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

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): 1258-1264.

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.

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:

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

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

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

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

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

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

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

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)

Hemoglobin A1c reflects average blood sugar over the previous 3 months

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

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

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

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

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

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

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

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

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.

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?

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.

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

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

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 2010. 16(42). 5280-5285

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

NAFLD – clinical signs Initial presentation: Asymptomatic with ALT

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

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

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

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

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

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

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.

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

Answer #3 Elevated total cholesterol Elevated LDL Low HDL Elevated triglycerides

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

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

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

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

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.

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 Endocrinol Metab 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 Paediatr 2010; 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.