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）是一种慢性肝病，其特征在于胰岛素抵抗和肝脏脂肪积聚（脂肪变性）。它影响约8000万美国人（布朗宁等人，2004）。在约30-40%的患者中，脂肪变性导致严重的脂肪性肝炎，伴有坏死性炎症和纤维化（即，非酒精性脂肪性肝炎或NASH）。NASH可能在约10%的患者中进展为肝硬化。寿命不仅因肝脏相关的发病率而缩短，而且因心血管疾病的发病率较高而缩短（Targher et al，2007）。 我的长期目标是帮助我们了解导致西班牙裔T2 DM患者NASH的众多因素，并改善当前的诊断和治疗策略。本申请的目的是通过系统性筛查方法（即磁共振波谱或MRS）确定南德克萨斯州西班牙裔T2 DM患者中NAFLD流行的真实程度（目的#1），并评估吡格列酮的长期安全性和疗效（目的#2）。在第一项同类对照试验中，我们报告了6个月的吡格列酮逆转NASH的代谢/组织学缺陷（贝尔福特et al，NEJM 2006）。本申请的中心假设是，NAFLD的真实患病率远高于先前估计的患病率，并且吡格列酮的长期治疗改变了疾病的自然史。 在目标1中，受试者接受初始病史/体格检查和常规实验室检查，以排除已知引起脂肪肝的其他疾病。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）通过OGTT的胰岛素分泌，ii）通过正葡萄糖胰岛素钳夹的肌肉/肝脏/脂肪组织胰岛素抵抗; iii）通过DXA的全身脂肪，以评估肥胖和肝脏脂肪之间的关系; iv）如果他们具有脂肪肝（MRS）和NASH的高风险特征，则进行肝脏活组织检查。将邀请活检证实的NASH受试者参加目标2，其中120例患者将随机（通过基于计算机的算法）接受饮食干预+吡格列酮（45 mg/d）vs.饮食干预（当前标准治疗）+安慰剂。将按照ADA指导原则优化糖化血红蛋白控制。将对患者进行q1-2个月随访，每6个月重复一次肝脏MRS。代谢研究（如目标1）和肝活检将在18个月时重复进行。 本研究将首次确定西班牙裔T2 DM患者中NAFLD的患病率。临床、代谢和分子（肝活检）评估将确定与疾病进展相关的变量，并帮助了解吡格列酮的作用机制。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。没有药物治疗。NASH是VA中日益严重的问题。此外，肥胖和糖尿病西班牙裔患者的疾病进展风险最高。因此，该项目对我们的圣安东尼奥VA（以及整个VISN 17）非常重要，因为肥胖患病率约为70%，糖尿病患病率约为30%，超过50%的患者为西班牙裔。 公共卫生相关性： 众所周知，非酒精性脂肪性肝病（NAFLD）和2型糖尿病（T2 DM）是主要的公共卫生问题。这对于美国各地的所有VA医疗保健设施来说尤其如此，因为他们为少数民族的老龄化人口提供护理。2型糖尿病是我们圣安东尼奥VA的主要问题，因为圣安东尼奥地区51%的人口为西班牙裔，该种族的2型糖尿病发病率是白人的2-3倍。 据我们所知，尚无已发表的研究检查了T2 DM中NAFLD的患病率，特别是在以西班牙裔为主的人群中。本研究将首次确定西班牙裔T2 DM患者中NAFLD的患病率。此外，之前没有研究尝试描述相当大的西班牙裔NAFLD人群的代谢和分子缺陷，并使用拟定的最先进方法在长期吡格列酮治疗后对其进行随访。临床、代谢和分子（肝活检）评价将确定与疾病进展相关的变量，并帮助了解吡格列酮如何在临床和最基础水平改变导致脂肪肝蓄积的疾病。没有这些知识，我们仅限于生活方式建议（当前的护理标准），这些建议经常失败，并且在大型对照试验中没有显示可以改善NASH的肝损伤（坏死性炎症和纤维化）。我们之前已经在短期对照试验中确定了pioglitaozne逆转NASH患者的代谢和组织学缺陷（贝尔福特等人，NEJM 2006）。因此，考虑到NASH患者没有其他可用的药物治疗，不能低估建立长期治疗的重要性。此外，NASH是VA医疗保健系统中日益严重的问题。此外，由于肥胖和糖尿病西班牙裔患者的疾病进展风险最高，因此该项目对我们的圣安东尼奥VA（和整个VISN 17）非常重要，我们的肥胖患病率约为70%，糖尿病患病率约为30%，超过50%的患者为西班牙裔。 总之，预计该资助提案的结果将导致对该疾病的新理解，并为预防T2 DM中与NAFLD相关的并发症的新型干预提供依据，目标人群为NASH（该疾病的最严重形式）风险最高的人群。

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. PUBLIC HEALTH RELEVANCE: It is well known that nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are major public health problems. This is especially true for all VA health care facilities across the United States, since they provide care to an aging population of minority individuals. T2DM is a major problem for our San Antonio VA, since 51% of the population in the San Antonio area is of Hispanic ancestry, an ethnic group with a 2-3 fold higher incidence of T2DM compared to Caucasians. To the best of our knowledge, there are no published studies that have examined the prevalence of NAFLD in T2DM and in particular in a predominantly Hispanic population. This study will define for the first time the prevalence of NAFLD in Hispanics with T2DM. In addition, no previous study has attempted to characterize the metabolic and molecular defects in a rather large population of Hispanics with NAFLD and follow them after long-term pioglitazone treatment using the proposed state-of-the-art methodologies. The clinical, metabolic and molecular (liver biopsy) evaluations will identify variables associated with disease progression and help understand how pioglitazone modifies at the clinical and most basic level disorders leading to fatty liver accumulation. Without this knowledge, we are limited to lifestyle recommendations (the current standard of care) that so frequently fail and have not shown in large controlled trials to improve liver damage (necroinflammation and fibrosis) in NASH. We have previously established in a short-term controlled trial that pioglitaozne reverses metabolic and histological defects in patients with NASH (Belfort et al, NEJM 2006). Therefore, the importance of establishing the long-term cannot be underestimated considering that there are no other pharmacological treatments available for patients with NASH. Moreover, NASH is an increasing problem across VA health care system. Moreover, because obese and diabetic Hispanic patients have the highest risk of disease progression, this project is important to our San Antonio VA (and the entire VISN 17) where our prevalence of obesity is ~70%, that of diabetes ~30 % and more than 50% of patients are of Hispanic ancestry. In summary, it is anticipated that the results of this grant proposal will lead to a new understanding of the disease and provide the rationale for a novel intervention to prevent the complications associated with NAFLD in T2DM, targeting a population with the highest risk of developing NASH, the most severe form of the disease.