Nonalcoholic Steatohepatitis: Natural History and Therapy

非酒精性脂肪性肝炎：自然史和治疗

• 批准号: 7734346
• 负责人: T. Jake Liang
• 金额: $ 46.61万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734346
• 关键词: 2,4-thiazolidinedione; Accounting; Adipocytes; Adult; Affect; Age; Alanine; Aspartate; Aspartate Transaminase; Biochemical; Body Composition; Body Weight; Body Weight decreased; Body fat; Cirrhosis; Clinical Research; Communities; Daily; Diabetes Mellitus; Diagnosis; Disease; Dose; End Point; Enrollment; Equation; Etiology; Evaluation; Fatty acid glycerol esters; Female; Fibrosis; Follow-Up Studies; Future; Genetic; Goals; Hepatic; Hepatocyte; Histologic; Histology; Individual; Inflammation; Insulin; Insulin Resistance; Label; Lead; Liver; Liver diseases; Malignant neoplasm of liver; Measurement; Mediating; Metabolic; Metabolic syndrome; Metformin; Natural History; Obesity; Odds Ratio; Overweight; Parents; Participant; Patients; Pilot Projects; Pioglitazone; Population; Predisposition; Prevention therapy; Reporting; Research Design; Sampling; Score; Series; Serum; Site; Staging; Subgroup; Testing; Thiazolidinediones; United States; Week; Weight; Weight Gain; Woman; adipokines; adiponectin; base; cannabinoid receptor; cell injury; cohort; cytokine; diabetes mellitus therapy; early onset; genetic linkage; improved; indexing; insulin sensitivity; insulin signaling; liver biopsy; liver imaging; liver transplantation; metabolic abnormality assessment; non-alcoholic fatty liver; non-diabetic; nonalcoholic steatohepatitis; prospective; research study; response; rimonabant

Nonalcoholic fatty liver disease (NAFLD) is marked by accumulation of fat in liver cells with accompanying inflammation and variable degrees of cell injury and fibrosis. When cell injury and fibrosis are present, the disease has a potential to progress and is referred to as nonalcoholic steatohepatitis (NASH). The etiology of NASH is not clear, but most patients are overweight or obese and have either insulin resistance or frank diabetes. Because of this association with obesity and diabetes, therapies for NASH have focused upon weight loss and improvement in insulin resistance. Starting in 2002, we conducted a series of clinical research studies in NASH. An initial study focused on the thiazolidinediones (TZDs), insulin sensitizing agents that are used widely in diabetes. In a pilot study, 22 non-diabetic patients with NASH were treated with pioglitazone (30 mg daily) and underwent extensive testing for metabolic status, body composition and liver disease (including liver biopsy) before and at the end of 48 weeks of therapy. Improvement was assessed by strict histological criteria. A preliminary report on this study showed that two-thirds of patients improved on therapy as judged by strict histological criteria. Improvements were accompanied by a marked decrease in hepatic fat despite an overall increase in body weight and total body fat. Thus, the effects of TZDs in NASH appeared to be due to the redirection of fat storage from the liver and central sites to the periphery. The histological improvements in the liver were not just in amount of fat (steatosis), but more strikingly in cell injury, inflammation and fibrosis. In follow up of this study, samples from patients were tested for a battery of cytokines and adipokines. Histological improvements correlated most clearly with changes in adiponectin, a adipokine that improves insulin signaling and induces maturation of adipocytes. When pioglitazone was stopped, the serum biochemical and histological features of NASH were reversed, histological scores returning to baseline by a year after discontinuation of pioglitazone. Importantly, the weight gain that occurred during pioglitazone therapy was not reversed; so that patients who received a one-year course of pioglitazone no longer had the histological benefit but were considerably heavier than before they were treated. These finds indicate that long-term improvement in NASH would require long-term therapy with a TZD and that the weight gain that often accompanies TZD therapy is likely to ultimately reverse any benefit. Recently, we initiated a prospective, open-labelled study of metformin as therapy for NASH. A total of 28 patients with NASH were enrolled. The design of the study was similar to that for pioglitazone, in that patients underwent extensive evaluation of body composition, metabolic status, insulin sensitivity and liver disease (including liver biopsy) before and at the end of a 48 week course of metformin (2000 mg daily). The primary endpoint was histologic improvement, defined as a 3-point improvement in the NASH activity index. Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty percent achieved a histologic response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both, p <0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histologic improvement. Thus, metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH probably by its effects in causing weight loss. Future studies in NASH will be directed at weight loss as a means of improving this liver disease. Possible therapies that are being considered include use of cannabinoid receptor antagonists (such as rimonabant) and use of high doses of metformin. To define the genetic linkage between NAFLD, obesity, and metabolic syndrome, we have initiated several genetic studies of NAFLD. Obesity is an important correlate of serum alanine (ALT) and aspartate (AST) aminotransferase levels. In the first study, we sought to examine the relations between parental obesity and the serum ALT and AST levels among offspring in a community-based sample. Participants (n=1732) of the Framingham Offspring Study (50% women, mean age 42 years) who had serum ALT and AST measurements and both parents in the Framingham Original cohort, were studied. Study participants were grouped into early-onset parental obesity n=193 (at least one parent obese), later-onset parental obesity n=460, and no parental obesity n=1079 subgroups. The association between elevated ALT or AST and parental obesity was tested using generalized estimating equations to account for familial correlations. In multivariable analysis including adjustment for offspring obesity, significantly higher ALT was observed among individuals with paternal early-onset obesity as compared to those without paternal obesity (p-value=0.02). Offspring with early-onset paternal obesity were more likely to have elevated ALT levels compared with those without paternal obesity (odds ratio OR 1.75 (95% CI 1.06-2.89; p=0.03). There was no association with elevated ALT among offspring with maternal early-onset obesity (OR 1.10, 95% CI 0.76-1.59; p=0.61). There was no association between parental obesity and serum AST levels. Early-onset paternal obesity, but not maternal obesity, increases the odds of elevated serum ALT levels in the offspring, suggesting a predisposition to developing elevated serum ALT levels that may be mediated through familial early-onset obesity.

非酒精性脂肪性肝病（NAFLD）的特征是脂肪在肝细胞中的积累，伴随炎症和不同程度的细胞损伤和纤维化。 当细胞损伤和纤维化存在时，疾病有可能进展，并被称为非酒精性脂肪性肝炎（NASH）。 NASH的病因尚不清楚，但大多数患者超重或肥胖，并患有胰岛素抵抗或明显的糖尿病。 由于与肥胖和糖尿病的这种关联，NASH的治疗集中在体重减轻和胰岛素抵抗的改善上。 从2002年开始，我们在NASH中进行了一系列临床研究。 最初的研究集中在噻唑烷二酮类（TZDs），广泛用于糖尿病的胰岛素增敏剂。在一项初步研究中，22例非糖尿病NASH患者接受吡格列酮（每日30 mg）治疗，并在48周治疗前和治疗结束时接受了代谢状态、身体组成和肝脏疾病（包括肝活检）的广泛检测。 通过严格的组织学标准评估改善。 这项研究的初步报告显示，根据严格的组织学标准判断，三分之二的患者在治疗后有所改善。 尽管体重和全身脂肪总体增加，但改善伴随着肝脂肪的显著减少。 因此，TZD在NASH中的作用似乎是由于脂肪储存从肝脏和中心部位重定向到外周。 肝脏的组织学改善不仅是脂肪量（脂肪变性），而且在细胞损伤，炎症和纤维化方面更显着。 在本研究的后续研究中，对来自患者的样品进行了细胞因子和脂肪因子的测试。 组织学改善与脂联素的变化相关性最明显，脂联素是一种脂肪因子，可改善胰岛素信号传导并诱导脂肪细胞成熟。 停用吡格列酮后，NASH的血清生化和组织学特征逆转，组织学评分在停用吡格列酮后一年恢复至基线水平。重要的是，吡格列酮治疗期间发生的体重增加没有逆转;因此接受吡格列酮1年疗程的患者不再具有组织学获益，但比治疗前明显加重。 这些发现表明，NASH的长期改善需要TZD的长期治疗，并且通常伴随TZD治疗的体重增加可能最终逆转任何益处。 最近，我们启动了一项关于二甲双胍治疗NASH的前瞻性、开放性研究。 共入组了28例NASH患者。 该研究的设计与吡格列酮相似，在二甲双胍（每日2000 mg）48周疗程之前和结束时，对患者的身体组成、代谢状态、胰岛素敏感性和肝脏疾病（包括肝脏活检）进行了广泛评价。 主要终点是组织学改善，定义为NASH活动指数改善3分。 在入组的28例患者中，26例（13例女性;平均年龄44岁）完成了48周的治疗，并接受了重复代谢研究、成像和肝活检。 30%的患者获得了组织学缓解。大多数患者体重减轻，平均为6公斤。体重减轻与NASH活性指数和ALT水平的改善之间存在显著相关性（两者，p <0.01）。胰岛素敏感性也有所改善，但变化程度与组织学改善无关。 因此，二甲双胍导致30%的NASH患者的肝脏组织学和ALT水平改善，可能是由于其引起体重减轻的作用。 NASH的未来研究将针对体重减轻作为改善这种肝脏疾病的手段。 正在考虑的可能疗法包括使用大麻素受体拮抗剂（如利莫那班）和使用高剂量的二甲双胍。 为了确定NAFLD、肥胖和代谢综合征之间的遗传联系，我们已经启动了几项NAFLD的遗传研究。肥胖是血清丙氨酸（ALT）和天冬氨酸（AST）转氨酶水平的重要相关因素。在第一项研究中，我们试图在一个社区为基础的样本中检查父母肥胖与后代血清ALT和AST水平之间的关系。研究了Frachial Offspring研究的参与者（n=1732）（50%女性，平均年龄42岁），他们具有血清ALT和AST测量值，父母双方都在Frachial Original队列中。研究参与者被分为早发性父母肥胖n=193（至少一个父母肥胖），晚发性父母肥胖n=460，和没有父母肥胖n=1079亚组。ALT或AST升高与父母肥胖之间的关联用广义估计方程来解释家族相关性。在包括校正后代肥胖的多变量分析中，与没有父亲肥胖的个体相比，在父亲早发性肥胖的个体中观察到显著更高的ALT（p值=0.02）。与无父亲肥胖的后代相比，父亲早发性肥胖的后代更有可能出现ALT水平升高（比值比OR 1.75（95% CI 1.06-2.89; p=0.03）。在母亲早发性肥胖的后代中，ALT升高与此无关（OR 1.10，95%CI 0.76-1.59; p=0.61）。父母肥胖和血清AST水平之间没有关联。早发性父亲肥胖，而不是母亲肥胖，增加了后代血清ALT水平升高的几率，这表明可能通过家族性早发性肥胖介导的血清ALT水平升高的倾向。