Hypercalcemia and cancer: Differential diagnosis and treatment.

Incidentally detected hypercalcemia usually presents in an indolent manner and is most likely caused by primary hyperparathyroidism. In contrast, hypercalcemia in the patient with a history of cancer presents in a wide range of clinical settings and may be severe enough to warrant hospitalization. This form of hypercalcemia is usually secondary to hypercalcemia of malignancy and can be fatal. Hypercalcemia of malignancy is most commonly mediated by tumoral production of parathyroid hormone-related protein or by cytokines activating osteoclast degradation of bone. The initial workup, differential diagnoses, confirmatory laboratory testing, imaging, and medical and surgical management of hypercalcemia are described in the patient with cancer.

Testing for Primary Hyperparathyroidism in 17,491 Patients With Hypercalcemia.

BACKGROUND: Primary hyperparathyroidism (PHPT) is underdiagnosed and associated with many adverse health effects. Historically, many hypercalcemic patients have not received parathyroid hormone (PTH) testing; however, underlying reasons are uncertain. Our goals are to determine the PTH testing rate among hypercalcemic individuals at a large academic health system and to assess for characteristics associated with testing versus not testing for PHPT to inform future strategies for closing testing gaps. METHODS: This retrospective study included adult patients with ≥1 elevated serum calcium result between 2018 and 2022. Based on the presence or absence of a serum PTH result, individuals were classified as "screened" versus "unscreened" for PHPT. Demographic and clinical characteristics of these groups were compared. RESULTS: The sample comprised 17,491 patients: 6567 male (37.5%), 10,924 female (62.5%), mean age 59 y. PTH testing was performed in 6096 (34.9%). Characteristics independently associated with the greatest odds of screening were 5+ elevated calcium results (odds ratio [OR] 5.02, P < 0.0001), chronic kidney disease (OR 3.63, P < 0.0001), maximum calcium >12.0 mg/dL (OR 2.48, P < 0.0001), and osteoporosis (OR 2.42, P < 0.0001). Characteristics associated with lowest odds of screening were age <35 y (OR 0.60, P < 0.0001), death during the study period (OR 0.68, P < 0.0001), age ≥85 y (OR 0.70, P = 0.0007), and depression (OR 0.84; P = 0.0081). CONCLUSIONS: Only 35% of hypercalcemic patients received PTH testing. Although the presence of PHPT-associated morbidity was generally associated with increased rates of screening, hypercalcemic patients with depression were 16% less likely to be tested.

Hypercalcemia and Postoperative Joint Symptoms Following Joint Replacement for Osteoarthritis.

INTRODUCTION: Calcium metabolism dysregulation in the setting of primary hyperparathyroidism (PHPT) mediated chondrocalcinosis is implicated in joint pain, a key element in the decision regarding arthroplasty for osteoarthritis. The relationship between hypercalcemia and joint pain, before and after arthroplasty, is unknown. This study investigates the association between preoperative hypercalcemia and postoperative outcomes following total knee (TKA) and total hip arthroplasty (THA). METHODS: A retrospective chart review was conducted on patients who underwent initial elective THA or TKA. Patients with a preoperative serum calcium >10.2 mg/dL were matched (1:2-1:4) with nearest neighbor to patients with normal serum calcium. THA and TKA functional outcomes were measured at baseline and 1-y postoperatively using patient-reported Hip Disability and Osteoarthritis Outcome Scores and Knee Injury and Osteoarthritis Outcome Scores surveys. Postoperative complications, readmissions, length of stay, and functional outcome scores were compared. RESULTS: Four hundred ninety-five patients (106 hypercalcemic cases, 389 matched controls) were included. Of these, 223 patients underwent THA (46 cases; 177 controls) and 272 patients underwent TKA (61 cases; 211 controls). There were no differences in Hip Disability and Osteoarthritis Outcome Scores and Knee Injury and Osteoarthritis Outcome Scores scores, postoperative complications, readmissions, or length of stay between cases and controls. Only 19/106 (18%) hypercalcemic patients had a parathyroid hormone (PTH); of these, 9 (47%) had possible PHPT (PTH > 40). CONCLUSIONS: Patients with hypercalcemia undergoing arthroplasty have similar functional and postoperative outcomes as normocalcemic patients. As PTH was obtained in <20% of hypercalcemic cases and 50% had possible PHPT, we recommend that hypercalcemic patients undergo PHPT workup. Additional investigation is needed to determine the effect of PHPT on arthroplasty outcomes.

Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2.

Infantile hypercalcemia (IH) is a rare genetic disorder characterized by hypercalcemia, hypercalciuria, low parathyroid hormone, and nephrocalcinosis during the first months of life. Biallelic variants in the genes CYP24A1 and SCL34A1 cause IH1 and 2, respectively. We present the case of a newborn with an antenatal diagnosis of IH2 due to the identification of echogenic, yet normal-sized kidneys at 23 weeks gestation. Trio whole-exome sequencing initially identified only a heterozygous pathogenic variant in SLC34A1. Re-analysis of the exome data because of the clinical suspicion of IH2 revealed a 21-basepair deletion in trans that had initially been filtered out because of its high allele frequency. The diagnosis of IH2 enabled postnatal screening for hypercalcemia, present already at week 1, resulting in early treatment with phosphate supplementation and vitamin D avoidance. In the subsequent course, biochemical parameters were normalized, and the patient showed no obvious clinical complications of IH2, apart from the nephrocalcinosis.

Denosumab in a pediatric kidney transplant recipient with late, resistant hypercalcemia secondary to Pneumocystis jirovecii pneumonia.

Kidney transplant recipients (KTR) are at an increased risk of developing Pneumocystis jirovecii pneumonia (PCP), especially during the first year after transplantation. This is the first reported pediatric KTR, with chronic kidney disease (CKD) secondary to kidney dysplasia and vesicoureteral reflux, who developed refractory and symptomatic hypercalcemia 5 years after transplantation. The hypercalcemia was resistant to treatment with intravenous hyperhydration, furosemide, and a low-calcium diet. A respiratory tract infection due to PCP treated with trimethoprim-sulfamethoxazole did not improve calcium levels. Due to the hypercalcemic symptom burden for the patient, a single dose of subcutaneous denosumab was used to achieve sustained clinical and biochemical improvement, without any severe adverse events. This case highlights the potential use of denosumab as a treatment option in pediatric KTR with refractory hypercalcemia related to PCP. Further study of denosumab in young people with CKD or kidney transplants is needed before routine use can be recommended.

Discrepancies in corrected calcium versus ionised calcium in a geriatric population: an observational study.

BACKGROUND: Calcium can be measured as ionised (Ca-ionised) or albumin-adjusted total calcium (Ca-albumin). Current clinical guidelines predominantly utilise Ca-albumin, despite Ca-ionised being the gold standard. Discrepancies can occur between these measurement modalities and can lead to clinical dilemmas. It remains unclear how large these discrepancies are in older patients. This study investigated the discrepancies between Ca-ionised and Ca-albumin in geriatric patients. METHODS: This is an observational study of all geriatric patients (n = 876) in the Jeroen Bosch Hospital (January 2018 and January 2021) in whom both Ca-ionised and Ca-albumin were measured. Misclassification of calcaemic state (i.e. low, normal or high) was calculated (percentages), the measure of agreement was described using Cohen's Kappa and for the continuous data Pearson's correlation coefficient was used. Relevant categories of age and renal function were considered for effect modification effects and studied by interaction terms in a regression model. RESULTS: In one-third of the measurements, there was a misclassification. Ca-albumin measurements failed to identify 28% of hypocalcaemia. In 3.5%, hypercalcemia based on Ca-albumin was not confirmed by Ca-ionised. The correlation coefficient between Ca-ionised and Ca-albumin was 0.743 (P = 0.01) and measure of agreement by Kappa was 0.213 (P < 0.001). In the oldest old (≥ 85 years) and patients with eGFR <30 ml/min/1.73 m2 ,the agreement by Kappa was lower, with values of 0.192 and 0.104, respectively. CONCLUSION: There is a discrepancy between Ca-albumin and Ca-ionised in one-third of the geriatric patients, leading to clinical dilemmas. In the oldest old and patients with renal dysfunction, this problem is most pronounced.

Hypercalcemia of malignancy: Cancer treatment can be a cause as well.

While the incidence of hypercalcemia of malignancy (HCM) is on the decline, it still occurs in up to 30% of patients with cancer. Immune checkpoint inhibitor (ICI)-related hypercalcemia is becoming increasingly recognized. We describe a case of cemiplimab-induced hypercalcemia in a patient with metastatic squamous cell carcinoma of the earlobe and discuss a management algorithm for HCM. Timely diagnosis and management of HCM is critical for optimal care and the prevention of complications.

Infantile hypercalcemia type 1 (HCINF1): a rare disease resulting in nephrolithiasis and nephrocalcinosis caused by mutations in the vitamin D catabolic enzyme, CYP24A1.

Infantile hypercalcemia type 1 (HCINF1), formerly known as Lightwood syndrome, is a subtype of hypercalcemia caused by loss-of-function biallelic mutations in the vitamin D catabolic enzyme, CYP24A1, which 24-hydroxylates the hormone 1,25-(OH)2D3. This short review focuses on the main features of the HCINF1 disease; emerging knowledge of the structure and function of the cytochrome P450, CYP24A1 and the location of inactivating mutations; the development of a rapid LC-MS/MS-based laboratory test for defective 24-hydroxylation; and future implications for bioanalytical assay and treatment of all types of vitamin D-related hypercalcemic conditions.

When to suspect infantile hypercalcemia-1?

PURPOSE: The screening test to suspect infantile hypercalcemia-1 (HCINF1) is the measure of 25(OH)D3/24,25(OH)2D3 ratio at mass spectroscopy (MS). When the ratio is > 80, the gold standard for the diagnosis is genetic analysis. Given its limited availability, MS may not represent a screening test and most cases of HCINF1 remain undiagnosed. Aim of the study is to identify cut-offs of serum calcium and PTH useful to suspect patients with HCINF1. METHODS: We compared the levels of total serum calcium and PTH of 6 patients with HCINF1 harboring biallelic CYP24A1 pathogenic variants with 3 different control groups: (1) 12 subjects wild type for CYP24A1; (2) 12 subjects matched for age and sex; (3) 12 subjects matched for vitamin D levels. We validated the cut-offs, testing the number of adult patients affected by HCINF1 reported in the literature that could be identified using these cut-offs. RESULTS: A serum calcium level > 9.6 mg/dL showed the highest sensitivity (100%) and specificity (91%) in the comparison between homozygous and wild-type subjects. A serum PTH index < 0.315 showed the highest sensitivity (100%) and specificity (83.3%). A serum calcium level > 9.6 mg/dL was able to identify all adult HCINF1 patients whereas a PTH ratio < 0.315 identified 89.8% of the cases. Superimposable results were obtained using the other control groups. CONCLUSION: Patients with serum calcium levels higher than 9.6 mg/dL and a PTH index lower than 0.315 are likely to be affected by HCINF1. Their diagnosis may be confirmed using MS and genetic analysis.

Twenty-four hour Holter ECG in normocalcemic and hypercalcemic patients with hyperparathyroidism.

PURPOSE: To investigate the occurrence of arrhythmias in patients with normocalcemic (NC) primary hyperparathyroidism (PHPT) compared to both hypercalcemic PHPT patients and control subjects by means of 24-h Holter ECG. METHODS: Thirteen NCPHPT postmenopausal patients were enrolled and age-matched with 13 hypercalcemic PHPT patients and 13 controls. Every subject underwent basal ECG, 24-h Holter ECG and mineral metabolism biochemical evaluation. RESULTS: PHPT patients had higher mean serum calcium levels compared to both NCPHPT and controls; there was no difference in mean serum calcium levels between NCPHPT and controls. Both NCPHPT and PHPT patients had significantly higher mean PTH levels compared with controls. There were no differences in ECG parameters between the three groups, except for QTc interval. PHPT patients had normal QTc interval values, but significantly shorter mean values compared with those of controls and NCPHPT patients. During 24-h Holter ECG recording, 100% of PHPT patients had supraventricular premature beats (SVPBs), compared to 46% of NCPHPT (p = 0.005) and to 53% of controls (p = 0.01). PHPT patients experienced ventricular premature beats (VPBs) (69.2%) vs 15% of NCPHPT patients (p = 0.01) and 23% of controls (p = 0.04). There was no difference between NCPHPT and controls subjects concerning occurrence of both VPBs and SVPBs. CONCLUSIONS: NCPHPT patients did not experience an increased occurrence of arrhythmias compared to controls, while PHPT patients showed an increased occurrence compared to both controls and NCPHPT. Our findings are most probably related to the short QTc interval caused by hypercalcemia observed in PHPT patients, but not in NCPHPT.

Measurement of plasma total calcium before plasma free ionized calcium - a possibility with affordable pitfalls.

Free ionized calcium (fCa) is considered the gold standard for assessing calcium status in patients, but it is relatively expensive and is associated with several preanalytical and analytical error sources. We investigated the feasibility of using a reflex test that involves first measuring total calcium (tCa) and if out of reference range, then measure fCa, with expectation of reducing the number of fCa measurements. We used data from 1815 unique patients with concurrent measurement of fCa, tCa and albumin adjusted calcium (aCa). Patients were stratified by albumin level, and the association of fCa to tCa and aCa respectively was assessed with linear regression. The regression analysis showed the best linearity for tCa and aCa at albumin <35 g/L (R2: 0.80-0.90), and the poorest at albumin >40 g/L (R2: tCa 0.58; aCa 0.59). We examined the accuracy of hypo- and hypercalcemia classifications for tCa, aCa and the reflex test. aCa had more misclassifications of hypo- and hypercalcemia than tCa, with respectively 25% and 21%. Implementation of the reflex test would correct any false hypo- or hypercalcemia classified by tCa, leaving only false negative results corresponding to 9% of all tCa measurements. False negative results were on average 0.04 mmol/L above or below the reference range of fCa. Implementation of the reflex test reduces the number of fCa by 68% without major errors diagnosing hyper- or hypocalcemia.

Electrolyte disorders related emergencies in children.

This article provides a comprehensive overview of electrolyte and water homeostasis in pediatric patients, focusing on some of the common serum electrolyte abnormalities encountered in clinical practice. Understanding pathophysiology, taking a detailed history, performing comprehensive physical examinations, and ordering basic laboratory investigations are essential for the timely proper management of these conditions. We will discuss the pathophysiology, clinical manifestations, diagnostic approaches, and treatment strategies for each electrolyte disorder. This article aims to enhance the clinical approach to pediatric patients with electrolyte imbalance-related emergencies, ultimately improving patient outcomes.Trial registration This manuscript does not include a clinical trial; instead, it provides an updated review of literature.

[First Report of a Family with Familial Hypocalciuric Hypercalcemia in Chile: Differential Diagnosis in a Patient with PTH-Dependent Hypercalcemia Post-Parathyroidectomy]. / Primer reporte de familia con hipercalcemia hipocalciúrica familiar en Chile: Diagnóstico diferencial en paciente con hipercalcemia PTH dependiente post-paratiroidectomía.

We report a 45-year-old woman with persistent post-parathyroidectomy PTH-dependent asymptomatic hypercalcemia who, after evaluation in our bone clinic, was diagnosed as having familial hypocalciuric hypercalcemia based on concomitant hypocalciuria and a family history of asymptomatic hypercalcemia. Genetic study shows a variant of uncertain significance in the CASR gene. To our knowledge, this is the first report on a Chilean family with HHF.

[Malignant hypercalcemia]. / Hypercalcémie maligne.

Malignant hypercalcemia is the main metabolic complication of cancer. Clinical presentation varies from asymptomatic to a medical emergency. The main causes include parathyroid hormone-related protein production and bone metastases, while hypervitaminosis D and hyperparathyroidism are rarer causes. Diagnosis is based on the demonstration of elevated serum calcium and low PTH in the context of known or suspected cancer. Treatment is aimed at correcting hypovolemia by hydration, reducing bone resorption, and treating the underlying cancer. The aims are to improve patients' quality of life, minimize delays in oncological management and reduce mortality associated with this condition.

L'hypercalcémie maligne est la principale complication métabolique du cancer. La présentation clinique peut être paucisymptomatique ou représenter une urgence médicale. Les causes principales sont la production de parathyroid hormone-related protein (PTHrP) et les métastases osseuses, tandis que l'hypervitaminose D et l'hyperparathyroïdie sont des causes plus rares. Le diagnostic repose sur la mise en évidence d'un calcium sérique élevé et d'une PTH basse dans le contexte d'un cancer connu ou suspecté. Le traitement a pour objectifs de corriger l'hypovolémie par hydratation, diminuer la résorption osseuse et traiter le cancer sous-jacent. Les objectifs sont d'améliorer la qualité de vie des patients, de minimiser les retards de prise en charge oncologique et de réduire la mortalité associée à cette condition.

Neurodevelopmental Abnormalities in Patients with Familial Hypocalciuric Hypercalcemia Type 3.

OBJECTIVES: To evaluate the prevalence and degree of any neurodevelopmental abnormalities in children with familial hypocalciuric hypercalcemia type 3 (FHH3). STUDY DESIGN: A formal neurodevelopmental assessment was performed in children diagnosed with FHH3. The Vineland Adaptive Behavior Scales, which is a standardized parent report assessment tool for adaptive behavior, was used to assess communication, social skills, and motor function and to generate a composite score. RESULTS: Six patients were diagnosed with hypercalcemia between 0.1 and 8 years of age. All had neurodevelopmental abnormalities in childhood consisting of either global developmental delay, motor delay, expressive speech disturbances, learning difficulties, hyperactivity, or autism spectrum disorder. Four out of the 6 probands had a composite Vineland Adaptive Behavior Scales SDS of < -2.0, indicating adaptive malfunctioning. Significant deficits were observed in the domains of communication (mean SDS: -2.0, P < .01), social skills (mean SDS: -1.3, P < .05), and motor skills (mean SDS: 2.6, P < .05). Individuals were equally affected across domains, with no clear genotype-phenotype correlation. All family members affected with FHH3 also described evidence of neurodevelopmental dysfunction, including mild-to-moderate learning difficulties, dyslexia, and hyperactivity. CONCLUSION: Neurodevelopmental abnormalities appear to be a highly penetrant and common feature of FHH3, and early detection is warranted to provide appropriate educational support. This case series also supports consideration of serum calcium measurement as part of the diagnostic work-up in any child presenting with unexplained neurodevelopmental abnormalities.

Missed Opportunities to Diagnose and Treat Tertiary Hyperparathyroidism After Transplant.

INTRODUCTION: Tertiary hyperparathyroidism (3HPT) is common after renal transplant. However, guidelines for diagnosis are not clear and few patients are treated surgically. This study aims to determine rates of diagnosis and treatment of 3HPT in renal transplant patients with hypercalcemia. MATERIALS AND METHODS: This retrospective chart review identified all renal transplant recipients at a single tertiary care institution between 2011 and 2021. Patients with post-transplant hypercalcemia (> 10.2 mg/dL) were identified. The time in months of index hypercalcemia was noted. Measurement of parathyroid hormone (PTH) levels after index hypercalcemia was determined and noted as elevated if > 64 pg/mL at least 6 mo after transplant. Documentation of symptoms of hyperparathyroidism, a diagnosis of hyperparathyroidism in the electronic medical record, and medical or surgical management of patients with classic 3HPT (elevated calcium and PTH) were determined. RESULTS: Of 383 renal transplant recipients, hypercalcemia was identified in 132 patients. The majority of hypercalcemic patients had PTH levels measured (127, 96.2%). PTH was elevated in 109 (82.6%). Among the 109 patients with classic 3HPT, 54 (49.5%) had a documented diagnosis of hyperparathyroidism in the electronic medical record (P = 0.01). Kidney stones or abnormal DEXA scan were present in 16 (14.7%) and 18 (16.5%), respectively. Most patients were managed non-surgically (101, 92.6%); calcimimetics were prescribed for 42 (38.5%, P = 0.01). Eight (7.3%) patients with classic 3HPT were referred to a surgeon (P = 0.35); all were initially prescribed calcimimetics (P = 0.001). CONCLUSIONS: 3HPT is underdiagnosed in patients with elevated calcium and PTH levels post-transplant. A significant percentage of these patients go without surgical referral and curative treatment.

Treatment of hypokalemia with amiloride unmasked hypercalcemia and hyperparathyroidism: A case report.

Colonic pseudo-obstruction, also called Ogilvie's syndrome, occurs due to impaired intestinal propulsion, and may be caused by electrolyte imbalances such as hypokalemia and some endocrine disorders such as hyperparathyroidism. Secretory diarrhea due to intestinal pseudo-obstruction can cause hypokalemia. Diuretics such as amiloride can be used to treat hypokalemia, however in this case, treatment with amiloride induced hypercalcemia and unmasked hyperparathyroidism. A 73-year-old female with a history of hypertension and parathyroid adenoma presented with recurrent colonic pseudo-obstruction and chronic hypokalemia. Her hypokalemia was treated with amiloride, causing hypercalcemia of 14.4 mg/dL, elevated PTH, and altered mental status. Amiloride was subsequently discontinued with improvement in her symptoms, and her hyperparathyroidism was treated with cinacalcet. To our knowledge, this is the first report of amiloride unmasking hyperparathyroidism and inducing hypercalcemia.

Renal sarcoidosis presenting with chronic kidney disease and hypercalcemia.

Sarcoidosis is a multisystem inflammatory disease that most frequently affects the lungs, lymph nodes, eyes, and skin. Renal involvement is clinically rare. We describe a 72-year-old male who presented with chronic kidney disease and elevated serum calcium and angiotensin-converting enzyme. Renal biopsy pathology showed chronic granulomatous interstitial nephritis. Renal function was significantly improved after glucocorticoid therapy. This case emphasizes that chronic kidney disease and hypercalcemia can be clues for renal sarcoidosis. Early renal biopsy and projective treatment is beneficial for renal outcome.

A Case of Adult Acute B-Cell Lymphoblastic Leukemia with Hypercalcemia and Osteolytic Bone Lesions.

BACKGROUND: We report a rare case of adult acute B-lymphoblastic leukemia (B-ALL) with hypercalcemia and osteolytic bone lesions in a 53-year-old man who died after chemotherapy. METHODS: The bone marrow examination was evaluated by Wright-Giemsa staining, tissue biopsy, immunohistochemical staining, and flow cytometry. Bone imaging was performed using positron emission tomography/computed tomography (PET/CT) technology. Total calcium levels were measured by biochemical analyzer. RESULTS: The result of PET/CT indicated the patient with B-ALL with severe osteolytic bone lesions. The serum total calcium level was as high as 4.09 mmol/L, and the cytokines interleukin-6 and 17A were significantly elevated. The patient was resistant to chemotherapy and had a poor prognosis. CONCLUSIONS: Hypercalcemia and osteolytic bone lesions are rare complications of adult B-ALL, and their co-occurrence may be an indicator of poor prognosis in patients with B-ALL.

Eclampsia as the First Manifestation of Primary Hyperparathyroidism: a Case Report.

BACKGROUND: This study aimed to explore the diagnosis and treatment strategies of eclampsia during pregnancy and postpartum acute pancreatitis caused by primary hyperparathyroidism. METHODS: This study reported a 26-year-old patient who had maternal eclampsia as her first symptom and was admitted to the hospital. The pregnancy was terminated by cesarean section immediately. Postpartum life-threatening complications, such as severe hypercalcemia and acute pancreatitis, occurred afterward. Following completion of the relevant examination, primary hyperparathyroidism was initially considered to be the cause. Symptomatic treatment is ongoing and will be improved, and the patient will be admitted again for parathyroidectomy. RESULTS: The patient gave birth to a premature neonate via cesarean section. The postpartum diagnosis was primary hyperparathyroidism, for which post-surgical pathology showed a parathyroid adenoma. CONCLUSIONS: The clinical manifestations of pregnancy with primary hyperparathyroidism are atypical but may cause serious maternal and fetal complications. Early diagnosis and appropriate treatment can prevent serious prenatal and postnatal complications and foster better pregnancy outcomes.