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The Metabolic Syndrome

Chapter 420 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. The metabolic syndrome is defined as a constellation of metabolic abnormalities conferring increased risk of cardiovascular disease (CVD) and diabetes mellitus.
  2. Diagnosis requires 3 of 5 criteria: Central obesity, Hypertriglyceridemia, Low HDL-C, Hypertension, or Fasting glucose ≥100 mg/dL.
  3. Waist circumference cutoffs vary by ethnicity: Europid/South African ≥94 cm (men)/≥80 cm (women); South Asian/Chinese ≥90 cm (men)/≥80 cm (women); Japanese ≥85 cm (men)/≥90 cm (women).
  4. Weight reduction of at least 5% (preferably 10%) improves insulin sensitivity and metabolic syndrome components.
  5. Statin therapy is first-line for LDL reduction; high-intensity statins (Atorvastatin 40-80 mg, Rosuvastatin 20-40 mg) for LDL ≥190 mg/dL or diabetes aged 40-75 years.
  6. GLP-1 receptor agonists (Semaglutide 2.4 mg, Liraglutide 3.0 mg) and Tirzepatide are approved for obesity/weight loss in metabolic syndrome.
  7. Metabolic syndrome prevalence in US adults is ~33.4% (NHANES 1999-2018), increasing with age (19.5% in 20-39 years to 48.6% in ≥60 years).
  8. Insulin resistance is the central pathophysiology, driven by excess circulating free fatty acids (FFAs) from adipose tissue lipolysis.
  9. Patients with metabolic syndrome are 1.5- to 3-fold at risk for new-onset CVD and 3- to 5-fold at risk for type 2 diabetes.
  10. Lipodystrophy (genetic or acquired) and certain antiretroviral therapies can cause severe insulin resistance mimicking metabolic syndrome.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Pathophysiology of the metabolic syndrome
2 🖼 Figure The frequency distribution of the metabolic syndrome for the U

1. DEFINITION & OVERVIEW

The metabolic syndrome (syndrome X, insulin resistance syndrome) consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus. The diagnosis relies on fulfillment of specific criteria assessed using tools at the bedside and in the laboratory.

1.1 Diagnostic Criteria

Harrison's defines the metabolic syndrome as requiring three or more of the following features (NCEP:ATPIII 2001) or three of the following (Harmonizing Definition).

Table 1 — Table 420-1: NCEP:ATPIII 2001 and Harmonizing Definition Criteria for the Metabolic Syndrome

Criterion NCEP:ATPIII 2001 Threshold Harmonizing Definition Threshold
Central Obesity (Waist Circumference) >102 cm (Males), >88 cm (Females) Men: ≥94 cm (Europid, Sub-Saharan African, Eastern/Middle Eastern); ≥90 cm (South Asian, Chinese, South/Central American); ≥85 cm (Japanese). Women: ≥80 cm (Europid, Sub-Saharan African, Eastern/Middle Eastern); ≥80 cm (South Asian, Chinese, South/Central American); ≥90 cm (Japanese).
Hypertriglyceridemia ≥150 mg/dL or specific medication Fasting triglyceride level >150 mg/dL or specific medication
Low HDL Cholesterol <40 mg/dL (Males), <50 mg/dL (Females) or specific medication HDL cholesterol level <40 mg/dL (Males), <50 mg/dL (Females) or specific medication
Hypertension ≥130 mmHg systolic or ≥85 mmHg diastolic or specific medication or previously diagnosed type 2 diabetes Blood pressure >130 mm systolic or >85 mm diastolic or previous diagnosis or specific medication
Fasting Plasma Glucose ≥100 mg/dL or specific medication or previously diagnosed type 2 diabetes Fasting plasma glucose level ≥100 mg/dL (alternative indication: drug treatment of elevated glucose levels)

1.2 Evolution of Criteria

The major features of metabolic syndrome include central obesity, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, hyperglycemia, and hypertension. The evolution of criteria reflects growing clinical evidence and analysis by consensus conferences and professional organizations.

1.3 Global Health & Epidemiology

The prevalence of metabolic syndrome varies around the world, reflecting age, ethnicity, and diagnostic criteria applied. In the U.S. adult population (NHANES 1999-2018), prevalence was 33.4%. Prevalence increases with age: 19.5% in those aged 20-39 years to 48.6% in those aged ≥60 years. The highest prevalence is age-dependent with reduction by age 80 among all subgroups.

2. ETIOLOGY & PATHOPHYSIOLOGY

The most accepted and unifying hypothesis to describe the pathophysiology of metabolic syndrome is insulin resistance, caused systemically by an incompletely understood defect in insulin action. The onset of insulin resistance is heralded by postprandial hyperinsulinemia, which is followed by fasting hyperinsulinemia and ultimately by hyperglycemia.

2.1 Insulin Resistance Mechanisms

An early major contributor to the development of insulin resistance is an overabundance of circulating fatty acids. Plasma albumin-bound free fatty acids are derived predominantly from adipose-tissue triglyceride stores released by intracellular lipolytic enzymes. The lipolysis of triglyceride-rich lipoproteins in tissues by lipoprotein lipase also produces free fatty acids. Insulin mediates both anti-lipolysis and the stimulation of lipoprotein lipase in adipose tissue. Of note, the inhibition of lipolysis in adipose tissue is the most sensitive pathway of insulin action. Thus, when insulin resistance develops, increased lipolysis produces more fatty acids, which further decreases the anti-lipolytic effect of insulin. Excessive fatty acids enhance substrate availability and create insulin resistance by modifying downstream signaling. Fatty acids impair insulin-mediated glucose uptake and are associated with accumulation of triglycerides in both skeletal and cardiac muscle, whereas increased fatty acid flux increases endogenous glucose production and triglyceride production, accumulation, and secretion in the liver.

2.2 Cardiovascular Disease Risk

Individuals with metabolic syndrome are twice as likely to die of CVD as those who do not, and their risk of acute myocardial infarction or stroke is threefold higher. The approximate prevalence of metabolic syndrome among patients with coronary heart disease (CHD) is up to 60% in persons >75 years, with a prevalence of ~35% among patients with premature coronary artery disease (age ≤45) and a particularly higher prevalence among women.

2.3 Dyslipidemia

In general, free fatty acid flux from adipose tissue to the liver results in increased production of apolipoprotein (apo) B–containing, triglyceride-rich, very-low-density lipoproteins (VLDLs). The direct effect of insulin on this process is complex, but hypertriglyceridemia is an excellent marker of the insulin-resistant condition. Not only is hypertriglyceridemia a feature of metabolic syndrome, but patients with metabolic syndrome have normal levels of apoC-III carried on VLDLs and other lipoproteins. This increase in apoC-III is inhibitory to lipoprotein lipase, reducing triglyceride-rich lipoprotein remnant removal, further contributing to hypertriglyceridemia, and confers more risk for atherosclerotic cardiovascular disease (ASCVD). The other major lipoprotein disturbance in metabolic syndrome is a reduction in HDL cholesterol. This reduction is a consequence of changes in HDL composition and metabolism. In the presence of hypertriglyceridemia, a decrease in the cholesterol content of HDL is a consequence of reduced cholesteryl ester content of the lipoprotein core in combination with cholesteryl ester transfer protein–mediated alterations in triglycerides that make the HDL particle small and dense. This change in lipoprotein composition also results in increased clearance of HDL from the circulation. In addition to HDLs, low-density lipoproteins (LDLs) have alterations in composition in metabolic syndrome. With fasting serum triglycerides at >2.0 mM (~180 mg/dL), there is usually a predominance of small dense LDLs, which are thought to be more atherogenic.

2.4 Hypertension Mechanisms

The relationship between insulin resistance and hypertension is well established. Paradoxically, under normal physiologic conditions, insulin-mediated increases in nitric oxide cause vasodilation with secondary effects on sodium reabsorption in the kidney. However, in the setting of insulin resistance, the vasodilatory effect of insulin is lost but the renal effect on sodium reabsorption is preserved. Sodium reabsorption is increased in Caucasians with metabolic syndrome but not in Africans or Asians. Insulin also increases the activity of the sympathetic nervous system, an effect that is preserved in the setting of insulin resistance. Insulin resistance is also associated with pathway-specific impairment in phosphatidylinositol-3-kinase signaling. In the endothelium, this impairment may cause an imbalance between the production of nitric oxide and the secretion of endothelin 1, with a consequent decrease in blood flow. In addition, increases in angiotensinogen gene expression in adipose tissue of obese subjects results in increases in circulating angiotensin II and vasoconstriction. Although these mechanisms are provocative, the inadequate evaluation of insulin action by measurement of fasting insulin levels or by homeostasis model assessment shows that insulin resistance contributes only partially to the increased prevalence of hypertension in metabolic syndrome. Another possible mechanism underlying hypertension in metabolic syndrome is the vasoactive role of perivascular adipose tissue. Reactive oxygen species released by NADPH oxidase impair endothelial function and result in local vasoconstriction. Other paracrine effects such as leptin or other proinflammatory cytokines released from adipose tissue, such as tumor necrosis factor α (TNF-α), may also be important.

2.5 Proinflammatory Cytokines

The increases in proinflammatory cytokines—including interleukins 1, 6, and 18; resistin; TNF-α; and the systemic biomarker C-reactive protein—reflect overproduction by the expanded adipose tissue mass. Adipose tissue–derived macrophages may be the primary source of proinflammatory cytokines locally and in the systemic circulation. It remains unclear, however, how much of the insulin resistance is caused by the paracrine effects of these cytokines and how much by the endocrine effects.

2.6 Other Etiologic Factors

Lipodystrophic disorders in general are associated with metabolic syndrome. Moreover, it is quite common for such patients to present with the metabolic syndrome. Both genetic lipodystrophy (e.g., Berardinelli-Seip congenital lipodystrophy, Dunnigan familial partial lipodystrophy) and acquired lipodystrophy (e.g., HIV-related lipodystrophy and in HIV patients receiving certain antiretroviral therapies) may give rise to severe insulin resistance and many of the components of metabolic syndrome.

3. CLINICAL FEATURES

Metabolic syndrome typically is not associated with symptoms. On physical examination, waist circumference and blood pressure are often elevated. The presence of either or both signs should prompt the clinician to search for other biochemical abnormalities that may be associated with metabolic syndrome. Much less frequently, lipoatrophy or acanthosis nigricans is present on examination. Because these physical findings characteristically are associated with severe insulin resistance, other components of metabolic syndrome are much more common.

3.1 Associated Diseases

The relative risk for new-onset CVD in patients with metabolic syndrome who do not have diabetes averages 1.5- to 3-fold. However, in INTERHEART, a study of 26,903 subjects from 52 countries, the risk for acute myocardial infarction in subjects with metabolic syndrome (World Health Organization or International Diabetes Federation definition) is comparable to that conferred by some, but not all, of the component risk factors. Diabetes mellitus (odds ratio [OR], 2.72) and hypertension (OR, 2.60) are stronger than other risk factors. Although congestive heart failure and metabolic syndrome can occur together, typically this consequence is secondary to metabolic syndrome–related ASCVD or hypertension. Metabolic syndrome is also associated with increases in the risk for stroke, peripheral vascular disease, and Alzheimer’s disease. However, as for myocardial infarction, the risk beyond the additive role of the components of metabolic syndrome remains debatable. In the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of black and white adults ≥45 years old across the United States, there were 9741 participants, and 41% had metabolic syndrome. After adjustment for multiple confounders, metabolic syndrome was associated with increases in high-sensitivity C-reactive protein (hsCRP), and this relationship was associated with a 1.34 relative risk for all-cause mortality, but <50% of deaths were from CVD. The population-attributable risk was 9.5% for metabolic syndrome alone and 14.7% for both metabolic syndrome and increased hsCRP. The relationship of metabolic syndrome and hsCRP to mortality was greater for whites than blacks.

4. DIFFERENTIAL DIAGNOSIS

The diagnosis of metabolic syndrome relies on fulfillment of the criteria listed in Table 420-1, as assessed using tools at the bedside and in the laboratory. The medical history should include evaluation of symptoms for obstructive sleep apnea in all patients and polycystic ovary syndrome in premenopausal women. Family history will help determine the risk for CVD and diabetes mellitus. Blood pressure and waist circumference measurements provide information necessary for the diagnosis.

4.1 Distinguishing Features

Patients who are of normal weight may also be insulin-resistant and may have metabolic syndrome. This phenotype is particularly evident for populations in India, Southeast Asia, and Central America. Lipodystrophic disorders in general are associated with metabolic syndrome. Moreover, it is quite common for such patients to present with the metabolic syndrome. Both genetic lipodystrophy (e.g., Berardinelli-Seip congenital lipodystrophy, Dunnigan familial partial lipodystrophy) and acquired lipodystrophy (e.g., HIV-related lipodystrophy and in HIV patients receiving certain antiretroviral therapies) may give rise to severe insulin resistance and many of the components of metabolic syndrome.

5. INVESTIGATIONS & DIAGNOSIS

The diagnosis of metabolic syndrome relies on fulfillment of the criteria listed in Table 420-1, as assessed using tools at the bedside and in the laboratory. The medical history should include evaluation of symptoms for obstructive sleep apnea in all patients and polycystic ovary syndrome in premenopausal women. Family history will help determine the risk for CVD and diabetes mellitus. Blood pressure and waist circumference measurements provide information necessary for the diagnosis.

5.1 Laboratory Tests

Measurement of fasting lipids and glucose is needed in determining whether metabolic syndrome is present. The measurement of additional biomarkers associated with insulin resistance can be individualized. Such tests might include those for apoB, hsCRP, fibrinogen, uric acid, urinary albumin/creatinine ratio, and liver function. A sleep study should be performed if symptoms of obstructive sleep apnea are present. If polycystic ovary syndrome is suspected based on clinical features and anovulation, testosterone, luteinizing hormone, and follicle-stimulating hormone should be measured. MAFLD can be further assessed by the MAFLD fibrosis score (FIB4) or elastography.

5.2 Diagnostic Algorithm

  1. Measure waist circumference and blood pressure at the bedside.
  2. Obtain fasting lipids and glucose in the laboratory.
  3. Assess for presence of 3 or more criteria (NCEP:ATPIII or Harmonizing Definition).
  4. If criteria met, evaluate for associated conditions (CVD, T2DM, Sleep Apnea, PCOS, MAFLD).
  5. Consider imaging (DEXA, CT, MRI) if fat distribution needs discrimination.
  6. Consider sleep study if symptoms of obstructive sleep apnea are present.

6. MANAGEMENT & TREATMENT

Obesity, particularly abdominal, is the driving force behind metabolic syndrome. Thus, weight reduction is the primary approach to the disorder. With at least 5% and more so with 10% weight reduction, improvement in insulin sensitivity results in favorable modifications in many components of metabolic syndrome. In general, recommendations for weight loss include a combination of caloric restriction, increased physical activity, and behavior modification. Caloric restriction is the most important component, whereas increases in physical activity are important for maintenance of weight loss. Some but not all evidence suggests that the addition of exercise to caloric restriction may promote greater weight loss from the visceral depot. The tendency for weight regains after successful weight reduction underscores the need for long-lasting behavioral changes.

6.1 Lifestyle Modifications

Diet Before prescribing a weight-loss diet, it is important to emphasize that it has taken the patient a long time to develop an expanded fat mass; thus, the correction need not occur quickly. Given, in general, that ~3500 kcal = 1 lb of adipose tissue, an ~500-kcal restriction daily equates to weight reduction of 1 lb per week. Diets restricted in carbohydrate typically provide a more rapid initial weight loss. However, after 1 year, the amount of weight reduction is minimally reduced or no different from that with caloric restriction alone. Thus, adherence to the diet is more important than the chosen diet. Moreover, there is concern about low-carbohydrate diets enriched in saturated fat, particularly for patients at risk for ASCVD. Therefore, a high-quality dietary pattern—i.e., a diet enriched in fruits, vegetables, whole grains, lean poultry, and fish—should be encouraged to maximize overall health benefit.

Physical Activity Before prescribing a physical activity program to patients with metabolic syndrome, it is important to ensure that the increased activity does not incur risk. Some high-risk patients should undergo formal cardiovascular evaluation before initiating an exercise program. For an inactive participant, gradual increases in physical activity should be encouraged to enhance adherence and avoid injury. Although increases in physical activity can lead to modest weight reduction, 60–90 min of moderate- to high-intensity daily activity is required to achieve this goal. Even if an overweight or obese adult is unable to undertake this level of activity, a health benefit will follow from at least 30 min of moderate-intensity activity daily. The caloric value of 30 min of a variety of activities can be found at https://www.health.harvard.edu/diet-and-weight-loss/calories-burned-in-30-minutes-of-leisure-and-routine-activities. Of note, a variety of routine activities, such as gardening, walking, and housecleaning, require moderate caloric expenditure. Thus, physical activity should not be defined solely in terms of formal exercise such as jogging, swimming, or tennis.

Behavior Modification Behavioral treatment typically includes recommendations for dietary restriction and more physical activity that predicts sufficient weight loss that benefits metabolic health. The subsequent challenge is the duration of the program because weight regain so often follows successful weight reduction. Improved long-term outcomes often follow a variety of methods, such as a personal or group counselor, the Internet, social media, and telephone follow-up to maintain contact between providers and patients.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Pathophysiology of the metabolic syndrome

Caption: FIGURE 420-2 Pathophysiology of the metabolic syndrome. Free fatty acids (FFAs) are result in increased production of glucose and triglycerides and secretion of reductions in high-density lipoprotein (HDL) cholesterol and an increased low-density inhibiting insulin-mediated glucose uptake. Associated defects include a reduction in (TG). The increase in circulating glucose, and to some extent FFAs, increases enhanced sodium reabsorption and increased sympathetic nervous system (SNS) proinflammatory state is superimposed and contributory to the insulin resistance necrosis factor α (TNF-α) produced by adipocytes and monocyte-derived macrophages to circulating FFAs. IL-6 and other cytokines also enhance hepatic glucose production, resistance also contributes to increased triglyceride accumulation in the liver fibrinogen and adipocyte production of plasminogen activator inhibitor 1 (PAI-1), resulting — Figure 420-1: Frequency distribution of the metabolic syndrome (MetS) and its components (Abdominal Obesity, Elevated FPG, Elevated BP, Elevated TG, Reduced HDL-C) by age across different races (Non-Hispanic White, Non-Hispanic Black, Mexican American, Han Chinese) based on NHANES III and Guangdong Gut Microbiome Project data.

Figure 2

The frequency distribution of the metabolic syndrome for the U

Caption: FIGURE 420-1 The frequency distribution of the metabolic syndrome for the U.S. the Guangdong Gut Microbiome Project of China. The prevalence of metabolic estimated using a SWAN algorithm (shown as dots). The trajectory of the prevalence of FPG, fasting plasma glucose; HDL-C, high-density lipid cholesterol; SWAN, sliding disparities in the epidemic of metabolic syndrome with increased age: A study from — Figure 420-2: Pathophysiology of the metabolic syndrome illustrating the release of free fatty acids (FFAs) from expanded adipose tissue, leading to hepatic glucose/triglyceride production, reduced HDL, increased small dense LDL, insulin resistance in muscle, proinflammatory cytokine release (IL-6, TNF-α), and prothrombotic state.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.