Novel Drugs for the Management of Hepatic Encephalopathy: Still a Long Journey to Travel

Abstract

Hepatic encephalopathy (HE) is one of the reversible complications of chronic liver disease, associated with a higher mortality rate. In current clinical practice, treatment with rifaximin and lactulose/lactitol is the first line of treatment in HE. With the advance in pathophysiology, a new class of ammonia lowering drugs has been revealed to overcome the hurdle and disease burden. The mechanism of the novel agents differs significantly and includes the alteration in intestinal microbiota, intestinal endothelial integrity, oxidative stress, inflammatory markers, and modulation of neurotoxins. Most of the trials have reported promising results in the treatment and prevention of HE with fecal microbiota transplantation, albumin, probiotics, flumazenil, polyethylene glycol, AST-120, glycerol phenylbutyrate, nitazoxanide, branched-chain amino acid, naloxone, and acetyl-l-carnitine. However, their clinical use is limited due to the presence of major drawbacks in their study design, sample size, safety profile, bias, and heterogenicity. This study will discuss the novel therapeutic targets for HE in liver cirrhosis patients with supporting clinical trial data.

Keywords: ALC, acetyl-L-carnitine; BCAA, branched-chain amino acid; BD, twice a day; BDI, Beck Depression Inventory; BUN, blood urea nitrogen; CHESS, Clinical Hepatic Encephalopathy Staging Scale; CLDQ, Chronic Liver Disease Questionnaire; ECT, estimated completion time; EEG, electroencephalogram; FMT, fecal microbiota transplantation; GPB, glycerol phenylbutyrate; HESA, Hepatic Encephalopathy Scoring Algorithm; HRQOL, health-related quality of life; IV, intravenous; MED, Modified Encephalopathy Scale; MELD, Model for End-stage Liver Disease; MMSE, Mini-Mental State Examination; NTZ, nitazoxanide; Nal, naloxone; OD, once a day; ORT, object recognition test; PEG, polyethylene glycol; QID, four times a day; QOL, quality of life; RBNS, Repeatable Battery for the Assessment of Neuropsychological Status; RCT, randomized control trial; RT-qPCR, real-time quantitative polymerase chain reaction; TID, three times a day; VSL#3, high concentration probiotic preparations; hepatic encephalopathy; liver cirrhosis; novel drugs; treatment outcome.