Hypocalcemia after parathyroidectomy in patients with a history of bariatric surgery

A growing body of literature has suggested that a history of bariatric surgery increases the risk of hypocalcemia after subsequent thyroidectomy, however little is known about the risk after parathyroidectomy. The purpose of this study was to determine the incidence of hypocalcemia after parathyroidectomy in patients with prior bariatric surgery. The TriNetX Research Network was queried using diagnosis and procedure codes to identify patients with a history of bariatric surgery who were subsequently diagnosed with primary hyperparathyroidism (PHP) and underwent parathyroidectomy between 2012 and 2022. The rate of hypocalcemia after parathyroidectomy was compared between those with a history of bariatric surgery and controls who underwent parathyroidectomy alone, matched for demographics, body mass index (BMI) ≥ 30 kg/m2, and history of calcium or vitamin D supplementation. There were 34,483 included patients diagnosed with PHP who underwent parathyroidectomy. Of this cohort, 1.4% (n = 472) had prior bariatric surgery. There were 90% females and 10% males in this subset of patients, and the average age was 58 years. Compared to matched controls who underwent parathyroidectomy alone, these patients had a significantly increased risk of hypocalcemia within 0–1 month (RR, 95% CI, P) (17.2% vs. 9.3%; 1.8, 1.3–2.6, P < 0.001), 1–6 months (8.5% vs. 2.5%; 3.3, 1.8–6.3, P < 0.001) and 6–12 months (6.8% vs. 2.3%; 2.9, 1.5–5.7, P < 0.001) following surgery. The current study is the first to indicate that patients with a history of bariatric surgery are at increased risk for short-term and permanent hypocalcemia after parathyroidectomy. Further research is required to determine optimal prevention and treatment strategies to decrease associated morbidity in this subset of patients.


Introduction
Obesity is associated with significant morbidity and mortality [1], and its prevalence continues to rise worldwide [2]. Bariatric surgery, which includes Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), gastric band (GB), and biliopancreatic diversion with duodenal switch (BPD), is performed on patients with morbid obesity when diet and exercise haven't succeeded or when a patient encounters serious health problems because of their weight [3,4]. Unfortunately, the malabsorptive and restrictive mechanisms by which these procedures contribute to weight loss are also responsible for some of their complications, which include vitamin D deficiency, hypocalcemia, and secondary hyperparathyroidism [5][6][7].
The number of bariatric operations being performed is increasing [8]. There are reports of patients who are postbariatric surgery going on to develop endocrine abnormalities of the thyroid and parathyroid glands, including primary hyperparathyroidism (PHP) [9][10][11][12][13][14]. Although there is a growing body of literature supporting that patients with a history of bariatric surgery who undergo subsequent thyroidectomy are at increased risk for hypocalcemia [15][16][17], hypocalcemia after parathyroidectomy is not well-studied. Therefore, this research aimed to utilize an extensive database to determine the risk of hypocalcemia after parathyroidectomy in patients with a history of bariatric surgery.

Materials and methods
Data was collected on September 17, 2022, from the Tri-NetX Research Network (Cambridge, MA), which included electronic medical records from over 100 million individuals and more than 50 healthcare organizations (HCOs). The TriNetX Research Network provides users with uniformly processed clinical data, including demographics, diagnoses, imaging, lab results, medications, procedures, and other interventions [18]. TriNetX complies with the Health Insurance Portability and Accountability Act (HIPAA). Any data displayed on the TriNetX platform in aggregate form, or any patient-level data provided in a data set generated by the TriNetX platform, only contains deidentified data as per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The Penn State Institutional Review Board reviewed and approved STUDY00018629 as exempt according to institutional policies and applicable federal regulations.
The database was queried using ICD-10 and CPT codes to identify a cohort of patients diagnosed with PHP who underwent a parathyroidectomy between 2012 and 2022. Among this group, patients with a history of bariatric surgery prior to parathyroidectomy were identified via procedure codes for bariatric surgery (RYGB, SG, GB, BPD) or the diagnosis code for bariatric surgery status. To account for potential pseudohypocalcemia due to hypoalbuminemia, patients with a serum albumin level ≤3.3 g/dL within one year following parathyroidectomy were excluded from analysis. The codes utilized to complete the search criteria are listed in Supplement 1. Of note, due to the fact that a large proportion of the cohort was identified via the code for bariatric surgery status, all patients with prior bariatric surgery were analyzed as a single group, and it was not possible to determine rates of hypocalcemia according to bariatric procedure type. The rates of hypocalcemia were compared between patients with a history of bariatric surgery who underwent parathyroidectomy and controls who underwent parathyroidectomy alone. Calcium levels were recorded during three time frames: 0-1 month, 1-6 months, and 6-12 months following surgery. Hypocalcemia was defined as a serum calcium ≤8.4 mg/dL or an ionized calcium ≤4.6 mg/dL or ≤1.1 mmol/L. Hypocalcemia was also defined using the diagnosis code for hypocalcemia for patients without biochemical values available. Although the definition of hypocalcemia may vary across laboratories, these values are commonly accepted [19]. To balance for potential confounders, an additional analysis was performed after matching each group for age, sex, race, ethnicity, body mass index (BMI) ≥30 kg/m 2 , and prior calcium and vitamin D supplementation. The rationale for matching for the number of patients with BMI ≥30 kg/m 2 was based on the fact that obesity has been reported to influence the rate of hypocalcemia after thyroidectomy [20].
All statistical analyses were performed within the Tri-NetX platform. Relative risks and associated 95% confidence intervals (CIs) were calculated to compare the incidence of hypocalcemia between each cohort. T-tests were also performed to compare the mean pre-and postoperative calcium, calcidiol, and parathyroid hormone (PTH) values between groups. Propensity score matching was performed via 1:1 nearest neighbor matching with a difference between propensity scores ≤0.1 and a tolerance level of 0.01. The matching algorithm involves matrices of covariates with rows in randomized fashion, and propensity scores obtained via logistic regression. Statistical significance was specified as P <0.05.

Discussion
According to the World Health Organization, obesity is one of the most severe worldwide epidemics of the twenty-first century [21]. Bariatric surgery has been demonstrated to be an effective treatment for achieving sustained weight loss [3]. However, both morbid obesity and subsequent bariatric surgery may cause nutritional and metabolic deficiencies. Patients with obesity may have abnormal calcium homeostasis because of an unbalanced diet and decreased sun exposure [22][23][24]. In addition, malabsorptive and restrictive processes induced by bariatric surgery may lead to disturbances in calcium homeostasis, changes in bone mass, and increased preexisting metabolic derangements [5][6][7].
While bariatric procedures are well known to be associated with secondary hyperparathyroidism [25][26][27][28], recent studies suggest that bariatric surgery may also raise the risk of developing primary hyperparathyroidism (PHP) and the formation of parathyroid adenomas [9][10][11][12][13][14]. Keskin et al. reported five cases of PHP in patients who underwent prior SG, and suggested that there may be a relationship between bariatric surgery and PHP [13]. In the present study, 1.4% of patients in our cohort with PHP who underwent parathyroidectomy had a history of bariatric surgery, which is evidence that this is a clinically relevant population.
There is a growing body of literature suggesting that patients with a history of bariatric surgery have an increased risk of hypocalcemia after thyroidectomy [15], however far less is known about hypocalcemia after parathyroidectomy. Patients with weight loss surgery rely on compensatory increases in PTH production by the parathyroid glands to maintain adequate serum calcium levels. Therefore, in the setting of parathyroid gland excision, whether incidental during a thyroidectomy or during a planned parathyroidectomy, these patients may be at increased risk for severe recalcitrant hypocalcemia. Palal et al. reported a case of life-threatening hypocalcemia in a patient with a previous RYGB who underwent subtotal parathyroidectomy to treat calciphylaxis associated with renal failure [29]. Monte et al. reported a case of hypocalcemia in a patient with prior RYGB who underwent parathyroidectomy for PHP, despite being discharged with calcium carbonate and calcitriol [9]. Conversely, Chen et al. described a series of ten patients with prior RYGB who underwent parathyroidectomy for PHP, however there were no postoperative complications [10]. In our current study, these patients were twice as likely to experience short-term hypocalcemia and three times as likely to suffer from permanent hypocalcemia compared to patients who underwent parathyroidectomy alone.
There are no guidelines for the prevention or management of hypocalcemia after parathyroidectomy in patients with a history of bariatric surgery. There is evidence that patients who are vitamin D deficient can safely begin supplementation prior to surgery [30]. Therefore, it may be beneficial to offer this cohort of patients preoperative  [31]. Patients who develop hypocalcemia should be prescribed the maximum doses of calcium citrate and calcitriol, and magnesium should be repleted. A prolonged hospital stay may be necessary for administration of intravenous calcium gluconate/acetate. Those with permanent hypocalcemia may consider adding the PTH analog teriparatide [30].
Although we are the first to present an analysis of a large sample size of patients with prior bariatric surgery who underwent parathyroidectomy, our study has limitations. First, a considerable portion of our cohort was identified using the diagnosis code for "bariatric surgery status," and therefore did not have information on the specific type of bariatric procedure they underwent. As such, it was not possible to compare the rates of hypocalcemia in patients who underwent malabsorptive versus restrictive operations. Although all bariatric procedures are associated with secondary hyperparathyroidism and an increased dependence on the parathyroid glands to maintain calcium homeostasis [25], research analyzing the rate of hypocalcemia after thyroidectomy has suggested that restrictive bariatric procedures may not be associated with increased risk [17,32]. Additionally, we do not have information regarding the number of patients who had multi-gland disease or underwent a focused surgical approach versus bilateral neck exploration. These represent important areas of future research.
In conclusion, patients with a history of bariatric surgery may be at increased risk for both short-term and permanent hypocalcemia after parathyroidectomy. Surgeons should discuss this increased risk with these patients when obtaining informed consent. Efforts to improve outcomes in this population should focus on determining optimal prevention and treatment guidelines.
Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by F.J.L. The first draft of the manuscript was written by F.J.L. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through Grant UL1 TR002014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Ethical approval This is an observational study. The Penn State Institutional Review Board reviewed and approved STUDY00018629 as exempt according to institutional policies and applicable federal regulations.
Consent to participate This is an observational study. Any data displayed on the TriNetX platform in aggregate form, or any patient level data provided in a data set generated by the TriNetX platform, only contains de-identified data. Therefore, the need for informed consent was waived.