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Postgraduate Medical Journal (1989) 65, 543 - 552 Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from

Difficult Decisions Borderline hypercholesterolaemia: when to introduce D. Bhatnagar and P.N. Durrington University Department ofMedicine, Manchester Royal Infirmary, Manchester, UK. Introduction 'Please do not write any more articles about can stimulate a therapeutic reflex response without the and coronary disease and the diet and proper diagnostic assessment of each individual drugs which are supposed to influence them. The facts patient. Supposing we limited ourselves to but a single about coronary disease are these: the less ather- therapeutic approach to hyponatraemia: what omatous your ancestors, the harder your water, and disasters would follow! Some knowledge of lipo- the more habitual exercise you take, the less likely you protein is essential to the clinician con- are to be troubled by it. Do stop bothering about templating the mangement of hypercholesterolaemia. whether your fats are saturated or unsaturated, help yourselves liberally to butter and stop propagating these erroneous legends." Lipoprotein physiology (Figure 1) This remains too frequently the view of medical practitioners in Britain. Sadly it must be one ofthe few The average Briton consumes almost 100 g offat every statements of Richard Asher which does not remain as day and much of this is . The products of penetratingly accurate today as it was when first made: fat digestion are absorbed in the small intestine where prescience had on this rare occasion deserted him. We they are synthesized into large triglyceride-rich lipo- still, of course, believe that susceptibility to coronary proteins called chylomicrons, which are secreted into by copyright. atheroma is in some individuals inherited, but this the lacteals. They enter the circulation from the does not mean that their risk is immutable. Evidence lymphatic system via the thoracic duct. As they that coronary disease morbidity and mortality can be circulate they come in contact with the enzyme, decreased by therapy aimed at lowering serum choles- lipoprotein lipase, located in the capillary beds of terol, is now strong. Indeed our patients are likely to tissues, such as muscle and , which have benefit more from this than from many other medical a high requirement for triglyceride as an energy source practices, which are accepted without question.2'0 and as an energy store respectively. That enzyme The debate concerning the 'cholesterol hypothesis' has releases fatty acids and glycerol from the chylomicron now moved on to consider how cholesterol or some triglyceride and the lipoprotein particle becomes pro- factor closely related to its metabolism provokes gressively smaller. Finally the small remnant particle, http://pmj.bmj.com/ atherogenesis and to determine the particular levels of which is formed, is cleared by a special on the cholesterol at which therapeutic intervention would be cells, which recognizes one ofthe proteins present expected to produce benefit." It is this latter issue in the remnant called E. This whole which is the subject of this article. process is usually completed within a few hours of a In some patients with hypercholesterolaemia (per- meal and chylomicrons are not normally present in the haps the minority) the decision to prescribe lipid- plasma following an overnight fast. lowering therapy, when diet has not produced a Triglyceride is extremely important to any animal on September 23, 2021 by guest. Protected satisfactory decrease in the serum cholesterol, is easy. organism (except perhaps one living our present In others, however, it may involve a difficult clinical cossetted existence when our only movement is to be judgement. Indeed the majority of patients with carried by car from one centrally heated, labour- hypercholesterolaemia must be regarded as borderline saving building to another!). This is because trigly- when drug therapy is to be considered. It is our ceride is a rich source of energy and is light and purpose to provide a background of ideas, which will compact to store. Being a lipid it eschews water and assist in making that decision. The origins and fate of thus the adipose cell comprises a-triglyceride droplet the different lipoproteins which transport cholesterol with only a tiny rim of cytoplasm: no more than 15% are diverse, and it is naive in the extreme to believe that of its weight is water and every gram ofadipose tissue any single numerical value for the serum cholesterol thus yields almost the full 9 Calories locked in each gram oftriglyceride. Compare this with carbohydrate. Correspondence: P.N. Durrington, M.D., F.R.C.P. Although refined carbohydrate contains 4 Calories per Received: 14 February 1989 gram, because it is osmotically active, even substances ) The Fellowship of Postgraduate Medicine, 1989 544 D. BHATNAGAR AND P.N. DURRINGTON Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from

tissues, such as muscle, or converted to ketone bodies by the liver to act as respiratory substrates for other tissues, constitutes one transport system. The other is provided by the secretion of a triglyceride-rich lipop- rotein by the liver, called very low density lipoprotein (VLDL). These lipoproteins, which are generally smaller than chylomicrons, are present in fasting plasma. Most of the triglyceride in a fasting blood sample is in VLDL. Within the circulation VLDL undergoes a similar sequence of events to the chylomicron: a progressive removal of its triglyceride load by the enzyme, lipoprotein lipase. This time the remnant particle, which is formed, is the low density lipoprotein (LDL). This lipoprotein is sufficiently small to cross the vascular endothelium and enter the extravascular extracellular fluid, where it comes in contact with all the cells of the body. It constitutes the system by which they receive cholesterol since it contains the cholesterol secreted by the liver as a component of VLDL, its precursor, and also cholesterol acquired during the circulation of VLDL and LDL from high density lipoprotein (HDL). Cholesterol is an essential component of cell memb- ranes and every cell thus has a requirement for it. Certain specialized tissues also require cholesterol as a Figure 1 An outline of lipoprotein metabolism. precursor for the synthesis of other sterols such as Triglyceride-rich lipoproteins secreted by the gut glucorticoids, , sex steroids, by copyright. (chylomicrons) and liver (VLDL) undergo lipolysis D and bile salts. The cellular requirement for (lipoprotein lipase) as they circulate, resulting in the cholesterol is met by a membrane receptor, the LDL formation of chylomicron remnants and LDL, which receptor, which recognizes LDL and allows its entry together with some partially metabolized VLDL, are cleared by receptors on the liver and peripheral cells. into the cell. Synthesis of the receptor is precisely Non-receptor mediated cell entry also occurs. HDL (not regulated in response to the metabolic demands for shown) probably participates in the return of excess cholesterol. In the liver, where the removal of cholesterol delivered to peripheral tissue back to the liver cholesterol from the body is possible in the bile, this (reverse cholesterol transport). receptor-mediated removal of LDL from the circula- tion constitutes a major means of LDL catabolism. In

addition to leaving the circulation by this means LDL http://pmj.bmj.com/ such as glycogen can only be stored in limited amounts may also exit by a non-receptor mediated route. This in any cell, meaning that the store of carbohydrate means of exit becomes increasingly significant as energy in a gram of muscle or liver is much less than plasma LDL levels increase, because, unlike the one Calorie. The 70 kg man has about 15 kg of stored receptor-mediated uptake of LDL, it is unregulated triglyceride representing 140,000 Calories (compare and remains concentration dependent. It can thus lead this to his 6 kg ofprotein equivalent to 24,000 Calories to the accumulation ofexcess cholesterol in the tissues and 225 mg of glycogen representing 900 Calories). and may contribute to atheroma. Even with an energy expenditure of 2000 Calories per Some four fifths of serum cholesterol is in LDL and on September 23, 2021 by guest. Protected day these triglyceride stores would not be completely about one fifth (more in women than men) is present in depleted after starvation for two months. This illus- HDL. Cholesterol present in LDL is the reason for the trates the very real difficulty experienced by patients, positive relationship between total serum cholesterol who are obese, in reducing their weight. To have an and the risk of ischaemic heart disease (Figure 2). The ideal weight of 70 kg, but to be 20% overweight, is to HDL cholesterol concentration on the other hand is have an extra 10 kg of triglyceride stored, which inversely related to risk. HDL is believed to have a key represents 90,000 Calories and many months of role in the removal of excess cholesterol from tissues suffering, if it is to be removed! and its return to the liver (reverse cholesterol trans- The primal importance of triglyceride dictates that port). Unlike the triglyceride-rich lipoproteins it is systems exist to transport it, at times other than after secreted by the liver and gut as protein-rich particles, meals. The release from adipose tissue of non- which contain little lipid. It is small and readily enters esterified fatty acids, which can be directly respired by the tissue fluid, where it is the most abundant lipo- BORDERLINE HYPERCHOLESTEROLAEMIA 545 Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from

'V - Secondary cause ofhyperlipoproteinaemia wD 40UA A n Total mortality .: 35 Those most frequently encountered are summarized X 30 in Table II. It is important to have fully excluded them, 0) O' 25 certainly by the stage when lipid lowering drug therapy -a is being considered. Sometimes adequate treatment of D 20 :1> /ZSCHD mortality the primary disorder will result in resolution of the co- 15 hyperlipidaemia, for example in hypothyroidism. X 10 0) Other disorders, such as diabetes, are important to V5 recognize and treat, but their treatment will often not

Cwa) n produce adequate control of the hyperlipidaemia (or reduce the risk of ischaemic heart disease) so that cD 160 200 240 280 320 mg/dl therapy specifically directed at the hyperlipidaemia is 4 5 6 7 8 mmol/I frequently still required.'2 Drugs contributing to Serum cholesterol hyperlipidaemia, such as and P-adreno- receptor blockers'3"4 can present difficult decisions. Figure 2 The relationship betwen cholesterol and mor- We tend to avoid them in the management of tality from coronary heart disease (CHD) and from all in patients with hyperlipidaemia unless causes in 361, 662 men screened in the Multiple Risk the blood pressure Factor Intervention Study.20 The line at 200 mg/dl is inadequately controlled by other (5.2 mmol/l) indicates what is currently considered an drugs. However, this approach would be considerably ideal cholesterol level. strengthened, ifthere was adequate evidence that some of the newer and better tolerated drugs, which can replace diuretics and P-blockers, actually do reduce protein. After its secretion it acquires cholesterol, mortality and morbidity from hypertension. In which it esterifies, and returns to the liver by passing it patients with established ischaemic heart disease we on to other lipoproteins or, perhaps in part, directly. would only rarely allow the presence of hyper-

lipidaemia to influence other clinical considerations in by copyright. the prescription of or P-blocking drugs. Laboratory tests Primary hyperlipidaemia Most laboratories measure total serum cholesterol, total serum and HDL cholesterol, and, if The British Hyperlipidaemia Association and the hypercholesterolaemia and/or hypertriglyceridaemia European Atherosclerosis Society have recommended is present, will report which lipoproteins are increased that as a society we should attempt to reduce our mean according to the WHO classification (popularly cholesterol to around 5 mmol/1.'5"6 This recommend- known as the Fredrickson classification) (Table I). It is ation is based on an appraisal of the epidemiological http://pmj.bmj.com/ important not to regard this classification as a diag- evidence linking cholesterol to ischaemic heart disease. nostic classification since the different types may have In those nations where the mean cholesterol is below a variety of causes both secondary and primary. 5 mmol/l coronary heart disease is uncommon.'7 In

Table I WHO classification of hyperlipoproteinaemia on September 23, 2021 by guest. Protected Lipoprotein Type elevated Cholesterol Triglyceride Frequency I Chylomicrons* Raised Markedly raised Very rare Ila LDL Raised Normal Common IIb VLDL and LDL Raised Raised Common III Beta VLDL Raised Raised Rare IV VLDL Normal Raised Common V Chylomicrons* Raised Markedly raised Rare and VLDL *Milky appearance of plasma; LDL = low density lipoprotein; VLDL = very low density lipoprotein; beta VLDL = remnants oftriglyceride-rich lipoprotein not normally present in any quantity. 546 D. BHATNAGAR AND P.N. DURRINGTON Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from

Table II Some common causes of secondary hyper- Overall we can calculate from the Registrar General's lipidaemia statistics and a measure of the excess risk due to cholesterol23 that some 2% ofmen whose cholesterol is Obesity less than 5 mmol/l will die by the age of 60 years and Drugs e.g., P-blockers, thiazide diuretics Diabetes mellitus about 4% of those with cholesterol of 6 mmol/l and Alcohol perhaps 6-8% ofthose at 7.5 mmol/l. Thus, ifthe aim Renal disease oftreatment was to prevent death before the age of60, Hypothyroidism then even at a level of 7.5 mmol/l more than 90% of Biliary obstruction people receiving such treatment would derive no Myeloma benefit from it and merely be exposed to its possible side effects. Ofcourse, we realize that the prevention of coronary morbidity is also a major objective of the UK the average cholesterol of middle-aged men is cholesterol-lowering therapy and that the figures for between 6 and 6.5 mmol/1'8"9 with levels of about combined mortality and morbidity before the age of 60 0.5 mmol/l less in premenopausal women and are about 3 times those for mortality alone. Also we 0.5 mmol/l greater afterwards. In a study of over realize that prevention ofdeath from coronary disease 360,000 men in the USA it was established that there before the age of 70 would be a more laudable was no threshold below which ischaemic heart disease objective. However, statistics for the likely benefits of did not occur (Figure 2).2o However, total mortality cholesterol reduction after the age of 60 are more reached a minimum at around 5 mmol/l and increased difficult to compute. The important point, however, is again as levels fell below 4 mmol/l. This latter that the decision to use drugs in the management of phenomenon was principally due to deaths from hyperlipidaemia would be greatly facilitated, if we neoplasia within the first year or two ofthe cholesterol were able to predict with greater certainty whether the measurement and it is generally considered that the patient was one of those destined to succumb low cholesterol was caused by the malignancy present prematurely to coronary disease or one who would at the initial examinations.2' However, erring on the escape such a fate. Our clinical decision to introduce side of caution,22 5 mmol/l rather than a lower level lipid-lowering drug therapy must therefore rely on an by copyright. has been chosen as an ideal level. appraisal of the factors, which are likely to make each This, ofcourse, is not a realistic therapeutic goal for individual patient with hypercholesterolaemia more most patients with hyperlipidaemia and it is important or less susceptible to accelerated atherogenesis. Fac- therefore in planning their management to have some tors critical to this are now considered (Table III). appreciation ofthe scale oftheir increased risk in order to balance it against any disadvantages and potential Table III Factors which would encourage the prescription side effects of therapy. Both the British Hyper- of lipid-lowering drugs in patients whose serum cholesterol lipidaemia Association and the European Athero- exceeds 6.5 mmol/l despite dietary therapy sclerosis Society after appraising the evidence from I . Genetic hyperlipidaemia clinical trials, in particular the Lipid http://pmj.bmj.com/ Research Clinics a) Familial hypercholesterolaemia trial with cholestyramine,3 4 concluded that lipid- b) Type III hyperlipoproteinaemia lowering drugs should only exceptionally be con- 2. Adverse family history sidered unless the cholesterol level exceeded 6.5 mmol/l 3. Other coronary risk factors after a reasonable period of appropriate dietary a) Diabetes mellitus modification. The results of the Helsinki Heart Study b) Hypertension became available after these recommendations were c) Smoking history published and it amply confirmed them by demon- 4. Manifestation of coronary disease or peripheral strating decreased coronary morbidity and mortality arterial disease on September 23, 2021 by guest. Protected without evidence ofadverse side effects when men with 5. Coronary artery bypass surgery cholesterol 6. Hypercholesterolaemia combined with hypertrigly- levels generally exceeding 6.4 mmol/l, ceridaemia and/or low HDL (actually non-HDL cholesterol > 5.2 mmol/l, average 7. Younger age HDL cholesterol 1.2 mmol/l), despite diet, received 8. Male sex as opposed to placebo.7'8 It must, however, be emphasized that it has not been recommended that failure of the cholesterol level to fall below 6.5 mmol/l with dietary treatment is in itself (i) The diagnosis an indication for lipid-lowering drug therapy: it is merely a starting point for its consideration. The risk Most hyperlipidaemia (types Ila, Ilb and IV) occur as of a serum cholesterol level greater than 6.5 mmol/l a result of environmental, particularly nutritional will vary tremendously from individual to individual. factors, interacting with some constitutional tendency BORDERLINE HYPERCHOLESTEROLAEMIA 547 Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from to hyperlipidaemia, which is probably largely Table IV Lipid-lowering drugs genetic.24 From inheritance studies and from the Gaussian distribution of the serum cholesterol con- 1. Bile acid sequestrants e.g. cholestyramine, centration, this tendency is clearly polygenic in the 2. Fibric acid derivatives majority of people with hyperlipidaemia. There are, e.g. , , gemfibrozil however, some individuals whose hyper- 3. cholesterolaemia does not originate in this way, but 4. Nicotinic acid and its derivatives depends to a large extent on a single gene, and whose e.g. coronary risk may be very much higher. One clinical 5. HMG-CoA reductase inhibitors syndrome which exemplifies this is familial hyper- e.g. , , cholesterolaemia.25,26 (a) Familial hypercholesterolaemia (FH) about the same extent. The diagnosis may be FH is a dominantly inherited condition. About 1 in confirmed in the laboratory by ultracentrifugation or 500 people in the UK are heterozygotes for FH. They identification of the patient's apolipoprotein E generally have a type Ila or occasionally type Ilb phenotype. In many cases, however, the diagnosis may pattern and on average their serum cholesterol is more be made clinically by the presence of striate palmar than 9 mmol/l. However, there is considerable vari- xanthomata and/or tubero-eruptive xanthomata over ation. In any patient with markedly elevated choles- the elbows and knees. The risk of coronary disease is terol levels it is important to consider FH as a possible similar to that in FH, but there is also a marked diagnosis, but in the young, even when there is only increase in peripheral arterial disease. Type III may be borderline elevation of the cholesterol, FH should be responsive to diet. Any persisting (even borderline) considered as a cause. The reason for this is that there elevation in cholesterol should, however, be treated is a pronounced increase in coronary risk in FH, which with lipid-lowering drugs, of which the most effective is not confined to those with the highest LDL are the fibrate drugs. cholesterol levels.27 Almost 60% of men and 15% of by copyright. women with FH will die before the age of 60 years (c) Familial combined hyperlipidaemia without treatment.28 FH is due to a defect in the LDL receptor gene on chromosome 19. It is, of course, Studies of the families of patients, who have heart present throughout life and increased cholesterol can attacks in early life, have indicated the possible be detected in most affected children, unlike polygenic existence of a hyperlipidaemia with a variable hypercholesterolaemia, which is often not detectable phenotype producing type Ila, IIb or type IV hyper- until the 3rd or even 4th decade. Most middle-aged lipoproteinaemia in different members of the same patients with FH will have tendon xanthomata usually family.3'-36 It has been suggested that the condition, in the tendons of the dorsum of the hands and in the which has been called familial combined hyper- Achilles tendons. In younger adults the diagnosis may lipidaemia (FCH), is a dominant disorder. The evi- http://pmj.bmj.com/ be difficult unless a first degree relative with tendon dence for this contention is inconclusive. The coronary xanthomata is found or the cholesterol is known to risk in FCH is believed to be greater than for patients have been raised in childhood. Death of a parent or with polygenic hyperlipidaemia. FCH has been sibling from ischaemic heart disease before the age of estimated to affect as many as 1 in 50 people, but since 50 is also strongly suggestive. it has no specific clinical features it remains ill-defined. FH usually responds incompletely to diet and It does, however, emphasize the increased risk of lipid-lowering drugs are almost invariably required hyperlipidaemia when it occurs in an individual with on September 23, 2021 by guest. Protected and should not be withheld. The best therapeutic an adverse family history of coronary heart disease. response is usually achieved with bile acid sequest- rating agents (cholestyramine or colestipol) or the new (d) Particularly high cholesterol associated with the HMG-CoA reductase inhibitors29 (Table IV). Fibrate type IIa or IIb phenotype drugs (gemfibrozil, bezafibrate, fenofibrate), probucol or nicotinic acid and its derivatives are sometimes The relationship between cholesterol and the risk of helpful in addition. ischaemic heart disease is exponential (Figure 2). It becomes progressively steeper. Thus levels of (b) Type III hyperlipoproteinaemia cholesterol exceeding 8.0 mmol/l after diet are associated with a sufficiently increased risk that, even This is an unusual cause ofhyperlipidaemia26,30 usually if other adverse factors have not been found, they inherited as an autosomal recessive of variable pene- would generally justify cholesterol-lowering medi- trance. Both cholesterol and triglycerides are raised to cation.37 548 D. BHATNAGAR AND P.N. DURRINGTON Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from

(e) Other hyperlipidaemias a) (O 20- Men 35-57 at M_O aged years e In type IV hyperlipoproteinaemia, triglycerides in 0 a VLDL are raised, but LDL cholesterol levels are - ?~15-Iw normal. There is no substantial evidence that treating type IV hyperlipoproteinaemia with drugs is °o Oiin 101 beneficial.38 Laboratories which report patients with C.) '- serum cholesterol levels in excess of6.5 mmol/l as type X 5- IV should cease to do so and report them as type lIb >.G) o- - hyperlipoproteinaemia to avoid confusion. ,@% -rrn rrr rrrrn rrrrn Occasionally patients have markedly raised Serum cholesterol 1_2345 14 145 12345 chylomicron levels, even in the fasting state, usually in (quintiles) association with raised VLDL concentrations (type V Diastolic blood <90 <90 >90 >90 hyperlipoproteinaemia).3639 Their fasting triglyceride pressure (mmHg) levels generally exceed 10 mmol/l. Often the Smokers No No Yes Yes cholesterol level is above 6.5 but this is not as mmol/l, Figure 3 The effect of progressively increasing concen- a result of raised LDL levels, which are, in fact, low. trations of serum cholesterol on coronary risk alone and The hypercholesterolaemia is due to cholesterol pres- in combination with raised blood pressure in cigarette- ent in VLDL and chylomicrons. The condition may be smokers and non-smokers. Data from 356, 222 men asymptomatic, but there is a definite increased screened in the Multiple Risk Factor Intervention likelihood of acute pancreatitis, which is the usual Study.23 justification for therapy. Unless there is coexistent diabetes an association with ischaemic heart disease is often not evident. interesting that in Japan, where the averge cholesterol for middle-aged men is around 4 mmol/l, coronary disease is uncommon even in smokers, and patients

(ii) Adverse family history with diabetes and hypertension.'7 The treatment of by copyright. glycaemia or high blood pressure appears to have little An adverse family history is a risk factor for ischaemic impact on the increased incidence of ischaemic heart heart disease. We usually regard this as the first disease in diabetes and hypertension. This emphasizes manifestation ofischaemic heart disease in father or a the importance of considering cholesterol-lowering brother before the age of 60 and in mother or sister drug therapy in patients with these conditions, whose before the age of 70. Some familial aggregation of cholesterol persists above 6.5 mmol/l despite dietary coronary disease must result from a shared environ- treatment.'4'42 Furthermore there can no longer be any ment and habits, such as smoking and diet. However, justification for initiating treatment of diabetes or there is evidence for a true genetic influence on hypertension without also establishing whether hyper- coronary disease susceptibility and, although this may lipidaemia is present. http://pmj.bmj.com/ operate to some extent through established risk factors It is obvious that smokers should be advised to stop. such as hypercholesterolaemia, there is also an However, even in those who do stop successfully, their independent genetic effect,24', which will enhance past smoking history many continue to increase the susceptibility to other risk factors such as cholesterol. likelihood of ischaemic heart disease for several years In practical terms this means that the decision to and may thus be another factor favouring drug introduce lipid-lowering is more likely to be made therapy, if hypercholesterolaemia remains after when there is an adverse family history of coronary dietary treatment. disease even when the diagnosis of FH has not been on September 23, 2021 by guest. Protected established. (iv) Manifestations of arteriosclerosis (iii) Other coronary risk factors Patients with hyperlipidaemia, who have already It is clear from epidemiological investigations that developed clinical evidence of ischaemic heart disease whereas a single risk factor may have only a modest or peripheral arterial disease, have declared effect, in combination with others it may increase the themselves as being at particular risk from their likelihood ofearly-onset myocardial infarction many- hyperlipidaemia. Some authorities argue that treating fold23'4 (Figure 3). Thus a hypertensive, diabetic, their hyperlipidaemia at this stage is closing the stable cigarette-smoker with hyperlipidaemia may be re- door after its occupant has bolted, citing some depres- garded as virtually certain of dying prematurely. It is sing early trials of secondary prevention as BORDERLINE HYPERCHOLESTEROLAEMIA 549 Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from justification for their opinion.43 This is, however, a (vi) Hypercholesterolaemia associated with view we are no longer able to share. Increasingly we hypertriglyceridaemia and/or low HDL are aware, as a result of coronary angiography, of patients who have sustained a myocardial infarction, The likelihood of a patient with hyper- but whose coronary disease has not spread throughout cholesterolaemia developing ischaemic heart disease is the coronary tree and who might yet benefit from increased if there is coexistent hypertriglyceridaemia treatment of their hyperlipidaemia. The outlook for (triglyceride > 2 mmol/1).47"' Generally a decreased patients following myocardial infarction has been level of HDL cholesterol (< 0.9 mmol/l) is also pres- transformed with the advent ofcardioprotective drugs ent when this occurs. There is no need for the clinician and of coronary artery bypass surgery. Except for the to be unduly concerned about the debate as to whether patient whose prognosis is poor because of heart the increased risk results from the raised triglyceride or failure, there seems little point in allowing their the low HDL:'5-'O the essential point is that either is a atheroma to proceed unchecked and we would be marker of increased risk and there is thus a stronger encouraged to introduce lipid-lowering drugs, where indication for drug therapy when diet proves inade- diet had been unsuccessful, in patients with hyper- quate. Fibrate drugs which, in addition to decreasing lipidaemia and manifestations of vascular disease. cholesterol, lower triglycerides and raise HDL Recent evidence for this view comes from a successful cholesterol, are the best first line therapy. Bile acid secondary prevention study'" and from studies involv- sequestrants may be added later to correct any remain- ing patients who had undergone coronary artery ing hypercholesterolaemia. Ifthey are used alone, they bypass surgery, in whom the rate of progress of tend to exacerbate the hypertriglyceridaemia and may atheroma in both the grafts and in the ungrafted not raise HDL. coronary arteries was reduced by lipid-lowering Very occasionally patients are found whose total therapy.9 serum cholesterol is raised above 6.5 mmol/l due to high levels of HDL cholesterol. Under these circum- stances drug treatment is inappropriate. The LDL cholesterol in such patients may be calculated from the

(v) Coronary artery bypass surgery following formula: LDL cholesterol = total by copyright. cholesterol - ([triglyceride + 2.2] + HDL choles- Several studies have indicated that the main factor terol). Only patients with LDL cholesterol levels determining the rate at which disease progresses in exceeding 4.5 mmol/l should be considered for further grafts and ungrafted coronary arteries following treatment. The formula is unsuitable for the calcul- bypass surgery is hyperlipoproteinaemia." 46 For this ation of LDL cholesterol when the serum triglyceride reason we regard effective treatment of hyperlipi- concentration exceeds 4.5 mmol/l, but it is exceedingly daemia, with drugs ifnecessary, as an essential part of unlikely that under those circumstances HDL would post-operative management. Furthermore there can be increased; rather it would be expected to be low. be little justification for making age any bar to such treatment or there would have been no point in http://pmj.bmj.com/ attempting to preserve the patient by the operation. A (vii) Younger age placebo-controlled trial of two year's lipid-lowering treatment compared to placebo following coronary When hypercholesterolaemia is discovered before the artery bypass surgery showed significantly less disease 4th or 5th decade it is a better determinant of risk than progression in the drug treated group assessed by when detected in later life.23'4' Thus, for example, a 35 coronary angiography.9 The initial average cholesterol year old man whose cholesterol is 8.00 mmol/l will level was 6.3 mmol/l and the level on treatment have about five times more likelihood ofhaving a heart on September 23, 2021 by guest. Protected 4.7 mmol/l. This study questions whether in selected attack in the next 16 years than a man of the same age groups ofpatients, such as those who have undergone whose cholesterol is 5 mmol/l. On the other hand, at coronary artery bypass surgery, the threshold for drug the age of 60 the risk of the man with the higher treatment of hypercholesterolaemia should be less cholesterol level would be only about 1.5 times that of than 6.5 mmol/l. It is essential to remember, when the other man. It is important to interpret this assessing the presence of hypercholesterolaemia in information correctly. One reason for the change in patients following coronary artery bypass surgery, relative risk is that the population of hyper- that the immediate effect of surgery, as is the case for cholesterolaemic older men is much larger than than myocardial infarction or acute coronary inefficiency, of young men. It has been swelled by men who have is to lower the cholesterol concentration. The serum become hypercholesterolaemic with advancing age,26 cholesterol level should not be determined until at whose risk is lower than those who have been hyper- least 6 weeks have elapsed, if levels within the normal cholesterolaemic since a young age. Therefore, range are to be considered valid. although the clinician must look more critically at the 550 D. BHATNAGAR AND P.N. DURRINGTON Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from decision to introduce lipid-lowering in have occurred. When medication is initiated the lipid older age groups, it must certainly not be dismissed, levels should be monitored regularly until a satisfac- particularly when the history suggests that hyper- tory response is achieved. The effectiveness offibrates cholesterolaemia may have been present for a long can be assessed after one month. The dose ofa bile acid while or there is an adverse family or personal history sequestrant should be gradually built up starting with ofvascular disease or other cardiovascular risk factors one sachet well soaked in fruit juice before breakfast, are present. Age is a major indicator of increased increasing to two sachets before breakfast after two cardiovascular risk which is, of course, in itself weeks. After a further two weeks, lipid levels can be immutable. However, to a large extent its influence measured and, if necessary additional sachets added may result from exposure to the cumulative action of before dinner and occasionally lunch, at monthly other risk factors. It seems reasonable therefore to intervals according to the cholesterol response. If suppose that the earlier measures aimed at coronary nicotinic acid is used a similar gradual build up to an prevention are adopted the greater will be the benefit, effective dose is required. Probucol takes at least but that advice about diet and smoking, and in selected 3 months to become fully effective. groups, the detection and treatment of hypertension When a satisfactory response has been achieved the and hyperlipidaemia may still have beneficial results, lipid levels should be checked every six months or even in later life. In women similar considerations annually. It is usually important to continue to check apply. There is often a fairly abrupt rise in cholesterol the lipids every year or so even in patients, who following the menopause.26 Although in general this is continue with diet alone and occasionally to revise the not associated with any abrupt change in their cor- decision to withhold lipid-lowering medication. As far onary rates,52 certain hyperlipidaemias requiring as possible, the treatment of patients with hyper- effective therapy, such as type III hyperlipopro- lipidaemia should be undertaken by the general practi- teinaemia, are not, however, usually clinically evident tioner with the hospital-based lipid clinic providing until the menopause.' treatment and further investigation of the more com- plicated or high risk disorders and providing a second opinion about whether to introduce lipid-lowering

(viii) Male sex medication or to continue with diet alone in some by copyright. borderline cases. It has to be considered, in assessing the probable benefits of lipid-lowering therapy, that the likelihood of premature ischaemic heart disease in men is five to Conclusions ten times that in women. In women with diabetes, however, this does not apply and their susceptibility Lipid-lowering medication may be considered in approaches that ofdiabetic men."3 Women with FH or patients whose serum cholesterol exceeds 6.5 mmol/l type III hyperlipoproteinaemia, although having a despite diet (occasionally at lower levels in patients better prognosis than men with these conditions, are at who have undergone coronary artery surgery). As greatly increased risk and lipid-lowering drug therapy precise a diagnosis as possible should be made before http://pmj.bmj.com/ should not be withheld on grounds of gender. The making the decision. All patients should have fasting same also applies to many women with multiple risk serum cholesterol, triglyceride and HDL cholesterol factors. Furthermore in the authors' experience, a measured. Urinalysis, serum creatinine (or urea), liver family history ofpremature ischaemic heart disease in enzymes, blood glucose and sometimes serum thyrox- a mother or sister is a particularly adverse factor both ine and occasionally immunoglobulins are required to for men and women. detect secondary causes of hyperlipidaemia. Patients considered to have familial or

hypercholesterolaemia on September 23, 2021 by guest. Protected type III hyperlipoproteinaemia, whose cholesterol Monitoring ofresponse to drug and dietary treatment level is persistently elevated, should generally receive lipid-lowering drugs. The decision to prescribe these It is never justifiable to commence lipid-lowering agents in other patients is based on an assessment of medication on the basis ofa single lipid determination. their individual risk. This takes into account factors Dietary treatment should be the initial approach to such as family history of premature arteriosclerosis, cholesterol reduction and generally a minimum oftwo personal history of arteriosclerosis, coronary artery or three lipid measurements will be required over at surgery, diabetes mellitus, smoking habit and least 3 or 4 months before the decision about lipid- hypertension. Associated hypertriglyceridaemia or lowering medication should be taken. In patients, low serum HDL cholesterol levels are also important whose hyperlipidaemia is associated with obesity, considerations and so is the height of the cholesterol longer may be required for satisfactory weight reduc- level. Treatment is more strongly indicated in younger tion and an adequate decrease in the cholesterol to age groups and in men. BORDERLINE HYPERCHOLESTEROLAEMIA 551 Postgrad Med J: first published as 10.1136/pgmj.65.766.543 on 1 August 1989. Downloaded from

Bile acid sequestrating agents should be the drug of to have a moderate triglyceride-lowering action. first choice when marked hypercholesterolaemia is 'There is no mystery about why the incidence of present except in patients with associated hypertrigly- vascular disease, like that of bronchial cancer and of ceridaemia when fibrate drugs should be the first line venereal disease, continues to rise for many decades therapy. Fibrates may also be useful for less marked after pathogenesis is established. Human beings, in- hypercholesterolaemia, particularly if there is coexis- cluding physicians and informed laymen, are eager for tent hypertriglyceridaemia, and as an adjunct to bile excuses not to face annoying facts . . . Let us now acid sequestrant therapy. Fibrates are also the usual grasp the nettle. first line therapy for diabetic hyperlipidaemia, unless significant nephropathy is present. Nicotinic acid and its derivatives and probucol are occasionally helpful. Acknowledgement The advent ofHMG-CoA reductase inhibitor drugs is expected to provide a further group of agents, which We are grateful to Miss J. Rogerson for expert secretarial will effectively lower cholesterol and are also proving assistance.

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