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BASICS

DESCRIPTION
- Metabolic syndrome (MetS) is a cluster of progressive metabolic abnormalities marked by:
- Insulin resistance
- Proinflammatory and prothrombotic state
- Correlates with increased risk of premature morbidity including:
- COVID-19 complications
- Type 2 diabetes mellitus (T2DM)
- Cardiovascular disease (CVD), stroke
- Nonalcoholic fatty liver disease (NAFLD)
- Certain cancers
- All-cause mortality
- Definitions: WHO 1999, NCEP ATP3 2005, IDF 2006.

EPIDEMIOLOGY

  • Incidence parallels obesity and T2DM incidence.
  • Prevalence: ~25% globally (2015), >33% in US adults (2016).

ETIOLOGY AND PATHOPHYSIOLOGY

  • Increase in intra-abdominal and visceral adipose tissue with abnormal fatty acid metabolism.
  • Hormone dysregulation:
  • Decreased adiponectin and ghrelin
  • Resistance to chronically elevated insulin and leptin
  • Systemic inflammation: ↑ IL-6, TNF-α, resistin, CRP.
  • Vascular endothelial dysfunction, prothrombotic state (↑ tissue plasminogen activator inhibitor-1).
  • Elevated renin-angiotensin system activation, oxidative stress → hypertension, atherosclerosis.
  • Genetic and obesogen exposures contribute; parental obesity and epigenetic changes affect offspring risk.

RISK FACTORS

  • Birth status: Small for gestational age (SGA), large for gestational age (LGA), gestational diabetes mellitus.
  • Demographics: Older age, ethnicity, family history of MetS, T2DM, stroke, CVD.
  • Lifestyle: Physical inactivity, high sugar/fructose intake, alcohol, smoking, poor sleep.
  • Gut microbiome alteration; disordered sleep.
  • Weight-promoting meds: corticosteroids, antipsychotics, β-blockers.

GENERAL PREVENTION

  • Healthy weight maintenance.
  • Regular physical activity.
  • Limit processed carbs, sugars, and alcohol.
  • Smoking cessation.

COMMONLY ASSOCIATED CONDITIONS

  • Polycystic ovarian syndrome (PCOS), obesity, acanthosis nigricans, NAFLD, obstructive sleep apnea (OSA), depression, anxiety, cognitive impairment, Alzheimer disease, GERD, gallstones, chronic kidney disease, erectile dysfunction, hyperuricemia, gout.

DIAGNOSIS

  • MetS defined by presence of ≥3 of:
  • Abdominal obesity: Waist circumference (WC)
    • WHO: Waist-hip ratio >0.90 men, >0.85 women or BMI >30 kg/m²
    • IDF: Men ≥94 cm (90 cm South Asian/Chinese/Japanese), Women ≥80 cm
    • NCEP: Men ≥102 cm, Women ≥88 cm
    • Pediatric: WC ≥90th percentile for age/sex
  • Elevated BP: >130/85 mm Hg (NCEP, IDF), >140/90 mm Hg (WHO), ≥90th percentile for age/height/sex (NCEP)
  • Dyslipidemia:
    • Elevated triglycerides (≥150 mg/dL or treated)
    • Decreased HDL: men <35-40 mg/dL, women <39-50 mg/dL (varies by criteria)
  • Elevated fasting glucose ≥100 mg/dL (consistent across definitions)

PHYSICAL EXAM
- WC, BP, signs of insulin resistance (acanthosis nigricans, hirsutism, acrochordons).

DIFFERENTIAL DIAGNOSIS

  • Thyroid dysfunction, Cushing syndrome, medication effects (psychotropics, anticonvulsants, steroids, β-blockers, thiazides).

DIAGNOSTIC TESTS & INTERPRETATION

  • Initial labs: fasting lipid panel, fasting glucose, HbA1c, optional fasting insulin.
  • Follow-up:
  • 75-mg oral glucose tolerance test or HbA1c for impaired glucose tolerance (IGT)/prediabetes.
  • Fasting insulin or TG-to-HDL ratio (insulin resistance markers).
  • Liver function tests (NAFLD evaluation).
  • Hyperuricemia, hs-CRP, microalbuminuria evaluation.
  • Lipid analysis, APOE-4 genotype testing.
  • OSA evaluation.

TREATMENT

MEDICATION
- Metformin and GLP-1RA/GIP effective for insulin resistance.
- Treat comorbid CAD, T2DM as per guidelines.
- Vitamin B12 supplementation for metformin users.

First Line
- Aggressive lifestyle modification (diet, exercise, sleep).
- Clinically effective weight loss ≥7% fat mass improves or reverses MetS risk factors.
- Diet: minimize alcohol; optimize meal timing (avoid night eating), limit snacking, reduce processed foods, added sugars, sugar-sweetened beverages.
- Mediterranean or DASH diet recommended.
- Consider time-restricted feeding or intermittent fasting.
- Physical activity: 30-60 min moderate aerobic exercise 5-7 days/week, resistance training 1-2 days/week; multiple shorter exercise bursts also helpful.
- For IGT/prediabetes: intensive lifestyle ± metformin ± GLP1-RA to reduce progression risk.

ISSUES FOR REFERRAL

  • Liver disease indicated by labs.
  • Suspected obstructive sleep apnea.
  • Mental health services (mood disorders, eating disorders, trauma).
  • Bariatric surgery consideration if comorbidities worsen despite treatment.

ADDITIONAL THERAPIES

  • FDA-approved superabsorbent hydrogel capsules with water before two meals daily to reduce intake and promote weight loss.

SURGERY/OTHER PROCEDURES

  • Bariatric surgery for severely obese patients (BMI >40 or >35 with comorbidities) failing lifestyle/pharmacotherapy.

COMPLEMENTARY & ALTERNATIVE MEDICINE

  • Insufficient evidence for garlic, resveratrol, cinnamon, berberine, green tea, L-carnitine, plant sterols, zinc.
  • Some evidence for probiotics and synbiotics.
  • Mind-body practices (hypnotherapy, mindfulness, acupuncture, yoga) generally safe, limited evidence for symptom relief.

ONGOING CARE

  • Regular monitoring of weight, WC, BP, fasting triglycerides, HDL, glucose/HbA1c.

DIET

  • Refer to treatment section for dietary recommendations.

COMPLICATIONS

  • Progression to CVD, T2DM.
  • Increased risk of NAFLD, stroke, chronic kidney disease, cognitive decline, and various cancers (breast, pancreatic, colon).

REFERENCES

  1. Fechner E, Smeets ETHC, Schrauwen P, et al. Effects of carbohydrate restriction on cardiometabolic risk markers: a systematic review and meta-analysis. Nutrients. 2020;12(4):991.
  2. Wang X, Li Q, Liu Y, et al. Intermittent fasting vs energy restriction for T2DM and MetS: systematic review/meta-analysis. Diab Res Clin Pract. 2021;179:109003.
  3. Liang M, Pan Y, Zhong T, et al. Effects of aerobic, resistance, and combined exercise on MetS parameters: systematic review and network meta-analysis. Rev Cardiovasc Med. 2021;22(4):1523-1533.

ICD10 Codes

  • E88.81 Metabolic syndrome

Clinical Pearls

  • Evaluate for MetS if sedentary lifestyle, sleep apnea, increased WC, elevated BP, increased TG-to-HDL ratio, or evidence of insulin resistance.
  • Lifestyle modification is the cornerstone and most potent treatment.
  • Avoid medications that promote weight gain or MetS (atypical antipsychotics, chronic steroids).
  • Early intervention with meds or referral is key to prevent progression and complications.