Metabolic Syndrome Susan L. Samson,
MD, PhD
a
, Alan J. Garber,
MD, PhD
b,c,d,
*
KEYWORDS Metabolic syndrome Obesity Dyslipidemia Hypertension Cardiovascular risk Diabetes risk National Cholesterol Education Program Adult Treatment Panel III KEY POINTS Metabolic syndrome is a clustering of clinical findings made up of abdominal obesity, high glucose, high triglyceride, and low high-density lipoprotein cholesterol levels, and hypertension. Several definitions of metabolic syndrome have been proposed, with varied requirements, including those by the International Diabetes Federation and the National Cholesterol Education Program Adult Treatment Panel III. There is a proposed harmonized international definition that incorporates the criteria for the National Cholesterol Education Program definition and suggests that populationspecific waist circumference thresholds should be used for obesity. Diagnosis of metabolic syndrome has a relative risk of approximately 2-fold for cardiovascular disease over 5 to 10 years and at least 5-fold for type 2 diabetes. Treatment involves diet and exercise to promote weight loss and pharmacologic treatment of atherogenic dyslipidemia, hypertension, and hyperglycemia.
INTRODUCTION
A medical syndrome is a clustering of clinical findings that occur together more often than would be expected by chance. The constellation of components that make up the metabolic syndrome (MetS) has had several labels over the years including the eponymous Reaven syndrome, syndrome X, dysmetabolic syndrome X (ICD-9 code 277.7), CHAOS, plurimetabolic syndrome, the deadly quartet, and insulin resistance syndrome. Although increased attention and research have been focused on MetS in the last 2 to 3 decades, syndromes analogous to MetS have been described in the
a Department of Medicine, Baylor College of Medicine, One Baylor Plaza, ABBR R615, Houston, TX 77030, USA; b Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030, USA; c Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030, USA; d Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030, USA * Corresponding author. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030. E-mail address: [email protected]
Endocrinol Metab Clin N Am 43 (2014) 1–23 http://dx.doi.org/10.1016/j.ecl.2013.09.009 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
2
Samson & Garber
medical literature for nearly a century. The descriptions of these syndromes may differ by components or criteria, but all point toward a similar dysmetabolic phenotype. Swedish physician Eskil Kylin, with a keen interest in hypertension, described its relationship with hyperglycemia and gout in 1923.1 In 1956, Dr Jean Vague of Marseilles, France published the association of atherosclerosis, diabetes, gout, and renal calculi with central obesity.2,3 Both Haller and Singer used the term “metabolic syndrome” in German language publications that reported on their observations from studies of patients with dyslipidemia. Haller4 included obesity, diabetes, hyperlipoproteinemia, gout, and fatty liver in the syndrome, whereas Singer5 included the first 4 components but added hypertension. Professor Phillips (Columbia University) recognized the coexistence of impaired glucose metabolism with hyperinsulinemia, hyperlipidemia, and hypertension, leading to increased risk for myocardial infarction (MI); in also observing the increased prevalence of this MetS with aging, he focused on changes in sex hormone levels as important to the underlying disease.6 However, it was Dr Gerald Reaven, in his 1988 Banting medal lecture for the American Diabetes Association (ADA), who discussed the constellation of metabolic findings of syndrome X, proposing a central role for insulin resistance in the pathophysiology of the syndrome and the risk of diabetes and cardiovascular disease (CVD), with the goal to foster new hypotheses and research in the field.7 According to the World Health Organization (WHO), worldwide prevalence of obesity has doubled in the last 3 decades and at least one-third of adults older than 20 years are overweight or obese.8 As the prevalence of obesity increases, it follows that the prevalence of MetS also will increase in parallel. Alarmingly, nearly one-half of the diabetes burden and one-quarter of the heart disease burden are attributable to being overweight or obese.9 DEFINITIONS
Despite multiple labels in the past, the term MetS is now used universally. It was first formalized by use in a working definition proposed by a diabetes consultation panel for WHO in 1998 and finalized in 1999.10 The section on MetS is a small portion of a document primarily focused on the diagnosis and classification of type 2 diabetes mellitus (T2DM),10 but it provoked discussion and position statements such as from the European Group for the Study of Insulin Resistance (EGIR)11 and the American Association of Clinical Endocrinologists (AACE) in 2003.12 In the United States, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) was published in 2001 to guide therapy for low-density lipoprotein (LDL) cholesterol (LDL-C) to reduce coronary heart disease (CHD).13 MetS was seen as an additional target beyond LDL decreasing that could result in reduction of CHD risk. The NCEP/ATPIII was followed by a similar definition from the International Diabetes Federation (IDF) in 2005.14 The commonality among the different definitions is that each recognizes the components of: (1) obesity, abdominal adiposity or indicators of insulin resistance, (2) impaired glucose metabolism, (3) hypertension, and (4) atherogenic dyslipidemia. The dissimilarities are in how the components are detected clinically and, in some cases, there is an emphasis on a particular trait that is obligate to meet the definition (Table 1). NCEP/ATPIII MetS criteria were proposed requiring 3 of 5 factors: abdominal obesity measured as sex-specific waist circumference (WC), triglyceride levels, low highdensity lipoprotein (HDL) cholesterol (HDL-C), hypertension, and increased fasting glucose (IFG), without exclusion of diabetes.13 A 2004 update was provided by the American Heart Association (AHA) and National Heart Lung and Blood Institute (NHLBI) to decrease the threshold for IFG from 110 mg/dL (6.1 mmol/L) to 100 mg/dL
Metabolic Syndrome
(5.6 mmol/L) as recommended by the ADA, and to clarify that it could include patients already on treatment of dyslipidemia or hypertension.15 Although the later IDF criteria were in agreement with the NCEP definition, abdominal obesity was made a requirement, as measured by WC, or it was assumed if body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) was 30 kg/m2 or higher.16 The IDF WC threshold for Europoids was lower than that used by NCEP, and the document also discussed the need for thresholds for WC dependent on ethnic background (Table 2).16 The clinical usefulness of a MetS diagnosis partially has been hampered by the multiple definitions. Efforts have been made to unify the definition of MetS. In 2009, 5 groups released a joint interim statement regarding the harmonization of the criteria: IDF, AHA, NHLBI, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity (see Table 1).17 Obesity was removed as an obligate component and HDL-C, triglyceride, blood pressure, and fasting glucose criteria were identical to the modified NCEP definition. The higher NCEP threshold for Europoid WC was kept for North American patients, but it was acknowledged that lower values used by the IDF could be important for those at higher risk.17 This document also noted that the criteria used for abdominal obesity, as WC, required refinement with regard to country-specific and population-specific definitions, as originally discussed by the IDF, with more study and evidence needed to determine the WC cutoffs in different populations that are associated with higher risk.17 The WC thresholds suggested for the harmonized definition of the joint interim statement are shown in Table 2,17 and the physician is left to clinical judgment regarding patients with mixed ethnicity. Adult MetS criteria have been modified for pediatric and adolescent age groups, and there have also been multiple MetS definitions used in this population.18 The earliest definition was proposed by Cook and colleagues19 and was a modification of the original NCEP criteria with WC and blood pressure equal to or greater than the 90th percentile for age, sex, and height with triglyceride levels greater than 110 mg/dL (1.23 mmol/L) and HDL levels less than 40 mg/dL (1.03 mmol/L). Additional definitions followed with varied age-specific and sex-specific triglyceride and HDL-C cutoffs, and differing approaches to measuring abdominal obesity with WC or BMI.20 In 2007, an IDF consensus panel proposed unified criteria.20 For children aged 10 to 16 years, obesity was diagnosed if WC was equal to or greater than the 90th percentile for age. Over 16 years, the criteria were the same as adult IDF WC criteria, with cutoffs of 94 cm or higher in males and 80 cm or higher in females.20 A MetS diagnosis required an additional 2 of increased triglyceride levels (1.7 mmol/L or 150 mg/dL), low HDL-C levels (1.03 mmol/L or 40 mg/dL), increased blood pressure (130 bpm systolic, 85 bpm diastolic), and impaired fasting glucose level (5.6 mmol/L or 100 mg/dL) or overt diabetes. For children younger than 10 years, obesity was defined as WC equal to or greater than the 90th percentile, but the panel did not support that a MetS diagnosis could be made in this age group, although testing for additional components could be undertaken in high-risk children. EPIDEMIOLOGY
The reported prevalence of MetS varies depending on the definition used, age, sex, socioeconomic status, and the ethnic background of study cohorts. However, from studies published in the last decade, an estimated one-quarter to one-third of adults meet MetS criteria in multiple ethnic backgrounds. Cross-sectional data from 1999 to 2010 from the National Health and Nutrition Examination Survey (NHANES) in the
3
4
Samson & Garber
Table 1 Comparison of definitions of MetS
WHO
EGIR
NCEP/ATPIII
AACE
AHA/NHLBI/ADA Updated NCEP/ ATPIII
Year
1999
1999
2001
2003
2004
2005
2009
Number of risk factors
IFG/IGT/T2DM or insulin resistanceb and 2 of.
Insulin resistancec and 3 or more of.
Three or more of..
IGT/IFG with any of the following.
Three or more of.
Obesity and 2 of.
Three or more of.
Obesity
Waist/hip ratio >0.9 M, >0.85 F or BMI >30 kg/m2
Waist circumference 94 cm M 80 cm F
Waist circumference 102 cm M 88 cm F
BMI 25 kg/m2
Waist circumference 102 cm M 88 cm F
Waist circumference 94 cm M 90 (Asian M) 80 cm F
Waist circumferenced Geographic and ethnic specific
Dyslipidemia
HDL-C
MD, PhD
a
, Alan J. Garber,
MD, PhD
b,c,d,
*
KEYWORDS Metabolic syndrome Obesity Dyslipidemia Hypertension Cardiovascular risk Diabetes risk National Cholesterol Education Program Adult Treatment Panel III KEY POINTS Metabolic syndrome is a clustering of clinical findings made up of abdominal obesity, high glucose, high triglyceride, and low high-density lipoprotein cholesterol levels, and hypertension. Several definitions of metabolic syndrome have been proposed, with varied requirements, including those by the International Diabetes Federation and the National Cholesterol Education Program Adult Treatment Panel III. There is a proposed harmonized international definition that incorporates the criteria for the National Cholesterol Education Program definition and suggests that populationspecific waist circumference thresholds should be used for obesity. Diagnosis of metabolic syndrome has a relative risk of approximately 2-fold for cardiovascular disease over 5 to 10 years and at least 5-fold for type 2 diabetes. Treatment involves diet and exercise to promote weight loss and pharmacologic treatment of atherogenic dyslipidemia, hypertension, and hyperglycemia.
INTRODUCTION
A medical syndrome is a clustering of clinical findings that occur together more often than would be expected by chance. The constellation of components that make up the metabolic syndrome (MetS) has had several labels over the years including the eponymous Reaven syndrome, syndrome X, dysmetabolic syndrome X (ICD-9 code 277.7), CHAOS, plurimetabolic syndrome, the deadly quartet, and insulin resistance syndrome. Although increased attention and research have been focused on MetS in the last 2 to 3 decades, syndromes analogous to MetS have been described in the
a Department of Medicine, Baylor College of Medicine, One Baylor Plaza, ABBR R615, Houston, TX 77030, USA; b Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030, USA; c Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030, USA; d Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030, USA * Corresponding author. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030. E-mail address: [email protected]
Endocrinol Metab Clin N Am 43 (2014) 1–23 http://dx.doi.org/10.1016/j.ecl.2013.09.009 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
2
Samson & Garber
medical literature for nearly a century. The descriptions of these syndromes may differ by components or criteria, but all point toward a similar dysmetabolic phenotype. Swedish physician Eskil Kylin, with a keen interest in hypertension, described its relationship with hyperglycemia and gout in 1923.1 In 1956, Dr Jean Vague of Marseilles, France published the association of atherosclerosis, diabetes, gout, and renal calculi with central obesity.2,3 Both Haller and Singer used the term “metabolic syndrome” in German language publications that reported on their observations from studies of patients with dyslipidemia. Haller4 included obesity, diabetes, hyperlipoproteinemia, gout, and fatty liver in the syndrome, whereas Singer5 included the first 4 components but added hypertension. Professor Phillips (Columbia University) recognized the coexistence of impaired glucose metabolism with hyperinsulinemia, hyperlipidemia, and hypertension, leading to increased risk for myocardial infarction (MI); in also observing the increased prevalence of this MetS with aging, he focused on changes in sex hormone levels as important to the underlying disease.6 However, it was Dr Gerald Reaven, in his 1988 Banting medal lecture for the American Diabetes Association (ADA), who discussed the constellation of metabolic findings of syndrome X, proposing a central role for insulin resistance in the pathophysiology of the syndrome and the risk of diabetes and cardiovascular disease (CVD), with the goal to foster new hypotheses and research in the field.7 According to the World Health Organization (WHO), worldwide prevalence of obesity has doubled in the last 3 decades and at least one-third of adults older than 20 years are overweight or obese.8 As the prevalence of obesity increases, it follows that the prevalence of MetS also will increase in parallel. Alarmingly, nearly one-half of the diabetes burden and one-quarter of the heart disease burden are attributable to being overweight or obese.9 DEFINITIONS
Despite multiple labels in the past, the term MetS is now used universally. It was first formalized by use in a working definition proposed by a diabetes consultation panel for WHO in 1998 and finalized in 1999.10 The section on MetS is a small portion of a document primarily focused on the diagnosis and classification of type 2 diabetes mellitus (T2DM),10 but it provoked discussion and position statements such as from the European Group for the Study of Insulin Resistance (EGIR)11 and the American Association of Clinical Endocrinologists (AACE) in 2003.12 In the United States, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) was published in 2001 to guide therapy for low-density lipoprotein (LDL) cholesterol (LDL-C) to reduce coronary heart disease (CHD).13 MetS was seen as an additional target beyond LDL decreasing that could result in reduction of CHD risk. The NCEP/ATPIII was followed by a similar definition from the International Diabetes Federation (IDF) in 2005.14 The commonality among the different definitions is that each recognizes the components of: (1) obesity, abdominal adiposity or indicators of insulin resistance, (2) impaired glucose metabolism, (3) hypertension, and (4) atherogenic dyslipidemia. The dissimilarities are in how the components are detected clinically and, in some cases, there is an emphasis on a particular trait that is obligate to meet the definition (Table 1). NCEP/ATPIII MetS criteria were proposed requiring 3 of 5 factors: abdominal obesity measured as sex-specific waist circumference (WC), triglyceride levels, low highdensity lipoprotein (HDL) cholesterol (HDL-C), hypertension, and increased fasting glucose (IFG), without exclusion of diabetes.13 A 2004 update was provided by the American Heart Association (AHA) and National Heart Lung and Blood Institute (NHLBI) to decrease the threshold for IFG from 110 mg/dL (6.1 mmol/L) to 100 mg/dL
Metabolic Syndrome
(5.6 mmol/L) as recommended by the ADA, and to clarify that it could include patients already on treatment of dyslipidemia or hypertension.15 Although the later IDF criteria were in agreement with the NCEP definition, abdominal obesity was made a requirement, as measured by WC, or it was assumed if body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) was 30 kg/m2 or higher.16 The IDF WC threshold for Europoids was lower than that used by NCEP, and the document also discussed the need for thresholds for WC dependent on ethnic background (Table 2).16 The clinical usefulness of a MetS diagnosis partially has been hampered by the multiple definitions. Efforts have been made to unify the definition of MetS. In 2009, 5 groups released a joint interim statement regarding the harmonization of the criteria: IDF, AHA, NHLBI, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity (see Table 1).17 Obesity was removed as an obligate component and HDL-C, triglyceride, blood pressure, and fasting glucose criteria were identical to the modified NCEP definition. The higher NCEP threshold for Europoid WC was kept for North American patients, but it was acknowledged that lower values used by the IDF could be important for those at higher risk.17 This document also noted that the criteria used for abdominal obesity, as WC, required refinement with regard to country-specific and population-specific definitions, as originally discussed by the IDF, with more study and evidence needed to determine the WC cutoffs in different populations that are associated with higher risk.17 The WC thresholds suggested for the harmonized definition of the joint interim statement are shown in Table 2,17 and the physician is left to clinical judgment regarding patients with mixed ethnicity. Adult MetS criteria have been modified for pediatric and adolescent age groups, and there have also been multiple MetS definitions used in this population.18 The earliest definition was proposed by Cook and colleagues19 and was a modification of the original NCEP criteria with WC and blood pressure equal to or greater than the 90th percentile for age, sex, and height with triglyceride levels greater than 110 mg/dL (1.23 mmol/L) and HDL levels less than 40 mg/dL (1.03 mmol/L). Additional definitions followed with varied age-specific and sex-specific triglyceride and HDL-C cutoffs, and differing approaches to measuring abdominal obesity with WC or BMI.20 In 2007, an IDF consensus panel proposed unified criteria.20 For children aged 10 to 16 years, obesity was diagnosed if WC was equal to or greater than the 90th percentile for age. Over 16 years, the criteria were the same as adult IDF WC criteria, with cutoffs of 94 cm or higher in males and 80 cm or higher in females.20 A MetS diagnosis required an additional 2 of increased triglyceride levels (1.7 mmol/L or 150 mg/dL), low HDL-C levels (1.03 mmol/L or 40 mg/dL), increased blood pressure (130 bpm systolic, 85 bpm diastolic), and impaired fasting glucose level (5.6 mmol/L or 100 mg/dL) or overt diabetes. For children younger than 10 years, obesity was defined as WC equal to or greater than the 90th percentile, but the panel did not support that a MetS diagnosis could be made in this age group, although testing for additional components could be undertaken in high-risk children. EPIDEMIOLOGY
The reported prevalence of MetS varies depending on the definition used, age, sex, socioeconomic status, and the ethnic background of study cohorts. However, from studies published in the last decade, an estimated one-quarter to one-third of adults meet MetS criteria in multiple ethnic backgrounds. Cross-sectional data from 1999 to 2010 from the National Health and Nutrition Examination Survey (NHANES) in the
3
4
Samson & Garber
Table 1 Comparison of definitions of MetS
WHO
EGIR
NCEP/ATPIII
AACE
AHA/NHLBI/ADA Updated NCEP/ ATPIII
Year
1999
1999
2001
2003
2004
2005
2009
Number of risk factors
IFG/IGT/T2DM or insulin resistanceb and 2 of.
Insulin resistancec and 3 or more of.
Three or more of..
IGT/IFG with any of the following.
Three or more of.
Obesity and 2 of.
Three or more of.
Obesity
Waist/hip ratio >0.9 M, >0.85 F or BMI >30 kg/m2
Waist circumference 94 cm M 80 cm F
Waist circumference 102 cm M 88 cm F
BMI 25 kg/m2
Waist circumference 102 cm M 88 cm F
Waist circumference 94 cm M 90 (Asian M) 80 cm F
Waist circumferenced Geographic and ethnic specific
Dyslipidemia
HDL-C
