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A Child With Metabolic Syndrome and Diabetes: Management Strategy

A Child With Metabolic Syndrome and Diabetes: Management Strategy. By Kulkanya Chokephaibukit , MD Professor of Pediatrics Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand. 7 th IAS 2013, KL, Malaysia, 30 June-3 July 2013.

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A Child With Metabolic Syndrome and Diabetes: Management Strategy

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  1. A Child With Metabolic Syndrome and Diabetes: Management Strategy By KulkanyaChokephaibukit, MD Professor of Pediatrics Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand 7th IAS 2013, KL, Malaysia, 30 June-3 July 2013. Session TUWS05: Optimizing pediatric treatment strategies: Case study for the clinicians

  2. Disclosure No conflict of interest

  3. Scope of discussion • Clinical picture of metabolic complications in HIV-infected children and adolescents receiving ART • How to make diagnosis of insulin resistance, diabetes, and metabolic syndrome • How to manage metabolic complications of children/adolescents with HIV infection receiving ART

  4. Metabolic Complications of HIV Infection and Its Therapy • HIV/HAART-associated lipodystrophy syndrome • Insulin resistance and glucose homeostasis abnormalities • Dyslipidemia • Metabolic syndrome

  5. Let’s start when he was 9 A 9 year-old boy with perinatal HIV Chief Complaint: Hyperpigmentation of neck and armpit for 2 years History: • Maternal HIV without perinatal treatment • Diagnosis of HIV infection by serology at 18 month-old , CD4: 256 cell/mm3(12.39%) • He was started on AZT+3TC (in 1998), then changed to HAART • At 7 year-old, started to gain weight, very good appetite, and noticed hyperpigmentation Familial Hx: Mom died from AIDS. Live with grandparents, both hadDM

  6. The 9 year-old boy with dark neck for 2 years

  7. The 9 year-old boy with dark neck for 2 years

  8. The 9 year-old boy with dark neck Physical Examination: • Wt 46.9 kg (>P97), Ht 140.8 cm (P97), 146% Ideal BW, BMI 23.9 kg/m2, WC76.5 cm, HC 73.7 cm W/H ratio 1.04 • GA: loss of pad of fat/ lower limbs, dorsocervical hump • Chest: gynecomastia • GU: testes 5 cc, PH Tanner II • Normal findings for heart, lungs, abdomen, and neuro examinations

  9. hump Hyperpigmentation of the neck and armpits, dorsocervical hump

  10. What is your diagnosis of his skin hyperpigmentation? • A. genetic plus poor hygeine • B. Acanthosis nigricans

  11. What is the common condition associated with this skin hyperpigmentation? • A. Insulin resistance and diabetes • B. Dyslipidemia

  12. AcanthosisnigricansA clue for IR • Hyperpigmented velvety macules and patches and progress to palpable plaques. Mostly observed at the intertriginous areas of the axilla, groin, and posterior neck • Causes: - Obesity, particularly with darker skin color. Children BMI>98th tile have AN in 62%.1 - Diabetes and Insulin resistance.2 - Polycystic ovarian syndrome - Malignancy: adenocarcinomas of the GI tract (70-90%), and others 1.Krawczyk M. Pol Arch Med Wewn. Mar 2009;119(3):180-3. 2. Sadeghian G. J Dermatol. Apr 2009;36(4):209-12

  13. Problem Lists • Obesity • Acanthosisnigricans • Lipodystrophy (mild facial lipoatrophy) • FBS = 159mg/dl (Provisional DM) • Metabolic syndrome?

  14. Lipodystrophy in HIV-infected children • Incidence vary 10-50%1-4 due to lack of consensus for definition • Associated with PI and stavudine • PI: Predominate with truncal obesity, buffalo hump, and less periheral lipoatrophy • d4T: Predominate with facial, associated with HLA-B*40015 and Fas gene6 • Likely to appear in early adolescence1,7 1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004 3. Amaya RA. Pediatr Infect Dis J. 2002. 4. Sawawiboon N. Int J STD AIDS 2012, 5. Wangsomboonsiri W. CID 2010;50(4):597-604, 6. Likanonsakul S,AIDS Res Hum Retroviruses. 2012 Jul 9., 7.Alam NM. J Acquir Immune Defic Syndr. 2012; 59(3): 314–324

  15. Characteristics of Lipodystrophy from Protease Inhibitors • Fat gain on abdomen, breast, and dorsocervical hump • Fat loss from peripheral extremities • Fat gain in visceral organs

  16. Lipodystrophy from d4T Facial and peripheral lipoatrophy following >6 months of stavudine treatment, found in 38% of d4T Rx, occur around early adolescence Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

  17. Body fat abnormality in HIV-infected children and adolescents: The difference of regions StudyPopulation Lipoatrophy 23% Lipohypertrophy or combine 2.5%% No fat maldistribution 75% Europe (N= 426, LD = 42% Receiving PI 60%, Received d4T 10% Thailand, N=202, LD = 25% Receiving PI 41%, Received d4T 60% Alam NM. J Acquir Immune Defic Syndr. 2012 March 1; 59(3): 314–324 Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

  18. Facial lipoatrophy Is it reversible? Facial Lipoatrophy may improve after stopping d4T Improvement found in 23%, at mean duration of 45 months after stopping d4T, around early adolescence Need to stop d4T before reaching adolescence Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

  19. What about impair FBS (FBS=159)? Need to diagnose and treat impair FBS and DM What would you do? A. Perform OGTT B. It’s mostly transient, repeat FBS in 6 months

  20. Interpretation of Fasting Blood Sugar Normal FBS Provisional DM Impaired FBS FBS 100 mg/dl 126 mg/dl

  21. Oral Glucose Challenge Test: Must be done in all cases of impair FBS Normal OGTT Provisional DM Impaired OGTT 2 hr PG 140 mg/dl 200 mg/dl

  22. Why do we need to worry about DM? • A lot of treatment and complication of DM to follow, interrupt normal life • DM increased risk of ART associated CVD • Early intervention (exercise and metformin) may prevent or delayed DM and complications

  23. Diagnosis of Diabetes Mellitus • Symptoms of DM plus casual BG ≥200 mg/dL (polyuria, polydipsia, and unexplained weight loss) or • FBS ≥126 mg/dL or • 2-hr BS ≥200 mg/dL during an OGTT or • HbA1C ≥ 6.5% • Pre-diabetes • Impaired FBS 100-125 mg/dL • Impaired OGTT: 2 hr glucose 140-199 mg/dL • HbA1c 5.7-6.4% American Diabetes Association. Diabetes Care 2010

  24. 9 yo. boy with acanthosis nigricans Oral Glucose Tolerance Test Diagnosis: Impaired OGTT with hyperinsulinemia>>Pre-diabetes Normal fasting lipid profile

  25. Insulin Resistance and Type 2 Diabetes in HIV-Infected Children • Prevalence in adults 10-20% • Increase prevalence in patients receiving HAART with lipodystrophy1 • Incidence in children is much lower • However, 19% of children receiving PI had impair OGTT2 • 1.Vigouroux C. Diabetes & Metabolism 1999 • 2. Bitnun A. J Clin Endocrinol Metab 2005

  26. Classical T2DM risk factors Obesity (abdominal) Physical inactivity Genetic Family history Race Older age Dyslipidemia HIV-associated risk factors Peripheral lipoatrophy Increased liver or muscle fat Inflammatory cytokines Low testosterone Oxidant stress HCV infection PIs therapy Insulin Resistance and HIV

  27. How can we prevent DM in this patient? A. Diet and exercise B. Diet and exercise and metformin

  28. 3234 patients with IFG or IGT Treatment; placebo, metformin, lifestyle-modification program Lifestyle-modification program: 7% weight loss and 150 mins of physical activity per week Average follow-up was 2.8 yr Exercise and Metformin can prevent DM Reduction in the Incidence of T2 DM with Lifestyle Intervention or Metformin Diabetes Prevention Program. N Engl J Med 2002:346:393-403

  29. Exercise and Metformin can prevent DM At 3 years 28.9% 21.7% 14.4% Lifestyle gr.: reduced the risk of converting to DM by 58% Metformin gr.: reduced the risk of converting to DM by 31% Incidence of DM in lifestyle gr.: 39% lower than metformin gr. Diabetes Prevention Program. N Engl J Med 2002:346:393-403

  30. Drugs that may delay or prevent the development of Type2 DM None is approved in children • Troglitazone (TRIPOD) (withdrawn due to rare hepatitis) Hispanic women with GDM  56% risk reduction Buchanan TA et al. Diabetes 2002 • Acarbose (STOPP-NIDDM) Subject with IGT 32% decreased conversion to T2DM Chiasson JL et al. JAMA 2003 • Xenical (XENDOS) Subject with BMI >29, lifestyle plus xenical vs placebo  37% risk reduction Torgerson JS et al. Diabetes care 2004

  31. A 9 Year-Old Boy with Perinatal HIV and Insulin-Resistance • Treatment: Metformin (500) 1 tab oral bid Encourage healthy life style, exercise Continue ART: AZT/3TC/LPV/r • Outcomes: 4 mo after treatment • Wt 44.4 kg (-2 kg), • Ht 142 cm, BMI 22 kg/m2 (-1.9) • WC 76.2 cm (-0.3 cm)

  32. After 4 months of Metformin Rx and exercise: Improved hyperinsulinemia and BS OGTT 8/11/06 OGTT 12/1/07

  33. 6 Months later…He developed hyperlipidemia Fasting lipid profile

  34. NCEP Definition for Dyslipidemia in Children and Adults TG was not established by NCEP; a TG level of 125 mg/dL approximates the mean 95th percentile for TGs in boys and girls during childhood and adolescence.

  35. Why do we need to care about dyslipidemia? Should we just leave it for the adult doctors to take care of the business when the child grown-up! • It is an important risk factor for CVD in adults • Atherosclerosis starts in childhood, esp. if TC>200 and LDL-C >130 mg/dl • Very common, found 60%-80% in children receiving HAART, particularly PI1-3, found more in patients with lipodystrophy • Some PI cause less dyslipidemia: ATV, DRV 1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002

  36. Metabolic complications: >>Start from lipodystrophy, >>dyslipidemia, insulin resistance End up with cardiovascular diseases, stroke, DM

  37. Dyslipidemia found 40%-80% in children, associated with receiving PIand lipodystrophy1-3 Prevalence of Dyslipidemia in a European cohort of HIV-infected children and adolescents (N=426), 60% receiving PI4 Fasting Hypertriglyceridemia 66% Hyper-cholesterolemia 49% 45% 21% 28% 1% Glucose intolerance 5% 4% 1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002, 4. Alam NM. J Acquir Immune DeficSyndr. 2012 March 1; 59(3): 314–324

  38. Frequency of abnormal lipid profile in Thai adolescentsSiriraj, Bangkok, 2013 49% receiving PI V. Poomlek. 7th IAS 2013, KL, MOPE047

  39. Risk of Myocardial Infarction in Patients Exposed to Specific Individual Antiretroviral Drugs : The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Worm SW. JID 2010;201:318-30.

  40. What else can we do other than even more encouraging lifestyle modification? • A: Change ARV • B: Start statin

  41. Treatment of dyslipidemia in children • Exercise at least 1 hr per day • Modified diet (<30% total fat and <7% of sat fat, <200 mg of cholesterol/day) • Statin only in those with persistent TC>200 mg/dl and LDL-C >130 mg/dl, not for < 8 yo, unknown long-term effect. • Fibrate for hypertriglyceridemia (>400 mg/dl) • ARV modification • Intervention in this patient: • Educate for life style modification: Low fat diet and exercise • Change LPV/r to ATV/r

  42. Lipid Changes at Week 48 with Baseline in PI Studies

  43. He started to be uneasy to take ARV **Once daily regimen Fasting Blood Sugar : 138mg/dl Cholesterol 155 mg/dl Triglyceride 159 mg/dl LDL 74 mg/dl HDL 50 mg/dl

  44. Diet education for dyslipidemia High Cholesterol Diet High Triglyceride Diet

  45. Diabetic diet education

  46. 5 Years after starting treatment And became a teenager He becomes an uneasy adolescent and start to have poor compliance to metformin and diet and weight control - He continue to gain more weight BP: 130/90 mmHg TG = 202 mg/dl, HDL 52 mg/dl, Cholesterol 224 mg/dL Follow-up • FBS 400 mg/dl • HbA1C 13.8 % Dx: DM Start Insulin SC Does he meet the criteria for metabolic syndrome? …..Yes or No

  47. Metabolic Syndrome A Cluster of • Abdominal obesity • Increased triglyceride levels • Decreased HDL-cholesterol levels • Hyperglycemia • Hypertension A meta-analysis of the prospective studies has shown that the presence of metabolic syndrome increases the risk of Type2 DM and CVD Galassi A. Am J Med. 2006

  48. Metabolic Syndrome in children and adolescents: The clusters of metabolic risk factors (International Diabetes Federation) Presence of metabolic syndrome increases risk of -CVD (RR 1.53; 1.26-1.87) -CHD(RR 1.52; 1.37-1.69) -Stroke (RR 1.76; 1.37-2.25). Galassi A. Am J Med 2006;119:812-9

  49. Criteria Dx Metabolic syndromein this patient • BW > P97 • Triglyceride > 150 mg/dl • FBS > 100 mg/dl • BP 120/80-128/80 mmHg • HDL 45-50 mg/dl

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