AVS and IPSS: The Basics and the Pearls

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1 AVS and IPSS: The Basics and the Pearls William F. Young, Jr., MD, MSc Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA 2018 Mayo Foundation for Medical Education and Research. All rights reserved.

2 DISCLOSURE* Relevant Financial Relationship(s) None Off Label Usage None And of course, ABIM *A provider must disclose the above information to learners prior to beginning of the educational activity (ACCME)

3 When Not to Do AVS Patient without confirmed PA Patient who does not want to pursue the surgical option Young patient (<35 yrs) with marked PA and unilateral adrenal macroadenoma on CT (and normal appearing contralateral adrenal)

4 APA clinical phenotype in a young patient (<35 yr) with unilateral adrenal macroadenoma (>1-cm) AVS not needed

5 Prevalence by Age -- Autopsy Data The development of adrenocortical nodules is, in part, a function of age 7%! Kloos et al., Endo Rev 16:460, 1995

6 Funder JW, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:

7 When to Do AVS Patient with confirmed PA and: o Who wants to pursue the surgical option and o Who is >35 yrs old or <35 yrs old and lack of unilateral macroadenoma on CT

8 68-Year-Old Man Hypertension x 9 yrs: Intermittent spontaneous hypokalemia noted on routine testing over the last 2 yrs Asymptomatic no spells Suboptimal BP control on a CCB, ACE-I, central α-2 agonist, and β-adrenergic blocker Also takes 40 meq KCl/d Physical exam: normal phenotype, BP = 140/83 mm Hg, HR 84 bpm, BMI 29.4 Initial labs: Na + = 144 meq/l, K + = 4.0 meq/l, creatinine = 1.0 mg/dl

9 PAC/PRA Ratio - PAC = 42 ng/dl (1165 pmol/l) - PRA = <0.6 ng/ml/hr

10 Case Detection Testing: Morning (8-10 a.m.) ambulatory paired plasma aldosterone concentration (PAC) & plasma renin activity (PRA) May be performed while the pt is taking BP meds & without posture stimulation K + reduces the secretion of aldo & it is optimal to restore serum K + to nl before performing dx tests Mineralocorticoid receptor (MR) antagonists (eg, spironolactone & eplerenone), & high-dose (> 5 mg/d) amiloride are the only meds that absolutely interfere & should be D/C at least 6 wks before testing if clinically feasible (but there is an important caveat here)*

11 Case Detection Testing: ACE inhibitors, ARBs, & diuretics have the potential to falsely elevate PRA therefore, in a pt Rx with an ACE inhibitor, ARB, or diuretic, the finding of a detectable PRA level or a low PAC/PRA ratio does not exclude PA However, when a PRA level is undetectably low in a pt taking an ACE inhibitor, ARB or a diuretic, PA should be highly suspect Thus, ACE inhibitors, ARBs, & non-potassium sparing diuretics do NOT need to be routinely discontinued to do so simply creates a barrier to diagnosing PA

12 Caveat on SPL and EPL* *UpToDate: Approach to the patient with hypertension and hypokalemia WF Young, NM Kaplan. Accessed February 18, 2017

13 PA Confirmatory Test 24-hr urine on ambient sodium diet: - Sodium = 269 meq - Aldosterone = 34 mcg (94 nmol)

14 Adrenal CT: Radiologist report: normal adrenals

15 Adrenal Venous Sampling

16 Adrenal Venous Sampling

17 Adrenal Vein Sampling* *Continuous cosyntropin infusion 50 mcg/hr Vein RT Adrenal Vein LT Adrenal Vein IVC Aldosteron e (A) ng/dl Cortisol (C) mcg/dl A/C Ratio Aldosterone Ratio Step 1: Was cannulation of both AVs successful? AV [cortisol] should be >5-fold higher than IVC [cortisol] from BOTH AVs If successful, go to step 2. If not successful, stop.

18 Adrenal Vein Sampling* *Continuous cosyntropin infusion 50 mcg/hr Vein RT Adrenal Vein LT Adrenal Vein IVC Aldosteron e (A) ng/dl Cortisol (C) mcg/dl A/C Ratio Aldosterone Ratio Step 2: Where is Aldo coming from? To correct for dilution (from inferior phrenic vein) on the LT AV sample, divide each AV [aldo] by it s respective AV [cortisol] for the A/C Ratio

19 Adrenal Vein Sampling* *Continuous cosyntropin infusion 50 mcg/hr Vein RT Adrenal Vein LT Adrenal Vein IVC Aldosteron e (A) ng/dl Cortisol (C) mcg/dl A/C Ratio Aldosterone Ratio 102 : 1 Step 3: Where is Aldo coming from? Unilateral if A/C ratio from the dominant adrenal is >4-fold higher than A/C ratio from lower adrenal May be unilateral or bilateral if aldosterone lateralization ratio (ALR) is between 3:1 and 4:1 Bilateral if ALR is <3:1

20 Aldosterone Lateralization Ratio APA (n=102) IHA (n=84) PAH (n=8) The patient I am presenting ALR = 4:1 Young WF, Stanson AW, Thompson GB, et al. Surgery. 2004;136:

21 Adrenal Vein Sampling* *Continuous cosyntropin infusion 50 mcg/hr Vein RT Adrenal Vein LT Adrenal Vein IVC Aldosteron e (A) ng/dl Cortisol (C) mcg/dl A/C Ratio Aldosterone Ratio 102 : 1 Step 4: Consider contralateral suppression The A/C ratio from the nondominant adrenal should be less than the A/C ratio from the IVC In this case example 0.2 is less than divided by 1.9 = 0.1

22 Contralateral A/C ratio APA (n=102) IHA (n=84) PAH (n=8) Contralateral A/C ratio divided by the IVC A/C ratio 0.1 Young WF, Stanson AW, Thompson GB, et al. Surgery. 2004;136:

23

24 Follow-up 3 yrs postop: - Hypokalemia resolved and BP = 125/65 mm Hg on low-doses of 2 BP meds

25

26

27

28 AVS Summary 203 patients; % success rate Based on CT: o 46 patients (24%) would have been bypassed for surgery o 42 pts (22%) would have had unnecessary surgery CT accuracy = 53% Surgery 136: , 2004.

29 AVS Case 2: 35-yr-old woman with new onset hypertension Normal serum potassium BP treated with ACE-I PAC = 16 ng/dl PRA = <0.6 ng/ml/hr ARR = > hr urine aldo (high Na + diet): 16 mcg (Na + = 418 meq) CT: 6-mm LT nodule

30 AVS Case 2: 35-yr-old woman with new onset hypertension Normal serum potassium BP treated with ACE-I PAC = 16 ng/dl PRA = <0.6 ng/ml/hr ARR = > hr urine aldo (high Na + diet): 16 mcg (Na + = 418 meq) CT: 6-mm LT nodule

31 LH 730

32 AVS Case 2: Results of Bilateral Adrenal Venous Sampling Vein R adrenal vein L adrenal vein Inferior vena cava Aldosterone (A), ng/dl Cortisol (C), g/dl A:C ratio *L adrenal vein A:C ratio divided by R adrenal vein A:C ratio. **Continuous cosyntropin infusion 50 mcg/hr Aldosterone ratio* 15.5 KKM019

33 The best next step in this case is: 1. RT adrenalectomy 2. LT adrenalectomy 3. Bilateral adrenalectomy 4. Repeat AVS 5. Option 5 (something else)

34 AVS Case 2: Results of Bilateral Adrenal Venous Sampling Vein Aldosterone (A), ng/dl Cortisol (C), g/dl A:C ratio Aldosterone ratio* R adrenal vein L adrenal vein Inferior vena cava *Continuous cosyntropin infusion 50 mcg/hr KKM019

35 AVS Case 3: 57-yr-old woman with BP x 20 yrs & accelerated x 2 yrs; spontaneous hypokalemia x 2 yrs BP treated with CCB, ACE-I, ARB & KCL 80 meq/d PAC = 37 ng/dl PRA = <0.6 ng/ml/hr ARR = > 45 CT: 11-mm RT nodule

36 AVS Case 3: 57-yr-old woman with BP x 20 yrs & accelerated x 2 yrs; spontaneous hypokalemia x 2 yrs BP treated with CCB, ACE-I, ARB & KCL 80 meq/d PAC = 37 ng/dl PRA = <0.6 ng/ml/hr ARR = > 45 CT: 11-mm RT nodule

37 LH 730

38 AVS Case 3: Results of Bilateral Adrenal Venous Sampling Vein R adrenal vein L adrenal vein Inferior vena cava Aldosterone (A), ng/dl Cortisol (C), g/dl A:C ratio *L adrenal vein A:C ratio divided by R adrenal vein A:C ratio. **Continuous cosyntropin infusion 50 mcg/hr Aldosterone ratio* 3.2

39 The best next step in this case is: 1. RT adrenalectomy 2. LT adrenalectomy 3. Bilateral adrenalectomy 4. Repeat AVS 5. Option 5 (something else)

40 DHY261

41

42 AVS Case 4: 39-yr-old woman with poorly controlled BP on 3 drugs Spontaneous hypokalemia PAC = 41 ng/dl PRA = <0.6 ng/ml/hr ARR = > 68 CT: 9-mm RT nodule & 8-mm LT nodule

43 AVS Case 4: 39-yr-old woman with poorly controlled BP on 3 drugs Spontaneous hypokalemia PAC = 41 ng/dl PRA = <0.6 ng/ml/hr ARR = > 68 CT: 9-mm RT nodule & 8-mm LT nodule GQH042

44

45 AVS Case 4: Results of Bilateral Adrenal Venous Sampling Vein R adrenal vein L adrenal vein Inferior vena cava Aldosterone (A), ng/dl Cortisol (C), g/dl A:C ratio *R adrenal vein A:C ratio divided by L adrenal vein A:C ratio. Aldosterone ratio* 22.1

46 The best next step in this case is: 1. RT adrenalectomy 2. LT adrenalectomy 3. Bilateral adrenalectomy 4. Repeat AVS 5. Option 5 (something else)

47

48 AVS and IPSS: The Basics and the Pearls William F. Young, Jr., MD, MSc Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA 2018 Mayo Foundation for Medical Education and Research. All rights reserved.

49 When Not to Do IPSS Patient without confirmed CS IPSS does NOT diagnose CS; IPSS only tells you where ACTH is coming from Patient with typical pituitary-dependent CS presentation + definite pituitary adenoma on MRI Patient with obvious ectopic ACTH and tumor is co-localized with cross sectional imaging (CT/MRI) and 68-Ga DOTATATE-PET or FDG-PET

50 41-Year-Old Woman Slowly developing symptoms over 5 yrs: Dx with DM 4 yrs ago Dx with hypertension 2 yrs ago Osteoporosis with 2 nontraumatic stress fractures Gained 100# over past 3 yrs Proximal muscle weakness; hirsutism Irritable I am always freaking out BMI 48.8 kg/m 2

51 41-Year-Old Woman Lab: Serum cortisol: 26 mcg/dl 8 AM; 19 mcg/dl 4 PM Midnight salivary cortisol = 296 ng/dl (N <100) 24-hr UFC = 63 and 97 mcg (N <45) 1-mg overnight DST = 12 mcg/dl ACTH = 63 pg/ml (N <60) Head MRI

52 41-Year-Old Woman

53 41-Year-Old Woman Do we need IPSS here? No, we need a pituitary surgeon Lost 30# of wt BP meds D/C

54 Confirmed Cushing s Syndrome (CS) Serum ACTH Undetectable Adrenal CT Mid-normal to increased Pituitary MRI Unilateral adrenal mass: Adenoma Carcinoma Bilateral adrenal masses: AIMAH PPNAD Bilateral cortisolsecreting adenomas Definite pituitary tumor IPSS usually not needed if clinical picture fits pituitary CS Normal or if clinical picture fits ectopic CS IPSS

55 Confirmed Cushing s Syndrome (CS) Serum ACTH Mid-normal to increased Pituitary MRI Definite pituitary tumor If clinical picture fits with pituitary-dependent CS (eg, female, slow onset, mild to moderate CS, UFC <600 mcg) then IPSS usually not needed Normal or if clinical picture fits ectopic CS IPSS

56 64-Year-Old Woman Well until 5 months ago: Severe reflux and preop Nissen labs showed serum K + = 2.2 meq/l Has noticed redness and rounding of the face; scalp hair thinning; easy bruising New onset DM BMI 25.2 kg/m 2

57 64-Year-Old Woman Lab: Serum cortisol: 46 mcg/dl 8 AM; 43 mcg/dl 4 PM Midnight salivary cortisol = ND 24-hr UFC = 1084 mcg (N <45) 1-mg overnight DST = ND ACTH = 151 pg/ml (N <60) Head MRI

58 64-Year-Old Woman

59 64-Year-Old Woman Do we need IPSS here? No, we need a cross sectional imaging + 68-Ga DOTATATE or FDG-PET

60 FDG-PET

61

62 When to Do IPSS Patient with confirmed ACTHdependent CS and: o Has rapid onset and severe CS and negative cross sectional imaging o Has mild or intermediate degree CS, but negative pituitary MRI

63 50-Year-Old Woman Signs & symptoms of CS slowly developed over 10 yrs: 80 pound central weight gain (130# to 210#) Dorsocervical & supraclavicular fat pads Easy bruising Decreased proximal muscle strength New onset hypertension & diabetes Patient says: I am trapped in a fat cocoon.. who am I and where did I go?

64

65 50-Year-Old Woman Serum cortisols = 36 mcg/dl a.m. 36 mcg/dl p.m. 24-hr UFC = 531 mcg ACTH = 151 pg/ml Na + = 139 meq/l; K + = 3.7 meq/l

66 Pituitary MRI shows a full sella, but no tumor

67

68 PV IPSS Cortisol ACTH with CRH increased Post Pre CRH: from / / to to = 356% 97 = % Time RT IPS LT IPS PV PV ACTH ACTH ACTH cortisol -5 min min min min min min min min If concerned about adequacy of IPSS, check PRL levels

69

70 IPSS Case 2: 50-year-old man with severe ACTH-dependent CS (note: + PRL gradient) Time RT IPS LT IPS PV PV ACTH ACTH ACTH cortisol -5 min min min min min min min min

71 Best next step is: 1. Repeat IPSS 2. Transsphenoidal surgery 3. Pursue imaging for ectopic ACTH tumor

AVS and IPSS: The Basics and the Pearls William F. Young, Jr., MD, MSc Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA

AVS and IPSS: The Basics and the Pearls William F. Young, Jr., MD, MSc Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA AVS and IPSS: The Basics and the Pearls William F. Young, Jr., MD, MSc Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA 2016 Mayo Foundation for Medical Education and Research.

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