1. Cushing’s Syndrome Hasan AYDIN, M.D. Endocrinology and Metabolism
Yeditepe University Hospital

2. Actions of Cortisol

3. What Stresses Your Body

4. Circadian Release of Cortisol

5. Cushing's Syndrome
In 1932, a physician by the name of Harvey Cushing described eight patients with central body obesity, glucose intolerance, hypertension, excess hair growth, osteoporosis, kidney stones, menstrual irregularity, and emotional liability. It is now known that these symptoms are the result of excess production of cortisol by the

6. Definition Cushing’s Sydrome
Chronic glucocorticoid excess, whatever it’s cause
Cushing’s diasease
A spesific type of Cushing’s sydrome due to excessive pituitary ACTH secretion from a pituitary tumor.

7. Cushing’s Syndrome: Major Causes
Exogenous (iatrogenic, factitious)
ACTH-dependent:
Pituitary adenoma 70%
Ectopic ACTH syndrome 15%
ACTH-independent:
Adrenal adenoma 10%
Adrenal carcinoma 5%

8. Cushing’s Syndrome: Causes
ACTH-dependent:
Pituitary adenoma 70%
Ectopic ACTH syndrome 15%
Ectopic CRH
(ACTH –dependent macronodular adrenal hyperplasia)

9. Cushing’s Syndrome: Causes
ACTH-independent:
Adrenal adenoma 10%
Adrenal carcinoma 5%
Bilateral macronodular hyperplasia
Primary pigmented nodular adrenal disease (PPNAD)
+/- Carney complex

10. Ectopic ACTH Hypersecretion
15-20 % of patients with ACTH dependent Cushing’s Sydrome
Tumors causing the ectopic ACTH syndrome
small cell carcinoma of the lung (50% of cases)
pancreatic islet tumors
carcinoid tumors (lung,thymus,gut,pancreas,ovary)
medullary carcinoma of the thyroid
pheochromocytoma

11. Rare Causes Bilateral Nodular Hyperplasia
ACTH – independent, adrenal dependent
Bilateral large nodules (3-6 cm in diameter)
Food dependent hypercortisolism:
The adrenal cortex expressed abnormal receptors for gastrointestinal inhibitory polypeptide (GIP).Food consumption stimulates GIP, which in turn binds to the receptors in the adrenal cortex,thereby stimulating adrenal growth and steroid biosynthesis.

12. Adrenal Carcinoma Hypersecrete multiple adrenocortical steroids
Androgen excess is usually even greater than that of cortisol
Hypertension and hypokalemia are frequent.

13. Overlapping Conditions
Some clinical features of may be present
Pregnancy
Depression and other psychiatric conditions
Alcohol dependence
Glucocorticoid resistance
Morbid obesity
Poorly controlled diabetes mellitus
Unlikely to have any clinical features
Physical stress (hospitalization, surgery, pain)
Malnutrition, Anorexia nervosa
Intense chronic excercise
Hypothalamic amenorrhea
CBG excess (increased serum but not urine cortisol)

14. Clinical Features of Cushing’s Sydrome
General
obesity 90 %
hypertension 85%
Skin
plethora 70%
hirsutism 75%
striae 50%
acne 35%
bruising 35%
Musculoskeletal
osteopenia 80%
weakness
Neuropsychiatric 85%
emotional lability
euphoria
depression
psychosis
Gonadal dysfunction
menstrual disorders 70%
impotence,decreased libido 85%
Metabolic
glucose intolerance 75 %
diabetes 20%
hyperlipidemia 70%
kidney stones 15%

15. Clinical Features

16. Cushing’s Syndrome Nonspecific findings Truncal obesity
Supraclavicular & dorsal fat pads
Hypertension
Hirsutism, acne
Amenorrhea
Depression

17. Cushing’s Syndrome More specific findings: Thin skin Easy bruising
Red striae
Facial plethora
Muscle weakness
Osteoporosis
Growth failure

18. Buffalo Hump

19. Truncal Obesity

20. Moon Face and Purple Striae

21. Laboratory Findings High normal hemoglobin Eosinophils < 100 mL
Fasting hyperglycemia
Serum calcium normal
Serum phosporus low normal
Hypercalciuria

22. Diagnosis Demonstration of hypercortisolism
24-h urine free cortisol
Midnight cortisol
Low dose Dxm suppresion test
Determination of ACTH dependence
Plasma ACTH level
Differentiation of ectopic ACTH from pituitary disease
High dose DXM suppression test
IPSS

23. Diagnosis Urine free cortisol
in 24 hour urine samples – mg/24 h is normal
Discrimination between patients with hypercortisolism and obese-non cushing patients

24. Diagnosis Absence of diurnal rhythm is the hallmark of diagnosis
Serum cortisol levels exceeding 7 mg/dL at midnight indicates absence of diurnal rhythm

25. Dexametasone Supression Test
Diagnosis
Dexametasone Supression Test
Low dose –for screening
1 mg dexametasone at bedtime (23 00hour)
Determine plasma cortisol early following morning
Plasma cortisol < 1,8 mg/dl - normal
Dexamethasone 4 x 0.5 mg for two days
17 hydroxycorticosteroid excretion greater than 4 mg/24 h on the second day of dx administration= Cushing syndrome

26. Diagnosis High dose Dx suppression test Overnight 8 mg Dx at bedtime
4 x 2 mg Dx for 2 days.
2nd day urine steroid decreases < 50% - indicates pituitary disease
Absence of supression indicates primary adrenal disease or ectopic ACTH
Overnight 8 mg Dx at bedtime
Supression plasma cortisol < 50% at baseline consistent with pituitary dependent Cushing’s syndrome
Distinguish pituitary and nonpitutitary ACTH dependent Cushing’s syndrome

27. Pitfalls of Dexamethasone Testing
Compliance
Taking dexamethasone
Collecting urine
Drug interference (eg phenytoin)
Role of plasma dexamethasone measurement
Other variation in dexamethasone metabolism
Lack of validation with newer cortisol assays

28. Drugs that may interfere with the tests
Drugs that accelerate DXM metabolism by inducing CYP 3A4
Phenobarbital
Phenytoin
Carbamazepine
Primidone
Rifampin, rifapentine
Ethosuximide
Pioglitazone
Drugs that impair DXM metabolism by inhibiting CYP 3A4
Aprepitant/fosapritant
Itraconazole
Ritonavir
Fluoxetine
Diltiazem
Cimetidine
Drugs that increase CBG and may falsely elevate cortisol results
Estrogens
Mitotane
Drugs that increase UFC results
Carbamazepine (increase)
Fenofibrate (increase if measured by HPLC)
Some synthetic corticosteroids (immunoassays)
Licorice, carbenexolone (inhibit 11β-HSD2)

29. Why is diagnosis is so hard?
Cortisol secretion is variable in normals & CS
In some patients, CS is intermittent
There may be overlap between mild CS and metabolic syndrome
There are many different cortisol assays

30. Differential Diagnosis
Plasma ACTH
>15 pg/ml: ACTH dependent
<5 pg/ml: ACTH independent
ONLY AFTER DIAGNOSIS IS CONFIRMED

31. Diagnosis Plasma ACTH: Pituitary MRI
Differentiate ACTH dependent and non dependent forms
Patients with ACTH –secreting neoplasms usually have plasma ACTH levels > 10 pg/ml frequently greater than 52 pg/ml.
Pituitary MRI
ACTH-dependent patients adenoma on MRI likehood of cushing disease 98-99%
Incidentaloma 10%

32. Referral to neurosurgeon
If high dose dexamethasone test diagnostic of pituitary Cushing’s disease:
Pituitary MRI
Referral to neurosurgeon

33. If urine cortisol very high or hypokalemia present:
If high dose dexamethasone test NOT diagnostic of pituitary Cushing’s disease:
If urine cortisol very high or hypokalemia present:
Chest & abdomen CT
Octreotide scan O/W
Petrosal sinus sampling

34. Inferior Petrosal Sinus Sampling

35. Inferior Petrosal Sinus Sampling
Distinguishing pituitary from non pituitary ACTH dependent Cushing’s syndrome
Simultaneous inferior petrosal sinus and peripheral ACTH measurements before and after CRH stimulation
IPS/P > pituitary ACTH secreting tumor
IPS/P < ectopic ACTH
Diagnostic accuracy 100% in the differantial dignosis of ACTH dependent Cushing’s syndrome

36. If IPSS not diagnostic of CD:
Chest & abdomen CT
Octreotide scan

37. Cushing’s Syndrome Radiographic Localization CT of sella turcica
Unenhanced and gadolinium enhanced MRI
Radionuclide imaging for somatostatin receptors
>60% sensitive
CT of chest/abdomen with 3 mm cuts through adrenal
Adrenal hyperplasia
Thickening and elongation of adrenal rami bilaterally
Multinodularity of cortex bilaterally

38. Cushing’s Syndrome Radiographic Localization CT of adrenal glands
Adenomas- usually >2cm but <5cm
Low attenuation (lipid content)
Atrophy of opposite gland
Carcinoma- indistinguishable from adenomas
>5cm
Necrosis, calcifications, irregularity, invasion
MRI of adrenal- usually not needed
Signal intensity much higher than in spleen = carcinoma
Adjacent organ and/or vascular involvement

39. Adrenal Nodule

40. Adrenal Nodule

41. Treatment of Cushings Syndrome
Obviously, the treatment of this disease depends upon the cause.
Pituitary tumors are usually removed surgically and often treated with radiation therapy.

42. Treatment
Remove or destroy the basic lesion correct the hypersecretion of adrenal hormones
microsurgery
radiation therapy
pharmocologic inhibition of ACTH secretion
ketoconasole, metyrapone, amimoglutethimide, mitotane

43. Cushing’s Syndrome Treatment: Surgical Cushing’s disease
Transphenoidal hypophysectomy
>90% cure rate 1st time, 50% salvage cure 2nd attempt
Exploration even if no obvious adenoma
Transient post-op diabetes insipidus, adrenal insufficiency, CSF rhinorrhea, meningitis
Tansphenoidal irradiation
High success rate in kids (80%)
Low success in adults (20%)

44. Cushing’s Syndrome Treatment: Surgical Cushing’s disease
Bilateral adrenalectomy
If failed pituitary surgery
Nelson’s syndrome (10-20%)
Life-long steroid replacement
Nelson’s syndrome
Rapid post-operative growth of ACTH-secreting pituitary adenomas that can be invasive
Hyperpigementation
Preoperative irradiation decreases incidence

45. Cushing’s Syndrome Treatment: Surgical Adrenal lesions/carcinoma
Removal of primary lesion
Survival based on underlying disease
Ectopic ACTH lesions
Remove lesion
Survival based on primary disease
May need bilateral adrenalectomy to control symptoms if primary tumor unresectable

46. Cushing’s Syndrome Treatment: Medical
Used as prep for surgery or poor operative candidate
Metyrapone- inhibits conversion of deoxycortisol to cortisol
Aminoglutethimide-inhibits desmolase
Cholesterol to pregnenolone
Blocks synthesis of all 3 corticosteroids
Side effects: N/V, anorexia, lethargy
Ketoconazole- an imidazole that blocks cholesterol synthesis
Mitotane (O-P-DDD)-inhibits conversion to pregnenolone
Inhibits final step in cortisol synthesis
Destroys adrenocortical cells (spares glomerulosa cells)

47. Cushing’s syndrome: therapy
Before treatment
After treatment

48. Treated Cushing Syndrome

49. T h a n k Y o u