Immune checkpoint inhibitor-related cholangitis and pancreatitis induced by penpulimab: a case report

Introduction

In recent years, immunotherapy has been increasingly utilized in the treatment of patients with various advanced malignant tumors. Among the most prevalent modalities in immunotherapy are immune checkpoint inhibitors (ICIs), with prominent examples including inhibitors targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (1,2). ICIs offer significant therapeutic advantages for patients with advanced gastric cancer. Nonetheless, during ICIs treatment, the overactivation of immune cells can lead to the unintended targeting of normal tissues and organs, resulting in immune-related adverse events (irAEs). It is worth noting that immune-related cholangitis (IRC) and immune-related pancreatitis (IRP) are rarely reported as irAEs, but they are associated with a poor prognosis (3,4).

Penpulimab, an innovative PD-1 inhibitor independently developed in China, is distinguished as the sole global PD-1 inhibitor utilizing the immunoglobulin G1 (IgG1) subtype with a modified Fc segment. Approved in August 2021, it is indicated for the treatment of Hodgkin’s lymphoma, nasopharyngeal carcinoma, non-small cell lung cancer, and other solid tumors (5).

This report presents a case of IRC and IRP induced by penpulimab at our institution. To our knowledge, this is the first report on penpulimab-induced cholangitis and pancreatitis. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-169/rc).

Case presentation

A young male patient with no prior history of acute, chronic, or autoimmune diseases and no known drug allergies presented with persistent acid reflux and upper abdominal pain persisting for over 2 years. After a follow-up gastroscopy, he was diagnosed pathologically as poorly differentiated adenocarcinoma of the gastric body, negative for Helicobacter pylori. And then a total gastrectomy with esophagojejunostomy was conducted. Intraoperatively, significant thickening of the entire stomach, tumor invasion of the greater curvature, and multiple metastases in the greater omentum and diaphragmatic dome were observed, leading to a palliative tumor resection. Finally, postoperative histopathological examination confirmed a diagnosis of gastric diffuse infiltrating adenocarcinoma, poorly differentiated, with some signet ring cell carcinoma (classified as T4bN3aM1, stage IV).

Following the surgical intervention, a comprehensive six-month course of chemotherapy was administered. This regimen included Oxaliplatin at a dosage of 200 mg on day 1, combined with Teysuno (S-1) at 60 mg administered twice daily from days 1 to 14, over a 3-week cycle, totaling eight courses. Subsequently, the patient received maintenance therapy with penpulimab at a dosage of 200 mg every 3 weeks, completing 18 cycles. To ensure patient confidentiality, the initiation of penpulimab infusion is utilized as the reference point on the x-axis to denote time (Figure 1).

Figure 1 The timeline utilized to denote time with the initiation of penpulimab infusion as the reference point. IMC, immune-mediated cholangitis.

On day 383, the results of the outpatient examination indicated elevated levels of bilirubin and transaminases, prompting her admission to the hospital. Upon admission, the patient presented with mild jaundice, while abdominal pain was not prominent. Laboratory findings were as follows: total bilirubin (T-Bil) at 23.7 µmol/L, direct bilirubin (D-Bil) at 6.7 µmol/L, indirect bilirubin (I-Bil) at 17.0 µmol/L, alanine aminotransferase (ALT) at 907 U/L, aspartate aminotransferase (AST) at 564 U/L, and γ-glutamyltransferase (γ-GT) at 394 U/L. In order to make it more intuitive, the laboratory data at each stage of disease progression are summarized in Table 1. The following laboratory data reveals no abnormalities: complete blood count, quantitative analysis of hepatitis B serology, thyroid function, tumor marker assays [including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4), carbohydrate antigen 50 (CA50), among others], detection of antibodies associated with autoimmune liver diseases [including anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-mitochondrial antibody (AMA), etc.], evaluation of immune function (specifically humoral immunity), and immunoglobulin G4 (IgG4). Contrast-enhanced magnetic resonance imaging (CE-MRI) revealed significant thickening of the common bile duct accompanied by luminal stenosis, as well as marked dilatation of both intrahepatic and extrahepatic bile ducts, indicating a potential diagnosis of cholangitis. Additionally, gallbladder enlargement and cholecystitis were observed. The uncinate process of the pancreas appeared notably full.

Following a multidisciplinary discussion, the clinical diagnosis of IRC was considered. A liver biopsy was recommended to ascertain the etiology, and glucocorticoid therapy was proposed as a potential intervention if deemed necessary. During the patient’s hospitalization, an intravenous infusion of magnesium isoglycyrrhizinate (200 mg) was administered once daily. Additionally, polyene phosphatidylcholine (30 mL, equivalent to 1.1625 g) was infused intravenously once daily, and silibinin capsules (105 mg) were administered orally three times daily to address liver injury. On day 387, an 80 mg dose of methylprednisolone was introduced via micro-pump once daily. Subsequent liver function tests conducted on day 389 revealed the following results: T-Bil at 106.4 µmol/L, D-Bil at 58.9 µmol/L, I-Bil at 47.5 µmol/L, ALT at 694 U/L, AST at 291 U/L, alkaline phosphatase (ALP): 868 U/L and γ-GT at 381 U/L.

On day 389, the positron emission tomography-computed tomography (PET-CT) scan showed soft tissue density shadow in the hilar area, involving the common bile duct and hilar bile duct, intrahepatic bile duct dilatation, and mildly increased fluorodeoxyglucose (FDG) metabolism, which considered the possibility of inflammatory lesions. A liver core needle biopsy was conducted on day 390, with the pathological sections presented in Figure 2. The pathological analysis of the core needle biopsy revealed the preservation of the lobular structure, accompanied by enlargement and fibrosis of certain portal areas. Additionally, there was infiltration of mixed inflammatory cells, including lymphocytes, plasma cells, and neutrophils, as well as localized mild interface inflammation and bile duct injury. Lymphocyte infiltration was observed in the bile duct epithelium, along with scattered focal necrosis within the lobules, focal cholestasis, and localized hepatic sinusoidal dilatation. Magnetic resonance cholangiopancreatography (MRCP) showed obvious dilatation of intrahepatic and extrahepatic bile ducts and slender common bile duct on day 396 (Figure 3A).

Figure 2 The liver pathological section (hematoxylin-eosin staining, 100×) of ultrasound-guided core needle biopsy.

Figure 3 The key imaging data in diagnosis and treatment. (A) Obvious dilatation of intrahepatic and extrahepatic bile ducts and a slender common bile duct. (B) Image after percutaneous intrahepatic bile duct drainage. (C) Obvious thickening of the common bile duct with luminal stenosis, and obvious dilatation of the intrahepatic and extrahepatic bile ducts. (D) The obstruction was relieved after pancreaticojejunostomy.

Between day 391 and day 396, the levels of T-Bil and transaminase exhibited a temporary decline followed by an increase. Subsequently, the treatment regimen was adjusted to include methylprednisolone at a dosage of 120 mg (administered from March 8 to 12), mycophenolate mofetil at 500 mg twice daily, and ursodeoxycholic acid at 250 mg twice daily. Additionally, an interventional radiologist performed biliary stent placement and percutaneous intrahepatic bile duct drainage.

On day 400, the patient experienced abdominal pain and elevated levels of blood and urine amylase. To mitigate pancreatic enzyme secretion, somatostatin at 3 mg every 12 hours and ulinastatin at 200,000 IU three times daily were administered. The symptoms improved after drug treatment and the percutaneous drainage (Figure 3B), but the persistent pancreatic duct obstruction that repeatedly caused pancreatitis (Figure 3C) was eventually treated with a pancreatic duct jejunostomy on day 421. Meanwhile, pharmacological interventions aimed at liver protection and enzyme reduction were continued. Postoperatively, there was a significant reduction in the pancreatic enzyme and liver function markers, accompanied by an improvement in abdominal symptoms (Figure 3D). The patient was discharged on day 442. During the last follow-up on day 448, liver function and amylase levels were found to be within normal ranges. Variations in AST, ALT and T-Bil as time progresses are summarized in Figure 4.

Figure 4 Variations in AST, ALT and T-Bil levels as time progresses. ALT, alanine aminotransferase; AST, aspartate aminotransferase; T-Bil, total bilirubin.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

With the widespread clinical application of ICIs, irAEs are being increasingly recognized. Among these, IRC is relatively rare, accounting for only about 0.7% of all irAEs. Although uncommon, the clinical manifestations it induces are often severe, resulting in a poor prognosis with a mortality rate of approximately 4.5% (6,7). The incidence of IRP ranges from 1.05% to 7.2% (8). Current management strategies primarily include corticosteroid therapy (e.g., methylprednisolone) and, when necessary, the use of immunosuppressive agents (e.g., mycophenolate mofetil). Analogously, IRP is a rare occurrence; however, in severe cases, it can be caused by pancreatic duct obstruction. Recent findings by Pan et al. indicate that a small number of IRP induced by nivolumab, the pharmacological interventions proved ineffective, necessitating pancreaticoduodenectomy for patient recovery (9).

In 2017, Gelsomino et al. reported the first documented case of IRC (10). Subsequently, various similar cases were reported. Under these conditions, our investigation identified a correlation between the administration of the novel immunosuppressant, penpulimab, and the onset of IRC and IRP.

IRC and IRP adverse events associated with PD-1 or PD-L1 inhibitors generally manifest between 12 and 16 weeks post-treatment (11). However, there is a paucity of research on the pathogenesis, imaging characteristics, and clinicopathological features of IRC. Existing studies suggest that IRC represents a distinct form of immune-related hepatotoxicity, primarily involving a T lymphocyte-mediated hypersensitivity reaction. The mechanisms underlying IRC induced by PD-1/PD-L1 inhibitors and CTLA-4 inhibitors exhibit subtle differences. Furthermore, while bile duct epithelial cells are capable of participating in the metabolism of exogenous substances, they lack protective mechanisms such as the glutathione redox metabolic cycle. These cells express toll-like receptors (TLRs) and human leukocyte antigen (HLA) class I and II molecules; however, they do not express these molecules at levels adequate for effective antigen presentation. Consequently, biliary epithelial cells may serve as initiators of T lymphocyte-mediated hypersensitivity reactions (12-14).

Based on the anatomical configuration of the biliary system, IRC is categorized into three types: small bile duct type, large bile duct type, and mixed type. Bile duct injury is more frequently associated with treatment involving PD-1/PD-L1 inhibitors. The imaging characteristics of intrahepatic and extrahepatic large bile duct IRC encompass three primary aspects: (I) non-obstructive bile duct dilatation or bile duct stenosis, which may be segmental or diffuse; (II) enhancement, thickening, and irregularity of the bile duct wall; and (III) changes in adjacent structures, such as gallbladder edema, thickening of the gallbladder wall, and edema of Gleason’s sheath. In contrast, small bile duct IRC typically lacks distinctive imaging features (15). The pathological manifestations of IRC lack specificity, which poses significant diagnostic challenges (16).

In this instance, observations included bile duct dilatation, thickening of the bile duct wall accompanied by lumen stenosis, and significantly elevated levels of bile duct and liver enzymes, while IgG4 and other immune function markers remained within normal ranges. A PET-CT examination suggested that the biliary obstruction was attributable to inflammatory lesions. A liver biopsy revealed lymphocyte infiltration, corroborating the aforementioned findings. However, due to the absence of a biopsy of the common bile duct, the potential presence of a malignant tumor could not be entirely excluded.

The incidence of IRP is relatively low, typically occurring within a timeframe of 3 weeks to 14 months following treatment. Most instances present atypically, characterized by elevated levels of amylase and/or lipase, and may not exhibit the typical imaging features associated with pancreatic exudation (17-20). In this instance, the patient experienced abdominal pain during treatment, accompanied by elevated blood and urine amylase levels. Imaging studies revealed pancreatic enlargement and dilation of the pancreatic duct. Pancreatitis in this patient may be related to obstruction of the common bile duct or ampulla caused by thickening and stenosis of the bile duct wall, or may be related to ICIs itself.

For severe irAEs, the majority of clinical guidelines advocate for the administration of glucocorticoids. In cases where there is no substantial improvement, it is advised to proceed with second-line immunosuppressive therapy, with mycophenolate mofetil being a frequently utilized option. Currently, glucocorticoids have demonstrated limited efficacy in the management of IRC and IRP, and ursodeoxycholic acid is also employed in the treatment of immune-mediated cholangitis (IMC) (15,21). There is no standard treatment for IRC, which is usually referred to immune-mediated hepatitis, and the treatment effect is worse than immune-mediated hepatitis. To date, reports of penpulimab-associated cholangitis and pancreatitis are scarce, and the underlying pathogenesis remains to be elucidated. Further clinical data are essential to inform treatment decisions for irAEs.

Conclusions

To the best of our knowledge, this report is the first to identify cholangitis and pancreatitis as complications associated with the treatment of tumors using the novel ICI, penpulimab. This case offers valuable insights into the diagnosis and treatment of irAEs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-169/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-169/prf

Funding: This report was supported by Zhejiang Province Medicine and Health Science and Technology Plan Project (Nos. 2021KY250, 2022KY966 and 2025KY1094).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-169/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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

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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