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

描述（由申请人提供）：肝脏疾病是艾滋病毒感染者发病和死亡的主要原因。丙型肝炎病毒（HCV）合并感染与许多这些病例有关，但其他原因的肝损伤在HIV感染中很常见。阐明伴有或不伴有HCV的hiv感染患者中导致肝脏疾病的因素，对于寻求了解肝脏疾病发病机制的研究人员和治疗这一大群患者的临床医生来说是重要的。肝脂肪变性（或脂肪肝）在HIV感染中很常见，并与纤维化加速进展相关，可导致肝硬化和死亡，特别是在HIV/HCV合并感染的患者中。然而，对HIV感染中脂肪变性的病因知之甚少。在HCV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，在基因1型HCV感染（在美国非常普遍）的人群中，肥胖可能是比HCV感染更重要的原因。在没有丙型肝炎病毒感染的情况下，肥胖是脂肪变性的常见原因；然而，内脏肥胖（内脏周围脂肪组织的积累）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（炎症细胞因子增加，脂联素减少，胰岛素抵抗，循环游离脂肪酸增加或肠道内毒素的微生物易位）可能诱发脂肪变性。这些潜在的介质也可以解释HIV感染（独立于内脏肥胖）和脂肪变性之间的联系。HIV复制与炎症标志物升高有关；HIV相关外周脂肪萎缩伴脂联素水平降低。HIV感染还与肠道相关淋巴组织的耗竭有关，导致“漏肠”和微生物易位。因此，有理由相信HIV感染将是脂肪变性的重要危险因素，独立于HCV和内脏肥胖。我们提出以下假设：（1.1）与未感染的患者相比，HIV感染（单独感染或合并感染HCV）与脂肪变性的严重程度相关；（1.2）内脏脂肪增加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相关因素；（2.1）在控制HIV、HCV和内脏脂肪变性后，胰岛素抵抗仍然与脂肪变性的严重程度密切相关；（2.2）循环游离脂肪酸水平将是脂肪变性的主要预测因素，因为内脏脂肪增加导致游离脂肪酸向肝脏的通量增加，并且在HIV相关的皮下脂肪组织损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的重要比例（3.1）由于脂肪变性的严重程度增加，HIV/HCV合并感染患者的组织学脂肪性肝炎和纤维化的患病率和程度高于HCV- single感染患者；（3.2）与HCV- single感染患者相比，炎症增加、脂联素降低、游离脂肪酸增加和胰岛素抵抗可以解释HIV/HCV合并感染患者的组织学脂肪性肝炎和纤维化的患病率和程度更高。该研究的目的是确定脂肪变性的主要生物介质，以便将未来的机制和干预性研究集中在与脂肪变性发病机制及其进展相关的关键途径上。为实现这一目标，将研究300名男性和100名女性艾滋病毒和丙型肝炎病毒单感染、艾滋病毒/丙型肝炎病毒合并感染和两种感染均不感染。最先进的非侵入性磁共振波谱（MRS）将测量脂肪变性。MRS研究比随机肝组织核心活检更大的区域，提供肝脏脂肪的连续测量，并允许研究HIV单一感染和未感染的患者；没有慢性肝病的患者临床不需要活检。

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. PUBLIC HEALTH RELEVANCE: Liver disease is a leading cause of morbidity and mortality in HIV-infected persons. Hepatic steatosis (or fatty liver) is a frequent cause of liver disease in the US and is a particular concern for HIV-infected persons. Steatosis is common in HIV infection and is associated with accelerated fibrosis progression, which can lead to cirrhosis and death, particularly in HIV/HCV-coinfected persons. HCV infection appears directly associated with steatosis, but the etiology of steatosis in HIV remains unclear. Obesity (in particular, visceral obesity) appears to be a key promoter of steatosis in the absence of viral infection. Studies show that about 50% of HIV-infected and 75% of HIV-uninfected persons in the US are overweight or obese. It is therefore critical to understand the relation of HIV, HCV, and visceral adiposity with steatosis, and to identify biologic mediators (microbial translocation, inflammation, adipokine and metabolic alterations) in the pathogenesis of steatosis, so that interventions targeted to the dominant factors can be developed and studied.