Hypercholesterolemia

Hypercholesterolemia
Formula structure of cholesterol
Classification and external resources
Specialty	Cardiology
ICD-10	E78.0
ICD-9-CM	272.0
DiseasesDB	6226
MedlinePlus	000403
eMedicine	med/1073
MeSH	D006937

Hypercholesterolemia (also spelled hypercholesterolaemia also called dyslipidemia) is the presence of high levels of cholesterol in the blood.^[1] It is a form of "hyperlipidemia" (elevated levels of lipids in the blood) and "hyperlipoproteinemia" (elevated levels of lipoproteins in the blood).^[1]

Cholesterol is a sterol; see the diagrammatic structure at the right. It is one of three major classes of lipids which all animal cells use to construct their membranes and is thus manufactured by all animal cells. Plant cells do not manufacture cholesterol. It is also the precursor of the steroid hormones and bile acids.

Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and high density lipoprotein (HDL).^[2] All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol, are associated with an increased risk of atherosclerosis and coronary heart disease.^[3] In contrast, higher levels of HDL cholesterol are protective.^[4] Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as diabetes and an underactive thyroid.^[1]

Reducing saturated dietary fat is recommended to reduce total blood cholesterol and LDL in adults.^[5] In people with very high cholesterol (e.g. familial hypercholesterolemia), diet is often insufficient to achieve the desired lowering of LDL, and lipid-lowering medications which reduce cholesterol production or absorption are usually required.^[6] If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed.^[6]

Signs and symptoms

Xanthelasma palpebrarum, yellowish patches consisting of cholesterol deposits above the eyelids. These are more common in people with familial hypercholesterolemia.

Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis.^[7] Over a period of decades, chronically elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive stenosis (narrowing) or even complete occlusion (blockage) of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow.^[8] A sudden occlusion of a coronary artery results in a myocardial infarction or heart attack. An occlusion of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. 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.^[1][9]

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),^[10] arcus senilis (white or gray discoloration of the peripheral cornea),^[11] and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers.^[12][13] Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.^[12]

Causes

Hypercholesterolemia is typically due to a combination of environmental and genetic factors.^[7] Environmental factors include obesity, diet, and stress.^[7][14] Genetic contributions are usually due to the additive effects of multiple genes, though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia.^[7] A number of secondary causes exist including: diabetes mellitus type 2, obesity, alcohol, monoclonal gammopathy, dialysis, nephrotic syndrome, hypothyroidism, Cushing’s syndrome, anorexia nervosa, medications (thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid).^[7]

Diet

Two bags of fresh frozen plasma: The bag on the left was obtained from a donor with hyperlipidemia, while the other bag was obtained from a donor with normal serum lipid levels.

Diet has an important effect on blood cholesterol, but the size of this effect varies substantially between individuals.^[15] About 50% of nonesterified cholesterol is absorbed in the intestine,^[16] but interindividual variations in the efficiency of uptake, and the effect of other dietary components such as plant sterols and fiber content affect absorption.^[16] Moreover, when dietary cholesterol intake goes down, production (principally by the liver^[17]) typically increases, though not always with complete compensation, so that reductions in blood cholesterol can be modest. Reductions in fat intake, particularly saturated fats, also reduce blood cholesterol.^[18] Dietary sucrose and fructose can raise LDL cholesterol levels in the blood.^[19] In the United States, the National Lipid Association Expert Panel on Familial Hypercholesterolemia recommends that people with familial hypercholesterolemia restrict intakes of total fat to 25 - 35% of energy intake, saturated fatty acids should make up less than 7% of energy intake, and cholesterol intake should be less than 200 mg per day.^[6] The inclusion of 2 g per day of plant stanol or sterol esters and 10 to 20 g per day of soluble fiber decrease dietary cholesterol absorption.^[6] Dietary changes can typically achieve reductions of 10 to 15% in blood cholesterol.^[6]

Maintaining a healthy body weight through increased physical activity and appropriate caloric intake is also important. Overweight or obese individuals can lower blood cholesterol by losing weight - on average a kilogram of weight loss can reduce LDL cholesterol by 0.8 mg/dl.^[6]

Genetics

Genetic abnormalities are in some cases completely responsible for hypercholesterolemia, such as in familial hypercholesterolemia, where one or more genetic mutations in the autosomal dominant APOB gene exist, the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene.^[20]

Even when no single mutation is responsible for hypercholesterolemia, genetic predisposition still plays a major role in combination with sedentary lifestyle, obesity, stress, or an atherogenic diet.^[14][21]

Diagnosis

Interpretation of cholesterol levels
cholesterol type	mg/dL	mmol/L	interpretation
total cholesterol	<200	<5.2	desirable[22]
	200-239	5.2-6.2	borderline[22]
	>240	>6.2	high[22]
LDL cholesterol	<100	<2.6	most desirable[22]
	100-129	2.6-3.3	good[22]
	130-159	3.4-4.1	borderline high[22]
	160-189	4.1-4.9	high and undesirable[22]
	>190	>4.9	very high[22]
HDL cholesterol	<40	<1.0	undesirable; risk increased[22]
	41-59	1.0-1.5	okay, but not optimal[22]
	>60	>1.55	good; risk lowered[22]

Indications to lower LDL cholesterol
Coronary risk	because they have...	should consider	reduction indicated
high	>20% risk of MI in 10 years, or risk factor such as coronary heart disease, diabetes, peripheral-artery disease, carotid-artery disease, or aortic aneurysm	>70 mg/dL, 3.88 mmol/L especially if there are risk factors[23][24]	>100 mg/dL, 5.55 mmol/L[23]
moderately high	10-20% risk of MI in 10 years and > 1 risk factors	>100 mg/dL, 5.55 mmol/L[23]	>130 mg/dL, 7.21 mmol/L[23]
moderate	<10% risk of MI in 10 years > 1 risk factors	>130 mg/dL, 7.21 mmol/L[23]	>160 mg/dL, 8.88 mmol/L[23]
low	No or one risk factor	>160 mg/dL, 8.88 mmol/L[23]	>190 mg/dL, 10.5 mmol/L[23]

Cholesterol is measured as milligrams per deciliter (mg/dL) of blood in the United States and some other countries. In the United Kingdom, most European countries, and Canada, millimoles per liter of blood (mmol/Ll) is the measure.^[25]

For healthy adults, the UK National Health Service recommends upper limits of total cholesterol of 5 mmol/L, and low-density lipoprotein cholesterol (LDL) of 3 mmol/L. For people at high risk of cardiovascular disease, the recommended limit for total cholesterol is 4 mmol/L, and 2 mmol/L for LDL.^[26]

In the United States, the National Heart, Lung, and Blood Institute within the National Institutes of Health classifies total cholesterol of less than 200 mg/dL as “desirable,” 200 to 239 mg/dL as “borderline high,” and 240 mg/dL or more as “high”.^[27]

No absolute cutoff between normal and abnormal cholesterol levels exists, and interpretation of values must be made in relation to other health conditions and risk factors.

Higher levels of total cholesterol increase the risk of cardiovascular disease, particularly coronary heart disease. Levels of LDL or non-HDL cholesterol both predict future coronary heart disease; which is the better predictor is disputed.^[28] High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction.^[28] In the past, LDL and VLDL levels were rarely measured directly due to cost. Levels of fasting triglycerides were taken as an indicator of VLDL levels (generally about 45% of fasting triglycerides is composed of VLDL), while LDL was usually estimated by the Friedewald formula:

LDL $\approx$ total cholesterol - HDL - (0.2 x fasting triglycerides).

However, this equation is not valid on nonfasting blood samples or if fasting triglycerides are elevated >4.5 mmol/L (> ∼400 mg/dL). Recent guidelines have, therefore, advocated the use of direct methods for measurement of LDL wherever possible.^[28] It may be useful to measure all lipoprotein subfractions ( VLDL, IDL, LDL, and HDL) when assessing hypercholesterolemia and measurement of apolipoproteins and lipoprotein (a) can also be of value.^[28] Genetic screening is now advised if a form of familial hypercholesterolemia is suspected.^[28]

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), more often a family history of premature, earlier onset atherosclerosis is found.

Screening

The U.S. Preventive Services Task Force strongly recommends routine screening for men 35 years and older and women 45 years and older for lipid disorders and the treatment 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.^[29] In Canada, screening is recommended for men 40 and older and women 50 and older.^[30] In those with normal cholesterol levels, screening is recommended once every five years.^[31] Once people are on a statin further testing provides little benefit except to possibly determine compliance with treatment.^[32]

Treatment

Recommendations for both primary prevention^[33] and secondary prevention^[34] have been published. For those at high risk, a combination of lifestyle modification and statins has been shown to decrease mortality.^[7]

Lifestyle

Lifestyle changes recommended for those with high cholesterol include: smoking cessation, limiting alcohol consumption, increasing physical activity, and maintaining a healthy weight. A diet that emphasizes low-cholesterol foods, restricts saturated fats,^[7] and avoids trans fat is also recommended.^[35] In strictly controlled surroundings, dietary changes 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.^[36]

Medication

Statins (or HMG-CoA reductase inhibitors) are commonly used to treat hypercholesterolemia if diet is ineffective. Other agents that may be used include: fibrates, nicotinic acid, and cholestyramine.^[37] These, however, are only recommended if statins are not tolerated or in pregnant women.^[37] Statins can reduce total cholesterol by about 50% in the majority of people;^[28] effects appear similar regardless of the statin used.^[38] While statins are effective in decreasing mortality in those who have had previous cardiovascular disease, debate exists over whether or not they are effective in those with high cholesterol but no other health problems.^[39] One review did not find a mortality benefit in those at high risk, but without prior cardiovascular disease.^[39] Other reviews concluded a mortality benefit does exist,^[38][40][41] but concerns regarding the quality of the evidence persist.^[42] Statins may improve quality of life when used in people without existing cardiovascular disease (i.e. for primary prevention).^[43] Statins decrease cholesterol in children with hypercholesterolemia, but no studies as of 2010 show improved clinical outcomes^[44] and diet is the mainstay of therapy in childhood.^[28] Injectable antibodies against the protein PCSK9 (evolocumab, bococizumab, alirocumab) can reduce LDL cholesterol and have been shown to reduce mortality.^[45]

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 the majority of individuals (55%) used it in conjunction with conventional medicine.^[46] A review of trials of phytosterols and/or phytostanols reported an average of 9% lowering of LDL-cholesterol.^[47] 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 g/day of phytosterols or phytostanols. Some researchers, however, are concerned about diet supplementation with plant sterol esters and draw attention to lack of long-term safety data.^[48]

Epidemiology

Rates of high total cholesterol in the United States in 2010 are just over 13%, down from 17% in 2000.^[49]

Average total cholesterol in the United Kingdom is 5.9 mmol/L, while in rural China and Japan, average total cholesterol is 4 mmol/L.^[7] Rates of coronary artery disease are high in Great Britain, but low in rural China and Japan.^[7]

Research

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia.

The National Cholesterol Education Program revised their guidelines;^[50] however, their 2004 revisions have been criticized for use of nonrandomized, observational data.^[51]

In the UK, the National Institute for Health and Clinical Excellence has made recommendations for the treatment of elevated cholesterol levels, published in 2008.^[37]

The Task Force for the management of dyslipidaemias of the European Society of Cardiology and the European Atherosclerosis Society published guidelines for the management of dyslipidaemias in 2011.^[28]

Special populations

Among people whose life expectancy is relatively short, hypercholesterolemia is not a risk factor for death by any cause including coronary heart disease.^[52] Among people older than 70, hypercholesterolemia is not a risk factor for being hospitalized with myocardial infarction or angina.^[52] There are also increased risks in people older than 85 in the use of statin drugs.^[52] Because of this, medications which lower lipid levels should not be routinely used among people with limited life expectancy.^[52]

The American College of Physicians recommends for hypercholesterolemia in people with diabetes:^[53]

1. Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all adults with known coronary artery disease and type 2 diabetes.
2. Statins should be used for primary prevention against macrovascular complications in adults with type 2 diabetes and other cardiovascular risk factors.
3. Once lipid-lowering therapy is initiated, people with type 2 diabetes mellitus should be taking at least moderate doses of a statin^[54]
4. For those people with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

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