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CUSHING’S SYNDROME
Ashley Grossman FMedSciGreen-Templeton College, University of Oxford,
Royal Free Hospital, LondonBarts and the London School of Medicine, London
Australian Endocrine Society, May 26th 2017
DISCLOSURES
• I have received lecture fees and attended advisory boards for the following relevant companies:
• Novartis
• HRA Pharma
PLAN OF TALK
• Diagnosis of Cushing’s syndrome
• Localisation of source
• Treatment protocols
• Molecular causation
• Case studies
• Conclusions
DIAGNOSIS OF CUSHING’S
SYNDROME
• Clinical symptoms and signs
• Biochemical confirmation
• Localisation of source (differential
diagnosis)
DIAGNOSIS OF CUSHING’S
SYNDROME
• Symptoms and signs of high specificity
• Easy bruising
• Myopathy
• Osteoporosis
• Growth failure in children
• ALWAYS TAKE A CAREFUL
DRUG HISTORY!
Inhaled steroids
Topical steroids
‘Skin whiteners’
Intra-articular injections
INHALED STEROIDS FOR ASTHMA ARE
POTENT SUPPRESSORS OF H-P-A AXIS
Cushing’s syndrome with
Undetectable cortisol and
ACTH
SENSITIVITY OF THE LOW-DOSE-
DEXAMETHASONE SUPPRESSION TEST
[0.5mg 6hrly for 48h]
• Dex 2 + 48 <50nmol/L = 94%
• Dex 2 + 24 and 48 <50nmol/L = 98%
(Isidori et al., 2003)
Confirmation of Cushing’s Syndrome
• Circadian Rhythm
09.00, 24.00 (asleep)
( Loss of circadian rhythm - N at 00.00 = <50nmol/l)
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, 414- 416, 2006)
SLEEPING MIDNIGHT CORTISOL IN
150 PATIENTS WITH CUSHING’S
SYNDROME
(Newell-Price et al., 1995)
50 nmol/l
100% sensitivity
SALIVARY CORTISOL
• Measures free cortisol (c.5%)
• Readily collected
• Can be used on an ambulatory basis
(Yaneva et al 2004)
Individual values of 24-h urinary cortisol and midnight salivary cortisol of inpatients (control obese group and Cushing's syndrome group; n = 117)
LATE-NIGHT SALIVARY
CORTISOL
• Pooled sensitivity 92%
• Pooled specificity 96%
• …but high degree of inconsistency between
studies (((Carroll, Raff & Findling, 2009)
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
URINARY FREE CORTISOL?
Moloney et al 2016
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)
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
Aetiology of Cushing’s syndrome
• ACTH-dependent Cushing’s Syndrome
[82% of all Cushing’s syndrome]
• Pituitary-dependent 86%
• Ectopic ACTH 14%
THE DIFFERENTIAL DIAGNOSIS
OF CUSHING’S SYNDROME
• Dynamic tests
– High-dose dexamethasone test
– CRH test
200
400
600
800
1000
1200
1400
1600
1800
-15 0 15 30 45 60 90 120
CD
[n=101]
ECTOPIC
[n=14]
Serum
cortisol
(nmol/l)
Time (min)
THE HUMAN CRH TEST IN THE
DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROME
(Newell-Price et al, 2002)
-50
0
50
100
150
200
250
%
Change
in serum
cortisol
CD ECTOPIC
[n=101] [n=14]
SPECIFICITY 100%
SENSITIVITY 85%
14%
THE HUMAN CRH TEST IN THE
DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROME
(Newell-Price et al, 2002)
THE D.S.T. IN THE DIAGNOSIS AND
DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROME
(Isidori et al. 2003)
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%
DYNAMIC TESTS IN THE
DIFFERENTIAL DIAGNOSIS OF ACTH-
DEPENDENT CUSHING’S SYNDROME
“BEST BUY”
A fall in the mean 24+48 hour cortisol level >20% of basal, or a rise in the mean 15+30 minute cortisol level >20% of basal, is 95% accurate in diagnosing whether the patient has a pituitary or ectopic source
Bilateral Simultaneous Inferior Petrosal Sinus Sampling
IPS
IJV
Cavernous
sinusPosition of
pituitary gland
IPSG >1.4
Right
ACTH
Left
ACTH
BILATERAL PETROSAL SINUS
SAMPLING:
Peak central to peripheral ratio
97% sensitivity
(Kaltsas et al, 1999)
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)
CUSHING’S DISEASE
(but where is the tumour?)SE MRI PRE
ContrastSE MRI Post
Contrast
11C-methionine-PET/MRI in Cushing’s disease
PROFILE THROUGH STRUCTURAL LESION – Right sided asymmetric uptake
MIDLIN
E
With the permission of Mark Gurnell, Addenbrooke’s Hospital, Cambridge
BIPSS confirmed centralisation
No clear lateralisation
First operation – no cure
Second operation explored right –
CURE!
• 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%
St. Bartholomew’s NIH
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!
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 10-20 CRH test
• ACTH >20 BIPSS
Cushing’s syndrome
Very low ACTH
D?
BMAH
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)
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
SURGICAL TREATMENT OF
CUSHING’S DISEASE
➢Transsphenoidal surgery
➢Single centre
➢All patients with CD operated 1969-2001
➢126 patients with >6y follow-up
➢Identical protocol
➢Two surgeons(Alexandraki et al 2012)
SURGICAL TREATMENT OF
CUSHING’S DISEASE
➢ Transsphenoidal surgery
➢ Cure - cortisol 09.00h <50nmol/L
➢ Remission
➢Clinical remission
➢Requirement for replacement therapy
➢Serum cortisol normal (150-300 nmol/L)
➢ Non-cure
(Alexandraki et al 2012)
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)
Kaplan-Meier curve of recurrence after surgery for
CD in patients with ‘cure’ and ‘remission’
0 100 200 300
Follow-up after operation (months)
0,0
0,2
0,4
0,6
0,8
1,0
Cum
Sur
viva
l
cured patients
remitted non-cured patients
censored
censored
Free of Recurrence Survival
P=0,12
.
(Alexandraki et al 2012)10y 20y
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 2012)
Post-surgical remission is not always long lasting
Pivonello R et al. Endocr Rev 2015;36:385‒486
Mean remission rate
82%
62% 19%
Mean recurrence rate
12%Microadenoma
Macroadenoma
Regular monitoring of cortisol levels and lifelong follow-up
are crucial for all patients with Cushing’s disease
The risk of disease recurrence persists for at least 10 years after surgery
Treatment options
Transsphenoidal surgery
Cure No cure
Repeat surgery
Radiotherapy
Adrenalectomy
Medical
therapy
ACTH secreting pituitary adenomas
RESIDUAL CUSHING‘S DISEASE
And if not cured by primary surgery?
• Re-operation (50% cure)
• Radiotherapy
– External beam radiotherapy
– Focussed radiosurgery
– Proton beam therapy
• Bilateral adrenalectomy
• Medical therapy
RADIOTHERAPY
• EXTERNAL BEAM RADIOTHERAPY
– 4500 cGy via 3-5 portals in 180cGy fractions
• RADIOSURGERY
– Cyberknife/gamma-knife
– Proton beam therapy
Gamma-knife radiosurgery
• 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
Castinetti et al., 2007
RADIOTHERAPY
• All modern RT is focussed, conformal and stereotactic!
• The rate of onset of effectiveness is probably similar for
all types, faster in children
• The major concern is whether the tumour is discrete,
localised, and away from the optic chiasm
Proton beam therapy for CD33 patients at MGH52% complete response at 5y Petit et al 2008
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)
LAPAROSCOPIC VERSUS OPEN
ADRENALECTOMY
(Ritzel et al 2013)
BILATERAL ADRENALECTOMY:
MUNICH CASE SERIES
(Ritzel et al 2013)
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)
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
WHY USE MEDICAL THERAPY?
• Urgent lowering of cortisol in very sick patients
• Preparation for surgery
• Awaiting effects of radiotherapy or radiosurgery
Metyrapone, LCI699
Etomidate
Mifepristone
Mitotane
Ketoconazole
Metyrapone
METYRAPONE• Blocks 11-hydroxylase
• Rapid in onset
• Maintained effect
• Precursors shunted to androgens and minor increase in mineralocorticoids
Number of patients
Duration of treatment
Near-Normalisation
Pre-Surgery 144 6.8 m 76%
Post Surgery 28 15.5 m 96%
Long-term treatment 48 22.2 m 83%
(Daniel et al, 2015)
Primary monotherapy – normalisation in 52%
Long-term therapy – normalisation in 72%
Clinical effectiveness of metyrapone monotherapy in
195 patients with Cushing’s syndrome
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)
EFFECTS OF LCI699 ON UFC IN 12
PATIENTS WITH CD
(Bertagna et al 2014)
EFFECTS OF LCI699 ON HORMONE
LEVELS IN 12 PATIENTS WITH CD
(Bertagna et al 2014)
LONG-TERM EFFECTS OF
OSILODROSTAT
(Fleseriu et al 2016)
▪ 16 of 17 patients who completed week 22 entered an extension to LINC 2
▪ The long-term safety profile of osilodrostat was similar to that after 22 weeks, with no new treatment-emergent signals identified
OSILODROSTAT; Median reductions in UFC were sustained up to
month 19 of an extension to LINC 2 study
Pivonello R et al. Endocrine Abstracts 2016
Me
an
UF
C (
nm
ol/
24h
)
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%)
Ketoconazole
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
LEVOKETOCONAZOLE in Cushing’s disease
Levoketoconazole
• The approved drug ketoconazole is a racemic mixture of two enantiomers
• Levoketoconazole is the (–)-enantiomer of ketoconazole
• Hypothesized to provide better safety (lower hepatic toxicity) and efficacy than racemic ketoconazole
Ketoconazole
Levoketoconazole
Etomidate
ETOMIDATE
• Imidazole, blocks 11-hydroxylase principally
• Parenterally active
• Fast onset
• Can be life-saving
An exceptional case of
Cushing’s disease in an 14 yr-old girl
Age 12 yr Age 13 yr
• 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
Treatment of life-threatening paediatric CD
(Chan et al. 2011)
Control of hypercortisolaemia with adrenolytic therapy
– IV etomidate
Co
rtis
ol
(nm
oll/l)
Days from start of etomidate
0 7 282114 35 42 49
0-21
1000
1500
2000
-14
500
Etomidate IV 3-3.5mg/hr
Adrenalectomy
IV HC post- op
IV HC sepsis
HC 10 mg tds
Hydrocortisone IV 0.25-0.5mg/hr
Ket
Dex
(Chan et al 2011)
Use of etomidate reviewed
by Preda et al EJE, 2012
Mifepristone
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
MIFEPRISTONE: THE SEISMIC
STUDY
• CONCLUSIONS
– 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
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
PASIREOTIDE
• Cyclic hexapeptide
• Broad spectrum activity at SSTR-subtypes
1,2,3 and 5
• Specifically, much more active at SSTR-5
than octreotide or lanreotide
Change in UFC from baseline to month 6
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
7000
Individual patients sorted by baseline UFC
UF
C (
nm
ol/24h
)
0
500
1000
1500
2000
4000
600 µg bid
900 µg bid
ULN†
Baseline UFCMonth 6 UFCMonth 6 UFC ULN*
Colao et al 2015
Primary efficacy endpoint:
mUFC ≤ULN regardless of prior dose up-titration in each dose groupR
AN
DO
MIZ
AT
ION
Screening
Washout
of other
medicines
Pasireotide LAR 10 mg/28
days
Dose for safety*
(30 to 10 mg; 10 to 5 mg)
Pasireotide LAR 30 mg/28 days
10 mg/28 days
30 mg/28 days
40 mg/28 days
30 mg/28 days
Dose titration†
Study design for pasireotide LAR in CD
Newell-Price J et al. Endocrine Abstracts 2016;abst GP153 Poster GP153 presented at ECE 2016, Munich, Germany
*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 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
Day 1Month –1 Month 4 Month 7 Month 9 Month 12
Results of an interim analysis at month 7 are available
▪ 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
Primary efficacy endpoint was met in both dose groups
Newell-Price J et al. Endocrine Abstracts 2016;abst GP153 Poster GP153 presented at ECE 2016, Munich, Germany CI, confidence interval
Sc
ree
nin
g m
UF
C
Responders (mUFC ≤ULN at month 7; %)
18/49
18/51
13/25
13/25
31/74
31/76
36.7%
35.3%
41.9%
40.8%
52.0%
52.0%
Monthly pasireotide LAR 10mg or 30mg
for CD
Control in around at 12 months 25-35%
Mainly in mild disease
Hyperglycaemia in 70-80%
Lacroix et al 2017
Baseline s.c. pasireotide LAR pasireotide0
2000
4000
6000
AC
TH
in
ng
/L
PASIREOTIDE TREATMENT IN 8 PATIENTS
WITH NELSON’S SYNDROME
(Daniel et al, submitted 2017)
(Pivonello et al. 2004)
CABERGOLINE THERAPY in 10 patients with DA receptor expression in their corticotroph tumours
SUMMARY FOR PITUITARY
MEDICAL THERAPY OF
CCUSHING’S DISEASE
• Cabergoline offers promise for some patients
• Pasireotide a consideration for occasional patients– Mild disease
– Hyperglycaemia
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)
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)
SIGNALLING CHANGES IN PITUITARY
TUMOURS
BRAF
MEK
PI(3)K
AKT
mTOR ERK
S6K4E-BP1 Cyclin D
C-Myc
(Dworakowska et al., 2009)
p27
GF-R
THE CAUSE OF CUSHING’S
DISEASE…?
Ten corticotroph adenomas
Whole-exome sequencing
4/10 showed somatic mutations of USP8 deubiquitinase
(Reincke et al 2014)
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)
Case study #1
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
– Thin skin and easy bruising
Admission bloodsSODIUM 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. 2.30 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 11.66
PLATELETS 188
HAEMATOCRIT 0.465
RED CELL COUNT 4.71
MEAN CELL VOL. 98.7
MEAN CELL HGB 32.9
MEAN CELL HGB% 33.3
NEUTROPHILS 10.38
LYMPHOCYTES 0.58
MONOCYTES 0.70
EOSINOPHILS 0.00
BASOPHILS 0.00
What is the Cause?
• ACTH = 455 ng/L (0–45)
• K = 2.5 mmol/L
Diagnosis so far
• ACTH-dependent Cushing’s
• Likely ectopic
CRH TestTime (mins) Cortisol ACTH (0-46)
-30 1932 570
-15 1918 522
0 1484 505
15 1817 521
30 2019 534
45 2056 534
60 2069 553
120 2029 572
150 2355 605
Inferior Petrosal Sinus Sampling
Baseline ACTH
(ng/L)
ACTH after CRH
(ng/L)
Right inferior petrosal
sinus
471 500
Left inferior petrosal
sinus
461 478
Peripheral 404 448
Radiology
• MRI pituitary – normal
CT chest/abdo/pelvis Small volume subcarinal lymphadenopathy measuring up to 19 x12mm
Octreotide scan
Bronchoscopy + FNA
• The morphological findings and immunostaining in keeping with aneuroendocrine neoplasm
• Low proliferative index it is more likely torepresent a bronchial carcinoid tumour
K+ and cortisol trends
0
1
2
3
4
5
6
0
500
1000
1500
2000
2500
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
cortisol
K
Time (days)
K+ mmol/L
Cortisol
KetoconazoleMetyrapone KCZ stopped Dex
VATS
• Undetectable cortisol post-lobectomy
• Pathology confirms ‘typical carcinoid’
• Needs long-term follow-up
• BUT CURED!
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+
Case study #2
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
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
Biochemistry
Baseline MRI
Biochemistry
Biochemistry
What next?
• Ectopic Cushing’s syndrome
OR
• Pituitary-dependent Cushing’s syndrome, Cushing’s disease
Search for ectopic ACTH source
Search for ectopic ACTH source
Inferior petrosal sinus sampling
Peak gradients
Central:
Peripheral
1850/366 = 5
At operation
• Pituitary exploration
• Tumour ‘identified’ and removed
• Post-op cortisol 77 nmol/L (2.5 μg/dL)
Pituitary adenoma with strong ACTH staining
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)
THANK YOU!