Adrenal Disorders I- Cushing Syndrome

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Cushing’s syndrome:

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Comprises the symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoids

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cushing
central obesity and relative thinning of extremities

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cushing
moon facies and red face

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cushing
abdominal striae; dark, wide, abdominal and axillary

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cushing
buffalo hump and hirsuitism

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relative freq of symptoms in cushing:

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Relatively Specific Features in cushing:

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Facial plethora
Wide purple striae
Spontaneous ecchymoses
Proximal muscle weakness

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Why “central” obesity in CS?

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*Glucocorticoids stimulate adipogenesis and adipocyte differentiation
-But this doesn’t explain the central nature of CS obesity

*Other possibilities
-Muscle atrophy makes the extremities look relatively thin
-Increased expression of glucocorticoid receptor and type 1 isoenzyme of 11β-hydroxysteroid dehydrogenase (converts cortisone to cortisol) in omental fat compared with subcutaneous fat

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Other fat deposits in CS besides central:

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Dorsocervical = “buffalo hump”
Supraclavicular
Cheeks and temples = “moon facies”
Epidural space – leads to neurologic deficits

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Hypertension in CS:

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*75% of cases

*Increase sensitivity to catecholamines and angiotensin II in vascular smooth muscle

*Increase angiotensinogen

*Decrease NO-mediated endothelial dilatation

*Sodium retention from mineralocorticoid activity

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How can cortisol act as a mineralocorticoid in CS?

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*Your body has taken multiple steps to separate the regulation of cortisol and the regulation of aldosterone

*YET cortisol is a strong agonist of MR

*Renal MR are “protected” from cortisol by 11B-HSD2 which locally converts cortisol (MR agonist) to cortisone (not an MR agonist)

*In CS, there is so much cortisol that 11B-HSD2 is overwhelmed, and the MR are activated by cortisol
-Sodium retention --> HTN
-Potassium loss and H+ loss --> Hypokalemic alkalosis

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Diabetes mellitus in CS:

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*1/3 of patients

*Glycogen deposition in the liver

*Increase hepatic glucose output

*Decrease peripheral glucose utilization

*Activation of lipolysis

*Permissive effect upon catecholamines and glucagon

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Mood changes in CS:

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*Brain is an important target tissue of GC

*Psychiatric abnormalities in 50% of patients with CS
-Agitated depression and lethargy
-Memory and cognitive dysfunction
-Insomnia
-Paranoia and psychosis (esp in hospital after high dose steroids)

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Describe issues in CS with:
-gonadal
-thyroid
-osteoporosis
-muscles
-skin

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*Gonadal dysfunction
Inhibited GnRH pulsatility and LH and FSH release

*Thyroid dysfunction--Suppress thyroid axis

*Osteoporosis
Inhibit osteoblast function
Induce negative calcium balance and increase PTH

*Muscle weakness--Reduced muscle protein synthesis with muscle atrophy

*Plethora/Ecchymoses/Striae
Catabolic effects of GC lead to atrophy of epidermis and underlying connective tissue

*Acne/Hirsutism--Increased adrenal androgens

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Who should be screened for CS?

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*Patients with unusual features for age (e.g. osteoporosis, hypertension)

*Patients with multiple and progressive features

*Patients with adrenal incidentaloma compatible with adenoma

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Steps to take in evaluating a pt for CS:

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*Most important thing is to exclude exogenous steroids!!

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CS due to exogenous glucocorticoids:

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*By far the most common cause of CS

*Widespread use of GC to treat a variety of diseases

*CS most commonly from longterm oral GC use, but can be from any route of delivery, even “local”

*Megestrol--a progesterone derivative used to treat metastatic breast CA or to stimulate appetite in AIDS wasting--can act as an agonist at GR, causing CS

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Describe the 1-mg Dexamethasonesuppression test:

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*Dexamethasone 1-mg at 11 PM

*Fasting plasma cortisol next day at 8-9 AM

*Cortisol > 1.8 μg/dL [sensitivity >95%; specificity 80%]

*False-positive results
- increased CBG (estrogens); 50% of women on OCP have false-positive DST
- increased metabolism of dexamethasone (antiseizure meds)

*False-negative results
- reduced dexamethasone clearance in liver or kidney failure

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Describe Urine Free Cortisol testing:

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*Measures plasma free cortisol
*Not affected by CBG levels
*Requires accurate 24 hour urine collection
*Sensitivity of 90%; specificity of 95%
*False-positive
-High fluid intake (>5 liter/day)
-Essentially any cause of Psuedo-Cushing’s

*False-negative
-Renal impairment
-Cyclic or mild CS

*Values above 4 times the upper limit of normal are diagnostic

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Describe testing for Late-night Salivary Cortisol:

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*Cortisol concentration in saliva is highly correlated with plasma free cortisol

*The loss of circadian rhythm with absence of a late-night cortisol nadir is a consistent biochemical abnormality in Cushing’s

*Sensitivity 93-100%; Specificity >92%

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How is the cortisol circadian rhythm in CS?

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Causes of Cushing’s syndrome:

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Summary of HPA axis:

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Levels of ACTH in CD vs Adrenal tumor vs ectopic ACTH:

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Causes of Cushing’s syndrome:

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Describe CS due to Adrenal Tumor:

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*Benign (adenoma) or malignant (carcinoma) neoplasms of adrenal origin
*ACTH is suppressed but hormone secretion by adrenal neoplams is ACTH-independent

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Primary pigmented nodular adrenocortical disease (PPNAD):

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-50 % familial as part of “Carney complex”
Autosomal dominant disorder of regulatory subunit of cAMP-dependent protein kinase A

-Carney complex
Mesenchymal tumors (atrial myxoma)
Spotty skin pigmentation
Peripheral nerve tumors (schwannomas)
GH-secreting pituitary tumor
Testicular tumor

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carney complex associated with CS

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Bilateral adrenal disorders causing CS:

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-PPNAD
-McCune-Albright Syndrome
-AIMAH

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McCune-Albright syndrome:

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-Activating mutation of G-protein subunit
-Constitutive steroidogenesis
-Fibrous dysplasia
-Cutaneous pigmentation (coast of maine cafe au lait)
-Pituitary/adrenal, thyroid, gonadal hyperfunction

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Coast of Maine cafe au lait in Mccune albright syndroms

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Various clinical manifestations of McCune Albright:

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ACTH-independent macronodular adrenal hyperplasia (AIMAH):

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Abberant regulation of cortisol production and adrenal growth mediated by the abnormal adrenal expression of receptors for a variety of hormones (e.g. GIP, HCG-LH, serotonin)

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Receptors involved in AIMAH:

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Caused by aberrant expression of hormone receptors on GC-secreting cells

Cortisol secretion driven by a hormone that is not suppressed by cortisol-mediated negative feedback (e.g. GIP, catecholamines, LH/hCG, vasopressin)

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macronodular adrenal hyperplasia in AIMAH

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ACTH-secreting Pituitary Adenoma (aka Cushing’s DISEASE)

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Pituitary neoplasm that secretes ACTH
Impairment of normal feedback suppression results in continued ACTH secretion despite high levels of cortisol

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CS due to Ectopic ACTH secretion:

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Non-pituitary neoplasms may secrete ACTH
Cortisol production suppresses pituitary ACTH production but not the ectopic ACTH production

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Ectopic ACTH Syndromes:

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Small-cell lung carcinoma
Bronchial carcinoid tumors
Pancreatic islet cell tumors
Medullary thyroid carcinoma
Pheochromocytoma
Carcinoma of the liver, prostate, breast and melanoma
*all rare

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Using ACTH in the diagnostic algorithm:

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The problem of ACTH-dependent CS:

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Imaging is not reliable
Pituitary MRI is normal in up to 50% patients with ACTH-secreting pituitary adenoma
10% of general population will have incidental pituitary tumor on MRI

Biochemical testing
High-dose dexamethasone test
CRH stimulation test

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Discuss the usefulness of the HDDST:

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Describe uses of the CRH test:

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ACTH-secreting pituitary adenomas remain responsive to CRH

Most ectopic ACTH-producing tumors are not responsive

Therefore can also be used to distinguish between ACTH-dependent causes of Cushing’s syndrome

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Describe the purpose of Inferior Petrosal Sinus Sampling:

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Last resort!

Used to establish if pituitary is source of ACTH

Frequently needed because of the ambiguous nature of imaging and biochemical testing in ACTH-dependent CS

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Management of Cushing’s Syndrome due to ACTH-secreting pituitary ademoma (aka Cushing’s disease):

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1st line: Neurosurgical resection of the pituitary tumor

If not curative--
Pituitary irradiation
Antiadrenal agents
Bilateral adrenalectomy

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Pituitary irradiation for Cushing’s disease:

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Used in patients with persistent disease activity after surgery

May take many years to be effective

Often results in deficiencies of other hormonal axes

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Antiadrenal agents:

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*generally inhibit one or more enzymes in the steroid biosynthetic pathway
-examples are ketoconazole, mifepristone

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Bilateral adrenalectomy for Cushing’s disease:

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Definitive

Patients need lifelong GC and MC replacement (i.e. they now have adrenal insufficiency)

Leads to Nelson’s syndrome
-Lack of feedback from high levels of GC results in aggressive growth of the remaining ACTH-secreting pituitary adenoma
-Very high levels of ACTH cause hyperpigmentation (see discussion of adrenal insufficiency)

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Management of Cushing’s Syndrome due to cortisol-secreting adrenal adenoma

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Surgery is curative

yay!!!!

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Management of Cushing’s Syndrome due to  adrenal carcinoma

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Surgery (usually not curative)

Antiadrenal agents

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Mitotane:

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Cousin of the insecticide DDT
Inhibits multiple steroidogenic enzymes
Cytotoxic to adrenocortical cells
Treatment of choice for adrenal cancer
Severe side effects (GI, neurologic)
Treatment dose limited by side effects

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Management of Cushing’s Syndrome due to the ectopic ACTH syndrome:

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Treatment of primary tumor (surgery, chemotherapy)
Antiadrenal agents
Bilateral adrenalectomy

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Pseudo-Cushing’s syndrome:

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Presence of some or all of the clinical features of Cushings syndrome together with some evidence for hypercortisolism

Alcoholism
Depression
Eating disorders
Chronic pain