Adrenal disorders pt I Flashcards
what are the 2 distinct tissues of the adrenal glands
- cortex
- medula
the adrenal gland is enclosed by connective tissue known as the ___
capsule
what are the 3 zones of the cortex
zona …
1. glomerulosa
2. fasciculata
3. reticularis
(GFR)
which zone of the cortex secrets mineralocorticoids, primarily aldosterone
glomerulosa (outer)
GMA - Glomerulosa, Mineralocorticoids, Aldosterone
what hormone regulates bp and electrolyte balance by the RAAS
aldosterone
sodium retention
water retention
potassium excretion
increases bp and blood volume
if there is excess aldosterone, what happens to the renin?
decreases
if there is an aldosterone deficiency, what happens to the renin
increases
which zone of the adrenal cortex secretes glucocorticoids, primarily cortisol?
zona fasciculata (middle)
FGC - Fasciculata, Glucocorticoids, Cortisol
increased cortisol release during stress via ?
ACTH stimulation (from the pituitary)
functions of the zona fasciculata (middle)
- gluconeogenesis in liver
- utilizes (decreases) protein stores - immune system suppression
- ↓ eosinophil, lymphocytes and lymph tissue - decreases inflammation
functions of the HPA axis
- controls glucocorticoid release
- Release occurs in a circadian rhythm, after meals and in response to endogenous and exogenous stressors
- Cortisol provides a negative feedback
describe the steps of the HPA axis
- hypothalamus releases corticotropin-releasing hormone (CRH).
- CRH binds to the anterior pituitary gland = adrenocorticotropic hormone (ACTH) releases
- ACTH binds to receptors on the adrenal cortex and stimulates adrenal release of cortisol
- Cortisol exerts negative feedback to the hypothalamic release of CRH and the pituitary release of ACTH (negative feedback).
Cortisol levels are highest during when (time) of the circadian rhythm cycle?
morning
lowest - PM
which zone of the adrenal cortex secretes gonadocorticoids, primarily dehydroepiandrosterone (DHEA)
zona reticularis (inner)
what hormone converts sex steroids in gonads
stimulates, controls, and maintains the development of sex characterstics
DHEA
RGD - Reticularis, Gonadocorticoids, DHEA
what part of the adrenal gland is composed of chromaffin cells
secretes epinephrine and norepinephrine aka our fight-or-flight response?
medulla
how would a destruction of the adrenal glands affect ACTH and CRH levels?
chronic increase
what hormone stimulates adrenal cells to begin steroid synthesis
ACTH
what does the adrenal cells require in order to synthesize steroid hormones?
cholesterol
what hormone is an important source of estrogen in the body
DHEA
what are the 2 adrenal disorders
cushing’s
adrenal insufficiency
if there is an adrenal gland dysfunction:
what happens to the hormones released?
what type of adrenal insufficiency is it?
↓cortisol/aldosterone
primary
if there is pituitary gland dysfunction:
what happens to the hormones released?
what type of adrenal insufficiency
↓ ACTH, ↓ cortisol
secondary
if there is a hypothalamic dysfunction:
what happens to the hormones released?
what type of adrenal insufficiency
↓ CRH
↓ ACTH
↓ cortisol
Tertiary
a destruction/dysfunction of the adrenal cortex resulting in insufficient production of glucocorticoids and mineralocorticoids.
what disease?
Addison’s Disease
Addison’s disease is MC cause by ?
autoimmune (80% in US)
- CYP21A2 (21-hydroxylase) - MC
- CYP11A1 (side-chain cleavage enzyme)
- CYP17 (17-alpha-hydroxylase)
describe the etiology of autoimmune Addison’s disease?
- adrenal function decreases over several years as it progresses to overt adrenal insufficiency
- presents between 2nd and 5th decade (10-40 y/o)
autoimmune = MC!
genetic disorder resulting in accumulation of very long-chain fatty acids in the adrenal cortex inhibiting the effects of ACTH on the adrenocortical cells
Adrenoleukodystrophy
genetic mutation or absence of adrenal cortex
Congenital adrenal insufficiency/hyperplasia
Causes of Addison’s disease
- autoimmune
- Adrenoleukodystrophy
- Congenital adrenal insufficiency/hyperplasia
- Infection - rare etiology
- MC - TB - Drugs
- Adrenal hemorrhage
- Adrenal “addisonian” Crisis
what drug is known to inhibit cortisol biosynthesis
ketoconazole - inhibits adrenal cytochrome P450
what drugs accelerate the metabolism of cortisol
phenytoin, barbiturates, rifampin
what adrenocorticolytic drug diminishes cortisol synthesis
mitotane - blocks steroid biosynthesis - used to treat adrenocortical carcinoma
what type of drug suppresses the CRH or ACTH production
glucocorticoids
what can cause adrenal hemorrhage
results from sepsis, heparin-induced thrombocytopenia, anticoagulation, antiphospholipid antibody syndrome, trauma, surgery
emergent condition resulting from insufficient cortisol
caused by a physical or emotional stressor in an Addison’s disease patient
Ex: infection, trauma, surgery, emotional turmoil
Adrenal “addisonian” Crisis
what is often the first and only symptom for years in Addison’s disease?
Skin and mucosal hyperpigmentation
prominent on:
- sun-exposed skin
- extensor surfaces
- palmar creases, nail beds
- mucosal membranes
what is the chronic presentation of Addison’s that results with patchy hypopigmentation
vitiligo
result of autoimmune destruction of dermal melanocytes
Chronic presentation of Addison’s
- First symptoms: anorexia, wt loss, fatigue, ↓ stamina
- Hypotension, dehydration, orthostatic lightheadedness
- Hypoglycemia, weakness
- Fevers, lymphoid tissue hyperplasia
- Abd pain, N/V/D
- Change in axillary, pubic and body hair
- generalized pain
- muscles, joints, chest, abdomen, back, legs, headache - psychiatric
- anxiety, irritability, depression - neurologic
- gait disturbance, cognitive dysfunction → coma - amenorrhea
if a pt comes in with a sudden onset of:
- 105℉
- severe abdominal pain, N/V
confusion
- hypotensive shock
what are they experiencing?
adrenal crisis
how is adrenal hemorrhage presented differently than adrenal crisis?
w/o fever
work up for Addison’s disease
- CBC
- eosinophilia, lymphocytosis - CMP
- hyponatremia, hyperkalemia
- ↑ BUN/Cr - results from dehydration
- hypoglycemia if fasting or may occur spontaneously - Cx - blood, sputum, urine
- Plasma Cortisol
- 8 AM: < 3 mcg/dL = diagnostic if accompanied by elevated ACTH
- Random cortisol > 25 mcg/dL = rules out Addison’s - Plasma ACTH
> 200 pg/mL (7-63 pg/mL - normal value 7-10 AM) - Rapid ACTH stimulation Test
- Utilized when serum cortisol and serum ACTH are non-diagnostic - Plasma renin
- multiple interfering factors tho - CXR
- if suspecting signs of TB (etiology) or pneumonia (precipitating crisis etiology)
CT abdomen - adrenal findings vary.
- vomiting/diarrhea may mask hyperkalemia
- use random cortisol in emergency setting
during rapid ACTH stimulation test, what serum lvl would be indicative of Addison’s
rise in serum cortisol < 20 mcg/dL
Normal = rise in serum cortisol ≥ 20 mcg/dL
- a rise could also indicated a secondary/tertiary etiology
factors to consider for Rapid ACTH stimulation test
- Hold hydrocortisone for 24 hours prior to test
- LA glucocorticoid (dexamethasone) - switch to SA (hydrocortisone) days prior to testing - Cost: must be performed in hospital setting
- Utilized when serum cortisol and serum ACTH are non-diagnostic
- SE: nausea, HA, dizziness, dyspnea, palpitations, flushing edema, local site reaction
what are the steps of administering the rapid ACTH stimulation test
Step 1: Measure serum cortisol
Step 2: Administer Cosyntropin (synthetic ACTH) 0.25 mg given IM
Step 3: Measure serum cortisol 45 minutes post injection
what happens to plasma renin [PRA] levels in Addison’s
increased due to diminished aldosterone resulting depleted intravascular volume
indicates need for mineralocorticoid replacement
during CT of abdomen you see small w/o calcifications, what is the etiology of Addison’s
autoimmune
during a CT of the abdomen it shows its enlarged, what is the etiology of Addison’s?
TB, fungal, adrenal hemorrhage, metastatic
during a CT of the abdomen it shows calcifications, what is the etiology of Addison’s?
TB, fungal, adrenal hemorrhage, pheochromocytoma, melanoma
baseline therapy for addison’s
Oral Glucocorticoids
1. Hydrocortisone 15-30 mg daily
- has both glucocorticoid and mineralocorticoid (at higher doses) effects
- ⅔ dose in morning and ⅓ dose in late afternoon/early evening
2. Alternatives
- Prednisone or methylprednisolone
- ⅔ am and ⅓ pm
what is the tx for chronic addison’s
Glucocorticoid Stress therapy
1. increase dose of steroid by up to 50%
2. Stressors: infection, surgery, trauma, pregnancy (3rd trimester), labor, stressful diagnostic procedures, severe emotional stress
3. Increase dosage based on severity of stress and symptoms
4. Return dose to baseline upon resolution of stressor
Mineralocorticoid therapy
1. Higher “stress” doses of glucocorticoids (> 100 mg/d of hydrocortisone) will supply sufficient mineralocorticoid activity
2. Lower maintenance glucocorticoid doses require mineralocorticoid supplementation
- Fludrocortisone 0.05 - 0.3 mg daily or every other day
— higher doses needed for orthostatic hypotension, hyponatremia, hyperkalemia
— monitor with PRA
+ oral Glucocorticoids
if a pt is taking fludrocortisone and their PRA is increased, what is the next step?
increase dosage
tx for acute adrenal crisis
- no previous dx = order serum cortisol and ACTH, start treatment anyways
- Hydrocortisone
- Step 1: Loading dose - IV hydrocortisone 100-300 mg in NS
- Step 2: IV hydrocortisone 50-100 mg q6h x 24 hours then tapered based upon patient condition
- Step 3: switch to oral hydrocortisone once pt can tolerate PO
— oral dose 10-20 mg q6h then reduce to maintenance levels - broad-spectrum abx
- adjust accordingly based upon cultures - treat all electrolyte/glucose/volume abnormalities
monitoring/management for addison’s
- Symptom resolution w/o development of Cushing syndrome
- WBC diff, electrolytes and renal function should return to normal
- DEXA scan: screen for osteoporosis
- increased risk due to chronic steroid use - Referral
- Endocrinologist should be involved in both acute and chronic disease management
pt education for addison’s
- Medical alert bracelet
- “Adrenal insufficiency - takes hydrocortisone” - All infections must be treated immediately
- Consider providing patient with injectable hydrocortisone
a condition that results from an excessive amount of systemic cortisol
Cushing’s Syndrome/Disease
difference between cushing’s syndrome and disease
syndrome
- manifestations of excessive corticosteroids
- other spontaneous production of corticosteroids by the adrenal gland
disease - manifestations of excessive corticosteroids due to hypersecretion of ACTH
MC cause of cushing’s disease is ?
benign anterior pituitary adenoma
females > male
causes of ACTH independent (aka Cushing Syndrome)
- Iatrogenic or factitious Cushing’s syndrome
- MC - exogenous steroids - Adrenocortical adenomas and carcinomas
etiology of ACTH Dependent (aka Cushing Disease)
manifestations of excessive corticosteroids due to hypersecretion of ACTH
1. Cushing’s disease
- pituitary hypersecretion of ACTH
2. Ectopic secretion of ACTH
- non-pituitary tumor - MC locations lungs, thymus, pancreas
3. Ectopic secretion of CRH
- non-hypothalamic tumors causing pituitary hypersecretion of ACTH - rare < 1 %
4. Iatrogenic/factitious Cushing’s syndrome
- due to administration of exogenous ACTH – rare <1%
presentation of cushing’s
- fatigue, reduced physical endurance
- often first & long lasting symptom - Weight gain
- central obesity with thin extremities
- plethoric “moon face”
- supraclavicular fat pads
- “buffalo hump” - skin atrophy with large purple striae
- easy bruisability
- proximal muscle weakness
- immune system suppression
- frequent infections
- menstrual irregularities
- Additional s/s associated with increased ACTH
- hyperpigmentation
- elevated BP
- hirsutism, male pattern hair loss
work up for cushing’s syndrome/disease
- CBC
- leukocytosis - neutrophilia, lymphocytopenia, ↓ eosinophils - CMP
- ↑ glucose
- +/- hypernatremia, hypokalemia - Establish presence of hypercortisolism
- 3 first line testing options - 2 positive tests = diagnosis
— Dexamethasone Suppression Test
— 24 Urine Free Cortisol (2 measurements)
— Late night salivary cortisol (2 measurements)
what are the diagnostic workup goals for cushing’s syndrome/disease
- Determine exogenous vs endogenous etiology
- Establish presence of hypercortisolism
- Determining cause for hypercortisolism
what is the Low-dose Dexamethasone Suppression Test
- dexamethasone 1 mg PO at 11 PM
- serum cortisol next morning at 8 AM
- Results - < 5 mcg/dL likely excludes Cushing’s syndrome
- 3% false-negative rate
— 8% Cushing disease have normal suppression of cortisol
antiseizure drugs, rifampin and estrogens diminish suppressibility
- 20-30% false-positive rate
— psychiatric disorders, emotional/physical stress
what is the 24 Hour Urine Free Cortisol test
- begin collection AFTER first morning void
- document time
- collect ALL urine thereafter until 24 hours is reached, include first morning void of the next day (end of 24 hours)
Positive test - elevated urine cortisol 3x upper limit of normal on both occasions
- normal values vary based upon age and sex
what is the Late night salivary cortisol (Salivette)
- collected by patient between 11 pm and midnight
- specimen stable at room temp for days
- Interfering factors: steroid use, brushed teeth, oral intake, inadequate collection - Normal at 11 p.m.-midnight: <100 ng/dL
- factors that elevate levels: erratic sleep schedules or shift work, pregnancy, exogenous steroid/estrogen use, anticonvulsants, mental illness,
chronic alcohol use, acute stress (hospitalization/surgery) - perform on 2 separate occasions
- both tests must yield an abnormal result (elevated cortisol) = positive test
what is the diagnostic testing interpretation for cushing’s syndrome/disease?
-
2 first line test with negative results
- low suspicion = monitor
- high suspicion = refer to endocrinologist -
1 out of the 2 tests are positive
- if saliva or 24-UFC is not confirmatory = repeat test at random intervals
- consider cyclic Cushing Disease as dx
— MC etiology - ACTH-secreting pituitary adenoma
- refer to endocrinologist -
both test are positive
- refer to endocrinologist for evaluation of underlying etiology
determining the cause for hypercortisolism
-
Serum ACTH
- differentiate ACTH-dependent vs. ACTH-independent etiology
- ensure proper collection
— preferred collection between 6-9 AM
— collected in EDTA tube - on ice, spun soon after collection, and stored at -20°C (-4°F) until assay
- interpretation
— < 20 pg/dL order adrenal CT
— > 20 pg/dL order pituitary MRI
red flags for malignant carcinoma of adrenal gland?
- > 4 cm (40 mm)
- growth of nodule (requires previous CT for comparison)
- density of lesion is > 10 Hounsfield units (HU)
- Hounsfield unit is a quantitative scale for describing radiodensity of an object.
- Air has a hounsfield unit of -1000; water has a hounsfield unit of 0.
imaging for cushing’s what are you looking at?
- CT - adrenal gland - benign vs malignant etiology
- MRI w/ contrast - pituitary gland
- Search for ectopic source if indicated
- CT scan of chest/abdomen, if negative perform whole body PET scan
From the pituitary gland a sample of the inferior petrosal sinus was taken showing elevated ACTH lvls, what does this indicate?
pituitary Cushing’s disease
from the pituitary gland a sample of the inferior petrosal sinus was taken showing normal ACTH lvls, what is the next step?
look for ectopic source of ACTH
during the MRI w/ contrast of the pituitary gland you find no lesions, what is the next step?
need inferior petrosal sinus sampling
(no lesions or lesion < 5mm)
what type of interpretation is needed to begin tx from a MRI w/ contrast of the pituitary gland?
a lesion >5 mm
management for Cushing’s syndrome (exogenous)
- Slowly titrate down glucocorticoid/ACTH therapy
-
Adrenal adenoma/carcinoma, pituitary adenoma, ectopic ACTH-secreting tumor
- surgical removal - post surgical adrenal insufficiency will require lifelong glucocorticoid replacement
- pituitary radiation
prolonged therapy can suppress the HPA axis; rapid withdrawal can result in ?
acute adrenal insufficiency
HPA axis is usually fully recovered within 6-12 months
what is the drug of choice to help with recovery of HPA axis
hydrocortisone - short acting glucocorticoid
indications for medical management for cushing’s syndrome/disease
surgical decline/contraindication or awaiting surgery
what medications are used for hypercortisolism during medical management for cushing’s syndrome/disease
-
11β-hydroxylase inhibitors - blocking cortisol steroidogenesis
- Rx: metyrapone and osilodrostat - ketoconazole - inhibits the early steps of steroidogenesis
what medication is used for a pituitary ACTH tumor
pasireotide (Signifor)
- somatostatin analog
- inhibits ACTH secretion
what is the DOC for Mineralocorticoid HTN
- Mineralocorticoid receptor antagonist (aka K+ sparing diuretic)
- spironolactone, eplerenone - ACEI (second line)
what is the DOC for Hyperandrogenism seen in women?
flutamide
- antiandrogen agent
- inhibits androgen uptake and/or inhibits binding of androgen in target tissues
cortisol related complications from cushing’s
- osteoporosis
- cardiovascular disease
- psychiatric disorders
- insomnia, depression, and memory loss - diabetes mellitus
- hypokalemia
- muscle weakness
- infections
- sleep apnea
