IUHS Student-2-Student USMLE Step 1 Recall
Endocrinology
Parathyroid
Normal Parathyroid
derived from the developing pharyngeal pouches that also give rise to the thymus...
most of the gland is composed of chief cells...the
chief cells vary from light to dark pink with hematoxyin and eosin stains, depending on their glycogen content...they contain secretory granules of parathyroid hormone (PTH)...
free calcium in the bloodstream, rather than by trophic hormones secreted by the hypothalmus and pituitary...normally,
decreased levels of free calcium stimulate the synthesis and secretion of PTH...circulating PTH is an 84 amino acid linear polypeptide derived by sequential cleavage in the chief cell of a larger pre-pro form...its biologic activity resides within the 34 residues at the amino terminus...smaller nonfunctional fragments of the hormone, apparently lacking the critical amino terminal domain, also circulate...these assume importance b/c, although they are biologically inert, they contain epitopes that react in certain radioimmunoassays for PTH...
the
hormone binds specifically to a seven trasmembrane receptor, which interacts with G proteins leading to the stimulation of adenylate cyclase and the generation of cAMP as well as the activation of phospholipase C and the conversion of phosphatidylinositol diphosphate (PIP2) and diacylglyceral (DAG)...the metabolic functions of PTH in supporting serum calcium level can be summarized as follows:
PTH activates osteoclasts, thereby mobilizing calcium from bone
...it increases the renal tubular reabsorptoin of calcium thereby conserving free calcium...it increases the conversion of vitamin D to its active dihydroxy form in the kidneys....it increases urinary phosphate excretion, thereby lowering serum phosphate level...it augments GI calcium absorption...hypercalcemia is one of a number of changes induced by elevated levels of PTH...hypercalcemia is a relatively common complicaton of malignancy, occurring with both solid tumors and hematologic malignancies,
notably breast and lung cancers and multiple myeloma...Primary Hyperparathyroidism
primary hyperparathyroidism is
one of the most common endocrine disorders, and it is an important cause of hypercalcemia...the frequency of the various parathyroid lesions underlying the hyperfuction is as follows...hypercalcemia leads to
increased gastrin production and peptic ulcer disease...Hypercalcemia produces cardiac arrythmias (or asystole).adenoma 75-80%...primary hyperplasia (diffuse of nodular) 10-15%...parathyroid carcinoma, less than 5%...
primary hyperparathyroidism is usually a diseaes of adults and is
more common in women
than in men...the annual incidence is now estimated to be about 25 cases per
100,000 population in the US and Europe...
most cases occur in the fifties or later in life...a history of irradiation to the head and neck on average 30-40 years before the developement of hyperparathyroidism, can be obtained in some patients..
studies have begun to provide a molecular understanding of the pathogenesis of primary hyperparathyroidism...in more than 95% of cases, the disorder is caused by sporadic parathyroid adenomas or sporadic hyperplasia...some cases are caused by inherited syndromes, such as MEN I...
parathyroid adenomas are often composed predominantly of fairly
uniform, polygonal chief cells with small, centrally placed nuclei...in most cases, at least a few nests of larger cells containing
oxyphil cells or cells with more abundant clear cytoplasm are present as well...primary hyperplasia may occur sporadically or as a component of MEN syndrome I or IIA...
microscopically the most common pattern seen is that of
chief cell hyperplasia, which may involve the glands in a diffuse or multinodular pattern...less commonly the constituent cells contain abundant water clear cells...morphologic changes in other organs deserving special mention include
skeletal and renal lesions...skeletal changes include prominence of osteoclasts, which, in turn, erode bone matrix and mobilize calcium salts, particularly in the metaphyses of long tubular bones...bone resorption is accompanied by
increased osteoblastic activity and the formation of new bone trabeculae...in many cases, the resultant bone contains widely spaced, delicate trabeculae reminiscent of those seen in osteoporosis...in more severe cases, the cortex is grossly thined, and the marrow contains increased amounts of fibrous tissue accompanied by foci of hemorrhage and cyst formation (
osteitis fibrosa cystica)...aggregates of osteoclasts, reactived giant cells, and hemorrhagic debris occasionally form masses that may be mistaken for neoplasms (brown tumors of hyperparathyroidism)
...
PTH induced hypercalcemia favors formation of urinary tract stones (nephrolithiasis) as well as calcification of the renal interstitium and tubules (nephrocalcinosis)
...in patients with parimay hyperparathyroidism,
serum PTH levels are inappropriately elevated for the level of serum calcium wheras PTH levels are low to undetectable in hypercalcemia b/c of nonparathyroid diseases...in patients with hypercalcemia caused by secretion of PTHrP by certain nonparathryoid tumors, radioimmunoassays specific for PTH and PTHrP can distinguish between the two molecules...
other laboratory alterations referable to PTH excess include
hypophosphatemia and increased urinary excretion of both calcium and phosphate....the signs and symptoms of hyperparathyroidism reflect the combined effects of increased PTH secretion and hypercalcemia...primary hyperparathyroidism has been traditionally associated with a constellation of symptoms that included
"painful bones, renal stones, abdominal groans, and psychic moan."...the symptomatic presentation involves a diversity of clinical manifestations...
bone disease includes bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica
...nephrolithiasis (renal stones) occurs in 20%
of newly diagnosed patients, with attendant pain and obstructive uropathy...chronic renal insufficiency and a variety of abnormalities in renal function are found, including polyuria and secondary polydipsia...GI disturbances include
constipation, nausea, peptic ulcers, pancreatitis, and gallstones...CNS alterations, include
depression, lethargy, and eventually seizures...neuromuscular abnormalities include complaints of
weakness and fatigue...cardiac manifestations include
aortic or mitral valve calcifications (or both)...the abnormalities most directly related to hyperparathyroidism are
nephrolithiasis and bone disease, whereas those attributable to hypercalcemia include fatigue, weakness, and constipation...the pathogenesis of many of the other manifestations of the disorder remain poorly understood... Secondary Hyperparathyroismsecondary hyperparathyroidism is caused by any condition associated with a
chronic depression in the serum calcium level b/c low serum calcium leads to compensatory overactivity of the parathyroid glands...renal failure is, by far, the most common cause of secondary hyperparathyroidism
, although a number of other diseases, including inadequate dietary intake of calcium, steatorrhea, and vitamin D deficiency, may also cause this disorder...chronic renal insufficiency is associated with decreased phosphate excretion, which results, in turn, in
hyperphosphatemia...the elevated serum phosphate levels directly depress serum calcium levels and thereby stimulate parathyroid gland activity...
high intact PTH...Chronic renal failure leads to an increased phosphate, depressing serum calcium and increasing the parathormone, which leads to secondary hyperparathyroidism...
the parathyroid glands in secondary hyperparathyroidism are hyperplastic...
as in the case of primary hyperplasia, the degree of glandular enlargement is not necessarily symmetric...
microscopically the hyperplastic glands contain an increased number of chief cells, or cells with more abundant, clear cytoplasm (so-called transition water clear cells) in a diffuse or multinodular distribution...
the clincial features of secondary hyperparathroidism are usually dominated by those associated with chronic renal failure...
bone abnormalities (renal osteodystrophy) and other changes associated with PTH excess are, in general, less severe than are those seen in primary hyperparathyroidism...
Hypoparathyroidism
surgically induced hypoparathyroidism occurs with
inadvertent removal of all the parathyroid glands during thyroidectomy, excision of the parathyroid glands in the mistaken belief that they are lymph nodes during radical neck dissection for some form of malignant disease, or removal of too large a proportion of parathyroid tissue in the treatment of primary hyperparathroidism...congenital absence of all glands, as in certain developmental abnormalities, such as thymic aplasia (DiGeorge syndrome)....
primary (idiopathic) atrophy of the glands most likely represents an autoimmune disease...
60% of the patients with this disorder have autoantiobdies directed against the calcium sensing receptor in the parathyroid gland......antibody binding to the receptor may prevent the release of PTH...referable to
hypocalcemia and are related to the severity and chronicity of the hypocalcemia...the hallmark of hypocalcemia is
tetany, which is characterized by neuromuscular irritability, resulting from decreased serum ionized calcium concentration...these findings can range from circumoral numbness or paresthesias (tingling) of the distal extremities and carpopedal spasm, to life-threatening laryngospasm and generalized seizures...calcification of basal ganglia
...the classic findings on physical examination of patients with neuromuscular irritability are
chvostek sign and trousseau sign...chvostek sign is elicted with subclinical disease by tapping along the course of the facial nerve, which induces contractions of the muscles of the eye, mouth, or nose...occluding the circulation to the forearm and hand by inflating a blood pressure cuff about the arm for several minutes induces carpal spasm, which disappears as soon as the cuff is deflated (trousseau sign)...mental status changes can include emotional instability, anxiety and depression, confusional states, hallucination, and frank psychosis
....intracranial manifestations include parkinsonian like movement disorders and papilledema...
ocular disease results in
calcification of the lens leading to cataract formation...cardiovascular manifestations include a conduction defect
, which produces a characteristic prolongation of the QT interval in the electrocardiogram...Pseudohypoparathyroidism
many patients with pseudohypoparathyroidism have a defect in binding of many hormones to guanine nucleotide-binding protein (G protein)...
resistance of the organs to normal or elevated levels of PTH
occurs with various forms of pseudohypoparathyroidism...the actions of PTH on bone and kidney are mediated by an interaction of the hormone receptor complex with GTP binding proteins and the generation of cyclic AMP...two types of defects have been identified in pseudohypoparathyroidism...
1) psudohypoparathyroidism type 1 is associated wtih diminished cyclic AMP response to PTH and is caused by a deficiency of the Gs-alpha protein or by abnormalities in the level of the hormone receptor complex...patients with this disorder often have round facies, short stature, and short metacarpal and metatarsal bones (
Albright hereditary osteodystrophy)...2) pseudohypoparathyroidism type 2 is characterized by normal PTH induced cylcic AMP, with a blunted response to the second messenger...
hypocalcemia results, leading to secondary
parathyroid hyperfunction, unanticipated elevated serum PTH levels, and a constellation of skeletal and other developmental abnormalities...