For the full versions of these articles see bmj.com CLINICAL REVIEW Hypercholesterolaemia and its management Deepak Bhatnagar,1,2 Handrean Soran,1 Paul N Durrington1 PRACTICE,pp509,510 Hypercholesterolaemia is one of the major causes of the optimal levels of plasma cholesterol should be atherosclerosis. Although there are many causes, ≤4 mmol/l (LDL cholesterol ≤2 mmol/l) in patients 1University of Manchester hypercholesterolaemia is the permissive factor that with pre-existing atherosclerotic disease or diabetes or Cardiovascular Research Group, allows other risk factors to operate.1 The incidence of in those who have a combination of other risk factors Core Technology Facility, Manchester M13 9NT coronary heart disease is usually low where population that produce a risk of cardiovascular disease (coronary 2 2Diabetes Centre, Royal Oldham plasma cholesterol concentrations are low. In Britain heart disease and stroke) of 20% or more over the next Hospital, Oldham OL1 2JH coronary heart disease is a major cause of mortality, 10 years.8 Theseriskfactorsincludemalesex, Correspondence to: D Bhatnagar, and a recent Department of Health survey suggested increased age, cigarette smoking, high blood pressure, Diabetes Centre, Royal Oldham that the average plasma cholesterol concentration in Hospital, Oldham OL1 2JH impaired fasting glucose concentration, low concen- [email protected] the United Kingdom was 5.9 mmol/l, much higher trations of high density lipoprotein (HDL) cholesterol, than the 4 mmol/l seen in rural China and Japan, where raised triglycerides, Indian subcontinent ancestry, and Cite this as: BMJ 2008;337:a993 3 doi:10.1136/bmj.a993 heart disease is uncommon. Many studies before and low socioeconomic class. after the introduction of statins have indicated that reducingthe prevalence of hypercholesterolaemia is an Who gets hyperlipidaemia? important means of decreasing coronary risk. Hypercholesterolaemia usually results from nutri- tional factors such as obesity and a diet high in What is hypercholesterolaemia? saturated fats combined with an underlying polygenic Cholesterol plays an important role as the precursor for predisposition. There is overproduction of LDL,9 and steroid hormones and bile acids and it is essential for the structural integrity of cell membranes. It is transported in the body in lipoproteins. Figure 1 Box 1 Causes of hyperlipidaemia shows the role of cholesterol in lipoprotein meta- Some causes of secondary hyperlipidaemia bolism. Conventionally the upper limit for laboratory Nephrotic syndrome reference ranges is based on the 95th or 90th centile Obstructive jaundice for a healthy population. This does not apply to plasma Hypothyroidism cholesterol, however, as several studies show that the Cushing’ssyndrome epidemiological relation between plasma cholesterol Anorexia nervosa and risk of coronary heart disease extends to the lower end of the cholesterol distribution. Although the Thiazide diuretics SOURCES AND relation becomes progressively steeper, there is no Ciclosporin SELECTION CRITERIA obvious threshold below which it ceases to exist.5 Some causes of mixed hyperlipidaemia* We selected references if Therefore, it is more rational to base a desirable or Type 2 diabetes mellitus they included a recent healthy concentration of plasma cholesterol on the Obesity, particularly if accompanied by features of the meta-analysis or value at which coronary risk is considered unaccep- metabolic syndrome provided a useful, tably high. Most patients developing coronary heart Alcohol excess objective, and disease have plasma cholesterol concentrations that are comprehensive account likely to be between the 30th and 90th centile for their Monoclonal gammopathy including extensive population of origin.6 A population is considered to be Renal dialysis recent references. We unhealthy when its average plasma cholesterol con- Glucocorticoids chosethemfroma centration exceeds 5 mmol/l (equivalent to low density β search of PubMed, blockers lipoprotein (LDL) cholesterol of 3 mmol/l).7 personal reference lists, Retinoic acid derivatives The Joint British Societies (JBS2) guidelines on and three textbooks26-28 *Increase in plasma cholesterol and triglycerides prevention of cardiovascular disease recommend that BMJ | 30 AUGUST 2008 | VOLUME 337 503 CLINICAL REVIEW its genetic component is unlikely to be monogenic, unless it is extreme. Hypercholesterolaemia can also Box2CalculatingLDLcholesterolandnon-HDLcholesterol concentrations* have an entirely genetic cause. A common example of = this is monogenic familial hypercholesterolaemia, an Low density lipoprotein cholesterol total serum cholesterol − (HDL cholesterol + (serum triglycerides/ autosomal dominant disorder in which the LDL 2.2)) cholesterol is raised from birth (table 1). 10 It is = − characterised by a dominant pattern of inheritance of Non-HDL cholesterol total cholesterol HDL cholesterol premature coronary disease and/or tendon *All values in mmol/l xanthomata. 11 Raised plasma triglyceride concentration in associa- tion with hypercholesterolaemia is common (table 2) pancreatitis may occur. Such patients should be and poses an additional risk of coronary heart referred to lipid clinics for treatment. disease. 12 Usually such patients have an increase in Remnant removal disease (type III hyperlipopro- both low density lipoprotein (VLDL) cholesterol and teinaemia) leads to combined hyperlipidaemia.14 LDL cholesterol and a decrease in HDL cholesterol. Although rare, it carries a high risk of both coronary This condition is called combined hyperlipidaemia or, heart disease and peripheral vascular disease early in if there is a strong familial tendency, familial combined life. Typically striate palmar and tuberoeruptive hyperlipidaemia. Usually the disorder is polygenic xanthomata occur.15 Chylomicron remnants accumu- with a strong overlap with glucose intolerance, late in the circulation owing to homozygosity for the diabetes, and the metabolic syndrome and may apo E2 isoform of apolipoprotein E, the ligand precede the onset of diabetes. 13 important for their hepatic clearance. It has variable Occasionally patients with hypercholesterolaemia penetrance, suggesting that some other cause such as have a plasma triglyceride concentration of >10 mmol/ obesity or insulin resistance is necessary for its l owing to an increasein both chylomicrons and VLDL. expression. The plasma has a milky appearance and eruptive xanthomata, and other features such as acute Table 2 and box 1 outline the diagnostic classifica- tion of hypercholesterolaemia. Before primary hypercholesterolaemia is diagnosed underlying sec- ondary causes should be excluded. Dietary cholesterol absorbed in the How to investigate the patient with gut is transported to the liver in chylomicrons, which are rich in hypercholesterolaemia triglyceride. Cholesterol is also Before treatment is started for hypercholesterolaemia a Gut Apo A1 synthesised de novo in the liver, gut, detailed history, clinical examination, and baseline Chylomicron and central nervous system. Apo B48 Cholesterol in the liver is packaged laboratory tests are needed to discover causes of along with triglycerides and secreted secondary hypercholesterolaemia, manifestations of TG as VLDL, which is then converted into LDL in the circulation. LDL delivers primary lipoprotein disorders, and any complications TG cholesterol to most tissues, and the related to atherosclerosis. A family and occupational Lipoprotein uptake of cholesterol is facilitated by — lipase TG LDL receptors. Excess cholesterol is history including a history of smoking, alcohol TG removed from cells by HDL and is intake, and dietary preferences—will help to indicate then either transferred to LDL and TG VLDL, whence it can return to the the extent to which these factors contribute to Apo A1 LRP liver via hepatic LDL receptors or be hypercholesterolaemia and/or to risk of cardiovascular ABC A1 Liver taken up directly from HDL via the Un ’ es disease and to gauge the patient s ability to change C te hepatic class B scavenger receptors. ho rif le ied LDL SR B1 C st Cholesterol is also excreted in bile lifestyle. The physical examination should include ho ero les l HDL receptor tero both as free cholesterol and as bile es l blood pressure, body weight, height, waist circumfer- ter acids, which are both subject to er enterohepatic circulation. Most of the ence, and a search for xanthomata. A family history is yl est plasma cholesterol is present in LDL, essential to facilitate cascade testing in primary with smaller amounts in VLDL and Apo B100 CholesterCETP 16 VLDL HDL. Total plasma cholesterol mainly hypercholesterolaemia. Reverse reflects LDL cholesterol. In the fasting TG cholesterol state, plasma triglyceride generally Laboratory assessment in hypercholesterolaemia Lipoprotein transport indicates the VLDL concentration. lipase TG IDL When screening for hypercholesterolaemia it is Tissue fluid LDL = low density lipoprotein advisable to take blood samples after a fast of at least TG LDL HDL = high density lipoprotein VLDL = very low density lipoprotein 10 hours to avoid the postprandial contribution to IDL = intermediate density lipoprotein plasma triglycerides. If plasma triglycerides do not Arterial wall LDL CETP = cholesteryl ester transfer protein receptor ABCAI = ATP binding cassette transporter 1 exceed 4.5 mmol/l, the LDL cholesterol concentration Modified LDL SRB 1 = class B scavenger receptors Foam LRP = lipoprotein related receptor can be calculated