The WELL Study (Wellness Education for Liver Health Study): Reducing liver disease in genetically predisposed adults

摘要 目前没有药物可用于治疗非酒精性脂肪性肝病(NAFLD)，以及 日益流行的疾病困扰着大约25%的美国成年人。非酒精性脂肪性肝病是由脂肪过度沉积引起的 在肝脏(脂肪变性)；可进展为非酒精性脂肪性肝炎(NASH)、纤维化、肝硬变、肝细胞 癌症、肝移植以及肝脏相关死亡率和全因死亡率的增加。我们有初步数据 (1)胰岛素抵抗是发展为NAFLD的最强的可改变的危险因素，以及(2)个体 携带PNPLA3 rs738409-GG基因易患非酒精性脂肪肝的风险增加约两倍 发生非酒精性脂肪性肝病和非酒精性脂肪性肝炎(NASH)的风险是胰岛素的6倍 抵抗。尽管患有胰岛素抵抗的rs738409-GG个体患肝病的风险很高，但并不是 特别针对帮助他们改善胰岛素敏感性，从而可能改善他们的非酒精性脂肪肝 结果。PI和其他人已经表明，极低碳水化合物饮食(VLCD)在 与许多其他类型的饮食相比，减少胰岛素抵抗，除了对减肥有效外， 降低全身炎症，降低肝内脂肪含量。我们假设一个非常低的- 碳水化合物饮食和行为支持计划可能能够实现成人NAFLD的逆转 脂肪变性和/或轻度纤维化，特别是在高危亚群中，rs738409-GG个体。为…做准备 我们将对NAFLD患者的需求和偏好进行初步探索 VLCD程序。然后我们会根据这些反馈来调整我们的材料。最后，我们将进行一次试点 在30名患有NAFLD的成人PNPLA3rs738409 GG中进行为期4个月的VLCD计划的可行性和可接受性试验。 这款R03是在PI当前的K01和NIDDK的基础上构建的，NIDDK正在优化一个为期12个月的VLCD计划， 患有2型糖尿病的成年人。我们预计，由这笔赠款产生的研究将导致未来的R-Level 国家糖尿病、消化和肾脏疾病研究所的赠款，因为它将为 多中心随机对照试验。

ABSTRACT No medications are currently available for treatment of nonalcoholic fatty liver disease (NAFLD), an increasingly prevalent disease afflicting about 25% of US adults. NAFLD is caused by excessive fat deposition in the liver (steatosis); can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, hepatocellular carcinoma, liver transplantation, and increased liver-related and all-cause mortality. We have preliminary data that (1) insulin resistance is the strongest modifiable risk factor for developing NAFLD, and (2) individuals genetically predisposed to NAFLD by carrying PNPLA3 rs738409-GG show about a two-fold increased risk of developing NAFLD and a six-fold risk of nonalcoholic steatohepatitis (NASH) when combined with insulin resistance. Despite being at high risk of liver disease, rs738409-GG individuals with insulin resistance are not being especially targeted to help them improve their insulin sensitivity and thus likely improve their NAFLD outcomes. The PI and others have shown that very low-carbohydrate diets (VLCD) are more effective at reducing insulin resistance than many other types of diets, in addition to being effective for weight loss, lowering overall inflammation, and reducing intrahepatic lipid content. We hypothesize that a very low- carbohydrate diet and behavioral support program may be able to achieve NAFLD reversal in adults with steatosis and/or mild fibrosis, especially in a high-risk subpopulation, rs738409-GG individuals. To prepare to test this we will conduct a preliminary exploration of the needs and preferences of individuals with NAFLD for a VLCD program. Then we will adapt our materials based on this feedback. Finally, we will conduct a pilot feasibility and acceptability trial of a 4-month VLCD program in 30 PNPLA3 rs738409 GG adults with NAFLD. This R03 builds off of the PI’s current K01 with NIDDK, which is optimizing a 12-month VLCD program with adults with type 2 diabetes. We anticipate that the research stemming from this grant will lead to future R-level grants at the National Institute of Diabetes and Digestive and Kidney Diseases, as it will provide support for a multicenter randomized controlled trial.