IAIH-PG consensus for histological criteria of AIH: Multicentre validation with focus on chronic liver diseases in China.

BACKGROUND AND AIMS: The International AIH Pathology Group (IAIH-PG) put forward the new histological criteria of autoimmune hepatitis (AIH) in 2022, which have not undergone adequate verification. In this study, we verified the applicability of the new histological criteria in the population of Chinese patients with chronic liver disease, comparing it with the simplified criteria. METHODS: The gold standard for diagnosis in all patients was based on histological findings, combined with clinical manifestations and laboratory tests and determined after a follow-up period of at least 3 years. A total of 640 patients with various chronic liver diseases from multiple centres underwent scoring using the new histological criteria and the simplified criteria, comparing their diagnostic performance. RESULTS: In this study, the new histological criteria showed a sensitivity of 73.6% and 100% for likely and possible AIH, with specificities of 100% and 69.0% respectively. The coincidence rates of possible AIH for the new histological criteria, simplified histological criteria and simplified score were 81.7%, 72.8% and 69.7% respectively. For likely AIH, the rates were 89.2%, 75.9% and 65.6% respectively. Based on the new histological criteria, all patients with AIH were correctly diagnosed. Specifically, 73.6% were diagnosed with likely AIH and 26.4% were possible AIH. Additionally, the simplified histological criteria achieved a diagnosis rate of 98.6% for AIH, while the simplified score could only diagnose 53.8% of AIH. CONCLUSIONS: Compared with the simplified score and simplified histological criteria, the sensitivity and specificity of the new histological criteria for AIH were significantly improved. The results indicate that the new histological criteria exhibit high sensitivity and specificity for diagnosing AIH in China.

Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate.

Background/Aims: : The histological characteristics and natural history of precirrhotic primary biliary cholangitis (PBC) with portal hypertension (PH) are unclear. Our aim was to clarify the prevalence, risk factors, and histological characteristics of precirrhotic PBC patients with PH. Methods: : This retrospective study compared the clinical features, histological characteristics, and response to ursodeoxycholic acid (UDCA) between the PH and non-PH groups of precirrhotic PBC patients. Results: : Out of 165 precirrhotic PBC patients, 40 (24.2%) also had PH. According to histological stage 1, 2 and 3 disease, 5.3% (1/19), 17.3% (17/98), and 45.8% (22/48) of patients also had PH, respectively. Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation (p<0.05). In addition, patients with PH were more likely to present with symptoms of jaundice, ascites, epigastric discomfort, a poorer response to UDCA, and more decompensation events (p<0.05). High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values were risk factors for precirrhotic PBC with PH. Conclusions: : Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH.

Development and validation of a noninvasive prediction model of autoimmune hepatitis in patients with liver diseases.

BACKGROUND AND AIMS: There is no golden standard for the diagnosis of autoimmune hepatitis which still dependent on liver biopsy currently. So, we developed a noninvasive prediction model to help optimize the diagnosis of autoimmune hepatitis. METHODS: From January 2017 to December 2019, 1739 patients who had undergone liver biopsy were seen in the second hospital of Nanjing, of which 128 were here for consultation. Clinical, laboratory, and histologic data were obtained retrospectively. Multivariable logistic regression analysis was employed to create a nomogram model that predicting the risk of autoimmune hepatitis. Internal and external validation was both performed to evaluate the model. RESULTS: A total of 1288 patients with liver biopsy were enrolled (1184 from the second hospital of Nanjing, the remaining 104 from other centers). After the univariate and multivariate logistic regression analysis, nine variables including ALT, IgG, ALP/AST, ALB, ANA, AMA, HBsAg, age, and gender were selected to establish the noninvasive prediction model. The nomogram model exhibits good prediction in diagnosing autoimmune hepatitis with AUROC of 0.967 (95% CI: 0.776-0.891) in internal validation and 0.835 (95% CI: 0.752-0.919) in external validation. CONCLUSIONS: ALT, IgG, ALP/AST, ALB, ANA, AMA, HBsAg, age, and gender are predictive factors for the diagnosis of autoimmune hepatitis in patients with unexplained liver diseases. The predictive nomogram model built by the nine predictors achieved good prediction for diagnosing autoimmune hepatitis.

Transjugular liver biopsy: enlarge the indications for liver biopsy with reliable diagnostic quality.

BACKGROUND: Complications and diagnostic efficiency for liver biopsy are main concerns for clinicians. This study aimed to assess the safety and efficacy of transjugular liver biopsy (TJLB) compared with percutaneous liver biopsy (PLB) when patients had equal level of liver function and number of passes, using propensity score matching (PSM). METHODS: The clinical and pathological data of patients who received TJLB or PLB between January 2012 and October 2022 were collected. Matching factors included age, gender, cirrhosis, portal hypertension, liver function, creatinine, number of passes, hemodialysis, history of anti-coagulation and anti-platelet, and comorbidities. Coagulation indexes were not considered as matching factors due to different indications of the two techniques. RESULTS: 2711 PLBs and 30 TJLBs were evaluated. By PSM, 75 patients (50 PLBs, 25 TJLBs) were matched. The complication rates for TJLB and PLB were 4.0% (1/25) and 10.0% (5/50) (P > 0.05). Two PLBs had hepatic hemorrhage, one of which required only close monitoring (Grade 1) and the other needed hemostasis and rehydration therapy (Grade 2). The other 3 cases presented with mild abdominal pain (Grade 1). And only one TJLB presented with mild pain. The median number of complete portal tracts were 6.0 and 10.0 for TJLBs and PLBs (P < 0.05). Moreover, the median length of sample for TJLBs and PLBs were 10.0 and 16.5 mm (P < 0.05). The diagnostic efficiency of hepatopathy of unknown etiology of TJLB versus PLB groups before and after matching were 96.4% vs. 94.1% and 95.7% vs. 93.2%, respectively (P > 0.05). CONCLUSION: TJLB is an effective invasive diagnostic procedure that expands indications for liver biopsy with reliable diagnostic quality.

Aberrant cytokeratin 7 expression by hepatocytes can predict the ductopenia grade in primary biliary cholangitis.

BACKGROUND: Aberrant cytokeratin 7 expression by hepatocytes (CK7+Hs) is the hallmark characteristic of cholestasis diseases, especially in ductopenia diseases such as primary biliary cholangitis (PBC). This study attempted to evaluate the differences and relationships between the clinical and histological features of aberrant cytokeratin 7 (CK7) expression by hepatocytes in PBC patients. METHODS: The clinicopathological data of patients diagnosed with PBC at the Second Hospital of Nanjing between January 2016 and September 2018 were analysed with SPSS 20.0. RESULTS: Eighty-nine PBC patients who underwent liver biopsy were enrolled in this study, and 15, 29 and 45 patients had aberrant CK7 expression by hepatocytes (CK7+Hs (2 +), CK7+Hs (1 +), and CK7-Hs, respectively). There were significant differences in TB, DB, ALP, TA, IgM, interface activity, and ductopenia grade between patients with CK7-Hs and CK7+Hs (2 +) (P < 0.05). The ductopenia grade was also significantly different between patients with CK7+Hs (2 +) and CK7+Hs (1 +) according to sex (P < 0.05). Upon merging the data of CK7+Hs (2 +) and CK7+Hs (1 +) into CK7+Hs, we found significant differences in AMA, AMA-M2, anti-gp210, TB, DB, ALP, TA, IgM, fibrosis, and ductopenia grade between CK7+Hs and CK7-Hs (P < 0.05). The odds ratios (ORs) (and 95% confidence intervals (CIs)) of CK7+Hs according to anti-gp210, ductopenia grade, and interface activity were 6.413 (95% CI 1.363-30.162), 4.145 (95% CI 1.898-9.052) and 3.247 (95% CI 1.556-6.775), respectively (P < 0.05). Spearman's rank correlation according to interface activity and ductopenia grade in patients with CK7+Hs (2 + , 1 + , 0) was r = 0.359 (P = 0.001) and r = 0.396 (P < 0.001), respectively. CONCLUSION: CK7+Hs serves as a cholestasis index of PBC and are associated with the ductopenia grade and interface activity. Aberrant cytokeratin 7 expression by hepatocytes can predict the ductopenia grade in primary biliary cholangitis.

Early predictors of acute hepatitis B progression to liver failure.

BACKGROUND AND AIMS: 1~4% of acute hepatitis B (AHB) cases in adults progresses to acute liver failure (ALF).The predictors of ALF and prognosis for patients with ALF are not clear. This study investigated some of predictive and prognostic factors for AHB progression to ALF. METHODS: A retrospective analysis was used to assess the clinical and laboratory features of 293 patients diagnosed with AHB; the patients were divided into the following two groups: ALF (n = 13) and non-ALF (n = 280). RESULTS: In total,13 of the 293 (4.43%) patients developed ALF (10 recovered、3 died). The variables of age, anti-HBc IgM titers≥10 S/CO, HBeAg negativity, and total bilirubin (TB) at admission were significantly higher in ALF patients than in non-ALF patients. Compared to non-ALF patients, ALF patients had significantly lower values for prothrombin time activity (PTA), serum albumin, and HBV DNA. At discharge, ALF patients had lower TB normalization rates and much faster clearance of HBsAg, HBeAg and HBVDNA than non-ALF patients. In multivariate analysis, TB≥5×upper limit of normal (ULN) and HBeAg negative status were independent predictors for ALF development at admission, with 84.6% sensitivity, 85.7% specificity, a likelihood ratio of 5.91 and an area under the receiver operating characteristics curve (AUROC) of 0.850.Those who died had lower levels of peak PTA (<20%) and higher levels of peak hepatic encephalopathy (HE) grade (III-IV) than those who recovered. CONCLUSIONS: Of the patients with ALF, 23.1% died. TB≥5×ULN and HBeAg negative status were the most effective and practicable factors distinguishing ALF from AHB at admission before the onset of encephalopathy. Peak PTA<20% and/or HE grade III-IV were independent predictors of a high probability of death or a need for transplantation.

Complete remission of hepatitis B virus-related membranous nephropathy after entecavir monotherapy.

We reported a case of Hepatitis B virus-related membranous nephropathy (HBV-MN) with improvement under an ongoing 4.5-year of entecavir monotherapy. A 37 years old man with a 5 years' history of chronic hepatitis B (CHB) who was taken to our department because of proteinuria and microscopic haematuria. A renal biopsy led to a diagnosis of HBV-MN with mesangioproliferative. Interferon-alpha 2b (IFN-α2b) was stopped after 24 weeks due to the increasement of HBV-DNA and sustained HBeAg positive. Therefore, we started using 0.5mg entecavir per day. After 2 months' treatment, HBV-DNA was not detected in the blood, and the ALT and AST decreased to normal degree. After 3 years of entecavir therapy, virological tests revealed HBeAg seroconversion. With no further intervention during the next one and a half years, there was improvement of proteinuria gradually. This suggested that entecavir monotherapy may induce and maintain complete remission of membranous nephropathy associated with hepatitis B.

Long-term efficacy of interferon alpha therapy on hepatitis B viral replication in patients with chronic hepatitis B: a meta-analysis.

BACKGROUND/AIMS: Interferon (IFN) alpha has been used in the treatment of chronic hepatitis B for decades. Beneficial effects including hepatitis B e antigen (HBeAg)/HBV DNA seroclearance have been documented. However, it remains unclear whether interferon has long-term efficacy on inhibiting hepatitis B viral replication. So we conducted a meta-analysis of available literature to assess the evidence obtained on the efficacy of IFN treatment in chronic HBV infection. METHODS: Seven clinical controlled trials, including 1550 patients and comparing IFN to no treatment, were selected. Data on the incidence of HBV DNA seroclearance, HBeAg seroclearance, and HBsAg seroclearance in IFN treated and untreated patients were extracted from each study. The evaluation of effectiveness was performed with an intention-to-treat (ITT) method. We used the relative risk (RR) and 95% confidence interval (CI) of the main outcomes as the measure of efficacy. Meta-analysis was performed using fixed-effect or random-effect methods, depending on absence or presence of significant heterogeneity. Analyses were performed with STATA version 9.0 and Review Manager Version 4.2. RESULTS: Four studies including the data of HBeAg seroclearance with significant heterogeneity were analyzed by random-effect method; six studies including the data of HBsAg seroclearance without significant heterogeneity were analyzed by fixed-effect method. A different incidence of HBeAg seroclearance and HBsAg seroclearance was observed between treated and untreated patients. The RR of HBeAg seroclearance and HBsAg seroclearance was 0.66 (95% CI: 0.44, 0.99) and 0.28 (95% CI: 0.17, 0.46), respectively. CONCLUSIONS: In conclusion, the results of this meta-analysis indicate that IFN increases the incidence of HBeAg seroclearance and HBsAg seroclearance after long-term follow-up of three to seven years.

[Comparison of curative effect of low flow rate plasma exchange combined with hemofiltration for treatment of liver failure].

OBJECTIVE: To investigate the effect of plasma exchange (PE) combined with hemofiltration (HF) on liver failure. METHODS: Seventy-seven inpatients with liver failure admitted during January 2006 to August 2007 were randomly assigned to receive PE combined with HF (PE+HF group, 38 cases), or PE alone (PE group, 39 cases). Forty-one inpatients with liver failure who had not received artificial liver support treatment were assigned to serve as control group. The survival rates and biochemical parameters of three groups were compared. RESULTS: There was no significant difference in biochemical parameters before treatment among three groups. Compared with pre-treatment values, albumin (Alb), cholinesterase (ChE) and prothrombin activity (PTA) of both PE group and PE+HF group were significantly increased after treatment, and total bilirubin (TBIL), alanine transaminase (ALT), aspartate transaminase (AST) of both PE group and PE+HF group were significantly decreased after treatment (P<0.05 or P<0.01). The survival rate of PE group, PE+HF group and control group was 48.7% (19/39), 68.4% (26/38), and 29.3% (12/41) respectively. The survival rate of PE+HF group was significantly higher than that of control group (chi(2)=12.11, P<0.01). The rate of recovery of consciousness of patients with hepatic encephalopathy in PE+HF group was higher than that of PE group (42.8% vs. 0, P<0.05). Compared with PE alone, the result was better when it was combined with HF in correction of electrolyte disturbance and acid-base imbalance (19/23 vs. 0/21, P<0.05). CONCLUSION: Treatment of liver failure by PE combined with HF is safe and effective, and its efficacy is higher than PE alone.

Comparison of the efficacy of thymosin alpha-1 and interferon alpha in the treatment of chronic hepatitis B: a meta-analysis.

Chronic hepatitis B virus (HBV) infection is a serious problem because of its worldwide distribution and possible adverse sequelae, such as cirrhosis and hepatocellular carcinoma. Thymosin alpha-1 (Talpha1) is an immune modifier that has been shown to be effective for chronic hepatitis B (CHB) in some trials. But the trials comparing Talpha1 vs. interferon alpha (IFNalpha) treatment in CHB have been small and the results have been inconsistent. So we conducted a meta-analysis to compare the efficacy of Talpha1 and IFNalpha in the treatment of CHB. Generally, four randomized controlled trials including 199 CHB patients who received Talpha1 or IFNalpha treatment were identified through MEDLINE and EMBASE online search. Virological (for hepatitis B e antigen (HBeAg) positive patients, loss of HBV DNA and HBeAg; for HBeAg negative patients, loss of HBV DNA), biochemical (normalization of transaminases) and complete responses (fulfill criteria of biochemical and virological response simultaneously) were analyzed using the intention-to-treat method. The odds ratio (OR) was used to measure the magnitude of the efficacy. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of 6 months treatment were 0.62 (0.35, 1.10), 0.60 (0.34, 1.05) and 0.54 (0.30, 0.97), respectively. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of follow-up (6 months post-treatment) were 3.71 (2.05, 6.71), 3.12 (1.74, 5.62) and 2.69 (1.47, 4.91), respectively. These data showed that compared with IFNalpha, the benefit of Talpha1 was not immediately significant at the end of therapy, but virological, biochemical and complete response had a tendency to increase or accumulate gradually after the therapy. For three of the four trials that studied HBeAg-negative patients, the results are mostly applicable to HBeAg-negative CHB.

Mycophenolate mofetil prevents lethal acute liver failure in mice induced by bacille Calmette-Guérin and lipopolysaccharide.

BACKGROUND/AIMS: To investigate the effect of mycophenolate mofetil (MMF) on acute liver injury induced by bacille Calmette-Guérin (BCG) and lipopolysaccharide (LPS). METHODS: Acute liver failure was induced in male Kunming strain mice by injecting the animals with BCG 2.5 mg per mouse, and LPS 10 microg per mouse 10 days later. The mice in the treatment groups were given MMF 2 h before, simultaneous with, or 2 h after administration of LPS, and the mice in the control group were given the same dose of saline. The 24-h survival rate, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were compared. Serum levels of tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin 6 (IL-6) were measured and the expressions of TNF-alpha, IFN-gamma, and IL-6 mRNA in the liver tissue were determined by reverse transcription-polymerase chain reaction (RT-PCR). Concanavalin A (Con A)-induced splenocyte proliferation were determined by methods of methyl thiazolyl tetrazolium. RESULTS: Injecting a small dose of LPS into BCG-primed mice caused a lethal hepatic injury mimicking acute hepatitis, from which 16 of the 20 mice died within 24 h (20% survival rate). Massive necrosis of parenchymal hepatocytes with marked inflammatory cell infiltration was observed by histological examination. In parallel, serum ALT and TNF-alpha, IFN-gamma, and IL-6 levels were increased. Expression of TNF-alpha, IFN-gamma, and IL-6 mRNA in the liver were significantly increased also. Treatment with MMF markedly reduced the death rate in a dose-dependent manner. It reached its maximal effect at the dosage of 150 mg per kg of body weight when pretreated 2 h before LPS injection, with improvement of histological feather and survival rate (84.2%, 16/19). MMF significantly inhibited serum levels of TNF-alpha, IFN-gamma, and IL-6, and significantly reduced TNF-alpha, IFN-gamma, and IL-6 expression in the liver, which increased after BCG and LPS injection. Moreover, splenocyte proliferation response induced by Con A was also inhibited by MMF treatment. CONCLUSIONS: Treatment with MMF has a protective effect on endotoxin-induced fatal liver failure by regulating the production of inflammatory cytokines and T-cell proliferation.

[Effect of Suanzaoren decoction on acute hepatic failure in mice].

OBJECTIVE: To investigate the effect of Suanzao nacute hepatic failure in mice. METHOD: Acute liver failure was induced in male Kunming strain mice by enterocoelia injecting the animals with D-Gal-N and LPS. The mice in treatment groups were given corresponding drug 2 h before administration of D-Ga1-N and LPS, and the mice in control group were given the same dose of distilled water. The 24 h survival rate, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels were compared. Serum the levels of TNF-alpha and IL-1 and the levels of SOD, MDA, GR, GSH, NO and NOS in the liver were determined. RESULT: Treatment with suanzaoren decoction could increase the survival rate and improve the liver histological feather. Suanzaoren decoction inhibited the serum the levels of ALT, AST, TNF-alpha and IL-1, and reduced the levels of MDA, NO and NOS and increased the levels of GR and SOD in the liver. CONCLUSION: Treatment with Suanzaoren decoction can suppress the D-Gal-N/LPS-induced acute hepatic failure. It may be the mechanism that Suanzaoren decocotion regulate the production of inflammatory cytokines and free radicals.