition of LDL-cholesterol around the cornea, appearing as an opaque, grayish ring.

In adult patients the recommended therapy is a HMG-CoA reductase inhibitor (statin). These drugs give a LDL-cholesterol reduction up to 50%. Since the introduction of statins in 1989, numerous clinical studies have proven the safety and effectiveness of statins in adults.

To decrease the likelihood of CHD later on in life it is important to initiate treatment at a young age. The recommended therapy for children is aimed at reducing the controllable risk factors for atherosclerosis, namely a high fat diet, obesity, smoking and physical inactivity. The long-term effectiveness of a lipid-lowering diet has been shown to be poor in different studies.

The National Cholesterol Education Program (NCEP) recommends drug therapy for children above 10 years whose LDL-cholesterol levels remains above 190 mg/dL (4.9 mmol/L) after dietary interventions or 160 mg/dL (4.1 mmol/L) in combination with a positive family history of premature CHD.

Bile-acid binding resins (Cholestyramine, Colestipol and Colesevelam) are considered the drugs of choice for treating hypercholesterolemia in children. Bile acid binding resins bind the cholesterol in the intestine, inhibiting its absorption by the body. The cholesterol bound to the resins is eliminated in the stool. These drugs induce a cholesterol lowering effect, but this effect is modest. Importantly, resins have many side effects, including constipation, bloating, nausea, and gas. Therefore, understandably, the compliance to the resins is poor in children with FH.

In the United States of America, the Food and Drug Administration (FDA) approved the statin lovastatin in 2002 for adolescent boys and girls with FH. Preferably, girls should not be treated until they have been menstruating for at least one year. The FDA also approved the statin pravastatin in the same year for the treatment of FH in children aged eight years and older. Lovastatin is not available in Europe, and therapy with any other statin has not yet been approved for use in children by the European Agency for the Evaluation of Medicinal Products (EMEA).

The question remains whether statin therapy is indicated in children. Early effective cholesterol-lowering therapy could prevent CHD. However, the safety of these drugs, and their effectiveness in children is the subject of clinical research around the world. In a study, recently published in a major American medical journal, the two-year effectiveness and safety of pravastatin therapy in young children with FH was investigated. Over 200 children with FH aged 8 to 18 years participated in this study.

The children were divided into two groups: one group received active medication, the other group received tablets that looked the same as, but didn't contain the actual medication (placebo tablets). The effectiveness of pravastatin was evaluated using ultrasound measurements of the arteries of the neck. Thicker vessel walls indicate the beginning of atherosclerosis and therefore an increased risk for CHD. Using ultrasound waves to perform these measurements is safe and non-invasive. The children in the study were seen on a regular basis in an outpatient research clinic.

To evaluate the safety of treatment with pravastatin, a thorough physical examination was performed by a pediatrician and blood was drawn. As mentioned previously, cholesterol is an essential component of growth and sex hormones. Since statins reduce cholesterol levels, the production of growth and sex hormones could be affected by lipid-lowering therapy. Pravastatin is metabolized by the liver, therefore liver function was monitored. In addition muscle enzymes were monitored, since statins can cause muscle tissue damage in a small number of patients.

After two years of treatment, LDL-cholesterol levels were 24% lower in the active treatment group. In addition to this effect, the arterial wall thickness in the children on active treatment was reduced compared to the measurement taken at their first visit to the research clinic. No adverse effects of the statin were shown on growth, sexual maturation, hormone levels, liver or muscle tissue. Progress at school, an important detail, didn't seem to be influenced by the drug.

This and other large clinical studies have clearly demonstrated the safety of statins in children. Growth and pubertal development are not affected by statin treatment. Moreover, this study demonstrated that two years of statin therapy reduced thickening of the arterial wall and LDL-cholesterol in children. It is hoped that reduction of arterial wall thickness will protect the children against developing CHD as adults. As a consequence, they will not suffer from premature CHD, in contrast to the parent from whom they inherited the disorder.

In summary, statins can be used safely in the treatment of children with FH. Statins do not only reduce LDL-cholesterol levels, but also reverse the thickening of the arterial wall known as atherosclerosis. In conclusion, the use of statins, along with regular physical activity and a healthy diet are recommended for LDL-cholesterol reduction in children with FH.

Jessica Rodenburg, M.D., specializes in children with familial hypercholesterolemia. She works and teaches at the Acadamic Medical Centre in Amsterdam, the Netherlands. This aticle was written with the help of students Suthesh Sivapalaratnam and Laura van Loendersloot.

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