Combined prednisone and levothyroxine improve treatment of severe thrombocytopenia in hepatitis B with compensatory cirrhosis accompanied by subclinical and overt hypothyroidism

The aim of the present study was to investigate the relationship between hypothyroidism and thrombocytopenia in hepatitis B-related compensatory liver cirrhosis and to determine whether treatment with levothyroxine and prednisone is superior in a multicenter, open-label, observational study in China. In total, 125 consecutive hepatitis B-related compensated liver cirrhosis patients with severe thrombocytopenia accompanied by hypothyroidism were included. The patients were divided into four groups according to treatment strategy: a control group (n=29), a prednisone group (n=25), a levothyroxine group (n=32) and a prednisone plus levothyroxine group (n=39). Severe thrombocytopenia was more prevalent in hepatitis B-associated compensatory liver cirrhosis patients with hypothyroidism than in euthyroid patients (29.6% vs. 14.7%, P<0.05). Combination treatment with prednisone and levothyroxine decreased the risk of bleeding and improved platelet recovery compared to control treatment and treatment with either prednisone or levothyroxine alone. The platelet count before therapy, serum thyroid stimulating hormone and combination treatment with prednisone and levothyroxine were associated with bleeding events. Therefore, the present study suggests that hypothyroidism is associated with severe thrombocytopenia in hepatitis B-associated compensatory liver cirrhosis. Treatment with prednisone plus levothyroxine may present a novel approach in these patients.     

Suspected hepatotoxicity by Cimicifugae racemosae rhizoma (black cohosh,root): Critical analysis and structured causality assessment

Severe hepatotoxicity has been described as spontaneous or case reports in 42 patients in assumed causal relationship with the treatment by Cimicifugae racemosae rhizoma corresponding to the root of black cohosh (BC) for postmenopausal symptoms. However, an assessment by EMEA (European Medicines Agency) has shown a possible or probable causality in only 4 out of 42 patients. A diagnostic algorithm was now applied in the 4 patients with suspected BC hepatotoxicity, which included the qualitative and quantitative causality assessment of the updated system of the Council for International Organizations of Medical Sciences (CIOMS), allowing the study to objectively assess, score and scale the probability in each case. Due to incomplete data, the case of 1 patient was not assessable. In the remaining 3 patients, a severe course of liver disease was apparent, and steroid therapy was initiated under the provisional diagnosis of drug-induced hepatic injury. The analysis shows, however, that the observed liver diseases were unrelated to drugs. Only 1 patient had a favourable course under continued steroid therapy, and the final diagnosis was autoimmune hepatitis. The 2 other patients required liver transplantation under the final diagnosis of herpetic hepatitis established now. Quantitative evaluation showed no causality for BC in all 3 patients regarding the observed severe liver disease. Using a thorough causality assessment in the form of a diagnostic algorithm we have shown that there is no evidence for a causal relationship between treatment by black cohosh and the observed liver disease in the 4 patients.     

Immune response to HBsAg and the spectrum of liver lesions in HBsAg-positive patients with chronic renal disease.

Evidence of chronic hepatitis was found on histological examination in nine out of 15 patients positive for hepatitis-B surface antigen (HBsAg) who had either chronic renal failure or a functioning renal transplant. Cirrhosis had already developed in three of the patients, who deteriorated rapidly and died. Liver biopsies from the remaining 12 patients showed the features of chronic aggressive hepatitis in two, chronic persistent hepatitis in four, and minor histological lesions in six. The persistence of HBsAg in patients with renal failure or in those receiving immunosuppressive drugs after a transplant must indicate some impairment of the normal immune response to hepatitis-B viral antigens. Nevertheless, cellular or humoral immunity to HBsAg was detected in all eight patients with chronic hepatitis tested compared with only one out of five with minimal liver lesions, which suggests that the severity of the liver damage may be directly related to the degree of immunocompetence.     

超声导入疗法治疗慢性乙型肝炎肝纤维化临床研究

目的：探讨超声导入疗法对乙型肝炎肝纤维化患者进行治疗的临床效果。方法：选择符合诊断标准的慢性乙型肝炎肝纤维化患者52例,随机分为试验组和对照组,各26例。对照组患者给予基本保肝治疗,试验组在对照组的基础上加用黄芪注射液进行超声导入,3个月为1个疗程。观察两组患者治疗前后症状、体征、血清肝纤维化指标、肝功能变化及影像学指标。结果：两组患者症状、体征均有不同程度的改善,差异无统计学意义（P〉0．05）;试验组血清肝纤维化指标明显改善,与对照组比较,差异有统计学意义（P〈0．05）;肝功能及影像学指标的改善更明显（P〈0．01）。结论：超声导入疗法对慢性乙型肝炎肝纤维化具有改善肝功能,减少肝细胞外基质的增生与沉积的效用,能够减轻或延缓肝纤维化的进展。     

Dynamics of immunological indices in patients with chronic viral hepatitis B and the effect of thymalin therapy

The work deals with the results of the study of T-lymphocytes and their subpopulations (active, thermostable, theophylline-sensitive and theophylline-resistant) in 102 children with chronic viral hepatitis B, depending on the effectiveness of thymalin therapy. The sensitization of lymphocytes to specific antigens was studied. Among patients with chronic viral hepatitis B and cirrhosis of the liver the homozygous phenotype of haptoglobin is registered essentially more frequently (63.6% and 82.4% respectively) than among healthy persons (44.0%). The patients of this group showed a decrease in the number of T-lymphocytes, disturbances in the suppressor/helper ratio: hypersuppression in persisting hepatitis and hyposuppression in active hepatitis. In 71.6% of cases thymalin therapy produced an effect manifested by clinico-biochemical remission, an increase in the number of T-lymphocytes, thermostable cells and the normalization of the T-suppressor/T-helper ratio. In these patients sensitization to HBsAg essentially decreased (from 30.5% to 13.9%), while sensitization to human liver lipoprotein retained its high level even after treatment with thymalin.     

IgM antibody against hepatitis B core antigen (IgM anti-HBc): diagnostic and prognostic significance in acute HBsAg positive hepatitis.

IgM antibody against hepatitis B core antigen (IgM anti-HBc), a marker of recent hepatitis B virus infection, was sought by radioimmunoassay in sera diluted 1/4000 from 376 patients presenting to four centres in Italy with acute, apparently type B hepatitis (hepatitis B surface antigen (HBsAg) positive). In 320 patients (85%) a positive IgM anti-HBc test result confirmed that hepatitis was due to primary infection with hepatitis B virus. In the remaining 56 patients absence of the IgM marker indicated that they were previously unrecognised long term carriers of HBsAg. Further serum analysis often showed delta infection and occasionally hepatitis A or cytomegalovirus infection as the true cause of their illness. After six to eight months circulating HBsAg persisted in 38 of 45 patients (84%) without IgM anti-HBc but in only six of 150 patients (4%) with the IgM antibody (p less than 0.0001). A negative IgM anti-HBc test result in patients with acute HBsAg positive hepatitis points to a factor other than hepatitis B virus as the cause of the liver damage and predicts the carriage of HBsAg.     

Association of cytomegalovirus with infantile hepatitis

Infantile hepatitis is occasionally seen in apparently healthy children. In most cases, the etiology of the infection is uncertain. However, cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human parvovirus B19, and TT virus (TTV) are considered to be associated with hepatitis in children. The objective of this study was to investigate the correlations between these viruses and infantile hepatitis. Twenty-six children from 1 to 24 months old (median age, 7 months) who had liver dysfunction of unknown etiology were enrolled in this study. Plasma samples were examined by a real-time PCR assay for CMV, EBV, HHV-6, HHV-7, parvovirus B19, and TTV DNA. The DNA of CMV was detected in the plasma of four patients (15.4%) and was detected significantly more often in the patient group than in the control group. The CMV-infected patients were 1 to 3 months old, which was significantly younger than the remaining patients. The serological findings did not always correlate with the results of the real-time PCR assay. The DNA of TTV was detected in four patients (15.4%), while human parvovirus B19 DNA was detected in three (11.5%). However, the detection frequencies of these viral DNAs were not significantly different from those in the control groups, and some of these patients had co-infections. These results indicate that CMV might be one of the major pathogens responsible for infantile hepatitis; however, serological tests have limited utility for the diagnosis of CMV infection in young children.     

Vitamin E Improves the Aminotransferase Status of Patients Suffering from Viral Hepatitis C: A Randomized,Double-Blind,Placebo-Controlled Study

Vitamin E has been shown to protect against liver damage induced by oxidative stress in animal experiments. Based on our previous findings of diminished vitamin E levels in patients suffering from viral hepatitis, we treated 23 hepatitis C patients refractory to a-interferon therapy with high doses of vitamin E (2 × 400 IU RRR-α-tocopherol/day) for 12 weeks. Study design: pro-spective randomized double-blind crossover design. Clinical parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined for monitoring the disease state, in parallel vitamin E plasma levels and plasma lipids were determined. The plasma levels of the a-tocopherol were increased about 2-fold in all 23 patients. In 11 of 23 patients the clinical parameters indicative of liver damage were improved during the phase of vitamin E treatment (48% responders). ALT levels in responders were lowered by 46% and AST levels were lowered by 35% after 12 weeks of vitamin E treatment. Cessation of vitamin E treatment was followed by a rapid relapse of ALT and AST elevation, whereas retreatment led to a reproducible ALT decrease by 45% and AST decrease of 37% after a 6 months followup. Since vitamin E is non-toxic even at elevated doses ingested over extended periods, we suggest the treatment of patients refractory to α-interferon therapy suffering from hepatitis C with vitamin E as a supportive therapy.     

An Interferon Response Gene Signature Is Associated with the Therapeutic Response of Hepatitis C Patients

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFNα, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.     

Epidemic focus of non-A, non-B viral hepatitis in a plasmapheresis unit]

Non-A, non-B hepatitis has been diagnosed in 12 blood donors in a plasmapheresis unit. The course of the disease has been symptomatic, accompanied by jaundice, fatigue, and nausea in 8 cases, and subclinical in the remaining 4 patients. Nine patients were followed-up to 2 years and only 2 patients liver biochemical tests were normalized permanently. The biopsies performed, a year after the acute phase of hepatitis period revealed chronic active disease in patients, chronic persistent hepatitis in 2 patients, acute hepatitis in one, and normal liver in one patient. Repeated liver biopsies, performed one year later, have basically shown similar lesions except one patient in whom chronic active hepatitis progressed to incipient liver cirrhosis. No symptoms of the disease have been usually noted in patients with chronic form of the disease, and liver function tests have occasionally been normal.     

重组人生长激素治疗重型肝炎的疗效观察

目的：观察重组人生长激素治疗重型肝炎的疗效。方法：回顾性分析我院住院治疗的60例重型肝炎患者并分组比较,对照组25例为包括血浆置换在内的综合内科治疗,治疗组35例为在对照组基础上联合重组人生长激素治疗;分析两组治疗前后的临床症状、体征和肝肾功能、凝血功能等指标变化,并对治疗结果进行分析,评价临床疗效。结果：治疗组临床症状改善有效率为93.3％,高于对照组（72．0％）（P〈0．05）;观察组肝功能指标好转率80．0％,优于对照组65．5％（P〈0．05）。结论：重组人生长激素治疗重型肝炎有较好的效果。     

Occult HBV infection and suppression of HCV replication in the early phase of combination therapy for chronic hepatitis C

BACKGROUND: Occult HBV infection in subjects with chronic hepatitis C is related to more severe disease outcome. It has been suggested that it might reduce sensitivity to antiviral treatment. AIMS: To assess in HBsAg negative subjects with chronic hepatitis C any effect of the presence of HBV genomes in the liver on the early kinetics of HCV-RNA under PEG-IFN plus ribavirin. PATIENTS AND METHODS: Twenty-two anti-HCV and HCV-RNA positive subjects, with biopsy-proven chronic hepatitis C (M/F 15/7; 50 +/- 8.6 years, 16 genotype 1b) were given PEG-IFN alpha 2b 1.0 microg qw plus ribavirin (800 to 1,200 mg daily according to body weight) for an intended 52 week period. Early virological response was assessed over the first 4 weeks of therapy by quantifying HCV-RNA. Occult HBV infection was assessed by testing for HBV-DNA in the liver before therapy. RESULTS: HBV genomes were found in the liver of 7 of 22 (31.4%) patients, unrelated to anti-HBc status. Kinetics of HCV-RNA during the first 4 weeks of antiviral treatment was unaffected by occult HBV infection, both in terms of absolute reduction of viral load and of number of cases with a reduction of > or = 2 log10 on treatment. CONCLUSIONS: Occult HBV infection does not affect the early phase of response to combination therapy. Further follow-up of patients into the maintenance phase of antiviral treatment and after stopping it will clarify if and when occult HBV has a role in reducing sustained virological response.     

Electroimmunoassay of factor IX in patients with liver damage and vitamin K unresponsive coagulation disorder.

Factor IX antigen and activity were assayed in a group of patients with liver disease and in a group of patients in coumarin therapy. In patients with liver disease there was a similar decrease in activity and antigen. On the other hand factor IX activity is decreased in coumarin treatment with factor IX antigen remaining normal. Factor IX electrophoretic mobility in liver disease is normal.     

Factors associated with efficacy of pegylated interferon-α plus ribavirin for chronic hepatitis C after renal transplantation

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease after renal transplantation (RT), which reduces both graft and patient survival. After RT, the most widely used approach is interferon (IFN)-based therapy of hepatitis C which may be unsatisfactory with both poor efficacy and an increasing risk of allograft rejection. Thus, it is not recommended unless patients develop fibrosing cholestatic hepatitis. Several recent studies, however, suggest that treatment was possible with preservation of both renal and liver functions. From the limited studies on HCV infection after RT, several factors have been identified as important tools for the management of therapy in these patients. Infection with HCV genotypes 2 and 3, low baseline viral load and absence of advanced fibrosis/cirrhosis in the liver are associated with a sustained virologic response (SVR). After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of SVR independent of HCV genotype. Furthermore, some factors must be taken into consideration in order to avoid allograft rejection, such as the time between transplantation and therapy for HCV, the dose and duration of regimen and renal function. Careful evaluation of predictions of stable renal function and SVR for those patients helps to reduce inefficient treatment regimes and to increase the cure rate in addition to reducing the possible risk. In this review, the latest information was collected and we focus on the discussion of the factors influencing the attainment of SVR after RT.     

Interferon therapy in acute lymphatic leukemia and hepatitis B in childhood

1. The use of interferon in hepatitis B will bring about a favourable course of the disease, which is reflected in a normalisation of liver function tests. 2. The concentration of surface antigens is distinctly reduced, with a lower titre remaining for a longer period of time. 3. The level of the dosage chosen seems to be optimal. However, treatment has to be continued for a period of several months, probably for about 1 year. 4. In childhood the side-effects of interferon are minimal, they are restricted to febrile reactions. 5. In our investigations no sure hematological deviations could be identified in the treatment with interferon. 6. The study must be complemented by analysing further antigens, such as E antigen, allowing the course of disease to be characterised more distinctly. 7. In order to give a final assessment of the therapy the observation of patients must be continued after terminating the treatment, the histological improvement in the further course having to be confirmed by liver biopsies.     

Liver-specific alpha 2 interferon gene expression results in protection from induced hepatitis

The current therapy for hepatitis B and C is based on systemic administration of recombinant human alpha interferon (r-hIFN-alpha). However, systemic delivery of r-hIFN-alpha is associated with severe side effects, but more importantly, it is effective in only a small percentage of patients. In an effort to maximize IFN-alpha antiviral efficacy, we have explored the therapeutic potential of murine IFN-alpha2 (mIFNalpha2) selectively expressed in the liver. To this end, we have developed a helper-dependent adenovirus vector (HD) containing the mIFN-alpha2 gene under the control of the liver-specific transthyretin promoter (HD-IFN). Comparison with a first-generation adenovirus carrying the same mIFN-alpha2 expression cassette indicates that at certain HD-IFN doses, induction of antiviral genes can be achieved in the absence of detectable circulating mIFN-alpha2. Challenge of injected mice with mouse hepatitis virus type 3 showed that HD-IFN provides high liver protection. Moreover, liver protection was also observed in acute nonviral liver inflammation hepatitis induced by concanavalin A at 1 month postinfection. These results hold promise for the development of a gene therapy treatment for chronic viral hepatitis based on liver-restricted expression of IFN-alpha2.     

微生态调节剂在慢性重型肝炎患者的治疗作用

目的探讨微生态调节剂整肠生和乳果糖在慢性重型肝炎的治疗作用。方法 162例慢性重型肝炎患者被随机分为治疗组(84例)和对照组(78例)。对照组给予常规的综合治疗,治疗组在对照组的基础上给予整肠生胶囊4粒、乳果糖口服液10 ml每日3次口服,疗程为4周。比较2组病例治疗后主要症状和体征、肝功能、凝血功能、内毒素、血氨、并发症发生率及病死率。结果与对照组比较,治疗组更有效地改善患者临床症状、肝功能及凝血功能,降低血浆内毒素、血氨浓度,减少自发性腹膜炎(SBP)、肝性脑病(HE)和肝肾综合征(HRS)等并发症发生率和患者病死率。结论微生态制通过调整肠道失调菌群,能改善患者肝功能和凝血功能,降低血氨和内毒素血症,减少并发症和病死率,对慢性重型肝炎有明显治疗作用。     

IL-1 beta attenuates IFN-alpha beta-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent pathway

IFN-alphabeta is the only established treatment for viral hepatitis; however, more than 60% of patients are poorly responsive. Because viral hepatitis is associated with inflammation, we hypothesized that inflammation may attenuate the efficacy of IFN therapy. To test this hypothesis, the effect of IL-1beta, one of the major proinflammatory cytokines, on IFN signaling pathway in the liver was examined. Administration of IL-1beta in vivo attenuated IFN-alphabeta-induced STAT1 tyrosine phosphorylation in the liver but not in the spleen. The inhibitory action of IL-1beta in vivo was not affected by depleting hepatic Kupffer cells, suggesting that IL-1beta may directly target IFN-alphabeta signaling in hepatocytes. Indeed, pretreatment of human hepatocellular carcinoma HepG2 cells with IL-1beta suppressed IFN-alphabeta-induced antiviral activity and antiviral protein MxA mRNA expression. Furthermore, IL-1beta attenuated IFN-alphabeta-induced STAT1 binding and tyrosine phosphorylation without affecting the level of STAT1 protein. This inhibitory effect can be reversed by pretreatment with either proteasome inhibitors or transfection of dominant negative NF-kappaB inducing kinase mutants. Taken together, these findings suggest that IL-1beta attenuates IFN-alphabeta-induced STAT1 activation by a proteasome-dependent mechanism. In view of high levels of IL-1beta in the serum or within the liver of patients with chronic liver diseases, attenuation of IFN-alphabeta signaling in the liver by IL-1beta could be one of the mechanisms underlying the resistance to IFN therapy in chronic hepatitis C, and IL-1beta could be a potential therapeutic target for improving the efficacy of IFN therapy.     

Increased severity and morbidity of acute hepatitis in drug abusers with simultaneously acquired hepatitis B and hepatitis D virus infections.

Hepatitis D virus (delta agent) markers were present in 111 (36%) of 308 intravenous drug abusers who were positive for hepatitis B surface antigen (HBsAg), 52 of these having hepatitis D virus antigenaemia. IgM antibody to hepatitis B core antigen (anti-HBc IgM) was present in 92 out of 95 subjects tested, indicating that hepatitis D virus and hepatitis B virus infections had been acquired simultaneously. Hepatitis D virus markers were present in three out of four patients with fulminant hepatitis, and in 80 of 223 (36%) with mild or moderate hepatitis compared with four of 29 (14%) of those who were asymptomatic. These proportional differences were significant (p less than 0.001). Hepatitis D virus markers were present in twice as many patients positive for anti-HBc IgM requiring admission to hospital with acute hepatitis compared with outpatients attending a drug treatment centre. Tests on one patient showed complete disappearance of HBsAg, but hepatitis D antigen (HDAg or delta antigen) and hepatitis B e antigen (HBeAg) were still present in serum samples. All five patients with chronic active hepatitis had hepatitis D antibody (anti-HD) compared with seven of 24 (29%) with chronic persistent hepatitis (p = 0.008). Blocking anti-HD persisted for long periods after simultaneous infections with hepatitis B virus and hepatitis D virus but at lower titres than in patients with chronic liver disease.