In 1941, Albright suggested that tumors may produce a substance with similar activity but chemically distinct from parathyroid hormone (PTH), to account for the hypercalcemia occurring during the course of certain malignancies (1). Forty years later, PTH-like bioactivity was found in serum of hypercalcemic cancer patients in 1981 (2) and identified in tumors associated with humoral hypercalcemia of malignancy in 1983 (3). This syndrome, which comprises increased renal tubular reabsorption of calcium and decreased renal tubular maximal transport of phosphate, together with elevated cyclic AMP production (4), can be encountered in the absence or in the presence of bone metastases (5). It can be reproduced in experimental animals by the implantation of non-metastasing tumors, indicating a humoral mechanism (6). Although this biochemical configuration, which can be observed in approximately 50% of the patients with malignant hypercalcemia (5), strongly suggests an excess of circulating PTH, the levels of the latter, measured
René Rizzoli and Serge Ferrari
René Rizzoli and Patrick Ammann
As stated in the conclusions of a recent consensus development conference on primary hyperparathyroidism (PHP), all patients with this disease should be considered as candidates for surgery, particularly those under the age of 50, since the outcome of several decades of PHP is not known (4). Potential indications to surgery could be total plasma calcium of more than 0.25 mmol/l above the upper limit of normal range, the presence of renal stone or of a marked elevation of daily urinary calcium excretion, significantly reduced creatinine clearance or substantially decreased bone mineral density. When performed by an experienced surgeon, surgical removal of abnormal gland(s)—solitary adenoma accounting for more than 9 out of 10 cases of PHP—is usually an efficacious and definitive therapy, even leading to a partial recovery of bone mass reduction (12). If a conservative strategy is adopted, the cost of careful follow-up should also be considered, since a twice
René Rizzoli and Jean-Philippe Bonjour
Parathyroid hormone (PTH) is a major regulator of calcium and phosphate metabolism. The peptide, composed of 84 amino acids, is the main secreted and circulating form of bioactive PTH (1). Its secretion by the parathyroid cells is under the control of extracellular calcium concentrations, which are recognized by a membrane-associated polypeptide structure characterized by seven transmembrane domains (2). In response to increasing calcium concentrations, this structure transmits a signal inside the cells through a pertussis toxin-sensitive mechanism, which leads to a reduction of PTH secretion. The gene coding for this calcium sensor has been cloned and several mutations reported, which can account for a number of disturbances in the relationship between PTH secretion and calcium concentrations such as familial benign hypocalciuric hypercalcemia or some cases of familial hypoparathyroidism (3). PTH and its tumoral analog parathyroid hormone-related protein (PTHrP) (4) share and interact with a membrane-associated receptor, which is connected with
Andrea Trombetti, Laura Richert, Karine Hadaya, Jean-Daniel Graf, François R Herrmann, Serge L Ferrari, Pierre-Yves Martin and René Rizzoli
We examined the hypothesis that high FGF-23 levels early after transplantation contribute to the onset of hypophosphatemia, independently of parathyroid hormone (PTH) and other factors regulating phosphate metabolism.
We measured serum phosphate levels (sPi), renal tubular reabsorption of Pi (TmPi/GFR), estimated GFR (eGFR), intact PTH (iPTH), calcitriol, intact (int) and C-terminal (Cter) FGF-23, dietary Pi intake and cumulative doses of glucocorticoids in 69 patients 12 days (95% confidence interval, 10–13) after renal transplantation.
Hypophosphatemia was observed in 43 (62%) of the patients 12 days after transplantation. Compared with non-hypophosphatemic subjects, their post-transplantation levels of intact and CterFGF-23 were higher (195 (108–288) vs 48 (40–64) ng/l, P<0.002 for intFGF-23; 205 (116–384) vs 81 (55–124) U/ml, P<0.002, for CterFGF-23). In all subjects, Cter and intFGF-23 correlated inversely with sPi (r=−0.35, P<0.003; −0.35, P<0.003, respectively), and TmPi/GFR (r=−0.50, P<0.001; −0.54, P<0.001, respectively). In multivariate models, sPi and TmPi/GFR were independently associated with FGF-23, iPTH and eGFR. Pre-transplant iPTH levels were significantly higher in patients developing hypophosphatemia after renal transplantation. Pre-transplant levels of FGF-23 were not associated with sPi at the time of transplantation.
In addition to PTH, elevated FGF-23 may contribute to hypophosphatemia during the early post-renal transplant period.
Aliya A Khan, Christian A Koch, Stan Van Uum, Jean Patrice Baillargeon, Jens Bollerslev, Maria Luisa Brandi, Claudio Marcocci, Lars Rejnmark, Rene Rizzoli, M Zakarea Shrayyef, Rajesh Thakker, Bulent O Yildiz and Bart Clarke
Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults.
Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords ‘hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy’. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism.
Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults.
Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.