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adrenal glands 2 (ADRENAL HYPERFUNCTION) (CUSHING’S SYNDROME (Symptoms…
adrenal glands 2
(ADRENAL HYPERFUNCTION)
glucocorticoid excess
Physiologic: stress, last trimester of pregnancy
Pathologic
:
-psychiatric conditions (
alcoholism
, depression, anorexia nervosa)
-ACTH-dependent
-ACTH-independent
-Exogenous sources
mineralocorticoid excess
Primary aldosteronism
Exogenous mineralocorticoids
• licorice, carbenoxolone, fludrocortisone
Adrenal enzymes defficiency
• 11β-hydroxylase • 11β HSD
Secondary hyperaldosteronism: with or without hypertension
catecholamines excess
pheochromocytoma
, paraganglioma
CUSHING’S SYNDROME
nonspecific name for any cause of excessive glucocorticoids
Cushing
disease results from pituitary Cushing syndrome (pituitary adenoma).
Causes:
Exogenous glucocorticoids
Pituitary Cushing’s syndrome
Ectopic production of ACTH
Adrenal causes of Cushing’s syndrome
Classification
ACTH-dependent (80%)
Pituitary=Cushing’s disease (85%) Androgen excess is common
.
Ectopic ACTH- syndrome (15%)
Ectopic CRH (<1%)
Nodal adrenal hypertrophy (<1%)
ACTH-independent (20%)
Adrenal adenoma (>50%)
.
Adrenal carcinoma,
Micronodular hyperplasia (PPNAD
Macronodular hyperplasia (MAH)
Exogenous corticosteriods
iatrogenic,
Exogenous Cushing’s syndrome is most common
endogenous causes
–
pituitary Cushing’s disease 70%
of cases
Ectopic ACTH secretion and adrenal tumors cause 15%
of cases each
Epidemiology
Cushing’s disease: 80% of patients are women (age is 20-40 years)
Ectopic ACTH syndrome: common in men (40-60 years)
Symptoms
Fat redistribution:
-
supraclavicular fat
pads
-dorsocervical fat pad =
buffalo hump
-„central” (truncal) obesity
-moon face
-temporal wasting
-wasting of the extremities
-weight gain
Skin:
-
thin
, easy bruising, poor wound healing, easy infection,
pigmentation
,
Patients with cushing disease may have hyperpigmentation due to elevated ACTH levels, whereas patients with Cushing syndrome due to other causes will not have hyperpigmentation.
-facial plethora
-red or violaceous
striae
, width
>1 cm
Muscle:
-proximal weakness and atrophy
Gonadal dysfunction:
-menstrual irregularities
-poor libido, impotence in men
Osteoporosis
:
-back pain, kyphosis
-patological fractures- vertebrae and ribs
Psychologic: -
depression
, euphoria,
insomnia
Hypertension
,
congestive heart failure
Diabetes mellitus/ glucose intolerance
Increased likelihood of infections (due to impaired immunity)
Diagnosis
Labotatory tests
Serum cortisol level at 8 am and 8 pm:
-basal (nonstress condition) cortisol is secreted in a diurnal manner: with high levels
early in the morning (8-25 μg/dl) and low levels late in the evening (<5μg/dl)
-
Cushing’s
syndrome: lack of the diurnal variation:
late afternoon or night plasma cortisol values >50% of the morning values
24-hour
urinary free cortisol
excretion:
• The
single best
screening test for hypercortisolism
• Extremely sensitive -UFC is elevated in 90% of patients
•
Cushing’s disease:100-500 μg/24h
• Ectopic ACTH syndrome, adrenal adenoma or carcinoma >500 μg/24h
• Should be repeted 2-3 times
Overnight dexamethasone suppression test (1mg dexamethasone):
• Dexamethasone 1mg p.o. at 11 pm
• Plasma cortisol at 8.oo next morning >3-5 μg/dl suggests hypercortisolism
• False-negative: in some pituitary adenomas sensitive to dexamethasone
• False-positive results to: in obese and depressed patients (activation of HPA axis because of stress)
Differential diagnosis
History taking:
• Exogenous glucocorticoids for inflammatory or autoimmune disease
• secret ingestion of steroids
• Short history, pigmentation, weight loss, unprovoked hypokalemia - suggests e-ACTH syndrome
• Severe hirsutism/ virilization suggests the malignant adrenal tumor
laboratory tests
Plasma ACTH level (repeated):
-undetectable or low
(<10 ng/l) =ACTH- independent disease
-„normal” or slightly elevated =Cushing’s disease
-marked elevation = e-ACTH syndrome
Associated laboratory findings:
•
hypokaliemic alkalosis
•
granulocytosis
• thrombocytosis
•
diabetes mellitus
Overnight high-dose (8mg) dexamethasone test:
-decrease in plasma cortisol <50% of the baseline level =pituitary CS
CRH test:
-↑ ACTH and ↑ cortisol = pituitary CS -no response =adrenal tumors or e-ACTH syndrome
Liddle test:
•
2-day low-dose and high-dose dexamethasone suppression test – to distinguish pituitary, ectopic and adrenal cause of CS
• failure of significant plasma cortisol and 24h UFC suppression – suggests e-ACTH syndrome or adrenal tumor
•
>50% suppression on the 2nd day of high dosage – suggests pituitary adenoma
Imaging
ACTH dependent CS
HR
MRI of the pituitary gland:
-with gadolinium and thin cuts is the next step after diagnosis of ACTH-dependent CS
-is diagnostic in CS only if shows large tumor -detects 50-60% of microadenomas
-cannot be sole criterion for diagnosis of CS
**BIPSS = bilateral inferior petrosal sinus sampling
The best test to distinguish a pituitary from ectopic source of ACTH**
No ACTH gradient between petrosal sinus and peripheral vein = ectopic source
Higher ACTH levels in the petrosal sinuses (ipsilateral gradient >1,6) and increased response to exogenous CRH = pituitary source
ACTH independent CS
Adrenal CT or MRI scan:
-the next step after diagnosis of ACTH- independent CS
-an adrenal mass is almost always present
-carcinoma is large, irregular, with signs of infiltration or metastases
-bilateral adrenal hyperplasia may be seen
Prognosis
Very bad in untreated CS
Death from:
pulmonary embolism
hypertension, MI, HF
Hypercortisolemia should be controlled, whatever the underlying cause, prior to surgery, pituitary irradiation or in patients who are not surgical candidates
Treatment
General overview
Treatment of Cushing syndrome is directed by the primary cause of the syndrome
In general, therapy should reduce the cortisol secretion to normal to reduce the risk of comorbidities associated with hypercortisolism and a culprit tumor should be removed if possible
The primary therapy for Cushing disease is transsphenoidal surgery, and the primary therapy for adrenal tumors is adrenalectomy
When surgery is not successful or cannot be used, control of hypercortisolism may be attempted with medication
The treatment for exogenous Cushing syndrome is gradual withdrawal of glucocorticoid
Pituitary radiation may be useful if surgery fails for Cushing disease
Reduction of hypercortisolism
Ketoconasole
– tabl. a 200 mg; 3x/d
Aminogluthetimide
tabl. a 250 mg; 3-4x/d
Mitotane
(o,p’-DDD) tabl. a 500mg; 3-4x/d
The aim: reduction of plasma cortisol during the day to 300 nmol/l
Casual
Pituitary Cushing’s disease:
transsphenoidal selective adenomectomy (treatment of choise, 75-80% of remission)
external pituitary irradiation – may take years to work, effective in 60%
total hypophysectomy – when tumor cannot be seen by surgeon
bilateral adrenalectomy – followed by life-long gluco- and mineralocorticoid replacement therapy
**Cortisol-secreting adrenal adenoma
unilateral adrenalectomy (treatment of choice)**
Adrenal carcinoma
surgery: tumor bulk reduction
medical therapy:
Mitotane (drug of choice)
Tumors secreting ACTH ectopically
surgery if possible
chemo/radiotherapy
bilateral adrenalectomy to control CS
Unclear source of ACTH
„pharmacological adrenalectomy”
Cushing’s syndrome - other causes
Ectopic ACTH syndrome:
-Due to malignant tumor: usually of the lung (SCLC)
-Due to carcinoid tumor: often located in the bronchus or abdomen
-Investigation:
• Chest X-ray, CT or MRI scans of the lung and abdomen, brochoscopy, octreoscan (somatostatin receptor scintigraphy)
•
BIPSS - blood samples taken throughout the body = search for ectopic sites
PPNAD =primary pigmented nodular adrenal dysplasia:
-adrenal CS with multiple adrenal masses
-an autoimmune disease? (adrenal-stimulating imunoglobulins)
-second decade of life (earlier than other causes of CS)
-unilateral or bilateral small pigmented nodules (tiny -3 cm)
-bilateral adrenalectomy is curative
MAH =macronodular adrenal hyperplasia:
-heterogenous group of patients with varying degree of adrenal autonomy
-longstanding stimulation of ACTH- formation of adrenal nodules - some of them may become autonomous
-whether the patient still has ACTH- dependent disease?
-treatment must be individualized
Nelson’s syndrome
ACTH-secreting agressive pituitary macroadenoma up to 30% of cases after bilateral adrenalectomy
Symptoms: hyperpigmentation, visual field deficit
Treatment:
pituitary surgery and/or radiotherapy
Ma6ar