1 Comorbidities of Childhood ObesitySandra G. Hassink, MD, FAAP Director of the Weight Management Clinic A.I. Dupont Hospital for Children Wilmington, DE

2 Insights Into Obesity Complex Dynamic Multisystem PathologicGene-Environment Interaction Dynamic Metabolically active organ system Multisystem Structural, Functional and Metabolic effects Pathologic

3 Complex Gene Environment InteractionGenetic Predisposition Parental obesity Risk for co morbidity Environmental interaction Intrauterine environment Periods of critical growth Nutritional Genomics

4 Dynamic Metabolically Active Organ System. Adipocytes StorageCytokine production Hormonal regulation Energy regulation at the level of the CNS and periphery.

5 Multisystem Effects on all major organ systems Skeletal MuscularEndocrine Gastrointestinal Reproductive Cardiovascular Pulmonary

6 Pathologic Results in earlier onset of adult diseaseType II diabetes Results in end stage disease NASH Provides new explanations for “old” disease Sleep apnea syndrome

7 Severe Obesity Related EmergenciesHyperglycemic Hyperosmolar state DKA Pulmonary emboli Cardiomyopathy of obesity

8 Hyperglycemic Hyperosmolar State“Death caused by hyperglycemic Hyperosmolar state at the onset of type 2 diabetes." Morales AE, Rosenbloom AL.J Pediatric 2004 Feb 144 (2) “Seven obese African American youth were considered to have died from diabetic ketoacidosis.”

9 Hyperglycemic Hyperosmolar State“Despite meeting the criteria for Hyperglycemic Hyperosmolar state and not for DKA.” “All had previously unrecognized type 2 diabetes, and death may have been prevented with earlier diagnosis or treatment.”

10 Hyperglycemic Hyperosmolar StatePatients presented to medical care with symptoms which were not linked to presentation of type 2 diabetes. Vomiting. Abdominal Pain. Dizziness. Weakness. Polyuria/Polydipsia. Weight loss. Diarrhea.

11 Hyperglycemic Hyperosmolar StateHHS- diagnostic criteria plasma glucose > 600mg/dl serum CO2 > 15 mmol/l small ketonuria absent to low ketonemia effective serum osmolality >320 mOsm/kg stupor or coma Rubin HM J Pediatr 1969:74:`77-86 Morales A J Pediatr 2004 Feb,

12 Diabetic KetoacidosisType 2 DM may present with diabetic ketoacidosis. In some studies up to 25%. If basal insulin sensitivity is low there is increasing susceptibility to relative insulin deficiency. May be more common in African American and Hispanic patients with Type 2 Diabetes.

13 Diabetic KetoacidosisHyperglycemia Beta Cell Toxicity Insulin secretion + Insulin resistance Relative Insulin Deficiency Free Fatty Acids Ketonemia Lipolysis Ketonuria

14 Pulmonary Embolism SymptomsDyspnea Chest pain Decreased O2 Hemoptysis Most common complication of gastric bypass/banding in adults

15 Pulmonary Embolism Has been reported in adolescence Risk factorsSugerman HJ, Sugerman EL, DeMaria EJ, Kellum JM, Kennedy C, Mowery Y, Wolfe LG. J Gastrointest Surg Jan: 7(1):102-07 Risk factors Obesity Obesity hypoventilation syndrome/OSAS Coagulation disorder (i.e. Leiden V)

16 Cardiomyopathy of ObesityHigh metabolic activity of excessive fat increases total blood volume and cardiac output. Left ventricular dysfunction. dilation increased left ventricular wall stress compensatory (eccentric) left ventricular hypertrophy left ventricular diastolic dysfunction Right Ventricular dysfunction Exacerbated by pulmonary hypertension due to UAO Alpert, MA Am J Med Sci 2001 Apr, 321(4);

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18 Co-morbidity's Requiring Immediate AttentionPseudotumor Cerebri Slipped Capital Femoral Epiphysis Blount’s Disease Sleep Apnea Non alcoholic hepatosteatosis Cholelithiasis

19 Pseudotumor Cerebri - Obesity Related Central Nervous System MorbidityDefinition. Raised intracranial pressure with papilledema and a normal cerebrospinal fluid in the absence of ventricular enlargement.

21 Pseudotumor Cerebri Diagnosis.May present with headaches, vomiting, blurred vision or diplopia. Neck, shoulder, and back pain have also been reported. Lessell S. Surv Ophthalmol 1992;37(3): Papilledema is part of pathology but may not occur on presentation.

22 Pseudotumor Cerebri Loss of peripheral visual fields and reduction in visual acuity may be present at diagnosis Baker RS, Carter D, Hendrick EB, Buncic JR. Arch Ophthalmol 1985;103(11): Increased intracranial pressure may lead to visual impairment or blindness.

23 Pseudotumor Cerebri Risk.Obesity occurs in 30%-80% of affected children. Scott Am J Opth 1997; 124: In a series of case-controlled studies in adolescents and adults, obesity and recent weight gain were the only factors found significantly more often in pseudotumor cerebri patients than control patients. Lessell S. Surg Ophthalmol 1992;37(3):

24 Drugs Associated With Pseudotumor CerebriGrowth hormone therapy Nalidixic acid,Ciprofloxacin,Tetracycline therapy No clear dose-response relationship Lessell S. Surv Ophthalmol 1992;37(3): Vitamin A and isoretinoin therapy are established causes of pseudotumor cerebri. Morrice G Jr, Havener WH, Kapetansky F. JAMA 1960;173: Roytman M, Frumkin A, Bohn TG. Cutis 1988;42(5):

25 Treatment Acetazolamide. Lumboperitoneal shunt (in severe cases),Weight loss. Newborg B. Arch Intern Med 1974;133(5):802-7.

26 Points to Remember A fundiscopic examination should be a routine part of the examination of the obese child Children may not complain of visual field disturbances. When suspicious – test Pseudotumor cerebri is essentially a diagnosis of exclusion after other causes of increased intracranial pressure are eliminated.

27 Slipped Capital Femoral EpiphysisDiagnosis Suspect and immediately evaluate in an obese patient who presents with limp. 50%-70% patients with SCFE are obese. Wilcox J Pediatr Orthop 1988:8: Can also present with complaints of groin, thigh, or knee pain referred by sensory cutaneous nerves passing close to the hip capsule.

28 Slipped Capital Femoral EpiphysisDiagnosis Motion of the hip in abduction and internal rotation is limited on examination. X- ray Anteroposterior view of the pelvis that includes both hips. Comparison of the hips Bilateral disease occurs in up to 20% of patients.

29 Busch MT, Morrissy RT. Orthop Clin North Am 1987;18(4):637-47.SCFE - Diagnosis Medial and posterior displacement of the femoral epiphysis through the growth plate relative to the femoral neck Busch MT, Morrissy RT. Orthop Clin North Am 1987;18(4): All studies have a small rate of false negative results, and so they can confirm, but not completely rule out, a slipped epiphysis when one is suspected clinically.

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31 SCFE- Pathology The preferential site of slipping within the epiphysis is a zone of hypertrophic cartilage cells under the influence of both gonadal hormones and growth hormone Kempers MJ, Noordam C, Rouwe CW, Otten BJ. CanJ Pediatr Endocrinol Metab 2001;14(6):

32 SCFE - Associated CausesContinued weight gain. Renal failure. History of radiation therapy. Primary hypothyroidism. Loder RT, Greenfield ML.. J Pediatr Orthop ;21(4):481-7. Gonadotropin-releasing hormone agonists. Growth hormone therapy. Kempers MJ, Noordam C, Rouwe CW, Otten BJ. J Pediatr Endocrinol Metab 2001;14(6): Grumbach MM, Bin-Abbas BS, Kaplan SL. Horm Res 1998;49(Suppl 2);41-57.

33 Points to Remember A careful hip and knee examination should be a routine part of the evaluation and follow-up of every obese child. An obese child complaining of or presenting with hip, knee, groin, or thigh pain should have a complete and thorough examination of his/her hips, including radiological studies. In an obese child, an unusual or abnormal gait should not be attributed to “excess weight” but should be thoroughly investigated with a careful hip and knee examination. `

34 Blount’s Disease - Obesity Related Orthopedic MorbidityDiagnosis Bowing of tibia and femur either unilateral or bilateral. Etiology Results from overgrowth of the medial aspect of the proximal tibial metaphysis. 2/3 of patients with Blount’s disease may be obese. Dietz J Pediatr 1982:101: Treatment Requires evaluation and correction by orthopedic surgeon. Weight loss

35 Obstructive Sleep Apnea- DefinitionOSAS in children is defined as a disorder of breathing during sleep characterized by. prolonged partial upper airway obstruction. and/or intermittent complete obstruction (obstructive apnea). that disrupts normal ventilation during sleep and normal sleep patterns. Schechter MS. Technical report: diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics 2002;109(4):e69-79.

36 OSAS -Symptoms Symptoms of sleep apnea can include.Nighttime awakening. Restless sleep. Difficulty awaking in the morning. Daytime somnolence. Napping. Enuresis. Decreased concentration. Poor school performance. Gozal D. Sleep-disordered breathing and school performance in children. Pediatrics 1998;102(3 Pt 1):

37 OSAS - Etiology Increased fat mass.Increased muscle relaxation during sleep. Enlarged tonsils and adenoids. Silvestri JM, Weese-Mayer DE, Bass MT, Kenny AS, Hauptman SA, Pearsall SM. Pediatr Pulmonol 1993;16(2):124-9. Elevated insulin de la Eva RC, Baur LA, Donaghue KC, Waters KA.. J Pediatr 2002;140(6):654-9.

38 OSAS-diagnosis History, audio and video taping, and overnight oximetry and daytime nap polysomnography are poor predictors of OSAS. The definitive diagnosis of OSAS is made by nighttime polysomnography. Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnea syndrome. [No authors listed.] Pediatrics 2002;109(4): Severity of obstruction may not correlate with either degree of obesity or severity of sleep symptoms.

39 OSAS Abnormal sleep patterns reported in 94% of obese children studied. Massumi RA, Sarin RK, Pooya M, Reichelderfer Dis Chest 1969;55(2): Obstructive sleep apnea has been noted in obese infants as young as five months of age. Kahn A, Mozin MJ, Rebuffat E, Sottiaux M, Burniat W, Shepherd S, et al. Sleep 1989;12(5):430-8. Obstructive sleep apnea has been noted in obese infants as young as five months of age.

40 Obstructive Sleep Apnea- RiskChildren with sleep apnea demonstrate significant decreases in learning and memory. Rhodes J Pediatr 1995;127: Deficits in attention, motor efficiency and graphomotor ability. Greenberg GD, Watson RK, Deptula D.. Sleep 1987;10(3): Pulmonary hypertension,systemic hypertension, right heart failure. .Tal A, Leiberman A, Margulis G, Sofer S. Pediatr Pulmonol 1988;4(3): Marcus CL, Greene MG, Carroll JL. Am J Respir Crit Care Med 1998;157(4 Pt 1): Massumi RA, Sarin RK, Pooya M, Reichelderfer Dis Chest 1969;55(2):110-4. Weight >200% above ideal had oxygen saturation <90% for half to total sleep time. 40% of severely obese children demonstrated central hypoventilation. Silvesti Pediar Pulmonol 1993;16:

41 OSAS - Treatment Weight loss reduced apneic episodes, hypoxemia, and daytime sleepiness in a group of obese children. Willi SM, Oexmann MJ, Wright NM, Collop NA, Key LL Jr. Pediatrics 1998;101(1 Pt 1):61-7. Tonsilladenoidectomy, if indicated Continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP).

42 Points to Remember Ask specifically about sleep disturbances, snoring, and sleep position. Families will often disregard these symptoms. Obstructive sleep apnea syndrome should be especially considered in obese children with poor school performance and concentration difficulties. Sleep symptoms can evolve over time. Keep asking about sleep disturbance as you follow these children. Weight gain, intercurrent upper respiratory infections, and Tonsillar enlargement can provoke symptoms.

43 NAFLD and NASH Nonalcoholic fatty liver disease (NAFLD) describes a continuum of conditions that range from simple steatosis at the most clinically benign end of the spectrum, through nonalcoholic steatohepatitis (NASH), to cirrhosis and end-stage liver disease Harrison SA, Diehl AM. Fat and the liver—a molecular overview. Semin Gastrointest Dis 2002;13(1): 3-16.

44 Non Alcoholic Steatohepatitis - Obesity Related Gastrointestinal Morbidity.Diagnosis Increased liver enzymes and fatty liver on ultrasound in the absence of other causes of liver disease. Liver Biopsy Etiology 20%-25% obese children have evidence of steatohepatitis. Tazawa Acta Paeditr 1997;86:

45 NAFLD to NASH Obesity Fatty Liver Genetic Predisposition 2nd “Hit”Inflammation Fibrosis Cirrhosis Day CP, James OF. Gastroenterology 1998;114(4):842-5.

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47 NASH - Risk Obesity and type 2 diabetes are the strongest predictors of progression of fibrosis Age is also a risk factor for cirrhosis which may reflect increased duration of risk for the “second hit” thought to initiate fibrosis. Angulo P, Keach JC, Batts KP, Lindor KD. Hepatology 1999;30(6):

48 NASH - Treatment In a small series of pediatric patients with elevated aminotransferases and fatty liver on ultrasound, those who lost at least 10% of their excess weight normalized ALT and AST values and decreased ultrasound evidence of fatty infiltration Vajro P, Fontanella A, Perna C, Orso G, Tedesco M, De Vincenzo A. J Pediatr 1994;125(2):

49 NASH - Cautions When liver biopsies were performed in adults after weight loss, all had reduced steatosis, but only 50% had a reduction in fibrosis. Rapid weight loss may actually increase fibrosis due to an increase of free fatty acids to the liver and increased lipid peroxidation with resultant increased oxidative stress, leading to the conclusion that rapid weight loss should be avoided in these patients Youssef W, McCullough AJ. Semin Gastrointest Dis 2002;13(1):17-30.

50 Points to Remember Obesity is a risk factor for NAFLD, and even mild obesity may be associated with elevation of liver enzymes and hepatic steatosis. Metabolic evaluation of the obese child should include evaluation of liver function. Nonalcoholic fatty liver disease is a diagnosis of exclusion; other causes of liver disease should be ruled out before a diagnosis is made.

51 Cholelithiasis- Obesity Related Gastrointestinal MorbidityDiagnosis Abdominal pain, tenderness . Ultrasound, laboratory studies. Etiology Obesity accounts for 8%-33% of gallstones in children. Friesen Clin Pediatr :294. May be associated with weight loss. Crichlow Dig Dis. 1972;17:68-72.

52 Cholelithiasis- Obesity Related Gastrointestinal MorbidityRisk 50% of cholecystitis in adolescents associated with obesity. Crichlow Dig Dis. 1972;17:68-72. Relative risk of gallstones in adolescent girls with obesity is 4.2. Honore Arch Surg 1980;115:62-64. Surgical Intervention

53 Chronic - Obesity Related Co Morbid ConditionsMetabolic Syndrome Type II Diabetes Polycystic Ovary Syndrome Hypertension Hyperlipidemia Psychological

54 Obesity Insulin Resistance Metabolic Syndrome Syndrome Type 2DMHypertension NASH Dyslipidemia PCOS

55 Components of the Metabolic Syndrome in ChildhoodObesity (BMI >95% for age and sex) Elevated blood pressure (SBP or DBP > 90% for age).

56 Components of the Metabolic Syndrome in ChildhoodAbnormal blood lipids (HDL cholesterol <40mg/dl or triglycerides >150mg/dl LDL>130mg/dl). Impaired glucose tolerance (fasting glucose > 100 (110) mg/dl, random glucose >200mg/dl). Sinaiko AR, Donahue RP, Jacobs DR, et al. The Minneapolis Children’s Blood Pressure Study. Circulation 1999;99(11)

58 Insulin Resistance and Fat DepositionMuscle Insulin resistance insulin Insulin resistance Liver Adipose tissue in obesity becomes refractory to insulin's suppression of fat mobilization., Insulin resistance increases the release of FFA from the adipocytes. In the postfrontal period there is an excess of FFA leading to fat deposition in other tissues Hyperinsulinemia stimulates fatty acid synthesis while inhibiting the oxidation of fatty acids.,elevated insulin may increase the degradation of apolipoprotein B100a component of VLDLcompromising triglyceride transport out of the liver causing anet accumulation of fat. ElevatedFFA and accumulated triacylglycerol appear to inhibit insulin signaling leading to a reduction in insulin stimulated muscle glucose transport,.The reduced muscle glucose transport leads to reduced glycogen syntethisisand glycolysis Adi Insulin resistance Free Fatty Acids

59 Polycystic Ovarian SyndromePolycystic Ovary Syndrome. Hyperandrogenism Oligomenorrhea/amenorrhea. Hirsuitism Acne Polycystic ovaries and eventual infertility. Increased risk Girls with premature adrenarche Bacha F, Arslanian S. Enod Trends 11(1)2004

60 Type 2 Diabetes Diagnosis Elevated fasting insulin and hyperglycemia.Only 20% present with polyuria, polydipsia, and weight loss. Etiology One third of new diabetics presenting between years had NIDDM. Pinhas-Hamiel J Pediatr 1996;128:

61 Type 2 Diabetes - One End of the ContinuumGenetic Predisposition Environmental Trigger Obesity Beta Hyperglycemia Cell Dysfunction Insulin Resistance Type 2 Diabetes

62 Pathologic Defect in Type 2 DMExcessive hepatic glucose production Defective beta-cell secretion and function (loss of first-phase response and erratic response to oscillations in glucose levels) Peripheral insulin resistance Duration and severity of hyperglycemia dictate the micro vascular complications NEDI Publications Practical Diabetology Haffner, S

63 Hypertension Diagnosis Screen all obese children with correct cuff.Etiology 60% of children with persistently elevated blood pressure had weight >120%. Lauer J Pediatr 1975;86: 20%-30% of obese children have elevated blood pressure.

64 Hypertension Risk InterventionOverweight adolescents have 8.5 fold risk of hypertension as adults. Srinivasan Metab 1996;45: Cardiac hypertrophy/LVH on ultrasound. Long term risk of CVD and stroke. Intervention Weight loss, low salt diet,pharmacotherapy.

65 Hyperlipidemia Diagnosis Etiology Screen all obese adolescents.Elevated LDL cholesterol, triglycerides and lowered HDL cholesterol . Component of the metabolic syndrome Etiology Increased central fat distribution Hyperinsulinemia

66 Hyperlipidemia Risk InterventionOverweight during adolescence associated with 2.4 fold increase in prevalence of cholesterol >240mg/dl, 3 fold increase in LDL values >160mg/dl and 8 fold increase in HDL values<35 mg/dl in adults years. Srinivasan Metab 1996;45: Intervention Weight loss

67 Psychological MorbidityObesity Associated Psychological Conditions Depression Anxiety Low self esteem Teasing/Bullying Associated conditions impacting treatment ADHD Bipolar Illness Adjustment Disorder

68 Conclusion Every obese child should be evaluated for the co morbid conditions of obesity. Obesity related comorbidities can be improved with weight loss. Reducing morbidity should be a primary goal of obesity therapy.