Primary Adrenal Disease

1. Primary Adrenal Disease Briana Patterson, M.D. Fellow, Pediatric Endocrinology Emory University School of Medicine

2. Objectives • Normal adrenal physiology • Common causes of primary adrenal insufficiency • Evaluation of suspected adrenal insufficiency • Acute and chronic management issues

3. Normal Adrenals

4. Medulla Adrenal Cortex Zona Glomerulosa: Mineralocorticoids Zona Fasiculata: Glucocorticoids Zona Reticularis: Androgens

5. Adrenal Histology Reticularis Glomerulosa Capsule Medulla Fasiculata

6. Adrenal physiology 1:HPA axis

7. Adrenal physiology 2:Renin-angiotensin system

8. ACTH 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 aromatase 21-hydroxylase 21-hydroxylase Progesterone 11-deoxycortisol 17βHSD Estrone 11β-hydroxylase 11β-hydroxylase DOC Testosterone Cortisol 17βHSD aromatase Corticosterone 18-hydroxylase Estradiol 18-oxidase 18-OH-Corticosterone Aldosterone Steroid Biosynthesis

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

10. Acquired Autoimmune AIDS Tuberculosis Bilateral injury Hemorrhage Necrosis Metastasis Idiopathic Primary adrenal insufficiency:Etiologies

11. Tuberculosis

12. Adrenal Hemorrhage:Meningiococcemia

13. Addison’s Disease • 1st described in 1855 by Dr. Thomas Addison • Refers to acquired primary adrenal insufficiency • Does not confer specific etiology • Usually autoimmune (~80%)

14. Addison’s Disease Addison’s Normal

15. Primary adrenal insufficiency:Symptoms • Fatigue • Weakness • Orthostatsis • Weight loss • Poor appetite • Neuropsychiatric • Apathy • Confusion • Nausea, vomiting • Abdominal pain • Salt craving

16. Primary adrenal insufficiency:Physical findings • Hyperpigmentation • Hypotension • Orthostatic changes • Weak pulses • Shock • Loss of axillary/pubic hair (women)

17. Primary adrenal insufficiency:Physical findings

18. Primary adrenal insufficiency:Laboratory findings • Hyponatremia • Hyperkalemia • Hypoglycemia • Narrow cardiac silhouette on CXR • Low voltage EKG

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

20. 21-hydroxylase deficiency: Pathophysiology Testosterone

21. 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 CAH: Pathophysiology

22. 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 CAH: Pathophysiology

23. 21-hydroxylase deficiency:Physical exam • Females are unremarkable other than genitalia • GU exam – Clitoromegaly, posterior labial fusion, no vaginal opening • Males appear normal

24. 21-hydroxylase deficiency CAH • Classification based on enzyme activity • Classic • Salt wasting (Complete deficiency) • Simple virilizing (Significant but partial defect) • Non Classic • Elevated enzyme levels (Mild deficiency)

25. Primary adrenal insufficiency:Etiologies Syndromes • Adrenoleukodystrophy • Kearns-Sayre • Autoimmune polyglandular syndrome 1 (APS1) • APS2

26. Primary adrenal insufficiency:Associated conditions • Autoimmune Polyglandular Syndrome I • Hypoparathyroidism • Chronic mucocutaneous candidiasis • Atrophic gastritis • Adrenal insufficiency in childhood • Pernicious anemia • Vitiligo • AIRE mutation • Transcription factor • Affects immune regulation

27. Primary adrenal insufficiency:Associated conditions • Autoimmune Polyglandular Syndrome II • Autoimmune thyroiditis • Type I diabetes mellitus • Adrenal insufficiency • Pernicious anemia • Premature ovarian failure • Genetic associations • HLA haplotype, CLTA4

28. Evaluation

29. Primary adrenal insufficiency:Evaluation • 0800 cortisol level • ACTH level • Random cortisol in ill patient • ACTH stimulation test • Suspected CAH • Needs special evaluation

30. Primary adrenal insufficiency:Evaluation • 0800 cortisol level • Levels less than 3 mcg/dL are suggestive of AI • Levels greater than 11 mcg/dL exclude AI • ACTH level • Elevated in adrenal insufficiency • ACTH readily degraded if not properly processed

31. Primary adrenal insufficiency:Evaluation • Random cortisol in ill patient • >20 mcg/dL reassuring • Adrenal Autoantibodies • ACA—adrenal cortex antibody • Anti-21-OH-hydroxylase antibody

32. Primary adrenal insufficiency:Evaluation—ACTH Stimulation • Low dose (1 mcg) test • Baseline and 30 minute cortisol levels • More physiological ACTH level/stimulation • Useful in central AI • Useful for assessing recovery after chronic steroid treatment • High dose (250 mcg) test • Baseline, 30 and 60 minute levels • Can be done IM • Stronger stimulation than 1 mcg test

33. Primary adrenal insufficiency:Evaluation—ACTH Stimulation • Cortisol peaks are controversial • Reported normals range between 16-25 mcg/dl • Some providers also look at the magnitude of rise • Also use ACTH to help differentiate primary vs secondary deficiency • Secondary may respond to high dose, but not low • Primary should fail both high and low dose

34. Newborn screening Call endo before you treat Need special evaluation ACTH stimulation can be helpful in well patients with suspected nonclassic disease 17-OH progesterone 17-OH pregnenolone 11-deoxycortisol Deoxycorticosterone Androstenedione DHEA Aldosterone Cortisol ACTH Plasma renin activity Suspected CAH:Evaluation

35. Diagnosis with 17-OH progesterone Baseline 10,000 - 90,000 Stimulated 20,000 - 100,000 Baseline 500 - 1,000 Stimulated 2,000-15,000 Baseline 20 - 1,000 Stimulated 200 - 1,000

36. Treatment

37. Primary adrenal insufficiency:Acute treatment • NS volume resusitation • Reverse shock • Look for/treat hypoglycemia • 25% dextrose • New problem, suspected AI • Labssteroids • Established patient with AI • Steroids

38. Stress dose steroids • Loading dose • 50-100 mg/M2 hydrocortisone IV/IM • Small/medium/large approach • 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 • May be 2-3x home dose

39. Primary adrenal insufficiency:Long term treatment • Daily glucocorticoid replacement (hydrocortisone) • 10-15 mg/m2/day divided TID • Option to change to prednisone in teen years • Daily mineralocorticoid replacement • Fludrocortisone 0.05-0.2 mg daily • Patient education • Stress coverage • Emergency steroid administration • IM hydrocortisone (Solucortef Actovial) • Medic Alert ID

40. Relative Steroid Potencies

41. Relative Steroid Potencies

42. When to consider AI:Patients at risk…Primary AI • History of TB • Refractory shock • Particularly meningococcal disease • Dehydration/shock with hyperpigmentation • Neonate with vomiting/dehydration/shock • Other autoimmune endocrine disease • History consistent with APS1 • Immunodeficiency/chronic mucocutaneous candidiasis

43. When to consider AI:Patients at risk…Secondary AI • Pituitary trauma/surgery • Brain tumor • Craniopharyngioma • Suprasellar germ cell tumor • Infiltrative pituitary disease • Sarcoidosis • Histiocytosis • Congenital pituitary abnormalities • May have progressive loss of corticotroph function • Chronic glucocorticoid therapy

44. Adrenal Insufficiency Summary • May be primary or secondary • May be congenital or acquired • Treatment is relatively simple • Diagnosis is often controversial • Baseline cortisol/ACTH before steroids • ACTH stim test if possible • Additional testing if CAH is suspected • Don’t forget to check the blood sugar!