Hepatic Encephalopathy (HE) is a neuropsychiatric disorder characterized by cerebral dysregulation due to hepatic metabolic dysfunction and/or porto-systemic shunting (PSS) resulting in bypass of portal blood flow to the systemic circulation without hepatic detoxification. Hepatic Encephalopathy manifests as a broad spectrum of neurological, cognitive or psychiatric abnormalities ranging from subclinical alterations of cerebral function to coma"(1). Subtle alterations in cerebral function are only detectable by neuropsychological or neurophysiological assessment in minimal hepatic encephalopathy. Weissenborn et al., define HE as a 'significant condition of severe chronic or acute liver insufficiency that is characterized mainly by modifications of motor function, cognition, consciousness, personality. HE was traditionally differentiated into 3 categories as Type A, Type B and Type C. Acute-on-chronic liver (ACLF) has emerged as an independent clinical entity in the field of chronic liver disease which is related to high short-term mortality. The pathogenesis of HE involves blood-derived precipitating factors that cause a neurological deficit in patients with cirrhosis. A major presumption of pathogenesis of HE was assumed to be the central role of ammonia. However, there is now a paradigm shift in our understanding of the etiology, pathogenesis, evolution, and clinical correlation of HE in critically ill patients with cirrhosis and ACLF, wherein systemic inflammation, neuronal dysfunction, cerebral edema, oxidative stress and immune dysregulation are key factors in the multifactorial pathogenesis of HE.

In liver failure, changes in gut microbiota and their by-products like amino acid metabolites, ammonia, endotoxin, oxidative stress, result in neurological transmission alterations like changes in glutamine (Glx), GABA transmission and oxidative stress. Systemic inflammation causes the release of pro inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. They act synergistically with ammonia in developing cognitive dysfunction in patients with HE in and cirrhosis. Currently, there is evidence of the role of neuroinflammation in liver failure. Neuroinflammation is characterized by microglial activation and increased synthesis of the in situ pro-inflammatory cytokines IL-6, IL-1β and TNF-α. Additionally, there is increased gut-liver-brain axis signaling that includes effects of chemokines and cytokines, increased monocytes demand after microglial activation, and changed permeability of the blood-brain barrier(BBB).

However, the exact mechanism by which cerebral edema and HE in ACLF is caused by inflammation is not well known. Thus, identification of novel biomarkers using markers of inflammation, metabolomics, and cerebral imaging techniques to assess the severity of HE in ACLF is essential. The presence of HE is a significant negative predictor of survival in patients with ACLF; hence, studies are needed to fill the gap that is present in the monitoring and prognostication of HE in critically ill patients.

Lactulose is mainstay treatment for HE currently and acts beyond mere ammonia reduction. Lactulose therapy over three months causes a reduction in levels of serum endotoxin, arterial ammonia, inflammatory cytokines and magnetic resonance spectroscopy (MRS) abnormalities(decreased Glx and increased choline and Myo-inositol) (10). Increased cerebral ammonia causes astrocyte swelling and leads to brain edema (11) Hence, most of the drugs used in the HE treatment primarily target ammonia level reduction in the blood. The therapeutic response and progression of HE in ACLF is yet unclear.