Early γGT and bilirubin levels as biomarkers for regeneration and outcomes in damaged bile ducts after liver transplantation.

BACKGROUND: Early patient and allograft survival after liver transplantation (LT) depend primarily on parenchymal function, but long-term allograft success relies often on biliary-tree function. We examined parameters related to cholangiocyte damage that predict poor long-term LT outcomes after donation after brain death (DBD). METHODS: Sixty bile ducts (BD) were assessed by a BD damage-score and divided into groups with "major" BD-damage (n = 33) and "no relevant" damage (n = 27) during static cold storage. Patients with "major" BD damage were further investigated by measuring biliary excretion parameters in the first 14 days post-LT (followed-up for 60-months). RESULTS: Patients who received LT showing "major" BD damage had significantly worse long-term patient survival, versus grafts with "no relevant" damage (p = .03). When "major" BD damage developed, low bilirubin levels (p = .012) and high gamma-glutamyl transferase (GGT)/bilirubin ratio (p = .0003) were evident in the early post-LT phase (7-14 days) in patients who survived (> 60 months), compared to those who did not. "High risk" patients with bile duct damage and low GGT/bilirubin ratio had significantly shorter overall survival (p < .0001). CONCLUSIONS: Once "major" BD damage occurs, a high GGT/bilirubin ratio in the early post-operative phase is likely indicator of liver and cholangiocyte regeneration, and thus a harbinger of good overall outcomes. "Major" BD damage without markers of regeneration identifies LT patients that could benefit from future repair therapies.

Prevalence and clinical significance of portal inflammation, portal plasma cells, interface hepatitis and biliary injury in liver biopsies from patients with non-alcoholic steatohepatitis.

The significance of portal tract histological changes in non-alcoholic fatty liver disease (NAFLD) remains unclear. In 2019, CymaBay Therapeutics halted clinical trials of seladelpar (a PPARδ agonist) because initial end-of-treatment liver biopsies of patients with non-alcoholic steatohepatitis (NASH) showed concerning features of portal inflammation with plasma cells, interface hepatitis and focal bile duct abnormalities. Adjudication concluded that these findings were present in the initial, as well as the subsequent biopsies. Thus, this study's aim was to determine the prevalence and clinical significance of portal inflammation, portal plasma cells, interface hepatitis and features of bile duct damage in liver biopsies of adult patients with NAFLD. The pathology database was searched for cases of NAFLD, including steatosis alone and NASH, from January 2016 to October 2020. Liver biopsies were selected from age and sex matched adult patients with diagnoses of steatosis alone (n=10), NASH fibrosis stage 1 (n=10), stage 2 (n=10), stage 3 (n=10), and stage 4 (n=10). There were 24 males and 26 females with a mean age of 48 years (range 20-79). Exclusion criteria included age <18 years, daily alcohol intake >14 drinks per week, elevation of alkaline phosphatase level, comorbid chronic liver disease, or liver biopsy performed as part of a clinical trial for NASH. Control liver biopsies were selected from age and sex matched persons without significant steatosis and normal liver biochemical tests (n=10). Histological parameters were evaluated in 10 portal tracts or 10 septal areas in each liver biopsy. Portal inflammation and interface hepatitis were graded on a scale of 0-4. Portal plasma cells and bile duct damage were scored from 0-3. Ductular proliferation was assessed by CK7 immunostain and graded from 0-4. NASH biopsies with advanced fibrosis (stage 3 and 4) showed portal inflammatory infiltrates (score 2-3) with readily identifiable plasma cells (score 2), and mild to moderate interface hepatitis (score 2-3). All cases and controls showed focal, mild cholangiocyte changes, characterised by cytoplasmic vacuolation, segmental loss of nuclei, nuclear disarray and apoptosis. NASH patients with advanced fibrosis had frequent and diffuse cholangiocyte changes, along with focal lymphocytic cholangitis and moderate to marked ductular reaction (score 3-4). Histopathological features of advanced NASH frequently include increased portal inflammation with plasma cells, interface hepatitis, cholangiocyte injury and prominent ductular reaction.

Cyr61 Alleviates Cholangitis by Inhibiting Cytotoxic Effects of CD8+ T Cells on Biliary Epithelial Cells.

OBJECTIVE: Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease. In recent years, researchers have found that cysteine-rich angiogenic inducer 61 (Cyr61, also known as CCN1) has a potential role in reducing portal inflammation in patients with PBC. This study aimed to explore the relationship between Cyr61 and PBC to provide new ideas and an experimental basis for the clinical treatment of PBC. METHODS: After induction of the overexpression of Cyr61 in a mouse model of PBC using recombinant adenovirus, hematoxylin and eosin staining and pathological scores were used to indicate intrahepatic inflammation and bile duct damage. Real-time PCR was used to detect changes in inflammation-related cytokines in the liver. To further study the mechanism, we assessed whether Cyr61 protects bile duct epithelial cells from cytotoxic effects. RESULTS: Serum and hepatic Cyr61 levels were increased in the murine model of PBC. Overexpression of Cyr61 alleviated hepatic inflammation and bile duct injury in vivo. Cyr61 inhibited the cytotoxic effects of CD8+ T cells by acting on biliary epithelial cells (BECs) in vitro. CONCLUSION: Our results provide novel insight into the pathogenesis of PBC and suggest that Cyr61 plays a dominant role in the cytotoxic effects on BECs in PBC. Consequently, therapeutic strategies targeting Cyr61 could be a potent therapy for PBC.

Novel mechanism of hepatobiliary system damage and immunoglobulin G4 elevation caused by Clonorchis sinensis infection.

Clonorchis sinensis infection is still a major public health problem. It is estimated that more than 15 million people worldwide are infected, especially in Northeast China, Taiwan, South Korea, and North Vietnam. The detection of Clonorchis sinensis eggs in feces and bile is still the only gold standard for the diagnosis of Clonorchis sinensis infection, and new detection methods are needed to improve the detection rate. After Clonorchis sinensis invades the human body, it mainly parasitizes the hepatobiliary tract. Therefore, it is closely related to hepatobiliary diseases such as cholangitis, bile duct stones, liver fibrosis, and cholangiocarcinoma. The increase in immunoglobulin G4 (IgG4) caused by Clonorchis sinensis infection is rare and there are few reports about the relevant mechanism. It may be related to the inflammatory factors interleukin (IL)-4, IL-10, and IL-13 produced by human phagocytes, T cells, B cells, and other immune cells in the process of resisting the invasion of Clonorchis sinensis. However, this finding still needs further clarification and confirmation. This article reviews the epidemiology, clinical manifestations, serology, imaging, pathogenic mechanism, and control measures of Clonorchis sinensis infection to help establish the diagnostic process for Clonorchis sinensis. We report novel mechanisms of IgG4 elevation due to Clonorchis sinensis infection to provide more experience and a theoretical basis for clinical diagnosis and treatment of this infection.

Expression and Implication of Interleukin-34 in Primary Biliary Cholangitis / 胃肠病学

Background: Interleukin-34 (IL-34) is an important immunomodulatory factor that plays a crucial role in a variety of autoimmune diseases. Aims: To investigate the expression of IL-34 in primary biliary cholangitis (PBC) and its influence on intrahepatic inflammation and bile duct damage. Methods: Liver tissues were obtained from 26 PBC patients and 10 hepatic hemangioma patients without PBC. Expression and localization of IL-34 were detected by immunohistochemistry. In animal experiment, Poly I:C intraperitoneal injection was used to construct PBC model in wild-type and IL-34-knockout C57BL/6 mice (WT-PBC group and IL-34KO-PBC group). Subsequently, the intrahepatic inflammation and bile duct damage were evaluated pathologically, and the expressions of IL-34 and associated cytokines in liver tissues were detected by real-time PCR and Western blotting. Results: Expression of IL-34 in liver tissues of PBC patients and PBC model mice was significantly higher as compared with those of the controls (all P<0.05). No morphological changes in hepatic pathological evaluation were observed in IL-34KO mice receiving intraperitoneal saline injection. In IL-34KO-PBC mice, the portal area inflammation and biliary epithelial cell damage were more severe than those in WT-PBC mice (all P<0.05). Expressions of proinflammatory cytokine interleukin-1β (IL-1β) and monocyte chemotactic protein-1 (MCP-1) in liver tissues of IL-34KO-PBC mice were significantly increased than those of WT-PBC mice, whereas expressions of antiinflammatory cytokine IL-10 and CD163, the surface marker of M2 macrophages, were significantly reduced (all P<0.05). Conclusions: IL-34 expression is increased in liver tissues of PBC patients and animals. It might reduce the portal area inflammation and bile duct damage via modulating cytokines expression and driving macrophages polarization to the M2 phenotype. IL-34 might act as a self-rescue factor which negatively regulates hepatic immune microenvironment and prevents disease progression.

Multi-modal and sequential treatment of liver cancer and its impact on the gastrointestinal tract.

Hepatic tumors include hepatocellular cancer (HCC) and cholangiocarcinoma (CC), a small subgroup of tumors (approx. 1%) are classified as combined hepatocellularcholangiocellular carcinomas. Different stage-dependent therapeutic approaches comprise resection, local ablative techniques, locoregional therapies, systemic treatment, liver transplantation in selected cases and possible combination of these treatment modalities. This review summarizes current knowledge on multi-modal treatment strategies for liver cancer focusing on gastrointestinal side effects.

Calidad de vida post-reconstrucción de vía biliar / Quality of life after bile duct damage and repair during cholecystectomy

Background: Bile duct reconstruction after surgical lesions during cholecystectomy is a complex procedure with impact on postoperative quality of life. Aim: To compare the quality of life of patients who suffered a bile duct lesion during cholecystectomy with their counterparts in whom bile duct was not damaged. Material and Methods: The SF-36 questionnaire for quality of life was applied to 20 patients aged 44 +/- 16 years (79 percent women), who required a bile duct reconstruction due to lesions during cholecystectomy and to 20 age and gender matched patients subjected to uneventful cholecystectomies. Results: The SF-36 scores obtained for patients subjected to bile duct reconstruction and those with uneventful cholecystectomies were 78.5 +/- 21.5 and 74.1 +/- 16.7 (p = 0.46) respectively for physical function, 75 +/- 22 and 72.5 +/- 28 (p = 0.75) respectively for physical role, 79.6 +/- 23.3 and 66.6 +/- 28.6 respectively (p = 0.12) for emotional role, 60.8 +/- 25.4 and 50.3 +/- 17.4 respectively (p = 0.13) for vitality, 69.2 +/- 22.4 and 56.8 +/- 18.7 respectively (p = 0.06) for mental health, 84.3 +/- 19 and 64.1 +/- 22.1 respectively (p < 0.01) for social role, 74.1 +/- 25.1 and 71.8 +/- 24.7 respectively (p = 0,76) for pain and 57 +/- 24.4 and 56.8 +/- 24,4 respectively (p = 0.97) for general health. Conclusions: No differences in quality of life were observed between patients subjected to bile duct reconstruction and those who experienced uneventful cholecystectomies.

Introducción: La reconstrucción de vía biliar (RVB) secundaria a lesión de vía biliar asociada a cole-cistectomía (LVBAC) es una cirugía compleja y un aspecto importante es la calidad de vida (CV) posterior. El objetivo del presente trabajo es comparar la calidad de vida de una cohorte de pacientes sometidos a RVB por LVBAC con una cohorte de pacientes sometidos a colecistectomía sin incidentes. Material y método: Estudio de calidad de vida realizado en una cohorte concurrente a conveniencia. La cohorte está compuesta por 20 pacientes sometidos a RVB por LVBAC. Para tener un grupo de comparación se eligió una cohorte de pacientes sometidos a colecistectomía sin incidentes. Estas cohortes se parearon 1:1 por edad (+/- 4 años), género y tipo de cirugía. Se aplicó el cuestionario SF-36 con la puntuación propuesta por el grupo RAND de manera personal o telefónica. Se utilizó t-test para la comparación de los promedios de la puntuación. Por ser una cohorte a conveniencia se hizo cálculo de potencia del estudio, que fue del 99 por ciento. Resultados: La cohorte de pacientes de RVB está conformada por 20 pacientes, con una edad promedio de 44 +/- 15,51 años; siendo el 79 por ciento de género femenino. El promedio de seguimiento fue de 68 +/- 44 meses. La puntuación obtenida por los pacientes sometidos a RVB y colecistectomía fue: función física: 78,5 +/- 21,46 vs 74,05 ± 16,69 (p = 0,46); rol físico: 75 +/- 22 vs 72,5 +/- 27,98 (p = 0,75); rol emocional: 79,58 +/- 23,33 vs 66,6 +/- 28,61 (p = 0,12); vitalidad: 60,75 +/- 25,35 vs 50,25 +/- 17,38 (p = 0,13); salud mental: 69,2 +/- 22,36 vs 56,8 +/- 18,65 (p = 0,06); rol social: 84,31+/- 18,98 vs 64,12 +/- 22,11 (p = 0,003); dolor: 74,12 +/- 25,09 vs 71,75 +/- 24,69 (p = 0,76); salud general: 57 +/- 24,35 vs 56,75 +/- 24,40 (p = 0,97). A manera de descripción se hizo una comparación de subgrupos según técnica de Hepp-Couinaud, tiempo de RVB y necesidad de procedimientos percutáneos después de RVB. Conclusión: En el...