1. Laboratory analysis of the obese child – recommendations and discussion
MacKenzi Hillard
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
From: Singhal V, Schwenk WF, and Kumar S. Evaluation and management of childhood and adolescent obesity. Mayo Clin Proc 2007; 82(10):

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 mg/dL
Impaired glucose tolerance (IGT)
plasma glucose after 2 hr oral glucose tolerance test (OGTT) is 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 (9702):

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
A Steatosis - 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 (42)

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 :

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 ceruloplasmin in 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
diabetes mellitus
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 June 1; 3(3): 271–281
Daniels S and Greer FR. Lipid Screening and Cardiovascular Health in Childhood Pediatrics 2008 , 122 (1):
Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. The Lancet (9702)
Executive Summary – Standards of medical care in diabetes – Diabetes Care (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 :
Fonseca VA. Identification and Treatment of prediabetes to prevent progression to type 2 diabetes. Clinical Cornerstone 2007 (8)2:
Goran M and Bower G. Longitudinal study on insulin resistance. Diabetes 2001, 50(1)
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 Endocrinol Metab 2010, 95(12):
Prevalence of abnormal lipids among youths – United States , 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:
Singhal V, Schwenk F, and Kuma S. Evaluation and Management of Childhood and Adolescent Obesity. Mayo Clin Proc 2007 (82(10):
Takahashi Y, Fuckusato T. Pediatric non-alcoholic fatty liver disease: emphasis on histology. World Journal of Histology (42)
Tsay J at al. Screening markers of impaired glucose tolerance in the pediatric population. Horm Res Paediatr 2010; 73:
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):