Paul D Simmons, MD 4 January 2017 Adrenal Diseases Paul D Simmons, MD 4 January 2017

The Road Ahead Review of adrenal anatomy and physiology Addison’s disease Secondary adrenal insufficiency Cushing’s disease Primary aldosteronism Adrenal “incidentalomas” Rarities not covered: congenital adrenal hyperplasia, pheochromocytoma, secondary aldosteronism

Review of Adrenal Anatomy and Physiology Cortex Glucocorticoids (cortisol) Mineralocorticoids (aldosterone) Androgens (DHEA & androstenedione) Medulla Chromaffin cells: epi, norepi, histamine, serotonin, etc.

Functions of Major Cortical Hormones HORMONE CLASS EXEMPLAR FUNCTIONS Glucocorticoids Cortisol Anti-inflammatory and hepatic gluconeogenesis Mineralocorticoids Aldosterone Regulates electrolyte exchange across membranes, esp Na/K Adrenal androgens DHEA and androstenedione Converted to testosterone and dihydrotestosterone

HYPOFUNCTION DISORDERS Failure produces TERTIARY hypofunction disorders Failure produces SECONDARY hypofunction disorders Failure produces PRIMARY hypofunction disorders Ex: Addison’s (primary adrenal insufficiency)

Hyperfunction Disorders HORMONE AFFECTED SYNDROME Adrenal androgens Adrenal virilism Glucocorticoids Cushing syndrome Aldosterone Hyperaldosteronism Catecholamines Pheochromocytoma

Addison Disease

Addison Disease (Primary Adrenal Insufficiency) Cause: Usually idiopathic (70%), possibly autoimmune; can be due to TB, amyloidosis, hemorrhage, metastasis or drugs blocking metabolism (e.g., ketoconazole). Pathophysiology Deficient mineralocorticoids and glucocorticoids Low aldo → increased Na excretion, decreased K excretion → hyponatremia, hyperkalemia Urinary Na and H2O loss → hypovolemia, acidosis, hypotension, shock Glucocorticoid deficiency → hypotension, increased insulin sensitivity, decreased gluconeogenesis and decreased glycogen stores, weakness, immunodeficiency Low cortisol → increased ACTH production → hyperpigmentation

Addison Disease (Primary Adrenal Insufficiency) Symptoms and Signs: Early: Weakness, fatigue, orthostatic hypotension Hyperpigmentation Anorexia, nausea, vomiting, diarrhea, intolerance to cold Late: Weight loss, dehydration, persistent hypotension

Addison Disease (Primary Adrenal Insufficiency) Diagnosis: Often “discovered” by incidental hyponatremia and hyperkalemia, low HCO3, high BUN and hypoglycemia Confirmatory testing: low morning serum cortisol and high morning serum ACTH (cf. low ACTH + low cortisol in secondary adrenal insufficiency) If borderline ACTH and cortisol, consider ACTH stim test - a dose of ACTH should increase the serum cortisol. If not, confirms Addison’s. Other findings: high hct, low WBC, lymphocytosis and eosinophilia

Addison Disease (Primary Adrenal Insufficiency) Treatment: Hydrocortisone or prednisone Hydrocortisone 20mg daily divided TID, usually 10mg AM, 5mg noon, 5mg evening. Prednisone 5mg AM, 2.5mg PM. Fludricortisone Replaces aldosterone 0.1 - 0.2 mg daily, dose adjusted to keep renin levels normal Watch for hypertension Dose increase during acute illness Double the usual doses of hydrocortisone or prednisone Rx a preloaded syringe of hydrocortisone 100mg for the patient Patient should wear a medical alert tag/bracelet

Secondary Adrenal Insufficiency

Secondary Adrenal Insufficiency Pituitary-Level Lack of ACTH Stimulation Causes: Panhypopituitarism, isolated failure of ACTH-secreting cells (corticotrophs), or sudden stop of exogenous steroids. Diagnosis: Low ACTH and low serum cortisol. Confirmatory ACTH stim test will have normal or subnormal bump in cortisol. All cases should have CT/MRI imaging of pituitary to rule out mass or atrophy. No hyperpigmentation and normal Na/K. Treatment: hydrocortisone or prednisone as in Addison’s disease; increase in acute illness. BUT...fludricortisone is not needed - the intact adrenals produce aldosterone.

Cushing Syndrome and Disease

Cushing Syndrome vs. Cushing Disease Constellation of symptoms and signs from chronic high levels of cortisol and other corticosteroids. Cushing DISEASE = Cushing syndrome caused specifically by excess pituitary secretion of ACTH, usually due to a pituitary adenoma.

Etiology of Cushing Syndrome ACTH Independent ACTH Dependent Hypersecretion by pituitary (Cushing disease) Steroids Rx Adrenal adenoma or carcinoma Secretion by non-pituitary tumor (SCLC, carcinoid) Exogenous ACTH

Cushings - Clinical Features Moon facies with plethora Truncal obesity (supraclavicular and dorsal cervical fatpads (“buffalo hump”)) Slender distal extremities, fingers Muscle wasting, weakness Skin thinning, easy bruising Purple abdominal striae HTN, renal calculi, glucose intolerance, immunosuppression

Diagnosis of Cushing Syndrome Urinary free cortisol Almost all Cushing pts have UFC > 120, but many pts with UFC 100-150 have obesity, PCOS or depression. If clinical syndrome + very high UFC (4x ULN) = diagnosis If clinical syndrome + mildly high or normal UFC → further testing Dexamethasone suppression test Give 1-2mg dexamethasone PO at 2300-0000, then check cortisol at 0800-0900 Normal: =< 1.8 ug/mL; if Cushing pts have higher levels Another option (low-dose): 0.5 mg PO q 6h x 2 days Midnight serum or salivary levels Normal diurnal cycle nadir is 1.8 ug/mL at midnight; Cushing pts have higher levels Serum ACTH levels; if detectable, provocative testing (dexameth or CRH) Undetectable ACTH = adrenal cause; high ACTH = pituitary cause

Diagnostic Tests in Cushing Syndrome Diagnosis Serum Cortisol, 9 am Salivary or Serum Cortisol, Midnight Urinary Free Cortisol Low-Dose or Overnight Dexamethasone High-Dose Dexamethasone Corticotropin-Releasing Hormone ACTH Level Normal N N* S Cushing disease N or ↑ ↑ NS Ectopic ACTH Flat ↑↑ Adrenal tumor ↓ *May be elevated in non-Cushing conditions. Flat = no significant rise in ACTH or cortisol; N = normal; NS =nonsuppression; S = suppression; ↑↑= greatly increased; ↑=increased; ↓=decreased.

Treatment of Cushing Syndrome High protein intake, potassium administration or potassium-sparing diuretics Acute treatment to stabilize patient Adrenal inhibitors Metyrapone or ketoconazole → inhibit cortisol secretion by the adrenals Surgery or radiation therapy for pituitary, adrenal or ectopic tumors Complex, and may need specialty centers in pediatric patients Somatostatin analogues, dopamine agonists (cabergoline) or mifeprestone (blocks cortisol receptors, but increases cortisol levels and can cause hypokalemia) Specialty consultation is recommended, especially if surgical/radiotherapy not an option (e.g., widespread metastatic disease).

Primary Aldosteronism (Conn Syndrome)

Aldosterone Most potent mineralocorticoid → Na retention in the renal distal tubule and K /H+ wasting → hypervolemic hypernatremia, hypokalemia, metabolic alkalosis. Primary aldosteronism is caused by an adrenal adenoma, carcinoma or hyperplasia (e.g., congenital adrenal hyperplasia).

Clinical Features of Primary Aldosteronism Hypervolemia Hypernatremia Hypokalemia Metabolic alkalosis Episodic weakness, paresthesias, transient paralysis, tetany Diastolic hypertension Hypokalemia nephropathy with polyuria, polydipsia Often, mild-moderate hypertension can be the only manifestation! Edema is UNCOMMON

Diagnosis of Primary Aldosteronism Illness script: Hypertension and hypokalemia. Plasma aldosterone level Plasma renin activity (PRA) Ideally, no renin-angiotensin-aldosterone drugs (thiazides, ACEI/ARB, beta-blockers) for 4-6 wks prior to testing PRA measured in the morning with patient recumbent Diagnosis: plasma aldosterone >15 ng/mL, low PRA, PAL:PRA > 20 Low PAL, low PRA = non-aldosterone mineralocorticoid excess (licorice, Cushing, Liddle synd.) High PAL, high PRA = secondary hyperaldosteronism Adrenal imaging and catheterization CT or MRI to distinguish between adenoma vs hyperplasia Adrenal vein catheterization to determine if unilateral (adenoma) or bilateral (hyperplasia)

Treatment of Primary Aldosteronism Surgical removal of adenomas Surgical adrenalectomy not effective in 70% of pts with hyperplasia, so not recommended Medical therapy for hyperplasia Spironolactone, eplerenone for hyperplasia Eplerenone is more specific, does not antagonize the testosterone receptor, so recommended in men Most hyperplasia patients need anti-HTN therapy

Adrenal Incidentalomas

Adrenal Masses Incidentally Found on Imaging The number to remember: If > 4cm, biopsy. Epidemiology: found on 3-4% of CTs and MRIs. One study: 1.2% of lesions were malignant, all were >5cm in diameter Metastases to the adrenals: bronchogenic carcinoma, renal cell cancer, melanoma.

Evaluation of Adrenal Incidentalomas Size Follow-up / Evaluation < 1 cm with fatty or cystic features No further follow-up needed 1-4 cm Most benign - repeat imaging in 6-12 mos, 10 HU or less on contrast CT, CT washout or other specialized tests > 4 cm (unless clearly benign, e.g. cyst or myelolipoma) Further specialized imaging, biopsy in most cases

What About Testing for Functioning Masses? If no symptoms or signs suggestive of functional mass (i.e., Cushingoid features, electrolyte abnormalities…) - no testing needed. Mayo Clinic recommends yearly surveillance with: 24-hour urine cortisol Plasma metanephrine/catecholamine levels Plasma renin activity, plasma aldosterone level Reference: ACR Appropriateness Criteria: https://acsearch.acr.org/docs/69366/Narrative/

Key Learning Points Primary = adrenal gland; secondary = pituitary; tertiary = hypothalamic Addison disease diagnosis - hyponatremia, hyperkalemia, hypotension, hyperpigmentation; diagnosis via low morning cortisol, high morning ACTH Addison disease treatment - hydrocortisone and fludricortisone; don’t forget increased stress doses in illness! Secondary adrenal insufficiency - low cortisol AND low ACTH; treat with hydrocortisone but no fludricortisone needed Cushing diagnosis - UFC, dexa suppression test, midnight cortisol levels Cushing treatment - surgery for adenoma; medication for hyperplasia Adrenal incidentaloma - <1cm benign; 1-4cm depends; > 4cm biopsy; check ACR Appropriateness for imaging