Hyperparathyroidism Carcinoma

Thiazides inhibit NaCI reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Q transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria. 

A. Although all of the conditions can present as an asymptomatic nodule in the thyroid, the marked hypercalcemia in this patient makes hyperparathyroidism the probable diagnosis. Carcinomas of the thyroid are common, and outcomes are improved with early diagnosis. Medullary carcinoma and hyperparathyroidism caused by hyperplasia may be inherited and are associated with the multiple endocrine neoplasia syndromes. 

Cinacalcet is the first representative of a new class of drugs that activates the calcium sensing receptor (CaR). CaR is widely distributed but has its greatest concentration in the parathyroid gland. Cinacalcet blocks PTH secretion by this mechanism and is approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of parathyroid carcinoma. 

Cinacalcet (Sensipar) [Hyperparathyroidism Agent/ Calcimimetic] Uses Secondary hyperparathyroidism in CRF T Ca2+ in parathyroid carcinoma Action 4- PTH by T Ca-sensing receptor sensitivity Dose ... 

Secondary> hyperparathyroidism 30 mg PO daily Parathyroid carcinoma 30 mg PO bid titrate q2—4wk based on Ca PTH levels swallow whole take w/ food Caution [C, /—] w/ Szs Disp Tabs SE N/V/D, myalgia, dizziness, 4- Ca2+ Interactions T Effects W/ CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin T effects OF drugs metabolized at CYP2D6 such as TCA, thioridazine, flecainide, vinblastine EMS Monitor ECG for signs of hypocalcemia (T QT interval) OD May cause severe hypocalcemia calcium salts can be given... 

In hyperkalaemia, oral administration or retention enemas of a polystyrene sulphonate resin may be used. A sodium phase resin (Resonium A) should obviously not be used in patients with renal or cardiac failure as sodium overload may result. A calcium phase resin (Calcium Resonium) may cause hypercalcaemia and should be avoided in predisposed patients, e.g. those with multiple myeloma, metastatic carcinoma, hyperparathyroidism and sarcoidosis. Enemas should be retained for as long as possible, although patients rarely manage for... 

One female and one male patient had hyperparathyroidism with elevated serum alkaline phosphatase activities and extensive bone changes characteristic of generalized osteitis fibrosa cystica. In both instances, the serum acid phosphatase activity of the serum fell to normal values after removal of the parathyroid adenoma despite transitorily increased serum alkaline phosphatase activity. The fifth patient was a female with osteopetrosis involving the major part of the skeleton. The serum acid phosphatase was 8.7 K.A. units, the highest in the control series— yet the serum alkaline phosphatase was within normal limits. It would appear, therefore, that some patients with skeletal disease may have a slight but definitely elevated serum acid phosphatase activity, at least as determined by the Gutman method (GIO, G14), which cannot be explained by concurrent prostatic carcinoma or by a spillover of alkaline phosphatase activity to a pH of 5.0. 

Primary hyperparathyroidism is characterized by excessive secretion of PTtI that results in hypercalcemia. It is most often due to a solitary adenoma (80% to 85% of cases), less frequently (about 15%) due to chief cell hyperplasia involving all glands, and rarely due to parathyroid carcinoma (<1%). 

Primary hyperparathyroidism results from hyperplasia, adenoma, or carcinoma of the parathyroid glands and from ectopic production of the hormone by squamous cell carcinoma of the lung or by adenocarcinoma of the kidney. In about 10% of hyperparathyroidism, hyperplasia or tumors of the parathyroid glands occur due to familial disorders known as multiple endocrine neoplasia (MEN). MEN syndromes consist of three subtypes (I, IIA, IIB) and are... 

A review of the use of cinacalcet HCl for secondary hyperparathyroidism is provided in Chap. 44. Cinacalcet HCl is administered at a starting dose of 30 mg given orally twice daily for the treatment of parathyroid carcinoma. The dosage is titrated every 2 to 4 weeks in 30-mg increments twice daily. The maximum approved dosage is 90 mg three to four times daily. 

Til. Gill AJ, Clarkson A, Gimm O, et al. Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor associated adenomas from sporadic parathyroid adenomas and hyperplasias. Am Surg Pathol. 2006 30 1140-1149. 

The drug presently has its main carcinolytic indication in the treatment of testicular carcinoma. An unrelated effect, probably on osteoclast bone cells, leads to a significant reduction of plasma calcium at one-tenth the antineoplastic dose. This has been useful in hypercalcemia of malignancy, Paget s disease, and hyperparathyroid conditions. 

In MEN type Ha. medullary carcin-omaof thyroid is present with hyperparathyroidism and bilateral adrenal phaeochromocytomas. Medullary carcinoma of thyroid is diagnosed on the basis of elevated calcitonin concentrations in serum, although provocation tests, such as a calcium infusion and/or administration of pentagastrin. may be necessary to demonstrate the abnormal calcitonin regulation (Fig., 1). Diagnosis of phacochromocytoma is not easy (p. 126). 

Cinacalcet is a calcimimetic agent that lowers parathyroid hormone (PTH) levels by increasing sensing receptor to extracellular calcium. This drug is indicated in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and hypercalcemia in patients with parathyroid carcinoma. 

Cinacalcet is available in 30-, 60-, and 90-mg tablets. Optimal doses have not been defined. The recommended starting dose for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis is 30 mg once daily, with a maximum of 180 mg/day. For treatment of parathyroid carcinoma, a starting dose of 30 mg twice daily is recommended, with a maximum of 90 mg four times daily. The starting dose is titrated upward every 2 to 4 weeks to maintain the PTH level between 150 and 300 pg/mL (secondary hyperparathyroidism) or to normalize serum calcium (parathyroid carcinoma). The principal adverse event with cinacalcet is hypocalcemia. Thus, the drug should not be used if the initial serum calcium concentration is less than 8.4 mg/dL serum calcium and phosphorus concentrations should be measured within 1 week, and PTH should be measured within 4 weeks after initiating therapy or after changing dosage. 

Calcimimetics mimic the action of calcium via the CaSR to inhibit PTH secretion by the parathyroid glands. Because of this enhanced sensitivity, they decrease PTH secretion for any given level of Ca. The calcimimetic cinacalcet (sensipar) is FDA-approved for the treatment of secondary hyperparathyroidism due to chronic renal disease and for patients with hypercalcemia associated with parathyroid carcinoma (Figure 61-9). In clinical trials, cinacalcet also effectively reduced PTH levels in patients with primary hyperparathyroidism and normalized serum calcium without altering bone mineral density for up to 2 years. 

In patients with hypercalcemia, treatment with a loop diuretic plus saline promotes calcium excretion and helps lower serum calcium. In patients with intact regulatory function, increases in calcium resorption promoted by thiazides have minor impact on serum calcium due to buffering in bone and gut. However, thiazides can unmask hypercalcemia that occurs in diseases that disrupt normal calcium regulation (eg, hyperparathyroidism, sarcoidosis, carcinoma). 

Elevated calcium concentrations in semm or plasma occur (besides increased intake) in different diseases. The reasons are excessive mobilization of calcium from the bones in diverse carcinomas (mamma, bronchus, kidney), endocrine dysregulations (hyperparathyroidism), or renal dysfunctions (diuretic phase after acute renal insufficiency). 

The tumors of the parathyroid that can cause hyperparathyroidism are of four different histological varieties adenoma, wasserhelle cell hyperplasia, chief cell hyperplasia, and carcinoma (see Fig. 5-8). 

Carcinomas of the parathyroid are rare. Only 1-4% of all cases of hyperparathyroidism are associated with the development of a carcinoma. The criteria for malignancy in cancer of the parathyroid are invasion, recurrence, and metastasis. Metastases are most common in the local lymph nodes, and the tumor, instead of being easy to decapsulate, strongly adheres to the surrounding tissue. Without clear-cut invasion of the capsule of the parathyroid or the development of metastasis, carcinomas may be difficult to diagnose. 

A comparison with the acid phosphatase (s) which may be increased in carcinoma of the prostate, Paget s disease, certain liver diseases, and hyperparathyroidism showed that the acid phosphatase of Gaucher s disease can be differentiated from the former with the use of various activators and inhibitors (Grundig et al. 1965). In contrast to prostatic phosphatases it is not inhibited by L-tartrate... 

If the semm calcium is greater than 11 mg/dL, the patient has nephrolithiasis, or the serum creatinine is elevated, dmg therapy is usually required. The drug of choice is prednisone at an initial daily dose of 20 to 40 mg/day (183). Corticosteroids cause a rapid decline in serum calcium within 5 days and in urinary calcium excretion in 7 to 10 days (183). Failure of the serum calcium to normalize within two weeks on this corticosteroid regimen should alert the clinician to an alternate or coexisting disorder such as hyperparathyroidism, lymphoma, carcinoma, and myeloma (183). Once the calcium disorder is brought under control, the corticosteroid dose can be lowered over four to six weeks (183). The serum calcium and urinary calcium excretion rate should be closely monitored. If the patient develops intolerable corticosteroid side effects or fails to respond, chloroquine (184), hydroxychloroquine (185), and ketoco-nizole (186) have been used successfully. 

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