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Letters to the Editor |
5 Highcroft Rd., London N19 3AQ, United Kingdom, Fax 44-20-7272-0282, E-mail amatheson{at}blueyonder.co.uk.
To the Editor:
In 2005 the American Diabetes Association and European Association for the Study of Diabetes questioned the value of the metabolic syndrome as a diagnostic category(1). In the same year, Reaven delivered a noted "obituary" for the metabolic syndrome in this journal, while defending the insulin resistance syndrome as a pathophysiologic entity(2). But despite these broadsides, the concept of the metabolic syndrome is attracting continued support. PubMed lists 1775 articles with "metabolic syndrome" in the title or abstract published during 2005, 2566 during 2006, and 1689 for the first 6 months of 2007. Clearly, rumors of the syndrome’s demise have been greatly exaggerated.
There are several reasons why the metabolic syndrome continues to thrive as a concept. First, there is a widespread sense that its components are sufficiently coupled mechanistically to suggest some kind of disease entity. Second, the term and concept retain utility simply for want of a fuller description of the underlying pathology. Third, the concept is self-sustaining, in that the existing body of research attracts further research and comment. Fourth, industry promotes the syndrome in symposia and review articles, alongside related concepts such as the "cardiometabolic syndrome" and "cardiometabolic risk".
But perhaps most interestingly, the metabolic syndrome thrives because the notion of a distinct pathophysiologic entity indulges the intuitive essentialism and predilections for simplification and category formation that inhere in human cognition as evolutionary legacies(3). To Homo sapiens, a unified syndrome has gut appeal and even mystique—as exemplified by the allure of the phrase "syndrome X"(4). A closely connected nosologic issue that reflects similar inclinations is the tendency to dichotomize continuous variables into crude categories of disease and health.
It is possible, however, that no consensus will ever be achieved on a definition for the metabolic syndrome as a diagnostic category, and that no disease entity will be conclusively delimited. This lack of resolution, in a different sense, is also a matter of our evolutionary legacy. The systems that transact the business of cells and regulate human physiology evolved not with rational foresight, but through bricolage, the selective but ramshackle accretion of countless innovations of contingent origin(5). Consequently the regulatory systems of higher organisms are highly complex, interconnected, and multifarious; riven with redundancies and lacunae; and resistant to systematization.
This form of complexity is the fundamental reason why it is so difficult to define the metabolic syndrome, either as disease entity or diagnostic category. It is also why the metabolic syndrome cannot be adequately described on any single level, such as that of genetics, molecular biology, intercellular signaling, or physiological subsystems. And hence too, the number of pathophysiologic factors implicated in the metabolic syndrome, such as hepatic, hemodynamic, endothelial, and inflammatory elements, continues to grow.
Human cognition is serial and weighted toward simplicity; cell and organismal physiology is parallel and complex. The error in our conceptualization of the metabolic syndrome lies in overintegration, for in this setting it is to be expected that a spectrum or range of pathology should exist rather than a single cardinal disease pathway. Perhaps at the top level it is therefore preferable to envisage not a metabolic syndrome, but a cardiovascular, renal, and metabolic pathophysiologic matrix (CRM matrix), within which a range of related benign and disease states may develop.
The characteristic range of disease states that emerge within this matrix might be described as CRM spectrum disorders. The insulin resistance syndrome of Reaven might prove to be one such disorder; alternatively, several distinct metabolic syndromes, or defined axes of variation within a pathologic continuum, might be characterized. That is a matter for research. But as research proceeds, its correct task might be framed not as one of unification, but of taxonomy, whose goal is to elaborate the nature and relationships of the full range of CRM spectrum disorders and identify appropriate interventions for each.
Such an approach might also impact on the assessment of risk. One might, for instance, conceive of a CRM risk profile with an associated scoring system.
The concepts of a CRM matrix and CRM spectrum disorders run counterto the instinct to overintegrate, but allow instead for a family of disorders or range of pathology to be comprehended within a single analytic perspective. These concepts also provide a more realistic frame-work for ongoing research. As population genetics and molecular physiology advance and a more meticulous parsing of disease states becomes possible, and as computer-based prediction models grow in sophistication, medicine will need to move beyond the era of the all-embracing syndrome and adopt a more systematic approach that better reflects the nature of biological systems and their evolutionary history.
Acknowledgments
Grant/funding support: None declared.
Financial disclosures: None declared.
Acknowledgments: The author is grateful to an unnamed reviewer for helpful comments on the manuscript.
References
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