Frontiers of Hormone Research最新文献

Primary hyperparathyroidism is among the most common causes of hypercalcemia. However, ingestion of medication, including hydrochlorathiazide, lithium, and foscarnet, excessive vitamin A ingestion, endocrinopathies such as hyperthyroidism, adrenal insufficiency, and acromegaly, abnormal nutrient intake such as parenteral nutrition in preterm infants and milk-alkali syndrome, and prolonged immobilization have all been associated with hypercalcemia. The most common cause of nonparathyroid hypercalcemia is neoplasia. Hypercalcemia is generally due to the secretion of parathyroid hormone (PTH)-related peptide (PTHrP) by a wide variety of nonmetastatic solid tumors, including squamous cell tumors but also hematologic tumors. PTHrP, although encoded by a distinct gene, shares amino acid sequence homology with PTH in the amino-terminal domain, which allows it to cross-react at a common G protein receptor, the type 1 PTH/PTHrP receptor (PTHR1), resulting in similar skeletal effects and effects on calcium and phosphorus metabolism. Increased PTHrP action with hypercalcemia may be seen in the benign disease Jansen's metaphyseal chondrodysplasia due to a gain-of-function mutation in PTHR1. Another humoral factor, 1,25-dihyroxyvitamin D [1,25(OH)2D] may be produced by lymphomas, but also by benign granulomatous disorders and may also cause hypercalcemia when its metabolism is genetically impaired. Vitamin D intoxication may cause hypercalcemia due to overproduction of the metabolite, 25 hydroxyvitamin D, apparently in the absence of conversion to 1,25(OH)2D. Malignancies metastatic to bone or arising in bone (such as multiple myeloma) may produce a variety of growth factors and cytokines, in addition to PTHrP, which can contribute to tumor growth as well as osteolysis and hypercalcemia.

Parathyroid hormone (PTH) disorders are characterized by a wide spectrum of clinical and biochemical presentations. The increasing use of serum PTH assay in the set of the diagnostic workout in patients with osteoporosis has identified patients with features of surgically confirmed primary hyperparathyroidism (PHPT) associated with persistent normal serum calcium levels, which has been recognized as a distinct entity from hypercalcemic PHPT (HPHPT) by the last international consensus. Normocalcemic PHPT (NPHPT) affects about 6-8% of PHPT patients. Although hypercalcemia is absent, patients with NPHPT experience kidney, bone, and cardiovascular impairments similar to those observed in HPHPT, suggesting that NPHPT may significantly affect the health of patients. Diagnosis of NPHPT requires an intensive diagnostic workup aimed to: (1) exclude all causes of secondary hyperparathyroidism, and (2) evaluate the occurrence of PTH-related diseases. The management of NPHPT is controversial in part due to lack of solid data about the natural history as well as the effects of surgical or medical treatments. Nonetheless, a clinical and biochemical follow-up is recommended in order to detect potential progression. When hypercalcemia and/or PTH-related disorders arise, parathyroidectomy can be considered. When surgery is not advisable, medical treatment aimed to increase bone mineral density may be a therapeutic option.

Several studies have investigated replacement therapy with recombinant human parathyroid hormone [rhPTH(1-84)] for patients affected by chronic hypoparathyroidism who are not adequately controlled with standard treatment. In 2015, the Food and Drug Administration (FDA) in the USA approved rhPTH(1-84), named Natpara®, for the pharmacological management of hypoparathyroidism. In Europe, in February 2017, the European Medicines Agency (EMA) recommended granting a conditional marketing authorization in the European Union for rhPTH(1-84). Here we review the studies conducted with rhPTH(1-84) and PTH(1-34) in patients with chronic hypoparathyroidism. The research done in this field has shown that replacement treatment with rhPTH(1-84) is an important therapeutic option for subjects with chronic hypoparathyroidism who are not well controlled with conventional treatment. However, further long-term investigations are needed.

Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are genetically determined variants of primary hyperparathyroidism. FHH usually has a benign course, and patients do not require treatment, whereas NSHPT is a severe disorder often requiring early parathyroidectomy for young patients to survive. Recent discoveries in the genetic basis and new findings in therapeutic approaches have led to a great interest in these rare diseases.

The treatment of hypoparathyroidism depends on the severity of hypocalcemia, how rapidly the hypocalcemia developed, and the symptomatology. Chronic hypoparathyroidism is usually treated with oral supplementations, including calcium, calcitriol, or other active vitamin D analogs, and at times, thiazide diuretics. Although the standard therapy can adequately control patients with this disease, sometimes very high doses are required to maintain serum calcium levels in the normal range, with poor compliance and risk of long-term complications.

Individuals with a familial predisposition to the development of parathyroid tumors constitute a small minority of all patients with primary hyperparathyroidism (PHPT). These familial syndromes exhibit Mendelian inheritance patterns and the main causative genes in most families have been identified. They include multiple endocrine neoplasia (MEN; types 1, 2A, and 4), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and neonatal severe PHPT. Each MEN type is associated with the various combinations of specific tumors. MEN1 is characterized by the occurrence of parathyroid, enteropancreatic, and pituitary tumors; MEN2A is characterized by medullary thyroid carcinoma and pheochromocytoma, and MEN4 is characterized by a pathological spectrum similar to that of MEN1 in association with tumors of the adrenal, kidney, and reproductive organs. HPT-JT is characterized by PHPT, ossifying fibromas of maxillary bones, kidney disease, and uterine neoplasias. The prompt diagnosis of these diseases is of great importance for planning appropriate surveillance of the mutant carriers and correct surgical management. The search for mutation is also useful for the identification of the family members who do not carry the mutation and can avoid unnecessary biochemical and instrumental evaluations. Surgery remains the treatment of choice in all familial forms except FHH.