Adrenal insufficiency

1. Adrenal insufficiency Anthony Worsham Best Practice Friday, January 14, 2011

2. Outline • Case • Normal physiology • Abnormal physiology • Treatment

3. Case ID: 43-year-old woman CC: increasing skin pigmentation and weight loss FMH: none Meds: none ROS: lethargy SH: married, two healthy children VS: supine systolic blood pressure of 50 mmHg (that became unrecordable when standing) Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

4. Case Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

5. The adrenal gland.. Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach. http://www.pathology.vcu.edu/education/endocrine/endocrine/adrenal/gross/Nladrgr.GIF http://www.pathology.vcu.edu/education/endocrine/endocrine/adrenal/micro/nlAdr10.GIF

6. Two, two, two glands in one! • Cortex (Remember GFR and date night) • Glomerulosa – first dinner (salt, mineralocorticoids) • Fasiculata – then desert (sugar, glucocorticoids) • Reticularis – then to your place? (sex, hormones) • Medulla – sympathetic functions

7. Adrenal products Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

9. Common bond of chemical engineering and medicine? Chau PC; Process control: a first course with MATLAB; Cambridge University Press, 2002.

10. Answer: Feedback control. Gordon H. Williams, Robert G. Dluhy. “Disorders of the Adrenal Cortex.” Harrison's Principles of Internal Medicine – 17th Ed. (2008)

11. Adrenal negative feedback control Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

12. Synthesis of adrenocorticotrophic hormone (ACTH) Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

13. Cortisol secretion is circadian Cortisol Androgens Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An intergrated approach.

14. Cortisol actions Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

15. Peripheral metabolism of adrenal androgens Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

16. Classification of adrenal disorders • Insufficiency • Primary adrenal insufficiency (Addison’s) • due to adrenal insufficiency (marked skin pigmentation due to high ACTH levels) • Secondary adrenal insufficiency • Pituitary or hypothalamic Insufficiency (no skin pigmentation) • Excess • Cushing's disease/syndrome • Primary hyperaldosteronism (Conn’s) • Resistance • adrenal virilism and congenital adrenal hyperplasia (21-hydroxylase deficiency) Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

17. “This singular discoloration usually increases with the advance of the disease; the anæmia, languor, failure of appetite, and feebleness of the heart, become aggravated; a darkish streak usually appears upon the commissure of the lips; the body wastes, but without the extreme emaciation and dry harsh condition of the surface so commonly observed in ordinary malignant diseases; the pulse becomes smaller and weaker, and without any special complaint of pain or uneasiness, the patient at length gradually sinks and expires.” Addison T. On the constitutional and local effects of disease of the supra-renal capsules. London: Samuel Highley, 1855. Thomas Addison (1793 - 1860) Thomas Addison. http://en.wikipedia.org/wiki/Thomas_Addison

18. Adrenal insufficiency • chronic primary adrenal insufficiency • prevalence: 39 to 60 per million • mean age at diagnosis: 40 years (17-72)

19. Celebrities with Addison’s disease

20. Primary adrenal insufficiency Causes • Autoimmune (Sporadic, Autoimmune polyendocrine syndrome types I & II) 70% • Infections (TB, Fungal [histo, crypto], CMV, HIV) • Infiltrations (Metastases, amyloid, hemochromatosis) • Drugs (ketoconazole, rifampin) • Intra-adrenal hemorrhage (Waterhouse-Friderichsen syndrome) after meningococcal (or other) septicemia • Adrenoleukodystrophies • Congenital adrenal hypoplasia (DAX-1, SF-1 mutations) • ACTH resistance syndromes (Mutations in MC2-R, Triple A syndrome) • Bilateral adrenalectomy Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

21. Primary adrenal insufficiencyAssociated endocrine disease None 53% Thyroid disease Hypothyroidism 8% Nontoxic goiter 7% Thyrotoxicosis 7% Gonadal failure Ovarian 20% Testicular 2% Insulin-dependent diabetes mellitus 11% Hypoparathyroidism 10% Pernicious anemia 5% Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

22. Secondary adrenal insufficiencyCauses • Exogenous glucocorticoid therapy • Hypopituitarism • Selective removal of ACTH-secreting pituitary adenoma • Pituitary tumors and pituitary surgery, craniopharyngiomas • Pituitary apoplexy • Granulomatous disease (tuberculosis, sarcoid, eosinophilic granuloma) • Secondary tumor deposits (breast, bronchus) • Postpartum pituitary infarction (Sheehan's syndrome) • Pituitary irradiation (effect usually delayed for several years) • Isolated ACTH deficiency • Idiopathic (Lymphocytic hypophysitis, TRIT gene mutations, POMC processing defect, POMC gene mutations) Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

23. Clinical features of primary adrenal insufficiency: Symptoms Weakness, tiredness, fatigue 100% Anorexia 100% Gastrointestinal symptoms 92% Nausea 86% Vomiting 75% Constipation 33% Abdominal pain 31% Diarrhea 16% Salt craving 16% Postural dizziness 12% Muscle or joint pains 6-13% Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

24. Clinical features of primary adrenal insufficiency: Signs Weight loss 100% Hyperpigmentation 94% Hypotension (<110 mm Hg systolic) 88-94% Vitiligo 10-20% Auricular calcification 5% Hypoglycemia (in adults) ~ <1% Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

25. Signs Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

26. Why hyperpigmentation?

27. Clinical features of primary adrenal insufficiency: laboratory Electrolyte disturbances 92% Hyponatremia 88% Hyperkalemia 64% Hypercalcemia 6% Azotemia 55% Anemia 40% Eosinophilia 17% Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

28. Adrenal crisis • Dehydration, hypotension, or shock out of proportion to severity of current illness • Nausea and vomiting with a history of weight loss and anorexia • Abdominal pain, so-called acute abdomen • Unexplained hypoglycemia • Unexplained fever • Hyponatremia, hyperkalemia, azotemia, hypercalcemia, or eosinophilia • Hyperpigmentation or vitiligo • Other autoimmune endocrine deficiencies, such as hypothyroidism or gonadal failure Stewart, PM;The adrenal cortex. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

29. Diagnosis: High index of suspicion

30. Diagnosis Bornstein SR; Predisposing Factors for Adrenal Insufficiency; NEJM 2009: 360:2328-2339

31. Diagnosis Nieman LK, Diagnosis of adrenal insufficiency in adults, UpToDate, 2011.

32. Cooper MS and Stewart PM, Corticosteroid insufficiency in acutely ill patients, NEJM 2003; 348:727-734.

33. Diagnosis1. Screening test • Early morning basal total/free serum cortisol and plasma corticotropin • Plasma aldosterone and renin activity • (salivary cortisol) • (Urinary free cortisol excretion)

34. Diagnosis2. Stimulation test Stimulation of adrenal function • administer 1 or 250 μg corticotropin(1-24) • measure cortisol after 30 and 60 minutes • increase in serum cortisol level to peak > 18 µg/dL indicates normal response Stimulation of pituitary-adrenal axis insulin-induced hypoglycemia • Regular insulin (0.1 U) administered intravenously • Basal and 30-60-90 minutes after start of insulin tolerance test of cortisol and corticotropin (and growth hormone in case of suspected multiple pituitary hormone deficiency) Stimulation with CRH • differentiate between hypothalamic and pituitary etiologies

35. Cooper MS, Stewart PM; NEJM 2003; 348:8.

36. Long courses of low dose corticosteroids reduce mortality at 28 days, in intensive care units, and in hospital Annane D et al. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 2004;329:480-488.

37. Effect of Steroids on Survival and Shock during Sepsis Depends on Dose Minneci PC et al. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47-56

38. Treatment • glucocorticoid replacement • two or three daily doses (total 15 to 30 mg of hydrocortisone) • one half to two thirds of the daily dose is given in the morning, in line with the physiologic cortisol-secretion pattern. • Mineralocorticoid replacement (0.05 to 0.2 mg of fludrocortisone daily as a morning dose) required only with primary adrenal insufficiency • dehydroepiandrosterone replacement (25 to 50 mg) optional treatment • acute adrenal crisis • immediate intravenous administration of 100 mg of hydrocortisone, then • 100 to 200 mg of hydrocortisone every 24 hours • continuous infusion of larger volumes of physiologic saline solution (initially 1 liter per hour) under continuous cardiac monitoring Bornstein SR; Predisposing Factors for Adrenal Insufficiency; NEJM 2009: Volume 360:2328-2339

39. Treatment Minor febrile illness or stress • Increase glucocorticoid dose twofold to threefold for the few days of illness; do not change mineralocorticoid dose. • Contact physician if illness worsens or persists for more than 3 days or if vomiting develops. Emergency treatment of severe stress or trauma • Inject contents of prefilled dexamethasone (4-mg) syringe intramuscularly. • Get to physician as quickly as possible.

40. Treatment: Inpatients Cooper MS and Stewart PM, Corticosteroid insufficiency in acutely ill patients, NEJM 2003; 348:727-734.

41. Areas of controversy Sprung, CL et al, the CORTICUS Study Group, (2008). Hydrocortisone Therapy for Patients with Septic Shock. NEJM 358: 111-124.

42. CORTICUS study design • multicenter, randomized, double-blind, placebo-controlled trial • 251 patients: hydrocortisone 50 mg IV q6h x5 days • 248 patients: placebo IV q6h x5 days • 6-day taper • primary outcome: death at 28 days among patients who did not have a response to a corticotropin test Sprung, CL et al, the CORTICUS Study Group, (2008). Hydrocortisone Therapy for Patients with Septic Shock. NEJM 358: 111-124.

43. CORTICUS Results • 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group) • No significant difference in mortality at 28 days between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P = 0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P = 1.00). • At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P = 0.51). • In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. Sprung, CL et al, the CORTICUS Study Group, (2008). Hydrocortisone Therapy for Patients with Septic Shock. NEJM 358: 111-124.

44. CORTICUS conclusion • Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. Sprung, CL et al, the CORTICUS Study Group, (2008). Hydrocortisone Therapy for Patients with Septic Shock. NEJM 358: 111-124.

45. CORTICUS weaknesses • Underpowered • The rate of death in the control group was lower than expected, and this factor, combined with early stopping of the study, meant that the study had a power of less than 35% to detect a 20% reduction in the relative risk of death • Selection bias? • Trial did not meet enrollment target of 800 patients, suggesting that the sickest patients, those that would show the most benefit from steroids, may have been sequestered from the trial by their physicians.

46. Questions • Exact cut offs • Adrenal insufficiency in liver disease • Order set

47. It may be better to consider “normal” to be situational — or even existential. Loriaux L, Glucocorticoid therapy in the intensive care unit,NEJM 2004; 350:1601-1602

48. Case serum cortisol concentration: 1.8 µg/dL Stim test: 1.9 µg/dL Immediate Tx: hydrocortisone 100 mg IV x1 normal saline 1 L bolus PATIENT REFUSED ADMISSION Maintenance Tx: fludrocortisone 100 μg daily as mineralocorticoid replacement 100 mg cortisol tid trailing to a maintenance of 20 mg daily in divided doses. Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

49. CaseBefore and after treatment Nussey SS, Whitehead SA; The adrenal gland. Endocrinology: An integrated approach.

50. Conclusions • Synthesis of adrenocorticosteroids and its regulation • Physiological roles of adrenocorticosteroids • Clinical sequelae of disorders of steroid synthesis and secretion • Investigation and treatment of adrenal disease