Table 1.

Overlapping and differing characteristics of hepatic encephalopathy in ALF and CLD.

NGVU disturbance	ALF/CLD overlap	ALF/CLD difference
Disturbed energy metabolism	•Reduced cerebral blood flow impairs supply of oxygen and nutrients to the brain44,45 •Increased cerebral lactate marks energy impairment41 •Ammonia inhibits Krebs cycle enzymes28 •Lactate is involved in cerebral oedema41,53	CLD: Deficient ketone body production in the cirrhotic liver, insufficient to compensate for glucose allocation to the immune system[46], [47], [48], [49]; Lactate elevation is inconsistent51,54
Blood-brain barrier disruption	•Increased BBB permeability. Barrier integrity disturbed through tight junction disruption[59], [60], [61],[64], [65], [66] •Altered function of efflux transporters, particularly BCRP69,79,80	ALF: Barrier integrity disruption results in vasogenic brain oedema50,52; MMP9 mediates breakdown of tight junctions63,72,73
		CLD: Evidence regarding BBB permeability, structure and tight junction alterations is inconsistent[67], [68], [69], [70]
Astrocyte swelling	•Cerebral glutamine accumulates secondary to increased ammonia exposure43,51,54,[87], [88], [89] •AQP4 dysregulation renders astrocytes more susceptible to osmotic shifts51,65,[98], [99], [100], [101]	ALF: Cellular swelling results in clinically significant brain oedema50,52; Hyperactivation of the ion channels NKCC1 and SUR1 creates ionic imbalances across the cell membrane and attracts water into the cell[93], [94], [95]
		CLD: Compensatory decrease of myoinositol and other osmolytes51,54,89; Low grade cerebral oedema of unclear clinical significance52
Oxidative stress	•Increased levels of oxidative stress in the brain, secondary to elevated ammonia concentrations[102], [103], [104], [105], [106], [107], [108],[110], [111],115	CLD: Possible disconnect, with only systemic oxidative stress in the absence of cerebral oxidative stress68; Senescence only studied in vitro and in patients with CLD111,113,116
Neuroinflammation	•Microglial activation is an important characteristic of patients with hepatic encephalopathy and animal models103,119,120,[122], [123], [124], [125], [126], [127],[130], [131], [132], [133],144 •Neuroinflammation is correlated with peripheral inflammation rather than elevated ammonia103,128,131,139,142,143 •Peripheral TNF is instrumental in eliciting a neuroinflammatory response129,135,139,142,143	ALF: TGFβ1144 and bile acids124 can contribute to microglial activation in mouse models of ALF
Glymphatic clearance		CLD: Decreased glymphatic clearance leads to neuroinflammation in BDL rats101,122

ALF, acute liver failure; AQP4, aquaporin 4; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; BDL, bile duct ligated; CLD, chronic liver disease; MMP9, matrix metalloproteinase 9; NKCC1, Na-K-2Cl cotransporter 1; SUR1, sulfonylurea receptor-1; TGFβ1, transforming growth factor β1; TNF, tumour necrosis factor