14. S
e
r
i
e
s
3
Grade
3
S
e
r
i
e
s
2
Grade
2
S
e
r
i
e
s
1
Grade 1
1
Controls 2 B
a
s
e
l
i
n
e
3 6 m
o
4 12 m
o
5 24 m
o
6 36 7
mo
Results
Anatomic Evaluation: Subjective Grading of Cerebral Atrophy
100%
90%
80%
*
70%
60%
50%
40%
30%
20%
10%
0%
*p value versus controls <0.05
*
*p value versus preceding value <0.05
20. th th
Cushing’s Syndrome
AIMAH
Presents 5 -6 decade
Radiological features
Bilateral adrenal masses
measuring up to 5 cm of soft
tissue density
Pathological features
Combined adrenal weight
>60 g 200g
Cut section: nodules yellow
(high lipid content)
Inter-nodular hyperplasia
21. Cushing’s Syndrome
AIMAH
Lacroix et al. NEJM 1992
First description of a patient with post-prandial hypercortisolism
Cortisol levels were correlated post-prandially with GIP levels
The presence of ectopic GIP receptors on the adrenal gland was further
supported by adrenal imaging following the injection of [123I] GIP
Shown to be ectopically expressed at the cell membrane in a non-
mutated form
Transfection of bovine adrenal cells with the GIP receptor leads to
hyperplastic adrenals and hypercortisolism
22. Cushing’s Syndrome
AIMAH
Lacroix et al. NEJM 1999
Patient with AIMAH who had transient CS during
pregnancy and persistent CS following menopause
Cortisol secretion was stimulated by the
exogenous administration of GnRH, h CG, or LH.
Treated succesfully with GnRH agonist
26. Cushing’s Syndrome
PPNAD
Adrenal CS caused by small
nodules that may not be
visualized on imaging
Adrenal glands contain
multiple small cortical black
pigmented micronodules
(<4 mm)
Positive stain synaptophysin
27. 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)
Second decade
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
30. 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
33. Cushing’s Syndrome
Diagnostic approach
Key physiological principles (cont.)
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
34. 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
35. Cushing’s Syndrome
Diagnostic approach
1. Establishing the diagnosis of CS
24-hour urinary free cortisol
Low-dose dexamethasone suppression tests
Midnight plasma cortisol or late-night salivary
cortisol
36. Cushing’s Syndrome
Establishing the dx
24-hr urinary free cortisol
Direct assessment of circulating free (biologically active) cortisol
Up to 3 collections if high suspicion
UFC>4X normal -- diagnostic
FN rate <6%
Assess whether collection is complete with urinary volume and creatinine
If GFR<30cc/min, UFC may be falsely low
FP rate <4%
Recently shown with fluid intake >5L/day
37. Cushing’s Syndrome
Establishing the dx
Low-dose DST (Overnight vs 48-hr DST)
Am cortisol <50nmol/L (traditionally <138nmol/L)
Excellent sensitivity but borderline specificity—false
positives
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
38. Cushing’s Syndrome
Establishing the dx
Midnight plasma cortisol
Most studies with inpatients, sleeping, and installed venous catheter—
VERY impractical and expensive
Level <50nmol virtually R/O the dx
Level >207 nmol/L virtually rules in the dx
Late-night salivary free cortisol
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
39. Cushing’s Syndrome
Establishing the dx
Differentiating between pseudo-Cushing’s and CS
Very difficult with coexistant depression, alcoholism,
obesity
Recently discovered and validated test at the NIH:
Combined low dose DST-CRH test
Cortisol >38nmol/L had 100% sensitivity, specificity, and
diagnostic accuracy
Recent literature not reproduced these results—midnight
cortisol>256
41. 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
42. Cushing’s Syndrome
Establishing the cause of
CS
Clinical features may
provide a clue
First step is to measure
plasma ACTH to
differentiate ACTH-
dependent from ACTH-
independent CS
If ACTH <1 pmol/L---
adrenal CS
If ACTH >3.3 pmol/L—
ACTH-dependent
If ACTH 1-3 CRH stim
43. Cushing’s Syndrome
Establishing the cause of
CS
ACTH-dependent CS
Distinguishing between pituitary vs non-pituitary sources is
a great challenge!!
Carcinoids can be clinically undistinguishable from CD
and are difficult to identify by imaging
40% of CD will have non-detectable AN on MRI
So, biochemical assessment rather than imaging used to
differentiate between pituitary and non-pituitary causes
45. Cushing’s Syndrome
Establishing the cause of
CS
High-dose DST
Principle that pituitary tumors are only partially
autonomous, retaining feedback inhibition at a higher
set point (80% of CD are suppressible)
In contrast, adrenal and ectopic tumors are usually
autonomous, and cortisol production will normally not
be suppressed by dexa
Two-day test (2mg q6hrs) with baseline and final
cortisol value—suppression >50 % suggestive of CD
46.
47. Cushing’s Syndrome
Establishing the cause of
CS
CRH stimulation test
Principle that pituitary tumors are responsive to an exogenous dose of
CRH whereas ectopic and adrenal tumors are not
Ovine CRH administered as an IV bolus and ACTH and cortisol drawn
at baseline at 30, 60, 90, and 120 min.
MC side effect facial flushing (20%)
CD: >50% rise in ACTH, >20% rise in cortisol---91% sensitivity and
95% specificity
In ectopic CS, levels are usually not altered. However, some reports of
ACTH rise but not cortisol
48. 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
49. Cushing’s Syndrome
Imaging
Adrenal CT
In cases of ACTH-independent CS
8% of N have incidentalomas and 20% of CD have at least 1 nodule
CXR and CT chest
In cases suggesting ectopic source
If negative, CT abdo, +/-pelvic, +/-neck
SS receptor scintigraphy
Head MRI
In cases suggesting pituitary source
>40% of CD have normal MRI (ave size 5mm)
3-27% have pituitary incidentalomas
51. Cushing’s Syndrome
Establishing the cause of
CS
So, pituitary or ectopic???
Bilateral inferior petrosal sinus sampling is the most
reliable test to differentiate the source of ACTH and
should be done in MOST PTS
Can be avoided:
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
52. Cushing’s Syndrome
Inferior Petrosal Sinus Sampling (IPPS)
The most direct way of knowing if the pituitary is
making excess ACTH is to measure it
The inferior petrosal sinuses receive the drainage of
the pituitary gland without admixture of blood from
other sources
Each half of the pituitary drains in the ipsilateral
petrosal sinus
53.
54. Cushing’s Syndrome
IPPS
INTERPRETATION
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
Lateralization
If the higher side/lower side >1.4/1, the tumor is on the side with
higher ACTH levels
--- accuracy only 70%
55. Cushing’s Syndrome
IPPS
Failure to localize Failure to lateralize
Inability to catheterize
Incorrect catheter
placement
Anomalous venous
drainage
Periodic hormonogenesis
Ectopic tumor secreting
CRH
Incorrect catheter
placement
Sample withdrawal too
rapid
Midline microadenoma
Prior transphenoidal
surgery
Ectopic tumor secreting
CRH
58. Cushing’s Syndrome
Surgical Treatment
Transphenoidal adenomectomy
Needs to be done by neurosurgeons who perform pituitary surgery
frequently
Remission rate of 80-90%--Most common surgical failures with
macroadenomas
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
Period of adrenal insufficiency requiring GC for up to 2 yrs (6-8 mo)
59. n
d
Cushing’s Syndrome
Surgical Treatment
Adrenal Surgery
Laparoscopic surgery is the treatment of choice for
unilateral adrenal adenomas
Laparotomy should be done for ACC but poor px
Bilateral adrenalectomy is also 2 line treatment for pts with
CD who have not been cured by pituitary surgery +/-
radiotx —Pitfalls
Permanent need for GC and MC
10-20% risk of Nelson’s syndrome
10% risk of recurrent CS due to remant or ectopic
60. Cushing’s Syndrome
Pituitary Irradiation
Conventional irradiation induces remission in only 20-83% of
adults
Onset of remission: 6mo-5 years
Disadvantages:
Delayed effectiveness
Significant risk of hypopituitarism
Risk of neurologic and cognitive damage
The role of newer stereotactic radiosurgery remains to be
determined
62. 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
63. Cushing’s Syndrome
Medical Therapy
Cortisol synthesis inhibitors
Ketoconazole
Inhibits 11ß hydroxylase
Hepatotoxicity
Metyrapone
Inhibits 11ß hydroxylase
Rapid fall in cortisol, trough at 2 hours
Aminoglutethimide
Inhibits side-chain cleavage of chol--pregnenolone
Mitotane—delayed onset but long-lasting action
adrenolytic
Inhibits side-chain cleavage and 11ß hydroxylase
Etomidate
65. 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
66. Case presentation
ROS and P/E:
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
68. 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
70. 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
71. 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
73. 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
74.
75. 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
76. “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
