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ADRENALS & INCIDENTALOMAS The Adrenal Physiology Adrenal Insufficiency, Primary & Secondary Adrenal Incidentaloma Adrenal Physiology Steroid Biosynthesis Glucocorticosteroids Aldosterone Androgen Steroid Biosynthesis Zona Fasiculata Cortisol Production • 10-20 mg/day • Controlled Primarily By ACTH • Negative and Positive Feedback Between Cortisol and ACTH at Pituitary and Hypothalamic Levels Hypothalamic-Pituitary Adrenal Axis CRH Hypothalamus Pituitary ACTH Adrenal Cortisol ACTH Cortisol = Stimulation = Inhibition Cortisol Davidsons 22nd Ed, 2015 Steroid Biosynthesis Zona Fasiculata Zona Glomerulosa Aldosterone Production • 100-150 ug/day • Stimulated by the Renin-Angiotensin System Decreased Perfusion Pressure • Hyperkalemia Stimulates and Hypokalemia Inhibits Aldosterone Secretion • ACTH Acutely May Stimulate Aldosterone Secretion Steroid Biosynthesis Zona Fasiculata Zona Glomerulosa Zona Reticularis Androgen Synthesis • ACTH: Capable of Stimulating Adrenal Androgens However, • Dissociated From Cortisol Production in Many Physiological and Pathological Situations Adrenal Physiology Steroid Biosynthesis Glucocorticosteroids Aldosterone Androgen Catecholamine Production Case 1: 42 Year Old Female Admitted for Abd Pain, Nausea, Vomiting x 5 Days Lightheaded on Standing x 6 Months; Fatigue x 2 Years; Amenorrhea x 3 Years PE: 108/60 76/40; P 120; Diffuse Hyperpigmentation with Buccal Discoloration Lab: Na 128, K+5.7, Cl 110, Bicarb 19 Adrenal Insufficiency: Clinical Manifestations Clinical Manifestations “…a morbid state, the leading and characteristic features of which are anemia, general languor and debility, remarkable feebleness of the heart’s action, irritability of the stomach and a peculiar change of color of the skin, occurring in connection with a diseased condition of the suprarenal capsules” Physiologic Functions • Glucocorticoid Production • Mineralcorticoid Production • Androgen Production General Fatigue Generalized Weakness Anorexia Weight Loss Diffuse Myalgias and Arthralgias Davidsons 22nd Ed, 2015 Hypoglycemia • Hypoglycemia Can Occur After Prolonged Fasting Or Several Hours After a High-CHO Meal • Rare in Adults in the Absence of Infection, Fever, or Alcohol Gastrointestinal Complaints • Nausea, Occasionally Vomiting • Diarrhea That May Alternate With Constipation • Vomiting and Abdominal Pain Often Herald Adrenal Crisis • Cause of GI Symptoms Unknown Hyperpigmentation • Seen in Primary Adrenal Insufficiency Only • Caused by High ACTH Concentrations Auricular-Cartilage Calcification • Calcification of the Auricular Cartilages Occurs in Primary or Secondary Adrenal Insufficiency • Occurs Mostly in Males Calcification of Auricular Cartilage in Addison’s Disease Psychiatric Manifestations Impairment of Memory Depression Psychosis Physiologic Functions • Glucocorticoid Production • Mineralcorticoid Production • Androgen Production Mineralocorticoid Deficiency: Salt Craving Increased Thirst for Ice Cold Liquids Hyperkalemia With a Mild Hyperchloremic Acidosis Hyponatremia: Inappropriate ADH Secretion Due To Cortisol Deficiency; Salt Wasting Cardiovascular • Hypotension • Postural Dizziness or Syncope • The Presence of Hypertension Is Strong Evidence Against a Diagnosis of Adrenal Insufficiency Adrenal Physiology Steroid Biosynthesis Glucocorticosteroids Aldosterone Androgen Sexual Dysfunction • Decreased Axillary and Pubic Hair and Loss of Libido Are Common in Women • Amenorrhea in 25% of Women Diagnosis • Are the Adrenals Functioning? • If Not, Why Not? Diagnosis Are the Adrenals Functioning? - Cortisol Concentration - Adrenal Stimulation Testing Always Remember Hormone Pairs Get The ACTH Level!!! Hypothalamic-Pituitary Adrenal Axis: Primary Adrenal Insufficiency CRH Hypothalamus Pituitary ACTH Cortisol ACTH Cortisol = Stimulation = Inhibition Cortisol Adrenal Adrenal Baseline Cortisol Concentration • Highest Cortisol Concentration Between 4:00 - 8:00 AM • < 3ug/dl Insufficiency • < 10 ug/dl Suggests Adrenal Insufficiency • But…. If Corticosteroid-Binding Globulin Deficiency, Interpretation May Be Incorrect Cosyntropin Stimulation Test 250 ug ACTH, IV or IM Cortisol Measured 30 and 60 Minutes Later Level > 18-20 ug/dl Normal Can Be Done At Any Time During The Day Davidsons 22nd Ed, 2015 In a patient who is already receiving glucocorticoids: The short ACTH stimulation test can be performed • first thing in the morning, more than 12 hours after the last dose of glucocorticoid • or • the treatment can be changed to a synthetic steroid such as dexamethasone (0.75 mg daily), which does not crossreact in the plasma cortisol immunoassay Diagnosis • Are the Adrenals Functioning? • If Not, Why Not? Davidsons 22nd Ed, 2015 Primary Adrenal Insufficiency: Etiology Autoimmune 80% Drugs Infection Hemorrhage Metastases Autoimmune Adrenalitis • Most Common Cause In Industrialized Nations • Caused by Autoantibodies That React With Several Steroidogenic Enzymes (Cyp21a2) • Can Be Isolated or Associated With Autoimmune Polyglandular Syndromes Primary Adrenal Insufficiency: Etiology Autoimmune 80% Infection Hemorrhage Drugs Metastases Infectious Causes • Disseminated TB: Most Common Cause Worldwide • Fungal Infections • HIV: Directly Or Through Opportunistic Infections • Syphilis • Tuberculosis causes adrenal calcification, visible on plain X-ray or ultrasound scan Primary Adrenal Insufficiency: Etiology Autoimmune 80% Infection Hemorrhage Drugs Metastases Hemorrhage • Sepsis: Meningococcemia or Pseudomonas Aeruginosa • Anticoagulant Therapy Primary Adrenal Insufficiency: Etiology Autoimmune 80% Drugs Infection Hemorrhage Metastases Drugs • • • • • • • Rifampin Megestrol Acetate Barbiturates Phenytoin Ketoconazole Aminogluthemide Metyrapone Primary Adrenal Insufficiency Autoimmune 80% Infection Hemorrhage Drugs Metastases Metastases Metastases To Adrenal Glands Common However, Metastases To Adrenal Glands An Uncommon Cause Of Adrenal Insufficiency Treatment • Chronic Adrenal Insufficiency • Acute Adrenal Insufficiency Chronic Treatment • Hydrocortisone: Short Acting • Cortisone Acetate: Short Acting, But Needs Liver Conversion to Become Active • Prednisone: Long Acting • Dexamethasone: Very Long Acting Steroid Preparations Steroid Half Life (minutes) Hydrocortisone Cortisone Prednisolone Prednisone Dexamethasone Glucocorticoid Mineralocorticoid Potency Potency 90 30 230 60 1.0 0.8 4.0 3.5-4.0 1.0 0.8 0.8 0.5 280 25.0-30.0 0.0 Davidsons 22nd Ed, 2015 Chronic Treatment Increase the dose in Stress / last TT Pregnancy Supra-physiologic GC replacement (doses > 30 mg HC will affect bone metabolism Wear a bracelet or necklace to identify Adrenal Insufficiency Carry a Dexamethasone Emergency kit when traveling Hydrocortisone • 15 mg AM, 5 mg at 6 PM Monitoring of Response • Clinical Monitoring • ACTH Not Reliable • 24 Hour Cortisol Excretion Between-Individual Variability Mineralcorticoids Replacement • Only in Primary Adrenal Disease • Fludrocortisone (9 α-fluoroHydrocortisone) : 50-100 mcg/day • Monitor Electrolytes and Perhaps Plasma Renin Activity Androgen Replacement in Women • Controversial • Lack of energy – despite optimised GC & MC replacement • Women with features of androgen deficiency, including loss of libido • DHEA 25-50 mg OD • Complications: Acne, Hirsuitism Treatment • Chronic Adrenal Insufficiency • Acute Adrenal Insufficiency Treatment High Dose IV Drip Steroids (300 mg Hydrocortisone Daily) IV Fluids (Isotonic) Treatment of Precipitating Illness Davidsons 22nd Ed, 2015 Case 2 73 Year Male Admitted to CCU With CHF; Hx CAD, DM, HTN, Dyslipidemia Hx of Low Back Pain, Treated at Local Pain Clinic x 4 Months PE: Pale, Frail, P112, RR 28, BP 110/60, Bilateral Rales, S3, LE Edema Lab: Cortisol (random) 6 mg/dl; ACTH 14 pg/ml Hypothalamic-Pituitary Adrenal Axis Secondary Adrenal Insufficiency CRH Hypothalamus Pituitary ACTH Cortisol Adrenal Cortisol ACTH = Stimulation = Inhibition Cortisol Primary Adrenal Insufficiency Hyperpigmentation Dehydration Hypotension Hyperkalemia Hyponatremia Hypoglycemia SECONDARY OR TERTIARY ADRENAL INSUFFICIENCY Hyperpigmentation Is Not Present Dehydration Is Not Present Hypotension Is Less Prominent Hyperkalemia Is Not Present Hyponatremia May Be Present Hypoglycemia Is More Common Secondary Adrenal Insufficiency: Causes • • • • Exogenous Corticosteroids Isolated ACTH Deficiency Isolated CRH Deficiency Lesions of the Hypothalamus or Pituitary Gland (Tumor, Infection, Granulomas) • Postpartum (Sheehan Syndrome) Secondary Adrenal Insufficiency: Diagnosis • Recent Onset Adrenal Glands May Respond To ACTH Stimulation • Time Needed for the Adrenal Glands to Become Unresponsive Varies Testing In Adrenal Insufficiency Adrenal Insufficiency Normal Serum Cortisol mg/dl ACTH pg/ml @ 8 AM Primary Secondary Recent Onset 20 Adrenal Insufficiency Long-Standing 20 Adrenal Insufficiency 10 Adrenal Insufficiency 0 = Normal Range 30 60 Time minutes Secondary Adrenal Insufficiency The Best Way To Stimulate Endogenous ACTH… Insulin Tolerance test Metyrapone Stimulation Test CRH Stimulation Test Insulin Tolerance Test (ITT) The Gold Standard Test Glucose Level <40 mg/dl After Insulin IV Cortisol Level > 18-20 ug/dl This Test Should Not Be Done In Patients With Seizures or Severe Cardiac Disease The Metyrapone Test ACTH 11 Deoxycortisol Metyrapone Cortisol CRH Stimulation Test • Used to Distinguish Hypothalamic and Pituitary Causes of Secondary AI • IV Bolus of CRH (1ug/kg/bw) • Blood Samples at –15, 0, 5, 10, 15, 30, 45, 60, 90, and 120 min for ACTH & Cortisol Adrenal Insufficiency: Evaluation of Patient at Risk (History of Steroid Administration) Serum Cortisol (6-8 am) Cortrosyn Stimulation Test (≥ 18 ug/dl) Insulin Tolerance Test (≥ 18 ug/dl) Metyrapone Test CRH Stimulation Test Diagnosis of Adrenal Insufficiency in Critical Illness “Relative” Insufficiency Evaluation of Adrenal Insufficiency in Critical Illness Glucocorticoid secretion increases during critical illness, yet the increase may not be detected if only total cortisol concentrations are measured. Serum free cortisol measurements may be helpful to avoid unnecessary glucocorticoid therapy. These assays are not yet widely available. Hamrahian AH; Oseni TS; Arafah BM N Engl J Med 2004 15;350:1629-38. Evaluation of Adrenal Insufficiency in Critical Illness: A Reasonable Approach Critical Illness: Random Cortisol < 15 ug/ml 15-34 ug/ml > 34 ug/l Adrenal Insuff Cortrosyn Stim Test Adrenal Insuff Unlikely Likely Free Cortisol & Treat < 9 ug/ml ≥ 9 ug/ml Evaluation of Adrenal Insufficiency in Critical Illness: The Bottom Line While some critically ill patients may have functional adrenal insufficiency, there is currently no consensus on diagnostic criteria or indications for treatment. Cooper MS; Stewart PM NEJM 2003; 348:727-34 Case 3 67 y/o Female Referred For An Adrenal Nodule Noted On A CT Done For Evaluation Of Abd Pain Hx HTN x 5 Years Controlled On Monotherapy Hx DM Controlled On Metformin and SU No Hypokalemia PE Unremarkable; BP 132/78 Adrenal Incidentaloma Epidemiology Figures Vary From O.4-6% Of CT Scans 2.1% Of Autopsy Series Incidence Increases With Age; 7% After 70 Seen More Commonly In Women NATIONAL INSTITUTES OF HEALTH Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). Final Statement. July 16, 2002 Adrenal Incidentaloma IS IT MALIGNANT? IS IT HYPERSECRETORY? Major Causes Benign Adenoma Cyst Myelolipoma 50% 10% 10% Pheochromocytoma 10% Metastases Adrenal Cancer 6-30% 0.01% The incidental adrenal mass. Am J Med 1996 Adrenal Carcinoma • Virilization (Production Rate of Androgen Is High) • Recent Onset of Symptoms (Months) Is It Malignant? • Size • Radiological Findings IS IT MALIGNANT? • Masses > 6 cm Usually Are Treated Surgically • Masses < 4 cm Are Generally Monitored • Masses Between 4 And 6 cm: Criteria Other Than Size Should Be Considered In Making The Decision To Monitor Or Proceed To Surgery National Institutes Of Health Management Of The Clinically Inapparent Adrenal Mass (Incidentaloma) 2002 Is It Malignant? • Size • Radiological Findings Computed Tomographic Scans • Attenuation On CT Scan Is Measured In Hounsfield Units (HU) • Lipid-Rich Masses Are Usually Benign • Lipid-Rich Lesions Have Low Attenuation • Low Attenuation Lesions Have Low HU Values Computed Tomographic Scans • Unenhanced CT: Adenomas: < 10 HU Malignancies: > 18 HU Sensitivity: 73% Specificity: 96% • Delayed Enhanced CT: Adenomas: < 30 HU Malignancies: > 30 HU Sensitivity 95% And Specificity: 100% MRI • Equally Effective As CT • Adenomas Are Iso-Intense With The Liver On T2-weighted Images • Carcinomas Have A Hyper-Intense Signal Compared With The Liver Fine-Needle Aspiration Biopsy CANNOT Distinguish A Benign Adrenal Mass From Adrenal Carcinoma Other Tests… • Iodinated Cholesterol Derivative (NP-59): Show Uptake In Functioning Lesions • I-131 Metaiodobenzyl Guanidine (MIBG): Evaluating Pheochromocytoma • Positron Emission Tomography (PET): Not Enough Data IS IT HYPERSECRETORY? Cortisol Catecholamines Mineralcorticoids Androgens Patients 1004 Non-Secretory 854 (85%) Sub-Clinical Cushings Syndrome (SCC) 92 (9.2%) Pheochromocytoma 42 (4.2%) Aldosterone-Producing Adenoma 15 (1.6%) Journal of Clinical Endocrinology & Metabolism 85 (2) 637-644, 2000 Subclinical Hypercortisolism Absence Of The Stigmata Of Cushing’s Syndrome Hypercortisolism • 24 Hour Urinary Free Cortisol • Positive: More Than 3-4 Times The Upper Limit Of Normal Range Problems With 24 Hour Urine Free Cortisol Mildly Elevated Levels Can Be Seen In Anxiety, Depression, Alcoholism When the 24 UFC Is Not Conclusive…….. Dexamethasone Suppression Test 1 mg Dexamethasone At 11 pm Measure Cortisol At 8 am Normal: Cortisol < 5 ug/dl Specificity Is Reduced In Acute Or Chronic Illness Subclinical Hypercortisolism Two Of The Following: Increased Urinary Free Cortisol (UFC) Unsuppressed Serum Cortisol Levels After 1-mg Overnight Dexamethasone Low ACTH Levels No Clinical Signs Of Cushing Syndrome Mantero F, Masini AM, Opocher G, Giovagnetti M, Arnaldi G. Horm Res 47:284–289, 1997 Is There A Problem With SCS? Increased Incidence Of: HTN Obesity DM IGT Increased CV Risk Bone Disease Patients 1004 Non-Secretory 854 (85%) Sub-Clinical Cushings Syndrome (SCC) 92 (9.2%) Pheochromocytoma 42 (4.2%) Aldosterone-Producing Adenoma 15 (1.6%) Journal of Clinical Endocrinology & Metabolism 85 (2) 637-644, 2000 Pheochromocytoma 19-76% Of Pheochromocytomas Not Diagnosed Until After Death 80% Of Patients With Unsuspected Pheochromocytomas Who Underwent Surgery Or Anesthesia Died Not Possible To Determine Which Will Present With Crisis Not Possible To Determine The Malignant Potential Of Pheochromocytoma Hypertension In Pheochromocytoma • Paroxysmal in 48% • Persistent in 29% • Normal in 13% Other Symptoms • Attacks of Headaches (80%) • Palpitations (64%) • Diaphoresis (57%) Symptomatic Triad Of Headache, Sweating, And Tachycardia In A Hypertensive Patient Sensitivity 90.9% And Specificity 93.8% Pheochromocytoma Therefore…. It Is Reasonable To Screen All Patients With Adrenal Incidentalomas For Pheochromocytoma How To Screen… • Urine Collection Of Catecholamines Or The Metabolites • Plasma Collection Of Catecholamines And Metabolites Which Is Better? Catecholamine-Secreting Tumors Histologically Proven In 31 of 340 Patients: Sensitivity Of Plasma Free Metanephrine 97% Specificity 98% Sensitivity Of Urinary Total Metanephrine And Catecholamines 90%; Specificity 85% Sawka et al. JCEM 88(2): 553-558. 2003. Pheochromocytoma Plasma-Free Metanephrines Are Recommended As The Test Of Choice For Excluding Or Confirming The Diagnosis Of Pheochromocytoma NATIONAL INSTITUTES OF HEALTH Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). Final Statement. July 16, 2002 Patients 1004 Non-Secretory 854 (85%) Sub-Clinical Cushings Syndrome (SCC) 92 (9.2%) Pheochromocytoma 42 (4.2%) Aldosterone-Producing Adenoma 15 (1.6%) Journal of Clinical Endocrinology & Metabolism 85 (2) 637-644, 2000 Signs and Symptoms in Primary Hyperaldosteronism Hypertension Headache Weakness And/Or Fatigue Paresthesias Muscle Cramps Polyuria, Polydipsia, Nocturia Arrhythmias Signs, Symptoms, and Laboratory Data in Primary Hyperaldosteronism Hypertension Hypokalemia Headache No Other Cause For Weakness/ Fatigue Hypertension Or Hypokalemia Metabolic Alkalosis Hyperaldosteronism Hyporeninemia Paresthesias Muscle Cramps Polyuria/ Polydipsia Arrhythmias In the Past… • Hypokalemia Was Considered Common In Primary Hyperaldosteronism • The Evaluation Was Difficult (Discontinuing All Antihypertensive Medications) Now… • Patients With PA Can Be Normokalemic • Not Necessary To Stop All Medications • Screening Is Easier Aldosterone-Producing Adenoma Serum Potassium And Aldosterone /Plasma Renin Activity Ratio Should Be Determined To Evaluate For Primary Aldosteronism NATIONAL INSTITUTES OF HEALTH Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). Final Statement. July 16, 2002 Aldosterone/PRA Ratio • Normals And Patients With Essential Hypertension < 20 • Primary Aldosteronism > 30 • > 90% Sensitivity And Specificity Medications and PAC/PRA • Impossible To Interpret PAC/PRA On Spironolactone • ACE Inhibitor: A Normal Test Does Not Exclude The Diagnosis ( PRA) • ACE Inhibitor: A Positive Test Increases The Specificity Of The Diagnosis Other Medications • Blockers Suppress PRA, But Do Not Alter PAC/PRA • Diuretics Increase PRA (Hypovolemia), But Do Not Alter the Ratio Adenoma (APA) vs Hyperplasia (IHA) • Very High PAC/PRA Adenoma • Increased 18-OH-Corticosterone APA if >100 mg/dl and IHA if <50 ng/dl • Adrenal Vein Sampling Sometimes Indicated Decision Matrix of the Incidental Adrenal Mass on CT or MRI Scan Solid Or With Cystic Degeneration >6 Cm Evaluate Biochemically And Operate Pure Cyst Remove Fluid <6 Cm Evaluate Biochemically Biochemically Active Operate Biochemically Inactive Clear Bloody Observe Evaluate Biochemically And Follow As For Solid Tumor Repeat Scan In 3, 6, 18, and 36 Months Larger Evaluate Biochemically And Operate Unchanged Observe Follow Up • Will The Mass Become Malignant? • Will The Mass Become Hypersecretory? Incidental Adrenal Mass Risk of Progression Adrenal Hyperfunction: Unlikely If Lesion < 3 cm Cortisol Hypersecretion Most Likely Disorder 4% After 1 Year 9.5% Within 3 Years None Thereafter Mass Enlargement: 8% After 1 Year 18% After 5 Years Most Enlargement Occurred Within 3 Years Barzon et al J Clin Endocrinol Metab 1999 Follow Up An Approach: Perform An Overnight 1mg Dexamethasone Suppression Test And Plasma Free Metanephrines Yearly Or Earlier If Clinically Indicated The Risk Of Tumor Hyperfunction Appears To Plateau After 3 Years National Institutes Of Health: Management Of The Clinically Inapparent Adrenal Mass (Incidentaloma). Final Statement. July 16, 2002 The Adrenal: Take Home Points Sx’s Adrenal Insufficiency Non-Specific Screen With Cortisol 6:00 - 8:00 am < 3ug/dl Insufficiency ACTH and Cortrosyn Stim Test In ICU Setting: Free Cortisol & Cortrosyn Stim < 15 Random or Increase < 9 After ACTH Treat Take Home Points… Incidental Adrenal Mass Size and HU units Important >6 cm Surgical Removal (After w/u) Exclude Hypersecretion: 24 Urine Free Cortisol Plasma Free Metanephrines Potassium and Aldo/Renin The Metyrapone Test • Metyrapone: 750 mg Q 4 Hours x 24 Hrs • 08:00 Cortisol Measured Day 2 • Cortisol < 7ug/dl and 11Deoxycortisol > 10ug/dl The Mayo Clinic Study • 342 Patients With Adrenal Incidentaloma Retrospectively Evaluated • Tumor Diameter Averaged 2.5 cm. • Most Malignant Tumors Measured > 5 cm. • Removing All Tumors > 4 cm Would Have Removed Eight Benign Tumors For Every Carcinoma Incidentally discovered adrenal tumors: an institutional perspective. Herrera MF; Grant CS; van Heerden JA; Sheedy PF; Ilstrup DM. Surgery 1991 Dec;110(6):1014-21 The Adrenal Incidentaloma Survey • Multicentric, Retrospective Survey • Review Of Adrenal Incidentalomas From 1980-1995 • 1004 Cases Of Asymptomatic IncidentallyFound Adrenal Masses J Clin Endo & Meta 85: 637-644 2000 Problems With the DST • Decreasing Dexamethasone Absorption • Increased Dexamethasone Metabolism • Increased Concentration of CBG (Estrogen and Pregnancy) Management • Hypersecretory With Symptoms And Signs: Adrenalectomy • Silent Pheochromocytoma: Adrenalectomy • Adrenalectomy Is An Option For An Individual With Hypertension And Aldosterone Excess Chronic Treatment Dose May Need to Be Increased in Obese Patients Or If On Drugs That Accelerate Hepatic Metabolism General Aspects Small, But Mighty…. • 2 to 3 cm Wide, 4 to 6 cm Long, ~ 1 cm Thick • Weight: 4-5 gm • Highly Vascular Organs 11% of Cardiac Output General Aspects Small, But Mighty…. • 2 to 3 cm Wide, 4 to 6 cm Long, ~ 1 cm Thick • Weight: 4-5 gm • Highly Vascular Organs 11% of Cardiac Output The Size…. The Mayo Clinic Study (n= 342) The Adrenal Incidentaloma Survey in Italy (n = 1004) Malignant Tumors > 6 cm Herrera MF et al: Incidentally discovered adrenal tumors: an institutional perspective. Surgery 1991; 110(6):1014-21. J Clin Endo & Meta 85: 637-644 2000 Benign Adenoma Adrenal Carcinoma Resources: Davidson’s 22nd Edition, 2015 Harrison’s 18 th Edition Net resources