NAFLD in T2DM: Prevalence in Hispanics and Role of Treatment

描述(由申请人提供)： 非酒精性脂肪性肝病(NAFLD)是一种以胰岛素抵抗和肝脏脂肪堆积(脂肪变性)为特征的慢性肝病。它影响了大约8000万美国人(Browning等人，2004年)。在约30-40%的患者中，脂肪变性会导致严重的脂肪性肝炎并伴有坏死性炎症和纤维化(即非酒精性脂肪性肝炎或NASH)。在约10%的患者中，NASH可能进展为肝硬变。寿命缩短不仅因为与肝脏相关的发病率，而且还因为心血管疾病的更高发病率(Targher等人，2007年)。我的长期目标是帮助我们了解导致患有T2 DM的西班牙裔人NASH的主要因素，并改进目前的诊断和治疗策略。这项应用的目标是通过系统筛查方法(即磁共振波谱或MRS)确定南得克萨斯州患有T2 DM的拉美裔人中NAFLD流行的真实规模(目标1)，并评估吡格列酮的长期安全性和有效性(目标2)。在第一个此类对照试验中，我们报告了6个月的吡格列酮逆转NASH的代谢/组织学缺陷(Belfort等人，NEJM 2006)。这一应用的中心假设是NAFLD的真实患病率比之前认识的要高得多，长期使用吡格列酮治疗改变了这种疾病的自然病史。在目标1中，受试者接受最初的病史/体检和常规实验室，以排除其他已知的导致脂肪肝的情况。然后在符合条件的患者中测量肝脏脂肪(通过MRS)。我们还将评估：i)OGTT的胰岛素分泌；ii)肌肉/肝脏/脂肪组织通过正常血糖的胰岛素钳夹产生的胰岛素抵抗；iii)DXA的全身脂肪，以评估肥胖与肝脏脂肪之间的关系；iv)如果他们有脂肪肝(MRS)和NASH的高危特征，则进行肝脏活检。活检证实为NASH的受试者将被邀请参加AIM#2，在那里，120名患者将被随机分为饮食干预+吡格列酮(45 mg/d)和饮食干预(目前的护理标准)+安慰剂。血糖控制将根据ADA指南进行优化。患者将进行Q1-2个月的随访，肝脏MRS每6个月重复一次。代谢研究(如目标1)和肝脏活检将在18个月时重复。这项研究将首次确定NAFLD在患有T2 DM的西班牙裔美国人中的患病率。临床、代谢和分子(肝脏活检)评估将确定与疾病进展相关的变量，并有助于了解吡格列酮的作用方式。如果没有这些知识，我们就不能超越生活方式建议来治疗NASH。目前还没有药物治疗。NASH是VAS中一个日益严重的问题。此外，肥胖和糖尿病的西班牙裔患者病情恶化的风险最高。因此，这个项目对我们的圣安东尼奥退伍军人管理局(以及整个VISN 17)非常重要，那里肥胖症的患病率约为70%，糖尿病的患病率约为30%，50%以上的患者是西班牙裔血统。

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance and hepatic fat accumulation (steatosis). It affects ~80 million Americans (Browning et al, 2004). In ~30-40% of patients steatosis leads severe steatohepatitis with necroinflammation and fibrosis (i.e., nonalcoholic steatohepatitis or NASH). NASH may progress to cirrhosis in ~10% of patients. Lifespan is not only shortened by liver-related morbidity, but also by a higher incidence of cardiovascular disease (Targher et al, 2007). My long-term goal is to contribute to our understanding of the host of factors that cause NASH in Hispanics with T2DM and improve the current diagnostic and treatment strategies. The objectives of this application, which are the next step in pursuit of that goal, are to determine the true magnitude of the NAFLD epidemic in Hispanics with T2DM in South Texas by means of a systematic screening approach (i.e, magnetic resonance spectroscopy or MRS) (Aim #1), and to assess the long-term safety and efficacy of pioglitazone (Aim #2). In the first controlled trial of its kind, we have reported that 6 months of pioglitazone reverse metabolic/histological defects in NASH (Belfort et al, NEJM 2006). The central hypothesis of this application is that that the true prevalence of NAFLD is much higher than previously appreciated and that long-term treatment with pioglitazone alters the natural history of the disease. In Aim 1 subjects undergo an initial history/physical and routine labs, to exclude other conditions known to cause a fatty liver. Liver fat (by MRS) is then measured in eligible patients. We will also assess: i) insulin secretion by an OGTT, ii) muscle/live/adipose tissue insulin resistance by a euglycemic insulin clamp; iii) total body fat by DXA, to assess the relationship between adiposity and liver fat; iv) a liver biopsy if they have a fatty liver (MRS) and a high-risk profile for NASH. Subjects with biopsy-proven NASH will be invited to Aim #2, where 120 patients will be randomized (by a computer-based algorithm) to dietary intervention plus pioglitazone (45 mg/d) vs. dietary intervention (the current standard of care) plus placebo. Glycemic control will be optimized following ADA guidelines. Patients will be followed q1-2 months and liver MRS repeated every 6 months. The metabolic studies (as in Aim#1) and liver biopsy will be repeated at 18 months. This study will define for the first time the prevalence of NAFLD in Hispanics with T2DM. The clinical, metabolic and molecular (liver biopsy) evaluations will identify variables associated with disease progression and help understand how pioglitazone works. Without this knowledge, we cannot move beyond lifestyle recommendations to treat NASH. There are no pharmacological treatments. NASH is an increasing problem across VAs. Moreover, obese and diabetic Hispanic patients have the highest risk of disease progression. Therefore, this project is important to our San Antonio VA (and the entire VISN 17) where the prevalence of obesity is ~70%, that of diabetes ~30 % and more than 50% of patients are of Hispanic ancestry.