Diagnosis of Cushings Syndrome

David W Ray FRCP PhD, University of Manchester

Professor of Medicine and Endocrinology

Cushings syndrome
Harvey Cushing 1912 50% 5 year survival Glucocorticoid excess
Iatrogenic Pituitary ACTH Ectopic ACTH Primary adrenal (ACTH independent)

Cushings disease
Pituitary ACTH producing adenoma 70% of adult Cushings Female:male 3:1 up to 10:1 Age 25-45 Incidence ? 1 per 100,000 per year (RARE)

Clinical features
Central obesity (fat re-distribution) Protein wasting (osteoporosis, myopathy) Plethora Acne Striae (red, purple) Hypertension (diastolic >105) Oedema Hirsutism Bruising Hypokalaemia

Clinical features NOT discriminating

Generalised obesity Oligomenorrhoea Headaches Abnormal GTT

Difficult diagnoses
One symptom may predominate Severity of disease (mild disease-less florid clinical features) Fluctuating cortisol secretion, cyclical Cushings Male gender (? Confounding effects of testicular androgens)

Diagnosis
Suspect it! Confirm hypercortisolaemia Identify the source
Planned, coordinated investigation essential Access to dedicated in-patients beds, trained nurses, lab support, modern imaging May take time!!

Hypercortisolaemia
Plasma cortisol (am vs pm vs midnight sleeping) Salivary cortisol Urine collection (urinary free cortisol) Dynamic tests
O/N Dex suppression test Low dose,2 day Dex suppression test

Urinary cortisol
24 hour collection: complete collection-loss of collection depends on timing Overnight collection Good distinction between normals and Cushings Sensitive Need repetition Repeated normal tests unlikely in Cushings Raised UFC obesity, PCOS, depression

Plasma cortisol
9am cortisol, significant overlap with normals 8-9pm cortisol 10-15% overlap Midnight sleeping cortisol 50nM/l separates normals from Cushings
Acclimatise patients to inpatient stay, in patient costs, timing of sample, stress free sample

Salivary cortisol
Sample collection RIA, ELISA, Platform, LC/MS Late night salivary cortisol highest sensitivity for diagnosis of Cushings
Raff JCEM 2009: 94;3647-3655

Two late night salivary cortisol measurements sensitivity 92%, specificity 96%

Salivary cortisol
Correlates with free serum cortisol CBG raised with oestrogens (eg OCP) CBG suppressed in illness (eg medical inpatients) ELISA cross-reacts with cortisone, and prednisolone ? Advantages in measuring salivary cortisone??

SST study: correlations in all groups

overall correlation SerF-FreeF
150 100

overall correlation SerF-SalF r=0.72

r=0.76
FreeF (nmol/L)
80 100

SalF (nmol/L)

60 40 20

50

0 0 500 1000 1500

0 0 500 1000 1500

SerF (nmol/L)

SerF (nmol/L)

overall correlation FreeF-SalF

100 80 150

Overall FreeF-SalE r=0.91

SalE (nmol/L)
100

r=0.85

SalF (nmol/L)

60 40 20 0 0 50 100 150

50

0 0 50 100 150

FreeF (nmol/L)

FreeF (nmol/L)

SST study: OCP group

OCP correl SerF-FreeF
150 80

OCP correl SerF-SalF r=0.74

SalF (nmol/L)
60 40 20 0

r=0.8
FreeF (nmol/L)
100

50

0 0 500 1000 1500

500

1000

1500

SerF (nmol/L)

SerF (nmol/L)

OCP correl FreeF-SalF

80 150

OCP correl FreeF-SalE r=0.95

SalF (nmol/L)
100

r=0.92
SalF (nmol/L)
60 40 20 0 0 50 100 150

50

0 0 50 100 150

FreeF (nmol/L)

FreeF (nmol/L)

IV physio: correlations in all groups

SerF-FreeF ALL
300

SerF-SalF ALL
r=0.8
400 300 200 100 0 500 1000 1500 2000

r=0.64

FreeF-SalF ALL
400 300 200 100

FreeF (nmol/L)

200

100

SalF (nmol/L)

0 0 500 1000 1500 2000 2500

2500

0 100 -100 200 300

-100

SerF (nmol/L)

SerF (nmol/L)

Suppression tests
Overnight 1mg Dex supp test:
1mg Dex at 11pm, serum cort at 8am Timing, compliance, metabolism (drugs) Threshold (<50 nM/l) 13% obese, 23% hospitalised false positive 0.5mg Dex every 6 hours for 2 days Serum cort at 9am day 0 and 9 am day 2 Cort <50nM/l >95% sensitivity and specificity Useful as a confirmatory test

Low dose, 2 day test

Screening tests
x2 salivary cortisol Confirmatory 48 hour LD dex suppression test (?as OP)

Cushings
ACTH dependent or not Measure ACTH when confirmed hypercortisolaemia If ACTH is easily detectable (ie normal range or raised) ACTH dependent Low ACTH compatible with primary adrenal causes (nodular adrenocortical hyperplasia); NB ACTH vs other peptides, assay performance, low ref ranges

ACTH dependent
Pit vs ectopic Aggressive ectopics usually obvious (CXR, systemic features) Small ectopics can mimic pit adenoma Pit can have adenomata incidentally Use dynamic tests, imaging, and venous sampling Time and patience required!!

High Dose Dex suppression

Pre ACTH assay means to differentiate adrenal from pituitary ACTH dependent 2mg Dex exactly every 6 hours Measure cortisol at 9am days 0,1 and 2 10% false +ve 10% false ve [circa 70+ % pituitary anyway]

CRH test
Overnight admission At 9am, insert cannula Obtain 3-4 basal samples IV CRH (human) 100ug Serial samples after Measure ACTH and cortisol Define increment (>25% increase) 10% false negative 10% false positive

CRH testing

Combined Tests
High dose Dex and CRH If either is positive, suggests pituitary If both are negative, suggests ectopic
Grossman et al 1988; Clin Endocrinol 29:167178

Venous sampling
Bilateral IPSS Most useful test Dependent on expertise Labour intensive Potentially dangerous NOT a test for Cushings! Only of use if patient is hypercortisolaemic at time of test

IPSS
All or selective? Cannulate the inferior petrosal sinuses, and peripheral vein Simultaneous sampling basally (repeated) Inject 100ug CRH Simultaneous sampling post injection Concurrent cortisol measurements (UFC, midnight serum) to ensure disease activity

IPSS

Basal

Peak post CRH

Ectopic
Failed dynamic tests Failed IPSS Pit imaging pitfalls!! Chest, pancreas, duodenum, adrenals, sympathetic chain CT with contrast

Adrenal
ACTH independent CT imaging Unilateral vs bilateral

Treatment
Medical Surgical Radiotherapy

44 year old man

Orbital radiotherapy as a child for rhabdomyosarcoma Opthalmic Graves TSH 0.05, T4 48 (50-150) Given T4 by GP Now, BP90/?20, nausea, vomiting, weight loss, [Na] 120mmol/l Diagnosis?

Adrenal Crisis
Sick patient, hypotension, hyponatraemia
Random serum cortisol and plasma ACTH TREAT, high dose, replacement hydrocortisone
100mg IV every 6 hours

Intravenous saline
2-3 l first hour, then 3-4 l per day

Screening Tests; Not Acutely Sick

Morning plasma cortisol. <140nM/l highly suggestive. >415nM/l diagnosis unlikely. Random levels >500nM/l make diagnosis unlikely.

Chronic Deficiency
High dose short Synacthen test
Convenient, catches are pituitary disease of recent onset. Peak cortisol >550 nM/l (NB variation amongst cortisol assays).

Metyrapone test
In-patient test. Patients may become acutely hypoadrenal.

Chronic Deficiency
CRH test
Expensive, variable responses, rarely used.

ITT
Significant risk (CV disease, epilepsy), not for use in patients with high probability of adrenal insufficiency.

Treatment
Replacement of the missing steroid(s). Primary adrenal disease: cortisol and aldosterone. Pituitary disease: cortisol. Hydrocortisone=cortisol. Once a day, twice a day, three times a day. Synthetic vs natural.

Treatment
Hydrocortisone 10, 5, 5mg Waking, lunch, late pm Longer acting steroids x1/day Prednisolone 2.5-7.5mg Dexamethasone 0.25-0.75mg Single dose at night, or on waking No evidence comparing these approaches

Monitoring
Clinical indices
Under replacement:
Weight loss, hyponatraemia, pigmentation

Over replacement:
Cushings syndrome (obesity/fat distribution, striae, hypertension, hyperglycaemia)

? Changes in bone turnover/osteoporosis

Biochemical tests
Measure cortisol after Hc dosing

Hc Day Curves
Hc on rising (approx 7am) Cortisol 9am, 12-30pm and 5-30pm; with 24hour UFC UFC (<300nmol/24hour) ie normal range 9am cortisol 100-700nM/l 12-30pm, and 5pm >50nM/l; ideally >100nM/l
After Howlett

Adequacy of glucocorticoid cover

NB hepatic enzyme inducers: phenytoin, rifampicin, barbiturates require increased doses. Intercurrent illness, patient education Steroid card and medic alert bracelet Injection kit of hydrocortisone or dexamethasone

Surgery, major stress

Estimated cortisol production increases to 200ug/day Therefore hydrocortisone 100mg iv/im every 6 hours. Half daily dosage each day post op Back to routine replacement by day 5-6 There is evidence that this approach is unnecessary, but it remains standard practice!