Free
Articles  |   March 2010
Metabolic syndrome: More questions than answers?
Article Information
Cardiovascular Disorders / Endocrinology / Hypertension/Kidney Disease / Pediatrics / Preventive Medicine / Diabetes
Articles   |   March 2010
Metabolic syndrome: More questions than answers?
The Journal of the American Osteopathic Association, March 2010, Vol. 110, eS18-eS22. doi:
The Journal of the American Osteopathic Association, March 2010, Vol. 110, eS18-eS22. doi:
A few years ago I accepted an invitation to speak in Phoenix for an American College of Osteopathic Internists' convention and scientific seminar. I received my topic assignment about a week later by e-mail and discovered that I was to debate Richard Kahn, PhD, chief scientific and medical officer of the American Diabetes Association. Dr. Kahn was going to present arguments and evidence that the metabolic syndrome was ill-defined, not a particularly useful tool for predicting cardiovascular disease risk and, in fact, was not even a “syndrome.” 
My job was to present evidence in support of the proposition that the metabolic syndrome was a bona fide cluster of metabolic abnormalities to predict the life-time risk of cardiovascular disease and diabetes. I sweated for months crafting my presentation because I knew that Dr. Kahn's arguments were going to be logical, detailed and complete. Here was the fundamental point of the debate: Is the predicted risk of cardiovascular disease and diabetes, based on the parameters defining metabolic syndrome, greater than the sum of the individual risk contributed by each parameter? Or, as Dr. Kahn asks, “Is the whole greater than the sum of its parts?” 
The forerunner of what we call metabolic syndrome was described by Kylin in 19231 and later by Vague in 1956.2 However, a clear articulation of what we now recognize as metabolic syndrome awaited the synthesis of data by Dr. G. M. Reaven and was presented in his Banting lecture to the American Diabetes Association in 1988.3 He proposed that the pathophysiological basis of atherosclerosis involved central obesity, hypertension, hyperlipidemia and glucose intolerance and coined the term “Syndrome X” to designate this cluster of risk factors. 
Over the years, Syndrome X has been called “dyslipidemic hypertension,” the “deadly quartet” and “insulin resistance syndrome,”4,5 and “hazardous waist,” to name a few. 
Why the various names? Part of the reason involved no agreement on the specific cut-points for parameters such as obesity or hypertension. Agreement not withstanding, the term “metabolic syndrome” has gained world wide acceptance and carries the ICD code of 277.7 
Defining metabolic syndrome
How do we define metabolic syndrome? Until recently that depended on whose criteria one followed: World Health Organization?6 European Group for the Study of Insulin resistance?7 National Cholesterol Education Program—Adult Treatment Panel III?8 American Association of Clinical Endocrinologists?9 International Diabetes Federation?10 
Different groups have issued different cut-points in their definition of metabolic syndrome. For example, the definition of hypertension had been ≥130/ ≥85 mmHg (ATP III, 2004) versus ≥130 or ≥85 mm Hg or on therapy for hypertension as defined by The American Heart Association (AHA) and The National Heart, Lung and Blood Institute (NHLBI) in 2005.11 
Is there a difference between these definitions for hypertension? Yes. According to Dr. Kahn, the AHA/NHLBI criterion picks up about 60% more individuals.12 The definition of central obesity was originally one specific value for men and another for women. However, this was soon challenged and revised to reflect that individuals were obese at different waist circumferences: In men, obesity began at ≥90 to 102 cm and for women ≥80 to 88 cm depending on their geographic/ethnic backgrounds. Another example concerned the definition of abnormal glucose: ≥100 mg/dL or ≥110 mg/dL. Thus, it was no surprise that confusion existed over how to diagnose metabolic syndrome. 
As of October 2009, a joint statement was issued by the International Diabetes Federation; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity to standardize the diagnostic criteria for the metabolic syndrome.13 Agreed cut-points for all the components of metabolic syndrome were published (see Table 1) and the diagnosis defined as the presence of any three or more abnormal findings. 
TABLE 1
Criteria for Clinical Diagnosis of the Metabolic Syndrome 13
 Criteria for Clinical Diagnosis of the Metabolic Syndrome   13
TABLE 1
Criteria for Clinical Diagnosis of the Metabolic Syndrome 13
 Criteria for Clinical Diagnosis of the Metabolic Syndrome   13   ×
Although the diagnostic scheme now appears straightforward, the devil is always in the details. For example, consider the definition of the elevated waist circumference (see Table 2). What is the cut-point for Caucasians? What would be the cut-point for a European male living in Sub-Saharan Africa? What would be the cut-point for persons of mixed ethnicity? The Joint Interim Statement suggests “...in these cases, pragmatic decisions will have to be made.”13 
TABLE 2
Current Recommended Waist Circumference Thresholds for Abdominal Obesity 13
 Current Recommended Waist Circumference Thresholds for Abdominal Obesity   13
TABLE 2
Current Recommended Waist Circumference Thresholds for Abdominal Obesity 13
 Current Recommended Waist Circumference Thresholds for Abdominal Obesity   13   ×
Prevalence of the metabolic syndrome
How prevalent is metabolic syndrome? The initial report of the prevalence of the metabolic syndrome in United States adults surveyed in 1988-1994 was approximately 47 million14 based on the original 2001 NCEP criteria. Since this initial survey, the prevalence of the metabolic syndrome in the United States has increased to approximately 35% using the NCEP/ATP III definition15 and to almost 40% based on the IDF definition.16 
Wide variations in the prevalence of the metabolic syndrome are observed across different parts of the world depending on the definition used. For instance, among Hong Kong Chinese, the prevalence of metabolic syndrome varied from 9.6% using the NCEP definition to 13.4% using the WHO definition.17 In a large United Kingdom study, South Asians had the highest prevalence of metabolic syndrome (29% in men and 32% in women using the NCEP definition) and European women the lowest (14%).18 Hu et al, studied 11 European cohort. The prevalence using a modified WHO definition was slightly higher in men (15.7%) than in women (14.2%).19 
In the United States, applying NCEP criteria to the National Health and Nutrition Examination Survey III, the prevalence of the metabolic syndrome increased with age from 6.7% in the 20 to 29 years-of-age range to 43.5% in the 60 to 69 years-of-age range. Hispanics were affected more than blacks or whites. When divided by sex, black women had greater prevalence than white women, whereas white men had greater prevalence than black men.20 
Overall, metabolic syndrome is present in about 25% of people who appear healthy and in 45% of persons with known cardiovascular disease.14,21 The significance of the presence of the metabolic syndrome is that it confers a two-fold increased risk of developing cardiovascular disease and a five-fold risk of developing diabetes over five years.13 Further, the seven-year cardiovascular mortality is increased more than five-fold: ie, 12% in those with metabolic syndrome and 2.2% in those without.22 
Do children develop the metabolic syndrome? The answer is “yes” but the diagnosis can be made only in children ≥10 years of age.23 Children between the ages of 6 and 10 can be diagnosed as obese and emphasis placed on their weight management. For children and adolescents between the ages of 10 and 16, metabolic syndrome is defined by waist circumference, blood pressure, triglycerides, HDL-C and glucose (See Table 3).23 The key to discovering metabolic syndrome in children is measuring the waist circumference. If abnormal, an evaluation of blood pressure, lipids and glucose needs to be performed, if not already done, as part of standard pediatric longitudinal care. 
TABLE 3
The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents 23
 The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents   23
TABLE 3
The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents 23
 The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents   23   ×
Waist circumference plays a similar role in children as it does in adults: Obesity and associated insulin resistance sets the stage for vascular disease. Just as obesity is increasing to unprecedented levels in adults, there is an alarming increase in the rate of obesity and type 2 diabetes mellitus in children in the United States.24,25 Several studies have examined the interactions among fasting insulin, lipids, blood pressure and weight in children, pursuing the hypothesis that metabolic syndrome is a developmental disorder strongly influenced by risk factors in the first two decades of life.26-28 
Sinaiko et al, examined the metabolic syndrome in children by measuring the relationships between obesity, insulin resistance, lipids and blood pressure in children aged 11 to 14.27,28 A total of 357 children were studied by using both fasting insulin level and euglycemic insulin clamp technique to assess insulin resistance. The results demonstrated that girls had higher insulin resistance than boys and that higher levels of fasting insulin and insulin resistance correlated with higher body mass indices, systolic blood pressure and triglycerides. 
The association of insulin resistance and body mass index (BMI) with systolic blood pressure, triglycerides and high-density lipoprotein cholesterol has been studied in black and non-Hispanic white adolescents at ages 13, 15 and 19 years of age. A multiple regression model was used to determine the risk factors that best predicted the development of the metabolic syndrome by age 19. The results were that BMI at 13 years did not predict the metabolic syndrome at age 19; however, an increase in BMI starting at age 13 predicted the development of the metabolic syndrome. Insulin resistance at age 13 predicted systolic hypertension and hypertriglyceridemia. Thus, insulin resistance and BMI affect different components of the metabolic syndrome. The clinical implication is that to reduce the prevalence of cardiovascular risk, the focus needs to be on weight loss and decreasing insulin resistance.29 
Ethnic differences in the prevalence of metabolic syndrome in children have been described. Among 403 third-grade children, Batey and colleagues found that a summary score of metabolic variables associated with insulin resistance was significantly higher in Mexican American children than in non-Hispanic white children.30 
Among 144 mother-child pairs examined by Peter Reaven and colleagues, Mexican American mothers and children had higher BMI, triglycerides, very low-density lipoprotein (VLDL), fasting insulin, and cholesterol /HDL ratio, and lower HDL levels than did non-Hispanic white mothers and children. Mother-child pairs also showed significant correlations of cardiovascular risk factors, owing to either genetic or environmental influences.31 These two studies suggest that the metabolic syndrome probably begins early in life and is possibly related to childhood obesity and could be mediated by genetic and/or environmental causes. 
Medical management
Is medical management indicated for children and adolescents with the metabolic syndrome? Yes. Medical nutrition therapy is prescribed for children. Orlistat may also be used in the pediatric population as an adjunct for weight loss. 
The oral antidiabetic agent metformin can be used in children starting at age 10 as part of the program to reduce insulin resistance, glucose and weight. All the statins are approved in children aged 10 and over, and pravastatin may be started at age 8 to treat hyperlipidemia. Similarly, there are antihypertensive agents approved for pediatric use. 
No one doubts that the components defining metabolic syndrome are important factors predicting the development of cardiovascular disease and diabetes. However, important questions arise. For example, are there better predictors of diabetes and vascular disease than those defining the metabolic syndrome? Why not measure fasting glucose or perform an oral glucose tolerance test to evaluate risk for diabetes. Why not use the Framingham score to predict cardiovascular disease? After all, Framingham includes smoking status and that alone confers a risk almost equal to all five parameters of the metabolic syndrome.32 
Returning to Dr. Kahn's original question of whether “...the whole is greater than the sum of its parts,” recent analyses of various data sets suggest that diagnosing the metabolic syndrome adds nothing beyond each individual risk factor for predicting cardiovascular disease or diabetes. Eddy et al32 reached this conclusion based on modeling NHANES data. 
Bayturan et al33 recently published an analysis on the progression of atherosclerosis in various clinical trials and concluded that the correlation of metabolic syndrome with disease was due to the individual risk factors and not the syndrome itself. The commentary to Bayturan's paper by Ding et al34 contains references to three additional studies where 
  • identifying metabolic syndrome in diabetics did not predict survival more than the individual components,
  • the individual components of metabolic syndrome predicted diabetes and cardiovascular disease as well as the syndrome, and
  • the metabolic syndrome did not predict cardiovascular mortality independently of the individual components.
Final notes
Is there a point to diagnosing the metabolic syndrome? Many would argue that other protocols for predicting cardiovascular disease and diabetes are equal or better tools than the metabolic syndrome criteria. Others argue that the term “syndrome” is inappropriate because the combination of parameters yields no more information than analyzing the individual parameters. However, in the clinical practice of medicine, there is another context to be considered. 
The real value of diagnosing the metabolic syndrome may be to engender clinicians with a mind-set to focus on prevention of disease. Look again at the components of the metabolic syndrome: obesity, lipid disorders, hypertension and hyperglycemia. Parameters beyond an individual's control such as age, genetics, family history, etc, are not part of the metabolic syndrome. Hence, one may consider that diagnosing and treating metabolic syndrome as a realistic “road map” approach to preventive medicine. 
 C.W. Spellman, PhD, DO, is associate dean for research and professor in the Department Internal Medicine, Division Endo–crinology at the Texas Tech University Health Science Center in Odessa, Texas. He also serves as the director of the Center for Diabetes and Metabolic Disorders Department of Internal Medicine, Division of Endocrinology at Texas Tech University Health Science Center-PB. Dr. Spellman can be reached at craig.spellman@ttuhsc.edu.
 
 Ramachandra Rahul V. Chemitiganti, MD, is assistant professor in the Department of Internal Medicine at Texas Tech University Health Science Center-PB in Odessa, Texas. He can be reached at rama.chemitiganti@ttuhsc.edu.
 
 This continuing medical education publication is supported by an educational grant from Merck & Co, Inc.
 
Kylin E. Studien ueber das Hypertonie-Hyperglykamie Hyperurikamiesyndrom. Zentralbl Innere Medizin.. (1923). ;44:105-127.
Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutrition.. (1956). ; 4:20-34.
Gerald Reven Role of insulin resistance in human disease. Diabetes. 1988;37 : 1595-1607.
Kaplan NM. The deadly quartet, upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med. 1989;149:1514-1520.
Lemieux I, Pascot A, Couillard C, Lamarche B, Tchernof A, Almeras N, et al. Hypertriglyceridemic waist: A marker of the atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men? Circulation.. (2000). ;102:179-184.
World Health Organisation. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation 1999.
Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med.. (1999). ;16:442-443.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA. 2001;285:2486-2497.
Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract. 2003;9 : 237-252.
Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet.. (2005). ;366:1059-1062.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and Management of the Metabolic Syndrome. An American Heart. Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation.. (2005). ;112:2735-52.
docstoc. The Metabolic Syndrome Does it Matter page. Available at: http://www.docstoc.com/docs/4552014/The-Metabolic-Syndrome-Does-it-Matter-Richard-Kahn-PhD.
Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart J-C, James WPT, Loria CM, Smith SC Jr. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation.. (2009). ;120:1640-1645.
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA.. (2002). ;287:356-359.
Third report of the National Cholesterol Education Program (NCEP) expert panel on the detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report. Circulation.. (2002). ;106:3143-3421.
Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the US. Diabetes Care. 2005;28:2745-2749.
Ko GT, Cockram CS, Chow CC et al. High prevalence of metabolic syndrome in Hong Kong Chinese-comparison of three diagnostic criteria. Diab Res Clin Pract.. (2005). ;69:160-168.
Tillin T, Forhouhi N, Johnston DG et al. Metabolic syndrome and coronary heart disease in South Asians, African-Caribbeans and white Europeans: a UK population-based cross-sectional study. Dibetologia.. (2005). ;48:649-656.
Hu G, Qiao Q, Tuomilehto J et al. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med.. (2004). ; 164:1066-1076.
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.
Gorter P, Olijhoek JK, Graaf van der Y, Algra A, Rabelink AJ, Visseren FJL. Prevalence of the metabolic syndrome in patients with coronary heart disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm. Athersclerosis.. (2004). ;173:361-370.
Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001; 24:683-689.
The IDF consensus definition of the metabolic syndrome in children and adolescents. 2005. http://www.idf.org/webdata/docs/Mets_definition_children.pdf.
Luepker RV, Jacobs DR, Prineas RJ, et al. Secular trends of blood pressure and body size in a multi-ethnic adolescent population:1986 to 1996. J Pediatr.. (1999). ;134:668-674.
Rosenbloom AL, Joe JR, Young RS, et al. Emerging epidemic of type 2 diabetes in youth. Diabetes Care.. (1999). ;22:345-354.
Jiang X, Srinivasan SR, Webber LS, et al. Association of fasting insulin level with serum lipid and lipoprotein levels in children, adolescents, and young adults: the Bogalusa Heart Study. Arch Intern Med. 1995;155:190-196.
Sinaiko AR, Gomez-Marin O, Prineas RJ. Relation of fasting insulin to blood pressure and lipids in adolescents and parents. Hypertension.. (1997). ;30:1554-1559.
Sinaiko AR, Jacobs Jr DR, Steinberger Jr J, et al. Insulin resistance syndrome in childhood: associations of the euglycemic insulin clamp and fasting insulin with fatness and other risk factors. J Pediatr. 2001; 139:700-707.
Sinaiko AR, Steinberger J, Moran A, Hong CP, Prineas RJ, Jacobs DR Jr. Influence of insulin resistance and body mass index at age 13 on systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol at age 19. Hypertension.. (2006). ;48:730-736.
Batey LS, Goff Jr DC, Tortolero Jr SR, et al. Summary measures of the insulin resistance syndrome are adverse among Mexican-American versus non-Hispanic white children: the Corpus Christi Child Heart Study. Circulation. 1997;96 : 4319-4325.
Reaven P, Nader PR, Berry C, et al. Cardiovascular disease insulin risk in Mexican-American and Anglo-American children and mothers. Pediatrics.. (1998). ;101:E12 .
Eddy DM, Schlessinger L, Keikes K. The metabolic syndrome and cardiovascular risk: implications for clinical practice. Intl J Obesity. 2008;32:S5-S10.
Bayturan O, Tuzcu EM, Lavoie A, et al. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med.. (2010). ;170:478-484.
Ding EL, Smit LA, Hu FB. The metabolic syndrome as a cluster of risk factors. Is the whole greater than the sum of its parts? Arch Intern Med. 2010;170:484-485.
TABLE 1
Criteria for Clinical Diagnosis of the Metabolic Syndrome 13
 Criteria for Clinical Diagnosis of the Metabolic Syndrome   13
TABLE 1
Criteria for Clinical Diagnosis of the Metabolic Syndrome 13
 Criteria for Clinical Diagnosis of the Metabolic Syndrome   13   ×
TABLE 2
Current Recommended Waist Circumference Thresholds for Abdominal Obesity 13
 Current Recommended Waist Circumference Thresholds for Abdominal Obesity   13
TABLE 2
Current Recommended Waist Circumference Thresholds for Abdominal Obesity 13
 Current Recommended Waist Circumference Thresholds for Abdominal Obesity   13   ×
TABLE 3
The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents 23
 The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents   23
TABLE 3
The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents 23
 The IDF Consensus Definition of the Metabolic Syndrome in Children and Adolescents   23   ×