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20091219 S Chan-Cua Diabetes Mellitus in the Pediatric Population Sioksoan Chan-Cua, MD Pediatric Endocrinologist.

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Presentation on theme: "20091219 S Chan-Cua Diabetes Mellitus in the Pediatric Population Sioksoan Chan-Cua, MD Pediatric Endocrinologist."— Presentation transcript:

1 S Chan-Cua Diabetes Mellitus in the Pediatric Population Sioksoan Chan-Cua, MD Pediatric Endocrinologist

2 S Chan-Cua Diabetes Mellitus in the Pediatric Population Diagnosis Types and Pathophysiology Clinical Presentation Management Acute complications

3 S Chan-Cua Diabetes Mellitus (DM) A heterogeneous group of disorders –Insulin production and/or insulin action  hyperglycemia

4 S Chan-Cua Diagnosis of DM Diseases of abnormal carbohydrate metabolism 1.FPG 126 mg/dl (7.0 mmol/l) 2.RBS 200 mg/dl (11.1 mmol/l) & symptoms of DM 3.2-h plasma glucose 200mg/dl (11.1mmol/l) during an OGTT

5 S Chan-Cua Polyuria, polydipsia, polyphagia and unexplained weight loss Clinical Presentation

6 S Chan-Cua Clinical Presentations of DM Non-emergency: –Recent onset of enuresis in a previously toilet-trained child –Vaginal candidiasis, especially in prepubertal girls –Vomiting –Irritability and decreasing school performance –Recurrent skin infections Emergency: DKA

7 S Chan-Cua Classification and Pathophysiology TYPEPATHOPHYSIOLOGY / Insulin secretion (IS) / Insulin resistance (IR) Type 1Autoimmune destruction of β cells Type 2 ↑ IR and β cell insufficiency Monogenic↓ IS SecondaryVarious: ↓ IS, ↑ IR

8 S Chan-Cua T1DM β cell specific autoimmunity Genes Viruses Toxins Diet Susceptibility DIABETES Triggering factors Autoantigens Autoantibodies

9 S Chan-Cua T1DM Type 1 DM –characterized by destruction of the pancreatic beta cells, leading to absolute insulin deficiency –autoimmune destruction of the pancreatic beta cells autoantibodies to –islet-cell (ICA) –glutamic acid decarboxylase (anti-GAD) –Insulin (IAA) –tyrosine phosphatase IA-2

10 S Chan-Cua T1 DM Local study (Metro Manila, ) 99 children (1-14 yr) –56 girls –33 boys Prevalence: 2.8 cases /100,000 Incidence: 0.55 – 0.60 cases /100,000 Sy RA, Chan-Cua S, 1999

11 S Chan-Cua Type 2 diabetes in youth from the Western Pacific region: glycemic control, diabetes care and complications Eppens MC, et al. Current Medical Research and Opinion® Vol. 22, No.5, 2006, 1013–1020 Philippines: Age of onset: 11 (9-13) yr; M:42%, F 58%; 47% overweight, 16% obese (Definition/ cut-off: Cole TF. BMJ. 2000)

12 S Chan-Cua T2DM Characterized by Insulin resistance secretory defect Obesity (BMI >95 th P for age & gender) Family hx: T2DM in a 1st or 2nd degree relative High-risk ethnic group (e.g., Aboriginal, African, Hispanic, South-Asian) A history of exposure to DM in utero Acanthosis nigricans (insulin resistance) Polycystic ovarian syndrome (PCOS)

13 S Chan-Cua T1 & T2 DM in children and adolescents Type 1Type 2 Age of onsetThroughout childhoodPubertal Prominent raceAll (low in Asians)Asians OnsetAcute, severeSubtle to severe Islet autoimmunityPresentUnusual Insulin secretionVery lowVariable Insulin sensitivityNormalDecreased Ketosis, DKA at onsetCommon, up to 40%Uncommon ObesityAs in population>90% % of probands with affected 1 o relatives 5-10%~80% Mode of inheritanceNon-Mendelian, gen’ly sporadic Non-Mendelian, strongly familial

14 S Chan-Cua Differentiating T1 from T2DM in Children and Adolescents DemographicsType 1Type 2 Family history3-5% % Age or pubertal statusVariable>10 yr or pubertal Presentation AsymptomaticRareCommon Symptom durationDays or weeksWeeks or months Physical findings BMI at diagnosis≤ 75 th P≥ 85 th P Acanthosis nigricansNoCommon Insulin/ C-peptideLow (may be normal early)Normal-high

15 S Chan-Cua Monogenic diabetes - MODY Autosomal dominant - (+) Family history Account for 1–5% of all cases of diabetes Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia 1995;38(12): causative gene mutations in insulin and glucose regulation and pancreatic beta cell function Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 2001;345(13): Maturity onset diabetes of the young (MODY)

16 S Chan-Cua Monogenic Diabetes - MODY MODY 1 MODY 2 MODY 3 MODY 4 MODY 5 MODY 6 Genetic defects of β-cell function Gene mutated Hepatocyte nuclear factor 4 α (HNF-4a) Glucokinase (GCK) - mild Hepatic nuclear factor 1 α (HNF-1α) – early treatment with insulin Insulin promoter factor-1 (IPF1) Hepatic transcription factor 1 b (HNF-1b) Neuro D1 Owen K, Hattersley AT. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 2001;15(3): Confirmed diagnosis by genetic testing Chromosome

17 S Chan-Cua Monogenic Diabetes - MODY Resembles T2DM Relatively mild May need no insulin (-) antibodies Different from T2DM not obese not insulin resistant

18 S Chan-Cua Monogenic diabetes - NDM Transient Half of NDM No need of insulin after a few weeks or months of age 2 genes (chromosome 6q24) HYMA1 and ZAC expressed only from paternal copy –A double dose of one or both genes Permanent – diverse etiology Mutation of KCNJ11 gene Encoding Kir6.2, a β-cell K channel crucial in regulation of insulin –Response to sulfonylureas (glibenclamide/ glyburide) Mutations of EIF2AK3 gene Neonatal Diabetes Mellitus (NDM): β-cell dysfunction

19 S Chan-Cua NDM - Mutation of KCNJ11 Gene Encoding Kir6.2 No insulin exocytosis Insulin secretion Hyperpolarization Abnormal K ATP channels with ↑ open probability Diabetes, in neonatal period NORMAL NDM K ATP channels affect insulin secretion - its closure is a central step in glucose-stimulated insulin release Targeted overactivity of ß-cell KATP channels induces profound NDM

20 S Chan-Cua NDM - Wolcott-Rallison syndrome (WRS) AR Neonatal onset / < 6 months Multiple epiphyseal dysplasia Convulsions Retarded development Short stature Liver disease Nephropathy TD Manna. J Pediatr (Rio J). 2007;83(5 Suppl):S Valerie Senee, et al.Diabetes 53:1876–1883, 2004 Mutations of EIF2AK3 gene – pancreatic e ukaryotic i nitiation f actor 2 k inase (2p12)

21 S Chan-Cua Genetic Defects/ Syndromes Genetic Syndromes Down syndrome Klinefelter syndrome Turner syndrome Prader-Willi syndrome Wolfram syndrome (DIDMOAD) –DI, DM, optic nerve atrophy, sensorineural deafness Genetic defects in insulin action Type A insulin resistance Leprechaunism Rabson-Mendenhall syndrome Lipoatrophic diabetes

22 S Chan-Cua Medication-induced DM Glucocorticoids- severe hyperglycemia requiring insulin therapy Chemo-therapeutic agents (L-asparaginase) and immunosuppressants (cyclosporine and tacrolimus) –direct pancreatic beta cell toxicity –interference with insulin secretion –induction of insulin resistance Atypical anti-psychotics and anti-seizure medications Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8.

23 S Chan-Cua Endocrine Diosorders Acromegaly Cushing's syndrome Glucagonoma Pheochromocyto ma ↓ glucose uptake/ ↑ gluconeogenesis ↓ glucose uptake ↑ gluconeogenesis/ ↑ glycogenolysis ↓ glucose uptake/ ↑ glycogenolysis Mostly ↑ counter-regulatory hormone effects

24 S Chan-Cua

25 S Chan-Cua Summary T1DM is generally seen in lean children with pancreatic autoimmunity. T2DM is generally seen in obese children with insulin resistance Monogenic DM generally have a strong family history of diabetes affecting multiple generations, a classically normal weight, and do not have features of insulin resistance or evidence of pancreatic autoimmunity Secondary DM: Medication-induced DM is diagnosed when hyperglycemia develops following the initiation of a known diabetogenic medication

26 S Chan-Cua DM Children differ from adults Insulin sensitivity related to sexual maturity Physical growth Ability to provide self-care Neurologic vulnerability to hypoglycemia

27 S Chan-Cua Principles of DM Management Aims – To attain good glycemic control To ensure normal growth (height & weight) To prevent acute complications To prevent long-term vascular complications

28 S Chan-Cua Monitoring NutritionExercise/ Insulin/ OHASport Management of Diabetes Mellitus Child & Family Multidisciplinary team of specialists

29 S Chan-Cua Insulin Types and Action Profiles Rapid- acting Short-acting Intermediate – acting (NPH) Intermediate- acting (Lente) Long-acting Premixed (75/25) Premixed (70/30) Premixed (50/50) Make a choice Combination Teach injection How Where Dosage U/ kg / day

30 S Chan-Cua Plasma blood glucose goals for T1DM by age-group Values by age (years) Plasma glucose goal range before meals Plasma glucose goal range at bedtime Toddlers and preschoolers (0 – <6) 100–180110–200 School age (>6 –12) 90–180100–180 Adolescents and young adults (13–19) 90–13090–150

31 S Chan-Cua Acute Complications DKA Diabetes Mellitus in the Pediatric Population

32 S Chan-Cua DKA – Presenting S/Sx and Diagnosis S/Sx Polyuria Polydipsia Weight loss Tiredness Abdominal pain Vomiting Confusion Dehydration Deep sighing respiration (Kussmaul) Smell of ketones Disordered sensorium Shock and hypotension The biochemical criteria: Hyperglycemia (BG >11 mmol/L = 200 mg/dL) Venous pH <7.3 Bicarbonate <15 mmol/L Ketonemia and ketonuria

33 S Chan-Cua Islets of Langerhans  -cell destruction Insulin Deficiency Adipocytes Muscle Liver Decreased Glucose Utilization & Increased Production Glucagon Increased Protein Catabolism Increased Ketogenesis Gluconeogenesis, Glycogenolysis Increased Lipolysis Hyperglycemia Ketoacidosis HyperTG Polyuria Volume Depletion Ketonuria Stress Epi,Cortisol GH Threshold 180 mg/dl

34 S Chan-Cua Management of DKA Assess clinical severity of dehydration Assess level of consciousness Obtain a blood sample for laboratory measurement of –glucose, electrolytes, ketones –venous / arterial (in critically ill patient) pH, HCO 3, PCO 2 –BUN, Cr, osmolality –CBC an ↑ WBC count in response to stress is characteristic of DKA and is not indicative of infection –HbA1c Check urine for ketones

35 S Chan-Cua Management of DKA Provide fluid therapy to correct dehydration Correct electrolyte imbalance and acidosis Give insulin to restore blood glucose to near normal Monitor blood glucose

36 S Chan-Cua DKA The 3 useful signs for assessing dehydration in young children and predicting acidosis are: prolonged capillary refill time (normal capillary refill is 1.5–2 s) abnormal skin turgor (tenting or inelastic skin) abnormal respiratory pattern (hyperpnea) 10% dehydration is suggested by the presence of weak or impalpable peripheral pulses hypotension oliguria

37 S Chan-Cua Fluid Therapy Begin with fluid replacement before insulin therapy Volume expansion (resuscitation) is required only if needed to restore peripheral circulation Subsequent fluid administration (including oral fluids) should rehydrate evenly over 48 h at a rate rarely in excess of 1.5–2 times the usual daily maintenance

38 S Chan-Cua Fluid Therapy Calculate fluid requirements Correct over 48 hours NSS (Saline) 0.9% A failure of measured serum Na levels to ↑, or a further ↓ in serum Na levels with therapy is thought to be a potentially ominous sign of impending cerebral edema When CBG <250 mg/dl, may add 5% glucose A failure of measured serum Na levels to ↑, or a further ↓ in serum Na levels with therapy is thought to be a potentially ominous sign of impending cerebral edema Monitor urine output

39 S Chan-Cua Insulin Insulin drip at 0.1 U / kg / hour –10 U regular insulin +100 ml NSS (1 U insulin in 10 ml solution) 10 kg child: 0.1 x 10 = 1U insulin / 10 ml NSS /hr –10 U regular insulin +10 ml NSS (1 insulin in 1 ml solution) 30 kg child: 0.1 x 30 = 3U insulin / 3 ml NSS /hr

40 S Chan-Cua Correction of Electrolytes Imbalance Even with normal or high levels of serum K at presentation, there is always a total body deficit of K Add KCl 20 – 40 mmol K/ L IVF If the patient is hyperkalemic, defer K replacement therapy until urine output is documented

41 S Chan-Cua Bicarbonate administration Generally, not needed Patients with severe acidemia (pH < 6.9) in whom –decreased cardiac contractility and peripheral vasodilatation can further impair tissue perfusion patients with life-threatening hyperkalemia There is no evidence that bicarbonate is either necessary or safe in DKA.

42 S Chan-Cua Anion gap = Na - (Cl + HCO 3 ) –normal is 12 ± 2 mmol/L In DKA the anion gap is typically 20–30 mmol/L; an anion gap >35 mmol/L suggests concomitant lactic acidosis Na corrected = Na measured +2 x ([glucose - 5.6] / 5.6) mmol/L Effective osmolality = 2 x (Na + K) + glucose mOsm/kg

43 S Chan-Cua Supportive measures Secure the airway Give oxygen to patients with severe circulatory impairment or shock Insert NGT – to empty the stomach Place a peripheral IV catheter Use a cardiac monitor for continuous ECG monitoring to assess T waves for evidence of hyper- or hypo-K Place urinary catheter to monitor urine output Give antibiotics to febrile patients after obtaining appropriate cultures of body fluids

44 S Chan-Cua Critical Observations Hourly blood glucose monitoring Hourly fluid input & output Neurological status at least hourly Repeat electrolytes after start of IV therapy Monitor ECG for T-wave changes

45 S Chan-Cua Warning signs and symptoms of cerebral edema Headache & slowing of heart rate Change in neurological status (restlessness, irritability, increased drowsiness, incontinence) Specific neurological signs (e.g., cranial nerve palsies) Rising BP Decreased O 2 saturation

46 S Chan-Cua Admit to ICU Children with severe DKA –long duration of symptoms –compromised circulation –depressed level of consciousness –those who are at increased risk for cerebral edema 5 yr of age severe acidosis low PCO 2, high BUN

47 S Chan-Cua Hypoglycemia Sweating Trembling Dizziness Mood changes Hunger Headache Blurred vision Extreme tiredness Paleness

48 S Chan-Cua Management of complications: Hypoglycemia Immediate source of glucose –Juice –Milk Glucagon Dextrose infusion Identify the precipitating factors


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