Covert hepatic encephalopathy as a multi-organ syndrome: the gut–liver–muscle–brain axis, diagnosis, treatment, and multidisciplinary care

Covert hepatic encephalopathy (CHE) is a highly prevalent complication of liver cirrhosis. Despite the absence of overt symptoms, CHE is strongly associated with impaired quality-of-life, overt hepatic encephalopathy, and mortality. Over the past two decades, evidence regarding the pathophysiology, diagnosis, and treatment of CHE has accumulated considerably, and clinical guidelines recommend screening in patients with cirrhosis. Nevertheless, diagnostic and therapeutic algorithms have not been fully implemented in real-world practice, and many patients remain undiagnosed and untreated. Understanding the natural history of CHE is essential to improve cirrhosis care, as it provides a framework for appropriate screening, treatment decision-making, and patient counseling. CHE is a multi-organ syndrome with complex interactions between the liver, gut, skeletal muscle, kidneys, and brain, with impaired ammonia handling and systemic inflammation acting as central drivers of this organ crosstalk. Hyperammonemia induces astrocytic dysfunction, brain edema, and neuroinflammation, while systemic inflammation, oxidative stress, sarcopenia, gut dysbiosis, and altered microbial metabolites, including bile acids and short-chain fatty acids, further modulate disease expression. In this review, we summarize current understanding of CHE pathophysiology, diagnostic testing, including psychometric batteries and point-of-care tools, such as the Stroop test and animal naming test, and therapeutic options, ranging from lactulose and rifaximin to microbiome-targeted approaches, including fecal microbiota transplantation. We also highlight major challenges in CHE management, including limited implementation of testing, inadequate biomarkers, diagnostic difficulties in geriatric cirrhosis, and unmet needs in fall and driving risk management, and emphasize the importance of multidisciplinary team-based approaches to improve patient outcomes.