Liver steatosis in children with chronic hepatitis C

OBJECTIVES: Steatosis is common in adults with chronic hepatitis C, and is involved in the progression of fibrosis. Because little is known about steatosis in pediatric hepatitis C, the aims of this study were to determine the prevalence and severity of steatosis in a pediatric population with chronic hepatitis C, and to evaluate its correlation with clinical parameters. METHODS: Liver biopsies were obtained from 66 consecutive Italian and Spanish children with chronic hepatitis C (87.6% genotype 1). Grade and stage were assessed according to Ishak's system. Steatosis was scored as absent, minimal (less than 5% of steatosic hepatocytes), mild (>5%, 33%, 66%); moderate and severe scores were combined for statistical purposes. The BMI-for-age percentile (BMI%) was calculated in all cases at the time of liver biopsy. Cholesterol and triglyceride serum levels were available in 55 cases. RESULTS: The prevalence of steatosis was 27% (18/66 cases, 16/18 with genotype 1), and it was higher in Italian than in Spanish patients (10/21 vs.7/45, P= 0.01). BMI% correlated significantly with both the presence of steatosis (P= 0.002) and its severity (P= 0.000). Steatosis also correlated with serum triglyceride levels (P= 0.04). CONCLUSION: Steatosis is associated with BMI in children with chronic hepatitis C due mainly to genotype 1, and with no confounding hepatotoxic factors (alcohol or drugs). This may reflect its metabolic rather than viral origin and raise new issues in the management of children with hepatitis C.     

重视对慢性病毒性肝炎合并肝脂肪变的研究

慢性乙型肝炎是我国最常见的慢性传染病之一,资料显示,全球至少有20亿人感染过HBV,我国HBV携带率为9.75%,约有1.2亿人感染过HBV.丙型肝炎呈全球性流行,以往文献报道我国一般人群抗HCV阳性率为3.2%,感染者约为4100万,根据中国疾病预防控制中心提供的数据,我国每年的新发丙型肝炎已从2003年的2万多人发展为2005年的近6万人.     

Liver steatosis in hepatitis C patients

There is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in “pure” steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients.     

Adherence to antiviral therapy in chronic hepatitis C

Adherence or compliance with the prescribed treatment regimen is an important factor that determines the success of therapy in chronic hepatitis C. A multidisciplinary team approach is required in order to educate and communicate effectively with the patient, individually tailor the prescribed regimen, provide organizational support, develop dispensing aids, and deal with side effects or psychosocial issues. Such measures can only improve patient confidence with the proposed treatment, hopefully resulting in improved healthrelated outcomes.     

慢性丙型肝炎抗病毒治疗进展

抗病毒是治疗慢性丙型肝炎最重要的手段。叙述了近年来抗病毒治疗包括聚乙二醇干扰素和利巴韦林联合治疗、特异性靶点治疗、基因治疗等的进展情况。认为未来抗HCV治疗还需要更有效的药物联用治疗方式、更短的用药疗程、更低的毒副作用以及更高的耐药阈值等。     

Individualisation of antiviral therapy for chronic hepatitis C

The combination of pegylated‐interferon (PEG‐IFN)/ribavirin is currently the standard of care antiviral treatment for chronic hepatitis C (CHC), but optimal results require an individual approach. Key issues are to deliver doses that confer optimal antiviral efficacy against hepatitis C virus (HCV) for a time sufficient to minimise relapse. Viral monitoring during therapy guides the subsequent treatment course, particularly HCV RNA results at 4 weeks (rapid viral response [RVR]) and 12 weeks (complete early viral response [cEVR]). There is strong evidence that for most patients with genotypes 2 or 3 HCV infection, RVR allows truncation of treatment to 16 weeks, provided ribavirin dose is weight‐based. However, those patients with cirrhosis, insulin resistance/diabetes or older than 50 years need 6–12 months treatment. For “difficult‐to‐treat” CHC (genotypes 1 and 4), RVR is infrequent (～15% in European studies), but allows treatment to be truncated from 48 to 24 weeks. Without RVR, there is some evidence that longer treatment (72 weeks) improves sustained viral response (SVR). However, “induction dosing” first 12 weeks of PEG‐IFN clearly does not improve SVR. To prevent dose reductions and complete therapy, it is critical to detect and treat depression and other disabling side‐effects, including judicious use of growth factors for severe anemia or neutropenia and possibly, thrombocytopenia. Another potentially important aspect may be attempts to counter central obesity and insulin resistance, which confer suboptimal antiviral response with any HCV genotype. Treatment partnerships with specialist nurses, psychological therapists and other healthcare workers are also essential for optimal individual management of patients with CHC.     

慢性丙型肝炎抗病毒治疗研究最新进展

基于长效干扰素和利巴韦林(ribavirin,RBV)的经典抗HCV疗法不良反应较大,疗效有待进一步提高.近年来抗HCV药物研发取得较快发展,以直接抗病毒药物(direct-acting antivirals,DAA)的研发最为活跃,在此基础上产生了多种新的抗HCV治疗策略.其中,针对病毒不同靶位的DAA联合治疗初露锋芒,Ⅱ期临床试验表明,不用干扰素,甚至不用RBV的DAA联合治疗可取得很好疗效,24周治疗后持续病毒学应答率最高可达100％,疗效可不受HCV基因型和患者IL-28B分型影响,患者耐受性通常良好.因此DAA联合治疗方案是今后治疗丙型肝炎的发展趋势.     

Liver HCV-antigens and steatosis in chronic hepatitis C: Role of different genotypes

BackgroundHCV infection is frequently associated with liver steatosis.Aims and methodsWe studied 126 frozen liver HCV positive specimens (genotype-3 = 27) without any features of metabolic syndrome, searching for a correlation between the number of HCV infected hepatocytes and the presence, amount and distribution of steatosis in relation to different genotypes.ResultsMean steatosis score was higher in genotype-3 with respect to non-3 (1.11 vs 0.66, p = 0.022). HCV-antigens were detected by an immunoperoxidase technique in 91/126 (72.2%) cases. A significant correlation between the number of HCV-antigen positive cells and the degree of liver steatosis was observed in genotype-3 (p = 0.01) but not in non-3 patients, matched for sex and age. Steatotic cells usually outnumbered HCV-infected cells. Steatosis was observed both in HCV-antigen positive and negative hepatocytes, and HCV-antigens were detected in both hepatocytes with and without steatosis: while no lobular codistribution was found in genotype non-3, in genotype-3 steatosis and HCV-antigens were usually found in the same areas.ConclusionOur data support the role of HCV-antigen liver expression in the pathogenesis of steatosis in genotype-3, however, since the presence of HCV-antigens is not directly related to steatosis within single hepatocytes, an indirect mechanism might be operative too.     

Impact of liver steatosis on the antiviral response in the hepatitis C virus-associated chronic hepatitis.

BACKGROUND/AIM: Liver steatosis (LS) has been variably associated with chronic hepatitis C (CHC) but whether it affects sustained virological response to antiviral treatment and by what mechanisms is a question still under debate, at least for some genotypes. The aim of this work was to assess the frequency of LS, its relationship with host and viral factors and to what extent it can influence the response to antiviral combination therapy with pegylated interferon (INF)+ribavirin in a group of patients with CHC from a single center. PATIENTS: One hundred and twelve patients with histologically proven CHC were treated with Peg INF-alpha 2a 180 microg a week subcutaneously for 48 weeks plus ribavirin 1000 or 1200 mg/day, according to the patient's body weight. Steatosis was graded according to Brunt et al. RESULTS: Forty-six out of 112 patients (41.1%) were sustained virological responders (SVR). Seventy-two out of 112 (64.3%) presented with LS at histology; in this group, there were 24 patients (33.3%) with SVR compared with 22 (55%) of the non-steatosis group (chi(2)=6.5, P<0.02). Variables associated with the steatosis group were: higher serum levels of AST (P<0.04), alanine aminotransferase (P<0.02), gamma-GT (P<0.004), genotype 3a (P<0.03) and severity of histology (staging P<0.05) but at multiple linear regression analysis only genotype 3a and staging were significantly associated with LS. In the SVR group, age and body mass index (BMI) were significantly lower (P<0001 and P<0.03, respectively) compared with non-responders; moreover, genotype 1 was more frequent in the NR group, while genotype 3 was more frequent in the SVR group. At histology, grading and staging were also lower in the SVR group. Multiple logistic regression showed that only the grade of steatosis and genotype 3a were the variables independently associated with SVR. CONCLUSIONS: This study showed a frequency of LS on the higher side of the range so far reported in the literature and confirmed that it negatively influences response to therapy. Genotype1 was confirmed to be the most frequent type in our area. It is more frequent in patients with mild-moderate steatosis and seems to condition therapeutic response negatively, together with BMI and age. In contrast, genotype 3a is more frequent in patients with severe steatosis, but is a favorable predictor of successful therapy.     

New targets for antiviral therapy of chronic hepatitis C

Until recently, chronic hepatitis C caused by persistent infection with the hepatitis C virus (HCV) has been treated with a combination of pegylated interferon-alpha (PEG-IFNα) and ribavirin (RBV). This situation has changed with the development of two drugs targeting the NS3/4A protease, approved for combination therapy with PEG-IFNα/RBV for patients infected with genotype 1 viruses. Moreover, two additional viral proteins, the RNA-dependent RNA polymerase (residing in NS5B) and the NS5A protein have emerged as promising drug targets and a large number of antivirals targeting these proteins are at different stages of clinical development. Although this progress is very promising, it is not clear whether these new compounds will suffice to eradicate the virus in an infected individual, ideally by using a PEG-IFNα/RBV-free regimen, or whether additional compounds targeting other factors that promote HCV replication are required. In this respect, host cell factors have emerged as a promising alternative. They reduce the risk of development of antiviral resistance and they increase the chance for broad-spectrum activity, ideally covering all HCV genotypes. Work in the last few years has identified several host cell factors used by HCV for productive replication. These include, amongst others, cyclophilins, especially cyclophilinA (cypA), microRNA-122 (miR-122) or phosphatidylinositol-4-kinase III alpha. For instance, cypA inhibitors have shown to be effective in combination therapy with PEG-IFN/RBV in increasing the sustained viral response (SVR) rate significantly compared to PEG-IFN/RBV. This review briefly summarizes recent advances in the development of novel antivirals against HCV.     

Emotional distress in chronic hepatitis C patients not receiving antiviral therapy

BACKGROUND/AIMS: The aim of our study was to determine the prevalence, type, and severity of emotional distress in a large group of consecutive chronic hepatitis C (CHC) patients not receiving anti-viral therapy. METHODS: The brief symptom inventory and a 67-item questionnaire with the SF-36 embedded within it were used to study 220 outpatients with compensated CHC. RESULTS: Seventy-seven (35%) participants reported significantly elevated global severity index (GSI) T-scores compared to an expected frequency of 10% in population controls. In addition, significantly elevated depression, anxiety, somatization, psychoticism, and obsessive-compulsive subscale T-scores were reported in 28-40% of subjects. Subjects with an active psychiatric co-morbidity had significantly higher GSI and subscale T-scores compared to subjects with active medical co-morbidities and subjects without medical or psychiatric co-morbidities (P<0.01). However, patients with CHC alone also had a higher frequency of elevated GSI T-scores compared to population controls (20 versus 10%). GSI and subscale T-scores were strongly associated with SF-36 summary scores (P<0.001). CONCLUSIONS: Clinically significant emotional distress was reported in 35% of CHC patients not receiving antiviral therapy. In addition to depression, a broad array of psychological symptoms were observed. Further investigation into the etiopathogenesis and treatment of emotional distress in CHC patients is warranted.     

氟西汀在慢性丙型肝炎抗病毒治疗中的作用

超过20%的慢性丙型肝炎(CHC)患者接受IFNα抗病毒治疗后出现抑郁症,氟西汀常用于缓解此症状。氟西汀具有抗炎特性,可改变肝脏脂质合成,但其对CHC抗病毒治疗的影响及机制仍未阐明。近期研究表明氟西汀可抑制HCV感染Huh7.5细胞,且缓解了胞内活性氧生成和脂质蓄积,并通过激活STAT1和JNK通路促进IFNα介导的抗病毒作用,降低患者HCV载量及ALT水平。此外,氟西汀增强了CHC患者过氧化物酶体增殖物激活受体(PPAR)反应元件活性,其对HCV感染和脂质蓄积的抑制效应可被PPARβ/γ等拮抗物一定程度逆转,表明氟西汀可能通过调节PPARβ/γ和JNK/STAT通路抑制HCV感染、活性氧生成及脂质蓄积。     

Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan

Aim: The aim of the present study was to assess the changes of liver stiffness (LS) and its associated factors in patients with chronic hepatitis C virus infection (HCV) after interferon (IFN)‐based therapy. Methods: Patients with chronic HCV who had previously undergone at least 20 weeks of IFN‐based therapy were enrolled. The patients’ initial LS measurement was taken at the time of enrollment, and a second LS measurement was made after an interval of at least 38 weeks. LS measurement was carried out with FibroScan®, and changes of LS and its associated factors were analyzed. Results: One hundred and forty‐four patients, including 95 sustained virological response (SVR) patients and 49 non‐sustained virological response (NSVR) patients, were enrolled. There was a significant decrease of LS among SVR patients (median, 0.6; P < 0.001). NSVR patients showed an increase of LS (median, 0.8; P = 0.557). For SVR patients, a high initial LS was the predictive factor of a rapid reduction of LS values. However, advanced fibrosis stage before therapy, higher body mass index (BMI) and longer time remission were predictive factors for slow reduction of LS values. Conclusions: LS decreases in sustained responders following IFN‐based therapy in patients with chronic HCV. Advanced fibrosis, higher BMI, longer time for remission and lower initial LS value are predictive factors for a slow improvement of LS in sustained responders.     

Use of growth factors with antiviral therapy for chronic hepatitis C

Interferon (IFN)-based regimens for the treatment of chronic hepatitis C virus (HCV) infection have become increasingly effective and are able to eradicate virus in more than one half of treated individuals. Treatment strategies are complex and involve self-administration of injectable IFN and oral ribavirin medication, frequent office visits, and laboratory testing. Current therapies have significant side effects that may impair performance and quality of life (QOL), necessitating dose reductions or interruption of therapy. As a consequence of these dose reductions or treatment interruptions, patients may not achieve a sustained virologic response (SVR). Recent data suggest that aggressive management of side effects may improve QOL and therefore patient adherence to therapy. Use of antidepressant and anxiolytic medications and off-label use of hemopoietic stem cell growth factors are increasing in the daily management of HCV therapy. Although these therapies may improve QOL, prevent dose reductions, and increase the number of patients completing therapy, there are no data available to definitively show that such tactics are associated with improvement in SVR rates in individual patients.     

Response to antiviral therapy and hepatic expression of cyclooxygenases in chronic hepatitis C

OBJECTIVES: The aims of this study were to investigate the expression of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) in chronic hepatitis C (CHC) by immunohistochemistry, based on the hypothesis that COXs expression could vary according to genotype, viral load, liver steatosis, BMI and response to therapy and to determine whether the addition of selective COX inhibitors could have a rationale in increasing the efficacy of antiviral therapy. METHODS: We used 35 formalin-fixed, paraffin-embedded liver tissue samples obtained by needle biopsy from patients with CHC (17F/18M) with one of two types of genotype (1b and 3a). The presence of COX-1 and COX-2 in the cytoplasm of hepatocytes was scored on the basis of: (i) maximum intensity; (ii) dominant intensity; and (iii) extent. RESULTS: No significant differences were found in COX-1 and COX-2 expression in CHC patients divided according to genotype or according to the type of response to combination therapy with pegylated-interferon and ribavirin. The only significant correlations were observed between the dominant intensity of COX-2 and the presence of histological steatosis (P<0.01) and an inverse correlation between COX-2 extent and the viral load (P<0.02). CONCLUSIONS: The lack of correlation between COXs tissue expression and response to antiviral treatment suggests that there is no rationale to adding selective COX inhibitors to increase the efficacy of antiviral therapy, although further studies on larger patient populations are needed. On the contrary, there is a potential application for their use in the prevention and treatment of liver steatosis.