Cushing’s Syndrome A Clinical Approach

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




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?


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


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”


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


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


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



Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005


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


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 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


Key physiological principlesKey physiological principles Cortisol hypersecretion in most patients with CS is Cortisol hypersecretion in most patients with CS is

cyclical cyclical


Key physiological principlesKey physiological principles Loss of circadian rhythm in pts with CSLoss of circadian rhythm in pts with CS


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




3. Imaging


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


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


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


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


Source: Newell-Price et al. Lancet 2006




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


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


Two biochemical tests in ACTH-dependent Two biochemical tests in ACTH-dependent CSCS

High dose DSTHigh dose DST

CRH stimulation testCRH stimulation test


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


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




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


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%


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


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


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


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


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




3. Imaging


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)




3. Imaging


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


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


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

Documents

Cushing’s Syndrome A Clinical Approach