1. Cushing’s Syndrome A Clinical Approach
Stavroula Christopoulos, MD, FRCPC

2. Cushing’s Syndrome Outline
Definitions
Clinical features
Differential diagnosis
Diagnostic approach
Treatment
Applied knowledge: a case presentation

3. Cushing’s Syndrome
1932: Harvey Cushing described a series of seven pts with basophilic adenomas of the pituitary --- CD

4. Cushing’s Syndrome Definitions
Cushing’s disease
Pseudo-Cushing’s syndrome

5. Cushing’s Syndrome Clinical features

7. Cushing’s Syndrome Clinical features

8. Cushing’s Syndrome Clinical features

9. Cushing’s Syndrome Clinical features
63y.o M admitted on 7W with L/E muscle weakness and a T6 sensory level
Diagnosis?

11. Cushing’s Syndrome Clinical features
General
Central obesity
Proximal muscle weakness
HTN
Headaches
Dermatologic
Wide purple striae
Spontaneous ecchymoses
Facial plethora
Hyperpigmentation
Acne, hirsutism
Fungal skin infections
Endocrine/Metabolic
Hypokalemic alkalosis
Hypokalemia
Osteopenia
Hypogonadism
Glucose intolerance
Hyperlipidemia
Hyperhomocysteinemia
Kidney stones
Polyuria
Hypercoagulability
Neuropsychiatric
Insomnia
Depression, frank psychosis
Impaired cognition and short-term memory
Depr us/ agitated

12. Post-operative Eucortisolism
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
Post-operative Eucortisolism
Curative
Surgery
Baseline
6 months
12 months
24 months
36 months
MRI
MRI
MRI
MRI
MRI
Psych
Psych
Psych
Psych
1H-MRS
1H-MRS
1H-MRS

13. Results
Pre-operative MRI
MRI 36 mo post eucortisolism

14. Results Anatomic Evaluation: Subjective Grading of Cerebral Atrophy *
Grade 3
Grade 2
Grade 1
Controls
Baseline
6 mo
12 mo
24 mo
36 mo
*p value versus preceding value <0.05
*p value versus controls <0.05

15. Discussion Excess GC enter the brain and act on MR and GR
Dendritic atrophy
Decreased cell excitability
Cell membrane
dysfunction
Pathophysiologic Mechanisms
The pathophysiology of the reversibility is largely unknown and may be related to the reversibility of 1 or many of the above pathophysiologic mechanisms.
Neuronal cell death
Measurable
Clinical Parameters
Brain volume
loss
on MRI
Neuropsychological and Cognitive Dysfunction
Neurometabolic Abnormalities on 1H MRS

16. Cushing’s Syndrome Clinical features
Most reliable differentiating signs from obesity are those of protein wasting:
Thin skin
Easy bruising
Proximal weakness

17. Cushing’s Syndrome Etiology

18. Cushing’s Syndrome Etiology
ACTH-dependent
(Pseudo-CS)
Pituitary (CD) (70%)
Microadenomas (95%)
Macroadenomas (5%)
Ectopic ACTH or CRH (10%)
Small cell lung ca
Carcinoids: lung, pancreas, thymus
ACTH-independent
(Factitious)
Unilateral
Adrenal adenoma (10%)
Adrenal carcinoma (5%)
Bilateral
Macronodular Hyperplasia (AIMAH) (<2%)
Primary pigmented Micronodular Adrenal disease (PPNAD) (<2%)
McCune Albright Syndrome
(<2%)

19. Cushing’s Syndrome AIMAH
Adrenal cortisol hypersecretion with radiological evidence of massive adrenal macronodules
“ACTH-independent macronodular adrenal hyperplasia”
“Massive macronodular adrecortical disease”
“Autonomous macronodular adrenal hyperplasia”
“Macronodular adrenal hyperplasia”

20. Cushing’s Syndrome AIMAH
Presents 5th-6th 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

23. Cushing’s Syndrome AIMAH

24. Cushing’s Syndrome AIMAH
3 days
1st= posture , mixed meal
2: gnrh, trh
3: glucagon, vasopressin, serotonin agonist (metoclopramide)
Acth, cortisol at min intervals x2-3 hours
>50%
Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005

25. Cushing’s Syndrome AIMAH
Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005

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

28. Cushing’s Syndrome PPNAD

30. 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

31. Cushing’s Syndrome Diagnostic approach
Key physiological principles
Cortisol hypersecretion in most patients with CS is cyclical

32. Cushing’s Syndrome Diagnostic approach
Key physiological principles
Loss of circadian rhythm in pts with CS

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. 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

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
Excess circ cortisol saturates the binding proteins and is excreted in the urine as free cortisol

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
48-hr: slightly more specific

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

40. Cushing’s Syndrome Establishing the dx
Source: Newell-Price et al. Lancet 2006

41. 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

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

44. Cushing’s Syndrome Establishing the cause of CS
Two biochemical tests in ACTH-dependent CS
High dose DST
CRH stimulation test

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

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. 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

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

50. Cushing’s Syndrome Imaging

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. Radiologists
Catheters are advanced bil from the fem veins to the inf petrosal sinuses
Confirm catheter location under fluoro
Samples drawn simultaneously from r, l, and peripherally
Baseline and 0.2,5,10,20,30 min post crh

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
Inability to catheterize
Incorrect catheter placement
Anomalous venous drainage
Periodic hormonogenesis
Ectopic tumor secreting CRH
Failure to lateralize
Incorrect catheter placement
Sample withdrawal too rapid
Midline microadenoma
Prior transphenoidal surgery
Ectopic tumor secreting CRH

56. Cushing’s Syndrome IPPS
Complications
Very infrequent
Most common:
Hematoma at the groin
Transient ear pain
Several cases of DVT reported
Neurological complications and SAH reported but extremely rare

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. 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 2nd 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
Nelson; locally aggressive pit tumor that secretes high concentration of acth--hyperpigmentation

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

61. Cushing’s Syndrome Treatment
Overview of treatment of CD

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
escape

63. Cushing’s Syndrome Medical Therapy
Cortisol synthesis inhibitors
Ketoconazole
Inhibits 11ß hydroxylase
Hepatotoxicity
Metyrapone
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
escape

64. Cushing’s Syndrome Medical Therapy
Drugs acting at the hypothalamic-pituitary level
PPARγ agonists
Dopamine agonists
SS analogs
Retinoic acid

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

67. 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

68. 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

69. 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, 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)

70. 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

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

72. Case presentation IPSS Petrosal sinus/periphery = 4.3 (>2)
Petrosal sinus/periphery post CRH = 8 (>3)
R/L petrosal sinus ratio=2.1 (>1.4)

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

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. James Findling, Diagnosis and Differential
“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