Maritz, F

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MAIN TOPICC M E J u l y  2 0 0 3   Vo l .2 1   N o . 7   365Dyslipidaemia predisposes to atheroscle-rosis, and where hypertriglyceridaemia issevere, also to pancreatitis. Althoughmost cases of dyslipidaemia have a prima-ry genetic pathogenesis, a significant pro-portion of patients have a secondary causethat can be modified (Table I). In manypopulations secondary causes, in particu-lar the insulin resistance (IR) syndrome(e.g. metabolic syndrome, syndrome X),play a dominant role in causing dyslipi-daemia and in the genesis of coronaryartery disease (CAD). Secondary causesof dyslipidaemia should always be consid-ered and may be important for severalreasons:• they uncover other underlying diseasesthat require specific treatment• they may explain why a previously treat-able dyslipidaemia has become resistantto treatment• they may point to an alternative andpossibly a safer treatment.In most cases of dyslipidaemia, a modifi-able secondary factor will be found. Evenwhere the treatment of the contributorysecondary cause results only in a smallchange in the lipogram, the aggressivemanagement of the modifiable secondarycause is justifiable and cost-effective, asthis may forestall costly increases in lipid-lowering medication.The secondary causes may convenientlybe remembered by the mnemonic of 5 ds(Table I):• diet• diabetes• other disorders of metabolism• drugs• diseases (non-metabolic).Pharmacogenetic studies, including thoseon the effect of genes on diet and environ-mental factors, indicate that genes play arole in determining how lipid profilesreact  to the environment.This alsoapplies to how a person reacts whenexposed to one of the secondary causes ofdyslipidaemia, and explains why only apercentage of those exposed to a sec-ondary cause will develop dyslipidaemia.This additional genetic influence is oftenresponsible for some perturbation in themetabolism of lipoprotein particles, mostoften the triglyceride (TG)-rich particles.Under normal metabolic conditions thesepatients may be entirely normal, but whenexposed to one of the secondary causesthis ‘excessive metabolic load’ precipitatesan ever-worsening cycle of impairment inlipoprotein metabolism.This may result inextremely high lipid (in particular TG)levels or a chylomicronaemia syndrome,which can in turn precipitate an attack ofpancreatitis. It is worth emphasising thatthe majority of patients with an extremelyhigh total cholesterol (TC) level (> 15mmol/l) very seldom have increased low-density lipoprotein cholesterol (LDL-C)levels such as those with familial hyper-FRANS MARITZMB ChB, MMed (Int),FCP (SA), PhDHeadInternal Medicine KarlBremer HospitalBellvilleSenior LecturerEndocrine UnitDepartment ofInternal MedicineTygerberg Hospitaland University ofStellenboschTygerbergFrans Maritz was aspecialist in generalmedicine at TygerbergHospital, University ofStellenbosch, but nowheads InternalMedicine at KarlBremer Hospitalwhere he managesthe CardiovascularRisk and Lipid Clinic.His special interest islipidology, in particu-lar the insulin resis-tance syndrome andthe non-lipid effects ofstatins.Secondary dyslipidaemiaDisorders associated with secondary dyslipidaemia are some of the commonest causesof morbidity and mortality in the South Africanpopulation. This article outlines the causes andmanagement of these disorders.Although most cases ofdyslipidaemia have a pri -mary genetic pathogene -sis, a significant propor -tion of patients have asecondary cause thatcan be modified. MAIN TOPIC366 C M E J u l y  2 0 0 3   Vo l .2 1   N o . 7cholesterolaemia. Usually thesepatients have very high TG levels,almost invariably precipitated by asecondary cause of which poorlycontrolled diabetes mellitus is thecommonest.The management of secondarydyslipidaemia should not focus onthe lipid profile of the patient.Thepatient should be treated as awhole — including all the other co-existent non-lipid risk factors. Afterdealing with the secondary cause, arisk assessment must be made bytaking all the risk factors intoaccount.The lipid profile must bejudged and managed by the com-pany it keeps — a person with anisolated hypercholesterolaemia andno other risk factors may notrequire pharmacological treatment,whereas a person with a lower cho-lesterol level may need aggressivetherapy because of massive cumu-lative risk.SECONDARY CAUSES OFDYSLIPIDAEMIASecondary causes of dyslipidaemiatend to produce characteristicchanges that may aid in finding thecause (Table II).DietOne should question the patientregarding dietary saturated fat andcholesterol intake, as these canraise the LDL-C level. Similarly,the patient should be questionedabout alcohol and carbohydrateintake, as well as recent weightgain, as these can increase the plas-ma TG level.Where the doctor’stime is at a premium, a referral toa capable dietician is well worthwhile.One should remember that someeating disorders such as anorexianervosa may present with dyslipi-daemia, in which case, paradoxical-ly, an increase in the caloric intakemay be indicated.DiabetesType 1 diabetesThe lipogram of patients with well-controlled type 1 diabetes fre-quently reflects the lipid profiles ofthe general population, i.e. thesepatients also inherit the other setsof genes that determine the lipidprofiles of the general population.However, where the diabetes ispoorly controlled, additional dys-lipidaemia may result, usually inthe form of increased TG and lowhigh-density lipoprotein cholesterol(HDL-C) levels. While thesechanges are generally modest,occasionally the severely raised TGlevel of a chylomicronaemia syn-drome is observed and pancreatitismay develop.Insulin resistance and type 2diabetesA large proportion of the popula-tion has IR as part of the IR syn-drome (e.g. metabolic syndrome,syndrome X).There is a strongcorrelation between IR and all themarkers of atherosclerosis, and IRis a strong predictor for the futuredevelopment of CAD. It is not sur-prising that in some populations ofSouth Africa IR is the commonestphenotype seen in patients present-ing with acute coronary syndrome(ACS).As IR progresses, the body is ableto compensate by secreting moreinsulin to maintain normogly-caemia. Hyperinsulinaemia mayhave adverse effects and manyyears may pass before failure of theDiet• Excess of saturated fats• Caloric excess• Weight gain• Alcohol• Anorexia nervosaDiabetes• Poorly controlled type 1 diabetes• Type 2 diabetesOther disorders of metabolism• Hypothyroidism• Pregnancy• ObesityDrugsCardiovascular drugs• Thiazide diuretics• Beta-adrenergic blockers• AmiodaroneEndocrine drugs• Anabolic steroids• Glucocorticoids• OestrogensOther drugs• Retinoids• Cyclosporine• Antiretroviral therapyDiseases (non-metabolic)• Biliary obstruction• Chronic renal disease• Systemic lupus erythematosus• Nephrotic syndromeTable I. Causes of secondary dyslipidaemiaMAIN TOPICC M E J u l y  2 0 0 3   Vo l . 2 1   N o . 7   367pancreatic beta-cells supervenes.Only then will glucose levels rise,with the development of impairedglucose tolerance and type 2 dia-betes. Type 2 diabetes may conve-niently be seen as the end result ofanother disease present for a longtime, namely IR. In the ‘pre-dia-betic’ phase of the IR syndromethese patients have the same riskfactors as type 2 diabetics, includ-ing dyslipidaemia, and are equallyprone to develop macrovasculardisease. Indeed, many of these‘pre-diabetic’ IR patients die oftheir macrovascular disease beforeever developing impaired glucosetolerance and diabetes. By the timetype 2 diabetes is diagnosed, thedamage has already been done andmacrovascular disease and CADare established. Remember thattype 2 diabetics without clinicalCAD have as high a probability ofexperiencing an adverse cardiacevent as a non-diabetic whoalready has clinical CAD.Accordingly, type 2 diabeticpatients, taking their lipogram intoconsideration, should be managedas for secondary prevention. It istragic that these ‘pre-diabetic’ IRpatients, who are so prone todevelop CAD, are more often thannot viewed as being ‘healthy’ anddo not receive the attention andrisk factor modification theyrequire!The abnormalities of the lipid pro-file seen in type 2 diabetics canresemble those of IR.The dyslipi-daemia resulting from IR (and type2 diabetes) is often subtle, withseemingly minor changes, and it istherefore not surprising that thisatherogenic lipid phenotype isoften poorly managed.The dyslipidaemia of this IR ismanifested by the following:• Raised TG levels. The TG levelis usually only slightly raised (< 3mmol/l), but at times a chylomi-cronaemia syndrome with mas-sively raised TG levels may devel-op in genetically susceptible indi-viduals.• Decreased HDL-C levels. TheHDL-C level is very often at, orjust below, the lower limit of nor-mal.This usually accompaniesthe raised TG level, and the highTG/low HDL syndrome is oftenmissed.• Post-prandial lipaemia. After afatty meal the TG level riseshigher and stays raised longerthan normal.The post-prandialhypertriglyceridaemia affectscholesterol ester exchange withLDL, and subsequent modula-tion of  TG-rich LDL by HDLyields small LDL species.Thishas still not been standardisedfor clinical investigative use.• Small dense LDL particles.These patients invariably have‘small dense LDL’ particles, afamily of LDL particles that arecholesterol-enriched, very proneto oxidisation and accordinglyextremely atherogenic.• Hyper-ApoB. Because of thesmall dense LDL particles, theTG excess Severe TGHigh mild to excess:Secondary cholesterol moderate chylomicronaemiacause (high LDL-C) (high VLDL) Low HDL-C syndromeDiet Saturated fats, Weight gain, Low-fat diet Alcohol and fat withcaloric excess, alcohol genetic lipidanorexia disorderDrugs Diuretics, Retinoids, Anabolic Glucocorticoids,glucocorticoids, beta-blockers, steroids, oestrogen,cyclosporin oestrogens, progestins, genetic lipidglucocorticoids beta-blockers, disordercigarettesDisorders of Diabetes poorly Type 2 diabetes, Type 2 Diabetes poorlymetabolism controlled, obesity, diabetes, controlled,hypothyroidism, pregnancy obesity hypothyroidism withpregnancy genetic lipid disorderDiseases Nephrotic Chronic renal Chronic renal SLE (rare)syndrome, failure with/ failure with/biliary without dialysis, without dialysisobstruction nephroticsyndromeLDL-C = low-density lipoprotein cholesterol; TG = triglyceride; VLDL = very low-density lipoprotein; HDL-C = high-density lipoprotein cholesterol;SLE = systemic lupus er ythematosus.Table II. Lipid profile of secondary causes of dyslipidaemiaMAIN TOPIC368 C M E J u l y  2 0 0 3   Vo l . 2 1   N o . 7number of LDL particles perunit volume is increased. Bearingin mind that LDL particles con-tain only one ApoB molecule perlipoprotein particle, IR patientsmay manifest with increasedApoB levels or hyper-ApoB.TheApoB/LDL-C ratio may beincreased, which is a reasonablygood marker for IR but is not yetaccepted for general use.Similarly, the measurement ofLDL size is difficult and notcost-effective.• IR patients inherit a set of genesdetermining their IR and alsotheir characteristic lipid profile.However, as in type 1 diabetes,these patients also inherit a total-ly different cluster of genes thatdetermine the lipid profiles in therest of the population. Thesegenes may simultaneously butindependently raise the LDL-Clevel, which must be managed inits own right.The IR syndrome is accompaniedby the following other componentsof a cardiovascular risk factor clus-ter that must be managed as well:• Hypertension.• Central obesity. This is part ofthe disease and not very easy toget rid of .• Impaired glucose tolerance orovert type 2 diabetes.• Increased fibrinogen.Thisdecreases with fibrate treatment.It is uncertain whether it trans-lates into a reduction of cardio-vascular mortality.• Increased plasminogen activatortype 1 (PAI-1).This impairedendogenous thrombolysis isalmost invariably present. Adviceas to its modification is uncer-tain.The treatment of these IR patientsis as follows:• Lifestyle modification. Thesepatients eat well because they livewell. Lifestyle modification hasbeen shown to be extremely cost-effective and pays tremendousdividends with regard to reduc-tions in cardiovascular mortality.• Dietary advice, incorporatingcaloric restriction for weight lossand low fat intake, can be veryeffective but requires propermotivation of the patient. A sym-pathetic dietician can be of greatvalue.• Lipid-modifying drugs . Statinspredominantly decrease LDL-Clevels and have lesser effects onTG and HDL-C levels, whereasfibrates have a major effect onlowering TG and raising HDL-Clevels but little effect on LDL-Clevels. Despite this it is stilladvised that treatment be startedwith a statin, as these drugs haveadditional non-lipid-loweringeffects on the vessel wall, whichare beneficial.Where TG levelsare markedly raised (> 5 mmol/l)treatment may be started with afibrate or a fibrate may be addedto a statin to improve the TGlevel further and raise the HDL-C level.Other disorders of metabolismHypothyroidism may present viaan increased TC and LDL-C level,which can be normalised with thy-roid replacement therapy.Occasionally hypothyroidism pre-cipitates dysbetalipoproteinaemiaor hypertriglyceridaemia. Somelipid clinics see a selected group ofpatients in whom the incidence ofhypothyroidism is high. However,the incidence of hypothyroidism ingeneral practice is low enough toquestion the cost-effectiveness ofperforming routine thyroid func-tion tests. Certainly, thyroid func-tion tests should be borne in mindwhere the pre-test probability ofhypothyroidism is high.In pregnanc y lipid levels continueto rise with each trimester, but thisis most dramatic during the secondtrimester. Pregnancy may unmaskan underlying genetic defect thatcan give rise to severe hypertriglyc-eridaemia and pancreatitis. Thiscan usually be controlled by dietand the lipid profile usually nor-malises postpartum.Obesity is often associated withabnormal lipograms, but manyseverely obese patients do not havedyslipidaemia. However, patientswith central obesity and increasedhip/waist ratios are prone to dyslip-idaemia.These patients are part ofthe IR syndrome discussed aboveand should be treated aggressively.DrugsDrugs should always be consideredas contributory to a dyslipidaemia.Cardiovascular drugsThiazide diuretics affect the lipidprofile in a dose-dependent fash-ion. Low-dose (12.5 mg/day)hydrochlorothiazide is metabolical-ly safe. Beta-blockers also affectthe lipid profile of patients, but thisadverse effect is not universal.These agents have a profound ben-eficial effect on cardiovascularmortality and careful considerationshould be given before withholdingthese drugs, even in diabetics!Amiodarone may cause dyslipi-daemia directly, but also by caus-ing hypothyroidism.Endocrine drugsAnabolic steroids profoundly lowerHDL-C levels soon after use.Glucocorticoids have a potenteffect on the lipid profile, which isaggravated by secondary weightDrugs should alwaysbe considered ascontributory to ad y s l i p i d a e m i a .MAIN TOPICC M E J u l y  2 0 0 3   Vo l . 2 1   N o . 7   369gain and glucose intolerance. Insusceptible persons alpha-oestro-gens can cause dramatic increasesin TG levels. Transdermal adminis-tration may have less input on plas-ma lipids.Other drugsRetinoids used for acne can haveprofound effects on the lipid pro-file, especially on TG levels. Oneshould check for dyslipidaemiabefore and during treatment. Thelipogram normalises promptly afterdiscontinuation of treatment.Cyclosporin can contribute to dyslipidaemia observed after trans-plantation, and may be aggravatedby the associated administration ofsteroids and by weight gain.Importantly, it can also interactwith some statins, the dosage ofwhich must be adjusted in this sit-uation.Antiretroviral therapy isbeing used increasingly.The pro-tease inhibitors can cause a sec-ondary lipodystrophy and dyslipi-daemia associated with severeincreases in TC and TG levels.Non-metabolic diseasesLiver diseaseCholestasis can be associated withsevere increases in TC levels, whichare partially comprised of lipopro-tein-X. Impaired liver functionmay be associated with impairedproduction of lipoproteins and thisshould be considered if treatmentresults appear to be too good to betrue.Renal diseaseChronic renal failure can be linkedto dyslipidaemia and may beaggravated by dialysis. Raised TClevels are a common feature of thenephrotic syndrome.Only rarely does systemic lupuserythematosus (SLE) cause dyslipi-daemia via the production enzymeinhibitors that impair lipoproteinmetabolism.TREATMENT OFSECONDARYDYSLIPIDAEMIASThe management of secondarydyslipidaemia should follow thegeneral principles listed below:• Discontinue the suspected drugand substitute with a lipid-neu-tral drug.• Treat the underlying disorder.• Apply the appropriate dietary fatrestriction.• Lipid-modifying agents. Withseverely raised TG levels, fibratesmay be needed as an adjunct tothe above.Where the LDL-Clevel does not normalise with theconservative approach, statinsmay be used.CONCLUSIONSecondary and contributory causesof dyslipidaemia should always beconsidered. Patients have much togain, both health wise and wealthwise, from recognition and appro-priate management of these causes.IN A NUTSHELLIn many populations secondarycauses play a dominant role incausing dyslipidaemia and in thegenesis of coronary artery dis-ease (CAD).  Genes also play an impor tant rolein secondary dyslipidaemia.Extremely raised total cholesterollevels ( > 15 mmol/l) are usually amanifestation of a severe hyper-triglyceridaemia.Poorly controlled diabetes is thecommonest secondary cause ofmassively raised triglyceride lev-els.Insulin resistance correlatesstrongly with the development ofmacrovascular disease.In some populations the insulinresistance syndrome is the com-monest phenotype seen inpatients with acute coronary syn -dromes.Type 2 diabetes may convenientlybe regarded as the end result ofanother disease that has beenpresent for a long time, namelyinsulin resistance.‘Pre-diabetic’ insulin-resistantpatients should be managedaggressively to prevent the pro-gression of macrovascular dis-ease.FURTHER READINGColagiuri S, Best J. Lipid-lowering therapy in people with type 2 diabetes. Curr OpinLipidol 2002; 13: 617-623.Components of the ‘metabolic syndrome’ and incidence of type 2 diabetes —http://www.medscape.com/viewarticle/442152Grundy SM. Approach to lipoprotein management in 2001. National CholesterolGuidelines.  Am J Cardiol.  2002; 90: 11i-21i.Pathogenesis and epidemiology of metabolic abnormalities — http://www.medscape.com/viewarticle/441490 (accessed 10 January 2003).The obesity epidemic: prevention and treatment of the metabolic syndrome —http://www.medscape.com/viewprogram/2015(accessed to January 2003).Update on the management of dyslipidemia —http://www.medscape.com/viewarticle/442031 (accessed to January 2003).

Secondary dyslipidaemia

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Secondary dyslipidaemia

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