Template:Short description Template:Infobox medical condition (new) Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood.<ref name=Durrington>Template:Cite journal</ref> It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), and dyslipidemia (any abnormalities of lipid and lipoprotein levels in the blood).<ref name=Durrington/>
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 type 2 diabetes and an underactive thyroid.<ref name=Durrington/>
Cholesterol is one of three major classes of lipids produced and used by all animal cells to form membranes. Plant cells manufacture phytosterols (similar to cholesterol) but in small quantities.<ref>Template:Cite journal</ref> Cholesterol is 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), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL).<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> In contrast, higher HDL cholesterol levels are protective.<ref>Template:Cite journal</ref>
Avoiding trans fats and replacing saturated fats in adult diets with polyunsaturated fats are recommended dietary measures to reduce total blood cholesterol and LDL in adults.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=BMJ2015/> In people with very high cholesterol (e.g., familial hypercholesterolemia), diet is often not sufficient to achieve the desired lowering of LDL, and lipid-lowering medications are usually required.<ref name=Ito2011>Template:Cite journal</ref> If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed.<ref name = Ito2011/> About 34 million adults in the United States have high blood cholesterol.<ref name=GHR2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:TOC limit
Signs and symptomsEdit
Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis (build-up of fatty plaques in the arteries, so-called 'hardening of the arteries').<ref name="BMJ2008">Template:Cite journal</ref> Over decades, elevated serum cholesterol contributes to the formation of atheromatous plaques in the arteries. This can lead to progressive narrowing of the involved arteries. Alternatively, smaller plaques may rupture and cause a clot to form and obstruct blood flow.<ref>Template:Cite journal</ref> A sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual, the blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point 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, difficulty speaking, weakness or numbness or tingling, usually on one side of the body. Insufficient blood supply to the heart may cause 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.<ref name=Durrington/><ref name=Grundy1998>Template:Cite journal</ref>
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),<ref name=Shields2008>Template:Cite book</ref> arcus senilis (white or gray discoloration of the peripheral cornea),<ref name=Zech2008>Template:Cite journal</ref> and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers.<ref name=Andrews2006>Template:Cite book</ref><ref name=Rapini2007>Template:Cite book</ref> Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.<ref name=Andrews2006/>
CausesEdit
Hypercholesterolemia is typically due to a combination of environmental and genetic factors.<ref name="BMJ2008"/> Environmental factors include weight, diet, and stress.<ref name=BMJ2008/><ref name="Calderon_1999">Template:Cite journal</ref> Loneliness is also a risk factor.<ref name="Cacioppo_2010">Template:Cite journal</ref>
DietEdit
Diet affects blood cholesterol, but the size of this effect varies between individuals.<ref name="ReferenceA">Template:Cite journal</ref><ref>Template:Cite journal</ref>
A diet high in sugar or saturated fats increases total cholesterol and LDL.<ref>Template:Cite journal</ref> Trans fats have been shown to reduce levels of high-density lipoprotein while increasing levels of LDL.<ref name="Ascherio_1997">Template:Cite journal</ref>
A 2016 review found tentative evidence that dietary cholesterol is associated with higher blood cholesterol.<ref>Template:Cite journal</ref> As of 2018 there appears to be a modest positive, dose-related relationship between cholesterol intake and LDL cholesterol.<ref>Template:Cite journal</ref>
Medical conditions and treatmentsEdit
A number of other conditions can also increase cholesterol levels including diabetes mellitus type 2, obesity, alcohol use, monoclonal gammopathy, dialysis therapy, nephrotic syndrome, hypothyroidism, Cushing's syndrome and anorexia nervosa.<ref name=BMJ2008/> Several medications and classes of medications may interfere with lipid metabolism: thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid, antipsychotics,<ref name=BMJ2008/> certain anticonvulsants and medications for HIV as well as interferons.<ref name="Herink">Template:Cite book</ref>
GeneticsEdit
Genetic contributions typically arise from the combined effects of multiple genes, known as "polygenic," although in certain cases, they may stem from a single gene defect, as seen in familial hypercholesterolemia.<ref name=BMJ2008/> In familial hypercholesterolemia, mutations may be present in the APOB gene (autosomal dominant), the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene.<ref name=ghr>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Familial hypercholesterolemia affects about one in 250 individuals.<ref name="pmid28864697">Template:Cite journal</ref>
The Lithuanian Jewish population may exhibit a genetic founder effect.<ref>Template:Cite journal</ref> One variation, G197del LDLR which is implicated in familial hypercholesterolemia, has been dated to the 14th century.<ref>Template:Citation</ref> The Template:Clarify of these variations has been the subject of debate.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
DiagnosisEdit
| Cholesterol type | mmol/L | mg/dL | Interpretation | |
|---|---|---|---|---|
| total cholesterol | <5.2 | <200 | Desirable<ref name="BBDstatins">Template:Cite journal which cites
|
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}}</ref> |
| 5.2–6.2 | 200–239 | Borderline<ref name="BBDstatins"/> | ||
| >6.2 | >240 | High<ref name="BBDstatins"/> | ||
| LDL cholesterol | <2.6 | <100 | Most desirable<ref name="BBDstatins"/> | |
| 2.6–3.3 | 100–129 | Good<ref name="BBDstatins"/> | ||
| 3.4–4.1 | 130–159 | Borderline high<ref name="BBDstatins"/> | ||
| 4.1–4.9 | 160–189 | High and undesirable<ref name="BBDstatins"/> | ||
| >4.9 | >190 | Very high<ref name="BBDstatins"/> | ||
| HDL cholesterol | <1.0 | <40 | Undesirable; risk increased<ref name="BBDstatins"/> | |
| 1.0–1.5 | 41–59 | Okay, but not optimal<ref name="BBDstatins"/> | ||
| >1.55 | >60 | Good; risk lowered<ref name="BBDstatins"/> |
Cholesterol is measured in 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/L) is the measure.<ref name="MayoClinic">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="NHScholesterol">Diagnosing High Cholesterol, NHS Choices. Retrieved 2013-03-09.</ref>
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".<ref name="NHLBIcholesterol">ATP III Guidelines At-A-Glance Quick Desk Reference, National Cholesterol Education Program. Retrieved 2013-03-09.</ref>
There is no absolute cutoff between normal and abnormal cholesterol levels, and values must be considered in relation to other health conditions and risk factors.<ref> {{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref> {{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref> Template:Cite journal</ref>
Higher levels of total cholesterol increase the risk of cardiovascular disease, particularly coronary heart disease.<ref>Template:Cite journal</ref> Levels of LDL or non-HDL cholesterol both predict future coronary heart disease; which is the better predictor is disputed.<ref name = "ESC 2011">Template:Cite journal</ref> High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction.<ref name = "ESC 2011" /> In the past, LDL and VLDL levels were rarely measured directly due to cost.<ref> Template:Cite journal</ref><ref> {{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref> {{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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 <math>\approx</math> total cholesterol – HDL – (0.2 x fasting triglycerides).<ref>Template:Cite journal</ref>
However, this equation is not valid on nonfasting blood samples or if fasting triglycerides are elevated (>4.5 mmol/L or >~400 mg/dL). Recent guidelines have, therefore, advocated the use of direct methods for the measurement of LDL wherever possible.<ref name = "ESC 2011"/> 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.<ref name = "ESC 2011"/> Genetic screening is now advised if a form of familial hypercholesterolemia is suspected.<ref name = "ESC 2011"/>
ClassificationEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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 between atherosclerosis progression and clinical consequences. If the hypercholesterolemia is hereditary (familial hypercholesterolemia), more often a family history of premature, earlier onset atherosclerosis is found.<ref>Template:Cite book</ref>
Screening methodEdit
The U.S. Preventive Services Task Force in 2008 strongly recommended 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 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.<ref name=Pignone>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2016 they concluded that testing the general population under the age of 40 without symptoms is of unclear benefit.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
In Canada, screening is recommended for men 40 and older and women 50 and older.<ref>Template:Cite journal</ref> In those with normal cholesterol levels, screening is recommended once every five years.<ref>Template:Cite journal</ref> Once people are on a statin further testing provides little benefit except possibly to determine compliance with treatment.<ref>Template:Cite journal</ref>
In the UK, after someone is diagnosed with familial hypercholesterolemia, clinicians, family, or both, contact first- and second-degree relatives to come forward for testing and treatment. Research suggests that clinician-only contact results in more people coming forward for testing.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
TreatmentEdit
Treatment recommendations have been based on four risk levels for heart disease.<ref name=Gru2004>Template:Cite journal</ref> For each risk level, LDL cholesterol levels representing goals and thresholds for treatment and other action are made.<ref name=Gru2004/> The higher the risk category, the lower the cholesterol thresholds.<ref name=Gru2004/>
| Risk category | Criteria for risk category | Consider lifestyle modifications | Consider medication | ||||
|---|---|---|---|---|---|---|---|
| No. of risk factors† | 10-year risk of myocardial ischemia |
mmol/litre | mg/dL | mmol/litre | mg/dL | ||
| High | Prior heart disease | OR | >20% | >2.6<ref name="BBDstatins2">Template:Cite journal</ref> | >100 | >2.6 | >100 |
| Moderately high | 2 or more | AND | 10–20% | >3.4 | >130 | >3.4 | >130 |
| Moderate | 2 or more | AND | <10% | >3.4 | >130 | >4.1 | >160 |
| Low | 0 or 1 | >4.1 | >160 | >4.9 | >190 | ||
| †Risk factors include cigarette smoking, hypertension (BP ≥140/90 mm Hg or on antihypertensive medication), low HDL cholesterol (<40 mg/dL), family history of premature heart disease, and age (men ≥45 years; women ≥55 years). | |||||||
For those at high risk, a combination of lifestyle modification and statins has been shown to decrease mortality.<ref name="BMJ2008"/>
LifestyleEdit
Lifestyle changes recommended for those with high cholesterol include: smoking cessation, limiting alcohol consumption, increasing physical activity, and maintaining a healthy weight.<ref name="ReferenceA"/>
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.<ref name =Ito2011/>
DietEdit
Eating a diet with a high proportion of vegetables, fruit, dietary fiber, and low in fats results in a modest decrease in total cholesterol.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name =Ito2011/>
Eating dietary cholesterol causes a small rise in serum cholesterol,<ref name="Brownawell 355–364">Template:Cite journal</ref><ref name="Berger 276–294">Template:Cite journal</ref> the magnitude of which can be predicted using the Keys<ref name="Keys 776–787">Template:Cite journal</ref> and Hegsted<ref name="Hegsted 281–295">Template:Cite journal</ref> equations. Dietary limits for cholesterol were proposed in the United States, but not in Canada, the United Kingdom, and Australia.<ref name="Brownawell 355–364"/> However, in 2015 the Dietary Guidelines Advisory Committee in the United States removed its recommendation of limiting cholesterol intake.<ref name=USDA2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
A 2020 Cochrane review found replacing saturated fat with polyunsaturated fat resulted in a small decrease in cardiovascular disease by decreasing blood cholesterol.<ref>Template:Cite journal</ref> Other reviews have not found an effect from saturated fats on cardiovascular disease.<ref>Template:Cite journal</ref><ref name=BMJ2015>Template:Cite journal</ref> Trans fats are recognized as a potential risk factor for cholesterol-related cardiovascular disease, and avoiding them in an adult diet is recommended.<ref name=BMJ2015/>
The National Lipid Association recommends that people with familial hypercholesterolemia restrict intakes of total fat to 25–35% of energy intake, saturated fat to less than 7% of energy intake, and cholesterol to less than 200 mg per day.<ref name =Ito2011/> Changes in total fat intake in low-calorie diets do not appear to affect blood cholesterol.<ref>Template:Cite journal</ref>
Increasing soluble fiber consumption has been shown to reduce levels of LDL cholesterol, with each additional gram of soluble fiber reducing LDL by an average of 2.2 mg/dL (0.057 mmol/L).<ref>Template:Cite journal</ref> Increasing consumption of whole grains also reduces LDL cholesterol, with whole grain oats being particularly effective.<ref>Template:Cite journal</ref> Inclusion of 2 g per day of phytosterols and phytostanols and 10 to 20 g per day of soluble fiber decreases dietary cholesterol absorption.<ref name =Ito2011/> A diet high in fructose can raise LDL cholesterol levels in the blood.<ref>Template:Cite journal</ref>
MedicationEdit
Statins are the typically used medications, in addition to healthy lifestyle interventions.<ref>Template:Cite journal</ref> Statins can reduce total cholesterol by about 50% in the majority of people,<ref name="ESC 2011" /> and are effective in reducing the risk of cardiovascular disease in both people with<ref>Template:Cite journal</ref> and without pre-existing cardiovascular disease.<ref name="CMAJ11">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In people without cardiovascular disease, statins have been shown to reduce all-cause mortality, fatal and non-fatal coronary heart disease, and strokes.<ref name=Tay2013>Template:Cite journal</ref> Greater benefit is observed with the use of high-intensity statin therapy.<ref>Template:Cite journal</ref> Statins may improve quality of life when used in people without existing cardiovascular disease (i.e. for primary prevention).<ref name=Tay2013/> Statins decrease cholesterol in children with hypercholesterolemia, but no studies as of 2010 show improved outcomes<ref name="Leben2010">Template:Cite journal</ref> and diet is the mainstay of therapy in childhood.<ref name="ESC 2011" />
Other agents that may be used include fibrates, nicotinic acid, and cholestyramine.<ref name="NICE67">Template:NICE</ref> These, however, are only recommended if statins are not tolerated or in pregnant women.<ref name="NICE67" /> Injectable antibodies against the protein PCSK9 (evolocumab, bococizumab, alirocumab) can reduce LDL cholesterol and have been shown to reduce mortality.<ref name="Navarese2015">Template:Cite journal</ref>
GuidelinesEdit
In the US, guidelines exist from the National Cholesterol Education Program (2004)<ref name=pmid15358046>Template:Cite journal</ref> and a joint body of professional societies led by the American Heart Association.<ref>Template:Cite journal</ref>
In the UK, the National Institute for Health and Clinical Excellence has made recommendations for the treatment of elevated cholesterol levels, published in 2008,<ref name=NICE67/> and a new guideline appeared in 2014 that covers the prevention of cardiovascular disease in general.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name ="ESC 2011"/>
Specific populationsEdit
Among people whose life expectancy is relatively short, hypercholesterolemia is not a risk factor for death by any cause including coronary heart disease.<ref name="AMDAten">Template:Citation</ref> Among people older than 70, hypercholesterolemia is not a risk factor for being hospitalized with myocardial infarction or angina.<ref name="AMDAten"/> There are also increased risks in people older than 85 in the use of statin drugs.<ref name="AMDAten"/> Because of this, medications that lower lipid levels should not be routinely used among people with limited life expectancy.<ref name="AMDAten"/>
The American College of Physicians recommends the following for hypercholesterolemia in people with diabetes:<ref name=pmid15096336>Template:Cite journal</ref>
- 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.
- Statins should be used for primary prevention against macrovascular (coronary artery disease, cerebrovascular disease, or peripheral vascular disease) complications in adults with type 2 diabetes and other cardiovascular risk factors.
- Once lipid-lowering therapy is initiated, people with type 2 diabetes mellitus should be taking at least moderate doses of a statin.<ref name=pmid15096337>Template:Cite journal</ref>
- 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.
Alternative medicineEdit
A 2002 survey found that 1.1% of U.S. adults who used alternative medicine did so to treat high cholesterol. Consistent with previous surveys, this one found the majority of individuals (55%) used it in conjunction with conventional medicine.<ref name=NCCIH>Template:Cite journal</ref> A systematic review<ref>Template:Cite journal</ref> of the effectiveness of herbal medicines used in traditional Chinese medicine had inconclusive results due to the poor methodological quality of the included studies. A review of trials of phytosterols and/or phytostanols, average dose 2.15 g/day, reported an average of 9% lowering of LDL-cholesterol.<ref name=PMID1909>Template:Cite journal</ref> 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 the lack of long-term safety data.<ref name=Wein2009>Template:Cite journal</ref>
EpidemiologyEdit
Rates of high total cholesterol in the United States in 2010 are just over 13%, down from 17% in 2000.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="BMJ2008"/> Rates of coronary artery disease are high in Great Britain, but low in rural China and Japan.<ref name="BMJ2008"/>
Research directionsEdit
Gene therapy is being studied as a potential treatment.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>