Download Cushing’s Syndrome

Cushing’s Syndrome
A Clinical Approach
Stavroula Christopoulos, MD, FRCPC
Cushing’s Syndrome
Outline

Definitions

Clinical features

Differential diagnosis

Diagnostic approach

Treatment

Applied knowledge: a case presentation
Cushing’s Syndrome

1932: Harvey Cushing
described a series of
seven pts with
basophilic adenomas of
the pituitary --- CD
Cushing’s Syndrome
Definitions

Cushing’s syndrome

Cushing’s disease

Pseudo-Cushing’s syndrome
Cushing’s Syndrome
Clinical features
Cushing’s Syndrome
Clinical features
Cushing’s Syndrome
Clinical features
Cushing’s Syndrome
Clinical features

63y.o M admitted on
7W with L/E muscle
weakness and a T6
sensory level

Diagnosis?
Cushing’s Syndrome
Clinical features

General

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
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Central obesity
Proximal muscle weakness
HTN
Headaches
Endocrine/Metabolic
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Dermatologic
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Wide purple striae
Spontaneous ecchymoses
Facial plethora
Hyperpigmentation
Acne, hirsutism
Fungal skin infections
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Hypokalemic alkalosis
Hypokalemia
Osteopenia
Hypogonadism
Glucose intolerance
Hyperlipidemia
Hyperhomocysteinemia
Kidney stones
Polyuria
Hypercoagulability
Neuropsychiatric
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Insomnia
Depression, frank psychosis
Impaired cognition and short-term
memory
Reversibility of Anatomic, Neuropsychological, and
Metabolic Brain Disturbances Following Treatment of
Endogenous Cushing’s Syndrome: A 3-Year Prospective Study

23 patients with endogenous CS
Curative
Surgery
Baseline
MRI
Post-operative
Eucortisolism
6 months 12 months
MRI
24 months
36 months
MRI
MRI
MRI
Psych
Psych
Psych
Psych
1H-MRS
1H-MRS
1H-MRS
Results
Pre-operative MRI
MRI 36 mo post eucortisolism
Results
Anatomic Evaluation: Subjective Grading of Cerebral Atrophy
100%
*
90%
80%
*
70%
Grade 3
Series3
Grade 2
Series2
Grade 1
Series1
60%
50%
40%
30%
20%
10%
0%
Controls
1
2
Baseline
3
*p value versus controls <0.05
6 mo
4
12 mo
5
24 mo
6
36 7
mo
*p value versus preceding value <0.05
Discussion
Excess GC enter the brain and act on MR and GR
Pathophysiologic
Mechanisms
Measurable
Clinical
Parameters
Dendritic atrophy
Neuronal cell death
Brain volume
loss
on MRI
Decreased cell
excitability
Neuropsychological
and Cognitive
Dysfunction
Cell membrane
dysfunction
Neurometabolic
Abnormalities on
1H MRS
Cushing’s Syndrome
Clinical features

Most reliable differentiating signs from obesity
are those of protein wasting:
Thin skin
 Easy bruising
 Proximal weakness

Cushing’s Syndrome
Etiology
Cushing’s Syndrome
Etiology
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ACTH-dependent
 (Pseudo-CS)
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Pituitary (CD) (70%)
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ACTH-independent
 (Factitious)
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Microadenomas (95%)
Macroadenomas (5%)
Ectopic ACTH or CRH
(10%)
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Small cell lung ca
Carcinoids: lung, pancreas,
thymus
Unilateral
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Adrenal adenoma (10%)
Adrenal carcinoma (5%)
Bilateral
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Macronodular Hyperplasia
(AIMAH) (<2%)
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Primary pigmented Micronodular
Adrenal disease (PPNAD) (<2%)
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McCune Albright Syndrome
(<2%)
Cushing’s Syndrome
AIMAH
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Adrenal cortisol hypersecretion with radiological
evidence of massive adrenal macronodules
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“ACTH-independent macronodular adrenal hyperplasia”
“Massive macronodular adrecortical disease”
“Autonomous macronodular adrenal hyperplasia”
“Macronodular adrenal hyperplasia”
Cushing’s Syndrome
AIMAH
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Presents 5th-6th decade
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Radiological features
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Bilateral adrenal masses
measuring up to 5 cm of soft
tissue density
Pathological features
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Combined adrenal weight
>60 g200g
Cut section: nodules yellow
(high lipid content)
Inter-nodular hyperplasia
Cushing’s Syndrome
AIMAH
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Lacroix et al. NEJM 1992
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First description of a patient with post-prandial hypercortisolism
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Cortisol levels were correlated post-prandially with GIP levels
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The presence of ectopic GIP receptors on the adrenal gland was further
supported by adrenal imaging following the injection of [123I] GIP
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Shown to be ectopically expressed at the cell membrane in a nonmutated form
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Transfection of bovine adrenal cells with the GIP receptor leads to
hyperplastic adrenals and hypercortisolism
Cushing’s Syndrome
AIMAH
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Lacroix et al. NEJM 1999
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Patient with AIMAH who had transient CS during
pregnancy and persistent CS following menopause
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Cortisol secretion was stimulated by the exogenous
administration of GnRH, h CG, or LH.

Treated succesfully with GnRH agonist
Cushing’s Syndrome
AIMAH
Cushing’s Syndrome
AIMAH
Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005
Cushing’s Syndrome
AIMAH
Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005
Cushing’s Syndrome
PPNAD
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Adrenal CS caused by small
nodules that may not be
visualized on imaging
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Adrenal glands contain
multiple small cortical black
pigmented micronodules
(<4 mm)
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Positive stain synaptophysin
Cushing’s Syndrome
PPNAD

Sporadic or part of Carney’s complex: pigmented
lentigines and blue nevi on the face, neck, trunk and
multiple endocrine and non-endocrine tumors (atrial
myxomas)
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Second decade
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PARADOXICAL increase of cortisol secretion during
Liddle test (0.5mg q6 –2mg q6)– 100% increase in
UFC at day 6 highly specific – study shown high
expression of GR in PPNAD nodules
Cushing’s Syndrome
PPNAD
Cushing’s Syndrome
Diagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CS
a. ACTH-dependent vs independent
b. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s Syndrome
Diagnostic approach

Key physiological principles
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Cortisol hypersecretion in most patients with CS is
cyclical
Cushing’s Syndrome
Diagnostic approach

Key physiological principles
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Loss of circadian rhythm in pts with CS
Cushing’s Syndrome
Diagnostic approach

Key physiological principles (cont.)
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Pituitary tumors are partially autonomous—they
retain feedback inhibition, but at a higher setpoint
than the normal pituitary gland

Adrenal and ectopic tumors have autonomous
hormone secretion and do NOT (usually) exhibit
feedback inhibition
Cushing’s Syndrome
Diagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CS
a. ACTH-dependent vs independent
b. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s Syndrome
Diagnostic approach

1. Establishing the diagnosis of CS
 24-hour urinary free cortisol
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Low-dose dexamethasone suppression tests
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Midnight plasma cortisol or late-night salivary
cortisol
Cushing’s Syndrome
Establishing the dx

24-hr urinary free cortisol
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Direct assessment of circulating free (biologically active) cortisol
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Up to 3 collections if high suspicion
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UFC>4X normal -- diagnostic
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FN rate <6%
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Assess whether collection is complete with urinary volume and creatinine
If GFR<30cc/min, UFC may be falsely low
FP rate <4%
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Recently shown with fluid intake >5L/day
Cushing’s Syndrome
Establishing the dx
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Low-dose DST (Overnight vs 48-hr DST)
 Am cortisol <50nmol/L (traditionally <138nmol/L)
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Excellent sensitivity but borderline specificity—false
positives
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Pseudo-Cushing’s
Pt’s error in taking medication
Decreased dex absorption
Drugs accelerating dexa metabolism (eg: dilantin, tegretol,
rifampin…)
Elevated CBG (pregnancy, OCP)
Assay error (interaction with reaction—atarax, librium…)
3-8% of pts with CD will retain sensitivity to low-dose dex
Cushing’s Syndrome
Establishing the dx
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Midnight plasma cortisol
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Most studies with inpatients, sleeping, and installed venous catheter—
VERY impractical and expensive
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Level <50nmol virtually R/O the dx
Level >207 nmol/L virtually rules in the dx
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Late-night salivary free cortisol
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Increasing interest in recent years
Pts collect saliva by chewing on cotton
However, a modified cortisol assay is required so not validated by all
labs
Excellent sensitivity and specificity—but exact cutoffs not established
Cushing’s Syndrome
Establishing the dx
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Differentiating between pseudo-Cushing’s and CS
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Very difficult with coexistant depression, alcoholism,
obesity
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Recently discovered and validated test at the NIH:
Combined low dose DST-CRH test
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Cortisol >38nmol/L had 100% sensitivity, specificity, and
diagnostic accuracy
Recent literature not reproduced these results—midnight
cortisol>256
Cushing’s Syndrome
Establishing the dx
Source: Newell-Price et al. Lancet 2006
Cushing’s Syndrome
Diagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CS
a. ACTH-dependent vs independent
b. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s Syndrome
Establishing the cause of CS
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Clinical features may
provide a clue
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First step is to measure
plasma ACTH to
differentiate ACTHdependent from ACTHindependent CS
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If ACTH <1 pmol/L--adrenal CS
If ACTH >3.3 pmol/L—
ACTH-dependent
If ACTH 1-3CRH stim
Cushing’s Syndrome
Establishing the cause of CS
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ACTH-dependent CS
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Distinguishing between pituitary vs non-pituitary sources is
a great challenge!!
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Carcinoids can be clinically undistinguishable from CD and
are difficult to identify by imaging
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40% of CD will have non-detectable AN on MRI
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So, biochemical assessment rather than imaging used to
differentiate between pituitary and non-pituitary causes
Cushing’s Syndrome
Establishing the cause of CS
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Two biochemical tests in ACTH-dependent CS
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High dose DST
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CRH stimulation test
Cushing’s Syndrome
Establishing the cause of CS
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High-dose DST
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Principle that pituitary tumors are only partially
autonomous, retaining feedback inhibition at a higher
set point (80% of CD are suppressible)
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In contrast, adrenal and ectopic tumors are usually
autonomous, and cortisol production will normally not
be suppressed by dexa
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Two-day test (2mg q6hrs) with baseline and final
cortisol value—suppression >50 % suggestive of CD
Cushing’s Syndrome
Establishing the cause of CS
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CRH stimulation test
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Principle that pituitary tumors are responsive to an exogenous dose of
CRH whereas ectopic and adrenal tumors are not
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Ovine CRH administered as an IV bolus and ACTH and cortisol drawn
at baseline at 30, 60, 90, and 120 min.
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MC side effect facial flushing (20%)
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CD: >50% rise in ACTH, >20% rise in cortisol---91% sensitivity and
95% specificity
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In ectopic CS, levels are usually not altered. However, some reports of
ACTH rise but not cortisol
Cushing’s Syndrome
Diagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CS
a. ACTH-dependent vs independent
b. Identifying the source in ACTH-dependent
3. Imaging
Cushing’s Syndrome
Imaging
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Adrenal CT
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CXR and CT chest
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In cases of ACTH-independent CS
8% of N have incidentalomas and 20% of CD have at least 1 nodule
In cases suggesting ectopic source
If negative, CT abdo, +/-pelvic, +/-neck
SS receptor scintigraphy
Head MRI
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In cases suggesting pituitary source
>40% of CD have normal MRI (ave size 5mm)
3-27% have pituitary incidentalomas
Cushing’s Syndrome
Imaging
Cushing’s Syndrome
Establishing the cause of CS
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So, pituitary or ectopic???
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Bilateral inferior petrosal sinus sampling is the most
reliable test to differentiate the source of ACTH and
should be done in MOST PTS
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Can be avoided:
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If a pt has ACTH dep CS with Concordant DST and CRH
stimulation test suggestive of CD AND an MRI lesion >6mm
At Mass General: only in macroadenomas
Cushing’s Syndrome
Inferior Petrosal Sinus Sampling (IPPS)
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The most direct way of knowing if the pituitary is
making excess ACTH is to measure it
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The inferior petrosal sinuses receive the drainage of
the pituitary gland without admixture of blood from
other sources
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Each half of the pituitary drains in the ipsilateral
petrosal sinus
Cushing’s Syndrome
IPPS
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INTERPRETATION
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Localization
If pituitary/periphery ratio >2 (>3 with CRH), the pt has CD
 If pituitary/periphery ratio <1.5 (<2 with CRH), the pt has ectopic
CS
--- 94% sensitivity and specificity with CRH
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Lateralization
If the higher side/lower side >1.4/1, the tumor is on the side with
higher ACTH levels
--- accuracy only 70%
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Cushing’s Syndrome
IPPS
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Failure to localize
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Inability to catheterize
Incorrect catheter
placement
Anomalous venous
drainage
Periodic hormonogenesis
Ectopic tumor secreting
CRH
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Failure to lateralize
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Incorrect catheter
placement
Sample withdrawal too
rapid
Midline microadenoma
Prior transphenoidal
surgery
Ectopic tumor secreting
CRH
Cushing’s Syndrome
IPPS
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Complications
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Very infrequent
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Most common:
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Hematoma at the groin
Transient ear pain
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Several cases of DVT reported
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Neurological complications and SAH reported but
extremely rare
Cushing’s Syndrome
Surgical Treatment
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Transphenoidal adenomectomy
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Needs to be done by neurosurgeons who perform pituitary surgery
frequently
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Remission rate of 80-90%--Most common surgical failures with
macroadenomas
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Cure is confirmed by demonstrating profound hypoadrenalism post-op
(am cortisol <50 nmol/L)

Morbidity extremely low with hypopituitarism and permanent DI very
rare with experienced surgeons
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Period of adrenal insufficiency requiring GC for up to 2 yrs (6-8 mo)
Cushing’s Syndrome
Surgical Treatment
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Adrenal Surgery
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Laparoscopic surgery is the treatment of choice for unilateral
adrenal adenomas
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Laparotomy should be done for ACC but poor px
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Bilateral adrenalectomy is also 2nd line treatment for pts with
CD who have not been cured by pituitary surgery +/radiotx—Pitfalls
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Permanent need for GC and MC
10-20% risk of Nelson’s syndrome
10% risk of recurrent CS due to remant or ectopic
Cushing’s Syndrome
Pituitary Irradiation
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Conventional irradiation induces remission in only 20-83% of
adults
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Onset of remission: 6mo-5 years
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Disadvantages:
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Delayed effectiveness
Significant risk of hypopituitarism
Risk of neurologic and cognitive damage
The role of newer stereotactic radiosurgery remains to be
determined
Cushing’s Syndrome
Treatment

Overview of treatment of CD
Cushing’s Syndrome
Medical Therapy

Uses of medical therapy
Selected cases of CD prior to surgery
 In cases of CD awaiting the effect of radiotherapy
 Ectopic CS due to an unresectable tumor
 Adrenal carcinoma

Cushing’s Syndrome
Medical Therapy
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Cortisol synthesis inhibitors
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Ketoconazole
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Metyrapone
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Inhibits side-chain cleavage of chol--pregnenolone
Mitotane—delayed onset but long-lasting action


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Inhibits 11ß hydroxylase
Rapid fall in cortisol, trough at 2 hours
Aminoglutethimide


Inhibits 11ß hydroxylase
Hepatotoxicity
adrenolytic
Inhibits side-chain cleavage and 11ß hydroxylase
Etomidate
Cushing’s Syndrome
Medical Therapy

Drugs acting at the hypothalamic-pituitary
level
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PPARγ agonists
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Dopamine agonists
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SS analogs
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Retinoic acid
Case presentation

41 y.o woman referred by her family doctor with
fatigue and weight gain

PMH significant for DM (1year),
hypercholesterolemia, and HTN resistant to 2
medications

She was followed for “subclinical hyperthyroidism”

Meds: Pravachol, Glucophage, Potassium, Ramipril,
Metoprolol, OCP
Case presentation
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ROS and P/E:
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Alterations in physical habitus with 50lbs wt gain over 1
year mainly in abdo area
Severe insomnia, depression and difficulty concentrating
Very evident dorsocervical and supraclavicular fat pads
Round, plethoric face
Wasted extremities with proximal muscle weakness
Abdominal striae and hyperpigmentation
Tender thoracic spine to palpation at T12
Case presentation

Laboratory data
Sodium= 135, K=3.3
 BUN, Cr N
 Glucose=12.4


WBC=10.7

TSH=0.1 (0.3-5) , N FT4
Cushing’s Syndrome
Diagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CS
a. ACTH-dependent vs independent
b. Identifying the source in ACTH-dependent
3. Imaging
Case presentation

Further investigations??

24hr UFC = 342 nmol/d (28-276)
1mg DST = > 8 am cortisol = 340 nmol/L (N<50)

Repeat 24 hr UFC X 2 = 420 nmol/d, 1243 nmol/d

D/C OCP X 6-8weeks– 1mg DST => cort = 280 nmol/d

Low-dose DEX-CRH test: cortisol = 120 nmol/L (>38 c/w
CS)

Cushing’s Syndrome
Diagnostic approach
1. Establishing the diagnosis of CS
2. Establishing the cause of CS
a. ACTH-dependent vs independent
b. Identifying the source in ACTH-dependent
3. Imaging
Case presentation

ACTH = 5.7 pmol/L (>3 c/w ACTH-dep)
High-dose DST => adequate suppression
 CRH stimulation test => response c/w CD

MRI pit: slight asymmetry with left sided bulge
but no definite adenoma visualized
 CXR, CT chest: normal

Case presentation

IPSS


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Petrosal sinus/periphery
= 4.3 (>2)
Petrosal sinus/periphery
post CRH = 8 (>3)
R/L petrosal sinus
ratio=2.1 (>1.4)
Case presentation

Patient underwent a transphenoidal surgery to resect the right
lobe of the pituitary

Post-operative transient DI resolved in 3-4 days

Pathology: 2 mm corticotroph adenoma

Placed on dexamethasone 4mg q 6 hrs and switched to
tapering doses of Pred

Am cortisol on dex: 25 nmol/L c/w cure
Conclusion

Diagnosis and management of CS remains a considerable
challenge

Our understanding of the pathogenesis has evolved, but mainly
with respect to the very rare causes of CS

Diagnostic algorithm (biochemical confirmation followed by
localisation) should be closely followed to avoid major pitfalls
and misdiagnosis

Tumour-specific surgery is the mainstay of treatment followed
by radiotherapy and/or medical treatment

However, treatment of CD remains disappointing and further
developments are needed in this area
“Clinicians who have never missed the diagnosis of
Cushing’s Syndrome or have never been fooled by
attempting to establish its cause should refer their
patients with suspected hypercortisolism to someone
who has.”
James Findling, Diagnosis and Differential
Diagnosis of Cushing’s Syndrome. 1991