Risk factors for liver-related mortality in chronic hepatitis C patients:A deceased case-living control study

AIM: To investigate the risk factors for liver-related mortality in chronic hepatitis C (CHC) patients.

Sofosbuvir and ABT-450: Terminator of hepatitis C virus?

Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.

Primary biliary cirrhosis-associated hepatocellular carcinoma in Chinese patients:Incidence and risk factors

AIM: To investigate the incidence, characteristics, and risk factors for hepatocellular carcinoma(HCC) in Chinese patients with primary biliary cirrhosis(PBC).METHODS: We reviewed the data of 52 PB Cassociated HCC patients treated at Beijing 302 Hospital from January 2002 to December 2013 and analyzed its incidence and characteristics between the two genders. The risk factors for PBC-associated HCC were analyzed via a case-control study comprising 20 PBC patients with HCC and 77 matched controls without HCC. The matched factors included gender, age, follow-up period and Child-Pugh scores. Conditional logistic regression was used to evaluate the odds ratios of potential risk factors for HCC development. A P < 0.05 was considered statistically significant. RESULTS: The incidence of HCC in Chinese PBC patients was 4.13%(52/1255) and was significantly higher in the males(9.52%) than in the females(3.31%). Among the 52 PBC patients with HCC, 55.76%(29/52) were diagnosed with HCC and PBC simultaneously, and 5.76%(3/52) were diagnosed with HCC before PBC. The males with PBC-associated HCCwere more likely than the females to have undergone blood transfusion(18.75% vs 8.33%, P = 0.043), consumed alcohol(31.25% vs 8.33%, P = 0.010), smoked(31.25% vs 8.33%, P = 0.010), had a family history of malignancy(25% vs 5.56%, P = 0.012), and had serious liver inflammation, as indicated by the elevated levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase(P < 0.05). Conditional logistic regression analysis revealed that body mass index(BMI) ≥ 25 [adjusted odds ratio(AOR) = 1.116, 95%CI: 1.002-1.244, P = 0.045] and history of alcohol intake(AOR = 10.294, 95%CI: 1.108-95.680, P = 0.040) were significantly associated with increased odds of HCC development in PBC patients. CONCLUSION: HCC is not rare in Chinese PBC patients. Risk factors for PBC-associated HCC include BMI ≥ 25 and a history of alcohol intake. In addition to regular monitoring, PBC patients may benefit from abstinence from alcohol and body weight control.

Guidelines for the Diagnosis and Management of Herb-Induced Liver Injury

Herb-induced liver injury （HILl） is a type of adverse drug reactions related to using Chinese medicine （CM） or herbal medicine （HM）, and is now a growing segment of drug-induced liver injury （DILl） worldwide. Owing to the complicated compositions and miscellaneous risk factors associated with the clinical usage of CM or HM, it is more challenging to diagnose and manage HILl than DILl. In the present guideline issued by the China Association of Chinese Medicine （CACM）, the authors present an evidence chain-based workflow with 9 structured judgment criteria for diagnosing HILl. The 3 diagnostic ending points--suspected diagnosis, clinical diagnosis, and confirmed diagnosis--could be reached according to the length of the evidence chain acquired in the structured diagnostic workflow. Either identifying the species of CM or HM or excluding adulterations and toxin contaminants was strongly recommended to improve the level of evidence for a clinical diagnosis of HILl. In addition, the authors report that the improper use of CM, which violates the general law of CM theory, is one of the most important factors that contributes to HILl and should be avoided. By contrast, based on syndrome differentiation, some CM can also be used to treat HILl if used in accordance with the general law of CM theory. Therefore, 9 recommendations are put forward in this guideline.

Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

Acute-on-chronic liver failure （ACLF） is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells （mDCs） and the efficacy of methylprednisolone （MP） treatment for hepatitis B virus （H BV）-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at lO-day intervals; 26 patients received conservative medical （CM） management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/ transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients.

The efficacy of miRNA122, a novel therapeutic target, for predicting the progression of hepatocellular carcinoma （HCC）

Hepatocellular carcinoma （HCC） is the fifth most prevalent malignancy worldwide, and it accounts for 85-90% ot all primary liver cancers. Owing to the limited therapeutic options available, the 5-year survival rate remains relatively low for patients with HCC. The development of HCC is a multistage process1 that involves changes in the expression of multiple oncogenes, tumor suppressor genes and microRNAs that are involved in the cell cycle, as well as in cell growth, apoptosis, migration and tumor metastasis.2,3 Finding an accurate biomarker that can predict HCC progression is import- ant for clinicians to be able to determine the optimal therapeutic strategy.

Implications of the immunoregulatory functions of mesenchymal stem cells in the treatment of human liver diseases

Transplantation of mesenchymal stem cells(MSCs)has been recently studied in animal models,and in clinical trials of patients with fulminant hepatic failure,end-stage liver diseases and inherited metabolic disorders.Modulatory cytokines produced by MSCs can inhibit immunocyte proliferation and migration to the liver,thereby attenuating inflammatory injury and reducing hepatocyte apoptosis.In addition,MSCs play an important role in regressing liver fibrosis and in supporting the function,proliferation and differentiation of endogenous hepatocytes under appropriate conditions.Although remarkable progress has been achieved in basic and clinical MSC studies,optimal therapeutic regimens for the clinical application of MSCs,such as optimal doses,transplantation routine and interval period for transplantation,need to be elucidated in detail.Furthermore,the long-term safety and therapeutic efficacy of MSC transplantation should be evaluated in future clinical trials.This review summarizes our current understanding of the immunomodulatory effects of MSC therapies on human liver diseases.

Liver fibrosis： mechanisms of immune-mediated liver injury

Liver fibrosis and its end-stage consequence, cirrhosis, represent the final common pathway of virtually all chronic liver diseases. Research into hepatic stellate cell activation, imbalance of the extracellular matrix synthesis and degradation and the contribution of cytokines and chemokines has further elucidated the mechanisms underlying fibrosis. Furthermore, clarification of changes in host adaptive and innate immune systems has accelerated our understanding of the association between liver inflammation and fibrosis. Continued elucidation of the mechanisms of hepatic fibrosis has provided a comprehensive model of fibrosis progression and regression. This review summarizes the current concepts of improvements that have been made in the field of fibrosis.

The role of neutrophils in the development of liver diseases

Liver disease encompasses a wide variety of liver conditions, including liver failure, liver cirrhosis and a spectrum of acute and chronic hepatitis, such as alcoholic, fatty, drug, viral and chronic hepatitis. Liver injury is a primary causative factor in liver disease; generally, these factors include direct liver damage and immune-mediated liver injury. Neutrophils （also known as neutrophilic granulocytes or polymorphonuclear leukocytes （PMNs）） are the most abundant circulating white blood cell type in humans, and PMNs are a major innate immune cell subset. Inappropriate activation and homing of neutrophils to the microvasculature contributes to the pathological manifestations of many types of liver disease. This review summarizes novel concepts of neutrophil-mediated liver iniurv that are based on current clinical and animal model studies.

Emerging Role of Interleukin 22 in Hepatitis B Virus Infection: a Double-edged Sword

Hepatitis B virus (HBV) infection remains a worldwide health problem,and is the major cause of hepatitis,liver cirrhosis,and hepatocellular carcinoma.The innate and adaptive immune responses of the HBV-infected host contribute greatly to the development and pathogenesis of chronic HBV infection,and often affect the efficacy of anti-HBV drugs.Interleukin (IL)-22 is a newly identified cytokine that is involved in the pathogenesis of liver disease,but its role in liver inflammation in patients with HBV infection remains controversial.In this report,we summarize the production and function of IL-22 in inflammatory environments,and review the current research into IL-22 biology in HBV infection.A better understanding of the intrahepatic micro-environments that directly influence the activity of IL-22 will be important for the development of new immunotherapeutic approaches that target IL-22-producing cells or IL-22 itself.

Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients

B cells play an important role in the clearance of hepatitis B virus （HBV） and protection against reinfection. However, the functional characteristics of these cells that are associated with the outcome of chronic HBV infection remain unknown. We comprehensively investigated the frequency, phenotype, and function of peripheral B-cell subsets from CHB patients in different phases： immune tolerance （IT）, immune activation （IA）, immune clearance （IC）, responders with HBsAg seroconversion （resolved patients, RP）, and healthy controls （HC）. IA patients displayed lower percentages of peripheral blood memory B cells compared with the other groups. Overall polyclonal activation of B cells, indicated by higher levels of activation markers and secretion of IgG and IgM, was observed in IA patients. This B-cell hyperactivation could be induced by increased IFN-a and soluble CD40 ligands in IA patients. Notably, the expression of the co-stimulator molecule CD80 and serum HBsAb and the frequency of HBsAg-specific B cells were significantly decreased in IT, IA, and IC patients compared with HC subjects. More importantly, the B-cell hyperactivation, co-stimulatory molecule downregulation and HBsAg-specific B-cell impairment were reversed in RP patients. The reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients.