CHAPTER 1 William J. Marshall; Marta Lapsley CHAPTER OUTLINE The science of biochemistry is fundamental to the practice of clinical medicine. Many diseases have long been known to have a biochemical basis and research in biochemistry is increasingly providing descriptions of pathological processes and explanations for disease at a molecular level. As a result of the application of biochemical principles and techniques to the analysis of body fluids and tissues, clinicians have an extensive and ever-increasing range of biochemical investigations that can be called upon to aid clinical decision-making. Such investigations can provide information vital to the diagnosis and management of many conditions, including both those with an obvious metabolic basis (e.g. diabetes mellitus) and those in which metabolic disturbances occur as a consequence of the disease (e.g. renal failure). On the other hand, many conditions are successfully diagnosed and treated without recourse to any biochemical investigation, while there remain conditions in which it might be expected that biochemical investigations should be of value but for which appropriate tests are not yet available. For example, there are, as yet, no practical biochemical investigations to assist in the diagnosis and management of the major affective disorders (see Chapter 35), although there is considerable evidence that biochemical disturbances are involved in the pathogenesis of these conditions. Biochemical analysers range from large, automated instruments capable of performing multiple tests on single serum samples to relatively simple instruments designed to measure only one or a few analytes. In general, they generate results quickly, reliably and economically. However, some tests, often more complex and expensive ones, are performed manually and may take longer to complete. Biochemical data are thus readily available to support clinical decision-making. Ordering a biochemical investigation is a simple procedure and there is no doubt that such investigations are often requested automatically, without regard for their potential value in the specific clinical setting. Clinical biochemists decry this but do themselves no favour by their use of the term, widely employed by clinicians, ‘routine investigations’ (usually meaning relatively simple investigations that are performed frequently) and even ‘routine laboratories’ (meaning the places where they are done). Ideally, investigations should always be performed because there is a specific indication for them, that is, because it is anticipated that their results will provide information of benefit to the management of the patient. However, it cannot be denied that investigations requested for no specific reason can sometimes provide valuable information. Most clinicians are able to recall occasions when an unexpected result from a ‘routine test’ has provided the essential clue to the diagnosis in a difficult case. More often, the finding of an unexpectedly abnormal result may engender considerable anxiety and involve further investigations to elucidate its cause, only for it to transpire that the biochemical abnormality is of no clinical significance. The potential range of investigations available to support the clinician is considerable, from simple low cost urine dip-stick tests to magnetic resonance imaging using hugely expensive equipment. There is an understandable tendency for clinical biochemists to think that biochemical investigations are pre-eminent among special investigations. In some conditions they are, in others they have no role, while in many, their value is greatly increased when their results are considered alongside those of other investigations, for example imaging. The clinician should be aware of the whole range of investigations that are available, but needs also to be able to appreciate their various advantages and limitations. The clinical biochemist, too, needs to be aware of the role of other investigations, so that he or she can view biochemical tests in context and advise on their suitability and the interpretation of their results in specific clinical circumstances. It has been the editors’ aim to ensure that this information is provided where relevant in this book. The processes of acquiring and interpreting biochemical data are complex. Correct interpretation requires that the clinical context and reason for requesting the test are properly understood, otherwise the result has little value. This chapter explores the variety of potential ways in which biochemical data can be used in clinical practice. It has been said that diagnosis in medicine is an art, not a science, yet the process of diagnosis is amenable to scientific analysis. Making a diagnosis is the equivalent of propounding a hypothesis. A hypothesis should be tested by experiment, the results of which may support or refute the hypothesis, which can then be extended, modified or discarded in favour of an alternative, as appropriate. The validity of a clinical diagnosis is tested by observation of the natural history of the condition or its response to appropriate treatment or by the results of definitive investigations: the diagnosis will be confirmed if these are as expected from knowledge of previous cases. If they are not, it must be reviewed. Clinical diagnosis is based on the patient’s history and clinical examination. Taking general and hospital practice together, it has been estimated that, in more than 80% of cases, a confident diagnosis can be made on the basis of the history or the history and clinical findings alone. Even when this cannot be done, it should be possible to formulate a differential diagnosis, that is, a list of diagnoses that could explain the clinical observations. The results of investigations may then lead to one of these being considered the most likely and providing a rational basis for treatment. Subsequent observation will indicate whether the diagnosis was correct. Although not necessarily required for the management of an individual patient, it may be possible to extend the clinical diagnosis by further investigation to determine the pathogenesis of the condition and ultimately, its underlying cause. For example, measurement of serum troponin concentration may confirm a clinical diagnosis of myocardial infarction in a patient with typical chest pain and electrocardiographic abnormalities; angiography could be used to demonstrate coronary atherosclerosis prior to surgery or angioplasty; the finding of hypercholesterolaemia would indicate a causative factor for the atherosclerosis; a family history of premature heart disease would suggest that the hypercholesterolaemia was familial and DNA mutation analysis might reveal the underlying genetic defect. The ideal diagnostic investigation would be 100% sensitive (all cases of the condition in question would be correctly diagnosed) and 100% specific (no individual without the condition would be wrongly diagnosed as having it). The concepts of specificity and sensitivity are examined fully in Chapter 2. In practice, the capacity of biochemical investigations to provide precise diagnostic information is extremely variable. At one end of the spectrum, the techniques of genetic analysis are making it possible to reliably diagnose inherited metabolic diseases in utero; at the other end of the spectrum, to take just one example, a decrease in plasma sodium concentration can occur in many different conditions and is, on its own, diagnostic of none of them. Molecular genetic analysis has become a separate discipline in its own right and is a special case for the use of biochemical investigations for diagnosis. It is used to detect the presence of a mutation responsible for a specific disease. Even when possession of a mutation does not inevitably result in the development of a disease, its presence can indicate increased susceptibility to a condition. However, even individuals with the same genotype for a characteristic may differ in their phenotypes. But, although molecular genetics is a rapidly developing field, many genetically determined conditions, including inherited metabolic diseases, are still diagnosed on the basis of their biochemical phenotype.
Uses of biochemical data in clinical medicine
INTRODUCTION
SPECIFIC USES OF BIOCHEMICAL TESTS
Diagnosis
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