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Hyperparathyroidism is due to increased activity of the parathyroid glands, either from an intrinsic abnormal change altering excretion of parathyroid hormone (primary or tertiary hyperparathyroidism) or from an extrinsic abnormal change affecting calcium homoeostasis stimulating production of parathyroid hormone (secondary hyperparathyroidism). Primary hyperparathyroidism is the third most common endocrine disorder, with the highest incidence in postmenopausal women. Asymptomatic disease is common, and severe disease with renal stones and metabolic bone disease arises less frequently now than it did 20–30 years ago. Primary hyperparathyroidism can be cured by surgical removal of an adenoma, increasingly by minimally invasive parathyroidectomy. Medical management of mild disease is possible with bisphosphonates, hormone replacement therapy, and calcimimetics. Vitamin D deficiency is a common cause of secondary hyperparathyroidism, particularly in elderly people. However, the biochemical definition of vitamin D deficiency and its treatment are subject to much debate. Secondary hyperparathyroidism as the result of chronic kidney disease is important in the genesis of renal bone disease, and several new treatments could help achieve the guidelines set out by the kidney disease outcomes quality initiative.

This article reviews the differential diagnosis and management of primary hyperparathyroidism. For most patients, parathyroidectomy (usually by a minimally invasive approach) is recommended, but surveillance is an option for asymptomatic patients who meet certain criteria. Foreword This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Stage A 62-year-old woman is found on routine laboratory testing to have a serum calcium level of 10.8 mg per deciliter (2.7 mmol per liter) (normal range, 8.4 to 10.4 [2.1 to 2.7]). The serum intact parathyroid hormone (PTH) concentration is 70 pg per milliliter (normal range, 15 to 75). Her history is notable only for hypertension that is well controlled with an angiotensin-receptor blocker; there is no history of kidney stones or fractures. Her family history is negative for hypercalcemia or endocrine tumors. Her 24-hour urinary calcium and creatinine levels are 280 mg and 1050 mg, respectively, and the ratio . . .

A 58-year-old man is found on laboratory testing to have a serum calcium level of 6.0 mg per deciliter (normal range, 8.5 to 10.5), an albumin level of 3.9 g per deciliter, and a phosphorus level of 6.0 mg per deciliter (normal range, 2.5 to 4.5). His medical history is notable only for long-standing hearing difficulties. He reports no history of neck surgery and is asymptomatic. His ionized calcium level is 0.75 mmol per liter (normal range, 1.10 to 1.32). How should his case be further evaluated and treated? A 58-year-old man is found on laboratory testing to have a serum calcium level of 6.0 mg per deciliter, an albumin level of 3.9 g per deciliter, and a phosphorus level of 6.0 mg per deciliter. His ionized calcium level is 0.75 mmol per liter. How should his case be further evaluated and treated? Foreword This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations. Stage A 58-year-old man is found on laboratory testing to have a serum calcium level of 6.0 mg per deciliter (1.5 mmol per liter) (normal range, 8.5 to 10.5 mg per deciliter [2.1 to 2.6 mmol per liter]), an albumin level of 3.9 g per deciliter, and a phosphorus level of 6.0 mg per deciliter (1.94 mmol per liter) (normal range, 2.5 to 4.5 mg per deciliter [0.81 to 1.45 mmol per liter]). His medical history is notable only for long-standing hearing difficulties. He reports no history of neck surgery and no throat tightness, muscle cramps, paresthesias, or seizures. His . . .

Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid glands to FGF23 in rats with the dietary adenine-induced model of chronic kidney disease. Quantitative immunohistochemical and reverse transcription–PCR analysis using laser capture microscopy showed that both Klotho and FGFR1 protein and mRNA levels were decreased in histological sections of the parathyroid glands. Recombinant FGF23 failed to decrease serum parathyroid hormone levels or activate the mitogen-activated protein kinase signaling pathway in the glands of rats with advanced experimental chronic kidney disease. In parathyroid gland organ culture, the addition of FGF23 decreased parathyroid hormone secretion and mRNA levels in control animals or rats with early but not advanced chronic kidney disease. Our results show that because of a downregulation of the Klotho–FGFR1c receptor complex, an increase of circulating FGF23 does not decrease parathyroid hormone levels in established chronic kidney disease. This in vivo resistance is sustained in parathyroid organ culture in vitro.

Hypercalcemia and hyperphosphatemia often complicate secondary hyperparathyroidism therapy in patients who are receiving dialysis. Unlike vitamin D and calcium, calcimimetic agents target the calcium-sensing receptor. This study reports the safety and effectiveness of the calcimimetic agent cinacalcet in patients receiving dialysis who had uncontrolled hyperparathyroidism. The mean parathyroid hormone values decreased 43 percent with cinacalcet therapy but increased 9 percent with placebo, and the calcium–phosphorus product declined with cinacalcet but not placebo. The safety and effectiveness of a calcimimetic agent in patients receiving dialysis. Secondary hyperparathyroidism is common in patients with chronic kidney disease, affecting most of those who are receiving hemodialysis. 1 , 2 The disorder is characterized by persistently elevated levels of parathyroid hormone and complicated by important disturbances in mineral metabolism. 3 Bone disease is the most widely recognized consequence of secondary hyperparathyroidism. 4 Several reports indicate, however, that alterations in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism or the therapeutic measures used to manage it, contribute to soft-tissue and vascular calcification, cardiovascular disease, and the risk of death. 5 – 10 Episodes of hypercalcemia and hyperphosphatemia are often aggravated by the use . . .

We compared the effects of calcitriol and doxercalciferol, in combination with either calcium carbonate or sevelamer, on bone, mineral, and fibroblast growth factor-23 (FGF-23) metabolism in patients with secondary hyperparathyroidism. A total of 60 pediatric patients treated with peritoneal dialysis were randomized to 8 months of therapy with either oral calcitriol or doxercalciferol, combined with either calcium carbonate or sevelamer. Bone formation rates decreased during therapy and final values were within the normal range in 72% of patients. A greater improvement in eroded surface was found in patients treated with doxercalciferol than in those given calcitriol. On initial bone biopsy, a mineralization defect was identified in the majority of patients which did not normalize with therapy. Serum phosphate concentrations were controlled equally well by both binders, but serum calcium levels increased during treatment with calcium carbonate, and serum parathyroid hormone levels were decreased by 35% in all groups. Baseline plasma FGF-23 values were significantly elevated and rose over fourfold with calcitriol and doxercalciferol, irrespective of phosphate binder. Thus, doxercalciferol is as effective as calcitriol in controlling serum parathyroid hormone levels and suppressing the bone formation rate. Sevelamer allows the use of higher doses of vitamin D. Implications of these changes on bone and cardiovascular biology remain to be established.

Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Secondary hyperparathyroidism (HPT) and abnormal mineral metabolism are thought to play an important role in bone and cardiovascular disease in patients with chronic kidney disease. Cinacalcet, a calcimimetic that modulates the calcium-sensing receptor, reduces parathyroid hormone (PTH) secretion and lowers serum calcium and phosphorus concentrations in patients with end-stage renal disease (ESRD) and secondary HPT. We undertook a combined analysis of safety data (parathyroidectomy, fracture, hospitalizations, and mortality) from 4 similarly designed randomized, double-blind, placebo-controlled clinical trials enrolling 1184 subjects (697 cinacalcet, 487 control) with ESRD and uncontrolled secondary HPT (intact PTH ≥300 pg/mL). Cinacalcet or placebo was administered to subjects receiving standard care for hyperphosphatemia and secondary HPT (phosphate binders and vitamin D). Relative risks (RR) and 95% CI were calculated using proportional hazards regression with follow-up times from 6 to 12 months. Health-related quality-of-life (HRQOL) data were obtained from the Medical Outcomes Study Short Form-36 (SF-36), and the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument (KDQOL-CF). Randomization to cinacalcet resulted in significant reductions in the risk of parathyroidectomy (RR 0.07, 95% CI 0.01-0.55), fracture (RR 0.46, 95% CI 0.22-0.95), and cardiovascular hospitalization (RR 0.61, 95% CI 0.43-0.86) compared with placebo. Changes in HRQOL favored cinacalcet, with significant changes observed for the SF-36 Physical Component Summary score and the specific domains of Bodily Pain and General Health Perception. Combining results from 4 clinical trials, randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical function and diminished pain. These data suggest that, in addition to its effects on PTH and mineral metabolism, cinacalcet had favorable effects on important clinical outcomes.

Secondary hyperparathyroidism is associated with mortality in patients undergoing maintenance dialysis treatment. We studied 515 male US veterans with chronic kidney disease, who were not yet on dialysis, to see what outcomes were associated with secondary hyperparathyroidism in this population. Relationships between intact parathyroid hormone levels and all-cause mortality along with the composite of mortality or incidence of dialysis were measured in unadjusted and adjusted Cox models for case-mix and laboratory variables. Elevated parathyroid hormone levels above the upper limit compared to the lower limit of the normal range were significantly associated with mortality after adjustments. Higher intact parathyroid hormone levels in the upper limit of normal were significantly associated with higher mortality overall and showed similar trends in subgroups of patients with stage 3 and stage 4–5 chronic kidney disease and with higher and lower serum calcium and phosphorus levels. Similar associations were found with the composite outcome of mortality or dialysis. Our study shows that secondary hyperparathyroidism is independently associated with higher mortality in patients with chronic kidney disease but not yet on dialysis.

The identification of the calcium-sensing receptor (CaSR) and the clarification of its role as the major regulator of parathyroid gland function have important implications for understanding the pathogenesis and evolution of secondary hyperthyroidism in chronic kidney disease (CKD). Signaling through the CaSR has direct effects on three discrete components of parathyroid gland function, which include parathyroid hormone (PTH) secretion, PTH synthesis, and parathyroid gland hyperplasia. Disturbances in calcium and vitamin D metabolism that arise owing to CKD diminish the level of activation of the CaSR, leading to increases in PTH secretion, PTH synthesis, and parathyroid gland hyperplasia. Each represents a physiological adaptive response by the parathyroid glands to maintain plasma calcium homeostasis. Studies of genetically modified mice indicate that signal transduction via the CaSR is a key determinant of parathyroid cell proliferation and parathyroid gland hyperplasia. Because enlargement of the parathyroid glands has important implications for disease progression and disease severity, it is possible that clinical management strategies that maintain adequate calcium-dependent signaling through the CaSR will ultimately prove useful in diminishing parathyroid gland hyperplasia and in modifying disease progression.

Because mutations in the parafibromin gene ( HRPT2 ) occur in a familial syndrome characterized by susceptibility to parathyroid carcinoma, such mutations were sought and found in patients with sporadic cases of parathyroid carcinoma. Moreover, germ-line mutations of HRPT2 were found in some patients with apparently sporadic parathyroid carcinoma. Germline mutations of HRPT2 in sporadic cases. Parathyroid carcinomas are an uncommon and often devastating cause of primary hyperparathyroidism. 1 , 2 These cancers characteristically result in more profound clinical manifestations of hyperparathyroidism than do parathyroid adenomas, the most frequent cause of primary hyperparathyroidism. If a parathyroid carcinoma spreads to distant sites, it can cause relentless hypercalcemia and severe metabolic complications that are notoriously difficult to control and often result in death. Affected patients may require repeated palliative surgical extirpation of metastatic nodules. 1 – 3 Early en bloc resection of the primary tumor is the only curative treatment. Because the histopathological features of parathyroid carcinoma and adenoma may overlap, a . . .