Abstract
Background/Aim: Recently, a decrease in serum zinc levels and the need for zinc preparations have been reported in the perioperative period of gastrointestinal surgery. In this study, we examined treatment outcomes among patients supplemented with zinc after pancreaticoduodenectomy (PD) and evaluated the significance of zinc replacement therapy. Patients and Methods: From June 2020 to April 2021, 56 patients who received zinc acetate hydrate (50 mg/day) from postoperative day 3 after PD in our department were retrospectively reviewed. Patients’ characteristics and preoperative as well as postoperative data, including serum zinc levels and surgical results at 1 month were reviewed. Results: Preoperative zinc deficiency was present in 86.1% (46/56) of the patients. Moreover, despite zinc supplementation, 17.8% (10/56) of patients had postoperative zinc deficiency. A comparison between the low zinc level group (Zn <80 μg/dl) and the normal zinc level group (Zn ≥80 μg/dl) after surgery showed siginificant differences among patients with malignant diseases (vs. benign diseases, p=0.044), those undergoing open surgery (vs. minimally invasive surgery, p=0.036), and those with intraoperative blood loss ≥346 ml (vs. <346 ml: p=0.041) in the univariate analysis. Multivariate analysis revealed that zinc deficiency was significantly associated with open surgery [odds ratio (OR)=15.885, 95% confidence interval (CI)=1.77-142.01, p=0.013] and intraoperative blood loss (OR=9.329, 95% CI=1.50-57.74, p=0.016). Conclusion: In patients undergoing open PD for pancreatic cancer, zinc preparations of 50 mg may not be sufficient and further supplementation may be necessary.
Pancreaticoduodenectomy (PD) is a highly invasive surgical procedure that necessitates both perioperative and postoperative care. An increasing number of reports highlight the importance of nutritional status, body composition and management of sarcopenia during the perioperative care (1). The former has also been reported as a prognostic factor for increased complications after pancreatic resection for pancreatic cancer (2-6). Therefore, perioperative nutritional management is indispensable, and in recent years, fluctuations in serum zinc levels have gained attention as being indicators of nutritional status (7). Zinc (Zn) is an essential trace element that is necessary for most of the enzymatic activity related to the human body and is involved in various physiological actions. Fluctuations in serum zinc levels in chronic liver and chronic kidney disease are known (8). However, there are a few reports on the fluctuations in serum zinc levels during perioperative gastrointestinal surgery and malignant diseases (9).
Zinc fractionation is known to occur in chronic liver disease and chronic kidney disease (10). It has been reported that trace element deficiency, especially zinc deficiency, is common in pancreatobiliary malignancies (11, 12), however, there are few reports of perioperative zinc deficiency in pancreatic resection (11, 13). Zinc supplementation at 50 mg/day has been widely used in gastrointestinal surgery, but it is unclear whether the same dose of zinc supplementation is sufficient for PD. To investigate the significance of zinc replacement therapy, we examined the postoperative zinc levels of patients who received 50 mg of zinc in this preliminary study. We examined the treatment outcomes of patients supplemented with zinc after pancreaticoduodenectomy (PD) and evaluated the significance of zinc replacement therapy.
Patients and Methods
Patients. The main inclusion criteria were pancreatic or bile duct tumor, age ≥20 years, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, oral intake capability, and adequate function of the major organs. The main exclusion criteria were serious concurrent disease, markedly impaired cardiac function, gastrointestinal bleeding, sensory neuropathy, serious diarrhoea, ascites beyond the pelvic cavity, pleural effusion, and interstitial pneumonia.
A total of 56 patients who underwent pylorus-ring-preserving PD at Tokyo Medical University Hospital between July 2020 and April 2021 were enrolled in this study. Patients for whom serum zinc concentration data were unavailable and those who did not receive oral zinc replenishment were excluded. The patients were diagnosed with malignant (n=42, 75.0%) and benign tumors (n=14, 25.0%). The clinical data collected included age, sex, body mass index, preoperative laboratory test results, duration of surgery, blood loss, perioperative complications, and final pathologic diagnosis. Postoperative complications were classified using the Clavien–Dindo classification.
Surgical procedure and perioperative management. A pylorus ring-preserving PD was performed. Moreover, we performed reconstruction using the modified child method. Minimally invasive surgery was performed for benign tumors and carcinomas in situ. Lymph node dissection was performed for pancreatic and bile duct cancer. Two courses of gemcitabine and tegafur/gimeracil/oteracil (S-1) were administered preoperatively for resectable pancreatic cancer. For borderline resectable pancreatic cancer, three courses of gemcitabine/nab-paclitaxel were administered as preoperative chemotherapy. Oral intake was initiated on postoperative day 7. Serum zinc levels were measured immediately before surgery and on postoperative day 30. Zinc acetate hydrate tablets, 50 mg twice daily, were taken orally from postoperative days 3 to 30.
Study design. This was a single-centre retrospective study that used clinical data. The primary endpoint was a risk factor for low serum zinc level on postoperative day 30. Patients were divided into two groups (low zinc group and normal zinc group) based on serum zinc levels on postoperative day 30. The normal serum zinc level was defined as 31-119 mg/dl. We examined the association between perioperative factors and low serum zinc levels after surgery. The logistic regression model was used to calculate the adjusted odds ratio (OR) with a 95% confidence interval (CI) for the risk of low serum zinc levels after surgery. This study was approved by the Institutional Review Board of Tokyo Medical University (SH4036), and the need for informed consent was waived because of the retrospective study design.
Statistical analysis. The results are shown as median values. The Mann–Whitney U-test or chi-square test was used for comparisons between two groups. The cut-off value for continuous variables was calculated using the receiver operating characteristic curve. Risk factors were analysed using logistic regression analysis. Statistical significance was set at p<0.05. IBM SPSS Statistics 26 (IBM Corp., Armonk, NY, USA) was used for statistical analyses.
Results
A total of 56 patients were enrolled in this study including 31 males and 25 females, and the median age was 71 years (range=23-89). The surgical procedures were open pancreaticoduodenectomy (OPD) and minimally invasive pancreatoduodenectomy (MIPD) in 34 and 22 cases, respectively. Fourteen patients (25.0%) received preoperative chemotherapy. Significant differences were observed among patients with pancreatic cancer who received preoperative chemotherapy (p=0.044) (Table I).
The median preoperative serum zinc level was 61 μg/dl (range=31-119), and 46 patients (82.1%) had normal serum zinc levels (≥80 μg/dl). In contrast, the median serum zinc level after one month of zinc acetate administration was 97 μg/dl (range=30-152), indicating a significant postoperative increase in serum zinc levels (p<0.01) (Figure 1). However, 10 patients (17.9%) had low serum zinc levels (<80 μg/dl), despite receiving zinc supplementation.
Univariate analysis of low serum zinc levels at 30 days after surgery was performed for each factor. There were significant differences in open surgery (open vs. laparoscopic, p=0.036), bleeding volume (<346 vs. ≥346 ml, p=0.041), and malignant tumors (malignant vs. benign, p=0.044). There were no differences in nutrition-related factors, such as body weight, serum albumin levels and postoperative complications (Table II).
Multivariate analysis with these factors revealed that open surgery (OR=15.885, 95% CI=1.77-142.01, p=0.013) and blood loss (OR=9.329, 95% CI=1.50-57.74, p=0.016) were independent risk factors (Table III).
Discussion
In this study, we found that 82.1% of the patients before undergoing PD had zinc deficiency, and postoperative zinc acetate administration improved the serum zinc levels. However, the serum zinc levels did not improve in patients with high intraoperative blood loss and open surgery, despite supplementation with zinc acetate hydrate.
This is the first report of the relationship between zinc acetate hydrate administration and serum zinc levels during perioperative pancreatic resection.
Zinc deficiency is common in patients after pancreaticoduodenectomy because pancreatic juice is inevitably deficient in pancreaticoduodenectomy. Yu et al. (13) reported that zinc deficiency occurred in 68% of patients after pancreaticoduo-denectomy. Furthermore, Murphy et al. (11) reported that preoperative zinc deficiency was present in 83% of patients suffering from malignant diseases of the biliary pancreas.
Zinc is an essential element and many roles of human health, is involved in and maintains the activation of more than 300 enzymes (12). Zinc deficiency is exhibited in a variety of clinical manifestations. It has been reported that it causes various symptoms, such as dermatitis, diarrhoea, immunocompromised hostism, hypogonadism in men, delayed wound healing and dysgeusia (14-19).
In recent years, there have been increasing reports that nutritional status and the prevention of sarcopenia in gastrointestinal cancer are related to the reduction of perioperative complications and prognosis. Similarly, there are increasing reports on the relationship between nutritional status and perioperative complications and prognosis in malignant diseases, especially pancreatic cancer, in the biliary pancreatic region (2-5, 20, 21).
Zinc deficiency is associated with many diseases, including malabsorption syndrome and malnutrition, and previous reports suggest that nutritional status, low zinc levels and malabsorption are associated with pancreatic cancer. Iseki et al. (22) reported a relationship between modified Glasgow prognostic scores and a higher neutrophil-to-lymphocyte ratio, which are indicators of nutritional status, as risk factors for low zinc levels during the perioperative period of pancreatic cancer. In this study, we showed that intraoperative blood loss and open surgery were risk factors for low serum zinc levels, despite the administration of zinc acetate hydrate. It has been suggested that open surgeries for pancreatic cancer and the intraoperative blood loss. Further research is needed to investigate the relationship between preoperative patient factors, nutritional status, and Zn levels, especially for pancreatic cancer cases.
This study had several limitations. The number of cases was small, it was a retrospective study, and there was bias in the background. It is necessary to examine patients, including healthy people, for each disease, and for this purpose, case-control studies are necessary.
Conclusion
Postoperative zinc replacement therapy improved serum zinc levels in most patients. However, despite zinc supplementation, serum zinc levels did not improve in patients who underwent open surgery or in patients with significant intraoperative blood loss. In addition, patients with malignant disease or pancreatic cancer may show low levels despite zinc supplementation and should be considered for dose escalation.
Footnotes
Authors’ Contributions
YN conceived the idea of the study. CT and HO developed the statistical analysis plan and conducted the statistical analyses. CT contributed to the interpretation of the results. CT drafted the original manuscript. YN supervised the conduct of this study. All Authors reviewed the manuscript draft and revised it critically on intellectual content. All Authors approved the final version of the manuscript to be published.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received September 1, 2022.
- Revision received September 23, 2022.
- Accepted October 13, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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