ABSTRACT

Aim:

Parathyroidectomy causes significant changes in mineral metabolism in patients with primary hyperparathyroidism (PHPT). Hypomagnesemia may be seen after parathyroidectomy with unknown mechanisms. Our study aimed to evaluate the severity of hypomagnesemia and its correlation with clinical and biochemical variables after the surgery.

Materials and Methods:

A retrospective study was conducted in the patients with parathyroidectomy for PHPT between January 2017 and December 2020 in a single tertiary hospital. All consecutive patients with preoperative and postoperative magnesium levels (n=80) were included. Patients were divided into two groups according to the postoperative first-day serum magnesium levels: patients whose serum magnesium was <1.9 mg/dL (group HypoMg) and patients whose serum magnesium was ≥1.9 mg/dL (group NorMg). Demographic and clinical parameters and biochemical findings were recorded. The incidence of postoperative hypomagnesemia was the primary outcome.

Results:

The mean age was 56.7±12.2 years. The female to male ratio was 3.21. There were 31 (38.8%) and 49 patients (61.2%) in group HypoMg and group NorMg, respectively. The groups were similar considering demographic and clinical parameters (p>0.05). There were no significant differences in the preoperative serum calcium, adjusted calcium, and parathyroid hormone levels between the groups (p>0.05). Preoperative magnesium levels were significantly lower in the HypoMg group (p<0.001). Postoperative serum magnesium levels were positively correlated with preoperative serum magnesium levels (r=0.719, p<0.001).

Conclusion:

Postoperative hypomagnesemia may be seen after parathyroidectomy. It was significantly correlated with preoperative hypomagnesemia.

INTRODUCTION

Primary hyperparathyroidism (PHPT) is a common endocrine disease. It occurs most commonly due to one or more autonomously functioning parathyroid adenomas. Parathyroid hyperplasia and rarely parathyroid carcinoma are other underlying pathologies for PHPT^1-3. Hypercalcemia and high or inappropriately normal parathyroid hormone (PTH) levels are the major diagnostic criteria for the disease. Parathyroidectomy is regarded as the only opportunity for a definitive cure for PHPT². The rapid decline in serum PTH and normalization or lowering of serum calcium following parathyroidectomy cause significant metabolic changes in the bone and mineral metabolism².

As the second most abundant intracellular cation and the fourth most abundant cation of the body, the metabolism of magnesium is directly related to that of calcium^2,4. It is generally known that there is a positive correlation between calcium and magnesium levels⁵. Considering the possible pathophysiological mechanisms between magnesium, calcium, and PTH, it has been reported that magnesium levels regulate PTH secretion and induces an end-organ resistance to PTH^6-8. Previous studies have shown that postoperative hypomagnesemia is linked to the onset of clinically relevant hypocalcemia following thyroidectomy^5,7-9. In several case reports, it has also been mentioned that severe hypomagnesemia could be seen following parathyroidectomy for PHPT^10-12. It seems very difficult to prove the exact mechanisms between serum magnesium and calcium levels in these patients^4,12.

Although there is no current guideline reporting serum magnesium measurements before and after parathyroidectomy, there may be a close relationship between postoperative serum levels of magnesium and calcium in PHPT patients after the surgery². So, the influence of parathyroidectomy on serum magnesium levels in PHPT patients remains controversial. We hypothesized that there might be some degree of correlation between serum magnesium, calcium, and PTH levels in PHPT patients following parathyroidectomy.

This study aimed to investigate the possible relationships between preoperative and postoperative serum magnesium levels and parathyroidectomy.

GİRİŞ

Primer hiperparatiroidizm (PHPT) yaygın bir endokrin hastalıktır. En sık olarak bir veya daha fazla otonom çalışan paratiroid adenomu nedeniyle oluşur. Paratiroid hiperplazisi ve nadiren paratiroid karsinomu PHPT için diğer altta yatan patolojilerdir^1-3. Hiperkalsemi ve yüksek ya da uygun olmayan normal paratiroid hormon (PTH) seviyeleri, hastalığın ana tanı kriterlerleridir. Paratiroidektomi, PHPT’nin kesin tedavisi için tek fırsat olarak kabul edilmektedir². Paratiroidektomiyi takiben serum PTH’deki hızlı düşüş ve serum kalsiyumunun normalleşmesi veya düşmesi, kemik ve mineral metabolizmasında önemli metabolik değişikliklere neden olur².

Vücutta en bol bulunan ikinci hücre içi katyon ve dördüncü en bol bulunan katyon olarak, magnezyumun metabolizması doğrudan kalsiyumunkiyle ilişkilidir^2,4. Kalsiyum ve magnezyum seviyeleri arasında pozitif bir ilişki olduğu genellikle bilinmektedir⁵. Magnezyum, kalsiyum ve PTH arasındaki olası patofizyolojik mekanizmalar göz önüne alındığında, magnezyum seviyelerinin PTH sekresyonunu düzenlediği ve PTH’ye karşı bir uç organ direncini indüklediği bildirilmiştir^6-8. Önceki çalışmalar, postoperatif hipomagnezeminin tiroidektomiyi takiben klinik olarak ilişkili hipokalseminin başlangıcı ile bağlantılı olduğunu göstermiştir^5,7-9. Birkaç vaka raporunda PHPT için paratiroidektomi sonrası ciddi hipomagnezemi görülebileceğinden de bahsedilmiştir^10-12. Bu hastalarda serum magnezyum ve kalsiyum seviyeleri arasındaki kesin mekanizmaları kanıtlamak çok zor görünmektedir^4,12.

Paratiroidektomi öncesi ve sonrası serum magnezyum ölçümlerini bildiren güncel bir kılavuz olmamasına rağmen, PHPT hastalarında ameliyat sonrası serum magnezyum ve kalsiyum seviyeleri arasında yakın bir ilişki olabilir². Bu nedenle PHPT hastalarında paratiroidektominin serum magnezyum düzeyleri üzerindeki etkisi tartışmalıdır. PHPT hastalarında paratiroidektomi sonrası serum magnezyum, kalsiyum ve PTH seviyeleri arasında bir dereceye kadar korelasyon olabileceğini varsaydık.

Bu çalışma, ameliyat öncesi ve sonrası serum magnezyum düzeyleri ile paratiroidektomi arasındaki olası ilişkileri araştırmayı amaçladı.

MATERIALS AND METHODS

Study

A retrospective study of the patients who underwent parathyroidectomy for PHPT was conducted between January 2017 and December 2020 in a single tertiary hospital. The Institutional Review Board of Bağcılar Training and Research Hospital approved the study (protocol no: 2021.01.1.05.005, date: 15.01.2021). All procedures in this study were in agreement with the Declaration of Helsinki. We applied the institutional guidelines during data collection to ensure patient privacy and confidentiality. Written consent could not be taken from the patients due to the retrospective design of the study and unanimity of data.

Patients

All consecutive patients with parathyroidectomy for PHPT were recruited using the hospital information system. Diagnostic criteria for PHPT were as follows: albumin-corrected serum calcium >10.2 mg/dL and increased or inappropriately normal plasma PTH¹. Patients with asymptomatic PHPT and simultaneous thyroidectomy were also included. The medical records of a total of 91 patients were analyzed. The patients without the measurements of preoperative and postoperative 1^st-day serum magnesium levels (n=11) were excluded. Familial PHPT and lack of medical data were regarded as the other exclusion criteria. So, 80 patients were finally evaluated in the study.

The type of surgery was determined as minimally invasive, one-sided, and two-sided parathyroidectomy at the Endocrine Surgery Board based on the preoperative imaging findings. The surgical procedures were performed by the consultant surgeons of our endocrine surgery unit.

Patients were divided into two groups according to the postoperative 1^st-day serum magnesium levels: patients whose serum magnesium was <1.9 mg/dL (group HypoMg) and patients whose serum magnesium was ≤1.9 mg/dL (group NorMg).

Variables

Demographic and clinical variables were collected using the medical records of the patients. Age, sex, history of osteoporosis, and medication use before or at the time of surgery (diuretics, proton pump inhibitors, bisphosphonates), operative details, and postoperative pathological diagnosis adenoma or double adenoma were recorded. Laboratory investigations included serum calcium and magnesium, serum adjusted calcium, PTH, and estimated glomerular filtration rate (eGFR) both preoperatively and on the postoperative first day. An intact PTH assay (Abbott Architect^®, Illinois, USA) was used to measure the concentration of PTH (range 12-88 pg/mL). The EPI-CKD formula was used to calculate eGFR¹. Patients were grouped based on the serum and plasma levels of calcium, adjusted calcium, and PTH as normal or high.

Statistical Analysis

The incidence of postoperative hypomagnesemia in the study group was the primary outcome. Postoperative hypomagnesemia with demographic, clinical, and laboratory parameters and the correlation of biochemical parameters with postoperative hypomagnesemia were the secondary outcomes.

Statistical analysis was performed using a statistical package (IBM, Statistical Package for the Social Sciences software, 21.0, Chicago, IL, USA). Descriptive statistics were given as mean±standard deviation and median with interquartile range (1-3) of 25% to 75% for continuous variables depending on their distribution. Numbers and percentages were used for categorical variables. The Kolmogorov-Smirnov test checked the normality of the numerical variables. In comparing two independent groups, the Independent Samples t-test was used where numerical variables had a normal distribution. In comparing the variables before and after the surgery, the paired t-test and Wilcoxon signed rank test were used. For variables without normal distribution, the Mann-Whitney U test was applied. To compare the differences between categorical variables, the Pearson chi-square and Fisher Freeman Halton tests were used in 2x2 tables. The Spearman and Pearson correlation coefficients depending on the type of distribution were calculated to analyze the relationships between numerical variables. Statistical significance was defined as p<0.05.

RESULTS

The mean age of all patients was 56.7±12.2 years. There were 19 (23.8%) male and 61 female patients (76.3%). There were 31 (38.8%) and 49 patients (61.2%) in group HypoMg and group NorMg. The groups were similar considering age and sex distribution (Table 1).

There were no significant associations between the postoperative hypomagnesemia and the incidence of osteoporosis and history of medications (diuretics, proton pump inhibitors, and bisphosphonates) between the groups (p>0.05).

The different types of parathyroidectomy showed almost equal distribution. Thyroidectomy was performed in 23 patients (28.8%). The types of parathyroidectomy and the incidence of coexisting thyroidectomy revealed no significant differences between the groups (Table 1).

In Table 2, the results of the preoperative biochemical investigations are given. The groups were similar regarding preoperative serum calcium, adjusted calcium, and PTH levels. The preoperative serum levels of magnesium were 1.76±0.26 mg/dL in the HypoMg group and 2.13±0.26 mg/dL in the NorMg group. The difference was statistically significant (p<0.001). The incidence of the patients with low preoperative serum magnesium was significantly higher in the HypoMg group (p<0.001).

Considering the postoperative biochemical investigations, there were no significant differences in postoperative serum calcium, adjusted calcium, and PTH levels (Table 3). In 11 patients (13.75%), we detected low adjusted serum calcium levels. Postoperative magnesium levels were 1.7±0.2 mg/dL and 2.1±0.1 mg/dL in the HypoMg and NorMg groups (p<0.001).

Preoperative serum adjusted calcium, PTH, and magnesium levels reduced significantly after parathyroidectomy (p<0.0001, p<0.001, and p=0.009, respectively) (Table 4). The percentage of the reduction in serum magnesium levels in patients with osteoporosis [-2.7% (-6.1-2.1)] was not significantly different from the changes in patients without osteoporosis [-5.1 (-8.6-1.9)] (p=0.159).

Postoperative serum magnesium levels were positively correlated with preoperative serum magnesium levels (r=0.719, p<0.001) (Figure 1). Other parameters showed no significant correlations (Table 5).

DISCUSSION

This retrospective study showed that postoperative hypomagnesemia was significantly associated with preoperative hypomagnesemia. We found a significant positive correlation between preoperative and postoperative magnesium levels. We could not find any demographic, clinical, and laboratory variables predicting postoperative hypomagnesemia except for low preoperative serum magnesium levels. The absence of any correlation between calcium, PTH, and magnesium levels in patients who underwent parathyroidectomy was another striking finding in this study.

Several pathophysiological mechanisms are proposed to develop hypomagnesemia, including impaired intestinal absorption, increased gastrointestinal losses, or disturbances in renal magnesium handling^2,4. Bowel preparation, blood transfusions, administration of catecholamines, and extracellular volume expansion are regarded as the other contributing mechanisms for hypomagnesemia². We thought these contributing factors, except for a rapid decline in PTH and normalization or lowering of serum calcium levels after parathyroid surgery, are unlikely. So, postoperative hypomagnesemia might be directly related to postoperative PTH and calcium metabolism.

A highly significant negative correlation between serum calcium and magnesium levels in patients with PHPT was reported in a limited number of older studies^13,14. Nevertheless, the association of serum magnesium, serum calcium, and PTH has been analyzed in patients with secondary hyperparathyroidism^4,6,15,16. Fang et al.⁴ studied the effect of PTH on serum magnesium levels in hemodialysis patients with secondary hyperparathyroidism. They found that hypermagnesemia was seen in 44% of the patients preoperatively, and there were significant decreases in serum magnesium levels immediately after the surgery. The severity was minimal at the first day, and gradually restored from the third day. Similar changes have been reported in patients with PHPT after parathyroidectomy^14,16. They concluded that PTH might influence magnesium metabolism. Although magnesium is essential for PTH synthesis and release, it has also been mentioned that PTH increases gastrointestinal absorption and bone resorption of magnesium, leading to an increase in serum levels of magnesium⁴. In this study, we did not find significant correlations between calcium, PTH, and magnesium. So, we have difficulty showing a possible association between hypomagnesemia and a rapid decrease in PTH levels after parathyroidectomy, which necessitates prospective large-scale studies.

Novodvorsky et al.² reported that a combination of hungry bone syndrome and hypoparathyroidism was the leading cause of early postoperative hypomagnesemia following parathyroidectomy. They found a rate of 7.1% for postoperative hypocalcemia in their parathyroidectomy series. There might be a shift of calcium and magnesium into the bones in these patients, which is the pathophysiological mechanism of the hungry bone syndrome². In our study, low postoperative levels of adjusted calcium were seen in 13.75% of the cases without any clinical symptoms and signs of hypocalcemia. Contrary to Novodvorsky et al.² study, we could not detect a significant difference in the postoperative serum calcium levels depending on the postoperative magnesium levels.

Previous studies have commented that postoperative hypomagnesemia is associated with generalized bone disease^8,11,14. King and Stanbury¹⁴ reported that significant decreases in serum magnesium levels after parathyroidectomy were common. Besides, it was shown that it was sustained only in those with bone diseases and associated with prolonged postoperative hypocalcemia. Due to the retrospective design, we did not evaluate bone diseases in the study group. Investigation of severe bone diseases in PHPT patients may help to understand the pathophysiology of hypomagnesemia.

Study Limitations

Retrospective design and lack of postoperative follow-up period were the major limitations of this study. We analyzed a single magnesium measurement taken on the first postoperative day. So, we could not contribute to trends in the postoperative magnesium levels. Due to the absence of preoperative or postoperative serum magnesium levels in some of our excluded cases, a selection bias might occur. We did not investigate these laboratory changes with clinical signs and symptoms of hypocalcemia and hypomagnesemia. Investigation of the clinical presentation of hypomagnesemia in these patients may help to increase the reliability of our results.

TARTIŞMA

Bu retrospektif çalışma, postoperatif hipomagnezemi ile preoperatif hipomagnezemi arasında anlamlı bir ilişki olduğunu göstermiştir. Ameliyat öncesi ve ameliyat sonrası magnezyum seviyeleri arasında anlamlı bir pozitif korelasyon bulduk. Düşük preoperatif serum magnezyum düzeyleri dışında postoperatif hipomagnezemiyi öngören herhangi bir demografik, klinik ve laboratuvar değişkeni bulamadık. Paratiroidektomi yapılan hastalarda kalsiyum, PTH ve magnezyum düzeyleri arasında korelasyon olmaması bu çalışmada dikkat çeken bir diğer bulgudur.

Bozulmuş intestinal absorpsiyon, artmış gastrointestinal kayıplar veya renal magnezyum kullanımındaki bozukluklar dahil olmak üzere hipomagnezemi geliştirmek için, çeşitli patofizyolojik mekanizmalar ileri sürülmektedir^2,4. Bağırsak hazırlığı, kan transfüzyonları, katekolaminlerin uygulanması ve hücre dışı hacim artışı, hipomagnezemi için katkıda bulunan diğer mekanizmalar olarak kabul edilmektedirler². Paratiroid cerrahisinden sonra PTH’de hızlı bir düşüş ve serum kalsiyum düzeylerinin normalleşmesi veya düşürülmesi dışında, bu katkıda bulunan faktörlerin olası olmadığını düşündük. Dolayısıyla postoperatif hipomagnezemi, postoperatif PTH ve kalsiyum metabolizması ile doğrudan ilişkili olabilir.

Sınırlı sayıdaki eski çalışmalarda, PHPT’li hastalarda serum kalsiyum ve magnezyum seviyeleri arasında oldukça anlamlı bir negatif korelasyon olduğu rapor edilmiştir^13,14. Bununla birlikte, sekonder hiperparatiroidizmi olan hastalarda serum magnezyum, serum kalsiyum ve PTH arasındaki ilişki analiz edilmiştir^4,6,15,16. Fang ve ark.⁴, sekonder hiperparatiroidizmi olan hemodiyaliz hastalarında PTH’nin serum magnezyum seviyeleri üzerindeki etkisini incelediler. Ameliyat öncesi hastaların %44’ünde hipermagnezemi görüldüğünü ve ameliyattan hemen sonra serum magnezyum seviyelerinde önemli düşüşler olduğunu bulmuşlardır. Şiddeti ilk gün minimaldi ve üçüncü günden itibaren kademeli olarak düzeldi. Paratiroidektomiden sonra PHPT’li hastalarda da benzer değişiklikler bildirilmiştir^14,16. PTH’nin magnezyum metabolizmasını etkileyebileceği sonucuna varmışlardır. Magnezyum PTH sentezi ve salınımı için gerekli olmasına rağmen, PTH’nin magnezyumun gastrointestinal absorpsiyonunu ve kemik rezorpsiyonunu arttırdığından, serum magnezyum seviyelerinde bir artışa yol açtığından da bahsedilmiştir⁴. Bu çalışmada kalsiyum, PTH ve magnezyum arasında anlamlı ilişkiler bulamadık. Bu nedenle hipomagnezemi ile paratiroidektomi sonrası PTH düzeylerindeki hızlı düşüş arasında olası bir ilişkiyi göstermekte güçlük çekiyoruz, bu da prospektif büyük ölçekli çalışmaları gerekli kılıyor.

Novodvorsky ve ark.² paratiroidektomiyi takiben erken postoperatif hipomagnezeminin önde gelen nedeninin aç kemik sendromu ve hipoparatiroidizm kombinasyonu olduğunu bildirmişlerdir. Paratiroidektomi serilerinde postoperatif hipokalsemi oranını %7,1 olarak buldular. Bu hastalarda aç kemik sendromunun patofizyolojik mekanizması olan, kalsiyum ve magnezyumun kemiklere geçişi olabilir². Çalışmamızda, hipokalsemiye ait herhangi bir klinik semptom ve bulgu olmaksızın olguların %13,75’inde düşük postoperatif ayarlanmış kalsiyum seviyeleri görülmüştür. Novodvorsky’nin çalışmasının² aksine, postoperatif magnezyum seviyelerine bağlı olarak postoperatif serum kalsiyum seviyelerinde anlamlı bir farklılık tespit edemedik.

Önceki çalışmalarda postoperatif hipomagnezeminin jeneralize kemik hastalığı ile ilişkili olduğu yorumlanmıştır^8,11,14. King ve Stanbury¹⁴ paratiroidektomi sonrası serum magnezyum düzeylerinde anlamlı düşüşlerin yaygın olduğunu bildirmişlerdir. Ayrıca sadece kemik hastalığı olanlarda devam ettiği ve postoperatif uzamış hipokalsemi ile ilişkili olduğu gösterilmiştir. Çalışmamızın retrospektif dizaynı nedeniyle çalışma grubunda kemik hastalıklarını değerlendirmedik. PHPT hastalarında ciddi kemik hastalıklarının araştırılması hipomagnezemi patofizyolojisinin anlaşılmasına yardımcı olabilir.

Çalışmanın Kısıtlılıkları

Retrospektif dizaynı ve postoperatif takip süresinin olmaması bu çalışmanın en önemli kısıtlılıklarıydı. Ameliyat sonrası ilk gün alınan tek bir magnezyum ölçümünü analiz ettik. Dolayısıyla ameliyat sonrası magnezyum seviyelerindeki eğilimlere katkıda bulunamadık. Hariç tutulan vakalarımızın bazılarında ameliyat öncesi veya sonrası serum magnezyum düzeylerinin olmaması nedeniyle, bir seçim yanlılığı meydana gelebilir. Bu laboratuvar değişikliklerini hipokalsemi ve hipomagnezeminin klinik belirti ve semptomlarıyla araştırmadık. Bu hastalarda hipomagnezeminin klinik prezentasyonunun araştırılması, sonuçlarımızın güvenilirliğini artırmaya yardımcı olabilir.

CONCLUSION

Hypomagnesemia may be seen after parathyroidectomy. It was significantly correlated with preoperative low magnesium levels. Prospective studies are needed to investigate the clinical importance of hypomagnesemia and its association with PTH and calcium metabolism.