CLINICAL PRACTICE
Metabolic syndrome: Clinical perspective for best practice Darin Olde, MSN, APRN, FNP (Family Nurse Practitioner)1 , Patricia Alpert, DrPh, MSN, APN, FNP, PNP, CNE, FAANP (Associate Professor)2,3 , & Alona Dalusung-Angosta, PhD, APN, FNP, NP-C (Assistant Professor)2,4 1
Silver Sage Center for Family Medicine, Reno, Nevada Las Vegas School of Nursing, University of Nevada, Las Vegas, Nevada 3 First Med Health & Wellness, Las Vegas, Nevada 4 Advanced Urgent Care, Las Vegas, Nevada 2
Keywords Metabolic syndrome; cardiovascular disease; dyslipidemia; diabetes. Correspondence Alona Dalusung-Angosta, PhD, APN, FNP, NP-C, University of Nevada, Las Vegas School of Nursing, 4505 Maryland Parkway Box 453018, Las Vegas, Nevada 89154. Tel: 702-895-3360, ext 1218 (work); Fax: 702-895-4807 (work); E-mail: [email protected] Received: July 2013; accepted: January 2012 doi: 10.1002/2327-6924.12048
Abstract Purpose: To explore current studies on metabolic syndrome (MetS), including its complex pathophysiology and to describe the unique role of the advanced practice nurse including management and ethical decision making utilizing a case study to exemplify salient points. Data sources: From original research articles extracted from nursing and medical databases. Conclusions: MetS is a constellation of characteristics that increases the risk for the development of diabetes and cardiovascular disease. The pathophysiology of MetS is not completely understood, but is thought to involve a complex interaction between the environment, genetic susceptibility, insulin resistance, and abnormal adipose tissue function. Implications for practice: The role of the advanced practice nurse is appropriate for early intervention and counseling of patients with MetS and those who are at risk, as well as addressing the ethical challenges that accompany their care.
Introduction Metabolic syndrome (MetS) is a constellation of risk factors that increase a person’s risk of developing cardiovascular disease (CVD). Also known as syndrome X, dysmetabolic syndrome, and insulin resistance syndrome, MetS has been increasingly studied in recent decades, partly because of increasing prevalence in the United States, and globally. Moreover, estimates suggest MetS confers twice the risk of developing coronary heart disease (CHD) over the next 5–10 years, and the risk of developing type 2 diabetes mellitus (T2DM) is fivefold higher than the population without the syndrome (Alberti et al., 2009). The purpose of this article is to (a) explore current studies on MetS including its complex pathophysiology, and (b) describe the unique role of the advanced practice nurse (APN) including management utilizing a case study to exemplify salient points.
Review of literature Definition, epidemiology, and prevalence According to the diagnostic criteria of the National Cholesterol Education Program Adult Treatment Panel 644
III (NCEP/ATP III), patients with MetS have at least three of five characteristics: elevated blood pressure (BP) ≥ 130/85 mmHg or treatment for hypertension (HTN); atherogenic hypertriglyceridemia (TG ≥ 150 mg/dL) or deficient high-density lipoprotein cholesterol (HDL-C < 40 mg/dL in males or 40% of individuals 60 years of age or older (Ford, 2005). Previous estimates from the 1988 to 1994 cohort of the National Health and Nutrition Examination Survey (NHANES) suggested the syndrome was less common, at approximately 22%–25% of the population ≥20 years old (Park et al., 2003). But as the definition of MetS becomes more consistent, and rates of obesity as well as life span increases, these estimates need to be revised upwards. MetS is on the rise worldwide, and is thought to parallel the increasing prevalence of obesity. About 34.2% of Americans are overweight (body mass index [BMI] 25–29.9 kg/m2 ) and 33.8% are obese (BMI ≥ 30 kg/m2 ) according to 2007–2008 NHANES data (Flegal, Carroll, Ogden, & Curtin, 2010). Obesity is increasing in younger cohorts as well. According to Grundy (2008) data from 1999 to 2004 suggested 16% of female and 18% of male children and adolescents were overweight. The 1999–2000 NHANES estimates suggested the prevalence was lower at 15% of children and adolescents in the United States being overweight (National Heart, Lung, and Blood Institute [NHLBI], 2010). Prevalence of the MetS is strongly correlated to both obesity and age, re-
Metabolic syndrome: Clinical perspective for best practice
gardless of gender or ethnicity. Early reports suggested the condition was more common in women than men, but some data suggested the margin of gender difference is less than previously estimated (Grundy, 2008). However, prevalence does change among men and women in specific ethnic groups, which has become increasingly studied in the last decade. Ford (2005) reported African American women had higher prevalence than men at 33.8% and 21.6%, respectively. Hispanic American women also showed higher prevalence than men at 37.8% and 32.2%, respectively. However, Caucasian men were more likely to have the syndrome than women by a small margin at 36.0% and 35.4%, respectively. Internationally, Americans and Canadians had a higher prevalence of the syndrome than many European or Asian nations. Using NCEP-ATP-III criteria, Grundy (2008) estimated the prevalence of the syndrome among Europeans at approximately 25%, with less than 20% prevalence in Southeast Asia. As of yet, a lack of large epidemiologic studies with adequate sample size substantially limited comparisons in other countries.
Emerging risk factors: Socioeconomic and environmental risk Low adulthood socioeconomic status (SES) was associated with higher rates of MetS in numerous studies (Chichlowska et al., 2009; Loucks, Magnusson et al., 2007). However, there were conflicting results regarding the association between gender and low SES in childhood, and development of MetS as an adult. In larger studies, the MetS was associated with low SES across the life span with women, but less so for men. The Atherosclerosis Risk in Communities (ARIC) study examined life course SES and prevalence of the MetS in more than 10,000 African American and Caucasian men and women and found significant correlations for both Caucasian and African American women. Of both ethnic groups, women with low SES in childhood, early adulthood, middle adulthood, or cumulatively, were more likely to develop the syndrome than women with high SES (Chichlowska et al., 2009). Similarly, Loucks, Magnusson et al. (2007) found women aged 25–65 with income below the poverty line were more likely to develop the syndrome than women with higher income ratios even after adjusting for age, race/ethnicity, and menopause status. Interestingly, income and education were not associated with the syndrome for males, or female adolescents and older adults (age > 65 years). Some authors suggested the higher prevalence of MetS among women has to do with economic disparities between men and women, particularly as a result of physical attributes. Chichlowska et al. (2009) cited two studies 645
Metabolic syndrome: Clinical perspective for best practice
that suggested obesity may affect economic trajectory for women more so than for men, particularly during adolescence and young adulthood (Gormaker, Must, Perrin, Sobol, & Dietz, 1993; Sargent & Blanchflower, 1994). The lower SES during this sensitive period of development was associated with increased prevalence of the syndrome. It was also suggested women with low SES are more likely to be unemployed, a single parent, or depressed (Thurston, Kubzansky, Kawaci, & Berkman, 2005). While smaller reports with limited samples showed conflicting data, theories linking cumulative economic challenges and different environmental stressors are gaining momentum as a risk factor for the syndrome, particularly for adult women. In the Coronary Artery Risk Development in Young Adults study, childhood SES and early family environment assessed through models that measured depression, hostility, and poor quality of social contacts, showed these factors were associated with metabolic function (Lehman, Taylor, Kiefe, & Seeman, 2005). Environmental associations have been well documented in the development of MetS. Cigarette smoking, excessive alcohol intake, and greater reliance on low-cost, high-energy dense foods with fewer nutrients such as sugar, fat, or refined-grain foods were all related to higher prevalence of the MetS, or obesity (Loucks, Rehkopf, Thurston, & Kawachi, 2007). Empty calories and high-energy dense foods were shown to cost less compared to low-density foods, such as fruits and vegetables, which may lead those with fewer economic resources to less desirable dietary choices. Similarly, the positive correlation between depression and low SES is well documented, and among this group smoking, alcohol use, and sedentary lifestyles as well as less compliance with medication regimens all showed positive correlations. Loucks, Rehkopf et al. (2007) cited research by Kawachi and Berkman (2003) indicating people with low SES tend to live in environments with greater crime rates, fewer recreational opportunities, more fast food restaurants, liquor stores, and billboard advertisements for cigarettes, fast food, and alcohol—all of which are associated with metabolic dysfunction or obesity. Finally, The U.S. Census Bureau showed the likelihood of being covered by health insurance increased with income along with the likelihood of seeking and receiving preventative care for diseases such as hypertension, obesity, mixed dyslipidemia, and hyperglycemia. Surveys from the U.S. Census Bureau suggested poverty and number of people without health insurance increased from 2008 to 2009 (DeNavas-Walt, Proctor, & Smith, 2009). As more and more individuals struggle with current economic chal-
646
D. Olde et al.
lenges, MetS is likely to increase concomitantly in the absence of adequate attention and treatment.
Pathophysiology Despite the substantial increase in research and clinical focus over the last two decades, the pathogenic interactions leading to MetS are still debated. Historically, insulin resistance was suspected as the underlying cause, and was initially incorporated as a diagnostic criterion. International focus lead to changes in the definition and diagnostic criteria, but insulin resistance remains a predominant etiologic theory. More recently, research suggested obesity, excess fat mass, or abnormal adipose metabolism ´ was the underlying cause (Grundy, 2007; Teran-Garcia & Bouchard, 2007). Both proposed mechanisms culminate in a proinflammatory and prothrombotic state associated with MetS as measured by serum inflammatory markers and procoagulation biomarkers. The proinflammatory and prothrombotic state sets the stage for endothelial dysfunction and the development of CVD.
Abnormal adipose metabolism Several authors suggested abnormal adipose metabolism is the driving force behind the MetS via four interrelated mechanisms: abnormal adipose tissue biology, excess fat mass, high levels of visceral fat, ´ and ectopic fat deposition (Teran-Garcia & Bouchard, 2007). Adipose tissue produces and secretes hormones, including cytokines—also known as adipokines—free fatty acids (FFAs), prostaglandins, and angiotensinogen. Among the predominant adipokines implicated in MetS are leptin, adiponectin, and resistin as well as other adipocyte products such as FFA, retinol binding protein 4, and fatty-acid binding protein. As excess fat tissue accumulates, adipocytes increase in size. The larger cells exhibit greater rates of triglyceride synthesis, lypolysis, and FFA transmembrane flux. Numerous adipokines are released into the blood stream, such as leptin, resistin, adiponectin, tumor necrosis factor α, angiotensinogen, interleukin 6, C-reactive peptide, and others. These proinflammatory products affect endothelial cells and stimulate other inflammatory modulators. Large omental adipocytes exhibit high rates of lypolysis. The products of these cells enter hepatic cir¨ culation. Bjorntorp (1990) suggested higher concentration of these products in hepatic circulation results in hepatic dysfunction as measured by insulin clearance, hepatic glucose, and very low-density lipoprotein (LDL) production. Other researchers suggested subcutaneous abdominal adipose tissue contributes in a similar fashion,
Metabolic syndrome: Clinical perspective for best practice
D. Olde et al.
and visceral adipocytes are not as large a contributor to ´ hepatic dysfunction as initially thought (Teran-Garcia & Bouchard, 2007). Ectopic fat deposition in nonadipose tissue, such as the liver, skeletal muscle, and pancreas, has also been implicated in insulin resistance. As adipocytes become more insulin resistant, researchers showed elevated rates of serum FFA, and greater ectopic fat accumulation via magnetic resonance spectroscopy, generating the “lipotoxic” effect. Researchers suggested ectopic fat accumulation may be one mechanism by which organ systems lose insulin sensitivity (Lee et al., 1994; Seppala-Lindroos et al., 2002). This suggests excess calories, fat mass, ectopic fat distribution, and the subsequent expulsion of FFA and adipokines may be how organ systems resist insulin. Among the diagnostic criteria of MetS are elevated TGs or low HDL-C. But other cholesterol abnormalities are associated with the syndrome, including a shift to smaller, denser, LDL cholesterol (LDL-C) particles. Smaller particle LDL-C is more strongly related to coronary atherosclerosis and cardiovascular (CV) events than direct measures of LDL-C. The smaller particle LDC-C may be more toxic to endothelium, more mobile through endothelial basement membranes, more adherent to endothelial cell walls, are more susceptible to oxidation, and are more selectively bound to macrophages (Singh, Arora, Goswami, & Mallika, 2009). Hence, measuring LDL particle distribution may be more indicative of CV risk than a single measure of LDL-C.
Insulin resistance Insulin resistance has long been recognized as a defining characteristic of the MetS. The extent to which it causes the syndrome is uncertain (Grundy, 2007) because insulin may have more endocrine functions than regulating glucose into cells. Insulin also prevents lipolysis and stimulates the enzyme lipoprotein lipase. This enzyme is thought to prevent the release of FFA into circulation via cyclic AMP-dependent enzyme-hormone sensitive lipase. As more FFA are released into circulation, this inhibits the antilipolytic action of insulin (Singh et al., 2009). Hyperinsulinemia may occur for several years with normal or near normal levels of fasting glucose. But as pancreatic cells slowly lose the ability to produce insulin and lipoprotein lipase activity diminishes, lipolysis increases, further leading to the downward spiral of FFA release, ectopic fat deposition, endocrine organ dysfunction, and insulin resistance. In later stages of the disease, DMT2 results. Grundy (2007) suggested metabolic susceptibility is an important precursor to the development of MetS with excess body fat leads the precursor. Susceptible risk fac-
Table 1 Commonly reported heritability estimates for components of the metabolic syndrome Phenotype Body composition BMI Body fat Abdominal obesity Insulin/glucose Fasting glucose Fasting insulin Insulin resistance of T2DM Lipids Triglycerides LDL-C HDL-C Blood pressure Systolic BP Diastolic BP Hypertension Microalbuminuria
Estimated heritability (%)
25–60 25–40 40–55 10–75 20–55 46–90 25–60 25–60 30–80 20–70 10–50 50 30
Argyropoulos et al. (2005).
tors include insulin signaling defects, adipose tissue disorders, as well as lifestyle and physical characteristics such as physical inactivity, mitochondrial defects, aging, polygenic variation, or drug use. Risk factors vary among different ethnic groups, with different rates of heritability. Hence, genetic susceptibility is thought to be a substantial risk factor for MetS possibly explaining why certain ethnic groups are more likely to exhibit metabolic disorders. Argyropoulos, Smith, and Bouchard (2005) reported BMI, body fat, and abdominal obesity have an estimated heritability of 25%–60%; insulin resistance or T2DM from 46% to 90%; LDL-C and triglycerides from 25% to 60%; and hypertension of approximately 50%. Overall, the heritability of MetS is about 30% (for a complete list of commonly reported heritability estimates see Table 1).
A patient with MetS Health history A 71-year-old Caucasian female, Ms. B, presented to a primary care clinic to establish care as her previous provider retired. She was recently hospitalized for chest pain and was diagnosed with mild CHD after undergoing a battery of tests that were negative for acute pathology. A myocardial perfusion study showed mild ischemia of the apex, anterior wall, and lateral wall without acute stenosis or obstruction. At discharge she was advised to follow up with a primary care provider. In addition to her diagnosis of mild CHD her past medical history indicated diagnoses of osteoarthritis in her left knee, essential 647
Metabolic syndrome: Clinical perspective for best practice
D. Olde et al.
Table 2 Ms. B’s fasting lipid profile Lab test Chemistry panel Sodium Potassium Chloride CO2 Glucose BUN Creatinine GFR Calcium Aspartate amino-tran Alanine amino tran Alkaline phosphatase Bilirubin total Albumin Total protein Globulin Albulin/globulin ratio Lipid panel Total cholesterol Triglycerides HDL-C LDL-C
Table 3 Diagnoses and plan of care
Result
Normal range
Unit
135 4.1 98 26 98 13 0.8 >90 9.6 32 31 96 0.5 3.9 7.2 3.0 1.3
135–145 3.6–5.5 96–112 20–33 65–99 8–22 0.5–1.4 >90 8.4–10.2 12–45 2–50 30–99 0.1–1.5 3.2–4.9 6.0–8.2 1.9–3.5
mmol/L mmol/L mmol/L mmol/L mg/dL mg/dL mg/dL mL/min/1.73 mg/dL U/L U/L U/L mg/dL g/dL g/dL g/dL g/dL
100–200 0–150 40–59
Metabolic syndrome: Clinical perspective for best practice Darin Olde, MSN, APRN, FNP (Family Nurse Practitioner)1 , Patricia Alpert, DrPh, MSN, APN, FNP, PNP, CNE, FAANP (Associate Professor)2,3 , & Alona Dalusung-Angosta, PhD, APN, FNP, NP-C (Assistant Professor)2,4 1
Silver Sage Center for Family Medicine, Reno, Nevada Las Vegas School of Nursing, University of Nevada, Las Vegas, Nevada 3 First Med Health & Wellness, Las Vegas, Nevada 4 Advanced Urgent Care, Las Vegas, Nevada 2
Keywords Metabolic syndrome; cardiovascular disease; dyslipidemia; diabetes. Correspondence Alona Dalusung-Angosta, PhD, APN, FNP, NP-C, University of Nevada, Las Vegas School of Nursing, 4505 Maryland Parkway Box 453018, Las Vegas, Nevada 89154. Tel: 702-895-3360, ext 1218 (work); Fax: 702-895-4807 (work); E-mail: [email protected] Received: July 2013; accepted: January 2012 doi: 10.1002/2327-6924.12048
Abstract Purpose: To explore current studies on metabolic syndrome (MetS), including its complex pathophysiology and to describe the unique role of the advanced practice nurse including management and ethical decision making utilizing a case study to exemplify salient points. Data sources: From original research articles extracted from nursing and medical databases. Conclusions: MetS is a constellation of characteristics that increases the risk for the development of diabetes and cardiovascular disease. The pathophysiology of MetS is not completely understood, but is thought to involve a complex interaction between the environment, genetic susceptibility, insulin resistance, and abnormal adipose tissue function. Implications for practice: The role of the advanced practice nurse is appropriate for early intervention and counseling of patients with MetS and those who are at risk, as well as addressing the ethical challenges that accompany their care.
Introduction Metabolic syndrome (MetS) is a constellation of risk factors that increase a person’s risk of developing cardiovascular disease (CVD). Also known as syndrome X, dysmetabolic syndrome, and insulin resistance syndrome, MetS has been increasingly studied in recent decades, partly because of increasing prevalence in the United States, and globally. Moreover, estimates suggest MetS confers twice the risk of developing coronary heart disease (CHD) over the next 5–10 years, and the risk of developing type 2 diabetes mellitus (T2DM) is fivefold higher than the population without the syndrome (Alberti et al., 2009). The purpose of this article is to (a) explore current studies on MetS including its complex pathophysiology, and (b) describe the unique role of the advanced practice nurse (APN) including management utilizing a case study to exemplify salient points.
Review of literature Definition, epidemiology, and prevalence According to the diagnostic criteria of the National Cholesterol Education Program Adult Treatment Panel 644
III (NCEP/ATP III), patients with MetS have at least three of five characteristics: elevated blood pressure (BP) ≥ 130/85 mmHg or treatment for hypertension (HTN); atherogenic hypertriglyceridemia (TG ≥ 150 mg/dL) or deficient high-density lipoprotein cholesterol (HDL-C < 40 mg/dL in males or 40% of individuals 60 years of age or older (Ford, 2005). Previous estimates from the 1988 to 1994 cohort of the National Health and Nutrition Examination Survey (NHANES) suggested the syndrome was less common, at approximately 22%–25% of the population ≥20 years old (Park et al., 2003). But as the definition of MetS becomes more consistent, and rates of obesity as well as life span increases, these estimates need to be revised upwards. MetS is on the rise worldwide, and is thought to parallel the increasing prevalence of obesity. About 34.2% of Americans are overweight (body mass index [BMI] 25–29.9 kg/m2 ) and 33.8% are obese (BMI ≥ 30 kg/m2 ) according to 2007–2008 NHANES data (Flegal, Carroll, Ogden, & Curtin, 2010). Obesity is increasing in younger cohorts as well. According to Grundy (2008) data from 1999 to 2004 suggested 16% of female and 18% of male children and adolescents were overweight. The 1999–2000 NHANES estimates suggested the prevalence was lower at 15% of children and adolescents in the United States being overweight (National Heart, Lung, and Blood Institute [NHLBI], 2010). Prevalence of the MetS is strongly correlated to both obesity and age, re-
Metabolic syndrome: Clinical perspective for best practice
gardless of gender or ethnicity. Early reports suggested the condition was more common in women than men, but some data suggested the margin of gender difference is less than previously estimated (Grundy, 2008). However, prevalence does change among men and women in specific ethnic groups, which has become increasingly studied in the last decade. Ford (2005) reported African American women had higher prevalence than men at 33.8% and 21.6%, respectively. Hispanic American women also showed higher prevalence than men at 37.8% and 32.2%, respectively. However, Caucasian men were more likely to have the syndrome than women by a small margin at 36.0% and 35.4%, respectively. Internationally, Americans and Canadians had a higher prevalence of the syndrome than many European or Asian nations. Using NCEP-ATP-III criteria, Grundy (2008) estimated the prevalence of the syndrome among Europeans at approximately 25%, with less than 20% prevalence in Southeast Asia. As of yet, a lack of large epidemiologic studies with adequate sample size substantially limited comparisons in other countries.
Emerging risk factors: Socioeconomic and environmental risk Low adulthood socioeconomic status (SES) was associated with higher rates of MetS in numerous studies (Chichlowska et al., 2009; Loucks, Magnusson et al., 2007). However, there were conflicting results regarding the association between gender and low SES in childhood, and development of MetS as an adult. In larger studies, the MetS was associated with low SES across the life span with women, but less so for men. The Atherosclerosis Risk in Communities (ARIC) study examined life course SES and prevalence of the MetS in more than 10,000 African American and Caucasian men and women and found significant correlations for both Caucasian and African American women. Of both ethnic groups, women with low SES in childhood, early adulthood, middle adulthood, or cumulatively, were more likely to develop the syndrome than women with high SES (Chichlowska et al., 2009). Similarly, Loucks, Magnusson et al. (2007) found women aged 25–65 with income below the poverty line were more likely to develop the syndrome than women with higher income ratios even after adjusting for age, race/ethnicity, and menopause status. Interestingly, income and education were not associated with the syndrome for males, or female adolescents and older adults (age > 65 years). Some authors suggested the higher prevalence of MetS among women has to do with economic disparities between men and women, particularly as a result of physical attributes. Chichlowska et al. (2009) cited two studies 645
Metabolic syndrome: Clinical perspective for best practice
that suggested obesity may affect economic trajectory for women more so than for men, particularly during adolescence and young adulthood (Gormaker, Must, Perrin, Sobol, & Dietz, 1993; Sargent & Blanchflower, 1994). The lower SES during this sensitive period of development was associated with increased prevalence of the syndrome. It was also suggested women with low SES are more likely to be unemployed, a single parent, or depressed (Thurston, Kubzansky, Kawaci, & Berkman, 2005). While smaller reports with limited samples showed conflicting data, theories linking cumulative economic challenges and different environmental stressors are gaining momentum as a risk factor for the syndrome, particularly for adult women. In the Coronary Artery Risk Development in Young Adults study, childhood SES and early family environment assessed through models that measured depression, hostility, and poor quality of social contacts, showed these factors were associated with metabolic function (Lehman, Taylor, Kiefe, & Seeman, 2005). Environmental associations have been well documented in the development of MetS. Cigarette smoking, excessive alcohol intake, and greater reliance on low-cost, high-energy dense foods with fewer nutrients such as sugar, fat, or refined-grain foods were all related to higher prevalence of the MetS, or obesity (Loucks, Rehkopf, Thurston, & Kawachi, 2007). Empty calories and high-energy dense foods were shown to cost less compared to low-density foods, such as fruits and vegetables, which may lead those with fewer economic resources to less desirable dietary choices. Similarly, the positive correlation between depression and low SES is well documented, and among this group smoking, alcohol use, and sedentary lifestyles as well as less compliance with medication regimens all showed positive correlations. Loucks, Rehkopf et al. (2007) cited research by Kawachi and Berkman (2003) indicating people with low SES tend to live in environments with greater crime rates, fewer recreational opportunities, more fast food restaurants, liquor stores, and billboard advertisements for cigarettes, fast food, and alcohol—all of which are associated with metabolic dysfunction or obesity. Finally, The U.S. Census Bureau showed the likelihood of being covered by health insurance increased with income along with the likelihood of seeking and receiving preventative care for diseases such as hypertension, obesity, mixed dyslipidemia, and hyperglycemia. Surveys from the U.S. Census Bureau suggested poverty and number of people without health insurance increased from 2008 to 2009 (DeNavas-Walt, Proctor, & Smith, 2009). As more and more individuals struggle with current economic chal-
646
D. Olde et al.
lenges, MetS is likely to increase concomitantly in the absence of adequate attention and treatment.
Pathophysiology Despite the substantial increase in research and clinical focus over the last two decades, the pathogenic interactions leading to MetS are still debated. Historically, insulin resistance was suspected as the underlying cause, and was initially incorporated as a diagnostic criterion. International focus lead to changes in the definition and diagnostic criteria, but insulin resistance remains a predominant etiologic theory. More recently, research suggested obesity, excess fat mass, or abnormal adipose metabolism ´ was the underlying cause (Grundy, 2007; Teran-Garcia & Bouchard, 2007). Both proposed mechanisms culminate in a proinflammatory and prothrombotic state associated with MetS as measured by serum inflammatory markers and procoagulation biomarkers. The proinflammatory and prothrombotic state sets the stage for endothelial dysfunction and the development of CVD.
Abnormal adipose metabolism Several authors suggested abnormal adipose metabolism is the driving force behind the MetS via four interrelated mechanisms: abnormal adipose tissue biology, excess fat mass, high levels of visceral fat, ´ and ectopic fat deposition (Teran-Garcia & Bouchard, 2007). Adipose tissue produces and secretes hormones, including cytokines—also known as adipokines—free fatty acids (FFAs), prostaglandins, and angiotensinogen. Among the predominant adipokines implicated in MetS are leptin, adiponectin, and resistin as well as other adipocyte products such as FFA, retinol binding protein 4, and fatty-acid binding protein. As excess fat tissue accumulates, adipocytes increase in size. The larger cells exhibit greater rates of triglyceride synthesis, lypolysis, and FFA transmembrane flux. Numerous adipokines are released into the blood stream, such as leptin, resistin, adiponectin, tumor necrosis factor α, angiotensinogen, interleukin 6, C-reactive peptide, and others. These proinflammatory products affect endothelial cells and stimulate other inflammatory modulators. Large omental adipocytes exhibit high rates of lypolysis. The products of these cells enter hepatic cir¨ culation. Bjorntorp (1990) suggested higher concentration of these products in hepatic circulation results in hepatic dysfunction as measured by insulin clearance, hepatic glucose, and very low-density lipoprotein (LDL) production. Other researchers suggested subcutaneous abdominal adipose tissue contributes in a similar fashion,
Metabolic syndrome: Clinical perspective for best practice
D. Olde et al.
and visceral adipocytes are not as large a contributor to ´ hepatic dysfunction as initially thought (Teran-Garcia & Bouchard, 2007). Ectopic fat deposition in nonadipose tissue, such as the liver, skeletal muscle, and pancreas, has also been implicated in insulin resistance. As adipocytes become more insulin resistant, researchers showed elevated rates of serum FFA, and greater ectopic fat accumulation via magnetic resonance spectroscopy, generating the “lipotoxic” effect. Researchers suggested ectopic fat accumulation may be one mechanism by which organ systems lose insulin sensitivity (Lee et al., 1994; Seppala-Lindroos et al., 2002). This suggests excess calories, fat mass, ectopic fat distribution, and the subsequent expulsion of FFA and adipokines may be how organ systems resist insulin. Among the diagnostic criteria of MetS are elevated TGs or low HDL-C. But other cholesterol abnormalities are associated with the syndrome, including a shift to smaller, denser, LDL cholesterol (LDL-C) particles. Smaller particle LDL-C is more strongly related to coronary atherosclerosis and cardiovascular (CV) events than direct measures of LDL-C. The smaller particle LDC-C may be more toxic to endothelium, more mobile through endothelial basement membranes, more adherent to endothelial cell walls, are more susceptible to oxidation, and are more selectively bound to macrophages (Singh, Arora, Goswami, & Mallika, 2009). Hence, measuring LDL particle distribution may be more indicative of CV risk than a single measure of LDL-C.
Insulin resistance Insulin resistance has long been recognized as a defining characteristic of the MetS. The extent to which it causes the syndrome is uncertain (Grundy, 2007) because insulin may have more endocrine functions than regulating glucose into cells. Insulin also prevents lipolysis and stimulates the enzyme lipoprotein lipase. This enzyme is thought to prevent the release of FFA into circulation via cyclic AMP-dependent enzyme-hormone sensitive lipase. As more FFA are released into circulation, this inhibits the antilipolytic action of insulin (Singh et al., 2009). Hyperinsulinemia may occur for several years with normal or near normal levels of fasting glucose. But as pancreatic cells slowly lose the ability to produce insulin and lipoprotein lipase activity diminishes, lipolysis increases, further leading to the downward spiral of FFA release, ectopic fat deposition, endocrine organ dysfunction, and insulin resistance. In later stages of the disease, DMT2 results. Grundy (2007) suggested metabolic susceptibility is an important precursor to the development of MetS with excess body fat leads the precursor. Susceptible risk fac-
Table 1 Commonly reported heritability estimates for components of the metabolic syndrome Phenotype Body composition BMI Body fat Abdominal obesity Insulin/glucose Fasting glucose Fasting insulin Insulin resistance of T2DM Lipids Triglycerides LDL-C HDL-C Blood pressure Systolic BP Diastolic BP Hypertension Microalbuminuria
Estimated heritability (%)
25–60 25–40 40–55 10–75 20–55 46–90 25–60 25–60 30–80 20–70 10–50 50 30
Argyropoulos et al. (2005).
tors include insulin signaling defects, adipose tissue disorders, as well as lifestyle and physical characteristics such as physical inactivity, mitochondrial defects, aging, polygenic variation, or drug use. Risk factors vary among different ethnic groups, with different rates of heritability. Hence, genetic susceptibility is thought to be a substantial risk factor for MetS possibly explaining why certain ethnic groups are more likely to exhibit metabolic disorders. Argyropoulos, Smith, and Bouchard (2005) reported BMI, body fat, and abdominal obesity have an estimated heritability of 25%–60%; insulin resistance or T2DM from 46% to 90%; LDL-C and triglycerides from 25% to 60%; and hypertension of approximately 50%. Overall, the heritability of MetS is about 30% (for a complete list of commonly reported heritability estimates see Table 1).
A patient with MetS Health history A 71-year-old Caucasian female, Ms. B, presented to a primary care clinic to establish care as her previous provider retired. She was recently hospitalized for chest pain and was diagnosed with mild CHD after undergoing a battery of tests that were negative for acute pathology. A myocardial perfusion study showed mild ischemia of the apex, anterior wall, and lateral wall without acute stenosis or obstruction. At discharge she was advised to follow up with a primary care provider. In addition to her diagnosis of mild CHD her past medical history indicated diagnoses of osteoarthritis in her left knee, essential 647
Metabolic syndrome: Clinical perspective for best practice
D. Olde et al.
Table 2 Ms. B’s fasting lipid profile Lab test Chemistry panel Sodium Potassium Chloride CO2 Glucose BUN Creatinine GFR Calcium Aspartate amino-tran Alanine amino tran Alkaline phosphatase Bilirubin total Albumin Total protein Globulin Albulin/globulin ratio Lipid panel Total cholesterol Triglycerides HDL-C LDL-C
Table 3 Diagnoses and plan of care
Result
Normal range
Unit
135 4.1 98 26 98 13 0.8 >90 9.6 32 31 96 0.5 3.9 7.2 3.0 1.3
135–145 3.6–5.5 96–112 20–33 65–99 8–22 0.5–1.4 >90 8.4–10.2 12–45 2–50 30–99 0.1–1.5 3.2–4.9 6.0–8.2 1.9–3.5
mmol/L mmol/L mmol/L mmol/L mg/dL mg/dL mg/dL mL/min/1.73 mg/dL U/L U/L U/L mg/dL g/dL g/dL g/dL g/dL
100–200 0–150 40–59
