Chronic liver disease and oxidative stress - a narrative review.

Introduction: Oxidative stress underlies the pathophysiology of various etiologies of chronic liver disease and contributes to the development of hepatocarcinogenesis.Areas covered: This review focuses on the impact of oxidative stress in various etiologies of chronic liver disease such as alcoholic liver disease (ALD), nonalcoholic steatohepatitis (NASH), hepatitis B virus (HBV), and hepatitis C virus (HCV) infection. The efficacy of antioxidants in laboratory, animal, and clinical studies in chronic liver disease is also reviewed.Expert opinion: Currently, there are limited targeted pharmacotherapeutics for NASH and no pharmacotherapeutics for ALD and antioxidant supplementation may be useful in these conditions to improve liver function and reverse fibrosis. Antioxidants may also be used in patients with HBV or HCV infection to supplement antiviral therapies. Specific genotypes of antioxidant and prooxidant genes render patients more susceptible to liver cirrhosis and hepatocellular carcinoma while other individual characteristics like age, genotype, and metabolomic profiling can influence the efficacy of antioxidants on CLD. More research needs to be done to establish the safety, efficacy, and dosage of antioxidants and to establish the ideal patient profile that will benefit the most from antioxidant treatment.

[Correlation of liver stiffness measured by FibroTouch and FibroScan with Ishak fibrosis score in patients with chronic hepatitis B].

Objective: To investigate the correlation of liver stiffness measured by FibroTouch (FT) and FibroScan (FS) with Ishak fibrosis score in patients with chronic hepatitis B. Methods: A total of 313 patients with chronic hepatitis B who visited Department of Liver Cirrhosis in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from November 2014 to May 2016 were enrolled. All the patients underwent liver biopsy, and FT and FS were used to determine liver stiffness measurement (LSM). Serum biochemical parameters were measured, and the aspartate aminotransferase-to-platelet ratio index (APRI) in a multi-parameter model of liver fibrosis and fibrosis-4 (FIB-4) index were calculated. The consistency between the results of four noninvasive examinations and Ishak fibrosis score was compared. The t-test was used for comparison of LSM determined by FT and FS. Pearson correlation analysis was used investigate the correlation between LSM determined by FT and FS; Spearman correlation analysis was used to investigate the correlation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and Knodell score with LSM determined by FT and FS; the correlation between LSM determined by FT and FS and fibrosis stage was analyzed by partial correlation analysis adjusted by Knodell score for liver inflammatory activity; Spearman correlation analysis was used for APRI, FIB-4, and fibrosis stage. Based on the Ishak fibrosis score, the receiver operating characteristic (ROC) curve was used to analyze the values of four noninvasive methods in the diagnosis of liver fibrosis. Results: There was no significant difference in LSM measured by FT and FS in all patients (15.75±9.42 kPa vs 15.42±10.52 kPa, P > 0.05) and Pearson correlation analysis indicated a significant positive correlation between them (r = 0.858, P < 0.01); serum ALT and AST levels and liver inflammatory activity were correlated with LSM determined by FT and FS. There was a significant positive correlation between LSM determined by FT and FS and fibrosis stage (r = 0.501 and 0.526, both P < 0.001), and APRI and FIB-4 were also positively correlated with fibrosis stage (r = 0.236 and 0.218, both P < 0.001). Based on the Ishak fibrosis score, in the diagnosis of fibrosis stages F3, F4, F5, and F6, the areas under the ROC curve were 0.915/0.856/0.839/0.816 for FT, 0.933/0.883/0.849/0.856 for FS, 0.618/0.630/0.608/0.638 for APRI, and 0.614/0.624/0.595/0.649 for FIB-4, and FT and FS had a significantly larger areas under the ROC curve than APRI and FIB-4. Conclusion: LSM determined by FT or FS has a good correlation with the Ishak fibrosis score, so FT and FS have a significantly better diagnostic performance for liver fibrosis than APRI and FIB-4.

[Spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon in treatment of chronic hepatitis B].

To observe the clinical efficacy of spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon in the treatment of HBeAg positive chronic hepatitis B(HP-HBV).One hundred and twenty-six patients with HP-HBV, who were treated in the hospital from June 2012 to December 2014, were selected and injected with polyethylene glycol interferon α-2a(or α-2b). The treatment course for the patients lasted for 24 weeks. Base on the level of HBV-DNA, patients are divided into response group and poor response group. According to random number table, the poor response group were randomized into control group and test group. Patients in the control group were injected with polyethylene glycol interferon α-2a(or α-2b), and patients in the test group were treated with spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon. Clinical efficacies of the 2 groups were observed, and changes in the level of HBeAg, ALT and HBV-DNA were observed before treatment and at the 24th week after treatment, and virological and serological response, biochemical responses, integral clinical symptoms and signs, adverse reactions were observed after 48 weeks of treatment.After 24 weeks of treatment, the response group was significantly better than the poor response group in HBeAg, ALT and the level of HBV-DNA(P<0.05). After 48 weeks of treatment, there was statistical significance in HBV-DNA negative conversion rate, HBeAg negative conversion rate between the 2 groups(P<0.05), and the test group was better in the two indicators. And the test group was significantly lower than the control group in clinical symptoms and signs score at the 48th week after treatment(P<0.05), with a significantly lower adverse reaction rate than the control group(P<0.05).Combination of spleen, liver and kidney-strengthening formula and polyethylene glycol interferon α-2a was effective and safe in the treatment of chronic hepatitis B, and so worth promoting in clinic.

Systemic diseases and biotherapies: understanding, evaluating, and preventing the risk of hepatitis B reactivation.

Hepatitis B virus (HBV) reactivation can occur in chronic carriers of the HBV surface antigen (HBsAg) and constitutes a well-known complication of immunosuppressive therapy. HBV reactivation has also been reported after contact with the HBV. The increasing use of biological agents (TNFα antagonists, rituximab, abatacept, and tocilizumab) to treat systemic diseases has resulted in numerous publications about the risk of HBV reactivation. The relevant scientific societies have issued recommendations designed to prevent HBV reactivation. The main measures consist of screening for markers indicating chronic HBV infection (HBsAg) or HBV infection in the distant past (antibodies to the HBV core antigen) before initiating biological therapies, vaccinating marker-negative patients, and considering close follow-up or antiviral treatment before immunosuppressive treatment initiation or in the event of HBV reactivation. Here, we discuss the pathophysiological mechanisms underlying HBV reactivation during biological treatments, most notably in patients with occult HBV infection or markers for remote HBV infection, whose hepatocyte nuclei may contain a resistance form of HBV DNA known as covalently closed circular DNA (cccDNA). Assessment of the risk of reactivation relies on the HBV status, drugs used, and data from the literature. Finally, we discuss the various recommendations and modalities for HBV vaccination, preemptive treatment, and patient management, according to the level of risk and to the circumstances in which reactivation occurs.

Clinical trial with traditional Chinese medicine intervention ''tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment'' for chronic hepatitis B-associated liver failure.

AIM: To study the clinical efficacy of traditional Chinese medicine (TCM) intervention "tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment" ("TTK") for treating liver failure due to chronic hepatitis B. METHODS: We designed the study as a randomized controlled clinical trial. Registration number of Chinese Clinical Trial Registry is ChiCTR-TRC-12002961. A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study. Participants were randomly assigned to the following three groups: (1) a modern medicine control group (MMC group, 36 patients); (2) a "tonifying qi and detoxification" ("TQD") group (72 patients); and (3) a "tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment" ("TTK") group (36 patients). Patients in the MMC group received general internal medicine treatment; patients in the "TQD" group were given a TCM formula "tonifying qi and detoxification" and general internal medicine treatment; patients in the "TTK" group were given a TCM formula of "TTK" and general internal medicine treatment. All participants were treated for 8 wk and then followed at 48 wk following their final treatment. The primary efficacy end point was the patient fatality rate in each group. Measurements of various virological and biochemical indicators served as secondary endpoints. The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups. RESULTS: At the 48-wk post-treatment time point, the patient fatality rates in the MMC, "TQD", and "TTK" groups were 51.61%, 35.38%, and 16.67%, respectively, and the differences between groups were statistically significant (P < 0.05). However, there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups (P > 0.05). Patients in the "TTK" group had significantly higher levels of serum total bilirubin compared to MMC subjects (339.40 µmol/L ± 270.09 µmol/L vs 176.13 µmol/L ± 185.70 µmol/L, P = 0.014). Serum albumin levels were significantly increased in both the "TQD" group and "TTK" group as compared with the MMC group (31.30 g/L ± 4.77 g/L, 30.72 g/L ± 2.89 g/L vs 28.57 g/L ± 4.56 g/L, P < 0.05). There were no significant differences in levels of alanine transaminase among the three groups (P > 0.05). Safety data showed that there was one case of stomachache in the "TQD" group and one case of gastrointestinal side effect in the "TTK" group. CONCLUSION: Treatment with "TTK" improved the survival rates of patients with liver failure due to chronic hepatitis B. Additionally, liver tissue was regenerated and liver function was restored.

IFN-γ inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice.

BACKGROUND & AIMS: Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. METHODS: We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. RESULTS: The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-γ did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1(-/-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. CONCLUSIONS: IFN-γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.

[The influence of low-intensity laser radiation on the vascular endothelium function and the cytokine system in patients with chronic viral hepatitis].

The objective of the present work was to study the influence of low-intensity laser therapy on the cytokine system and the function of vascular endothelium in patients presenting with chronic viral hepatitis. The measurement of blood cytokine levels by an immunoenzyme assay revealed a decrease in the levels of anti-inflammatory IL-1-beta, IL-6, and TNF-alpha and a rise in proinflammatory IL-4 in the treated patients compared with the untreated ones. Medicamental therapy of chronic viral hepatitis did not cause a significant reduction in the plasma nitric oxide level whereas inclusion of low-intense laser irradiation in the combined treatment resulted in its normalization. It is concluded that the use of low-intense laser irradiation as a component of combined therapy of patients presenting with chronic viral hepatitis has marked beneficial effect on the cytokine system. Moreover, various methods of such laser therapy improve the functional activity of vascular endothelium and its NO-producing capacity.

Effects of the Ganning formula on liver fibrosis in patients with chronic hepatitis B.

OBJECTIVE: To investigate the clinical efficacy and safety of the Ganning formula for the treatment of liver fibrosis in patients with chronic hepatitis B. METHODS: In a multicenter, randomized, controlled clinical trial, 150 patients with liver fibrosis secondary to hepatitis B virus (HBV) infection were randomly assigned in equal numbers to receive either the Ganning formula (a Chinese herbal decoction; active treatment group) or oral entecavir (control group) for two 3-month courses. Patients were monitored for any treatment-induced changes in liver function test parameters (ALT, AST, and GGT), liver fibrosis markers (LN, HA, IV-C, and PCIII), HBV DNA level, hepatosplenic imaging, quality of life scores, or psychological and social functioning scores. Patients were also observed for any adverse effects. RESULTS: After treatment, patients in both groups experienced significant improvements in liver function, HBV DNA load, hepatosplenic B-mode ultrasonography, quality of life, and psychological and social functioning (P < 0.05 or P < 0.01). Patients receiving the Ganning formula achieved greater improvements in HA, IV-C, quality of life, and psychological and social functioning compared with those on entecavir (P < 0.05 or P < 0.01). There were no abnormal changes in blood tests, urine, feces, renal function, or electrocardiogram. Additionally, no adverse effects were observed in any patients in either group. CONCLUSIONS: The Ganning formula appears to have the potential to inhibit liver fibrosis and therefore improve liver function by inhibiting HBV replication in patients with chronic hepatitis B. Additionally, this formula is helpful in improving quality of life and psychological and social functioning.

[Effects of Danqi Huogan Capsule in protecting the liver, promoting circulation and removing clots in patients with chronic hepatitis B].

OBJECTIVE: To assess the effect of Danqi Huogan Capsule in protecting the liver, promoting the circulation and removing blood clots in patients with chronic hepatitis B (CHB). METHODS: A total of 104 CHB patients were randomized into two groups. Routine therapies for liver protection were given in the control group (n=50), and Danqi Huogan Capsule was administered in the therapeutic group (n=54) in addition to the routine therapies. The changes in the clinical symptoms, physical signs, liver functions, and hemorrheology were observed after the 3-month therapies. RESULTS: Danqi Huogan Capsule treatment obvious improved the clinical symptoms, physical signs and liver functions of the patients (P<0.01), and significantly decreased the hematocrit, low-shear blood viscosity, plasma viscosity and index of red blood cell aggregation (P<0.05). CONCLUSION: Danqi Huogan Capsule is effective in protecting the liver, improving hemorrheology, promoting the blood circulation and removing clots in patients with chronic hepatitis B.

[Effect of low-intensity laser radiation on the function of vascular endothelium in patients with chronic viral hepatitis].

The aim of the study was to measure plasma levels of stable metabolites of nitric oxide, nitrates, and nitrites (NOx) in patients with chronic viral hepatitis and evaluate the possibility of their correction by low-power laser irradiation. NO metabolites (total nitrites and nitrates) were measured colorimetrically from the development of colour in the reaction of nitrite with sulfanilamide diazotization in Griess reagent. Colour intensity was determined with Victor2 enzyme immunoanalyzer, Perkin Elmaer (Finland). The patients were divided into three groups. In group 1 (control, n = 30) they received combined medicamentous therapy, in group 2 (n = 45) medicamentous therapy and a course of intravenous laser therapy, in goup 3 (n = 45) medicamentous therapy and skin laserotherapy. The results indicate that medicamentous treatment of patients with chronic hepatitis does not bring any beneficial changes in plasma NOx whose levels are significantly improved in case of simultaneous laser therapy. It is concluded that different laserotherapeutic modalities have beneficial effect on NO-producing function of endothelium and thereby improve its functional state. Compensation of NO deficit by laser therapy ensures overall protection of the organism against free radicals and decreases severity of oxidative stress.

Influence of TCM therapy for supplementing Pi and nourishing Shen on dendritic cell function in patients with chronic hepatitis B treated by lamivudine.

OBJECTIVE: To observe the influence of traditional Chinese medicine (TCM) therapy for supplementing Pi () and nourishing Shen (, SPNS) on dendritic cell function in patients with chronic hepatitis B (CHB) treated by lamivudine. METHODS: Sixty CHB patients with positive HBeAg were equally randomized by digital table into two groups: the observation group and the control group. Patients in the control group were treated with lamivudine only, while patients in the observation group were treated with lamivudine combined with SPNS fomula, for 12 weeks. The phenotype and function of dendritic cell, as well as its secretion factor interleukin 12 (IL-12) in all patients were determined after termination of therapy and the impacts on alanine transaminase (ALT) and HBVDNA were observed. RESULTS: The phenotypes of dendritic cells such as CD1a, CD80, CD86, human leukocyte antigen (HLA-DR) and intercellular adhesion molecule-1, as well as the levels of stimulation index (SI) and IL-12 were higher in the observation group than those in the control group (P<0.05 or P<0.01). Meanwhile, signififi cant difference between the two groups was also shown in the normalizing rates of ALT and HBV-DNA (P<0.05). CONCLUSION: TCM therapy for SPNS can signifificantly improve the function of dendritic cells in patients with CHB treated by lamivudine and enhance the early stage response of patients to the treatment.

[Combined treatment including ozonotherapy of patients with viral hepatitis ].

Patients with viral hepatitis have disturbances of biliary tract motor function with the tendency to hypertonus of Oddi's sphincter, changes of physic-colloid properties of bile with increase in density of gall and hepatic bile, pH shift to acid side, microlites formation, disorders in biochemical composition of bile. More than 80% patients have biliar insufficiency. According to our data, with the purpose to correct of disturbances of hepatic exocrine function in patients with viral hepatitis and to prevent stone formation, it is reasonable to use together with antiviral therapy also intravenous injection of ozonated physiological solution and preparations of ursodeoxycholic acid.

[Effects of Kang Gang Qian Granule (KGQG) on clinical and pathological features in chronic hepatitis B patients].

OBJECTIVE: To explore the efficacy of KGQG and its therapeutic mechanisms in chronic hepatitis B patients with liver fibrosis. METHODS: 57 chronic hepatitis B patients with liver fibrosis were randomly divided into two groups: 45 cases in KGQG group were treated by KGQG and routine medications; 12 cases in control group were treated by routine medications only. Serum liver function test results, PCIII, CIV, HA and liver biopsy results of these 57 patients were simultaneously collected and analyzed before and after this intervention. RESULTS: KGQG group showed better efficacy over control group in liver function recovery, decrease of serum PCIII, CIV, HA levels and liver pathologic grades (P 0.05 or 0.01). CONCLUSION: The KGQG could effectively ameliorate liver function and facilitate the inhibition and degradation of liver fibrosis in chronic hepatitis B patients, which may be developed as a novel therapeusis to treat this hard-to-cure disease.

Two-year observation of the clinical efficacy in treating chronic hepatitis B Patients with Ganxian recipe and lamivudine.

OBJECTIVE: To evaluate the clinical efficacy of Ganxian recipe (GXR) and lamivudine (LVD) in a two-year treatment of chronic hepatitis B (CHB). METHODS: One hundred and twenty patients with CHB were randomly divided into the combinedly treated group (combined group) of 40 CHB patients who were treated with GXR combined with LVD. Another 40 CHB patients were treated with LVD alone (WM group), and still another 40 CHB patients were treated with GXR alone (TCM group). All these cases were randomly controlled and observed for two years. RESULTS: Comprehensive efficacy: Total effective rate of the combined group (complete response and partial response) was 92.5%, while that of the WM group was 67.5% and TCM group 57.5%, respectively, with the difference between them was significant (P < 0.01); after treatment, the hepatic functions (AST, ALT, SB) of the three groups were all reduced, and the reduction in the combined group was particularly significant in comparison with the WM group or TCM group, P < 0.05 or P < 0.01 respectively, suggesting that the effect in the combined group was better than that in the other two groups; the rate of tyrosine-methionine-aspartate-aspartate (YMDD) virus mutation: it was 7.5% in the combined group, 40.0% in the WM group, and 5.0% in the TCM group; liver fibrosis improvement parameter: after treatment, the results in the combined group got better than those in the other two groups. CONCLUSION: GXR could inhibit the appearance of YMDD after long-term application of LVD, and combined use has marked synergism.

A comparative study of Phyllanthus amarus compound and interferon in the treatment of chronic viral hepatitis B.

Fifty-five patients with chronic viral hepatitis B were randomly divided into two groups. Thirty patients were treated with Phyllanthus amarus compound (PA Co) for three months in the treatment group, another 25 patients were treated with domestic recombinant human interferon alpha-1b (IFN-alpha 1b) for three months as controls. The total effective rate in the treatment group was 83.3%, showing no significant difference from the control (p>0.05). The normalization rates of ALT, A/G and SB in the treatment group were 73.3%, 80.0% and 78.2% respectively, which were significantly higher than that in the control (p<0.05). The negative conversion rates of HBeAg and HBV-DNA in the treatment group were 42.3% and 47.8%, showing no significant difference from the control (p>0.005). It is indicated that PA Co has remarkable effect for chronic viral hepatitis B in recovery of liver function and inhibition of the replication of HBV.