Cushing’s Syndrome A Clinical Approach Stavroula Christopoulos, MD, FRCPC.
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Transcript of Cushing’s Syndrome A Clinical Approach Stavroula Christopoulos, MD, FRCPC.
Cushing’s Cushing’s SyndromeSyndrome
A Clinical ApproachA Clinical Approach
Stavroula Christopoulos, MD, FRCPC
Cushing’s SyndromeCushing’s SyndromeOutlineOutline
DefinitionsDefinitions
Clinical featuresClinical features
Differential diagnosisDifferential diagnosis
Diagnostic approachDiagnostic approach
TreatmentTreatment
Applied knowledge: a case presentationApplied knowledge: a case presentation
Cushing’s SyndromeCushing’s Syndrome
1932: Harvey Cushing 1932: Harvey Cushing described a series of described a series of seven pts with seven pts with basophilic adenomas of basophilic adenomas of the pituitary --- CDthe pituitary --- CD
Cushing’s SyndromeCushing’s SyndromeDefinitionsDefinitions
Cushing’s syndromeCushing’s syndrome
Cushing’s diseaseCushing’s disease
Pseudo-Cushing’s syndrome Pseudo-Cushing’s syndrome
Cushing’s SyndromeCushing’s SyndromeClinical featuresClinical features
Cushing’s SyndromeCushing’s SyndromeClinical featuresClinical features
Cushing’s SyndromeCushing’s SyndromeClinical featuresClinical features
Cushing’s SyndromeCushing’s SyndromeClinical featuresClinical features
63y.o M admitted on 63y.o M admitted on 7W with L/E muscle 7W with L/E muscle weakness and a T6 weakness and a T6 sensory levelsensory level
Diagnosis?Diagnosis?
Cushing’s SyndromeCushing’s SyndromeClinical featuresClinical features
GeneralGeneral Central obesityCentral obesity Proximal muscle weaknessProximal muscle weakness HTNHTN HeadachesHeadaches
DermatologicDermatologic Wide purple striaeWide purple striae Spontaneous ecchymosesSpontaneous ecchymoses Facial plethora Facial plethora HyperpigmentationHyperpigmentation Acne, hirsutismAcne, hirsutism Fungal skin infectionsFungal skin infections
Endocrine/MetabolicEndocrine/Metabolic Hypokalemic alkalosisHypokalemic alkalosis HypokalemiaHypokalemia OsteopeniaOsteopenia HypogonadismHypogonadism Glucose intoleranceGlucose intolerance HyperlipidemiaHyperlipidemia HyperhomocysteinemiaHyperhomocysteinemia Kidney stonesKidney stones PolyuriaPolyuria HypercoagulabilityHypercoagulability
NeuropsychiatricNeuropsychiatric InsomniaInsomnia Depression, frank psychosisDepression, frank psychosis Impaired cognition and short-term Impaired cognition and short-term
memorymemory
Reversibility of Anatomic, Neuropsychological, Reversibility of Anatomic, Neuropsychological, and Metabolic Brain Disturbances Following and Metabolic Brain Disturbances Following
Treatment of Endogenous Cushing’s Treatment of Endogenous Cushing’s Syndrome: A 3-Year Prospective StudySyndrome: A 3-Year Prospective Study
23 patients with endogenous CS23 patients with endogenous CS
Baseline
6 months
Post-operative
Eucortisolism
24 months
MRI
Psych
1H-MRS
12 months 36 months
Curative Surgery
MRIMRI MRI MRI
Psych Psych Psych
1H-MRS 1H-MRS
ResultsResults
Pre-operative MRI MRI 36 mo post eucortisolism
ResultsResults
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 5 6 7
Series3
Series2
Series1
Controls
Baseline
6 mo 12 mo 24 mo 36 mo
Grade 3
Grade 1
Grade 2
Anatomic Evaluation: Subjective Grading of Cerebral Atrophy
*
*
*p value versus preceding value <0.05*p value versus controls <0.05
DiscussionDiscussion
Pathophysiologic
Mechanisms
Measurable
Clinical Parameter
s
Excess GC enter the brain and act on MR and GR
Dendritic atrophy
Neuronal cell death
Cell membrane dysfunction
Decreased cell
excitability
Brain volume
loss on MRI
Neuropsychological and
Cognitive Dysfunction
Neurometabolic
Abnormalities on 1H MRS
Cushing’s SyndromeCushing’s SyndromeClinical featuresClinical features
Most reliable differentiating signs from Most reliable differentiating signs from obesity are those of protein wasting:obesity are those of protein wasting: Thin skinThin skin Easy bruisingEasy bruising Proximal weaknessProximal weakness
Cushing’s SyndromeCushing’s SyndromeEtiologyEtiology
ACTH-independentACTH-independent (Factitious)(Factitious)
UnilateralUnilateral Adrenal adenoma (10%)Adrenal adenoma (10%) Adrenal carcinoma (5%)Adrenal carcinoma (5%)
BilateralBilateral Macronodular Hyperplasia Macronodular Hyperplasia
(AIMAH) (<2%)(AIMAH) (<2%)
Primary pigmented Micronodular Primary pigmented Micronodular Adrenal disease (PPNAD) (<2%)Adrenal disease (PPNAD) (<2%)
McCune Albright SyndromeMcCune Albright Syndrome (<2%)(<2%)
Cushing’s SyndromeCushing’s SyndromeEtiologyEtiology
ACTH-dependentACTH-dependent (Pseudo-CS)(Pseudo-CS)
Pituitary (CD) Pituitary (CD) (70%)(70%) Microadenomas (95%)Microadenomas (95%) Macroadenomas (5%)Macroadenomas (5%)
Ectopic ACTH or CRH Ectopic ACTH or CRH (10%)(10%)
Small cell lung caSmall cell lung ca Carcinoids: lung, pancreas, Carcinoids: lung, pancreas,
thymusthymus
Cushing’s SyndromeCushing’s SyndromeAIMAHAIMAH
Adrenal cortisol hypersecretion with radiological Adrenal cortisol hypersecretion with radiological evidence of massive adrenal macronodulesevidence of massive adrenal macronodules
““ACTH-independent macronodular adrenal hyperplasia”ACTH-independent macronodular adrenal hyperplasia” ““Massive macronodular adrecortical disease”Massive macronodular adrecortical disease” ““Autonomous macronodular adrenal hyperplasia”Autonomous macronodular adrenal hyperplasia” ““Macronodular adrenal hyperplasia”Macronodular adrenal hyperplasia”
Cushing’s SyndromeCushing’s SyndromeAIMAHAIMAH
Presents 5Presents 5thth-6-6thth decade decade
Radiological featuresRadiological features Bilateral adrenal masses Bilateral adrenal masses
measuring up to 5 cm of soft measuring up to 5 cm of soft tissue densitytissue density
Pathological featuresPathological features Combined adrenal weight Combined adrenal weight >60 g>60 g200g200g Cut section: nodules yellow Cut section: nodules yellow
(high lipid content)(high lipid content) Inter-nodular hyperplasiaInter-nodular hyperplasia
Cushing’s SyndromeCushing’s SyndromeAIMAHAIMAH
Lacroix et al. NEJM 1992Lacroix et al. NEJM 1992 First description of a patient with post-prandial hypercortisolismFirst description of a patient with post-prandial hypercortisolism
Cortisol levels were correlated post-prandially with GIP levelsCortisol levels were correlated post-prandially with GIP levels
The presence of ectopic GIP receptors on the adrenal gland was further The presence of ectopic GIP receptors on the adrenal gland was further supported by adrenal imaging following the injection of [123I] GIPsupported by adrenal imaging following the injection of [123I] GIP
Shown to be ectopically expressed at the cell membrane in a non-Shown to be ectopically expressed at the cell membrane in a non-mutated formmutated form
Transfection of bovine adrenal cells with the GIP receptor leads to Transfection of bovine adrenal cells with the GIP receptor leads to hyperplastic adrenals and hypercortisolismhyperplastic adrenals and hypercortisolism
Cushing’s SyndromeCushing’s SyndromeAIMAHAIMAH
Lacroix et al. NEJM 1999Lacroix et al. NEJM 1999 Patient with AIMAH who had transient CS during Patient with AIMAH who had transient CS during
pregnancy and persistent CS following menopausepregnancy and persistent CS following menopause
Cortisol secretion was stimulated by the Cortisol secretion was stimulated by the exogenous administration of GnRH, h CG, or LH.exogenous administration of GnRH, h CG, or LH.
Treated succesfully with GnRH agonist Treated succesfully with GnRH agonist
Cushing’s SyndromeCushing’s SyndromeAIMAHAIMAH
Cushing’s SyndromeCushing’s SyndromeAIMAHAIMAH
Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005
Cushing’s SyndromeCushing’s SyndromeAIMAHAIMAH
Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005
Cushing’s SyndromeCushing’s SyndromePPNADPPNAD
Adrenal CS caused by small Adrenal CS caused by small nodules that may not be nodules that may not be visualized on imagingvisualized on imaging
Adrenal glands contain Adrenal glands contain multiple small cortical black multiple small cortical black pigmented micronodules pigmented micronodules (<4 mm)(<4 mm)
Positive stain synaptophysinPositive stain synaptophysin
Cushing’s SyndromeCushing’s SyndromePPNADPPNAD
Sporadic or part of Carney’s complex: pigmented Sporadic or part of Carney’s complex: pigmented lentigines and blue nevi on the face, neck, trunk and lentigines and blue nevi on the face, neck, trunk and multiple endocrine and non-endocrine tumors (atrial multiple endocrine and non-endocrine tumors (atrial myxomas)myxomas)
Second decadeSecond decade
PARADOXICAL increase of cortisol secretion PARADOXICAL increase of cortisol secretion during Liddle test (0.5mg q6 –2mg q6)– 100% during Liddle test (0.5mg q6 –2mg q6)– 100% increase in UFC at day 6 highly specific – study increase in UFC at day 6 highly specific – study shown high expression of GR in PPNAD nodulesshown high expression of GR in PPNAD nodules
Cushing’s SyndromeCushing’s SyndromePPNADPPNAD
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CSa. ACTH-dependent vs independentb. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
Key physiological principlesKey physiological principles Cortisol hypersecretion in most patients with CS is Cortisol hypersecretion in most patients with CS is
cyclical cyclical
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
Key physiological principlesKey physiological principles Loss of circadian rhythm in pts with CSLoss of circadian rhythm in pts with CS
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
Key physiological principles (cont.)Key physiological principles (cont.)
Pituitary tumors are partially autonomous—they Pituitary tumors are partially autonomous—they retain feedback inhibition, but at a higher setpoint retain feedback inhibition, but at a higher setpoint than the normal pituitary glandthan the normal pituitary gland
Adrenal and ectopic tumors have autonomous Adrenal and ectopic tumors have autonomous hormone secretion and do NOT (usually) exhibit hormone secretion and do NOT (usually) exhibit feedback inhibitionfeedback inhibition
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CSa. ACTH-dependent vs independentb. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
1. Establishing the diagnosis of CS1. Establishing the diagnosis of CS 24-hour urinary free cortisol24-hour urinary free cortisol
Low-dose dexamethasone suppression testsLow-dose dexamethasone suppression tests
Midnight plasma cortisol or late-night salivary Midnight plasma cortisol or late-night salivary cortisolcortisol
Cushing’s SyndromeCushing’s SyndromeEstablishing the dxEstablishing the dx
24-hr urinary free cortisol24-hr urinary free cortisol Direct assessment of circulating free (biologically active) cortisolDirect assessment of circulating free (biologically active) cortisol
Up to 3 collections if high suspicionUp to 3 collections if high suspicion
UFC>4X normal -- diagnosticUFC>4X normal -- diagnostic
FN rate <6%FN rate <6% Assess whether collection is complete with urinary volume and creatinineAssess whether collection is complete with urinary volume and creatinine If GFR<30cc/min, UFC may be falsely lowIf GFR<30cc/min, UFC may be falsely low
FP rate <4%FP rate <4% Recently shown with fluid intake >5L/dayRecently shown with fluid intake >5L/day
Cushing’s SyndromeCushing’s SyndromeEstablishing the dxEstablishing the dx
Low-dose DST (Overnight vs 48-hr DST)Low-dose DST (Overnight vs 48-hr DST) Am cortisol <50nmol/L (traditionally <138nmol/L)Am cortisol <50nmol/L (traditionally <138nmol/L)
Excellent sensitivity but borderline specificity—false Excellent sensitivity but borderline specificity—false positivespositives
Pseudo-Cushing’sPseudo-Cushing’s Pt’s error in taking medicationPt’s error in taking medication Decreased dex absorptionDecreased dex absorption Drugs accelerating dexa metabolism (eg: dilantin, tegretol, Drugs accelerating dexa metabolism (eg: dilantin, tegretol,
rifampin…)rifampin…) Elevated CBG (pregnancy, OCP)Elevated CBG (pregnancy, OCP) Assay error (interaction with reaction—atarax, librium…)Assay error (interaction with reaction—atarax, librium…)
3-8% of pts with CD will retain sensitivity to low-dose dex 3-8% of pts with CD will retain sensitivity to low-dose dex
Cushing’s SyndromeCushing’s SyndromeEstablishing the dxEstablishing the dx
Midnight plasma cortisolMidnight plasma cortisol Most studies with inpatients, sleeping, and installed venous catheter—Most studies with inpatients, sleeping, and installed venous catheter—
VERY impractical and expensiveVERY impractical and expensive
Level <50nmol virtually R/O the dxLevel <50nmol virtually R/O the dx Level >207 nmol/L virtually rules in the dx Level >207 nmol/L virtually rules in the dx
Late-night salivary free cortisolLate-night salivary free cortisol Increasing interest in recent yearsIncreasing interest in recent years Pts collect saliva by chewing on cottonPts collect saliva by chewing on cotton However, a modified cortisol assay is required so not validated by all However, a modified cortisol assay is required so not validated by all
labslabs Excellent sensitivity and specificity—but exact cutoffs not establishedExcellent sensitivity and specificity—but exact cutoffs not established
Cushing’s SyndromeCushing’s SyndromeEstablishing the dxEstablishing the dx
Differentiating between pseudo-Cushing’s and CSDifferentiating between pseudo-Cushing’s and CS Very difficult with coexistant depression, alcoholism, Very difficult with coexistant depression, alcoholism,
obesityobesity
Recently discovered and validated test at the NIH: Recently discovered and validated test at the NIH: Combined low dose DST-CRH testCombined low dose DST-CRH test
Cortisol >38nmol/L had 100% sensitivity, specificity, and Cortisol >38nmol/L had 100% sensitivity, specificity, and diagnostic accuracydiagnostic accuracy
Recent literature not reproduced these results—midnight Recent literature not reproduced these results—midnight cortisol>256cortisol>256
Cushing’s SyndromeCushing’s SyndromeEstablishing the dxEstablishing the dx
Source: Newell-Price et al. Lancet 2006
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CSa. ACTH-dependent vs independentb. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s SyndromeCushing’s SyndromeEstablishing the cause of CSEstablishing the cause of CS
Clinical features may Clinical features may provide a clueprovide a clue
First step is to measure First step is to measure plasma ACTHplasma ACTH to to differentiate ACTH-differentiate ACTH-dependent from ACTH-dependent from ACTH-independent CSindependent CS If ACTH <1 pmol/L---If ACTH <1 pmol/L---
adrenal CSadrenal CS If ACTH >3.3 pmol/L—If ACTH >3.3 pmol/L—
ACTH-dependentACTH-dependent If ACTH 1-3If ACTH 1-3CRH stimCRH stim
Cushing’s SyndromeCushing’s SyndromeEstablishing the cause of CSEstablishing the cause of CS
ACTH-dependent CSACTH-dependent CS Distinguishing between pituitary vs non-pituitary sources is Distinguishing between pituitary vs non-pituitary sources is
a great challenge!!a great challenge!!
Carcinoids can be clinically undistinguishable from CD Carcinoids can be clinically undistinguishable from CD and are difficult to identify by imagingand are difficult to identify by imaging
40% of CD will have non-detectable AN on MRI40% of CD will have non-detectable AN on MRI
So, biochemical assessment rather than imaging used to So, biochemical assessment rather than imaging used to differentiate between pituitary and non-pituitary causesdifferentiate between pituitary and non-pituitary causes
Cushing’s SyndromeCushing’s SyndromeEstablishing the cause of CSEstablishing the cause of CS
Two biochemical tests in ACTH-dependent Two biochemical tests in ACTH-dependent CSCS
High dose DSTHigh dose DST
CRH stimulation testCRH stimulation test
Cushing’s SyndromeCushing’s SyndromeEstablishing the cause of CSEstablishing the cause of CS
High-dose DSTHigh-dose DST Principle that pituitary tumors are only partially Principle that pituitary tumors are only partially
autonomous, retaining feedback inhibition at a higher autonomous, retaining feedback inhibition at a higher set point (80% of CD are suppressible)set point (80% of CD are suppressible)
In contrast, adrenal and ectopic tumors are usually In contrast, adrenal and ectopic tumors are usually autonomous, and cortisol production will normally not autonomous, and cortisol production will normally not be suppressed by dexabe suppressed by dexa
Two-day test (2mg q6hrs) with baseline and final Two-day test (2mg q6hrs) with baseline and final cortisol value—suppression >50 % suggestive of CDcortisol value—suppression >50 % suggestive of CD
Cushing’s SyndromeCushing’s SyndromeEstablishing the cause of CSEstablishing the cause of CS
CRH stimulation testCRH stimulation test Principle that pituitary tumors are responsive to an exogenous dose of Principle that pituitary tumors are responsive to an exogenous dose of
CRH whereas ectopic and adrenal tumors are notCRH whereas ectopic and adrenal tumors are not
Ovine CRH administered as an IV bolus and ACTH and cortisol drawn Ovine CRH administered as an IV bolus and ACTH and cortisol drawn at baseline at 30, 60, 90, and 120 min.at baseline at 30, 60, 90, and 120 min.
MC side effect facial flushing (20%)MC side effect facial flushing (20%)
CD: >50% rise in ACTH, >20% rise in cortisol---91% sensitivity and CD: >50% rise in ACTH, >20% rise in cortisol---91% sensitivity and 95% specificity95% specificity
In ectopic CS, levels are usually not altered. However, some reports of In ectopic CS, levels are usually not altered. However, some reports of ACTH rise but not cortisolACTH rise but not cortisol
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CSa. ACTH-dependent vs independentb. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s SyndromeCushing’s SyndromeImaging Imaging
Adrenal CTAdrenal CT In cases of ACTH-independent CSIn cases of ACTH-independent CS 8% of N have incidentalomas and 20% of CD have at least 1 nodule8% of N have incidentalomas and 20% of CD have at least 1 nodule
CXR and CT chestCXR and CT chest In cases suggesting ectopic sourceIn cases suggesting ectopic source If negative, CT abdo, +/-pelvic, +/-neckIf negative, CT abdo, +/-pelvic, +/-neck SS receptor scintigraphySS receptor scintigraphy
Head MRIHead MRI In cases suggesting pituitary sourceIn cases suggesting pituitary source >40% of CD have normal MRI (ave size 5mm)>40% of CD have normal MRI (ave size 5mm) 3-27% have pituitary incidentalomas3-27% have pituitary incidentalomas
Cushing’s SyndromeCushing’s SyndromeImagingImaging
Cushing’s SyndromeCushing’s SyndromeEstablishing the cause of CSEstablishing the cause of CS
So, pituitary or ectopic???So, pituitary or ectopic???
Bilateral inferior petrosal sinus sampling is the most Bilateral inferior petrosal sinus sampling is the most reliable test to differentiate the source of ACTH and reliable test to differentiate the source of ACTH and should be done in MOST PTSshould be done in MOST PTS
Can be avoided:Can be avoided: If a pt has ACTH dep CS with Concordant DST and CRH If a pt has ACTH dep CS with Concordant DST and CRH
stimulation test suggestive of CD AND an MRI lesion >6mmstimulation test suggestive of CD AND an MRI lesion >6mm At Mass General: only in macroadenomas At Mass General: only in macroadenomas
Cushing’s SyndromeCushing’s SyndromeInferior Petrosal Sinus Sampling Inferior Petrosal Sinus Sampling
(IPPS)(IPPS) The most direct way of knowing if the pituitary is The most direct way of knowing if the pituitary is
making excess ACTH is to measure itmaking excess ACTH is to measure it
The inferior petrosal sinuses receive the drainage of The inferior petrosal sinuses receive the drainage of the pituitary gland without admixture of blood from the pituitary gland without admixture of blood from other sourcesother sources
Each half of the pituitary drains in the ipsilateral Each half of the pituitary drains in the ipsilateral petrosal sinuspetrosal sinus
Cushing’s SyndromeCushing’s SyndromeIPPSIPPS
INTERPRETATIONINTERPRETATION LocalizationLocalization
If pituitary/periphery ratio >2 (>3 with CRH), the pt has CDIf pituitary/periphery ratio >2 (>3 with CRH), the pt has CD If pituitary/periphery ratio <1.5 (<2 with CRH), the pt has ectopic If pituitary/periphery ratio <1.5 (<2 with CRH), the pt has ectopic
CSCS
--- 94% sensitivity and specificity with CRH--- 94% sensitivity and specificity with CRH
LateralizationLateralization If the higher side/lower side >1.4/1, the tumor is on the side with If the higher side/lower side >1.4/1, the tumor is on the side with
higher ACTH levelshigher ACTH levels
--- accuracy only 70%--- accuracy only 70%
Cushing’s SyndromeCushing’s SyndromeIPPSIPPS
Failure to localizeFailure to localize Inability to catheterizeInability to catheterize Incorrect catheter Incorrect catheter
placementplacement Anomalous venous Anomalous venous
drainagedrainage Periodic hormonogenesisPeriodic hormonogenesis Ectopic tumor secreting Ectopic tumor secreting
CRHCRH
Failure to lateralizeFailure to lateralize Incorrect catheter Incorrect catheter
placementplacement Sample withdrawal too Sample withdrawal too
rapidrapid Midline microadenomaMidline microadenoma Prior transphenoidal Prior transphenoidal
surgerysurgery Ectopic tumor secreting Ectopic tumor secreting
CRHCRH
Cushing’s SyndromeCushing’s SyndromeIPPSIPPS
ComplicationsComplications Very infrequentVery infrequent
Most common:Most common: Hematoma at the groinHematoma at the groin Transient ear painTransient ear pain
Several cases of DVT reportedSeveral cases of DVT reported
Neurological complications and SAH reported but Neurological complications and SAH reported but extremely rareextremely rare
Cushing’s SyndromeCushing’s SyndromeSurgical TreatmentSurgical Treatment
Transphenoidal adenomectomyTransphenoidal adenomectomy Needs to be done by neurosurgeons who perform pituitary surgery Needs to be done by neurosurgeons who perform pituitary surgery
frequentlyfrequently
Remission rate of 80-90%--Most common surgical failures with Remission rate of 80-90%--Most common surgical failures with macroadenomasmacroadenomas
Cure is confirmed by demonstrating profound hypoadrenalism post-op Cure is confirmed by demonstrating profound hypoadrenalism post-op (am cortisol <50 nmol/L)(am cortisol <50 nmol/L)
Morbidity extremely low with hypopituitarism and permanent DI very Morbidity extremely low with hypopituitarism and permanent DI very rare with experienced surgeonsrare with experienced surgeons
Period of adrenal insufficiency requiring GC for up to 2 yrs (6-8 mo)Period of adrenal insufficiency requiring GC for up to 2 yrs (6-8 mo)
Cushing’s SyndromeCushing’s SyndromeSurgical TreatmentSurgical Treatment
Adrenal SurgeryAdrenal Surgery Laparoscopic surgery is the treatment of choice for Laparoscopic surgery is the treatment of choice for
unilateral adrenal adenomasunilateral adrenal adenomas
Laparotomy should be done for ACC but poor pxLaparotomy should be done for ACC but poor px
Bilateral adrenalectomy is also 2Bilateral adrenalectomy is also 2ndnd line treatment for pts with line treatment for pts with CD who have not been cured by pituitary surgery +/-radiotxCD who have not been cured by pituitary surgery +/-radiotx—Pitfalls—Pitfalls
Permanent need for GC and MCPermanent need for GC and MC 10-20% risk of Nelson’s syndrome10-20% risk of Nelson’s syndrome 10% risk of recurrent CS due to remant or ectopic10% risk of recurrent CS due to remant or ectopic
Cushing’s SyndromeCushing’s SyndromePituitary IrradiationPituitary Irradiation
Conventional irradiation induces remission in only 20-83% of Conventional irradiation induces remission in only 20-83% of adultsadults
Onset of remission: 6mo-5 yearsOnset of remission: 6mo-5 years
Disadvantages:Disadvantages: Delayed effectivenessDelayed effectiveness Significant risk of hypopituitarismSignificant risk of hypopituitarism Risk of neurologic and cognitive damageRisk of neurologic and cognitive damage
The role of newer stereotactic radiosurgery remains to be The role of newer stereotactic radiosurgery remains to be determineddetermined
Cushing’s SyndromeCushing’s SyndromeTreatment Treatment
Overview of treatment of CDOverview of treatment of CD
Cushing’s SyndromeCushing’s SyndromeMedical TherapyMedical Therapy
Uses of medical therapyUses of medical therapy Selected cases of CD prior to surgerySelected cases of CD prior to surgery In cases of CD awaiting the effect of radiotherapyIn cases of CD awaiting the effect of radiotherapy Ectopic CS due to an unresectable tumorEctopic CS due to an unresectable tumor Adrenal carcinomaAdrenal carcinoma
Cushing’s SyndromeCushing’s SyndromeMedical TherapyMedical Therapy
Cortisol synthesis inhibitorsCortisol synthesis inhibitors KetoconazoleKetoconazole
Inhibits 11Inhibits 11ß hydroxylaseß hydroxylase HepatotoxicityHepatotoxicity
MetyraponeMetyrapone Inhibits 11Inhibits 11ß hydroxylaseß hydroxylase Rapid fall in cortisol, trough at 2 hoursRapid fall in cortisol, trough at 2 hours
AminoglutethimideAminoglutethimide Inhibits side-chain cleavage of chol--pregnenoloneInhibits side-chain cleavage of chol--pregnenolone
Mitotane—delayed onset but long-lasting actionMitotane—delayed onset but long-lasting action adrenolyticadrenolytic Inhibits side-chain cleavage and 11Inhibits side-chain cleavage and 11ß hydroxylaseß hydroxylase
EtomidateEtomidate
Cushing’s SyndromeCushing’s SyndromeMedical TherapyMedical Therapy
Drugs acting at the hypothalamic-pituitary Drugs acting at the hypothalamic-pituitary levellevel PPARPPARγγ agonists agonists
Dopamine agonistsDopamine agonists
SS analogsSS analogs
Retinoic acidRetinoic acid
Case presentationCase presentation 41 y.o woman referred by her family doctor with 41 y.o woman referred by her family doctor with
fatigue and weight gainfatigue and weight gain
PMH significant for DM (1year), PMH significant for DM (1year), hypercholesterolemia, and HTN resistant to 2 hypercholesterolemia, and HTN resistant to 2 medicationsmedications
She was followed for “subclinical hyperthyroidism”She was followed for “subclinical hyperthyroidism”
Meds: Pravachol, Glucophage, Potassium, Ramipril, Meds: Pravachol, Glucophage, Potassium, Ramipril, Metoprolol, OCPMetoprolol, OCP
Case presentationCase presentation
ROS and P/E: ROS and P/E: Alterations in physical habitus with 50lbs wt gain over 1 Alterations in physical habitus with 50lbs wt gain over 1
year mainly in abdo areayear mainly in abdo area Severe insomnia, depression and difficulty concentratingSevere insomnia, depression and difficulty concentrating Very evident dorsocervical and supraclavicular fat padsVery evident dorsocervical and supraclavicular fat pads Round, plethoric faceRound, plethoric face Wasted extremities with proximal muscle weaknessWasted extremities with proximal muscle weakness Abdominal striae and hyperpigmentationAbdominal striae and hyperpigmentation Tender thoracic spine to palpation at T12Tender thoracic spine to palpation at T12
Case presentationCase presentation
Laboratory dataLaboratory data Sodium= 135, K=3.3Sodium= 135, K=3.3 BUN, Cr NBUN, Cr N Glucose=12.4Glucose=12.4
WBC=10.7WBC=10.7
TSH=0.1 (0.3-5) , N FT4TSH=0.1 (0.3-5) , N FT4
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CSa. ACTH-dependent vs independentb. Identifying the source in ACTH-dependent
3. Imaging
Case presentationCase presentation
Further investigations??Further investigations?? 24hr UFC = 342 nmol/d (28-276)24hr UFC = 342 nmol/d (28-276) 1mg DST = > 8 am cortisol = 340 nmol/L (N<50)1mg DST = > 8 am cortisol = 340 nmol/L (N<50)
Repeat 24 hr UFC X 2 = 420 nmol/d, 1243 nmol/dRepeat 24 hr UFC X 2 = 420 nmol/d, 1243 nmol/d
D/C OCP X 6-8weeks– 1mg DST => cort = 280 nmol/dD/C OCP X 6-8weeks– 1mg DST => cort = 280 nmol/d
Low-dose DEX-CRH test: cortisol = 120 nmol/L (>38 c/w Low-dose DEX-CRH test: cortisol = 120 nmol/L (>38 c/w CS)CS)
Cushing’s SyndromeCushing’s SyndromeDiagnostic approachDiagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CSa. ACTH-dependent vs independentb. Identifying the source in ACTH-dependent
3. Imaging
Case presentationCase presentation
ACTH = 5.7 pmol/L (>3 c/w ACTH-dep)ACTH = 5.7 pmol/L (>3 c/w ACTH-dep)
High-dose DST => adequate suppressionHigh-dose DST => adequate suppression CRH stimulation test => response c/w CDCRH stimulation test => response c/w CD
MRI pit: slight asymmetry with left sided bulge MRI pit: slight asymmetry with left sided bulge but no definite adenoma visualizedbut no definite adenoma visualized
CXR, CT chest: normalCXR, CT chest: normal
Case presentationCase presentation
IPSSIPSS
Petrosal sinus/periphery Petrosal sinus/periphery = 4.3 (>2)= 4.3 (>2)
Petrosal sinus/periphery Petrosal sinus/periphery post CRH = 8 (>3)post CRH = 8 (>3)
R/L petrosal sinus R/L petrosal sinus ratio=2.1 (>1.4)ratio=2.1 (>1.4)
Patient underwent a transphenoidal surgery to resect the right Patient underwent a transphenoidal surgery to resect the right lobe of the pituitarylobe of the pituitary
Post-operative transient DI resolved in 3-4 daysPost-operative transient DI resolved in 3-4 days
Pathology: 2 mm corticotroph adenomaPathology: 2 mm corticotroph adenoma
Placed on dexamethasone 4mg q 6 hrs and switched to Placed on dexamethasone 4mg q 6 hrs and switched to tapering doses of Predtapering doses of Pred
Am cortisol on dex: 25 nmol/L c/w cureAm cortisol on dex: 25 nmol/L c/w cure
Case presentationCase presentation
ConclusionConclusion Diagnosis and management of CS remains a considerable Diagnosis and management of CS remains a considerable
challengechallenge
Our understanding of the pathogenesis has evolved, but mainly Our understanding of the pathogenesis has evolved, but mainly with respect to the very rare causes of CSwith respect to the very rare causes of CS
Diagnostic algorithm (biochemical confirmation followed by Diagnostic algorithm (biochemical confirmation followed by localisation) should be closely followed to avoid major pitfalls localisation) should be closely followed to avoid major pitfalls and misdiagnosisand misdiagnosis
Tumour-specific surgery is the mainstay of treatment followed Tumour-specific surgery is the mainstay of treatment followed by radiotherapy and/or medical treatmentby radiotherapy and/or medical treatment
However, treatment of CD remains disappointing and further However, treatment of CD remains disappointing and further developments are needed in this areadevelopments are needed in this area
““Clinicians who have never missed the diagnosis of Clinicians who have never missed the diagnosis of Cushing’s Syndrome or have never been fooled by Cushing’s Syndrome or have never been fooled by attempting to establish its cause should refer their attempting to establish its cause should refer their patients with suspected hypercortisolism to someone patients with suspected hypercortisolism to someone who has.”who has.”
James Findling, Diagnosis and Differential James Findling, Diagnosis and Differential
Diagnosis of Cushing’s Syndrome. 1991Diagnosis of Cushing’s Syndrome. 1991