Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis B: A randomized clinical trial.

BACKGROUND AND AIM: HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB. APPROACH AND RESULTS: A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo. CONCLUSIONS: Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

Hepatic Histopathology Among Excessive Drinkers Without Advanced Liver Disease.

AIMS: Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis. METHODS: We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase. RESULTS: Among 62 patients with aspartate aminotransferase (AST) ≤ 50 U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST > 50 U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells. CONCLUSION: Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed.

Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience.

COVID-19 has become one of the worst infectious disease outbreaks of recent times, with over 2.1 million cases and 120,000 deaths so far. Our study investigated the demographic, clinical, laboratory and imaging features of 63 patients with COVID-19 in Beijing. Patients were classified into four groups, mild, moderate, severe and critically ill. The mean age of our patients was 47 years of age (range 3-85) and there was a slight male predominance (58.7%). Thirty percent of our patients had severe or critically ill disease, but only 20% of severe and 33% of critically ill patients had been to Wuhan. Fever was the most common presentation (84.1%), but cough was present in only slightly over half of the patients. We found that lymphocyte and eosinophils count were significantly decreased in patients with severe disease (p = 0.001 and p = 0.000, respectively). Eosinopenia was a feature of higher levels of severity. Peripheral CD4+, CD8+ T lymphocytes, and B lymphocytes were significantly decreased in severe and critically ill patients, but there was only a non-statistically significant downward trend in NK cell numbers with severity. Of note is that liver function tests including AST, ALT, GGT and LDH were elevated, and albumin was decreased. The inflammatory markers CRP, ESR and ferritin were elevated in patients with severe disease or worse. IL-6 levels were also higher, indicating that the presence of a hyperimmune inflammatory state portends higher morbidity and mortality. In a binary logistic regression model, C-reactive protein level (OR 1.073, [CI, 1.013-1.136]; p = 0.017), CD8 T lymphocyte counts (OR 0.989, [CI, 0.979-1.000]; p = 0.043), and D-dimer (OR 5.313, [CI, 0.325-86.816]; p = 0.241) were independent predictors of disease severity.

Changes in Etiologies of Hospitalized Patients with Liver Cirrhosis in Beijing 302 Hospital from 2002 to 2013.

BACKGROUND: Over the last 20 years, the prevalence of hepatitis B virus (HBV) infection in China has decreased gradually due to the application of a national HBV vaccination program. In contrast, the prevalence of alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune liver disease, and drug-induced liver injury has markedly increased. METHODS: We conducted a retrospective review of 82,562 hospitalized patients diagnosed with liver cirrhosis in Beijing 302 Hospital from 2002 to 2013. RESULTS: The top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. The percentage of HBV cirrhosis decreased from 81.53% in 2002 to 66.0% in 2013, whereas the frequency of alcoholic cirrhosis increased from 3.34% in 2002 to 8.40% in 2013. Females (84.34%) accounted for the majority of cirrhotic patients with autoimmune liver diseases. Males accounted for 80.16% of HBV cirrhosis patients and 98.02% of alcoholic cirrhosis patients. CONCLUSION: In Beijing 302 Hospital, the top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. Over the last 12 years, the prevalence of HBV cirrhosis has decreased gradually, whereas that of alcoholic cirrhosis has increased significantly.

CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis.

UNLABELLED: There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5(+) CD4(+) Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)-21 production (P < 0.05), the ability to promote B-cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA-treated nonresponders, in both cross-sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. CONCLUSION: These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches.

Metabolomic Profiling of Autoimmune Hepatitis: The Diagnostic Utility of Nuclear Magnetic Resonance Spectroscopy.

Autoimmune hepatitis (AIH) is often confused with other liver diseases because of their shared nonspecific symptoms and serological and histological overlap. This study compared the plasma metabolomic profiles of patients with AIH, primary biliary cirrhosis (PBC), PBC/AIH overlap syndrome (OS), and drug-induced liver injury (DILI) with those of healthy subjects to identify potential biomarkers of AIH. Metabolomic profiling and biomarker screening were performed using proton nuclear magnetic resonance spectroscopy (1H NMR) coupled with a partial least-squares discriminant analysis. Compared with the levels in healthy volunteers and other liver disease patients, AIH patients exhibited relatively high levels of plasma pyruvate, lactate, acetate, acetoacetate, and glucose. Such metabolites are typically related to energy metabolism alterations and may be a sign of metabolic conversion to the aerobic glycolysis phenotype of excessive immune activation. Increased aromatic amino acids and decreased branched-chain amino acids were found in the plasma of AIH patients. The whole NMR profiles were stepwise-reduced, and nine metabolomic biomarkers having the greatest significance in the discriminant analysis were obtained. The diagnostic utility of the selected metabolites was assessed, and these biomarkers achieved good sensitivity, specificity, and accuracy (all above 93%) in distinguishing AIH from PBC, DILI, and OS. This report is the first to present the metabolic phenotype of AIH and the potential utility of 1H NMR metabolomics in the diagnosis of AIH.

Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis.

BACKGROUND AND AIM: Ursodeoxycholic acid (UDCA) treatment is an effective medical therapy for patients with primary biliary cirrhosis (PBC); however, 40% of PBC patients show an incomplete response to the UDCA therapy. This study aimed to investigate the safety and efficacy of umbilical cord-derived mesenchymal stem cell (UC-MSC) transfusion in PBC patients with an incomplete response to UDCA. METHODS: We conducted a single-arm trial that included seven PBC patients with a suboptimal response to UDCA treatment. UC-MSCs were first cultured, and then 0.5 × 10(6) cells/kg body weights were infused through a peripheral vein. UC-MSCs were given three times at 4-week intervals, and patients were followed up for 48 weeks. Primary outcomes were to evaluate the safety and feasibility of UC-MSC treatment, and secondary outcomes were to evaluate liver functions and patient's quality of life. RESULTS: No obvious side-effects were found in the patients treated with UC-MSCs. Symptoms such as fatigue and pruritus were obviously alleviated in most patients after UC-MSC treatment. There was a significant decrease in serum alkaline phosphatase and γ-glutamyltransferase levels at the end of the follow-up period as compared with baseline. No significant changes were observed in serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, prothrombin time activity, international normalized ratio, or immunoglobulin M levels. The Mayo risk score, a prognostic index, was also stable during the treatment and follow-up period. CONCLUSIONS: UC-MSC transfusion is feasible and well tolerated in patients with PBC who respond only partially to UDCA treatment, thus representing a novel therapeutic approach for patients in this subgroup. A larger, randomized controlled cohort study is warranted to confirm the clinical efficacy of UC-MSC transfusion.

Combination therapy of low-dose of PegIFNa-2a and ribavirin for patients with HCV-infected decompensated cirrhosis.

BACKGROUND/AIMS: This study aims to evaluate the efficacy and tolerability of low-dose PEGylated interferon (PEG-IFN) a-2a combined with standard of care ribavirin (RBV). The therapy was administered to patients with chronic hepatitis C virus (HCV) with decompensated cirrhosis who underwent splenectomy or partial splenic artery embolization. METHODOLOGY: A total of 106 patients with decompensated liver cirrhosis with chronic HCV infection were subjected to splenectomy (n = 89) or partial spleen artery embolization (n = 17) without the possibility of starting or continuing PEG-IFN and RBV because of neutropenia and/or thrombocytopenia. Antiviral treatment was started when the neutrocyte and platelet counts were increased and without severe surgical complications. A sustained virological response was obtained in 38 genotype 1 patients (59.3%) and 14 non-genotype 1 patients (56%) who underwent splenectomy and 6 genotype 1 patients (46.15%) and 3 non-genotype 1 patients (75%) who underwent partial splenic embolization. In the splenectomy group, the non-response rate of the genotype 1 patients was 28.13%, whereas that for non-genotype 1 patients was 24%. RESULTS: In the PSE group, the non-response rate among genotype 1 patients was 23.08%. All patients in the non-genotype 1 group obtained virological responses. The side effect was neutropenia. No patient died while on therapy. CONCLUSIONS: Both splenectomy and partial spleen artery embolization could be beneficial for low-dose PEG-IFNa-2a plus RBV antiviral therapy for early decompensated liver cirrhosis patients with chronic HCV infection and would not influence antiviral efficacy. However, patients should undergo complete follow-up.

Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients.

UNLABELLED: Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection. Although NK cells have been implicated in inducing hepatocellular damage in patients with chronic hepatitis virus infections, the roles that hepatic NK cells play in chronic hepatitis B virus (HBV) infections remain obscure. In this study, we comprehensively characterized intrahepatic and peripheral NK cells and investigated their impact on liver pathology in a cohort of HBV-infected individuals; this cohort included 51 immune-activated (IA) patients, 27 immune-tolerant (IT) carriers, and 26 healthy subjects. We found that NK cells expressing NK receptors (activation receptors) preferentially accumulated in the livers of IA patients, in which they were activated and skewed toward cytolytic activity but without a concomitant increase in interferon-γ production, in comparison with those of IT carriers and healthy subjects. Further analysis showed that the livers of IA patients, in comparison with those of IT and healthy subjects, expressed higher levels of interleukin-12 (IL-12), IL-15, and IL-18 in situ and lower levels of IL-10, which in vitro can induce the activation and degranulation of NK cells from healthy individuals. Finally, hepatic NK cells displayed more cytolytic activity than peripheral NK cells, and this was found to be positively correlated with the liver histological activity index and serum alanine aminotransferase levels in these IA patients. CONCLUSION: In IA patients, hepatic NK cells are activated and preferentially skew toward cytolytic activity, which depends on an imbalanced cytokine milieu and correlates with liver injury during chronic HBV infection.

[Clinical and pathological analysis of 566 patients with cryptogenic liver diseases].

OBJECTIVE: To investigate the etiology, pathology, and clinical characteristics of cryptogenic liver diseases in order to develop a pathogenic profile for clinical diagnosis and therapeutic design. METHODS: The data of the 566 patients diagnosed with abnormal liver function and who had undergone liver biopsy at our institute between January 2006 to March 2010 were retrospectively analyzed. The Chi-squared (x²) test was used to assess disease correlation with sex and the rank sum test was used to assess disease correlation with continuous data since all data had asymmetric distribution. RESULTS: Among the 566 patients, abnormal liver function was attributed to alcoholic liver disease (n=175; 30.92%), drug-induced or environmentally-induced liver disease (n=101; 17.84%), hereditary and metabolic disease (n=93; 16.43%), infectious hepatitis disease (n=84; 14.84%), fatty liver disease (n=53; 9.36%), and autoimmune liver disease (n=30; 53.00%). Thirty patients had unknown etiology, despite liver biopsy analysis. Among these disease subgroups, there were distinct correlations with sex, age, and levels of alanine transaminase (ALT) and gamma-glutamyltransferase (GGT). The autoimmune liver disease group was correlated with sex (q=9.14, 7.435, 5.071, 9.529, and 12.5, respectively; P less than or equal to 0.01). The alcoholic liver disease group and autoimmune liver disease group were correlated with age (vs. genetic metabolic disease group: q=17.254 and 10.302; infectious hepatitis group: q=17.523 and 10.697); drug/environmentally-induced liver damage group: q=9.170 and 5.266); fatty liver group: q=7.118 and 4.661) (P less than or equal to 0.01). In addition, the alcoholic and autoimmune liver disease groups were correlated with GGT levels (vs. genetic metabolic disease group: q=8.003; infectious hepatitis group: q=4.793; drug/environmentally-induced liver damage group: q=4.404) (P less than or equal to 0.01). CONCLUSION: Liver pathology is important for the diagnosis of cryptogenic liver diseases. Patient age, sex, and biochemistry index may facilitate diagnosis and treatment in the absence of pathology.

Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B.

BACKGROUND & AIMS: Recent studies have shown that programmed death 1 (PD-1) expression can impair virus-specific CD8 T-cell responses during chronic viral infection, including hepatitis B virus (HBV). This study aimed to characterize the PD-1 expression during acute hepatitis B (AHB) and further address whether and how the PD-1-mediated pathway balances antiviral immunity versus immunopathology, possibly contributing to disease progression. METHODS: Peripheral and intrahepatic PD-1 expression was investigated longitudinally in 23 human HLA-A2-positive patients with acute hepatitis B. Four patients with HBV-related acute liver failure, 13 patients with chronic hepatitis B, and 9 healthy individuals were enrolled as controls. Flow cytometric, immunohistochemical, and immunofunctional assays were performed to analyze the impact of PD-1 expression. RESULTS: PD-1 expression was significantly up-regulated on HBV-specific CD8 T cells in the early phase of acute HBV infection, and successful viral clearance correlated with a subsequent decrease in PD-1 expression. Blocking the PD-1-mediated pathway in vitro enhanced HBV-specific CD8 T-cell proliferation and inflammatory cytokine production, while reducing interleukin-10 production and apoptosis, confirming the essential role of PD-1 in tempering the T-cell response during the acute phase of infection. In contrast, delayed PD-1 expression on HBV-specific CD8 T cells was associated with acute liver failure. CONCLUSIONS: PD-1 up-regulation may efficiently mitigate pathogenic CD8 T-cell responses and liver damage, correlating with disease progression of acute HBV infection. This study therefore shows how this negative signaling pathway functions in such early HBV infection, which will be important for better clinical management, prognosis, and new HBV treatments.

Imbalanced intrahepatic cytokine expression of interferon-gamma, tumor necrosis factor-alpha, and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis B virus infection.

GOALS: This study attempts to determine expressions of intrahepatic proinflammatory and anti-inflammatory cytokines and their secreting immunocytes to evaluate their roles in the pathogenesis of acute-on-chronic liver failure (ACLF) in chronically hepatitis B virus (HBV)-infected patients. BACKGROUND: ACLF generally affects patients with established, compensated chronic liver diseases who develop an acute deterioration in liver function. In China, HBV-associated ACLF patients account for more than 80% of ACLF patients owing to a high prevalence of chronic HBV infection. Clinical observation showed that the deterioration of this disease may correlate with host immune responses, but related underlying mechanism remains largely unknown. STUDY: In situ expressions of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and their secreting CD4, CD8 T cells, and Kupffer cells (KCs) were analyzed in the livers of patients with ACLF, chronic hepatitis B (CHB), and normal controls (NC) using immunohistochemistry. RESULTS: Intrahepatic proinflammatory IFN-gamma and TNF-alpha expressions were markedly up-regulated in ACLF compared with CHB and NC. However, similar anti-inflammatory IL-10 expressions were observed in ACLF and CHB. IFN-gamma overexpression correlated significantly with increased CD4 and CD8 T-cell accumulation. TNF-alpha up-regulation also correlated significantly with increased KCs. CONCLUSIONS: The imbalanced expression of proinflammatory and anti-inflammatory cytokines and increased accumulation of CD4, CD8 T cells, and KCs may contribute to immunopathogenesis in HBV-infected ACLF.

Association Between Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism and Alcoholic Liver Disease.

BACKGROUND: Only a subset of patients with excessive alcohol use develop alcoholic liver disease (ALD), though the exact mechanism is not completely understood. Once ingested, alcohol is metabolized by 2 key oxidative enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are 2 major ALDH isoforms, cytosolic and mitochondrial, encoded by the aldehyde ALDH1 and ALDH2 genes, respectively. The ALDH2 gene was hypothesized to alter genetic susceptibility to alcohol dependence and alcohol-induced liver diseases. The aim of this study is to determine the association between aldehyde dehydrogenase 2 (rs671) glu504lys polymorphism and ALD. METHODS: ALDH2 genotyping was performed in 535 healthy controls and 281 patients with ALD. RESULTS: The prevalence of the common form of the single nucleotide polymorphism rs671, 504glu (glu/glu) was significantly higher in patients with ALD (95.4%) compared to that of controls (73.7%, P < 0.0001). Among controls, 23.7% had the heterozygous (glu/lys) genotype compared to 4.6% in those with ALD (odds ratio [OR] = 0.16, 95% CI: 0.09-0.28). The allele frequency for 504lys allele in patients with ALD was 2.3%, compared to 14.5% in healthy controls (OR = 0.13, 95% CI: 0.07-0.24). CONCLUSIONS: Patients with ALDH2 504lys variant were less associated with ALD compared to those with ALDH2 504glu using both genotypic and allelic analyses.

[Immunologically-competent cells in liver infiltrating lymphocytes in patients with chronic severe hepatitis B].

OBJECTIVE: To investigate the frequencies of immunologically competent cells (ICCs) in the liver-infiltrating lymphocytes (LILs) and peripheral blood and their possible role in pathogenesis in patients with chronic severe hepatitis B (CSHB). METHODS: LILs were isolated from the liver tissue samples from 11 CSHB patients and 5 normal controls (NCs) by the method of combined grinding with semi-frosted microscopic slides and sedimentation of hepatic cells. The frequency of isolated ICCs, including CD3(+), CD4(+), and CD8(+) T-cells, NK cells, NKT cells, and B cells was examined and compared with that of the circulating ICCs in the CSHB patients. Comparison was conducted between the CSHB patients and the controls. RESULTS: (1) In the CSHB patients, the frequencies of CD4(+) T cells and B cells in LILs were 17% +/- 6% and 3.0% +/- 1.0% respectively, both significantly lower than those in the circulating blood (32% +/- 8% and 21.4% +/- 12.2% respectively, both P < 0.01); however, the frequencies of CD8(+) T cells, NK cells, and NKT cells in LILs were 38% +/- 13%, 34% +/- 18%, and 10% +/- 4% respectively, all significantly lower than those in the circulating blood (26% +/- 6%, 15% +/- 9%, and 6% +/- 4%, all P < 0.05). (2) The frequencies of infiltrating CD3(+) T cells and CD4(+) T cells of the CSHB patients were both significantly higher than those of the NCs (P = 0.042 and P = 0.001); and the frequency of infiltrating CD8(+) T cells of the CSHB patients was higher than that of the NCs, and the and the frequencies of infiltrating NK cells and NKT cells in LILs were lower than those of the NCs, however, not significantly. (3) Compared with the liver tissues from the NCs, the liver tissues from the CSHB patients exhibited a significantly higher ratio of liver-infiltrating CD4(+) T cells to peripheral blood CD4(+) T-cell subsets (P = 0.001), and significantly lower ratios of liver-infiltrating NKT cells and B cells to the peripheral blood NKT-cells and B cells (P = 0.029 and P = 0.001 respectively). CONCLUSION: The abundant infiltrating immune active cells, especially the CD4(+) T cells, CD8(+) T cells, and NK cells, may be the causal factors that drive the progressive development of CSHB.

Disease spectrum of alcoholic liver disease in Beijing 302 Hospital from 2002 to 2013: A large tertiary referral hospital experience from 7422 patients.

Alcohol consumption in China has substantially increased over the last 3 decades and the number of patients with alcoholic liver disease (ALD) is rising at an alarming rate. However, accurate and representative data on time trends in its hospitalization rates are not available. The aim of this study is to assess the current status and burden of ALD in China by analyzing the data from a large tertiary referral hospital, Beijing 302 Hospital.Data were retrospectively recorded from patients diagnosed as ALD in Beijing 302 Hospital from 2002 to 2013. The disease spectrum and biochemical parameters of each patient were collected.The patients with ALD accounted for 3.93% (7422) of all patients (188,902) with liver diseases between 2002 and 2013. The number of patients hospitalized with ALD increased from 110 in 2002 to 1672 in 2013. The ratio of patients hospitalized with ALD to all patients hospitalized with liver diseases was rising almost continuously and increased from 1.68% in 2002 to 4.59% in 2013. Most patients with ALD were male. Age distribution of ALD hospitalization showed that the highest rate was in 40- to 49-year-old group in subjects. Notably, the annual proportion of severe alcoholic hepatitis (SAH) increased 2.43 times from 2002 to 2013. We found the highest levels of mean corpuscular volume, the aspartate aminotransferase/alanine aminotransferase ratio, total bilirubin, international normalized ratio, and alkaline phosphatase in SAH patients, while serum levels of hemoglobin, albumin, and cholinesterase were significantly decreased in SAH group. Among these ALD, the SAH patient population has the worst prognosis. Alcoholic cirrhosis (ALC) is the most common ALD, and annual admissions for ALC increased significantly during the analyzed period.The number of hospitalized patients with ALD and the annual hospitalization rate of ALD were increasing continuously in Beijing 302 Hospital from 2002 to 2013. More attention should be paid to develop population-based effective strategy to control ALD.

Proposed therapies in primary biliary cholangitis.

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.

Changes of four common non-infectious liver diseases for the hospitalized patients in Beijing 302 hospital from 2002 to 2013.

The implementation of a hepatitis B vaccination program in China has led to a significant decline in the prevalence and incidence of liver diseases secondary to hepatitis B virus over the past two decades. With recent changes in the economy and increases in average incomes in China during the same period, there has been a rapid rise in per capita alcohol consumption and an epidemic of obesity. We hypothesized that the burden of liver diseases in China has shifted from infectious to non-infectious etiologies. We retrospectively analyzed the data of 20,378 patients who were hospitalized in Beijing 302 hospital between 2002 and 2013. We found that the total admission rate secondary to alcoholic liver disease (ALD), non-alcoholic liver disease (NAFLD), autoimmune liver disease (AILD), and drug-induced liver injury (DILI) was 10.7%. ALD was the leading cause of inpatient hospitalization (3.9% of total admissions). The rate of inpatient admission for ALD, AILD, and DILI increased by 170%, 111%, and 107%, respectively during the study period. Chinese herbal medicine was the primary cause of DILI in our subjects. The burden of non-infectious liver diseases has increased over the last decade among hospitalized patients in a large tertiary hospital in China. The increase in the rate of admission for ALD and DILI from Chinese herbal medicine suggests that strategies to reduce harmful use of alcohol and increase awareness and education on the use of herbal medicine are needed.

Women and primary biliary cirrhosis.

Primary biliary cirrhosis occurs more frequently in women, and previous studies indicated that the average age of primary biliary cirrhosis (PBC) onset makes pregnancy in PBC patients uncommon. However, more recently, improved diagnostic testing has enabled detection of PBC in younger women, including those of childbearing age. This has led investigators to become increasingly interested in the relationship between the ontogeny of PBC and pregnancy. Published cases indicate that the typical age for pregnant women to be diagnosed with PBC is in the early 30s, and that during gestation, pruritus and jaundice are the most common symptoms. During gestation, susceptible women may experience onset of PBC resulting from the drastic changes in female hormones; this would include not only the mitochondrial damage due to accumulation of bile acids but also changes in the immune response during the different stages of pregnancy that might play an important role in the breakdown of self-tolerance. The mechanisms underlying the potential relationship between PBC and pregnancy warrant further investigation. For women first diagnosed with PBC during gestation, or those for whom first appearance of a flare up occurs during and postpartum, investigation of the immune response throughout gestation could provide new avenues for immunologic therapeutic intervention and the discovery of new treatment strategies for PBC.

The coexistence of Sjögren's syndrome and primary biliary cirrhosis: a comprehensive review.

Organ-specific and systemic autoimmune diseases share numerous features and often coexist in the same patient. Autoimmune cholangitis/primary biliary cirrhosis and Sjogren syndrome represent paradigmatic examples of the common grounds of different autoimmunity phenotypes based on similarities in clinical manifestations and immunopathogenesis. In fact, primary biliary cirrhosis and Sjogren's syndrome have both been coined as an autoimmune epithelitis in which apoptosis may be in both cases the key element to explain the organ-specific immune-mediated injury against the biliary and exocrine gland epithelia, respectively. Further, growing evidence supports in both diseases the view that B cells, T cytotoxic cells, and T helper cells are involved in chronic inflammation, likely via the altered expression of pro-inflammatory cytokines. The presence of estrogen receptors on the biliary and exocrine gland epithelia has been advocated as a key to the female predominance encountered in primary biliary cirrhosis and Sjogren's syndrome. Sadly, despite available data, therapeutic approaches remain largely unsatisfactory and recent studies with mechanistic approaches (as in the case of B cell depletion with rituximab) have been of partial benefit only. Future studies should focus on new molecular tools (single-cell transcriptomics, microRNA, epigenetics) to provide unique insights into common mechanisms.

Serum soluble CD40 is associated with liver injury in patients with chronic hepatitis B.

Soluble cluster of differentiation 40 (sCD40) is proteolytically cleaved from membrane-bound CD40 and binds to CD154, thereby inhibiting CD40-CD154-mediated immune responses. The aim of the present study was to clarify the role of sCD40 in chronic hepatitis B (CHB). The sCD40 levels in sera from 132 patients with CHB and 33 healthy individuals were retrospectively measured. sCD40 concentrations in patients with CHB were higher than those in healthy controls, and sCD40 levels correlated positively with serum levels of the liver dysfunction biomarkers alanine transaminase (ALT) and aspartate transaminase (AST). sCD40 concentrations increased with a rise in the severity of liver necroinflammation and fibrosis. Patients with >75% liver tissue staining positive for hepatitis B virus (HBV) antigen expression showed significantly lower sCD40 levels than those who stained negative for the HBV antigen. The area under the receiver operating characteristic curve of sCD40 was greater than that of ALT and AST; thus, sCD40 levels have a high diagnostic accuracy for detecting severe liver inflammation in patients with CHB, and could serve as an immunological marker of hepatic tissue injury.