Dasarathy Jaividhya, McCullough Arthur J, Dasarathy Srinivasan
Department of Family Medicine, MetroHealth Medical Center, Cleveland, Ohio.
Department of Gastreoenterology, Hepatology and Pathobiology, Cleveland Clinic, Cleveland, Ohio.
Alcohol Clin Exp Res. 2017 Aug;41(8):1419-1431. doi: 10.1111/acer.13425. Epub 2017 Jul 11.
Despite advances in treatment of alcohol use disorders that focus on increasing abstinence and reducing recidivism, alcoholic liver disease (ALD) is projected to be the major cause of cirrhosis and its complications. Malnutrition is recognized as the most frequent complication in ALD, and despite the high clinical significance, there are no effective therapies to reverse malnutrition in ALD. Malnutrition is a relatively imprecise term, and sarcopenia or skeletal muscle loss, the major component of malnutrition, is primarily responsible for the adverse clinical consequences in patients with liver disease. It is, therefore, critical to define the specific abnormality (sarcopenia) rather than malnutrition in ALD, so that therapies targeting sarcopenia can be developed. Skeletal muscle mass is maintained by a balance between protein synthesis and proteolysis. Both direct effects of ethanol (EtOH) and its metabolites on the skeletal muscle and the consequences of liver disease result in disturbed proteostasis (protein homeostasis) and consequent sarcopenia. Once cirrhosis develops in patients with ALD, abstinence is unlikely to be effective in completely reversing sarcopenia, as other contributors including hyperammonemia, hormonal, and cytokine abnormalities aggravate sarcopenia and maintain a state of anabolic resistance initiated by EtOH. Cirrhosis is also a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from signaling and substrate functions. Novel therapeutic options are being recognized that are likely to supplant the current "deficiency replacement" approach and instead focus on specific molecular perturbations, given the increasing availability of small molecules that can target specific signaling components. Myostatin antagonists, leucine supplementation, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis in general, and ALD, specifically. Translation of these data to human studies and clinical application requires priority for allocation of resources.
尽管在酒精使用障碍治疗方面取得了进展，重点是增加戒酒率和降低复发率，但酒精性肝病（ALD）预计仍将是肝硬化及其并发症的主要原因。营养不良被认为是ALD最常见的并发症，尽管具有很高的临床意义，但目前尚无有效的疗法来逆转ALD中的营养不良。营养不良是一个相对不精确的术语，而肌肉减少症或骨骼肌丢失作为营养不良的主要组成部分，是肝病患者不良临床后果的主要原因。因此，在ALD中明确特定异常（肌肉减少症）而非营养不良至关重要，以便开发针对肌肉减少症的疗法。骨骼肌质量通过蛋白质合成与蛋白水解之间的平衡来维持。乙醇（EtOH）及其代谢产物对骨骼肌的直接作用以及肝病的后果都会导致蛋白质稳态（蛋白质平衡）紊乱，进而导致肌肉减少症。一旦ALD患者发展为肝硬化，戒酒不太可能完全逆转肌肉减少症，因为包括高氨血症、激素和细胞因子异常在内的其他因素会加重肌肉减少症，并维持由EtOH引发的合成代谢抵抗状态。肝硬化也是一种加速饥饿的状态，糖异生增加，这需要从信号传导和底物功能中转移氨基酸。鉴于能够靶向特定信号成分的小分子越来越多，人们认识到一些新的治疗选择可能会取代当前的“缺乏替代”方法，转而关注特定的分子扰动。肌肉生长抑制素拮抗剂、补充亮氨酸和线粒体保护剂目前在临床前研究的不同阶段进行评估，以预防和逆转一般肝硬化和特定ALD中的肌肉减少症。将这些数据转化为人体研究和临床应用需要优先分配资源。
