Endocrine Emergencies in Pediatrics

1. Endocrine Emergencies in Pediatrics Dr. Majedah Abdul-Rasoul Assistant Professor-Department of Pediatrics Kuwait University The 1st Pediatric Emergency Conference-Kuwait 2011

2. Diabetic Ketoacidosis • Diabetic-related hypoglycemia • Neonatal/pediatric hypoglycemia • Acute adrenal insufficiency • Neonatal • Pediatric • Acute hypercalcemia • Acute hypocalcaemia • Thyrotoxicosis: Rare Spectrum of Pediatric Endocrine Emergencies

3. Case 1

4. A 12-year-old white girl • 5-days H/O: • Periumbilical abdominal pain • Non-bilious vomiting • Fatigue • PURPLE discoloration of lips and hands • No past medical history, no significant family history History

5. Physical Examination: SICK • BP: 60/32, HR: 113 BPM, RR 14 BPM. • Dry mucous membranes, lips were “intensely cyanotic”, skin was tanned. • Initial investigation results: • CBC: WBC 17,000/ml (4.5-11,000/ml), Hb 16.7 g/dl (12-15.4). • Na 126, K 6.2, HCO3 10 (all mEq/L) • Glucose 2.8 mmol/L • CXR: normal ER Assessment ICU

6. Required ventilatory and high inotropic support, BP still low • Initial investigation results: • Cortisol level in ER was less than 1.0µ/dl (5-25). • Maintenance HC was continued  BP improved  inotropic agents stopped. Endocrine Consultation Hydrocortisone 100 mg/m² IV Subsequent Course

7. ACTH: 1200 (10-60 pg/ml) • Renin: 31,488 (50-330 ng/dl/hr) • 21-hydroxylase antibody deficiency: 194.3 (< 1.0µ/ml) • Discharged on HC and Florinef Other Results Primary Autoimmune Adrenal Insufficiency

8. Case 2

9. 1 yr 9 m Syrian girl presented with: • Lethargy • Loss of weight • Vomiting • Refusal of feed • Up rolling eyes and loss of consciousness of 15 min duration • Depressed level of consciousness 2 weeks History

10. Product FTND • H/O poly-hydramnios • Normal milestones • Vaccinated up to age • At 10 m age became ill in Syria required IVF !!!! Past History

11. No H/O neonatal deaths • 8 sibs married & having N kids 15 healthy sibs both gender Family History

12. Physical Examination: • Febrile 38.9ºC, BP 90/50, stable other vital signs. • Drowsy, moderately dehydrated, CYANOSIS OF THE LIPS • Investigation: • RBS, renal function with electrolytes, toxicology screening • Management: • D 10% bolus given followed by 0.45 NS D5 % Initial Assessment in ER

13. Failing to thrive, wt below 5thcentile (50th of 12 months) • O2 sat 99% • Conscious, oriented, crying • Generalized tanning of skin • Increased pigmentation of lips, gums, nape of neck & abdomen In the Ward

15. Abdomen was soft, liver 2cm BCM • Normal female external genitalia • Bilateral slippery masses felt in inguinal region

16. RBS 0.6 mmol/l • Na 113 mmol/l • K 6.6 mmol/l • Cl 86 mmol/l • Urea 8.9 mmol/l • pH 7.2 • HCO313 Results of the Investigations

17. RBS check by glucometer normal • Bolus of NS followed by 0.45 NS D5 • IV hydrocortisone • Blood sent for hormonal investigation • Other investigations for diagnosis Subsequent Management

18. US abd & inguinal region • Gonads seen in both inguinal regions with testis like echo texture measuring 0.4 cm • No uterus or ovaries visualized • Adrenals were reported “normal” • Genitogram: • Vagina seen blind ended separate from urethra • Chromosomal analysis: • 46XY Other Investigations

19. ACTH Cholesterol PregnenoloneProgesterone 11-deoxycorticosteroneAldosterone (<0.5),(<0.5) (<1),(<1) (<30) (<30 ) 17-OH Pregn.17OHP11-DeoxycortisolCortisol (-),(<10)(<0.3) (<0.3) (16.5) (16.9) DHEAAndrostenedioneEsterone (<0.8) (<0.8) AndrostenediolTestosterone Estradiol (0.24),(0.29) StAR P450scc 3BHSD 21OH 11BOH 17a-OH 17a-OH 21OH 3BHSD 11BOH C-17,21 Lyase 3BHSD 17BHSD Low values (before) (after) ACTH Stimulation) 3BHSD

20. DNA sample sent to Dr Katsumata (Japan): • StARmuataion was –ve • DAX1 mutation –ve • SF-1 –ve • The patient had homozygous mutation A359V in exon of P450scc gene. • Parents are heterozygous for A359V mutation. Special Investigations Congenital Adrenal Hyperplasia: P450 mutation

21. Subsequent management: • Bilateral gonadectomy • Reconstruction of vagina at later stage • Sex hormone replacement around puberty to induce secondary sexual characteristics to have a sexually functioning infertile female.

22. Adrenal Insufficiency

23. Medulla ZonaGlomerulosa: Mineralocorticoids ZonaFasiculata: Glucocorticoids ZonaReticularis: Androgens Back to Basic: Adrenal Anatomy

24. Back to Basic: HPA axis

25. Back to Basic: RA System

26. Adrenal Physiology • Cyclic secretion controlled by time of day, HPA • axis, renin-angiotensin system, serum potassium • levels • Stress increases basal glucocorticoid and mineralcorticoid levels 5-10 fold • Occurs within minutes

27. Corticosteroids • Three classes (by effect): • Glucocorticoids • Mineralcorticoids • Androgenic steroids

28. Corticosteroids • Regulate fat, glucose, protein metabolism • Catecholamine and b-adrenergic receptor synthesis • Maintain vascular tone and cardiac contractility • Control endothelial integrity/vascular permeability

29. Corticosteroids • Cortisol • Controlled by HPA axis • Hypothalamus  CRH and arginine vasopressin in circadian rhythm (max 2-4am) • Anterior Pituitary  ACTH • Adrenal cortex  cortisol • Peak @ 8am; declines throughout day

30. Miniralocorticoids • Regulated via renin-angiotensin system & serum potassium levels: • Diminished GFR juxtaglomerular apparatus release of prorenin • Aldosterone release  Na & H2O resorption at distal tubules (K is lost) • Minor hyperkalemia can stimulate aldosterone secretion directly

31. Adrenal Insufficiency vs Crisis • Basal failure in adrenal insufficiency • Leads to insidious wasting disease • Stress failure results in adrenal crisis • Life-threatening • Absence of glucocorticoids is most critical

32. Adrenal Insufficiency • Primary = failure of adrenal glands • Secondary = failure of HPA axis • Usually due to chronic exogenous glucocorticoid administration • pituitary failure • Tertiary = Hypothalamic dysfunction

33. Primary Adrenal Insufficiency : Etiologies Acquired Autoimmune AIDS Tuberculosis Bilateral injury Hemorrhage Necrosis Metastasis Idiopathic Congenital Congenital adrenal hyperplasia Wolman disease Adrenal hypoplasia congenita Allgrove syndrome (AAA) • Syndromes • Adrenoleukodystrophy • Kearns-Sayre • Autoimmune polyglandular • syndrome 1 (APS1) • APS2

34. Primary Adrenal Insufficiency : Etiologies Acquired: Addison’s Dis Autoimmune AIDS Tuberculosis Bilateral injury Hemorrhage Necrosis Metastasis Idiopathic

35. 1st described in 1855 • Refers to acquired primary adrenal insufficiency • Does not confer specific etiology • Usually autoimmune (~80%) Thomas Addison:(1860-1793)

36. John F. Kennedy was one of the best-known Addison's disease sufferers, and also possibly one of the first to survive major surgery

37. Addison’s Disease Addison’s Normal

38. Primary Adrenal Insufficiency : S/S • Fatigue • Weight loss • Poor appetite • Increased pigmentation in non-exposed areas • Neuropsychiatric • Apathy • Confusion • Nausea, vomiting • Abdominal pain • Salt craving

41. Primary Adrenal Insufficiency : Investigations • Hyponatremia • Hyperkalemia • Hypoglycemia • Narrow cardiac silhouette on CXR • Low voltage EKG

42. Primary Adrenal Insufficiency : Etiologies Congenital Congenital adrenal hyperplasia Wolman disease Adrenal hypoplasia congenita Allgrove syndrome (AAA)

43. Primary Adrenal Insufficiency : Etiologies Congenital Congenital adrenal hyperplasia Wolman disease Adrenal hypoplasia congenita Allgrove syndrome (AAA)

44. Congenital Adrenal Hyperplasia StAR, 20,22-desmolase Cholesterol 17α-hydroxylase 17,20-lyase 17-OH-Pregnenolone DHEA 3βHSD 3βHSD 3βHSD Pregnenolone 17α-hydroxylase 17,20-lyase 17-OH-Progesterone Androstenedione 21-hydroxylase 21-hydroxylase Progesterone 11-deoxycortisol Estrone 11β-hydroxylase 11β-hydroxylase DOC Testosterone Cortisol Corticosterone 18-hydroxylase Estradiol 18-oxidase 18-OH-Corticosterone Aldosterone

45. Congenital Adrenal Hyperplasia • Females are unremarkable other than genitalia • Males appear normal • GU exam – Clitoromegaly, posterior labial fusion, no vaginal opening

46. Adrenal Insufficiency: Management

47. If diagnosis not known, treatment should go parallel with establishing the Dix. • Volume replacement with NS: • Usually moderate –severe dehydration • Dextrose (0.5g/kg IV) for hypoglycemia • Inotropes may be needed for the hypotension (until glucocorticoids given). In patients presenting with adrenal crisis:

48. Stress dose steroids should be given : • Should not be deferred till diagnosis is established

49. Stress Dose Steroids: • Loading dose • 50-100 mg/M2 hydrocortisone IV • Small/medium/large approach (2mg/kg max 100mg) • Infants: Hydrocortisone 25 mg • Small children: Hydrocortisone 50 mg • Larger children/teens: Hydrocortisone 100 mg • Continue hydrocortisone with 50-100 mg/M2/day • Divide q6-8 hours • Established cases: • May be 2-3x home dose

50. Relative Steroid Potency