Onset Of Hypercalcemia Research Articles

Incidence of Post-denosumab Rebound Hypercalcaemia in Bony-Metastatic Breast Cancer.

Denosumab reduces incidence of skeletal related events in patients with bony-metastatic breast cancer, however cessation is associated with a rebound phenomenon which, rarely, has been associated with hypercalcaemia. We aimed to identify the incidence of post-denosumab cessation rebound hypercalcaemia amongst patients with breast cancer-related bony metastases. We performed a single-centre retrospective cohort analysis to determine the incident of rebound hypercalcaemia amongst patients treated with antiresorptive agents for bony metastatic breast cancer between 2016-2020. 22,320 outpatient encounters were reviewed, which identified 97 patients with bonymetastatic disease treated with antiresorptive therapy. Of the 21 patients who had denosumab ceased, six (28.6%) developed hypercalcaemia. Interval between last denosumab dose and onset of hypercalcaemia was a median 7.5 (range 2-13) months. There was a significant difference in both denosumab treatment duration as well as total treatment dose exposure between patients who developed hypercalcaemia post-denosumab cessation (median 41 months, 40 doses) and those who remained normocalcaemic (median 10 months, 5 doses), p = 0.009. In our study, hypercalcaemia occurred between two and thirteen months after denosumab cessation. Greater denosumab treatment duration as well as total denosumab dose exposure was associated with higher risk of hypercalcaemia after denosumab cessation. Hormonal therapy or previous bisphosphonate treatment was not seen to impact upon development of hypercalcaemia. Rebound hypercalcaemia is a rare but important diagnosis to consider in patients experiencing hypercalcaemia after denosumab cessation.

Clinical manifestation of hypercalcemia caused by adrenal insufficiency in hemodialysis patients: a case-series study.

The goal of this study was to clarify the clinical manifestation of hypercalcemia due to hypoadrenalism in hemodialysis (HD) patients. We retrospectively analyzed the clinical characteristics of five HD patients who had presented with hypercalcemia due to adrenal insufficiency (age: 69 ± 7 [58-75] years old, time on HD: 13 ± 11 [2-32] years). We conducted corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) stimulation tests. We also examined serum bone turnover markers before and after glucocorticoid replacement. All patients had critical illnesses at the onset of hypercalcemia. They had at least one symptom, such as eosinophilia, hypoglycemia, or fever. The prevalence of hypercalcemia due to adrenal insufficiency was 1.3% in maintenance HD patients on admission. The causes of adrenal insufficiency were isolated ACTH deficiency, pituitary apoplexy, pituitary atrophy, glucocorticoid withdrawal syndrome, and unilateral adrenalectomy. Serum calcium (Ca) levels corrected by serum albumin were maximally increased to 12.9 to 14.3 mg/dL in four anuric HD patients and mildly elevated to 10.4 mg/dL in a patient with residual diuresis. Their basal serum cortisol levels ranged from <1.0 to 15.4 μg/dL. Single CRH injections failed to increase serum cortisol in any of the patients. Glucocorticoid replacement acutely normalized serum Ca and decreased levels of carboxy-terminal telopeptide of type I collagen, a marker of bone resorption. Adrenal insufficiency could therefore be an occult cause of hypercalcemia in anuric HD patients who are critically ill.

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Introduction: Hypercalcemia in critically ill patients can evolve into life threatening arrhythmias and recently, extreme levels of hypercalcemia have been associated with increased mortality. Bisphosphonates are commonly used in treatment of hypercalcemia. We evaluated the use of pamidronate in the treatment of hypercalcemia in our critically ill population. Hypothesis: The use of pamidronate in critically ill patients with hypercalcemia can affect outcomes. Methods: This retrospective study evaluated 30 critically ill patients from 1/09 to 4/12 with hypercalcemia (defined as ionized calcium (ioCa) >1.25 mmol/L corrected for pH). Patients admitted to the ICU > 48 hrs were 1:1 case matched based on age and APACHE II: hypercalcemia treated with pamidronate (P) vs no pamidronate (NP). Patients with primary hyperparathyroidism were excluded. P-value <0.05 was considered significant. Results: Of the 30 patients (15 P vs 15 NP), the mean age was 54 ± 13 yrs with an overall APACHE II of 22 ± 9, SOFA of 8 ± 5, and 93% admitted to a surgery service. The admission ioCa were similar, 1.16 ± 0.27 P vs 1.12 ± 0.16 NP, p=0.61. Admission until onset of hypercalcemia was shorter in the P group, 6 ± 3 P vs 18 ± 12 NP days, p=0.003. Both the duration of hypercalcemia (18 ± 9 P vs 6 ± 7 NP days, p<0.001) and time to normalization after therapy (11 ± 10 P vs 4 ± 5 NP days, p=0.01) were longer in the P group. The number of hypercalcemia episodes was similar between groups, 2 ± 1 P vs 2 ± 1 NP, p=0.20. Renal failure requiring dialysis tended to occur more frequently with P, 53% vs 20%, p=0.12. Overall, 66% of the patients developed an arrhythmia with the most common being sinus tachycardia (55%) although the type of arrhythmias did not differ between groups. ICU length of stay tended to be longer in the P group, 41 ± 30 vs 25 ± 22 days, p=0.12; however, in-hospital mortality was not different. Conclusions: Hypercalcemia in the critically ill is a significant problem. Time to hypercalcemia normalization was longer and the incidence of renal failure also tended to be higher with pamidronate therapy. More study is needed to address pamidronate’s role in hypercalcemia of critical illness.

高カルシウム血症を随伴した口腔扁平上皮癌の１０例

Ten cases of terminal oral squamous cell carcinoma with hypercalcemia are presented to provide a perspective on palliative medicine. The initial primary site was the tongue in 6 patients and the gingiva in 4, including one case with delayed occurrence of multiple oral cancers (lower gingiva, tongue, and palate). There were 6 men and 4 women, with a mean age of 57.4 years (29-80 years). Serum calcium levels ranged from 10.8 to 17.1mg/dl (mean 13.05±2.07mg/dl). The serum parathyroid hormone-related protein level was above the normal range in 9 of the patients. Mean survival from the onset of hypercalcemia was 68.6 days (13-209 days), except for 1 patient who died on the day of diagnosis. The causes of death were respiratory failure in 8 patients and hemorrhage in 2 both of which are common causes of death in patients with oral cancer. There were no deaths due to kidney failure caused by hypercalcemia. For treatment, excluding the patient who died on the day of diagnosis, bisphosphonates were given at 2-week intervals. In patients who received palliative therapy against recurrence, delayed lymph node metastasis, or both bisphosphonate treatment improved the main symptoms, including nausea, vomiting, and anorexia. Furthermore, oral ingestion of food, feeding-tube nutrition, or both could be continued longer in the 7 patients (maximal survival: 209 days) who received palliative therapy than in the 3 who underwent aggressive treatment (radical neck dissection combined with high-dose radiation therapy. These latter patients had large areas of necrosis in the neck extending to the soft tissue or orofacial-neck lymphedema.)(mean survival: 13.7 days). Our findings in this series suggest that the survival time of patients with oral squamous cell carcinoma who have hypercalcemia depends on the aggressiveness of treatment, which is considered a cause of malnutrition, before the onset of hypercalcemia.

Cytostéatonécrose néonatale : attention à l’hypercalcémie sévère

Hypercalcemia associated with subcutaneous fat necrosis (SCN) is a well known but rare event in the newborn. A newborn infant with a history of SCN was admitted because of anorexia, adynamia, polyuria and polydipsia at 6 weeks of age. Serum calcium was markedly increased on admission, while it was normal on the first day of life. Evolution was favourable after treatment including isotonic saline solution, furosemide, corticosteroids, calcitonin and a low calcium and vitamin D diet. Hypercalcemia was severe enough to potentially induces fatal complications in this case. Neonates who develop skin lesions consistent with SCN should be followed-up for possible onset of hypercalcemia and treated in due time. The treatment of hypercalcemia in SCN is reviewed.

Hypercalcemia associated with parathyroid hormone–related protein at the terminal stage of uncomplicated squamous cell carcinoma in the head and neck region

Background Parathyroid hormone–related protein (PTHrP) is mainly responsible for hypercalcemia in squamous cell carcinomas (SCCs). Methods We retrospectively checked the appearance of hypercalcemia among 33 patients who died with head and neck SCC. Serum concentrations of C-terminal region of PTHrP (C-PTHrP) were measured in 15 of them. The intracellular PTHrP expression was immunohistochemically stained in 42 SCC sections obtained from the 33 before the appearance of hypercalcemia. Results Hypercalcemia appeared in 24 of the 33, and increased serum C-PTHrP levels were confirmed in 11 of 12 hypercalcemic patients. PTHrP was identified in all SCC sections, and a stronger intensity than in normal squamous epithelia was observed in 50% of those obtained within 1 year before the onset of hypercalcemia. Conclusion A high incidence of PTHrP-induced hypercalcemia was shown among patients dying with head and neck SCCs. The intracellular increase in PTHrP might be observed preceding hypercalcemia. © 2002 John Wiley & Sons, Inc. Head Neck 24: 56–62, 2002.

Idiopathic Hypercalcemia in Cats

Unexplained hypercalcemia has been increasingly recognized in cats since 1990. In some instances, hypercalcemia has been associated with calcium oxalate urolithiasis, and some affected cats have been fed acidifying diets. We studied the laboratory findings, clinical course, and treatment of 20 cats with idiopathic hypercalcemia. Eight (40%) of the cats were longhaired and all 14 cats for which adequate dietary history was available had been fed acidifying diets. Clinical signs included vomiting (6 cats), weight loss (4 cats), dysuria (4 cats), anorexia (3 cats), and inappropriate urinations (3 cats). Hypercalcemia was mild to moderate in severity, and serum parathyroid hormone concentrations were normal or low. Serum concentrations of phosphorus, parathyroid hormone‐related peptide, 25‐hydroxycholecalciferol, and calcitriol were within the reference range in most cats. Diseases commonly associated with hypercalcemia (eg, neoplasia, primary hyperparathyroidism) were not identified despite thorough medical evaluations and long‐term clinical follow‐up. Azotemia either did not develop (10 cats) or developed after the onset of hypercalcemia (3 cats), suggesting that renal failure was not the cause of hypercalcemia in affected cats. Seven of 20 cats (35%) had urolithiasis, and in 2 cats uroliths were composed of calcium oxalate. Subtotal parathyroidectomy in 2 cats and dietary modification in 11 cats did not result in resolution of hypercalcemia. Treatment with prednisone resulted in complete resolution of hypercalcemia in 4 cats.

Hypercalcemia during the osteogenic phase after rat marrow ablation coincides with increased bone resorption assessed by the NTx marker

Marrow ablation is a model of bone turnover in which the excavated tibial intramedullary cavity is rapidly and reproducibly filled by osteoblasts with new woven bone (days 6–8), which is then rapidly resorbed by osteoclasts (days 10–15). We showed previously (Magnuson et al., 1997) that marrow ablation induces a dramatic hypercalcemia and hypercalciuria in rats that unexpectedly peaked at the time of maximal osteogenesis and continued throughout the subsequent resorption phase. Based upon the amount of calcium mobilized and a peak of urinary hydroxyproline, we suggested that the hypercalcemia and hypercalciuria were due to increased systemic osteoclastic bone resorption induced by marrow ablation. We now apply a new enzyme-linked immunosorbent assay for rodent α 2(I) N-telopeptide (NTx), a marker of bone resorption, to the marrow ablation model to demonstrate that excretion of NTx parallels that of calcium release in the operated control group. Specifically, maximal NTx/creatinine excretion coincides with the onset of hypercalcemia on days 7–8. A peak of NTx was also observed in methylprednisolone- and deflazacort-treated ablated animals. Analyses for urinary free deoxypyridinoline crosslink failed to detect a significant ablation-induced change in excretion. Interleukin 6 activity was increased in all operated control and glucocorticoid-treated groups after marrow ablation, whereas serum parathyroid hormone remained at presurgical levels in operated controls throughout the 15-day study period. The NTx results confirm that bilateral tibial marrow ablation induces a burst of extratibial bone resorption and hypercalcemia 7–8 days later. We have estimated that the osteogenic phase of the ablation model deposits 40 mg of calcium as hydroxyapatite crystals within the intramedullary cavity on days 6–8; this represents 33%–50% of the total blood calcium content of a young rat. We hypothesize that the size and rapidity of this demand for ionized calcium is met through an extratibial bone resorption pathway of osteoclast formation and activation that anticipates and fulfills this need, and that is initiated at the time of marrow ablation.

Idiopathic hypercalcemia in cats.

Unexplained hypercalcemia has been increasingly recognized in cats since 1990. In some instances, hypercalcemia has been associated with calcium oxalate urolithiasis, and some affected cats have been fed acidifying diets. We studied the laboratory findings, clinical course, and treatment of 20 cats with idiopathic hypercalcemia. Eight (40%) of the cats were longhaired and all 14 cats for which adequate dietary history was available had been fed acidifying diets. Clinical signs included vomiting (6 cats), weight loss (4 cats), dysuria (4 cats), anorexia (3 cats), and inappropriate urinations (3 cats). Hypercalcemia was mild to moderate in severity. and serum parathyroid hormone concentrations were normal or low. Serum concentrations of phosphorus, parathyroid hormone-related peptide, 25-hydroxycholecalciferol, and calcitriol were within the reference range in most cats. Diseases commonly associated with hypercalcemia (eg, neoplasia, primary hyperparathyroidism) were not identified despite thorough medical evaluations and long-term clinical follow-up. Azotemia either did not develop (10 cats) or developed after the onset of hypercalcemia (3 cats), suggesting that renal failure was not the cause of hypercalcemia in affected cats. Seven of 20 cats (35%) had urolithiasis, and in 2 cats uroliths were composed of calcium oxalate. Subtotal parathyroidectomy in 2 cats and dietary modification in 11 cats did not result in resolution of hypercalcemia. Treatment with prednisone resulted in complete resolution of hypercalcemia in 4 cats.

Survival in hypercalcaemic patients with cancer and co-existing primary hyperparathyroidism

Hypercalcaemia associated with malignancy is generally thought to carry a poor prognosis. Of 47 consecutive patients with hypercalcaemia and malignancy, serum parathyroid hormone (PTH) was elevated in seven, consistent with co-existing hyperparathyroidism. Median survival from onset of hypercalcaemia in these seven patients was 817 days; compared to 33 days in the remaining 40 patients with hypercalcaemia of malignancy, in whom PTH was suppressed (p = 0.007). Among patients with hypercalcaemia of malignancy, plasma PTH-related protein (PTHrP) concentration showed no correlation with survival (r2 = 2.1%), but one patient with increased levels of both PTH and PTHrP survived only nine days after the onset of hypercalcaemia. A raised PTH had a positive predictive value of 86% for survival > 100 days, and of 71% for survival > 1 year. A raised plasma PTHrP predicted death within 100 days with a positive predictive value of 69%. We conclude that measurement of serum PTH is indicated in patients with hypercalcaemia and malignancy to identify the 15% with hyperparathyroidism, since this is associated with prolonged survival. In patients with hyperparathyroidism, assay of plasma PTHrP may indicate concurrent hypercalcaemia of malignancy, with an associated poor prognosis.

Tumour induced hypercalcaemia: A case for active treatment

This paper reports a retrospective survey of the diagnosis, management and outcome of hypercalcaemia in patients admitted to a regional oncology centre over a 12-month period; 168 cases of tumour induced hypercalcaemia were identified. In 69 patients (41%) the presence of hypercalcaemia was not noted in the case records; in a further 15 patients (9%) a positive decision was made not to treat the condition, although some of these patients continued to receive other forms of active treatment. Of the remaining patients, 20 (12%) received intravenous fluids alone and 64 (38%) received bisphosphonate therapy. Of those patients with initial serum calcium >3 mmol/171% were treated with bisphosphonates. Median survival from onset of hypercalcaemia was only 2 months, but in the bisphosphonate treated group, 98% experienced a fall in serum calcium within a week of treatment. We believe that the symptomatic relief associated with a fall in serum calcium justifies active management even in the face of a poor prognosis. A large proportion of cases of tumour induced hypercalcaemia remain undiagnosed or untreated and we believe that this deserves further attention.

Neonatal Hyperparathyroidism: The Natural Course in the Absence of Surgical Intervention

The case of a premature infant with the onset of hypercalcemia and apparent primary hyperparathyroidism in the immediate neonatal period is presented. Although the treatment in most such cases has been parathyroidectomy, this infant was managed medically and survived infancy without apparent complications. We believe her disorder represents the neonatal manifestations of familial hypocalciuric hypercalcemia. Her course supports the contention that this disorder may be self-limited in some infants and that appropriate medical management can preclude the need for surgical intervention in selected cases.

Renal phosphate transport in humoral hypercalcemia of malignancy.

Fisher rats bearing the H-500 Leydig cell tumor (LCT) develop humoral hypercalcemia of malignancy (HHM), which is accompanied by hypophosphatemia and hyperphosphaturia. To better define the mechanisms underlying the changes in phosphate metabolism, the activity of sodium-dependent phosphate uptake (Na+-Pi) in microvillus membrane vesicles (MMV) isolated from the renal cortex of LCT-bearing rats was studied. Ten days after tumor transplantation the animals became hypercalcemic, hypophosphatemic, and hyperphosphaturic, and LCT-MMV showed a specific decrease in Na+-Pi. A kinetic analysis revealed evidence for both a high- and a low-affinity system of Na+-Pi. The Vmax of both the low-affinity system and the high-affinity system were significantly reduced in LCT-MMV. These changes in Na+-Pi transport were similar to those induced by parathyroid hormone. In day-10 tumor-bearing animals, daily injections of dichloromethylene diphosphonate (2.5 mg.kg-1.day-1) prevented the onset of hypercalcemia but not the reduction in Na+-Pi in LCT-MMV. Our data suggest that in this animal model of HHM there is a specific and persistent impairment of Na+-Pi uptake at the level of the renal cortical brush-border membrane, which contributes to the derangement in phosphate metabolism.

Hypercalcemia and Parathyroid Function after Renal Transplantation

Hypercalcemia after renal transplantation (post-T hypercalcemia) has been detected in 29 (16.7%) of 174 long-term survivors. The mean time of onset of hypercalcemia was 69 days after renal transplantation (range 3-210). In 18 patients the hypercalcemia was mild and resolved spontaneously (transient) from 2-65 months (mean 19) after onset. In 4 patients serum calcium normalized concurrently with rejection episodes. In 7 patients the hypercalcemia was more pronounced (permanent), being terminated by subtotal parathyroidectomy in 5 and persisting in 2 recipients. The hypercalcemia was asymptomatic except in one patient, who developed calculi in the graft and a fall in graft function, all of which disappeared after parathyroidectomy. At operation the parathyroid glands showed hyperplasia, except in one case with an adenoma in one of the hyperplastic glands. Serum phosphorus was markedly decreased, to the same extent in transiently and permanently hypercalcemic recipients. Serum parathyroid hormone (S-PTH) was increased in all of 5 patients with permanent and in 3 of 8 with transient post-T hypercalcemia. In normocalcemic and in transiently hypercalcemic recipients the mean S-PTH was identical, but significantly lower than in the permanently hypercalcemic recipients. S-PTH was suppressed to the same extent during an i.v. calcium infusion in patients with post-T hypercalcemia and with primary hyperparathyroidism.