A 40-year-old female presented to her primary care provider with a chief complaint of weight gain over the past year. She wants to be fully evaluated for any kind of medical disorder that could have caused it. She has been seen by multiple specialists but no one can give her a “straight diagnosis”. Their advice is for her to lose weight. She insists she never had problems with her weight in the past and has no known medical disorders. Her physical exam is significant for a blood pressure of 130/80 and excess fat around her waistline. Her labs show an elevated serum glucose, an increased total cholesterol and LDL, and a decreased HDL. Otherwise, she has normal endocrine markers. Her primary care provider discussed the findings of her workup with her and tells her that she has metabolic syndrome. The patient is grateful for finally finding out what is wrong with her.
Many Americans suffer from the same disorder. According to the CDC, 34% of American adults have metabolic syndrome.(18) With such a high prevalence, clinicians have to understand what it is and what it means for their patient. Researchers and clinicians have been trying to clearly define Metabolic Syndrome since its original inception in the 1980’s. Thirty years later, it seems the medical community has finally come to a consensus.
During the beginning, Metabolic Syndrome was an explanation for epidemiological trends of patients with concurrent hypertension and hyperglycemia. A Stanford physician postulated that these conditions were inter-related having one causal pathway related to hyperglycemia, leading to hyperinsulinemia, leading to excess free fatty acids. This original idea was termed, Syndrome X. The pathophysiology of Syndrome X was that high levels of free fatty acids induce a state of insulin resistance both in the muscle (glucose uptake) and in the liver (glucose release). The effect of hyperinsulinemia to increase renal sodium absorption was thought to contribute to hypertension through increased circulating blood volume.
Three years later, the same Stanford physician expanded his definition by discussing how insulin resistance leads to an increase in plasma triglycerides and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure. For this reason, he extrapolated that Syndrome X plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease.  The cause- effect relationship interested physicians across disciplines leading to a boom of research related to the etiology, pathophysiology, effects and prognosis of the syndrome.
After further examination, some physicians felt that the syndrome’s original definition was not adequate. The same population of patients with syndrome X were noted to have a disproportionate prevalence of obesity. They felt that obesity was likely to play the central role in the syndrome in causing insulin resistance. Research suggested that excess adipose tissue releases free fatty acids and glycerol into the circulation by lipolysis, therefore contributing if not initiating insulin resistance. Obesity linked with insulin resistance, hypertension and hyperlipidemia became known as the “deadly quartet”. This addition did not end debate, however. If anything, it opened more controversy. Scientists debated whether obesity causes insulin resistance or vice versa? Others debated whether obesity or diabetes played any role in the syndrome at all.
The World Health Organization saw the activity and controversy spurred by these theories and in 1998, compiled definitions and described what became recognized as the “metabolic syndrome”: obesity, insulin resistance, dyslipidemia, and hypertension—focusing on insulin resistance as a central tenet. This was a huge step in validating the syndrome. However, even after the WHO made the definition official and gave it an ICD code, clinicians continued to question the clinical utility of the definition.
Interdisciplinary meetings further examined research and decided that the clinical utility of describing these patients was to identify a high risk group for cardiovascular disease. Atherosclerosis was shown to be associated with all the parameters of metabolic syndrome.  In addition, by this time, scientists had discovered other diseases to be associated with the syndrome as well, such as fatty liver, polycystic ovary syndrome, cholesterol gallstones, sleep apnea, lipodystrophies, and protease-inhibitor therapy for HIV. Prevention and intervention of the syndrome was viewed as a necessity.
Fast forward to 2005 when the research and discussion up to this point convinced almost all of the major medical associations to agree on the existence and importance of metabolic syndrome. The American Heart Association in conjunction with the National Heart, Lung, and Blood Institute came up with the most current and widely accepted definition of metabolic syndrome. In order to be diagnosed with Metabolic Syndrome, a patient needs 3 of 5 of the following:
- Elevated waist circumference: 102 cm (40 inches) in men, 88 cm (35 inches) in women
- Elevated triglycerides 150 mg/dL (1.7 mmol/L) or on drug treatment for elevated triglycerides
- Reduced HDL-C, < 40 mg/dL (1.03 mmol/L) in men, <50 mg/dL (1.3 mmol/L) in women or on drug treatment for reduced HDL
- Elevated blood pressure 130 mm Hg systolic blood pressure or 85 mm Hg diastolic blood pressure or on antihypertensive drug treatment in a patient with a history of hypertension
- Elevated fasting glucose 100 mg/dL or on drug treatment for elevated fasting glucose
The five criteria listed represent abnormal physical and lab findings that suggest but do not necessarily meet the requirements for a diagnosis of obesity, hyperlipidemia, hypertension, and diabetes, respectively. The creators seemed to want to catch patients with pre-morbid conditions that increase their risk for morbid conditions. Being able to have a combination of any three allowed for more sensitivity in diagnosis.
Even with the verified definition. there still remained inconsistencies in the pathophysiology behind the disease. Either there is an inherit metabolic disorder (with or without obesity) causing insulin resistance with subsequent release of free fatty acids and pro-inflammatory factors, or it is the adipose tissue in obese people that is insulin resistant, which in and of itself worsens metabolism by muscle and the liver, also releasing adipokines, a pro-inflammatory byproduct. 
Without a set pathophysiology or single pathway of disease, the ability to establish evidence base treatment strategies was stalled. There were no articles published that suggest any treatment strategies better than those that have already existed for each individual part of the syndrome alone. For example, if the patient is overweight, he or she should still try behavioral modification to lose weight. If he or she has hyperlipidemia, diet and pharmacologic therapy is still tried and true. Glycemic control would not differ between some one with or without metabolic syndrome who has insulin resistance. It depends on already established parameters such as fasting glucose or glycosylated hemoglobin.
Another flaw exposed after the formation of a widely accepted definition was the fact that there was no established prognostic evidence for the syndrome. Studies showed that there is a higher mortality and cardiovascular risk for patients with metabolic syndrome. [9-11] However, the degree of severity of morbid conditions affected mortality risk to a greater extent rather than whether or not patients met the criterion of metabolic syndrome. Ten year risk for these patients seemed better predicted by degree of glycemic control or Framingham Risk analysis.  Therefore, questions about clinical utility of the diagnosis lingered.
The World Health Organization met again in 2009 to re-evaluate a consensus statement regarding metabolic syndrome after a decade of shifting meanings and research. The conclusion was that “While [metabolic syndrome] may be considered useful as an educational concept, it has limited practical utility as a diagnostic or management tool.”  Furthermore the WHO deemed that clinicians should not use this term as a clinical diagnosis and that further research regarding the syndrome would be an inappropriate use of resources. Even more recently, the proginitor of it all—the Stanford physician that originally created the idea of Syndrome X—published a review article in December of 2010. In it, he states that “despite the many publications…it is not clear that it is a diagnostic category worth continuing”.
What all of this means is that our patient from the case at the beginning does have metabolic syndrome. Having metabolic syndrome may place this patient at a higher risk for cardiovascular disease and/or death. It may not change the advice that she receives from her doctors regarding lifestyle changes or medical treatment; however it may appropriately target her for aggressive intervention.
In conclusion, Metabolic Syndrome has not proven to be as solid of a “disease” as it was once theorized. It describes a set of pre-morbid conditions without a unifying underlying disease, making it fall shy of the official definition of a “syndrome”. And it is important to understand that the international community does not view it as a valid diagnosis. Although, physicians may still use the terminology as a way to describe a patient or a way to closely watch patients at higher risk for developing co-morbidities. In this way, it may still prove to have clinical utility as a descriptor.
Dr. Vicky Jones is a 3rd year resident at NYU Langone Medical Center
Image courtesy of Wikimedia Commons
- Reaven G.M.: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37. (12): 1595-1607.1988.
- Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med. 1993;44:121-31.
- Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med. 1989; 149:1514 –1520
- “Obesity” Goldman: Cecil Medicine, 23rd ed. 2007.
- Gallagher E G, LeRoith D, Karnieli E. The Metabolic Syndrome – from insulin resistance to Obesity and Diabetes. Endocrinol Metab Clin N Am 37 (2008) 559–579.
- Grundy S, Cleeman J, Daniels S, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112(17):2735–-52. http://circ.ahajournals.org/content/112/17/2735.full
- National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. Circulation. 2002;106:3143–3421.
- Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92:347–355. http://journals.cambridge.org/download.php?file=%2FBJN%2FBJN92_03%2FS0007114504001795a.pdf&code=560b41b8c0825a15a8274c4fdfabca59
- Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683– 689.
- Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288: 2709–2716.
- Sattar N, Gaw A, Scherbakova O, Ford I, O’Reilly DS, Haffner SM, Isles C, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003 Jul 29;108(4):414-9. Epub 2003 Jul 14.
- McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, Ballantyne CM, Heiss G. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care. 2005;28:385–390.
- Solymoss BC, Bourassa MG, Lesperance J, Levesque S, Marcil M, Varga S, Campeau L. Incidence and clinical characteristics of the metabolic syndrome in patients with coronary artery disease. Coron Artery Dis. 2003;14:207–212.
- Turhan H, Yasar AS, Basar N, Bicer A, Erbay AR, Yetkin E. High prevalence of metabolic syndrome among young women with premature coronary artery disease. Coron Artery Dis. 2005;16:37– 40.
- Simmons RK, Alberti KG, Gale EA, Colagiuri S, Tuomilehto J, Qiao Q, Ramachandran A, Tajima N, Brajkovich Mirchov I, Ben-Nakhi A, Reaven G, Hama Sambo B, Mendis S, Roglic G. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010 Apr;53(4):600-5. Epub 2009 Dec 11.
- Reaven GM. The metabolic syndrome: time to get off the merry-go-round? (Review) J Intern Med 2011; 269: 127–136. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02325.x/abstract
- “Syndrome.” Oxford English Dictionary. 2nd edition. 1989.
- Ervin RB. Prevalence of Metabolic Syndrome Among Adults 20 Years of Age and Over, by Sex, Age, Race and Ethnicity, and Body Mass Index: United States, 2003–2006. National Health Statistics Reports. Number 13. May 5, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19634296