Mechanistic Insights into Tanshinone IIA in the Amelioration of Post-Thyroidectomy Hypoparathyroidism.

BACKGROUND: Thyroidectomy causes impaired blood supply to the parathyroid glands, which leads to hypoparathyroidism. Tanshinone IIA (Tan IIA) is helpful in blood activation and cardiovascular protection. Therefore, the efficacy of Tan IIA in improving hypoparathyroidism was explored in this study. METHODS: New Zealand white rabbits were utilized to establish a unilateral parathyroid gland ischemia injury model. The model was created by selectively ligating the main blood supply vessel of one parathyroid gland, and the rabbits were then divided into three groups receiving 1, 5, and 10 mg/kg of Tan IIA. Serum calcium and parathyroid hormone (PTH) levels were measured using specialized assay kits. Immunohistochemistry was used to assess the microvessel density (MVD) in parathyroid glands. Western blotting (WB) was used to analyze protein expression related to the PI3K/AKT signaling pathway and the pathway-associated HIF-1α and VEGF. Moreover, MMP-2 and MMP-9 involved in angiogenesis were detected by WB. RESULTS: Tan IIA treatment effectively restored serum calcium and PTH levels in a dose-dependent manner. Notably, MVD in the parathyroid glands increased significantly, especially at higher doses. The Tan IIA treatment also elevated the p-PI3K/PI3K and p-AKT/AKT ratios, indicating that the PI3K/AKT pathway was reactivated. Moreover, Tan IIA significantly restored the decreased expression levels of VEGF and HIF-1α caused by parathyroid surgery. Additionally, Tan IIA increased MMP-2 and MMP-9 levels. CONCLUSION: Tan IIA activates the PI3K/AKT pathway, promotes angiogenesis by modulating VEGF, HIF-1α, MMP-2, and MMP-9, thereby further enhancing MVD within the parathyroid glands. This study demonstrates that Tan IIA improved post-thyroidectomy hypoparathyroidism.

Hypoparathyroidism and mortality after total thyroidectomy: A nationwide matched cohort study.

OBJECTIVE: Total thyroidectomy (TT) carries a risk of hypoparathyroidism (hypoPT). Recently, hypoPT has been associated with higher overall mortality rates. We aimed to evaluate the frequency of hypoPT and mortality in patients undergoing TT in Denmark covering 20 years. DESIGN: Retrospective Cohort study. PATIENTS AND MEASUREMENTS: Using population-based registries, we identified all Danish individuals who had undergone TT between January 1998 and December 2017. We included a comparison cohort by randomly selecting 10 citizens for each patient, matched on sex and birth year. HypoPT was defined as treatment with active vitamin D after 12 months postoperatively. We used cumulative incidence to calculate risks and Cox regression to compare the rate of mortality between patients and the comparison cohort. We evaluated patients in different comorbidity groups using the Charlson Comorbidity Index and by different indications for surgery. RESULTS: 7912 patients underwent TT in the period. The prevalence of hypoPT in the study period was 16.6%, 12 months postoperatively. After adjusting for potential confounders the risk of death due to any causes (hazard ratio; 95% confidence intervals) following TT was significantly increased (1.34; 1.15-1.56) for patients who developed hypoPT. However, subgroup analysis revealed mortality was only increased in malignancy cases (2.48; 1.99-3.10) whereas mortality was not increased when surgery was due to benign indications such as goitre (0.88; 0.68-1.15) or thyrotoxicosis (0.86; 0.57-1.28). CONCLUSIONS: The use of active vitamin D for hypoPT was prevalent one year after TT. Patients with hypoPT did not have an increased risk of mortality following TT unless the indication was due to malignancy.

Validating the risk of hypoparathyroidism after total thyroidectomy in a population-based cohort: plea for improved follow-up.

BACKGROUND: A previous nationwide study from Sweden showed that the rate of permanent hypoparathyroidism is high and under-rated in the Swedish Quality Register. This retrospective population-based study aimed to validate the rate and diagnosis of permanent hypoparathyroidism found in the previous study. A secondary aim was to assess the relationship between the rate of low parathyroid hormone (PTH) levels within 24 h after surgery and the rate of permanent hypoparathyroidism. METHODS: All patients who underwent total thyroidectomy from 2005 to 2015 in a region of Sweden were included. Data were retrieved from local health records, the National Patient Registry, the Swedish Prescribed Drug Registry, and the Swedish Quality Register. A strict definition of permanent hypoparathyroidism was used, including biochemical data and attempts to stop the treatment. RESULTS: A total of 1636 patients were included. Altogether, 143 patients (8.7 per cent) developed permanent hypoparathyroidism. Of these, 102 (6.2 per cent) had definitive permanent hypoparathyroidism, whereas 41 (2.5 per cent) had possible permanent hypoparathyroidism, because attempts to stop the treatment were lacking (28) or patients were lost to follow-up (13). The agreement between the Swedish Quality Register and the chart review was 29.3 per cent. A proportion of 23.2 per cent with a PTH level below the reference value corresponded to a 6.7 per cent rate of permanent hypoparathyroidism. CONCLUSION: The risk of permanent hypoparathyroidism after total thyroidectomy is high. Some patients are overtreated because attempts to stop the treatment are lacking. Quality registers might underestimate the risk of permanent hypoparathyroidism. Approximately one-quarter of all patients with low PTH levels immediately after surgery developed permanent hypoparathyroidism.

The parathyroid glands control calcium levels in the blood. If they do not make enough hormone, calcium levels are low. Parathyroid dysfunction can happen after thyroid surgery, if the glands are hurt or removed by mistake. This is a problem because people with this condition may have symptoms and need ongoing treatment with vitamin D and calcium. They might also face other health issues and need regular visits to their doctor. Finding out how often long-term parathyroid dysfunction happens can be tricky because it requires a full year of follow-up and attempts to stop the treatment. This information is often missing from many studies and registers. Some recent studies have shown that this condition is more common than previously thought. It would be helpful to have a quick way to know how common long-term parathyroid gland dysfunction will be within a unit or hospital, without having to wait for the follow-up. This would help doctors to assess how good they are at taking care of patients. It would also support research on new methods to avoid parathyroid dysfunction. The goal of the study was to see how often long-term parathyroid dysfunction occurs after thyroid surgery, using a strict definition and complete long-term follow-up. Another aim was to assess the link between low parathyroid hormone levels right after surgery and the rate of long-term parathyroid dysfunction. All individuals who had the entire thyroid gland removed for benign disease between 2005 and 2015 in a region of Sweden were included. Data were collected from local health records at six hospitals. Patient information, surgical details, blood tests, and treatment details were gathered from the medical charts. Data were also collected from the national quality register. A high rate of long-term parathyroid dysfunction was seen in this large study of 1636 patients, Some patients may have been overtreated, because no attempts had been made to stop the treatment. The rate of long-term parathyroid dysfunction in patients with a normal early parathyroid hormone level was very low. About 23 per cent of all patients had a low early parathyroid hormone level, which corresponded to a 6.7 per cent rate of long-term parathyroid dysfunction. The authors believe that parathyroid hormone measurement could help predict the rate of permanent hypoparathyroidism, but more studies are needed to be sure.

Impact of near-infrared fluorescence imaging plus indocyanine green fluorescence on postoperative hypoparathyroidism rates after total thyroidectomy and central neck lymph node dissection.

BACKGROUND: Patients with thyroid carcinoma often undergo cervical lymph node dissection, which is associated with high rates of both transient and permanent postoperative hypoparathyroidism. The impact of near-infrared fluorescence imaging + indocyanine green (ICG) fluorescence on postoperative hypoparathyroidism rates after total thyroidectomy and central neck lymph node dissection was evaluated. METHODS: All patients undergoing surgery between January 2019 and March 2023 were included and divided into three groups: a control group (parathyroid glands identified visually), a near-infrared fluorescence imaging alone group, and a near-infrared fluorescence imaging + ICG fluorescence group. The primary outcome was the transient and permanent postoperative hypoparathyroidism rates. Secondary outcomes were: length of surgery and number of parathyroid glands identified, inadvertently resected, and autotransplanted. RESULTS: A total of 131 patients were included in the study (47 in the control group, 45 in the near-infrared fluorescence imaging alone group, and 39 in the near-infrared fluorescence imaging + ICG fluorescence group). The transient hypoparathyroidism rate was 48.9% in the control group, 37.8% in the near-infrared fluorescence imaging alone, and 5.1% in the near-infrared fluorescence imaging + ICG fluorescence group (P < 0.0001), while the permanent hypoparathyroidism rate was 8.5% in the control group, 2.2% in the near-infrared fluorescence imaging alone group, and 0% in the near-infrared fluorescence imaging + ICG fluorescence group (P = 0.096). The number of parathyroid glands identified was 159 of 188 in the control group, 165 of 180 in the near-infrared fluorescence imaging alone group, and 149 of 156 in the near-infrared fluorescence imaging + ICG fluorescence group (P = 0.002). Inadvertent resection of parathyroid glands occurred for 29 of 188 in the control group, 15 of 180 in the near-infrared fluorescence imaging alone group, and 7 of 156 in the near-infrared fluorescence imaging + ICG fluorescence group (P = 0.002), with subsequent parathyroid gland autotransplantation for 2 of 29 in the control group, 2 of 15 in the near-infrared fluorescence imaging alone group, and 3 of 7 in the near-infrared fluorescence imaging + ICG fluorescence group (P = 0.040). There was no difference in the median operating time between groups. CONCLUSION: The use of near-infrared fluorescence imaging + ICG fluorescence decreased both transient and permanent hypoparathyroidism rates in patients undergoing total thyroidectomy and central neck lymph node dissection.

Outcomes of Preoperative Medical Therapy for Thyroidectomy in Autoimmune Thyroid Disease.

INTRODUCTION: Thyroidectomy provides definitive treatment for autoimmune thyroid disease (AITD) often resulting in improved quality of life. Historically, patients with AITD undergoing thyroidectomy have increased rates of postoperative hypoparathyroidism and recurrent laryngeal nerve palsy. We investigated the outcomes of preoperative medications in patients with AITD undergoing thyroidectomy. METHODS: We performed a retrospective analysis of patients who underwent thyroidectomy for AITD at a single institution from 2015 to 2021. Surgical outcomes and perioperative laboratory values were analyzed by type of AITD and type of preoperative medical treatment: none, saturated solution of potassium iodide (SSKI), corticosteroids, or both SSKI and corticosteroids. RESULTS: A total of 123 patients underwent thyroidectomy for AITD and were included in analysis: 50 received no preoperative medications, 40 received SSKI, 20 received corticosteroids, and 13 received both. Seventy-six patients had Graves' disease and 47 had Hashimoto's thyroiditis. There were no significant differences in blood loss, operative time, wound complications, hematoma, or recurrent laryngeal nerve injury for patients treated with preoperative corticosteroids compared to those who were not. Patients who received corticosteroids and patients with Graves' disease more commonly had at least one instance of hypocalcemia postoperatively (P < 0.01, P = 0.01), although only on postoperative day 1 was mean calcium < 8.5 mg/dL. There was no difference in rate of transient or permanent hypoparathyroidism. CONCLUSIONS: Patients who received corticosteroids preoperatively had no increased risk of complications. They did have mildly lower calcium levels in the early postoperative period, although no difference in hypoparathyroidism. Further exploration is warranted to investigate the impact of preoperative corticosteroids on operative difficulty, quality of life, and autoantibody clearance.

Impact of autofluorescence-guided surgery of parathyroid glands during total thyroidectomy in experienced surgeons: A randomized clinical trial.

INTRODUCTION: Post-surgical hypoparathyroidism often occurs after total thyroidectomy (TT). The aim of this study is to investigate whether the use of near-infrared autofluorescence (NIRAF) of parathyroid glands (PGs) can aid experienced surgeons in identifying more PGs during surgery, potentially reducing unintended resection, and assessing its impact on post-surgical hypoparathyroidism. MATERIALS AND METHODS: All patients undergoing at least a TT by two experienced surgeons, between 2020 and 2021, were enrolled and randomized into two cohorts: NIRAF group (NG) and CONTROL group (CG). Transient hypoparathyroidism was defined by serum concentration of PTH<12 ng/mL at the 1st post-operative day and permanent by the need of calcium-active vitamin D treatment >6 months from the surgery with still undetectable PTH or <12 ng/m. RESULTS: Among 236 patients (111 in NG, 125 in CG), the number of PGs identified was higher in NG (93.9%, 417/444) compared to CG (81.4%, 407/500) (p < 0.001), with a mean of 3.76 ± 0.44 PGs per patient in NG and 3.25 ± 0.79 in CG. The number of unintendedly resected PGs was 14 in NG and 42 in CG (p < 0.0001). Transient hypoparathyroidism was observed in 18 patients (16.2%) in NG and 40 patients (32.0%) in CG (p = 0.004). Permanent hypoparathyroidism affected 1 patient in NG and 7 patients in CG (p = 0.06). The mean operative time was longer in NG (104.3 ± 32.08 min) compared to CG (85.5 ± 40.62 min) (p < 0.001). CONCLUSIONS: NIRAF enhances the identification of PGs, preventing their inadvertent resection and reducing the overall incidence of post-surgical hypoparathyroidism.

Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro.

PURPOSE: Hypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro. METHODS: C2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated. RESULTS: The combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells. CONCLUSIONS: Our results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

Features of patients and fracture risk in hypoparathyroidism; a single center study.

PURPOSE: Patients with hypoparathyroidism (hypoPT) have low bone turnover and high bone mineral density (BMD). However, data on fracture risk are conflicting. The objectives of this study were: 1. To describe clinical/biochemical characteristics of hypoPT patients followed at a single medical center. 2. To identify postsurgical hypoPT patients and investigate their fracture rate compared with gender/age-matched post-surgical normocalcemic patients. METHODS: Retrospective analysis of patient's medical records treated at the tertiary medical center in 2010-2021 identified by computerized medical database search. RESULTS: The cohort included 133 patients (91% women, mean age 64 ± 13 years) of whom 105 (79%) had post-thyroidectomy hypoparathyroidism and the remainder had an autoimmune/idiopathic/other etiology. Mean follow-up time was 21 ± 12 and 27 ± 12 years, respectively. The control group included 142 post-thyroidectomy patients without hypoparathyroidism. Patients in the postsurgical hypoparathyroidism group were older and had higher calcium and PTH levels at diagnosis than the non-surgical hypoPT patients. Comparing the postsurgical hypoPT and postsurgical normocalcemic control patients revealed a significantly higher BMD in the hypoPT group. Yet, fracture rates were 31% in the postsurgical hypoparathyroidism group and 21% in the control group (P = 0.1) over a similar median follow-up period (17 and 18.4 years, respectively). In both groups the most common fracture site was the spine (50% and 70%, respectively; p = 0.33), mainly nonclinical morphometric fractures. Higher phosphorus blood level was associated with increased fracture risk. CONCLUSIONS: The relatively high BMD in patients with postsurgical hypoparathyroidism is not associated with lower fracture risk. Silent morphometric fractures are quite common in this group of patients.

The application of autofluorescence system contributes to the preservation of parathyroid function during thyroid surgery.

PURPOSE: The purpose of this study was to investigate the impact of autofluorescence technology on postoperative parathyroid function and short-term outcomes in patients undergoing thyroid surgery. METHODS: A total of 546 patients were included in the study, with 287 in the conventional treatment group and 259 in the autofluorescence group. Both groups underwent central lymph node dissection, which is known to affect parathyroid function. Short-term outcomes, including rates of postoperative hypocalcemia and parathyroid dysfunction, serum calcium and PTH levels on the first postoperative day, as well as the need for calcium supplementation, were analyzed. A multivariable analysis was also conducted to assess the impact of autofluorescence on postoperative parathyroid dysfunction, considering factors such as age, BMI, and preoperative calcium levels. RESULTS: The autofluorescence group demonstrated significantly lower rates of postoperative hypocalcemia and parathyroid dysfunction compared to the conventional treatment group. The autofluorescence group also had better serum calcium and PTH levels on the first postoperative day, and a reduced need for calcium supplementation. Surprisingly, the use of autofluorescence technology did not prolong surgical time; instead, it led to a shorter hospitalization duration. The multivariable analysis showed that autofluorescence significantly reduced the risk of postoperative parathyroid dysfunction, while factors such as age, BMI, and preoperative calcium levels did not show a significant correlation. CONCLUSION: This study provides evidence that autofluorescence technology can improve the preservation of parathyroid function during thyroid surgery, leading to better short-term outcomes and reduced postoperative complications. The findings highlight the potential of autofluorescence as a valuable tool in the management of parathyroid hypofunction. Further research and validation are needed to establish the routine use of autofluorescence technology in the thyroid.

Dynamics of PTH levels in the development of post-operative hypoparathyroidism.

BACKGROUND: Post-operative hypoparathyroidism is the most frequent complication after total thyroidectomy. The identification of preoperative predictors could be helpful to identify patients at risk. This study aimed to evaluate the potential influence of preoperative PTH levels and their perioperative dynamics as a predictor of transient, protracted, and permanent post-operative hypoparathyroidism. METHODS: A prospective, observational study that includes 100 patients who underwent total thyroidectomy between September 2018 and September 2020. RESULTS: Transient hypoparathyroidism was present in 42% (42/100) of patients, 11% (11/100) developed protracted hypoparathyroidism, and 5% (5/100) permanent hypoparathyroidism. Patients who presented protracted hypoparathyroidism had higher preoperative PTH levels. The protracted and permanent hypoparathyroidism rate was higher in groups with greater preoperative PTH [0% group 1 (<40 pg/mL) vs. 5.7% group 2 (40-70 pg/mL) vs. 21.6% group 3 (>70 pg/mL); p = 0.03] and (0 vs. 8.3 vs. 20%; p = 0.442), respectively. The rate of protracted and permanent hypoparathyroidism was higher in patients with PTH at 24 h lower than 6.6 pg/mL and whose percentage of PTH decline was higher than 90%. The rate of transient hypoparathyroidism was higher in patients who showed a PTH decline rate of more than 60%. The percentage of PTH increase one week after surgery in patients with permanent hypoparathyroidism was significantly lower. CONCLUSION: The prevalence of protracted hypoparathyroidism was higher in groups with higher preoperative PTH levels. PTH levels 24 h after surgery lower than 6.6 pg/mL and a decline of more than 90% predict protracted and permanent hypoparathyroidism. The percentage of PTH increase a week after surgery could predict permanent hypoparathyroidism.

Patients who presented protracted and permanent hypoparathyroidism had higher preoperative PTH levels.Patients in groups with higher preoperative PTH levels showed higher rates of protracted and permanent hypoparathyroidism.The percentage of PTH variance one week after surgery in patients with permanent hypoparathyroidism was significantly lower and could predict permanent hypoparathyroidism.

Impact of autofluorescence for detection of parathyroid glands during thyroidectomy on postoperative parathyroid hormone levels: parallel multicentre randomized clinical trial.

BACKGROUND: Techniques for autofluorescence have been introduced to visualize the parathyroid glands during surgery and to reduce hypoparathyroidism after thyroidectomy. METHODS: This parallel multicentre RCT investigated the use of Fluobeam® LX to visualize the parathyroid glands by autofluorescence during total thyroidectomy compared with no use. There was no restriction on the indication for surgery. Patients were randomized 1 : 1 and were blinded to the group allocation. The hypothesis was that autofluorescence enables identification and protection of the parathyroid glands during thyroidectomy. The primary endpoint was the rate of low parathyroid hormone (PTH) levels the day after surgery. RESULTS: Some 535 patients were randomized, and 486 patients received an intervention according to the study protocol, 246 in the Fluobeam® LX group and 240 in the control group. Some 64 patients (26.0 per cent) in the Fluobeam® LX group and 77 (32.1 per cent) in the control group had low levels of PTH after thyroidectomy (P = 0.141; relative risk (RR) 0.81, 95 per cent c.i. 0.61 to 1.07). Subanalysis of 174 patients undergoing central lymph node clearance showed that 15 of 82 (18 per cent) in the Fluobeam® LX group and 31 of 92 (33 per cent) in the control group had low levels of PTH on postoperative day 1 (P = 0.021; RR 0.54, 0.31 to 0.93). More parathyroid glands were identified during operation in patients who had surgery with Fluobeam® LX, and fewer parathyroid glands in the surgical specimen on definitive histopathology. No specific harm related to the use of Fluobeam® LX was reported. CONCLUSION: The use of autofluorescence during thyroidectomy did not reduce the rate of low PTH levels on postoperative day 1 in the whole group of patients. It did, however, reduce the rate in a subgroup of patients. Registration number: NCT04509011 (http://www.clinicaltrials.gov).

Increased Risk of Complications Associated With Concurrent Parathyroidectomy in Patients Undergoing Total Thyroidectomy.

INTRODUCTION: We sought to investigate the association of concurrent parathyroidectomy (PTX) with risks of total thyroidectomy (TTX) through analysis of Collaborative Endocrine Surgery Quality Improvement Program data. TTXis a common operation with complications including recurrent laryngeal nerve injury, neck hematoma, and hypoparathyroidism. A subset of patients undergoing thyroidectomy undergoes planned concurrent PTX for treatment of primary hyperparathyroidism. There are limited data on the risk profile of TTX with concurrent PTX (TTX + PTX). METHODS: We queried the Collaborative Endocrine Surgery Quality Improvement Program database for patients who underwent TTX or TTX + PTX from January 2014 through April 2020. Multivariable logistic regression was performed to predict hypoparathyroidism, vocal cord dysfunction, neck hematoma, and postoperative emergency department visit. Covariates included patient demographics, patient body mass index, indication for surgery, central neck dissection, anticoagulation use, and surgeon volume. RESULTS: Thirteen thousand six hundred forty seven patients underwent TTX and 654 patients underwent TTX + PTX. Unadjusted rates of hypoparathyroidism were higher in TTX + PTX patients at 30 d (9.6% versus 7.4%, P = 0.04) and 6 mo (7.9% versus 3.1%, P < 0.001). On multivariable regression, TTX + PTX was associated with an increased risk of hypoparathyroidism at 30 d (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.57-2.79) and 6 mo (OR 4.63, 95% CI 3.06-7.00) and an increased risk of postoperative emergency department visit (OR 1.66, 95% CI 1.20-2.31). TTX + PTX was not associated with recurrent laryngeal nerve injury or neck hematoma. CONCLUSIONS: Concurrent PTX in patients undergoing TTX is associated with increased risk of immediate and long-term hypoparathyroidism, which should be considered in informed consent discussions and operative decision-making.

Postoperative Hypocalcemia in Hyperthyroid Patients: The Parathyroids Aren't Always to Blame.

INTRODUCTION: Hypocalcemia is commonly reported after thyroidectomy and has multiple possible etiologies including: parathyroid devascularization, reactive hypoparathyroidism from relative hypercalcemia in thyrotoxicosis, and abrupt reversal of thyrotoxic osteodystrophy. In patients that are actively hyperthyroid and undergoing thyroidectomy, it is not known how many experience hypocalcemia from nonhypoparathyroidism etiologies. Therefore, our aim was to examine the relationship among thyrotoxicosis, hypocalcemia, and hypoparathyroidism. METHODS: A retrospective review was performed of prospectively-collected data from all patients undergoing thyroidectomy for hyperthyroidism by 4 surgeons from 2016 to 2020. All patients carried a diagnosis of Graves' disease or toxic multinodular goiter. Patient demographics, preoperative medications, laboratory reports, and postoperative medications were reviewed. Hypocalcemia within the first month of surgery despite a normal parathyroid hormone (PTH) level was the primary outcome of interest and was compared between patients with and without thyrotoxicosis. Secondary outcomes were duration of postoperative calcium use and the relationship between preoperative calcium supplementation and postoperative calcium supplementation. Descriptive statistics, Wilcoxon rank-sum, and chi-square tests were used for bivariate analysis, as appropriate. RESULTS: A total of 191 patients were identified, with mean age of 40.5 y (range 6-86). Most patients were female (80%) and had Graves' disease (80%). At the time of surgery, 116 (61%) had uncontrolled hyperthyroidism (thyrotoxic group, Free Thyroxine >1.64 ng/dL or Free Triiodothyronine > 4.4 ng/dL), with the remaining 75 (39%) considered euthyroid. Postoperative hypocalcemia (calcium < 8.4 mg/dL) developed in 27 (14%), while hypoparathyroidism (PTH < 12 pg/mL) was observed in 39 (26%). Thyrotoxic patients comprised a majority of those with hypocalcemia (n = 22, 81%, P = 0.01) and hypoparathyroidism immediately following surgery (n = 14, 77%, P = 0.04). However, a majority of initially hypocalcemic, thyrotoxic patients had normal PTH values within the first month after surgery (n = 17, 85%), pointing to a potential nonparathyroid etiology. On bivariate analysis, no significant relationship was found for thyrotoxic patients with initial postoperative hypocalcemia (18%) and hypoparathyroidism <1-month after surgery (29%, P = 0.29) or between 1 and 6 mo after surgery (2%, P = 0.24). Of the 19 patients in the nonhypoparathyroidism group, 17 (89%) were off all calcium supplements by 6 mo postop. CONCLUSIONS: In patients with hyperthyroidism, those in active thyrotoxicosis at time of surgery have a higher rate of postoperative hypocalcemia compared to euthyroid patients. When hypocalcemia lasts >1 mo postoperatively, data from this study suggest that hypoparathyroidism may not be the primary etiology in many of these patients, who typically require calcium supplementation no more than 6 mo postoperatively.

Intraoperative indocyanine green angiography for predicting postoperative hypoparathyroidism.

BACKGROUND: Postoperative hypocalcemia is a common complication of thyroidectomy. This problem is most often associated with accidental devascularization or excision of the parathyroid glands (PG). AIM: Aim was to study near-infrared (NIR) fluorescent imaging with intraoperative PG indocyanine green (ICG) angiography to help identify and preserve PG during total thyroidectomy in order to avoid postoperative hypocalcemia. MATERIAL AND METHODS: From 2017 to 2022, a total of 92 patients underwent total thyroidectomy at Odessa Regional Hospital. Indications for surgery were multinodular goiter (n = 42), thyroid cancer (n = 43), and Graves' disease (n = 7). By randomization all patients were divided into two groups: in the control group, 48 patients underwent standard total thyroidectomy, and in the main group, 44 patients underwent NIR-assisted total thyroidectomy with ICG angiography. Serum calcium and parathyroid hormone levels were compared between the two groups of patients in 1, 7-15 days after surgery and then 3, 6 months later. RESULTS: In the control group, based on a visual assessment of the PG, autotransplantation of the PG was conducted in only five cases. In the second group, autotransplantation was performed in 16 patients. The transient postoperative hypocalcemia was observed in 8 patients of the control group (16, 70%) and in the 2 patients of ICG group (4, 50%) on 5-10 postoperative days. In the first group, 2 patients at 3 months after surgery had permanent hypocalcaemia. CONCLUSION: NIR fluorescent imaging with intraoperative PG ICG angiography is a safe and an easily repeatable method. This technique provides improved detecting and assessment of the perfusion of the PG. The need for autotransplantation of the PG can be determined more objectively using ICG imaging than simple visualization.

Transoral Thyroidectomy: Initial Results of the European TOETVA Study Group.

BACKGROUND: The aim of this study was to evaluate a new surgical technique by the European Transoral Endoscopic Thyroidectomy Vestibular Approach (TOETVA) Study Group. METHODS: This study included 391 patients (47 [(12%]) male and 344 [(88%)] female) who had undergone endoscopic thyroid or parathyroid surgery via the vestibular approach between February 2016 and May 2022 at nine centers. The data were analyzed with regard to complications, surgery time and specimen retrieval. RESULTS: Overall, 376 (96.2%) TOETVA and 15 (3.8%) transoral endoscopic parathyroidectomy vestibular approach interventions were performed with an average surgery time of 145 (± 61.2) minutes and 509 nerves at risk. The specimens were retrieved via a transoral vestibular and retroauricular approach in 66 (16.9%) patients and via a transaxillary approach in 8 (2%). Benign histology including Grave's disease was identified in 272 (69.6%) patients, 1 (0.3%) presented noninvasive follicular thyroid neoplasms with papillary-like nuclear features, and 103 (26.3%) showed differentiated thyroid carcinoma. Solitary parathyroid adenoma were removed in 15 (3.8%) patients. Conversion to open surgery was necessary in 13 (3.3%) and revision had to be performed in 2 (0.5%) patients. Transient recurrent laryngeal nerve palsy (RLNP) was present in 18 (4.6%) and permanent RLNP in 2 (0.5%) patients. Fifteen (3.8%) patients experienced transient hypoparathyroidism after thyroidectomy. No case of permanent hypoparathyroidism was observed. Postoperative surgical site infection occurred in 1 (0.3%) patient. Despite a higher rate of sensory and motor disorders and skin discoloration at discharge, permanent disorders were present in only 3 (0.8%) and 16 (4.1%) patients, respectively. CONCLUSION: Our results show that transoral endoscopic surgery, performed by experienced endocrine surgeons, is a safe alternative to conventional thyroid surgery.

Usefulness of ICG Angiography-Guided Thyroidectomy for Preserving Parathyroid Function.

INTRODUCTION: Hypoparathyroidism is the most frequent complication after total thyroidectomy and, when permanent, it becomes a severe chronic disease. We assessed the usefulness of indocyanine green (ICG) angiography-guided thyroidectomy to reduce the postoperative hypocalcemia. METHODS: Prospective study with two consecutive cohorts of patients who underwent total thyroidectomy: historical control group (CG) and angiography-guided thyroidectomy group (AG). In all patients, ICG-angiography was performed at the end of the surgery to predict immediate parathyroid gland (PG) function. In the AG, ICG-angiography was also done after PG identification to show their vascular supply. We compared the rate of postoperative hypocalcemia (calcium supplementation needed due to hypocalcemia symptoms or calcium levels < 1.8 mmol/L on the first postoperative day) and permanent hypocalcemia (need of calcium ± vitamin D supplementation 12 months after thyroidectomy). RESULTS: We included 120 consecutive patients (84 CG; 36 AG). Thyroid cancer was the most common diagnostic (63.1% CG-69.4% AG; p = 0.646) and central neck dissection was also frequent (54.8% CG-64.3% AG; p = 0.468). The AG developed a lower rate of postoperative (26.2-5.6%; p = 0.011) and permanent hypocalcemia (11.9-0%; p = 0.032). The OR for permanent hypocalcemia was 0.673 (95% CI 0.591-0.766). A significant higher rate of well vascularized PG at the end of the surgery (score 2) in the AG (39.2-52.9%; p = 0.018) was also seen. CONCLUSION: ICG angiography-guided thyroidectomy is a useful tool to identify PG vascularization, allowing a better PG preservation and a significant decrease in hypocalcemia rates.

Microencapsulation of parathyroid cells via electric field and non-surgical transplantation approach.

PURPOSE: Hypoparathyroidism is a rare disease with low PTH, mostly seen as a consequence of neck surgery. Current management is the prescription of calcium and vitamin D, but the definitive treatment is parathyroid allotransplantation, which frequently triggers an immune response, thus cannot achieve the expected success. To overcome this problem, encapsulation of allogeneic cells is the most promising method. By optimizing the standard alginate cell encapsulation technique with parathyroid cells under high-voltage application, the authors reduced the size of parathyroid-encapsulated beads and evaluated these samples in vitro and in vivo. METHODS: Parathyroid cells were isolated, and standard-sized alginate macrobeads were prepared without any electrical field application, while microbeads in smaller sizes (< 500 µm), by the application of 13 kV. Bead morphologies, cell viability, and PTH secretion were evaluated in vitro for four weeks. For the in vivo part, beads were transplanted into Sprague-Dawley rats, and after retrieval, immunohistochemistry and PTH release were evaluated in addition to the assessment of cytokine/chemokine levels. RESULTS: The viability of parathyroid cells in micro- and macrobeads did not differ significantly. However, the amount of in vitro PTH secretion from microencapsulated cells was significantly lower than that from macroencapsulated cells, although it increased throughout the incubation period. Immunohistochemistry of PTH staining in both of the encapsulated cells identified as positive after retrieval. CONCLUSION: Contrary to the literature, a minimal in vivo immune response was developed for alginate-encapsulated parathyroid cells, regardless of bead size. Our findings suggest that injectable, micro-sized beads obtained using high-voltage may be a promising method for a non-surgical transplantation approach.

Sonographic evaluation of subclinical entheseal involvement in patients with hypoparathyroidism: a case control study.

PURPOSE: Hypoparathyroidism is a disease characterized by low serum calcium, increased serum phosphorus and low PTH levels. Although patients are treated with active vitamin D and calcium, a proper serum calcium phosphorus balance cannot always be achieved. Ectopic calcifications that develop in organs during treatment are the most common complications. To date, there is not any published study on enthesopathy in patients with hypoparathyroidism. The aim of this study was to evaluate subclinical enthesopathy in patients with hypoparathyroidism with ultrasound and to compare the results with those of the control group. METHODS: The study included patients aged 18-65 years with postoperative hypoparathyroidism and hypothyroidism (group hypoP + hypoT), patients with postoperative hypothyroidism (group hypoT), and healthy age and sex-matched volunteers (group C). Ultrasonographic findings of enthesopathy in both extremities were documented according to the Glasgow Ultrasound Enthesitis Scoring System (GUESS). RESULTS: GUESS scores in group hypoP + hypoT, were significantly higher when compared to the other groups. There was a statistically significant correlation between the total GUESS scores and total enthesophyte scores and the duration of hypoparathyroidism (p < 0.05, r = 0.43) (p < 0.05, r = 0.39) respectively. In the correlation analysis of all groups, a significant negative correlation was found between serum Ca and PTH levels and the total GUESS scores (p < 0.01, r = - 0.37; p < 0.01, r = - 0.54, respectively). CONCLUSION: This study showed that GUESS scores were significantly higher in patients with hypoparathyroidism compared to those with hypothyroidism and control subjects. GUESS scores were positively correlated with disease duration. Patients with hypoparathyroidism need to be evaluated for subclinical enthesopathy during follow-up.

Accidental parathyroidectomy during total thyroidectomy and hypoparathyroidism in a large series of 766 patients: incidence and consequences in a referral center.

PURPOSE: Transient hypoparathyroidism is the most common complication after total thyroidectomy, and accidental parathyroidectomy (AP) may be a cause. The aim of this study was to investigate the incidence of AP and its impact on postoperative calcemia. MATERIALS AND METHODS: From February 2016 to May 2018, 766 patients undergoing total thyroidectomy were prospectively included. Surgical indications, hormonal status, definitive histology, and postoperative calcium and PTH levels were analyzed. RESULTS: 578/(75.45%) were women and 188/(24.55%) men with mean age of 53.4 years. Parathyroid tissue on the thyroid specimen was observed in 40 (5.2%) patients: 30 APs and 10 parathyroid fragments. Among the 30 APs, 12 glands were intrathyroid and 18 (2.3%) in eutopic location. 97 (12.6%) patients were treated for postoperative hypocalcemia: 90 (11.7%) had transient and 5 (0.6%) definitive hypoparathyroidism; 2 were lost in follow-up. 13/30 (43.3%) with AP had transient hypoparathyroidism. A strong correlation was found (p < 0.0001) between AP and postoperative hypocalcemia. 1/30 (3.3%) patient with APs had definitive hypoparathyroidism. Transient and persistent nerve palsies were found in 10 (1.3%) and 3 (0.4%) patients, respectively. DISCUSSION: A careful examination of the thyroid gland after resection help to identify an AP that could be autotransplanted. Surgeon and hospital activity volume per years seem to reduce the risk of hypoparathyroidism. CONCLUSION: Total thyroidectomy and intrathyroid localization of parathyroid glands are risk factors for the AP. The incidence of AP was 2.3%, and this remains low due to our longstanding experience in thyroid and parathyroid surgery.

Low serum iPTH at the end of surgery is the earliest predictor of postoperative hypocalcemia after total thyroidectomy.

BACKGROUND: The most frequent complication of total thyroidectomy remains hypocalcemia due to low postoperative levels of serum intact parathyroid hormone (iPTH). The purpose of this study was to investigate the role of decreased iPTH at the end of surgery in predicting hypocalcemia. In addition, we examined the percentage decrease of iPTH as potential indicator of hypocalcemia. METHODS: We retrospectively collected the data of patients who underwent total thyroidectomy for benign and malignant diseases at our institution between 2010 and 2022. The iPTH level was measured before and at the end of surgery, and serum calcium levels on the first postoperative day. Demographic, clinical, and biochemical characteristics of patients with low iPTH were compared with patients with normal iPTH levels using ANOVA for continuous variables and χ2-tests for categorical variables. Multivariable logistic regression analysis evaluated the association of iPTH at the end of surgery and the relative reduction of iPTH with postoperative hypocalcemia. RESULTS: The mean age of the 607 patients in this study was 55.6 years, and the female-to-male ratio was 5:1. Goiter was the most common indication for surgery (N = 382, 62.9%), followed by Graves' disease (N = 135, 22.2%). The mean preoperative iPTH was 49.0 pg/ml, while the mean postoperative iPTH was 29.3 pg/ml. A total of 197 patients (32.5%) had an iPTH level below normal, 77 patients (39%), had iPTH levels of 10-15.0 pg/ml and 120 patients (61%) of < 10.0 pg/ml at the end of surgery. Among all patients, 124 (20.4%) developed hypocalcemia on the first postoperative day. The mean percentage of decrease of iPTH was highest among patients with iPTH < 10 pg/ml (76.9%, p < 0.01); this group of patients had also the highest rate of postoperative hypocalcemia on day one (45.0% vs. 26.0% vs 12.2%, p < 0.01). CONCLUSIONS: Measurement of iPTH at the end of total thyroidectomy predicts patients who are at risk for postoperative hypocalcemia. The combination of low serum iPTH with a decrease in iPTH level of ≥ 50% may improve prediction of hypocalcemia compared to iPTH levels alone allowing for early calcium substitution in these patients at high risk of developing postoperative hypocalcemia.