Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

Persistent hypercalcemia with similar familial Hypocalciuric hypercalcemia features: a case report and literature review.

BACKGROUND: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are the most important differential diagnosis of parathyroid hormone (PTH)-dependent hypercalcemia. The clinical features of FHH and PHPT can overlap in some cases. Therefore, these two diseases must be differentiated to prevent unnecessary parathyroidectomy. Here, we present a case that was not entirely matched with any of the known differential diagnoses of hypercalcemia. CASE PRESENTATION: A 19-year-old girl with no history of any disease presented with persistent hypercalcemia without any specific musculoskeletal complaint. We found persistent hypercalcemia in her routine laboratory data from 3 years ago; while no data was available during the childhood period. Her dietary calcium intake was normal. She did not mention any history of renal stone, bone fracture as well as family history of hypercalcemia. Biochemical features showed normal values of serum creatinine, high normal serum calcium (range, 10.3-11.3 mg/dL; (normal range: 8.8-10.4)), and non-suppressed PTH levels (range, 37.2-58.1 pg/mL; (normal range: 10-65)). Serum 25 OH vitamin D level at the first visit was 16.1 ng/mL that treated by vitamin D supplementation. Since then, all 25 OH vitamin D levels were in the acceptable range. After correction of vitamin D deficiency during the follow-up period the calcium creatinine clearance ratio(s) (CCCR) were calculated in the range of 0.009 to 0.014 (means below 1%). The clinical and laboratory data indicate more FHH rather than PHPT. Genetic studies were negative for the common genes associated with FHH (CASR, GNA11, and AP2S1 genes) and multiple endocrine neoplasia type1 (MEN1). On the other hand, no evidence of autoimmunity was found in her to support an autoimmune FHH-like syndrome. Hence, the case did not match completely to any diagnosis of FHH and PHPT, so we decided to follow her. CONCLUSION: We presented a patient with FHH phenotype whose common genetic tests were negative. Further research is needed to ascertain other causes leading to similar manifestations.

Mild Idiopathic Infantile Hypercalcemia-Part 1: Biochemical and Genetic Findings.

CONTEXT: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. OBJECTIVE: This work aims to characterize the genetic associations and biochemical profile of mild IIH. METHODS: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. RESULTS: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. CONCLUSION: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.

Anesthetic considerations in hyperparathyroid crisis: A case report.

INTRODUCTION: Hyperparathyroid crisis is a rare and potentially life-threatening complication of severe calcium intoxication. Parathyroidectomy is the only curative method for hyperparathyroid crisis. Several case reports and case series have been published on the medical and surgical treatments for hyperparathyroid crisis, however, few reports have focused on the associated perioperative anesthetic management. PATIENT CONCERNS: A 48-year-old Chinese woman presented with a 2-week history of nausea and vomiting and complained of mental status alteration including confusion and agitation in the 24 hours prior to her admission. She denied any history of past illness. Laboratory tests showed severe hypercalcemia crisis with a serum calcium level of 5.21 mmol/L and a serum intact parathyroid hormone level of > 5000 pg/mL. DIAGNOSIS: The diagnosis was hyperparathyroid crisis, acute kidney injury, acute liver injury, rhabdomyolysis, infection, and shock. INTERVENTIONS: She underwent initial management with aggressive intravenous fluid resuscitation, loop diuretic treatment, vitamin D supplement, intravenous bisphosphonates, and calcitonin therapy. However, her condition worsened, and she was transferred to the operating theater for a parathyroidectomy under general anesthesia. She was under general anesthesia and monitored with electrocardiogram, pulse oxygen saturation, continuous arterial blood pressure, central venous pressure and nasopharyngeal temperature. Cardiac output and stroke volume variation were monitored from the FloTrac system. After liberal fluid rehydration, circulatory support, cooling treatment and calcium supplement after tumor removal, her unstable vital signs gradually improved. OUTCOMES: After meticulous anesthetic management by the anesthesiologist and complete tumor resection by the surgeon, she survived this fatal disease. The patients was discharged on postoperative day 37 without any sequelae. LESSONS: Patients with hyperparathyroid crisis should undergo a thorough preoperative evaluation. Difficult airway, fluid depletion, multiple organ dysfunction, hypercoagulability, and concomitant diseases are the primary challenges in anesthetic management. After tumor removal, the serum calcium level should be monitored closely and calcium should be supplemented in a timely manner to prevent serious complications.

Successful Use of Denosumab for Life-Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is rare and usually symptomatic in children. There is no approved medication to lower serum calcium levels in this patient group. Denosumab is used in adult patients with osteoporosis and hyperparathyroidism. To our knowledge, only 1 case of denosumab treatment in a child with severe PHPT has been reported to date. CASE PRESENTATION: A 16-year-old female was referred to our clinic with symptoms including pathologic fractures, nausea, emesis, and progressive weight loss. At admission, her serum total calcium was 4.17 mmol/L (reference range 2.15-2.55), parathyroid hormone 2,151 pg/mL (15-65), and phosphate 1.07 mmol/L (1.45-1.78). Due to potentially life-threatening hypercalcemia, denosumab 60 mg subcutaneously was administered after obtaining informed consent. Serum calcium levels were reduced within 12 h of injection and the patient's condition rapidly improved, which allowed genetic testing to be done prior to surgery. A heterozygous mutation in the CDC73 gene was revealed, and a parathyroidectomy was performed on day 22 after denosumab administration. Morphological examination revealed solitary parathyroid adenoma. After surgery, hypocalcemia developed requiring high doses of alfacalcidol and calcium supplements. CONCLUSION: Our case supports the previous observations in adults that denosumab can be safely and effectively used as a preoperative treatment in patients with PHPT and severe hypercalcemia and shows that it may be used in pediatric patients.

Long-term hypervitaminosis D-induced hypercalcaemia treated with glucocorticoids and bisphosphonates.

Hypercalcaemia is a common diagnosis with the majority of cases resulting from hyperparathyroidism or malignancy. We report a rare case of persistent symptomatic hypervitaminosis D-induced hypercalcaemia in an individual taking 50 000 IU of vitamin D supplement daily for several months following a diagnosis of vitamin D deficiency. His hypercalcaemia was initially treated with calcitonin and intravenous fluids, but due to recurrent symptomatic hypercalcaemia after discharge, additional treatment with glucocorticoids and bisphosphonates was warranted during his second admission. The pathophysiology of hypercalcaemia from vitamin D intoxication results from the long-term effects of vitamin D storage in adipose tissue. In the present case, we discuss this pathophysiology and treatment approaches in the context of increasing awareness of and testing for vitamin D deficiency, and growing access to over-the-counter supplements.

A Dimorphic Diagnosis of a Pleomorphic Disease: An Unusual Cause of Hypercalcemia.

BACKGROUND: Histoplasmosis is a rare cause of 1, 25-dihydroxy vitamin-D-mediated hypercalcemia. In this study, we report 2 cases of hypercalcemia secondary to histoplasmosis seen at Mayo Clinic, Rochester and a review of cases reported in the literature. METHODS: We conducted a PubMed search using the keywords "hypercalcemia" and "histoplasmosis." Fourteen cases of hypercalcemia secondary to histoplasmosis were reported between 1977 and 2020. We identified an additional 2 patients from our institution. RESULTS: We reviewed a total of 16 cases. The median age at presentation was 58.5 years (interquartile range, 41.5-68.75 years), and 13 of 16 patients (81.2%) were men. Serum parathyroid hormone level was available in 13 of 16 (81.25%) patients, of whom 11 patients (84.6%) had a low level, 1 patient (7.6%) had a normal level, and 1 patient (7.6%) had an elevated level. 1, 25-dihydroxy vitamin D level was reported in 9 of 16 (56.25%) patients. Of these, 5 patients (55.5%) had levels within normal limits, and 4 patients (44.4%) had levels above normal. Serum angiotensin-converting enzyme level was evaluated in 4 of 16 patients (25%), and it was elevated in all 4 (100%) cases. Four patients received corticosteroids before a diagnosis of histoplasmosis was made, which resulted in rapidly progressive disease and death in 2 patients. CONCLUSIONS: In patients with granulomatous disorder and hypercalcemia, it is crucial to rule out infectious etiologies before initiating steroids. Histoplasmosis can cause nonparathyroid hormone-mediated hypercalcemia and, if not suspected, may have catastrophic implications.

Hypercalcemia Without Hypervitaminosis D During Cholecalciferol Supplementation in Critically Ill Patients.

BACKGROUND: Vitamin D deficiency during critical illness has been associated with worsened outcomes. Because most critically ill patients with severe traumatic injuries are vitamin D deficient, we investigated the efficacy and safety of cholecalciferol therapy for these patients. METHODS: Fifty-three patients (>17 years of age) admitted to the trauma intensive care unit who had a serum 25-hydroxy vitamin D (25-OH vit D) concentration <20 ng/mL were given 10,000 IU of cholecalciferol daily. Efficacy was defined as achievement of a 25-OH vit D of 30-79.9 ng/mL. Safety was evaluated by the presence of hypercalcemia (serum ionized calcium [iCa] >1.32 mmol/L) or hypervitaminosis D (25-OH vit D >79.9 nmol/L). Patients were monitored for 2 weeks during cholecalciferol therapy. RESULTS: Twenty-four patients (45%) achieved target 25-OH vit D. No patients experienced hypervitaminosis D. Hypercalcemia occurred in 40% (n = 21) of patients; 2 patients experienced an iCa >1.49 nmol/L. 25-OH vit D was significantly greater for those who developed hypercalcemia (37.2 + 11.2 vs 28.4 + 5.6 ng/mL, respectively, P < 0.001) by the second week of cholecalciferol. Of 24 patients who achieved target 25-OH vit D, 14 (58%) experienced hypercalcemia in contrast to 24% of patients (7 out of 29) who did not achieve target 25-OH vit D (P = 0.024). CONCLUSIONS: Cholecalciferol normalized serum 25-OH vit D concentrations in less than half of patients yet was associated with a substantial proportion of patients with hypercalcemia without hypervitaminosis D.

Sarcoidosis and calcium homeostasis disturbances-Do we know where we stand?

The majority of cases involving hypercalcemia in the setting of sarcoidosis are explained by the overproduction of calcitriol by activated macrophages. Vitamin D takes part in the regulation of granuloma formation. However, using vitamin D metabolites to assess the activity of the disease is still problematic, and its usefulness is disputable. In some cases, though, a calcium metabolism disorder could be a valuable tool (i.e. as a marker of extrathoracic sarcoidosis). Although sarcoidosis does not cause a decrease in bone mineral density, increased incidence of vertebral deformities is noted. Despite increasing knowledge about calcium homeostasis disorders in patients with sarcoidosis, there is still a need for clear guidelines regarding calcium and vitamin D supplementation in these patients.

Is Hypercalcemia a Frequent Complication following Local Use of Calcium Sulfate with Antibiotics for the Treatment of Extremity Posttraumatic Osteomyelitis? A Preliminary Study.

BACKGROUND: Previous study had reported hypercalcemia as a frequent complication (20%) following local use of antibiotic-eluting calcium sulfate (CS) during treatment of periprosthetic joint infections (PJIs). However, whether this complication may occur in patients who receive local CS implantation for management of posttraumatic osteomyelitis (OM) remains unclear. METHODS: Between April 2016 and May 2017, we included 55 patients with extremity posttraumatic OM who received local antibiotic-loaded CS therapy. Serum calcium levels were detected preoperatively and on the 1st, 3rd, and 7th postoperative days (PODs). Comparisons were performed regarding serum calcium levels among the four time points and between two different CS volume groups (≤ 20 cc group and > 20 cc group). Additionally, potential associations were examined regarding CS volume and preoperative calcium level with postoperative calcium levels, respectively. RESULTS: Altogether 46 males and 9 females were included, with a median CS volume of 20 cc. Outcomes showed that prevalence of asymptomatic hypocalcemia was more frequent, with 16.4% before surgery and 60%, 53.8%, and 25% on the 1st, 3rd, and 7th PODs, respectively. Hypercalcemia was not found in any patients, at any time point. In addition, significant differences were identified regarding serum calcium levels among different time points, suggesting significantly decreased calcium levels on the 1st (P < 0.001) and 3rd PODs (P < 0.001) and back to near preoperative level on the 7th POD (P = 0.334). However, no statistical differences were observed regarding serum calcium levels between the two CS volume groups at any time points (P > 0.05). Moreover, no significant links were identified between CS volume and postoperative calcium levels (P > 0.05). Serum calcium levels on the 3rd (P = 0.019) and 7th PODs (P = 0.036) were significantly associated with the preoperative calcium level. CONCLUSIONS: In contrast to what had occurred in PJI patients, asymptomatic hypocalcemia appeared to be more frequent in this cohort with posttraumatic OM. Hypercalcemia may be an infrequent complication before and after local CS use for the treatment of extremity posttraumatic OM.

Monthly high-dose vitamin D supplementation does not increase kidney stone risk or serum calcium: results from a randomized controlled trial.

BACKGROUND: A growing number of randomized controlled trials (RCTs) are investigating the potential health benefits of high-dose vitamin D supplementation. However, there are limited RCT data on the safety of calcium-related adverse effects. OBJECTIVE: We investigated the incidence of kidney stone and hypercalcemia events in a large, population-based RCT of vitamin D supplementation. DESIGN: The Vitamin D Assessment (ViDA) study was a randomized, double-blind, placebo-controlled trial of vitamin D supplementation in 5110 participants in Auckland, New Zealand. This trial investigated the impact of monthly 100,000 IU vitamin D3 supplementation over several years on cardiovascular events, respiratory infections, and falls/fractures. Participants provided information about recent kidney stone events in regular questionnaires sent to them with study capsules. Hospitalization data for kidney stones were collected from health authorities. Serum calcium was measured in an 8% subsample of participants who returned annually for blood tests. HRs of time to the first kidney stone event were calculated by Cox regression. RESULTS: During a median follow-up of 3.3 y, 158 participants reported a kidney stone event (76 vitamin D, 82 placebo). The HR of reporting the first kidney stone event was 0.90 (95% CI: 0.66, 1.23; P = 0.51) for participants in the vitamin D arm compared with the placebo arm. There were 18 urolithiasis events in the hospitalization records: 7 in the vitamin D arm and 11 from the placebo arm. The HR to the first hospitalization urolithiasis event was 0.62 (95% CI: 0.24, 1.26; P = 0.30) in the vitamin D arm compared with the placebo arm. From the subsample annual blood test, there was no case of hypercalcemia in the vitamin D arm, compared with 1 in the placebo arm. CONCLUSION: Over a median of 3.3 y, monthly supplementation with 100,000 IU vitamin D3 did not affect the incidence rate of kidney stone events, or hypercalcemia. This study was registered at clinicaltrials.gov as ACTRN12611000402943.

Failure to Diagnose and Treat Hyperparathyroidism Among Patients with Hypercalcemia: Opportunities for Intervention at the Patient and Physician Level to Increase Surgical Referral.

BACKGROUND: Hyperparathyroidism is both underdiagnosed and undertreated, but the reasons for these deficiencies have not been described. The purpose of this study was to identify reasons for underdiagnosis and undertreatment of hyperparathyroidism that could be addressed by targeted interventions. MATERIALS AND METHODS: We identified 3,200 patients with hypercalcemia (serum calcium >10.5 mg/dL) who had parathyroid hormone (PTH) levels evaluated at our institution from 2011 to 2016. We randomly sampled 60 patients and divided them into three groups based on their PTH levels. Two independent reviewers examined clinical notes and diagnostic data to identify reasons for delayed diagnosis or referral for treatment. RESULTS: The mean age of the patients was 61 ± 16.5 years, 68% were women, and 55% were white. Fifty percent of patients had ≥1 elevated calcium that was missed by their primary care provider. Hypercalcemia was frequently attributed to causes other than hyperparathyroidism, including diuretics (12%), calcium supplements (12%), dehydration (5%), and renal dysfunction (3%). Even when calcium and PTH were both elevated, the diagnosis was missed or delayed in 40% of patients. For 7% of patients, a nonsurgeon stated that surgery offered no benefit; 22% of patients were offered medical treatment or observation, and 8% opted not to see a surgeon. Only 20% of patients were referred for surgical evaluation, and they waited a median of 16 months before seeing a surgeon. CONCLUSION: To address common causes for delayed diagnosis and treatment of hyperparathyroidism, we must improve systems for recognizing hypercalcemia and better educate patients and providers about the consequences of untreated disease. IMPLICATIONS FOR PRACTICE: This study identified reasons why patients experience delays in workup, diagnosis, and treatment of primary hyperparathyroidism. These data provide valuable information for developing interventions that increase rates of diagnosis and referral.

Comparison of Treatment Regimens in Management of Severe Hypercalcemia Due to Vitamin D Intoxication in Children

Objective: No large study has been conducted to date to compare the effectiveness of prednisolone, alendronate and pamidronate as first-line treatment in children with hypercalcemia due to vitamin D intoxication. The aim was to perform a multicenter, retrospective study assessing clinical characteristics and treatment results. Methods: A standard questionnaire was uploaded to an online national database system to collect data on children with hypercalcemia (serum calcium level >10.5 mg/dL) due to vitamin D intoxication [serum 25-hydroxyvitamin D (25(OH)D) level >150 ng/mL] who were treated in pediatric endocrinology clinics. Results: Seventy-four children [median (range) age 1.06 (0.65-1.60) years, 45 males (61%) from 11 centers] were included. High-dose vitamin D intake was evident in 77% of the cases. At diagnosis, serum calcium, phosphorus, alkaline phosphatase, 25(OH)D and parathyroid hormone concentrations were 15±3.2 mg/dL, 5.2±1.2 mg/dL, 268±132 IU/L, 322 (236-454) ng/mL, and 5.5 (3-10.5) pg/mL, respectively. Calcium levels showed moderate correlation with 25(OH)D levels (rs=0.402, p<0.001). Patients were designated into five groups according to the initial specific treatment regimens (hydration-only, prednisolone, alendronate, pamidronate, and combination). Need for another type of specific drug treatment was higher in children who initially received prednisolone (p<0.001). Recurrence rate of hypercalcemia was significantly lower in children who were treated with pamidronate (p=0.02). Conclusion: Prednisolone is less effective in the treatment of children with severe hypercalcaemia secondary to vitamin D intoxication and timely implementation of other treatment regimens should be considered.

Safety of calcium and vitamin D supplements, a randomized controlled trial.

OBJECTIVE: It is anticipated that an intake of vitamin D found acceptable by Endocrine Society Guidelines (10 000 IU/day) with co-administered calcium supplements may result in frequent hypercalciuria and hypercalcaemia. This combination may be associated with kidney stones. The objective of this study was to compare the episodes of hypercalciuria and hypercalcaemia from calcium supplements co-administered with 10 000 IU or 600 IU vitamin D daily. This design allows a comparison of the Institute of Medicine recommendation for the RDA of vitamin D along with the upper limit of calcium intake with the high intake of vitamin D suggested by the Endocrine Society. CONTEXT: Harms of currently recommended high intake of vitamin D have not been studied. DESIGN: The design was a randomized controlled trial with 2 groups with evaluation every 3 months for one year: (a) CaCO3 1200 mg/day with 10 000 IU vitamin D3 /day or (b) CaCO3 1200 mg/day with 600 IU vitamin D3 /day. PATIENTS: This study was conducted in an ambulatory research centre in healthy, white postmenopausal women. MEASUREMENTS: Serum and 24-hour urine calcium were measured. RESULTS: Hypercalcaemia and hypercalciuria occurred in both groups. At the final visit, 19/48 in the high dose D group had hypercalciuria. The odds of developing hypercalciuria were 3.6 [OR = 3.6(1.39, 9.3)] times higher in the high dose D group. The odds of developing hypercalcaemia did not differ between groups. CONCLUSIONS: The safe upper level of vitamin D recommended by the Endocrine Society when accompanied by calcium supplements results in frequent hypercalciuria. The risk of kidney stones at these levels should be investigated.

A Fatal Case of Amlodipine Toxicity Following Iatrogenic Hypercalcemia.

Using calcium salts in management of amlodipine overdose is challenging. A 25-year-old male with known history of adult polycystic kidney disease presented with hypotension, tachycardia, and intact neurological status after ingestion of 450 mg of amlodipine. Immediately, normal saline infusion and norepinephrine were initiated. Two grams of calcium gluconate was injected, followed by intravenous infusion of 1.16 mg/kg/h. The patient was put on insulin-glucose protocol to maintain euglycemia and hyperinsulinemia. Electrocardiography demonstrated junctional rhythm. Serum creatinine was 2.5 mg/dL with metabolic acidosis. By the end of 24 h post-admission, his consciousness, blood pressure, and urine output were normal. Almost 32 h post-admission, he became disoriented and his oxygen saturation decreased and therefore was mechanically ventilated. Second chest X-ray showed pulmonary edema. Serum calcium level increased to 26.1 mg/dL. Calcium was discontinued, and furosemide infusion and calcitonin were intravenously administrated. Urine output increased and hemodialysis improved pulmonary edema and serum calcium level with no change in consciousness. Three days after admission, the patient became anuric and developed multi-organ failure and died 5 days post-admission. To avoid the consequences of excessive infusion of calcium in renal failure patients, the minimum calcium dose with close monitoring is recommended.

Impact of admission serum calcium levels on mortality in hospitalized patients.

OBJECTIVES: To assess the relationship between admission serum calcium levels and in-hospital mortality in all hospitalized patients. METHODS: All adult hospitalized patients who had admission serum calcium levels available between years 2009 and 2013 were enrolled. Admission serum calcium was categorized based on its distribution into six groups (<7.9, 7.9 to <8.4, 8.4 to <9.0, 9.0 to <9.6, 9.6 to <10.1, and ≥10.1 mg/dL). The odds ratio (OR) of in-hospital mortality by admission serum calcium, using the calcium category of 9.6-10.1 mg/dL as the reference group, was obtained by logistic regression analysis. RESULTS: 18,437 patients were studied. The lowest incidence of in-hospital mortality was associated with admission serum calcium within 9.6 to <10.1 mg/dL. A higher in-hospital mortality rate was observed in patients with serum calcium <9.6 and ≥10.1 mg/dL. Also, 38% and 33% of patients with admission serum calcium <7.9 and ≥10.1 mg/dL were on calcium supplements before admission, respectively. After adjusting for potential confounders, both serum calcium <8.4 and ≥10.1 mg/dL were associated with an increased risk of in-hospital mortality with ORs of 2.86 [95% confidence interval (CI) 1.98-4.17], 1.74 (95% CI 1.21-2.53), and 1.69 (95% CI 1.10-2.59) when serum calcium were within <7.9, 7.9 to <8.4, and ≥10.1 mg/dL, respectively. CONCLUSION: Hypocalcemia and hypercalcemia on admission were associated with in-hospital mortality. Highest mortality risk is observed in patients with admission hypocalcemia (<7.9 mg/dL). One-third of patients with hypercalcemia on admission were on calcium supplements.

Vitamin D supplementation guidelines.

Research carried out during the past two-decades extended the understanding of actions of vitamin D, from regulating calcium and phosphate absorption and bone metabolism to many pleiotropic actions in organs and tissues in the body. Most observational and ecological studies report association of higher serum 25-hydroxyvitamin D [25(OH)D] concentrations with improved outcomes for several chronic, communicable and non-communicable diseases. Consequently, numerous agencies and scientific organizations have developed recommendations for vitamin D supplementation and guidance on optimal serum 25(OH)D concentrations. The bone-centric guidelines recommend a target 25(OH)D concentration of 20ng/mL (50nmol/L), and age-dependent daily vitamin D doses of 400-800IU. The guidelines focused on pleiotropic effects of vitamin D recommend a target 25(OH)D concentration of 30ng/mL (75nmol/L), and age-, body weight-, disease-status, and ethnicity dependent vitamin D doses ranging between 400 and 2000IU/day. The wise and balanced choice of the recommendations to follow depends on one's individual health outcome concerns, age, body weight, latitude of residence, dietary and cultural habits, making the regional or nationwide guidelines more applicable in clinical practice. While natural sources of vitamin D can raise 25(OH)D concentrations, relative to dietary preferences and latitude of residence, in the context of general population, these sources are regarded ineffective to maintain the year-round 25(OH)D concentrations in the range of 30-50ng/mL (75-125nmol/L). Vitamin D self-administration related adverse effects, such as hypercalcemia and hypercalciuria are rare, and usually result from taking extremely high doses of vitamin D for a prolonged time.

Sporadic primary hyperparathyroidism and stone disease: a comprehensive metabolic evaluation before and after parathyroidectomy.

OBJECTIVES: To characterize the stone risk and the impact of parathyroidectomy on the metabolic profile of patients with primary hyperparathyroidism (PHPT) and urolithiasis. PATIENTS AND METHODS: We analysed the prospectively collected charts of patients treated at our stone clinic between January 2001 and January 2016 searching for patients with PHPT and urolithiasis. Imaging evaluation of the kidneys, bones and parathyroid glands was assessed. We analysed the demographic data, serum and urinary variables before and after parathyroidectomy. We used a paired t-test, Fisher's test, Spearman's test and anova in the statistical analysis. RESULTS: A total of 51 patients were included. The mean patient age was 57.1 ± 12.1 years and 82.4% were women. Before parathyroidectomy, mean calcium and parathyroid hormone (PTH) levels were 11.2 ± 1.0 mg/dL and 331 ± 584 pg/dL, respectively. Hypercalcaemia was present in 84.3% of patients. All eight patients with normal calcium levels had elevated PTH levels. Only two patients did not have PTH above the normal range, although both had elevated calcium levels. The most common urinary disorders were low urinary volume (64.7%), hypercalciuria (60.8%), high urinary pH (41.2%) and hypocitraturia (31.4%). After parathyroidectomy, the number of patients with hypercalcaemia (n = 4; 7.8%), elevated PTH (n = 17; 33.3%) and hypophosphataemia (n = 3; 5.9%) significantly decreased (P < 0.001). The number of urinary abnormalities decreased and there was a reduction in urinary calcium (P < 0.001), pH (P = 0.001) and citrate levels (P = 0.003). CONCLUSION: Individuals with PHPT and nephrolithiasis frequently have elevated baseline PTH and calcium levels. Low volume, hypercalciuria, high urinary pH, and hypocitraturia are the most frequent urinary disorders. Parathyroidectomy is effective in normalizing serum calcium and PTH levels, although other urinary metabolic may persist. Patients should be monitored for the need for citrate supplementation.

How much is too much? Two contrasting cases of excessive vitamin D supplementation.

BACKGROUND: In this report, we describe 2 contrasting cases of hypervitaminosis D. CASE PRESENTATION: Patient 1 was a 75-y old man who developed symptomatic hypercalcemia (peak serum calcium concentration of 15.3mg/dl; reference range: 8.5-10.6mg/dl), cardiac injury, and a high total serum vitamin D concentration of 243ng/ml (30-80ng/ml) as a result of daily consumption of prescribed 50,000IU ergocalciferol (vitamin D2) and 500mg calcium-citrate for 1y. Patient 2 was a 60-y old woman who consumed 40,000IU of cholecalciferol (vitamin D3) daily for >10months with a peak total serum vitamin D concentration of 479ng/ml (30-80ng/ml), but did not present with symptoms related to vitamin D toxicity. CONCLUSION: These cases demonstrate that individual responses to supraphysiologic concentrations of vitamin D for extended periods of time vary widely, and that defining a toxic concentration of this vitamin is difficult. The different outcomes in these two patients, despite months of high-dose vitamin D therapy, demonstrates that individual patient pharmacodynamics determine clinical sequelae.

[Hypercalcemic crisis and hypocalcemic tetany]. / Hyperkalzämische Krise und hypokalzämische Tetanie.

A serum calcium level >3.5 mmol/l together with clinical symptoms such as muscle weakness, fatigue, nausea, vomiting, pancreatitis or even coma are characteristic for a hypercalcemic crisis (HC). Primary hyperparathyroidism (1HPT) and malignancy-associated hypercalcemia are the most frequent causal diseases for a HC. The analysis of serum levels for calcium, phosphorous, intact parathyroid hormone, electrophoresis and renal function parameters indicate which further radiological, scintigraphic or serum diagnostic steps are adequate to identify the cause of the patient's acute situation (i. e. most frequently 1HPT or malignant disease with bone involvement, e. g. myeloma) and thus to initiate the required surgical or oncological intervention. However, the primary goals in the treatment of HC include correcting dehydration and improving kidney function, lowering calcium levels and decreasing osteoclastic bone resorption. The goals are accomplished by volume repletion, forced diuresis, antiresorptive agents and hemodialysis on an intensive care unit. Hypocalcemic tetany (HT) is the consequence of severely lowered calcium levels (<2.0 mmol/l), usually in patients with chronic hypocalcemia. The causal disease for hypocalcemic tetany is frequently a lack of parathyroid hormone (PTH), (e. g. as a complication of thyroid surgery) or, rarely, resistance to PTH. HT due to severe and painful clinical symptoms requires rapid i. v. calcium replacement by central venous catheter on an intensive care unit. For the treatment of chronic hypocalcemia oral calcium and 25OH-vitamin D or even 1,25(OH)2-vitamin D3 and magnesium supplements may be necessary to achieve the desired low normal calcium levels. Thiazides are useful to reduce renal calcium loss and to stabilize the calcium levels. Some patients continue to exhibit clinical symptoms despite adequate calcium levels; in these cases s. c. parathyroid hormone 1-84 should be considered to stabilize calcium levels and to lower the dosage of calcium and vitamin D supplements.