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342 Cards in this Set

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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***