Hypoxia stimulates angiogenesis and a metabolic switch in human parathyroid adenoma cells

Hypoxia, a primary stimulus for angiogenesis, is important for tumour proliferation and survival. The effects of hypoxia on parathyroid tumour cells, which may also be important for parathyroid autotransplantation in patients, are however, unknown. We therefore assessed the effects of hypoxia on gene expression in parathyroid adenoma (PA) cells from patients with primary hyperparathyroidism. Cell suspensions from human PAs were cultured under normoxic or hypoxic conditions and then subjected to cDNA expression analysis. In total, 549 genes were significantly upregulated and 873 significantly downregulated. The most highly upregulated genes (carbonic andydrase 9 (CA9), solute carrier family 2A1 (SLC2A1) and hypoxia-inducible lipid droplet-associated protein (HIG2)) had known involvement in hypoxia responses. Dysregulation of oxidative phosphorylation and glycolysis pathway genes were also observed, consistent with data indicating that cells shift metabolic strategy of ATP production in hypoxic conditions, and that tumour cells predominantly utilise anaerobic glycolysis for energy production. Proliferation- and angiogenesis-associated genes linked with growth factor signalling such as mitogen-activated protein kinase kinase 1 (MAP2K1), Jun proto-oncogene (JUN) and ETS proto-oncogene 1 (ETS1) were increased, however Ras association domain family member 1 (RASSF1), an inhibitor of proliferation was also upregulated, indicating these pathways are unlikely to be biasing towards proliferation. Overall, there appeared to be a shift in growth factor signaling pathways from Jak-Stat and Ras signaling, to extracellular signal-regulated kinases (ERKs) and hypoxia-inducible factor (HIF)-1α signalling. Thus, our data demonstrate that PAs, under hypoxic conditions, promote expression of genes known to stimulate angiogenesis, as well as undergoing a metabolic switch.

Selective Parathyroid Autotransplantation During Total Thyroidectomy for Papillary Thyroid Carcinoma: A Cohort Study

Purpose: The relationship between the selective parathyroid gland (PG) autotransplantation and hypoparathyroidism is still not completely clear. The aim was to ascertain whether the number of autotransplanted PGs affected the incidence of hypoparathyroidism and recovery of parathyroid function in the long-term for patients with papillary thyroid carcinoma (PTC).Methods: A retrospective cohort study included all patients with PTC who had underwent primary total thyroidectomy with central neck dissection between January 2013 and December 2017. The patients were divided into three groups (0, 1, and 2 PGs autotransplanted, respectively).Results: Of the 2,477 patients, 634 (25.6%) received no PG autotransplantation, 1,078 (43.5%) and 765 (30.9%) were autotransplanted 1 and 2 PGs, respectively, and the incidence of permanent hypoparathyroidism (>1 year) was 1.7%, 0.7%, and 0.4% (P = 0.0228). Both 1 or 2 PGs autotransplanted increased the incidence of transient biochemical hypoparathyroidism (odds ratio [OR], 1.567; 95% confidence interval [CI], 1.258–1.953; P < 0.0001; OR, 2.983; 95% CI, 2.336–3.810; P < 0.0001, respectively) but reduced the incidence of permanent hypoparathyroidism (OR, 0.373; 95% CI, 0.145–0.958; P = 0.0404; OR, 0.144; 95% CI, 0.037–0.560; P = 0.0052, respectively). Both 1 or 2 PGs autotransplanted did not independently influence the occurrence of hypocalcemia symptoms.Conclusion: Selective parathyroid autotransplantation is less likely to lead to post-operative symptomatic hypocalcemia, although it could lead to a transient decrease in parathyroid hormone. However, in the long run, it is still an effective strategy to preserve parathyroid function.

Risks and prediction of postoperative hypoparathyroidism due to thyroid surgery

We aimed to investigate the prevalence of postoperative hypoparathyroidism (PoH), the relevant factors, and predictors of transient or permanent hypoparathyroidism. The files of 352 patients who underwent bilateral total thyroidectomy alone or with central lymph node dissection and/or lateral neck dissection between June 1, 2019, and November 30, 2019, were retrospectively evaluated. Also, calcium and parathyroid hormone levels measured preoperatively and 4–6 h after surgery, follow-up examination results, and time to resolution of transient PoH were recorded. 16.48% (n = 58) of the surgical patients developed transient PoH and 3.98% (n = 14) developed permanent PoH. Length of hospital stay increased in patients who developed PoH (p < 0.001). Transient PoH developed less in patients who underwent parathyroid autotransplantation, while permanent PoH was not detected (p = 0.001). PoH development was not significantly correlated with nodule size as measured by preoperative thyroid ultrasonography (p = 0.944). Patients who had a serum PTH level ≤ 5.95 pmol/L 4–6 h after surgery had a greater risk of developing permanent PoH (OR 134.84, 95% CI 17.25–1053.82). PoH is more common in female gender and is not significantly correlated with nodule size. Parathyroid autotransplantation can prevent the development of PoH.

A Meta-Analysis of Risk Factors for Transient and Permanent Hypocalcemia After Total Thyroidectomy

BackgroundAs hypocalcemia is the most common complication of total thyroidectomy, identifying its risk factors should guide prevention and management. The purpose of this study was to determine the risk factors for postthyroidectomy hypocalcemia.MethodsWe searched PubMed, Web of Science and EMBASE through January 31, 2019, and assessed study quality using the Newcastle–Ottawa Scale.ResultsFifty studies with 22,940 patients met the inclusion criteria, of which 24.92% (5716/22,940) had transient hypocalcemia and 1.96% (232/11,808) had permanent hypocalcemia. Significant (P &lt; 0.05) predictors of transient hypocalcemia were: younger age, female, parathyroid autotransplantation (PA), inadvertent parathyroid excision (IPE), Graves’ disease (GD), thyroid cancer, central lymph node dissection, preoperative severe Vitamin D deficiency, preoperative Vitamin D deficiency and a lower postoperative 24 h parathyroid hormone (PTH) level. Preoperative magnesium, preoperative PTH and Hashimoto’s thyroiditis were not significant predictors of transient hypocalcemia. IPE, GD, and thyroid cancer were associated with an increased rate of permanent hypocalcemia, but gender and PA did not predict permanent hypocalcemia.ConclusionImportant risk factors for transient and permanent hypocalcemia were identified. However, given the limited sample size and heterogeneity of this meta-analysis, further studies are required to confirm our preliminary findings.

A Cohort Study Assessing the Association Between Body Composition Parameters and Symptomatic Hypocalcemia After Total Thyroidectomy

Background Postoperative hypocalcemia is one of the major concerns following thyroidectomy and the most frequent cause of prolonged hospital stay. The aim of this study was to evaluate the relationship between body composition parameters and symptomatic hypocalcemia following total thyroidectomy. In addition, the effects of disease- and patient-related factors on hypocalcemia were investigated. Methods A total of 144 patients were prospectively included between March 2014 and September 2017. Patients were divided into 2 groups according to the presence or absence of clinical symptoms of hypocalcemia. Subsequently, the relationship between body composition parameters and hypocalcemia was evaluated. Results Postoperative hypocalcemia-related symptoms occurred in 28 patients (19.4%). Permanent hypocalcemia was not encountered in any patient. Patients with hypocalcemic symptoms were more likely to have nodules ≥40 mm (39.3% vs. 17.2%, P = .011), retrosternal goiters (25.0% vs. 7.8%, P = .017), central lymph node dissection (LND) (32.1% vs. 11.2%, P = .015), and parathyroid autotransplantation (28.6% vs. 3.4%, P < .001) than those without symptoms. However, no differences were observed in the body composition parameters between symptomatic and asymptomatic patients. On multivariate analysis, lower preoperative intact parathyroid hormone (iPTH) levels (odds ratios (ORs) .96, 95% confidence intervals (CIs) .93-.99), the presence of retrosternal goiters (OR 10.26, 95% CI 2.23-47.14), central LND (OR 16.05, 95% CI 3.90-66.07), and parathyroid autotransplantation (OR 36.22, 95% CI 6.76-194.13) predicted hypocalcemia. Discussion This study demonstrates that patients with lower preoperative iPTH levels, retrosternal goiters, central LND, and parathyroid autotransplantation are at an increased risk of developing clinical symptoms of hypocalcemia. Body composition parameters have no effect on the incidence of hypocalcemia after total thyroidectomy.

Causes of hypocalcemia after thyroid surgery

Aim. To identify the causes affecting hypocalcemia and its frequency of causing after thyroidectomy. Methods. The study included 402 patients after thyroidectomy, 361 (89.8%) women and 41 (10.2%) men, for the period 20152019. The patients were between the ages of 14 and 77 years (average 4527.2 years). Patients were tested for the presence of hyperthyroidism, the volume of tissue removed and type of thyroidectomy, presence of repeated thyroid operations and accidental parathyroidectomy, the results of parathyroid autotransplantation and pathohistological reports. To determine the effect of these factors on hypocalcemia, patients were divided into three groups. The first group included patients (n=51, 12.7%) were underwent surgery for Graves disease, the second (n=335, 83.3%) for nodular goiter, and the third (n=16, 4%) for recurrent goiter. Statistical data analysis was performed with IBM SPSS 16.0. The results were analyzed by one-way analysis of variance or KruskalWallis test and the median test. Results were considered statistically significant at p 0.05 (two-sided criterion). Results. In the early postoperative period, 20 (5%) of 402 patients had hypocalcemia, of which 12 (3%) had transient hypocalcemia, and 8 (2%) had permanent hypocalcemia. Postoperative hypocalcemia was detected in 9 (17.6%) patients the first group, 8 (2.4%) patients in the second group, and 3 (18.8%) patients of the third group. Patients hypocalcemia was characterized based on the types of underwent operations as follows: in 14 (5.3%; p 0.05) patients after total thyroidectomy, in 1 (3.2%) patient after close to total thyroidectomy, in 1 (16.7%) patient after total thyroidectomy with central lymphatic dissection, in 1 (20%) patient after total thyroidectomy with central and lateral lymphatic dissection, in 3 (18.8%) patients after repeated surgery. Postoperative hypocalcemia was identified in 5 of 44 patients of the second group with thyroid carcinoma, as well as in 1 patient of the third group with the same pathology (p=0.246). Conclusion. Incidence of hypocalcemia was more frequent after surgery for hyperthyroidism, especially after total thyroidectomy; in 40% of cases, transient hypocalcemia was identified in patients with autotransplantation of the parathyroid gland after an accidental parathyroidectomy.

Calcium-Alkali Syndrome Associated with Hypoparathyroidism Following Total Thyroidectomy

Background: Patients with permanent postsurgical hypoparathyroidism, a complication of total thyroidectomy, often require high calcium supplementation with vitamin D to maintain serum calcium levels. The epidemiology of calcium-alkali syndrome (CAS) in patients with hypoparathyroidism after total thyroidectomy remains unclear. This study aimed to investigate the incidence of hypercalcemia, renal impairment, metabolic alkalosis, and CAS in patients treated for presumed hypoparathyroidism after total thyroidectomy. Methods: Twenty-seven patients with neck cancers who underwent total thyroidectomy without parathyroid autotransplantation between January 2010 and October 2013 at our hospital were consecutively included. All patients received calcium lactate and alfacalcidol for postsurgical hypocalcemia. We defined hypercalcemia as a corrected serum calcium level (cCa) ≥10.5 mg/dL, metabolic alkalosis as a difference in serum sodium and serum chloride ([sNa-sCl]) ≥39 mEq/L, and renal impairment as a ≥50% increase in serum creatine and/or ≥35% decrease in estimated glomerular filtration rate (eGFR) compared to baseline. Results: cCa peaked (11.1 ± 1.5 mg/dL) at a median of 326 days (interquartile range 78–869) after surgery. At peak cCa, [sNa-sCl] was significantly higher (p < 0.01), and eGFR was significantly lower (p < 0.01) than that at baseline. Fifteen patients (55.6%) had hypercalcemia, 19 (70.3%) had alkalosis, 12 (44.4%) had renal impairment, and 9 (33.3%) had CAS. Patients with CAS (mean age 67.1 ± 10.8 years) were older than those without CAS (56.7 ± 13.6 years, p = 0.06). The mean dose of alfacalcidol in the CAS group (3.1 ± 1.2 μg/day) was significantly larger than that in the non-CAS group (2.1 ± 1.0 μg/day, p = 0.03). Conclusions: This retrospective study reveals the high incidence of CAS in patients with hypoparathyroidism after total thyroidectomy. Furthermore, these findings suggest that the serum calcium level, acid-base balance, and renal function should be closely monitored in patients with postsurgical hypoparathyroidism who receive large doses of active vitamin D.

Relationship of Vitamin D Deficiency and Intraoperative Parathyroid Hormone Elevation in Completion and Total Thyroidectomy

Objective To quantify how frequently intraoperative parathyroid hormone levels increase during thyroid surgery and to explore a possible relationship between secondary hyperparathyroidism due to vitamin D deficiency and elevation in intraoperative parathyroid hormone. Study Design Case series with chart review. Setting Tertiary academic center. Subjects and Methods A total of 428 consecutive patients undergoing completion and total thyroidectomy by the senior author over a 7-year period were included for analysis. All patients had baseline and postexcision intraoperative parathyroid hormone levels as well as vitamin D levels from the same laboratory. Institute of Medicine criteria were employed for vitamin D stratification (>30, normal; 20-29.9, insufficient; <20, deficient) . Other data analyzed include sex, age, neck dissection status, and parathyroid autotransplantation. Results A total of 118 patients (27.6%) had an intraoperative parathyroid hormone elevation above baseline. Patients with vitamin D deficiency were significantly more likely to experience hormone elevation ( P = .04). When parathyroid hormone rose, it did so by a mean 32.1 pg/mL. Patients with vitamin D deficiency demonstrated significantly larger hormone increases ( P = .03). Conclusion Elevation in intraoperative parathyroid hormone levels above baseline after completion and total thyroidectomy occurs in over one-fourth of cases and is significantly associated with vitamin D deficiency. This study is the first to report this observation. We hypothesize that vitamin D deficiency in these patients may create a subclinical secondary hyperparathyroidism that leads to intraoperative parathyroid hormone elevation when the glands are manipulated. Additional studies will be needed to explore this physiologic mechanism and its clinical significance.