Nonalcoholic Steatohepatitis: Natural History, Pathogenesis and Therapy

非酒精性脂肪性肝炎：自然史、发病机制和治疗

• 批准号: 7967807
• 负责人: T. Jake Liang
• 金额: $ 48.34万
• 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/7967807
• 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; Diabetes Mellitus; Diagnosis; Disease; Dose; Enrollment; Equation; Etiology; Evaluation; Fatty acid glycerol esters; Female; Fibrosis; Follow-Up Studies; Future; Genetic; Genetic Markers; Goals; Hepatic; Hepatocyte; Histologic; Histology; Image; Individual; Inflammation; Insulin; Insulin Resistance; Lead; Liver; Liver diseases; Malignant neoplasm of liver; Measurement; Mediating; Metabolic; Metabolic syndrome; Metformin; Natural History; Obesity; Odds Ratio; Overweight; Parents; Participant; Pathogenesis; Patients; Pilot Projects; Pioglitazone; Population; Predisposition; Prevention therapy; Reporting; Research Design; Sampling; Series; Serum; Site; Staging; Subgroup; Testing; Thiazolidinediones; United States; Weight; Weight Gain; Woman; adipokines; adiponectin; base; cannabinoid receptor; cell injury; cohort; cytokine; diabetes mellitus therapy; diabetic patient; early onset; genetic linkage; improved; indexing; insulin sensitivity; insulin signaling; liver biopsy; liver transplantation; metabolic abnormality assessment; non-alcoholic fatty liver; non-diabetic; nonalcoholic steatohepatitis; offspring; open label; 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 completed 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. Currently we are also collaborating with a large NASH consortium to identify potential genetic markers for NAFLD.

非酒精性脂肪性肝病（NAFLD）的特点是肝细胞中脂肪堆积，并伴有炎症以及不同程度的细胞损伤和纤维化。 当存在细胞损伤和纤维化时，该疾病有可能进展，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，并且患有胰岛素抵抗或明显的糖尿病。 由于 NASH 与肥胖和糖尿病相关，因此 NASH 的治疗重点是减轻体重和改善胰岛素抵抗。 从2002年开始，我们针对NASH进行了一系列的临床研究。 最初的研究重点是噻唑烷二酮类 (TZD)，这是一种广泛用于治疗糖尿病的胰岛素增敏剂。在一项试点研究中，22 名患有 NASH 的非糖尿病患者接受了吡格列酮（每天 30 毫克）治疗，并在治疗 48 周之前和治疗结束时接受了代谢状态、身体成分和肝脏疾病（包括肝活检）的广泛测试。 通过严格的组织学标准评估改善情况。 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着减少。 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转移到外周所致。 肝脏的组织学改善不仅体现在脂肪量（脂肪变性）方面，更显着体现在细胞损伤、炎症和纤维化方面。 在这项研究的后续工作中，对患者样本进行了一系列细胞因子和脂肪因子的检测。 组织学改善与脂联素的变化最明显相关，脂联素是一种改善胰岛素信号传导并诱导脂肪细胞成熟的脂肪因子。 当吡格列酮停药后，NASH 的血清生化和组织学特征发生逆转，组织学评分在停药一年后恢复到基线。重要的是，吡格列酮治疗期间发生的体重增加并未逆转；因此，接受一年吡格列酮疗程的患者不再具有组织学益处，但体重比治疗前要重得多。 这些发现表明，NASH 的长期改善需要长期使用 TZD 治疗，并且 TZD 治疗经常伴随的体重增加可能最终会逆转任何益处。 最近，我们完成了一项二甲双胍治疗 NASH 的前瞻性、开放性研究。 共有 28 名 NASH 患者入组。 该研究的设计与吡格列酮相似，患者在接受为期 48 周的二甲双胍（每天 2000 毫克）疗程之前和结束时对身体成分、代谢状态、胰岛素敏感性和肝脏疾病（包括肝活检）进行了广泛的评估。 主要终点是组织学改善，定义为 NASH 活动指数改善 3 点。 在纳入的 28 名患者中，26 名（13 名女性；平均年龄 44 岁）完成了 48 周的治疗，并接受了重复代谢研究、影像学和肝活检。 百分之三十达到了组织学反应。大多数患者体重减轻，平均体重减轻6公斤。体重减轻与 NASH 活动指数和 ALT 水平的改善之间存在显着关联（两者均 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，二甲双胍可能通过其减轻体重的作用，改善了 30% 的 NASH 患者的肝脏组织学和 ALT 水平。 NASH 的未来研究将针对减肥作为改善这种肝脏疾病的一种手段。 正在考虑的可能疗法包括使用大麻素受体拮抗剂（例如利莫那班）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，我们试图在社区样本中检查父母肥胖与后代血清 ​​ALT 和 AST 水平之间的关系。对进行了血清 ALT 和 AST 测量的弗雷明汉后代研究的参与者 (n=1732)（50% 为女性，平均年龄 42 岁）以及弗雷明汉原始队列中的父母进行了研究。研究参与者被分为早发性父母肥胖 n=193（至少一名父母肥胖）、晚发性父母肥胖 n=460 和无父母肥胖 n=1079 亚组。使用广义估计方程来测试 ALT 或 AST 升高与父母肥胖之间的关联，以解释家族相关性。在包括对后代肥胖进行调整的多变量分析中，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 ALT 显着升高（p 值 = 0.02）。与父亲没有肥胖的后代相比，父亲早发性肥胖的后代更有可能出现 ALT 水平升高的情况（比值比 OR 1.75 (95% CI 1.06-2.89；p=0.03)。母亲早发性肥胖的后代与 ALT 升高没有关联（OR 1.10，95% CI 0.76-1.59；p=0.61）。 父母肥胖和血清 AST 水平。早发性父亲肥胖（而非母亲肥胖）会增加后代血清 ALT 水平升高的几率，这表明血清 ALT 水平升高的倾向可能是通过家族性早发性肥胖介导的。目前，我们还与一个大型 NASH 联盟合作，以确定 NAFLD 的潜在遗传标记。