Hypercholesterolemia

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

Elevated cholesterol in the blood is due to abnormalities in the levels of lipoproteins, the particles that carry cholesterol in the bloodstream. This may be related to diet, genetic factors (such as LDL receptor mutations in familial hypercholesterolemia) and the presence of other diseases such as diabetes and an underactive thyroid. The type of hypercholesterolemia depends on which type of particle (such as low-density lipoprotein) is present in excess.

Hypercholesterolemia is treated by reducing dietary cholesterol intake, administration of certain medications, and rarely with other treatments including surgery (for particular severe subtypes).

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.

Signs and symptoms


Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis. Over a period of decades, chronically elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This leads to progressive stenosis (narrowing) or even complete occlusion (blockage) of the involved arteries. Blood supply to the tissues and organs served by these stenotic or occluded arteries gradually diminishes until organ function becomes impaired. It is at this point that tissue ischemia (restriction in blood supply) may manifest as specific symptoms. For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, aphasia (difficulty speaking), paresis (weakness) and paresthesia (numbness or tingling), usually on one side of the body. Insufficient blood supply to the heart may manifest as chest pain, and ischemia of the eye may manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal. Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids), arcus senilis (white or gray discoloration of the peripheral cornea), and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers. Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.

Causes
Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include: obesity and dietary choices. Genetic contributions are usually due to the additive effects of multiple genes however occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia. A number of secondary causes exist including: diabetes mellitus type 2, obesity, alcohol, monoclonal gammopathy, dialysis, nephrotic syndrome, obstructive jaundice, hypothyroidism, Cushing’s syndrome, anorexia nervosa, medications (thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid).

Diet
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.

Genetics
Genetic abnormalities are in some cases completely responsible for hypercholesterolemia, such as in familial hypercholesterolemia where there is one or more genetic mutations in, for example, the LDL receptor.

Even when there is no single responsible mutation to explain hypercholesterolemia, genetic predisposition still plays a major role, potentially adding to lifestyle factors and multiplying the risk of late complications. Multiple genes are involved, and hypercholesterolemia where there is probably a genetic predisposition is called polygenic hypercholesterolemia. The involved genes have yet to be discovered.

Diagnosis


There is not an absolute cutoff between normal and abnormal cholesterol levels and interpretation of values needs to occur in relation to other health factors. The ideal cholesterol level should be less than 4 mmol/l with a LDL cholesterol less than 2 mmol/l in those at high risk of cardiovascular disease.

Higher cholesterol levels lead to increased risk of several diseases, most notably cardiovascular diseases. Specifically, high levels of small LDL cholesterol particles are associated with increased risk. Larger LDL particles do not carry the same risk.

When measuring cholesterol, it is important to measure its subfractions before drawing a conclusion as to 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; to be specific: LDL ~= Total Cholesterol - HDL - (0.2 x Triglycerides).

Less expensive (and less accurate) laboratory methods and the Friedewald calculation have long been used because of the complexity, labor, and expense of the electrophoretic methods developed in the 1970s to identify the different lipoprotein particles that transport cholesterol in the blood. In 1980, the original methods, developed by research work in the mid-1970s cost about $5,000, in US 1980 dollars, per blood sample/person.

With time, more advanced laboratory analyses that do measure LDL and VLDL particle sizes and levels have been developed, 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
The U.S. Preventive Services Task Force (USPSTF) has strongly recommends routine screen for men 35 years and older and women 45 years and older for lipid disorders and the treat of abnormal lipids in people who are at increased risk of coronary heart disease. They also recommend routinely screening men aged 20 to 35 years and women aged 20 to 45 years if they have other risk factors for coronary heart disease. In Canada screening is recommended for men 40 and older and women 50 and older. In those with normal cholesterol levels screening is recommended once every five years. Once people are on a statin further testing provides little benefit except to possibly determine compliance with treatment.

Treatment
Recommendations for both primary prevention and secondary prevention have been published. For those at high risk a combination of lifestyle modification and statins has been shown to decrease mortality.

Lifestyle
A number of lifestyle changes are recommended in those with high cholesterol including: smoking cessation, limiting alcohol consumption, physical activity, maintaining a healthy weight, and a diet low in saturated fats.

In strictly controlled surroundings, a diet can reduce cholesterol levels by 15%. In practice, dietary advice can provide a modest decrease in cholesterol levels and may be sufficient in the treatment of mildly elevated cholesterol.

Medication
While statins are effective in decreasing mortality in those who have had previous cardiovascular disease, there is debate over whether or not they are effective in those with high cholesterol but no other health problems. One review did not find a mortality benefit in those at high-risk but without prior cardiovascular disease. Other reviews concluded that there is a mortality benefit but there was concerns regarding the quality of the evidence. With respect to quality of life there is limited evidence of improvement when statins are used for primary prevention. No studies as of 2010 show improved clinical outcomes in children with high cholesterol even though statins decrease cholesterol levels.

Guidelines
Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes. Their four recommendations are:
 * 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.
 * 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.
 * 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").
 * 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; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.

In the UK, the National Institute for Health and Clinical Excellence (NICE) has made recommendations for the treatment of elevated cholesterol levels, published in 2008.

Alternative medicine
According to a survey in 2002, alternative medicine was used in an attempt to treat cholesterol by 1.1% of U.S. adults. Consistent with previous surveys, this one found that the majority of individuals (i.e., 55%) used it in conjunction with conventional medicine. A review trials of phytosterols and/or phytostanols reported an average of 9% lowering of LDL-cholesterol. In 2000 the Food and Drug Administration approved the labeling of foods containing specified amounts of phytosterol esters or phytostanol esters as cholesterol lowering; in 2003 an FDA Interim Health Claim Rule extended that label claim to foods or dietary supplements delivering more than 0.8 grams/day of phytosterols or phytostanols. Some researchers, however, are concerned about diet supplementation with plant sterol esters and draw attention to significant safety issues. Health Canada does not allow the sale of foods enriched with plant sterol esters.