IUHS Student-2-Student USMLE Step 1 Recall
Endocrinology
Adrenal Cortex
Normal Adrenal Cortex
the adrenal cortex synthesizes three different types of steroids...
1)
minerolocorticoids, the most important being aldosterone, which is generated in the zona glomerulosa...2)
glucocorticoids (principally cortisol), which are synthesized primarily in the zona fasciculata with a small contribution from the zona reticularis...3)
sex steroids (estrogens and androgens), which are produced largely in the zona reticularis...G - aldosterone
F - cortisol
R - estrogens and androgens
glomerulosa and fasiculata require 21 and 11 hydroxylase...
fasciculata and reticularis respond to ACTH...
Hypercortisolism (Cushing Syndrome)
primary hypothalamic pituitary diseases associated with hypersecretion of ACTH...
(60%)...hypersecretion of cortisol by an adrenal ade
noma,
carcinoma, or nodular hyperplasia...(20%)...the
secretion of ectopic ACTH by a nonendocrine neoplasm...(15%)...
Lymphopenia, decreased lymphocytes...
primary hypersecretion of ACTH accounts for more than half of cases of endogenous hypercortisolism...out of deference to the neurosurgeon who first published the full description of this syndrome and related it to a pituitary lesion, this
pituitary form of cushing syndrome is referred to as cushing disease...the disorder affects women about five times more frequently than men, and it occurs most frequently during the twenties to thirties...
in most of these patients, the
pituitary gland contains a small ACTH-producing adenoma that does not produce mass effects in the brain...the responsible adenoma may be composed of either basophilic or chromophobe cells...primary adrenal neoplasms, such as
adrenal adenoma carcinoma, and cortical hyperplasia, are responsible for about 15-30% of cases of endogenous cushing syndrome...this form of cushing syndrome is also
designated ACTH-independent cushing syndrome or adrenal cushing syndrome b/c the adrenals function autonomously...secretion of ectopic ACTH by nonpituitary tumors accounts for most of the remaining cases of cushing syndrome...in many instances, the responsible tumor is a
small cell carcinoma of the lung, although other neoplasms, including carcinoid tumors, medullary carcinomas of the thyroid, and islet cell tumors of the pancreas, have been associated with the syndrome....the most common alteration, resulting from high levels of endogenous or exogeous glucocorticoids, is termed
crook hyaline change...in this condition, the normal granular,
basophilic cytoplasm of the ACTH producing cells in the anterior pituitary is replaced by homogenous, lightly basophilic material...this alteration is the result of the
accumulation of intermediate keratin filaments in their cytoplasm...developing slowly over time, cusing syndrome, similar to many other endocrine abnormalities, can be quite subtle in its early manifestations...early stages of the disorder include
hypertension and weight gain...
with time, the more characteristic central pattern of adipose tissue deposition becomes apparent, with resultant
truncal obesity, moon facies, and acumulation of fat in the posterior neck and back (buffalo hump)....hypercortisolism causes
selective atrophy of fast twitch (type II) myofibers, resulting in decreased muscle mass and proximal limb weakness...glucocorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells with resultant
hyperglycemia, glucosuria, and polydipsia...the catabolic effects on proteins cause
loss of collagen and resorption of bones...consequently the skin is thin, fragile,and easily bruised; wound healing is poor; cutaneous striae are particularly common in the abdominal area...bone resorption results in a development of osteoporosis, with consequent backache and increased susceptibility to fractures
...patients with cushing syndrome are at increased risk for a variety of infections b/c glucocorticoids suppress the immune response...additional manifestations include a number fo mental disturbances, including mood swings, depression, and frank psychosis, as well as hirsutism and menstrual abnormalities...Diagnosis - initial step should be a dexamethasone suppression test...
cushing syndrome is diagnosed in the laboratory with the following: (1) the 24 hour urine free corisol level, which is increased, and (2) loss of normal diurnal pattern of cortisol secretion
...determing the cause of cushing syndrome depends on the level of serum ACTH and measurement of urinary steroid excetion after administration of dexamethasone...
three general patterns can be obtained:
1) in pituitary cushing syndrome, the most common form, ACTH levels are elevated and cannot be suppressed by the
adminstration of a low dose of dexamethasone...hence there is no reduction in urinary excretion of 17-hydroxycorticosteroids...after higher doses of injected dexamethasone, however, the pituitary responds by reducing ACTH secretion, which is reflected by suppresssion of urinary steroid secetion...2) ectopic ACTH secretion results in an elevated level of ACTH , but its secretion is completely insensitive to low or high doses of exogenous dexamethasone...
3) when cushing syndrome is caused by an adrenal tumor, the ACTH level is quite low b/c of feeback inhibition of the pituitary...
use an abdominal CT to diagnosis...as with ectopic ACTH secretion, both low-dose and high-dose dexamethasone fail to suppress cortisol excretion...Primary and Secondary Hyperaldosteronism (Conn Syndrome)
primary hyperaldosteronism is the generic term for a small group of closely
related, uncommon syndromes, all characterized by chronic excessive aldosterone
secretion...
excessive levels of aldosterone cause
sodium retention and potassium excretion, wth resultant hypertension and hypokalemia...hyperaldosteronism may be primary, or it may be secondary event resulting from a extra-adrenal cause...primary hyperaldosteronism indicates an autonomous overprodution of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity...primary hyperaldosteronism is caued either by an aldosterone-producing adrenocortical neoplasm, usually by an aldosterone producing adrenocoritcal neoplasm, usually an adenoma, or by primary adrenocortical hyperplasia...
in approxiamately
80% of cases, primary hyperaldosteronism is caused by an aldosterone-secreting adenoma in one adrenal gland, a condition referred to as Conn syndrome...this syndrome occurs most frequently in adult middle life and is more comon in women than in men (2:1)...adenoma is in the zona glomerulosa and renin is suppressed...in secondary hyperaldosteronism, in contrast, aldosterone releaes occurs in respones to activation of the renin-angiotensin system
...it is characterized by increased levels of plasma renin and is encountered in conditions such as congestive heart failure, decreased renal perfusion (arteriolar nephrosclerosis, renal arterial stenosis), hypoalbuminemia, and pregnancy (owing to estrogen-induced increases in plasma renin substrate)...bilateral idiopathic hyperplasia is marked by diffuse and focal hyperplasia of cells resembling those of the normal zona glomerulsa
interspersed with small adrenocortical nodules composed of lipid laden cells having the electron microscopic features of normal zona fasciculata...the clincial manifestations of primary hyepraldosteronism are
hypertension and hypokalemia...serum renin, as mentioned previously, is low...hypokalemia results from renal potassium wasting and can cause a variety of neuromuscular manifestations, including weakness, paresthesias, visual disturbances, and occasionally frank tetany
...
sodium retention increases the total body sodium and expands the extracellular fluid volume, leading to elevation of the serum sodium concentration and an increase in intracellular sodium with increased vascular reactivity...the hypertension is, in some part, a result of the sodium retention...
the expanded extracellular fluid volume and hypokalemia both impose a burden on the heart, sometimes causing electocadiographic changes and cardiac decompensation...
the diagnosis of primary hyperaldosteronism is confirmed by the elevated levels of aldosterone and depressed levels of renin in the circulation
...even when the diagnosis of primary hyperaldosteronism is made, it is necessary to distinuish among the various causes, particulary the differentiation of an adenoma, which is amenable to surgical excision, and bilateral idiopathic hyperplasia, calling for medical therapy...21-Hydroxylase Deficiency in the conversion of progesterone to 11-deoxycorticosterone
defective conversion of progesterone to 11-deoxycorticosterone by 21-hydroxylase (CYP21A2) accounts for
approximately 90% of cases of congenital adrenal hyperplasia...21-hydroxylase deficiency may range from a total lack to a mild loss, depending on the nature of the mutations...three distinctive syndromes have been segregated:
1) salt-wasting adrenogenitalism...
2) simple virilzing adrenogenitalism...
3) nonclassic adrenogenitalism, which implies mild disease that may be entirely asymptomatic or associated only with symptoms of androgen excess during childhood or puberty...
thus, there is virtually no synthesis of mineralcorticoids and concomitantly a block in the conversion of hydroxyprogesterone into deoxycortisol with deficient cortisol synthesis...
this pattern usually comes to light soon after birth b/c in utero the electrolytes and fluids can be maintained by the maternal kidneys...
there is salt wasting, hyponatremia, and hyperkalemia, which induce acidosis, hypotension, cardiovascular collapse, and possibly death...the concomitant block in cortisol synthesis and excess production of androgens, however, lead to virilization, which is easily recognized in the female at birth or in utero but is dificult to recognize in the male...
various degrees of virilization are encountered, ranging from mild clitoral enlargement to complete labioscrotal fusion to mared clitoral enlargement enclosing the urethra, thus producing a phalloid organ...males with this disorder are generally unrecognized at birth but come to clinical attention 5-15 days later b/c of some salt losing crisis...
for example, in 21-hydroxylase deficiency, excessive androgenic activity causes signs of masculinization in females, ranging from clitoral hypertrophy and pseudohermaphroditism in infants, to oligomenorrhea, hirsutism, and acne in postpubertal females...
in males, androgen excess is associated with enlargement of the external genitalia and other evidence of precocious puberty in prepubertal patients and oligospermia in older males...
Waterhouse-Friederichsen Syndrome
this uncommon but catastrophic syndrome is characterized by the following:
an overwhelming bacterial infection, which is classically associated with
neisseria meningitidis septicemia but occasionally is caused by other highly virulent organisms, such as pseudomonas species, pneumococci, haemophilus influenzae, or staphylococci...rapidly progressive hypotension leading to shock
...disseminated intravascular coagulation with widespread purpura, particularly of the skin
...the waterhouse-friderichsen syndrome may occur at any age but is somewhat more common in children...
history of pharyngitis, fever, and severe headache
...the basis for the adrenal hemorrhage is uncertain but could be attribuatable to direct bacterial seeding of small vessels in the adrenal, the development of disseminated intravascular coagulation, endotoxin-induced vasculitis, or some form of hypersensitivity vasculitis...
whatever the basis, the adrenals are converted to sacs of clotted blood virtually obscuring all underlying detail...
histologic examination reveals that the hemorrhage starts within the medulla in relationship to thin-walled venous sinusoids, then suffuses peripherally into the cortex, often leaving islands of recognizable cortical cells...
Addison Disease
addison disease, or
bilateral chronic adrenocortical insufficiency, is an uncommon disorder resulting from progressive destruction of the adrenal cortex...in general, clinical manifestations of adrenocortical insufficiency do not appear until at least 90% of the adrenal cortex has been compromised...
although all races and both sexes may be affected, certain causes of addison disease (such as
autoimmune adrenalitis) are much more common in whites, particularly in women...High ACTH
...more than
90% of all cases are attributable to autoimmune adrenalitis, tuberculosis, or metastatic cancers...autoimmune adrenalitis accounts for about 60-70% of cases...it may occur as a sporadic or familial disorder...in about half of these cases, the
adrenal is the sole target of an autoimmune reaction, but in the remainder, other autoimmune diseases, such as hashimoto disease, pernicious anemia, type I diabetes mellitus, and idiopathic hypoparathyroidism, coexist...
the term polyglandular syndromes has been used to designate the various combinations of organ involvement that may be encountered...
circulating antiadrenal antibodies are present in bout half of the cases of autoimmune adrenalitis as well as other types of antibodies related to involvement of other organs or tissues...the frequency of autoimmune adrenalitisis increased in association with certain histocompatibility antigens, particularly
HLA-B8 and DR-3, suggesting some genetic predisposition...as with other autoimmune endocrine disorders, the factors that initiate autoimmunity remain obscure...infections, particulary
TB and those produced by fungi, may also cause primary chronic adrenocortical insufficiency...TB adrenalitis, which once accounted for as much as 90% of addison disease, has become less common with the development of anti-TB agents...among the fungi, disseminated infections caused by
histoplasma capsulatum and coccidioides immitis may also result in chronic adrenocortical insufficiency...metastatic neoplasms
involving the adrenals are another potential cause of adrenal insufficiency...the adrenals are a fairly common site for metastase in patients with disseminated carcinomas...
although adrenal function is preserved in most such patients, the
metastatic tumors occasionally destroy enough adrenal cortex to produce a degree of adrenal insufficiency...carcinomas of the lung and breast are the source of a majority of metastases in the adrenals
, although many other neoplasms, including GI carcinomas, malignant melanoma, and hematopoietic neoplasms, may also metastasize to this organ...addison disease begins insidiously and
does not come to attention until at least 90% of the cortex of both glands is destroyed, and the levels of circlating glucocorticoids and mineralocorticoids are significantly decreased...the initial manifestations include
progressive weakness and easy fatigability, which may be dismissed as nonspecific complaints...GI disturbances are common and include
anorexia, nausea, vomiting, weight loss, and diarrhea...in patients with priamry adrenal disease, increased circulating levels of ACTH precursor hormone stimulate melanocytes, with resultant
hyperpigmentation of the skin, particularly of sun-exposed areas and pressure points, such as the neck, elbows, knees, and knuckles...by contrast, hyperpigmentation is not seen in patients with adrenocortical insufficiency caused by primary pituitary or hypopthalamic disease...
decreased mineralocorticoid activity in patients with primary adrenal insufficiency results in
potassium and sodium loss, with consequent hyperkalemia, hyponatremia, volume depletion, and hypotension...the
heart is frequently smaller than normal, probably b/c of chronic hypovolemia...hypoglycemia may occasionally occur as a result of glucocorticoid deficiency and impaired glucogenesis...stresses such as
infections, trauma, or surgical procedures in such patients may precipitate an acute adrenal crisis, manifested by intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse...death occurs rapidly unless corticosteroid therapy begins immediately...