Adrenal Incidentaloma Pheochromocytoma Primary Aldosteronism

1. Adrenal IncidentalomaPheochromocytomaPrimary Aldosteronism Denise Joffe, M.D. Cooper Endocrinology March 22, 2010

3. Case #1 Patient is a 70 yo female who is incidentally found to have a 3 X 2.5 cm adrenal mass when she has a CT of the abdomen because of chronic abdominal pain. PMH: HTN High Cholesterol Meds: HCTZ 25 mg daily, Lipitor 20mg daily

4. Adrenal Incidentiloma Adrenal mass generally > 1 cm discovered “serendipitously” during a radiologic exam for evaluation other than adrenal disease Prevalence of adrenal incidentaloma discovered on CT is 4% Prevalence Increases With Age Age 20-29yo: 0.2% Age > 70yo: 7%

5. Adrenal Incidentalomas Can Be: Benign Non-Secreting Cortical Adenoma (Majority) Cushing’s Pheochromocytoma Adrenocortical Carcinoma Metastatic Carcinoma Aldosterone Secreting

6. Step 1 in Evaluation:History and Physical Exam To Evaluate for Cushing’s Can be asymptomatic (subclinical) Symptoms May Include: Weight Gain and Central Adiposity Facial Rounding and Plethora Supraclavicular and Dorsocervical Fat Pad Easy Bruising Poor Wound Healing Purple Striae Proximal Muscle Weakness Emotional and Cognitive Changes Opportunistic and Fungal Infections Altered Reproductive Function Acne Hirsutism

7. Step 1 in Evaluation:History and Physical Exam Signs of Cushing’s HTN Osteopenia Osteoporosis Fasting Hyperglycemia DM Hypokalemia Hyperlipidemia Leukocytosis with relative lymphopenia

9. Step 1 in Evaluation:History and Physical Exam To Evaluate For Pheochromocytoma Symptoms Include: Can be asymptomatic Episodic symptoms may occur in “spells” Forceful Heartbeat Pallor Tremor Headache Diaphoresis “Spells” can be spontaneous or precipitated by: Postural Change Anxiety Medications(Anesthesia) Maneuvers that increase intraabdominal pressure (lifting, defacation, exercise, trauma, colonoscopy, pregnancy)

10. Step 1 in Evaluation:History and Physical Exam Signs of Pheochromocytoma HTN (Sustained or Paroxysmal) Orthostatic Hypotension Pallor Retinopathy (Grades 1-4) Tremor Fever

11. Step 1 in Evaluation:History and Physical Exam To Evaluate Primary Aldosteronism Symptoms Include: If hypokalemia is present: Nocturia Polyuria Muscle Cramps Palpitations Signs Include: HTN (mild or severe) Possible hypokalemia and mild hypernatremia

12. Step 1 in Evaluation:History and Physical Exam To Evaluate for Adrenocortical Carcinoma Symptoms Include: Mass Effect (Abdominal Pain) Symptoms related to adrenal hypersecretion Cushing’s Syndrome Hyperandrogenemia (hirsutism, acne, amenorrhea or oligomenorrhea, oily skin, increased libido) Estrogens (gynecomastia) Aldosterone (Sx of hypokalemia)

13. Step 1 in Evaluation:History and Physical Exam To Evaluate for Adrenocortical Carcinoma Signs Include: HTN Osteopenia Osteoporosis Fasting Hyperglycemia DM Hypokalemia Hyperlipidemia Leukocytosis with Relative Lymphopenia

15. Step 1 in Evaluation:History and Physical Exam To Evaluate for Metastatic Cancer History of Extraadrenal Cancer Cancer Specific Signs

16. Case #1 HPI: Patient reports no history of palpitations, no diaphoresis, no weight gain, no weight loss, no proximal muscle weakness, no easy bruising, no muscle cramps, no acne, no hirsutism, no headaches, no palpitations Physical Exam: Unremarkable

17. Hormonal Evaluation Patients can have “subclinical Cushing’s” : Don’t have typical signs of cortisol excess But may have adverse effects of too much cortisol HTN Obesity DM Osteoporosis

18. Hormonal Evaluation Adrenal Autonomy Can be Assessed by: Overnight Dex Suppression Test (1mg) Specificity 91% for cutoff of 5 µg per dl If result is abnormal, confirmatory testing should be done to rule out false positive Surgery in “Subclinical Cushing’s” Consider in patients < 40 Consider in patients with disorders potentially worsened by autonomous cortisol secretion: HTN DM Obesity Osteoporosis

19. Hormonal Evaluation “Subclinical Cushing’s” Not enough data for optimal management Need long term prospective studies to better understand the natural history and to guide decision making regarding surgery Some Case Series Show After Adrenalectomy: Weight Loss Improvement in bp control/glycemic control Normalization of markers of bone turnover

20. Hormonal Evaluation Cortisol secretion may be normal when an adrenal incidentaloma is first discovered but can become autonomous up to 4 years later Reasonable to repeat hormonal screening annually for 4 years

21. Hormonal Evaluation

22. Hormonal Evaluation Approximately 5% of adrenal incidentalomas are pheochromocytomas Biochemical testing is warranted in all patients: Fractionated metanephrines and catecholamines in 24 hour urinary specimen If suspicion is high-recommend plasma free metanephrines (high sensitivity (96-100%) and low specificity (85-89%) –only use if suspicion is high to avoid false positives

23. Hormonal Evaluation Approximately 1% of adrenal incidentalomas are aldosterone-producing adenomas Screening is recommended in patients with adrenal incidentaloma and HTN Morning plasma aldo/renin ratio Can have normal potassium levels so this should not be used as screening test

24. Hormonal Evaluation Sex hormone-secreting adrenocortical tumors are rare Typically occur in the presence of clinical manifestations (hirsutism or virilization) Routine screening for excess androgens or estrogen is not routinely suggested

25. Case # 1 Biochemical Testing was performed: 24 hour urine metanephrines was normal 1 mg dex suppression test - 1µg Aldo-5 renin-2

26. Assessment of Malignant Potential Among 2005 patients in whom adrenal incidentaloma was detected, adrenocortical carcinoma was found in 4.7% of the patients and metastatic cancer in 2.5% Major predictors of malignant potential: Size Imaging characterisitics

27. Size of Adrenal Mass A diameter > 4 cm was shown to have 90% sensitivity for detection of adrenocortical carcinoma but low specificity The smaller the adrenocortical carcinoma is at time of diagnosis, the better the prognosis

28. Imaging Phenotype CT/MRI features used to distinguish adenoma from nonadenomas: Lipid content of the adrenal mass Intracytoplasmic fat of adenomas has low attenuation on unenhanced CT (Less than 10 Hounsfield units) Chemical shift MRI-benign adenomas lose signal on out-of-phase images as compared to in-phase images

29. Imaging Phenotype CT/MRI features used to distinguish adenoma from nonadenomas: Rapidity of the washout of contrast medium on contrast-enhanced CT : Adenomas-rapid washout of medium A washout greater than 50% at 10 minutes is 100% sensitive and specific for adenoma Nonadenomas-delayed washout of contrast medium Surgery should be considered in patients with suspicious imaging phenotypes

31. Case #1

32. Metastatic Disease Mets are the cause of adrenal incidentalomas in one half of patients with history of malignant disease Frequently bilateral Primary cancer has usually been recognized when discovered Tumors that commonly metastasize to the adrenals: Carcinoma of Lung Carcinoma of Kidney Carcinoma of Breast Carcinoma of Esophagus, Pancreas, Liver, and Stomach

33. FNA Biopsy Used to diagnose malignancy or infection Relatively safe procedure Risks include: Hematoma Abdominal pain Hematuria Pancreatitis Pneumothorax Adrenal abscess Tumor recurrence along needle track

34. FNA Biopsy FNA of a pheochromocytoma: May result in hemorrhage May result in hypertensive crisis The possibility of a pheochromocytoma must be ruled out biochemically before an FNA can be done

35. Bilateral Adrenal Masses Discovered Incidentally Most likely diagnoses are: Metastatic disease CAH Bilateral Cortical Adenomas Infiltrative Diseases Adrenocortical hypofunction can occur in patients with bilateral adrenal masses

36. Frequency and Duration of Follow-up Repeated imaging is recommended in non-secretory adenomas at: 6 months 12 months 24 months To consider at 3 months if “imaging phenotype” is suspicious Repeat biochemical testing is suggested annually for 4 years

37. Indications for Surgery Adrenal mass > 4 cm If nodule grows > 1 cm over period of observation Evidence of autonomous hormonal secretion is detected

38. Conclusion of Case # 1 Summary of findings: 3 X 2.5 cm right adrenal mass discovered incidentally Only sign was HTN Denies symptoms of hormonal hypersecretion Biochemical workup was within normal limits Imaging phenotype was <10 HU, with > 50% washout at 10 minutes

39. Case #1

41. Primary Aldosteronism Usually seen in 3rd-6th decade of life Few symptoms are specific to the syndrome In patients with hypokalemia: Muscle weakness and cramping Headaches Palpitations Polydipsia, polyuria, and nocturia

42. Primary Aldosteronism HTN: Usually moderate to severe May be resistant to usual pharmacologic tratments Hypokalemia is often not seen Patients may be at higher risk for end-organ damage of heart and kidney due to the HTN Increased rates of CVA, MI, afib compared to age-matched essential hypertensive patients

43. Primary AldosteronismCase Finding Testing Who Should Be Screened? HTN and hypokalemia Resistant HTN (3 drugs and poor control) Adrenal incidentaloma and HTN Onset of HTN at young age (Age < 20) Severe HTN (SBP > 160, DBP > 100mg/dl Whenever considering secondary HTN

44. Primary AldosteronismIdeal Screening Test Measure a morning (8AM-10AM): Plasma aldosterone concentraton Plasma renin activity Increased plasma aldo concentration (>15ng/dl) Decreased plasma renin activity (<1ng/ml per hour) or plasma renin concentration (Less than lower detection of assay) PAC/PRA ratio > 20 ng/dl per ng/ml per hour

45. Primary AldosteronismIdeal Screening Test Hypokalemia reduces aldosterone secretion, and one should replete K before doing testing Aldosterone receptor antagonists should be stopped 6 weeks before testing Eplerenone spiranolactone

46. Primary AldosteronismIdeal Screening Test ACE inhibitors can “falsely elevate” plasma renin activity Important Clinical Point: When a PRA is undetectably low in a patient on an ACE inhibitor, primary aldosteronism is likely

47. Primary AldosteronismIdeal Screening Test PAC/PRA ratio is only a screening test!! Needs to be followed by a confirmatory test

48. Primary AldosteronismConfirmatory Test Oral Salt Loading Test: HTN and hypokalemia must be treated before doing this test Patients eat a high Na diet for 3 days (goal intake of 5000 mg), may need RX for NaCl Tabs On Day #3: 24 hour urine collection for aldosterone, Na, and creatinine

49. Primary AldosteronismConfirmatory Test To document adequate Na collection, collection must contain > 200meq of Na Positive Test: 24 hour urinary aldosterone > 12 µg/24 hours

50. Primary AldosteronismConfirmatory Test Saline Infusion Test: Normal subjects show suppression of PAC after volume expansion but patients with primary aldo do not Overnight fast 2 Liters of normal saline are infused over 4 hours in a recumbent patient (bp and HR are monitored) At end of study, PAC is drawn: Normal subject: PAC < 5ng/dl Primary Aldo: PAC > 10ng/dl

51. Primary AldosteronismImaging

52. PheochromocytomaWho do you test? Patients with adrenergic “spells” Paroxysmal episodes of non-exertional palpitations, diaphoresis, headache, tremor, or pallor Resistant HTN A familial syndrome (MEN2, NF1, VHL) FH of pheochromocytoma Adrenal incidentaloma Pressor response during anesthesia, surgery or angiography Onset of HTN at Age < 20 Idiopathic Dilated Cardiomyopathy A history of gastric stromal tumor or pulmonary chondroma (Carney Triad)

53. PheochromocytomaBiochemical Testing 24 hour urinary metanephrines and catecholamines Plasma Free Metanephrines (high suspicion)-Predicitive value of a negative test is very high Sensitivity: 96-100% Specificity: 85-89% and decreases to 77% in patients > 60

54. PheochromocytomaBiochemical Testing Medications that may increase measured levels of catecholamines and metanephrines Tricyclic Anti-depressants Levodopa Drugs containing adrenergic receptor antagonists (decongestants) Amphetamines Buspar and most antipsychotics (Not SSRIs) Prochlorperazine Reserpine Withdrawal from Clonidine Ethanol Acetaminophen (may falsely elevate plasma free metanephrines)

55. PheochromocytomaBiochemical Testing Clonidine Suppression Test: Confirmatory test: Check plasma free metanephrines at baseline Give Clonidine 0.3mg PO X 1 dose Measure metanephrines after 3 hours Normal patient: > 40 % decrease in metanephrines Pheo patient: Metanephrines remain elevated

56. Pheochromocytoma Imaging should not take place until there is biochemical testing suggestive of pheochromocytoma!!

58. PheochromocytomaMIBG Used if abdominal imaging is negative or if patient has Large adrenal mass >10 cm or paraganglioma as the patient is more at risk of malignant disease MIBG preferentially accumulates in catecholamine producing tumor

59. PheochromocytomaMIBG Drugs that Interfere With Accuracy of test: Anti emetic (prochlorperazine) Antipsychotics Cocaine Labetalol TCA Amphetamines Dopamine Reserpine Calcium Channel Blockers

60. Preoperative Preparation Alpha-Blockade-drug of choice is phenoxybenzamine Follow with B-Blockade

62. Case # 2: Endocrine Emergency Consult to PACU Patient is a 46 year old male with an 8cm “renal mass” who one month ago was having a laporoscopic nephrectomy when he went into ventricular tachycardia/PEA during induction of anesthesia, surgery was aborted. Patient transferred to the current hospital for cardiac cath ?no coronary blockages, EF-10%

63. Case # 2: Endocrine Emergency Consult to PACU

64. Case # 2: Endocrine Emergency Consult to PACU Patient was pretreated with Carvedilol 6.25 mg PO q 12 prior to repeat surgery for the renal mass for cardioprotection 2 days prior to the nephrectomy, an intern sends off a plasma free metanephrines test (Results not followed up)

65. Case # 2: Endocrine Emergency Consult to PACU During induction of anesthesia for the repeat procedure, patient has hypertensive crisis and SBP goes up to 250, started on nitroprusside drip and procedure was aborted.

66. Case # 2: Endocrine Emergency Consult to PACU STAT ENDOCRINE CONSULT CALLED WHAT DOES THIS PATIENT HAVE? HOW SHOULD HE HAVE BEEN EVALUATED PRE OP? HOW SHOULD HE HAVE BEEN TREATED PREOPERATIVELY?

67. Case # 2: Endocrine Emergency Consult to PACU Plasma free metanephrine (0.05-1.2) 10.3 VMA (0.25-3.5) 10

68. Conclusions Adrenal Incidentaloma Must do biochemical testing to rule out hypersecretion Imaging “phenotype” is important in the evaluation Benign non-secretory adenoma should be followed at 6 months, 12 months, 24 months Primary Aldosteronism Screening: PAC/PRA > 20 Confirmatory Testing: Salt Loading Test Lap Adrenalectomy for Solitary Aldosterone Producing adenoma and unilateral hyperplasia Pheochromocytoma: Screening:24 hour urine metanephrines with catecholamines High Suspicion-Plasma Free Metanephrines Be Aware of Medications that interfere with testing Imaging Phenotype is helpful, hyperintense on MRI Preop Preparation should be with Alpha Blocker First!!