Precipitating factors can be identified in nearly all bouts of episodic hepatic encephalopathy and should be actively sought and treated when found. Septic screening (including diagnostic paracentesis in patients with ascites), renal function, electrolyte and metabolic panel (including glucose and thyroid function), psychoactive drugs and toxicology screening, and exclusion of gastrointestinal hemorrhage should be performed. Plasma ammonia should be measured, as a normal value brings the diagnosis of hepatic encephalopathy into question. Other diagnostic work-up should be performed depending on clinical suspicion: brain imaging to exclude cerebral lesion and hemorrhage, or if there is no response to treatment, lumbar puncture to rule out meningitis/encephalitis, and an electroencephalogram to exclude non-convulsive seizures.

Non-adherence to laxative therapies can be a contributing factor to treatment failure. This may often result from excessive laxative effects, sweet taste and gastrointestinal intolerance (nausea, bloating, and/or flatulence). Therefore, patients and their carers should be given clear advice on how to titrate the lactulose dose to maximize efficacy and reduce side-effects. If individuals are intolerant of lactulose, they should add or switch to rifaximin. Education of patients and of their relatives or carers is paramount to reducing recurrence and hospital admissions. Key education points include the effects of medication and potential side-effects, the importance of adherence, and early signs of recurrence and appropriate actions.

Despite the well-known relationship between malnutrition/sarcopenia and hepatic encephalopathy, clinicians often forget the importance of nutritional intervention in the management of this complication. Patients should be given a hypercaloric and hyperproteic diet, a late evening snack and an effort should be made to avoid prolonged fasting periods and dietary restrictions. They should also be offered daily multivitamin and protein energy supplementation. In hospitalized patients, clinicians should try to minimize fasting periods for procedures/exams and start parenteral fluids with 5% dextrose during those occasions. If the patients caloric needs are not achieved by oral route, enteral or parenteral nutrition should be started. It is also important to that emphasize that protein restriction in patients with hepatic encephalopathy is not recommended.

Large portosystemic shunts (mainly splenorenal shunts) are found upon radiological screening in nearly half of patients with refractory encephalopathy – frequently patients with a fairly preserved liver function or in whom an encephalopathy-precipitating factor cannot be found. Obliteration of accessible portosystemic shunts in patients with cirrhosis with recurrent or persistent encephalopathy (despite adequate medical treatment) can be considered in stable patients with a MELD score <11 as it has shown to safely improve encephalopathy, survival and liver function in selected patients.