High cholesterol

Signs and symptoms

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'). 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. 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.

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 weight, diet, and stress. Loneliness is also a risk factor.

Diet

Diet affects blood cholesterol, but the size of this effect varies between individuals.

A diet high in sugar or saturated fats increases total cholesterol and LDL. Trans fats have been shown to reduce levels of high-density lipoprotein while increasing levels of LDL.

A 2016 review found tentative evidence that dietary cholesterol is associated with higher blood cholesterol. As of 2018 there appears to be a modest positive, dose-related relationship between cholesterol intake and LDL cholesterol.

Medical conditions and treatments

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.

Genetics

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. Familial hypercholesterolemia affects about one in 250 individuals.

The Lithuanian Jewish population may exhibit a genetic founder effect. One variation, G197del LDLR which is implicated in familial hypercholesterolemia, has been dated to the 14th century. The of these variations has been the subject of debate.

Diagnosis

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.

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.

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".

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.

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. High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction. 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 or ~400 mg/dL). Recent guidelines have, therefore, advocated the use of direct methods for the measurement of LDL wherever possible. 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. Genetic screening is now advised if a form of familial hypercholesterolemia is suspected.

Classification

Main article: Hyperlipidemia

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.

Screening method

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. In 2016 they concluded that testing the general population under the age of 40 without symptoms is of unclear benefit.

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 possibly to determine compliance with treatment.

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.

Treatment

Treatment recommendations have been based on four risk levels for heart disease. For each risk level, LDL cholesterol levels representing goals and thresholds for treatment and other action are made. The higher the risk category, the lower the cholesterol thresholds.

For those at high risk, a combination of lifestyle modification and statins has been shown to decrease mortality.

Lifestyle

Lifestyle changes recommended for those with high cholesterol include: smoking cessation, limiting alcohol consumption, increasing physical activity, and maintaining a healthy weight.

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.

Diet

Eating a diet with a high proportion of vegetables, fruit, dietary fiber, and low in fats results in a modest decrease in total cholesterol.

Eating dietary cholesterol causes a small rise in serum cholesterol, the magnitude of which can be predicted using the Keys and Hegsted equations. Dietary limits for cholesterol were proposed in the United States, but not in Canada, the United Kingdom, and Australia. However, in 2015 the Dietary Guidelines Advisory Committee in the United States removed its recommendation of limiting cholesterol intake.

A 2020 Cochrane review found replacing saturated fat with polyunsaturated fat resulted in a small decrease in cardiovascular disease by decreasing blood cholesterol. Other reviews have not found an effect from saturated fats on cardiovascular disease. Trans fats are recognized as a potential risk factor for cholesterol-related cardiovascular disease, and avoiding them in an adult diet is recommended.

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.

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). Increasing consumption of whole grains also reduces LDL cholesterol, with whole grain oats being particularly effective. Inclusion of 2 g per day of phytosterols and phytostanols and 10 to 20 g per day of soluble fiber decreases dietary cholesterol absorption.

Medication

Statins are the typically used medications, in addition to healthy lifestyle interventions. Statins can reduce total cholesterol by about 50% in the majority of people, and are effective in reducing the risk of cardiovascular disease in both people with and without pre-existing cardiovascular disease. In people without cardiovascular disease, statins have been shown to reduce all-cause mortality, fatal and non-fatal coronary heart disease, and strokes. Greater benefit is observed with the use of high-intensity statin therapy. Statins may improve quality of life when used in people without existing cardiovascular disease (i.e. for primary prevention). and diet is the mainstay of therapy in childhood.

Other agents that may be used include fibrates, nicotinic acid, and cholestyramine. These, however, are only recommended if statins are not tolerated or in pregnant women. Injectable antibodies against the protein PCSK9 (evolocumab, bococizumab, alirocumab) can reduce LDL cholesterol and have been shown to reduce mortality.

Guidelines

In the US, guidelines exist from the National Cholesterol Education Program (2004) and a joint body of professional societies led by the American Heart Association.

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

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.

Specific populations

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

The American College of Physicians recommends the following for hypercholesterolemia in people with diabetes:

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 (coronary artery disease, cerebrovascular disease, or peripheral vascular disease) 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.
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.

Alternative medicine

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. A systematic review 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. 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.

Epidemiology

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

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. Rates of coronary artery disease are high in Great Britain, but low in rural China and Japan.

Research directions

Gene therapy is being studied as a potential treatment.

References

References

1. (August 2003). "Dyslipidaemia". Lancet.
2. (December 2005). "Cholesterol and Plants". Journal of Chemical Education.
3. (December 2004). "Understanding lipoproteins as transporters of cholesterol and other lipids". Advances in Physiology Education.
4. (June 2004). "Atherogenic lipoprotein particles in atherosclerosis". Circulation.
5. (March 2006). "Antiatherogenic small, dense HDL--guardian angel of the arterial wall?". Nature Clinical Practice. Cardiovascular Medicine.
6. (September 2015). "Healthy diet – Fact sheet N°394". [[World Health Organization]].
7. (June 2011). "Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia". Journal of Clinical Lipidology.
8. "Hypercholesterolemia".
9. (August 2008). "Hypercholesterolaemia and its management". BMJ.
10. (July 2010). "Concept of vulnerable/unstable plaque". Arteriosclerosis, Thrombosis, and Vascular Biology.
11. (May 1998). "Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction. American Heart Association". Circulation.
12. (2008). "Eyelid, conjunctival, and orbital tumors: atlas and textbook". Lippincott Williams & Wilkins.
13. (March 2008). "Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia". Lipids in Health and Disease.
14. (2006). "Andrews' Diseases of the Skin: Clinical Dermatology". Saunders Elsevier.
15. (2007). "Dermatology: 2-Volume Set". Mosby.
16. (1999). "Stress, stress reduction and hypercholesterolemia in African Americans: a review". Ethnicity & Disease.
17. (October 2010). "Loneliness matters: a theoretical and empirical review of consequences and mechanisms". Annals of Behavioral Medicine.
18. (February 2013). "Evidence of lifestyle modification in the management of hypercholesterolemia". Current Cardiology Reviews.
19. (June 1997). "Plasma lipid and lipoprotein responses to dietary fat and cholesterol: a meta-analysis". The American Journal of Clinical Nutrition.
20. (2016). "The Evidence for Saturated Fat and for Sugar Related to Coronary Heart Disease". Progress in Cardiovascular Diseases.
21. (October 1997). "Health effects of trans fatty acids". The American Journal of Clinical Nutrition.
22. (November 2016). "Does Dietary Cholesterol Matter?". Current Atherosclerosis Reports.
23. (January 2019). "Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol". The American Journal of Clinical Nutrition.
24. (September 2017). "Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis". BMJ Open.
25. (August 2004). "A Population-Genetic Test of Founder Effects and Implications for Ashkenazi Jewish Diseases". [[American Society of Human Genetics]] via [[PubMed]].
26. Durst, Ronen. (May 2001). "Recent Origin and Spread of a Common Lithuanian Mutation, G197del LDLR, Causing Familial Hypercholesterolemia: Positive Selection Is Not Always Necessary to Account for Disease Incidence among Ashkenazi Jews". American Journal of Human Genetics.
27. "Jewish Genetics, Part 3: Jewish Genetic Diseases (Mediterranean Fever, Tay–Sachs, pemphigus vulgaris, Mutations)".
28. (2023-01-11). "Diagnosis and treatment".
29. [http://www.nhs.uk/Conditions/Cholesterol/Pages/Diagnosis.aspx Diagnosing High Cholesterol] {{Webarchive. link. (2017-07-28 , NHS Choices. Retrieved 2013-03-09.)
30. [https://www.nhlbi.nih.gov/files/docs/guidelines/atglance.pdf ATP III Guidelines At-A-Glance Quick Desk Reference], National Cholesterol Education Program. Retrieved 2013-03-09.
31. (May 2016). "Total cholesterol as a risk factor for coronary heart disease and stroke in women compared with men: A systematic review and meta-analysis". Atherosclerosis.
32. (July 2011). "ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)". European Heart Journal.
33. (June 1972). "Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge". Clinical Chemistry.
34. (1993). "GeneReviews". University of Washington, Seattle.
35. U.S. Preventive Services Task Force. "Screening for Lipid Disorders: Recommendations and Rationale".
36. (October 2016). "Screening for Dyslipidemia in Younger Adults: A Systematic Review for the U.S. Preventive Services Task Force". Annals of Internal Medicine.
37. (August 2016). "Screening for Lipid Disorders in Children and Adolescents: US Preventive Services Task Force Recommendation Statement". JAMA.
38. (October 2003). "Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update". CMAJ.
39. (December 2002). "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report". Circulation.
40. (2011). "Statins for secondary prevention of cardiovascular disease: the right dose". Pharmacology.
41. (2023-10-24). "Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis". Health Technology Assessment.
42. (30 April 2024). "What is the best way to identify people with inherited high cholesterol?". NIHR Evidence.
43. (July 2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines". Circulation.
44. (March 2013). "Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price". Consumer Reports.
45. (December 2013). "Effectiveness of interventions to promote healthy diet in primary care: systematic review and meta-analysis of randomised controlled trials". BMC Public Health.
46. (June 2013). "Increased consumption of fruit and vegetables for the primary prevention of cardiovascular diseases". The Cochrane Database of Systematic Reviews.
47. (June 2010). "Cholesterol: where science and public health policy intersect". Nutrition Reviews.
48. (August 2015). "Dietary cholesterol and cardiovascular disease: a systematic review and meta-analysis". The American Journal of Clinical Nutrition.
49. (July 1965). "Serum cholesterol response to changes in the diet: IV. Particular saturated fatty acids in the diet". Metabolism.
50. (November 1965). "Quantitative effects of dietary fat on serum cholesterol in man". The American Journal of Clinical Nutrition.
51. (2015). "Scientific Report of the 2015 Dietary Guidelines Advisory Committee".
52. (August 2020). "Reduction in saturated fat intake for cardiovascular disease". The Cochrane Database of Systematic Reviews.
53. (March 2014). "Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis". Annals of Internal Medicine.
54. (August 2015). "Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies". BMJ.
55. (January 1999). "Cholesterol-lowering effects of dietary fiber: a meta-analysis". The American Journal of Clinical Nutrition.
56. (September 2015). "Whole-grain and blood lipid changes in apparently healthy adults: a systematic review and meta-analysis of randomized controlled studies". The American Journal of Clinical Nutrition.
57. (June 2019). "2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Circulation.
58. (April 2018). "Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials". European Heart Journal.
59. (November 2011). "Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis". CMAJ.
60. (February 2011). "Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials". QJM.
61. (August 2012). "The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials". Lancet.
62. (November 2016). "Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force". JAMA.
63. (January 2013). "Statins for the primary prevention of cardiovascular disease". The Cochrane Database of Systematic Reviews.
64. (February 2015). "Ongoing challenges for pharmacotherapy for dyslipidemia". Expert Opinion on Pharmacotherapy.
65. (September 2010). "Are treatment targets for hypercholesterolemia evidence based? Systematic review and meta-analysis of randomised controlled trials". Archives of Disease in Childhood.
66. {{NICE. 67. Lipid modification. 2008
67. (July 2015). "Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis". Annals of Internal Medicine.
68. (August 2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines". Journal of the American College of Cardiology.
69. (June 2019). "2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Circulation.
70. (18 July 2014). "Cardiovascular disease: risk assessment and reduction, including lipid modification".
71. (February 2014). "Ten Things Physicians and Patients Should Question". AMDA – The Society for Post-Acute and Long-Term Care Medicine.
72. (April 2004). "Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians". Annals of Internal Medicine.
73. (April 2004). "Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians". Annals of Internal Medicine.
74. (May 2004). "Complementary and alternative medicine use among adults: United States, 2002". Advance Data.
75. (July 2011). "Chinese herbal medicines for hypercholesterolemia". The Cochrane Database of Systematic Reviews.
76. (February 2009). "Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake". The Journal of Nutrition.
77. (February 2009). "Controversial role of plant sterol esters in the management of hypercholesterolaemia". European Heart Journal.
78. Carrol, Margaret. (April 2012). "Total and High-density Lipoprotein Cholesterol in Adults: National Health and Nutrition Examination Survey, 2009–2010". CDC.
79. (2011). "Gene therapy for familial hypercholesterolemia". Current Pharmaceutical Design.
80. (December 2010). "LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives". International Archives of Medicine.