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Hypercholesterolemia

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Hypercholesterolemia
SpecialtyEndocrinology Edit this on Wikidata

Hypercholesterolemia 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, a sort of fat; see the diagrammatic structure at the right. It is one of three major classes of lipids which all animal cells utilize 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, bile acids and vitamin D.

Since cholesterol is essentially insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). While all the fat carrying particles carry cholesterol, the low density lipoprotein (LDL) particles are the major carrier of fat molecules which are small enough to move out of the blood plasma into the artery wall in humans, thus acting to drive arterial disease.[2] Elevated levels of these fat carrying particles 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 dietary fat to reduce total blood cholesterol and LDL particle numbes in adults,[3] has long been recommended for people with familial hypercholesterolemia, although usually insufficient to achieve excellent lowering of LDL particles and medications which reduce cholesterol production or absorption are usually required.[4] If necessary other treatments, including LDL apheresis or even surgery (for particularly severe subtypes) are performed.[4].

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.[5] 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.[1][6] 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),[7] arcus senilis (white or gray discoloration of the peripheral cornea),[8] and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers.[9][10] Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.[9]

Causes

Hypercholesterolemia is typically due to a combination of environmental and genetic factors.[5] Environmental factors include: obesity and dietary choices.[5] 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.[5] 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).[5]

Diet

Diet has an important effect on blood cholesterol but the size of this effect varies substantially between individuals.[11] Approximately 50% of non-esterified cholesterol is absorbed in the intestine,[12] but inter-individual variations in the efficiency of uptake, and the effect of other dietary components such as plant sterols and fiber content affect absorption.[12] Moreover, when dietary cholesterol intake goes down, production (principally by the liver[2]) 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.[13] Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia in 2011 were that people with familial hypercholesterolemia should follow the The National Cholesterol Education Program (NCEP) Third Adult Treatment Panel (ATP III) Therapeutic Lifestyle Changes (TLC) diet and restrict intakes of total fat to 25 - 35% of energy intake; that saturated fatty acids should make up less than 7% of energy intake, and that cholesterol intake should be less than 200 mg per day.[4] There is also evidence that 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.[4] Dietary changes can typically achieve reductions of 10 to 15% in blood cholesterol.[4]

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.[4]

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.[14]

Diagnosis

See also: High-density lipoprotein § Recommended ranges, and Low-density lipoprotein § Normal ranges
A color photograph of two bags of thawed fresh frozen plasma. The bag on the left was obtained from a donor with hypercholesterolemia, and contains cloudy yellow fluid, while the bag obtained from a normal donor contains clear yellow fluid.
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.

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.[5]

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.[15][16] 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 from the other fractions using the equation LDL total cholesterol - HDL - (0.2 x triglycerides). This formula is known as the Friedewald calculation

Since the relative content of the fat carrying particles tend to shift to lower ratios of triglyceride versus cholesterol fat molecules within the particles as they deliver fat molecules to cells around the body, it has long been promoted to rely on measuring only cholesterol in blood as a surrogate for LDL, to reduce cost of lab measurements. To improve this surrogate, two additional tests are commonly added: (a) measurement of triglycerides (more abundant within the larger particles) and (b) cholesterol chemically associated with HDL. Thus the commonly used formula: , offers a more accurate estimation of the amount of cholesterol associated with all the LDL particles.

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 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.

Screening

The U.S. Preventive Services Task Force (USPSTF) has 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.[17] In Canada screening is recommended for men 40 and older and women 50 and older.[18] In those with normal cholesterol levels screening is recommended once every five years.[19] Once people are on a statin further testing provides little benefit except to possibly determine compliance with treatment.[20]

Treatment

Recommendations for both primary prevention[21] and secondary prevention[22] have been published. For those at high risk a combination of lifestyle modification and statins has been shown to decrease mortality.[5]

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,[5] trans fat-free and low cholesterol foods.[23] 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.[24]

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.[25] One review did not find a mortality benefit in those at high-risk but without prior cardiovascular disease.[25] Other reviews concluded that there is a mortality benefit[26][27][28] but there were concerns regarding the quality of the evidence.[29] With respect to quality of life there is limited evidence of improvement when statins are used for primary prevention.[29] No studies as of 2010 show improved clinical outcomes in children with high cholesterol even though statins decrease cholesterol levels.[30] Effects appear similar regardless of the statin used.[27] Other agents that may be used for elevated cholesterol levels including: fibrates, nicotinic acid and cholestyramine .[31] These however are only recommended for primary prevention if statins are not tolerated.[31]

Guidelines

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes.[32] 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").[33]
  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;[34] however, their 2004 revisions have been criticized for use of nonrandomized, observational data.[35]

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.[31]

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.[36] A review trials of phytosterols and/or phytostanols reported an average of 9% lowering of LDL-cholesterol.[37] 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 lack of long-term safety data.[38]


Epidemiology

Rates of high cholesterol in the United States in 2010 are just over 13% down from 17% in 2000.[39]

References

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  26. ^ Mills, EJ (2011 Feb). "Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials". QJM : monthly journal of the Association of Physicians. 104 (2): 109–24. doi:10.1093/qjmed/hcq165. PMID 20934984. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  27. ^ a b Tonelli, M (2011-11-08). "Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis". CMAJ : Canadian Medical Association. 183 (16): E1189–E1202. doi:10.1503/cmaj.101280. PMC 3216447. PMID 21989464. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  28. ^ Cholesterol Treatment Trialists' (CTT) Collaborators (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. Online first. doi:10.1016/S0140-6736(12)60367-5. {{cite journal}}: |author= has generic name (help)
  29. ^ a b Taylor F, Ward K, Moore TH; et al. (2011). Taylor, Fiona (ed.). "Statins for the primary prevention of cardiovascular disease". Cochrane Database Syst Rev (1): CD004816. doi:10.1002/14651858.CD004816.pub4. PMID 21249663. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  30. ^ Lebenthal Y, Horvath A, Dziechciarz P, Szajewska H, Shamir R (2010). "Are treatment targets for hypercholesterolemia evidence based? Systematic review and meta-analysis of randomised controlled trials". Arch Dis Child. 95 (9): 673–80. doi:10.1136/adc.2008.157024. PMID 20515970.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ a b c National Institute for Health and Clinical Excellence. Clinical guideline 67: Lipid modification. London, 2008.
  32. ^ 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. doi:10.1059/0003-4819-140-8-200404200-00012. PMID 15096336. Retrieved 2010-11-04.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  33. ^ Vijan, S; Hayward, RA; American College Of, Physicians (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. doi:10.1059/0003-4819-140-8-200404200-00013. PMID 15096337. Retrieved 2010-11-04.
  34. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  36. ^ Barnes PM, Powell-Griner E, McFann K, Nahin RL (May 27, 2004). "Complementary and Alternative Medicine Use Among Adults: United States, 2002" (PDF). Advance Data. http://nccam.nih.gov/news/2004/052704.htm (343): 6–9. Retrieved 2010-11-04. {{cite journal}}: External link in |version= (help)CS1 maint: multiple names: authors list (link)
  37. ^ Demonty I, Ras RT, van der Knaap HC, Duchateau GS, Meijer L, Zock PL, Geleijnse JM, Trautwein EA (February 2009). "Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake". J Nutr. 139 (2): 271–84. doi:10.3945/jn.108.095125. PMID 19091798.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  38. ^ Weingärtner O.; et al. (2009). "Controversial role of plant sterol esters in the management of hypercholesterolaemia". European Heart Journal. 30 (4): 404–9. doi:10.1093/eurheartj/ehn580. PMC 2642922. PMID 19158117. {{cite journal}}: Explicit use of et al. in: |author= (help)
  39. ^ Carrol, Margaret (2012). "Total and High-density Lipoprotein Cholesterol in Adults: National Health and Nutrition Examination Survey, 2009–2010" (PDF). CDC. {{cite web}}: Unknown parameter |month= ignored (help)
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