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Diagnosis of Cushing’s Syndrome. William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University. Nomenclature. Cushing’s Syndrome Hypercortisolism of any cause Cushing’s Disease Corticotropin (ACTH) secreting pituitary adenoma.

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diagnosis of cushing s syndrome

Diagnosis of Cushing’s Syndrome

William Harper, MD, FRCPC

Endocrinology & Metabolism

Assistant Professor of Medicine

McMaster University

nomenclature
Nomenclature
  • Cushing’s Syndrome
    • Hypercortisolism of any cause
  • Cushing’s Disease
    • Corticotropin (ACTH) secreting pituitary adenoma
cushing s syndrome ddx
Cushing’s Syndrome Ddx
  • Exogenous Corticosteroids
  • Oral
  • Inhaled/Topical – hi potency
  • Surreptitious

1) ACTH Dependent 80%

Pituitary adenoma (65-75%)

Ectopc ACTH (10-15%)

Carcinoid (usually bronchial)

Small cell lung cancer

Pheochromocytoma (rare)

Ectopic CRH (<1%)

2) ACTH Independent 20%

Adrenal Adenoma (10%)

Adrenal Carcinoma (10%)

Nodular adrenal hyperplasia

Primary pigmented

Massive macronodular

Food dependent (GIP mediated)

3) Pseudo-Cushing’s

pseudo cushing s
Pseudo-Cushing’s
  • Drug/alcohol abuse and withdrawal.
  • Depression/mania
  • Panic disorder
  • Anorexia nervosa
  • Obesity
  • Malnutrition
  • Operations, trauma
  • Chronic exercise
  • Hypothalmic amenorrhea
  • Elevated CBG (estrogens, pregnancy, hyperthyroidism).
  • Glucocorticoid resistance (family history of adrenal insuff).
  • Complicated DM
management of cushing s syndrome
Management of Cushing\'s Syndrome
  • When to clinically suspect Cushing’s syndrome?

Rare: overall prevalence 1/100,000

  • Establish hypercortisolism (Cushing’s syndrome)

Screening Tests

Confirmatory Tests

  • Biochemical Localization
  • Imaging

Pituitary Incidentaloma 10%

Adrenal Incidentaloma 1-9%

  • IPSS (if necessary)
  • Treatment
when to clinically suspect cushing s syndrome1
When to clinically suspect Cushing’s syndrome?

Specific S&S:

  • Centripetal Obesity
  • Facial plethora
  • Proximal muscle atrophy/weakness
  • Wide (>1cm) depressed purple striae
  • Spontaneous ecchymoses
  • Hypokalemic alkalosis
  • Osteopenia
management of cushing s syndrome1
Management of Cushing\'s Syndrome
  • When to clinically suspect Cushing’s syndrome?

Rare: overall prevalence 1/100,000

  • Establish hypercortisolism (Cushing’s syndrome)

Screening Tests

Confirmatory Tests

  • Biochemical Localization
  • Imaging

Pituitary Incidentaloma 10%

Adrenal Incidentaloma 1-9%

  • IPSS (if necessary)
  • Treatment
establish hypercortisolism cushing s syndrome
Establish hypercortisolism (Cushing’s syndrome)
  • “Screening” tests
  • 1 mg O/N DMST
      • DXM 1 mg po 11PM  8AM plasma cortisol
      • < 140 nM R/O Cushing’s Syndrome
          • SEN 98% SPEC 71-80%
          • < 50 nM SEN ~100% SPEC ? (Poor)
  • 24 UFC
      • < 248 nM/d R/O Cushing’s Syndrome (SEN 95-100%)
      • 248-840 nM/d Equivocal
      • > 840 nM/d consistent with Cushing’s Syndrome (SPEC 98%)
establish hypercortisolism cushing s syndrome1
Establish hypercortisolism (Cushing’s syndrome)
  • Screening test problems!
  • 1 mg O/N DMST
      • False Positive: Pseudo-Cushing’s, elevated CBG (pregnancy, OCP, hyperthyroid), drugs which induce hepatic metabolism of DXM (dilantin, tegretol, phenobarbitol, rifampin)
      • False Negative: Decreased metabolism or clearance of DXM (liver failure, CrCl < 15 mL/min)
  • 24 UFC
      • False positive: Alcoholism (must abstain from alcohol for 1-2 mos prior to test)
evening cortisol measurement
Evening Cortisol Measurement
  • Measured at Midnight (physiological nadir)
  • Plasma
    • Patient admitted, asleep during blood draw VS outpatient with hep lock
    • < 207 nM rules out Cushing’s Syndrome (SEN 96% SPEC 100%)
    • < 50 nM cutoff (SEN 100% SPEC 26%)
  • Salivary
    • < 3.6 nM rules out Cushing’s (SEN 92% SPEC 100%)
management of cushing s syndrome2
Management of Cushing\'s Syndrome
  • When to clinically suspect Cushing’s syndrome?

Rare: overall prevalence 1/100,000

  • Establish hypercortisolism (Cushing’s syndrome)

Screening Tests

Confirmatory Tests

  • Biochemical Localization
  • Imaging

Pituitary Incidentaloma 10%

Adrenal Incidentaloma 1-9%

  • IPSS (if necessary)
  • Treatment
establish hypercortisolism cushing s syndrome2
Establish hypercortisolism (Cushing’s syndrome)
  • “Confirmatory Tests”
  • 24 UFC
      • > 840 nM/d Establishes Cushing’s Syndrome on 2 or more collections AND clear clinical findings of Cushing’s makes diagnosis of Cushing’s with SPEC 98%
      • Otherwise, need an additional confirmatory test.
  • LDDST (Liddle Test)
      • 2 baseline 24h urine for cortisol and 17-OH steroids
      • DXM 0.5 mg q6h x 48h
      • During 2nd day on DXM repeat 24h urine collection
      • UFC > 100 nM/d or 17OHS > 11 uM/d indicates Cushing’s
      • Historical gold standard but SEN 56-69%, SPEC 74-100%
      • Obsolete test!
establish hypercortisolism cushing s syndrome3
Establish hypercortisolism (Cushing’s syndrome)
  • CRH/DXM test
      • Nieman et al, JAMA, 269:2232-2238, 1993.
      • 58 adults with MILD hypercortisolism
      • Diagnosis of Cushing’s confirmed at surgery
      • Diagnosis of Pseudo-Cushing’s based on extended f/up (28 mos) without progression
      • DXM 0.5 mg po q6h start @ noon for total of 8 doses
      • Last dose 6AM
      • 8AM: CRH 1ug/kg IV bolus
      • Plasma cortisol 15 minutes later: > 38 nM confirms Cushing’s
      • SEN 100% SPEC 100%
      • Effectively distinguishes Cushing’s from Pseudo-Cushing’s
management of cushing s syndrome3
Management of Cushing\'s Syndrome
  • When to clinically suspect Cushing’s syndrome?

Rare: overall prevalence 1/100,000

  • Establish hypercortisolism (Cushing’s syndrome)

Screening Tests

Confirmatory Tests

  • Biochemical Localization
  • Imaging

Pituitary Incidentaloma 10%

Adrenal Incidentaloma 1-9%

  • IPSS (if necessary)
  • Treatment
biochemical localization
Biochemical Localization
  • Plasma ACTH:

< 1.1 pM ACTH Independent (adrenal source)

1.1-2.2 pM Equivocal

> 2.2 pM ACTH Dependent

> 110 pM Suggests ectopic ACTH source

  • If Equivocal (1.1-2.2 pM) do CRH Stimulation test
      • No stimulation  ACTH independent
      • Stimulation  ACTH dependent
biochemical localization acth dependent
Biochemical Localization: ACTH Dependent
  • CRH Stimulation Test
      • Pituitary adenoma but not adrenal or ectopic sources should respond to CRH by increasing ACTH release
      • CRH 1 ug/kg IV
      • Plasma ACTH & cortisol: -5, -1, 0, 15, 30, 45 min
      • Pituitary disease indicated if:
        • ↑ ACTH > 35% @ 15/30 min (mean) from baseline

or

        • ↑ cortisol > 20% @ 30/45 min (mean) from baseline
      • SEN 88-93% SPEC 100%
biochemical localization acth dependent1
Biochemical Localization: ACTH Dependent
  • HDDST
      • Baseline 24h urine for UFC and 17OHS
      • DXM 2mg q6h x 48h, repeat 24h urine on 2nd day
      • Suppression of UFC < 10% basal and/or 17OHS < 36% basal indicates pituitary source (Cushing’s Disease)
      • SEN 70% SPEC ~100%
      • Not 100% SPEC as 10% of ectopic tumors (usually bronchial carcinoids) will suppress on HDDST
  • 8 mg O/N DST
      • Baseline 8AM plasma cortisol, 11PM DXM 8 mg po
      • Next day 8AM plasma cortisol suppress > 50% indicates pituitary Cushing’s with SEN 88-92% SPEC 57-100%
biochemical localization acth dependent2
Biochemical Localization: ACTH Dependent

*Probably Pituitary: High pre-test probability (80-90% ACTH dependent Cushing’s pituitary) combined with at least 1 test pointing to pituitary as source

management of cushing s syndrome4
Management of Cushing\'s Syndrome
  • When to clinically suspect Cushing’s syndrome?

Rare: overall prevalence 1/100,000

  • Establish hypercortisolism (Cushing’s syndrome)

Screening Tests

Confirmatory Tests

  • Biochemical Localization
  • Imaging

Pituitary Incidentaloma 10%

Adrenal Incidentaloma 1-9%

  • IPSS (if necessary)
  • Treatment
imaging
Imaging
  • Choice of test dependent on biochemical work-up
  • Pituitary MRI
      • Definitive lesion > 0.8-1.0 cm (otherwise incidentaloma)
      • Note: many corticotroph adenomas much smaller than this, some you can’t even see on MRI.
  • If biochemical w/up points towards ectopic source
      • CT Thorax 1st
      • Then CT abdomen/pelvis
      • Then Thyroid U/S to R/O MTC
      • Octreotide Scan: Ectopic ACTH or CRH source (80% SEN?)
management of cushing s syndrome5
Management of Cushing\'s Syndrome
  • When to clinically suspect Cushing’s syndrome?

Rare: overall prevalence 1/100,000

  • Establish hypercortisolism (Cushing’s syndrome)

Screening Tests

Confirmatory Tests

  • Biochemical Localization
  • Imaging

Pituitary Incidentaloma 10%

Adrenal Incidentaloma 1-9%

  • IPSS (if necessary)
  • Treatment
slide28
IPSS
  • Bilateral catheterization of petrosal venous sinuses via femoral veins
  • Invasive but complication risk low in experienced hands:
      • CVA 0.2%, Cavernous sinus thrombosis
      • Inguinal hematoma, transient tachyarrythmia
slide29
IPSS
  • Measure Central:Peripheral ACTH ratios before & after CRH stimulation
  • Pituitary: basal > 2 post CRH > 3
  • Ectopic: basal < 1.5 post CRH < 2
  • SEN 95% SPEC 100% (basal)
  • SEN 100% SPEC 100% (post CRH)

Basal

Post CRH

ipss indications
IPSS: Indications
  • ACTH dependent Cushing’s with both HDDST and CRH Stim Test negative
  • One or both of HDDST and CRH StimTest positive but no definitive lesion on MRI and surgeon requires laterlization
slide31

Clinical Suspicion

Screen Test: 24 UFC or 1mg O/N DST (+/- evening plasma/salivary cortisol)

Confirmatory Testing:

Repeat 24 UFC +/- CRH/DXM Test (+/- evening plasma/salivary cortisol)

ACTH

< 1.1pM

>2.2pM

1.1-2.2pM

ACTH

Independent

CT abdo

ACTH dependent

1st 8mg O/N DST or HDDST

2nd CRH Test if above test negative

CRH Test

No Stim

Positive

Stim

No CRH stim

No DXM suppression

Stim by CRH or

DXM suppresses

Adrenal Surgery

  • Ectopic ACTH
  • CT thorax, abdo
  • Thyroid U/S
  • Octreotide Scan

Pituitary

MRI

Conclusive

(>0.8-1.0cm)

Inconclusive

IPSS

>2 basal

>3 CRH

<1.5 basal

<2 CRH

Conclusive

Pituitary Surgery

Continue search for ectopic source

Remove ectopic source

treatment of cushing s
Treatment of Cushing’s
  • 1˚ Rx is Surgery
      • Pituitary
        • TSS, adenectomy (if possible), hemihypophysectomy (want fertility), subtotal resection (85-90%) of anterior pituitary (fertility not an issue).
        • Initial cure rate: microadenoma 70-80%

macroadenoma < 60%

        • Permanent cure rate: microadenoma 60-70%
        • Assessment of Cure Post-op:
          • 8AM Plasma cortisol 28-56 nM (undetectable)
          • 8AM ACTH < 1-2 pM (undetectable)
          • 24h UFC < 28 nM/d
          • Persistantly detectable plasma cortisol post-op, even if it is DXM suppressible probably means incomplete resection and almost certain recurrence
      • Non-pituitary:Resection of adrenal or ectopic source
treatment of cushing s1
Treatment of Cushing’s
  • TSS: Incomplete Resection
      • Repeat surgery if no initial biochemical cure
  • Hypercortisolism recalcitrant to surgery:
      • XRT: 2nd line (max benefit achieved @ 3-12 mos)
      • Medical (adrenal enzyme inhibitors)
        • Ketoconazole
        • Metyrapone
        • Aminoglutethimide
        • Etomidate
      • Adrenelectomy
        • Surgical versus Medical (Mitotane)
        • Nelson’s Syndrome
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