Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
342 Cards in this Set
- Front
- Back
|
ADRENAL - WHITLEY - WEDNESDAY JAN 31
|
|
|
|
|
|
|
|
what are the three functional zones of the adrenal cortex, from the outside in?
|
1) glomerulosa; 2) fasciculata; 3) reticularis
|
|
|
what does the zona glomerulosa secrete?
|
mineralocorticoids
|
|
|
what about the zona fasciculata?
|
glucocorticoids
|
|
|
what does the zona reticularis secrete (2)?
|
1) sex steroids; 2) glucocorticoids
|
|
|
what are the three major classes of cortical steroids, and what is the main example of each?
|
1) glucocorticoids - cortisol; 2) mineralocorticoids - aldosterone; 3) androgens/estrogens - DHEA
|
|
|
what are the four types of endocrine lab tests?
|
1) blood; 2) saliva; 3) urine; 4) dynamic tests of hormone reserve/regulation
|
|
|
in what forms can circulating cortisol be (3) and what % is each?
|
1) bound to CBG (cortisol binding globulin) - 80%; 2) bound to albumin - 15%; 3) free - 5%
|
|
|
what are three classes of diseases of the adrenal cortex?
|
1) cortical hyperfunction; 2) cortical hypofunction; 3) nonfunctional cortical neoplasms
|
|
|
what are three diseases caused by cortical hyperfunction?
|
1) Cushing's; 2) hyperaldosteronism; 3) congenital adrenal hyperplasia
|
|
|
what disease was mentioned to occur in the adrenal medulla?
|
pheochromocytomas
|
|
|
|
|
|
|
CUSHING'S SYNDROME
|
|
|
|
|
|
|
|
what is Cushing's syndrome due to?
|
prolonged cortisol excess (hypercortisolism)
|
|
|
in what four settings can Cushing's syndrome arise?
|
1) exogenous glucocorticoid therapy; 2) pituitary hypersecretion of ACTH; 3) ectopic ACTH or CRH production by nonpituitary neoplasms; 4) hypersecretion of cortisol by autonomous adrenal adenoma, carcinoma, or nodular hyperplasia
|
|
|
which of these settings is known as Cushing's disease?
|
pituitary hypersecretion of ACTH
|
|
|
what is Pseudo-Cushing's syndrome?
|
temporary cortisol excess
|
|
|
what conditions can cause Pseudo-Cushing's syndrome (6 examples)?
|
1) depression; 2) alcoholism; 3) eating disorders; 4) severe obesity; 5) severe stress; 6) acute illness
|
|
|
what should be done to correct Pseudo-Cushing's syndrome?
|
treat underlying condition
|
|
|
how can the shape of the body change in Cushing's syndrome (4)?
|
1) central obesity; 2) supraclavicular fat pads; 3) buffalo hump; 4) facial plethora/moon facies
|
|
|
what can be seen on the face (3)?
|
1) hirsutism; 2) oily skin; 3) acne
|
|
|
what problems occur in the cardiovascular system (2)?
|
1) hypertension; 2) cardiovascular disease
|
|
|
what problem will occur in Cushing's only if there is excess ACTH?
|
hyperpigmentation
|
|
|
what problems will occur in the skin?
|
1) thin skin; 2) pigmented striae; 3) easy bruising
|
|
|
what problems will occur in the reproductive system (2)?
|
1) menstrual abnormalities; 2) gonadal dysfunction
|
|
|
what will happen to bones?
|
osteoporosis, fractures
|
|
|
what will happen to metabolism?
|
glucose intolerance
|
|
|
what other problems will occur in Cushing's (2)?
|
1) neuropsychiatric; 2) increased incidence of infection
|
|
|
|
|
|
|
PATHOGENESIS - CUSHING'S SYNDROME
|
|
|
|
|
|
|
|
what is the most common source of exogenous glucocorticoid administration that causes Cushing's?
|
prescribed prednisone
|
|
|
what happens to ACTH secretion in this situation?
|
it is inhibited
|
|
|
what do the adrenals look like when there is exogenous glucocorticoid administration?
|
small/shrunken - barely visible rim of cortex surrounds medulla
|
|
|
what two zones of cortex are primarily affected?
|
inner two zones of cortex - fasciculata and reticularis
|
|
|
why is the zona glomerulosa not affected by exogenous glucocorticoid administration?
|
it secretes aldosterone, and is not ACTH-dependent
|
|
|
what is the most common cause of endogenous Cushing's syndrome, and what % of cases does it account for?
|
pituitary Cushing's disease - 60-80% of cases
|
|
|
what is the most common type of tumor in the pituitary (number, malignant/benign, staining property)?
|
single benign basophilic pituitary microadinoma
|
|
|
what does this tumor secrete?
|
ACTH
|
|
|
in what % of cases is no pituitary adenoma found?
|
about 15%
|
|
|
what happens to the adrenals in response to ACTH?
|
they undergo diffuse bilateral hyperplasia
|
|
|
what may or may not be present in the adrenals?
|
areas of nodularity
|
|
|
what does the cortex look like in this situation, and why?
|
cortex is diffusely thickened and yellow, due to an increase in the size and number of lipid-rich cells in the fasciculata and reticularis
|
|
|
in what age and sex is this most common?
|
five times more common in females than males, usually during twenties and thirties
|
|
|
what % of cases of endogenous syndrome arise from ectopic ACTH syndrome?
|
about 10%
|
|
|
what different tumors may secrete ACTH (7)?
|
1) small cell carcinoma of lung; 2) bronchial carcinoid; 3) pancreatic carcinoid; 4) malignant thymoma; 5) pheochromocytoma; 6) medullary thyroid carcinoma; 7) gastrinomas
|
|
|
in response to ectopic ACTH, what happens to adrenals?
|
they undergo diffuse bilateral hyperplasia
|
|
|
what may cut short adrenal enlargement?
|
rapid downhill course of patient
|
|
|
in what sex and age is ectopic ACTH secretion more common?
|
in men, fourth or fifth decades
|
|
|
what % of endogenous Cushing's occur from adrenal neoplasm?
|
10-20%
|
|
|
in children, do adenomas or carcinomas predominate?
|
carcinomas
|
|
|
in adults, do adenomas or carcinomas predominate?
|
equally common
|
|
|
what happens to ACTH secretion in this situation, and why?
|
increased secretion of cortisol by tumor suppresses CRH synthesis and pituitary ACTH secretion
|
|
|
with a unilateral neoplasm, what happens to the adjacent uninvolved cortex, and what happens to the contralateral adrenal cortex?
|
both undergo atrophy
|
|
|
how large are most adenomas, and how large are most carcinomas?
|
most adenomas weight <30g, most carcinomas are >200g
|
|
|
do adenomas or carcinomas show areas of necrosis, hemorrhage, anaplasia, and high mitotic activity?
|
carcinomas
|
|
|
what else are carcinomas often associated with?
|
virilism
|
|
|
what do these carcinomas have a strong tendency to invade (3)?
|
1) adrenal vein; 2) vena cava; 3) lymphatics
|
|
|
where do carcinomas often metastasize (2)?
|
1) renal nodes; 2) periaortic nodes
|
|
|
|
|
|
|
DETECTION/DIAGNOSIS - CUSHING'S SYNDROME
|
|
|
|
|
|
|
|
what is the most direct and reliable index of cortisol secretion?
|
elevated 24-hour urinary free cortisol
|
|
|
what levels of cortisol in the 24-hour urinary free cortisol indicate that Cushing's syndrome should be assumed?
|
if basal level >3 times upper limit of normal
|
|
|
what change occurs in Cushing's syndrome as far as the timing of cortisol secretion?
|
loss of diurnal rhythm
|
|
|
at what time of day does cortisol level have no diagnostic value unless clearly above the range?
|
morning cortisol
|
|
|
what is elevated late evening cortisol useful for?
|
it is a sensitive and efficient method to confirm or clarify a diagnosis
|
|
|
in what case is a low dose dexamethasone suppression test used?
|
for patients with indeterminate changes in urinary free cortisol or late evening serum/saliva cortisol
|
|
|
what types of low dose dexamethasone suppression tests are there (2)?
|
1) overnight single low dose test; 2) standard multiple low dose test
|
|
|
how sensitive is the overnight single low dose test?
|
95%
|
|
|
what is the rationale of the overnight single low dose test (what is the primary effect, and secondary result)?
|
low dose of dexamethasone, a cortisol analog, suppresses pituitary ACTH secretion (with a consequent fall in adrenal cortisol secretion) in normal subjects, but not in patients with Cushing's syndrome
|
|
|
what is the method of the single low dose dexamethasone test?
|
1mg of dexamethasone is given orally at bedtime - blood is drawn for determination of serum cortisol the next morning
|
|
|
in normal individuals, what will the serum cortisol be after the overnight single low dose test?
|
suppressed to <5 ug/dL
|
|
|
what will levels be like in most patients with Cushing's syndrome?
|
inadequate suppression - cortisol levels will usually be >10 ug/dL
|
|
|
in what other conditions may inadequate suppression be seen (list)?
|
stress, obseity, infection, acute or chronic illness, alcohol abuse, severe depression, oral contraceptives, pregnancy, estrogen therapy, failure to take the dexamethasone, or treatment with phenobarbital and phenytoin (enhancement of dexamethasone metabolism)
|
|
|
what is the purpose of standard multiple low dose test?
|
classical test that confirms Cushing's syndrome
|
|
|
|
|
|
|
DIFFERENTIATION - CUSHING'S SYNDROME
|
|
|
|
|
|
|
|
what test is used to determine whether hypercortisolism is ACTH-dependent (pituitary or nonpituitary ACTH-secreting tumors), or ACTH-independent (adrenal source)?
|
plasma ACTH
|
|
|
what is the reference range for plasma ACTH?
|
9-52 pg/mL
|
|
|
what is plasma ACTH like in pituitary Cushing's disease?
|
20-200 pg/mL
|
|
|
what is the plasma ACTH in ectopic ACTH syndrome?
|
>200 pg/mL
|
|
|
what is the plasma ACTH like in adrenal tumors?
|
low/undetectable
|
|
|
what is a low plasma ACTH concentration in a patient with high serum/saliva cortisol concentration evidence for?
|
ACTH-independent disease
|
|
|
what is the next and final procedure in these patients?
|
CT or MR imaging of the adrenal glands
|
|
|
what noninvasive test is used to identify the majority of patients with pituitary ACTH-dependent Cushing's disease?
|
high dose dexamethasone test
|
|
|
what types of high dose dexamethasone suppression tests are there (2)?
|
1) standard multiple high dose test; 2) overnight high dose test
|
|
|
what is the rationale for the standard multiple high dose test?
|
ACTH secretion in pituitary Cushing's disease is not completely, but only relatively, resistant to glucocorticoid negative feedback inhibition - large doses of dexamethasone will reduce ACTH secretion by a pituitary tumor, but not ACTH secretion by an autonomous ectopic tumor
|
|
|
in the case of an autonomous ectopic tumor, what is pituitary ACTH secretion like prior to any medication?
|
it is already suppressed, therefore dexamethasone cannot suppress ACTH secretion further, and has no effect on cortisol secretion at any dose
|
|
|
what is the method of the standard multiple high dose test?
|
for four days, collect 24-h urine specimens for free cortisol - give 2mg dexamethasone orally every six hours on days 3 and 4 for a total of 8 doses (16mg)
|
|
|
what % of patients with disease due to an ACTH-producing pituitary adenoma suppress urinary cortisol on day four, and by how much?
|
70% suppress urinary cortisol on day four to <90% of baseline
|
|
|
which patients with Cushing's syndrome due to ectopic production of ACTH will suppress urinary free cortisol?
|
almost none, only exception is bronchial carcinoid - about one-half of patients with ACTH-secreting bronchial carcinoids will suppress urinary free cortisol after a high dose of dexamethasone
|
|
|
if cortisol fails to suppress, what must be done?
|
source of ACTH must be determined
|
|
|
in patients where cortisol secretions fail to suppress, what will 60-70% of them have, and what will the rest have?
|
pituitary Cushing's (remainder will have nonpituitary tumors)
|
|
|
what group of patients are not subjected to the high dose dexamethasone test, and why?
|
patients with primary adrenal disease, because they would have already been identified as having an ACTH-independent Cushing's syndrome
|
|
|
how is the overnight high dose test done, and what are its advantages?
|
a single serum cortisol is collected after giving the patient 8mg dexamethasone at bedtime the previous night - the test is simpler and less expensive than the standard multiple dose test, and exhibits similar sensitivity and specificity
|
|
|
what ttechnique is used to locate elusive ectopic ACTH-secreting tumors?
|
radionuclide scintigraphy
|
|
|
what test may be used as a confirmatory test for differentiating Cushing's disease from ectopic ACTH syndrome?
|
CRH stimulation test
|
|
|
what is the most reliable way to separate pituitary from ectopic causes of Cushing's syndrome?
|
inferior petrosal sinus sampling for ACTH
|
|
|
what is the rationale for inferior petrosal sinus sampling?
|
pituitary venous blood drains into the cavernous sinuses and then into the inferior petrosal venous sinuses - bilateral sampling of ACTH in the inferior petrosal sinuses is used to confirm a pituitary source and to establish the site of excess production
|
|
|
where are blood specimens collected from in this method (3)?
|
1) right IPS; 2) left IPS; 3) forearm vein
|
|
|
what else is done during the test, and why?
|
an IV injection of CRH is given during the test to stimulate an ACTH secretory episode
|
|
|
what result will be obtained in patients with pituitary ACTH-producing adenoma?
|
ratio of IPS to forearm ACTH is greater than 3 to 1
|
|
|
what result is demonstrated in patients with ectopic ACTH syndrome?
|
no gradient
|
|
|
|
|
|
|
CUSHING'S FLOWCHART
|
|
|
|
|
|
|
|
what is the first step in testing for Cushing's syndrome?
|
measure 24-h urinary free cortisol / AM/PM serum or saliva cortisols
|
|
|
what confirms Cushing's syndrome?
|
raised levels - normal levels and rhythm excludes
|
|
|
what can be done if results are intermediate (2)?
|
1) repeat tests; 2) low dose dexamethasone suppression tests
|
|
|
in the low dose dexamethasone test, what confirms Cushing's syndrome, and what excludes it?
|
confirmed by inadequate suppression, suppression excludes Cushing's
|
|
|
what test is performed once Cushing's is confirmed?
|
measure plasma ACTH
|
|
|
what groups of results can be obtained (2) and what does each mean?
|
1) ACTH low/undetectable = ACTH-independent Cushing's; 2) ACTH normal/high = ACTH-dependent Cushing's
|
|
|
which of these results requires another test be done, and what is that test?
|
if ACTH is normal/high, and there is ACTH-dependent Cushing's syndrome, a high dose dexamethasone test is performed
|
|
|
what does suppression mean, and what does inadequate suppression mean?
|
suppression confirms pituitary Cushing's disease, and inadequate suppression means it could still be ectopic or pituitary Cushing's disease
|
|
|
what other tests can be done to confirm (4)?
|
1) inferior petrosal sinus ACTH sampling; 2) CT/MRI imaging; 3) octreotide uptake; 4) CRH stimulation test
|
|
|
|
|
|
|
PRIMARY ALDOSTERONISM
|
|
|
|
|
|
|
|
what are the two main categories of aldosterone excess?
|
1) primary; 2) secondary
|
|
|
what is primary aldosteroneism characterized by?
|
chronic excess aldosterone secretion independent of the renin-angiotensin system
|
|
|
what else is primary aldoestronism known as?
|
low-renin aldosteronism
|
|
|
in what % of hypertensive cases (range) is there primary aldosteronism?
|
0.05-2.2%
|
|
|
what is increase in aldosterone secondary to in secondary aldosteronism?
|
secondary to increased activation of renin-angiotensin system
|
|
|
what are four examples of causes of secondary aldosteronism?
|
1) renal artery stenosis; 2) renin-producing tumor; 3) chronic edematous state; 4) pregnancy
|
|
|
what problems occur as far as electrolyte and acid base balance due to aldosteronism (3)?
|
1) hypokalemia; 2) kaliuresis; 3) metabolic acidosis
|
|
|
what problem can happen in the heart?
|
decompensation
|
|
|
what other major clinical features occur from aldosteronism besides hypertension, increased ECF volume, and those already mentioned (5)?
|
1) weakness; 2) parasthesias; 3) visual disturbances; 4) tetany; 5) headaches
|
|
|
|
|
|
|
ALDOSTERONISM - PATHOGENESIS
|
|
|
|
|
|
|
|
what is the most common pathogenesis of primary aldosteronism, and what % of cases is it?
|
aldosterone-secreting adenoma (Conn's syndrome) in about 80% of cases
|
|
|
what occurs in the other 20% of cases?
|
bilateral idiopathic adrenal hyperplasia
|
|
|
what size is the adenoma in Conn's syndrome, and what does it look like?
|
solitary, small (<2cm) and well circumscribed
|
|
|
what side does it occur more often on?
|
the left
|
|
|
what sex and age do they occur in most?
|
women more than men, third and fourth decades of life
|
|
|
what do aldosterone-secreting adenomas appear like on cut section, what are they composed of, and what do they resemble?
|
surprisingly composed of lipid-laden cortical cells resembling fasciculatata
|
|
|
what are cells like in size and shape, and is anaplasia common?
|
cells tend to be uniform in size and shape - no evidence of anaplasia
|
|
|
what happens to pituitary ACTH secretion?
|
not suppressed
|
|
|
what happens to adjacent adrenal cortex and contralateral adrenal cortex?
|
no atrophy occurs
|
|
|
what is bilateral idiopathic adrenal hyperplasia, and what do cells resemble?
|
diffuse and focal hyperplasia of cells resembling normal glomerulosa cells
|
|
|
what is hyperplasia often shaped like, and where does it extend (from where to where)?
|
often wedge-shaped, often extending from periphery toward center of gland
|
|
|
|
|
|
|
ALDOSTERONISM - DETECTION/DIAGNOSIS
|
|
|
|
|
|
|
|
what specific feature in blood pressure is seen in aldosteronism?
|
diastolic hypertension
|
|
|
what substance's concentration is altered in the serum and urine?
|
potassium
|
|
|
what is serum potassium in aldosteronism?
|
<3.5 mmol/L
|
|
|
what is urine potassium?
|
>30 mEq/day
|
|
|
what hormone has low activity in the plasma?
|
renin
|
|
|
what test is used to provide a stimulus to increase plasma renin production?
|
furosemide, a potent diuretic
|
|
|
what is the method, and what must the patient do?
|
60 mg of furosemide is administered orally in the morning, and the patient is maintained in an upright posture
|
|
|
at what points are plasma collected (2 times)?
|
1) before furosemide administration; 2) five hours after furosemide administration
|
|
|
what is measured in the plasma?
|
PRA (plasma renin activity)
|
|
|
what does it mean if PRA (peripheral renin activity) is undetectible?
|
patients probably have hypertension from mineralocorticoid excess, such as primary aldoestronism
|
|
|
what will be seen in patients with renin-dependent forms of hypertension (PRA values)?
|
PRA values about five times normal
|
|
|
what results will be obtained in patients with hyporeninemic hypoaldosteronism?
|
low levels of PRA (as well as low aldosterone)
|
|
|
in hyperaldosteronism, will there be high plasma and/or urine aldosterone?
|
yes, both will be high
|
|
|
what test will suppress plasma aldosterone in normal subjects?
|
saline suppression test
|
|
|
what is the rationale for this test, and what will happen in patients with primary aldosteronism?
|
IV saline will suppress plasma aldosterone in normal subjects, but not in patients with primary aldosteronism
|
|
|
what should be done prior to the saline test?
|
keep patient upright for two hours
|
|
|
when should plasma aldosterone be tested?
|
before and after four hour saline infusion
|
|
|
what do normal individuals show after saline infusion (plasma aldosterone level)?
|
<5 ng/dL after saline infusion
|
|
|
what are levels like in patients with primary aldosteronism?
|
>10 ng/dL
|
|
|
what techniques are used to differentiate structures causing aldosteronism (adenomas, etc. - 2)?
|
1) adrenal vein sampling; 2) imaging (CT scan)
|
|
|
*** look over aldosteronism flowchart ***
|
|
|
|
|
|
|
|
CONGENITAL ADRENAL HYPERPLASIA
|
|
|
|
|
|
|
|
what are congenital adrenal hyperplasias, and what type of defects cause them?
|
a group of metabolic disorders resulting from hereditary defects in the enzymes of adrenal steroid hormone biosynthesis
|
|
|
what do clinical features of each disorder depend on?
|
position of the defective enzyme in synthetic pathway
|
|
|
what is a common biochemical feature of CAH disorders?
|
decreased negative feedback inhibition of cortisol on pituitary ACTH secretion (thus increased ACTH)
|
|
|
how are all of these disorders inherited?
|
all are autosomal recessive disorders
|
|
|
what is the most common cause of CAH, and what % of cases does it account for?
|
21-Hydroxylase (21-OHase; CYP21) deficiency - 90% of all cases
|
|
|
what is the next most common cause of CAH?
|
11-beta-hydroxylase deficiency
|
|
|
what is an uncommon cause of CAH?
|
17-alpha-hydroxylase deficiency
|
|
|
|
|
|
|
21-HYDROXYLASE DEFICIENCY
|
|
|
|
|
|
|
|
what is it the most common cause of?
|
ambiguous genitalia in newborn
|
|
|
what is the incidence?
|
1 in 13,000 live births
|
|
|
what are the three distinct syndromes of 21-hydroxylase deficiency?
|
1) classic salt-wasting syndrome; 2) classic simple virilizing syndrome without salt wasting; 3) nonclassical syndrome
|
|
|
what % of patients with classic deficiency have classic salt wasting syndrome?
|
75% of patients with classic deficiency
|
|
|
what are the two main blocks in the classic salt-wasting syndrome?
|
1) complete block in mineralocorticoid synthesis; 2) concomitant block in cortisol synthesis
|
|
|
why is mineralocorticoid synthesis completely blocked?
|
because progesterone cannot be converted into deoxycorticosterone - there is low plasma aldosterone
|
|
|
what hormone's activity is high for this reason?
|
high plasma renin activity
|
|
|
what does inadequate mineralocorticoid synthesis lead to in neonates (list)?
|
salt-wasting, hyponatremia, hyperkalemia, acidosis, hypotension, CV collapse, and possible death
|
|
|
why is there a concomitant block in cortisol synthesis?
|
cannot convert 17-hydroxyprogesterone into 11-deoxycortisol
|
|
|
what is a characteristic feature of this problem that can be detected in laboratory tests?
|
increased serum levels of 17-OHP
|
|
|
what does disruption of cortisol feedback lead to (4)?
|
1) overproduction of pituitary ACTH; 2) bilateral enlargement of adrenal glands (10 to 15 times normal weight); 3) increased flow of cortisol precursors into the androgen pathway; 4) virilization
|
|
|
what does androgen excess lead to increased serum levels of (3)?
|
1) DHEAs; 2) androstenedione; 3) testosterone
|
|
|
when is virilization apparent in females, and when is it apparent in males?
|
at birth in females, within 2-3 years of life in males
|
|
|
what allows for treatment for prevention of virilization?
|
prenatal diagnosis of CYP21 (21-hydroxylase) deficiency
|
|
|
what is the carrier frequency of this deficiency?
|
1 in 60
|
|
|
what % of patients with classic deficiency have simple virilizing syndrome without salt wasting?
|
25% of patients with classic deficiency
|
|
|
why is there not salt wasting in these cases?
|
partial block in mineralocorticoid synthesis, which reduces aldosterone synthesis, but is sufficient for salt reabsorption - aldosterone levels are normal or only mildly reduced
|
|
|
what is block in cortisol synthesis like, and what is the effect on cortisol levels?
|
partial block in cortisol synthesis reduces serum cortisols
|
|
|
what does lower cortisol in serum lead to (3)?
|
1) increased ACTH secretion; 2) androgen excess; 3) virilization
|
|
|
what does classic simple virilizing syndrome often present as?
|
genital ambiguity
|
|
|
what else is nonclassical syndrome known as?
|
late onset syndrome
|
|
|
how severe are manifestations?
|
mild or asymptomatic
|
|
|
what is salt metabolism like?
|
normal
|
|
|
what is virilization like?
|
postnatal (late childhood or adolescence) and less severe
|
|
|
what may distinguish the nonclassical forms from the classical forms (3)?
|
1) lesser elevation of serum 17-OHP; 2) different HLA associations; 3) different genetic mutations
|
|
|
what is the treatment for 21-hydroxylase deficiency?
|
replace glucocorticoids and mineralocorticoids as necessary to reduce ACTH secretion and suppress adrenal androgens
|
|
|
|
|
|
|
11-BETA-HYDROXYLASE (11B-OHASE; CYP11B1) DEFICIENCY
|
|
|
|
|
|
|
|
what is the incidence of 11-beta-hydroxylase deficiency?
|
1 in 100,000 live births (second most common cause of CAH)
|
|
|
what are the defects in the classic form of 11-beta-hydroxylase deficiency (2)?
|
1) 11-deoxycorticosterone (DOC) is not converted to corticosterone; 2) 11-deoxycortisol is not converted to cortisol
|
|
|
activities of what hormones are suppressed due to DOC not being converted to corticosterone (2)?
|
1) renin; 2) aldosterone
|
|
|
what substance has its levels in the serum increased due to failure of DOC to be converted to corticosterone?
|
DOC
|
|
|
what does DOC elevation lead to (2) and why?
|
1) hypokalemia; 2) hypertension - DOC has significant mineralocorticoid activity
|
|
|
what is the result of 11-deoxycortisol not being converted to cortisol?
|
ACTH secretion increases
|
|
|
what does ACTH stimulate?
|
production of adrenal androgens
|
|
|
what do these androgens cause?
|
virilization
|
|
|
|
|
|
|
17-ALPHA-HYDROXYLASE (17a-OHASE; CYP17) DEFICIENCY
|
|
|
|
|
|
|
|
what does the defective enzyme block production of (2)?
|
1) all glucocorticoids; 2) all sex steroids
|
|
|
what problem occurs with steroidogenesis precursors?
|
they are shunted into the mineralocorticoid pathway
|
|
|
what results (2) and what disease is this analogous to?
|
hypertension and hypokalemia result, analogous to that in primary aldosteronism
|
|
|
|
|
|
|
CORTICAL HYPOFUNCTION
|
|
|
|
|
|
|
|
what are the three patterns of adrenocortical insufficiency?
|
1) primary acute insufficiency (adrenal crisis); 2) primary chronic insufficiency (Addison's disease); 3) chronic secondary/tertiary insufficiency
|
|
|
in what three clinical settings may primary acute insufficiency appear?
|
1) immediate need for steroids from glands incapable of responding; 2) rapid withdrawal of steroid from patients on long-term steroid therapy; 3) massive destruction of adrenals
|
|
|
what causes massive destruction of adrenals in neonates?
|
adrenal hemorrhage following difficult delivery
|
|
|
what causes it in adults?
|
bacteremic infection
|
|
|
what type of therapy causes some patients to have massive destruction of adrenals?
|
anticoagulant therapy
|
|
|
what condition in postsurgical patients results in hemorrhagic adrenal infarction?
|
DIC
|
|
|
|
|
|
|
CORTICAL HYPOFUNCTION - PRIMARY CHRONIC INSUFFICIENCY
|
|
|
|
|
|
|
|
what are the possible causes of primary chronic insufficiency (2)?
|
1) destruction of cortex (Addison's disease); 2) metabolic failure of cortisol production
|
|
|
what is the most common cause of Addison's disease, and how frequently does it occur?
|
idiopathic (autoimmune) atrophy - 60 to 70% of cases
|
|
|
in what fraction of cases is the adrenal the sole target of autoimmune reaction?
|
half
|
|
|
in the remainder, what else is affected, what are these syndromes called, and how many are there?
|
other endocrine glands - these are type 1 and type 2 polyglandular syndromes
|
|
|
what problems occur in type 1 polyglandular syndrome (3)?
|
1) adrenal insufficiency; 2) hypoparathyroidism; 3) candidiasis
|
|
|
what problems occur in type 2 polyglandular syndrome (3)?
|
1) adrenal insufficiency; 2) autoiummune thyroid disease; 3) T1DM
|
|
|
what may adrenals be like in size, in primary chronic insufficiency?
|
markedly reduced in size (combined weight of 2 to 3 gm) - difficult to find
|
|
|
what may happen to cortex and what happens to medulla?
|
may be reduced to a thin ribbon composed largely of glomerulosa cells; medulla is unaffected
|
|
|
what does the cortex contain, histologically?
|
scattered residual cortical cells in a collapsed network of connective tissue
|
|
|
what is seen around and between the cells in the cortex?
|
variable lymphocytic infiltration
|
|
|
what is the second most common cause of cortical destruction in the US?
|
tuberculosis: 10-15% of cases in the US - much more common in other parts of world
|
|
|
what are other causes of adrenal atrophy (list)?
|
fungal infection, metastatic carcinoma, AIDS, opportunistic microbes, amyloidosis, sarcoidosis, hemochromatosis, surgical adrenalectomy
|
|
|
what can cause primary chronic insufficiency besides destruction of cortex?
|
metabolic failure in cortisol production
|
|
|
what can cause this metabolic failure (2)?
|
1) congenital adrenal hyperplasia; 2) enzyme inhibitors (metyrapone, ketoconazole, aminogluthethimide)
|
|
|
what do patients with Addison's disease crave?
|
salt
|
|
|
what happens to their skin?
|
hyperpigmentation
|
|
|
what happens to levels of sugar, fluid balance, and electrolytes in blood (2)?
|
1) hypoglycemia; 2) electrolyte imbalances; 3) dehydration
|
|
|
what happens to blood pressure?
|
hypotension
|
|
|
what happens to body weight?
|
loss
|
|
|
what happens to musculoskeletal system?
|
muscle weakness
|
|
|
what other symptoms occur (2)?
|
1) GI disturbances; 2) fatigue
|
|
|
what is onset of clinical manifestations like in Addison's disease?
|
gradual/progressive
|
|
|
what does degree/severity of symptoms depend on?
|
extent of adrenal failure
|
|
|
what may precipitate an acute adrenal crisis?
|
stress
|
|
|
|
|
|
|
CORTICAL HYPOFUNCTION - SECONDARY/TERTIARY INSUFFICIENCY
|
|
|
|
|
|
|
|
what are two groups of causes of secondary/tertiary insufficiency?
|
1) pituitary or hypothalamic disorders reducing ACTH output; 2) pituitary or hypothalamic suppression of ACTH
|
|
|
what are four pituitary or hypothalamic disorders that reduce ACTH output?
|
1) carcinoma; 2) infection; 3) irradiation; 4) infarction
|
|
|
what may cause pituitary or hypothalamic suppression of ACTH (what is the most common cause of ACTH deficiency)?
|
prolonged use of pharmacologic doses of glucocorticoids is the most common cause of ACTH deficiency
|
|
|
what is secondary/tertiary insufficiency similar to?
|
primary chronic insufficiency
|
|
|
what things are lacking in secondary/tertiary insufficiency that are present in primary (3)?
|
1) hyperpigmentation is not present; 2) ACTH excess is not seen; 3) hypotension is less severe
|
|
|
what other features may be included in secondary/tertiary insufficiency?
|
features of panhypopituitarism
|
|
|
|
|
|
|
DETECTION/DIAGNOSIS OF ADRENOCORTICAL INSUFFICIENCY
|
|
|
|
|
|
|
|
what are five biochemical clues that there is adrenocortical insufficiency?
|
1) hyponatremia; 2) hyperkalemia; 3) hypoglycemia; 4) pre-renal azotemia; 4) metabolic acidosis
|
|
|
as far as cortisol production, what measurement suggests adrenal insufficiency, and what value precludes diagnosis?
|
a low morning serum cortisol below 5 ug/dL suggests adrenal insufficency, and a value greater than 20ug/dL precludes diagnosis
|
|
|
how frequently do patients with adrenocortical insufficiency have basal morning cortisols within the normal reference range?
|
it is common
|
|
|
what is the single best and simplest screening test for confirming adrenal insufficiency?
|
short (rapid) ACTH stimulation test
|
|
|
what will patients present with, where this test is the most rapid and reliable way to determine quickly whether primary adrenal insufficiency is the cause?
|
hypotensive crisis
|
|
|
what is the rationale for this test (what will happen in patients with and without adrenal insufficiency)?
|
administration of exogenous synthetic ACTH results in a rapid rise in cortisol in normal subjects, but not in patients with adrenal insufficiency
|
|
|
what is the method?
|
collect serum for cortisol determinations 0 and 60 mins after injecting 250 ug cosyntropin
|
|
|
in normal individuals, what is the peak cortisol response?
|
>20 ug/dL
|
|
|
what does a normal response rule out (2)?
|
1) primary adrenal insufficiency; 2) overt secondary adrenal insufficiency
|
|
|
what does a normal response not rule out (2)?
|
1) recent insufficiency; 2) partial ACTH deficiency
|
|
|
what does a subnormal response indicate?
|
decreased adrenal reserve and a diagnosis of insufficiency
|
|
|
what can the etiology of the insufficiency be (3)?
|
1) primary to adrenal failure (Addison's disease); 2) secondary to pituitary disease; 3) secondary to suppression by steroid medications
|
|
|
what is the importance of plasma concentration of endogenous ACTH in this test?
|
it is irrelevant for interpreting this test
|
|
|
|
|
|
|
DIFFERENTIATION OF ADRENOCORTICAL INSUFFICIENCY
|
|
|
|
|
|
|
|
what tests are done to differentiation of adrenocortical insufficiency (2)?
|
1) plasma ACTH, 8am; 2) prolonged (two-day) ACTH stimulation test
|
|
|
what is the 8am plasma ACTH in primary, secondary, and tertiary adrenal insufficiency?
|
in primary adrenal insufficiency ACTH is high, in secondary or tertiary adrenal insufficiency, ACTH is low or normal
|
|
|
when is the prolonged (two-day) ACTH stimulation test necessary?
|
when the 8am plasma ACTH test is messed up - if the 8am test is drawn in the proper setting and reliable, it is usually sufficient to establish the cause
|
|
|
what is the rationale for the prolonged (two-day) ACTH stimulation test (what happens in primary vs. secondary or tertiary cause)?
|
adrenal glands are partially or completely destroyed in primary disease and cannot respond to additional ACTH; atrophic adrenal glands in secondary or tertiary insufficiency recover cortisol secretory capacity if they are chronically exposed to ACTH
|
|
|
what is the method of the prolonged ACTH stimulation test?
|
synthetic ACTH is infused, and serum and 24-h urines are collected for cortisol measurements
|
|
|
what is a normal peak cortisol in the prolonged test?
|
>20 ug/dL
|
|
|
what response is seen in primary adrenal failure?
|
no response or inadequate response
|
|
|
what happens in cortisol secretion in adrenal insufficiency secondary to pituitary/hypothalamic disease or steroid suppression?
|
progressive increase in cortisol secretion
|
|
|
what is seen in CAH due to 21-hydroxylase and 17-hydroxylase deficiencies?
|
little or no responses
|
|
|
|
|
|
|
NONFUNCTIONAL CORTICAL NEOPLASMS
|
|
|
|
|
|
|
|
what morphologic features can be used to distinguish functional and nonfunctional cortical neoplasms?
|
they cannot be distinguished on basis of morphologic features
|
|
|
what feature of tissue surrounding cortical adenomas can distinguish if they are functional and non-functional?
|
in contrast to functional adenomas, the cortex adjacent to non-functional adenomas is of normal thickness
|
|
|
***look over adrenocortical insufficiency flowchart***
|
|
|
|
|
|
|
|
PHEOCHROMOCYTOMAS
|
|
|
|
|
|
|
|
what hormones do pheochromocytomas (pheos) produce?
|
catecholamines
|
|
|
what cells are they commonly derived from?
|
adrenomedullary chromaffin cells
|
|
|
what % of hypertension is caused by pheochromocytomas?
|
rare - 0.1 to 0.3 of all hypertensives
|
|
|
what is the usual treatment?
|
surgery
|
|
|
are they ever inherited?
|
occasionally, either alone or in combination with other familial traits
|
|
|
what traits can they be inherited with (4)?
|
1) multiple endocrine neoplasia (MEN) syndromes; 2) type I neurofibromatosis; 3) von Hippel-Lindau syndrome; 4) Sturge-Weber syndrome
|
|
|
how many MEN syndromes are there, and which ones may pheos be the first clue to?
|
there are three types, and pheos may be the first clue to the presence of types 2 or 3
|
|
|
what is MEN-1 also known as, and what three tumor types are seen?
|
Wermer syndrome - 1) parathyroid hyperplasia/adenomas; 2) pituitary adenomas; 3) pancreatic islet cell tumors - the three P's
|
|
|
what is MEN-2 also known as, and what mutation is it linked to?
|
also known as Sipple syndrome; linked to mutant RET protooncogene
|
|
|
what three types of tumors are seen in MEN-2 (Sipple syndrome)?
|
1) pheochromocytoma; 2) medullary thyroid carcinoma; 3) parathyroid hyperplasia
|
|
|
what three types of tumors are seen in MEN-3?
|
1) pheochromocytoma; 2) medullary thyroid carcinoma; 3) mucosal neuromas/Marfanoid features
|
|
|
what is the dominant feature when there is a pheochromocytoma?
|
hypertension
|
|
|
what types of hypertension can occur, and what is the frequency of each type?
|
all have frequency of 1/3: 1) sustained hypertension with paroxysmal attacks; 2) sustained hypertension without paroxysmal attacks; 3) intermittent hypertension
|
|
|
what are some symptoms of pheochromocytoma (list)?
|
paroxysmal attacks (spells), headaches, excessive sweating, abdomen/chest pain, fever, weight loss, nausea/vomiting, anxiety, apprehension, palpitations (with or without tachycardia), orthostatic hypotension, cardiac manifestations, numbness, parasthesia
|
|
|
what can provoke paroxysms (4 examples)?
|
1) exercise; 2) stress; 3) change in posture; 4) palpation in region of tumor
|
|
|
are most pheos solitary or multiple, and where are they located?
|
solitary and in adrenal medulla
|
|
|
what rule explains how many pheos have abnormal characteristics?
|
rule of 10's (10% incidence of various abnormal characteristics)
|
|
|
what characteristics of pheos have 10% incidence (5)?
|
1) extraadrenal; 2) bilateral (nonfamilial cases); 3) malignant (intra-adrenal cases); 4) familial; 5) 10% are in children
|
|
|
what sex has more cases in children?
|
males
|
|
|
what is the average weight of an adrenal pheochromocytoma, and what is the range?
|
100 gm - range 1 gm to 4000 gm
|
|
|
what are the cut surfaces of smaller tumors like on section?
|
yellow-tan
|
|
|
what is seen in larger tumors (3)?
|
areas of hemorrhage, necrosis, or cyst formation
|
|
|
are larger tumors well-demarcated?
|
yes
|
|
|
what do pheochromocytomas look like microscopically (what cells are they composed of, and what do they contain)?
|
composed of large chromaffin cells and contain membrane-bound secretory granules in which catecholamines are stored
|
|
|
histologically, what is the difference between benign vs. malignant pheochromocytomas?
|
they are identical histologically
|
|
|
what is the criterion of malignancy?
|
metastasis
|
|
|
where may they metastasize (4)?
|
1) regional lymph nodes; 2) liver; 3) lung; 4) bone
|
|
|
what is the best test for excluding or confirming pheochromocytoma, and how sensitive is it?
|
normetanephrine and metanephrine in plasma - 99% sensitive - relatively new test
|
|
|
what is a reliable screening test, and how sensitive is it?
|
normetanephrine and metanephrine in 24-h urine - 97% sensitive
|
|
|
what is a useful adjunct test, and what does it provide?
|
norepinephrine and epinephrine in 24-h urine - provides an "integrated" picture of catecholamine production
|
|
|
what other test is favored by some clinicians as an adjunct test, and when is it useful?
|
norepinephrine and epinephrine in plasma - useful when clinical suspicion is high but other test results are equivocal
|
|
|
what other test is useful to exclude the diagnosis in some situations, and what cases is it useful in?
|
clonidine suppression test - useful in cases with suggestive clinical features and moderately elevated or equivocal catecholamine levels
|
|
|
if clonidine promptly suppresses plasma norepinephrine, what does this indicate?
|
can exclude diagnosis in cases with suggestive clinical features and moderately elevated or equivocal catecholamine levels
|
|
|
***see flowchart on pheochromocytoma***
|
|
|
|
|
|
