INTRODUCTION
The liver, gallbladder, and pancreas are the main organs of nutritional metabolism, including protein synthesis, glycogen storage, fat digestion, and detoxification. In patients with malignant diseases, these functions are altered, resulting in various metabolic disorders. Disturbed nutritional conditions are associated with disease progression in patients with malignancies. In a population at risk for nutritional deficiencies, prealbumin appears to be a good indicator of protein status [1]. Prealbumin is influenced by inflammatory processes [2] and has a short half-life of approximately 2 days. Recent studies have shown that malnutrition and a systemic inflammatory response reduce survival times, reduce response rate, and carry a higher risk of treatment-induced complications in patients with malignancies [3,4]. Although there are many studies on prealbumin in individual diseases, such as malignant or inflammatory diseases, few are comparative studies.
Thus, we conducted this study to determine the clinical differences between prealbumin levels in benign symptomatic gall bladder diseases and pancreaticobiliary malignancies, as well as to investigate the clinical impact of low prealbumin levels in pancreaticobiliary malignancies.
METHODS
Research plan
The aim of this study was to compare the clinical differences between prealbumin levels in cholecystitis and pancreaticobiliary malignancies and investigate the clinical impact of low prealbumin levels in pancreaticobiliary malignancies. To achieve this aim, patients who underwent pancreaticobiliary surgery between June 2021 to September 2021 were enrolled in the study. The clinicopathological data of these patients were retrospectively analyzed.
Patients
The study population comprised patients with symptomatic gallbladder stones (27 patients) and various pancreaticobiliary malignancies (34 patients). This retrospective study was conducted in accordance with the relevant guidelines and regulations. The study was approved by the Pusan National University Hospital Institutional Review Board at the Clinical Trial Center (IRB No. 2202-024-112, 2022-03-03). The informed consent was waived because this study design is a retrospective review.
Sampling of prealbumin and other markers
All patients with malignancies were admitted to the hospital 36 hours before surgery, while those with benign diseases were admitted to the hospital 12 hours before surgery. Baseline preoperative data were obtained immediately before the operation. For patients with cholangitis, preoperative endoscopic or percutaneous transhepatic biliary drainage was performed, and these patients were enrolled in the study only after their liver function improved. The reference ranges used were as follows: prealbumin, 20–40 mg/dL; C-reactive protein (CRP), <0.5 mg/dL; carcinoembryonic antigen (CEA), <5 ng/mL; and carbohydrate antigen 19-9 (CA19-9), <39 U/mL.
Operative methods
Patients with symptomatic gallstone disease (pain and dyspepsia) underwent laparoscopic cholecystectomy. Patients with malignant diseases, including periampullary cancer, pancreatic body and tail cancer, and cholangiocarcinoma, were surgically treated with curative intent according to the disease location. Distant metastasis was diagnosed when para-aortic lymph node metastasis and seeding metastasis were confirmed during the intraoperative or postoperative period, and both were resected.
Statistical analysis
Categorical variables between the symptomatic gallstone disease and pancreaticobiliary malignancy groups were compared using chi-square or Fisher exact tests. Continuous variables are presented as mean±standard deviation. Intergroup comparisons were performed using the independent t-test or Wilcoxon rank-sum test. The predictability of malignancy using low prealbumin levels (<20 mg/dL) was determined using receiver operating characteristic curve analysis. Statistical significance was set at P<0.05. Statistical analyses were performed using the SPSS software version 20.0 (IBM Corp., Armonk, NY, USA).
RESULTS
Demographics of patients with gallbladder disease and malignant disease
The demographics of patients with gallstone diseases and pancreaticobiliary malignant diseases were compared, and significant differences were identified. Patients with malignant diseases were older than those in the benign group (67.74 years vs. 58.07 years, P=0.002). The proportion of females in the malignancy group was lower than that in the benign group (32.4% vs. 70.4%, P=0.003). The American Society of Anesthesiologists (ASA) scores 3 and 4 were more frequently observed in the malignancy group than in the benign group (58.8% vs. 7.4%, P<0.001). CRP levels and platelet lymphocyte ratio (PLR) were significantly higher in the malignancy group than those in the benign group (0.90 mg/dL vs. 0.08 mg/dL, P=0.004; 168.7 vs. 123.6, P=0.046, respectively). Hemoglobin level in the malignancy group was lower than that in the benign group (12.41 g/dL vs. 13.46 g/dL, P=0.011). Serum prealbumin levels were significantly different between the benign and malignancy groups (25.94 mg/dL vs. 21.66 mg/dL, P=0.006). The incidence of low prealbumin (<20 mg/dL) was significantly higher in the malignancy group than that in the benign group (44.1% vs 11.1%, P=0.005). Significantly higher levels of CEA and CA19-9 were observed in the malignancy group than those in the benign group (29.4% vs. 3.7%, P=0.009; 50.1% vs. 0.0%, P<0.001; respectively) (Table 1).
Analysis of clinical features according to serum prealbumin level
We analyzed the clinical features according to serum prealbumin levels. ASA score was significantly higher (66.7% vs. 21.4%, P=0.001), and body mass index (BMI) was significantly lower (22.26 kg/m2 vs. 24.96 kg/m2, P=0.014) in the low prealbumin group than that in the normal prealbumin group. Hemoglobin and albumin levels were also significantly lower in the low prealbumin group than those in the normal prealbumin group (11.76 g/dL vs. 13.33 g/dL, P<0.001; 4.18 g/dL vs. 4.53 g/dL, P=0.023, respectively). Inflammatory factors such as CRP, PLR, and neutrophil lymphocyte ratio (NLR) were significantly higher in the low prealbumin group (P=0.008, P=0.006, and P=0.038, respectively). Significantly higher levels of CA19-9 were observed in the low prealbumin group than in the normal prealbumin group (55.6% vs. 16.3%, P=0.002) (Table 2).
Efficacy of serum prealbumin for predicting malignancy
We compared the efficacy of serum prealbumin with that of conventional tumor markers such as serum CEA and CA19-9 in predicting malignancy. We analyzed the area under the receiver operating characteristic curve (AUC) for each value. The AUC of CEA was higher than that of prealbumin, but the difference was not significant (0.775 vs. 0.693, P=0.334). There was also no significant difference between prealbumin and CA19-9 levels (0.693 vs. 0.794, P=0.242) (Table 3).
Clinical impact of prealbumin in malignancy
In the malignancy group, the low prealbumin group had significantly lower BMI and hemoglobin levels than did the normal prealbumin group (22.26 kg/m2 vs. 25.44 kg/m2, P=0.009; 11.61 g/dL vs. 13.04 g/dL, P=0.017, respectively). Patients with low prealbumin levels had more advanced disease according to the TNM staging. Advanced T stage (≥3) was more frequently observed in the low prealbumin group than in the normal prealbumin group (73.3% vs. 36.8%, P=0.034). There were also significant differences in the presence of positive nodal status and distant metastasis between the low and normal prealbumin groups (positive N status: 73.3% vs. 31.6%, P=0.016; distant metastasis: 26.7% vs. 0.0%, P=0.017, respectively) (Table 4).
DISCUSSION
Serum prealbumin, a negative acute-phase protein synthesized by the liver, is often used to evaluate the nutritional status of patients with malignant tumors [5–10]. However, serum prealbumin levels are also decreased during inflammation (negative acute-phase protein) due to the transfer of plasma proteins to the reactants of the acute phase, such as CRP [1]. In the present study, low prealbumin levels were noted in three out of 27 (11.1%) and 15 out of 34 (44.1%) patients with symptomatic gallstone disease and pancreaticobiliary malignancies, respectively. We showed that preoperative low serum prealbumin levels in patients with benign and malignant diseases correlated with low BMI, hemoglobin, and albumin levels. This can be assumed to be due to poor nutritional status in patients with low prealbumin levels. It is well accepted that nutrition is an important determinant of immune responses, and malnutrition is the most common cause of immunodeficiency [11–14]. As a negative acute-phase protein, prealbumin synthesis is suppressed in the inflammatory state, which mainly involves tumor necrosis factor α, interleukin-1, and interleukin-6, resulting in increased degeneration of CRP and decreased synthesis of prealbumin by the liver [15–17]. Inflammatory indices, such as CRP, NLR, and PLR, were derived from complete blood counts. CRP, NLR, and PLR were higher in patients with low prealbumin levels. Our results confirmed that low prealbumin level in pancreaticobiliary malignancies is a biomarker that reflects nutritional and inflammation status, as shown in previous studies.
Malnutrition can impair the immune system and suppress immune functions that are fundamental to host protection against tumor progression and metastasis [18]. In this study, we showed that the preoperative level of serum prealbumin in patients with pancreaticobiliary malignancies was closely associated with TNM staging. Our results support the conclusion that low prealbumin levels are significantly associated with advanced malignancies (higher T stage, lymph node metastasis, and distant metastasis).
Tumor biomarkers are not only helpful for diagnosing and staging malignant diseases but also for follow-up monitoring and evaluating the prognosis of the patient after treatment. CEA and CA19-9 are commonly used for predicting pancreaticobiliary malignancies in clinical settings. The present study evaluated serum prealbumin levels as a predictor of pancreaticobiliary malignancies. In our study, preoperative low prealbumin level had an AUC of 0.69, suggesting that it can be used for predicting pancreaticobiliary malignancies. However, it cannot be said that it is superior to CEA and CA19-9.
This study had some limitations. First, this was a single-center study; therefore, the number of patients was small and meaningful cutoff values of prealbumin could not be investigated. Second, since the follow-up period was very short, its association with prognosis could not be investigated. Third, because various malignant diseases in the biliary pancreatic regions were included, disease-specific differences could not be assessed.
In conclusion, this study confirmed the relationship between serum prealbumin levels and inflammatory indices (CRP, NLR, and PLR). Low prealbumin level was associated with a more advanced stage of pancreaticobiliary malignancy. However, its value as a biomarker needs further verification through additional research.
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