Obesity

1
Obesity

• Sandra G. Hassink, MD, FAAP
• Director of the Weight Management Clinic
• A.I. Dupont Hospital for Children
• Wilmington, DE
• Assistant Professor of Pediatrics
• Thomas Jefferson University
• Philadelphia, PA

2
Adipose Tissue Growth Trajectory
50 weight
3
Obesity

• Excess adipose tissue
• Research
• Densitometry (Underwater weighing)
• DEXA
• CT/MRI
• Clinical
• Anthropometry
• Bioelectrical impedance
• BMI

4
(No Transcript)
5
Adipose Tissue

• White adipose tissue
• Adipocytes
• Multipotent stem cells which can differentiate
  into
• Muscle
• Cartilage
• Adipose Tissue
• Bone
• Macrophages
• Progressive infiltration with degree of obesity
• Endothelial/Vascular tissue

6
White adipose tissue
7
Adipose Tissue

• Metabolically Active Organ System.
• Adipocytes
• Storage of fuel
• Cytokine production
• Hormonal regulation
• Energy regulation at the level of the CNS and
  periphery.

8
Adipose Tissue

• Leptin
• Adiponectin
• Angiotensinogen
• Resistin
• Acylation stimulating protein
• Retinol binding protein
• Tumor necrosis factor alpha
• Interleukin 6
• Plasminogen activator inhibitor 1

9
Leptin

• Cytokine product of Lep(ob) gene
• Produced in white adipose tissue
• Also brown adipose tissue, stomach, placenta,
  mammary gland, ovarian follicles, fetal organs
• Leptin receptors found in most tissues
• Hypothalamic nuclei involved in energy regulation
  are a major target

10
Hypothalamus

Neuropeptide-Y
Leptin

• Decreases Hunger
• Increases Activity
• Increases
• Thermogenesis

Adipocyte
11
Hypothalamus- Energy Regulation and Obesity
Input from Lateral Hypothalamus (hunger)
Feeding behavior
Energy stores
DMN
PVN

Sympathetic regulation
ARC
VMN
Vagal Regulation of Insulin Secretion
Energy stores
Autonomic regulation of leptin secretion from fat
12
Adipose Tissue Function

• Cytokine production
• TNF alpha- alters insulin signaling, increasing
  insulin resistance
• IL-6 increases acute phase proteins (CRP)
• Adiponectin modulation of endothelial adhesion
  molecules and inhibit inflammatory responses.
• Resistin effects on insulin resistance

13
Obesity-Inflammation

• Macrophages migrate into adipose tissue
• Adipocyte secreted TNF alpha stimulates
  preadipocytes/endothelial cells to produce
  monocyte chemoattractant protein- 1
• Increased leptin, decreased adiponectin
  stimulates transport of macrophages to adipose
  tissue .
• Kathryn E. Wellen and Gökhan S. Hotamisligil
  Obesity-induced inflammatory changes in adipose
  tissue
• J. Clin. Invest. 1121785-1788 (2003).

14
Complex

• Gene Environment Interaction
• Genetic Predisposition
• Parental obesity
• Risk for co morbidity
• Environmental interaction
• Intrauterine environment
• Periods of critical growth
• Nutritional Genomics

15
Multisystem

• Effects on all major organ systems
• Skeletal
• Muscular
• Endocrine
• Gastrointestinal
• Reproductive
• Cardiovascular
• Pulmonary

16
Pathologic

• Results in earlier onset of adult disease
• Type II diabetes
• Results in end stage disease
• NASH
• Provides new explanations for old disease
• Sleep apnea syndrome

17
Individual

• Obese children and adolescents have their unique
  weight gain trajectory, genetic predisposition
  and co morbidities
• Obese children and adolescents also have unique
  family situations, psychological needs and
  community settings.

18
(No Transcript)
19
Obese children

• Patient A
• Morbidly obese parent, issues of satiety and
  sneaking food, OSA on BiPAP, ankle pathology.
• Patient C
• Type 2 diabetes in both parents, loss of father,
  NASH, type 2 diabetes age 12
• Patient B
• Problems with peers at school, mild elevation of
  cholesterol

20
Severe Obesity Related Emergencies

• Hyperglycemic Hyperosmolar state
• DKA
• Pulmonary emboli
• Cardiomyopathy of obesity

21
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) 270-3.
• Seven obese African American youth were
  considered to have died from diabetic
  ketoacidosis.

22
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.

23
Hyperglycemic Hyperosmolar State

• Patients 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.

24
Hyperglycemic Hyperosmolar State

• HHS- diagnostic criteria
• plasma glucose gt 600mg/dl
• serum CO2 gt 15 mmol/l
• small ketonuria
• no or small ketonemia
• effective serum osmolality gt320 mOsm/kg
• stupor or coma
• Rubin HM J Pediatr 19697477-86
• Morales A J Pediatr 2004 Feb, 270-273

25
Diabetic Ketoacidosis

• Type 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.

26
Diabetic Ketoacidosis
Hyperglycemia
Beta Cell Toxicity
Insulin resistance 2o obesity

Insulin secretion

Relative Insulin Deficiency
Ketonemia
Free Fatty Acids
Lipolysis
Ketonuria
27
Pulmonary Embolism

• Symptoms
• Dyspnea
• Chest pain
• Hypoxia
• Hemoptysis
• Surgery, trauma

28
Pulmonary Embolism

• Has been reported in adolescence
• Sugerman HJ, Sugerman EL, DeMaria EJ, Kellum JM,
  Kennedy C, Mowery Y, Wolfe LG. J Gastrointest
  Surg. 2003 Jan 7(1)102-07
• Risk factors
• Obesity
• Obesity hypoventilation syndrome/OSAS
• Coagulation disorder (i.e. Leiden V)

29
Cardiomyopathy of Obesity

• High 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)225-36.

30
(No Transcript)
31
Co-morbidity's Requiring Immediate Attention

• Pseudotumor Cerebri
• Slipped Capital Femoral Epiphysis
• Blounts Disease
• Sleep Apnea
• Non alcoholic hepatosteatosis
• Cholelithiasis

32
Pseudotumor Cerebri

• Definition.
• Raised intracranial pressure with papilledema and
  a normal cerebrospinal fluid in the absence of
  ventricular enlargement.

33
John A Moran Eye Center, Salt Lake City UT
34
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 199237(3)155-66.
• Papilledema is part of pathology but may not
  occur on presentation.

35
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 1985103(11)1681-6.
• Increased intracranial pressure may lead to
  visual impairment or blindness.

36
Pseudotumor Cerebri

• Risk.
• Obesity occurs in 30-80 of affected children.
• Scott Am J Opth 1997 124253-255
• 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 199237(3)155-66.

37
Drugs Associated With Pseudotumor Cerebri

• Growth hormone therapy
• Nalidixic acid,Ciprofloxacin,Tetracycline therapy
  
• No clear dose-response relationship
• Lessell S. Surv Ophthalmol 199237(3)155-66.
• Vitamin A and isoretinoin therapy are
  established causes of pseudotumor cerebri.
• Morrice G Jr, Havener WH, Kapetansky F. JAMA
  19601731802-5.
• Roytman M, Frumkin A, Bohn TG. Cutis
  198842(5)399-400.

38
Treatment

• Acetazolamide.
• Lumboperitoneal shunt (in severe cases),
• Weight loss.
• Newborg B. Arch Intern Med 1974133(5)802-7.

39
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.

40
Slipped Capital Femoral Epiphysis

• Diagnosis
• Suspect and immediately evaluate in an obese
  patient who presents with limp.
• 50-70 patients with SCFE are obese.
• Wilcox J Pediatr Orthop 19888196-200.
• Can also present with complaints of groin, thigh,
  or knee pain referred by sensory cutaneous nerves
  passing close to the hip capsule.

41
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
  198718(4)637-47.
• .

42
Slipped Capital Femoral Epiphysis

• Diagnosis
• 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.

43
(No Transcript)
44
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 200114(6)729-34.

45
SCFE - Associated Causes

• Continued weight gain.
• Renal failure.
• History of radiation therapy.
• Primary hypothyroidism.
• Loder RT, Greenfield ML.. J Pediatr Orthop .
  200121(4)481-7.
• Gonadotropin-releasing hormone agonists.
• Growth hormone therapy.
• Kempers MJ, Noordam C, Rouwe CW, Otten BJ. J
  Pediatr Endocrinol Metab 200114(6)729-34.
• Grumbach MM, Bin-Abbas BS, Kaplan SL. Horm Res
  199849(Suppl 2)41-57.

46
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.

47
SCFE prevalence

• In Japan- 1997-1999 Annual incidence estimated
  as 2.22 for boys and 0.76 for girls /100,000
  10-14 year olds. (5x higher than 1976 estimates)
• Noguchi Y, Sakamaki T Multicenter Study
  Committee of the Jananese Pediatric Orthopaedic
  Association Epidemiology and demographics of
  slipped captialfemoral epiphysis in Japan a
  multicenter study by the Japanese Paediatric
  Orthopaedic Association J Orthop Sci 2002 7(6)
  610-617

48
Blounts Disease - Obesity Related Orthopedic
Morbidity

• Diagnosis
• 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 Blounts disease may be
  obese.
• Dietz J Pediatr 1982101735-737.
• Treatment
• Requires evaluation and correction by orthopedic
  surgeon.
• Weight loss

49
Obstructive Sleep Apnea- Definition

• OSAS 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 2002109(4)e69-79.

50
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 1998102(3 Pt
  1)616-20.

51
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
  199316(2)124-9.
• Elevated insulin
• de la Eva RC, Baur LA, Donaghue KC, Waters KA.. J
  Pediatr 2002140(6)654-9.

52
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
  2002109(4)704-12.
• Severity of obstruction may not correlate with
  either degree of obesity or severity of sleep
  symptoms.

53
OSAS

• Abnormal sleep patterns reported in 94 of obese
  children studied.
• Massumi RA, Sarin RK, Pooya M, Reichelderfer Dis
  Chest 196955(2)110-4. 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 198912(5)430-8.
• 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 198912(5)430-8.

54
Obstructive Sleep Apnea- Risk

• Children with sleep apnea demonstrate significant
  decreases in learning and memory.
• Rhodes J Pediatr 1995127741-744.
• Deficits in attention, motor efficiency and
  graphomotor ability.
• Greenberg GD, Watson RK, Deptula D.. Sleep
  198710(3)254-62.
• Pulmonary hypertension,systemic hypertension,
  right heart failure.
• .Tal A, Leiberman A, Margulis G, Sofer S. Pediatr
  Pulmonol 19884(3)139-43.
• Marcus CL, Greene MG, Carroll JL. Am J Respir
  Crit Care Med 1998157(4 Pt 1)1098-103.
• Massumi RA, Sarin RK, Pooya M, Reichelderfer Dis
  Chest 196955(2)110-4.
• Weight gt200 above ideal had oxygen saturation
  lt90 for half to total sleep time.
• 40 of severely obese children demonstrated
  central hypoventilation.
• Silvesti Pediar Pulmonol 199316124-139.

55
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 1998101(1 Pt 1)61-7.
• Tonsilladenoidectomy, if indicated
• Continuous positive airway pressure (CPAP) or
  bilevel positive airway pressure (BPAP).

56
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.

57
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 livera
  molecular overview. Semin Gastrointest Dis
  200213(1) 3-16.

58
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 199786238-241.

59
NAFLD to NASH
Obesity
Fatty Liver
Genetic Predisposition
2nd Hit
Inflammation
Fibrosis
Cirrhosis

• Day CP, James OF. Gastroenterology
  1998114(4)842-5.

60
(No Transcript)
61
Nonalcoholic fatty liver disease

• In Japan NALFD prevalence of 2.6 has been
  reported
• Tominaga K, Kurata JH, Chen YK, Fujimoto E,
  Miyagawa S, Abe I, Kusano Y. Prevalence of fatty
  liver in Japanese children and relationship to
  obesity an epidemiological ultrasonographic
  survey. Dig Dis Sci 1995 40 20022009.,
• Which rises to 52.8 in obese children  
• Franzese A, Vajro P, Argenziano A, Puzziello A,
  Iannucci MP, Saviano MC, Brunetti M, Rubino A.
  Liver involvement in obese children.
  Ultrasonography and liver enzyme levels at
  diagnosing and during follow-up in an Italian
  population. Dig Dis Sci 1997 42 14381442.

62
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 199930(6)1356-62.

63
NASH risk

• A liver NAFLD runs a higher risk of being
  damaged by other factors, from viruses to
  endotoxins, from alcohol to industrial toxic
  compounds
• Yang SO, Lin HZ, Lane MD, Clemens M, Diehl AM.
  Obesity increases sensitivity to endotoxin liver
  injury implications for the pathogenesis of
  steatohepatitis. Proc Natl Acd Sci USA 1997 94
  25572562

64
NASH risk

• Predictors of elevated serum ALT
• Male gender
• Hispanic ethnicity
• Elevated BMI
• Schwimmer JB, McGreal N,Deutsch R, Finegold MJ,
  Lavine JE. Influence of gender, race, and
  ethnicity on suspected fatty liver in obese
  adolescents. Pediatrics. 115(5)e561-5, 2005 May.

65
NASH risk

• Predictors of fibrosis
• Obesity (BMI z score)
• Insulin resistance
• Leptin (?)
• Schwimmer, Jeffrey B. MD Deutsch, Reena
  PhDRauch, Jeffrey B. BA Behling, Cynthia
  MDNewbury, Robert MD Lavine, Joel E. MD,
  PhDObesity, insulin resistance, and other
  clinicopathological correlates of pediatric
  nonalcoholic fatty liver disease.J Pedia
  143(4), October 2003, pp 500-505

66
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 1994125(2)239-41.

67
NASH - Treatment

• Metformin normalizes liver enzymes in 40-50 of
  children with biopsy proven NASH.
• Reduction in heapatosteatosis by 23-30
• Improved insulin sensitivity
• Schwimmer JB,Middleton MS, Deutsch R, Lavine JE A
  phase 2 clinical trial of metformin as a
  treatment for non-diabetic paediatric
  non-alcoholic steatohepatitis Alimentary
  Pharmacology Therapeutics. 21(7)871-9, 2005
  Apr 1.

68
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
  200213(1)17-30.

69
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.

70
Cholelithiasis- Obesity Related Gastrointestinal
Morbidity

• Diagnosis
• Abdominal pain, tenderness .
• Ultrasound, laboratory studies.
• Etiology
• Obesity accounts for 8-33 of gallstones in
  children.
• Friesen Clin Pediatr 1989.7294.
• May be associated with weight loss.
• Crichlow Dig Dis. 19721768-72.

71
Cholelithiasis- Obesity Related Gastrointestinal
Morbidity

• Risk
• 50 of cholecystitis in adolescents associated
  with obesity.
• Crichlow Dig Dis. 19721768-72.
• Relative risk of gallstones in adolescent girls
  with obesity is 4.2.
• Honore Arch Surg 198011562-64.
• Surgical Intervention

72
Chronic - Obesity Related Co Morbid Conditions

• Insulin Resistance (Metabolic Syndrome)
• Type II Diabetes
• Polycystic Ovary Syndrome
• Hypertension
• Hyperlipidemia
• Psychological

73

Obesity
Insulin Resistance
Metabolic Syndrome
Type 2DM
Hypertension
NASH
Dyslipidemia
PCOS
74
Insulin Resistance

• Insulin mediated glucose disposal by muscle
  varies almost 10 fold in healthy individuals.
• The more insulin sensitive the muscle the less
  insulin needs to be secreted to maintain normal
  glucose homeostasis.
• The more insulin resistant an individual and the
  greater the degree of compensatory
  hyperinsulinemia the more likely they are to
  develop disease.

75
Central Nervous System and Insulin

• Energy regulation and control of Insulin are also
  CNS phenomenon
• CNS integrates afferent signals regarding energy
  intake
• Normally the CNS exerts an inhibitory effect on
  insulin secretion
• Obesity can result from neuroendocrine pathology

76
Obesity and Insulin Resistanceat the level of
the adipocyte

• Adipose tissue in obesity becomes refractory to
  insulins suppression of fat mobilization
• Insulin resistance increases release of Free
  Fatty Acids from adipocytes.
• Elevated FFA concentrations are linked with the
  onset of peripheral muscle and hepatic insulin
  resistance.
• Therefore in the postprandial period there is an
  excess of circulating lipid metabolites and leads
  to fat deposition in other tissues.

77
Insulin Resistance and the Liver

• Hyperinsulinemia stimulates fatty acid synthesis
  while inhibiting the oxidation of fatty acids.
• Elevated insulin may increase the degradation of
  apolipoprotien B100 (a component of VLDL,
  compromising triglycerides transport out of the
  liver.
• Net accumulation of fat

78
Muscle and insulin resistance

• Elevated FFA and accumulated triacylglycerol
  appear to inhibit insulin signaling, leading to a
  reduction in insulin-stimulated muscle glucose
  transport.
• The resulting suppression of muscle glucose
  transport leads to reduced muscle glycogen
  synthesis and glycolysis.

79
Components of the Metabolic Syndrome in
Childhood

• Abnormal blood lipids (HDL cholesterol lt40mg/dl
  or triglycerides gt150mg/dl LDLgt130mg/dl).
• Impaired glucose tolerance (fasting glucose gt 100
  (110) mg/dl, random glucose gt200mg/dl).
• Sinaiko AR, Donahue RP, Jacobs DR, et al. The
  Minneapolis Childrens Blood Pressure Study.
  Circulation 199999(11)1471-6.

80
Components of the Metabolic Syndrome
in Childhood

• Obesity (BMI gt95 for age and sex)
• Elevated blood pressure (SBP or DBP gt 90 for
  age).

81
Impaired glucose tolerance

• Increased incidence of impaired glucose tolerance
  in obesity clinic population
• 25 of obese children (aged 4-10yrs)
• 21 of obese adolescents (aged11-18 yrs)
• Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas
  B, Allen K, Savoye M, Rieger V, Taksali S,
  Barbetta G, Sherwin RS, Caprio S Prevalence of
  impaired glucose tolerance among children and
  adolescents with marked obesity. N Engl J Med
  346802810, 2002

82
Acanthosis Nigricans
Dr. George Datto
83
Acanthosis Nigricans

• Skin lesion characterized by hyperpigmentation
  and velvety thickening that occurs in neck,
  axilla, and other skin folds
• In pediatrics, seen most commonly in obese
  children. Also seen in malignancies and other
  insulin resistant syndromes.
• Obese pediatric pts with acanthosis have higher
  fasting insulin and lower insulin sensitivity
  than acanthosis negative obese patients
• Insulin resistant pts were more likely to be
  obese (88) than have acanthosis (65)
• Yanovski et al, Journal of Peds 2001

84
Diabetes - Diagnosis

• Symptoms of diabetes plus random plasma glucose
  gt200mg/dl (11.1mmol/l) or
• Fasting plasma glucose gt126 mg/dl (7.0 mmol/l) or
• 2 hour plasma glucose gt200 mg/dl during an oral
  glucose tolerance test
• American Diabetes Association Consensus Statement
  Type 2 Diabetes in Children and Adolescents
  Diabetes Care 200023(3) 381-389.

85
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
  10-19 years had NIDDM.
• Pinhas-Hamiel J Pediatr 1996128608-615.

86
Type 2 Diabetes - One End of the Continuum
Genetic Predisposition
Environmental Trigger
Obesity
Beta
Hyperglycemia
Cell
Dysfunction
Insulin Resistance
Type 2 Diabetes
87
Pathologic Defect in Type 2 DM

• Excessive 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

88
Type 2 Diabetes - Risk

• Lifetime risk of diabetes for individuals born in
  2000
• 1 in 3 for males
• 2 in 5 for females
• Narayan KM, Boyle JP, Thompson TJ, Sorensen SW,
  Williamson DF Lifetime risk for diabetes
  mellitus in the United States. JAMA290 1884
  1890,2003

89
Type 2 Diabetes - Risk factors

• Obesity 85 overweight or obese on diagnosis
• American Diabetes Association Type 2 diabetes in
  children and adolescents (Consensus Statement).
  Diabetes Care 23381389, 2000).
• 65 of children with type 2 diabetes have first
  degree relative with Type 2 diabetes
• Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford
  D, Khoury PR, Zeitler P. Increased incidence of
  non-insulin-dependent diabetes mellitus among
  adolescents. J Pediatr.1996 128 608 615
• 74-100 have first or second degree relative
  with type 2 diabetes
• American Diabetes Association Type 2 diabetes in
  children and adolescents (Consensus Statement).
  Diabetes Care 23381389, 2000).

90
Type 2 Diabetes Risk factors

• African American, Hispanic, Asian, Native
  American descent
• American Diabetes Association Consensus Statement
  Type 2 Diabetes in Children and Adolescents
  Diabetes Care 200023(3) 381-389.
• Increased insulin resistance (puberty,ethnicity,
  inactivity,visceral fat distribution,PCOS)
• American Diabetes Association Consensus Statement
  Type 2 Diabetes in Children and Adolescents
  Diabetes Care 200023(3) 381-389.
• Female/male 1.71
• Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford
  D, Khoury PR, Zeitler P. Increased incidence of
  non-insulin-dependent diabetes mellitus among
  adolescents. J Pediatr.1996 128 608 615

91
Type 2 Diabetes Risk factors

• Maternal diabetes or impaired glucose tolerance
  during gestation
• Gungor N, Arslanian S Pathophysiology of type 2
  diabetes in children and adolescents treatment
  implications.Treatments in Endocrinology
  20021(6)359-371.

92
Type 2 Diabetes- Prevalence

• 4.1/100,000 for all 15-19 year old American
  Indians up to 50.9/100,000 for 15-19 yr old Pima
  Indian
• Fagot-Campagna A, Pettitt DJ, Engelgau MM, Ríos
  Burrows N, Geiss LS, Valdez R, et al. Type
  2 diabetes among North American children and
  adolescents an epidemiological review and a
  public health perspective. J Pediatr 2000 136
  664-672
• Estimated incidence of type 2 diabetes
  7.2/100,000/yr (Ohio 1994)
• 10 fold increase from 1982-1994
• Pinhas-Hamiel O, Dolan LM, Daniels SR,
  Standiford D, Khoury PR, Zeitler P. Increased
  incidence of non-insulin-dependent diabetes
  mellitus among adolescents. J Pediatr.1996 128
  608 615

93
Type 2 Diabetes

• Worldwide incidence has tripled since 1985
• Bloomgarden ZT, Type 2 diabetes in the Young, the
  evolving epidemic Diabetes Care 27998-1010,
  2004..

94
Type 2 Diabetes Associated findings

• Polycystic ovarian syndrome
• Acanthosis nigricans
• Dyslipidemia
• Hypertension

95
Polycystic Ovarian Syndrome

• Polycystic 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

96
PCOS

• Prevalence of 6.6 (26/400) in unselected female
  population.
• Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer
  ES, Yildiz BO The prevalence and features of the
  polycystic ovary syndrome in an unselected
  population.Journal of Clinical Endocrinology and
  Metabolism 89(6)2745-27492004

97
Hypertension

• Etiology
• 60 of children with persistently elevated blood
  pressure had weight gt120.
• Lauer J Pediatr 197586697-706.
• 20-30 of obese children have elevated blood
  pressure.

98
Hypertension

• Risk
• Overweight adolescents have 8.5 fold risk of
  hypertension as adults.
• Srinivasan Metab 199645235-240.
• Cardiac hypertrophy/LVH on ultrasound.
• Long term risk of CVD and stroke.
• Intervention
• Weight loss, low salt diet,pharmacotherapy.

99
Hyperlipidemia

• Diagnosis
• Elevated LDL cholesterol, triglycerides and
  lowered HDL cholesterol .
• Component of the metabolic syndrome
• Etiology
• Increased central fat distribution
• Hyperinsulinemia

100
Hyperlipidemia

• Risk
• Overweight adolescents
• 2.4 fold increase in prevalence of cholesterol
  gt240mg/dl
• 3 fold increase in LDL values gt160mg/dl
• 8 fold increase in HDL valueslt35 mg/dl as adults
  27-31 years.
• Srinivasan Metab 199645235-240

101
Psychological Morbidity

• Obesity Associated Psychological Conditions
• Depression
• Anxiety
• Low self esteem
• Teasing/Bullying
• Binge eating disorder

102
Psychological Morbidity

• Additional psychological conditions with may
  impact treatment
• ADHD/ADD
• Bipolar Illness
• Adjustment Disorder
• Oppositional Defiant Disorder

103
Depression and Obesity

• In adolescents 7-12 grade depressed mood
  predicted follow-up obesity
• Baseline obesity did not predict follow-up
  depression
• Data from the National Longitudinal Study of
  Adolescent Health (Add Health), a nationally
  representative, comprehensive, school-based study
  of youth in grades 7 to 12
• Elizabeth Goodman, MD, and Robert C. Whitaker,
  MD, MPH, A Prospective Study of the Role of
  Depression in the Development and Persistence of
  Adolescent Obesity PEDIATRICS Vol. 110 No. 3
  September 2002, pp. 497-504

104
Obesity Trajectory and Depression/ODD

• Chronically obese children had significantly
  higher rates of oppositional defiant disorder,
  and (for boys) depression.
• No difference among groups in gender, family
  structure, parenting style, family history of
  mental illness, drug abuse, crime, or traumatic
  events.
• Chronic and childhood obesity were associated
  with having uneducated parents and low family
  income.
• Study of children over a 4 year period in
  Appalachia
• Sarah Mustillo, PhD, Carol Worthman, PhD,
  Alaattin Erkanli, PhD, Gordon Keeler, MS,
  Adrian Angold, MRCPsych and E. Jane Costello,
  PhD Obesity and Psychiatric Disorder
  Developmental Trajectories PEDIATRICS Vol. 111
  No. 4 April 2003, pp. 851-859

105
Health related quality of life

• Obese children and adolescents likelihood of
  having impaired health related quality of life
  5.5 greater than healthy child/adolescent
• Reported lower pediatric health related quality
  of life cores in all domains, physical,
  psychosocial, emotional, social, and school
  functioning than healthy children and
  adolescents
• Parents scores were even lower than children's

106
Health related quality of life

• Obese children and adolescents with OSA reported
  lower quality of life scores than other obese
  children
• Health-related QOL did not vary by age, sex, SES,
  or race
• BMI z score among obese children and adolescents
  was inversely correlated with physical
  functioning.
• Schwimmer JB,Burwinkle T, Varni JW.Health-Related
  Quality of Life of Severely Obese Children and
  Adolescents JAMA. 20032891813-1819.

107
Obesity in children and adolescents

• Unique
• Complex
• Pathologic
• Multifactorial
• Complex