Nivolumab-induced large-duct cholangiopathy treated with ursodeoxycholic acid and tocilizumab.

Immune checkpoint inhibitor therapy has become a cornerstone in the management of many oncologic diseases. Although it is well tolerated in most patients, a wide spectrum of adverse events has been described as a result of immune system alteration. We present a case of a woman with metastatic bronchogenic adenocarcinoma who was initially thought to have immune-mediated hepatitis, but eventually discovered to have a rarely described immune-mediated cholangiopathy. Her cholangiopathy appeared to stabilize following ursodeoxycholic acid and tocilizumab after several lines of guideline-directed therapy. Awareness of this unique toxicity following immune checkpoint inhibitor, and potential treatment options may help clinicians manage this rare but serious complication.

[A consensus statement on the standardized application of antibacterial agents in biliary tract surgery (2019)].

The standardized application of antibacterial agents in the treatment of biliary tract diseases is of great significance.On the basis of international and domestic guidelines and consensuses, combining with the actual situation of Chinese biliary tract infection, Study Group of biliary Tract Surgery in Chinese Society of Surgery of Chinese Medical Association and Enhanced Recovery After Surgery Committee of Chinese Research Hospital Association and Editorial Board of Chinese Journal of Surgery organized experts to make recommendations which adopted a problem-oriented approach on the severity grade of biliary tract infection, the protocol of specimen examination, the use of antibiotics, the indication of drug withdrawal, the agents application strategy of drug-resistant bacteria infection and special situation to guide surgeons getting the accurate judgement of the severity of biliary tract infection and the formulation of standard protocols for the use of antibacterial agents on the premise of following the bacteriological and drug resistance monitoring information.

Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases ß-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1ß and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.

Brentuximab vedotin in combination with sequential procarbazine, cyclophosphamide and prednisolone for the management of Hodgkin's lymphoma-associated vanishing bile duct syndrome (VBDS) with severe obstructive liver failure.

We present a novel treatment protocol that was successful in the management of Hodgkin's-associated vanishing bile duct syndrome, a rare but serious complication of Hodgkin's lymphoma. We believe that publication of this treatment protocol and the rationale for its development will be of interest to anyone faced with treating this challenging condition.

Cholangiocyte death in ductopenic cholestatic cholangiopathies: Mechanistic basis and emerging therapeutic strategies.

Among hepatic diseases, cholestatic ductopenic cholangiopathies are poorly studied, and they are rarely given the importance they deserve, especially considering their high incidence in clinical practice. Although cholestatic ductopenic cholangiopathies have different etiologies and pathogenesis, all have the same target (the cholangiocyte) and similar mechanistic basis of cell death. Cholestatic cholangiopathies are characterized, predominantly, by obstructive or functional damage in the biliary epithelium, resulting in an imbalance between proliferation and cholangiocellular death; this leads to the progressive disappearance of bile ducts, as has been shown to occur in primary sclerosing cholangitis, primary biliary cholangitis, low-phospholipid-associated cholelithiasis syndrome, cystic fibrosis-related liver disease, and drug-induced ductopenia, among other biliary disorders. This review summarizes the features of the more common ductopenic syndromes and the cellular mechanisms involved in cholengiocellular death, with focus on the main forms of cholangiocyte death described so far, namely apoptosis, autophagy, necrosis, and necroptosis. It also emphasizes the importance to study in depth the molecular mechanisms of cholengiocyte death to make possible to counteract them with therapeutic purposes. These therapeutic strategies are limited in number and efficacy at present, and this is why it is important to find complementary, safe strategies to stimulate cholangiocellular proliferation in order favor bile duct replenishment as well. Successful in finding appropriate treatments would prevent the patient from having liver transplantation as the only therapeutic alternative.

Unusual case of duodenobiliary fistula complicating Crohn's disease successfully treated with Adalimumab.

Crohn's disease (CD) is characterized by transmural inflammation of the gastrointestinal tract, which predisposes to the formation of fistula. Duodenal involvement occurs in less than 5% of cases and often leads to clinically relevant strictures. However, fistula formation in the duodenum is exceptional. Herein, we report an unusual case of duodenobiliary fistula due to CD occurring in a 65-year-old patient who was successfully treated by anti-tumor necrosis factor (TNF) agents. This case report highlights the efficacy of anti-TNF alpha agents in the treatment of a bilioenteric fistula because it increases the probability of clinical remission and mucosal healing and therefore reduces the need for surgical treatment which may be associated morbidity.

Bevacizumab to Treat Cholangiopathy in Hereditary Hemorrhagic Telangiectasia: Be Cautious: A Case Report.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular dysplasia characterized by mucocutaneous telangiectasia and visceral arteriovenous malformations. Hepatic involvement with vascular malformations may lead to portal hypertension, biliary ischemia, and high-output cardiac failure. There is no curative treatment for the disease. Liver transplantation is indicated for life-threatening complications, but it carries significant risk due to surgery and immunosuppressive treatment. Some case reports or small open studies suggest that bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, should be efficient in limiting bleeding and in reducing liver disease in HHT.We report a case of a 63-year-old woman with HHT presenting with ischemic cholangiopathy. Liver transplant was indicated, but given a previous encouraging report showing a regression of biliary disease with bevacizumab in 3 patients with HHT this drug was proposed. No significant efficacy but a severe adverse effect was observed after 3 months: bilateral pulmonary embolisms, thrombosis in the right atrial cavity, and thrombosis of the right hepatic vein were evidenced. Bevacizumab was stopped; anticoagulant started. Four months later, the patient received a transplanted liver. She feels well 1 year later.This case report intends to provide the information for clinicians to consider the use of bevacizumab in HHT. Whereas several uncontrolled series and case reports have suggested the efficacy of this drug in reducing bleeding and liver disease, no severe side effects were mentioned to date. For the first time in HHT we report a life-threatening side effect of this drug and no efficacy. Moreover, systemic thrombosis, the observed complication, may preclude transplantation. To date, caution seems still indispensable when considering the use of bevacizumab in HHT.

[The therapeutic mechanisms of sirolimus treatment for ischemic-type biliary lesions after liver transplantation].

OBJECTIVE: To investigate the pathogenesis of ischemic-type biliary lesions (ITBLs) in post-liver transplant patients and the possible therapeutic mechanisms of sirolimus. METHODS: The clinic data of 32 post-liver transplant patients with ITBLs from May 2004 to December 2010 was analyzed. There were including 25 male and 7 female patients with a median age of 46 years (ranging from 19 to 61 years). Patients were divided into those who received sirolimus (sirolimus group) and those who did not (control group). The expression of IL-2, FoxP3, and IL-10 in the portal area, liver function indexes, and bile duct injury score were assessed pre-ITBL, when ITBLs were identified, and after 6 months of sirolimus treatment. RESULTS: Compared with pre-ITBL optical density (OD) values, there was a significantly increase in IL-2 OD(0.138 ± 0.050 in control group and 0.141 ± 0.052 in sirolimus group), but not FoxP3 and IL-10 OD in both groups at the time ITBLs were diagnosed. After 6 months of treatment, the IL-2, FoxP3, and IL-10 OD values in the control group were not different from those when ITBLs were diagnosed. There was a significant reduction in post-therapy IL-2 OD(0.107 ± 0.043, t = 2.087, P = 0.044), and a significant elevation in FoxP3(0.213 ± 0.039) and IL-10 OD(0.187 ± 0.048) in sirolimus group as compared with those when ITBLs were diagnosed(t = -3.822 and -4.350, both P < 0.01). There was a significant increase in serum levels of ALT, AST, total bilirubin, γ-glutamyl transpeptidase and ALP at the time ITBLs were diagnosed compared with pre-ITBL levels in both groups. After 6 months of treatment, the above indexes had not changed in the control group, but significantly improved in the sirolimus group, and the bile duct injury score in the sirolimus group had significantly decreased(4.4 ± 2.4, Z = -2.568, P = 0.010). The 1-year and 3-year graft survival rates in the control group were 6/13 and 5/13, respectively, and 17/19 and 13/19, respectively, in the sirolimus group (χ(2) = 7.166, P = 0.007; χ(2) = 5.398, P = 0.020, respectively). CONCLUSIONS: Sirolimus can downregulate IL-2 expression and upregulate FoxP3 and IL-10 expression, thereby stimulating FoxP3+ Treg cells, suppressing immunopathological damage, and promoting epithelial repair in bile ducts.

Endoscopic ultrasound-guided injection therapy for hepatobiliary disease.

Endoscopic ultrasound (EUS)-guided injection therapy is the new frontier in the management of patients with hepatobiliary disease. Celiac plexus block/neurolysis was the first form of injection therapy and has been validated in many subsequent trials. Cyst ablation therapy, fiducial insertion, angiography, portal hypertensive therapy, endoscopic portosystemic shunt creation, portal vein embolization and injection of chemotherapeutic/biologic agents for antitumor therapy are more recent uses and will be discussed. Celiac plexus neurolysis is currently well established in providing adjunct pain control in patients with advanced malignancy. There are limited data available for its use in benign conditions. EUS-guided ablative therapy for pancreatic cysts remains an area for future research but seems to have a role for small thin-walled non-septated cysts. EUS-guided implantation of fiducials is technically feasible but its exact impact on tumor regression is unknown. Several case reports have documented EUS-guided alcohol and thrombin injection into pseudoaneurysms and cyanoacrylate and coil embolization for variceal therapy. Injection of viral vectors and immunomodulating cell cultures as antitumor therapy has been described but the evidence is still preliminary and further data are awaited.

[Survival benefits of chemotherapy for unresectable biliary tract cancer--a multicenter retrospective analysis].

There is no agreement on the standard chemotherapeutic regimen for biliary tract cancer(BTC), although multi-drug regimens such as gemcitabine and/or S-1 have been tested in clinical trials. This study retrospectively reviewed data from patients with BTC who were seen at hospitals in the Kitakyushu and Fukuoka areas between 2005 and 2006, and examined the effect of systemic chemotherapy regimen on survival benefits in patients with unresectable BTC. Chemotherapy may benefit patients with BTC any age group, regardless of the primary site.

Cholangiociliopathies: genetics, molecular mechanisms and potential therapies.

PURPOSE OF REVIEW: The present review summarizes recent knowledge on polycystic liver diseases (PCLDs), mechanisms of hepatic cystogenesis and potential therapies for these conditions. RECENT FINDINGS: PCLD may be classified as cholangiociliopathies. In PCLD associated with polycystic kidney disease, cell proliferation is one of the major mechanisms of cystogenesis, whereas in isolated PCLD (autosomal dominant polycystic liver disease), disrupted cell adhesion may be more important in cyst progression. In cystic cholangiocytes, overexpression of ion transporters and water channels facilitates fluid secretion into the cystic lumen, and growth factors, estrogens and cytokines promote cholangiocyte proliferation. With age, cholangiocytes lining liver cysts acquire features of mesenchymal cells contributing to hepatic fibrocystogenesis. A novel mechanism of liver cyst expansion in PCLD involves microRNA regulatory pathways. Hyperproliferation of cystic cholangiocytes is linked to abnormalities in cell cycle progression and microRNA expression. Decreased levels of miR-15a are coupled to upregulation of its target--the cell cycle regulator, Cdc25A. Cholangiocyte cilia in liver cysts are structurally abnormal. Somatostatin analogues and sirolimus reduce liver cyst volume in PCLD patients. SUMMARY: Clarification of molecular mechanisms of hepatic cystogenesis provides an opportunity for the development of targeted therapeutic options in PCLD.

Treatment of hepatolithiasis by chemical bile duct embolization: report on 2 cases.

The high recurrence of hepatolithiasis has not been settled effectively until now, which lead us to present a new therapy of the chemical bile duct embolization to resolve it. In our selected 2 patients, multiple biliary calculi, complicated by biliary stricture, were found in the inferior branch of left lateral bile duct via preoperative cholangiography. After the choledochoscopic cholelithotomy, the combination of absolute ethanol and N-butyl-cyanoacrylate were injected into the diseased biliary duct lumen. Two months later, their T-tube cholangiography demonstrated that the targeted biliary ducts were completely embolized, thus effectively preventing the calculous recurrence. Twelve and 15 months later, their computed tomography scan showed that the inferior segments of left lateral lobes were almost completely atrophied and disappeared, thus successfully achieving the chemical "resection" of the diseased hepatic lobe. Chemical bile duct embolization may be a feasible and safe technique to prevent the calculous recurrence and concurrently achieve the effect of chemical hepatectomy for highly selected hepatolithiasis cases.

Biliary tract infection and bacteraemia: presentation, structural abnormalities, causative organisms and clinical outcomes.

BACKGROUND: Biliary tract infection is a common cause of bacteraemia and is associated with high morbidity and mortality. Few papers describe blood culture isolates, underlying structural abnormalities and clinical outcomes in patients with bacteraemia. AIMS: To determine the proportion of bacteraemias caused by biliary tract infection and to describe patient demographics, underlying structural abnormalities and clinical outcomes in patients with bacteraemia. DESIGN: Prospective cohort study. METHODS: Biliary tract infection that caused bacteraemia was defined as a compatible clinical syndrome and a blood culture isolate consistent with ascending cholangitis. Patients aged 16 years and over were included in the study. From June 2003 to May 2005, demographic and clinical data were collected prospectively on all adult patients with bacteraemia. Radiological and endoscopic retrograde cholangiopancreatography findings were collected retrospectively. RESULTS: In 49 patients, the biliary tract was the site of infection for 39/592 (6.6%) community-acquired and 19/466 (4.1%) hospital-acquired episodes of bacteraemia. Three patients had mixed bacteraemias, and four had recurrent bacteraemia. The proportion of patients presenting with a structural abnormality was 34/49 (69%), and, of these structural abnormalities, 18/34 (53%) were pre-existing or newly diagnosed malignancies. Gram-negative organisms caused 55/58 (95%) episodes of bacteraemia. The most common Gram-negative organisms were Escherichia coli (34/55; 62%) and Klebsiella pneumoniae (14/55; 26%). Of the E coli isolates, 6/34 (18%) were extended spectrum beta-lactamase producers or multiply drug resistant. Thirty-day mortality was 7/49 (14%). There was no difference in time taken to administer an effective antibiotic to survivors and non-survivors (0.86 vs 1.05 days, respectively, p = 0.92). Of the seven who died, four died from septic shock within 48 h of admission caused by "susceptible" Gram-negative organisms. Two others died from disseminated malignancy. CONCLUSIONS: The proportion of bacteraemias caused by biliary tract infection was 5.5%. The most common infecting organisms were E coli and K pneumoniae. There was a strong association with choledocholithiasis and malignancies, both pre-existing and newly diagnosed. Death was uncommon but when it occurred was often caused by septic shock within 48 h of presentation.