Hypocalcemia

Calcium (Ca2+) homeostasis is maintained through coordination between intestinal absorption, renal reabsorption, and bone remodeling. Intestinal and renal (re)absorption occurs via transcellular and paracellular pathways. The latter contributes the bulk of (re)absorption under conditions of adequate intake. Epithelial paracellular permeability is conferred by tight-junction proteins called claudins. However, the molecular identity of the paracellular Ca2+ pore remains to be delineated. Claudins (Cldn)-2 and -12 confer Ca2+ permeability, but deletion of either claudin does not result in a negative Ca2+ balance or increased calciotropic hormone levels, suggesting the existence of additional transport pathways or parallel roles for the two claudins. To test this, we generated a Cldn2/12 double knockout mouse (DKO). These animals have reduced intestinal Ca2+ absorption. Colonic Ca2+ permeability is also reduced in DKO mice and significantly lower than single-null animals, while small intestine Ca2+ permeability is unaltered. The DKO mice display significantly greater urinary Ca2+ wasting than Cldn2 null animals. These perturbations lead to hypocalcemia and reduced bone mineral density, which was not observed in single-KO animals. Both claudins were localized to colonic epithelial crypts and renal proximal tubule cells, but they do not physically interact in vitro. Overexpression of either claudin increased Ca2+ permeability in cell models with endogenous expression of the other claudin. We find claudin-2 and claudin-12 form partially redundant, independent Ca2+ permeable pores in renal and colonic epithelia that enable paracellular Ca2+ (re)absorption in these segments, with either one sufficient to maintain Ca2+ balance.

ImportanceUsing albumin-adjusted calcium is commonly recommended for for measuring calcium, but with little empirical evidence to support the practice.ObjectiveTo assess the correlation between total calcium measurements (with or without adjustment) vs the ionized calcium level as a reference standard.Design, setting, and participantsThis was a population-based cross-sectional study in the province of Alberta, Canada, including adults tested for serum total calcium and ionized calcium simultaneously between January 1, 2013, and October 31, 2019. Statistical analysis was performed from March 2023 to October 2024.Main measures and outcomesThe correlation between unadjusted and adjusted total calcium measurements (using 10 formulas) and the ionized calcium level was evaluated, along with the potential association with the classification of calcium status.ResultsAmong 22 658 patients included, 11 889 (52.5%) were female and 10 769 (47.5%) were male; the median (IQR) age was 60 (47-72) years. The unadjusted total calcium (R2 = 71.7%; 95% CI, 71.1%-72.2%) had a stronger correlation with ionized calcium than the commonly used simplified Payne formula (ie, total calcium [mmol/L] + 0.02 [40 - albumin (g/L)]) (R2 = 68.9%; 95% CI, 68.0%-69.6%) and correlated similarly to other formulas (Payne: lowest R2 = 60.3%; 95% CI, 59.3%-61.3%; and James: highest R2 = 76.7%; 95% CI, 76.1%-77.3%). When classifying patients into categories of hypocalcemia, normocalcemia, or hypercalcemia, unadjusted total calcium had the best overall agreement (74.5%) with ionized calcium compared with albumin-adjusted calcium using the original Payne and simplified Payne formulas (agreement 63.0% and 58.7%, respectively). Misclassification using the adjustment formulas was worse in the presence of hypoalbuminemia (albumin level Conclusions and relevanceIn this cross-sectional study drawn from a contemporaneous population, there appeared to be heavy reliance on adjustment formulas for calcium in clinical practice with little gain but considerable risk of misclassification of true calcium status, especially in the presence of hypoalbuminemia. These results suggest that unadjusted total calcium was the best and most practical alternative to ionized calcium.

BackgroundPostsurgical hypoparathyroidism (PH) is the most frequent complication after thyroid surgery. The aim of this systematic review and meta-analysis is to summarize a unifying definition of PH and to elucidate the best possible approach for early detection of PH.MethodsA systematic review of the literature according to the PICO framework using Embase, PUBMED and the Cochrane library was carried out on 1 December 2021 followed by analysis for risk of bias, data extraction and meta-analysis. All studies addressing the definition of postoperative hypoparathyroidism and/or diagnostic approaches for early detection and diagnosis were included. Case reports, commentaries, non-English articles, book chapters and pilot studies and reviews were excluded.ResultsFrom 13 704 articles, 188 articles were eligible for inclusion and further analysis. These articles provided heterogeneous definitions of PH. Meta-analysis revealed that postoperative measurements of parathormone (PTH) levels have a higher sensitivity and specificity than intraoperative PTH measurements to predict PH after thyroid surgery. None of the timeframes analysed after surgery within the first postoperative day (POD1) was superior to predict the onset of PH. PTH levels of less than 15 pg/ml and less than 10 pg/ml are both reliable threshold levels to predict the postoperative onset of PH. A relative reduction of mean(s.d.) PTH levels from pre- to postoperative values of 73 (standard deviation 11) per cent may also be predictive for the development of PH. The estimation of calcium levels on POD1 are recommended.ConclusionPH is best defined as an undetectable or inappropriately low postoperative PTH level in the context of hypocalcaemia with or without hypocalcaemic symptoms. PTH levels should be measured after surgery within 24 h. Both threshold levels below 10 and 15 pg/ml or relative loss of PTH before/after thyroid surgery are reliable to predict the onset of PH.