Cholestatic liver disease ( CSLD) is a group of liver diseases which can cause cholestasis and has a complex etiology. Its pathogenesis remains unclear, and there are still no effective treatment measures. In the recent decade, new achievements have been made on various aspects of CSLD, which provides more help to accurate diagnosis and treatment and reflects many pending issues which need further research. This article introduces the research advances and problems in CSLD from the following six aspects: the“ascending”pathophysiology of CSLD, mechanisms of cholestasis-induced liver fibrosis and related management measures, association of enterohepatic circulation and intestinal microbiota with CSLD, pathogenesis and diagnosis/treatment of drug-induced cholestasis, pathogenesis and management of liver failure-associated cholestasis, and research advances in treatment targets and drug research and development for CSLD.

Cholestasis refers to a pathological state of disorders in the formation, secretion, and excretion of bile flow, and liver fibrosis is a process of tissue repair induced by liver injury. Cholestatic liver disease is a chronic liver disease caused by cholestasis, progressive bile duct injury, and persistent intrahepatic inflammation, and it may cause cholangiocyte and hepatocyte injury, which will gradually progress to liver fibrosis. With reference to the current research advances, this article reviews the pathogenesis of cholestasis-induced liver fibrosis and the strategies for blockade.

Drug-induced cholestasis ( DRIC) mainly includes cholestasis-type and mixed-type drug-induced liver injury ( DILI) . The Roussel Uclaf Causality Assessment Method scale should be used to determine the causality between drug and cholestasis and other etiologies should be excluded. Liver biopsy may help with differential diagnosis. Drugs should be stopped after the development of DRIC to avoid stimulation, and ursodeoxycholic acid should be administered for treatment. DRIC has a complex pathogenesis, which involves the direct toxicity of drugs and their metabolites on hepatocytes and the biliary tree, immune and inflammatory response, gene polymorphism and inhibition of key enzymes and transporters in the pathways of drug metabolism and efflux, and HLA gene polymorphisms. Clarification of these pathogeneses helps with the early warning, prevention, and optimized treatment of DRIC.

Liver failure is severe liver injury caused by a variety of factors. Liver failure-associated cholestasis is serious hepatocellular intrahepatic cholestasis with massive hepatocyte necrosis, which manifests as rapid increases in both conjugated and unconjugated bilirubin, and the level of bilirubin is directly proportional to the severity of liver failure. Structural changes of liver tissue aggravate intrahepatic cholestasis, and intestinal microbiota can affect bilirubin and bile acid metabolism. The management strategies for liver failure-associated cholestasis include eliminating causes, promoting hepatocyte regeneration, and facilitating liver function recovery.

Cholestatic liver disease is caused by the damage of bile duct cells and hepatocytes due to bile duct injury, accumulation of bile acids, and persistent inflammation. If it is not treated in time, cholestasis can lead to liver fibrosis, liver cirrhosis, and even end-stage liver disease. Primary biliary cholangitis ( PBC) and primary sclerosing cholangitis ( PSC) are the two most common cholestatic liver diseases in adults, with unknown causes. Although ursodeoxycholic acid ( UDCA) can improve the prognosis of PBC patients and prolong survival time after liver transplantation, some patients have no response to UDCA. In addition, there are still no effective pharmacotherapies for PSC.With the research advances in molecular mechanism of bile acid regulation and a deeper understanding of immune pathways in recent years, several new drugs have emerged. This article introduces the new therapeutic targets and drugs for PBC and PSC.

In recent years, some scholars have put forward the“ascending”pathophysiology of cholestatic liver disease, especially in primary biliary cholangitis ( PBC) and primary sclerosing cholangitis ( PSC) . According to this theory, cholestatic liver disease develops from the bottom to the top of the anatomical structure over time. Primary or early lesions are usually located in the “downstream”bile duct, with a major cause of immune-mediated biliary necrotizing inflammatory injury. When cholestasis occurs, the toxic effect mediated by bile salt will lead to the injury in the“upstream”liver parenchyma. Therefore, bile toxicity is of great importance during disease progression. According to this theory of“ascending”pathophysiology, there are different locations and causes of the disease in different disease stages, and therefore, it is necessary to establish a staging system for cholestatic liver disease and use different drugs in different stages, in order to use the existing drugs in a more effective manner and give directions for new drug development. However, there are still no early biochemical markers for cholestatic liver disease, and current clinical work should focus on the search for biomarkers with strong specificity and high sensitivity.

Cholestatic liver disease refers to a liver disorder caused by cholestasis, which arise from a series of etiologies such as viruses, bacteria, parasites, drugs, poisons, autoimmunity, alcohol, stones, tumors, genetics, and metabolism. This disease has the main manifestations of a change in bile flow and excessive accumulation of bile acid toxicity. In the pathogenesis of cholestatic liver disease, not only does the enterohepatic circulation of endogenous bile acids work, but also the intestinal microbiota plays an important role by regulating metabolism and causing immune responses. In addition, more attention has been paid to the close interaction between intestinal microbiota and the enterohepatic circulation of bile acids. Bile acids can alter the composition of intestinal microbiota, which in turn affects the bile acid pool.In recent years, there has been increasing research on the relationship of the enterohepatic circulation of bile acids and intestinal microbiota with cholestatic liver disease, which may provide new research directions for the pathogenesis and treatment of cholestatic liver disease.

Objective To investigate the clinical effect and safety of pegylated interferon-α-2 a ( PEG-IFN-α-2 a) versus pegylated interferon-α-2 b ( PEG-IFN-α-2 b) in the treatment of chronic hepatitis B ( CHB) . Methods The CHB patients who were treated with PEG-IFN-α-2 a ( 180 μg/week) or PEG-IFN-α-2 b ( 180 μg/week) in Department of Infectious Diseases in our hospital from January 2017 to June 2018 were enrolled. The two groups were compared in terms of the levels of HBsAg, HBV DNA, HBeAg, and alanine aminotransferase ( ALT) at 4, 12, 24, and 48 weeks of treatment, and the indices for antiviral effect at 48 weeks were used as main outcome measures. The above indices were compared between response group and non-response group. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. Results There were no significant differences between the PEG-IFN-α-2 a group and the PEG-IFN-α-2 b group in serum HBV DNA clearance rate ( 67. 6% vs 59. 4%, P > 0. 05) and HBeAg seroconversion rate ( 27. 2% vs 34. 6%, P >0. 05) . In the PEG-IFN-α-2 a group, the HBV DNA response group had a significantly lower baseline ALT level than the HBV DNA non-response group ( Z = 2. 390, P = 0. 016) ; the HBeAg response group had a significantly lower baseline HBeAg level than the HBeAg non-response group ( Z = 2. 286, P = 0. 021) . In the PEG-IFN-α-2 b group, the HBV DNA response group had significantly lower baseline HBV DNA level and baseline HBeAg level than the HBV DNA non-response group ( Z = 2. 154 and 2. 057, P = 0. 030 and0. 041) ; the HBeAg response group had a significantly lower baseline HBV DNA level than the HBeAg non-response group ( Z = 2. 052, P = 0. 042) . There were no significant differences in the incidence rates of adverse reactions between the two groups ( P > 0. 05) ; in the PEG-IFN-α-2 b group, one patient experienced Purtscher's retinopathy and one experienced thrombocytopenia, while no similar adverse reactions were observed in the PEG-IFN-α-2 a group. Conclusion Both PEG-IFN-α-2 a and PEG-IFN-α-2 b have strong antiviral and immunomodulatory effects in the treatment of CHB, with similar clinical effect and safety.

Objective To investigate the serum level of interferon-λ3 ( IFN-λ3) and its clinical significance in patients with chronic hepatitis B ( CHB) , as well as its association with nucleos ( t) ide analogue ( NA) treatment. Methods A total of 119 CHB patients who were treated in The Second Affiliated Hospital of Anhui Medical University from January 2017 to May 2018 were enrolled, and 22 HBsAg-negative individuals who underwent physical examination were enrolled as healthy control group. ELISA was used to measure the serum level of IFN-λ3, which was compared between CHB patients and healthy individuals. The association between serum IFN-λ3 level and HBeAg in CHB patients was analyzed; serum IFN-λ3 level was compared between the patients treated with different NAs; the influence of NAs on the level of IFN-λ3 in the supernatant of peripheral blood mononuclear cells ( PBMCs) was analyzed. An analysis of variance was used for comparison of normally distributed continuous data with homogeneity of variance between multiple groups; the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data or continuous data with heterogeneity of variance between two groups, the Kruskal-Wallis H test was used for comparison between multiple groups, and the Nemenyi test was used for further comparison between two groups. A Spearman correlation analysis was also performed. Results The CHB group had a significantly lower serum IFN-λ3 level than the healthy control group [14. 7 ( 5. 9-28. 5) pg/ml vs 76. 1 ( 39. 4-112. 0) pg/ml, Z =-10. 114, P < 0. 001]. In the CHB patients who did not receive antiviral therapy, serum IFN-λ3 level was negatively correlated with log HBV DNA ( r =-0. 621, P < 0. 001) . The HBeAg-negative CHB patients had a significantly higher serum IFN-λ3 level than the HBeAg-positive CHB patients [16. 4 ( 9. 0-31. 3) pg/ml vs 8. 7 ( 2. 9-23. 2) pg/ml, Z =-2. 205, P = 0. 02]. The patients who received antiviral therapy with adefovir dipivoxil had a significantly higher serum IFN-λ3 level than those who were treated with entecavir, tenofovir, telbivudine, or lamivudine ( P < 0. 05) . In vitro experiment showed that there was no significant increase in serum IFN-λ3 level in the supernatant of PBMCs treated with NAs. Conclusion CHB patients have a significantly lower serum IFN-λ3 level than healthy individuals, and the CHB patients receiving antiviral therapy with adefovir dipivoxil have a relatively high serum IFN-λ3 level.

Objective To investigate the influencing factors for ribavirin ( RBV) -induced hemolytic anemia during the treatment of chronic hepatitis C using RBV combined with pegylated interferon-α ( PEG-IFNα) , and to provide a reference for early prediction of RBV-related hemolytic anemia in clinical practice. Methods A total of 235 patients with chronic hepatitis C who were given antiviral therapy with PEG-IFNα combined with RBV in Beijing YouAn Hospital from March 2016 to March 2018 were enrolled. Parameters of routine blood test, liver function parameters, liver stiffness measurement, HCV RNA, HCV viral genotype, and inosine triphosphate pyrophosphatase ( ITPA) genotype were determined before the antiviral therapy, and routine blood tests were performed at weeks 2, 4, 8, and 12 of treatment. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for non-normally distributed continuous data between groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. Univariate analysis and multivariate logistic regression analyses were used to determine the influencing factors for RBV-related hemolytic anemia, and a predictive model was established accordingly; the receiver operating characteristic curve was used to analyze the predictive value of this model for RBV-related hemolytic anemia. Results At weeks 2, 4, 8, and 12 of treatment, the ITPA ( rs1127354) genotype CC group had a significantly greater reduction in hemoglobin ( Hb) than the ITPA ( rs1127354) genotype AA + AC group ( all P < 0. 05) . At week 4 of treatment, there was a significant difference between the AA + AC group and the CC group in the proportion of patients with a > 30 g/L reduction in Hb ( 2. 38% vs 39. 9%, X2= 23. 175, P < 0. 001) or an Hb level of < 100 g/L ( 0 vs10. 88%, P = 0. 018) . The degree of reduction in Hb at week 2 ( odds ratio ( OR) = 1. 073, P < 0. 001) , ITPA ( rs1127354) genotype ( OR = 18. 920, P = 0. 005) , and baseline Hb level ( OR = 1. 032, P = 0. 024) were independent risk factors for a > 30 g/L reduction in Hb at week 4. Conclusion Patients with ITPA ( rs1127354) genotype CC tend to develop RBV-related hemolytic anemia. ITPA ( rs1127354) genotype, baseline Hb level, and degree of reduction in Hb at week 2 can be used to predict the development of RBV-related hemolysis during anti-HCV treatment, in order to achieve early warning and guide early intervention.

Objective To investigate the mRNA expression of tumor necrosis factor-alpha-induced protein 8-like 2 ( TIPE2) , Foxp3 ( a functional molecule for regulatory T cells) , and cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4) in peripheral blood mononuclear cells ( PBMCs) in patients with chronic hepatitis C ( CHC) and their clinical significance. Methods A total of 80 CHC patients who were hospitalized in The Third Hospital of Hebei Medical University from May 2012 to December 2016 and did not receive antiviral drugs or immunoregulatory drugs were enrolled as CHC group, and 45 healthy volunteers were enrolled as controls. Quantitative real-time PCR was used to measure the mRNA expression of TIPE2, Foxp3, and CTLA-4 in PBMCs; the correlation between liver biochemical parameters and HCV RNA was observed, as well as the influence of TIPE2 on Foxp3 and CTLA-4. The t-test was used for comparison of continuous data between two groups, the chi-square test was used for comparison of categorical data between two groups, and Pearson correlation was used for correlation analysis. Results Compared with the healthy control group, the CHC group had a significant reduction in the mRNA expression of TIPE2 ( 0. 564 ± 0. 232 vs 0. 704 ± 0. 165, t = 3. 569, P < 0. 001) and significant increases in the mRNA expression of Foxp3 ( 0. 701 ± 0. 405 vs 0. 527 ± 0. 184, t = 2. 725, P = 0. 007) and CTLA-4 ( 0. 638 ± 0. 211 vs 0. 448 ± 0. 134, t = 5. 449, P < 0. 001) . The mRNA expression of TIPE2 was negatively correlated with serum alanine aminotransferase ( r =-0. 368, P = 0. 001) , aspartate aminotransferase ( r =-0. 417, P < 0. 001) , total bilirubin ( r =-0. 416, P < 0. 001) , and HCV RNA load ( r =-0. 327, P = 0. 003) and was positively correlated with the mRNA expression of Foxp3 ( r = 0. 461, P < 0. 001) and CTLA-4 ( r = 0. 257, P = 0. 021) . The mRNA expression of Foxp3 was negatively correlated with total bilirubin ( r =-0. 284, P = 0. 011) . Conclusion CHC patients have abnormalities in the mRNA expression of TIPE2 and the mRNA expression and function of Foxp3 and CTLA-4, which is associated with the degree of hepatocellular injury and viral replication. The TIPE2 gene may be involved in the pathogenesis of CHC by positively regulating immune response mediated by regulatory T cells.

Objective To investigate the clinical value of hepatitis B virus core-related antigen ( HBcrAg) in predicting the natural course of chronic hepatitis B ( CHB) and liver fibrosis regression. Methods A total of 138 CHB patients who were admitted to 302 Hospital of PLA, The First Affiliated Hospital of Zhengzhou University, and Fuzhou Infectious Disease Hospital from January 2013 to December 2015 were enrolled and divided into HBeAg-positive group with 69 patients and HBeAg-negative group with 69 patients. Of all patients, 109 with an Ishak score of ≥3 were treated with entecavir for 72 weeks. Liver biopsy specimens and serum were collected at baseline and after 72 weeks of treatment to observe histopathology and HBcrAg level. The t-test was used for comparison of normally distributed continuous data between two groups, and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two group. The chi-square test was used for comparison of categorical data between groups. A Spearman correlation analysis was also performed. The area under the receiver operating characteristic curve ( AUC) was used to analyze the value of HBcrAg in the diagnosis of liver fibrosis. Results In HBeAg-positive CHB patients, serum HBcrAg level was negatively correlated with liver fibrosis stage ( r =-0. 342, P = 0. 004) ; in HBeAg-negative CHB patients, serum HBcrAg level was positively correlated with liver fibrosis stage and inflammation ( r = 0. 439 and 0. 437, both P < 0. 001) . In HBeAg-positive patients, serum HBcrAg level had an AUC of 0. 705 in predicting advanced liver fibrosis and 0. 701 in predicting liver cirrhosis ( both P < 0. 05) ; in HBeAg-negative CHB patients, serum HBcrAg level had AUCs of0. 815, 0. 815, 0. 726, and 0. 675 in predicting mild liver fibrosis, marked liver fibrosis, advanced liver fibrosis, and liver cirrhosis, respectively ( all P < 0. 05) . After antiviral therapy, the group with a high serum HBcrAg level was more likely to experience liver fibrosis regression than that with a low level ( 53. 7% vs 32. 7%, χ2= 4. 888, P = 0. 027) . The patients with liver fibrosis regression had a significantly greater reduction in serum HBcrAg level than those without regression[1. 5 ( 0. 4-3. 2) log IU/ml vs 0. 8 ( 0. 1-1. 8) log IU/ml, Z =-1. 724, P = 0. 042]. Conclusion Serum HBcrAg can be used as a new marker in predicting liver fibrosis stage and liver fibrosis regression in clinical practice.

Objective To investigate the value of FibroScan combined with gamma-glutamyl transpeptidase-to-platelet ratio ( GPR) in predicting liver fibrosis stage in patients with chronic hepatitis B ( CHB) . Methods A total of 278 patients who were diagnosed with CHB by liver biopsy in Guangzhou Eighth People's Hospital from January 2012 to December 2016 were enrolled. The value of GPR and FibroScan used alone or in combination in predicting liver fibrosis stage ( F0-F4) was analyzed. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups and the Mann-Whitney U test was used for further comparison between two groups. The Spearman's correlation coefficient was used for correlation analysis. The area under the receiver operating characteristic curve ( AUC) was used to evaluate liver fibrosis stage. Results With liver biopsy as the gold standard, of all patients, 50 had stage F1 fibrosis, 104 had stage F2 fibrosis, 92 had stage F3 fibrosis, and 32 had stage F4 fibrosis. Liver stiffness measurement by FibroScan gradually increased with the increase in liver fibrosis stage ( P < 0. 05) , and GPR also increased gradually in patients with stage F1, F2, and F3 liver fibrosis ( P < 0. 05) . GPR and FibroScan were positively correlated with liver fibrosis ( r = 0. 419 and 0. 481, both P < 0. 001) , and GPR was positively correlated with FibroScan ( r = 0. 436, P < 0. 001) . According to AUC, FibroScan combined with GPR had a better diagnostic efficiency than FibroScan ( 0. 793 vs 0. 739, Z = 3. 044, P = 0. 002) or GPR ( 0. 793 vs 0. 740, Z = 2. 389, P = 0. 037) alone in predicting progressive liver fibrosis ( ≥F3) ; FibroScan combined with GPR had a better diagnostic efficiency than GPR alone ( 0. 782 vs0. 714, Z = 2. 130, P = 0. 033) in predicting marked liver fibrosis ( ≥F2) . Conclusion FibroScan combined with GPR has a certain advantage in predicting progressive liver fibrosis ( ≥F3) in CHB patients and can improve diagnostic efficiency.

Objective To investigate the changes in positive staining of CD34, CK7, and CK19 and amount of fibrous collagen deposition in patients with chronic hepatitis B ( CHB) and the pathological basis affecting FibroTouch measurements. Methods A retrospective analysis was performed for the clinical data of 72 CHB patients who visited Department of Liver Cirrhosis in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January 2015 to December 2017. The amount of positive immunohistochemical staining of CD34, CK7, and CK19 was calculated, as well as the amount of fibrous collagen deposition in Masson trichrome staining and liver stiffness measurement ( LSM) by FibroTouch. The t-test was used for comparison of normally distributed continuous data between two groups. The Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data or continuous data with heterogeneity of variance between two groups. The chi-square test was used for comparison of categorical data between groups, and the Kruskal-Wallis H test was used for comparison of ranked data between multiple groups. The receiver operating characteristic ( ROC) curve was used to analyze the value of LSM in the diagnosis of hepatitis B cirrhosis, and the logistic regression model was used for multivariate analysis. Results With the increase in inflammation degree, there was no significant change in the amount of positive staining of CD34 ( P > 0. 05) , while there were significant increases in the amount of positive staining of CK19 and the amount of fibrous collagen deposition ( H = 9. 02 and 14. 12, P =0. 011 and 0. 001) . With the progression of liver fibrosis, there were significant increases in the amount of positive staining of CD34 and CK7 and the amount of fibrous collagen deposition ( H = 10. 26, 16. 29, and 22. 97, P = 0. 016, 0. 001, and < 0. 001) . The logistic regression analysis showed that the amount of positive staining of CK7 ( Wald = 4. 756, P = 0. 029) and the amount of fibrous collagen deposition ( Wald = 4. 757, P = 0. 029) were independent influencing factors for FibroTouch measurements. Conclusion Increases in the amount of fibrous collagen deposition and the amount of positive staining of CK7 may lead to increased FibroTouch measurements.

Objective To compare the clinical features of autoimmune hepatitis ( AIH) and primary biliary cholangitis ( PBC) , and to provide a reference for differentiation and early diagnosis of these two diseases. Methods A retrospective analysis was performed for the clinical data of 83 patients with AIH and 108 patients with PBC who were diagnosed and treated in Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January 2010 to February 2018, including age, sex, serum biochemical parameters, immunological indices, and liver pathology. The clinical features of AIH and PBC were compared. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of continuous data with skewed distribution between two groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. Results Most of the patients with AIH or PBC were female, with a peak age of onset of 40-60 years. There was no obvious specificity in the clinical features of AIH or PBC, with cardinal symptoms and signs of weakness, abdominal distension, jaundice, and poor appetite, and compared with the PBC group, the AIH group had a significantly higher proportion of patients with poor appetite ( 25% vs 14%, X2= 6. 52, P = 0. 011) . Compared with the PBC group, the AIH group also had significantly higher proportions of patients with liver cirrhosis ( 59. 0% vs 40. 7%, X2= 6. 23, P = 0. 012) and rheumatic diseases ( 23. 5% vs 15. 7%, X2= 7. 46, P = 0. 006) . Compared with the PBC group, the AIH group had significantly lower platelet count ( PLT) , alkaline phosphatase ( ALP) , gamma-glutamyl transpeptidase ( GGT) , immunoglobulin M, erythrocyte sedimentation rate ( ESR) , and complement C3 and significantly higher prothrombin time ( PT) , international normalized ratio ( INR) , and immunoglobulin G ( all P < 0. 05) . Compared with the AIH group, the PBC group had significantly higher positive rates of anti-mitochondrial antibody M2 ( 78. 8% vs 14. 8%, X2= 74. 70, P<0. 001) , anti-gp210 antibody ( 46. 4% vs 5. 3%, X2= 7. 31, P = 0. 007) , and anti-BCOADC-E2 PDC-E2 OGDC-E2 ( anti-3 E-BPO) antibodies ( 75. 0% vs 31. 6%, X2= 8. 73, P = 0. 003) . As for liver histological features, PBC was characterized by bile duct injury, including small cholangitis, biliary granuloma, absence of bile duct, and reactive hyperplasia of bile capillaries, while AIH was characterized by interface hepatitis ( X2= 31. 00 and 5. 88, P < 0. 001 and P = 0. 015) . Conclusion AIH and PBC often occur in women and lack specific clinical manifestations. PLT, ALP, GGT, PT, INR, ESR, complement, and immunoglobulins on admission, type of serological antibodies, and liver pathological features can be used for the differential diagnosis of AIH and PBC, and anti-3 E-BPO antibody can help with the diagnosis of PBC.

Objective To investigate the clinical features of patients with drug-induced liver injury ( DILI) and vanishing bile duct syndrome ( VBDS) and patients with primary biliary cholangitis ( PBC) and VBDS. Methods A retrospective analysis was performed for the clinical data of 42 DILI patients and 43 PBC patients who visited Shijiazhuang Fifth Hospital from January 2003 to January 2018 were diagnosed with VBDS by liver biopsy, including general information, clinical symptoms and signs, and serological markers, and pathomorphological features were observed. The Mann-Whitney U rank sum test was used for comparison between two groups; the chi-square test was used for comparison of categorical data between groups. Results Most of the patients in the two groups were female patients aged 40-50 years. The D-VBDS group had a significantly higher incidence rate of yellow staining of skin and sclera than the P-VBDS group ( X2=5. 683, P = 0. 017) . Comparison of the peak values of liver biochemical indices showed that compared with the P-VBDS group, the D-VBDS group had significantly higher total bilirubin ( Z =-2. 020, P = 0. 043) and direct bilirubin ( Z =-2. 910, P = 0. 004) . According to the results of pathomorphological analysis and morphological scores of the portal area, the P-VBDS group had significantly higher morphological scores of portal inflammation, fibrosis, and granuloma than the D-VBDS group ( Z =-3. 136, -2. 710, and-2. 913, P =0. 002, 0. 007, and 0. 005) . The morphological scores of the hepatic lobules showed that compared with the P-VBDS group, the D-VBDS group had significantly higher morphological scores of intralobular inflammation, bile thrombus in bile capillary, and activated phagocytes ( Z =-3. 255, -2. 455, and-4. 398, P = 0. 001, 0. 014, and < 0. 001) . Conclusion Pathomorphological features of the liver are objective and accurate indices for the differentiation between DILI with VBDS and PBS with VBDS and have great significance in making a definite diagnosis, understanding the degree of injury, and predicting prognosis.

Objective To investigate the protective effect of hepatocyte growth-promoting factor ( PHGF) against liver ischemia-reperfusion injury in rats and its mechanism of its action. Methods A total of 80 healthy male Sprague-Dawley rats were randomly divided into experimental group ( PHGF group) and control group ( NS group) , with 40 rats in each group. A rat model of liver ischemia-reperfusion injury was established by 70% liver ischemia caused by the occlusion of blood flow in the middle and left lobes of the liver, with an ischemia time of 21 minutes. The rats in the PHGF group were given intraperitoneal injection of PHGF for intervention before surgery, and those in the NS group were given an equal volume of normal saline. Serum and liver tissue samples were collected before surgery and on days 1, 3, 5, and 7 after surgery, and the levels of alanine aminotransferase ( ALT) , aspartate aminotransferase ( AST) , and total bilirubin ( TBil) were measured; HE staining was used to observe pathological changes; real-time PCR was used to measure the mRNA expression of mitochondrial transcription factor A ( TFAM) in the liver. The independent samples t-test was used for comparison of continuous data between two groups. Results HE staining showed that compared with the NS group, the PHGF group had significantly lower degrees of hepatocyte swelling, inflammatory cell infiltration, and hepatocyte necrosis under a light microscope. Liver biochemistry showed that on days 1, 3, 5, and 7 after surgery, the PHGF group had significantly lower serum levels of ALT, AST, and TBil than the NS group ( t = 11. 879, 16. 019, 22. 168, 10. 235, 9. 041, 12. 936, 18. 759, 8. 142, 10. 108, 11. 014, 13. 245, and 9. 968, all P < 0. 001) . Real-time PCR showed that on days 1, 3, and 5 after surgery, the PHGF group had a significantly higher mRNA level of TFAM in the liver than the NS group ( t =7. 998, 14. 764, and 13. 861, all P < 0. 001) . Conclusion PHGF preconditioning exerts a protective effect against liver ischemia-reperfusion injury in rats, possibly by upregulating the expression of TFAM to alleviate liver ischemia-reperfusion injury.

Objective To investigate the dynamic expression of Mindin protein in mice with acute liver injury induced by carbon tetrachloride ( CCl4) and its mechanism of action. Methods A total of 48 male C57 B1/6 mice were selected and divided into experimental group ( n= 40) and control group ( n = 8) . The mice in the experimental group were given intraperitoneal injection of CCl4 olive oil to induce acute liver injury, and the liver tissue was collected for pathological observation at 6, 12, 24, 48, and 72 hours after modeling. The mice in the control group were given intraperitoneal injection of olive oil. Western blot was used to measure the protein expression of Mindin and its change trend, and quantitative real-time PCR was used to measure the mRNA expression of Mindin. The t-test was used for comparison of continuous data between two groups. Results Abnormal liver structure was observed after liver injury was induced by CCl4, with the most significant pathological change at 48 hours. There was a low protein expression level of Mindin within 12-72 hours after the injection of CCl4. The mRNA expression of Mindin reached the lowest level at 12 hours after CCl4 injection and there was a significant difference between the experimental group and the control group at this time point ( 0. 183 ± 0. 105 vs 1. 023 ± 0. 247, t = 8. 841, P < 0. 01) ; then there was a gradual increase in the mRNA expression of Mindin, and at 48 and 72 hours, the mRNA expression of Mindin in the experimental group was more than 2 times that in the control group ( 48 hours: 2. 548 ± 0. 775 vs 1. 023 ± 0. 247, t = 5. 428, P < 0. 01; 72 hours: 2. 699 ± 0. 995 vs 1. 023± 0. 247, t = 4. 621, P < 0. 01) . Conclusion There is a significant change in Mindin protein during the process of acute liver injury induced by CCl4 in mice, which is characterized by the downregulation of protein expression and the regulation of post-transcriptional mRNA level, suggesting that Mindin may play an important role in the process of acute liver injury induced by CCl4.

Liver failure is severe liver injury due to a variety of causes and has complex and diverse complications. Fungal infection is one of the serious complications of liver failure which often occurs in the advanced stage of liver failure, greatly affects prognosis, and leads to a significant increase in mortality, and therefore, it has become a difficult problem in clinical practice. This article introduces the research advances in high-risk factors, clinical features, diagnostic methods, and prognostic factors in patients with liver failure and fungal infections and provides a theoretical basis for improving the level of clinical diagnosis and treatment, in order to reduce the mortality of such patients and improve their quality of life.

Polypoid lesions of the gallbladder ( PLG) is a common gallbladder disease in clinical practice. Most patients have non-adenomatous polyps, while adenomatous polyps are observed in a small number of patients. This article summarizes the epidemiology of PLG and related risk factors and points out that PLG is caused by the combined effect of various factors including sex, hepatitis B virus infection, metabolic syndrome, visceral obesity, a low level of low-density lipoprotein, gallbladder wall thickening, and diabetes. With the gradual increase in the incidence rate of PLG, epidemiological data should be used for health screening among the high-risk population, and standardized follow-up should be performed for patients with a confirmed diagnosis. PLG which may progress to cancer should be identified and intervention should be given as early as possible.