Advances in understanding, diagnosing, and treating hepatic encephalopathy: from epidemiology to emerging therapies

This comprehensive review explores the multifaceted landscape of hepatic encephalopathy (HE), encompassing its epidemiology, pathophysiology, classification, and evolving therapeutic approaches. Delving into the prevalence and incidence of HE, it is found that the burden of this condition is on individuals and healthcare systems. The intricate mechanisms underlying HE, including abnormalities in synapse transmission, the ammonia hypothesis, the false neurotransmitter theory, the GABAergic theory, and the benzodiazepine theory, are scrutinized, providing a nuanced understanding of the disorder. The review examines altered gene expression, hyponatremia, neurosteroids, oxidative stress, electrolyte imbalance, and manganese accumulation as contributing factors to HE. Classifying HE and identifying precipitating risk factors form crucial aspects of the discussion, shedding light on the most widely used diagnostic tools. Conventional approaches for HE management are discussed, focusing on reducing elevated ammonia formation, improving ammonia-detoxifying liver capacity, and inhibiting false neurotransmitters. Antibiotics, metabolic ammonia scavengers, albumin, probiotics, dietary management, zinc, and secondary prophylaxis are analyzed as current therapeutic targets. Furthermore, the review examines emerging therapies at various stages, including clinical and pre-clinical development, such as glycerol/sodium phenylbutyrate, ornithine phenylacetate, fecal microbiota transplantation, engineered bacteria, liposome-supported peritoneal dialysis, GABA_A receptor modulating steroid antagonists (GAMSA), activated carbon microspheres, and glutamine synthetase replacement. This review consolidates knowledge on HE, providing a comprehensive resource for clinicians, researchers, and healthcare professionals involved in managing this complex disorder. The synthesis of epidemiological data, pathophysiological insights, and therapeutic advancements offers a holistic view of HE, paving the way for improved diagnosis and targeted interventions.