Negro Francesco
Services de Gastroentérologie et d'Hépatologie et de Pathologie Clinique, Genève, Switzerland.
World J Gastroenterol. 2006 Nov 14;12(42):6756-65. doi: 10.3748/wjg.v12.i42.6756.
The pathogenesis of liver damage associated with chronic hepatitis C virus (HCV) infection is thought to be largely immunomediated. However, some frequent histopathological features, such as steatosis, suggest a direct cytopathic effect of HCV. The direct responsibility of HCV in the pathogenesis of steatosis is shown by: (1) the association with HCV genotype 3 infection, suggesting that some viral sequences are involved in the intracellular accumulation of lipids; (2) the correlation between severity of steatosis and HCV replication levels; (3) association between response to treatment and disappearance of steatosis. Experimental studies have shown that the nucleocapsid protein of HCV (core protein) is capable and sufficient to induce lipid accumulation in hepatocytes. Moreover, the observation that chronic hepatitis C patients have reduced serum levels of ApoB suggests an interference with the very-low density lipoprotein (VLDL) assembly, although other mechanisms are possible. In patients with sustained virological response induced by antiviral therapy, such levels are normalized. Other observations suggest that the pathogenesis of steatosis in chronic hepatitis C is not solely due to HCV. The origin of the mild steatosis observed in most patients may be metabolic, since its severity correlates with body mass index and insulin resistance. Most studies have shown a correlation between presence and/or severity of steatosis and fibrosis stage, but it is unclear whether this effect is direct or mediated by the associated insulin resistance, increased susceptibility to apoptosis, or by inflammatory cytokines. Finally, steatosis negatively influences the rate of response to antiviral treatment, as confirmed by large clinical trials. Management of steatosis in chronic hepatitis C requires knowledge of its pathogenesis and may involve both life-style changes and pharmacological interventions, although the latter remain largely experimental.
与慢性丙型肝炎病毒（HCV）感染相关的肝损伤发病机制在很大程度上被认为是免疫介导的。然而，一些常见的组织病理学特征，如脂肪变性，提示HCV具有直接的细胞病变效应。HCV在脂肪变性发病机制中的直接作用表现为：（1）与HCV 3型感染相关，提示某些病毒序列参与脂质的细胞内蓄积；（2）脂肪变性严重程度与HCV复制水平之间的相关性；（3）治疗反应与脂肪变性消失之间的关联。实验研究表明，HCV的核衣壳蛋白（核心蛋白）能够且足以诱导肝细胞内脂质蓄积。此外，慢性丙型肝炎患者血清载脂蛋白B水平降低这一观察结果提示对极低密度脂蛋白（VLDL）组装存在干扰，尽管也可能存在其他机制。在抗病毒治疗诱导获得持续病毒学应答的患者中，此类水平可恢复正常。其他观察结果提示，慢性丙型肝炎中脂肪变性的发病机制并非仅由HCV所致。大多数患者中观察到的轻度脂肪变性可能源于代谢，因为其严重程度与体重指数和胰岛素抵抗相关。大多数研究表明脂肪变性的存在和/或严重程度与纤维化阶段之间存在相关性，但尚不清楚这种影响是直接的，还是由相关的胰岛素抵抗、对凋亡的易感性增加或炎性细胞因子介导的。最后，大型临床试验证实，脂肪变性对抗病毒治疗的反应率有负面影响。慢性丙型肝炎中脂肪变性的管理需要了解其发病机制，可能涉及生活方式改变和药物干预，尽管后者在很大程度上仍处于实验阶段。
