Diagnosis of Cushing s Syndrome David W Ray FRCP PhD

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Diagnosis of Cushings Syndrome
David W Ray FRCP PhD, University of
Manchester Professor of Medicine and Endocrinology
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Cushings syndrome

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

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Cushings disease

• Pituitary ACTH producing adenoma
• 70 of adult Cushings
• Femalemale 31 up to 101
• Age 25-45
• Incidence ? 1 per 100,000 per year (RARE)

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Clinical features

• Central obesity (fat re-distribution)
• Protein wasting (osteoporosis, myopathy)
• Plethora
• Acne
• Striae (red, purple)
• Hypertension (diastolic gt105)
• Oedema
• Hirsutism
• Bruising
• Hypokalaemia

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Clinical features NOT discriminating

• Generalised obesity
• Oligomenorrhoea
• Headaches
• Abnormal GTT

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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)

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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!!

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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

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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

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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

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Salivary cortisol

• Sample collection
• RIA, ELISA, Platform, LC/MS
• Late night salivary cortisol highest sensitivity
  for diagnosis of Cushings
• Raff JCEM 2009 943647-3655
• Two late night salivary cortisol measurements
  sensitivity 92, specificity 96

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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??

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SST study correlations in all groups
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SST study OCP group
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IV physio correlations in all groups
SerF-SalF ALL
FreeF-SalF ALL
SerF-FreeF ALL
r0.64
300
r0.8
400
400
300
300
200
200
200
FreeF (nmol/L)
SalF (nmol/L)
100
100
100
0
0
500
1000
1500
2000
2500
0
100
200
300
SerF (nmol/L)
0
500
1000
1500
2000
2500
-100
SerF (nmol/L)
-100
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Suppression tests

• Overnight 1mg Dex supp test
• 1mg Dex at 11pm, serum cort at 8am
• Timing, compliance, metabolism (drugs)
• Threshold (lt50 nM/l)
• 13 obese, 23 hospitalised false positive
• Low dose, 2 day test
• 0.5mg Dex every 6 hours for 2 days
• Serum cort at 9am day 0 and 9 am day 2
• Cort lt50nM/l
• gt95 sensitivity and specificity
• Useful as a confirmatory test

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Screening tests

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

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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

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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!!

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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

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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 (gt25 increase)
• 10 false negative
• 10 false positive

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CRH testing
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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 29167-178

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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

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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

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IPSS
Peak post CRH
Basal
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Ectopic

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

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Adrenal

• ACTH independent
• CT imaging
• Unilateral vs bilateral

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Treatment

• Medical
• Surgical
• Radiotherapy

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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?

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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

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Screening Tests Not Acutely Sick

• Morning plasma cortisol.
• lt140nM/l highly suggestive.
• gt415nM/l diagnosis unlikely.
• Random levels gt500nM/l make diagnosis unlikely.

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Chronic Deficiency

• High dose short Synacthen test
• Convenient, catches are pituitary disease of
  recent onset.
• Peak cortisol gt550 nM/l (NB variation amongst
  cortisol assays).
• Metyrapone test
• In-patient test. Patients may become acutely
  hypoadrenal.

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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.

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Treatment

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

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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

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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

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Hc Day Curves

• Hc on rising (approx 7am)
• Cortisol 9am, 12-30pm and 5-30pm with 24hour UFC
• UFC (lt300nmol/24hour) ie normal range
• 9am cortisol 100-700nM/l
• 12-30pm, and 5pm gt50nM/l ideally gt100nM/l
• After Howlett

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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

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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!