Cushing’s, Adrenal Insufficiency and Other Glucocorticoid Related Issues Family Practice Residency Program Waterloo, IA September 11, 2013 Janet A. Schlechte, M.D.

Disclosure of Financial Relationships Janet A. Schlechte, M.D. has no relationships with any proprietary entity producing health care goods or services consumed by or used on patients.

Objectives Approach to glucocorticoid excess Management of adrenal insufficiency Peri-op management of glucocorticoids Steroid taper

Cushing’s Syndrome Causes ACTH secreting pituitary tumor Adrenal adenoma/carcinoma Ectopic ACTH production Exogenous glucocorticoid

Classic Features of Cushing’s Centripetal obesity Violaceous striae Proximal muscle weakness Amenorrhea Thin skin Bruising

Other Features of Cushing’s Hypertension Glucose intolerance Diabetes Hypokalemia Bone loss

Causes of Cushing’s Syndrome ACTH secreting pituitary tumor Adrenal adenoma/carcinoma Ectopic ACTH production Exogenous glucocorticoid

Pituitary versus Adrenal Cushing’s

Ectopic ACTH Secretion Severe hypokalemia Metabolic alkalosis Muscle weakness Few of the classic stigmata Hyperpigmentation

Cushing’s Syndrome Rare disorder How often will it present in the primary care setting?

Many people complain of weight gain and bruising but few have Cushing’s Even astute clinicians should screen for glucocorticoid excess

Screening Tests 24 hour urine cortisol 1 mg dex test 11 p.m. salivary cortisol

24 Hour Urine Cortisol Inconvenient but most sensitive May need to do more than one unless results are 2-3x normal Occasional false positives

Diurnal Variation of Cortisol Pre-Dex Cortisol Post-Dex Time

1 mg Dex Test 1 mg dexamethasone at 11 p.m. and measure 8 a.m. cortisol the next day Healthy subjects will have cortisol <2 µg/dl

1 mg Dex Test false positives - dilantin - obesity - estrogen - stress - depression

A 30 y. o. woman has gained 20 pounds over the last six months A 30 y.o. woman has gained 20 pounds over the last six months. She has also noted leg swelling and her blood pressure is harder to control. She takes HCTZ and a BCP. B/P 140/100, BMI 35, bruises on legs, buffalo hump, pale pink striae.

She has read about Cushing’s syndrome and is worried about a pituitary tumor Potassium 3.8, A1C 5.6%, CBC nl

She takes 1 mg of dex at 11 p. m. and an 8 a. m She takes 1 mg of dex at 11 p.m. and an 8 a.m. cortisol the next day is 10 µg/dl. Does she have Cushing’s?

She collects a 24 hour UFC and the result is 53 µg/dl (<50) Does she have Cushing’s?

A 40 y. o. man has poorly controlled hypertension A 40 y.o. man has poorly controlled hypertension. His weight has increased by 50 lb in the last year. He has bright purple striae and significant muscle weakness. A 1 mg DST shows a cortisol of 20 so screening test is positive.

To rule out a false positive do confirmatory test He collects a 24 hour UFC and the value is 350 µg/dl (<50) Test is positive – he has Cushing’s Now what?

When cortisol excess is confirmed draw ACTH  ACTH  Pituitary tumor Adrenal tumor Ectopic

Glucocorticoid Excess Screening Test Normal Abnormal Confirm Test Stop Abnormal Normal Get ACTH Stop Undetectable Elevated Adrenal Pituitary Ectopic Do DST to differentiate

Urinary free cortisol baseline 2 mg 8 mg ACTH 300 µg 180 40 989 µg 991 Pituitary Hyperfunction Adrenal Tumor Ectopic Production Urinary free cortisol baseline 2 mg 8 mg ACTH 300 µg 180 40 989 µg 991 990 undet. 4034 µg 4000 3989

A 41 y. o. collapsed on the golf course in August A 41 y.o. collapsed on the golf course in August. For 6 months he has been tired with intermittent nausea, abdominal pain and deterioration of his golf game. In the ER his BP was 60/- with a pulse of 130. He has a deep tan, pigmented buccal mucosa, a small thyroid and a normal neuro exam.

In The ER Sodium 125 Potassium 6.4 Chloride 98 CO2 18 Creatinine 1.4 Glucose 75

Features of Primary AI Hyperpigmentation Fatigue and weakness Hypotension Postural dizziness Abdominal pain Weight loss

Causes of Primary Adrenal Insufficiency Autoimmune Adrenal hemorrhage Granulomatous disease

Your working diagnosis is primary adrenal insufficiency. How do you confirm your suspicion?

Cortrosyn stimulation test - Measure plasma cortisol before and 1 hour after IM injection of 250 µg ACTH (cortrosyn)

Short Cortrosyn Stimulation Test Cortisol Normal 1° AI

After cortrosyn stimulation test begin steroid replacement. Little practical reason to start dexamethasone before cortrosyn.

Stimulated cortisol 0.1 µg/dl After the cortrosyn test the IV saline is continued and you give the 100 mg of hydrocortisone. One hour later the lab calls with the cortisol results. Basal cortisol 0.1 µg/dl Stimulated cortisol 0.1 µg/dl

Stimulated cortisol 25 µg/dl What if the results were Basal cortisol 9 µg/dl Stimulated cortisol 25 µg/dl

Classical Glucocorticoid Equivalents Daily Replacement Doses 5 mg Prednisone 20-25 mg Hydrocortisone 0.75 mg Dexamethasone 37.5 mg Cortisone acetate

More Physiologic Equivalents Daily Replacement Doses 5 mg Prednisone 10-15 mg Hydrocortisone 0.75 mg Dexamethasone

Treatment Guidelines Monitor therapy clinically and with electrolytes. Can’t use ACTH or cortisol to monitor therapy. Consider other autoimmune disease.

Long-Term Therapy Hydrocortisone (10-15 mg/day) Start with hydrocortisone and add florinef as needed. Florinef (0.05-0.1 mg/day)

Educate patient about use of steroid during “stress” Yearly follow-up

Stress dose? Pulling wisdom teeth Colonoscopy Endometrial biopsy Flu with aches and pains

Stress dose? CABG Hip replacement Final exams Death in the family

A 45 y.o. woman with RA has been treated with 10 mg of prednisone for 3 years. She will undergo laparoscopic surgery in 2 days. Her surgeon wants you to write pre-op orders.

Pituitary adrenal axis is suppressed  ACTH due to exogenous glucocorticoid Stopping glucocorticoid and/or stress of surgery could lead to adrenal crisis

Peri-Operative Corticosteroid Coverage Minor surgical stress - usual dose day of procedure Moderate surgical stress - 50 mg HC day of procedure then resume usual dose Ann Surg 219:416, 1994

Peri-Operative Corticosteroid Coverage Major surgical stress - 100 mg HC on day of procedure - 50 mg HC on post-op day 1 Resume usual dose unless clinical condition deteriorates Ann Surg 219:416, 1994

Avoid too much glucocorticoid After a stress dose rapidly resume the replacement dose Don’t use cortisol or ACTH to try to monitor therapy

A 60 y.o. man has taken 60 mg of prednisone daily for 6 months for anterior ischemic optic neuropathy. His ophthalmologist has seen no improvement and wants to stop the steroid.

The Dilemma Stopping the drug will lead to secondary adrenal insufficiency He has muscle weakness and weight gain and his T score is -2.9. The glucocorticoid needs to be stopped as rapidly as possible

Taper Option # 1 January 1 January 15 January 30 February 1 March 1 60 mg 40 mg 20 mg 10 mg 5 mg Off

Taper Option # 2 January 1 January 15 February 1 March 1 April 1 60 mg 60 mg q.o.d. 30 mg q.o.d. 10 mg q.o.d. Off

Taper Option # 3 January 1 January 2 February 1 March 1 April 1 May 1 etc. until off 60 mg 10 mg 9 mg 8 mg 7 mg 6 mg

Questions to Ask What is the reason for the taper? Is it to avoid recurrence of disease? Is it to avoid adrenal crisis?

Effect of Dose of Hydrocortisone on Mortality RR 95% CI p 0<HC<20 1.3 0.7-2.6 ns 20<HC<25 1.4 0.6-3.3 ns 25<HC<30 1.6 1.1-2.4 .014 HC>30 2.9 1.4-5.9 .003 JCEM 94:4216, 2009

Take Home Points Remember glucocorticoid equivalencies Use stress doses sparingly When HPA axis is suppressed, taper slowly beginning at a maintenance dose

A 42 y.o. with a history of chronic back pain has severe fatigue and the lab pages you because his cortisol is 1.0 and his TSH is 1.4.

One of your patients takes 5 mg of prednisone daily after an organ transplant. She is having her wisdom teeth pulled tomorrow morning and calls to find out what to do about her prednisone since she will be NPO.