Diagnosis of cushing s syndrome
This presentation is the property of its rightful owner.
Sponsored Links
1 / 33

Diagnosis of Cushing’s Syndrome PowerPoint PPT Presentation


  • 127 Views
  • Uploaded on
  • Presentation posted in: General

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.

Download Presentation

Diagnosis of Cushing’s Syndrome

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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 syndrome

When to clinically suspect Cushing’s syndrome?


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


Facial plethora centripetal obesity

Facial Plethora & Centripetal Obesity


Centripetal obesity

Centripetal Obesity


Proximal muscle atrophy

Proximal Muscle Atrophy


Wide 1cm purple striae

Wide (>1cm) Purple Striae


Spontaneous ecchymoses

Spontaneous Ecchymoses


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 pMACTH Independent (adrenal source)

      1.1-2.2 pMEquivocal

      > 2.2 pMACTH Dependent

      > 110 pMSuggests 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


    Diagnosis of cushing s syndrome

    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


    Diagnosis of cushing s syndrome

    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


    Diagnosis of cushing s syndrome

    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


  • Login