Syndrome X is a major and escalating global public health and clinical challenge, happening in lieu of urbanisation, surplus energy intake, increasing obesity, and sedentary lifestyles. Patients suffering from the syndrome have an increased risk of developing cardiovascular diseases such as stroke and myocardial infarction. Moreover, patients have a two-fold increased risk of death in case they suffer from any of the above conditions.

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What is the origin?

Syndrome X started as a concept rather than a diagnosis. The origin of the syndrome dates back to the 1920s when the association between hypertension, hyperglycemia and gout was established. Later an association between visceral obesity with CVD and T2DM was established.

Further on some clinicians described a syndrome that comprised of hypertension, hyperglycaemia and obesity. Later, in 1988, Dr Reaven described 'a cluster of risk factors for diabetes and cardiovascular diseases' and named it “Syndrome X”. He introduced the concept of insulin resistance.

The collection of unhealthy body measurements and abnormal laboratory test results include:

• Atherogenic dyslipidemia
• Hypertension
• Glucose intolerance
• Proinflammatory state
• Prothrombotic state

The American Association of Clinical Endocrinologists (AACE), World Health Organisation (WHO), and European Group for the study of Insulin Resistance (EGIR) define the metabolic syndrome as being largely focused on insulin resistance, which is determined by an oral glucose tolerance test and hyperinsulinaemic-euglycaemic clamp.

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Pathophysiology

Syndrome X is a state of chronic low-grade inflammation as a consequence of the complex interplay between genetic and environmental factors. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors that constitute the syndrome.

The main trigger starts with the lifestyle conditions wherein there has been an increase in physical inactivity, consumption of high energy diet, smoking and stress. The genetic predisposition adds up to the condition wherein the individual might have a thrifty genotype and phenotype. These environmental and genetic conditions predispose individuals to syndrome X.

These cause positive energy storage in the body and over time leads to adipose tissue hyperplasia and hypertrophy. This leads to altered free fatty acid (FFA) metabolism and release of adipokines. This further leads to increased production of FFA, increased gluconeogenesis and occurrence of insulin resistance causing hyperinsulinaemia which further leads to dyslipidaemia, hyperglycaemia and T2DM.

The adipokines released cause an inflammatory condition leading to vasoconstriction that causes hypertension and endothelial dysfunction as well as a proinflammatory condition leading to the formation of a hypercoagulable state of body.

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Diagnostic criteria by AACE, WHO and EGIR

Clinical criteria	WHO (1998)	EGIR (1999)	AACE (2003)
Insulin resistance	IGT, IFG, T2DM, or lowered insulin sensitivity (plus any 2 of the following)	Plasma insulin >75th percentile (plus any 2 of the following)	IGT or IFG (plus any of the following based on clinical judgement)
Bodyweight	Men: waist-to-hip ratio >0.90; women: waist-to-hip ratio >0.85 and/or BMI >30 kg/m­2	WC ≥94 cm in men or ≥80 cm in women	BMI ≥25 kg/m2
Lipids	TGs ≥150 mg/dL and/or HDL-C <35 mg/dL in men or <39 mg/dL in women	TGs ≥150 mg/dL and/or HDL-C <39 mg/dL in men or women	TGs ≥150 mg/dL and HDL-C <40 mg/dL in men or <50 mg/dL in women
Blood pressure	≥140/90 mmHg	≥140/90 mmHg or on hypertension Rx	≥130/85 mmHg
Glucose	IGT, IFG, or T2DM	IGT or IFG (but not diabetes)	IGT or IFG (but not diabetes)

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Differential diagnosis and misinterpretations

The syndrome is a cluster of many major disease processes, hence a clinician has to look at all the conditions equally so as to not miss the diagnosis for Syndrome X. Often, clinicians just pay attention to the pharmacological management of the major issues such as diabetes or hypertension and fail to weigh the other risk factors too. This in the long run may lead to higher mortality conditions as well as a poor prognosis of the patient overall.

Apart from the major diagnosis of T2DM, hypertension and hyperlipidaemia, additional diagnoses should be considered for each of the criteria used to identify patients with metabolic syndrome. For example, in patients with hypertension, investigation for secondary causes, such as obstructive sleep apnoea or other sleep-related breathing disorders, renovascular disease, or disorders of renin and aldosterone metabolism should be considered as well.

Patients with dyslipidaemia in the setting of a strong family history of dyslipidaemia may be manifesting hereditary diseases. Alternative causes of hyperglycaemia may include not only diabetes mellitus but also thyroid dysfunction and rarer endocrinopathies, such as glucagonomas and pheochromocytomas.

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Treatment and management

Syndrome X is a state of chronic low-grade inflammation with some profound systemic effects that not only affect the renal, hepatic, cardiovascular and reproductive systems but also affects the eyes, skin and sleep patterns.

Effective preventive approaches include lifestyle changes, primarily weight loss, diet, and exercise, and the treatment comprises the appropriate use of pharmacological agents to reduce the specific risk factors. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with preventive measures and lifestyle changes.

Following is the treatment guideline recommended by the National Cholesterol Education Programme (NCEP), the seventh Joint National Commission (JNC-VII) for blood pressure treatment, the American Diabetes Association (ADA), the American Heart Association (AHA), and the National Institute of Health Obesity Initiative.

Risk assessment

1. The goals of therapy are to reduce both short-term and lifetime risks. The presence of Syndrome X per se indicates a higher lifetime risk.
2. The standard Framingham risk equations, which include cigarette smoking, blood pressure, total cholesterol, HDL-C, and age, capture most of the risk of CVD in patients with the syndrome.
3. This equation triages patients into 3 risk categories based on a 10-year risk of CHD:
   1. High risk (10-year risk ≥20%)
   2. Moderately high risk (10-year risk 10% to 20%)
   3. Lower to moderate risk (10-year risk ≤10%)
4. Affected patients with ASCVD or diabetes are already in a high-risk category without the need for Framingham risk scoring.

Lifestyle modification

1. Lifestyle modification treatment should be delivered by a team composed of physicians and non-physician health professionals, such as dieticians or professionals in exercise physiology, behavioural psychology, or health education.
2. Daily moderate-intensity activity of minimum 30 minutes for most days of the week. Recommend use of pedometer with goal >10,000 steps/day.

Weight reduction

Four therapies can be used for weight reduction:

• Calorie restriction (e.g., 500 kcal/d deficit)
• Increased physical activity
• Behavioural modification
• In some patients, FDA-approved weight-reducing drugs

Diet

1. The effective and healthful methods for long-term weight loss are reduced-energy diets, consisting of a 500 to 1000 calories/day reduction.
2. Sustained dietary changes may require a referral to a dietician to help ensure an adequate micronutrient intake (e.g., calcium, iron, and folate) while reducing calories.

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Insulin resistance, visceral adiposity, atherogenic dyslipidaemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors that constitute Syndrome X.

Lifestyle modification remains the initial intervention of choice for this population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.