Visceral Adiposity, HIV, and HCV: Biologic Mediators of Hepatic Steatosis

描述(申请人提供)：肝病是艾滋病毒感染者发病和死亡的主要原因。其中许多病例与丙型肝炎病毒(丙型肝炎病毒)合并感染有关，但在艾滋病毒感染中，肝损伤的其他原因也很常见。对于试图了解肝病发病机制的研究人员以及治疗这一大群患者的临床医生来说，阐明导致HIV感染患者肝脏疾病的因素，无论是否合并丙型肝炎病毒，都是重要的。肝脏脂肪变性(或脂肪肝)在HIV感染中很常见，并与加速纤维化进展有关，这可能导致肝硬化和死亡，特别是在那些艾滋病毒/丙型肝炎合并感染的人中。然而，人们对艾滋病毒感染中脂肪变性的病因知之甚少。在丙型肝炎病毒感染中，基因3型似乎与脂肪变性直接相关，但在美国并不常见。相比之下，在那些感染1型丙型肝炎病毒(在美国非常流行)的人中，肥胖可能是比丙型肝炎病毒感染更重要的原因。在没有感染丙型肝炎的情况下，肥胖是脂肪变性的常见原因；然而，内脏肥胖(即内脏脂肪组织在内脏周围的积聚)可能是比整体体重更重要的脂肪变性风险因素。不同的研究表明，内脏肥胖的后果(炎性细胞因子增加、脂联素减少、胰岛素抵抗、循环中游离脂肪酸增加或肠道来源的内毒素微生物移位)可能会导致脂肪变性。这些潜在的中介也可以解释HIV感染(独立于内脏肥胖)和脂肪变性之间的拟议联系。HIV复制与炎症标志物的升高有关；HIV相关性外周脂肪萎缩与脂联素水平降低有关。艾滋病毒感染还与肠道相关淋巴组织耗尽有关，导致“肠漏”和微生物易位。因此，有理由相信艾滋病毒感染将是脂肪变性的重要危险因素，与丙型肝炎和内脏肥胖症无关。我们提出以下假设：(1.1)HIV感染(单独或与丙型肝炎病毒合并感染)将与未感染的人相比更严重的脂肪变性；(1.2)内脏脂肪增加将与脂肪变性的严重程度相关；(1.3)外周脂肪萎缩和肠道相关微生物易位将是HIV感染患者脂肪变性的主要因素；(2.1)在控制了艾滋病毒、丙型肝炎和内脏肥胖后，胰岛素抵抗仍将与脂肪变性的严重程度密切相关；(2.2)循环中的游离脂肪酸水平将是脂肪变性的主要预测因子，这是由于内脏脂肪增加而流入肝脏的游离脂肪酸增加，以及在HIV相关的皮下脂肪组织丢失的情况下无法储存脂肪酸；(2.3)脂联素水平降低(由于HIV相关的脂肪萎缩和炎症)将解释HIV对脂肪变性的很大比例的影响；(3.1)由于脂肪变性的严重程度增加，与单一感染丙肝病毒的患者相比，艾滋病毒/丙型肝炎合并感染的患者将有更多的组织学脂肪性肝炎和纤维化的患病率和程度；(3.2)炎症增加、脂联素减少、游离脂肪酸增加和胰岛素抵抗将解释与单一感染丙型肝炎患者相比，混合感染的艾滋病毒/丙型肝炎患者组织学脂肪性肝炎和纤维化的发生率和程度更高。这项研究的目的是确定脂肪变性的主要生物介质，以便将未来的机械性和干预性研究集中在与脂肪变性的发病机制及其进展相关的关键途径上。为了实现这一目标，300名男性和100名女性单独感染艾滋病毒和丙型肝炎病毒，艾滋病毒/丙型肝炎病毒混合感染和两者都不感染的情况将被研究。最先进的非侵入性磁共振波谱(MRS)将测量脂肪变性。MRS研究的区域比肝组织的随机核心活检更大，提供了连续的肝脏脂肪测量，并允许研究艾滋病毒单一感染但既不感染的患者；活组织检查不适用于那些没有慢性肝病的患者。

DESCRIPTION (provided by applicant): Liver disease is a leading cause of morbidity and mortality in HIV-infected persons. Hepatitis C virus (HCV) coinfection is implicated in many of these cases, but other causes of liver injury are common in HIV infection. Elucidation of the factors responsible for liver disease among HIV-infected patients, with or without concurrent HCV is important for researchers who seek to understand the pathogenesis of liver disease, and for clinicians who treat this large group of patients. Hepatic steatosis (or fatty liver) is common in HIV infection and is associated with accelerated fibrosis progression, which can lead to cirrhosis and death, particularly in those with HIV/HCV coinfection. However, relatively little is known about the etiology of steatosis in HIV infection. In HCV infection, genotype 3 appears to be directly associated with steatosis, but is uncommon in the US. By contrast, in those with genotype 1 HCV infection (which is highly prevalent in the US), obesity may be a more important cause than HCV infection. In the absence of HCV infection, obesity is a common cause of steatosis; however, visceral obesity (which is the accumulation of adipose tissue around the viscera) may be a more important risk factor than overall body mass for steatosis. Different studies suggest that the consequences of visceral obesity (increased inflammatory cytokines, decreased adiponectin, insulin resistance, increased circulating free fatty acids or microbial translocation of gut-derived endotoxins) may induce steatosis. These potential mediators could also explain the proposed link between HIV infection (independent of visceral obesity) and steatosis. HIV replication has been associated with elevations in inflammatory markers; HIV- associated peripheral lipoatrophy with decreased adiponectin levels. HIV infection has also been associated with depletion of gut-associated lymphoid tissue leading to a "leaky gut" and microbial translocation. Thus there is reason to believe that HIV infection will be an important risk factor for steatosis, independent of HCV and visceral adiposity. We propose the following hypotheses: (1.1) HIV infection (alone or in combination with HCV) will be associated with a greater severity of steatosis than in those with neither infection;(1.2) Increased visceral adiposity will be associated with severity of steatosis;(1.3) Peripheral lipoatrophy and gut-associated microbial translocation will be the dominant factors associated with steatosis in HIV-infected patients;(2.1) After controlling for HIV, HCV, and visceral adiposity, insulin resistance will remain strongly associated with the severity of steatosis;(2.2) Circulating free fatty acid levels will be a dominant predictor of steatosis due to the increased free fatty acid flux to the liver from increased visceral adiposity and the inability to store fatty acids in the setting of HIV-associated subcutaneous adipose tissue loss;(2.3) Decreased adiponectin levels (due to HIV-associated lipoatrophy and inflammation) will explain a significant proportion of the HIV effect on steatosis;(3.1) HIV/HCV-coinfected will have a greater prevalence and degree of histologic steatohepatitis and fibrosis than HCV-monoinfected patients, due to an increased severity of steatosis;(3.2) Increased inflammation, decreased adiponectin, increased free fatty acids, and insulin resistance will explain the greater prevalence and degree of histologic steatohepatitis and fibrosis in HIV/HCV-coinfected compared to HCV- monoinfected patients. The objective of the proposed study is to identify the dominant biologic mediators of steatosis, in order to focus future mechanistic and interventional studies on the key pathways associated with the pathogenesis of steatosis and its progression. To accomplish this, 300 men and 100 women with HIV and HCV monoinfection, HIV/HCV coinfection and neither infection will be studied. State-of-the-art non-invasive magnetic resonance spectroscopy (MRS) will measure steatosis. MRS studies a larger area than a random core biopsy of liver tissue, provides a continuous measure of liver fat, and allows for the study of patients with HIV monoinfection and neither infection; biopsy is not clinically indicated in those without chronic liver disease.