Association of pre-drainage bilirubin levels and pathological features with survival in patients undergoing preoperative biliary drainage: a single-center retrospective study

Introduction

Obstructive jaundice most frequently results from mechanical blockage of the bile duct, which is commonly caused by benign or malignant tumors at the ampullary region. When the liver-produced bile cannot be discharged through the bile duct, it leads to pruritus and yellowing, as well as severe courses such as hyperbilirubinemia and lipid peroxidation (1). The location and pathological origin of ampullary tumors also affect the time and severity of obstruction, thus influencing postoperative survival prognosis. Therefore, clinical analysis should account for variations in pathological subtype (2,3).

Although timely surgery is currently considered to yield better prognostic outcomes than preoperative biliary drainage (PBD), for patients who are unable to undergo surgery promptly, PBD constitutes a key component in the preoperative management of patients with malignant ampullary tumors (4,5). At the same time, the choice of drainage timing has also been widely debated. The focus of controversy comes from the impact of jaundice severity on disease progression. Some studies suggest that bile accumulates in the bile duct and liver due to a pancreatic head mass, resulting in obstructive jaundice and a pro-inflammatory state characterized by elevated levels of endotoxins and cytokines in the systemic circulation and that there is a causal relationship between them (6). Consequently, PBD is thought to facilitate bile excretion and mitigate systemic inflammation. In contrast, a large-scale clinical trial by van der Gaag et al. indicated that PBD may increase the risk of procedure-related bleeding and inflammatory complications, offering no significant advantage over early surgical intervention (7). Despite these findings, PBD continues to be widely employed as a primary strategy for relieving acute symptoms in patients with obstructive jaundice. Some scholars believe that PBD can be performed when total bilirubin (TB) is higher than 250 µmol/L (8). Others believe that in actual diagnosis and treatment, considering that some patients have severe concurrent symptoms, PBD can be performed when TB is lower than 250 µmol/L (7). In addition, some studies have confirmed that some patients undergoing PBD may develop cholangitis during neoadjuvant therapy, and cholangitis is associated with an increased postoperative mortality rate [hazard ratio (HR) 2.67, 95% confidence interval (CI): 1.16–6.13] (9). Therefore, when performing PBD at lower levels of jaundice, it needs to be considered whether this procedure will provide more benefits to patients than severe jaundice in the short and long term. Such an assessment should incorporate both perioperative and long-term outcome measures. However, this study used retrograde biliary drainage and patients had received preoperative chemotherapy and other neoadjuvant treatments, which may not reflect outcomes of other PBD approaches in patients undergoing pancreaticoduodenectomy. At the same time, Costa Santos and others have studied case-control analysis in recent years, believing that PBD (both antegrade and retrograde) does not result in higher mortality rates but only extends hospitalization time. The contrasting conclusions of the two people may be due to differences in drainage methods (10). In addition, a multicenter randomized controlled trial by van der Gaag was conducted on patients with pancreatic head cancer who received PBD at a concentration of preoperative bilirubin levels between 40–250 µmol/L. The results showed that the PBD group reduced operative time, less intraoperative blood loss, and incidence of postoperative complications compared to the control group, and the tumor resection rate in the drainage group was higher than that in the control group (7).

However, the study by van der Gaag et al. did not include patients with bilirubin levels higher than 250 µmol/L (7). Recently, a study divided patients into subgroups based on a bilirubin value of 14.6 mg/dL (249.9 µmol/L) to investigate surgical prognosis (11). Therefore, in the present study, patients were also stratified into mild and severe jaundice groups using a cutoff of 250 µmol/L to evaluate the prognostic implications of PBD. In summary, beyond assessing the efficacy of PBD in patients with mild to severe jaundice, it is also essential to examine how biliary pathological origin, vascular invasion and drainage methods affect short-term and long-term postoperative indicators. This study was therefore designed as a retrospective analysis to address these specific questions. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-147/rc).

Methods

PBD and surgery

Endoscopic nasobiliary drainage (ENBD), endoscopic retrograde biliary drainage (ERBD), T-tube drainage and percutaneous transhepatic cholangial drainage (PTCD) were performed by experienced surgeons. All patients underwent laparoscopic or open pancreaticoduodenectomy and lymph node dissection after PBD. The digestive tract reconstruction method was all Child’s method.

Observation indicators

The main outcomes were postoperative short-term complications, including pancreatic fistula, infection, gastric paralysis, and bleeding, as well as long-term prognostic indicators such as overall survival (OS) rate and progression-free survival (PFS) rate. The secondary outcomes were perioperative-related indicators, including operation time, intraoperative blood loss, and postoperative biliary and pancreatic drainage tube retention time. Complication grading: The severity of postoperative complications was classified according to the Clavien-Dindo model. Grade I–II was defined as mild complications and grade III–IV was defined as severe complications. Pancreatic fistula: referral to the consensus of the International Pancreatic Surgical Study Group, postoperative drainage fluid amylase value greater than three times the upper limit of normal blood amylase value for more than 3 days, with relevant clinical symptoms such as abdominal pain, and pancreatic fistula was divided into grades A, B, and C. Abdominal hemorrhage and gastrointestinal bleeding: abdominal drainage tube or gastrointestinal decompression tube withdrew blood-tinged fluid, or manifested as hematochezia, accompanied by changes in vital signs and decreased hemoglobin concentration; Abdominal infection: within 3 days after surgery, with chills, high fever, abdominal distension, and bowel paralysis symptoms persisting for more than 24 hours. Laboratory test results showed a significant increase in inflammatory indicators such as white blood cell count. Imaging suggested intra-abdominal fluid accumulation, which can be diagnosed as abdominal infection. Puncturing and extracting purulent fluid or the detection of bacteria in the fluid can confirm the diagnosis.

Subgroup analysis

ENBD and ERBD were selected as the subgrouping basis for different biliary drainage methods because they are retrograde drainage methods, while PTCD and T-tube drainage are antegrade drainage methods. The effects of different biliary drainage methods on perioperative-related indicators and long-term prognosis in patients with mild or severe jaundice were evaluated. In addition, the pathological source of the ampulla of Vater tumors is mainly divided into pancreaticobiliary type (including bile duct and pancreatic origin) and intestinal type (duodenal origin). Different pathological sources may have different prognoses. Therefore, the treatment and progression of different pathological types of diseases were evaluated based on perioperative-related indicators and long-term prognosis.

Materials

Patients diagnosed with obstructive jaundice and underwent pancreaticoduodenectomy after PBD at Beijing Friendship Hospital, Capital Medical University between January 2014 and April 2023 were collected. Data collected included general information such as gender, age, body mass index, comorbidities, tumor stage, tumor type, and drainage method. P<0.05 was considered statistically significant. Surgical indicators included operation time, postoperative complications, days of biliary and pancreatic drainage, OS rate, PFS rate, etc. Inclusion criteria: (I) surgery was pancreaticoduodenectomy without combined with other surgeries; (II) PBD was performed by various methods; (III) preoperative chemotherapy and radiotherapy were not received; (IV) clinical data were complete for this study. Exclusion criteria: (I) combined with other surgeries or reoperation; (II) preoperative neoadjuvant radiotherapy and chemotherapy; (III) clinical data were incomplete.

Ethical statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Capital Medical University (No. 2022-P2-104-01) and informed consent was taken from all the patients.

Statistical analysis

SPSS 26.0 software was used for data analysis. The comparison of count data was performed using the χ² test. When the predicted frequency was less than 5, Fisher’s exact test was used. The measurement data that conformed to normal distribution was expressed by mean [standard deviation (SD)], and an independent sample t-test was used. For data that did not conform to a normal distribution, median and interquartile ranges were used and the Mann-Whitney U test was adopted. When P≤0.05, it was considered statistically significant. Using Graphpad prism9 to test the proportional risk assumption of patient OS rate and PFS rate, and fit survival regression. When P≤0.05, it was considered statistically significant.

Results

A total of 141 patients who met the screening criteria were included in the study, there were 78 individuals in the mild jaundice group and 63 individuals in the severe jaundice group. There were no statistically significant differences (P>0.05) in gender ratio (P=0.42), age categorized by 65 years (P=0.81), body mass index (BMI) categorized by 24 kg/m² (P=0.70), American Joint Committee on Cancer (AJCC) pathological stage (P=0.62), history of chronic diseases (P=0.87), and total PBD time (Z=−0.628, P=0.59) between the two groups of patients with mild and severe bilirubin levels. Additionally, among the laboratory test items, only TB showed significant differences as it was the basis for grouping (P<0.001), while aspartate aminotransferase (AST) (Z=−1.487, P=0.14), alanine aminotransferase (ALT) (Z=−0.703, P=0.48), and albumin (ALB) (F=1.067, P=0.40) did not. The statistical results of the study indicated significant differences in the choice of PBD methods (P<0.001). In the mild jaundice group, 29.5% (23/78) of patients underwent ERBD, 44.9% (35/78) underwent ENBD, 23.1% (18/78) underwent PTCD, and only 2 patients underwent T-tube drainage. In the severe jaundice group, 9.5% (6/63) of patients underwent ERBD, 55.6% (35/63) underwent PTCD, 33.3% (21/63) underwent ENBD, and only 1 patient underwent T-tube drainage. Antegrade biliary drainage includes PTCD and T-tube drainage, while retrograde biliary drainage includes ENBD and ERBD (Table 1).

In the perioperative indicators, including operation time (Z=−1.284, P=0.20), days of bilioenteric drainage (Z=−0.276, P=0.78), and days of pancreatoenteric drainage (Z=−1.007, P=0.31), there were no statistically significant differences between the mild jaundice group and the severe jaundice group. Additionally, there were no statistically significant differences between the two groups in postoperative pathological type (P=0.56), pathological origin (P=0.07), number of lymph nodes dissected (Z=−1.304, P=0.19), presence of lymph node metastasis (P=0.30), and neural invasion (P=0.27). However, a higher proportion of vascular invasion was found in the severe jaundice group (P=0.04). In the comparison of postoperative complications using the Clavien-Dindo classification, the mild jaundice group had 36 cases (46.2%) with no complications, 42 cases (53.8%) with grade I–II complications, and no grade III–IV complications; the severe jaundice group had 22 cases (34.9%) with no complications, 39 cases (61.9%) with grade I–II complications, and 2 cases (3.2%) with grade III–IV complications, but there was no statistical difference (P=0.12). For severe postoperative complications (including gastroparesis, infection, abdominal hemorrhage, and in-hospital mortality), the incidence rate was 5.1% (4/78) in the mild jaundice group and 11.1% (7/63) in the severe jaundice group, with a higher incidence of severe complications in the severe jaundice group, but the difference was not statistically significant (P=0.22). In the survival analysis, the OS rate of the mild jaundice group (97.43% at 1, 3, and 5 years) was higher than that of the severe jaundice group (91.58%, 85.43%, and 78.31% at 1, 3, and 5 years, respectively) (P=0.02). However, there was no statistically significant difference in disease-free survival between the two groups (P=0.92) (Table 2 and Figure 1).

Figure 1 Comparison of overall survival and progression-free survival after pancreaticoduodenectomy in the mild and severe jaundice groups.

The results of the subgroup analysis regarding drainage methods indicate that there were no statistically significant differences in operation time (Z=−0.315, P=0.75), days of bilioenteric drainage (Z=−0.169, P=0.87), and days of pancreatoenteric drainage (Z=−0.432, P=0.67) between antegrade and retrograde drainage groups. In the survival analysis, there were also no statistically significant differences in OS (P=0.16) and PFS (P=0.20) between the two groups, suggesting that the drainage method has minimal impact on long-term postoperative prognostic indicators. Furthermore, in the subgroup analysis based on pathological types during the follow-up period, there were no statistically significant differences in operation time (Z=−1.576, P=0.12), days of bilioenteric drainage (Z=−0.470, P=0.64), and days of pancreatoenteric drainage (Z=−0.434, P=0.66) between the biliary-pancreatic and intestinal-adenocarcinoma groups. Additionally, although there was no difference in OS between the biliary-pancreatic type (96.9%) and the intestinal-adenocarcinoma type (91.8%) (P=0.26), the PFS rate of the biliary-pancreatic type (75.55%, 61.93%, and 35.99% at 1, 3, and 5 years, respectively) was significantly worse than that of the intestinal-adenocarcinoma type (90.32%, 82.84%, and 82.84% at 1, 3, and 5 years, respectively) (P=0.02) (Tables 3,4 and Figures 2,3). Patients were divided into vascular invasion group and non-invasion group based on pathological reports, there were statistically significant differences in operative time (P=0.047) and pancreatic drainage time (P=0.006) between the two groups. In contrast, the results of univariate survival analysis indicated no statistically significant differences in OS (P=0.87) or PFS (P=0.91) between the two groups (Table 5 and Figure 4).

Figure 2 Comparison of overall survival and progression-free survival after pancreaticoduodenectomy in the retrograde and anterograde drainage groups.

Figure 3 Comparison of overall survival and progression-free survival after pancreaticoduodenectomy in the intestinal and biliary pancreatic type patients.

Figure 4 Comparison of overall survival and progression-free survival of non-vascular invasion and vascular invasion patients.

Patients’ bilirubin levels, drainage methods, pathological types, and vascular invasion were incorporated into the multivariate Cox regression analysis. The results indicated that pathological type (P=0.044) had a statistically significant impact on PFS, while the remaining outcomes showed no statistical significance (Tables 6,7).

Discussion

In this study, baseline data of the severe and mild jaundice groups in the two groups were comparable between gender, age, and body mass index, except for the different choice of biliary drainage methods. Therefore, in addition to analyzing the impact of different degrees of jaundice on postoperative outcomes, it is also important to investigate whether the difference in drainage methods can interfere with short-term and long-term outcomes after surgery. In the analysis of overall postoperative short-term outcomes, no significant differences were found in complications such as pancreatic fistula, surgical site infection, hemorrhage, or gastroparesis. However, one in-hospital death occurred in the severe jaundice group, which alerts doctors to pay attention to the prognosis of patients with severe jaundice.

During the initial phase of obstructive jaundice, increased hepatocellular permeability promotes bile release, elevating biliary pressure and contributing to hepatic dysfunction and necrosis. This pathological process is characterized by elevated plasma levels of unconjugated bilirubin and transaminases (12,13). Components in stagnant bile can damage mitochondrial structures in liver cells, accelerating the damage of peroxides to liver cells and leading to cell death and cirrhosis (14,15). Serum bilirubin levels cannot fully reflect a patient’s liver function and physical condition, but they also reflect the severity of jaundice to a certain extent, which may affect perioperative and long-term prognostic indicators. Silina et al. suggests that in the process of obstructive jaundice formation, acute severe jaundice can quickly lead to hepatorenal failure, while gradual jaundice will not cause serious damage within several months (16). Therefore, dividing patients into different groups based on bilirubin levels can help us understand the impact of the severity of jaundice on prognosis.

Compared with patients without obstructive jaundice, those with obstructive jaundice secondary to periampullary tumors may predict a poor survival prognosis. A retrospective study by Nakata et al. found that patients with jaundice had a significantly shorter OS (P=0.049) and more lymph node metastasis (P=0.008) and neural invasion (P=0.016) (17). Our study also found that patients with severe jaundice had more vessel invasion (P=0.04), which supports the conclusions of Bunzo Nakata et al. However, this may be attributed to the fact that most cases of vascular invasion are detected under microscope, and some only involve the walls of small blood vessels and lymphatic vessels. Consequently, no statistically significant difference was observed in the univariate survival analysis. Obstructive jaundice is seen in 70% of patients with tumors around the ampulla (18). Due to progressive accumulation of bilirubin increasing over time, it can even lead to liver failure or multiple organ dysfunction syndrome in severe cases. In this study, although the bilirubin levels between the two groups remained different after biliary decompression, both decreased to the mild range. Timely biliary drainage for obstructive jaundice patients can rapidly improve symptoms and reduce inflammation damage (6,19). However, some researchers still believe that PBD will not improve prognosis. Arkadopoulos et al. compared PBD with early surgery without drainage in patients with severe hyperbilirubinemia and found that PBD may increase the incidence of infection, bleeding, and other serious complications (20). A retrospective study by van Gils et al. also found that drainage methods may cause pancreatitis, cholangitis, stent blockage, and perforation. However, they believed that there was no significant difference in postoperative complication rates between mild and severe jaundice groups (P>0.05) (21). On the contrary, another study had suggested that a preoperative bilirubin level >14.6 mg/dL (>250 µmol/L) is an independent predictive factor for 90-day mortality (11). There was no significant difference in perioperative indicators or PFS between mild and severe jaundice groups (P>0.05) but mild jaundice patients had a better OS rate (P=0.02) in our study. However, the multivariate Cox regression analysis showed no differences, which is consistent with the conclusions of previous studies. Additional research is required to confirm that severe jaundice does not affect prognosis.

PTCD has been widely applied in patients with inoperable obstructive jaundice due to its significant improvement in survival rates and quality of life in recent years (22). Although PTCD prolongs average length of hospital stay, compared with endoscopic biliary stent placement, PTCD can quickly relieve intrahepatic bile duct distension, effectively reduce biliary pressure, and cause relatively minor trauma with a simpler approach (23). Meanwhile, after conducting a meta-analysis, researchers had concluded that ERCP is the preferred procedure for PBD, while PTCD serves as a viable alternative (24). For patients with severe biliary obstruction, PTCD is preferred for PBD. Our study also found that patients with severe jaundice were more likely to use PTCD for anterograde drainage as a subanalysis to understand the impact of anterograde and retrograde drainage methods on surgical outcomes.

The results showed that there were no differences in intraoperative indicators and short-term postoperative complications among different drainage methods (P>0.05). In the long-term prognosis, there were no significant differences in OS (P=0.16) and PFS (P=0.20) between the patients, indicating that different drainage methods did not affect the prognosis of patients with mild to severe jaundice.

Notably there may be significant differences in prognosis among tumors of different pathological types. For example, tumors originating from the periampullary-originated tumors, including ampullary carcinoma and duodenal carcinoma, have a lower degree of malignancy and higher surgical resection rates, and superior 5-year survival rates compared to pancreatic carcinoma. As early as the beginning of this century, Shyr et al. found that the 5-year survival rate of ampullary carcinoma was 23%, while that of pancreatic carcinoma was only 5.5% (25). Binziad et al. found in a follow-up study of patients undergoing pancreaticoduodenectomy for more than 3 years that gastrointestinal-originated tumors exhibit symptoms earlier and can receive timely treatment, resulting in better overall prognosis compared to pancreatic and biliary tumors based on pathological classification (26). In our study, there was no significant difference in OS between the intestinal-type and biliary-type subgroups (P=0.26), but the recurrence rate of the intestinal type was significantly lower than that of the biliary type in PFS (P=0.02), which also supports the conclusion of Binziad et al. At the pathological level, biliary and pancreatic tumors are more prone to exhibit invasive growth patterns, perineural invasion, and lymphovascular emboli formation, while intestinal tumors tend to show localized growth with more mature glandular differentiation (27); at the molecular level, beyond KRAS mutations, biliary and pancreatic tumors are frequently accompanied by TP53 inactivation and SMAD4 deletion, and these molecular abnormalities collectively drive their invasive and metastatic potential, whereas intestinal tumors mostly retain the normal regulation of the APC-Wnt pathway, which further attenuates their malignant progression capacity (28,29). In the multivariate Cox regression analysis of this study, pathological type was identified as a significant factor influencing PFS (P=0.044), which further corroborates the findings of previous studies.

Conclusions

This study analyzed the perioperative outcomes and long-term prognostic outcomes of pancreaticoduodenectomy after biliary drainage in patients with different degrees of hyperbilirubinemia. It was found that patients with mild jaundice who underwent PBD had overall postoperative complications and other perioperative indicators that were not inferior to patients with severe jaundice (P>0.05) and even had a higher OS rate than patients with severe jaundice (P=0.02). This indicates that PBD can be actively implemented in patients with obstructive jaundice-related mild hyperbilirubinemia, and it can achieve good results. Additionally, subgroup analysis of different drainage methods showed that patients with severe jaundice were more likely to use anterograde biliary drainage compared to patients with mild jaundice, but this did not affect the final prognosis. Furthermore, subgroup analysis based on pathological type confirmed that patients with biliary-pancreatic type tumors may have a worse long-term prognosis, necessitating greater attention to disease progression and recurrence in this group of patients.

However, the present study was designed as a retrospective analysis, which inherently carries certain limitations. Specifically, the cutoff value of bilirubin used for grouping patients may not fully capture the actual physiological status of the enrolled subjects. This limitation is partially ascribed to the lack of standardized protocols for interventions aimed at reducing jaundice in the study population. Although the application of different biliary drainage modalities did not exert a significant impact on OS or PFS in the current analysis, retrospective studies are inherently susceptible to selection bias due to the non-randomized nature of patient enrollment. Therefore, additional well-designed prospective cohort studies with standardized intervention protocols are warranted to further validate these preliminary findings and comprehensively clarify the potential effects of the aforementioned factors on patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-147/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-147/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-147/prf

Funding: This work was supported by the National Key Technologies R&D Program (No. 2015BAI13B09).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-147/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Capital Medical University (No. 2022-P2-104-01) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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