Term
| what do the parathyroid glands consist of? |
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Definition
| mainly *chief cells (polygonal w/central nuclei) which have various amounts of glycogen as well as secretory granules containing parathyroid hormone. *oxyphil cells are also found in the parathyroid glands, alone or in clusters, and are slightly larger than chief cells w/abundant mitochondria. oxyphil cells have minimal or no secretory granules. the fat level of the gland increases to a max of 25% by age 25. |
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Term
| what regulates parathyroid gland function? |
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Definition
| the level of free/ionized Ca++ in the blood. *decreased levels of serum Ca++ stimulate synthesis and secretion of parathyroid hormone (PTH). |
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Term
| what is the mechanism of PTH function? |
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Definition
| PTH increases renal tubular reabsorption of Ca++, increases the conversion of vit D to its active form in the kidneys, increases urinary phosphate excretion (lowers serum phosphate), and augments GI Ca++ absorption. the net result: an increase in the level of free Ca++, which inhibits PTH secretion. |
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Term
| what is hypercalcemia often due to? |
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Definition
| increased PTH levels and/or malignancies (most CA is osteoclastic w/the exception of prostate CA). |
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Term
| how can CA lead to hypercalcemia? |
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Definition
| if CA mets to bone = resorption of Ca++ from that bone. also, solid tumors may secrete a PTH-like hormone, *PTHrP, which promotes expression of the receptor activator of nuclear factor kappa beta ligand (*RANKL) on osteoblasts (which is an osteoclast differentiation factor that binds to RANK on the surface of osteoclast progenitor cells - promoting their differentiation to osteoclasts). *osteoprotegrin is a decoy receptor of RANKL, which removes excess ligand and prevents unbalanced bone absorption - but PTHrP can inhibit osteoprotegrin secretion = increased osteoclastogenesis. |
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Term
| what characterizes primary hyperparathyroidism? |
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Definition
| primary hyperparathyroidism is a common endocrine disorder and important cause of hypercalcemia. causes include: adenomas, primary hyperplasia, and more rarely parathyroid CA. primary hyperparathyroidism is more common in adult women and the *most common cause is a sporadic solitary parathyroid adenoma. familial primary hyperparathyroidism is associated with MEN-1, MEN-2 and familial hypocalciuric hypercalcemia. |
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Term
| how does MEN-1 lead to primary hyperparathyroidism? |
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Definition
| the inactivated MEN-1 gene on chr 11 is seen in *parathyroid adenomas and *parathyroid hyperplasia. |
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Term
| how does MEN-2 lead to primary hyperparathyroidism? |
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Definition
| this is associated w/activating mutations in the tyrosine kinase receptor RET on chr 10 leading to *parathyroid hyperplasia. |
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Term
| how does familial hypocalciuric hypercalcemia lead to primary hyperparathyroidism? |
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Definition
| this autosomal dominant disorder is associated w/enhanced parathyroid function due to *decreased sensitivity to extracellular Ca++ from inactivating mutations in parathyroid Ca++ sensing receptor gene (*CASR) on chr 3. |
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Term
| what 2 molecular defects contribute to sporadic parathyroid adenoma formation? |
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Definition
| *cyclin D1 gene inversions: cyclin D1 protein is overexpressed, causing cells to proliferate. *MEN1 mutations: even some parathyroid tumors not associated w/MEN syndrome have mutations in both MEN gene copies. |
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Term
| how do parathyroid adenomas appear grossly? histologically? |
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Definition
| grossly: usually solitary, well circumscribed, soft, tan reddish-brown nodules with a capsule. histologically: chief cells are uniform w/polygonal shape and small central nuclei (though some pleomorphic cells may be seen). minimal fat is seen and glands outside the adenoma are normal/slightly shrunken. nests of larger oxyphil cells may also be seen - there is a subtype of parathyroid adenoma called an "oxyphil adenoma". |
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Term
| what characterizes primary parathyroid hyperplasia? |
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Definition
| this is more likely to involve all 4 glands (diffuse form) and may occur sporadically or as part of MEN syndrome. generally the hyperplasia consists of chief cells w/minimal fat. |
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Term
| what do skeletal changes in hyperparathyroidism consist of? |
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Definition
| there is an *increased number of osteoclasts which erode bone matrix to mobilize Ca++ salts (esp in the metaphyses of long bones), bone resorption is *associated w/increased osteoblast activity and the formation of new boney trabeculae (though possibly abnormal), *brown tumor formation (aggregates of osteoclasts, hemorrhage, and giant cells - *resemble neoplasms), and a *thinned cortex w/the *marrow containing large amounts of fibrous tissue w/foci of hemorrhage and cyst formation (osteitis fibrosa cystica). |
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Term
| what are some systemic effects of hyperparathyroidism? |
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Definition
| renal stones (due to hypercalcemia), calcification of the renal tubules/interstitium, and metastatic calcification of the stomach/lungs/myocardium/blood vessels may be seen (metastatic Ca++ deposition occurs usually in the context of hypercalcemia, while dystrophic deposition does not). |
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Term
| what characterizes parathyroid CA? |
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Definition
| this is rare and can mimic an adenoma - may be circumscribed or clearly invasive. grossly, parathyroid CA usually involves one parathyroid w/an irregular mass that may be greater than 10 g. histologically: cells are uniform, can resemble normal cells (histology unreliable) and grow in trabecular patterns w/a dense capsule (hard to differentiate from an adenoma). invasion of surrounding tissue/metastasis must be established to make the dx of malignancy. |
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Term
| what is asymptomatic hyperparathyroidism? |
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Definition
| asymptomatic hyperparathyroidism is usually due to primary hyperparathyroidism which has not had time to manifest itself clinically and may detected through routine blood work. |
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Term
| what will hormone studies show for primary hyperparathyroidism? nonparathyroid disease? non-parathyroid tumors? |
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Definition
| primary hyperparathyroidism: inappropriately elevated PTH relative to serum Ca++. non-parathyroid disease: low to undetectable PTH. non-parathyroid tumors: these may secrete PTHrP. |
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Term
| how will an increase in PTH affect phosphate levels? how might secondary renal disease affect this? |
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Definition
| increased PTH = hypophosphatemia due to increased urinary secretion of phosphate. secondary renal disease may lead to phosphate retention w/normalization of phosphate serum levels. |
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Term
| what characterizes symptomatic primary hyperparathyroidism? |
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Definition
| bone disease: bone pain w/fractures of bones weakened by osteoporosis or osteitis fibrosa cystica. renal: nephrolithiasis w/pain and obstructive uropathy. GI: constipation, nausea, peptic ulcers, pancreatitis, and gallstones. CNS: depression, lethargy, seizures. neuromuscular abnormalities: weakness and fatigue. cardiac: calcifications on the aortic/mitral valve. these signs and symptoms all reflect the effects of increased PTH secretion and hypercalcemia. |
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Term
| what is characterizes secondary hyperparathyroidism? |
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Definition
| secondary hyperthyroidism can arise in any condition that causes chronic hypocalcemia (results in compensatory overactivity of the parathyroids), *renal failure being the most common cause but decreased dietary Ca2+, malabsorption w/steatorrhea (IBS etc), and vit D deficiency (pts w/less sun exposure) are also potential causes. |
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Term
| what characterizes chronic renal failure as a cause of secondary hypoparathyroidism? |
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Definition
| chronic renal failure causes decreased phosphate excretion = hyperphosphatemia, which leads to decreased serum Ca2+ levels and stimulation of parathyroid gland activity. loss of renal parenchyma also reduces the availability of alpha 2 hydroxylase which is needed for the synthesis of active vit D, which causes a decrease in the intestinal absorption of Ca2+, again leading to hyperparathyroidism. |
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Term
| what characterizes parathyroid glands affected by secondary hyperparathyroidism? |
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Definition
| the glands are hyperplastic, but not necessarily symmetric. there are increased numbers of chief cells, fat cells are decreased, and bone changes are similar to primary hyperparathyroidism. |
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Term
| what effects does hyperparathyroidism have systemically? |
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Definition
| metastatic calcifications may appear in the lung, heart, stomach and blood vessels (may cause ischemia). however, symptoms are usually dominated by chronic renal failure. |
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Term
| what is tertiary hypoparathyroidism? |
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Definition
| this occurs when parathyroid activity becomes autonomous (loss of negative feedback) and excessive = hypercalcemia |
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Term
| what characterizes hypoparathyroidism? etiologies? |
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Definition
| this is more rare than the hyper- variant and is often aquired through removal of the glands during sx. autoimmune polyendocrine syndrome type 1 (APS1) can also cause hypoparathyroidism which is associated w/mucocutaneous candidiasis and primary adrenal insufficiency. genetically: autosomal dominant hypoparathyroidism can occur due to gain of function mutations in the Ca2+ sensing receptor (CASR) which suppresses PTH, causing hypocalcemia and hypercalciuria, familial isolated hypoparathyroidism, and congenital absence of the parathyroid glands which may be seen in conjunction w/thymic dysplasia (digeorge) and/or cardiac defects. |
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Term
| what are the clinical manifestations of hypoparathyroidism? |
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Definition
| tetany (neuromuscular irritability due to decreased serum Ca2+: numbness, laryngospasm, or seizures), chvostek sign (tapping of the facial nerve: contraction of the eye, nose, and mouth), trousseau sign (carpal spasms produced by BP cuff occlusion), mental status changes (emotional instability, anxiety, depression psychosis, and hallucinations), intracranial manifestations (calcifications of the basal ganglia due to increased phosphate levels and thus deposits of locally produced Ca2+ = parkinsons-like movement + increased ICP), ocular disease (calcification of the lens w/cataract formation), CV manifestations (conduction defect w/prolongation of the QT interval), and dental abnormalities (dental hypoplasia, failure of teeth eruption, and defective enamel+caries) |
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Term
| what is pseudohypoparathyroidism? |
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Definition
| PTH levels are normal/elevated but defects in G-protein triggered second messengers = end organ resistance to the actions of PTH. this presents as hypocalcemia, hyperphosphatemia, and elevated PTH. |
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