Hyperparathyroidism, primary secondary

The rate of osteosarcoma in animal and human trials of parathyroid hormone has been reviewed (20,6). Rats treated with parathyroid hormone for 2 years had a high dose-dependent rate of osteosarcoma, up to 48% in animals given 75 micrograms/kg human trials were therefore interrupted (21). However, the anabolic effect of parathyroid hormone is much greater and occurs much earlier in rats than in humans, possibly because of fundamental differences in bone biology moreover, osteosarcoma has never been associated with primary, secondary, or tertiary hyperparathyroidism in humans (20). There has been no evidence of osteosarcoma in several hundred patients involved in parathyroid hormone clinical trials lasting up to 3 years, after 5 years minimum follow-up (20). 

Q6 The cause of excessive PTH secretion maybe primary, secondary, or tertiary. In primary hyperparathyroidism one or more glands show exaggerated functions, do not respond to the normal feedback via serum calcium and secrete PTH autonomously. However, the most common cause (80% of the cases) is a benign tumour of parathyroid tissue in one of the glands. Secondary hyperparathyroidism is due to the development of hypocalcaemia. There is an increase in the level of PTH however, the kidneys, which are major target organs for this hormone, fail to respond and therefore the level of calcium remains low. In tertiary hyperparathyroidism, which occurs in chronic renal failure, the hyperplastic parathyroid cells lose their sensitivity to circulating calcium levels. This leads to autonomous secretion of PTH. 

Increased renal losses of phosphorus can occur in hyperparathyroid (primary and secondary) patients with normal renal function and... 

Hyperparathyroidism results from oversecretion of PTH. This condition leads to excessive bone turnover and demineralization and must be treated by removal of the parathyroid gland. The disorder is classified into primary, secondary, and tertiary hyperparathyroidism. Sporadic primary hyperparathyroidism is the third most common endocrine disorder, after diabetes and hyperthyroidism. It is most common in females older than 55 years of age and the leading cause is a single adenoma, which secretes the hormone constitu-tively, without regulation. Symptoms can include osteopenia and bone fractures, renal stones resulting from hypercalciuria, peptic ulcer disease, and pancreatitis. In milder cases, patients are asymptomatic or suffer only muscle weakness, fatigue, and/or depression. 

Primary hyperparathyroidism occurs as a result of hyperplasia or the occurrence of adenoma. Secondary hyperparathyroidism may result from renal failure because of the associated phosphate retention, resistance to the metabolic actions of PTH, or impaired vitamin D metabolism. The last-mentioned factor is primarily responsible for the development of osteomalacia. Muscle symptoms are much more common in patients with osteomalacia than in primary hyperparathyroidism. Muscle biopsy has revealed disseminated atrophy, sometimes confined to type 2 fibers, but in other cases involving both fiber types. Clinical features of osteomalacic myopathy are proximal limb weakness and associated bone pain the condition responds well to treatment with vitamin D. 

Contraindications Primary or secondary hyperparathyroidism, including hypercalci-uria (renal calcium leak), hypomagnesemic states (serum magnesium less than 1.5 mg/dl), bone disease (osteoporosis, osteomalacia, osteitis), hypocalcemic states (e.g., hypoparathyroidism, intestinal malabsorption), normal or low intestinal absorption and renal excretion of calcium, enteric hyperoxaluria, and patients with high fasting urinary calcium or hypophosphatemia. 

This rather common disease, if associated with symptoms and significant hypercalcemia, is best treated surgically. Oral phosphate and bisphosphonates have been tried but cannot be recommended. Asymptomatic patients with mild disease often do not get worse and may be left untreated. The calcimimetic agent cinacalcet, discussed previously, has been approved for secondary hyperparathyroidism and is in clinical trials for the treatment of primary hyperparathyroidism. If such drugs prove efficacious, medical management of this disease will need to be reconsidered. 

Polymorphisms in the VDR gene may be related to bone mineral density and predispose an individual to osteoporosis [337], The use of restriction length fragment polymorphism (RFLP) analysis and other markers of VDR polymorphisms could be an additional early assessment parameter for the future risk of developing osteoporosis. Identification of the defective allele also referred to as BB or bb, depending on the laboratory from which the studies first originated, has been correlated to an increased risk of primary and secondary osteoporosis and primary hyperparathyroidism. But... 

Primary or secondary hyperparathyroidism Renal tubular defects... 

Elevated concentrations of telopeptides and DPD have been reported in osteoporosis, Paget s disease, metastatic bone disease, primary and secondary hyperparathyroidism, hyperthyroidism, and other diseases with increased bone... 

A. D Amour P, Brossard I-H, Rousseau L, Roy L> Gao P, Cantor T. Amino-terminal form of parathyroid hormone (PTH) with immunologic similarities to hPTH(l-84) is overproduced in primary and secondary hyperparathyroidism. Clin Chem 2003 49 2037-44. 

Marked elevations of plasma peptide hydroxyproline have been observed by Dubovsky et al. in chronic renal failure (D7). The highest levels were seen when uremia and severe bone disease occurred together. Removal of the parathyroids in four patients (three primary and one secondary hyperparathyroidism) was associated with return to normal levels when renal function was normal, and significant reduction when renal failure was present. It seems possible that plasma peptide hydroxyproline might be a rapidly changing and sensitive indicator of bone metabolism which could be studied even with renal impairment, a major obstacle to most current techniques in the diagnosis of hyperparathyroid states. 

Franceschini N, Joy MS, Kshirsagar A. Cincacet HCl a calcimimetic agent for the management of primary and secondary hyperparathyroidism. Expert Opin Investig Drugs 2003 12 1413-1421. 

The most common cause of hypercalcemia in outpatients is primary hyperparathyroidism, due either to a single adenoma or diffuse hyperplasia. Primary hyperparathyroidism is often associated with significant hypophosphatemia due to PTH effects on renal phosphate reabsorption. The diagnosis is generally apparent from the elevated serum CcP associated with an inappropriately high PTH level. In contrast, secondary hyperparathyroidism is a disorder in which PTH levels are elevated in response to persistent threats to norrruil calcium homeostasis such as hyperphosphatemia from chronic renal disease. 

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. 

Although all cases of renal insufficiency may lead to moderate hyperplasia of the parathyroid associated with mild signs of demineralization of the skeleton, only in those cases in which slow and progressive destruction of the renal parenchyma occurs does renal osteitis fibrosa cystica generalisata (a disease resembling von Recklinghausen s disease) develop. In these advanced cases, metastatic calcification in soft tissue may also be found. Renal biopsy may prove useful in the differential diagnosis of primary and secondary hyperparathyroidism. 

Many conditions result in the increased concentration of special solutes in the urine, and many of these have been or will be described in more detail in other chapters. For example, primary or secondary hyperparathyroidism releases calcium from bone and leads to its precipitation in kidneys. In some inborn errors of metabolism, metabolites accumulate in the blood, are excreted in the kidney, and under the appropriate conditions are precipitated in the excretory system. Gout, cysteinuria, and oxaluria are among those diseases that cause renal lithiasis. 

Bone conditions Elevated levels are found in those bone diseases which have increased osteoblastic activity, the highest levels being found in bone cancers and in Paget s disease (osteitis deformans). Moderate increases are found in osteomalacia, rickets and primary and secondary hyperparathyroidism. The raised serum alkaline phosphatase of normal children is due to increased osteoblastic activity. 

Hypermagnesuria is encountered in the case of metabolic and iatrogenic disorders, such as primary and secondary hyperaldosteronism (extracellular volume expansion), hypercalcemia (competition Ca/Mg at the thick ascending loop of Henle), hyperparathyroidism, and phosphate or potassium depletion. Hypermagnesuria may also result from tubulopathy, as the selective defect of the Mg tubular reabsorption (chromosome Hq23), Bartter s syndrome (thick ascending loop of Henle), or Gitelman s syndrome (distal convoluted tubule). 

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