1. Dr. Sachin Verma MD, FICM, FCCS, ICFC
Fellowship in Intensive Care Medicine
Infection Control Fellows Course
Consultant Internal Medicine and Critical Care
Web:-
http://www.medicinedoctorinchandigarh.com
Mob:- +91-7508677495

2. INVESTIGATION
Hb 12.4 gm/dl,TLC 4100/mm3
Sr creat 0.9 mg/dl,
RBS 98mg/dl
S Na/K/Ca 140 /2.2/4.26
Sr ACTH=10.06 pg/ml
LOW DOSE DST= 85 microgm/dl
USG-WHOLE ABDOMEN:
?SOL in tail of pancreas
?SOL in lt adrenal gland,sol in
liver,spleen and multiple lymphnodes.

3. Case presentation
cushing syndrome

4. Approach to cushing syndrome
 In 1972 harvey cushings first described a 23
years old female with obesity, hirsutism and
amenorrhea and 20 years later postulated that
this “polyglandular syndrome” was due to
primary pituitary abnormality causing adrenal
hyperplasia.
 Traditionally, cushing syndrome is used to
describe all causes.
 Cushing’s disease is reserved for cases of
pituitaty dependent cushing’s syndrome.

5. Classification and etiology of
cushing syndrome
ACTH Dependent
 Cushing disease (pituitary dependent).
 Ectopic ACTH syndrome.
 Ectopic CRH syndrome
 Macronodular hyperplasia
 Iatrogenic (Treatment with ACTH).

6. Classification and etiology of
cushing syndrome
ACTH Independent
 Adrenal adenoma and carcinoma
 Primary pigmented nodular adrenal hyperplasia and
carney’s complex.
 McCune albright syndrome
 Aberrant receptor expression
 Iatrogenic (Pharmacologic doses of prednisolone,
dexamethasone)
Pseudo-cushing’s
 Alcoholism
 Deposiiton
 Obesity

7. Symptoms of Excess Cortisol
 Truncal obesity
 Moon face
 Fat deposits supraclavicular fossa
and posterior neck- buffalo hump
 HTN
 Hirsutism
 Amenorrhea or impotence
 Depression
 Thin skin
 Easy bruising
 Purplish abdominal striae
 Proximal muscle weakness
 Osteoporosis
 Diabetes Mellitus
 Avascular necrosis
 Wound healing impaired
 Pysch symptoms
 Hyperpigmentation
 Hypokalemic alkalosis

8. Investigation of a patient with
cushing syndrome
 There are two stages in the investigation of a
patient with cushing’s syndrome.
 Stage I - Does this patient have cushing syndrome?
 Stage II - If yes what is the cause?
 Note : Radiological investigations to be deferred
until cushing’s syndorme has been confirmed
biochemically.

9. Diagnosis
 Q1 Does this patient have cushing’s syndorme?
Circadian rhythm of plasma cortisol.
 In normal subjetcs plasma cortical levels are
highest in morning lowest at around midnight.
 This circadian rhythm is lost in cushing syndrome.
– Midnight cortisol >7.5 µg/dl indicates cushing
syndrome.
– Sensitive test but due to many false positives not
used .

10. Screening test
 Salivary cortisol
– >2.0 ng/ml (5.5 nmol/L)
– 100% sensitive
– 96% specific
 Urinary free cortisol excretion
– Normal : <220 to 330 nmol/24 hrs (80 to 120
µg/d)
– Useful screening test
 Spot - Urinary cortisol - creatinine ratio
– >25 nmol cortisol/mmol creat

11. Screening test(cont)
Low dose/ overnight Dexamethasone
suppression test
Procedure:
Oral adm of 1 mg dexamethasone
previous night and next day 8.00 am
plasma cortisol < 5µg /d is normal and <
2µg/day excludes cushings syndrome.
0.5mg dexamethasone 6 hourly for 2
consecutive day and plasma cortisol at
48 hrs < 5µg/dl is normal <2µg/dl
excludes cushing’s.

12. Low dose DST
differentiates those
who have cushing’s
from those who
donot have.

13. Screening test
Loperamide test :
 To differentiate true cushing’s from
pseudocushing’s lopermide lowers cortisol
values in patients with pseudocushing’s but
not in true cushing’s.
Q.2 Haring confirmed cushing’s syndrome
clinically and biochemically then go for the
causative factor.
 Plasma ACTH:
 A Midnight ACTH > 5 pmol/L. (> 22pg/ml).
In a patient with biochemical hypercortisolism
confers that the underlying disease is ACTH
dependant.
Note : pts with bilateral MAH and Adrenal
carcinoma /adenoma have variable levels.

14. Screening test
Plasma potassium
 Hypokalemia alkalosis is present in more than 95% of
patients with ectopic ACTH syndrome but is present in
fever than 10% of patients with cushing’s disease.
High dose dexamethasone suppression test
 2 mg dexamethasone 6 hourly for 48 hours and greater
than 50% decrease in urinary cortisol at 48 hours
defines or positive response.
 Alternating 8 mg give at 11.00 pm plasma cortisol at
8.00 am next morning can be done.
 Note : 50% of patients with ectopic ACTH syndrome
exhibit suppression and conversely patients with
putuitary ACTH macroadenoma show no suppression.

15. High dose DST distinguish
tose pts with cushing’s
disease from those having
ectopic ACTH
syndrome/adrenal tumor

16. PITUITARY PITUITARY ECTOPIC ADRENAL
MACROADEN MICRO ACTH TUMOR
OMA SYNDROME
ACTH
HIGH
< 10% >95% <10% <10%
DOSE
DST
CRH
>90% >90% <10% <10%

17. Metyrapone test
Cholesterol
↓
Pregnenolone
↓
Progesterone  17OH-progesterone
↓ ↓
DOC11deoxy cortisol
↓ 11 beta OH ase ↓
Corticosterone cortisol
↓
Aldosterone Metyrapone
750 mg 4 hrly for 24 hrs.

18. Exaggerated rise in ACTH and 11
deoxycortisol val > 35µ/dl at 24 hours.
Used to distinguish cushing’s disease
from adrenal cause.
Value of this test is questioned in
modern endocrine practice due to more
false positive result.

19. CRF Test
PROCEDURE
 IV CRF 1 µg/kg (or) 100 µg bolous 
measure plasma ACTH and cotisol every 15
mins for 1 to 2 hours.
Results
 Normal  ACTH and cortisol increase by 15
to 20%.in cushing disease  ACTH increase
by 50%; Cortisol increase by 20%
 In ectopic ACTH syndrome  no response.

20. Inferior petrous sinus sampling
 Selective venous catheterisation
 Most robust test to distinguish cushing
disease from ectopic ACTH syndrome is
IPSS.
Normal value
 Pituitary ACTH : Peripheral ACTH < 1.4 : 1
 Cushing disease >2
Or
 Post CRF pituitary/peripheral ACTH >3
(97% sensitive, 100% specific)

21. Investigation algorithm
Screening tests :
– 24 hours urinary free cortisol
(or)
– 1 mg overnight DST
Or
– 11 PM midnight salivary cortisol
Confirmation :
– Low dose DST
or
– Midnight plasma cortisol

22. Defining the cause
ACTH +high dose DST
<50% suppression of UFC
(or) plasma cortisol
Suppression on high Fails to suppress on Fail to suppress on high
dose DST and ↑ ACTH high dose + ↑ ACTH dose and ACTH
Cushing disease or Ectopic ACTH •Adrenal tumor
bronchial carcinoid syndrome
•Adrenal macro nodular
hyperplasia
CT chest/adrenal •Surreptitous use of
MRI/CT of Pituitary glucocorticoids
Pituitary tumor present No Pituitary mass
CT of the adrenals
Surgery Do CRH stimulation
test
IPSS with CRH  ectopic ACTH
syndrome
↑ >50% ACTH Inconclusive
↑ 20% cortisol Cushing’s disease Repeat radiological
studies

24. False Positives
Severe depression
Severe stress
Phenytoin/phenobarbital/rifampin
(accelerated metabolism of dex)
Estrogen (pregnancy or OCP)
Morbid obesity

25. Imaging Modalities
Plain abdominal film
Ultrasound (grey scale and
Doppler)
 CT scan
MRI
Adrenal scintigraphy
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26. Plain Abdominal Film
Plain abdominal film finding are non
specific
May be helpful in detecting
Mass in adrenal area
Calcification in adrenal
26

27. Ultrasound
Adult appearance
Entirely hypoechoic
Concave with straight margin
Newborn
Cortex hypoechoic, Medulla
hyperechoic
Cortex>>medulla thickness
Convex border 27

28. Ultrasound
Investigation of first choice in
infant , children and pregnant
women
Indication
adrenal masses ( larger than 2
cm)
28

29. CT Scan
On precontrast scan adrenal have
soft tissue density similar to that of
liver
Normal adrenal appear inverted V
or Y shape within retroperitoneal
fat
Consist of body , medial limb and
lateral limb 29

30. Ct Scan
Thickness of each limb is 5 mm
Maximum width of the body is 10-
12mm
Indication
masses (adenoma & cancer)
Cyst
abscess
metastasis 30

31. CT Scan
Attenuation is measured in Hounsfield
unit (HU)
Benign masses have low attenuation
values (< 20 HU )
Malignant masses have high
attenuation values (> 20 HU )
31

32. CT Scan
Unenhanced CT Scan
Adenomas : < 10 HU
Malignancies : > 20 HU
Delayed enhanced CT Scan
Adenoma : < 30 HU
Malignancies : > 30 HU
32

33. MRI
Equally effective as CT in imaging
adrenal disorder
Normal adrenal is intermediate signal
intensity to liver and hypo intense to fat
on TIW1 image
On T2W2 image adrenal hypo intense
to fat, iso intense to liver &hyper
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intense to crus

34. MRI
Carcinoma have hyper-intense signal
on T2W2 and hypointense on T1W1
images
On contrast enhancement show rapid
enhancement with sluggish washout
Adenoma are hypointense, show mild
enhancement & rapid 34
contrast washout

35. Adrenal scintigraphy
Usual role of scintigraphy is to clarify
inconclusive result of imaging
Indication
Functional status of adrenal nodule
Assess contralateral adrenal
function
Detect functional metastasis
Detect recurrence after surgery
35

36. Adrenal Scintigraphy
Adrenocortical imaging agent
NP-59 ( 6-B-iodomethyl-19-
norcholesterol )
Selenium-75 6-B-
selenomethylnorcholesterol
Sympathoadrenal imaging agent
MIBG ( metaiodobenzylguanidine )
36

37. Adrenal Scintigraphy
Indication for MIBG
Pheochromocytoma
Neuroblastoma, carcinoid, adrenal
metastasis
Indication for NP-59
Adrenocortical carcinoma
Adenoma
Adrenal hyperplasia
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38. MIBG Scintigraphy
38

39. MIBG Scintigraphy
MIBG : Inc tracer accumulation in lt adrenal
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40. Treatment
Cushing’s Disease: Transphenoidal
resection of pituitary adenoma
Adrenal neoplasms: resection
Ectopic ACTH: resection if possible
Bilateral adrenal hyperplasia: may
need adrenalectomies (lifelong
glucocorticoid and mineralcorticoid
replacement)

41. ‘Medical’ Adrenalectomy
Medications that inhibit steroidogenesis
Ketoconazole (600 to 1200 mg/day)
metyrapone (exacerbates female
virilization) (2-3 g/day)
Mitotane(2-3 G/day)- slow onset
Aminoglutethinide (1g/day)
Ocreotide can work in 1/3 of patients.
Major side affect is adrenal insufficiency,
therefore start at lowest dose and titrate

42. Complications of Cushing's if
Untreated
Diabetes
HTN
Osteoporotic fractures and
avascular necrosis
Infections
Nephrolithiasis
Psychosis
Death from vascular causes within
5yrs

43. Prognosis
Benign adrenal adenoma- 95% 5 year
survival, 90% 10 year
Cushing’s disease (pituitary adenoma)
same survival, but 10-20%
transphenoidal resection failure rate
over 10 years.
Ectopic ACTH survival depends on
malignancy
Unknown cause of elevated ACTH- 65%
5 year survival, 55% 10 year survival
Adrenal carcinoma- median survival 7
months upto 2 yrs

44. THANK YOU
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