Cushing's Syndrome, its pathophysiology of clinical features, diagnosis and treatment

1. Anish Dhakal (Aryan)
Cushing’s syndrome
20th
June, 2019

2. Regulation of the hypothalamic-pituitary-adrenal (HPA) axis

3. Physiologic cortisol circadian rhythm

4. Introduction
 Constellation of clinical features that result from
chronic exposure to excess glucocorticoids
(cortisol) of any etiology
 Cushing's disease---->Cushing's syndrome
caused by a pituitary corticotrope adenoma

5. Etiology
 ACTH-dependent Cushing syndrome
Hypothalamic lesions--- increased CRH
 Pituitary lesions (75%)– Microadenoma,
macroadenoma
 Ectopic production of ACTH(10%)---islet cell
carcinoma of the pancreas, neuroblastoma or
ganglioneuroblastoma, hemangiopericytoma,
Wilms tumor, and thymic carcinoid

6.  ACTHindependent causes
 Adrenal carcinoma and adenoma
 Pigmented nodular hyperplasia
 McCune Albright syndrome
 Exogenous administration
 Glucocorticoids
 ACTH

7. Clinical Manifestations
Most Specific Nonspecific
- Spontaneous
Bruising
- Proximal
Myopathy
- Abdominal striae
- Central obesity w/
extremity wasting
- Dorsocervical fat
pads (“Buffalo
Hump”
- Round facies
(“Moon Facies”)
- DM
- HTN
- Obesity
- Oligomenorrhea
- Osteoporosis
- Depression
- Insomnia
- Psychosis
- Impaired Cognition
- Hirsutism
- Fungal Skin
Infections
- Nephrolithiasis
- Polyuria

8. Bruising & Abdominal striae
 Loss of subcutaneous
connective tissue due to
catabolic effects of
glucocorticoids exposes
underlying vessels prone
to rupture
 Catabolic effect on
Fibroblasts
 Mechanism is similar with
abdominal striae

9. Cushingoid Habitus:
 Glucocorticoids
decrease AMP kinase
enzyme in Visceral
adipose tissues
(increased lipogenesis,
lipid stores & lipolysis)
 In hypothalamus,
glucocorticoids increase
AMPK which stimulates
appetite
 The cause for characteristic
preferential deposition in
face (moon facies and

10. Hirsutism:
 No clear
mechanism
 Excess ACTH
stimulates zona
glomerulosa, zona
fasciculata, zona
reticularis
producing cortisol,
androgens and
probably hirsutism

11. Plethora:
 Excess cortisol
causes
degradation and
atrophy of
epidermis and
underlying
connective
tissues
 Thinning of the
skin and facial
plethora

12. Polyuria:
 Excess glucocorticoids block osmosis
dependent ADH secretion from hypothalamus
 Directly also enhances free water clearence

13. Proximal myopathy:
 Glucocorticoids cause breakdown of muscle
proteins (decreased sarcolemmal activity and
increased myosin degeneration)
 Hypokalemia associated causes
hyperpolarization causing it more difficult for
the cells to fire
 ACTH directly blocks muscle transmission by
decreasing endplate potential
 Patient tend to have low levels of physical
acticity

14. System Signs and symptoms
Body fat Weight gain, central obesity, rounded face,
fat pad on back of neck ("buffalo hump")
Skin Facial plethora, thin and brittle skin, easy
bruising, broad and purple stretch marks,
acne, hirsutism
Bone Osteopenia, osteoporosis (vertebral
fractures), decreased linear growth in children
Muscle Weakness, proximal myopathy (prominent
atrophy of gluteal and upper leg muscles)
Cardiovascular
system
Hypertension, hypokalemia, edema,
atherosclerosis

15. System Signs and symptoms
Metabolism Glucose intolerance/diabetes, dyslipidemia
Reproductive
system
Decreased libido, in women amenorrhea (due
to cortisol-mediated inhibition of gonadotropin
release)
CNS Irritability, emotional lability, depression,
sometimes cognitive defects, in severe cases,
paranoid psychosis
Blood and
immune
system
Increased susceptibility to infections, increased
white blood cell count, eosinopenia,
hypercoagulation with increased risk of deep
vein thrombosis and pulmonary embolism

16. Laboratory diagnosis
 Circadian rhythm is lost; midnight cortisol
levels >4.4 mcg/dL--- strongly suggest the
diagnosis
 Elevated nighttime salivary cortisol levels
raise suspicion for Cushing syndrome.
 A single-dose dexamethasone suppression
test
 A dose of 25-30 mcg/kg (maximum of 2 mg) given
at 11 pm ------> results in a plasma cortisol level

17.  Level of ACTH
 CRH and High dose dexamethasone
suppression test
 Inferior petrosal sinus sampling---for ACTH
level
 CT/MRI

20. Management
 Transsphenoidal pituitary microsurgery
 Treatment of choice in pituitary Cushing disease in
children
 Cyproheptadine, a centrally acting serotonin
antagonist that blocks ACTHrelease, has been
used to treat Cushing disease in adults
 If a pituitary adenoma does not respond to
treatment or if ACTH is secreted by an ectopic
metastatic tumor, the adrenal glands may need to
be removed

21.  Pituitary irradiation
 Considered as primary therapy for children under age 18.
 Pituitary irradiation is one of the next treatment options in
 Whom fertility is an important concern
 Whom a tumor is not found
 Who are not cured by transsphenoidal resection of a tumor

22.  Management of patients undergoing
adrenalectomy
 Adequate preoperative and postoperative
replacement therapy with a corticosteroid
 Tumors that produce corticosteroids----> atrophy
of the normal adrenal tissue, and replacement with
cortisol (10 mg/m2/24 hr in 3 divided doses after
the immediate postoperative period) is required
until there is recovery of the hypothalamic-pituitary-
adrenal axis
 Postoperative complicatios---sepsis, pancreatitis,

23.  After adrenalectomy
 May lead to increased ACTH secretion by an unresected
pituitary adenoma, evidenced mainly by marked
hyperpigmentation: Nelson Syndrome.

24. Reference
 Kliegman et al, Nelson Textbook of Pediatrics,
19th
edition
 Ghai, Essential Pediatrics, 8th
edition
 Harrison’s principle of Internal Medicine 20th
edition
 Davidson’s Principles & Practices of Medicine

25. Thankyou