Cushing

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Cushings Syndrome
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Nomenclature

• Cushings Syndrome
• Hypercortisolism of any cause
• Cushings Disease
• Corticotropin (ACTH) secreting pituitary adenoma

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Cushing's Syndrome

• When to clinically suspect Cushings syndrome?
• Rare overall prevalence 1/100,000

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When to clinically suspect Cushings syndrome?

• Specific SS
• Centripetal Obesity
• Facial plethora
• Proximal muscle atrophy/weakness
• Wide (gt1cm) depressed purple striae
• Spontaneous ecchymoses
• Hypokalemic alkalosis
• Osteopenia

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Facial Plethora Centripetal Obesity
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Centripetal Obesity
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Proximal Muscle Atrophy
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Wide (gt1cm) Purple Striae
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Spontaneous Ecchymoses
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When to clinically suspect Cushings syndrome?
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Cushings Syndrome

• 1) ACTH Dependent 80
• Pituitary adenoma (65-75)
• Ectopc ACTH (10-15)
• Carcinoid (usually bronchial)
• Small cell lung cancer
• Pheochromocytoma (rare)
• Ectopic CRH (lt1)
• 2) ACTH Independent 20
• Adrenal Adenoma (10)
• Adrenal Carcinoma (10)
• Nodular adrenal hyperplasia
• Primary pigmented
• Massive macronodular
• Food dependent (GIP mediated)
• 3) Pseudo-Cushings

• Exogenous Corticosteroids
• Oral
• Inhaled/Topical hi potency
• Surreptitious

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Pseudo-Cushings

• 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

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Cushing's Syndrome

• When to clinically suspect Cushings syndrome?
• Rare overall prevalence 1/100,000
• Establish hypercortisolism (Cushings syndrome)
• Screening Tests
• Confirmatory Tests

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Establish hypercortisolism (Cushings syndrome)

• Screening tests
• 1 mg O/N DMST
• DXM 1 mg po 11PM ? 8AM plasma cortisol
• R/O Cushings Syndrome
• lt 50 nM SEN 100 SPEC ? (Poor)
• 24 UFC (urinary free cortisol)
• lt 248 nM/d R/O Cushings Syndrome (SEN 95-100)
• 248-840 nM/d Equivocal
• gt 840 nM/d (gt3x normal) consistent with
  Cushings Syndrome (SPEC 98)

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Establish hypercortisolism (Cushings syndrome)

• Screening test problems!
• 1 mg O/N DMST
• False Positive Pseudo-Cushings, 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 lt 15 mL/min)
• 24 UFC
• False positive Alcoholism (must abstain from
  alcohol for 1-2 mos prior to test)

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Evening Cortisol Measurement

• Measured at Midnight (physiological nadir)
• Plasma
• Patient admitted, asleep during blood draw VS
  outpatient with hep lock
• lt 207 nM rules out Cushings Syndrome (SEN 96
  SPEC 100)
• lt 50 nM cutoff (SEN 100 SPEC 26)
• Salivary
• lt 3.6 nM rules out Cushings (SEN 92 SPEC 100)

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Cushing's Syndrome

• When to clinically suspect Cushings syndrome?
• Rare overall prevalence 1/100,000
• Establish hypercortisolism (Cushings syndrome)
• Screening Tests
• Confirmatory Tests

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Establish hypercortisolism (Cushings syndrome)

• Confirmatory Tests
• 24 UFC
• gt 840 nM/d Establishes Cushings Syndrome on 2
  or more collections AND clear clinical findings
  of Cushings makes diagnosis of Cushings with
  SPEC 98
• Otherwise, need an additional confirmatory test.
• LDDST (Liddle Test)
• DXM 0.5 mg q6h x 48h
• Normal lt 50 nM day 3 at 8 am
• Historical gold standard but SEN 56-69, SPEC
  74-100

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Establish hypercortisolism (Cushings syndrome)

• CRH/DXM test
• Diagnosis of Pseudo-Cushings
• DXM 0.5 mg po q6h start _at_ noon for total of 8
  doses
• Last dose 6AM
• 8AM CRH 1ug/kg IV bolus
• Plasma cortisol 15 minutes later gt 38 nM
  confirms Cushings
• SEN 100 SPEC 100
• Effectively distinguishes Cushings from
  Pseudo-Cushings

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Management of Cushing's Syndrome

• When to clinically suspect Cushings syndrome?
• Rare overall prevalence 1/100,000
• Establish hypercortisolism (Cushings syndrome)
• Screening Tests
• Confirmatory Tests
• Biochemical Localization

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Biochemical Localization

• Plasma ACTH
• lt 1.1 pM ACTH Independent (adrenal source)
• 1.1-2.2 pM Equivocal
• gt 2.2 pM ACTH Dependent
• gt 110 pM Suggests ectopic ACTH source
• If Equivocal (1.1-2.2 pM) do CRH Stimulation test
• No stimulation ? ACTH independent
• Stimulation ? ACTH dependent

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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 gt 35 _at_ 15/30 min (mean) from baseline
• or
• ? cortisol gt 20 _at_ 30/45 min (mean) from baseline
• SEN 88-93 SPEC 100

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Biochemical Localization ACTH Dependent

• HDDST
• DXM 2mg q6h x 48h, repeat 24h urine on 2nd day
• Suppression of UFC lt 10 basal indicates
  pituitary source (Cushings 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 gt 50
  indicates pituitary Cushings with SEN 88-92
  SPEC 57-100

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Management of Cushing's Syndrome

• When to clinically suspect Cushings syndrome?
• Rare overall prevalence 1/100,000
• Establish hypercortisolism (Cushings syndrome)
• Screening Tests
• Confirmatory Tests
• Biochemical Localization
• Imaging
• Pituitary Incidentaloma 10
• Adrenal Incidentaloma 1-9

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Imaging

• Choice of test dependent on biochemical work-up
• Pituitary MRI
• Definitive lesion gt 0.8-1.0 cm (otherwise
  incidentaloma)
• Note many corticotroph adenomas much smaller
  than this, some you cant 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?)

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Management of Cushing's Syndrome

• When to clinically suspect Cushings syndrome?
• Rare overall prevalence 1/100,000
• Establish hypercortisolism (Cushings syndrome)
• Screening Tests
• Confirmatory Tests
• Biochemical Localization
• Imaging
• Pituitary Incidentaloma 10
• Adrenal Incidentaloma 1-9
• IPSS (if necessary)

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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

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IPSS

• Measure CentralPeripheral ACTH ratios before
  after CRH stimulation
• Pituitary basal gt 2 post CRH gt 3
• Ectopic basal lt 1.5 post CRH lt 2
• SEN 95 SPEC 100 (basal)
• SEN 100 SPEC 100 (post CRH)

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IPSS Indications

• ACTH dependent Cushings with both HDDST and CRH
  Stim Test negative
• One or both of HDDST and CRH Stim Test positive
  but no definitive lesion on MRI and surgeon
  requires laterlization

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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
lt 1.1pM
gt2.2pM
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 (gt0.8-1.0cm)
Inconclusive
IPSS
gt2 basal gt3 CRH
lt1.5 basal lt2 CRH
Conclusive
Pituitary Surgery
Continue search for ectopic source
Remove ectopic source
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Treatment of Cushings

• 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 lt 60
• Permanent cure rate microadenoma 60-70
• Assessment of Cure Post-op
• 8AM Plasma cortisol 28-56 nM (undetectable)
• 8AM ACTH lt 1-2 pM (undetectable)
• 24h UFC lt 28 nM/d
• Persistantly detectable plasma cortisol post-op,
  even if it is DXM suppressible probably means
  incomplete resection and almost certain
  recurrence
• Non-pituitaryResection of adrenal or ectopic
  source

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Treatment of Cushings

• TSS Incomplete Resection
• Repeat surgery if no initial biochemical cure
• Hypercortisolism recalcitrant to surgery
• XRT 2nd line (max benefit achieved _at_ 3-12 mos)
• Medical (adrenal enzyme inhibitors)
• Ketoconazole
• Metyrapone
• Aminoglutethimide
• Etomidate
• Adrenelectomy
• Surgical versus Medical (Mitotane)
• Nelsons Syndrome