Pathogenesis of Hepatitis B Virus

StephenW

http://www.clinicaloptions.com/inPractice/Hepatology/Hepatology/ch3_Hep_B_Epidemiology_Pathogenesis_Diagnosis_and_Natural_History.aspx
Pathogenesis of Hepatitis B Virus
Successful control of hepatitis B virus (HBV) is dependent on the complex interplay between the innate, cellular, and humoral responses to the infecting virus.[Chang 2007; Chisari 2010]  At the same time, the immune response may be responsible for mediating clinical hepatitis and disease progression. The exact role of the innate response in acute HBV infection is unclear. The nonspecific innate immune response involves production of interferon, activation of natural killer cells, and activation of Kupffer cells, all of which may help to control viral replication and limit the spread of the virus during the early stages of infection.[Wieland 2000; Tang 2003; Webster 2002]  
The roles of the cellular and humoral responses are better defined. The T-cell response during acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell response.[Ferrari 1990; Thimme 2003]  Clinical hepatitis is associated with an influx of inflammatory cells, including both HBV-specific and non–HBV-specific T cells.[Thimme 2003]  In particular, CD8+ T cells that mediate cytolytic activity against HBV-infected hepatocytes correlate with an increase in serum alanine aminotransferase level.[Thimme 2003]  By contrast, the CD4+ and CD8+ response in chronic carriers is feeble or undetectable.[Rehermann 1995]  However, their presence in the peripheral blood and liver of chronically infected persons with elevated alanine aminotransferase levels suggest a pathogenic role for the cellular immune response. Therefore, the cell-mediated immune response is a doubled-edged sword: a vigorous response leads to viral clearance, whereas an ineffective response leads to hepatocellular injury.
HBV-specific CD8+ cytotoxic T cells appear to be important for initiating liver injury. Upon activation, they secrete a number of cytokines, including interferons, that recruit a variety of nonspecific inflammatory cells in the liver, resulting in more extensive liver injury. Infiltrating macrophages probably mediate most of the hepatic damage.[Chang 2007]

Natural HistoryPrimary Infection and Acute Hepatitis
               Following exposure to hepatitis B virus (HBV), two thirds of patients present with an asymptomatic, subclinical infection and one third present with an acute hepatitis with jaundice, of whom a minority (< 1%) develop fulminant hepatitis (Figure 3).[Kao 2008]  The outcome of acute infection is largely dependent on age at exposure: 90% to 95% of individuals who acquire the infection as infants progress to chronic infection compared with 25% of those infected during childhood, and ≤ 5% of those infected as adults (Figure 3).[Hyams 1995]
Acute hepatitis B infection is more likely to resolve in patients who present with jaundice or who are not immunosuppressed at the time of infection compared with those who present with a subclinical infection or who are immunosuppressed. With sensitive assays for hepatitis B virus (HBV) DNA, low-level viral replication can be detected in up to 15% to 20% of persons who recover from acute HBV.[Yuki 2003]  Indeed, it is now believed that low-level viral replication probably occurs throughout an individual’s lifetime and is held in check by the immune system.[Liang 2009]  This explains why reactivation of hepatitis B might occur if the immune system becomes compromised by chemotherapy, bone marrow or stem cell transplantation, or HIV infection.
Chronic Hepatitis and Its Sequelae
               The outcome of chronic hepatitis B is variable and dependent on a complex interplay between the level of viral replication and the host immune response. Approximately one half of individuals transition to an inactive carrier state, 30% progress to cirrhosis, and the remainder have varying degrees of chronic hepatitis (Figure 3).[Kao 2008]  Although all patients with chronic hepatitis B are at risk for hepatocellular carcinoma, the rate is highest for those with cirrhosis or persistently high viral replication.[McClune 2010; Chen 2006]  Understanding the natural history of chronic hepatitis B virus (HBV) infection is crucial for determining who requires therapy, when to initiate treatment, and establishing realistic therapeutic goals.

StephenW

B型肝炎病毒的发病机制
成功控制B型肝炎病毒（HBV）感染病毒的先天之本，细胞和体液免疫反应之间的复杂相互作用的依赖[张2007 Chisari 2010]与此同时，免疫反应，可能是负责调解临床肝炎和疾病的进展。在急性HBV感染的先天反应的确切作用尚不清楚。非特异性先天免疫反应涉及生产干扰素，激活自然杀伤细胞，Kupffer细胞的活化，所有这些都可能有助于控制病毒的复制和限制病毒的传播，在感染的早期阶段[2000维兰德;唐2003年，2002年韦伯斯特]
的细胞和体液免疫反应的作用，更好地界定。 [法拉利1990年期间的特点是急性，自限性HBV感染的T细胞反应强烈的，多克隆，multispecific细胞毒性和辅助性T细胞的反应; Thimme 2003]。临床肝炎伴有炎性细胞的涌入，包括乙肝病毒的特定和非-乙肝病毒，特定的T细胞。[Thimme 2003]在特定，CD8 + T细胞的细胞，调解对HBV感染的肝细胞的杀伤活性与1血清丙氨酸转氨酶水平的提高。[Thimme 2003]通过对比，在CD4 +相关+和CD8 +慢性携带者的反应是软弱或不到。Rehermann 1995]然而，他们在与谷丙转氨酶升高水平的慢性感染者外周血和肝的存在，表明细胞免疫反应的致病作用。因此，细胞介导的​​免疫反应是加倍的双刃剑：积极的回应，导致清除病毒，而无效的响应，导致肝细胞损伤。
乙肝病毒特异性CD8 +细胞毒性T细胞似乎是启动肝损伤的重要。激活后，他们分泌的细胞因子，包括干扰素，​​招募各种非特异性炎性细胞，在肝脏中产生更广泛的肝损伤。浸润的巨噬细胞介导的​​肝损伤。[张2007]

HistoryPrimary自然感染与急性肝炎
               在接触到B型肝炎病毒（HBV）无症状，亚临床感染和一个第三个目前与急性黄疸型肝炎患者，少数（<1％），其中重型肝炎发展的两个三分之二（图3）。花王2008]急性感染的结果在很大程度上依赖于暴露的年龄：90％至95％的个人获得感染的婴幼儿进展到慢性感染与儿童时期的感染者，25％和≤5％的感染者相比，作为成年人（图3）。[Hyams 1995年]
急性B型肝炎感染是呈现黄疸或那些没有感染的时间比那些提出了亚临床感染或那些免疫抑制免疫抑制的患者更容易解决。 [纪]（2003）与敏感的B型肝炎病毒（HBV）DNA检测，可以检测到低级别的病毒复制，高达15％至20％的人士从急性HBV恢复。事实上，它现在认为，低级别病毒复制可能发生一个人的整个生命周期，是在检查举行的免疫系统[梁2009]这解释了为什么乙型肝炎再激活可能发生，如果免疫系统变得化疗，骨骨髓或干细胞移植，或感染艾滋病毒的损害。
慢性乙型肝炎及其后遗症
               慢性乙型肝炎的结果是可变的，依赖于病毒复制水平与宿主的免疫反应之间复杂的相互作用。个人过渡到一个无效的载波状态，30％进展为肝硬化，其余的一半，约一有不同程度的慢性肝炎（图3）。[高2008]虽然所有慢性乙型肝炎患者肝癌的风险，率最高为肝硬化或持续高病毒复制[McClune 2010，2006]。了解慢性乙型肝炎病毒（HBV）感染的自然史的关键是确定需要治疗的人，何时开始治疗，并制订切合实际的治疗目标。

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把握当下

乙肝病毒发病机理
对乙肝病毒的成功控制取决于针对感染病毒产生的内在细胞体液间的复杂相互影响。同时免疫反应可能对临床肝炎与疾病进展有直接责任。急性感染后内部反应情况还不清楚。不明的内部免疫反应包括产生干扰素，激活nk细胞，激活k细胞，这些都可能在感染早期帮助控制病毒复制和限制病毒蔓延。

细胞和体液反应的角色较容易定义。急性自限型乙肝感染中，t细胞反应强烈，繁殖快，具备多种特定毒性，t辅助细胞反应。（The T-cell response during acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell response）.
临床肝炎通常意味着出现大量炎症细胞、HBV相关/不相关T细胞。
特别是CD8+ T细胞，能通过升高alt水平调整针对感染乙肝病毒肝细胞的细胞溶解活动。相应的，病毒携带者的CD4+和CD8+反应比较小或检测不到。然而，它们在alt升高的感染患者的外周血和肝内仍然存在，说明仍会引起细胞免疫反应。因此细胞级免疫相应调整是双刃剑：强力反应导致病毒清除，但如果失败将导致肝损伤。HBV相关的CD8+ 毒性T细胞在开始导致肝损伤方面似乎非常重要。激活之后将分泌一些列毒素，包括干扰素。干扰素将在肝内吸引许多不相关的炎症细胞，导致出现更强烈的肝损伤。渗透巨噬细胞可能对肝损伤程度影响最大。

感染自然史和急性肝炎
接触乙肝病毒后，三分之二人群出现无症状，亚临床感染，三分之一出现急性黄疸肝炎，其中少数(< 1%)发生爆发性肝炎。急性感染结果很大程度上取决于感染时年龄：90% - 95%婴幼儿感染者，25%童年期感染者，≤ 5%成年感染者发展为慢性感染。感染时有黄疸或没有免疫抑制的急性乙肝感染患者比只有亚临床感染或免疫抑制的患者更可能痊愈。通过对DNA进行精确定量检查发现，急性HBV恢复期约15% -20%人群仍能被检测到低载量病毒。现在普遍认为低载量病毒很可能终身存在，并且被免疫系统所控制。这解释了乙肝为什么在化疗、骨髓或干细胞移植、HIV感染导致免疫系统受损时复发。

慢性肝病与后续发展
慢性乙肝结果差别很大，取决于病毒复制和宿主免疫响应间的复杂影响。大概一半人到达非活动性携带阶段，30%进展到肝硬化，剩下的有不同程度的炎症。虽然所有慢性乙肝患者有可能发生肝癌，但最可能的是肝硬化或高病毒复制量患者。理解慢性乙肝感染自然史对决定谁需要治疗，什么时候开始治疗，治疗目标是什么非常重要。

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