CUSHING S SYNDROME. Australian Endocrine Society, May 26 th 2017

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1 CUSHING S SYNDROME Ashley Grossman FMedSci Green-Templeton College, University of Oxford, Royal Free Hospital, London Barts and the London School of Medicine, London Australian Endocrine Society, May 26 th 2017

2 DISCLOSURES I have received lecture fees and attended advisory boards for the following relevant companies: Novartis HRA Pharma

3 PLAN OF TALK Diagnosis of Cushing s syndrome Localisation of source Treatment protocols Molecular causation Case studies Conclusions

4 DIAGNOSIS OF CUSHING S SYNDROME Clinical symptoms and signs Biochemical confirmation Localisation of source (differential diagnosis)

5 DIAGNOSIS OF CUSHING S SYNDROME Symptoms and signs of high specificity Easy bruising Myopathy Osteoporosis Growth failure in children

6 ALWAYS TAKE A CAREFUL DRUG HISTORY! Inhaled steroids Topical steroids Skin whiteners Intra-articular injections

7 INHALED STEROIDS FOR ASTHMA ARE POTENT SUPPRESSORS OF H-P-A AXIS Cushing s syndrome with Undetectable cortisol and ACTH

8 SENSITIVITY OF THE LOW-DOSE- DEXAMETHASONE SUPPRESSION TEST [0.5mg 6hrly for 48h] Dex <50nmol/L = 94% Dex and 48 <50nmol/L = 98% (Isidori et al., 2003)

9 Confirmation of Cushing s Syndrome Circadian Rhythm 09.00, (asleep) ( Loss of circadian rhythm - N at = <50nmol/l)

10 THE OVERNIGHT DEXAMETHASONE TEST 52 patients with confirmed Cushing s syndrome 153 controls (pseudo-cushing s) Dexamethasone 1mg given at midnight 09.00h serum cortisol <50 nmol/l: 100% sensitivity and 78.4% specificity (Wu et al., Chin. J. Endocrinol. Metab., 22, , 2006)

11 SLEEPING MIDNIGHT CORTISOL IN 150 PATIENTS WITH CUSHING S SYNDROME 50 nmol/l 100% sensitivity (Newell-Price et al., 1995)

12 SALIVARY CORTISOL Measures free cortisol (c.5%) Readily collected Can be used on an ambulatory basis

13 Individual values of 24-h urinary cortisol and midnight salivary cortisol of inpatients (control obese group and Cushing's syndrome group; n = 117) (Yaneva et al 2004)

14 LATE-NIGHT SALIVARY Pooled sensitivity 92% CORTISOL Pooled specificity 96% but high degree of inconsistency between studies (((Carroll, Raff & Findling, 2009)

15 LESSONS. The diagnosis of mild Cushing s disease is increasingly difficult Most of the diagnostic tests have been designed for more obvious cases Do not use tests for differential diagnosis until you are sure you have made the diagnosis Do not rely on imaging

16 URINARY FREE CORTISOL? In patients with Cushing s disease, it is not uncommon to find a normal UFC (Friedman et al, 2010; Alexandraki and Grossman, 2011) but it may be more useful in children (Shapiro et al, 2016) Moloney et al 2016

17 SUMMARY OF THE DIAGNOSIS OF CUSHING S SYNDROME Use overnight dexamethasone to screen Use low-dose dexamethasone and midnight cortisol to confirm Midnight salivary cortisol may be as good but need to establish local criteria Urinary free cortisol only useful if >4x upper limit of normal Then check 09.00h plasma ACTH

18 Aetiology of Cushing s syndrome ACTH-dependent Cushing s Syndrome [82% of all Cushing s syndrome] Pituitary-dependent 86% Ectopic ACTH 14%

19 THE DIFFERENTIAL DIAGNOSIS OF CUSHING S SYNDROME Dynamic tests High-dose dexamethasone test CRH test

20 THE HUMAN CRH TEST IN THE DIFFERENTIAL DIAGNOSIS OF CUSHING S SYNDROME Serum cortisol (nmol/l) Time (min) ECTOPIC [n=14] CD [n=101] (Newell-Price et al, 2002)

21 THE HUMAN CRH TEST IN THE DIFFERENTIAL DIAGNOSIS OF CUSHING S SYNDROME SPECIFICITY 100% % Change in serum cortisol SENSITIVITY 85% 0 14% -50 CD [n=101] ECTOPIC [n=14] (Newell-Price et al, 2002)

22 THE D.S.T. IN THE DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF CUSHING S SYNDROME (Isidori et al. 2003)

23 SENSITIVITY AND SPECIFICITY OF THE HIGH-DOSE-DEXAMETHASONE SUPPRESSION TEST Test Sensitivity Specificity HDDST Response (>60% fall) 80% 90% LDDST Response (>20% fall) 74% 84% LDDST or CRH response 94% 97%

24 DYNAMIC TESTS IN THE DIFFERENTIAL DIAGNOSIS OF ACTH- DEPENDENT CUSHING S SYNDROME BEST BUY A fall in the mean hour cortisol level >20% of basal, or a rise in the mean minute cortisol level >20% of basal, is 95% accurate in diagnosing whether the patient has a pituitary or ectopic source

25 Bilateral Simultaneous Inferior Petrosal Sinus Sampling Position of pituitary gland Cavernous sinus Right ACTH Left ACTH IPS IPSG >1.4 IJV

26 BILATERAL PETROSAL SINUS SAMPLING: Peak central to peripheral ratio (Kaltsas et al, 1999) 97% sensitivity

27 THE DIFFERENTIAL DIAGNOSIS OF CUSHING S SYNDROME BILATERAL INFERIOR PETROSAL SINUS CATHETERISATION When both petrosals catheterised and CRH given, this is 97% accurate in centralisation Lateralisation in 75% (90% in children)

28 SE MRI PRE Contrast CUSHING S DISEASE (but where is the tumour?) SE MRI Post Contrast

29 With the permission of Mark Gurnell, Addenbrooke s Hospital, Cambridge 11 C-methionine-PET/MRI in Cushing s disease PROFILE THROUGH STRUCTURAL LESION Right sided asymmetric uptake BIPSS confirmed centralisation No clear lateralisation First operation no cure MIDLIN E Second operation explored right CURE!

30 St. Bartholomew s NIH LUNG 47.5% (major organ) - CARCINOID 30% - SCLC 17.5% Intrathoracic in general 55% OCCULT 12.5% LUNG 42.2% (major organ) - CARCINOID 38% - SCLC 3% - Tumorlets 0.9% Intrathoracic in general 52% OCCULT 19%

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32 ECTOPIC ACTH SYNDROME: Lessons ~15% of ACTH-dependent Cushing s BIPSS essential With modern imaging (especially CT) should be apparent, usually chest or neck Some may never be found!

33 DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF CUSHING S SYNDROME Start with clinical symptoms and signs Dexamethasone and midnight cortisol confirm Cushing s syndrome ACTH <10 Look for adrenal source ACTH CRH test ACTH >20 BIPSS

34 Cushing s syndrome Very low ACTH D? BMAH

35 BILATERAL MACRONODULAR ADRENAL HYPERPLASIA Massive bilateral adrenal enlargement Undetectable ACTH May be aberrant responses to food (GIP), posture (AVP), DA, 5HT, pregnancy (LH/hCG) Germline mutation of ARMC5 identified (Assie et al 2013)

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37 TREATMENT OF CUSHING S DISEASE Transsphenoidal surgery Curative in 60%-80% (Cortisol <50nmol/l at 09.00h) Normal cortisol in 20%-30 Not cured in c. 20% Radiotherapy if persistent disease Radiosurgery (g-knife) Bilateral adrenalectomy

38 SURGICAL TREATMENT OF CUSHING S DISEASE Transsphenoidal surgery Single centre All patients with CD operated patients with >6y follow-up Identical protocol Two surgeons (Alexandraki et al 20

39 SURGICAL TREATMENT OF CUSHING S DISEASE Transsphenoidal surgery Cure - cortisol 09.00h <50nmol/L Remission Clinical remission Requirement for replacement therapy Serum cortisol normal ( nmol/l) Non-cure (Alexandraki et al 2012)

40 SURGICAL TREATMENT OF CUSHING S DISEASE Transsphenoidal surgery Mean follow-up 15.6 years Cure in 55.6% Recurrence in 10% Cure or remission in 79.3% Recurrence in 15% Predictive features were positive histology but not imaging All patients showing recurrence had recovery of HPA axis within 3 years. If no recovery within 3 years, no recurrence either (Alexandraki et al 2012)

41 Cum Survival. Kaplan-Meier curve of recurrence after surgery for CD in patients with cure and remission Free of Recurrence Survival 1,0 0,8 cured patients remitted noncured patients censored censored 0,6 0,4 0,2 0, Follow-up after operation (months) 10y 20y P=0,12 (Alexandraki et al 2012)

42 SURGICAL TREATMENT OF CUSHING S DISEASE TAKE-HOME MESSAGES FROM THIS SERIES Recurrence occurs even in those who appear to be cured by most recent and stringent criteria Many patients who have normalised cortisol levels remain in long-term remission (Alexandraki et al 20

43 Post-surgical remission is not always long lasting Microadenoma Mean remission rate 82% Mean recurrence rate 12% Macroadenoma 62% 19% The risk of disease recurrence persists for at least 10 years after surgery Regular monitoring of cortisol levels and lifelong follow-up are crucial for all patients with Cushing s disease Pivonello R et al. Endocr Rev 2015;36:

44 RESIDUAL CUSHING S DISEASE Treatment options ACTH secreting pituitary adenomas Transsphenoidal surgery Cure No cure Repeat surgery Radiotherapy Adrenalectomy Medical therapy

45 And if not cured by primary surgery? Re-operation (50% cure) Radiotherapy External beam radiotherapy Focussed radiosurgery Proton beam therapy Bilateral adrenalectomy Medical therapy

46 RADIOTHERAPY EXTERNAL BEAM RADIOTHERAPY 4500 cgy via 3-5 portals in 180cGy fractions RADIOSURGERY Cyberknife/gamma-knife Proton beam therapy

47 Gamma-knife radiosurgery Castinetti et al., 2007 Prospective study (n=40), mean follow-up 54.7 months, GK as primary treatment (n=11) Median dose 29.5 Gy, remission rate 42.5% (17/40), mean 22 months

48 RADIOTHERAPY All modern RT is focussed, conformal and stereotactic! Proton beam therapy for CD The rate 33 of patients onset of at effectiveness MGH is probably similar for all types, 52% faster complete in children response at 5y Petit et al 2008 The major concern is whether the tumour is discrete, localised, and away from the optic chiasm

49 BILATERAL ADRENALECTOMY Review of 739 patients in 23 studies Mortality at 30 days 3% (<1% in CD) Laparoscopic adrenalectomy in 129 patients Median stay 5 days (cf. Martin Walz) Residual cortisol secretion often seen, but <3% relapse (Ritzel et al 2013)

50 LAPAROSCOPIC VERSUS OPEN ADRENALECTOMY (Ritzel et al 2013)

51 BILATERAL ADRENALECTOMY: MUNICH CASE SERIES (Ritzel et al 2013)

52 BILATERAL ADRENALECTOMY Nelson s syndrome investigated in two studies At 5y, present in 21% Basal ACTH Nelson s absent 369, 266ng/l Nelson s present 1369, 1710ng/l (Ritzel et al 2013)

53 BILATERAL ADRENALECTOMY: CONCLUSIONS Rapid, efficient and safe cure of Cushing s disease Nelson s in 20%, role of RT 50%RT-, 25%RT+ (Jenkins et al 1995) Life-long replacement with cortisol and fludrocortisone, SMR 2x normal

54 WHY USE MEDICAL THERAPY? Urgent lowering of cortisol in very sick patients Preparation for surgery Awaiting effects of radiotherapy or radiosurgery

55 Mitotane Ketoconazole Mifepristone Metyrapone, LCI699 Etomidate

56 Metyrapone

57 METYRAPONE Blocks 11-hydroxylase Rapid in onset Maintained effect Precursors shunted to androgens and minor increase in mineralocorticoids

58 Clinical effectiveness of metyrapone monotherapy in 195 patients with Cushing s syndrome Number of patients Duration of treatment Near-Normalisation Pre-Surgery m 76% Post Surgery m 96% Long-term treatment m 83% Primary monotherapy normalisation in 52% Long-term therapy normalisation in 72% (Daniel et al, 2015)

59 LC1699, A NOVEL 11-b- HYDROXYLASE INHIBITOR Blocks CYP11B1 and B2, half-life 4h Open-label proof-of-concept study 12 patients with Cushing s disease All had failed surgery Treated for 70d with twice-daily LCI699 Measurement of UFC as assessment of success (Bertagna et al 2014)

60 EFFECTS OF LCI699 ON UFC IN 12 PATIENTS WITH CD (Bertagna et al 2014)

61 EFFECTS OF LCI699 ON HORMONE LEVELS IN 12 PATIENTS WITH CD (Bertagna et al 2014)

62 LONG-TERM EFFECTS OF OSILODROSTAT (Fleseriu et al 2016)

63 Mean UFC (nmol/24h) OSILODROSTAT; Median reductions in UFC were sustained up to month 19 of an extension to LINC 2 study 16 of 17 patients who completed week 22 entered an extension to LINC 2 Response at month 19: Controlled, n=11 (68.8%) Partially controlled, n=1 (6.3%) Uncontrolled, n=2 (12.5%)* or discontinued, n=2 (12.5%) The long-term safety profile of osilodrostat was similar to that after 22 weeks, with no new treatment-emergent signals identified Pivonello R et al. Endocrine Abstracts 2016

64 Ketoconazole

65 KETOCONAZOLE Imidazole, proximal block: 17,20-lyase, 11-OH-lase, 17-OH-lase Slow in onset, lowers all steroid metabolites Watch androgens in males Rare but important hepatotoxicity Abnormal LFTs in 10% Acute liver failure 1/15,000 Dose from 200mg od to 400mg tds Normalisation of serum cortisol in 50% Other analogues, eg, fluconazole, have been used

66 LEVOKETOCONAZOLE in Cushing s disease Levoketoconazole The approved drug ketoconazole is a racemic mixture of two enantiomers Levoketoconazole Levoketoconazole is the ( )- enantiomer of ketoconazole Hypothesized to provide better safety (lower hepatic toxicity) and efficacy than racemic ketoconazole Ketoconazole

67 Etomidate

68 ETOMIDATE Imidazole, blocks 11-hydroxylase principally Parenterally active Fast onset Can be life-saving

69 An exceptional case of Cushing s disease in an 14 yr-old girl Age 12 yr Age 13 yr

70 Treatment of life-threatening paediatric CD Treatment initiated with metyrapone with clinical improvement in mental state Acute confusional state Reduction in cognitive functioning Serum cortisol 986 nmol/l Catatonic state precluded oral therapy (Chan et al. 2011)

71 Cortisol (nmoll/l) Control of hypercortisolaemia with adrenolytic therapy IV etomidate Hydrocortisone IV mg/hr Adrenalectomy 2000 Etomidate IV 3-3.5mg/hr HC 10 mg tds Ket Dex 500 IV HC post- op IV HC sepsis Days from start of etomidate

72 Use of etomidate reviewed by Preda et al EJE, 2012

73 Mifepristone

74 MIFEPRISTONE Competitive receptor to GR No effect on MR Cortisol may remain the same or rise MR usually protected from cortisol by 11b-HSD2 Thus, MR may be overwhelmed by cortisol to induce hypokalaemia

75 MIFEPRISTONE: THE SEISMIC CONCLUSIONS STUDY Mifepristone causes progressive improvement in Cushingoid features and QoL in patients with Cushing s syndrome Hypokalaemia is common but easily managed Hypertension appears to be less problematic

76 ADRENAL THERAPY IN PERSISTENT CUSHING S DISEASE Metyrapone HRA as first choice as rapid in onset and very effective, soon osilodrostat Ketoconazole HRA as second choice as slower in onset but no virilisation May be used in combination Etomidate when immediate parenteral effect required Mifepristone may occasionally be of value

77 Cyclic hexapeptide PASIREOTIDE Broad spectrum activity at SSTR-subtypes 1,2,3 and 5 Specifically, much more active at SSTR-5 than octreotide or lanreotide

78 UFC (nmol/24h) Change in UFC from baseline to month µg bid 900 µg bid * Baseline UFC Month 6 UFC Month 6 UFC ULN Individual patients sorted by baseline UFC ULN Change in UFC at month 6 in the 103 patients with baseline and month-6 UFC measurements, sorted by baseline UFC value *Reference line is the upper limit normal UFC, which is 145 nmol/24h Colao et al 2015

79 RANDOMIZATION Study design for pasireotide LAR in CD Primary efficacy endpoint: mufc ULN regardless of prior dose up-titration in each dose group 30 mg/28 days Screening Washout of other medicines Pasireotide LAR 10 mg/28 days Dose for safety* (30 to 10 mg; 10 to 5 mg) 10 mg/28 days 40 mg/28 days Results of an interim analysis at month 7 are available Dose titration Pasireotide LAR 30 mg/28 days 30 mg/28 days Month 1 Day 1 Month 4 Month 7 Month 9 Month 12 *One dose-level reduction only during the first 7 months; If 5 mg not tolerated, patient will discontinue drug. Pasireotide LAR dose was up-titrated (10 to 30 mg; 30 to Newell-Price J et al. Endocrine Abstracts 2016;abst GP153 Poster GP153 presented at ECE 2016, Munich, Germany 40 mg) at month 4 if mufc >1.5 x ULN, and/or at months 7, 9, and 12 if mufc >1.0 x ULN

80 Screening mufc Primary efficacy endpoint was met in both dose groups 41.9% (95% CI: 30.5, 53.9) and 40.8% (95% CI: 29.7, 52.7) of patients in the pasireotide LAR 10 mg and 30 mg groups achieved mufc ULN after 7 months of treatment Higher response rates were seen in patients with lower mufc levels at screening 31/74 Monthly pasireotide LAR 10mg 41.9% or 30mg 31/ % for CD Control in around at 12 months 25-35% 18/ % Mainly in mild disease 18/ % Hyperglycaemia in 70-80% Lacroix et al /25 13/ % 52.0% Newell-Price J et al. Endocrine Abstracts 2016;abst GP153 Poster GP153 presented at ECE 2016, Munich, Germany Responders (mufc ULN at month 7; %) CI, confidence interval

81 ACTH in ng/l PASIREOTIDE TREATMENT IN 8 PATIENTS WITH NELSON S SYNDROME Baseline s.c. pasireotide LAR pasireotide (Daniel et al, submitted 2017)

82 CABERGOLINE THERAPY in 10 patients with DA receptor expression in their corticotroph tumours (Pivonello et al. 2004)

83 SUMMARY FOR PITUITARY MEDICAL THERAPY OF CCUSHING S DISEASE Cabergoline offers promise for some patients Pasireotide a consideration for occasional patients Mild disease Hyperglycaemia

84 LONG-TERM OUTCOMES OF TREATMENT FOR CUSHING S SYNDROME Oxford and Athens series CD 418 patients, adrenal adenomas 74 patients Standardised mortality ratio (SMR) CD 9.3, AA normal (Ntali et al 2013)

85 LONG-TERM OUTCOMES OF TREATMENT FOR CUSHING S SYNDROME Meta-analysis of long-term mortality Cure for a minimum of 10 years 320 patients Median follow-up 11.8 years Standardised mortality ratio Overall 1.61 (P<0.0001) Cure by surgery alone then SMR was normal (Clayton et al 2016)

86 SIGNALLING CHANGES IN PITUITARY TUMOURS GF-R PI(3)K BRAF p27 C-Myc AKT mtor MEK ERK 4E-BP1 S6K Cyclin D (Dworakowska et al., 2009)

87 THE CAUSE OF CUSHING S DISEASE? Ten corticotroph adenomas Whole-exome sequencing 4/10 showed somatic mutations of USP8 deubiquitinase (Reincke et al 2014)

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89 USP8- An International Survey 145 patients with corticotroph tumours Somatic mutations of USP8 in 36% Adult>paediatric Diagnosed at earlier age Mean size 10mm All mutations at Ser718 or Pro720 USP8 mutants enhanced POMC promoter in AtT20 cells (Perez-Rivas et al 2015)

90 Case study #1

91 35 Year-old Project Manager 8 week history of Hirsutism with male pattern hair loss Amenorrhoea Acne Change in appearance with weight gain Lower limb wasting and weakness

92 Admission bloods SODIUM 144 mmol/l POTASSIUM 2.5 mmol/l UREA 5.2 mmol/l GLUCOSE 8.2 mmol/l CREATININE 53 umol/l BILIRUBIN 12 umol/l ALT 67 IU/L ALP 152 IU/L ALBUMIN 43 g/l ADJUSTED CALC mmol/l PHOSPHATE 0.65 mmol/l T. CHOLESTEROL 3.2 mmol/l TRIGLYCERIDE 0.76 mmol/l HDL CHOL 1.6 mmol/l LDL 1.3 mmol/l CHOL/HDL RATIO 2.0 ratio CORTISOL 2003 nmol/l TESTOSTERONE 3.5 nmol/l OESTRADIOL 55 pmol/l LH 0.6 IU/L FSH 2.9 IU/L PROLACTIN 96 mu/l TSH 0.13 mu/l THYROXINE 25.7 pmol/l FREE T3 3.5 pmol/l E.S.R 5 HAEMOGLOBIN 15.5 WHITE CELLS PLATELETS 188 HAEMATOCRIT RED CELL COUNT 4.71 MEAN CELL VOL MEAN CELL HGB 32.9 MEAN CELL HGB% 33.3 NEUTROPHILS LYMPHOCYTES 0.58 MONOCYTES 0.70 EOSINOPHILS 0.00 BASOPHILS 0.00

93 What is the Cause? ACTH = 455 ng/l (0 45) K = 2.5 mmol/l

94 Diagnosis so far ACTH-dependent Cushing s Likely ectopic

95 CRH Test Time (mins) Cortisol ACTH (0-46)

96 Inferior Petrosal Sinus Sampling Right inferior petrosal sinus Left inferior petrosal sinus Baseline ACTH (ng/l) Peripheral ACTH after CRH (ng/l)

97 Radiology MRI pituitary normal CT chest/abdo/pelvis Small volume subcarinal lymphadenopathy measuring up to 19 x12mm

98 Octreotide scan

99 Bronchoscopy + FNA The morphological findings and immunostaining in keeping with a neuroendocrine neoplasm Low proliferative index it is more likely to represent a bronchial carcinoid tumour

100 K+ and cortisol trends K+ mmol/l Cortisol cortisol K Time (days) Metyrapone Ketoconazole KCZ stopped Dex

101 VATS Undetectable cortisol post-lobectomy Pathology confirms typical carcinoid Needs long-term follow-up BUT CURED!

102 Key points Acute severe Cushing s: Think ectopic ACTH Hypokalaemia a good marker of ectopic Finding the primary lesion may take >20 years After primary investigations, blockade can hypertension, hyperglycaemia risk of infection. K+

103 Case study #2

104 The patient 26-year-old black male referred from Trinidad Cushing s syndrome and abnormal pituitary MRI scan Admitted to St Bart s Hospital Previously fit and well mathematics graduate, extensively travelled and studying international trade in China 5-year history of: Abdominal striae Central weight gain despite exercise Borderline hypertension

105 More recently Proximal myopathy Fatigue, loss of concentration, agitation, near paranoia, uncharacteristic violent action Worsening striae on abdomen and upper arm Easy bruising, thin skin Low libido, reduced erectile function Peripheral oedema Itraconazole for fungal nail infection Secondary diabetes diagnosed

106 Biochemistry

107 Baseline MRI

108 Biochemistry

109 Biochemistry

110 What next? Ectopic Cushing s syndrome OR Pituitary-dependent Cushing s syndrome, Cushing s disease

111 Search for ectopic ACTH source

112 Search for ectopic ACTH source

113 Inferior petrosal sinus sampling Peak gradients Central: Peripheral 1850/366 = 5

114 At operation Pituitary exploration Tumour identified and removed Post-op cortisol 77 nmol/l (2.5 μg/dl)

115 Pituitary adenoma with strong ACTH staining

116 CONCLUSIONS Diagnosis depends on clinical suspicion, exclusion of drugs, non-suppression on dexamethasone and elevated midnight cortisol Confirm Cushing s disease with LDDST, CRH and often BIPSS Diagnosis is probabalistic not algorithmic Treatment is surgical whenever possible, with a role for radiotherapy and bilateral adrenalectomy Adrenostatic drugs (metyrapone, ketoconazole, etomidate, osilodrostat) temporarily helpful, central drugs occasionally so (cabergoline, pasireotide)

117 THANK YOU!