Kingdom of Bahrain Arabian Gulf University College of Medicine and Medical Sciences

1. Kingdom of BahrainArabian Gulf UniversityCollege of Medicine and Medical Sciences Unit IV – Problem 5 – Clinical Disease of Adrenal Gland Prepared by: Ali JassimAlhashli Based on: Kaplan Step 2 CK Internal Medicine

2. Adrenal gland anatomy: it is divided into • Cortex: which is further subdivided into 3 layers • Zonaglomerulosa: producing aldosterone which is under the regulation of renin-angiotensin system and potassium level. • Zonafasciculata: producing cortisol which is under the regulation of ACTH from adenohypophysis. • Zonareticularis: producing androgens which is under the regulation of ACTH from adenohypophysis. • Medulla: producing epinephrine and is under the control of autonomic nervous system. • Hyperfunctioning of adrenal gland: • Cushing syndrome: • Definition: clinical abnormalities which result from prolonged exposure to increased level of cortisol in the body. • Etiology: • Most common cause: exogenous (prolonged use of glucocorticoids). • Cushing disease: which can be caused by ACTH-producing pituitary adenoma or an ectopic tumor which is secreting ACTH or Coticotropin-Releasing Hormone (CRH). • Adrenal neoplasia(adenoma or carcinoma). • Clinical manifestations: • Truncal obesity with thin limbs. • Moon-face with buffalo hump. • Purplish striae especially on the abdomen. • Females might have: acne, hirsutism and menstrual irregularities (die to ↑androgen secretion). • Osteoporosis. • Hypertension. • Glucose intolerance (with 20% of patients having diabetes). • Hypokalemia (due to mineralocorticoids effect of increased glucocorticoids). • Increased risk for infections (neutrophils do not function well with ↑glucocorticoids). Diseases of Adrenal Gland

3. Diseases of Adrenal Gland

4. Hyperfunctioning of adrenal gland (continued): • Cushing syndrome (continued): • Diagnosis: • There are 3 diagnostic tests which tell you if patient has cushing syndrome (↑cortisol level): • 24-hour urinary free cortisol (gold standard). • Low-dose (1 mg) dexamethasone suppression test. • Midnight salivary cortisol. • You start with low-dose (1 mg) dexamethasone suppression test which is given at 11:00 pm. Cortisol level will be measured at 8:00 am (next morning). Normally, dexamethasone will suppress cortisol production but in patients with cushing syndrome cortisol will remain high and will not be suppressed. • Then, you confirm your diagnosis with 24-hour urinary free cortisol which will reveal high level of cortisol. • When you establish the diagnosis of cushing syndrome, you have to determine the specific etiology. This is done by measuring ACTH level. If it is low → this indicates that the source is from adrenal gland (adenoma, carcinoma or hyperplasia) → you have to confirm by doing abdominal CT/MRI. • If ACTH level is high, this can be due to pituitary adenoma or ectopic tumor. To differentiate between them, you will do the high-dose (2 mg) dexamethasone suppression test. If ACTH is suppressed, this is an ACTH-producing pituitary adenoma and you will confirm that by MRI of pituitary. If ACTH is not suppressed, this is an ectopic tumor and you will confirm that by CT-scan of the chest. • Management: this depends on the etiology and can be medical or surgical. Notice that unresectable adrenal tumors will be managed with metyrapone (which blocks the production of cortisol). Diseases of Adrenal Gland

5. Diseases of Adrenal Gland

6. Hyperfunctioning of adrenal gland (continued): • Hyperaldosteronism: • Definition: increased level of aldosterone. Notice that the normal function of aldosterone is: • Reabsoprtion of sodium followed by water (and this will lead to increased intravascular volume). • Excretion of potassium (resulting in hypokalemia and its manifestations: muscle weakness, polyuria and polydypsia). • Excretion of hydrogen ions (resulting in metabolic alkalosis). • Etiology: • Primary hyperaldosteronism (problem is in adrenal gland itself): most commonly caused by unilateral adrenal adenoma (70% of cases). It can also be caused by bilateral adrenal hyperplasia. Increased aldosterone production will result in increased rebasorption of sodium followed by water to increase the intravascular volume. Therefore, renin-angiotensin system will be suppressed. • Secondary hyperaldosteronism(etiology is extra-adrenal): there is decreased intravascular volume leading to activation of renin-angiotensin system which in turn results in increased production of aldosterone. • Clinical manifestations (primary hyperaldosteronism): • Hypernatremia and Hypertesnion. • Hypokalemia (with muscle weakness, polyuria/polydypsia). • Metabolic alkalosis. • Diagnosis: • Positive screening: Plasma Aldosterone Concentration (PAC) < 15; PAC to Plasma Renin Activity (PRA) ratio < 20:1 • Confirming the diagnosis by NaCl challenge: in which PAC will remain elevated (not suppressed). • Traatment: • Unilateral adrenal adenoma: surgical removal. • Bilateral adrenal hyperplasia: potassium-sparing diuretic (spironolactone) which blocks aldosterone. Diseases of Adrenal Gland

7. Hypofunctioning of the gland: • Adrenal insufficiency: • Etiology: it is divided to: • Primary adrenal insufficiency (Addison’s disease): which is commonly due to autoimmune destruction of adrenal gland (80% of cases). It can also result from trauma, hemorrhage, surgical removal or infections (TB) of adrenal gland. It this condition, there is ↓cortisol and aldosterone with ↑ACTH (because there is no negative feedback). • Secondary adrenal insufficiency: the problem is at the level of pituitary gland in which there is ↓ACTH production. Therefore, there is ↓cortisol but aldosterone will be normal (because aldosterone is not regulated by ACTH). • Clinical manifestations (Addison’s disease): • ↓cortisol: weakness, cramping, intolerance to stress, hypoglycemia, anorexia with weight loss and hypotension. • ↓aldosterone: hyponatremia, hyperkalmeia and metabolic acidosis. • ↑ACTH: hyperpigmentation with tanning of exposed and un-exposed body parts. • Differences between primary and secondary adrenal insufficiency: hyperpigmentation (which occurs only with primary adrenal insufficiency), electrolyte abnormalities and hypotension. • Diagnosis: • Primary adrenal insufficiency: there is ↓cortisol and ↑ACTH. With ACTH-stimulation test → there is absent or minimal increase in cortisol level. • Acute Secondary adrenal insufficiency: there is ↓ACTH resulting in ↓cortisol. With ACTH-stimulation test → there is increased in cortisol level. • Chronic secondary adrenal insufficiency: there is ↓ACTH resulting in ↓cortisol. With ACTH-stimulation test → cortisol level will NOT increase (because adrenal glands are atrophied by that time due to prolonged lack of ACTH). • Management (Addison’s disease): • Glucocorticoid + mineralocorticoid. • Adrenal crisis: • Occurs in: • Patient who stops glucocorticoid therapy suddenly. • Previously undiagnosed patient with adrenal insufficiency undergoing surgery, infection or major stress. • Bilateral adrenal hemorrhage or infarction. • Clinical manifestations: fever, vomiting, abdominal pain, altered mental status and vascular collapse. • Management: get a cortisol level then immediately replace with IV fluid and hydrocortisone. Diseases of Adrenal Gland

8. Diseases of Adrenal Gland

9. Pheochromocytoma: • Definition: it is a usually benign tumor arising from chromaffin cells of sympathetic nervous system. Remember the rule of 10%: • 10% extra-adrenal. • 10% malignant. • 10% in children. • 10% bilateral. • 10% NOT associated with hypertension. • Epidemiology: • Pheochromocytoma comprises 0.1% of hypertension cases. • Familial pheochromocytoma is inherited as autosomal dominant trait. • Pathology: • Adults: pheochromocytoma is usually a unilateral solitary tumor (usually on the right side) with 10% being bilateral and 10% being extra-adrenal. • Children: 25% extra-adrenal and 25% bilateral • Catecholamines are secreted (dopamine, epinephrine and norepinephrine). Epinephrine causes: sweating, tachycardia, flushing and hypertension. • Clinical manifestations: attack has a sudden onset, lasting from few minutes to several hours and characterized by headache, profuse sweating, palpitations, flushing, hypertension, anxiety and tremor. Notice that <33% of pheochromocytomas will cause death prior to diagnosis due to arrhythmias or stroke. • Diagnosis: urinary metanephrine (most sensitive and specific), urinary free catecholamines, plasma catecholamines and urinary VMA. Then, confirm the presence of the tumor by CT/MRI. • Management: • Α-blockers (phentolamine) to stabilize blood pressure of the patient. This is followed by β-blockers (propranolol) to control tachycardia. • Then, surgical removal of the tumor (don’t forget IV phentolamine during surgery). Diseases of Adrenal Gland