HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

This study aimed to evaluate the association between serum calcium level and the risk of acute kidney injury (AKI) in patients with subarachnoid hemorrhage (SAH). In this retrospective cohort study, data on adults from the Medical Information Mart for Intensive Care (MIMIC-III and MIMIC-IV) databases, spanning from 2008 to 2019, were extracted. In the logistic regression models, confounding variables, including age, white blood cell (WBC), systolic blood pressure (SBP), heart rate, blood urea nitrogen (BUN), glucose, international normalized ratio (INR), and the Charlson Comorbidity Index (CCI), were finally adjusted by stepwise regression. The outcome event was the occurrence of AKI after intensive care unit (ICU) admission. The univariate and multivariate logistic regression models were utilized to assess the association between serum calcium level and the risk of AKI in SAH patients, with odds ratios (ORs) and 95% confidence intervals (CIs). To further explore the association, subgroup analyses were performed, stratified by age, Glasgow Coma Scale (GCS) scores, drugs, and surgical methods. A total of 1,128 patients with SAH were included in the study, of which 457 patients developed AKI. Low levels of serum calcium were significantly associated with a high risk of AKI in patients with SAH, with an OR (95%CI) of 1.38 (1.01-1.89). Further subgroup analyses showed that low levels of calcium were significantly associated with a high risk of AKI in SAH patients aged ≥60 years (OR = 0.27, 95%CI: 0.09-0.83), who had GCS score ≥13 (OR = 1.57, 95%CI: 1.08-2.30), who did not use calcium channel blockers (CCB) (OR = 2.22, 95%CI: 1.16-4.25) and angiotensin-converting enzyme (ACE) inhibitors (OR = 1.51, 95%CI: 1.06-2.14), and who did not undergo aneurysm embolization (OR = 1.48, 95%CI: 1.01-2.17) and aneurysm clipping (OR = 1.45, 95%CI: 1.04-2.01). The results of our study indicated that low levels of serum calcium were significantly associated with the risk of AKI in patients with SAH.

The term hypoparathyroidism encompasses a huge group of disorders all characterized by an abnormal mineral homeostasis determined by inadequate secretion of parathyroid hormone. Postsurgical hypoparathyroidism is a complication of neck surgery (thyroidectomy, parathyroidectomy, lymph node, and cancer neck dissection), closely related to the extent of the surgical procedure and the experience of the surgeon. If lasting more than 6 months it is defined as chronic hypoparathyroidism, requiring life-long replacement therapy with active vitamin D metabolites. All the other forms of nonsurgical hypoparathyroidism, previously referred to as idiopathic hypoparathyroidism, have several causes, the majority of them genetic, which can be grouped into 3 main categories: disorder of parathyroid development, disorders of parathyroid function, and acquired damage to the parathyroids. Hypoparathyroidism can manifest as the sole disease in an individual (isolated hypoparathyroidism) or be associated with other manifestations within complex syndromes (syndromic hypoparathyroidism). Functional hypoparathyroidism, which may be caused by magnesium disturbances, has always to be ruled out before commencing the genetic diagnostic workup in nonsurgical forms. The search for signs of autoimmunity can drive the diagnosis towards an autoimmune pathogenesis of the disease, since a routine assessment of parathyroid autoantibodies is neither available nor specific.

Despite the pivotal role of calcium signaling in immune response, little is known about immune function in patients affected by hypoparathyroidism. This work aimed to evaluate immune function in hypoparathyroidism. The Evaluation of iMmune function in Postsurgical and AuToimmune HYpoparathyroidism (NCT04059380) is a case-control, cross-sectional study set in an Italian referral center. Participants included 20 patients with postsurgical hypoparathyroidism (12 females) and 20 age- and sex-matched controls. Main outcome measures included calcium metabolism assessment, peripheral blood mononuclear cells (PBMC) profiling via flow cytometry, parathyroid hormone receptor 1 (PTHr1) expression analysis using immunofluorescence and PrimeFlow RNA assay, gene expression analysis via real-time polymerase chain reaction, cytokine measurement, and evaluation of infectious disease frequency and severity. Immune cell profiling revealed decreased monocytes, regulatory, naive, and total CD4+ T lymphocytes, which correlated with total calcium, ionized calcium, and PTH levels, in patients with hypoparathyroidism. Patients with hypoparathyroidism had a higher CD3-CD56+ natural killer (NK) cell count, which inversely correlated with calcium, PTH, and vitamin D levels. Furthermore, they exhibited decreased tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor gene expression and decreased circulating TNF levels. Gene expression and immunofluorescence analysis confirmed PTHr1 expression in all PBMC lineages; however, the percentage of cells expressing PTHr1 was lower, whereas the intensity of PTHr1 expression in monocytes, total T lymphocytes, CD8+CD4+ and CD4+ T lymphocytes, and total NK cells was higher in patients with hypoparathyroidism. This study describes for the first time the immune alterations in patients with hypoparathyroidism receiving conventional therapies, supporting the immunoregulatory role of PTH and proposing an explanation for the increased susceptibility to infections observed in epidemiological studies.

Hypoparathyroidism Counteracts Risk Factors for Osteoporosis

Background: Psoriasis is a common chronic inflammatory skin disease characterized by erythematous papules and plaques with silvery scales. The hyper proliferation and keratinocyte differentiation in psoriasis is controlled by calcium inside the cells and disturbance in the metabolism of calcium has been observed in cases with psoriasis. The aim of this study was to find out the prevalence of deranged serum calcium in patients with psoriasis. Methods: A cross-sectional study was conducted in the Department of Dermatology, Bir Hospital from June 2019 to December 2020. Any patient presenting at dermatology OPD above 16 years of age with psoriasis were taken as cases. Age and gender matched patients with skin disease other than psoriasis were taken as controls. Determination of serum calcium level was done by fully automated random-access clinical chemistry analyzer Erba Manheim XL-300 in Biochemistry lab, Bir Hospital. The study was approved by the institutional review board. A p-value of <0.05 was considered statistically significant. Results: Out of 51 cases and 51 controls, low serum calcium level was found in 15(29.41%) of psoriasis patients and 12(23.53%) of the controls. This showed that hypocalcemia was observed more in psoriasis patients than the controls. However, the difference was not statistically significant (p=0.327). Conclusions: This study showed that hypocalcemia was observed more frequently in cases of psoriasis as compared to controls. However, the finding was not statistically significant.

The serum calcium (Ca)-to-phosphorus (P) ratio has been proposed to identify patients with primary hyperparathyroidism and chronic hypoparathyroidism (HPT), but it has never been tested in pseudohypoparathyroidism (PHP). The aim of this study was to test the performance of Ca/P ratio in PHP diagnosis compared with that in healthy subjects and patients with HPT for differential diagnosis. A retrospective, cross-sectional, and observational study was carried out. Serum Ca, P, creatinine, parathyroid hormone (PTH), and albumin were collected. Ca and P were expressed in mmol/L. Ca/P diagnostic performance was evaluated by receiver operating characteristic curve, sensitivity, specificity, and accuracy. A total of 60 patients with PHP, 60 patients with HPT, and 120 controls were enrolled. The Ca/P ratio was lower in patients with PHP and HPT than that in controls (p < 0.0001). The cutoff of 1.78 (2.32 if Ca and P measured in mg/dL) for Ca/P ratio could identify patients with PHP and HPT among the entire cohort (sensitivity and specificity of 76%). No valid cutoff of Ca/P was found to distinguish patients with PHP from patients with HPT; in this case, PTH above 53.0 ng/dL identified patients with PHP (sensitivity and specificity of 100%). The index (Ca/P × PTH) above 116 ng/L recognized patients with PHP from controls (sensitivity of 84.7% and specificity of 87.4%), whereas (Ca/P × PTH) below 34 ng/L recognized patients with HPT from controls (sensitivity of 88.9% and specificity of 90.8%). The Ca/P ratio below 1.78 (2.32 CU) is highly accurate to identify patients with PHP and HPT, although it is not reliable to differentiate these two conditions. The index (Ca/P × PTH) is excellent to specifically recognize PHP or HPT from healthy subjects.

To explore the potential role of serum calcium levels at admission in the expansion of acute traumatic intracerebral hematoma (tICH) and to construct a novel nomogram to predict tICH expansion. In this multicenter retrospective study, 640 and 237 patients were included in the training and validation datasets, respectively. Risk factors for acute tICH expansion were selected by logistic regression analysis. Causal mediation and interaction analysis were used to explore the relationship between serum calcium promotion of tICH expansion and inflammatory response. Receiver operating characteristic, calibration and clinical decision curves were applied to estimate the performance of multivariate models. Low serum calcium level was strongly associated with acute tICH expansion in patients with brain contusion. There was no significant interaction of hypocalcemia across multiple subgroups including sex, age, and coagulation dysfunction. 24.5% of the mechanisms by which hypocalcemia promotes acute tICH expansion can be explained by an inflammatory response. The addition of serum calcium made the modified model (serum calcium plus basic model) more accurate than basic model with subdural hematoma, multihematoma fuzzy sign, time to baseline CT, level on Glasgow Coma Scale score, platelet count, baseline tICH volume ≥ 5 mL, and monocyte-to-lymphocyte ratio. Low serum calcium level is a novel risk factor for acute tICH expansion, the mechanism of which may be mediated in part through the response of immune cell. The online dynamic nomogram provides a user-friendly tool for the prediction of acute tICH expansion.

BackgroundOsteoarthritis is a prevalent musculoskeletal condition, but the role of specific serum biomarkers, such as calcium, vitamin D, and C-reactive protein (CRP), in predicting mortality among individuals with osteoarthritis remains unclear.MethodsThis observational study analyzed longitudinal data from over 500,000 participants in the UK Biobank, identifying those with osteoarthritis using ICD-9/10 codes or self-reported history. We performed multivariable cox-regression and flexible parametric survival model (FPSM) for survival analysis, with adjustments made through the inverse probability of treatment weight (IPTW) for baseline covariates identified by directed acyclic graphs (DAGs).ResultsOf the 49,082 osteoarthritis population, the average age was 60.69 years, with 58.7% being female. During the follow-up period exceeding 15 years, a total of 5,522 people with osteoarthritis died. High serum calcium levels, compared to normal serum calcium levels, were significantly associated with all-cause mortality (hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11, 1.59), cardiovascular diseases (CVD)-related deaths (HR 1.55, 95% CI 1.05, 2.29), and other deaths (HR 1.59, 95% CI 1.20, 2.11). Low serum calcium levels, compared to normal serum calcium levels, was linked with CVD-related deaths (HR 2.06, 95% CI 1.02, 4.14). Vitamin D insufficiency, compared to sufficient vitamin D levels, was correlated with all-cause mortality (HR 1.22, 95% CI 1.13, 1.33), CVD-related deaths (HR 1.43, 95% CI 1.20, 1.72), and other deaths (HR 1.26, 95% CI 1.09, 1.45) but not with cancer-related deaths. High serum CRP levels, compared to normal CRP levels, were associated with all outcomes (all-cause mortality: HR 1.22, 95% CI 1.12, 1.33; CVD-related death: HR 1.24, 95%CI 1.03, 1.49; cancer-related death: HR 1.23, 95% CI 1.09, 1.40; other deaths: HR 1.19, 95%CI 1.03, 1.38).ConclusionsBoth high and low serum calcium levels, elevated CRP, and vitamin D insufficiency are potential predictors of increased mortality risk in the osteoarthritis population. These findings emphasize the importance of monitoring and possibly addressing these serum biomarkers in osteoarthritis populations to improve long-term outcomes. Further studies are needed to understand the underlying mechanisms and to propose therapeutic interventions.

PurposeThe purpose of this study was to conduct cognitive debriefing (CD) interviews with adults diagnosed with chronic hypoparathyroidism (HP) to assess the content validity of the SF-36v2® Health Survey Acute (SF-36v2) measure in this population.MethodsCD interviews were conducted with adults with HP in the United States (US). Interviews were conducted by a trained moderator using a semi-structured interview guide, employing a think-aloud method in conjunction with verbal probing. Participants were asked whether each item was understandable, relevant, important, and sensitive to change in relation to HP. Additionally, comprehension of instructions, response options, and the appropriateness of a 1-week recall period was assessed.ResultsSixteen adults with HP participated in individual CD telephone interviews. All items in the SF-36v2 were reported to be understood, relevant, important, and sensitive to change by at least half, and in most cases, by a strong majority of study participants. Most of the study sample confirmed comprehension of the instructions and the entire sample understood all response options.ConclusionThe study findings show that the items in the SF-36v2® are applicable to adults with HP. The overall high levels of endorsement of items provide strong evidence of the measure’s content validity for this population. The SF-36v2 is therefore recommended for usage in clinical trials examining adults with HP, although it is recommended that this generic measure be supplemented with disease-specific instruments such as the recently developed Hypoparathyroidism Patient Experience Scale—Symptom (HPES-Symptom) and Hypoparathyroidism Patient Experience Scale—Impact (HPES-Impact) measures.

ABSTRACTQuality of life (QoL) is impaired in patients with chronic hypoparathyroidism (HypoPT). With a recently developed specific patient questionnaire, the 28‐item Hypoparathyroid Patient Questionnaire (HPQ 28), we were able to demonstrate an effect of laboratory parameters on symptoms and complaints identified by scales and items of the HPQ 28. Here, we evaluated the effect of conventional treatment modalities on QoL using this specific questionnaire. In this cross‐sectional study, we included 49 HypoPT (41 female and 8 male) patients. Laboratory values of total serum calcium, magnesium, phosphate, calcium‐phosphate product (CPP), and 24‐hour urine for calcium and phosphate were analyzed. Patients completed the HPQ 28 questionnaire during the corresponding visit. Mean age was 57.3 ± 10.5 years and duration of disease 12.6 ± 9.8 years. Most patients (86%, n = 42) were treated with the active vitamin D analogs calcitriol, alfacalcidol, or dihydrotachysterol (DHT). The use of calcium and magnesium supplements influenced scales on HPQ 28 in a dose‐dependent manner. We detected a dose‐dependent increase on the HPQ 28 scales “depression and anxiety” and “pain and cramps,” and the item “numbness and tingling” related to calcitriol. This effect was independent of gender, age, underlying disease, kind of surgery, serum 25‐hydroxyvitamin D3, calcium, or phosphate values. This study presents the first data on specific symptoms of HypoPT patients dependent on different treatment modalities. Our data suggest that in part the reduced QoL in these patients might be caused by conventional treatment. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels

Disclosure: J. Zhang: Employee; Self; Septerna Inc.. I. Gomez: None. C. He: Employee; Self; Septerna Inc. J. Wang: Employee; Self; Septerna Inc. X. Du: Employee; Self; Septerna Inc. K. Nguyen: Employee; Self; Septerna Inc. K. Alvarez: Employee; Self; Septerna Inc. A.M. Mirza: Employee; Self; Septerna Inc.. Hypoparathyroidism (HP), a rare endocrine disorder characterized by insufficient levels of parathyroid hormone (PTH), leads to hypocalcemia and hyperphosphatemia. Most HP cases arise due to damage of the parathyroid glands during thyroid or neck surgery. HP symptoms include severe muscle cramps, tingling, burning and numbness, memory loss, and headaches, all leading to a decreased quality of life. Calcium and vitamin D supplementation do not fully ameliorate the disease and may contribute to renal disease. Chronic HP increases the risk of major complications, such as calcium depositions in the brain, eye, and kidneys. Similarly, it can lead to low bone turnover and increased bone mineral density with associated increased bone mineralization. In comparison to standard of care and traditional injectable peptide-based therapies, oral small molecules may have multiple advantages clinically. However, there are no oral small molecules currently in development. PTH functions through activation of the parathyroid hormone 1 receptor (PTH1R), a class B G protein-coupled receptor. The main target tissues for PTH1R activation include bone and kidney. In the kidney, PTH increases tubular reabsorption of calcium and promotes renal excretion of phosphate. In bone, PTH stimulates bone turnover and mobilizes calcium into the circulation to maintain serum calcium. Here we describe the characterization of SP-1462, a novel, potent, and selective oral small molecule, and show that, like the PTH peptides, it acts on PTH1R as an agonist and elicits similar downstream functions in vitro and in vivo. To assess PTH1R engagement in the major targeted organs, kidney and bone, primary human renal proximal epithelial cells (RPTEC) and a human osteoblast cell line (Saos-2) were used, respectively. RPTECs treated with PTH and SP-1462 showed significant changes in transporter genes (SLC22A2 and SLC13A1), immune related genes (CCL2 &amp; DPP4), and matrix reorganization genes (ITGA5 and COL1A1). Saos-2 cells treated with PTH and SP-1462 both significantly affected the expression of Wnt signaling genes (DKK1 and TCF7) and the expression of coupling genes that bridge anabolic/catabolic activities (M-CSF, RANKL, HDAC4, and OPG). Importantly, oral administration of a single dose of SP-1805 in a rat surgical thyroparathyroidectomy (TPTx) model resulted in significant upregulation of serum calcium levels for a period of 24 hours in a dose dependent manner at 3, 10 and 30 mg/kg. The window of calcium upregulation is comparable to injectable PTH peptides currently in development to treat hypoparathyroidism. These data suggest that oral small molecule PTH1R agonists engage PTH pathways similar to native PTH and have the potential to replace injectable PTH peptides to treat PTH-related disorders, including hypoparathyroidism. Presentation: 6/3/2024

Hypocalcemia following parathyroid-sparing total thyroidectomy is frequent and can prolong hospital stay. We undertook this study to identify preoperative predictors of postoperative hypocalcemia useful in the postoperative management of these patients. We examined patients undergoing total thyroidectomy for benign disease with preservation of at least three parathyroids from January 2000 to January 2001. Low serum calcium was considered below 8.0 mg/dL. Age, gender, preoperative serum calcium, thyroid stimulating hormone (TSH), T3, T4, albumin, cholesterol, and tryglicerides were compared in patients with normal and low serum calcium level on the second postoperative day and on discharge day by using chi2 test and a model of logistic regression. Data were reported using their frequency distribution among the two groups of patients. Eighty patients, 60 females (F) and 20 males (M), underwent parathyroid-sparing total thyroidectomy. On second postoperative day, hypocalcemia occurred in 42 patients, and 56 per cent were symptomatic. Only female gender (88% F vs 12% M) (P < 0.05) and TSH <0.27 mUI/mL (38% vs 18%) (P < 0.05) predicted hypocalcemia. Similarly, female gender predicted hypocalcemia in a logistic regression analysis (P < 0.05). On the day of discharge, 22 patients had low serum calcium levels, and 50 per cent were symptomatic. At this time, only TSH value < 0.27 mlU/mL significantly predicted hypocalcemia (48% vs 17%) (P < 0.05). This was confirmed in a logistic regression analysis (P < 0.05). All but one patient (98%) eventually returned to normal serum calium levels. Despite preservation of parathyroids, transient symptomatic hypocalcemia is common after total thyroidectomy. Female gender and low TSH serum level predicted hypocalcemia. Therefore, female patients undergoing total thyroidectomy with preoperative low TSH levels should receive calcium prophylaxis to decrease morbidity, shorten hospital stay, and decrease costs.

Calcium plays a central role in ventricular function. We report a 37 year-old woman with chronic hypoparathyroidism and hypocalcemia secondary to a thyroidectomy performed when she was 18 years old, as treatment for a Graves Basedow's disease. She did not have previous cardiac symptoms and rapid progressive congestive heart failure developed after the beginning of levothyroxin supplementation for post operative hypothyroidism. Echocardiography revealed severe systolic and diastolic left ventricular dysfunction, mitral and tricuspid valve insufficiency, systolic pulmonary hypertension, left atrial enlargement and pericardial effusion. Calcium supplementation in addition to diuretics, captopril and digoxin were followed by rapid clinical improvement. Follow up until 18 months showed persistent left ventricular dilatation and systolic dysfunction, with improvement of all the other echocardiographic findings.

Spinal epidural haematoma (SEH) is a common complication after lumbar spinal decompression surgery, and symptomatic SEH usually causes devastating neurological deficits. Although different risk factors for post-operative SEH have been reported, few studies focused on patients' laboratory tests. The purpose of this study was to analyze the incidence of symptomatic SEH following lumbar spinal surgery, as well as identify the risk factors for it. Patients who underwent posterior lumbar spinal decompression surgery between January 2010 and August 2016 were included in this study and their medical records were retrospectively reviewed. Those who developed post-operative symptomatic SEH after the surgery were identified. The risk factors for SEH were analyzed by univariate and multivariate regression analysis. In total, 2715 patients were included in this study and 31 (1.14%) were identified with post-operative symptomatic SEH. Of these patients, 19 were males and 12 were females, with an average age of 59.39±11.66years. After multivariate logistic regression analysis, low serum calcium level (P=0.025), blood type A (P=0.04), increased estimated blood loss (P=0.032), prolonged surgical duration (P=0.018), and decreased post-operative globulin (P=0.016) were identified as the independent risk factors for post-operative SEH following lumbar spinal surgery. Furthermore, prolonged surgical duration (odds ratio=3.105) was the strongest risk factor for SEH. Based on a large population investigation, the incidence of symptomatic SEH following lumbar spinal decompression surgery was 1.14%. Blood type A, increased estimated blood loss, and prolonged surgical duration were identified as the independent risk factors for post-operative SEH while two new risk factors, including low serum calcium level and decreased post-operative globulin, were firstly identified in this study.