Chronic hepatitis B: role of anti-platelet therapy in inflammation control

Platelets play a known role in the maintenance of vascular homeostasis, but these cells are emerging as important cellular mediators of acute and chronic inflammatory diseases. Platelets are key elements in the pathogenesis of acute and chronic liver disease associated with hepatitis B virus (HBV) infection by promoting the accumulation of virus-specific CD8⁺ T cells and nonspecific inflammatory cells into the liver parenchyma. This review discusses major platelet functions in immune and inflammatory responses, with an emphasis on recent pre-clinical studies that suggest that the inhibition of platelet activation pathways represent an alternative therapeutic strategy with potential use in the reduction of virus-specific T cell-mediated chronic inflammation, liver fibrosis and hepatocellular carcinoma in patients who are chronically infected with HBV.     

回肠B细胞淋巴瘤合并戊型肝炎一例临床分析

目的:探讨回肠B细胞淋巴瘤合并戊型肝炎(hepatitis E virus,HEV)的诊断及治疗,提高对淋巴瘤合并病毒性肝炎的认识。方法:回顾性分析收治的一例回肠B细胞淋巴瘤合并HEV的临床特点、组织病理学特征及HEV的诊断及治疗过程,并复习相关文献。结果:组织病理学及免疫组织化学染色诊断为回肠粘膜相关淋巴组织淋巴瘤(mucosa associated lymphoid tissue lymphoma,MALT)伴弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)转化。血清学方法诊断为HEV。结论:回肠B细胞淋巴瘤合并HEV少见,肿块切除并同时进行保肝退黄等对症治疗有助于明确诊断及肝功能好转。     

鳖甲煎丸对慢性乙型肝炎早期肝硬化患者血清肿瘤坏死因子-α和白细胞介素-6的影响

[目的]观察鳖甲煎丸对慢性乙型肝炎早期肝硬化患者血清肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的影响及其作用机制。[方法]将76例慢性乙型肝炎早期肝硬化患者随机分为对照组和治疗组,对照组给予恩替卡韦片治疗,治疗组在对照组治疗基础上加用鳖甲煎丸治疗,2组均治疗12周,治疗前后检测2组患者肝功能、肝纤维化指标和血清TNF-α、IL-6水平变化。[结果]治疗后,2组患者肝功能、肝纤维化指标和血清TNF-α、IL-6水平均明显降低,治疗组较对照组下降更明显（P〈O．01）。[结论]鳖甲煎丸治疗慢性乙型肝炎早期肝硬化的疗效确切,其作用机制可能与减少TNF-α和IL-6的释放、抑制炎症反应有关。     

全身炎性反应综合征在乙型肝炎肝硬化合并腹水患者住院结局中的临床意义

目的探讨全身炎性反应综合征(SIRS)在乙型肝炎肝硬化合并腹水住院患者中的发生率及其对患者住院结局的影响。方法收集2013年1月至2018年1月东南大学医学院附属南京市第二医院住院的乙型肝炎肝硬化腹水患者的临床资料,分析SIRS的发生率及其与患者临床指标、住院期间出现死亡及门静脉高压并发症(包括食管胃底静脉曲张破裂出血、肝性脑病、肝肾综合征)的关系,分析乙型肝炎肝硬化合并腹水患者住院期间发生死亡和门静脉高压并发症的预测因素。结果乙型肝炎肝硬化合并腹水住院患者共461例,其中出现SIRS的有185例,发生率为40.1%;合并SIRS组患者与未合并SIRS组相比,存在较高的黄疸发生率、细菌感染率、血清胆红素(TBil)、国际标准化比值(INR)、Child-Pugh评分、MELD评分以及较长的住院时间,存在较低的血红蛋白浓度(Hb)、血小板(PLT)计数、钠离子浓度,差异均有统计学意义(P<0.05)。住院期间,共计22例患者死亡(5.8%),8例发生消化道出血(1.7%),4例发生1型肝肾综合征(0.9%),20例发生肝性脑病(4.3%)。SIRS的发生与患者的死亡(P<0.001)及门静脉高压并发症的出现(P<0.001)均有关。MELD评分可同时预测死亡和门静脉高压相关并发症的发生(P<0.001),而SIRS和血红蛋白可预测门静脉高压并发症的发生(P<0.05)。结论SIRS在乙型肝炎肝硬化合并腹水住院患者中较为常见,可加重患者肝损害,导致其住院期间的病死率和门静脉高压并发症的发生率增高,SIRS的存在可预测患者门静脉高压并发症的发生。     

Elastography for Longitudinal Assessment of Liver Fibrosis after Antiviral Therapy: A Review

Chronic hepatitis B or C viral infection is a common cause of liver cirrhosis and hepatocellular carcinoma. Fibrosis regression can be achieved after long-term antiviral therapy (AVT). Monitoring of dynamic changes in liver fibrosis after treatment is essential for establishing prognosis and formulation of a follow-up surveillance program. Routine surveillance of fibrosis after AVT by liver biopsy, the gold standard for fibrosis assessment, is hindered by its invasive nature, sampling error and observer variability. Elastography is a noninvasive quantitative alternative that has been widely used and validated for the staging of liver fibrosis prior to treatment. Recently, increasing research interest has been focused on the role of elastography in longitudinal assessment of liver fibrosis after AVT. In this review, the basic principles, acquisition techniques, diagnostic performances, and strengths and limitations of ultrasound elastography and magnetic resonance elastography are presented. Emerging evidence regarding the use of elastography techniques for the monitoring of liver fibrosis after AVT is summarized. Current challenges and future directions are also discussed, designed to optimize the application of these techniques in clinical practice.     

Boceprevir and telaprevir‐based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and model for end‐stage liver disease score

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)‐NS3/NS4A protease inhibitors (PI)] in association with PEG‐IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow‐up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty‐one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non‐response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non‐responders to 59.1% in partial non‐responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end‐stage liver disease (MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI‐based triple therapy leads to high rates of virological response even in previously non‐responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.     

Enhanced high‐mobility group box 1 (HMGB1) modulates regulatory T cells (Treg)/T helper 17 (Th17) balance via toll‐like receptor (TLR)‐4‐interleukin (IL)‐6 pathway in patients with chronic hepatitis B

High‐mobility group box 1 (HMGB1) proteins are substantially up‐regulated in acute and chronic hepatitis. However, the immunopathogenic role of HMGB1 in patients with chronic hepatitis B (CHB) has not been elucidated. In this study, using a cohort of 36 CHB patients, we demonstrated a crucial role for HMGB1 to modulate balance between regulatory T (Treg) and T helper 17 (Th17) cells via the toll‐like receptor (TLR)‐4‐interleukin (IL)‐6 pathway. Serum HMGB1 levels were dramatically higher in CHB patients and increased along with liver injury, inflammation and fibrosis. Notably, HMGB1 increased along with decreased Treg/Th17 cells ratios in the periphery or intrahepatic microenvironment, which provides a clue for HMGB1 to favour Th17 responses whereas inhibit Treg responses. For in vitro studies, serum pools were constructed with serum from CHB patients at an advanced stage, whereas peripheral blood mononuclear cells (PBMC) pools were constructed with cells from those at an early stage. CHB‐serum significantly enhanced retinoic acid‐related orphan receptor‐γt (RORγt), whereas they inhibited forkhead box P3 (Foxp3) expression in CHB‐PBMC, which could be reversed by blocking of HMGB1, TLR4, or IL‐6. Besides, recombinant HMGB1 (rHMGB1) dose‐dependently up‐regulated RORγt whereas down‐regulated Foxp3 expression in CHB‐PBMC, and meanwhile, rHMGB1 enhanced TLR4 and IL‐6 expression in CHB‐PBMC. Moreover, the axis of HMGB1–TLR4‐IL‐6–Treg/Th17 required noncontact interactions between CD4 and non‐CD4 cells. In addition, rHMGB1 down‐regulated anti‐inflammatory proteins on CD4⁺CD25⁺ cells whereas up‐regulated pro‐inflammatory cytokines in CD4⁺CD25⁻ cells. In summary, enriched HMGB1 in CHB patients shifts Treg/Th17 balance to Th17 dominance via the TLR4‐IL‐6 pathway, which exacerbates liver injury and inflammation.     

Attendance at specialist hepatitis clinics and initiation of antiviral treatment among persons chronically infected with hepatitis C: examining the early impact of Scotland's Hepatitis C Action Plan

Primary goals of the Hepatitis C Action Plan for Scotland Phase II (May 2008–March 2011) were to increase, among persons chronically infected with the hepatitis C (HCV) virus, attendance at specialist outpatient clinics and initiation on antiviral therapy. We evaluated progress towards these goals by comparing the odds, across time, of (a) first clinic attendance within 12 months of HCV diagnosis (n = 9747) and (b) initiation on antiviral treatment within 12 months of first attendance (n = 5736). Record linkage between the national HCV diagnosis (1996–2009) and HCV clinical (1996–2010) databases and logistic regression analyses were conducted for both outcomes. For outcome (a), 32% and 45% in the respective pre‐Phase II (before 1 May 2008) and Phase II periods attended a specialist clinic within 12 months of diagnosis; the odds of attendance within 12 months increased over time (OR = 1.05 per year, 95% CI: 1.04–1.07), but was not significantly greater for persons diagnosed with HCV in the Phase II era, compared with the pre‐Phase II era (OR = 1.1, 95% CI: 0.9–1.3), after adjustment for temporal trend. For outcome (b), 13% and 28% were initiated on treatment within 12 months of their first clinic attendance in the pre‐Phase II and Phase II periods, respectively. Higher odds of treatment initiation were associated with first clinic attendance in the Phase II (OR = 1.9, 95% CI: 1.5–2.4), compared with the pre‐Phase II era. Results were consistent with a positive impact of the Hepatitis C Action Plan on the treatment of chronically infected individuals, but further monitoring is required to confirm a sustained effect.     

An ORF1‐rearranged hepatitis E virus derived from a chronically infected patient efficiently replicates in cell culture

Hepatitis E is an increasingly reported disease in industrialized countries. Studies on the replication cycle of hepatitis E virus (HEV) are hampered due to the lack of efficient and robust cell culture systems for this virus. We describe the successful isolation of HEV derived from a chronically infected kidney transplant patient held under immunosuppressive therapy. Inoculation of serum sample 47832 onto the human lung carcinoma cell line A549 resulted in the replication of the virus as shown by RT‐qPCR. This novel human‐derived HEV strain is closely related to a wild boar‐derived genotype 3 strain, which did not replicate in A549 cells. It carries a 186 nucleotide insertion in the hypervariable ORF1‐region, derived from two parts of its ORF1. By passaging of the infected cells, a cell line continuously producing HEV particles was generated as demonstrated by RT‐qPCR, immuno‐electron microscopy, density gradient centrifugation and immunohistochemistry. Replication of the produced virus was demonstrated after its inoculation onto fresh A549 cells and two consecutive passages, whereas heating at 65 °C for 2 min abolished its infectivity. Several point mutations scattered along the whole genome were present in the HEV strain from the second passage; however, the ORF1 insertion was still present. Previously, cell culture isolation of two other HEV strains carrying insertions in their hypervariable regions, but originating from human ribosomal protein genes, has been described. The findings may indicate that cell culture adaptation of is mostly dependent on the length and position of the insertion, rather than from the sequence itself.     

Neutrophil–lymphocyte ratio: a novel predictor for short‐term prognosis in acute‐on‐chronic hepatitis B liver failure

Acute‐on‐chronic hepatitis B liver failure (ACHBLF) has a poor prognosis in patients with hepatitis B virus infection. The role of the neutrophil–lymphocyte ratio (NLR), which reflects the inflammatory status of the patient before treatment, has never been studied in this setting. To investigate the predictive value of NLR in patients with ACHBLF, a retrospective cohort with 216 patients and a prospective validation cohort with 73 patients were recruited. Multivariate analyses showed that total bilirubin (TBIL), NLR, age and model for end‐stage liver disease (MELD) score had prognostic significance for survival. Both NLR (0.781) and MELD score (0.744) had higher ROC curves, which differed significantly from those for age (0.615) and TBIL (0.691), but not from each other (P = 0.94). NLR ≤2.36 predicted lower mortality (with 91.6% sensitivity and 86.0% negative predictive value), and NLR >6.12 was a warning sign for higher mortality risk (with 90.1% specificity and 80.3% positive predictive value). These results demonstrated that pretreatment NLR was associated with the prognosis of patients with ACHBLF, and elevated NLR predicted poor outcome within 8 weeks. We suggest that NLR cut‐offs of ≤2.36 and >6.12 are powerful markers for predicting mortality in ACHBLF.