1. Adrenal insufficiency

2. Objectives At the end of this lecture, the student should be able to: Define adrenal insufficiency Recognize the causes of adrenal insufficiency. Describe clinical presentation of Addison’s disease. List the investigations and outline the management plan of Addison’s disease. Describe the clinical features and treatment of adrenal crisis.

3. CASE SCENARIO A 32-year-old woman with known hypothyroidism is admitted to hospital. Her Blood pressure is 86/53 mmHg and her pulse 100 bpm. Investigations reveal: Serum sodium 126 mmol/L (137-144) Serum potassium 5.8 mmol/L (3.5-4.9) Serum glucose 3.0 mmol/L (3.0-6.0) 1- What is the most likely diagnosis? 2- What is the most appropriate investigation to confirm your diagnosis?

4. Definition There is a decrease in the secretion of cortisol and or aldosterone Clinical suspicion is important because the presentation of AI may be insidious and subtle Clinical diagnosis is frequently delayed or missed early  if unrecognized, may present in a life-threatening crisis with acute cardiovascular collapse (adrenal crisis) prevalence of well-documented, permanent adrenal insufficiency is 5 in 10,000 in the general population

5. Classification Secondary (low ACTH) Hypothalamic or pituitary disease: - Chronic glucocorticoid excess (endogenous or exogenous) - Pituitary tumors (active and inactive adenomas, carcinoma) - Mass lesions affecting the hypothalamic-pituitary region: Craniopharyngioma, meningioma, metastases - Pituitary irradiation - Autoimmune hypophysitis - Pituitary apoplexy/hemorrhage - Pituitary infiltration (TB, actinomycosis, sarcoidosis, histiocytosis X, Wegener's granulomatosis, metastases

6. Primary adrenal insufficiency (high ACTH) (Addison’s disease) Autoimmune: - Isolated autoimmune adrenalitis (30- 40%) - Polyglandular syndrome 1 &2 (60- 70%) Infection:TB, HIV, CMV, cryptococcosis, histoplasmosis, coccidioidomycosis AIDS Metastases Bilateral adrenalectomy

7. Rare causes: Lymphoma Adrenal hemorrhage in meningococcal sepsis (Waterhouse-Friderichsen syndrome) Amyloidosis, sarcoidosis Hemochromatosis Imparied Steriodiogensis CAH Drugs (Mitotane, aminoglutethimide, etomidate, ketoconazole, suramin

8. Addison’s disease First discovered by Thomas Addison in 1855 First described as an infection of the adrenal gland- most commonly TB. Now instead of infection, its most commonly characterized by an autoimmune destruction of the adrenal glands

9. Epidemiology Addison’s disease is a rare and chronic disease. 6-110 cases diagnosed per 100,000 in the world per year. 1.4 million deaths per year around the world. Usually effects 30-50 year-olds, but can be seen in all ages.

10. Clinical Features Signs and Symptoms of Glucocorticoid Deficiency: Fatigue, lack of energy Anorexia, Weight loss Myalgia, joint pain Fever Anemia, lymphocytosis, eosinophilia Slightly increased TSH (due to loss of feedback inhibition of TSH release) Hypoglycemia (more frequent in children) Low blood pressure, postural hypotension Hyponatremia (due to loss of feedback inhibition of ADH release)

11. Signs and Symptoms Caused by Mineralocorticoid Deficiency (Primary AI Only) Abdominal pain, nausea, vomiting Dizziness, postural hypotension Salt craving Low blood pressure, postural hypotension Increased serum creatinine (due to volume depletion) Hyponatremia Hyperkalemia

12. Signs and Symptoms Caused by Adrenal Androgen Deficiency Lack of energy Dry and itchy skin (in women) Loss of libido (in women) Loss of axillary and pubic hair (in women) Other Signs and Symptoms Hyperpigmentation (primary AI only) [due to excess of pro- opiomelanocortin (POMC)–derived peptides] Alabaster-colored pale skin (secondary AI only) (due to deficiency of POMC-derived peptides)

14. Acute adrenal insufficiency - Occurs after a prolonged period of nonspecific complaints - More frequently observed in patients with primary AI. - Postural hypotension may progress to hypovolemic shock. - Adrenal insufficiency may mimic features of acute abdomen with abdominal tenderness, nausea, vomiting, and fever. - In some cases, decreased responsiveness, progressing to stupor and coma.

15. Addisonian Crisis: Severely low blood pressure (shock) Hyperkalemia Hyponatremia Hypoglycemia Hypercalcemia Unexplained fever, diarrhea, vomiting Coma and death Precipitated by infection, surgery or intercurrent disease

16. Management It is a medical emergency IV fluid (normal saline 1 L/h with continuous cardiac monitoring and 10% dextrose) Hydrocortisone 100 mg bolus followed by 100– 200 mg hydrocortisone over 24 h infusion or i.v doses until GI symptoms improve then start oral therapy Mineralocorticoid replacement can be initiated once the daily hydrocortisone dose has been reduced to <50 mg Treat precipitating cause

17. Diagnosis of AI Determined by low level of adrenal hormone after stimulation with synthetic ACTH hormone tetracosactide Short Test: 250 micrograms of tetracosactide or cosyntropin (ACTH 1-24), i.m or i.v injection Blood cortisol levels at 0, 30 and 60 min ACTH at 0 min Normal is 500–550 nmol/L (18–20 µg/dL) 30–60 minutes after ACTH stimulation

18. For Ddx: - Plasma ACTH, renin, aldosterone - Adrenal Autoantibody - MRI pituitary - CT or MRI of adrenals CBC Blood Ca and glucose Thyroid function test CXR HIV test Serum Na and K

19. Insulin tolerance test (ITT): Administration of regular insulin 0.1 U/kg IV and collection of blood samples at 0, 30, 60, and 120 minutes for glucose, cortisol, and growth hormone (GH), if also assessing the GH axis. Oral or IV glucose is administered after the patient has achieved symptomatic hypoglycemia (usually glucose <40 mg/dL). A normal response is defined as a cortisol >20 µg/dL and GH >5.1µg/L. It is contraindicated in patients with DM, coronary disease, cerebrovascular disease, or seizure disorders. ITT involves administration of regular insulin 0.1 U/kg IV (dose should be lower if hypopituitarism is likely) and collection of blood samples at 0, 30, 60, and 120 minutes for glucose, cortisol, and growth hormone (GH), if also assessing the GH axis. Oral or IV glucose is administered after the patient has achieved symptomatic hypoglycemia (usually glucose 20 g/dL and GH >5.1 g/L.

20. Treatment Replacement ( always need glucocorticoids and usually mineralcorticoid therapy) Hydrocortison orally 15 mg at morning and 5 mg at evening Doses change according to lifestyle: - doubling the routine oral dose in the case of intercurrent illness with fever - IV hydrocortisone injection at a daily dose of 100 mg in cases of prolonged vomiting, surgery, or trauma Have to carry emergency injection of hydrocortisone and card/bracelet indentifying their condition

21. Mineralocorticoid replacement in primary AI (100–150 g fludrocortisone). The adequacy of treatment can be evaluated by measuring BP, sitting and standing to detect a postural drop indicative of hypovolemia, serum Na, k, and plasma renin should be measured regularly. Adrenal androgen replacement is an option in patients with lack of energy, and in women with loss of libido. - It can be achieved by once-daily administration of 25–50 mg DHEA. Treatment is monitored by measurement of DHEAS, androstenedione, testosterone.

22. References Davidson’s Principles of Internal Medicine 20 th Edition. Harrison’s Principles of Internal Medicine 18 th Edition.