Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop.

The last international guidelines on the evaluation and management of primary hyperparathyroidism (PHPT) were published in 2014. Research since that time has led to new insights into epidemiology, pathophysiology, diagnosis, measurements, genetics, outcomes, presentations, new imaging modalities, target and other organ systems, pregnancy, evaluation, and management. Advances in all these areas are demonstrated by the reference list in which the majority of listings were published after the last set of guidelines. It was thus, timely to convene an international group of over 50 experts to review these advances in our knowledge. Four Task Forces considered: 1. Epidemiology, Pathophysiology, and Genetics; 2. Classical and Nonclassical Features; 3. Surgical Aspects; and 4. Management. For Task Force 4 on the Management of PHPT, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology addressed surgical management of asymptomatic PHPT and non-surgical medical management of PHPT. The findings of this systematic review that applied GRADE methods to randomized trials are published as part of this series. Task Force 4 also reviewed a much larger body of new knowledge from observations studies that did not specifically fit the criteria of GRADE methodology. The full reports of these 4 Task Forces immediately follow this summary statement. Distilling the essence of all deliberations of all Task Force reports and Methodological reviews, we offer, in this summary statement, evidence-based recommendations and guidelines for the evaluation and management of PHPT. Different from the conclusions of the last workshop, these deliberations have led to revisions of renal guidelines and more evidence for the other recommendations. The accompanying papers present an in-depth discussion of topics summarized in this report. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review.

The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Surgical Aspects of Primary Hyperparathyroidism.

Parathyroidectomy (PTX) is the treatment of choice for symptomatic primary hyperparathyroidism (PHPT). It is also the treatment of choice in asymptomatic PHPT with evidence for target organ involvement. This review updates surgical aspects of PHPT and proposes the following definitions based on international expert consensus: selective PTX (and reasons for conversion to an extended procedure), bilateral neck exploration for non-localized or multigland disease, subtotal PTX, total PTX with immediate or delayed autotransplantation, and transcervical thymectomy and extended en bloc PTX for parathyroid carcinoma. The systematic literature reviews discussed covered (i) the use of intraoperative PTH (ioPTH) for localized single-gland disease and (ii) the management of low BMD after PTX. Updates based on prospective observational studies are presented concerning PTX for multigland disease and hereditary PHPT syndromes, histopathology, intraoperative adjuncts, localization techniques, perioperative management, "reoperative" surgery and volume/outcome data. Postoperative complications are few and uncommon (<3%) in centers performing over 40 PTXs per year. This review is the first global consensus about surgery in PHPT and reflects the current practice in leading endocrine surgery units worldwide. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Etiology and Diagnosis of Permanent Hypoparathyroidism after Total Thyroidectomy.

Postoperative parathyroid failure is the commonest adverse effect of total thyroidectomy, which is a widely used surgical procedure to treat both benign and malignant thyroid disorders. The present review focuses on the scientific gap and lack of data regarding the time period elapsed between the immediate postoperative period, when hypocalcemia is usually detected by the surgeon, and permanent hypoparathyroidism often seen by an endocrinologist months or years later. Parathyroid failure after thyroidectomy results from a combination of trauma, devascularization, inadvertent resection, and/or autotransplantation, all resulting in an early drop of iPTH (intact parathyroid hormone) requiring replacement therapy with calcium and calcitriol. There is very little or no role for other factors such as vitamin D deficiency, calcitonin, or magnesium. Recovery of the parathyroid function is a dynamic process evolving over months and cannot be predicted on the basis of early serum calcium and iPTH measurements; it depends on the number of parathyroid glands remaining in situ (PGRIS)-not autotransplanted nor inadvertently excised-and on early administration of full-dose replacement therapy to avoid hypocalcemia during the first days/weeks after thyroidectomy.

Recidiva local de adenomas de paratiroides como causa infrecuente de hiperparatiroidismo primario recurrente / Local relapse of parathyroid adenomas: an uncommon cause of recurrent primary hyperparathyroidism

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Muscle strength, physical performance, and metabolic changes after subtotal parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: Hyperparathyroidism in patients on chronic hemodialysis presents with bone pain, pruritus, and extra-skeletal calcifications. Little attention has been paid to low plasma protein concentrations and muscle weakness in these patients. The present study was undertaken to characterize the impact of subtotal parathyroidectomy for chronic hemodialysis on body composition, muscle strength, plasma proteins, quality of life, and long-term clinical course. METHODS: We performed a prospective observational before-after assessment study of consecutive chronic hemodialysis patients referred for parathyroidectomy. Patients were investigated at baseline before parathyroidectomy and then at 1 and 6 months after surgery, with the aim to assess changes in metabolic parameters, body composition by bioimpedance, muscle strength, and quality of life (36-items Short Form Health Survey questionnaire). Follow-up was terminated when patients reached 1 of the 3 pre-defined end points: recurrence of secondary hyperparathyroidism, transplantation, or death. RESULTS: A group of 23 patients on hemodialysis were included. Preoperative handgrip strength was diminished by 52.4 ± 17%. After parathyroidectomy, a drop of immunoreactive parathyroid hormone concentrations (1,153 vs 237 pg/mL; P < .001) was observed together with increases in plasma protein (total: 6.8 vs7.8 g/dL, s-albumin 3.7 vs 4.4 g/dL and prealbumin: 31.7 vs 35.2 mg/dL; P < .001), handgrip strength (18.3 vs 22.9 kg: P = .001) as well as an improvement in physical dimension (32.9 vs 35.6; P = .004) and vitality (32.3 vs 47.1; P = .002) domains of the 36-items Short Form Health Survey questionnaire. After10 years, one-third of the patients had died, one-third of the patients had a recurrence of secondary hyperparathyroidism, and one-third of patients had received a kidney transplant and maintained a normal parathyroid function. CONCLUSION: Subtotal parathyroidectomy improves protein metabolic markers, muscle strength, and physical performance in chronic hemodialysis patients.

Prevalence of basal ganglia and carotid artery calcifications in patients with permanent hypoparathyroidism after total thyroidectomy.

OBJECTIVE: Permanent hypoparathyroidism is an uncommon disease resulting most frequently from neck surgery. It has been associated with visceral calcifications but few studies have specifically this in patients with post-surgical hypoparathyroidism. The aim of the present study was to assess the prevalence of basal ganglia and carotid artery calcifications in patients with long-term post-thyroidectomy hypoparathyroidism compared with a control population. DESIGN: Case-control study. METHODS: A cross-sectional review comparing 29 consecutive patients with permanent postoperative hypoparathyroidism followed-up in a tertiary reference unit for Endocrine Surgery with a contemporary control group of 501 patients who had an emergency brain CT scan. Clinical variables and prevalence of basal ganglia and carotid artery calcifications were recorded. RESULTS: From a cohort of 46 patients diagnosed with permanent hypoparathyroidism, 29 were included in the study. The mean duration of disease was 9.2 ± 7 years. Age, diabetes, hypertension, smoking and dyslipidemia were similarly distributed in case and control groups. The prevalence of carotid artery and basal ganglia calcifications was 4 and 20 times more frequent in patients with permanent hypoparathyroidism, respectively. After propensity score matching of the 28 the female patients, 68 controls were matched for age and presence of cardiovascular factors. Cases showed a four-fold prevalence of basal ganglia calcifications, whereas that of carotid calcifications was similar between cases and controls. CONCLUSION: A high prevalence of basal ganglia calcifications was observed in patients with post-surgical permanent hypoparathyroidism. It remains unclear whether carotid artery calcification may also be increased.

Influence of gender and women's age on the prevalence of parathyroid failure after total thyroidectomy for multinodular goiter.

BACKGROUND: Female gender, particularly of a young age, has been reported as a risk factor for hypocalcemia after total thyroidectomy. There are no studies, however, addressing specifically the influence of women's age and menstrual status on postoperative parathyroid function. METHODS: Cohort study of consecutive patients undergoing total thyroidectomy for benign goiter between 2000-2017, excluding those with associated hyperparathyroidism, reoperation or conservative procedures. Prevalence of postoperative hypocalcemia (s-Ca <8 mg/dL at 24 hours), protracted (1-month) and permanent hypoparathyroidism (>1 year) were the main variables studied. Complete >1-year follow-up was achieved for all patients developing post-thyroidectomy hypocalcemia. Demographic, disease-related, number of parathyroid glands remaining in situ (PGRIS), biochemical and surgical variables were recorded. The impact of menstrual status on parathyroid function was analyzed by comparing two groups of women using a cut-off age of 45 years. RESULTS: A total of 811 patients were included: 14 percent were males and 86 percent females with a mean age of 53.2 years. The prevalence of postoperative hypocalcemia was ten points higher in women than in men (23.7% vs. 36.4%; P=0.008). Permanent hypoparathyroidism was more common in women than in men (5% vs. 0.9%; P=0.048). Compared to females ≥45 years, young women presented higher rates of all three parathyroid failure syndromes despite similar PGRIS scores. Age <45 years and low PGRIS scores were the only independent variables predicting postoperative hypocalcemia in females. CONCLUSIONS: Premenopausal patients presented a higher prevalence of parathyroid failure and permanent hypoparathyroidism with similar PGRIS scores suggesting the presence of a sex-hormone factor influencing post-thyroidectomy parathyroid function.

Las modas en la Cirugía General / Fashions in General Surger

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Late Recovery of Parathyroid Function after Total Thyroidectomy in Children and Adults: Is There a Difference?

BACKGROUND: Parathyroid failure after total thyroidectomy is the commonest adverse event amongst both children and adults. The phenomenon of late recovery of parathyroid function, especially in young patients with persistent hypoparathyroidism, is not well understood. This study investigated differences in rates of parathyroid recovery in children and adults and factors influencing this. METHODS: A joint dual-centre database of patients who underwent a total thyroidectomy between 1998 and 2018 was searched for patients with persistent hypoparathyroidism, defined as dependence on oral calcium and vitamin D supplementation at 6 months. Demographic, surgical, pathological, and biochemical data were collected and analysed. Parathyroid Glands Remaining in Situ (PGRIS) score was calculated. RESULTS: Out of 960 patients who had total thyroidectomy, 94 (9.8%) had persistent hypoparathyroidism at 6 months, 23 (24.5%) children with a median [range] age 10 [0-17], and 71 (75.5%) adults aged 55 [25-82] years, respectively. Both groups were comparable regarding sex, indication, extent of surgery, and PGRIS score. After a median follow-up of 20 months, the parathyroid recovery rate was identical for children and adults (11 [47.8%] vs. 34 [47.9%]; p = 0.92). Sex, extent, and indication for surgery had no effect on recovery (all p > 0.05). PGRIS score = 4 (HR = 0.48) and serum calcium >2.25 mmol/L (HR = 0.24) at 1 month were associated with a decreased risk of persistent hypoparathyroidism on multivariate analysis (p < 0.05). CONCLUSION: Almost half of patients recovered from persistent hypoparathyroidism after 6 months; therefore, the term persistent instead of permanent hypoparathyroidism should be used. Recovery rates of parathyroid function in children and adults were similar. Regardless of age, predictive factors for recovery were PGRIS score = 4 and a serum calcium >2.25 mmol/L at 1 month.

MANAGEMENT OF ENDOCRINE DISEASE: Unmet therapeutic, educational and scientific needs in parathyroid disorders.

PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed. PHPT has a high prevalence in Western communities, PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations, or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas Quality of Life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with an increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity, and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy. HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function, and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy. Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field.

Parathyroid autotransplantation in thyroid surgery.

BACKGROUND: Careful parathyroid gland dissection and in situ preservation was the time-honored approach to prevent parathyroid failure after total thyroidectomy. The relative success of parathyroid autotransplantation of hyperplastic parathyroid tissue in patients with renal or hereditary hyperparathyroidism did popularize the use of normal parathyroid tissue autografts during thyroidectomy to prevent permanent hypoparathyroidism. Proof of autograft function in this setting, however, is controversial. PURPOSE: This narrative review aims at reviewing critically the current status of parathyroid autotransplantation during total thyroidectomy. It is also meant to analyze from the historical, methodological, and clinical points of view the claimed benefit of normal parathyroid gland autotransplantation. A focus is placed on the prevention of permanent hypoparathyroidism by parathyroid autotransplantation. CONCLUSIONS: Liberal parathyroid autotransplantation was proposed in the mid 1970s but evidence of function is scarce. Proofs are accumulating that parathyroid autografts not only increase the rate of postoperative hypocalcemia, but may be also contribute to permanent hypoparathyroidism.

Time to parathyroid function recovery in patients with protracted hypoparathyroidism after total thyroidectomy.

OBJECTIVE: Hypocalcaemia is the most common adverse effect after total thyroidectomy. It recovers in about two-thirds of the patients within the first postoperative month. Little is known, however, about recovery of the parathyroid function (RPF) after this time period. The aim of the present study was to investigate the time to RPF in patients with protracted (>1 month) hypoparathyroidism after total thyroidectomy. DESIGN: Cohort prospective observational study. METHODS: Adult patients undergoing total thyroidectomy for goitre or thyroid cancer. Cases with protracted hypoparathyroidism were studied for RPF during the following months. Time to RPF and variables associated with RPF or permanent hypoparathyroidism were recorded. RESULTS: Out of 854 patients undergoing total thyroidectomy, 142 developed protracted hypoparathyroidism. Of these, 36 (4.2% of the entire cohort) developed permanent hypoparathyroidism and 106 recovered: 73 before 6 months, 21 within 6-12 months and 12 after 1 year follow-up. Variables significantly associated with RPF were the number of parathyroid glands remaining in situ (not autografted nor inadvertently resected) and a serum calcium concentration >2.25 mmol/L at one postoperative month. Late RPF (>6 months) was associated with surgery for thyroid cancer. RPF was still possible after one year in patients with four parathyroid glands preserved in situ and serum calcium concentration at one month >2.25 mmol/L. CONCLUSIONS: Permanent hypoparathyroidism should not be diagnosed in patients requiring replacement therapy for more than six months, especially if the four parathyroid glands were preserved.

Short and Long-Term Outcomes After Surgical Procedures Lasting for More Than Six Hours.

Long-term all-cause mortality and dependency after complex surgical procedures have not been assessed in the framework of value-based medicine. The aim of this study was to investigate the postoperative and long-term outcomes after surgical procedures lasting for more than six hours. Retrospective cohort study of patients undergoing a first elective complex surgical procedure between 2004 and 2013. Heart and transplant surgery was excluded. Mortality and dependency from the healthcare system were selected as outcome variables. Gender, age, ASA, creatinine, albumin kinetics, complications, benign vs malignant underlying condition, number of drugs at discharge, and admission and length of stay in the ICU were recorded as predictive variables. Some 620 adult patients were included in the study. Postoperative, <1year and <5years cumulative mortality was 6.8%, 17.6% and 45%, respectively. Of patients discharged from hospital after surgery, 76% remained dependent on the healthcare system. In multivariate analysis for postoperative, <1year and <5years mortality, postoperative albumin concentration, ASA score and an ICU stay >7days, were the most significant independent predictive variables. Prolonged surgery carries a significant short and long-term mortality and disability. These data may contribute to more informed decisions taken concerning major surgery in the framework of value-based medicine.

Failure of fragmented parathyroid gland autotransplantation to prevent permanent hypoparathyroidism after total thyroidectomy.

PURPOSE: Parathyroid autotransplantation during total thyroidectomy leads to higher rates of postoperative hypocalcaemia. It has been argued, however, that it prevents permanent hypoparathyroidism. The impact of autografted normal parathyroid gland fragments on long-term parathyroid status has not been assessed properly. To clarify this, the short- and long-term parathyroid function was assessed in patients with three glands remaining in situ after total thyroidectomy, in whom the fourth gland was either autotransplanted (Tx) or accidentally resected (AR). METHODS: Consecutive patients (n = 669) undergoing first-time total thyroidectomy were prospectively studied recording the number of parathyroid glands remaining in situ: PGRIS =4-(glands autografted + glands in the specimen). The study was focused on the subgroup of 186 patients with three parathyroid glands remaining in situ as a result of either accidental resection (AR, n = 76) or autotransplantation into the sternocleidomastoid muscle (Tx, n = 110). Prevalence of postoperative hypocalcaemia, protracted, and permanent hypoparathyroidism were compared between the two groups. Demographic, disease-related, laboratory, and surgical variables were recorded. All patients were followed for at least 1 year. RESULTS: Both groups were comparable in terms of disease and extent of surgery. Mean postoperative serum calcium was the same (AR: 1.97 ± 0.2 vs Tx: 1.97 ± 0.22 mmol/L). Rates of protracted (AR: 24% vs Tx: 25.5%) and permanent hypoparathyroidism (AR: 5.3% vs Tx: 7.3%) were similar in both groups. CONCLUSIONS: The prevalence of parathyroid failure syndromes after total thyroidectomy was similar whether a parathyroid gland was inadvertently excised or autotransplanted. Autotransplantation did not influence the permanent hypoparathyroidism rate.

Clinical profile and long-term follow-up of 32 patients with postoperative permanent hypoparathyroidism.

BACKGROUND: Parathyroid failure is the most common complication after total thyroidectomy but permanent impairment of the parathyroid function is unusual. Limited data is available assessing long-term follow-up, quality of life and complications occurring in patients with permanent hypoparathyroidism (PH). We aimed to assess the incidence of complications derived from PH status, their influence on the quality of life perceived by PH patients and its relation to standard medical treatment with calcium salts and active vitamin D analogues. METHODS: Cross-sectional observational study of consecutive patients undergoing total thyroidectomy who developed PH and were followed at least twice a year at a referral endocrine surgery unit. PH was defined as intact parathyroid hormone (iPTH) levels <13 pg/mL and the need for replacement therapy with calcium and/or vitamin D for at least 1 year after surgery. Quality of life was assessed using the SF-36 questionnaire. Data regarding doses and type of vitamin D analogues and calcium supplementation, serum calcium fluctuations, bone densitometry and renal ultrasound were recorded. RESULTS: The cohort included 32 patients (3 male/29 female) with a mean age of 51.2±15.2 years. The mean follow-up was 78±68 months and the total follow-up length was 70,080 PH patient/days. Five (15.6%) patients showed a decreased renal function. At least one clinical adverse event was observed in 18 (56.3%) patients. There was a slight decrease of the punctuation in the SF-36 questionnaire for the perceived quality of life that was only significant for the emotional role. CONCLUSIONS: PH and its treatment carry a mild to moderate burden of illness if followed closely. During a mean follow-up of nearly 6 years, only half of the patients suffered a relevant clinical event with little impact on their quality of life.

A nomogram to predict the likelihood of permanent hypoparathyroidism after total thyroidectomy based on delayed serum calcium and iPTH measurements.

BACKGROUND: Retrospective studies have shown that delayed high-normal serum calcium and detectable iPTH are independent variables positively influencing outcome of prolonged parathyroid failure after total thyroidectomy (TT). The aim of the present study was to examine prospectively the ability of these two variables to predict permanent hypoparathyroidism in patients under replacement therapy for postoperative hypocalcemia. METHODS: Prospective observational multicenter study of patients undergoing TT followed by postoperative parathyroid failure (serum calcium <8 mg/dL within 24 h and PTH <15 pg/mL 4 h after surgery). Serum calcium, vitamin D and iPTH were determined before thyroidectomy, 24 h after surgery, at 1 month and then periodically until recovery of the parathyroid function or permanent hypoparathyroidism was diagnosed after at least 1 year follow-up. RESULTS: Some 145 patients with postoperative hypocalcemia were investigated [s-Ca24h 7.5 (0.5) mg/dL]. Hypocalcemia recovered within 30 days in 91 (63%) patients and 54 (37%) developed protracted hypoparathyroidism {iPTH 5.8 [4] pg/mL at 1 month}, of whom 32 recovered within 1 year and 22 developed permanent hypoparathyroidism. Protracted hypoparathyroidism was related to few parathyroid glands remaining in situ (PGRIS). Serum calcium concentration (mg/dL) at 1 postoperative month correlated positively with the rate of recovery (percent) from protracted hypoparathyroidism: <8.5 (20%); 8.5-9 (29%); 9.1-9.5 (70%); 9.6-10 (89%); >10 (83%) (P=0.013). Serum iPTH at 1 month was also higher (7.3 vs. 3.7 pg/mL; P=0.002) in recovered protracted hypoparathyroidism. The combination of both variables predicts the likelihood of recovery of the parathyroid function with >90% accuracy. CONCLUSIONS: High-normal serum calcium and low but detectable iPTH concentrations at 1 month after TT were associated with better outcome of protracted hypoparathyroidism. A nomogram combining both variables may guide medical treatment and monitoring of post-thyroidectomy prolonged hypoparathyroidism.