Basics
Description
- A systemic disorder of energy regulation associated with ectopic fat deposition, immune activation, insulin resistance, and increased risk for 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, gender, race, and ethnicity, so no established pediatric thresholds have been defined.
- Extrapolation from adult criteria permits diagnosis when ≥3 of the following 5 elements are present (approximate levels):
- Waist circumference >90th percentile (waist to height ratio >0.6)
- Low high-density lipoprotein cholesterol (HDL-c) <10th percentile (<40 mg/dL)
- High triglycerides (TG) >90th percentile (>90 mg/dL to age 9 years, then >110 mg/dL)
- Hypertension: systolic and/or diastolic BP >95th percentile for age, height, and gender
- Elevated fasting blood sugar (>99 mg/dL)
Epidemiology
Prevalence
- Uncommon in children of normal weight
- Up to 60% of obese children meet criteria for the metabolic syndrome.
- Rates correlate with visceral, ectopic fat depot.
- Highest rates in Hispanics > non " Hispanic (NH) Whites and ’ Ό Asians > NH Blacks
- More prevalent with age and in males than females
Risk Factors
- Prenatal and postnatal stressors
- Family history of T2DM and/or CVD
- Diet high in processed foods, added sugars, and trans fats
- 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, and circadian clock genes as well as the mitochondrial genome.
Pathophysiology
- Subcutaneous adipose capacity (which varies in individuals for both genetic and environmental reasons) is exceeded.
- Deposition of fat in hypertrophied adipose cells within nonadipose depots, notably visceral, hepatic, and muscular
- Triglyceride-engorged adipocytes trigger major histocompatibility complex (MHC) II response and immune activation. Antigen presentation may be endotoxin from microbial translocation.
- Stimulated monocyte/macrophage infiltration into ectopic adipose depots release TNF alpha, IL-6, and MCP-1
- Chronic low level inflammation
- Mitochondrial dysfunction and excessive intracellular oxidative stress
- Insulin resistance and systemic consequences
Etiology
- Decreased mitochondrial reserve with age and physical inactivity
- Excessive caloric load, particularly a diet high in refined carbohydrate and/or trans fat
- Genetic and epigenetic predisposition
Commonly Associated Conditions
- Nonalcoholic fatty liver disease (NAFLD)
- Disordered sleep ± obstructive sleep apnea
- Polycystic ovarian syndrome (PCOS)
- Low vitamin D level
Diagnosis
History
- Prenatal stress
- Small or large for gestational age
- Maternal gestational diabetes or eclampsia
- Maternal or pregnancy-related overweight
- History of accelerated weight gain
- Age at which weight gain started (Physiologic insulin resistance of peripubertal years is a common trigger.)
- Previous difficulty losing weight (difficult to lose weight if hyperinsulinemic)
- Psychosocial stressors: teasing, food insecurity
- Family history: early CVD and T2DM
- Lifestyle
- Eating behavior
- Sugared beverage consumption
- Frequency and content of processed snacks
- Poor produce and whole grain intake
- Aberrant eating structure (skipping breakfast, lack of balanced meals)
- Physical activity
- Increased hours of screen time
- Low sports and activity participation
- Poor sleep hygiene
- Parenting skills
- Ability to set boundaries
- Lifestyle role modeling
- Smoke exposure and smoking history
- Signs and symptoms
- Obese patients with metabolic syndrome are usually asymptomatic but may have
- Easy and rapid weight gain
- Excessive hunger, carbohydrate craving
- Snoring, gasps during sleep (OSA)
- Fatigue, disinterest in activity
- Headaches (may be symptom of OSA or pseudotumor cerebri)
- Thickened, darkened skin in flexures, notably at the nape of the neck and axillae (suggestive of acanthosis nigricans) and skin tags
- Polydipsia, polyuria, nocturia (concerning for diabetes)
- Depression, bullying, teasing
- Abnormal menses, male-pattern hair growth, acne (concerning for PCOS)
Physical Exam
A complete physical should be done on all patients. Special attention should be paid to the following:
- Weight, height, and BMI
- Waist circumference and waist to height ratio
- Blood pressure
- Papilledema
- Tanner stage
- Abdominal striae
- Hepatomegaly
- Acanthosis nigricans and skin tags
- Hirsutism, acne
- Affect, mood
Diagnostic Tests & Interpretation
Lab
Metabolic screening (preferably fasting specimens) should be done on all obese patients:
- Fasting lipid profile: total cholesterol, HDL-c and TG. Metabolic syndrome is a condition of hypertriglyceridemia not increased cholesterol. LDL-c is typically unremarkable; but in the presence of high TG, LDL particles are smaller and less well cleared so they are more numerous, whereas HDL particles, also smaller, are less stable and decreased in number and thus HDL-c is low.
- Nonfasting lipid profile: non " HDL-c elevation
- Fasting glucose and insulin: Compensatory hyperinsulinism suggests (although not definitive) insulin resistance; homeostasis model assessment ’ insulin resistance (HOMA-IR) = (fasting insulin FBG)/405: measure of insulin resistance
- Hemoglobin A1c (HbA1c): may be a helpful indication of chronic caloric overload in nonfasting state; potential screen for diabetes
- Liver function tests (LFTs): ALT and AST elevation are nonsensitive indicators of NAFLD.
- Thyroid function tests: may find very mild elevations of TSH with normal T4
- 25-OH vitamin D level: often low
- 2-hour OGTT: suggested when fasting blood sugar >99 mg/dL, elevated HbA1c (>5.6% but can use clinical judgment), and/or symptoms of diabetes (polydipsia, polyuria, nocturia) to assess for impaired glucose tolerance and T2DM
- Abnormal lab tests should be repeated after a trial of weight management.
Imaging/Additional Studies
- All patients with hypertension should have an ECG to evaluate for LVH; ambulatory BP monitoring can also be useful.
- Patients with elevated ALT or AST (particularly ALT) could have a 2-D echo to assess for hepatic fat infiltration of NAFLD.
- MRI is currently the gold standard for ectopic/visceral fat evaluation.
- A history of disordered sleep and heavy snoring, especially with pauses in breathing, warrants a sleep study (polysomnogram).
Differential Diagnosis
The full cardiometabolic constellation of findings is unique to this syndrome, but individual features may present in other conditions:
- Hereditary combined dyslipidemia
- Hereditary hypertriglyceridemia
- Essential hypertension
- Type 1 diabetes mellitus
- Lipodystrophies
Treatment
Medication
There are no pharmacologic treatments approved for the treatment of metabolic syndrome as a whole. Medications can be used to treat individual components. See "Additional Therapies. "
General Measures
Comprehensive behavioral modification through both improved diet and increased physical activity is the first-line treatment for metabolic syndrome. It decreases body weight, improves body composition and insulin sensitivity, and can positively affect CVD risk factors even if weight loss is not achieved due to redistribution of fat from ectopic to subcutaneous depots and/or a favorable shift to lean muscle weight.
- Physical activity: ≥60 minutes per day of moderate to vigorous physical activity (can be in short intervals) defined as a level of effort that increases heart rate and produces heavier than at-rest breathing.
- Diet: upgrade carbohydrate and fat quality
- Avoid/limit sugar-sweetened beverages, specifically juice and soda. Limit sugar substitutes. Encourage water.
- Primary dairy beverage for 2 " 21 years old: low-fat or fat-free unflavored milk
- Increase fiber intake
- ≥5 servings of whole fruits and vegetables per day
- Increase whole grains in diet; avoid grains with <3 g fiber/serving.
- Limit foods containing high-fructose corn syrup; limit added sugars; aim for total sugar to fiber ratio <5, ideally <3.
- Fat content
- Total fat, 25 " 30% of daily kcal/estimated energy requirement (EER)
- Saturated fat, 8 " 10% of daily kcal/EER
- Avoid trans fat
- Monounsaturated and polyunsaturated fat (PUFA) up to 20% of daily kcal/EER
- Favor omega-3 PUFA
- Cholesterol <300 mg/day
- Sedentary activity/screen time
- Includes television, video games, texting, or computer not related to school
- Limit to ≤2 hours per day for children older than 2 years (no screen time if <2 years)
- No TV in bedroom or screens after bedtime
- Smoking
- Explicitly counsel about the dangers of smoking and advocate smoking cessation.
- Counsel to avoid secondhand smoke.
Additional Therapies
For individual elements of the metabolic syndrome
- Dyslipidemia: ≥10 " 21 years of age
- LDL-c will not exceed 190 mg/dL with metabolic syndrome alone.
- LDL-c >160mg/dL unusual in metabolic syndrome but hypercholesterolemia may coexist (See "Hyperlipidemia " chapter.)
- LDL-c 130 " 159mg/dL + 2 high-level risk factors OR 1 high-level + ≥ 2 moderate-level risk factors OR clinical CVD
- Risk factor algorithm helps identify risk for small dense LDL and a higher LDL particle burden.
- HMG-CoA reductase inhibitors (statins) " pravastatin or rosuvastatin preferred. Note side effects; needs monitoring.
- TG ≥110 " 499, non " HDL-c ≥145 (mg/dL)
- Restrict refined carbohydrate intake.
- Consider daily fish oil over-the-counter preparations with ’ Ό400 mg DHA + EPA.
- TG >500 " 700 mg/dL and >10 years of age
- Consider adjunct fibrate (off label).
- TG ≥1,000 mg/dL
- Not likely in metabolic syndrome alone; rule out primary hypertriglyceridemia
- Hypertension: stage 1 with no response to lifestyle changes 3 to 6 months and stage 2
- Rule out primary renal etiology (check U/A, BUN, creatinine, renin)
- ACE inhibitors, angiotensin receptor blockers, diuretics, and vasodilators are used most commonly in pediatrics. Note side effects and needs monitoring.
- T2DM
- OGTT: fasting blood glucose ≥126mg/dL or 2-hour ≥200mg/dL or HbA1c ≥6.5%
- Metformin or metformin XR are the only oral agents approved for the treatment of T2DM in children.
- To minimize GI distress, titrate up over weeks to 1,000 mg PO b.i.d. with meals.
- Common side effects: nausea, bloating, diarrhea, and gas, which often resolve within 2 weeks
- Rare side effects: lactic acidosis, megaloblastic anemia; prophylax with a daily multivitamin
- Monitor LFTs, creatinine, and Hb/Hct.
- Discontinue 48 hours prior to contrast administration or surgery.
- Counsel to use contraceptive methods to avoid pregnancy.
- Insulin injections " refer to endocrinology
- Prediabetes
- Impaired fasting glucose: 100 " 125 mg/dL
- Impaired glucose tolerance: 2-hour glucose on OGTT, 140 " 199 mg/dL
- HbA1c, 5.7 " 6.4% (debated whether synonymous with prediabetes)
- Consider OGTT to rule out prediabetes and diabetes.
- No consensus on the use of metformin in prediabetic states but some evidence of efficacy
Issues for Referral
- Referral to pediatric lipid specialist for LDL-c ≥130 and/or TG ≥200 (mg/dL)
- Referral to pediatric endocrinologist for diabetes, prediabetes, or PCOS
- Referral to pediatric gastroenterologist for ALT >2 times normal to rule out NAFLD
- Referral to pediatric hypertension specialist for stage 1 hypertension not responsive to lifestyle or stage 2 hypertension
- Consider referral to multidisciplinary pediatric weight management clinic for intensive lifestyle counseling.
Surgery/Other Procedures
Bariatric surgery is a potential weight loss treatment for extreme obesity with cardiometabolic complications in older adolescents with potential for significant insulin sensitization. Refer to a pediatric center experienced in bariatric surgery.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Ongoing weight management
- Children ≥10 years of age with BMI from 85th " 94th percentile: Check lipid profile at least every 2 years; if other risk factors are present, include glucose and LFTs.
- Children ≥10 years of age with BMI ≥95th percentile: Check fasting lipid panel, glucose, and AST/ALT at least every 2 years and other tests as indicated.
Prognosis
Multiple studies have shown that without aggressive intervention, cardiometabolic risk factors track from childhood to adulthood, increasing lifetime risk for T2DM and CVD.
Additional Reading
- Bremer AA, Mietus-Snyder M, Lustig RH. Toward a unifying hypothesis of metabolic syndrome. Pediatrics. 2012;129(3):557 " 570. [View Abstract]
- D 'Adamo E, Santoro N, Caprio S. Metabolic syndrome in pediatrics: old concepts revised, new concepts discussed. Curr Probl Pediatr Adolesc Health Care. 2013;43(5):114 " 123. [View Abstract]
- Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128(6):S1 " S44. [View Abstract]
- Steinberger J, Daniels SR, Eckel RH, et al. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2009;119(4):628 " 647. [View Abstract]
Codes
ICD09
- 277.7 Dysmetabolic syndrome X
ICD10
- E88.81 Metabolic Syndrome
SNOMED
- 237602007 metabolic syndrome X (disorder)
FAQ
- Q: Why is it important to diagnose metabolic syndrome?
- A: Although obesity increases metabolic risk, not everyone who is obese develops complications; those at the greatest cardiometabolic risk need additional screening and intervention.
- Q: Do children with the metabolic syndrome have it when they become adults?
- A: If children with the metabolic syndrome do not use diet and exercise to treat it, they will likely have it as adults.
- Q: Does cardiovascular risk improve if these children lose weight?
- A: Yes, 5 " 10% body weight loss can result in improvement of CVD risk factors due to preferential weight loss from the ectopic visceral fat depot.