C.R.Kannan, M.D. Endocrinologist, Southwest Medical Associates, Las Vegas Former Chairman of Endocrinology, Cook Count

1. Adrenal Insufficiency C.R.Kannan, M.D. Endocrinologist, Southwest Medical Associates, Las Vegas Former Chairman of Endocrinology, Cook County Hospital, Chicago Professor of Medicine, Rush University, Chicago

2. “ What’s on your mind today?”

3. What is the attention span of an audience during a formal lecture? 17 minutes! What is the point of no return? I.e, after this point NOTHING that you say gets to the audience 30 minutes! What is the half-life of any lecture? 2 hrs, if you are lucky!

4. 35 year old woman 12 month hx of fatigue, mild depression and anorexia. She has lost 7 pounds. She complained of dizziness and Her menses had become irregular. She saw her internist who performed several tests and found mild macrocytic anemia secondary to B12 deficiency. She was started on monthly B12 injections. Oral contraceptives were prescribed to regulate menses

5. She felt only slightly better. She continued to remain tired and lost 4 more pounds Her TFT were normal, as were the CBC and a CMP The urine was negative Tests for SLE were negative. She started to develop frequent abdominal pain and diarrhea. She had a complete GI work up which was negative Na 128 K 4.0

6. 35 year old woman fatigue weight loss weakness dizziness depression irregular periods abdominal pain diarrhea anemia Appeared chronically ill 90/70 supine; PR 72 72/50 standing; PR 84 No pigmentary changes Na 128 K 4.0 An 8 am cortisol was 7 mcg (5-18 mcg)

7. She was reassured that her tests look good and was placed on antidepressants 5 weeks later she developed fever and cough. Within 24 hours she became nauseous, vomited and became very dehydrated. She was seen in the ER with severe hypotension and “shock” and the initial diagnosis was gastroenteritis. Na 118 K 6.2 A single physical finding impressed the ER resident and prompted the request for a cortisol level

8. 1.2 microgram Almost complete loss of pubic hair and axillary hair

9. 1.2 microgram Almost complete loss of pubic hair and axillary hair

10. What went wrong? Cortisol secretion is pulsatile

11. Cortisol is secreted in episodic bursts Cortisol secretion is pulsatile Plasma cortisol level is one moment in time

12. Although 85-90 % of patients with Adrenal Insufficiency (“AI”) have low 8 am plasma cortisol levels 10-15% have “normal” levels between 5-10 mcg Cortisol secretion is pulsatile What went wrong? Estrogens increase cortisol binding globulin and can falsely elevate the bound cortisol in plasma

13. Adrenal Insufficiency (AI) Clinical Presentation Diagnostic work up Acute adrenal crisis Treatment

14. Adrenal Insufficiency (AI) Clinical Suspicion often based on vague Sx Fatigue (95%) Weight loss (68% Fatigability (90%) Anorexia, (60%) Diarrhea (33%) Depression (72%) Dizziness (70% Weakness (20%) Pigmentary changes (38%) Impotence Menstrual Irregularities salt craving

15. Specific Clues: Change in Skin Pigmentation Orthostatic Hypotension Background Disease Hyponatremia (70%) Hyperkalemia (35%) Hypoglycemia Acute Adrenal Crisis- “SHOCK”

16. Primary adrenal failure “Addison’s Disease” Adrenal Insufficiency Secondary adrenal failure Pituitary ACTH deficiency

17. Feedback Regulation CRH (-) (+) (-) ACTH (+) Cortisol

18. Value of history in the evaluation of a patient with adrenal failure Prior use of steroids for long duration Suppression of HPA axis Current use of warfarin Adrenal hemorrhage Recent use of megace Suppression of HPA axis History of TB, fungal disease in past (Histo, cocci, nocardia) Adrenal destruction History of cirrhosis, diabetes and heart disease Hemochromatosis

19. Value of history in the evaluation of a patient with adrenal failure History of cancer Mets to the adrenal History of concomitant thyroid disease Autoimmune or pituitary History of SLE Anti Phospholipid syndrome HIV disease multifactorial

20. Clinical Presentation Diagnostic work up Acute adrenal crisis Treatment Adrenal Insufficiency

21. Zona Glomerulosa Aldosterone Zona Fasciculata- Reticularis Cortisol Adrenal cortex Zona Fasciculata- Reticularis Sex Steroids

22. RAAS Angiotensin 2 ACTH Zona Fasciculata Reticularis Zona Glomerulosa

23. ACTH PRA Cortisol DHEA Aldo Primary AI Zona Fasciculata Reticularis Zona Glomerulosa

24. RAAS Not affected ACTH Aldo Normal Cortisol DHEA Secondary AI Zona Fasciculata Reticularis Zona Glomerulosa

25. Adrenal Steroidogenesis Cholesterol 11 OH 21 OH Pregnenalone progesterone 11 deoxy Corticosterone Corticosterone Aldosterone 17 OH 17 OH 21 OH 11 OH 17 alpha OH 17 alpha OH 11 deoxy pregnanolone Progesterone Cortisol Cortisol De Hydro Androstenedione Estradiol Epi Androsterone DHEA Testosterone

26. Diagnosis of Adrenal Insufficiency Screening for Adrenal Insufficiency • Basal Cortisol level • Cortrosyn Stim Test Primary versus Secondary • Aldo Response to cortrosyn • Plasma ACTH level Confirmation Standard Cortrosyn Stim Test • For Addison’s • CT adrenals • Antibodies • Test for PGA Establishing Etiology • For Hypopit • MRI Sella • Pit. reserve

27. Basal Plasma Cortisol Cortrosyn Stimulation Test Screening for Adrenal Insufficiency

28. Screening for Adrenal Insufficiency Diagnostic ONLY when the AM plasma Cortisol is < 4 mcg/dl Basal Plasma Cortisol A level > 20 excludes Adrenal Insufficiency A “Normal” Basal Cortisol Does NOT exclude AI

29. Screening for Adrenal Insufficiency Determines the ability of the Adrenal Cortices to respond to an IV bolus of Synthetic ACTH Cortrosyn Stimulation Test The purist method The minimalist method

30. The Cortrosyn Stim Test: classic Plasma Cortisol, Aldosterone at -15 and 0 minutes 250 mcg Cortrosyn IV Push at 0 min Plasma Cortisol, Aldosterone at 30 and 60 minutes What is a normal response to Cortrosyn?

31. A Rise in Cortisol Double the baseline plus at least 8 mcg over Basal and absolute peak > 20

32. Physiology Behind the Cortrosyn Stim test 1. The 3 prerequisites for a “ Normal response are: Viable adrenal cortices Adequate “priming” by endogenous ACTH Adequate preformed releasable pool 2. Lack of response is seen in both Primary as well as Secondary Adrenal Insufficiency 3. A completely normal response validates Integrity of the entire HPA axis

33. The Cortrosyn Stim Test: minimalist 250 mcg Cortrosyn IV Push at 0 min Plasma Cortisol, 60 minutes Plasma Cortisol A cortisol level > 20 mcg after cortrosyn rules out Complete adrenal insufficiency

34. A 62 year old man seen in the MICU Admitted for pneumonia and hypoxia. On a ventilator. His BP level dropped to 90/60 and was unresponsive to fluids and pressors A random cortisol level was drawn. The cortrosyn test was not performed. Therapy was instituted with intravenous hydrocortisone at stress doses(100 mg q 8 hourly)

35. What are your conclusions if……... The random cortisol level came back as 35 mcg The random cortisol level came back as 5.8 mcg The random cortisol level came back as 15 mcg

36. What are your conclusions if……... The patient clinically improved and eventually went home Strong support for AI but not infalliable The patient showed no response and remained hpotensive 95% Probability not AI The patient died Definitely not AI

37. Primary versus Secondary Adrenal Insufficiency Secondary AI PrimaryAI mcg/ng 20- 10- 5- 3- Cortisol Aldosterone Pre 60’ post Pre 60 ‘ post

38. True or False? A normal Cortrosyn test 7 days after Hypophsectomy Implies adquate ACTH reserve The Cortrosyn test is a better test for adrenal reserve than for testing ACTH reserve The I mcg Cortrosyn test is more sensitive than the 250 mcg test for evaluation of ACTH reserve

39. Screening for Adrenal Insufficiency (AI) Primary versus Secondary Establishing Etiology Diagnosis of Adrenal Insufficiency Confirmation

40. Confirmation of Adrenal Insufficiency Standard Cortrosyn Stim Test Plasma ACTH Level

41. HIGH ACTH 100-1000 pg LOW CORTISOL

42. Confirmation of Adrenal Insufficiency 250 mcg Cortrosyn IM, b.I.d for 3 days Standard Cortrosyn Stim Test Repeat IV Cortrosyn Test

43. Post Priming Cortrosyn Test mcg 50- 40- 20- 5- 3- Primary Secondary Pre 60’ post Pre 60 ‘ post

44. Screening for Adrenal Insufficiency (AI) Primary versus Secondary Confirmation Diagnosis of Adrenal Insufficiency Establishing Etiology

45. Etiology of Adrenal Insufficiency Primary Secondary Autoimmune Metastatic TB Fungal AIDS -Pituitary Tumor -Vascular MRI Sella CT Adrenals

46. Etiology of Addison’s Disease CT adrenals Small Unenlarged Enlarged Biopsy Autoimmune

47. Clinical Presentation Diagnostic work up Acute adrenal crisis Treatment Adrenal Insufficiency

48. Acute Adrenal Crisis Adrenal Decompensation Triggered by infections, anesthesia, surgery etc Fatal if untreated Easy when the patient is known Addisonian Difficult when crisis is the first manifestation of AI When in doubt treat first- diagnosis can be confirmed or excluded later

49. Adrenal Crisis Rapid evolution Nausea Vomiting Abdominal Pain Dizziness Hypotension Dehydration Lethargy Muscle stiffness Cardiac arrythmia Shock Hyponatremia Hyperkalemia Hypoglycemia Hyperuricemia pre renal azotemia Eosinophilia Natriuresis

50. Adrenal Crisis Treat as emergency If 60 minutes time is available Cortrosyn stim test Draw cortisol and start treatment If patient is too sick IV fluids with 0.9 saline IV Hydrocortisone 100 mg tid Mineralocorticoids not necessary