Novel Agents in the Management of Hepatic Encephalopathy: A Review

Abstract

Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions. complication of liver dysfunction, encompassing a broad spectrum of neurocognitive and psychomotor dysfunction ranging from disorientation to coma.1 It is classified into three major subtypes, based on the underlaying etiology, as follows: Type A, resulting from acute liver failure; type B, resulting from portosystemic shunt; and type C, resulting from liver cirrhosis. 2 HE, especially due to liver cirrhosis, is associated with significant mortality, reaching up to 64% at 1 year.3 In addition to the high mortality rate, HE imposes a great burden on various aspects of patient lives and healthcare systems.4 The management of HE starts with identifying and treating any precipitating cause, especially in patients with chronic liver diseases who may develop acute HE secondary to infection, bleeding, etc. Currently, several medications are utilized to treat HE, with a primary focus on decreasing ammonia production and absorption, such as by lactulose and rifaximin. Newer therapies are emerging and currently under study for the management of HE targeting traditional mechanisms of ammonia clearance in addition to novel mechanisms related to altering gut microbiome, reducing inflammation and oxidative stress, protecting endothelial integrity, and modifying neuronal responses (Fig. 1). In this article, we aim to review the management of HE, starting with the efficacy and limitations of traditional agents with a focus on the evidence supporting newer therapies in HE (Table 1).