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!