Metabolic Syndrome

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Increased abdominal circumference

Elevated BP

Elevated triglycerides

Decreased High density lipoprotein (HDL)

Elevated fasting glucose

Also involves the following metabolic abnormalities:

Insulin resistance with or without impaired glucose tolerance
Proinflammatory state
Prothrombotic state

EPIDEMIOLOGY

Predominant age: >60 years old ( ¢ ¼50% of cases)
Predominant sex: male = female
Ethnicity: Mexican Americans (highest risk)

Prevalence

Affects 34% of U.S. adults aged >20 years; increasing with the aging population and the prevalence of obesity (1)
Data vary among race and ethnicity with different trends for women and men. The available literature suggests that metabolic syndrome is a rapidly growing epidemic worldwide.

Pediatric Considerations

Obese children and adolescents are at high risk of metabolic syndrome (prevalence of 6.4% in the United States). Risk factors in children and adolescents include heredity, low birth weight, childhood weight gain and obesity, endocrine abnormalities, hostility, maternal gestational diabetes, and poor health habits.
International Diabetes Federation consensus report defined criteria in three age groups (6 to ≤10 years; 10 to ≤16 years; 16+ years, adult criteria applicable) (2)[C]. Obesity defined by waist circumference ≥90th percentile; rest of the diagnostic criteria (triglycerides [TGs], high-density lipoprotein cholesterol [HDL-C], hypertension [HTN], and fasting blood sugar/T2DM) are largely the same as in adults for children ≥10 years, with some exceptions, and warrant treatment. Clinical significance of metabolic syndrome in pediatric population is not well established using these criteria (2). BMI used alone is as accurate as using IDF criteria to predict adult MetSyn, subclinical atherosclerosis and diabetes mellitus type 2 (3)[C]. Focus on promoting healthy lifestyle habits and weight management rather than diagnosis.

ETIOLOGY AND PATHOPHYSIOLOGY

Increase in intra-abdominal and visceral adipose tissue
Adipose tissue dysfunction and insulin resistance
Decreased levels of adiponectin, an adipocytokine, known to protect against T2DM, HTN, atherosclerosis, and inflammation
Abnormal fatty acid metabolism, endothelial dysfunction, systemic inflammation, oxidative stress, elevated renin-angiotensin system activation, and a prothrombotic state (increased tissue plasminogen activator inhibitor-1) are also associated.
The main etiologic factors are the following:
- Obesity (particularly abdominal)/excess visceral adipose tissue
- Insulin resistance
- Other contributing factors:
  - Advancing age
  - Proinflammatory state
  - Genetics
Endocrine (e.g., postmenopausal state)

Genetics
Genetic factors contribute significantly to causation. Most identified genes are transcription factors or regulators of transcription and translation. It is a multifactorial disease with evidence of complex interactions between genetics and environment.

RISK FACTORS

Obesity/intra-abdominal obesity
Childhood obesity
Insulin resistance
Older age
Ethnicity
Family history
Physical inactivity
High-carbohydrate diet
Sugar-sweetened beverages daily
Smoking
Postmenopausal status
Low socioeconomic status
Alteration of gut flora

GENERAL PREVENTION

Effective weight loss and maintenance of normal body weight long term
Regular and sustained physical activity
Diet low in saturated fats and simple sugars

COMMONLY ASSOCIATED CONDITIONS

Polycystic ovary syndrome
Nonalcoholic fatty liver disease (NAFLD)
Acanthosis nigricans
Chronic renal disease
Depression
Cognitive impairment
Obstructive sleep apnea
Gallstones (cholesterol)
Erectile dysfunction (in men)
Hyperuricemia and gout

DIAGNOSIS

HISTORY

Not necessary for diagnosis of metabolic syndrome
Family history of metabolic syndrome, T2DM, and cardiovascular disease
Symptoms indicating cardiovascular disease or diabetes
Comprehensive lifestyle history:
- Diet, including intake of carbohydrates and fats
- Weight history, including onset of obesity and previous weight loss attempts
- Exercise regimen
- Alcohol intake
Cigarette smoking
Assess cardiovascular risk with Framingham risk assessment tool.

PHYSICAL EXAM

Various criteria-based definitions have been proposed and in 2009, harmonized (4). A diagnosis of metabolic syndrome can be made when ≥3 of the following 5 characteristics are present:

Abdominal obesity: men >102 cm, women >88 cm (ATP III recommends lowering threshold in population susceptible to insulin resistance, especially Asian Americans)
BP ≥130/85 mm Hg or treatment
TGs ≥150 mg/dL or treatment
HDL: men <40 mg/dL, women <50 mg/dL or treatment
Fasting glucose ≥100 mg/dL or treatment

DIFFERENTIAL DIAGNOSIS

Individual components of the syndrome may be present without fulfilling all the diagnostic criteria. Obstructive sleep apnea, thyroid abnormalities, Cushing syndrome, medication effect (especially psychotropic, chronic steroids, ²-blockers and thiazide diuretic [5] medications) may also be considered in the differential.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Fasting lipids (particularly TGs and HDL)
Fasting glucose

Follow-Up Tests & Special Considerations

Formal 75-mg oral glucose tolerance test or Hemoglobin A1C for diagnosis of impaired glucose tolerance (IGT)
Liver function tests
Measurement of fasting insulin levels is controversial.
None necessary to diagnose metabolic syndrome

Diagnostic Procedures/Other

Home BP monitoring or 24-hour BP monitoring may be used to rule out white coat hypertension.
ECG, stress test, and coronary angiography may be used for diagnosis of cardiovascular disease arising as a complication of the syndrome.

Test Interpretation

Microalbuminuria
Increased WBC count
Increased C-reactive protein
Increased fibrinogen
Increased proinflammatory cytokines (e.g., tumor necrosis factor-α)
Increased uric acid
Increased homocysteine
T2DM
Fatty liver (complicated by end-stage liver disease and hepatocellular carcinoma)
Hypertensive and/or diabetic eye disease
Renal impairment/failure
Peripheral vascular disease
Coronary artery disease
Cerebrovascular disease

TREATMENT

Primary therapeutic goal is to prevent or reduce obesity and risk factors. Aggressive lifestyle modification (diet and exercise) is considered first-line therapy and most clinically effective (6)[C].

GENERAL MEASURES

Aggressive treatment of individual risk factors
Increase daily physical activity.
Avoid or stop smoking.
Avoid excess alcohol intake.
Avoid sugar sweetened beverages.
Increase leafy green vegetables.

MEDICATION

Daily treatment with aspirin is recommended for patients with cardiovascular disease or those at high risk.
Consult clinical guidelines for treatment of dyslipidemia, hypertension, IGT, and diabetes.
Multiple medications usually are required to achieve adequate BP control.
Diagnosis and treatment of insulin resistance is controversial.

First Line
Lifestyle modification alone as initial strategy is applicable to individuals with low 10-year risk for coronary artery disease (CAD). In individuals with higher 10-year risk, more aggressive risk factor " based approach is recommended in addition to lifestyle modifications:

Obesity: Lifestyle changes are the cornerstone of treatment. Aim for a ¢ ¼5 " 10% weight reduction. Any amount of weight loss is associated with significant benefits.
- Phentermine " topiramate (delayed release) (Qsymia) (7)[A] and lorcaserin (Belviq) (8)[A] have been approved by the FDA for nonpregnant, non-lactating adults for management of obesity with promising outcomes on weight, BP, dylipidemia, and other metabolic/glycemic parameters.
Physical activity: Endurance exercise may reverse metabolic syndrome (9)[A]. 30 to 60 minutes of moderate-intensity aerobic activities such as brisk walking 5 to 7 days/week; increase in daily lifestyle activities and resistance training 1 to 2 days/week (10)[A]. In patients with established CAD, assess detailed history of physical activity and exercise tolerance to guide activity prescription. Advise medically supervised programs for high-risk population (recent acute coronary syndrome [ACS], congestive heart failure, recent revascularization). Cumulative exercise time over the day contributes to health benefit.
Dyslipidemia: Drug therapy can be commenced after 6 weeks of lifestyle modification. See section on "Dyslipidemia. "
HTN: Aim for similar targets to patients with diabetes (<140/80 mm Hg based on ADA guidelines). See section on "Hypertension. "
- ACE inhibitor or angiotensin receptor blocker (e.g., losartan 50 mg/day if ACE inhibitor intolerance) is usually prescribed for patients with diabetes.
Impaired glucose tolerance
- Current guidelines emphasize that treatment should be with diet and exercise. The role of oral hypoglycemic agents to prevent diabetes in patients with the metabolic syndrome is unclear. Metformin, 500 mg to 1 g, 1 to 2 times daily, may be considered.
If CAD or T2DM is already evident, treat as per guidelines. Use ASA 81 mg for primary prevention as indicated per USPSTF if benefits outweigh bleeding risk.

ISSUES FOR REFERRAL

Obesity management
Nutrition
Exercise program
Smoking cessation

SURGERY/OTHER PROCEDURES

Bariatric surgery to treat obesity in severely obese patients who have failed trials of lifestyle modification and pharmacotherapy; surgery is recommended in appropriate individual if body mass index (BMI) >40 or BMI >35 with obesity-related comorbidities.
Liposuction of abdominal adipose tissue does not reduce insulin resistance or cardiovascular risk factors.

COMPLEMENTARY & ALTERNATIVE MEDICINE

Fish oils and plant sterol esters for cardioprotective effects

INPATIENT CONSIDERATIONS

Management usually does not require admission.
Admission Criteria/Initial Stabilization
Serious complications (e.g., ACS, hypertensive crisis, diabetic coma)

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Regular 30-minute exercise will improve all components of the metabolic syndrome. Cumulative small periods of exercise over the day provide significant health benefits.
Encourage changing sedentary activity choices (e.g., driving car, taking elevator, and the like) to more active ones (e.g., walking, cycling).
Regular monitoring of weight, abdominal circumference measurements, BP, fasting lipids, and sugar levels

Patient Monitoring

Regular monitoring of weight, abdominal circumference measurements, BP, fasting lipids, and sugar levels
Fasting lipids, fasting sugar, and/or oral glucose tolerance test should be checked annually.

DIET

Weight reduction to correct abdominal obesity is a primary goal achieved by dietary modification and increased physical activity.
Dietary recommendations may include limiting simple carbohydrates in diet, eating a Mediterranean or DASH (Dietary Approaches to Stop Hypertension) diet.
Increased consumption of leafy green vegetables may decrease risk of developing T2DM (11)[A]. Encourage increasing intake of vegetables and fiber and keep fruit and alcohol in moderation.
Avoid sugar-sweetened beverages.

PROGNOSIS

Increased risk of T2DM ( ¢ ¼5-fold), CAD ( ¢ ¼1.5 to 3-fold), acute myocardial infarction ( ¢ ¼2.5-fold), and all-cause mortality ( ¢ ¼1.5-fold)

COMPLICATIONS

Long-term complications are primarily CAD and T2DM. Recent evidence demonstrates an increased risk of NAFLD, stroke, and an increased risk of developing certain cancers, especially breast cancer in postmenopausal women.

REFERENCES

11 Ford ES, Li C, Zhao G. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US. J Diabetes. 2010;2(3):180 " 193.22 Zimmet P, Alberti KG, Kaufman F, et al. The metabolic syndrome in children and adolescents " an IDF consensus report. Pediatr Diabetes. 2007;8(5):299 " 306.33 Magnussen CG, Koskinen J, Chen W, et al. Pediatric metabolic syndrome predicts adulthood metabolic syndrome, subclinical atherosclerosis, type 2 diabetes mellitus but is no better than body mass index alone: the Bogalusa Heart Study and the Cardiovascular Risk in Young Finns Study. Circulation. 2010;122(16):1604 " 1611.44 Alberti KG, Eckel RH, Grudy SM, et al. 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 Health Federation; International Association for the Study of Obesity. Circulation. 2009;120(16):1640 " 1645.55 Wofford MR, King DS, Harrell TK. Drug-induced metabolic syndrome. J Clin Hypertens (Greenwich). 2006;8(2):114 " 119.66 Dunkley AJ, Charles K, Gray LJ, et al. Effectiveness of interventions for reducing diabetes and cardiovascular disease risk in people with metabolic syndrome: systematic review and mixed treatment comparison meta-analysis. Diabetes Obes Metab. 2012;14(7):616 " 625.77 Shin JH, Gadde KM. Clinical utility of phentermine/topiramate (Qsymia ¢ ¢) combination for the treatment of obesity. Diabetes Metab Syndr Obes. 2013;6:131 " 139.88 Chan EW, He Y, Chui CS, et al. Efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled trials (RCTs) and narrative review of short-term RCTs. Obes Rev. 2013;14(5):383 " 392.99 Pattyn N, Cornelissen VA, Eshghi SR, et al. The effect of exercise on the cardiovascular risk factors constituting the metabolic syndrome: a meta-analysis of controlled trials. Sports Med. 2013;43(2):121 " 133.1010 Lakka TA, Laaksonen DE. Physical activity in prevention and treatment of the metabolic syndrome. Appl Physiol Nutr Metab. 2007;32(1):76 " 88.1111 Carter P, Gray LJ, Troughton J, et al. Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis. BMJ. 2010;341:c4229.

ADDITIONAL READING

Samson SL, Garber AJ. Metabolic syndrome. Endocrinol Metab Clin North Am. 2014;43(1):1 " 23.

CODES

ICD10

E88.81 Metabolic syndrome

ICD9

277.7 Dysmetabolic syndrome X

SNOMED

237602007 metabolic syndrome X (disorder)

CLINICAL PEARLS

Abdominal circumference should be measured as part of a cardiovascular risk assessment.
Recognizing metabolic syndrome in the clinic can help prioritize treatment goals and guidance to work to reduce associated risk factors.
Prevention or reduction of obesity is the cornerstone of management of metabolic syndrome.
Increasing cumulative physical activity over the day significantly adds to the benefit of regular 30 to 60-minute exercise regimen.
Aggressive lifestyle modification is first-line lifelong treatment for all patients.

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