Behind The Medical Headlines

The metabolic syndrome – does it really exist?

• Dr K Hughes, Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, Scotland
• Dr MWJ Strachan, Metabolic Unit, Western General Hospital, Edinburgh, Scotland

Summary

In this companion to our article on non-alcoholic fatty liver disease Dr Katherine Hughes and Dr Mark Strachan review the evidence in relation to the existence of the metabolic syndrome – the clustering of metabolic abnormalities including obesity and diabetes which can lead to the development of non-alcoholic fatty liver disease.

Declaration of interests: No conflict of interests declared

Introduction

The Metabolic Syndrome is a construct that reflects the well-recognised clustering of metabolic abnormalities that are associated with an increased risk of type 2 diabetes and cardiovascular disease. The principal features of the Metabolic Syndrome are insulin resistance (IR), central abdominal obesity, abnormalities of glucose and lipid metabolism, hypertension, and a pro-inflammatory state. Although each component of the Metabolic Syndrome can occur singly, these components co-exist more frequently than would be predicted by chance alone.¹ Other clinical conditions associated with the Metabolic Syndrome include Polycystic Ovarian Syndrome (PCOS), Non-Alcoholic Fatty Liver Disease (NAFLD), cholesterol gall-stones, sleep apnoea, and some lipodystrophies.

The key mechanisms involved in the development of the metabolic syndrome have not been fully established. When first described by Gerald Reaven,² insulin resistance was felt to be the primary underlying abnormality and that all other manifestations of the Metabolic Syndrome stemmed from this. In recent years, the importance of central obesity (and in particular of visceral fat) has been recognised, along with the ability of adipose tissue to produce a wide variety of cytokines, known as adipokines (see Figure 1). Most adipokines are pro-inflammatory in nature, but the most abundant, Adiponectin, enhances insulin sensitivity and inhibits the effects of the inflammatory process. Perhaps unsurprisingly, Adiponectin is found in lower levels in individuals with the Metabolic Syndrome,³ but it is not known whether this is a primary or secondary phenomenon.

Diagnosis

The World Health Organisation (WHO), the National Cholesterol Education Programme (NCEP), the European Group for the study of Insulin Resistance (EGIR), the American Association of Clinical Endocrinology (AACE) and more recently the International Diabetes Federation (IDF) have all published definitions of the Metabolic Syndrome… and all are subtly different (Table 1).

The WHO criteria are based around the primacy of insulin resistance and so require the individual to have insulin levels in the upper 25% of the population, raised fasting glucose or impaired glucose tolerance and at least two of the following variables: low high density lipoproteins (HDL), raised triglycerides, hypertension or a raised waist-hip ratio.⁴ The EGIR definition also uses insulin levels in the top 25% percent and any further two criteria from elevated fasting glucose, low HDL, raised triglycerides, hypertension or increased waist size.⁵ The AACE definition requires an individual to be at high risk of insulin resistance, for example age >40 years, have a sedentary lifestyle, have a history of glucose intolerance or gestational (pregnancy) diabetes, a family history of cardiovascular disease, diabetes or hypertension, have PCOS, acanthosis nigricans or NAFLD and satisfy a further two criteria of raised fasting glucose or impaired glucose tolerance, low HDL, raised triglycerides, or hypertension.⁶

The NCEP and IDF definitions recognise that some individuals may have features of the Metabolic Syndrome and yet not have elevated insulin concentrations,⁷ and also recognise that measurement of serum insulin concentrations is not performed routinely in clinical practice. Neither, therefore, include a measure of insulin resistance, and are easier to apply in clinical practice. Thus, the NCEP definition requires any three of: elevated fasting plasma glucose, low HDL, high triglycerides, hypertension and increased waist circumference.⁸ The International Diabetes Federation (IDF) considers an individual to have the Metabolic Syndrome if he/she has central obesity, and any two of the following: raised triglyceride, reduced HDL, hypertension, or raised fasting glucose/previously diagnosed type 2 diabetes. The Metabolic Syndrome is being recognised in ever younger individuals, and separate criteria have been suggested for those under 16 years. (Table 2) ⁹

None of the above definitions has become accepted as an international standard.

Controversies

The use of the Metabolic Syndrome as a clinical concept has not been universally accepted.⁷

Definitions

All current definitions are based on essentially arbitrary criteria, because there is no established genetic or biochemical marker for the Metabolic Syndrome. There is obviously a danger in employing arbitrary cut-offs for physiological measurements, in an attempt to separate clearly what are actually continuous variables. Thus, for example, an HDL cholesterol of 1.05 mmol/l in a man would not be an eligible criterion in any of the current definitions, but one of 0.99 mmol/l would. There is clearly no clinical difference between these measurements, and indeed they might occur in the same individual on two separate occasions, but depending on which one is used, an individual may or may not meet one of the criteria for the Metabolic Syndrome.

Moreover, there are subtle and, in some cases, substantial, differences between the various definitions. Any epidemiological data derived about the Metabolic Syndrome will be subject to inter-definition variability. This is illustrated by data from a Dutch population-based cohort study in which the prevalence of the Metabolic Syndrome varied from 19% (NCEP criteria) to 32% (WHO criteria) depending on the definition employed.¹⁰ Of course, it may be that the Metabolic Syndrome is not a discrete entity, and that different phenotypes exist. As such, each of the different definitions may be describing different phenotypes¹¹ and indeed there may be as yet undiscovered biological variables that might further refine these phenotypes.

Cardiovascular risk prediction

The main controversy surrounding the metabolic syndrome is its usefulness as a tool to predict cardiovascular risk. Studies have shown that non-diabetic individuals with features of the Metabolic Syndrome have a ~3.0 fold increased risk of developing type 2 diabetes and a ~1.5-2.0 fold excess risk of cardiovascular disease.¹² However, once more, the precise level of increased risk depends on the definition employed. Thus, for example, in the Hoorn study of Dutch men and women aged 50-75 years, the increased risk of cardiovascular events ranged from 91% using NCEP criteria, 45% using the WHO criteria, and 30% using the AACE definition.¹⁰

Proponents of the Metabolic Syndrome concept argue that it is more than the sum of its parts and that the syndrome defines cardiovascular risk better than its individual components alone or in combination. Those who support this concept can cite the recent prospective study from Uppsala, Sweden,¹³ in which the diagnosis of the Metabolic Syndrome using the NCEP criteria was associated with a 1.59–fold increased risk of cardiovascular mortality after adjustment for smoking, diabetes, hypertension and serum cholesterol. In other studies, however, increased cardiovascular risk was found to be attributable to the accumulation of individual cardiometabolic risk factors and the Metabolic Syndrome definitions were not more strongly associated with cardiovascular risk.¹⁰

Conclusions

The Metabolic Syndrome as a general concept, namely the clustering of individual cardiovascular risk factors, is useful as it should serve as a reminder to clinicians to search for other cardiovascular risk factors when an individual is recognised as having one or more of the component parts. In addition, it highlights the need to consider risk of diabetes mellitus and cardiovascular disease in associated disorders such as PCOS and NAFLD. It is only when specific diagnostic criteria are proposed that difficulties and controversies arise. Further prospective data on the predictive ability of the Metabolic Syndrome in cardiovascular disease are required and if such data support the value of this construct, then there should be a move to wards an international consensus on specific diagnostic criteria.

References

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2. Reaven G. Banting Lecture 1988. Role of Insulin Resistance in Human Disease. Diabetes 1998; 37:1595-1607.
3. Xydakis AM, Case CC, Jones PH et al. Adiponectin, Inflammation, and the Expression of the Metabolic Syndrome in Obese Individuals: The Impact of Rapid Weight Loss through Caloric Restriction. J Clin Endocrin Metab 2004; 89(6):2697–2703.
4. World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its complications. Part 1: Diagnosis and classification of Diabetes Mellitus. World Health Organization; 1999.
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