Rational use of lipid investigations.

Dyslipidaemia is a common and an important problem. It accounts for almost 50% of the population-attributable risk of myocardial infarction. Clinicians must therefore detect, treat and monitor lipid disorders, while keeping laboratory expenses reasonable. As with all laboratory investigations testing needs to be individualised.

Screening

International guidelines recommend 5-yearly screening intervals in low-risk patients. (1,2) However, in the South African public sector, with its limited resources, one should aim to screen all adults at least once. (3,4) A random total cholesterol level is sufficient for screening, but it should be followed up by a full lipid profile on a fasting sample if the total cholesterol is >5 mmol/l. Exceptions are patients with existing cardiovascular disease (CVD), a family history of premature CVD (men <55 years, women <65 years), or clinical signs of dyslipidaemia--in these patients a full fasting lipogram should be the initial investigation.

In cases of abdominal obesity, highdensity lipoprotein cholesterol (HDLC) and fasting triglyceride (TG) levels will contribute towards identifying patients with the metabolic syndrome. Decreased HDLC (<1.03 mmol/l in men and <1.29 mmol/l in women) and elevated TG (>1.7 mmol/l) levels are 2 of the 5 International Diabetes Federation (IDF) diagnostic criteria of the metabolic syndrome. (5) This syndrome signals increased cardiovascular and diabetes risk.

Basic tests

Before a fasting lipogram is done, patients must receive clear instructions to ensure reliable results. They should not eat, drink (except water) or smoke for 12 hours before the blood test. Patients should maintain their usual diet, weight and activity level for at least 2 weeks before the test. Total cholesterol can be measured with good accuracy for opportunistic screening in patients who have not fasted. Diabetes may cause secondary hyperlipidaemia, and hyperglycaemia is an important contributor to cardiovascular risk. If the patient is fasting for a lipogram, glucose should also be measured.

Although laboratories often refer to 'normal' lipid ranges, it is important that the result be interpreted in the context of the individual patient. Many patients with 'normal' lipid values need lipid-lowering therapy, but there are also patients with 'elevated' levels who do not need treatment. When titrating therapy, a fasting lipid profile every 4-12 weeks is recommended. Thereafter, annual reassessment is probably sufficient.

In cases of hypercholesterolaemia, secondary causes should always be considered. Screening can be done for suspected alcohol abuse with gammaglutamyl transferase, carbohydrate deficient transferrin and mean corpuscular volume. Obstructive liver disease (bilirubin and alkaline phosphatase), hypothyroidism (thyroid-stimulating hormone [+ or -] free T4) and renal disease (creatinine, estimated glomerular filtration rate and urine dipstick/protein:creatinine ratio) are other important causes of secondary hyperlipidaemia.

If a patient is taking an HMG-CoA reductase inhibitor (statin), laboratory investigations can contribute towards detecting the development of side-effects. Muscular toxicity will cause raised creatine kinase (CK) levels and drug-induced hepatitis will manifest as elevated alanine aminotransferase and aspartate aminotransferase levels. Pre-treatment transaminase and CK levels should be considered for establishing a baseline, but routine long-term monitoring is not necessary in the absence of symptoms.

Valuable 'optional' tests

In patients with borderline cardiovascular risk, measurement of lipoprotein(a) (Lp(a)) should be considered--if elevated in the presence of dyslipidaemia it signifies an added risk. An Lp(a) level >0.03 g/l (>30 mg/dl) is considered unfavourable. A once-off measurement of Lp(a) will suffice, as the concentration is genetically determined and relatively fixed for each individual.

Not all low-density lipoprotein (LDL) particles are equally atherogenic. Small, dense LDL particles are associated with hypertriglyceridaemia and carry a 2-3 times higher CVD risk. Assessment of LDL particle size by electrophoresis is performed in lipid reference laboratories and may be done in patients with raised TG levels as part of optimal CVD risk assessment.

Apolipoprotein B100 (apoB) is the structural protein of the atherogenic lipoproteins. Large epidemiological studies have shown that apoB is a better marker of CVD risk than total cholesterol or LDL cholesterol (LDLC), but use of a lipogram for this purpose is still firmly entrenched. An apoB level that is disproportionally high compared with the LDLC level may also suggest small, dense LDL particles.

In patients with very high lipid levels (total cholesterol >8 mmol/l or LDLC >6 mmol/ l), a family history of severe dyslipidaemia or physical signs suggestive of a severe genetic lipid disorder, genetic analysis may be useful. (3) A monogenic disorder affects treatment goals and genetic counselling may be offered.

Non-lipid cardiovascular risk factors

Non-traditional cardiovascular risk factors include high-sensitivity C-reactive protein (CRP) and homocysteine. Elevated CRP is strongly associated with CVD in epidemiological studies, but the benefit of routinely also measuring CRP in conventional risk assessment is controversial. (6)

Moderate elevations of homocysteine may be caused by insuffi cient folate and vitamin [B.sub.12], a polymorphism in the methylenetetrahydofolate reductase gene, renal failure or incorrect specimen handling. An increased homocysteine concentration is an independent epidemiological risk factor for CVD, but opinions differ with regard to the routine measurement of homocysteine. Intervention studies targeting homocysteine have generally disappointed. (7) Homocysteinuria is a rare genetic disorder that presents with arterial and venous thromboses in young patients--in such cases, with otherwise unexplained CVD or thromboses, homocysteine testing is important.

Conclusion

During cardiovascular risk assessment the laboratory tests performed will depend on the individual patient, the financial resources available and the complexity of the clinical scenario. Consultation with a chemical pathologist should be considered, as the use and interpretation of laboratory tests are not always straightforward.

References

(1.) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of the 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). JAMA 2001; 285: 2486-2497.

(2.) De Backer G, Ambrosioni E, Borsch-Johnson K, et al. European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003; 24: 1601-1610.

(3.) South African Medical Association and Lipid and Atherosclerosis Society of South Africa Working Group. Diagnosis, Management and Prevention of the Common Dyslipidaemias in South Africa--Clinical Guideline, 2000. S Afr Med J 2000; 90: 164-178.

(4.) Raal FJ, Marais AD, Schamroth C. Adoption of the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice--Guide to Lipid Management. South African Heart Journal 2006; 3: Supplement.

(5.) Alberti KGMM, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet 2005; 366: 1059-1062.

(6.) Wang TJ. New cardiovascular risk factors exist, but are they clinically useful? Eur Heart J 2008; 29: 441-444.

(7.) Lonn E. Homocysteine in the prevention of ischemic heart disease, stroke and venous thromboembolism: therapeutic target or just another distraction? Curr Opin Hematol 2007; 14: 481-487.

MIA LE RICHE, MB ChB, MMed (Chem Path)

Chemical Pathologist, Dr Davies Pathologists, Thornton, Cape Town