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 the Frequently Used Cinacalcet for pHPT during the COVID-19 Pandemic on Perioperative Decrease in Parathyroid Hormone.

BACKGROUND: Cinacalcet is a calcimimetic drug that has increasingly been used as a bridging therapy for primary hyperparathyroidism (pHPT), especially during the COVID-19 pandemic. The aim of our study was to investigate if preoperative cinacalcet therapy affects intraoperative parathyroid hormone (IOPTH) monitoring during parathyroidectomy, which is an important indicator for the success of surgery. METHODS: In this single-center retrospective analysis, we studied the outcomes of 72 patients who underwent surgery for pHPT. We evaluated two groups: those with cinacalcet therapy before operation-the cinacalcet group (CG)-and those without medical therapy preoperatively (non-CG). In order to perform a between-group comparison of time trends, we fit a linear mixed-effects model with PTH as the response variable and predictors PTH levels preoperatively, group (cinacalcet yes/no), time, the group-by-time interaction, and a random intercept (per subject). RESULTS: Our cohort included 51 (71%) women and 21 (29%) men, who were operated upon for pHPT in the period from January 2018 until August 2021. All patients were diagnosed with pHPT and 54% of the cohort were symptomatic for hypercalcemia. Moreover, 30% of the patients were treated with cinacalcet as a bridging therapy preoperatively, and this increased during the COVID-19 pandemic, as 64% of this group were treated in the last two years. Calcium values were significantly different before (p < 0.001) and after (p = 0.0089) surgery, but calcium level change did not differ significantly between the CG and non-CG. Parathyroid hormone (PTH) levels dropped significantly in both groups during 10 min IOPTH monitoring (p < 0.001), but there was no significant difference between the two groups (p = 0.212). CONCLUSIONS: In the examined patient cohort, the use of cinacalcet did not affect the value of IOPTH monitoring during surgery for pHPT.

Vitamin D: Bolus Is Bogus-A Narrative Review.

In this review we summarize the impact of bolus versus daily dosing of vitamin D on 25(OH)D and 1,25(OH)2D levels, as well as on key countervailing factors that block vitamin D functions at the cellular level. Further, we discuss the role of bolus versus daily dosing of vitamin D for several health outcomes, including respiratory infections and coronavirus disease 2019 (COVID-19), rickets, falls and fractures, any cancer, and cancer-related mortality. This discussion appears timely because bolus doses continue to be tested for various disease outcomes despite a growing amount of evidence suggesting lack of efficacy or even detrimental effects of bolus dosing of vitamin D for outcomes where daily dosing at modest levels was effective in the vitamin D deficient. As a result, these discordant results may bias health recommendations for vitamin D if the recommendations are based on meta-analyses combining both daily and bolus dosing trials. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Hypocalcemia in COVID-19 is associated with low vitamin D levels and impaired compensatory PTH response.

BACKGROUND: Hypocalcemia has been identified as a major distinctive feature of COVID-19, predicting poor clinical outcomes. Among the mechanisms underlying this biochemical finding, high prevalence of vitamin D (VD) deficiency in COVID-19 patients reported so far in several studies was advocated. However, robust data in favor of this hypothesis are still lacking. Therefore, aim of our study was to investigate the role of hypovitaminosis D and parathyroid hormone (PTH) levels in the development of hypocalcemia in COVID-19 patients. METHODS: Patients admitted to IRCCS Ospedale San Raffaele for COVID-19 were enrolled in this study, excluding those with comorbidities and therapies influencing calcium and VD metabolism. Serum levels of total calcium (tCa), ionized calcium (Ca2+), 25-OH-VD, and PTH were evaluated at admission. We defined VD deficiency as VD below 20 ng/mL, hypocalcemia as tCa below 2.2 mmol/L or as Ca2+ below 1.18 mmol/L, and hyperparathyroidism as PTH above 65 pg/mL. RESULTS: A total of 78 patients were included in the study. Median tCa and Ca2+ levels were 2.15 and 1.15 mmol/L, respectively. Total and ionized hypocalcemia were observed in 53 (67.9%) and 55 (70.5%) patients, respectively. VD deficiency was found in 67.9% of patients, but secondary hyperparathyroidism was detected in 20.5% of them, only. tCa levels were significantly lower in patients with VD deficiency and regression analyses showed a positive correlation between VD and tCa. CONCLUSIONS: In conclusion, we confirmed a high prevalence of hypocalcemia in COVID-19 patients and we showed for the first time that it occurred largely in the context of marked hypovitaminosis D not adequately compensated by secondary hyperparathyroidism.

Vitamin D deficiency, secondary hyperparathyroidism and respiratory insufficiency in hospitalized patients with COVID-19.

PURPOSE: Hypovitaminosis D has emerged as potential risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the general population with variable effects on the outcome of the coronavirus disease-19 (COVID-19). The aim of this retrospective single-center study was to investigate the impact of hypovitaminosis D and secondary hyperparathyroidism on respiratory outcomes of COVID-19. METHODS: Three-hundred-forty-eight consecutive patients hospitalized for COVID-19 at the IRCCS Humanitas Research Hospital, Rozzano, Milan (Italy) were evaluated for arterial partial pressure oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio, serum 25hydroxy-vitamin D [25(OH)D], parathyroid hormone (PTH) and inflammatory parameters at study entry and need of ventilation during the hospital stay. RESULTS: In the entire population, vitamin D deficiency (i.e., 25(OH)D values < 12 ng/mL) was significantly associated with acute hypoxemic respiratory failure at the study entry [adjusted odds ratio (OR) 2.48, 95% confidence interval 1.29-4.74; P = 0.006], independently of age and sex of subjects, serum calcium and inflammatory parameters. In patients evaluated for serum PTH (97 cases), secondary hyperparathyroidism combined with vitamin D deficiency was significantly associated with acute hypoxemic respiratory failure at study entry (P = 0.001) and need of ventilation during the hospital stay (P = 0.031). CONCLUSION: This study provides evidence that vitamin D deficiency, when associated with secondary hyperparathyroidism, may negatively impact the clinical outcome of SARS-CoV-2-related pneumonia.

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection.

BACKGROUND: The role of vitamin D status in COVID-19 patients is a matter of debate. OBJECTIVES: To assess serum 25-hydroxyvitamin D (25OHD) levels in hospitalized patients with COVID-19 and to analyze the possible influence of vitamin D status on disease severity. METHODS: Retrospective case-control study of 216 COVID-19 patients and 197 population-based controls. Serum 25OHD levels were measured in both groups. The association of serum 25OHD levels with COVID-19 severity (admission to the intensive care unit, requirements for mechanical ventilation, or mortality) was also evaluated. RESULTS: Of the 216 patients, 19 were on vitamin D supplements and were analyzed separately. In COVID-19 patients, mean ±â€…standard deviation 25OHD levels were 13.8 ±â€…7.2 ng/mL, compared with 20.9 ±â€…7.4 ng/mL in controls (P < .0001). 25OHD values were lower in men than in women. Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (P < .0001). 25OHD inversely correlates with serum ferritin (P = .013) and D-dimer levels (P = .027). Vitamin D-deficient COVID-19 patients had a greater prevalence of hypertension and cardiovascular diseases, raised serum ferritin and troponin levels, as well as a longer length of hospital stay than those with serum 25OHD levels ≥20 ng/mL. No causal relationship was found between vitamin D deficiency and COVID-19 severity as a combined endpoint or as its separate components. CONCLUSIONS: 25OHD levels are lower in hospitalized COVID-19 patients than in population-based controls and these patients had a higher prevalence of deficiency. We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease.

A Mysterious Paratracheal Mass: Parathyroid Carcinoma.

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. We detail a 60-years-old gentleman who was otherwise healthy presented to the hospital due to acute encephalopathy. He was subsequently found to have parathyroid carcinoma as the cause of the acute encephalopathy with impressive serum calcium and parathyroid hormone levels. The parathyroid carcinoma was later surgically resected with the diagnosis confirmed via pathology specimen. The patient was safely discharged from the hospital with recommendations of close routine outpatient followup.