Cholesterol
Cholesterol
Cholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important precursor molecule for the biosynthesis of bile acids, steroid hormones, and several fat soluble vitamins. Cholesterol is the principal sterol synthesized by animals, but small quantities are synthesized in other eukaryotes, such as plants and fungi. It is almost completely absent among prokaryotes, which include bacteria.
The name cholesterol originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as François Poulletier de la Salle first identified cholesterol in solid form in gallstones, in 1769. However, it was only in 1815 that chemist Eugène Chevreul named the compound "cholesterine".
Hypercholesterolemia
According to the lipid hypothesis, abnormally high cholesterol levels (hypercholesterolemia), or, more correctly, higher concentrations of LDL and lower concentrations of functional HDL are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke and peripheral vascular disease. Since higher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than the cholesterol content of the LDL particles, LDL particles are often termed "bad cholesterol" because they have been linked to atheroma formation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protection and are sometimes referred to colloquially as "good cholesterol". These balances are mostly genetically determined but can be changed by body build, medications, food choices and other factors.
Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression. A 2007 study pooling data on almost 900,000 subjects in 61 cohorts demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with the association more pronounced in younger subjects. Still, because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is still larger in older people.
Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration. Recently, a post-hoc analysis of the IDEAL and the EPIC prospective studies found an association between high levels of HDL cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and increased risk of cardiovascular disease, casting doubt on the cardioprotective role of "good cholesterol"
Multiple human trials utilizing HMG-CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults.[citation needed] As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels, and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention").[31] Primary prevention in women is practiced only by extension of the findings in studies on men, since in women, none of the large statin trials has shown a reduction in overall mortality or in cardiovascular end points.
The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be: < 200 mg/dL normal blood cholesterol, 200–239 mg/dL borderline-high, > 240 mg/dL high cholesterol. The American Heart Association provides a similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:
| Level mg/dL | Level mmol/L | Interpretation |
| < 200 | < 5.0 | Desirable level corresponding to lower risk for heart disease |
| 200–240 | 5.2–6.2 | Borderline high risk |
| > 240 | > 6.2 | High risk |
However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, this simplistic view has become somewhat outdated. The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L), although a newer target of < 70 mg/dL can be considered in higher risk individuals based on some of the above-mentioned trials. A ratio of total cholesterol to HDL—another useful measure—of far less than 5:1 is thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to develop is 35 mg/dL.
Most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula (or a variant): [total cholesterol] − [total HDL] − 20% of the triglyceride value = estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the total, HDL, and triglycerides are actually measured. The VLDL is estimated as one-fifth of the triglycerides. It is important to fast for at least eight hours before the blood test because the triglyceride level varies significantly with food intake.
Given the well-recognized role of cholesterol in cardiovascular disease, it is surprising that some studies have shown an inverse correlation between cholesterol levels and mortality in subjects over 50 years of age—an 11% increase overall and 14% increase in CVD mortality per 1 mg/dL per year drop in cholesterol levels. In the Framingham Heart Study, the researchers attributed this phenomenon to the fact that people with severe chronic diseases or cancer tend to have below-normal cholesterol levels. This explanation is not supported by the Vorarlberg Health Monitoring and Promotion Programme, in which men of all ages and women over 50 with very low cholesterol were increasingly likely to die of cancer, liver diseases, and mental diseases. This result indicates that the low cholesterol effect occurs even among younger respondents, contradicting the previous assessment among cohorts of older people that this is a proxy or marker for frailty occurring with age.
A small group of scientists, united in The International Network of Cholesterol Skeptics, continues to question the link between cholesterol and atherosclerosis. However, the vast majority of doctors and medical scientists accepts the link as fact.
Treatment
Many primary physicians and heart specialists will initially prescribe medication in combination with diet and exercise. According to various resources, statins are the most commonly used and effective forms of medication for the treatment of high cholesterol. The U.S. Preventive Services Task Force (USPSTF) estimated that after 5 to 7 years of treatment, the relative risk reduction by statins on coronary heart disease events is decreased by approximately 30%. More recently, a meta-analysis reported an almost identical relative risk reduction of 29.2% in low risk patients treated for 4.3 years. A relative risk reduction of 19% in coronary mortality was found in a meta-analysis of patients at all levels of risk.
The statins are divided into two groups: fermentation-derived and synthetic.The statins include, in alphabetical order (brand names vary in different countries):
| Statin | Image | Brand name | Derivation |
| Atorvastatin |
|
Lipitor, Torvast | Synthetic |
| Cerivastatin |
|
Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis) | Synthetic |
| Fluvastatin |
|
Lescol, Lescol XL | Synthetic |
| Lovastatin |
|
Mevacor, Altocor, Altoprev | Fermentation-derived. Naturally-occurring compound. Found in oyster mushrooms and red yeast rice. |
| Mevastatin |
|
- | Naturally-occurring compound. Found in red yeast rice. |
| Pitavastatin |
|
Livalo, Pitava | Synthetic |
| Pravastatin |
|
Pravachol, Selektine, Lipostat | Fermentation-derived |
| Rosuvastatin |
|
Crestor | Synthetic |
| Simvastatin |
|
Zocor, Lipex | Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product) |
| Simvastatin+Ezetimibe | Vytorin | Combination therapy | |
| Niacin extended-release | Advicor | Combination therapy | |
| Atorvastatin+Amlodipine Besylate | Caduet | Combination therapy - Cholesterol+Blood Pressure | |
| Simvastatin+Niacin extended-release | Simcor | Combination therapy |
LDL-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency), rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potency of pitavastatin has not yet been fully established.
