Endoscopic ultrasound‐guided biliary drainage of hilar biliary obstruction

Only 20–30% of patients with hilar cholangiocarcinoma (CC) are candidates for potentially curative resection. However, even after curative (R0) resection, these patients have a disease recurrence rate of up to 76%. The prognosis of hilar cholangiocarcinoma (CC) is limited by tumor spread along the biliary tree leading to obstructive jaundice, cholangitis, and liver failure. Therefore, palliative biliary drainage may be a major goal for patients with hilar CC. Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is an established method for palliation of patients with malignant biliary obstruction. However, there are patients for whom endoscopic stent placement is not possible because of failed biliary cannulation or tumor infiltration that limits transpapillary access. In this situation, percutaneous transhepatic biliary drainage (PTBD) is an alternative method. However, PTBD has a relatively high rate of complications and is frequently associated with patient discomfort related to external drainage. Endoscopic ultrasound‐guided biliary drainage has therefore been introduced as an alternative to PTBD in cases of biliary obstruction when ERCP is unsuccessful. In this review, the indications, technical tips, outcomes, and the future role of EUS‐guided intrahepatic biliary drainage, such as hepaticogastrostomy or hepaticoduodenostomy, for hilar biliary obstruction will be summarized.     

Recent advances in endoscopic ultrasound‐guided biliary drainage

Endoscopic ultrasound‐guided biliary drainage (EUS‐BD) is increasingly used as an alternative in patients with biliary obstruction who fail standard endoscopic retrograde cholangiopancreatography (ERCP). The two major endoscopic approach routes for EUS‐BD are the transgastric intrahepatic and the transduodenal extrahepatic approaches. Biliary drainage can be achieved by three different methods, transluminal biliary stenting, transpapillary rendezvous technique, and antegrade biliary stenting. Choice of approach route and drainage method depends on individual anatomy, underlying disease, and location of the biliary stricture. Recent meta‐analyses have revealed that cumulative technical success and adverse event rates were 90–94% and 16–23%, respectively. Development of new dedicated devices for EUS‐BD would help refine the technical aspects and minimize the possibility of complications, making it a more promising procedure.     

Antimitochondrial antibody‐negative primary biliary cirrhosis: a subset of primary biliary cirrhosis

Objective: Antimitochondrial antibodies (AMA) are the hallmark in primary biliary cirrhosis (PBC); nevertheless, it has long been recognized that 5–10% patients with typical features compatible with PBC do not have detectable AMA, and they were referred to as ‘AMA‐negative PBC’. This study aimed to evaluate whether AMA‐negative/positive PBC represents different clinical entities. Methods: We compared the clinical, laboratory, percentage of regulatory T cells (Tregs) in peripheral blood, liver biopsy features and response to treatment of the two groups of patients. The first group was comprised of 12 patients with ‘AMA‐negative PBC’. The second was made up of another 12 PBC patients with positive AMA. Results: Antimitochondrial antibodies‐negative/positive patients were remarkably similar in terms of clinical manifestations, liver biochemistries and histological findings. The frequency of anti‐nuclear antibodies, anti‐smooth‐muscle antibody, anti‐gp210 and anti‐sp100 antibody showed no significant difference between the two groups. A significantly lower mean percentage of CD4⁺CD25^high T cells was observed in peripheral blood mononuclear cells of AMA‐negative/positive PBC patients compared with that of the 12 control subjects (5.8±1.8 and 5.4±1.4% vs. 7.6±1.7% respectively; P=0.014 and 0.004). However, no difference could be found between AMA‐negative and AMA‐positive PBC patients (P=0.599). After 1 year treatment with ursodeoxycholic acid, the two groups showed similar response. Conclusion: Antimitochondrial antibody‐negative/positive PBC patients are similar in clinical, laboratory, percentage of Treg in peripheral blood, liver biopsy features and response to treatment. This suggests that AMA‐negative PBC may be a variant of AMA‐positive PBC rather than a separate clinical entity.     

Endoscopy after radiology: Two‐step combined therapy for biliary stricture after Roux‐en‐Y hepaticojejunostomy

Benign postoperative anastomotic strictures after hepaticojejunostomy are difficult to manage. Before interventional techniques were developed, surgical intervention was the only option for treatment. A 28‐year‐old man underwent Whipple procedure with Roux‐en‐Y hepaticojejunostomy for abdominal trauma. Two years later, a late anastomotic biliary stricture was diagnosed. A percutaneous cholangiography showed a severe stricture in the hepaticojejunostomy. Because of the severity and length of the stricture, and the failure of repeated percutaneous balloon‐dilations, we percutaneously placed a self‐expandable metal stent, a nitinol polytetrafluoroethylene fully covered flared‐type stent, 3 cm in length, with 10 mm of diameter. The patient was soon discharged home in good general condition that remained stable in the 6 months of follow up. To remove the biliary stent, we carried out single‐balloon enteroscopy. The stent was captured with a standard polypectomy snare. To avoid injury to the mucosa, the stent was removed through the overtube, which remained in situ. Cholangiogram showed a normal biliary tree, with resolution of the anastomotic stenosis. The patient remained stable throughout the 8 months of follow up, and required no further biliary procedures. In cases of failure of standard procedures, this new two‐step, combined percutaneous and endoscopic approach can be useful and feasible, avoiding surgery‐related morbidity and mortality. However, the fact that these procedures should be carried out only by highly experienced endoscopists and interventional radiologists familiar with these specialized procedures cannot be overstressed.     

Significance of periductal Langerhans cells and biliary epithelial cell‐derived macrophage inflammatory protein‐3α in the pathogenesis of primary biliary cirrhosis

Background/aims: To clarify the primary biliary cirrhosis (PBC)‐specific antigen‐presenting mechanism, we examined the distribution and phenotypic characteristics of infiltrating dendritic cells (DCs) with respect to bile ducts and the mechanism of migration in terms of the periductal cytokine milieu and biliary innate immunity. Methods and results: Immunohistochemistry using liver sections from patients with PBC and controls revealed that blood dendritic cell antigen (BDCA)‐2⁺ plasmacytoid DCs were found mainly in the portal tracts in PBC and the controls, but their distribution was not related to bile ducts. BDCA‐1⁺ and CD19^? myeloid DCs were also found in portal tracts in PBC and the controls and, in particular, Langerin+Langerhans cells (LCs) were dominantly scattered around or within biliary epithelial layers of the damaged bile ducts in PBC. Moreover, experiments with cultured human biliary epithelial cells (BECs) showed that an LC‐attracting chemokine, macrophage inflammatory protein‐3α, was produced by BECs in the response to cytokines [interleukin (IL)‐1β, tumour necrosis factor‐α and IL‐17] and pathogen‐associated molecular patterns. Conclusions: LCs existing around or within biliary epithelial layers are important as periductal antigen‐presenting cells in PBC and the migration of LCs into bile ducts is closely associated with the periductal cytokine milieu and biliary innate immunity in PBC.     

Hepatic Met‐enkephalin immunoreactivity is enhanced in primary biliary cirrhosis

Abstract: Background/aims: In contrast to the normal adult liver, the fetal human and rat livers, and the liver of rats with cholestasis secondary to bile duct resection (BDR) express the preproenkephalin (ppENK) mRNA, which codes for the endogenous opioid peptide Met‐enkephalin. In addition, Met‐enkephalin immunoreactivity (MEIR) is detected in hepatocytes and in proliferating bile ductules in the cholestatic rat liver. These data suggest that cholestasis is associated with the resurgence of cells that produce Met‐enkephalin. To explore further the status of opioids in cholestasis, we studied the expression of MEIR in liver tissue. Methods: The MEIR was sought in paraffin‐preserved liver tissues from patients with primary biliary cirrhosis (PBC) (n = 10). Results: The MEIR was detected in all the PBC livers. Its intensity varied from weak to strong on hepatocytes and bile ducts and the strongest expression appeared as coarse granules. The MEIR was either absent or only faintly expressed by some hepatocytes from disease and nondisease control biopsies, but absent from bile ducts. Conclusion: These results suggest that the human liver in cholestasis may be a source of endogenous opioids.     

Interleukin‐8: A critical chemokine in biliary atresia

Biliary atresia (BA) is characterized by periductular inflammation and fibrosis and is associated with the progressive obliteration of the bile ducts. The induction and maintenance of systemic and local inflammatory responses plays a pivotal role in this process. Interleukin‐8 (IL‐8) is an important mediator of inflammation and the immune response in human disease. IL‐8 is overexpressed in BA, and its expression positively correlates with inflammation and liver fibrosis. In this review, we focus on the available evidence, recent insights, and future clinical and preclinical possibilities regarding the role of IL‐8 in BA.