Hypercholesterolemia

Hypercholesterolemia (literally: high blood cholesterol) is the presence of high levels of cholesterol in the blood ^[1]. 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). Familial hypercholesterolemia is a rare genetic disorder that can occur in families, wherein those affected cannot properly metabolise cholesterol.

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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. In 1980, the original methods, developed by research work in the mid-1970s costed about $5,000, in 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.

Screening

Screening for a disease refers to testing for a disease, such as hypercholesterolemia, in patients who have no signs or symptoms of the disease.

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.

The U.S. Preventive Services Task Force (USPSTF) has evaluated screening for hypercholesterolemia ^{[2] [3]}.

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 more often a family history of premature, earlier onset atherosclerosis, as well as familial occurrence of the signs mentioned above.

Secondary causes

There are 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 raises blood cholesterol levels. Although dietary cholesterol exerts some influence, the regulatory mechanism of the liver upon absorption of cholesterol decreases the effect of dietary cholesterol on total cholesterol levels. Thus it is mainly by limiting the amount of saturated fat in one's diet that helps lower total serum cholesterol.^{[citation needed]}
• 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.^{[citation needed]}

Trans fats

An increasing number of researchers are suggesting that a major dietary risk factor for cardiovascular diseases is trans fatty acids, and in the US the FDA has revised food labeling requirements to include listing trans fat quantities.^{[citation needed]}

Treatment

Clinical Evidence has summarized treatment for both primary prevention ^[4] and secondary prevention ^[5]. Two factors to consider when choosing therapy are the patient's risk of coronary disease and their lipoprotein pattern.

Risk of coronary disease. To calculate the benefit of treatment, there are two online calculators that can estimate baseline risk ^{[6] [7]}. Combining the baseline risk with the relative risk reduction of a treatment can lead to the absolute risk reduction of number needed to treat. For example, one of the calculators projects that a patient had a 10% risk of coronary disease over ten years. As noted below, the relative risk reduction of a statin is 30%. Thus, after 4-7 years of treatment with a statin, a patient's risk will drop to 7%. This equates to an absolute risk reduction of 3%, or a number needed to treat of 33. Thirty three such patients must be treated for 4-7 years for one to benefit.

Lipoprotein patterns. (See hyperlipoproteinemia for details) The treatment depends on the type of hypercholesterolemia. 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. 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 (niacin), bile acid sequestrants (colestipol, cholestyramine), LDL apheresis and in hereditary severe cases liver transplantation.

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^{[citation needed]}.

Diet

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.

Dietary changes can potentially be very strong.^[8]

Medications

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% ^{[2] [3]}. More recently, a meta-analysis reported an almost identical relative risk reduction of 29.2% in low risk patients treated for 4.3 years ^[9]. A relative risk reduction of 19% in coronary mortality was found in a meta-analysis of patients at all levels of risk.^[10]

Clinical practice guidelines

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes ^[11]. Their recommendations are:

• Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
• Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
• Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin")^[12].
• Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

The National Cholesterol Education Program revised their guidelines^[13]; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.^[14]

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 ([1] 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).

References

1. ^ Durrington P (2003). "Dyslipidaemia". Lancet 362 (9385): 717-31. PMID 12957096.
2. ^ ^{a b} Pignone M, Phillips C, Atkins D, Teutsch S, Mulrow C, Lohr K (2001). "Screening and treating adults for lipid disorders". Am J Prev Med 20 (3 Suppl): 77-89. doi:10.1016/S0749-3797(01)00255-0. PMID 11306236.
3. ^ ^{a b} U.S. Preventive Services Task Force. Screening for Lipid Disorders: Recommendations and Rationale. Retrieved on Feb 26, 2007.
4. ^ Pignone M. "Primary prevention: dyslipidaemia". Clin Evid: 142-50. PMID 16620402.
5. ^ Gami A. "Secondary prevention of ischaemic cardiac events". Clin Evid: 195-228. PMID 16973010.
6. ^ Pignone MP; Sheridan SL. med-decisions.com. Retrieved on Feb 26, 2007.
7. ^ National Cholesterol Education Program. 10-year CVD Risk Calculator (Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD (Myocardial Infarction and Coronary Death) Version). Retrieved on Feb 26, 2007.
8. ^ McMurry MP, Cerqueira MT, Connor SL, Connor WE (1991). "Changes in lipid and lipoprotein levels and body weight in Tarahumara Indians after consumption of an affluent diet". N. Engl. J. Med. 325 (24): 1704-8. PMID 1944471.
9. ^ Thavendiranathan P, Bagai A, Brookhart M, Choudhry N (2006). "Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials". Arch Intern Med 166 (21): 2307-13. PMID 17130382.
10. ^ Baigent C, Keech A, Kearney PM, et al (2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet 366 (9493): 1267-78. doi:10.1016/S0140-6736(05)67394-1. PMID 16214597.
11. ^ Snow V, Aronson M, Hornbake E, Mottur-Pilson C, Weiss K (2004). "Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians". Ann Intern Med 140 (8): 644-9. PMID 15096336.
12. ^ Vijan S, Hayward RA (2004). "Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians". Ann. Intern. Med. 140 (8): 650-8. PMID 15096337.
13. ^ Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ (2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines". J. Am. Coll. Cardiol. 44 (3): 720-32. doi:10.1016/j.jacc.2004.07.001. PMID 15358046.
14. ^ Hayward RA, Hofer TP, Vijan S (2006). "Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem". Ann. Intern. Med. 145 (7): 520-30. PMID 17015870.

See also

• Familial hypercholesterolemia