Cushing's syndrome Flashcards
1
Q
Glucocorticoid action (6)
A
- catabolic hormones - proteolysis, lipolysis, gluconeogenesis
- inhibit immune reactions
- induce neutrophilia, lymphocytopenia and eosinophilopenia
- induce euphoria, psychosis
- potentiate vasoconstrictive catecholamines action
- increase gastric acidity and the development of peptic ulcers
2
Q
Regulation of glucocorticoid secretion (3)
A
- ACTH –> stimulates cortisol secretion and adrenal cortex hyperplasia
- secretion of ACTH is enhanced by corticotropin-releasing hormone (CRH) and vasopressin (AVP) produced in the hypothalamus
- cortisol suppresses ACTH and CRH secretion
3
Q
Cushing’s syndrome
- definition
- classification
A
-chronic exposure to excess glucocorticoids
- exogenous - due to administration of exogenous glucocorticoids
- endogenous:
1. ACTH dependent (ACTH producing pituitary adenoma and Ectopic ACTH or CRH secretion)
2. ACTH Independent (Adrenocortical adenoma, adrenocortical carcinoma, micro and macronodular adrenal hyperplasia)
4
Q
Cushing’s syndrome
-epidemiology (3)
A
- most often cause –> iatrogenic administration of glucocorticoids for immunosuppression or treatment of inflammatory disease
- most often cause of endogenous –> ACTH producing pituitary adenoma (90-95% microadenoma)
- women are 3-8 times more likely than men
5
Q
Iatrogenic Cushing’s syndrome (3)
A
- caused by administration of excessive amounts of synthetic glucocorticoid and only rarely by ACTH administration
- iatrogenic administration of glucocorticoids –> inhibition of ACTH and CRH secretion –> atrophy of adrenal cortex
- lab test –> reduced ACTH concentration and reduced cortisol concentration in serum, saliva and urine
6
Q
Adrenal insufficiency after glucocorticoid intake (3)
A
- <3 weeks of any dose of glucocorticoids intake does not cause dysfunction of hypothalamus-pituitary (HPA) axis
- exogeneous glucocorticoids –> inhibition of CRH and ACTH secretion –> adrenal cortex atrophy
- abrupt discontinuation of glucocorticoid intake may cause the development of acute adrenal insufficiency
7
Q
Cushing’s syndrome
-pathogenesis (2)
A
- autonomous ACTH secretion –> bilateral adrenal cortex hyperplasia –> glucocorticoid + adrenal androgen hypersecretion
- normal ACTH and cortisol circadian rhythm is usually lost but pre-bedtime concentrations are high
8
Q
Ectopic ACTH secretion
-pathogenesis (3)
A
- ectopic tumors may secrete CRH and/or ACTH
- most non-pituitary tumors are completely resistant to feedback inhibition
- high dose (8mg) dexamethasone suppression test is used to differentiate pituitary adenoma and ectopic ACTH secretion
9
Q
Cortisol-secreting adrenal tumors
-pathogenesis (4)
A
- increased cortisol secretion –> suppresses CRH and ACTH secretion –> pituitary corticotropes and adrenal glands atrophy
- adrenal adenomas produce cortisol very efficiently
- adrenal carcinomas are inefficient in terms of steroid production
- most are monoclonal –> result from accumulated genetic abnormalities
10
Q
Bilateral adrenal hyperplasia
-pathogenesis (4)
A
-Bilateral adrenal micronodular hyperplasia –> both sporadic and familial
- Bilateral adrenal macronodular hyperplasia –> adrenal glands contain multiple non-pigmented nodules greater than 5mm in diameter.
- Increases in cortisol secretion –> mediated by overexpression of receptors or have activating protein G alpha subunit mutations
- most are sporadic
11
Q
Cushing’s syndrome
-signs and symptoms (7)
A
- weight gain, central obesity, rounded fact, fat pad on back of neck
- osteopenia, osteoporosis
- weakness, proximal myopathy
- hypertension, hypokalemia, edema, atherosclerosis, increase in plasma concentration of clotting factors
- decreased libido, amenorrhea
- irritability, depression
- hypokalemia –> due to decreased renal conversion of cortisol
12
Q
Cushing’s syndrome
-dermatologic changes (5)
A
- easy bruisability - loss of subcutaneous connective tissue due to the catabolic effects of glucocorticoids
- Purple + wide striae
- Skin atrophy - loss of subcutaneous fat
- Fungal infections - especially tinea versicolor
- Hyperpigmentation - often in patients with Ectopic ACTH syndrome - ACTH binds to melanocyte stimulating hormone receptors
13
Q
Cushing’s syndrome
-metabolic alterations (5)
A
- glucocorticoids stimulate gluconeogenesis
- obesity causes increased insulin resistance
- glucose intolerance
- dyslipidemia
- hyperglycemia becomes much easier to control and may completely remit if hypercortisolism is reversed
14
Q
Cushing’s syndrome
-bone changes (3)
A
- osteoporosis (even in young patients) due to: decrease intestinal calcium absorption, decreased renal calcium reabsorption, decreased bone formation and increase bone resorption
- pathologic fractures may occur
- osteopenia
15
Q
Cushing’s syndrome
-psychologic symptoms (5)
A
- emotional lability
- depression
- irritability
- anxiety
- panic attacks
16
Q
Cushing’s syndrome
-infections and immune function impairments (4)
A
- increases susceptibility to infections,
- increase WBC, eosinopenia,
- hypercoagulation
- glucocorticoids inhibit immune functions
17
Q
Cushing’s syndrome
-impairments of reproductive system (6)
A
- menstrual irregularities –> due to suppression of secretion of gonadotropin-releasing hormone
- low FSH, LH and estradiol
- abnormal menstrual cycle, oligomenorrhea, amenorrhea
- hirsutism, oily facial skin, acne
- increase libido
- virilization
18
Q
Cushing’s syndrome
-diagnosis steps
A
- Clinical suspicion
- Screening/ confirmation - dexamethasone suppression test, 24h urinary free cortisol, midnight salivary or plasma cortisol
- Differential diagnosis: plasma ACTH
- it is essential to exclude exogeneous glucocorticoid intake
- testing is recommended in all patients with adrenal incidentalomas
19
Q
Pseudo-Cushing’s syndrome (2)
A
- mild hypercortisolism
- can occur in disorders other than CS like: pregnancy, severe obesity, prolonged psychological stress, poorly controlled diabetes mellitus, chronic alcoholism
20
Q
Cushing’s syndrome
-screening tests
A
diagnosis is made when at least two different first line tests are abnormal:
1. Overnight 1mg dexamethasone suppression test –> plasma cortisol >50 nmol/L at 8-9am after 1mg at 11pm
- 24h urinary free cortisol (UFC) excretion (two measurements) –> increased above normal (3x)
- Late night salivary or plasma cortisol –> >130 nmol/or midnight salivary cortisol >5nmol/L
- Low dose DEX test if further confirmation is needed –> plasma cortisol >50 nmol/L
21
Q
Cushing’s syndrome
-differential diagnosis
A
- plasma ACTH
1. ACTH normal or high –>ACTH- dependent Cushing’s syndrome
2. ACTH suppressed to <5 pg/ml –> ACTH independent Cushing’s syndrome
22
Q
Cushing’s syndrome
- bilateral sinus petrosus sampling - complications
- bilateral sinus petrosus sampling - results
A
- cranial nerve palsy, hemiparesis, petrosal and/or cavernous sinus venous thrombosis, pulmonary embolism, inguinal or jugular hematomas
- increased central/peripheral plasma ACTH ratio >2 at baseline and >3 at 2-5min after CRH injection –> Cushing’s disease
23
Q
Cushing’s syndrome
-treatment (5)
A
- depends on the type!
- glucocorticoid replacement needs to be initiated at the time of surgery and slowly tapered following recovery
- it may require 6-18 months, years or it may not even recover
- if surgery contraindicated –> medical therapy
- pituitary irradiation or bilateral adrenalectomy –> when operation is contraindicated
24
Q
Ectopic ACTH syndrome
-treatment (3)
A
- surgical excision of the tumor
- if surgery not possible –> adrenal enzyme inhibitors or bilateral adrenalectomy
- glucocorticoid receptor antagonist and somatostatin analogs are also useful
25
Q
ACTH- independent Cushing’s syndrome
-treatment (4)
A
- removal of affected adrenal gland
- glucocorticoid replacement needs to be initiated at the time of surgery and slowly tapered following recovery
- it may require 6-18 months, years or it may not even recover
- surgical bilateral adrenalectomy is used in patients with micronodular or macronodular adrenal hyperplasia –> life long glucocorticoid and mineralocorticoid replacement is required
26
Q
ACTH- independent Cushing’s syndrome vs. dependent
A
primary - ACTH- independent Cushing’s syndrome –> high levels of cortisol, decrease CRH and decrease ACTH
secondary ACTH- dependent Cushing’s syndrome
27
Q
ACTH-dependent Cushing’s syndrome
-differential diagnosis
A
- MRI - pituitary
- CRH test
- High dose DEX test
- if CRH test and high dose DEX positive –> Cushing’s disease –> Transsphenoidal surgery
- if CRH test and high dose DEX negative –> Ectopic ACTH production –> inferior petrosal sinus sampling –> locate and remove ectopic source –> bilateral adrenalectomy (if neg.)
28
Q
ACTH-independent Cushing’s syndrome
-differential diagnosis
A
- Unenhanced CT of adrenal gland
- if unilateral mass –> adrenal tumor workup –> unilateral adrenalectomy
- if bilateral micronodular or macronodular adrenal hyperplasia –> bilateral adrenalectomy
29
Q
If surgery is contraindicated, what are the possible medications?
A
- Adrenal enzyme inhibitors - metyrapone, ketoconazole, mitotane, etomidate
- Medical therapy targeting corticotroph tumor (carbergoline - dopamine agonist, pasireotide - somatostatin analogues)
