Adrenal insufficiency

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

Medulla – sympathetic functions Cortex (Remember GFR) Glomerulosa – (mineralocorticoids) Fasiculata – (glucocorticoids) Reticularis – (androgens) Medulla – sympathetic functions

Adrenal products

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

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

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

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

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

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

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

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.

Primary adrenal insufficiency Associated 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.

Secondary adrenal insufficiency Causes 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.

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.

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.

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

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

Why hyperpigmentation?

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.

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.

Diagnosis 1. Screening test Early morning basal total/free serum cortisol and plasma corticotropin Plasma aldosterone and renin activity (salivary cortisol) (Urinary free cortisol excretion)

Diagnosis 2. 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

Treatment glucocorticoid replacement acute adrenal crisis 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. Prednisone 5 mg daily 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

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.

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