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Metabolic Syndrome

Synonyms: Syndrome X

The metabolic syndrome refers to a clustering of cardiovascular disease (CVD) risk factors whose underlying pathophysiology is thought to be related to insulin resistance. However, there is uncertainty as to whether all patients with the syndrome are indeed insulin resistant, so the aetiology has been broadened to include concepts of obesity, adipose tissue disorders and other factors.1

The clustering of CVD risk factors with type 2 diabetes, hyperlipidaemia, hypertension and obesity was first noted in the 1960s-70s. The concept of the metabolic syndrome was proposed in 1988, when Reaven published a landmark paper describing Syndrome X.2 Subsequently, the name metabolic syndrome was coined to reflect the range of metabolic features involved. Various definitions of the syndrome have been created. More recently, some have questioned the usefulness of the metabolic syndrome as a clinical diagnosis.1,3

Diagnostic criteria

There have been various definitions of the metabolic syndrome since 1998.3,4 Recent SIGN guidelines on CVD prevention use the following definition:

Metabolic syndrome definition5

This is based on the International Diabetes Federation and American Heart Association criteria.4

Any 3 of the following:

  • Increased waist circumference (≥ 102 cm in men and ≥ 88 cm in women; ≥ 90 cm in Asian men and ≥ 80 cm in Asian women), indicating central obesity
  • Elevated triglycerides (≥ 1.7 mmol/l)
  • Decreased HDL cholesterol (<1.03 mmol/l for men, <1.29 mmol/l for women)
  • Blood pressure > 130/85 mm Hg or active treatment for hypertension
  • Fasting plasma glucose level > 5.6 mmol/l or active treatment for hyperglycaemia

Epidemiology6

The prevalence of the metabolic syndrome varies with country, race and the definition used. One study in the USA using the ATP III criteria found a prevalence of 24%, increasing to 44% in the over-60s.

It is likely that the prevalence of metabolic syndrome will increase together with the rising rates of obesity which have been observed, both in the West and in the developing world.7

Aetiology

The underlying aetiology of the metabolic syndrome is still debated, and many factors seem to be involved:

  • Insulin resistance, and its consequent hyperinsulinaemia, is recognised as an important or even essential factor in the metabolic syndrome:
    • Reaven proposes that insulin resistance is central to the syndrome's aetiology and is the unifying pathological feature,3 but some authors are less certain.4
    • Insulin resistance itself seems to be due to a combination of genetic factors, physical activity and obesity.8 Genetic factors predispose to the metabolic syndrome, but are insufficient to create it without the lifestyle factors.3 There are ethnic differences in predisposition to insulin resistance and CVD, with south Asians being more at risk.4
    • Hypertension and insulin resistance are closely linked.3
    • Elevated glucose and frank diabetes are both atherogenic.4
    • Sphingolipids, such as ceramide, may play a role in the regulation of insulin sensitivity.9
  • Lifestyle factors:
    • Obesity: Body mass index, abdominal obesity and upper body obesity are all linked to the metabolic syndrome; some experts suggest that abdominal obesity or upper body obesity are closer linked than BMI. Adipose tissue in obese people is insulin resistant, and adversely affects lipids, inflammatory mediators and other mediators which influence insulin resistance and CVD.4
    • Physical inactivity: is thought to interact with genetic factors and obesity to produce the metabolic syndrome.6 Increased physical activity helps control body weight and blood pressure, improves lipid profiles and reduces cardiovascular risk and the risk of diabetes.10
    • Atherogenic diet: Modern Western diets are very different in composition from traditional human diets. Notably, they are high in refined carbohydrates and refined vegetable oils; and low in omega-3 fatty acids, fresh fruit and vegetables. All these have a role in obesity, adverse lipid profiles and the metabolic syndrome.7,11
  • A pro-inflammatory state:
    Obesity, inflammation and cardiovascular risk seem to be connected.8 CRP levels and white cell counts both seem to increase with obesity or the metabolic syndrome, and there is some evidence linking them to CVD risk. The mechanism may again be related to the behaviour of adipose tissue which, in the presence of obesity, produces excess (proinflammatory) cytokines and less of the protective adiponectin.4
  • A pro-thrombotic state:
    There is evidence for high circulating levels of prothrombotic factors in the metabolic syndrome, which could contribute to CVD.4
  • Atherogenic dyslipidaemia:
    The metabolic syndrome and insulin resistance are linked to an atherogenic lipid profile, which includes:4,6
    • Raised triglycerides, including the atherogenic remnant lipoproteins
    • Increased LDL and small LDL particles
    • Increased apoB-containing lipoproteins
    • Reduced HDL-C
  • Other factors which may be involved:
    • Antiretroviral therapy12
    • Catecholamines may have a role13
Complications4

The metabolic syndrome and insulin resistance are associated with:

  • Cardiovascular disease: the cardiovascular risk approaches that of full diabetes5
  • Diabetes mellitus: the natural progression of metabolic syndrome is to develop overt type 2 diabetes.5
  • Chronic kidney disease (CKD): Patients with the metabolic syndrome are at significantly higher risk for microalbuminuria and/or CKD, and the level of risk is related to the number of components of the syndrome itself. It is currently unclear how much of the risk is due to individual metabolic syndrome components such as hypertension and impaired glucose metabolism, and how much may be due to aspects of the metabolic syndrome itself, such as abdominal obesity.14
  • Non-alcoholic fatty liver disease (the "hepatic manifestation of insulin resistance")13
  • Polycystic ovary syndrome15
  • Cholesterol gallstones
  • Obstructive sleep apnoea
  • Lipodystrophies
Management

The management of the metabolic syndrome is not specific to the syndrome, but consists of management of the underlying risk factors for CVD and diabetes, and treatment of any established disease such as hypertension, heart disease or diabetes.

Recommendations are that clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the metabolic syndrome.1,3

Lifestyle modification

This is the cornerstone of treatment for the metabolic syndrome.

Lifestyle advice for the metabolic syndrome

This advice concords with the general recommendations for lifestyle changes to reduce cardiovascular risk.10 SIGN advises that those with metabolic syndrome should have professional help regarding diet, exercise and weight.5

Exercise

30-60 minutes daily of moderate-intensity aerobic activity plus an increase in daily lifestyle activities (depending on individual fitness and coexisting disease). Many studies have shown the benefits of exercise,4 and it also improves liver function tests in non-alcoholic fatty liver disease.16

Weight loss

Weight reduction is important for those with abdominal obesity and the metabolic syndrome. The initial aim is a slow reduction of 7-10% in baseline weight, with normal BMI as the ultimate goal.4

Diet composition
  • Fresh fruit and vegetables (at least 5 portions/day).10
  • Complex rather than simple carbohydrates (starch not sugar); wholegrain or high-fibre rather than refined carbohydrate.4
  • Fats:
    • Reduction of dietary fat is traditional advice. However, "Low fat" is too simplistic5 and may even be detrimental. The composition of dietary fats is more important.5,17
    • Avoid trans fats (often labelled as 'hydrogenated' or 'partially hydrogenated' vegetable oils) found in many margarines and processed foods.10
    • Increase the proportion of monounsaturated fats (e.g. olive oil).10
    • Increase the amount of omega-3 polyunsaturated fatty acids compared with a Western diet - these are found in oily fish, marine fish oils, nuts, linseed or flax oil, and green leafy vegetables.18,11 (SIGN recommends "two portions of 140g fish, one of which should be fatty fish, per week" as being evidence-based and consistent advice.5)
    • There is evidence that addition of nuts, such as almonds, in the diet is beneficial.19,20
    • A Mediterranean-style diet encompasses these recommendations and has been found beneficial in the metabolic syndrome.21
  • Protein/carbohydrate ratio:
    • The established view is that complex carbohydrates should form the major proportion of calories in the diet.4
    • More recently there has been interest in high protein/low carbohydrate diets, both as a method of weight loss and to improve lipid or glucose profiles.22 One review proposes this type of diet as the definitive treatment of the metabolic syndrome.23
Other lifestyle factors
  • Smoking cessation
  • Moderate alcohol consumption

Dietary fats explained11

Fats may be classified as saturated (mainly animal fats) or unsaturated (mainly vegetable fats and fish oils). Unsaturated fats may be:

  • Monounsaturated - olive oil is the most common example
  • Polyunsaturated fatty acids (PUFAs) - most vegetable and seed oils are in this category.
    Some of these are the essential fatty acids, which humans cannot synthesize. Of these there are 2 main families:
    • n-3 (or omega-3) PUFAs, mainly:
      • Linolenic acid (LNA), found in flax and linseed oil, some nuts and green leafy vegetables.
      • Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), found in marine fish oils.
    • n-6 (or omega-6) PUFAs, mainly linoleic acid (LA), found in vegetable oils such as corn, sunflower, safflower and soybean.

The ratio of n-6 to n-3 PUFAs is important: in modern Western diets, n-6 predominates, and this is probably detrimental to health. The n-3 PUFAs seem to have many metabolic benefits, such as hypolipaemic, anti-inflammatory and anti-thrombotic effects. They are also thought to be important in brain and eye development, and seem protective against cardiac arrhythmias.

Trans fats - also known as hydrogenated or partially hydrogenated fats - are created by the artificial hydrogenation of polyunsaturated fats: this makes them solid at room temperatures and hence commercially useful for processed foods. They are harmful and linked to CVD.24

Drug treatment

  • The manifestations and complications of metabolic syndrome should be treated according to established guidelines for the treatment of hyperlipidaemia, cardiovascular disease, hypertension and diabetes.1,3 This may therefore involve the use of:
    • Low dose aspirin
    • Antihypertensives
    • Statins and/or fibrates
    • Anti-diabetic drugs
  • There is no specific drug treatment for the metabolic syndrome itself. Metformin, glitazones and acarbarose have been suggested as either improving the syndrome or delaying progression to type 2 diabetes,5,25 though recent safety concerns do not favour glitazones. The American Heart Association currently does not recommend drugs solely for the purpose of preventing diabetes, because their cost-effectiveness and safety in this role has not been documented.4 Metformin may have a role in polycystic ovary syndrome.15

Follow-up

  • People identified with the metabolic syndrome should have regular follow up to monitor their progress in reducing cardiovascular risk.5
  • Arguably, a glucose tolerance test should be performed for people with the metabolic syndrome who have normal fasting glucose, as this may identify some with occult diabetes.4
Areas of controversy

Is the metabolic syndrome a true syndrome?1

A cluster of factors can be defined as a syndrome either if it predicts future events, or if it identifies a unifying pathological process. In the case of metabolic syndrome, it is not clear that either of these apply:

  • There is no conclusive evidence that the metabolic syndrome itself increases CVD risk above that of the existing individual risk factors.26,27 The syndrome can predict diabetes, but this is unsurprising given the definitions involving abnormal glucose values or insulin resistance.
  • A unifying pathological process is not clear: insulin resistance as the underlying aetiology is uncertain.

Is a diagnosis of metabolic syndrome clinically useful?

  • As mentioned earlier, it is unclear whether the metabolic syndrome adds anything to existing cardiovascular risk. It is anyway recommended that doctors should evaluate and treat all CVD risk factors regardless of whether or not the patient has metabolic syndrome3,1 and this concords with the Joint British Societies' Guidelines10 and current UK targets for primary care.
  • Reaven,3 the American Diabetes Association and the European Association for the Study of Diabetes,1 conclude that identifying the metabolic syndrome is not useful clinically. Other authors26 and recent SIGN guidelines,5 on the contrary, suggest that it is still a useful concept to identify people at high CVD risk who need primary prevention and risk monitoring.
  • Some argue that a diagnosis of metabolic syndrome is a medicalisation of Western lifestyle and will label large numbers of people as diseased.13

Diet debates

Fats

There is an established conception that low fat diets are beneficial to cardiovascular risk, and that unsaturated fats are preferable to saturated fat. However, there are arguments to the contrary:13

  • Diets containing too little fat can exacerbate dyslipidaemia.17 Meanwhile, we are left with a variety of recommendations as to the ideal fat content of the diet, varying from <30%10 to 30-35%.4
  • Diets high in unsaturated fats may be harmful, and saturated fats may be preferable or even protective.13 It is noted that:
    • High vegetable oil intakes are a new phenomenon in the history of mankind's diet.11 There are concerns about the increasing use of refined vegetable oils in the developing world.7
    • High intakes of unsaturated fats will generally be of the omega-6 class; this increases the n-6:n-3 fatty acid ratio, which is unfavorable to cardiovascular health.11
    • Israel has an exceptionally high consumption of refined vegetable oils, with high rates of heart disease and diabetes.28

Carbohydrate and protein

As discussed earlier, protein may be better than carbohydrate as the main energy source for those with metabolic syndrome.

Document references
  1. Kahn R, Buse J, Ferrannini E, et al; The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005 Sep;28(9):2289-304. [abstract]
  2. Reaven GM; Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595-607. [abstract]
  3. Reaven GM; The metabolic syndrome: is this diagnosis necessary?; Am J Clin Nutr. 2006 Jun;83(6):1237-47 [abstract]
  4. Grundy SM, Cleeman JI, Daniels SR, et al; Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005 Oct 25;112(17):2735-52. Epub 2005 Sep 12.
  5. SIGN guideline: Risk estimation and prevention of cardiovascular disease, Feb 2007
  6. Kolovou GD, Anagnostopoulou KK, Cokkinos DV; Pathophysiology of dyslipidaemia in the metabolic syndrome. Postgrad Med J. 2005 Jun;81(956):358-66. [abstract]
  7. Prentice AM; The emerging epidemic of obesity in developing countries. Int J Epidemiol. 2006 Feb;35(1):93-9. Epub 2005 Dec 2. [abstract]
  8. Dandona P, Aljada A, Chaudhuri A, et al; Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005 Mar 22;111(11):1448-54.
  9. Summers SA, Nelson DH; A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing's syndrome. Diabetes. 2005 Mar;54(3):591-602. [abstract]
  10. No authors listed; JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice.; Heart. 2005 Dec;91 Suppl 5:v1-52.
  11. Benatti P, Peluso G, Nicolai R, et al; Polyunsaturated fatty acids: biochemical, nutritional and epigenetic properties. J Am Coll Nutr. 2004 Aug;23(4):281-302. [abstract]
  12. Barbaro G, Barbarini G; Highly active antiretroviral therapy-associated metabolic syndrome and cardiovascular risk. Chemotherapy. 2006;52(4):161-5. Epub 2006 May 2. [abstract]
  13. Rapid responses to: editorials: Khunti K and Davies M: Metabolic syndrome; BMJ 2005; 331: 1153-1154
  14. Locatelli F, Pozzoni P, Del Vecchio L; Renal manifestations in the metabolic syndrome. J Am Soc Nephrol. 2006 Apr;17(4 Suppl 2):S81-5. [abstract]
  15. Hopkinson ZE, Sattar N, Fleming R, et al; Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology. BMJ. 1998 Aug 1;317(7154):329-32.
  16. Sreenivasa Baba C, Alexander G, Kalyani B, et al; Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 2006 Jan;21(1 Pt 1):191-8. [abstract]
  17. Feldeisen SE, Tucker KL; Nutritional strategies in the prevention and treatment of metabolic syndrome. Appl Physiol Nutr Metab. 2007 Feb;32(1):46-60. [abstract]
  18. Carpentier YA, Portois L, Malaisse WJ; n-3 fatty acids and the metabolic syndrome. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1499S-1504S. [abstract]
  19. Mukuddem-Petersen J, Oosthuizen W, Jerling JC; A systematic review of the effects of nuts on blood lipid profiles in humans. J Nutr. 2005 Sep;135(9):2082-9. [abstract]
  20. Wien MA, Sabate JM, Ikle DN, et al; Almonds vs complex carbohydrates in a weight reduction program. Int J Obes Relat Metab Disord. 2003 Nov;27(11):1365-72. [abstract]
  21. Esposito K, Marfella R, Ciotola M, et al; Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004 Sep 22;292(12):1440-6. [abstract]
  22. Meckling KA, Sherfey R; A randomized trial of a hypocaloric high-protein diet, with and without exercise, on weight loss, fitness, and markers of the Metabolic Syndrome in overweight and obese women. Appl Physiol Nutr Metab. 2007 Aug;32(4):743-52. [abstract]
  23. Volek JS, Feinman RD; Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction. Nutr Metab (Lond). 2005 Nov 16;2:31. [abstract]
  24. Willett WC; The Mediterranean diet: science and practice. Public Health Nutr. 2006 Feb;9(1A):105-10. [abstract]
  25. Petersen JL, McGuire DK; Impaired glucose tolerance and impaired fasting glucose--a review of diagnosis, clinical implications and management. Diab Vasc Dis Res. 2005 Feb;2(1):9-15. [abstract]
  26. Khunti K, Davies M; Metabolic syndrome. BMJ. 2005 Nov 19;331(7526):1153-4.
  27. Farmer A; Metabolic syndrome and mortality. BMJ. 2006 Apr 15;332(7546):882.
  28. Yam D, Eliraz A, Berry EM; Diet and disease--the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet. Isr J Med Sci. 1996 Nov;32(11):1134-43. [abstract]
Acknowledgements EMIS is grateful to Dr N Hartree for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2007.
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Document Version: 20
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Last Updated: 7 Nov 2007
Review Date: 6 Nov 2009






















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