This document discusses disorders of the adrenal glands. It provides objectives and describes the anatomy and physiology of the adrenal glands. It discusses various adrenal disorders including Cushing's syndrome, Cushing's disease, Conn's disease/hyperaldosteronism, Addison's disease, adrenal crisis, and pheochromocytoma. It describes the signs, symptoms, diagnostic workup, and treatment for each condition.

1. Disorders of the Adrenal Glands Patrick Carter MPAS, PA-C Clinical Medicine I March 25, 2011

2. Objectives Describe the anatomy and physiology of the adrenal glands Discuss the anatomical and embryological relationship of the adrenal cortex contrasting with the adrenal medulla List and describe which hormones are produced in the adrenal glands, factors influencing their production and secretion For each of the hormones produced by the adrenal glands, describe their effects on the metabolism of the body Describe Cushing’s syndrome, discussing its: Differentiation from Cushing’s disease Etiology Signs and symptoms Diagnostic tests Significant historical and physical exam findings Management

3. Objectives For Cushing’s syndrome and disease, identify the outcomes of inappropriate or inadequate treatment Discuss how to suspect and diagnose Conn’s Disease or hyperaldosteronism and the significance of hypoaldosteronism For Addison’s Disease, describe the epidemiology, risk factors, signs and symptoms, significant historical and physical exam findings, pathophysiology, diagnostic work-up and management For Addison’s Disease, identify the outcomes of inappropriate or inadequate treatment

4. Anatomy

5. Adrenal Blood Supply

7. Emotional Issues

8. Trauma

9. Infectionstimulate the Hypothalamus to produce corticotropin releasing factor (CRF) which stimulates the Anterior pituitaryto release adrenocorticotropin hormone (ACTH) which causes the Adrenal glands to produce and release cortisol

10. Daily Cortisol Concentration

11. What does Cortisol do?? Actions are directed at enhancing the production of high-energy fuel (glucose) and reducing all other metabolic activity not directly involved in that process Antagonizes the secretion and actions of insulin Promotes hepatic gluconeogensis Inhibits inflammation Suppress the immune response

12. Adrenal Crisis Considerations Causes weakness, abdominal pain, fever, confusion, nausea, vomiting, diarrhea Associated with hypotension, dehydration, hyperpigmentation High Potassium, Low Sodium, High BUN Inability to elevate serum Cortisol An emergency caused by insufficient cortisol

13. Adrenal Crisis Causes Rapid withdrawal of steroids from pts with adrenal atrophy owing to chronic steroid administration (most common) Intensification of chronic adrenal insufficiency that may be rapid and overwhelming Usually precipitated by sepsis or surgical stress

14. Adrenal Crisis Causes (cont’d) Acute hemorrhagic destruction of both adrenal glands Newborns - bilateral adrenal hemorrhage from birth trauma Children – associated with septicemia with Pseudomonas or meningococcemia Adults – trauma, anticoagulant therapy or a coagulation disorder (bilateral adrenal hemorrhage)

15. Adrenal Crisis Causes (con’t) Following sudden destruction of pituitary gland Pituitary necrosis Thyroid hormone given to a patient with hypoadrenalism Following bilateral adrenalectomy or removal of functioning adrenal tumor

16. Adrenal Crisis Signs and symptoms Headache, lethargy N/V, abdominal pain, and diarrhea Confusion or coma Fever, as high as 40.6°C or more Low blood pressure Dehydration Recurrent Hypoglycemia symptoms

17. Adrenal Crisis Laboratory Elevated Eosinophil count Hyponatremia, Hyperkalemia, Elevated BUN and BUN/Cr ratio Positive Blood Cultures if caused by infection Cortisolis protein bound so if low albumin check serum free cortisol level Differential Diagnosis Must be distinguished from other forms of shock

18. Adrenal Crisis Treatment Immediately pull labs including cortisol level Treat immediately with bolus hydrocortisone 100 mg IV with D5NS Continue hydrocortisone 10mg/h or 100mg bolus q6h Following improvement, the steroid dosage is tapered over the next few days to maintenance levels and add fludrocortisone Broad-spectrum antibiotics given empirically

19. Adrenal Crisis Complications Shock and death if untreated Prognosis Rapid treatment usually lifesaving Lack of treatment leads to shock that is unresponsive to volume replacement and vasopressors, resulting in death

20. Addison’s Disease Considerations Weakness, fatigability, anorexia, weight loss, N/V/D, abdominal pain, myalgia, arthralgia, amenorrhea Sparse axillary hair, hyperpigmentation of creases, pressure areas, nipples Hypotension Hyponatremia, Hyperkalemia, Hypercalcemia, Elevated BUN and BUN/Cr ratio, Neuropenia, Mild Anemia, Eosinophilia, Lymphocytosis

21. Addison’s Disease Further Considerations Results from progressive autoimmune destruction of the adrenals (80% in US) May be part of Polyglandular Autoimmune Syndrome Tuberculosis outside of US where it is common Bilateral adrenal hemorrhage Adrenoleukodystrophy >90% of the glands must be involved before adrenal insufficiency appears

22. Addison’s Disease Signs and symptoms Onset is variable and manifestations vary from mild chronic fatigue to fulminating shock Weakness and fatigability Anorexia, nausea and vomiting, weight loss Irritability and restlessness Hypotension 90% have BP <110/70mmHg Hypoglycemia, when present, may worsen weakness and mental functioning

23. Addison’s Disease Signs and symptoms In diabetics, increased insulin sensitivity and hypoglycemic reactions Cutaneousand mucosal pigmentation Diffuse brown, tan or bronze darkening of elbows, creases of hand or areolae Bluish-black patches on the mucous membranes Scant axillary and pubic hair as well as amenorrhea

25. Addison’s Disease Laboratory Tests Early in the disease labs may be normal More advanced stages of destruction result in: Hyponatremia (90%) Hyperkalemia (65%) Fasting blood glucose may be low Hypercalcemia (10-20%)

26. Addison’s Disease Diagnosis Low plasma cortisol at 8am Cosyntropinstimulation test Synthetic ACTH (cosyntropin), 250 μg, given parenterally (IM or IV) Serum cortisol obtained 30 - 60 min later Normally, cortisol rises to >20μg/dL For patients taking steroids, hydrocortisone must not be given for at least 8 h before the test Other corticosteroids do not interfere with specific assays for cortisol(predisone, decadron)

27. Addison’s Disease Diagnosis DHEA > 1000 ng/ml RULES OUT diagnosis Serum DHEA (Dihydroepiandrosterone) levels are <1000 ng/ml in 100% of patients with Addison’s disease (not much help 15% normal patients also)

28. Addison’s Disease Imaging studies (if diagnosis not clear) Chest x-ray for TB, fungal infection, or cancer Abdominal CT Small noncalcified adrenals in autoimmune Addison's disease Adrenals enlarged in about 85% of cases of metastatic or granulomatous disease Calcification noted in cases of tuberculosis (~50%), hemorrhage, fungal infection, and melanoma

29. Addison’s Disease Medications – glucocorticoid and mineralocorticoid replacement required Hydrocortisone (cortisol) Drug of choice Usually 15-30 mg/d Take with food Want to simulate normal diurnal adrenal rhythm 2/3 of dose is taken in the morning 1/3 taken in the late afternoon

30. Addison’s Disease Medications Dose adjusted according to clinical response Corticosteroid dose increased in cases of infection, trauma, surgery, diagnostic procedures, or other stress Mineralocorticoid Fludrocortisone0.05–0.3 mg PO once daily Maintain ample intake of sodium (3-4g/d) Assess adequacy by measuring BP and serum electrolytes (should be normal)

31. Addison’s Disease Medications DHEA 50 mg PO daily may improve loss of muscle mass and reverse bone loss and aid in symptom relief Use prescription form, OTC unreliable dosing

32. Addison’s Disease Follow-Up Follow clinically and adjust corticosteroid and (if required) mineralocorticoid doses Fatigue often persists despite treatment but may indicate Suboptimal dosing of medication Electrolyte imbalance Concurrent problems, such as hypothyroidism or diabetes mellitus

33. Addison’s Disease Complications Adrenal crisis may be precipitated by infection Associated autoimmune diseases are common Excessive corticosteroid replacement can cause Cushing's syndrome

34. Addison’s Disease Prognosis Most patients able to live fully active lives Life expectancy is normal if adrenal insufficiency is diagnosed and treated Corticosteroid and mineralocorticoid replacement must not be stopped Patients should wear medical alert bracelet Higher doses of corticosteroids must be administered to patients with infection, trauma, or surgery to prevent adrenal crisis

35. Hypercortisolism AKA Cushing’s Cushing's "disease" Pituitary tumor that produces ACTH hypersecretion Cushing's "syndrome" refers to manifestations of excessive corticosteroids Rarely spontaneous Cushing’s disease (most common) Autonomous secretion of cortisol by adrenals (unilateral adrenal tumor) Unknown ACTH secretion source Nonpituitary ACTH secreting neoplasms (small cell lung cancer)

36. Hypercortisolism Signs and symptoms Central obesity with thin extremities (“moon facies” or “buffalo hump”) HTN Fatigability and weakness Osteoporosis Females –acne, hirsutism, oligomenorrhea or amenorrhea Males – impotence

37. Hypercortisolism

38. Hypercortisolism Signs and symptoms Insulin resistance and impaired glucose tolerance Skin Acne Purple striae Easy bruising, impaired wound healing

39. Hypercortisolism Signs and symptoms Mental symptoms Diminished concentration Irritability Depression Psychosis Increased susceptibility to opportunistic infections

40. Hypercortisolism

41. Hypercortisolism Differential Diagnosis Chronic alcoholism (alcoholic pseudo-Cushing's syndrome) GHB Abuse “Party Drug” Diabetes mellitus Depression (may have hypercortisolism) Osteoporosis due to other cause Obesity due to other cause Primary hyperaldosteronism

42. Hypercortisolism Laboratory Tests Glucose tolerance impaired - hyperglycemia CBC - leukocytosis Hypokalemia particularly with ectopic ACTH secretion Dexamethasone suppression test Initial screening test Administer 1 mg of dexamethasone orally at 11PM Obtain serum cortisol level at 8 AM next morning Cortisol level < 2 mcg/dL excludes Cushing's syndrome with 98% certainty

43. Hypercortisolism Laboratory Tests 24 Hour urine for free cortisol Order if dexamethasone suppression test shows cortisol level >2 mcg/dL >50μg/d helps confirm hypercortisolism Increased: Pregnancy, Carbamazepine, Fenofibrate If Cushing’s syndrome is confirmed Obtain plasma ACTH <20 pg/ml indicates probable adrenal tumor >60 pg/ml ACTH indicates pituitary or ectopic ACTH-secreting tumors

44. Hypercortisolism Imaging Studies If patient thought to have hypersecretion of pituitary ACTH Pituitary MRI with gadolinium contrast If patient thought to have adrenal tumor CT scan of the abdomen is best CT scan of the chest can help locate source of ectopic ACTH in lungs or thymus Fails to detect the source of ACTH in about 40% of patients with ectopic ACTH secretion Somatostatin receptor scintigraphy – occult tumors

45. Hypercortisolism Treatment Pituitary Adenoma Transsphenoidal resection or Gamma Knife Adrenal Neoplasms ResectedLaparoscopically Metastatic – mitotane, ketoconazole, etc. If unable to locate Laparoscopic bilateral adrenalectomy Watch for cortisol withdrawal syndrome Hypotension, nausea, fatigue, myalgias, etc.

46. Hypercortisolism Prognosis Benign Adrenal Adenoma & Pitutitary Adenoma 5-year survival 95% 10-year survival 90% Ectopic ACTH secreting tumors Varies based on tumor type and location ACTH secretion unknown source 5-year survival 65% 10-year survival 55% Adrenal carcinoma Live only for 7 months

47. Woman who had undergone subtotal adrenalectomy – picture taken 6 months post procedure. So what did this woman have – Cushing’s Disease or Syndrome?

48. Primary Aldosteronism Considerations HTN that maybe drug resistant Hypokalemia Polyuria, Polydipsia Muscle weakness Elevated plasma and urine aldosterone levels Low plasma renin level

49. Primary Aldosteronism Hypersecretionof aldosterone Etiology A benign unilateral adrenal adenoma (Conn’s Syndrome) [Most Common Cause] Unilateral or Bilateral hyperplasia of adrenals Adrenal carcinoma (rare) Epidemiology Very common accounting for 5-10% all cases HTN Affects women more than men (2:1 ratio) Peak years of occurrence from age 30-60

50. Primary Aldosteronism Signs and symptoms Hypertension (typically moderate and diastolic) Hypokalemia due to renal loss Polyuria, polydipsia Muscle weakness (episodic paralysis) Fatigue Parasthesias Headache

51. Primary Aldosteronism Should be suspected in all patients with HTN, especially if Low serum potassium HTN is difficult to control (>2 meds needed) Family history of endocrine tumor

52. Primary Aldosteronism Laboratory findings Serum Electrolytes Hypokalemia(37%) Hypernatremia - infrequent Metabolic alkalosis - may be present with an elevated serum bicarb

53. Primary Aldosteronism Laboratory findings (cont’d) Aldosterone to Plasma Renin Assay ratio If ratio < 24 – excludes primary aldosteronism If ratio >30 Order 24-hour urine collection which is assayed for aldosterone, free cortisol, and creatinine Low PRA (< 5mcg/L/h) with an elevated urine aldosterone (>20 mcg/24h) indicates primary aldosteronism

54. Primary Aldosteronism Management Referral to endocrinologist for initial work-up, if Conn’s suspected Abdominal CT to localize adenoma and r/o carcinoma Adrenal vein sampling if CT is negative

55. Primary Aldosteronism Initial treatment Unilateral Adenoma – laparoscopic surgical excision Bilateral hyperplasia (and pt who don’t want surgery for adenoma) Dietary sodium restriction Spironolactone (aldosteroneantag) 25mg Daily Controls HTN and hypokalemia Side effects in men – gynecomastia, decreased libido, impotence Eplerenone(less potent) 50-150mg TID with minimal antiandrogeneffects – better in men

56. Primary Aldosteronism Prognosis Reverse HTN in 2/3 cases with treatment Single adenoma Able to stop medication after surgery Will need to be monitored for life Bilateral hyperplasia Lifelong medication Life-long monitoring of effectiveness and side effects Only 2% aldosterone secreting tumors are malignant

58. Pheochromocytoma Well vascularized tumors that arise from cells derived from paraglangia of the Sympathetic – adrenal medulla Parasympathetic

59. Pheochromocytoma Epidemiology Rare Occurs in 2-8 out of 1 million persons/yr < 0.1% of hypertensive patients harbor a pheochromocytoma Mean age at diagnosis is 40 years Can occur from early childhood until late in life

60. Pheochromocytoma Signs and symptoms Variable clinical presentation and known as the “great masquerader” Classic triad Episodes of headache, profuse perspiration, and palpitations Hypertension in is the dominant sign May be sustained or episodic

61. Pheochromocytoma Signs and symptoms Paroxysms generally last <1 hour During episodes of hormone release patients are anxious, pale and they experience tachycardia and palpitations May be precipitated by surgery, positional changes, exercise, pregnancy, urination and various medications (TCAs, opiates)

62. Pheochromocytoma Catecholamine crisis can lead to Heart failure Pulmonary edema Arrhythmias Intracranial hemorrhage

63. Pheochromocytoma Differential Diagnosis Essential hypertension Panic attacks Use of cocaine or amphetamines Intracranial lesions Thyrotoxicosis Paroxysmal tachycardia

64. Pheochromocytoma Diagnosis Documentation of catecholamine excess by biochemical testing and localization of the tumor by imaging Biochemical testing These tumors store catecholamines, which include epi, norepi and dopamine High plasma and urine catecholamine and metanephrine during or shortly after attack

65. Pheochromocytoma Biochemical testing (cont’d) 24 hour Urinary vanillylmandelic acid (VMA) and catecholamines Free plasma metanephrine When values are increased 2-3 times the upper limit of normal, a pheo is highly likely For borderline elevations – likely false positive Repeated testing may clarify the diagnosis

66. Pheochromocytoma Imaging Studies Thin-section CT or MRI of adrenals Sensitivity of ~90% for adrenal pheochromocytoma They are similar in sensitivity If no adrenal tumor found, CT scan extended to abdomen, pelvis, and chest

67. Pheochromocytoma Treatment Surgical Laparoscopic removal of tumor is the treatment of choice HTN must be controlled prior to surgery Preoperatively Alpha-adrenergic blockader Phenoxybenzamine, starting with a low dose and increasing about every 3 days until hypertension is controlled Calcium channel blockers Beta blockers Can be added after alpha blockers and calcium channel blockers if tachycardia persists

68. Pheochromocytoma Malignant pheo Term is generally restricted to tumors with distant metastases Most commonly found in lungs, bone or liver Treatment options Tumor mass reduction Alpha blockers for symptoms Chemotherapy Nuclear medicine radiotherapy 5 year survival is 30-60%

69. Pheochromocytoma Complications Severe hypertension  end organ damage Catecholamine-induced cardiomyopathy Sudden death from cardiac arrhythmia Hypertensive crises with stroke

70. Pheochromocytoma Prognosis Complete cure usually achieved if tumor successfully removed before irreparable cardiovascular damage In about 25%, hypertension persists or returns in spite of successful surgery Surgical mortality rate < 3% Death may occur from hypertensive crisis

71. Questions???