Treatment of Hepatic Encephalopathy

Primary Recommendation: Lactulose

The American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) recommend lactulose as the first-choice treatment for overt hepatic encephalopathy, with a Grade 1+ recommendation, due to its strong evidence base and mortality benefit 1, 2, 3, 4
Lactulose is associated with significantly more frequent resolution of acute or chronic overt hepatic encephalopathy and a reduction in mortality compared to placebo or no intervention, in a meta-analysis of 16 randomized controlled trials 1, 2
Treatment with lactulose reduces the risk of severe adverse effects, including gastrointestinal bleeding, bacterial infections, and hepatorenal syndrome, in patients with hepatic encephalopathy 1, 2
For covert hepatic encephalopathy, lactulose significantly reduces progression to overt hepatic encephalopathy, with a reduction from 28% to 7% (p < 0.01) 1, 2

The AASLD and EASL recommend oral branched-chain amino acids (BCAAs) as an alternative or additional agent to treat patients nonresponsive to conventional therapy, with a Grade I, B, 2 recommendation 3, 4
Oral BCAAs improve manifestations of minimal hepatic encephalopathy, according to an updated meta-analysis of 8 randomized controlled trials 3
IV L-Ornithine L-Aspartate (LOLA) can be used as an alternative or additional agent to treat patients nonresponsive to conventional therapy, with a Grade I, B, 2 recommendation, and has been shown to improve psychometric testing and post-prandial venous ammonia levels in patients with persistent hepatic encephalopathy 3, 4

The AASLD and EASL recommend initiating lactulose 25 mL every 12 hours, titrating to 2-3 soft bowel movements per day, as first-line therapy for hepatic encephalopathy 4
If there is an inadequate response to lactulose alone, rifaximin 550 mg twice daily can be added, but not BCAA or LOLA as first add-on 1, 5, 6
If patients are nonresponsive to lactulose + rifaximin, consider adding oral BCAAs or IV LOLA as adjunctive therapy, as recommended by the AASLD and EASL 3, 4

Simple laxatives alone should not be used, as they lack the prebiotic properties of disaccharides and are ineffective, according to the AASLD and EASL 3, 4
Lactulose overuse should be avoided, as excessive dosing leads to dehydration, hypernatremia, aspiration risk, and paradoxically worsens hepatic encephalopathy, as warned by the AASLD and EASL 4
Precipitating factors, such as infection, GI bleeding, electrolyte disturbances, and constipation, should always be identified and treated first, as nearly 90% of patients can be managed by correcting these factors alone, according to the AASLD and EASL 4, 6