ACTH-dependent Cushing s Syndrome Update AACE MI Chapter Annual Meeting September 22, Lynnette K. Nieman DEOB, NIDDK, NIH, DHHS

Transcription

1 ACTH-dependent Cushing s Syndrome Update AACE MI Chapter Annual Meeting September 22, 2018 Lynnette K. Nieman DEOB, NIDDK, NIH, DHHS

2 Objectives At the conclusion of this presentation, participants should be able to Individualize the choice of screening tests for a specific patient Modify evaluation of a patient with cyclic hypercortisolism Individualize the choice of medical therapy for a specific patient

3 Conflict of Interest Editor and author, UpToDate adrenal cortex chapters NIH has received research funding from HRA Pharma to support investigation of medical treatment of CS Honoraria, the Endocrine Society Previous member of the ABIM Endocrinology/Metabolism subspecialty group that writes questions for the boards

4 Case: Cushing s Syndrome Diagnosis A 28 year old woman bartender is referred with a possible dx of CS Over the last few years in stressful job, she gained 30 pounds, became amenorrheic and hypertensive; sometimes forgets what cocktail was ordered.and is easily irritated Started OCPs for her bones PE: BMI 32, BP 140/85; flushed face, temporal fullness, scattered bruises, trouble with serial seven subtractions, no acne, striae, edema; strength normal

5 Case: Cushing s Syndrome Diagnosis What is best test to use to screen for CS in this patient? 1. 1 mg Dexamethasone suppression test 2. Dexamethasone-CRH test 3. Midnight salivary cortisol 4. UFC 5. Not sure, need more information.

6 Case: Evaluation when UFCs are normal A 50 year old man is referred to you by an orthopedic colleague to evaluate for secondary cause of osteoporosis that led to multiple vertebral fractures. On history, he also has had a 20 pound weight gain over a few years, and is depressed. Two UFCs are normal. How should you evaluate whether hypercortisolism is the cause of osteoporosis? a. Perform a 1 mg dexamethasone suppression test b. Obtain weekly UFC for a month c. Measure bone turnover markers d. Do not evaluate further, his normal UFC excludes CS

7 Case: CS Treatment 63 year old woman with pathologically-proven Cushing s disease, hypertension, type 2 DM and hypopituitarism S/P XRT x 5 years with no new pituitary target Previous Rx mitotane, cyproheptadine, ketoconazole ineffective: UFC ug/d Rx: metoprolol, diltiazem, PPI, LT4, calcium, Vitamin D, alendronate, metformin

8 What is the best approach to her treatment now? 1. Adjust meds and repeat TSS 2. Adjust meds and start ketoconazole 3. Adjust meds and start metyrapone 4. Adjust meds and start pasireotide

9 Cushing s Syndrome A symptom complex that reflects excessive tissue exposure to cortisol The diagnosis requires both clinical and biochemical signs of hypercortisolism Without treatment, increased mortality & morbidity Etiology-specific tumor resection allows HPA axis recovery Increasing recognition of continued morbidity after cure

10 Overview Diagnosis of CS Salivary cortisol UFC Dexamethasone suppression Differential Diagnosis of CS IPSS false negative results false positive results can IPSS predict tumor location TSS: technique and assessment of cure Medical treatment of ACTH-dependent CS

11 Overview Diagnosis of CS Salivary cortisol UFC Dexamethasone suppression Differential Diagnosis of CS IPSS false negative results false positive results can IPSS predict tumor location TSS: technique and assessment of cure Medical treatment of ACTH-dependent CS

12 Cushing s syndrome suspected Exclude exogenous glucocorticoid exposure Perform one of the following tests 24-h UFC Overnight Late night salivary (> 2 tests) 1-mg DST cortisol (> 2 tests) Consider caveats for each test Use 48-h, 2-mg DST in certain populations ANY ABNORMAL RESULT Normal (CS unlikely) Exclude physiologic causes of hypercortisolism Consult endocrinologist Perform 1 or 2 other studies shown above Suggest consider or repeating the abnormal study Suggest Dex-CRH or midnight serum cortisol in certain populations Discrepant (additional evaluation) Nieman L et al. JCEM 93:1526, 2008 ABNORMAL Cushing s syndrome Normal (CS unlikely)

13 Cortisol (ug/dl) Late Night Salivary Cortisol

14 Cortisol (ug/dl) Late Night Salivary Cortisol

15 Raff H et al. J Clin Endocrinol Metab 83: , 1998 Late-night Salivary Cortisol #1 Excitement can elevate LNSC Can nonspecific excitement or anxiety could influence LNSC? 15 HVs were studied at 2300h and 0700h after watching a Sunday evening Green Bay Packers football game ( h). Despite a reported high level of excitement, only one subject had an abnormal 2300h salivary cortisol (22.8 nmol/l).

16 LNSC in older, diabetic, hypertensive male veterans 43% #2 Confounders may lead to abnormal LNSC Liu H et al. Clin Endo 2005;63:642

17 LNSC by RIA and LC-MS/MS in 387 overweight subjects (112 men) age No subject had CS. Abnormal LNSC was seen in 40/254 (16%; 11 men) subjects by RIA and 22/290 (8%; 4 men) LC-MS/MS. Using RIA, an elevated LNSC was more likely in the presence of HTN (20% vs 10%, P=0.0343) or with age >55 years, HTN and DM (39% vs. 13%, P = ). Age, HTN and/or DM did not affect LC-MS/MS results.

18 10 1 LNSC: Esoterix RIA LNSC by RIA and LC- MS/MS in 387 subjects HT mayo men esoterix HTmen esoterix HT+ men mayo HT- #3 HTN independently associated with men mayo HT+ abnormal LNSC by RIA Women mayo HT- Women mayo HT+ LNSC: Mayo LC-MS/MS women esoterix HTwomen esoterix HT Men no HTN Men + HTN mayo HTmayo HT+ Women no HTN mayo HTmayo HT+ Women + HTN

19 UFC for the diagnosis of Cushing s Syndrome #4 Compression Cyclic CS may give fractures normal UFC results Cyclic Mild CS weight occurs at gain all ages, all etiologies May Depression be associated with variable s/s Regular or irregular periodicity (4 d years) Regular or irregular duration (1 d months) Time (6 months)

20 Consequences of Cyclic Cushing s Syndrome Mis-diagnosis of condition Mis-diagnosis of cause (usually CD) Difficulty in determining cure

21 Approaches to Possible Cyclic Cushing s Syndrome Be suspicious in the face of clinical features Repeat UFC weekly for 2-3 months or when symptoms are present Consider repeated frequent salivary cortisol Perform differential diagnostic tests after 4-6 weeks of hypercortisolism

22 1 mg Overnight Dexamethasone Suppression Test Morning cortisol < 1.8 ug/dl as screening cut-off ACTH Dexamethasone Cortisol Very close to assay detection Up to 30% false positive rate 5% false negative rate in CD

23 Effect of Medications on Post- LDDST cortisol Cut-off 1.4 ug/dl (38nmol) Sensitivity % (95% CI) Specificity % (95% CI) Meds No Meds 73.3 ( ) 85.7 ( ) 70 (59 81) 96.1 ( ) p = Valassi E et al. J Clin Endocrinol Metab 94:4851-9, 2009

24 #5 Drugs may interfere with DST results Drugs that induce CYP 3A4 and accelerate dexamethasone metabolism Phenobarbital Phenytoin Carbamazepine Primidone Rifampin Rifapentine Ethosuximide Pioglitazone Drugs that inhibit CYP 3A4 and impair dexamethasone metabolism Aprepitant/fosaprepitant Itraconazole Ritonavir Fluoxetin Diltiazem Cimetidine Drugs that increase CBG and may falsely elevate serum cortisol Estrogens Mitotane Drugs that increase UFC results (may depend on assay) Carbamazepine Fenofibrate Some synthetic glucocorticoids (immunoassays) Drugs that inhibit 11β-HSD2 (licorice, carbenoxolone)

25 Overview Diagnosis of CS Salivary cortisol UFC Dexamethasone suppression Differential Diagnosis of CS IPSS false negative results false positive results can IPSS predict tumor location TSS: technique and assessment of cure Medical treatment of ACTH-dependent CS

26 Inferior Petrosal Sinus Sampling (IPSS) Catheterize petrosal sinuses and peripheral vein Bilateral and simultaneous sampling Use of CRH (FDA: peripheral test) Samples: Two Basal, 2, 5, 10 min post- CRH Measure ACTH Criteria: Central-to-peripheral ACTH > 2 before or > 3 after CRH Any positive response = CD About 95% sensitivity and specificity

27 False negative IPSS Nl venogram L venogram Atrophic R 4/501 patients with surgically-proven CD had falsenegative IPSS. Each had hypoplastic or plexiform IPS ipsilateral to an ACTH-secreting tumor. Of 100 control patients, 75% had large, bilaterally symmetrical IPSs. 18% had asymmetrical IPSs; 11 L, 7 R 7% had bilaterally small petrosal sinuses. Of the 25% with unilateral or bilateral atrophic sinuses, none had false-negative sampling results. Plexiform L #6 Review the venogram if IPSS does not show C:P gradient Doppman JL et al. J Clin Endocrinol Metab 84:533, 1999

28 False positive IPSS Cyclic CS ~5 weeks before admission had sustained hypercortisolism (UFC > 1000 ug/d) IPSS (UFC 27 ug/d; 3 d later 755; ref < 45) CD based on CRH response and C:P IPSS ratio min R L P Chest CT/MRI--> mass Hypocortisolemic after resection of carcinoid #7 Beware IPSS with insufficient suppression

29 Results IPSS Inferior petrosal sinus to peripheral (IPS:P) gradients indicated CD in 491/501 patients (98%) All 10 pts with false negative IPSS had peak petrosal sinus ACTH concentrations <400 pg/ml (~90 pmol/l) Wind JJ, et al. J Clin Endocrinol Metab. 2013;98: #8 Beware IPSS with petrosal sinus ACTH < 400 pg/ml

30 Ability of interpetrosal gradient > 1.4 and MRI to predict tumor location IPSS correctly predicted location in 273 patients (69%) with a lateral tumor Accuracy was increased by left-sided lateralization and consistent lateralization before and after CRH A positive MRI correlated with adenoma location in 171/201 patients (86%) Wind JJ, et al. J Clin Endocrinol Metab. 2013;98: #9 MRI gives false lateralization in 10 15%

31 Overview Diagnosis of CS Salivary cortisol UFC Dexamethasone suppression Differential Diagnosis of CS IPSS false negative results false positive results can IPSS predict tumor location TSS: technique and assessment of cure Medical treatment of ACTH-dependent CS

32 Treatment of Cushing s Syndrome ACTH-dependent CS Cushing s syndrome and etiology established biochemically Treat comorbidities ACTH-independent CS Presumed EAS, imaging: no tumor Presumed CD by IPSS or > 6mm mass Presumed EAS, imaging: + tumor Adrenal imaging Repeat imaging Remission Monitor for recurrence Tumor resection Resection not possible Unilateral or bilateral Adx Control hypercortisolism If CD, consider: repeat TSS pituitary-directed medical treatment RT & steroidogenesis inhibitors For all etiologies, consider: steroidogenesis inhibitors GC receptor antagonist bilateral Adx Failed surgery, no surgery, or recurrence Treat metastatic disease if applicable Nieman LK, et al. J Clin Endocrinol Metab.100: , 2015.

33 #10 Surgical technique affects results Oldfield EH, Vortmeyer, AO. J Neurosurg 104:7, 2006

34 Effect of preoperative medical therapy on assessment of cure 688 CD patients undergoing TSS 176 had preoperative steroidogenesis inhibitor Rx for days (IQR ) 40/176 (23%) with preoperative steroidogenesis inhibitor Rx had normal post-op cortisols vs 56/448(13%) with only TSS. (P=0.006) #11 pre-operative Rx can disinhibit the normal corticotropes and confuse Valassi E, et al. Eur J Endocrinol. 2018;178: interpretation of cure

35 #12 Early post-op cortisol < 3.3 ug/dl predicts durable remission Retrospective review of 257 CD patients Median follow-up 11 months after 291 TSS Remission in 241/268 admissions Cortisol nadir 5 μg/dl 9% recurrence Cortisol nadir 2 μg/dl 6% recurrence Morning POD-1 cortisol <3.3 μg/dl: 100% PPV durable remission Cortisol 5 µg/dl by 15 h (post-operative) 95% sensitivity with NPV 98% for durable remission Ironside N, et al. Eur J Endocrinol. 2018;178:

36 Predictors of sustained remission 66/79 pts post-tss nadir cortisol < 3 ug/dl 11/66 had recurrence; median F/U 131 mos At nadir hypocortisolemia, perioperative ACTH levels were >20 in all RECUR pts and <20 ng/l in the REMISSION group. 36 h post-op RECUR REMISSION P Cortisol (ug/dl) 3.4 ± ± ACTH (ng/ml) 33 ± ± 5.4 < DHEA (ng/ml) 3.8 ± ± DHEAS (ug/dl) ± ± 38.2 < El Asmar N, et al. J Clin Endocrinol Metab. 2018;103:

37 #13 DHEAS and ACTH predict long-term remission when F is < 3.3 ug/dl El Asmar N, et al. J Clin Endocrinol Metab. 2018;103:

38 Overview Diagnosis of CS Salivary cortisol UFC Dexamethasone suppression Differential Diagnosis of CS IPSS false negative results false positive results can IPSS predict tumor location TSS: technique and assessment of cure Medical treatment of ACTH-dependent CS

39 Treatment of Cushing s Syndrome ACTH-dependent CS Cushing s syndrome and etiology established biochemically Treat comorbidities ACTH-independent CS Presumed EAS, imaging: no tumor Presumed CD by IPSS or > 6mm mass Presumed EAS, imaging: + tumor Adrenal imaging Repeat imaging Remission Monitor for recurrence Tumor resection Resection not possible Unilateral or bilateral Adx Control hypercortisolism If CD, consider: repeat TSS pituitary-directed medical treatment RT & steroidogenesis inhibitors For all etiologies, consider: steroidogenesis inhibitors GC receptor antagonist bilateral Adx Failed surgery, no surgery, or recurrence Treat metastatic disease if applicable Nieman LK, et al. J Clin Endocrinol Metab.100: , 2015.

40 Medical treatment of ACTH-dependent Cushing s syndrome Pituitary-Directed ACTH Steroidogenesis-Directed Receptor-Directed ACTH Ectopic tumor-directed

41 Medical Therapies: Tumor and receptor-directed Mifepristone Pituitary-directed Cabergoline AEs: asthenia, GI, dizziness Pasireotide Works best if UFC <2- fold normal SQ; AEs: diarrhea, nausea, cholelithiasis, glucose, transient LFTs; QTc interval Ectopic tumor-directed Octreotide Little data AEs: impaired glucose tolerance, gallstones Glucocorticoid receptor-directed FDAapproved for pts with HT/DM AEs: fatigue, hypokalemia, nausea, edema, vomiting, arthralgias, headache, endometrial thickening; hypertension, abortifacient; Hard to titrate-no biomarker;

42 Medical Therapies: Steroidogenesis Inhibitors Metyrapone g/d; Q 6-8 h dosing Ketoconazole mg/d; Q 6-8 h dosing Mitotane Starting dose 250 mg; 500 mg 8 g/d Etomidate IV Quick onset of action Quick onset of action Adrenolytic; approved for adrenal cancer quick onset of action Adverse effects (AEs): GI, hirsutism, HT,variable access; hypokalemia AEs:hypogonadism (men), GI, hepatic dyscrasia; Acid needed for bioavailability Slow onset; long half life, teratogenic; AEs: GI, CNS, low WBC &T4, LFTs; gynecomastia, CBG Requires monitoring in ICU

43 Monitoring treatment with steroidogenesis inhibitors Monitoring strategy UK: Mean serum cortisol day-curve (CDC) US: 0900h serum cortisol US: Urinary free cortisol (UFC) Eucortisolemia target Cortisol day curve: mean value 10.8 μg/dl 9am cortisol: below upper limit of normal for assay or 9-12 ug/dl UFC: in normal range for assay

44 Centaur XP - LC-MS/MS (nmol/l) Centaur XP - LC-MS/MS (nmol/l) A comparison of cortisol measured by RIA and mass spectroscopy (MS) #14 11-deoxycortisol cross reacts with many Cushing s group no treatment Metyrapone group cortisol immunoassays Risk is that serum cortisol 50 0 RIA levels will actually 50 0 RIA be lower than measured by immunoassay (ie over treatment) Mean of all methods Mean of all methods MS Bias = -1.3% MS Bias = +23.0% Therefore, use assays specific for cortisol Slide courtesy of J Newell-Price Monaghan Ann Clin Biochem 48: 441, 2011

45 Summary: New medical treatments for CD Cabergoline and Pasireotide have low rates of UFC normalization (40%, 20%) Mifepristone also has low rates of clinical normalization Combination therapy may be effective, but not thoroughly tested Normalization of clinical features is the goal Adrenalectomy is an alternative New agents are in clinical trials (LCI699,Osilodrostat & COR-003, levoketoconazole)

46 Harvey Cushing "I would like to see the day when somebody would be appointed surgeon somewhere who had no hands, for the operative part is the least part of the work Letter to Dr Henry Christian Nov 20, 1911 Slide courtesy of J Newell-Price

47 Thank you!

48 Case: Cushing s Syndrome Diagnosis A 28 year old woman bartender is referred with a possible dx of CS Over the last few years in stressful job, she gained 30 pounds, became amenorrheic and hypertensive; sometimes forgets what cocktail was ordered.and is easily irritated Started OCPs for her bones PE: BMI 32, BP 140/85; flushed face, temporal fullness, scattered bruises, trouble with serial seven subtractions, no acne, striae, edema; strength normal

49 Case: Cushing s Syndrome Diagnosis What is best test to use to screen for CS in this patient? 1. 1 mg Dexamethasone suppression test 2. Dexamethasone-CRH test 3. Midnight salivary cortisol 4. UFC 5. Not sure, need more information.

50 Case: Evaluation when UFCs are normal A 50 year old man is referred to you by an orthopedic colleague to evaluate for secondary cause of osteoporosis that led to multiple vertebral fractures. On history, he also has had a 20 pound weight gain over a few years, and is depressed. Two UFCs are normal. How should you evaluate whether hypercortisolism is the cause of osteoporosis? a. Perform a 1 mg dexamethasone suppression test b. Obtain weekly UFC for a month c. Measure bone turnover markers d. Do not evaluate further, his normal UFC excludes CS

51 Case: CS Treatment 63 year old woman with pathologically-proven Cushing s disease, hypertension, type 2 DM and hypopituitarism S/P XRT x 5 years with no new pituitary target Previous Rx mitotane, cyproheptadine, ketoconazole ineffective: UFC ug/d Rx: metoprolol, diltiazem, PPI, LT4, calcium, Vitamin D, alendronate, metformin

52 What is the best approach to her treatment now? 1. Adjust meds and repeat TSS 2. Adjust meds and start ketoconazole 3. Adjust meds and start metyrapone 4. Adjust meds and start pasireotide

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