Pathophysiology Of Hypercalcemia Research Articles

A Review of Current Clinical Concepts in the Pathophysiology, Etiology, Diagnosis, and Management of Hypercalcemia.

Calcium is the most abundant extracellular cation in the body, and it is responsible for structural and enzymatic functions. Calcium homeostasis is regulated by 3 factors: calcitonin, vitamin D, and parathyroid hormone (PTH). Hypercalcemia is defined by a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values. Most cases are caused by primary hyperparathyroidism and malignancies. Various mechanisms are involved in the pathophysiology of hypercalcemia, such as excessive PTH production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion. The initial approach is similar in most cases, but a definitive treatment depends on etiology, that is why etiological investigation is mandatory in all cases. The majority of patients are asymptomatic and diagnosed during routine exams; only a small percentage of patients present with severe manifestations which can affect neurological, muscular, gastrointestinal, renal, and cardiovascular systems. Clinical manifestations are related to calcium levels, with higher values leading to more pronounced symptoms. Critically ill patients should receive treatment as soon as diagnosis is made. Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption such as bisphosphonates and, more recently, denosumab, in refractory cases; also, corticosteroids and calcitonin can be used in specific cases. This review aims to provide a clinical update on current concepts of the pathophysiology of calcium homeostasis, epidemiology, screening, clinical presentation, diagnosis, and management of hypercalcemia.

MON-254 Fragility Fracture in a Pediatric Patient with Williams-Beuren Syndrome

Background: Williams-Beuren syndrome (WBS) is a genetic disorder arising from a microdeletion involving the elastin gene. There are several well-defined effects of WBS across multiple organ systems, but less clear is the effect of this syndrome on bone metabolism. While there is literature to suggest that adults with WBS have premature osteopenia and osteoporosis, an increased risk of fracture has not been described in children with WBS . We describe an 11 year old girl with WBS who presented with back pain and was found to have 2 vertebral compression fractures. Clinical Case: The patient was diagnosed with WBS at 1 year of age via genetic testing obtained during a work-up for failure to thrive. She has no prior history of hypercalcemia. At the age of 11 years she complained of severe mid-thoracic back pain lasting several days. There was no history of trauma or cutaneous signs of injury. A plain film revealed compression fracture of 2 thoracic vertebrae; she was then referred to orthopedics and endocrinology. The patient had no history of prior fractures and family denied other episodes of severe pain. Parents reported normal intake and denied any dietary restrictions; there was no family history of bone disease. Her exam was unremarkable and she had normal vital signs, height, weight, and height velocity. Laboratory findings, including calcium, albumin, phosphorus, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, alkaline phosphatase and urine Ca/Cr ratio, were all within normal limits. The remainder of CMP as well as CBC, ESR, celiac panel, and thyroid function tests were also unremarkable. DEXA was significant for whole body Z-score -1.1, spine -1.6. Following risk-benefit discussion with family, treatment with bisphosphonate therapy was not initiated. Patient was instructed to increase weight-bearing exercise and has had no subsequent fractures. Conclusions: The pathophysiology of hypercalcemia in WBS remains unclear. As it is likely related to a dysregulation of the calcium-PTH axis, these patients may be at risk for abnormal bone turnover and formation. Vitamin D and calcium supplementation are typically not recommended in WBS because these patients remain at risk for hypercalcemia. Therefore, we suggest that these patients may benefit from weight bearing exercise and potentially monitoring of bone density from an earlier age.

Hypercalcemia in Breast Cancer: An Echo of Bone Mobilization During Lactation?

Hypercalcemia is a frequent complication of breast cancer which causes significant morbidity and mortality. Most commonly, it occurs in patients with multiple skeletal metastases. However, in a significant minority of patients, calcium levels become elevated in the absence of skeletal disease. In both instances, hypercalcemia is the result of pathological bone resorption caused by the secretion of cytokines that stimulate osteoclast differentiation and activity. One of these cytokines is parathyroid hormone-related protein (PTHrP). PTHrP is also secreted by normal breast cells during lactation to increase bone resorption and liberate skeletal calcium stores for the purposes of milk production. Therefore, the pathophysiology of hypercalcemia in breast cancer patients mimics the physiological processes that normally regulate calcium metabolism during lactation. Current therapy for hypercalcemia in breast cancer patients relies on the inhibition of bone resorption by a class of drugs known as bisphophonates. Newer therapies in development target cytokines involved in the recruitment and activation of osteoclasts by tumor cells.

Pathophysiology of hypercalcemia and the therapeutic role of bisphosphonates

When hypercalcemia is found in patients with malignancy, it is necessary to measure circulating parathyroid hormone -related peptide concentrations and to search for bone lesions. Because accelerated bone resorption mainly contributes to malignancy associated hypercalcemia, bisphosphonates, which strongly suppress osteoclastic resorption, is most effective. Upon administration of bisphosphonates, serum calcium begins to fall within two days, reaches the bottom after one week, and the effects disappear after two or three weeks. In case of need to lower the serum calcium concentration rapidly, calcitonin should be used at the same time.

The management of hypercalcemia of malignancy

Hypercalcemia (HCM) occurs in 10-15% of all malignancies, predominantly in patients with solid tumors. This metabolic complication leads to significant morbidity and impairment of quality of life. Recent insights into the pathophysiology of HCM include an understanding of the role of parathyroid-hormone-related peptide and several cytokines secreted by tumors. The osteoclast plays a central role as the final common pathway through which these hormones and cytokines act to cause bone lysis. These findings have led to the development of new treatment strategies. Foremost among these has been the introduction of agents such as the newer bisphosphonates and gallium nitrate, which are potent inhibitors of osteoclast-mediated bone resorption. The clinician can now choose from an array of therapeutic approaches based on a consideration of the mechanisms of action, individual clinical circumstances, efficacy, toxicities and costs of available agents. In addition to their use in the management of HCM, non-toxic drugs that effectively inhibit osteoclast function, such as the bisphosphonates, are playing an emerging role in the palliative treatment of the more common clinical problems of painful lytic bone metastases and osteoporosis.

Hypercalcemic crisis

Hypercalcemic crisis or severe hypercalcemia represents a life-threatening emergency. The most common cause is hypercalcemia of malignancy, although granulomatous diseases, previously undetected primary hyperparathyroidism, medication-induced hypercalcemia, and a few rarer causes may result in this endocrine emergency as well. The clinical presentation and prognosis depend on the acuity of the development of hypercalcemia, the degree of hypercalcemia, and the underlying cause. Certainly, patients with malignancy who develop hypercalcemia superimposed on their already debilitated state are more likely to have a poor outcome than a previously relatively healthy patient with thiazide-induced hypercalcemia, for example. The clinical presentation of patients with hypercalcemic crisis varies depending once again on the underlying cause and degree and rapidity of the hypercalcemia. Most patients experience some constitutional symptoms, neurologic symptoms, gastrointestinal symptoms, and renal manifestations of hypercalcemia. Immediate and effective therapy directed toward the pathophysiology of hypercalcemia is essential. General measures must be implemented to reverse the dehydration, to promote urinary calcium excretion, to avoid prolonged immobilization, and to identify the underlying cause of hypercalcemia. Specific measures directed at inhibiting bone resorption, increasing renal sodium and calcium excretion, and occasionally at decreasing intestinal absorption of calcium (or more specifically blocking vitamin D metabolism) should also be implemented. Obviously the more reversible the underlying cause of hypercalcemia, the more aggressive one should be with the therapy. The literature was reviewed to compile comparative data that practitioners may use in choosing among the various pharmacologic therapies available for the treatment of acute hypercalcemia. Despite all the advances in the field, hypercalcemic crisis still carries a significant mortality risk, although with appropriate therapy with the aforementioned general and specific measures, the calcium level can effectively be lowered in most patients.

Incidence and pathophysiology of hypercalcemia

Hypercalcemia occurs for various reasons in patients with malignant diseases. Most of these patients show a relative increase in bone resorption over bone formation. Increased renal tubular calcium reabsorption is also important for maintaining hypercalcemia in the majority of patients. Calcium absorption from the gut is usually decreased. In a few patients, fixed impairment of glomerular filtration contributes to hypercalcemia. Because the pathophysiology of hypercalcemia is heterogeneous, it may be considered as three separate syndromes: the humoral hypercalcemia of malignancy caused by systemic mediators; the hypercalcemia associated with localized osteolytic disease; and the hypercalcemia associated with myeloma and related hematologic malignancies. Increased bone resorption is a key feature in each of these syndromes. In malignant disease, bone resorption is enhanced because osteoclast activity is increased by the production of humoral mediators. These mediators are often produced by the tumor cells but are also produced by normal host cells that have been activated by the presence of the tumor. some of these mediators of hypercalcemia are systemic factors, but some act only locally. They include parathyroid hormone-related protein, transforming growth factor alpha, lymphotoxin, tumor necrosis factor, interleukin-1 alpha and 1,25-dihydroxyvitamin D.

Expression of parathyroid hormone-related protein in a human T cell lymphotrophic virus type I-infected T cell line

We analyzed human T cell lymphotrophic virus type I (HTLV-I)-infected T cells for the presence of mRNA coding for parathyroid hormone-related protein (PTHrP) by Northern blotting using synthetic DNA probes. We report here that PTHrP mRNAs were detected in a HTLV-I-infected T cell line, MT-2, but not in uninfected T cell or B cell lines, and that PTH-like bioactivity was detected only in the conditioned medium of MT-2 cells. Our study suggests that the pathophysiology of hypercalcemia in patients with adult T cell leukemia/lymphoma may resemble that which occurs with solid tumors.

The pathophysiology of hypercalcemia

The pathophysiology of hypercalcemia