ADRENAL DISORDERS Anand Vaidya, MD MMSc

Transcription

1 ADRENAL DISORDERS Anand Vaidya, MD MMSc Director, Center for Adrenal Disorders Division of Endocrinology, Diabetes, & Hypertension Brigham and Women s Hospital Assistant Professor of Medicine, Harvard Medical School

2 None Disclosures

3 Learning Objectives 1. Review the role of the adrenal gland in physiology and pathophysiology 2. Evaluation of adrenal insufficiency 3. Evaluation of an adrenal mass 4. Biochemical work up for hyperaldosteronism, hypercortisolism, and pheochromocytoma TUTORIAL VIDEOS: ADRENAL PHYSIOLOGY: ADRENAL INSUFFICIENCY: PRIMARY ALDOSTERONISM: PHEOCHROMOCYTOMA:

4 Take Home Points The adrenal glands synthesize and secrete hormones that play a vital role in hemodynamic homestasis. Understanding the physiology of adrenal hormone feedback and the relative interpretations of adrenal testing is crucial for accurate assessments. Carefully timed cortisol and ACTH measurements can help decipher whether the HPA axis is functioning appropriately The prevalence of adrenal masses increases with age, and their incidental discovery has increased. All adrenal masses should be carefully evaluated for malignant potential and hormone hyperfunction Consider involving endocrine/adrenal colleagues at any time in the evaluation

5 28yoF presents to ER 6 weeks after having a baby Cannot breastfeed well Presents with progressive fatigue, dizziness, orthostasis, salt craving, hyperpigmentation, anorexia, and weight loss BP=60/40 mmhg Case 1 IV saline (8L) and BP improves Cortisol 0.80 mcg/dl (60mins after 250 mcg cosyntropin)= 1.0 mcg/dl ACTH>1000pg/mL

6 The most likely diagnosis is: Question 1 A) Primary adrenal insufficiency B) Acute secondary adrenal insufficiency C) Chronic secondary adrenal insufficiency D) Ectopic ACTH syndrome E) Cushing s disease

7 This most likely diagnosis is: Question 1 A) Primary adrenal insufficiency B) Acute secondary adrenal insufficiency C) Chronic secondary adrenal insufficiency D) Ectopic ACTH syndrome E) Cushing s disease

8 Cholesterol Adrenal Cortex: Steroidogenesis Zona Glomerulosa Zona Fasiculata Zona Reticularis Pregnenolone 17-Hydroxypregnenolone DHEA Progesterone 17-Hydroxyprogesterone Androstenedione 11-Deoxycorticosterone 11-Deoxycortisol Testosterone Corticosterone Cortisol Estradiol Aldosterone

9 Hypothalamic-Pituitary-Adrenal Axis H P Adrenal Glucocorticoid Receptor Mineralocorticoid Receptor Target Organ Cell

10 The Glucocorticoid Receptor Physiologic Activation of the GR Increase Blood Glucose Increase gluconeogenesis Promote protein breakdown Augment epinephrine-mediated lipolysis Increase Cardiovascular tone Increase pressor response to NE, AngII Stimulate synthesis of Epi Inhibit synthesis of NO Immune Modulation CNS Effects Appetite Mood Sleep/wake Promote fetal tissue and development Involved in parturition Many other magical things

11 The Mineralocorticoid Receptor Physiologic Activation of the MR Sodium reabsorption Expansion of plasma volume Urinary potassium secretion

12 Hypothalamic-Pituitary-Adrenal Physiology: NEWTON s 3 rd LAW: For every action, there is an equal and opposite reaction (feedback)

13 Hypothalamic-Pituitary-Adrenal Physiology H CRH Glucocorticoid Receptor P POMC ACTH (MSH) Cortisol Adrenal Cortisol 11βOH-steroid dehydrogenase 2 Inactivates cortisol to cortisone Glucocorticoid Receptor Mineralocorticoid Receptor Target Organ Cell

14 Hypothalamic-Pituitary-Adrenal Physiology H CRH P ACTH AGT Renin Ang-I Adrenal Ang-II ACE K+ Aldosterone Glucocortic Recepto Mineralocorticoid Receptor Target Organ Cell

15 The HPA axis 1) Cortisol secretion is entirely dependent on ACTH 2) Aldosterone is not dependent on ACTH. It is regulated in part by: Angiotensin II (Renin-angiotensin system) K + balance ACTH 3) HPA axis responds to: Diurnal variation/clock stress : ACTH & cortisol secretion is augmented relative to the degree of stress

16 Hypothalamic-Pituitary-Target Organ Physiology: Cortisol (µg/dl) TIME

17 Testing the HPA axis STATIC TEST (entire HPA axis): Morning cortisol (and ACTH) An appropriate AM cortisol should ideally be >15-18 µg/dl, reflecting a morning peak, but values > µg/dl when pre-test probability is low Vaidya et al. NEJM 2010; 362(6): e16

18 Testing the HPA axis STATIC TEST (entire HPA axis): Morning cortisol (and ACTH) An appropriate AM cortisol should ideally be >15-18 µg/dl, reflecting a morning peak, but values > µg/dl when pre-test probability is low PROVOCATIVE TEST (adrenal glands): 250 µg cosyntropin stimulation test Vaidya et al. NEJM 2010; 362(6): e16

19 Primary Adrenal Insufficiency (Addison s Disease) H ACTH P CRH Manifestations/Characteristics: Labs: low cortisol high ACTH low aldosterone -hyperkalemia, hyponatremia, hypovolemia Adrenal Physical Exam: Cortisol fatigue/lethargy/anorexia Aldosterone hypotension/orthostasis/salt craving weight loss hyperpigmentation abdominal pain many many more Glucocortic Recepto Mineralocorticoid Receptor Target Organ Cell

20 Primary Adrenal Insufficiency (Addison s Disease) H ACTH P CRH Response to Cosyntropin: sub-optimal EXAMPLE: Cosyntropin Morning 60 mins following 250 µg cosyntropin Cortisol (µg/dl) ACTH (pg/ml) 1100 Adrenal Cortisol Glucocortic Recepto Mineralocorticoid Receptor Target Organ Cell

21 Primary Adrenal Insufficiency (Addison s) Causes: Autoimmune Infiltrative infections (TB, fungal) Hemorrhage Infiltrative malignancy Medications: Anti-fungal medications Heparin Etomidate

22 ACUTE Secondary Adrenal Insufficiency H CRH Manifestations/Characteristics: ACTH P Labs: low basal cortisol inappropriately low ACTH ± hyponatremia Normal K and aldosterone regulation Adrenal Physical: Cortisol completely normal mild, progressive, fatigue at baseline severe fatigue, orthostasis, hypotension, in situations of stress Glucocortic Recepto Mineralocorticoid Receptor Target Organ Cell

23 ACUTE Secondary Adrenal Insufficiency H ACTH P CRH Adrenal Response to Cosyntropin: NORMAL EXAMPLE: Cosyntropin Morning ACTH (pg/ml) 10 Cortisol 60 mins following 250 µg cosyntropin Cortisol (µg/dl) Glucocortic Recepto Mineralocorticoid Receptor Target Organ Cell

24 CHRONIC Secondary Adrenal Insufficiency H CRH With chronic ACTH deficiency, adrenal cortex (ZF) will atrophy, and will progressively respond less to cosyntoprin stimulation ACTH P EXAMPLE: Cosyntropin Morning 60 mins following 250 µg cosyntropin Cortisol (µg/dl) ACTH (pg/ml) 10 Adrenal Cortisol Glucocortic Recepto Mineralocorticoid Receptor Target Organ Cell

25 Secondary Adrenal Insufficiency Causes: Pituitary mass: adenoma or metastatic lesion Pituitary infection Pituitary infiltration (granulomatous disease, iron) Medications: Glucocorticoids Megesterol Opioids

26 Case 1 Diagnosed with primary adrenal insufficiency (Addison s) Treated with IV saline (8L) IV hydrocortisone initially Transitioned to PO hydrocortisone/fludrocortisone

27 46 year old pre-menopausal woman was in a car accident. No known medical conditions Case 2 Brought to ER and complained of some abdominal pain. Had a rapid unenhanced Abdominal CT that revealed no hemorrhage or other injuries Incidental discovery of a 2.2 cm R adrenal mass, with 5 HU unenhanced density What, if anything, do you tell her about the incidental adrenal mass??

28 Incidentally Disovered Adrenal Masses Adrenal tumors are incidentally discovered in 1-10% of adults. A minority represent malignant entities (primary adrenal malignancy or extraadrenal metastasis) The majority are determined to be benign and nonfunctional and therefore are considered to pose no health risk. In contrast, ~10-15% of adrenal tumors autonomously secrete adrenal hormones. These functional tumors are associated with an increased risk for cardiometabolic outcomes, such as CV disease, diabetes, and osteoporosis/fracture. Therefore, all incidentally discovered adrenal tumors should be carefully evaluated to determine whether they are: 1) malignant and/or 2) functional. Nieman LK. JCEM 2010; Young et al. NEJM 2007; Zeiger et al. Endocr Pract 2009; Fassnacht EJE 2016

29 Differential Diagnosis of Adrenal Mass NON-FUNCTIONAL FUNCTIONAL BENIGN MALIGNANT

30 Differential Diagnosis of Adrenal Mass NON-FUNCTIONAL (85-95%) Adrenocortical Adenoma Myelolipoma Neuroblastoma FUNCTIONAL (5-15%) BENIGN (~90-95%) Ganglioneuroma Cyst Hemorrhage Infection (fungal, tuberculous) Hemangioma MALIGNANT (~5%)

31 Differential Diagnosis of Adrenal Mass BENIGN (~90-95%) MALIGNANT (~5%) NON-FUNCTIONAL (85-95%) Adrenocortical Adenoma Myelolipoma Neuroblastoma Ganglioneuroma Cyst Hemorrhage Infection (fungal, tuberculous) Hemangioma FUNCTIONAL (5-15%) Adrenocortical Adenoma Aldosterone producing Cortisol producing Micro- or Macro-nodular Disease Pheochromocytoma Aldosterone producing Cortisol producing

32 Differential Diagnosis of Adrenal Mass BENIGN (~90-95%) MALIGNANT (~5%) NON-FUNCTIONAL (85-95%) Adrenocortical Adenoma Myelolipoma Neuroblastoma Ganglioneuroma Cyst Hemorrhage Infection (fungal, tuberculous) Hemangioma Adrenocortical carcinoma Metastatic cancer from a nonadrenal primary FUNCTIONAL (5-15%) Adrenocortical Adenoma Aldosterone producing Cortisol producing Micro- or Macro-nodular Disease Pheochromocytoma Aldosterone producing Adrenocortical carcinoma Pheochromocytoma Cortisol producing

33 General Diagnostic Approach 1. Is there evidence for malignancy? 2. Is there adrenal hormone excess? Clinical Phenotype Biochemical Phenotype Radiographic Phenotype History and physical exam for evidence of hormone excess or malignancy Laboratory evaluation for evidence of adrenal hormone excess Radiographic evidence supportive of a benign or malignant mass

34 Clinical Phenotype Overt Cortisol Excess Obesity/weight gain Lipodystrophy ocentral adiposity osupraclavicular fat pads odorsocervical fat pad orounded face Hyperglycemia/Diabetes Hypertension Insomnia Mood disorder/psychosis Osteoporosis Immunesuppression Platelet dysfunction Hypercoagulable state Myopathy Atrophic skin Overt Catecholamine Excess Episodic symptoms o Hypertension o Palpitations o Anxiety/Panic o Sweats/Tremors o Headache o Arrhythmia Overt Aldosterone Excess Hypertension Hypokalemia

35 Case 2 Clinical Phenotype No symptoms No signs to suggest hypercortisolism, pheochromocytoma, hyperaldosteronism, or hirsutism. No evidence of weight loss, abdominal distention, or androgen excess, to suggest metastatic cancer or hyperfunctioning adrenocortical carcinoma Clinical Phenotype Unrevealing

36 Case 2 Radiographic Phenotype Normal comparison Patient s non-contrast CT 2.2cm right adrenal mass 5 Hounsfield units Round, homogenous

37 Question 2 A 2.2 cm adrenal nodule with an unenhanced density of 5 HU on CT is most suggestive of: A)Myelolipoma B)Adrenocortical adenoma C)Pheochromocytoma D)Metastatic lung cancer to the adrenal gland E)Adrenocortical carcinoma

38 Question 2 A 2.2 cm adrenal nodule with an unenhanced density of 5 HU on CT is most suggestive of: A)Myelolipoma B)Adrenocortical adenoma C)Pheochromocytoma D)Metastatic lung cancer to the adrenal gland E)Adrenocortical carcinoma

39 Case 2 Radiographic Phenotype Characteristic Likely Benign Potentially Malignant Size < 4 cm > 4-6 cm Attenuation on unenhanced CT Contrast washout on CT protocol at 15 minutes MRI chemical shift suggestive of lipid-rich content <10 HU > 10 HU Absolute>60% Absolute<60% Relative >40% Relative<40% Yes No Radiographic Phenotype FDG avidity on PET No Yes Irregular Borders No Yes Heterogeneous content No Yes Necrosis No Yes Calcifications No Yes BENIGN: Suggestive of adrenocortical adenoma Rate of Growth < 1cm/y >1cm/y Miller. Nature Rev Endo 2014 Vaidya. Scientific American Medicine 2015

40 Case 2 Biochemical Phenotype Suggested screening biochemical evaluation for adrenal masses: Condition Patients Test Abnormal Value Autonomous cortisol secretion ALL 1 mg Dexamethasone Suppression Test Nonfunctional: 1.8 mcg/dl Possible: mcg/dl Autonomous: 5.0 mcg/dl Primary Aldosteronism HTN and/or hypokalemia Serum aldosterone to plasma renin activity ratio (ARR) Suppressed PRA ARR>20-25 Pheochromocytoma ALL (almost) Plasma (or urinary) fractionated metanephrines >2-4x ULRR Adrenal androgen excess Hirsutism or virilization DHEAS Total Testosterone Higher than ULN Fassnacht EJE 2016

41 Case 2 Biochemical Phenotype 1mg DST #1 => cortisol: 8.0 µg/dl 1mg DST #2 => 7.8 µg/dl, ACTH<5 pg/ml 8mg DST => 8.1 µg/dl, ACTH<5 pg/ml 24h Urine Free Cortisol: 45 µg/24h (<45) Biochemical Phenotype Midnight Salivary Cortisol: 3.7, 3.9, 4.6, 4.3 nmol/l (<4.3) Random ACTH: 5 pg/ml Plasma metanephrines: normal Aldosterone/PRA: not suggestive DHEAS: normal Autonomous cortisol secretion?

42 Case 2 Clinical Diagnosis Benign adrenocorticol adenoma Autonomous cortisol secretion No clinical signs of hypercortisolism Should surgery be recommended?

43 Case 2 Outcome BP = 122/75 mmhg Fasting Blood Glucose = 99 mg/dl HbA1c = 5.8% Bone Mineral Density: Spine T= -3.2 Femoral Neck T= -2.2 Total Hip T= -2.0 INDIVIDUALIZED DECISION: Laparoscopic R adrenalectomy Peri-operative IV hydrocortisone considered, but not given Pathology revealed 2.5 cm adrenal cortical adenoma Post-op AM cortisol 4 mcg/dl, ACTH<10 pg/ml (asymptomatic) 1 week post-op, morning cortisol = 17 µg/dl

44 Suggested Diagnostic Algorithm for Incidentally Discovered Adrenal Mass Adrenal Mass Clinical Phenotype (+) Confirm Overt Hormone Excess with Clinical Syndrome Biochemical Phenotype (-/+) Radiographic Phenotype Radiographic Phenotype and Localization Suspicious >4-6cm, >10 HU, contrast avid, heterogeneous Benign Appearing <10HU, <4cm, non-contrast avid, homogeneous Consider surgery Growth>0.5cm/year or +20% Suspicious radiographic features New or worsening hormonal excess ((Consider alternative imaging: CT with washout, MRI)) If Unilateral: Consider surgery?metastases or infection: Biopsy Unsure? =>Surveillance: repeat imaging in 3-6 months Surveillance Considerations: If initially nonfunctional : No strong evidence for repeated biochemical testing Repeat biochemical testing if worsening comorbidities (HTN, DM, low BMD) If autonomous cortisol secretion without clinical syndrome: Individualized consideration for surgery based on comorbidities and other factors. Repeat biochemical testing annually No firm evidence for radiographic surveillance

45 Adrenal Tumors with Autonomous Cortisol Secretion & Risk for CVD, Diabetes, Skeletal Disease

46 Comorbidities associated with adrenal tumors with autonomous and subclinical cortisol secretion Comorbidities Hypertension Glucose intolerance/type 2 diabetes Obesity Dyslipidemia Osteoporosis/Vertebral Fracture Fassnacht et al. EJE 2016

47 Proportion with Cardiovascular Disease (%) Proportion with Cardiovascular Mortality (%) Autonomous Cortisol Secretion Stable nonfunctional DST 1.8 mcg/dl Worsening 1.8 => or => >5.0 Stable, but Any Autonomous Cortisol DST mcg/dl DST >5.0 mcg/dl Stable, but Any Autonomous Cortisol DST mcg/dl DST >5.0 mcg/dl Worsening 1.8 => or => >5.0 Stable nonfunctional DST 1.8 mcg/dl Di Dalmazi et al. Lancet Diabetes & Endo 2014

48 DeBono et al. JCEM 2014 Morelli et al. JCEM 2015 Autonomous Cortisol Secretion Most deaths due to cardiovascular or infectious causes

49 DeBone et al. JCEM 2014 Morelli et al. JCEM 2015 Autonomous Cortisol Secretion Participants with adrenal incidentalomas who developed incident subclinical vertebral fractures detected on BMD and higher 1mg DST (2.7 vs 2.0 mcg/dl). Autnomous cortisol secretion associated with ~10-fold higher risk of incident (~3y follow-up) vertebral fracture.

50 Incident Composite Diabetes (%) Adjusted HR: 2.36 (1.45, 3.84) Absolute Risk: 15.6 % (6.9, 24.3) Years of Follow-Up 27.3% 11.7% Non-Functional Adrenal Tumor (1mg DST 1.8 mcg/dl) No Adrenal Tumor

51 Incident Composite Diabetes (%) Adjusted HR: 2.36 (1.45, 3.84) Absolute Risk: 15.6 % (6.9, 24.3) Adrenal Tumor with Subclinical Hypercortisolism 32.0% (1mg DST mcg/dl) 27.3% Non-Functional Adrenal Tumor (1mg DST 1.8 mcg/dl) Years of Follow-Up 11.7% No Adrenal Tumor

52 Continuum of Cardiometabolic Risk Lopez et al. Ann Int Med 2016 Adrenal Tumor With Overt Cushing Syndrome Adrenal tumor with Autonomous Cortisol Secretion but no Cushing syndrome Nonfunctional adrenal tumor Morphologically Normal with no hormone excess Prevalence of Condition

53 Should Intervention be Performed? HTN Improved SBP DM Improved FBG Bancos et al. EJE 2016

54 Case 3 42yoF healthy woman New HTN /80 Spontaneous headache => BP 200/100 Over several months treated with: Lisinopril+amlodipine+labetolol: BP still 140/90 Hypokalemia (2.3 mmol/l) on more than one occasion Clinical Phenotype Concerning for excess aldosterone No clinical signs of hypercortisolism

55 Hyperaldosteronism: who to screen? Endocrine Society Recommendations Moderate to severe HTN JNC Stage 2 or 3 Drug-resistant HTN SBP>140/90 with 3+ anti-hypertensive medications HTN + spontaneous or diuretic-induced hypokalemia HTN + adrenal mass HTN and family member with primary hyperaldosteronism HTN + Family history of early-onset HTN or cerebrovascular accident (<40yrs) Funder et al. JCEM 2016

56 Case 3 Biochemical Phenotype Diagnostic Testing for Adrenal Aldosterone Excess: Screening Goal Test Method Desired Value Aldosterone-to-Renin Ratio (ARR) Peripheral blood Confirmation Salt Suppression Test Oral salt x4-5 days to achieve 24h UNa>200mmol/24h suppressed Plasma renin activity (PRA) ARR>20-25 Non-suppressible aldosterone IV saline Localization CT imaging AVS CT: surgical planning AVS: lateralization of hormone function CT: N/A AVS: lateralization or nonlateralization

57 Case 3 Biochemical Phenotype Aldosterone 22 ng/dl (on anti-htnives) PRA <0.6 ng/ml/h ARR >>>40 Biochemical Phenotype Highly suggestive of Primary Aldosteronism

58 Case 3 Biochemical Phenotype Oral Salt Suppression Test: 24h Urine Na: 378mmol/24h 24h Urine Aldosterone: 25.5 mcg/24h Biochemical Phenotype Primary Aldosteronism

59 Case 3 Radiographic Phenotype

60 Suggested Diagnostic Algorithm Adrenal Mass 1. Clinical Phenotype (+) 2. Biochemical Phenotype Confirm Aldosterone Excess 3. Radiographic Phenotype and Localization Bilateral Disease Medical therapy with MRA Unilateral Disease Surgery Improve BP and reduce anti-htn medications Lower CVD risk

61 Case 3 Outcome Laparoscopic L adrenalectomy Pathology revealed 2.4 cm adrenal cortical adenoma Post-op, BP 105/60 mmhg on lisinopril 10mg daily; no hypokalemia

62 Case 3 Clinical Diagnosis Primary Aldosteronism Benign L adrenal cortical adenoma (Conn s tumor)

63 Case 4 28yo healthy, athletic, woman Runs 4-6 miles a day Excessive sweating Anxiety BP 140/90mmHg (new) Clinical Phenotype No palpitations, chest pain, tremors, etc Concerning for pheochromocytoma?

64 Case 4 Biochemical Phenotype Test Plasma fractionated metanephrines 24h urinary fractionated metanephrines (and creatinine) Desired Value in true catecholamineproducing tumors >2-4x ULRR in clinically apparent functional tumor Comment Excellent Screening tests (LC-MS/MS) Sensitivity: %, Specificity: ~85-90% Lenders et al. JCEM 2014

65 Case 4 Biochemical Phenotype Plasma metanephrines: 20 (<62) Plasma normetanephrines 615 (<145) 24h urine NE: 1508 (<135) 24h urine Normetanephrines 3156 (<1050) 24h urine Epi: 2 (<20) 24h urine metanephrines: 151 (<460) Biochemical Phenotype Pheochromocytoma

66 Case 4 Radiographic Phenotype RIGHT 2 cm mass 35 HU T2 hyperintense on MRI

67 Peri-operative Management The goal of pre-operative medical therapy is to: block the peripheral effects of catecholamines (and rarely their synthesis) to minimize excessive intraoperative - and -agonism that may result in end-organ damage, while simultaneously minimizing the risk for post-operative hypotension 1) Identify experienced surgeon and anesthesia team 2) alpha-blockade (selective when possible) 3) Intra-vascular volume expansion (salt or saline) 4) beta-blockade (particularly in those with known heart disease) 5) calcium-channel blockade (if needed) 6) Metyrosine (if needed) Lenders et al. JCEM 2014

68 Suggested Diagnostic Algorithm for Suspected or Known Adrenal Mass Adrenal Mass Clinical Phenotype (+) Confirm Overt Hormone Excess with Clinical Syndrome Biochemical Phenotype (-/+) Radiographic Phenotype Radiographic Phenotype and Localization Suspicious >4-6cm, >10 HU, contrast avid, heterogeneous Benign Appearing <10HU, <4cm, non-contrast avid, homogeneous Consider surgery Growth>0.5cm/year or +20% Suspicious radiographic features New or worsening hormonal excess ((Consider alternative imaging: CT with washout, MRI)) If Unilateral: Consider surgery?metastases or infection: Biopsy Unsure? =>Surveillance: repeat imaging in 3-6 months AACE guidelines 2009, Young NEJM 2007, Vaidya. Scientific American Medicine 2015 Surveillance Considerations: If initially nonfunctional : No strong evidence for repeated biochemical testing Repeat biochemical testing if worsening comorbidities (HTN, DM, low BMD) If autonomous cortisol secretion without clinical syndrome: Individualized consideration for surgery based on comorbidities and other factors. Repeat biochemical testing annually No firm evidence for radiographic surveillance

69 Case 4 Outcome Alpha-blocked and hydrated in preparation for surgery Laparoscopic R adrenalectomy Pathology revealed pheochromocytoma Post-op: sweats, anxiety, hypertension all resolved

70 Case 4 Clinical Diagnosis Pheochromocytoma

71 Case 5 37yo healthy woman had an abdominal CT for RLQ pain No cause of pain found Incidental RIGHT 2.8cm Adrenal mass (<10HU), LEFT ~3cm adrenal mass (18HU) Was told that these are likely benign adenomas and to follow up in 1 year.

72 Case 5 Radiographic Phenotype R: 2.8 cm, <10 HU L: 3.0 cm, 18 HU What would you recommend?

73 Suggested Diagnostic Algorithm for Suspected or Known Adrenal Mass Adrenal Mass Clinical Phenotype (+) Confirm Overt Hormone Excess with Clinical Syndrome Biochemical Phenotype (-/+) Radiographic Phenotype Radiographic Phenotype and Localization Suspicious >4-6cm, >10 HU, contrast avid, heterogeneous Benign Appearing <10HU, <4cm, non-contrast avid, homogeneous Consider surgery Growth>0.5cm/year or +20% Suspicious radiographic features New or worsening hormonal excess ((Consider alternative imaging: CT with washout, MRI)) If Unilateral: Consider surgery?metastases or infection: Biopsy Unsure? =>Surveillance: repeat imaging in 3-6 months AACE guidelines 2009, Young NEJM 2007, Vaidya. Scientific American Medicine 2015 Surveillance Considerations: If initially nonfunctional : No strong evidence for repeated biochemical testing Repeat biochemical testing if worsening comorbidities (HTN, DM, low BMD) If autonomous cortisol secretion without clinical syndrome: Individualized consideration for surgery based on comorbidities and other factors. Repeat biochemical testing annually No firm evidence for radiographic surveillance

74 Case 5 She returned 1.5 years later Has new hirsutism on face and upper chest Repeat imaging was performed

75 Case 5 Radiographic Phenotype R: Unchanged 2.8 cm, <10 HU L: 4.3 cm, 30 HU Larger Heterogeneous Nodular Fat stranding

76 Case 5 Underwent a radical L adrenalectomy Pathology revealed a high grade stage I Adrenocortical carcinoma

77 Case 5 Clincial Diagnosis STAGE I, HIGH GRADE, ADRENOCORTICAL CARCINOMA Adrenal carcinomas are rare, highly aggressive, fast growing, and can produce multiple adrenal hormones Only known cure is early recognition and radical surgery 50-70% are metastatic at time of presentation Median survival < 12 months from time of diagnosis; can be prolonged with cytoreduction (surgery/ir)or adjuvant mitotane/edp therapy Morbidity and mortality associated with rapid tumor growth and spread, but also uncontrolled hormone excess states (i.e. Cushing s syndrome, mineralocorticoid excess).

78 Take Home Points The adrenal glands synthesize and secrete hormones that play a vital role in hemodynamic homestasis. Understanding the physiology of adrenal hormone feedback and the relative interpretations of adrenal testing is crucial for accurate assessments. Carefully timed cortisol and ACTH measurements can help decipher whether the HPA axis is functioning appropriately The prevalence of adrenal masses increases with age, and their incidental discovery has increased. All adrenal masses should be carefully evaluated for malignant potential and hormone hyperfunction Consider involving endocrine/adrenal colleagues at any time in the evaluation

79 Supplemental References TUTORIAL VIDEOS: ADRENAL PHYSIOLOGY: ADRENAL INSUFFICIENCY: PRIMARY ALDOSTERONISM: PHEOCHROMOCYTOMA: Fassnacht et al. Management of adrenal incidentalomas: European guidelines. European Journal of Endocrinology 2016 Young WF, Jr. Clinical practice. The incidentally discovered adrenal mass. New England Journal of Medicine 2007;356: Vaidya A, Hamrahian AH, Auchus RJ. Genetics of Primary Aldosteronism. Endocrine Practice 2015; 21(4): Funder JW, et al. Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2016 Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2014; 99: Bornstein et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2015

80 ADRENAL DISORDERS Anand Vaidya, MD MMSc Director, Center for Adrenal Disorders Division of Endocrinology, Diabetes, & Hypertension Brigham and Women s Hospital Assistant Professor of Medicine, Harvard Medical School