Adrenal insufficiency and cushings

Question 1

Cortisol- cortisone shuttle

Answer 1

if cortisol is high enough it can surpass 11 b HSD (making it to cortisone) and can bind to mineralocorticoid receptors and act like aldosterone

Cortisone is activated to cortisol in the liver

Question 2

Adrenal insufficiency

Answer 2

Hypothalamus makes CRH which activates Pituitary to make ACTH which stimulates adrenals to make aldoserone (more stimulated by RAAS) and cortisol

happens in a diurnal way- moring

in primary adrenal insufficiency there is something wrong with the adrenals so they dont respond to ACTH

in secondary adrenal insufficiency the pituitary goes awry and doesnt make ACTH

In tertiary adrenal insufficiecny the hypothalamus doesnt make CRH

Question 3

Clinical presentation of adrenal insufficiency

Answer 3

Signs and symptoms- fatigue, malaise, lack of energy, GI (nausea, vomiting, anorexia–> wt loss), hypotension–> dizziness, orthostasis, increased skin pigmentation, salt craving (primary)

Lab abnormalities (hyponatremia- vasopressin, hyperkalemia, hypercalcemia, hypoglycemia, lymphocytosis)

Imaging abnormailty (bilateral adrenal enlargement, pituitary mass)

Concurrent med problems- severe critical illness with hypotension, pituitary disease, traumatic brain injury, brain radiation

Drug: withdrawal from corticosteroids (oral, inhaled, topical, parenteral), narctoics (suppress CRH/ACTH, common cause of adrenal tertiary insufficiency), Adrenostatic/lytic (ketoconazole, metyrapone, etomidate, mitotane), Glucocorticoid receptor antagonist (mifeprestone)

Genetic: Congental adrenal hyperplasia, adrenoleukodystrophy

Question 4

Adrenal Insufficiency diagnosis

Answer 4

Plasma cortisol 30-60 mins after cosvntropin IM or IV, CBC, serum sodium, potassium, creatinin, urea, TSH

Cosyntropin stimulation test evaluates maximum adrenocortical secretory capacity and tests for adrenal destruction (primary adrenal insufficiency) or adrenal atrophy (secondary adrenal insufficiency)

Question 5

Adrenal insufficiency differential diagnosis

Answer 5

Primary adrenal insufficiency (High ACTH, high PRA, low aldosterone), glucocorticoid and mineralocorticoid replacement–> Adrenal P450c21 (antibodies) can be due to autoimmune adrenalitis, autoimmune polyglandular syndrome. Chest X ray, in men plasma VLCFA, adrenal CT
Tb, infiltration, CAH, autoimmune

Plasma ACTH and PRA are increased in primary AI because of loss of cortisol and indirect aldosterone negative feedback

Question 6

changes in plasma binding proteins

Answer 6

Medications such as estrogen (OCP) and pregnancy will cause over time a significant increase in total cortisol levels in the blood that reflect an increase in CBG rather than an alteration of adrenal function

Question 7

Causes of primary adrenal insufficiency

Answer 7

Autoimmune: Autoimmune polyglandular syndromes
Malignancy: Metastatic lung, breast, melanoma, GI or primary adrenal lymphome
Adrenal hemorrhage (bilateral): Associated with coagulapathies (anticoagulation therapu, antiphospholipid syndrome, heparin- induced thrombocytopenia and usuaally due to bilateral adrenal vein thrombosis

Infectious (TB, Fungi- histo, coccoidios, HIV)

Genetic (Congenital Adrenal hyperplasia, familial glucocorticoid deficiency, adrenoleukodystrophy)

Infiltatrive disrorders (amyloidosis, hemochromatosis), Drugs (Ketoconazole, metyrapone, mitotane, etomidate)

Question 8

Causes of secondary adrenal insufficiency

Answer 8

withdrawal from exogenous corticosteroid therapy : dose/duration dependent, but variable from patient to patient, physiologic correlation: The adrenals are atrophied due to negative feedback inhibition of ACTH

Pituitary/ hypothalamic disease, especially hypophysitis (autoimmune, granulomatosis, drug induced (checkpoint inhibitors) may cause isolated ACTH deficiency

Question 9

Treatment for primary adrenal insufficiency

Answer 9

Chronic: endogenous cortisol production rate is only 8-12 mg/day

Hydrocortisone (authentic cortisol)- 10-15 mg in AM and 5-10 mg in the afternoon, monitor sense of well being, plasma ACTH should remain elevated even with adequate hydrocortisone (low/normal levels may reflect over-replacement), Injectable hydrocortisone (solu-cortef) should be available for emergency use

Fludrocortisone daily (aldosterone analog, monitor electrolyte composition, plasma renin activity

Question 10

Acute adrenal crisis and steroid coverage for surgery

Answer 10

IV hydrocortisone at high dose, then taper it

Common problem: 5-10 % of patients with AI have an episode of adrenal crisis anually

Question 11

Treatment for secondary Adrenal insufficiency

Answer 11

hydrocortisone saily in divided doses, lower doses needed than in primary (there is still some cortisol secretion from the adrenals), mineralocorticoids replacement NOT needed since RAAS system and zona glomerulosa remain intact

Principles of sick day management, adrenal crisis, and surgical steroid coverage still all apply

Question 12

Cushings syndrome

Answer 12

ACTH dependent hypercortisolism

Weight gain, facial fullness, increased supraclavicular fat, diabetes, osteoporosis, increased BP, myopathy, neuropsych disorders, edema, hypogonadism, androgen excess

Adrenal dependend hypercortisolism: intermittent cortisl excess, hypertension, hyperglycemia, metabolic syndrome, osteoporosis, vertebral compression, very long durration
Contralateral adrenal is usually atrophied due to negative feedback inhibition of ACTH duue to autonomous cortisol secretion from the adenoma

physiological hypercortisolism: stress alcohol, neuropsych disorders, satrvation

Question 13

Signs and symptoms of cushings

Answer 13

Wt gain (unexplained) in trunkal distribution, increased supraclavicular and dorsocervical fat accumulation

Facial rounding and plethora, proximal muscle weakness, hirsutism/androgen excess in women, wide violaceous striae, cutaneous wasting, easy bruising, neuropsychiatric problems, cognitive difficulty, deprssion, psychosis, growth retardation

Question 14

Diagnostic Tests for cushing syndrome

Answer 14

late night salivary cortisol: measurment of salivary cortisol (reflection of biologically active free cortisol) is performed around 11 pm to midnight, provides very sensitive and specific for the presence or absence of Cushing syndrome

Overnight low dose (1 mg)- dexa methasone suppression test: simple sensitive test for cushing: you give dexamethasone orally at 11 pm with a measurement of cortisol the following morning, normal suppression= cortisol low, particularly sensitive in patients with adrenal nodules but there are many false positives limiting specfiicty

24 hour urine free cortisol, reflects daily cortisol section poor sensitivity should probably not be used as an initial screening test

Question 15

Causes of cushing syndrome

Answer 15

ACTH dependent: Escess ACTH despite glucocorticoid negative feedback, ACTH secreting pituitary tumor (Cushings disease), Non pituitary ACTH secreting tumor (ectopic ACTH)

ACTH independent (primary increase in glucocorticoid activity with suppressed ACTH due to negative feedback), exogenous glucocorticoid therapy (oral, intra articular, dermal or inhaled, most common cause of cushings, Adrenal adenoma or carcinoma, nodular adrenal hyperplasia

Question 16

Cushings syndrome Differential diagnosis

Answer 16

Measure Plasma ACTH,
If ACTH is low- indepenent cushings, Adrenal CT
If ACTH is normal or elecated- dependent, MRI the pituitary

if abnormal?–> cushings
if normal - > bilateral petrosal sinus sample ACTH with CRH addmin- no pituitary gradient for ACTH–> Occult ectopic ACTH

If really high significat gradient of ActH–> sushings

Question 17

Treatment of cushing syndrome

Answer 17

the best treatment for cushing is always dependnet of the accurate differential diagnosis

surgery- remove the offending tumor (pituitary/ adrenal)

pituitary surgery has 70-85% remission rate with experienced surgeons but 10-20% recurrence rate over 10 yrs
Laproscopic adrenal surgery in patients with benign adrenal tumors has high success rate

bilateral adrenalectomy- indicated in pts who have failed other modalities of treatment, definitive treatment but confers decreased QOL issues associated with life long dependence on steroid support, also concern with re growth of pituitary tumor as a loss of GC neg feedback –> nelsons syndrome

Question 18

treatment of cushings

Answer 18

Radiotherapy- used in pituitary cushings as adjunctive therapy after failed surgery, modest sucess rates in inudcing a remission of hypercortisolism and there is a high incidence of hypopituitarism within 5-10 yrs after pituitary radiation- not inde=icated for adrenal cushing

Pituitary directed- pasireotide (SST receptor agonis), Cabergoline (dopamine receptor agonisit)

Adrenal steroidogenisi inhibitors: Ketoconazole, metyrapone, mitotane, etomidate, mifepresone