Frontiers of Hormone Research最新文献

Secondary hyperparathyroidism (SHP) is a frequent complication of kidney diseases. At variance with all the other forms of SHP, which are compensatory conditions, renal SHP has many pathogenetic peculiarities, which have been only in part defined. Furthermore, in the long course of chronic kidney diseases (CKD), SHP sometimes transforms into a hypercalcemic condition resembling the autonomous form of hyperparathyroidism (tertiary hyperparathyroidism; THP). The clinical consequences of SHP in CKD patients are manifold, encompassing not only bone and mineral disorders, but also other metabolic and organic changes which frequently burden these patients. Although the medical therapeutic tools have substantially increased in number and improved in their efficacy in recent decades, we have as yet no demonstration of a clear benefit regarding the major clinical outcomes. Furthermore, some of these patients, particularly when the autonomous THP develops, still require a surgical approach.

The regulation of plasma calcium levels is essential for the normal physiologic function of every cell. Parathyroid hormone (PTH) is the principal regulator of serum calcium and phosphate homeostasis. PTH is synthesized and secreted by the parathyroid chief cells in the parathyroid glands primarily in response to a decline in serum calcium levels. The causes of hypocalcemia can be broadly classified as inadequate PTH or vitamin D production, PTH resistance, or miscellaneous causes. The term "hypoparathyroidism" refers to a metabolic disorder in which hypocalcemia and hyperphosphatemia occur either from a failure of the parathyroid glands to secrete sufficient amounts of biologically active PTH, or from an inability of PTH to appropriately induce a biological response in its target tissues. The most common cause of acquired hypoparathyroidism is surgery, accounting for 75% of all cases. Nonsurgical causes of hypoparathyroidism include autoimmune, genetic variants, infiltrative, metastatic, radiation, mineral deposition, magnesium deficiency or excess or idiopathic. The objective of this chapter is to provide a comprehensive review of the physiology of calcium homeostasis, the causes of hypocalcemia, and the epidemiology of hypoparathyroidism. It is very important to determine the underlying cause of the hypoparathyroidism in order to effectively treat our patients and improve quality of life.

Parathyroid carcinoma (PC) is a rare endocrine malignancy, accounting for <1% of all cases of sporadic primary hyperparathyroidism (PHPT) and up to 15% in the hereditary hyperparathyroidism-jaw tumor syndrome. Genomic alterations identified in PC are mostly represented by CDC73 gene mutations, codifying for a loss-of-function protein termed parafibromin. Whole exome sequencing identified mutations in other genes, such as mTOR, KMT2D, CDKN2C, THRAP3, PIK3CA, and EZH2 genes, CCND1 gene amplification. The diagnosis of PC is quite difficult due to the lack of reliable clinical diagnostic criteria, and in the majority of cases is made postoperatively at histological examination. The clinical manifestations of PC are primarily due to the excessive secretion of PTH by the tumor rather than spread to local or distant organs. En bloc resection of the parathyroid tumor represents the initial mainstay treatment of patients with PC. Multiple surgical procedures may be required, although surgical morbidity should be taken into account. A 5- and 10-year survival between 77-100 and 49-91%, respectively, has been reported. When the tumor is no more resectable, medical treatment of hypercalcemia has a pivotal role in the management of these patients.

Chronic hyponatremia may not cause overt symptoms, and therefore frequently remains untreated. More recently, growing evidence indicate that this condition is not benign, and can lead to unsteady gait, deterioration of bone mass and strength, increased fragility, and increased all-cause mortality. We provided the first evidence for hyponatremia-induced osteoporosis based on markedly reduced bone mineral density and bone structural changes in hyponatremic rats, which is an experimental model of the syndrome of inappropriate antidiuresis (SIAD). These animal data were supported by results of the analysis of the National Health and Nutrition Examination Survey III dataset showing a 2.5-fold increased OR of osteoporosis in participants with serum sodium concentration [Na+] below 135 mmol/L. A subsequent cross-sectional study from Michigan analyzed data from 25,000 patients and found a strong association between the odds of osteoporosis by bone density and hyponatremia. This study pointed out that age-dependent decline in bone density may mask hyponatremia-induced bone loss. Multiple independent retrospective studies, epidemiological studies, and prospective clinical studies have since confirmed and extended our findings, reporting evidence for increased bone fractures and increased mortality in patients with hyponatremia. Cell culture studies have elucidated some of the adaptive mechanisms by which low extracellular fluid [Na+] increases osteoclast formation and bone resorbing activity, thereby liberating stored sodium from the bone matrix. Studies on older SIAD rats indicated that the damage may not be restricted to bone alone, but may involve other organs, including the heart, testis, kidney, and the brain. Finally, compelling open questions and future research directions about the effect of hyponatremia on bone are outlined.

Euvolemic hyponatremia is the most common cause of hyponatremia in both hospitalized patients and outpatients. The most common etiology of euvolemic hyponatremia is the syndrome of inappropriate antidiuresis (SIAD). Diagnosis of SIAD involves evaluation of a set of long-standing clinical and laboratory criteria for this diagnosis. Many treatment options for SIAD exist, and choosing among them should be based on the chronicity of the hyponatremia and neurological symptomatology. Importantly, clinical judgment and risk/benefit analysis that is individualized for specific patients should drive therapeutic decisions, because there is no single treatment that represents the "best" therapy for all patients with SIAD.

Numerous observational studies have confirmed that inadequate investigation of hyponatremia leads to diagnostic errors and incorrect treatment. In fact, only one out of five patients diagnosed as having syndrome of inappropriate antidiuresis (SIAD) have had all the tests necessary to meet the diagnostic criteria. Diagnostic errors could help explain why a majority of patients presenting hyponatremia during hospitalization are discharged while still hyponatremic. The correct differentiation of hypovolemic from euvolemic patients is a clinical diagnostic challenge. Yet the value of the physical examination in the volemic classification of the patient with hyponatremia has been reinforced by ultrasound studies revalidating the utility of the measurement of internal jugular vein pulse height in the clinical evaluation of intravascular volume. In this chapter, we review the data available on current approaches to the diagnosis of hyponatremia, and suggest our recommended approach to the evaluation of patients with hyponatremia, and more specifically, patients with SIAD. In addition, we will explore how specialized input from multidisciplinary hospital "hyponatremia teams," supported by technologies such as automated electronic alert systems, and computerized physician-support systems can aid the diagnostic pathway and clinical care delivery for patients with hyponatremia.

Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels. All these disorders are caused by impairments in the cAMP-mediated signal transduction pathway and, in particular, in the PTH/PTHrP signaling pathway: the main subtypes of PHP and related disorders are caused by de novo or autosomal dominantly inherited inactivating genetic mutations, and/or epigenetic, sporadic, or genetic-based alterations within or upstream of GNAS, PRKAR1A, PDE4D, and PDE3A. Here we will review the impressive progress that has been made over the past 30 years on the pathophysiology of these diseases and will describe the recently proposed novel nomenclature and classification. The new term "inactivating PTH/PTHrP signaling disorder," iPPSD: (1) defines the common mechanism responsible for all diseases, (2) does not require a confirmed genetic defect, (3) avoids ambiguous terms like "pseudo," and (4) eliminates the clinical or molecular overlap between diseases.

In hypotonic hyponatremia, which is the most common form of hyponatremia, clinical manifestations are largely due to brain swelling caused by entry of water into the cells. In acute and severe hyponatremia, dramatic symptoms, such as seizures, acute psychosis, permanent brain damage, brain-stem herniation, leading to coma and death may occur. In chronic hyponatremia, symptoms are generally less dramatic and may include headache, nausea, vomiting, gait alterations, muscle cramps, restlessness, and disorientation. It has become evident in recent years that mild forms of chronic hyponatremia may also be associated with clinical signs, if carefully investigated. Several studies also reported an increased length of stay in the hospital of patients with hyponatremia in different clinical settings, leading to increased costs. Most important, this condition has been clearly associated with a significantly increased risk of death, even when serum [Na+] is slightly reduced. On the contrary, there is convincing evidence that the mortality risk is reduced when hyponatremia improves.