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Measurement in blood of lipids, such as total cholesterol and fasting triglyceride, and lipoproteins, such as high-density and low-density cholesterol (HDL-C, LDL-C) has become one of the most frequently performed assays in clinical chemistry laboratories. This increase in utilisation reflects the independent roles of both LDL-C and HDL-C in the aetiology of cardiovascular disease (CVD). The importance of these tests has been augmented by the substantial clinical benefit associated with the use of strategies and treatments that modify serum LDL-C and HDL-C concentrations. These tests are used as part of a broader clinical assessment and monitoring process and, as a result, the usual assumptions about test results and the presence or absence of disease no longer apply. CVD remains the major cause of morbidity and mortality in developed countries such as Australia, so public health organisations here and elsewhere have developed evidence-based guidelines to optimise various aspects of management including interpretation of test results. The role of pathology providers in this process has largely been overlooked and previous patterns of reporting have become unsuitable. A group of chemical pathologists representing both private and public laboratory services has prepared Recommendations on Lipid Testing and Reporting by Pathology Laboratories, published in this issue, to address these circumstances.1 It is important for laboratory scientists and pathologists to appreciate the broader issues concerning guidelines in order to provide appropriate input to the process of interpretation of laboratory results in future. This commentary provides a context for these recommendations.
There are several reasons why traditional laboratory concepts such as a “normal” reference population and its associated reference interval are not suitable for the interpretation of lipid results in the clinical setting. Firstly, the tests are often used in the context of predicting future disease, rather than indicating the presence of current disease. Secondly, the disease in question, CVD, is the most prevalent future cause of morbidity and mortality amongst the general population. As a result, the appropriate reference population should consist of healthy individuals from a population that is unlikely to develop CVD in future. Epidemiological studies suggest that the “normal” level of serum total cholesterol would be approximately 4 mmol/L under such circumstances.2 Diet and exercise patterns differ so much in developed countries that there would need to be a profound change in lifestyle and social habits for the majority of Australians to achieve this serum cholesterol without the need for pharmacological treatment. Indeed, an alternative philosophy is provided by the “polypill” approach, which abandons the assessment of CVD risk factors in individuals and provides treatment to everyone beyond a certain age.3
Faced with this dilemma, the current public health strategy favours an approach that is a combination of population-wide and individual patient strategies. The latter are tailored towards the individual patients at high risk of future CVD. This approach also recognises that CVD is multifactorial such that the overall significance of the patient’s serum lipid and lipoprotein concentrations will depend on other risk factors and clinical circumstances. For example, the presence of symptomatic CVD demonstrates that the patient is susceptible to their underlying risk factor status. In view of the self-perpetuating nature of the pathological processes underlying CVD, these patients should aim for lower levels of all risk factors, including lipids, even if they seem relatively benign by the standards of the general population.4 There is also recognition of the synergistic effect of different risk factors and their tendency to cluster, particularly in circumstances typified by insulin resistance.5 As a result, advice concerning lipid and lipoprotein levels needs to be stratified according to other factors such as age, the number and severity of other risk factors, etc. The most comprehensive approach to this situation has been the use of epidemiological data to create models that predict the absolute risk of a CVD event in a 5 to 10-year timeframe. For example, data from the Framingham Study has been used in New Zealand to create a risk table.6 This table has been adopted elsewhere, including Australia. The algorithms that generate these risk tables are suitable for computer programming that could be linked to the reporting of laboratory results. Unfortunately, the clinical data that is required for optimal risk assessment exceeds the amount that usually accompanies requests for laboratory tests. This impairs the ability of the laboratory to respond to the clinical need to report lipid and laboratory findings in the context of the individual patient’s circumstances.
Clinical care depends heavily on the individual judgment of the responsible clinician, which in turn depends on individual experience. The same may be said of textbook recommendations concerning clinical care. Public health guidelines require broad applicability, and so their development has been designed to encourage broad-based multi-disciplinary input.7 Likewise, there is a need to retain objectivity in a setting which fosters diversity of opinion, and to this end, formal assessment and grading of all available sources of evidence is required.
The clinical importance of lipids and lipoproteins has generated a very extensive body of evidence on which to base public health guidelines. Major sets of guidelines have been developed and regularly updated by organisations such as the National Cholesterol Education Panel in the United States8 and a combination of European Societies for the Prevention of Coronary Heart Disease.9 In Australia, this task has been undertaken by the National Heart Foundation of Australia (NHFA), more recently in conjunction with other relevant organisations such as the Cardiac Society of Australia and New Zealand (CSANZ). The most recent update of the guidelines for the management of hyperlipidaemia was released at the end of 2005.10 These guidelines were designed to recommend the key features of best practice based on up-to-date evidence, and as a result, they include target levels for treatment. The other important document concerning lipid management in Australia is the Pharmaceutical Benefit Schedule (PBS) which governs eligibility for subsidised treatment. This requires a more stringent cost-benefit perspective and, as a result, it provides a more quantitative description of the thresholds at which high risk patients could qualify for subsidised treatment.
Previous contrast between the roles of the NHFA and PBS guidelines, together with discrepancies in the times at which they were updated, created the potential for inconsistency. The recent review of the PBS guidelines has gone a long way towards reducing such discrepancies, at least for the time being. Both sets of guidelines now reflect recent evidence that suggests that aggressive reduction of LDL-C offers significant additional reduction in CVD events in very high risk patients.11,12 Accordingly, NHFA guidelines recommend LDL-C <2 mmol/L for all patients with CVD [coronary heart disease (CHD), cerebrovascular disease or peripheral vascular disease] whilst the PBS guidelines do not require any LDL-C threshold for the use of lipid-lowering therapy in these patients. The guidelines are consistent, but not identical, concerning high risk patients with diabetes or Familial Hypercholesterolaemia (FH). NHFA guidelines nominate both categories as amongst those with highest risk. PBS guidelines stratify risk within diabetes, avoiding thresholds for those with microalbuminuria, age beyond 60 or Aboriginal and Torres Strait Islander background. They also require criteria for the diagnosis of FH based on mutation, xanthomas or family history of xanthomas, or premature CVD. The difference in roles between the two sets of guidelines explains the difference in their approach to patients with individual or multiple risk factors. The NHFA guidelines are in a position to recognise features such as the clustering of risk factors in metabolic syndrome and the need to amalgamate overall risk by quantification of absolute risk. Levels in excess of 15% over 5 years (10% if associated with metabolic syndrome or family history of premature CVD) are regarded as excessive. The PBS guidelines are constrained from using absolute risk because this would require certainty that all practitioners have access to resources that allow its calculation. At this stage it is necessary to rely on lipid and lipoprotein thresholds for different risk factor scenarios. One important point to note is the opportunity that exists for the treatment of first and second degree relatives of patients with premature CVD.
Although the assessment and management of all major CVD risk factors embraces the concept of absolute risk, current guidelines, such as those for lipids and lipoproteins, retain a single risk factor perspective of the concept of absolute risk. The process of moving to an integrated approach that uses absolute risk to guide management as well as risk assessment will involve a paradigm shift that is difficult to co-ordinate without wide-spread access to risk assessment tools.13 Even when such tools are widely available, it will be important to ensure that risk assessment techniques are appropriate for the populations to which they are to be applied. The Framingham algorithms are based on studies conducted in white Caucasians in an affluent society over 40 years ago. Since that time, the prevalence of smoking and obesity has changed substantially, patterns and levels of economic development have varied and ethnic background has become more heterogenous in many populations in which CVD risk needs to be assessed. It has already been demonstrated that local algorithms misclassify risk in several European populations,14 and that the Framingham algorithm misclassifies risk in different socioeconomic groups.15 When risk algorithms are converted into charts to make them more accessible, important continuous data such as age may need to be converted to intervals or categories, resulting in the loss of accuracy for risk factor assessment.
Guidelines are also compromised by the conflicting needs to be both comprehensive and succinct. Similarly, there is a potential conflict between revision to keep up to date with latest data and the time required to obtain consensus and disseminate information. Furthermore, it may be difficult to incorporate new biomarkers such as high sensitivity C-reactive protein (hs-CRP) or B-type natriuretic peptide because they were not components of the original epidemiological studies.16
The NHFA guidelines nominate several areas in which changes in clinical practice are anticipated. The guidelines acknowledged that inflammatory markers such as hs-CRP represent a possible independent CHD risk factor, but concluded that there was insufficient data to justify treatments that modify these factors. No recommendations have been made regarding desirable levels of hs-CRP. The guidelines also anticipated more widespread use of alternative measurements such as apolipoprotein B or non-HDL cholesterol, particularly in subjects with elevated triglyceride levels.
In the longer term, diagnostic and therapeutic advances may alter the whole paradigm of CVD prevention. Techniques such as non-invasive imaging may allow the detection of pre-clinical CVD. This could lead to monitoring programmes in which metabolic assessment and intervention is reserved for high risk cases in whom arterial damage has been demonstrated. Proponents of the polypill envisage universal therapy beyond a certain age, thereby eliminating the concept of individual risk assessment, except in cases where onset of CVD may occur before the initiation of such treatment.
Pathology laboratories play a pivotal role in the current management of CVD risk. There is a case for greater participation by representatives of pathology in the formulation of future guidelines. The publication of Recommendations on Lipid Testing and Reporting by Australian Pathology Laboratories brings laboratory medicine into the fold of this multidisciplinary public health initiative. It supports approaches that will ensure the quality of results and reports. Most importantly, it positions the pathology profession to contribute constructively and influence the appropriateness of future developments.
Competing Interests: David Sullivan is a Member of several advisory panels within the pharmaceutical industry including Pfizer Australia, AstraZenica, Merck Sharp and Dohme, Schering Plough, Sanofi Aventis etc. David Tognarini is occasionally employed as a consultant to Pfizer Australia.