Biobehavioral Pathways Underlying Alcohol Use Disorder and Alcohol-associated Liver Disease

酒精相关性肝病(AALD)和酒精使用障碍(AUD)是相互交织的疾病，大大增加了全球疾病和死亡的负担。酒精相关性肝病是指长期过量饮酒导致的一系列肝组织损伤，可能导致纤维化，然后是以过度疤痕为特征的肝硬变，最终导致肝功能衰竭。虽然戒酒是一个主要的治疗目标，但对于许多肝病患者来说，戒酒往往是无法实现的，因为潜在的AUD以渴望、负面影响和不顾伤害而寻求酒精为特征。大约三分之一的酗酒者患上晚期急性酒精性肝病，在美国，由于有害饮酒的增加，死于肝病的人数正在上升。尤其令人担忧的是，在过去十年中，AALD风险较高的人群，即西班牙裔妇女和个人的AUD比率上升了50%。虽然许多高质量的研究证明了短暂的心理社会干预对AUD的有效性，但只有五个对照试验测试了心理社会干预对AALD患者减少饮酒的有效性。这些研究的严谨性主要受到男性样本的限制，这些样本与酒精相关的医学病理各不相同。这项名为《酒精使用障碍和酒精相关肝病的生物行为路径》的提案将成瘾科学家和肝病学家团队联合起来，在科布雷成瘾和疾病风险加剧中心、罗德岛医院的寿命肝病诊所、普罗维登斯VA医学中心和其他布朗大学网络之间建立合作伙伴关系，并为未来测试AUD干预措施与AALD护理相结合的工作提供了平台。这项建议的主要目的是证明实施一项与AALD医疗护理相结合的短暂心理社会AUD干预的可行性。干预措施将包括来自肝功能、饮酒模式生物标志物的个性化反馈，以及通过智能手机报告对日常生活中的渴望和负面影响进行自我监测。在过去的一个月里，平均每天饮酒24g/&gt；36g的酗酒者(n=44)将从当地医院、诊所和更大的社区招募。我们的参与者中有一半将患有晚期AALD和AUD，另一半将患有AUD而不是AALD，两组的饮酒水平相匹配。招募的目标将是男女代表平等，并对三分之一的西班牙裔人进行过抽样。该方案包括为期1周的筛查阶段、3周的干预阶段和3个月的随访。除了证明可行性外，该项目还旨在测试临床试验中与酒精使用结果相关的行为内表型是否比仅患有AUD的AUD患者在AUD干预期间更耐受变化。最终目的是探索炎症和免疫激活的生物标志物作为内表型持续存在的机制，特别是促炎细胞因子、趋化因子和其他与AALD发病有关的水平。

Alcohol-associated liver disease (AALD) and alcohol use disorder (AUD) are intersecting diseases that add substantially to the global burden of disease and mortality. Alcohol-associated liver disease refers to a spectrum of liver tissue injury caused by chronic and excessive alcohol use, which can lead to fibrosis, followed by cirrhosis characterized by excessive scarring, and eventually, liver failure. Although alcohol abstinence is a main treatment goal, stopping drinking is often unachievable for many liver disease patients due to an underlying AUD characterized by craving, negative affect, and alcohol seeking despite harms. Approximately 1/3 of problem drinkers develop advanced AALD, and deaths from liver diseases are rising in the U.S., driven largely by increases in harmful drinking. Of particular concern, AUD rates have risen 50% in the past decade for those at greater risk of AALD, i.e., women and individuals of Hispanic ethnicity. While numerous, high-quality studies demonstrate effectiveness of brief psychosocial interventions for AUD, only five controlled trials have tested the efficacy of psychosocial interventions to reduce drinking in AALD patients. The rigor of these studies is limited by primarily male, nondiverse samples with varied alcohol-related medical pathology. This proposal, Biobehavioral Pathways Underlying Alcohol Use Disorder and Alcohol-associated Liver Disease, unites a team of addiction scientists and hepatologists for a partnership between the COBRE Center for Addiction and Disease Risk Exacerbation, Lifespan Hepatology Clinic at Rhode Island Hospital, Providence VA Medical Center, and other Brown University networks, and provides a platform for future work testing AUD interventions integrated with AALD care. The primary aim of this proposal is to demonstrate the feasibility of implementing a brief psychosocial AUD intervention integrated with AALD medical care. The intervention will include personalized feedback from biomarkers of liver function, drinking patterns, and self-monitoring of craving and negative affect via smartphone reports in daily life. Excessive drinkers (n = 44) consuming >24g/>36g per day, on average, for women/men in the past month, will be recruited from local hospitals, clinics, and the greater community. Half of our participants will have advanced AALD and AUD, and half will have AUD without AALD, with groups matched on drinking level. Recruitment will target equal representation of men and women and oversample for 1/3 individuals of Hispanic ethnicity. The protocol includes a 1-week screening phase, 3-week intervention phase, and 3-month follow-up. In addition to demonstrating feasibility, this project aims to test whether behavioral endophenotypes associated with alcohol-use outcomes in clinical trials are more resistant to change during AUD intervention for AALD patients with AUD relative to those with AUD only. A final aim is to explore biomarkers of inflammation and immune activation as mechanisms of persistence of endophenotypes, specifically levels of pro-inflammatory cytokines, chemokines, and others implicated in the pathogenesis of AALD.