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Laboratory analysis of the obese child – recommendations and discussion

Laboratory analysis of the obese child – recommendations and discussion. MacKenzi Hillard May 4, 2011. aka: What to do with “Fasting Labs”. The Obesity Epidemic. The prevalence of obesity in adolescents has tripled since 1980 31% of children are overweight and 17% are obese. The Concern.

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Laboratory analysis of the obese child – recommendations and discussion

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  1. Laboratory analysis of the obese child – recommendations and discussion MacKenziHillard May 4, 2011

  2. aka: What to do with “Fasting Labs”

  3. The Obesity Epidemic • The prevalence of obesity in adolescents has tripled since 1980 • 31% of children are overweight and 17% are obese

  4. The Concern • Obesity is associated with numerous medical comorbidities: • Elevated blood pressure • Dyslipidemia • Impaired glucose tolerance / Type 2 DM • Non-alcoholic fatty liver disease

  5. From: Singhal V, Schwenk WF, and Kumar S. Evaluation and management of childhood and adolescent obesity. Mayo Clin Proc 2007; 82(10): 1258-1264.

  6. Objectives • Discuss the role of the primary care physician to identify obese children with three common comorbidities - altered glucose tolerance, NAFLD and dyslipidemia. • Discuss the appropriate utilization and interpretation of laboratory screening tests and subsequent management.

  7. Question #1 You are seeing an obese 14 year old female patient. Her mother asks you to test her for diabetes because it runs in the family. You order a fasting blood glucose and it is 120. You tell her mother:

  8. Answers #1 • Your daughter’s labs are normal. • Your daughter has impaired glucose tolerance. • Your daughter has diabetes. • Your daughter has prediabetes.

  9. Altered glucose tolerance • Insulin resistance and altered glucose metabolism is a component of the metabolic syndrome

  10. Altered glucose tolerance • Prediabetes • Impaired fasting glucose (IFG) fasting glucose 100-125 mg/dL • Impaired glucose tolerance (IGT) plasma glucose after 2 hr oral glucose tolerance test (OGTT) is 140-199 mg/dL • Type 2 DM • Fasting glucose >126 mg/dL • plasma glucose after OGTT > 200 mg/dL • Two random plasma glucose values >200

  11. Altered glucose tolerance • 10-30% of obese children have prediabetes • 45% convert to normal glucose tolerance over 2 years • 20% convert to type 2 DM • Goal of screening is to detect these at-risk patients and intervene before disease progresses

  12. Who should be screened? • The American Diabetes Association recommends obtaining a fasting plasma glucose in any obese individual who has 2 additional risk factors …. • Family history • Ethnicity: African-American, American Indian, Hispanic, Pacific-Islander • Signs of insulin resistance or of conditions associated with insulin resistance: acanthosis, PCOS, SGA, HTN, dyslipidemia • Mother with GDM in pregnancy … beginning at age 10 or at the onset of puberty and repeating every 3 years

  13. Fasting plasma glucose • Easy to obtain, easily reproducible, relatively inexpensive • Problem: only identifies a portion of patients who are prediabetic.

  14. Impaired fasting glucose vs. impaired glucose tolerance • FG alone only has a 21% sensitivity to detect IGT Tsai J et al, Horm Res Paediatr 2010

  15. Who should get an oral glucose tolerance test? • OGTT is not recommended for a first line screen • Inconvenient • Not readily reproducible • No specific recommendations exist for when to order an OGTT in an obese child • Consider when fasting glucose is normal and you have a high suspicion for a pre-diabetic state (PCOS, strong family history)

  16. Hemoglobin A1c • reflects average blood sugar over the previous 3 months

  17. What about using HbA1c as a screening test? • HbA1C has been looked at as a predictor of impaired glucose tolerance • Cut-off of 5.5% has the best combined sensitivity (85.7%) and specificity (56.9%) for IGT • However, low specificity means that other tests will still be indicated to make a diagnosis so not currently recommended as a screen

  18. Screening for hyperinsulinemia • Fasting insulin levels have been historically used as a marker of insulin resistance

  19. Screening for hyperinsulinemia A few problems …. • Insulin levels normally rise in puberty while insulin sensitivity decreases to facilitate rapid growth • Fasting insulin levels do not correlate well with the euglycemic hyperinsulinemic clamp measure of insulin sensitivity (gold standard) • Correlation of 0.42 at age 13 and 0.29 at age 15

  20. Screening for hyperinsulinemia • Fasting insulin levels should not be routinely obtained and applied to clinical decision making

  21. Management of altered glucose tolerance by the PCP • Prediabetes: goal of treatment is to slow the progression to diabetes 1. lifestyle modification: • Weight loss + physical activity

  22. Management of altered glucose tolerance by the PCP 2. metformin • has been shown to slow the progression from prediabetes -> diabetes in adults • may initiate treatment at diagnosis of altered glucose tolerance or wait 3-6 months to see effects of lifestyle changes

  23. Risk of Diabetes Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. The Lancet 2009. 374 (9702): 1677-1686

  24. Management • T2 DM • lifestyle modification • metformin • Consider referral to endocrinology (especially if HbA1c is >8) • insulin if needed

  25. Summary • The ADA recommends obtaining a fasting blood glucose as an initial screen. • This test will miss some patients who might have IGT on an OGTT –> obtain an OGTT if you have additional concerns. • Fasting insulin levels and HbA1C are not recommended as screening tests. • Advise lifestyle changes and consider starting metformin in obese children with prediabetes.

  26. Question #2 You obtain a hepatic panel on a 15 year old obese male patient. His ALT measures 110 u/L and his AST is 100 u/L. He has no previous labs on record and is asymptomatic. There is no family history of liver disease. You advise which of the following?

  27. Answer #2 • Counsel on lifestyle changes and repeat a hepatic panel with other labs in 2 years. • Counsel on lifestyle changes and repeat labs in 3 months. • Obtain a liver ultrasound. • Refer immediately to GI.

  28. Non-alcoholic fatty liver disease • The most common liver disease among adolescents in North America • Autopsies suggest a prevalence of 9.8% in American children, 38% of obese children • Male predominance (2:1) • More prevalent in Hispanics and Asians, less prevalent in African-Americans

  29. Non-alcoholic fatty liver disease • Strongly associated with other components of the metabolic syndrome, particularly insulin resistance and increased visceral fat

  30. Non-alcoholic fatty liver disease • Characterized by accumulation of triglycerides in hepatocytes ASteatosis- triglyceride deposition in hepatocytes (reversible) B Steatohepatitis (NASH) - inflammation and fibrosis (may be irreversible) Increased fibrosis, cirrhosis From : Takahashi Y, Fuckusato T. Pediatric non-alcoholic fatty liver disease: emphasis on histology. World Journal of Histology 2010. 16(42). 5280-5285

  31. NAFLD – what’s the risk • Children with NAFL have a 13.8 times greater risk of dying or requiring liver transplant in 20 years after diagnosis Children diagnosed with NAFLD From: Fieldstein AE et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009 58: 1538-1544

  32. NAFLD – clinical signs Initial presentation: Asymptomatic with ALT

  33. NAFLD – screening • Recommendation is to measure transaminases on all obese children, especially those with other components of metabolic syndrome • No consistent recommendations for timing of initiation or frequency of screening • ALT > 2x normal that persists for > 3 months suggests the diagnosis

  34. NAFLD – a diagnosis of exclusion • Need to rule-out • hepatitis B and C • autoimmune hepatitis • Wilson’s disease • alpha-1 antitrypsin deficiency • drug-induced liver injury

  35. NAFLD – interpreting results • Consider checking a ceruloplasminin any patient with elevated transaminases and screen for autoimmune hepatitis in females with a family history before waiting for repeat labs. • Obtain a full CMP with PT/INR to evaluate liver function when labs are repeated

  36. NAFLD – interpreting results • Transaminase measurement is the only acceptable screening test, but realize … • not extremely sensitive - 23% of patients with evidence of NAFLD on biopsy have normal ALT • Liver biopsy is gold standard of diagnosis to assess the degree of steatosis, inflammation and/or fibrosis • Expensive, invasive – not recommended for routine screening

  37. NAFLD – further evaluation • Ultrasound may reveal an enlarged, echogenic liver but is not always needed • Patients with suspected NAFLD should be referred to and followed by GI

  38. NAFLD - management • Address the metabolic comorbidities • OBESITY : Diet/Lifestyle modification • Moderate weight loss can decrease the transaminitis and inflammation but does not consistently reverse fibrosis • INSULIN RESISTANCE: • Metformin may help to reduce transaminitis? • ANTIOXIDANT THERAPY – Vitamin E

  39. Summary • NAFLD is common and often asymptomatic. • All obese patients should have transaminases measured as a screening test. • If initial screen is abnormal, r/o Wilson’s and autoimmune hepatitis in at risk patients, then repeat a CMP with INR in 3 months. • Recommend lifestyle changes, consider GI referral.

  40. Question #3 Which is the most common lipid abnormality in obese children …

  41. Answer #3 • Elevated total cholesterol • Elevated LDL • Low HDL • Elevated triglycerides

  42. Dyslipidemia • Elevated LDL and triglycerides and a low HDL increase risk for CVD • Atherosclerosis begins in childhood • 42% of obese youth • 24% elevated triglycerides • 20% have low HDL • 14.2 % have high LDL

  43. Dyslipidemia • Metabolic syndrome • HDL < 50 (women) or <40 (men) • Triglycerides > 150

  44. Dyslipidemia – AAP screening recommendations • Screen pediatric patients with a fasting lipid profile who have any of the following risk factors: • family history of dyslipidemia • overweight or obesity • hypertension • diabetesmellitus • cigarette smoking • Begin screening between ages 2 and 10, repeat every 3-5 years

  45. Dyspidemia - management • Low HDL or elevated triglycerides -> weight management and increased physical activity • Consider pharmacologic treatment for LDL >190 (or >160 if multiple risk factors) with initial goal <160 • Statins • Fish Oil • Plant Sterols

  46. Conclusions • The initial laboratory evaluation of the obese child who is developmentally normal and growing (too) well should include a fasting glucose, a hepatic panel, and a lipid panel. • There is a room for a great deal of inter-provider variability in the interpretation of these results and selection of subsequent tests. • Lifestyle changes are the answer to just about everything.

  47. References • Barshop NJ, Francis CS, Schwimmer JB, Lavine JE. Nonalcoholic fatty liver disease as a comorbidity of childhood obesity. Ped Health. 2009 June 1; 3(3): 271–281 • Daniels S and Greer FR. Lipid Screening and Cardiovascular Health in Childhood Pediatrics 2008 , 122 (1): 198-208 • Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. The Lancet 2009. 374 (9702). 1677-1686. • Executive Summary – Standards of medical care in diabetes – 2009. Diabetes Care 2009 32(Supp 1): S6-S12. • Fieldstein AE et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009 58: 1538-1544. • Fonseca VA. Identification and Treatment of prediabetes to prevent progression to type 2 diabetes. Clinical Cornerstone 2007 (8)2: 10-20. • Goran M and Bower G. Longitudinal study on insulin resistance. Diabetes 2001, 50(1) 2444-2450. • Widhalm K and Ghods E. Nonalcoholic fatty liver disease: a challenge for pediatricians. International Journal of Obesity (2010): 1-17. • Levy-Mitchell C at al. Insulin resistance in Children: Consensus, perspective and future directions. J EndocrinolMetab 2010, 95(12): 5189-5198. • Prevalence of abnormal lipids among youths – United States ,199-2006. Centers of Disease Control and Prevention Morbidity and Mortality Weekly Report 59(2) Published January 22, 2010. • Rodriquez G, et al. Is liver transaminases assessment an appropriate tool for the screening of non-alcoholic fatty liver disease in at risk obese children and adolescents? Nutr Hosp. 2010;25:712-717. • Singhal V, Schwenk F, and Kuma S. Evaluation and Management of Childhood and Adolescent Obesity. Mayo Clin Proc 2007 (82(10): 1258-1264. • Takahashi Y, Fuckusato T. Pediatric non-alcoholic fatty liver disease: emphasis on histology. World Journal of Histology 2010. 16(42). 5280-5285. • Tsay J at al. Screening markers of impaired glucose tolerance in the pediatric population. Horm Res Paediatr2010; 73: 102-107. • Weiss R and Kaufman FR. Metabolic complications of childhood obesity – identifying and mitigating the risk. Diabets Care Supp 2 200: S310-S316. • Wilfred de Alwis and Day CP. Current and future therapeutic strategies in NAFLD. Current Pharmaceutical Design 2010 (16): 1958-1962.

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