metricas
covid
Buscar en
Endocrinología, Diabetes y Nutrición
Toda la web
Inicio Endocrinología, Diabetes y Nutrición Recovery of parathyroid function in patients with thyroid cancer treated by tota...
Información de la revista
Vol. 68. Núm. 6.
Páginas 398-407 (junio - julio 2021)
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Visitas
1628
Vol. 68. Núm. 6.
Páginas 398-407 (junio - julio 2021)
Original article
Acceso a texto completo
Recovery of parathyroid function in patients with thyroid cancer treated by total thyroidectomy: An analysis of 685 patients with hypoparathyroidism at discharge of surgery
Recuperación de la función paratiroidea en pacientes con cáncer de tiroides, tratados mediante tiroidectomía total: análisis de 685 pacientes con hipoparatiroidismo al alta de la cirugía
Visitas
1628
Juan J. Díeza,1,
Autor para correspondencia
juanjose.diez@salud.madrid.org

Corresponding author.
, Emma Andab, Julia Sastrec, Begoña Pérez-Corrald, Cristina Álvarez-Escoláe, Laura Manjónf, Miguel Pajag, Marcel Samboh, Piedad Santiago-Fernándezi, Concepción Blanco-Carreraj, Juan C. Galofrék, Elena Navarrol, Carles Zafónm, Eva Sanzm, Amelia Oleagag, Orosia Bandrésn, Sergio Donnayo, Ana Megíap, María Picalloh, Cecilia Sánchez-Ragnarssonf..., Gloria Baena-Nietoq, José Carlos Fernández-Garcíar, Beatriz Lecumberrie, Manel Sahún de la Vegas, Ana R. Romero-Lluchl, Pedro Iglesiasa,1Ver más
a Department of Endocrinology, Hospital Universitario Ramón y Cajal, Madrid, Spain
b Department of Endocrinology, Complejo Hospitalario de Navarra, Pamplona, Spain
c Department of Endocrinology, Complejo Hospitalario de Toledo, Toledo, Spain
d Department of Endocrinology, Complejo Asistencial Universitario de León, León, Spain
e Department of Endocrinology, Hospital Universitario La Paz, Madrid, Spain
f Department of Endocrinology, Hospital Universitario Central de Asturias, Oviedo, Spain
g Department of Endocrinology, Hospital Universitario de Basurto, Bilbao, Spain
h Department of Endocrinology, Hospital Universitario Gregorio Marañón, Madrid, Spain
i Department of Endocrinology, Complejo Hospitalario de Jaén, Jaén, Spain
j Department of Endocrinology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
k Department of Endocrinology, Clínica Universidad de Navarra, Pamplona, Spain
l Department of Endocrinology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
m Department of Endocrinology, Hospital Universitario Vall d’Hebron, Barcelona, Spain
n Department of Endocrinology, Hospital Royo Villanova, Zaragoza, Spain
o Department of Endocrinology, Fundación Hospital de Alcorcón, Alcorcón, Madrid, Spain
p Department of Endocrinology, Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Ciberdem, Tarragona, Spain
q Department of Endocrinology, Hospital de Jerez, Jerez de la Frontera, Cádiz, Spain
r Department of Endocrinology, Hospital Virgen de la Victoria, Málaga, Spain
s Department of Endocrinology, Hospital Moisès Broggi, Sant Joan Despí, Barcelona, Spain
Ver más
Este artículo ha recibido
Información del artículo
Resumen
Texto completo
Bibliografía
Descargar PDF
Estadísticas
Figuras (2)
Tablas (4)
Table 1. Clinical and histopathological features of 1453 patients with thyroid cancer classified according to the presence of hypoparathyroidism at discharge of surgery.
Table 2. Number and percentage of patients with recovery of parathyroid function and with hypoparathyroidism at the different stages considered in the study.
Table 3. Comparison of patients who recover parathyroid function with those who persist with hypoparathyroidism at the end of the study: A, Clinical and surgery related variables; B, variables related to thyroid cancer.
Table 4. Nonadjusted and adjusted hazard ratios (with 95% CI) for the development of recovery of parathyroid function (Cox models) in several clinical, surgery-related, and cancer-related variables.
Mostrar másMostrar menos
Abstract
Objective

We aimed to study the predictive factors for recovery of parathyroid function in hypoparathyroid patients after total thyroidectomy for thyroid cancer.

Methods

We designed a retrospective, multicentre and nation-wide analysis of patients with total thyroidectomy who were seen in twenty endocrinology departments from January to March 2018. We selected patients with histologically proven thyroid cancer and retrieved information related to surgical procedure and thyroid cancer features. Survival analysis and Cox regression analysis were used to study the relationship between these variables and the recovery of parathyroid function.

Results

From 685 patients with hypoparathyroidism at discharge of surgery, 495 (72.3%) recovered parathyroid function over time. Kaplan–Meier analysis showed that this recovery was significantly related to the presence of specialized surgical team (P<0.001), identification of parathyroid glands at surgery (P<0.001), papillary histopathology (P=0.040), and higher levels of postoperative calcium (Ca) (P<0.001) and parathyroid hormone (PTH) (P<0.001). Subjects with gross extrathyroidal extension (P=0.040), lymph node metastases (P=0.004), and surgical re-intervention after initial surgery (P=0.024) exhibited a significant risk of persistence of hypoparathyroidism. Multivariate Cox regression analysis showed that the significant and independent factors for recovery of parathyroid function were postoperative concentrations of Ca (P=0.038) and PTH (P=0.049). The presence of lymph node metastases was a negative predictor of recuperation of parathyroid function (P=0.042) in this analysis.

Conclusion

In patients with thyroid cancer, recovery of parathyroid function after total thyroidectomy was directly related to postoperative Ca and PTH concentrations, and inversely related to lymph node metastases.

Keywords:
Permanent hypoparathyroidism
Thyroid cancer
Recovery
Thyroidectomy
Resumen
Objetivo

Estudiar los factores predictivos de la recuperación de la función paratiroidea en pacientes hipoparatiroideos después de tiroidectomía total por cáncer de tiroides.

Métodos

Se diseñó un estudio nacional, retrospectivo y multicéntrico de pacientes con tiroidectomía total, que fueron seguidos en 20 servicios de endocrinología desde enero a marzo de 2018. Se seleccionaron pacientes con demostración histológica de cáncer de tiroides y datos sobre el procedimiento quirúrgico y las características tumorales. Se emplearon el análisis de supervivencia y el análisis de regresión de Cox para analizar las relaciones entre estas variables y la recuperación de la función paratiroidea.

Resultados

De un total de 685 pacientes con hipoparatiroidismo tras cirugía, 495 (72,3%) recuperaron la función paratiroidea a lo largo del tiempo. El análisis de Kaplan-Meier mostró que esta recuperación estaba significativamente relacionada con la presencia de equipo quirúrgico especializado (p < 0,001), identificación de las glándulas paratiroideas en la cirugía (p < 0,001), histología papilar (p = 0,040) y mayores concentraciones postoperatorias de calcio (Ca) (p < 0,001) y parathormona (p < 0,001). Los pacientes con extensión extratiroidea macroscópica (p = 0,040), metástasis ganglionares (p = 0,004) y reintervención tras cirugía inicial (p = 0,024) mostraron un riesgo significativo de persistencia del hipoparatiroidismo. El análisis de regresión multivariante de Cox mostró que los factores significativos e independientes para la recuperación de la función paratiroidea fueron las concentraciones postoperatorias de Ca (p = 0,038) y parathormona (p = 0,049). La presencia de metástasis ganglionares fue un predictor negativo de la recuperación de la función paratiroidea (p = 0,042) en este análisis.

Conclusión

En pacientes con cáncer de tiroides, la recuperación de la función paratiroidea tras la tiroidectomía total se relacionó de forma directa con las concentraciones postoperatorias de Ca y parathormona, e inversamente con las metástasis ganglionares linfáticas.

Palabras clave:
Hipoparatiroidismo permanente
Cáncer de tiroides
Recuperación
Tiroidectomía
Texto completo
Introduction

Parathyroid hormone (PTH) deficiency or insufficiency as a result of inadvertent injury, devascularization or removal of the parathyroid glands after cervical surgery (post-surgical hypoparathyroidism) is the most common etiology of chronic hypoparathyroidism and, therefore, of the permanent need for treatment with calcium (Ca) and calcitriol.1 In turn, total thyroidectomy due to benign thyroid disease or thyroid cancer is the most usual cause of post-surgical hypoparathyroidism.2

The prevalence of transient and permanent hypoparathyroidism after cervical surgery has been the subject of diverse surveys by several authors with remarkably variable results.3–10 Concurrently, the analysis of the risk factors for definitive hypoparathyroidism associated with thyroid surgery has also been an issue of intense research in last years.7,9–13 The recent meta-analysis by Edafe et al.10 showed the existence of biochemical (perioperative PTH, preoperative vitamin D, postoperative changes in Ca) and clinical (female sex, Graves’ disease, need for parathyroid autotransplantation, and inadvertent excision of parathyroid glands) predictors for post-thyroidectomy hypocalcemia. Our recent report showed that lymph node dissection, two-stage thyroidectomy, and the presence of parathyroid tissue in the specimen were risk factors for permanent hypoparathyroidism. Postoperative serum Ca levels and the intervention performed by a specialized surgical team appear to be protective factors for hypoparathyroidism. Surprisingly, in this study we found that the presence of thyroid cancer histology was an independent and significant protective factor for the development of chronic hypoparathyroidism.14

Therefore, to delve into this issue, in the present study we set out to investigate which variables related to surgical procedure and also related to the diverse features of thyroid cancer were predictors of the recovery of parathyroid function in patients with histologically proven thyroid carcinoma who have undergone total thyroidectomy and have been diagnosed with hypoparathyroidism at discharge of surgery.

MethodsStudy design

This study was carried out by members of the Thyroid Task Force of the Spanish Society of Endocrinology (SEEN), after receiving the approval of the board of directors of the SEEN and the ethical committee of the Hospital Universitario Ramón y Cajal (Madrid). All the details on patients and methodology have been previously described.14 Briefly, each researcher recruited all patients with total thyroidectomy who attended their outpatient clinic between January 1 and March 31, 2018. Inclusion criteria were: age>14 years at the time of thyroidectomy, availability of surgical and pathological reports, and follow-up in the same hospital for at least one year after thyroidectomy.

In every patient demographic data, details on hospital, details on surgical procedure, histopathological data, analytical data on Ca metabolism, and information on therapy with Ca and calcitriol were retrospectively collected. All investigators retrieved clinical information at various stages, i.e., at discharge from hospital after surgery, 3–6 months after surgery, 12 months after the surgery, and at last visit.

For this study we have considered two groups of variables. On one hand, clinical and surgery related variables, i.e., sex, age, specialized surgical team, lymph node dissection, type of surgery, identification of parathyroid glands by the surgeon, autotransplantation, presence of parathyroid tissue in the specimen, surgical complications and serum concentrations of Ca and PTH. The concept of specialized surgical team was used in a qualitative way, that is, the team of surgeons who usually perform most thyroidectomies in each hospital and with whom the endocrinologist participating in the study usually associates. Serum Ca and PTH levels were quantified according to standard methods used in the clinical laboratories of each participating hospital. On the other hand, we considered variables related to thyroid cancer itself, i.e., incidentally found tumor, histological type, multifocality, tumor size, extrathyroidal extension, lymph node metastases, distant metastases, radioiodine ablation, surgical re-intervention after initial surgery, neck radiotherapy, and treatment with targeted therapy.

Definitions and criteria

We considered the presence of hypoparathyroidism at discharge in patients who showed, in the immediate postoperative period, serum Ca levels<8.5mg/dl with inappropriate low PTH levels (<15pg/ml), and/or who needed treatment with Ca or calcitriol at discharge from surgery.15,16 Definitive hypoparathyroidism was diagnosed in subjects who needed treatment with Ca or calcitriol at the last visit (always with at least 12 months of follow-up). Recovery of parathyroid function was considered in patients who initially exhibited hypoparathyroidism at discharge of surgery and lastly demonstrated absence of need for Ca and calcitriol therapy at a subsequent visit.12,16

Since this is a retrospective study, analytical data (preoperative Ca, postoperative Ca and PTH) were only available in a fraction of patients. In cases where this information was available, the corrected Ca (mg/dl) was calculated as Ca (mg/dl)+0.8 (4-albumin [g/dl]), or Ca/[(total proteins (g/dl)/16)+0.55].

Statistical analysis

For quantitative variables, results are expressed as mean±SD for normally distributed data and as median (interquartile range, IQR) for nonparametric data. Adjustment to normal distribution was tested by the Kolmogorov test. Categorical variables are described as ratios or percentages. For comparisons of means between two groups of patients, the Student's t test was used for normally distributed data, and the Mann–Whitney test was used for nonparametric data. For ratio comparisons, the chi-square test or Fisher's exact test was used.

To assess the influence of putative predictive factors for the recovery of parathyroid function over time, we performed a survival analysis using the Kaplan–Meier method, with the log-rank test used to compare arms. In the survival analysis some quantitative variables were transformed into categorical of two categories dividing the patients by the median value. Univariate and stepwise multivariate Cox regression models were used to assess the independent effect of several quantitative and qualitative variables on the likelihood of development of euparathyroidism. Two-sided tests were used, and differences were considered significant when P<0.05.

ResultsStudied patients

From a cohort of 1792 patients with total thyroidectomy and follow-up longer than 12 months, we selected 1453 subject with histologically proven thyroid cancer. Mean (±SD) age of these patients was 47.9±15.0 yr, and 1131 (77.8%) were women. Histologic subtypes in these subjects were: papillary thyroid cancer in 1213 patients (83.5%), follicular or Hürthle cell carcinoma in 162 (11.1%), poorly differentiated thyroid cancer in 12 (0.8%), medullary thyroid cancer in 65 (4.5%), and other type in 1 (0.1%) patient. Median (IQR) tumor size was 1.6 (1.0–2.9) cm, lymph node metastases were present at diagnosis in 485 patients (33.4%), and distant metastases were found in 53 patients (3.7%). Median follow-up in the endocrinology clinic was 59 (27–108) months.

From this cohort of thyroid cancer patients, 768 subjects presented euparathyroidism and 685 hypoparathyroidism at discharge of surgery (Fig. 1). In 233 of these 685 patients (34.2%) the diagnostic criteria was the need for treatment with Ca or calcitriol at discharge, with no evidence of low Ca or PTH levels. Patients with hypoparathyroidism at discharge exhibited higher percentages of lymph node dissection, identification of parathyroid glands at surgery, autotransplantation, presence of parathyroid tissue in the specimen, surgical complications, papillary histopathology, multifocality of the tumor, extrathyroidal extension, lymph node metastases, and distant metastases, and lower percentages of two-stage thyroidectomy and incidentally found tumor. Serum concentrations of preoperative Ca, postoperative corrected Ca, and postoperative PTH were significantly lower in patients who developed hypoparathyroidism at discharge (Table 1).

Figure 1.

Flow chart of the investigated cohort of patient with total thyroidectomy.

(0.16MB).
Table 1.

Clinical and histopathological features of 1453 patients with thyroid cancer classified according to the presence of hypoparathyroidism at discharge of surgery.

  Euparathyroid patients at discharge (n=768)Patients with hypoparathyroidism at discharge (n=685) 
  n  Value  n  Value  P 
Sex, female  768  579 (75.4)  685  552 (80.6)  0.019 
Age, yr  758  48.7±15.0  685  47.0±14.9  0.034 
Specialized surgical team  768  663 (86.3)  685  602 (87.9)  0.390 
Lymph node dissection  767  297 (38.7)  680  435 (64.0)  <0.001 
2-Stage thyroidectomy  768  162 (21.1)  685  69 (10.1)  <0.001 
Identification of parathyroid glands  768  545 (71.0)  685  536 (78.2)  0.002 
Autotransplantation  767  42 (5.5)  685  82 (12.0)  <0.001 
Parathyroid tissue at histology  767  141 (18.4)  684  206 (30.1)  <0.001 
Surgical complications  759  59 (7.8)  681  80 (11.7)  0.012 
Incidental  753  198 (26.3)  674  97 (14.4)  <0.001 
Papillary histology  768  617 (80.3)  685  596 (87.0)  0.001 
Multifocal  766  242 (31.6)  682  246 (36.1)  0.075 
Tumor size, cm  753  1.6 (0.9–2.9)  670  1.7 (1.0–3.0)   
Extrathyroidal extension  758    667    <0.001 
None    618 (81.5)    464 (69.6)   
Microscopic    112 (14.8)    159 (23.8)   
Macroscopic    28 (3.7)    44 (6.6)   
Lymph node metastasis  767    683    <0.001 
Nx    235 (30.6)    126 (18.4)   
N0    341 (44.5)    263 (38.5)   
N1    191 (24.9)    294 (43.0)   
Distant metastasis  763  21 (2.8)  683  32 (4.7)  0.067 
Radioiodine ablation  765  630 (82.4)  685  579 (84.5)  0.289 
Preoperative Ca (mg/dl)  509  9.55±0.56  438  9.46±0.51  0.007 
Postoperative corrected Ca (mg/dl)  474  8.92  440  7.87±0.68  <0.001 
Postoperative PTH (pg/ml)  304  37 (27–51)  309  8 (3–16)  <0.001 

Data are the number of patients (percentage), mean±SD for normally distributed data and median (interquartile range) for nonparametric data. The total number of patients used to calculate the values of means, medians and percentages in each group is indicated by n.

Abbreviations: Ca, calcium; PTH, parathyroid hormone.

Recovery of parathyroid function

The time course of recovery of parathyroid function and the number of patients with hypoparathyroidism at different stages of follow-up is summarized in Table 2. As it is shown, 495 out of 685 patients (72.3%) recovered parathyroid function throughout the time of follow-up, and 190 (27.7%) were diagnosed with permanent hypoparathyroidism. We analyzed clinical and surgery related variables in these patients and found that patients who recovered parathyroid function had higher percentages of specialized surgical team, and identification of parathyroid glands, and lower percentage of surgical complication (Table 3A). Six hundred and two patients were operated on by a specialized surgical team. The percentage of parathyroid function recovery in these patients was 75.2% (453/602), while this percentage only reached 50.6% (42/83) in patients who underwent surgery by non-specialized surgeons (P<0.001). Furthermore, postoperative corrected Ca and PTH were significantly higher in subjects who recovered parathyroid function (Table 3A).

Table 2.

Number and percentage of patients with recovery of parathyroid function and with hypoparathyroidism at the different stages considered in the study.

  Time after thyroidectomy
  At discharge  3–6 months  12 months  Last visit 
Recovery of parathyroid function
No.  372  462  495 
%a  25.6  31.8  34.1 
%b  54.3  67.4  72.3 
Hypoparathyroidism at different stages
No.  685  313  223  190 
%a  47.1  21.5  15.3  13.1 
%b  100  45.7  33.0  27.7 
a

Percentage of the complete cohort of patients with thyroidectomy (n=1453).

b

Percentage of the total of patients who developed hypoparathyroidism at discharge from surgery (n=685).

Table 3.

Comparison of patients who recover parathyroid function with those who persist with hypoparathyroidism at the end of the study: A, Clinical and surgery related variables; B, variables related to thyroid cancer.

  Patients who recover parathyroid function (n=495)Non-recovery patients(n=190) 
  n  Value  n  Value  P 
A: Clinical and surgical related variables
Sex, female  495  404 (81.6)  190  148 (77.9)  0.282 
Age, yr  495  47.3±14.9  190  46.2±14.8  0.376 
Time of follow-up, mo           
Specialized surgical team  495  453 (91.5)  190  149 (78.4)  <0.001 
Lymph node dissection  490  303 (61.8)  190  132 (69.5)  0.075 
2-stage thyroidectomy  495  46 (9.3)  190  23 (12.1)  0.321 
Identification of parathyroid glands  495  410 (82.8)  190  126 (66.3)  <0.001 
Autotransplantation  495  64 (12.9)  190  18 (9.5)  0.238 
Parathyroid tissue at histology  494  139 (28.1)  190  67 (35.3)  0.077 
Surgical complications  491  50 (10.2)  190  30 (15.8)  0.047 
Postoperative corrected Ca (mg/dl)  309  7.94±0.66  131  7.69±0.69  <0.001 
Postoperative PTH (pg/ml)  214  10.2 (4.0–20)  95  5.4 (3.0–9.9)  <0.001 
B: Variables related to thyroid cancer
Incidental  487  72 (14.8)  187  25 (13.4)  0.714 
Papillary histology  495  440 (88.9)  190  156 (82.1)  0.022 
Multifocal  495  178 (36.0)  187  68 (36.4)  0.929 
Tumor size, cm  488  1.6 (1.0–2.8)  182  2.0 (1.1–3.0)  0.132 
Extrathyroidal extension  481    186    0.049 
None    336 (69.9)    128 (68.8)   
Microscopic    120 (5.2)    39 (21.0)   
Macroscopic    25 (5.2)    19 (10.2)   
Lymph node metastasis  494    189    0.004 
Nx    102 (20.6)    24 (12.7)   
N0    197 (39.9)    66 (34.9)   
N1    195 (39.5)    99 (52.4)   
Distant metastasis  494  22 (4.5)  189  10 (5.3)  0.686 
Radioiodine ablation  495  417 (84.2)  190  168 (85.3)  0.814 
Surgical re-intervention  494  61 (12.3)  190  37 (19.5)  0.021 
Neck radiotherapy  494  12 (2.4)  189  10 (5.3)  0.086 
Multitargeted kinase inhibitors therapy  493  11 (2.2)  184  9 (4.9)  0.077 

Data are the number of patients (percentage), mean±SD for normally distributed data and median (interquartile range) for nonparametric data. The total number of patients used to calculate the values of means, medians and percentages in each group is indicated by n.

Abbreviations: Ca, calcium; PTH, parathyroid hormone.

When studying variables related to thyroid cancer (Table 3B), we found that subjects who were diagnosed with definitive hypoparathyroidism had higher percentages of extrathyroidal extension, lymph node metastases, and surgical re-intervention, and a lower proportion of patients with papillary histology.

Survival analysis

We analyzed the clinical, surgery-related, and cancer-related variables that were found to be significant or near significant (P<0.10) in the comparison performed in Table 3A and B.

Surgical complications, lymph node dissection, the presence of parathyroid surgery in the specimen, neck radiotherapy, and therapy with kinase inhibitors had no influence on the time to parathyroid function recovery. However, we found that the proportion of patients who recovered parathyroid function was higher in the subgroups of patients with specialized surgical team, identification of parathyroid glands at surgery, papillary histopathology, and serum concentrations of corrected Ca and PTH above the median value (7.86mg/dl and 8.0pg/ml, respectively). On the contrary, patients who had gross extrathyroidal extension of their tumors, lymph node metastases, and those who underwent a subsequent neck surgery after the initial operation exhibited a significant lower time to recovery of parathyroid function (Fig. 2).

Figure 2.

Kaplan–Meier curves for time of follow-up up to recuperation of parathyroid function in 685 thyroid cancer patients classified according to the following factors: specialized surgical team, identification of parathyhroid glands at surgery, papillary histopathology, extrathyroidal extension, lymph node metastasis, neck re-intervention after initial surgery, postoperative corrected calcium (n=440), and postoperative PTH concentrations (n=309). Ordinate scale: proportion of patients who recover parathyroid function. Abscissa scale: time of follow-up after thyroidectomy (months).

(0.38MB).
Univariate and multivariate analysis

A stepwise Cox proportional hazards regression univariate and multivariate analysis was conducted to evaluate the relative importance of individual factors for the development of recuperation of parathyroid function (Table 4). In the univariate analysis, the probability of recover parathyroid function was significantly greater for patients with specialized surgical team, identification of parathyroid glands, corrected Ca levels>7.86mg/dl, and PTH levels>8.0pg/ml. The presence of lymph node metastases significantly increased the hazard of persisting with hypoparathyroidism.

Table 4.

Nonadjusted and adjusted hazard ratios (with 95% CI) for the development of recovery of parathyroid function (Cox models) in several clinical, surgery-related, and cancer-related variables.

  Univariate (unadjusted) analysisMultivariate (adjusted) analysisc
        Model 1Model 2
  Hazard ratio  95% CI  P  Hazard ratio  95% CI  P  Hazard ratio  95% CI  P 
Specialized surgical team
No               
Yes  1.75  1.28–2.41  0.001  1.55  1.10–2.18  0.013      N.S. 
Identification of parathyroid glands
No  1               
Yes  1.57  1.24–1.99  <0.001  1.40  1.09–1.80  0.009      N.S. 
Histopathology
Non-papillary                 
Papillary  1.24  0.94–1.65  0.129      N.S.      N.S. 
Extrathyroidal extension
No or micro                 
Macro  0.73  0.49–1.09  0.128      N.S.      N.S. 
Lymph node metastasis
Nx or N0  1      1      1     
N1  0.82  0.69–0.99  0.036  0.81  0.67–0.98  0.031  0.70  0.50–0.98  0.042 
Surgical re-intervention
No                 
Yes  0.80  0.61–1.04  0.093      N.S.    N.S.   
Postoperative correctedCaa
≤7.86mg/dl  1      –      1     
>7.86mg/dl  1.54  1.23–1.94  <0.001  –      1.44  1.02–2.02  0.038 
PostoperativePTHb
≤8.0pg/ml  1      –      1     
>8.0pg/ml  1.63  1.24–2.14  0.001  –      1.40  1.001–1.97  0.049 

Abbrteviations: CI, confidence interval; N.S., non significant; Ca, calcium; PTH, parathyroid hormone.

a

Available in 440 patients

b

Available in 309 patients

c

Two models of multivariate analysis have been used: model 1, adjusted for specialized surgical team, identification of parathyroid glands, histopathology, extrathyroidal extension, lymph node metastasis, and surgical re-intervention; model 2, adjusted for the same co-variates, and postoperative corrected Ca and postoperative PTH.

Data are the number of patients (percentage), mean±SD for normally distributed data and median (interquartile range) for nonparametric data. The total number of patients used to calculate the values of means, medians and percentages in each group is indicated by n.

Abbreviations: Ca, calcium; PTH, parathyroid hormone.

Two multivariate models were used. Model 1 did not include the analytical variables and encompassed 6 variables and 664 patients. Model 2 contained 8 variables, but only 228 patients. In model 1, the findings of the univariate analysis were retained (except for the analytical variables). In model 2, serum Ca and PTH were significant factors for recovery of parathyroid function. The presence of lymph node metastasis continued to be a significant factor for the maintenance of chronic hypoparathyroidism.

Discussion

The present results in patients with thyroid cancer treated by total thyroidectomy show that the recovery of parathyroid function is directly and independently related to the expertise of the surgical team and to the identification of the parathyroid glands at surgery and also, negatively, with the presence of lymph node metastasis. Furthermore, in a group of 228 patients we have found that higher levels of both postoperative Ca and PTH favor functional recovery over time. Our results suggest that patients with postsurgical hypoparathyroidism should be closely monitored because the recovery of parathyroid function can occur at any time during the natural course of the disease.

Although some authors recommend that the diagnosis of definitive hypoparathyroidism is made at least 6 months after surgery,1,17 our results confirm that recovery of parathyroid function in thyroid cancer patients is a dynamic process which may occur long after surgery, as stated by other authors in patients with thyroidectomy because of benign or malignant disease.13,15,18–20 Our values on the prevalence of hypoparathyroidism in the various stages of follow-up are higher than those previously reported by others.3,5–10,22 This might be accounted for by the setting were patients were recruited, that is, the endocrinology clinics, where patients with more complications or who need more intensive follow-up are cared for.

Factors influencing the recovery of parathyroid function have been studied by some investigators.7,9–11,13,20 In a group of 135 thyroid cancer patients with postoperative hypoparathyroidism, Paek et al.9 found that autotransplantation, bilateral central neck dissection, gross extrathyroidal extension and the presence of parathyroid tissue in the specimen were risk factors for transient hypoparathyroidism, but only the presence of parathyroid gland in the specimen and the early period of the surgeon's practice were significant risk factors for permanent hypoparathyroidism. However, to our knowledge, the detailed evaluation of the different features of thyroid cancer and their relationships with the recovery of parathyroid function, using multivariate analysis in a large number of subjects, is absent in the literature.

The expertise of the surgical team is a recognized protective factor for parathyroid function9,11 and our survival analysis and regression analysis (model 1) confirm this in our cohort of thyroid cancer patients. Identification of parathyroid glands at surgery and the number of parathyroid glands remaining in situ have been reported to be protective factor for permanent hypoparathyroidism.10,11,13,21 Data of the present study seem to confirm the predictive value of surgical identification of parathyroid glands (model 1), although we could not quantify the number of glands remaining in situ. It is possible that the loss of statistical significance of the specialized surgical team and identification of parathyroid glands in the model 2 of our regression analysis is due to the decrease in sample size that occurs when introducing the analytical variables in the model. Our survival analysis showed that patients with papillary thyroid cancer and those without gross extrathyroidal extension had better prognosis concerning functional recovery. However, in the stepwise Cox proportional hazards regression analysis these variables were non-significant. We are not aware of data from the literature that support or oppose these results.

Despite not having analytical data in all our thyroid cancer patients, we have been able to demonstrate that patients with postoperative concentrations of Ca and PTH above the median values exhibited a significantly better prognosis than subjects with lower values. Several researchers have shown the relationship between low Ca and PTH levels after thyroidectomy and permanent hypoparathyroidism.7,10,16,20–24 The protective influence of high-normal Ca concentrations during the first weeks after surgery has been accounted for by a parathyroid splinting effect.7 According to this hypothesis, high-normal Ca levels would allow the injured, but viable, glands to rest, which would favor their long-term recovery.26

PTH concentration after thyroidectomy is a predictor of early postoperative hypocalcemia and also has been related to recovery of parathyroid function by several researchers.6,7,11,16,21,23,24 Our results seem to suggest that a cutoff value of 8pg/ml for serum PTH at short term after surgery could be a predictor of recovery of long-term parathyroid function. This value is slightly higher than that described by other authors, ranging between 3.15 and 7pg/ml.16,23,26–28 These differences may be due to the large number of hospitals that participated in our study and the diversity of analytical methods for measuring serum PTH. However, the value of 8pg/ml is above the limit of quantification of most PTH assays currently used in clinical laboratories.29

It is assumed that lymph node dissection implies an increased risk of parathyroid injury. In patients with thyroid cancer, Lee et al.5 reported that the extent of surgery was related with postoperative hypoparathyroidism, but the influence of lymph node metastases was not assessed. Paek et al.9 found that lymph node metastases were not risk factors for permanent hypoparathyroidism. However, in our cohort, the presence of lymph node metastases was significantly related to the functional outcome of the patients.

Different mechanisms have been argued to explain the recovery of parathyroid function. A slow but steady recovery of blood flow via neovascularization occurring over the small surface area of the remaining parathyroid has been proposed.19 Medical therapy may also exert a beneficial effect. Vitamin D and calcium are known to negatively regulate parathyroid function,30 and their supplementation might result in a splinting of the parathyroid glands for a time, thus facilitating their subsequent recovery.25 It is also possible that different episodes of hypocalcemia throughout the natural history of the disease progressively stimulate the numb glands and bring on their final reactivation.

Our study is a multicenter survey of national scope and with a high sample size, which are its main strengths. The design of our analysis allows not only to provide data on the chronology of the recovery of parathyroid function, but also to shed light on the factors, related with surgery and also with cancer itself, that influence this recovery. We acknowledge several limitations such as the retrospective nature of the study, the differences in the volume of thyroid surgery, the use of different protocols for clinical assessment, diagnostic procedures, treatments and laboratory measurements, and the fact that we could not assess several variables (i.e., number of parathyroid glands remaining in situ, vitamin D status, and magnesium concentrations). It is possible that the number of patients with hypoparathyroidism at discharge is slightly overestimated, since some patients lacked Ca and PTH values. Our study cannot offer a quantitative definition of expert surgical team since it is heterogeneous in terms of participation from different hospitals. Another limitation is the loss of sample size when analyzing analytical variables (Ca and PTH), since we could not retrieve these data in all patients.

In conclusion, our study emphasizes the need for thyroid cancer patients to be operated by expert surgeons and allows the identification of profiles of patients in whom parathyroid function recovery is more likely. In some of these patients, the judicious and periodic withdrawal of calcium and vitamin D replacement could prevent the maintenance of unnecessary life-long medication.

Financial support

The present investigation has not received any financial support from public sector agencies, commercial sector or non-profit entities.

Conflict of interests

The authors declare that they have no conflict of interests.

References
[1]
L.A. Orloff, S.M. Wiseman, V.J. Bernet, T.J. Faheylll, A.R. Shaha, M.L. Shindo, et al.
American Thyroid Association statement on postoperative hypoparathyroidism: diagnosis, prevention, and management in adults.
Thyroid, 28 (2018), pp. 830-841
[2]
P. Iglesias, J.J. Díez.
Endocrine complications of surgical treatment of thyroid cancer: an update.
Exp Clin Endocrinol Diabetes, 125 (2017), pp. 497-505
[3]
A. Bergenfelz, S. Jansson, A. Kristofferson, H. Martenson, E. Reihnér, G. Wallin, et al.
Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3660 patients.
Langenbecks Arch Surg, 393 (2008), pp. 667-673
[4]
J.J. Jeong, S.W. Kang, J.S. Yun, T.Y. Sung, S.C. Lee, Y.S. Lee, et al.
Comparative study of endoscopic thyroidectomy versus conventional open thyroidectomy in papillary thyroid microcarcinoma (PTMC) patients.
J Surg Oncol, 100 (2009), pp. 477-480
[5]
Y.S. Lee, K.H. Nam, W.Y. Chung, H.S. Chang, C.S. Park.
Postoperative complications of thyroid cancer in a single center experience.
J Korean Med Sci, 25 (2010), pp. 541-545
[6]
L. Youngwirth, J. Benavidez, R. Sippel, H. Chen.
Parathyroid hormone deficiency after total thyroidectomy: incidence and time.
J Surg Res, 163 (2010), pp. 69-71
[7]
A. Sitges-Serra, S. Ruiz, M. Girvent, H. Manjón, J.P. Dueñas, J.J. Sancho.
Outcome of protracted hypoparathyroidism after total thyroidectomy.
Br J Surg, 97 (2010), pp. 1687-1695
[8]
D. Giordano, R. Valcavi, G.B. Thompson, C. Pedroni, L. Renna, P. Gradoni, et al.
Complications of central neck dissection in patients with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature.
Thyroid, 22 (2012), pp. 911-917
[9]
S.H. Paek, Y.M. Lee, S.Y. Min, S.W. Kim, K.W. Chung, Y.K. Youn.
Risk factors of hypoparathyroidism following total thyroidectomy for thyroid cancer.
World J Surg, 37 (2013), pp. 94-101
[10]
O. Edafe, R. Antakia, N. Laskar, L. Uttley, S.P. Balasubramanian.
Systematic review and meta-analysis of predictors of post-thyroidectomy hipocalcemia.
Br J Surg, 101 (2014), pp. 307-320
[11]
O. Thomusch, A. Machens, C. Sekulla, J. Ukkat, M. Brauckhoff, H. Dralle.
The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients.
Surgery, 133 (2003), pp. 180-185
[12]
I. Nawrot, A. Pragacz, K. Pragacz, W. Grzesiuk, M. Barczynski.
Total thyroidectomy is associated with increased prevalence of permanent hypoparathyroidism.
Med Sci Monit, 20 (2014), pp. 1675-1681
[13]
L. Lorente-Poch, J.J. Sancho, S. Ruiz, A. Sitges-Serra.
Importance of in situ preservation of parathyroid glands during total thyroidectomy.
Br J Surg, 102 (2015), pp. 359-367
[14]
J.J. Díez, E. Anda, J. Sastre, B. Pérez Corral, C. Álvarez-Escolá, L. Manjón, et al.
Prevalence and risk factors for hypoparathyroidism following total thyroidectomy in Spain: a multicentric and nation-wide retrospective analysis.
Endocrine, 66 (2019), pp. 405-415
[15]
B.C. Stack Jr., D.N. Bimston, D.L. Bodenner, E.M. Brett, H. Dralle, L.A. Orloff, et al.
American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism – definitions and management.
Endocr Pract, 21 (2015), pp. 674-685
[16]
M. Almquist, P. Hallgrimsson, E. Nordenström, A. Bergenfelz.
Prediction of permanent hypoparathyroidism after total thyroidectomy.
World J Surg, 38 (2014), pp. 2613-2620
[17]
M.L. Brandi, J.P. Bilezikian, D. Shoback, R. Bouillon, B.L. Clarke, R.V. Thakker, et al.
Management of hypoparathyroidism: summary statement and guidelines.
J Clin Endocrinol Metab, 101 (2016), pp. 2273-2283
[18]
L. Lorente-Poch, J.J. Sancho, J.L. Muñoz-Nova, P. Sánchez-Velázquez, A. Sitges-Serra.
Defining the syndromes of parathyroid failure after total thyroidectomy.
[19]
S.M. Kim, H.K. Kim, K.J. Kim, H.J. Chang, B.W. Kim, Y.S. Lee, et al.
Recovery from permanent hypoparathyroidism after total thyroidectomy.
Thyroid, 25 (2015), pp. 830-833
[20]
I. Villarroya-Marquina, J. Sancho, L. Lorente-Poch, L. Gallego-Otaegui, A. Sitges-Serra.
Time to parathyroid function recovery in patients with protracted hypoparathyroidism after total thyroidectomy.
Eur J Endocrinol, 178 (2018), pp. 103-111
[21]
A. Sitges-Serra, J. Gómez, M. Barczynski, L. Lorente-Poch, M. Iacobone, J. Sancho.
A nomogram to predict the likelihood of permanent hypoparathyroidism after total thyroidectomy based on delayed serum calcium and iPTH measurements.
Gland Surg, 6 (2017), pp. S11-S19
[22]
K. Ritter, D. Elfenbein, D.F. Schneider, D.F. Schneider, H. Chen, R.S. Sippel.
Hypoparathyroidism after total thyroidectomy: incidence and resolution.
J Surg Res, 197 (2015), pp. 348-353
[23]
M. Hermann, J. Ott, R. Promberger, F. Kober, M. Karik, M. Freissmuth.
Kinetics of serum parathyroid hormone during and after thyroid surgery.
Br J Surg, 95 (2008), pp. 1480-1487
[24]
B.H. Lang, P.C. Yih, K.K. Ng.
A prospective evaluation of quick intraoperative parathyroid hormone assay at the time of skin closure in predicting clinically relevant hypocalcemia after thyroidectomy.
World J Surg, 36 (2012), pp. 1300-1306
[25]
A. Sitges-Serra.
The PGRIS and parathyroid splinting concepts for the analysis and prognosis of protracted hypoparathyroidism.
Gland Surg, 6 (2017), pp. S86-S93
[26]
M.T. Julián, J.M. Balibrea, M.L. Granada, P. Moreno, A. Alastrué, M. Puig-Domingo, et al.
Intact parathyroid hormone measurement at 24hours after thyroid surgery as predictor of parathyroid function at long term.
Am J Surg, 206 (2013), pp. 783-789
[27]
J.B. Wang, H.L. Sun, C.Y. Song, L. Gao.
Association between decreased serum parathyroid hormone after total thyroidectomy and persistent hypoparathyroidism.
Med Sci Monit, 21 (2015), pp. 1223-1231
[28]
W. Wang, F. Xia, C. Meng, Z. Zhang, N. Bai, X. Li.
Prediction of permanent hypoparathyroidism by parathyroid hormone and serum calcium 24h after thyroidectomy.
Am J Otolaryngol, 39 (2018), pp. 746-750
[29]
S.L. La’ulu, W.L. Roberts.
Performance characteristics of six intact parathyroid hormone assays.
Am J Clin Pathol, 134 (2010), pp. 930-938
[30]
L.K. Cantley, J. Russell, D. Lettieri, L.M. Sherwood.
1,25-Dihydroxyvitamin D3 suppresses parathyroid hormone secretion from bovine parathyroid cells in tissue culture.
Endocrinology, 117 (1985), pp. 2114-2119

Present address: Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Madrid, Spain.

Copyright © 2020. SEEN y SED
Descargar PDF
Opciones de artículo
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos