The role of systemic inflammation in hepatic encephalopathy: advances in inflammatory mechanisms, prevention and treatment research.

OBJECTIVES

This review synthesizes current evidence establishing systemic inflammation as a key pathogenic driver in hepatic encephalopathy (HE) beyond hyperammonemia. It does not replace the ammonia hypothesis but rather acts as a critical synergistic factor, modulating and amplifying ammonia neurotoxicity. It further evaluates the mechanisms linking inflammation to HE and the therapeutic advances in inflammation-targeted prevention and treatment strategies.

METHODS

A comprehensive narrative literature review was conducted, analyzing relevant preclinical models and clinical studies. The search and synthesis focused on inflammatory mechanisms in chronic liver disease, gut-liver-brain axis dysfunction, cirrhosis-associated immune dysfunction (CAID), and resulting neuroinflammatory pathways.

RESULTS

Systemic inflammation, driven by gut dysbiosis, barrier failure, and CAID, amplifies ammonia neurotoxicity and independently contributes to neuroinflammation, blood-brain barrier disruption, and cerebral metabolic dysfunction in HE. Key inflammatory markers, such as IL-6, correlate with disease severity. Therapies targeting inflammation - particularly gut microbiota modulation with rifaximin and fecal microbiota transplantation (FMT) - demonstrate significant efficacy in reducing HE recurrence, lowering systemic inflammation, and improving cognitive outcomes. Other approaches, including albumin infusion, also show promise.

CONCLUSIONS

Systemic inflammation is a pivotal and synergistic factor in HE pathogenesis. Combining anti-inflammatory strategies that target the gut-liver-brain axis with traditional ammonia-lowering therapies offers a more comprehensive and effective treatment paradigm. Future research should prioritize protocol optimization, long-term safety assessment, and the development of personalized treatment approaches.