Hypercholesterolemia

Hypercholesterolemia (literally: high blood cholesterol) is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be secondary to many diseases and can contribute to many forms of disease, most notably cardiovascular disease. It is closely related to the terms "hyperlipidemia" (elevated levels of lipids) and "hyperlipoproteinemia" (elevated levels of lipoproteins).

Signs and symptoms
Elevated cholesterol does not lead to specific symptoms unless it has been longstanding. Some types of hypercholesterolemia lead to specific physical findings: xanthoma (thickening of tendons due to accumulation of cholesterol), xanthelasma palpabrum (yellowish patches around the eyelids) and arcus senilis (white discoloration of the peripheral cornea).

Longstanding elevated hypercholesterolemia leads to accelerated atherosclerosis; this can express itself in a number of cardiovascular diseases:
 * Angina pectoris, leading to PTCA or CABG
 * Myocardial infarction (heart attack)
 * Transient ischemic attacks (TIAs)
 * Cerebrovascular accidents/Strokes
 * Peripheral artery disease (PAD)

Diagnosis
When measuring cholesterol, it is important to measure its subfractions before drawing a conclusion on the cause of the problem. The subfractions are LDL, HDL and VLDL. In the past, LDL and VLDL levels were rarely measured directly due to cost concerns. VLDL levels are reflected in the levels of triglycerides (generally about 45% of triglycerides is composed of VLDL). LDL was usually estimated as a calculated value from the other fractions (total cholesterol minus HDL and VLDL); this method is called the Friedewald calculation; specifically: LDL ~= Total Cholesterol - HDL - (0.2 x Triglycerides).

Less expensive (and less accurate) laboratory methods and the Friedewald calculation have long been utilized because of the complexity, labor and expense of the electrophoretic methods developed in the 1970s to identify the different lipoprotein particles which transport cholesterol in the blood. As of 1980, the original methods, developed by research work in the mid-1970s cost about $5K, US 1980 dollars, per blood sample/person.

With time, more advanced laboratory analyses have been developed which do measure LDL and VLDL particle sizes and levels, and at far lower cost. These have partly been developed and become more popular as a result of the increasing clinical trial evidence that intentionally changing cholesterol transport patterns, including to certain abnormal values compared to most adults, often has a dramatic effect on reducing, even partially reversing, the atherosclerotic process. With ongoing research and advances in laboratory methods, the prices for more sophisticated analyses have markedly decreased, to less than $100, US 2004, by some labs, and with simultaneous increases in the accuracy of measurement for some of the methods.

Classification
See also hyperlipoproteinemia for biochemical details

Fredrickson classification
Classically, hypercholesterolemia was categorized by lipoprotein electrophoresis and the Fredrickson classification. Newer methods, such as "lipoprotein subclass analysis" have offered significant improvements in understanding the connection with atherosclerosis progression and clinical consequences.

If the hypercholesterolemia is hereditary (familial hypercholesterolemia), there is often a family history of premature, earlier onset atherosclerosis, as well as familial occurrence of the signs mentioned above.

Secondary causes
There is a number of secondary causes for high cholesterol:
 * Diabetes mellitus and metabolic syndrome
 * Kidney disease (nephrotic syndrome)
 * Hypothyroidism
 * Anorexia nervosa
 * Zieve's syndrome
 * Family history
 * Diet: Saturated fat and cholesterol in the food you eat make  blood cholesterol levels rise. Saturated fat is the main culprit, but dietary cholesterol also matters. Limiting the amount of saturated fat and cholesterol in your diet helps lower one's cholesterol level.
 * Weight. Being overweight is a definite risk factor for heart disease. It also tends to increase your cholesterol. Losing weight can help lower your LDL and total cholesterol levels, as well as raise your HDL and lower your triglyceride levels.
 * Physical Activity. Lack of physical activity is a risk factor for heart disease. Regular physical activity can also help lower LDL (bad) cholesterol and raise HDL (good) cholesterol levels. It also helps you lose weight.

All three of these activities done together can have a positive effect on one's blood cholesterol level.

Dietary influence
While part of the circulating cholesterol originates from diet, and restricting cholesterol intake may reduce blood cholesterol levels, there are various other links between the dietary pattern and cholesterol levels. The American Heart Association also compiles a list of the acceptable/unacceptable foods for those who are diagnosed with hypercholesterolemia.

Carbohydrates
Evidence is accumulating that eating more carbohydrates - especially simpler, more refined carbohydrates - increases levels of triglycerides in the blood, lowers HDL, and may shift the LDL particle distribution pattern into unhealthy atherogenic patterns. Thus a low fat diet, which often means a higher carbohydrate intake, may actually be an unhealthy change.

Trans fats
An increasing number of researchers are suggesting that a major dietary risk factor for cardiovascular diseases is trans fatty acids, not saturated fats, as had been suggested by the Framingham Heart Study and the FDA plans revised food labeling to include listing trans fat quantities, by 2007. Meanwhile, amount of trans fat can be calculated from the food label by subtracting the various reported fats from the total fat: trans fat = ( total fats - saturated fats - monounsaturates - polyunsaturates).

Modalities
The treatment depends on the type of hypercholesterolemia. Fredrickson Types IIa and IIb can be treated with diet, statins (most prominently rosuvastatin, atorvastatin, simvastatin, or pravastatin), cholesterol absorption inhibitors (ezetimibe), fibrates (gemfibrozil, bezafibrate, fenofibrate or ciprofibrate), vitamin B3 (nicotinic acid), bile acid sequestrants (colestipol, cholestyramine), LDL apheresis and in hereditary severe cases liver transplantation. The treatment is made more complex when elevated levels of asymmetric dimethylarginine (ADMA) are present in endothelial blood, since ADMA down-reguates the production of endothelial nitric oxide production and hence aggravates the extent of oxidized LDL.

Need to treat
In patients without any other risk factors, moderate hypercholesterolemia is often not treated. According to Framingham Heart Study, people with an age greater than 50 years have no increased overall mortality with either high or low serum cholesterol levels. There is, however, a correlation between falling cholesterol levels over the first 14 years and mortality over the following 18 years (11% overall and 14% CVD death rate increase per 1 mg/dL per year drop in cholesterol levels). This, however, does not mean that a decrease in serum levels is dangerous, as there has not yet been a recorded heart attack in the study in a person with a total cholesterol below 150 mg/dL.

On the other hand, and though less dramatic than the many cardiovascular procedures, some people, especially with newer and more sophisticated information, are changing their eating and especially food supplement patterns, many of the supplements still being prescription agents. Though generally not aware of the internal changes in their cholesterol transport patterns, recent trials have demonstrated increasing success with some of these strategies; see the LDL, HDL and IVUS sections.

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.

Lipoprotein patterns
In other words, clinical trials, starting in the 1970s, have repeatedly and increasingly found that normal cholesterol values do not necessarily reflect healthy cholesterol values. This has increasingly lead to the newer concept of dyslipidemia, despite normo-cholesterolemia. Thus there has been increasing recognition of the importance of "lipoprotein subclass analysis" as an important approach to better understand and change the connection between cholesterol transport and atherosclerosis progression.

Multiple clinical trials, each, by design, examining only one of multiple relevant issues, have increasingly examined the connection between these issues and atherosclerosis clinical consequences. Some of the better recent randomized human outcome trials include ASTEROID, ASCOT-LLA, REVERSAL, PROVE-IT, CARDS, Heart Protection Study, HOPE, PROGRESS, COPERNICUS, and especially a newer research approach utilizing a synthetically produced and IV administered human HDL, the Apo A-I Milano Trial.

Alternative medicine
A survey released in May 2004 by the National Center for Complementary and Alternative Medicine focused on who used complementary and alternative medicine (CAM), what was used, and why it was used in the United States by adults age 18 years and over during 2002. According to this survey, CAM was used to treat cholesterol by 1.1% of U.S. adults who used CAM during 2002 ( table 3 on page 9). Consistent with previous studies, this study found that the majority of individuals (i.e., 54.9%) used CAM in conjunction with conventional medicine (page 6).

Reference

 * Durrington P. Dyslipidaemia. Lancet 2003;362:717-31. PMID 12957096.

Hypercholesterinämie Hypercholestérolémie Ipercolesterolemia Hypercholesterolemie Hipercholesterolemia Hipercolesterolemia Hypercholesterolemia