Metabolic Syndrome

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • A disorder of energy regulation associated with ectopic fat deposition, immune dysregulation, insulin resistance, and increased risk for cardiometabolic disease, including cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM)
  • Recognized by central adiposity, dyslipidemia, hypertension, and abnormal glucose tolerance
  • These metabolic parameters change with age, sex, race, and ethnicity, so no established pediatric thresholds have been defined.
  • Extrapolation from adult criteria permits diagnosis when ≥3 of the following five elements are present (approximate levels):
    • Waist circumference >90th percentile (waist-to-height ratio ≥0.5)
    • Low high-density lipoprotein cholesterol (HDL-c) <10th percentile (<40 mg/dL)
    • High triglycerides (TG) >90th percentile (≥90 mg/dL to age 9 years and then ≥110 mg/dL)
    • Hypertension: systolic and/or diastolic blood pressure (BP) ≥95th percentile for age, height, and gender
    • Elevated fasting blood sugar (>99 mg/dL) in youth with insulin resistance; hyperinsulinemia is more common than hyperglycemia.

EPIDEMIOLOGY

  • Uncommon in children of normal weight
  • From one third to 57.4% of obese children meet criteria for the metabolic syndrome, varying with criteria used
  • Rates correlate with all ectopic fat depots.
  • More prevalent with age and in males than females

ETIOLOGY

  • Excessive caloric load, particularly a diet high in refined carbohydrates (CHO) and saturated and/or trans fat
  • Decreased mitochondrial reserve with age, stress, nutrient insufficiency, and physical inactivity
  • Genetic and epigenetic predisposition

RISK FACTORS

  • Prenatal and postnatal stressors
  • Family history of T2DM and/or early CVD
  • Diet high in processed foods, simple CHO, added sugars, trans fats; low in vegetables, fruits, whole grains, fiber, and essential fatty acids
  • Sedentary lifestyle
  • Smoking or passive smoke exposure

Genetics

Sequence and epigenetic modification of genes involved in energy regulation have been implicated in disease progression, including adipose tissue differentiation, insulin signaling, circadian clock, and lipid metabolism genes as well as genes within the mitochondrial genome.

PATHOPHYSIOLOGY

  • Subcutaneous adipose storage capacity (which varies in individuals for both genetic and environmental reasons) is exceeded.
  • De novo lipogenesis (DNL) in hepatic, adipose, and intestinal cells triggered by excess dietary sugar and simple CHO contributes to adipose loading.
  • TG-engorged adipocytes trigger major histocompatibility complex (MHC) II response and immune activation. Antigen presentation may be endotoxin from microbial translocation within chylomicrons.
  • Deposition of overflow fat within nonadipose depots, notably visceral, hepatic, and muscular, is lipotoxic.
  • Among the many lipid subtypes that accumulate are sphingolipid ceramides that impair mitochondrial function and induce the nucleotide-binding domain and leucine-rich repeat (NLR) family pryin domain containing 3 (NLRP3) inflammasome.
  • Mitochondrial dysfunction leads to intracellular oxidative stress and increased branched chain amino acids.
  • Insulin resistance and systemic comorbidities develop.

COMMONLY ASSOCIATED CONDITIONS

  • Nonalcoholic fatty liver disease (NAFLD)
  • Disordered sleep ± obstructive sleep apnea (OSA)
  • Polycystic ovary syndrome (PCOS)
  • Low 25-OH vitamin D level
  • Anxiety and depression

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