Parathyroid carcinoma presenting as severe hypercalcaemia responding to steroids.

A man in his 50s was referred with profound, symptomatic hypercalcaemia. He was diagnosed with primary hyperparathyroidism, confirmed on 99mTc-sestamibi scan. He was treated for the hypercalcaemia and referred to ear, nose and throat (ENT) surgeons for parathyroidectomy, which was delayed due to the COVID-19 pandemic. In the ensuing 18 months, he had five hospital admissions with severe hypercalcaemia requiring intravenous fluids and bisphosphonate infusions. During the last admission, hypercalcaemia was resistant to maximal medical management. Emergency parathyroidectomy was planned, but delayed due to intervening COVID-19 infection. Due to persistent severe hypercalcaemia (serum calcium: 4.23 mmol/L), he was commenced on intravenous steroids, following which serum calcium normalised. Subsequently, he underwent emergency parathyroidectomy, which normalised his serum parathyroid and calcium levels. On histopathological examination, a diagnosis of parathyroid carcinoma was made. On follow-up, patient remained well and normocalcaemic. In patients with primary hyperparathyroidism unresponsive to standard therapy, but responsive to steroids, underlying parathyroid malignancy should be considered.

Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports.

BACKGROUND: Familial hypocalciuric hypercalcaemia (FHH) is a rare, inherited disorder of extracellular calcium sensing. It is clinically characterised by mild to moderate parathyroid hormone dependent hypercalcaemia, an autosomal dominant pattern of inheritance, and a normal to reduced urinary calcium excretion in spite of high serum calcium. CASE PRESENTATION: We report two cases of FHH in a family caused by a novel pathogenic missense variant in the CaSR gene, p. His41Arg. Case 1, describes a 17 year old female with no significant past medical history, admitted with acute appendicitis requiring laparoscopic appendectomy and reporting a six month history of polydipsia. Routine investigations were significant for hypercalcaemia, corrected calcium 3.19 mmol/L (2.21-2.52mmol/L), elevated parathyroid hormone of 84pg/ml (15-65pg/ml) and a low 24-hour urine calcium of 0.75mmol/24 (2.50-7.50mmol/24). She was initially managed with intravenous fluids and Zolendronic acid with temporary normalisation of calcium though ultimately required commencement of Cinacalcet 30 mg daily for persistent symptomatic hypercalcaemia. Genetic analysis was subsequently positive for the above variant. Case 2, a 50-year-old female, was referred to the endocrine outpatient clinic for the management of type 2 diabetes and reported a longstanding history of asymptomatic hypercalcaemia which had not been investigated previously. Investigation revealed hypercalcaemia; corrected calcium of 2.6 mmol/L (reference range: 2.21-2.52 mmol/L); PTH of 53.7ng/L (reference range: 15-65 ng/L) and an elevated 24-hour urine calcium of 10 mmol/24 (2.50-7.50 mmol/24hr) with positive genetic analysis and is managed conservatively. Despite sharing this novel mutation, these cases have different phenotypes and their natural history is yet to be determined. Two further relatives are currently undergoing investigation for hypercalcaemia and the family have been referred for genetic counselling. CONCLUSION: Accurate diagnosis of FHH and differentiation from classic primary hyperparathyroidism can be challenging, however it is essential to avoid unnecessary investigations and parathyroid surgery. Genetic analysis may be helpful in establishing a diagnosis of FHH in light of the biochemical heterogeneity in this population and overlap with other causes of hypercalcaemia.

The effect of vitamin D and magnesium supplementation on clinical symptoms, and serum inflammatory and oxidative stress markers in patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial (preprint)

Objectives: This study aims to evaluate the effect of vitamin D and magnesium supplementation on clinical symptoms and serum inflammatory and oxidative stress markers in patients with COVID-19. Trial design: This study is a 4-arm randomized, double-blind, placebo-controlled clinical trial with a factorial design and the intervention period is 3 weeks. Participants: This study is conducted on COVID-19 patients admitted to the Shahid Mohammadi hospital in Bandar Abbas, Iran who be eligible for inclusion in the study. Patients are included only if they meet all of the following criteria: 1) aged from 18 to 65 years old, 2) confirmation of COVID-19 by RT-PCR test, 3) completing informed consent, 4) passing less than 48 hours since the patient's hospitalization, 5) no skin or gastrointestinal allergies due to taking multivitamin supplements, vitamin D, and magnesium, 6) having more than 30 breaths per minute and less than 93% oxygen saturation in room air and sea level. Patients are excluded if they have any of the following conditions: 1) pregnancy or lactation, 2) take a daily multivitamin or take a vitamin D or magnesium supplement in the last month, 3) participating in other clinical trials, 4) renal failure or dialysis, severe liver disease or cirrhosis, 5) known diagnosis of hypercalcemia, 6) discharging from the hospital less than 24 hours after the start of the intervention, 7) history of kidney stones in the last year, 8) transfer the patient to the ICU, 9) baseline vitamin D levels above 80 ng/ml, 9) baseline magnesium levels above 2.6 mg/dl. Intervention and comparator: Participants will be randomly allocated to one of the four following groups: A) Vitamin D (two 50,000 IU capsules at the beginning of the study, two 50,000 IU capsules on the 4th day, one 50,000 IU capsule on the 11th day, and one 50,000 IU capsule on the 17th day) and magnesium supplement (300 mg/day). B) Vitamin D capsule and magnesium placebo. C) Magnesium supplement and vitamin D placebo. D) Vitamin D placebo and magnesium placebo. Main outcomes: Clinical symptoms (fever, dry cough, shortness of breath, headache, myalgia, oxygen saturation, and mortality) and laboratory markers (CRP, MDA, TAC, WBC, neutrophils count, lymphocytes count, ratio of neutrophils to lymphocytes, levels of 25 hydroxyvitamin D and magnesium) Randomization: A computer-generated block randomization list is used for randomization. Blinding (masking): Investigators and patients are blinded to group allocation and treatment. A double-blind design is achieved using matched placebos. Numbers to be randomized (sample size): A total of 104 eligible patients are randomized into four groups of 26 subjects (1:1:1:1 allocation ratio). Discussion With the rapid prevalence of COVID-19 in recent years, more attention has been paid to effective dietary supplementation to improve clinical symptoms and biochemical parameters in these patients. To our knowledge, this is the first study to evaluate the effects of vitamin D supplementation in combination with magnesium or alone with respect to this infectious disease. The findings of the current RCT will provide evidence regarding the effectiveness of dietary supplementation strategies to improve COVID-19 outcomes. Trial Status: Ethical approval of the first version of the study protocol was obtained from the medical ethics committee of Hormozgan University of Medical Sciences, Bandar Abbas, Iran on May 30th, 2021 (IR.HUMS.REC.1400.085). Currently, the recruitment phase is ongoing since August 23th, 2021 and is anticipated to be complete by the end of August 2022. Trial registration: The study protocol was registered in the Iranian Registry of Clinical Trials (https://www.irct.ir; IRCT20210702051763N1) on August 14th, 2021. https://www.irct.ir/trial/57413 Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Results From the REsCue Trial: A Randomized Controlled Trial with Extended-Release Calcifediol in Symptomatic Outpatients with COVID-19. (preprint)

Importance: The benefit of vitamin D treatment for coronavirus disease 2019 (COVID-19) remains unclear. Objective: To investigate the effect of raising serum total 25-hydroxyvitamin D (25D) to 50-100 ng/mL with oral extended-release calcifediol (ERC) on time to symptom resolution in mild to moderate COVID-19. Design, Setting, and Participants: A multicenter, randomized, double-blind, placebo-controlled study evaluated treatment of 160 outpatients with COVID-19 diagnosed between November 2020 and October 2021. Interventions: Patients were treated for 4 weeks with ERC (30 mcg/capsule; 300 mcg on Days 1-3 and 60 mcg on Days 4-27) or placebo. Outcome Measures: Primary endpoints were raising serum 25D to >=50 ng/mL at Day 14 and resolution time for five aggregated symptoms. Secondary endpoints included resolution time for aggregated and individual symptoms as a function of serum 25D and changes in clinical biomarkers. Results: 171 subjects randomized, 160 treated and 134 (65 ERC and 69 placebo) retained. Average age was 43 (range: 18-71); 59% female, 92% White, 80% Hispanic, 7% African-American, 1% Other, 76% overweight, 40% obese, 26% comorbidities, mean baseline 25D of 37+-1 (SE) ng/mL. ERC increased mean 25D to 82+-ng/mL (p<0.001) by Day 7; 88% of subjects attained a level >=50 ng/mL; the placebo group trended lower. Resolution time for five aggregated symptoms was unchanged by ERC given that two composite non-respiratory symptoms responded poorly. Prespecified analyses showed that respiratory symptoms tended to resolve earlier when serum 25D levels reached >=50 ng/mL, but statistical significance was limited by small sample size and non-compliance: 25D increased in seven placebo subjects (unauthorized supplementation) and none occurred in five ERC subjects (failure to dose). A post-hoc composite of three respiratory symptoms (trouble breathing, chest congestion and dry or hacking cough) resolved 3.0 days faster when 25D was elevated at Days 7 and 14 (p<0.05); chest congestion resolved 4.0 days faster with 25D increases of >=25 ng/mL (p<0.05). Safety concerns including hypercalcemia were absent with ERC treatment. Conclusions and Relevance: ERC was effective in increasing serum 25D in outpatients with COVID-19, which may have accelerated resolution of respiratory symptoms suggesting mitigation of COVID-19 pneumonia risk, findings which warrant further study. Trial Registration: ClinicalTrials.gov identifier NCT04551911

Immobilization-Related Hypercalcemia in a COVID-19 Patient With Prolonged Intensive Care Unit Stay.

ABSTRACT: Immobilization-related hypercalcemia is an uncommon finding in patients admitted to intensive care unit. We report a case of severe hypercalcemia in a COVID-19 patient admitted to intensive care unit for hypoxemic respiratory failure. He developed an acute kidney injury requiring continuous renal replacement therapy with regional citrate anticoagulation. Citrate chelates ionized calcium and stop the coagulation cascade locally, preventing filter clotting. Calcium is then given intravenously to a specific target (normocalcemia). It is only when calcium infusion has been stopped that bone resorption and hypercalcemia were unmasked.

Severe hypercalcemia requiring acute hemodialysis: A retrospective cohort study with increased incidence during the Covid-19 pandemic.

BACKGROUND: The Covid-19 pandemic has had dramatic consequences on the progression of numerous pathologies, especially neoplastic ones. The orientation of hospital activities toward the care of patients with SARS-Cov2 infection has caused significant delays in the diagnosis and therapy of many other pathologies. What about severe hypercalcemia? The aim of this work was to determine the clinical and biological presentation, etiologies, mortality, and the impact of the Covid-19 pandemic on severe hypercalcemia. MATERIAL AND METHODS: we conducted a retrospective study for 84 months (September 2014 to September 2021) at the Nephrology Unit in University Hospital Mohammed VI, Oujda, Morocco. Included were all adult patients diagnosed with severe hypercalcemia (defined as corrected total serum calcium of >3.5 mmol/l or > 14.0 mg/dl) and who had benefited from one or more hemodialysis sessions. RESULTS: 66 episodes of severe hypercalcemia occurred in 64 patients. The mean age was 57 ± 15 years and 57.6% were female. The mean corrected serum calcium at admission was 16.9 ± 2.1 mg/dl and 33.3% had more than 18.0 mg/dl. Malignancies represented 80.4% of all etiologies. Acute kidney injury was observed in 69.7%. The delta drop in serum calcium 48 h after initiation of medical treatment was 4.64 ± 1.63 mg /dl. Mortality was noted in 14% of all cases. Electrocardiographic abnormalities were observed in 58.3%, 87.5% and 85.7%, respectively, in group 1 (14.0-16.0 mg/dl), group 2 (16.1-18.0 mg/dl), and group 3 (> 18.0 mg/dl) (p = 0.04). The mean serum potassium value was 5.1 ± 1.3, 4.0 ± 1.0, and 3.7 ± 0.7 respectively, in group 1 (14.0-16.0 mg/dl), group 2 (16.1-18.0 mg/dl), and group 3 (> 18.0 mg/dl) (p < 0.001). Newly diagnosed neoplasia, severe hypercalcemia (> 16.0 mg/dl), and mortality have been observed in 15.4% vs. 23.7% (p = 0.31), 25% vs. 50% (p = 0.03), and 35.7% vs. 52.6% (p = 0.13) respectively, in patients before and during the Covid-19 pandemic. CONCLUSIONS: The Covid-19 pandemic caused an increase in both the incidence and severity of hypercalcemia and the hemodialysis practiced in this context remains efficient and safe.

Hypercalcemia as a Biomarker of Poor Prognosis in Frail Elderly Patients with COVID-19.

The objective of this cohort study was to determine whether hypercalcemia in early COVID-19 was associated with 3-month mortality in frail elderly patients. Circulating calcium and albumin concentrations at hospital admission and 3-month mortality were assessed in geriatric patients hospitalized for COVID-19 with normal-to-high calcium concentrations. Hypercalcemia was defined as corrected calcium >2.5mmol/L. Covariables were age, sex, functional abilities, malignancies, hypertension, cardiomyopathy, number of acute health issues, use antibiotics and respiratory treatments. In total, 94 participants (mean±SD 88.0±5.5years; 47.9% women; 22.3% hypercalcemia; 0% hypocalcemia) were included. Sixty-five participants who survived at 3months exhibited less often hypercalcemia at baseline than the others (13.9% versus 41.4%, P=0.003). Hypercalcemia was associated with 3-month mortality (fully-adjusted HR=3.03, P=0.009) with specificity=0.86 and sensitivity=0.41. Those with hypercalcemia had shorter survival time than those with normocalcemia (log-rank P=0.002). In conclusion, hypercalcemia was associated with poorer survival in hospitalized frail elderly COVID-19 patients.

Case Series: Hypercalcemia From Granulomatous Silicosis Developing After COVID-19 Infection.

Hypercalcemia is one of the most commonly encountered laboratory abnormalities in clinical medicine. Various causes have been well established. However, it is likely that the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may be a newly found cause of this frequent finding, especially amongst those with a history of cosmetic surgery, specifically by means of silicone injection. In this case series, we describe 2 patients presenting with symptomatic hypercalcemia likely from their prior silicone injections. Interestingly, each patient only developed symptoms of hypercalcemia following infection with SARS-CoV-2.

Denosumab can be used successfully as a bridge to surgery in patients with severe hypercalcemia due to primary hyperparathyroidism.

Severe hypercalcemia is a medical emergency that requires immediate and aggressive management. Primary hyperparathyroidism (PHPT) often causes severe hypercalcemia. Volume resuscitation, parenteral salmon calcitonin, and administration of intravenous bisphosphonates are common measures used to stabilize patients. However, the use of these measures is inadequate in several patients and may even be contraindicated in individuals with renal insufficiency or severe systemic illness. This study demonstrated the efficacy and safety of denosumab in patients with severe hypercalcemia due to PHPT, when immediate surgery was not feasible. We present four patients with severe hypercalcemia due to PHPT. Immediate surgery was not feasible because the patients had severe systemic illness, such as seizures and altered sensorium (case 1); acute severe pancreatitis (cases 2 and 3); or coronavirus disease 2019 pneumonia (case 4). Intravenous normal saline and parenteral salmon calcitonin were inadequate for controlling hypercalcemia. Intravenous bisphosphonates were avoided because of severe systemic illness in all cases and impaired renal function in three cases. Denosumab was administered to control hypercalcemia and allow the stabilization of patients for definitive surgical management. Following denosumab administration, serum calcium levels normalized, and general condition improved in all patients. Three patients underwent parathyroidectomy after two weeks and another patient after eight weeks. The use of denosumab for the management of severe hypercalcemia due to PHPT is efficacious and safe in patients when immediate surgical management is not feasible due to severe systemic illness.

Management of Primary Hyperparathyroidism With Severe Hypercalcemia During the COVID-19 Pandemic.

PURPOSE: In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019 (COVID-19) pandemic, when many hospital visits are suspended and surgeries cannot be performed, the management of these patients represents a challenging clinical situation. This article presents a literature review and discussion of the pharmacologic management of PHPT and severe hypercalcemia, which can be used as a temporary measure during the COVID-19 pandemic until parathyroidectomy can be performed safely. METHODS: This narrative review was conducted by searching literature on the PubMed, Medline, and Google Scholar databases using the terms primary hyperparathyroidism, hypercalcemia, cinacalcet, bisphosphonates, denosumab, vitamin D, raloxifene, hormone replacement therapy, coronavirus, and COVID-19. FINDINGS: Appropriate monitoring and remote medical follow-up of these patients are essential until the resolution of the pandemic. Cinacalcet is the drug of choice for controlling hypercalcemia, whereas bisphosphonate or denosumab is the drug for improving bone mineral density. Combined therapy with cinacalcet and bisphosphonates or cinacalcet and denosumab should be considered when the effects on serum calcium and bone mineral density are simultaneously desired. IMPLICATIONS: Medical management of PHPT and severe hypercalcemia presents a reasonable alternative for parathyroid surgery during the COVID-19 outbreak and should be instituted until the pandemic ends and surgery can be performed safely.

Delayed health consequences of COVID-19 lockdown in an older adult.

We report a case of a retired school teacher who presented with rapid cognitive and functional decline following the COVID-19 lockdown period that was diagnosed as worsening depression by referring physician. This highlights the potentially life-threatening consequences of delayed diagnosis and management of delirium, an often reversible syndrome, due to lockdown restrictions. As the pandemic outlives its initial projections, its downstream impact on an already vulnerable population continues to emerge.

Controversies in the use of new bone-modifying therapies in multiple myeloma.

Bone-modifying therapies are essential in the treatment of patients with multiple myeloma. Zoledronic acid is preferred over other bisphosphonates due to its superiority in reducing the incidence of skeletal-related events and improving survival. The anti-receptor activator of nuclear factor-κΒ ligand (RANKL)-targeted agent denosumab has shown its non-inferiority compared to bisphosphonates in preventing skeletal-related events among newly diagnosed patients with myeloma bone disease. Denosumab may confer a survival benefit in patients eligible for autologous transplantation. Denosumab may present a safer profile for patients with renal impairment. Discontinuation of bone-directed therapies can be considered for patients with deep responses and after an adequate time period on treatment; however, a rebound effect may become evident especially in the case of denosumab. Three-monthly infusions of zoledronic acid or at-home denosumab administration should be considered during the coronavirus disease 2019 (COVID-19) pandemic. Measures to prevent hypocalcaemia, renal toxicity and osteonecrosis of the jaw are important for all bone-modifying agents.

Low serum 25-hydroxyvitamin D (25D) levels in patients hospitalised with COVID-19 are associated with greater disease severity: results of a local audit of practice. (preprint)

Objectives: To audit implementation of a local protocol for the treatment of vitamin D deficiency (VDD) among patients hospitalized for Coronavirus Disease 2019 (COVID-19), including an assessment of the prevalence of VDD in these patients, and of potential associations with disease severity and fatality. Design: This was not a study or clinical trial, but rather a retrospective interim audit (Newcastle-upon-Tyne Hospitals Registration No. 10075) of a local clinical care pathway for hospitalized patients with COVID-19-related illness. The Information (Caldicott) Guardian permitted these data to be shared beyond the confines of our institution. Setting: A large tertiary academic NHS Foundation Trust in the North East of England, UK, providing care to COVID-19 patients. Participants: One hundred thirty-four hospitalized patients with documented COVID-19 infection. Main outcome measures: Adherence to local investigation and treatment protocol; prevalence of VDD, and relationship of baseline serum 25(OH)D with markers of COVID-19 severity and inpatient fatality versus recovery. Results: 55.8% of eligible patients received Colecalciferol replacement, albeit not always loaded as rapidly as our protocol suggested, and no cases of new hypercalcaemia occurred following treatment. Patients admitted to ITU were younger than those managed on medical wards (61.1 years +/- 11.8 vs. 76.4 years +/- 14.9, p<0.001), with greater prevalence of hypertension, and higher baseline respiratory rate, National Early Warning Score-2 and C-reactive protein level. While mean serum 25(OH)D levels were comparable [i.e. ITU: 33.5 nmol/L +/- 16.8 vs. Non-ITU: 48.1 nmol/L +/- 38.2, mean difference for Ln-transformed-25(OH)D: 0.14, 95% Confidence Interval (CI) (-0.15, 0.41), p=0.3], only 19% of ITU patients had 25(OH)D levels greater than 50 nmol/L vs. 60.9% of non-ITU patients (p=0.02). However, we found no association with fatality, potentially due to small sample size, limitations of no-trial data and, potentially, the prompt diagnosis and treatment of VDD. Conclusions: Subject to the inherent limitations of observational (non-trial) audit data, analysed retrospectively, we found that patients requiring ITU admission were more frequently vitamin D deficient than those managed on medical wards, despite being significantly younger. Larger prospective studies and/or clinical trials are needed to elucidate the role of vitamin D as a preventive and/or therapeutic strategy for mitigating the effects of COVID-19 infection in patients with VDD.