Postoperative Cholestasis and Cholangitis After Total Pancreatectomy with Biliary Reconstruction Impair the Function of Autotransplanted Islets

Total pancreatectomy (TP) with islet autotransplantation (IAT) is a good therapeutic option for benign pancreatic diseases that require TP (1). In general, TP requires resection and reconstruction of the common bile duct by choledochojejunostomy. Therefore, postoperative cholangitis may occur after reconstruction of the biliary tract (2). Although TP with IAT has usually been performed into the liver (3), the influence of postoperative cholestasis and cholangitis on transplanted islets remains unclear. Herein, we report a case that underwent TP with IAT for pancreatic arteriovenous malformation and had repeated postoperative cholangitis and subsequent impairment of glucose tolerance. A 59-year-old man with abdominal pain was admitted to our hospital. The diagnosis was acute pancreatitis caused by pancreatic arteriovenous malformation. He had a re-attack of pancreatitis with pseudocystic hemorrhage after admission. Considering the situation of repeated pancreatitis with hemorrhage and infection, and the possibility of recurrence after palliative transarterial chemoembolization, we performed emergency TP with IAT. Biliary reconstruction was performed by choledochojejunostomy in a Roux-en-Y fashion. Islet isolation was performed by a modified Ricordi method using Liberase MTF-C/T (Roche, Indianapolis, IN). Warm and cold ischemia times were within 10 and 74 min. In total, 355,270 islet equivalents were acquired and transplanted into the liver. After transplantation, control of the blood glucose level was continued with intensive insulin therapy and glucagon-like peptide-1 receptor agonists (Fig. 1). Six months after transplantation, the patient suffered from postoperative cholangitis with a high fever. Laboratory data showed elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), and a slight increase of total and direct bilirubin (Fig. 1C,D). Enhanced computed tomography showed dilatation and enhanced walls of the bilateral intrahepatic bile duct. Because the general condition of the patient was good and laboratory data showed only a mild increase in the inflammatory response, he was initially treated with antibiotics and careful observation in an outpatient setting. The cholangitis showed immediate remission after the initial treatment. It was considered that the cause of the postoperative cholangitis was mainly the transient cholestasis and that there was no significant anastomotic stricture requiring additional interventional therapy. Consequently, oral administration of ursodeoxycholic acid (UDCA) was administered for the prevention of biliary cholestasis. In terms of endocrine function, although laboratory data showed a high C-peptide level (1.17 ng/mL at 3 months after transplantation), it eventually decreased to 0.32 mg/mL after the cholangitis and the hemoglobin A1c (HbA1c) level (5.3% at 3 months after transplantation) gradually increased after the cholangitis (Fig. 1B).FIGURE 1: Time courses of daily insulin use with GLP-1 receptor agonist (A), serum C-peptide, and HbA1c (B). Time courses of serum biliary enzymes (ALP and γ-GTP; C) and serum liver enzymes (AST and ALT) and total bilirubin (D).The patient was diagnosed as postoperative cholangitis again 13 months after transplantation. After the administration of oral antibiotics again, the patient immediately recovered from the cholangitis. However, laboratory data showed a tendency toward increased ALP levels as well as γ-GTP levels (Fig. 1C). Furthermore, the AST and ALT levels occasionally showed slight elevations, although within normal limits (Fig. 1D). The HbA1c levels showed an upward tendency and reached 7% (Fig. 1B). Daily insulin use gradually increased (Fig. 1A). The C-peptide levels decreased markedly 18 months after transplantation, eventually reaching 0.14 ng/mL at 23 months after transplantation (Fig. 1B). It is unknown how postoperative cholestasis and cholangitis may affect the viability of transplanted pancreatic islets, but we speculated that both factors, the cholestasis and the local or systemic inflammation, were major contributors. The mechanism is unclear, but some studies have provided clues. Muchova et al. revealed a mechanism of liver damage due to bile acid accumulation resulting from cholestasis. They mentioned that bile acid accumulating in hepatocytes led to liver damage including structural and functional injuries of the hepatocyte membrane, cell death, and activation of inflammatory signaling pathways (4). Furthermore, bile acids are implicated in the pathogenesis of cholestatic liver damage through mechanisms involving oxidative stress, which is critically involved in the impairment of β-cell function (5, 6). UDCA has major beneficial effects in protecting against cytotoxity due to bile acid, involving mechanisms that stimulate hepatobiliary secretion and antioxidant activity and inhibit hepatocyte apoptosis (7). In the present case, although the patient had been continuously treated using UDCA since the first episode, unfortunately, he developed cholangitis again. Dilation or the reconstruction of choledochojejunostomy might be a suitable choice for preventing cholangitis and islet impairment. Therefore, for the purpose of protecting the transplanted islets, patients who undergo TP with IAT should be intensively monitored for the early detection and treatment of cholangitis. Further investigations concerning the influence of cholestasis and cholangitis on the viability or function of transplanted islets into liver will be needed. Tatsuo Hata 1 Naoaki Sakata1 Takeshi Aoki1 Gumpei Yoshimatsu1 Haruyuki Tsuchiya1 Hiroki Hayashi1 Fuyuhiko Motoi1 Masafumi Goto2 Yu Katayose1,3 Shinichi Egawa4 Michiaki Unno1 1 Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. 2 New Industry Creation Hatchery Center, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. 3 Division of Integrated Surgery and Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. 4 Division of International Cooperation for Disaster Medicine, International Research Institute of Disaster Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. ACKNOWLEDGMENT The authors thank all the staff members who joined this clinical project.