Clinical Characteristics and Management of Hypercalcemic Crisis in 155 Patients: A Single Center Retrospective Study

Objective This study aimed to analyse the etiology and clinical characteristics of hypercalcemic crisis in a large cohort of Chinese patients and summarised our clinical experience in the management of this serious endocrinological emergency. Methods This was a retrospective analysis of a cohort of patients with hypercalcemic crisis hospitalized in the First Medical Center of Chinese PLA General Hospital between January 2009 and March 2024. The general data, clinical manifestations, etiology, photographic examination, emergency treatment, etiological treatment, and prognosis were analysed. Results A total of 155 patients with hypercalcemic crisis (91 males and 64 females) with a mean age of 54.60 ± 16.99 years old were enrolled. The most frequent disease-causing hypercalcemic crisis was hyperparathyroidism (41.94%), followed by solid malignancy (41.29%) and multiple myeloma (9.03%), et al. Patients mainly presented with symptoms of the digestive system (78.10%), nervous system (63.30%), skeletal system (59.60%), urinary system (59.50%), and cardiovascular system (34.90%). These 155 patients with hypercalcemic crisis got effective therapies that included simultaneous administration of intravenous injection (IV) isotonic saline, subcutaneous calcitonin, bisphosphonate, or hemodialysis in serious cases. After emergency treatment, all the symptoms in the patients were relieved obviously. The cure rate of hypercalcemic with etiological treatments was 84.50% (131/155). Conclusion Hypercalcemic crisis is a serious endocrinological emergency with a variety of etiologies and a high risk of mortality. A prompt diagnosis and the implementation of a comprehensive and effective treatment can efficiently alleviate this endocrinological emergency. Etiological treatment targeting different causes can improve prognosis significantly.


Introduction
Hypercalcemic is one of the most prevalent endocrine disorders with the total serum calcium (SCa) level above the upper limit of the normal reference range (usually above 10.5 mg/dl).Te severity of hypercalcemic can be classifed as mild (SCa <12 mg/dL or 3 mmol/L), moderate (SCa 12−14 mg/dL that is 3-3.5 mmol/L), and severe (SCa >14 mg/dL that is 3.5 mmol/L).Te total SCa level above 14 mg/dL accompanied by a series of serious clinical signs is called a hypercalcemic crisis.Due to the wide spectrum of the emergency and the lack of specifc constitutional symptoms, the association between hypercalcemic and its clinical manifestations has often been covered up by other primary diseases and ignored.It easily leads to misdiagnosis and delayed treatment.Terefore, emergency treatments are often required before the cause is discovered.Identifcation of the etiology of hypercalcemic and efective targeted therapy are essential to improve the prognosis [1,2].Till now, there have been few reports on the diagnosis and management of hypercalcemic crisis in a large sample of the Chinese population.In this report, we analysed the clinical data of 155 patients with hypercalcemic crisis in our hospital and summarized the characteristics, spectrum, and our clinical experience in the diagnosis and therapy of this serious endocrinological emergency.

Materials and Methods
2.1.Patients.One hundred and ffty-fve patients with a confrmed diagnosis of hypercalcemic crisis between January 2009 and March 2024 were collected from the medical database of the First Medical Center of Chinese PLA General Hospital.Patients with the level of total SCa corrected for albumin above 14 mg/dL and accompanied by diferent clinical manifestations were involved.

Statistical Analysis.
Statistical analyses were performed with IBM SPSS Statistics version 22.0.Continuous data were presented as mean ± standard deviation.Quantitative data with nonnormal distribution were presented as median (r) or interquartile range (P25 and P75).
Te various systematic clinical manifestations of hypercalcemic crisis caused by primary hyperparathyroidism included the skeletal system, gastrointestinal system, urinary system, nervous system, and cardiovascular system.All patients with tertiary hyperparathyroidism had chronic renal failure with an average duration of 3.9 ± 0.2 years (Table 1).

Solid Malignancy.
Tere were 64 patients with solid malignancies.In 75.00% (48/64) of the patients, the secondary hypercalcemic crisis was due to a long history of primary diseases.Oesophageal cancer, lung cancer, and leukemia accounted for 20.83% (10/48), 18.75% (9/48), and 12.50% (6/48), respectively.In addition to the primary tumour disease, clinical manifestations of other systems were also combined, with the digestive system being the most common, followed by the nervous system, cardiovascular system, and urinary system.Hypercalcemic crisis was the initial manifestation in 25.00% (16/64) of patients with solid malignancies, of which lung cancer accounted for 37.50% (6/ 16) and leukemia for 25.00% (4/16) (Table 1).

Diagnosis.
A total of 3.87% (6/155) of patients experienced misdiagnosis or missed diagnosis.One case had acute abdominal symptoms, leading to a misdiagnosis of obstructive jaundice.Other 1.94% (3/155) of the patients had been initially revisited for malignancy (one case of liver metastasis from hepatocellular carcinoma and two cases of multiple myeloma).However, none of them presented with 2 International Journal of Endocrinology A total of 33.33% (6/18) of patients with triphasic hyperparathyroidism underwent surgery, and postoperative pathology (5/5) confrmed the diagnosis of parathyroid adenoma-like hyperplasia.Te mean preoperative serum PTH level was 434.35 (262.32,833.37) pg/mL, which decreased to 15.81 (13.11, 103.41) pg/mL after surgery, and the mean corrected postoperative SCa level decreased from 14.44 ± 2.44 mg/dL to 10.44 ± 0.88 mg/dL.Patients who underwent surgery showed signifcant improvement in clinical symptoms and signs.Forty-eight patients with a history of a primary solid malignancy and secondary hypercalcemic crisis underwent targeted treatment of the primary diseases.Te response rate was 60.42% (29/48) in these patients treated with chemotherapy (62.50%, 30/48) and radiotherapy (6.25%, 3/48).In 16 patients with a primary malignancy, the response rate was 87.50% (14/16) after targeted treatment of the primary diseases.Among the 71.43% (10/14) of patients with multiple myeloma who were treated with chemotherapy, the response rate was 78.57% (11/14).With efective targeted therapy of the primary disease, SCa levels were signifcantly reduced and the associated symptoms were signifcantly alleviated in these patients.

Discussion
Hypercalcemic crisis is a serious life-threatening metabolic disorder, and the most common causes are primary hyperparathyroidism, solid malignancies, and multiple myeloma, accounting for over 90% of all precipitating factors.Other causes of hypercalcemic crisis are relatively rare [3,4].In a large sample of Chinese patients, our study identifed that the most common conditions were hyperparathyroidism (41.94%), solid malignancies (41.29%), and multiple myeloma (9.03%).In hyperparathyroidism, PTH can activate the osteoclasts, leading to the release of large amounts of bone calcium into the bloodstream, promoting kidney reabsorption of calcium and the synthesis of more vitamin D, and causing the hypercalcemic crisis [5].In patients with solid malignancies, in addition to osteolytic hypercalcemic caused by bone metastases, systemic fuid factors secreted by tumour cells, such as PTH-related protein (PTHrP), are important mechanisms.Such fuid factors can activate PTH receptors, leading to a hypercalcemic crisis.
Te clinical manifestations of hypercalcemic crisis are highly variable and easily confused with other diseases, hence early recognition of the symptoms and signs of hypercalcemic crisis is critical.Te onset of clinical symptoms and signs associated with hypercalcemic depends on factors such as the rate of calcium elevation, the degree of elevation, and the patient's tolerance to hypercalcemic [6].Te normal functioning of the nervous system requires an adequate SCa concentration.Terefore, high SCa can lead to cognitive dysfunction, ataxia, and even coma.Te cardiovascular system exhibits hypertension, bradycardia, arrhythmias, and QT interval shortening.Te gastrointestinal tract manifests as anorexia, nausea, vomiting, and constipation.Te urinary system manifestations include polyuria, kidney stones, renal calcifcations, decreased glomerular fltration rate, and hyperchloremic acidosis [7,8].In this study, the proportion of patients with cardiovascular manifestations was relatively low, indicating that cardiovascular complications may not be common in hypercalcemic crisis [9].It has been reported in the literature that hypercalcemic crisis can usually be misdiagnosed as chronic gastritis or urinary tract stones [6].Te complex and variable clinical manifestations can easily lead 4 International Journal of Endocrinology International Journal of Endocrinology to misdiagnosis.Terefore, specialists should be alert to the occurrence of a hypercalcemic crisis when analysing similar clinical manifestations.In addition, it is necessary to promptly monitor SCa levels in patients with malignant tumours to avoid misdiagnosis of hypercalcemic.Primary hyperparathyroidism can be diagnosed on the basis of clinical presentations, bone lesions, renal lithiasis, and high SCa levels with concomitant high levels of PTH.Moreover, high alkaline phosphatase levels and urinary calcium excretion, low serum phosphorus, and specifc Xray image changes support such a diagnosis.Triple hyperparathyroidism occurs as a result of long-term secondary hyperparathyroidism [10].Prolonged and intense stimulation of the parathyroid tissue leads to the development of autonomous hyperplasia or adenoma, resulting in SCa levels above normal and often requiring surgical intervention.With regard to the location of parathyroid adenomas, this study showed that 99mTc MIBI had a higher sensitivity compared to ultrasound and CT scans.Combining these two techniques could signifcantly improve the detection rate of tumours, particularly for ectopic and small adenomas [11].
Multiple myeloma is classifed into monoclonal immunoglobulin G (IgG) excess syndrome of unknown signifcance, smoldering myeloma and active multiple myeloma.It is characterised by a tumour-like proliferation of plasma cells in the bone marrow, which stimulate osteoclasts and destroy bone tissues, leading to hypercalcemic, bone pain, and pathological fractures [12].Fourteen patients were diagnosed with multiple myeloma after immunological tests and histological biopsies in diferent departments in this study.
In the treatment of hypercalcemic crisis, rapid reduction of calcium is of paramount importance, and etiological treatments play a key role.Te emergency reduction of calcium involves various aspects, such as fuid infusion, promoting renal calcium excretion, preventing intestinal calcium absorption, reducing bone absorption, and so on.Fluid hydration is the initial therapy.Usually, 3 to 4 litres of normal saline should be infused within the frst 24 hours.Blood electrolytes and electrocardiograms should be monitored frequently during fuid hydration to detect electrolyte disturbances.When blood volume is normalized, loop diuretics can be administered, while thiazide-type diuretics should be avoided.
Calcitonin inhibits bone resorption and increases urinary calcium excretion.It is efective in rapidly reducing calcium in patients with hypercalcemic crisis.Calcitonin 100-400 U injected once every 6 hours via either intravenously or subcutaneously is commonly administrated in 2-3 doses per day, but it often shows "escape" phenomena within a few hours or days and reduces its efcacy.
Intravenous bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and provide longerterm control of hypercalcemic than saline.Zoledronic acid, one of the most widely used and efective bisphosphonates, is highly recommended.Before zoledronic acid intravenous injection, it is important to ensure adequate hydration and pretreatment of drug heat.Te efects of fuid resuscitation, diuretics, calcitonin, and dialysis treatment are rapid and short-lived.On the other hand, the efects of bisphosphonates and glucocorticoids are slow and take longer to reduce calcium [13].Denosumab is a human monoclonal antibody targeting nuclear factor-κB ligand-receptor activator.It acts as an antiresorption agent by reducing osteoclastogenesis and is a novel therapeutic approach for osteoporotic fractures and skeletal-related events in patients with high bone turnover [14].Denosumab has been proven to reduce SCa levels.In this study, a total of 155 patients were treated with efective calcium-lowering therapies, and the cure rate was 100% (155/155).Hence, this may provide a favourable condition for subsequent targeted treatments.
Once the hypercalcemic crisis has been relieved with efective emergency therapies, etiological treatment can achieve a high cure rate of hypercalcemic and get a better prognosis [15].Te most efective treatment for patients with primary hyperparathyroidism is surgery.After the removal of the parathyroid tumour, hypercalcemic can be cured.For solid malignancies, various factors are evaluated and multiple treatment modalities including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy should be performed.For other causes of hypercalcemic, medication is usually the primary treatment, as reported in previous studies [1,16].In this study, all 37 patients with primary hyperparathyroidism underwent surgery and achieved a complete cure with normal serum PTH and SCa.Following targeted treatment in patients with solid malignancies, the level of SCa also decreased signifcantly.Forty-four patients with solid malignancies got better responses.Te chemotherapy rate, improvement rate, and response rate in multiple myeloma patients were also signifcantly increased (Table 2).
In conclusion, our study retrospectively analysed a large sample of cases of hypercalcemic crisis.Te disease spectrum of hypercalcemic crisis is various.Te top three etiologies of the emergency disorder were hyperparathyroidism, solid malignancies, and multiple myeloma.Te clinical manifestations involved multiple systems, and the complex clinical manifestations easily lead to misdiagnosis.Terefore, the early recognition, emergency treatment, and etiological treatment of hypercalcemic crisis are critical.Comprehensive emergency treatment for hypercalcemic crisis, including fuid hydration, calcitonin, bisphosphonates, and hemodialysis, can rapidly reduce SCa levels and achieve symptomatic relief.

Table 1 :
Distribution of clinical fndings and biochemical tests of 155 hypercalcemic crisis patients.ray bone mineral density, radionuclide bone imaging, etc.), the rapid diagnosis of hypercalcemic crisis (diagnosis days: 0.9 ± 0.1 days) was confrmed after admitting in our hospital, and the cause of this serious disorder was identifed in 89.68% (139/155) of patients (interval time: 7.0 ± 0.3 days).Later, further targeted treatments were then performed.Among the 155 patients, emergency calcium-lowering treatments such as water intake (4000 ml of water per day) or hydration therapy (intravenous infusion of 4000 ml of normal saline) were performed in 78.80% (122/155) of patients, diuretic therapy in 56.70%, (88/155) of patients, calcitonin therapy in 45.10% (70/155) of patients, bisphosphonate therapy in 69.00% (107/155) of patients, glucocorticoids in 34.10% (53/155) of patients, and hemodialysis in 7.70% (12/155) of patients.After emergency treatment, the mean corrected SCa level in these patients decreased from 15.64 ± 1.96 mg/dL to 10.68 ± 2.08 mg/dL (normal range: 8.36-10.16mg/dL).Te treatment efectively reduced the SCa levels in all 155 patients with various causes of hypercalcemic crisis.Te symptoms were all relieved signifcantly.Te average duration of emergency treatment was 3.3 ± 1.2 days.No patient died from hypercalcemic crisis.
Te concentration of ALP and PTH was quantitative data with nonnormal distribution, which presented as median (r) or interquartile range (P25 and P75).

Table 2 :
Treatment plan and outcome of 155 hypercalcemic crisis patients.