Hepatic encephalopathy in adults: Treatment

INTRODUCTION — 

Hepatic encephalopathy represents a reversible impairment of neuropsychiatric function associated with impaired liver function. Despite the frequency of the condition, we lack a clear understanding of its pathogenesis. However, an increase in ammonia concentration is implicated, as is the impact of increased systemic inflammatory burden.

This topic will review the management of hepatic encephalopathy in patients with cirrhosis. The pathogenesis, clinical manifestations, and diagnosis of hepatic encephalopathy and the approach to patients with hepatic encephalopathy in the setting of acute liver failure are discussed elsewhere. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis" and "Acute liver failure in adults: Management and prognosis", section on 'Hepatic encephalopathy'.)

The management of hepatic encephalopathy has also been addressed by society guidelines, and the discussion that follows is generally consistent with these guidelines [1].

MANAGEMENT OVERVIEW

Overt hepatic encephalopathy — Patients with overt hepatic encephalopathy have clinically apparent impairments in cognitive and neuromuscular function. Treatment includes determining the appropriate setting for care, correcting any predisposing conditions (particularly dehydration or infection), and medications such as lactulose. Restricting dietary protein is not recommended.

The severity of overt hepatic encephalopathy is graded from I to IV based on the clinical manifestations (table 1 and figure 1). (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.):

●Grade I: Changes in behavior, disordered sleep

●Grade II: Lethargy, moderate confusion

●Grade III: Marked confusion (stupor), incoherent speech, sleeping but arousable

●Grade IV: Coma, unresponsive to pain

Management will vary depending on the severity of hepatic encephalopathy. An elevated serum ammonia level in the absence of clinical signs of hepatic encephalopathy is not an indication for treatment. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Ammonia'.)

Patient triage — Patients with mild hepatic encephalopathy (grade I) may be managed as outpatients, provided that caregivers are available to look for signs of worsening hepatic encephalopathy and to bring the patient to the hospital if needed. Whether to admit a patient with grade II encephalopathy to the hospital will depend on the degree of lethargy and confusion. If there is any concern that a patient may not be able to adhere to treatment or if caregivers are not available who can monitor the patient, the patient should be admitted to the hospital. Patients with more severe hepatic encephalopathy (grades III to IV) require hospital admission for treatment, typically to an intensive care unit. In addition, consideration should be given to intubating such patients for airway protection. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Categorization and grading'.)

The decision to hospitalize the patient is also informed by the evaluation and treatment for a precipitating event. (See 'Correction of precipitating causes' below.)

General supportive care — General supportive care for patients with hepatic encephalopathy includes providing appropriate nutritional support, avoiding dehydration and electrolyte abnormalities, and providing a safe environment. Precautions to prevent falls should be instituted for patients who are disoriented. (See "Falls: Prevention in nursing care facilities and the hospital setting".)

Patients hospitalized with hepatic encephalopathy may be agitated. Agitation often resolves with treatment of the hepatic encephalopathy; however, patients may represent a hazard to themselves and their caregivers until treatment takes effect. Management may include judicious use of restraints, which may be a safer option than pharmacologic treatment since patients with decompensated cirrhosis and hepatic encephalopathy may be particularly vulnerable to oversedation with medications. Patients with decompensated cirrhosis may be sensitive to benzodiazepines because of an increased concentration of benzodiazepine receptor ligands in the brain. (See "The acutely agitated or violent adult: Pharmacologic management".)

Nutritional support — Nutritional support should include maintaining an energy intake of 35 to 40 kcal/kg/day, with a protein intake of 1.2 to 1.5 g/kg ideal body weight/day (a convenient calculation is protein intake of 1 g/kg actual body weight/day). Patients with cirrhosis are often malnourished and protein restrictions are associated with increased mortality, so patients with hepatic encephalopathy should generally not have their protein intake restricted [2-4]. Patients with mild to moderate hepatic encephalopathy can typically take nutrition orally. Patients with severe hepatic encephalopathy usually do not receive oral nutrition. As soon as they improve, a standard diet can be given. Patients should be instructed to eat small meals throughout the day with a late-night snack of complex carbohydrates because fasting results in the production of glucose from amino acids, with resultant ammonia production [5]. (See "Nutritional issues in adult patients with cirrhosis".)

Acute therapy — The initial management of acute hepatic encephalopathy in patients with cirrhosis involves the following:

●Identification and correction of precipitating causes

●Pharmacologic therapy (eg, lactulose)

Correction of precipitating causes — The first step in the treatment of hepatic encephalopathy is the identification and correction of precipitating causes. Treatment of precipitating causes combined with pharmacologic therapy is typically associated with prompt improvement in mental status and hepatic encephalopathy. (See 'Pharmacologic therapy' below.)

Careful evaluation should be performed to determine if any of the following are present (table 2) (see "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Evaluation for precipitating causes'):

●Gastrointestinal bleeding

●Infection (including spontaneous bacterial peritonitis and urinary tract infections)

●Hypokalemia and/or metabolic alkalosis

●Kidney failure

●Hypovolemia

●Hypoxia

●Sedative or benzodiazepine use

●Hypoglycemia

●Constipation

●Rarely, hepatocellular carcinoma and/or vascular occlusion (hepatic vein or portal vein thrombosis)

When possible, these precipitating causes should be treated.

Correction of hypokalemia is also an essential component of therapy since hypokalemia increases kidney ammonia production. However, dietary protein restriction is generally not recommended. (See 'Nutritional support' above.)

Pharmacologic therapy — Drug therapy is the mainstay of treatment to lower the blood ammonia concentration (algorithm 1):

●We suggest initiating drug therapy for acute hepatic encephalopathy with a nonabsorbable disaccharide (lactulose or lactitol). Lactulose and lactitol act through a variety of mechanisms that lead to decreased absorption of ammonia from the gastrointestinal tract. The typical dose of oral lactulose is 30 to 45 mL (20 to 30 grams), two to four times per day. The goal is to achieve two to three soft stools per day without diarrhea (which can worsen hepatic encephalopathy). An equivalent dose of lactitol is approximately 30 to 60 grams (powder), diluted according to the label (eg, in 100 mL of water), given orally in two to four divided doses per day. Lactulose enemas can be given if the patient cannot take a nonabsorbable disaccharide orally. We do not administer therapy by nasogastric tube because of the risk of aspiration. (See 'Lactulose and lactitol' below.)

●For patients without improvement in mental status within 48 hours or who cannot take lactulose or lactitol, we typically add rifaximin with a dosing regimen of 550 mg, orally, two times daily. The effectiveness of rifaximin in reducing recovery time from overt hepatic encephalopathy has not been demonstrated in randomized trials. In contrast, rifaximin reduced the risk of recurrent, overt hepatic encephalopathy. We typically add rifaximin after the acute event resolves, especially for patients with a history of recurrent hepatic encephalopathy on lactulose monotherapy. The safety and tolerability of rifaximin has been demonstrated for up to 24 months [6]. (See 'Oral antibiotics' below.)

In general, antibiotics are added to, rather than substituted for, lactulose or lactitol. (See 'Oral antibiotics' below.)

Neomycin was proposed as a second-line therapy in patients who have not responded to disaccharides, but it has not been shown to be effective in randomized trials and can be associated with ototoxicity and kidney toxicity. Other antibiotics that have been studied include vancomycin and metronidazole, but their efficacy is also limited.

Polyethylene glycol has also been studied for treating overt hepatic encephalopathy, and this is discussed below. (See 'Other therapies' below.)

Chronic therapy — In patients with recurrent encephalopathy, we suggest continual administration of lactulose or lactitol. The dose of lactulose (30 to 45 mL [20 to 30 grams] orally two to four times per day) or lactitol (30 to 60 grams [powder] diluted according to the label [eg, in 100 mL water], given orally in two to four divided doses per day) should be titrated to achieve two to three soft stools per day. If hepatic encephalopathy recurs despite lactulose or lactitol, rifaximin can be added to the regimen. (See 'Lactulose and lactitol' below and 'Oral antibiotics' below.)

As with the acute treatment of hepatic encephalopathy, patients receiving chronic therapy should generally not have their protein intake restricted. (See 'Nutritional support' above.)

If the precipitating factors that were responsible for the recurrent hepatic encephalopathy are controlled, prophylactic therapy may be discontinued. It should only be given if necessary.

Adherence to the lactulose regimen is typically very low. In our experience, many patients do not adhere to therapy without support from a caregiver. Hepatic encephalopathy related to medication nonadherence is a common indication for hospitalization among patients with cirrhosis [7]. Many clinicians advise their patients to mix lactulose in other beverages to reduce the sweetness or replace some doses with polyethylene glycol, however neither strategy has been evaluated in randomized trials.

Patients with covert hepatic encephalopathy — Compared with patients who have cirrhosis but do not have covert hepatic encephalopathy, patients with covert hepatic encephalopathy appear to be at increased risk for developing overt hepatic encephalopathy, requiring hospitalization, requiring liver transplantation, or dying [8]. However, data are limited on the value of treatment in these patients [9].

●Indications for drug therapy – Patients with covert hepatic encephalopathy may benefit from treatment with lactulose or rifaximin, but the decision to treat should be individualized based on the results of psychometric testing and the degree to which the encephalopathy has an impact on quality of life [10]. We typically reserve treatment with lactulose or lactitol for patients with covert hepatic encephalopathy who have impaired quality of life attributable to the hepatic encephalopathy.

An elevated serum ammonia level in the absence of clinical signs of hepatic encephalopathy is not an indication for treatment. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

●Nutritional support – Patients with covert hepatic encephalopathy are advised to use oral nutritional therapy. Some studies have suggested that nutritional therapy resulted in higher rates of reversing covert hepatic encephalopathy compared with no dietary intervention [2,11]. The risk of developing overt hepatic encephalopathy may be lower with oral nutritional therapy. (See 'Nutritional support' above.)  

SPECIFIC TREATMENTS — 

Commonly used treatments for hepatic encephalopathy aim to reduce ammonia production and absorption. This is accomplished by correcting hypokalemia and giving synthetic disaccharides (such as lactulose) and/or antibiotics.

The gastrointestinal tract is the primary source of ammonia, which enters the circulation via the portal vein. Ammonia is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested protein and secreted urea. A healthy liver clears almost all the portal vein ammonia, converting it into glutamine and preventing its entry into the systemic circulation. Elevations of ammonia may often be detected patients with hepatic encephalopathy, and therapy aimed at reducing the circulating ammonia level usually results in improvement in mental status and resolution of encephalopathy. However, an elevated serum ammonia level in the absence of clinical signs of hepatic encephalopathy is not an indication for treatment. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Ammonia'.)

Correct hypokalemia — Correction of hypokalemia, if present, is an essential component of therapy for hepatic encephalopathy since hypokalemia increases renal ammonia production. The often concurrent metabolic alkalosis may contribute to hepatic encephalopathy by promoting ammonia entry into the brain by favoring the conversion of ammonium (NH₄+), which is a charged particle that cannot cross the blood-brain barrier, into ammonia (NH₃), a neutral particle that can [12]. (See "Hypokalemia-induced kidney dysfunction", section on 'Increased ammonia production'.)

Lactulose and lactitol — Lactulose and lactitol are synthetic disaccharides that are a mainstay of therapy of overt hepatic encephalopathy, albeit there is limited evidence from well-designed randomized trials showing their efficacy. The available data suggest that approximately 70 to 80 percent of patients with hepatic encephalopathy improve on lactulose treatment [13-15]. Lactulose is widely available, but lactitol is not available in some countries, including the United States.

The dose of medication should be titrated to achieve two to three soft stools per day. (See 'Acute therapy' above and 'Chronic therapy' above.)

Treatment is usually well tolerated, and the principal side effects include abdominal cramping, diarrhea, and flatulence. Lactulose and lactitol may also be given as enemas in patients who are unable to take them orally (refer to the drug database included within UpToDate for disaccharide enema dosing and administration).

Mechanism of action — Treatment with lactulose or lactitol is based on the absence of a specific disaccharidase on the microvillus membrane of enterocytes in the human small bowel, thereby permitting entry of the disaccharides into the colon. In the colon, lactulose (beta-galactosidofructose) and lactitol (beta-galactosidosorbitol) are catabolized by the bacterial flora, resulting in an acidic pH. The reduction in pH favors the formation of the nonabsorbable NH₄+ from NH₃, trapping NH₄+ in the colon and thus reducing plasma ammonia concentrations.

Other effects that may contribute to the clinical effectiveness of lactulose and lactitol include [13]:

●Increased incorporation of ammonia by bacteria for synthesis of nitrogenous compounds.

●Modification of colonic flora, resulting in displacement of urease-producing bacteria with non-urease-producing Lactobacillus [16].

●Cathartic effects of a hyperosmolar load in the colon that improves gastrointestinal transit, allowing less time for ammonia absorption.

●Increased fecal nitrogen excretion (up to fourfold) due to the increase in stool volume [17].

●Reduced formation of potentially toxic short-chain fatty acids (eg, propionate, butyrate, valerate) [18].

Efficacy — A systematic review found that the use of lactulose or lactitol was more effective than placebo in improving hepatic encephalopathy (relative risk of no improvement 0.6, 95% CI 0.5-0.8) but did not improve survival [19]. However, the benefit on encephalopathy no longer reached statistical significance when the analysis was confined to studies with the highest methodologic quality. The authors also found that antibiotics appeared to be more effective than lactulose or lactitol. (See 'Oral antibiotics' below.)

At least two meta-analyses suggest that lactitol is at least as effective as lactulose, is more palatable, and may have fewer side effects [20-22]. In patients with lactase deficiency, non-digested lactose has most of the same effects as the synthetic disaccharides and is much less expensive [23].

Lactulose has also been studied for the prevention of recurrent hepatic encephalopathy. In a randomized trial with 140 patients who had recovered from hepatic encephalopathy, patients assigned to lactulose (30 to 60 mL in two to three divided doses so that patients passed two to three soft stools per day) had fewer episodes of recurrent overt hepatic encephalopathy than patients who received placebo during 14 months of follow-up (20 versus 47 percent) [24]. However, there were no significant differences in deaths or rates of readmission for causes other than hepatic encephalopathy.

Disaccharide enemas are also effective for removing ammoniagenic substrates from the colon. A randomized trial that included 20 patients with hepatic encephalopathy suggested that 1 to 3 L of a 20 percent lactose or lactitol solution given as an enema was more effective than tap water enemas [25]. A possible explanation for this finding is that colonic acidification rather than bowel cleansing was the therapeutic mechanism.

It is unclear whether the route of administration of nonabsorbable disaccharides affects their efficacy. However, the convenience of oral administration generally makes it the preferred route.

Most trials of disaccharides included patients with overt hepatic encephalopathy. However, the use of nonabsorbable disaccharides may also benefit patients with covert hepatic encephalopathy [9,26]. One trial that showed this included 61 patients with covert hepatic encephalopathy [27]. Treatment with lactulose was associated with improvement in health-related quality of life and cognitive function. However, other trials have failed to show a benefit of treating patients with covert hepatic encephalopathy. As a result, whether treatment should be routine in patients with covert hepatic encephalopathy is unclear. (See 'Patients with covert hepatic encephalopathy' above.)

Oral antibiotics — Nonabsorbable antibiotics are also effective for treating acute or preventing recurrent hepatic encephalopathy. Rifaximin is used most often. (See 'Overt hepatic encephalopathy' above.)

For treating acute hepatic encephalopathy or to prevent recurrent episodes, antibiotics are typically added to (rather than substituted for) lactulose or lactitol. However, all antibiotics cause alterations in gut flora and some are substantially more costly than nonabsorbable disaccharides. As a result, they may be best suited for patients who cannot tolerate or do not respond sufficiently to disaccharides.

A meta-analysis of 13 randomized trials of rifaximin found that it had similar efficacy to nonabsorbable disaccharides for treating hepatic encephalopathy [28]. In one trial with six months of follow-up, rifaximin was more effective than a placebo in preventing recurrent episodes of hepatic encephalopathy in patients with cirrhosis who had a documented history of recurrent hepatic encephalopathy and were in remission at the start of the trial [29]. Eighty-two patients in the placebo group of the phase 3 trial joined a 24-month open-label maintenance (OLM) study [30]. Thirty-nine of the patients (48 percent) had experienced an episode of hepatic encephalopathy during the original trial compared with 14 patients (17 percent) during the OLM study. Other randomized trials found that rifaximin improved quality of life [31,32] and improved performance on a simulated driving test in patients with covert hepatic encephalopathy [33].

Another randomized trial compared the combination of rifaximin and lactulose with lactulose alone in 120 patients hospitalized with overt hepatic encephalopathy [34]. Patients were followed until they were discharged from the hospital or died. Patients who received rifaximin and lactulose were more likely than those who received lactulose alone to have complete resolution of hepatic encephalopathy (76 versus 44 percent) and lower mortality (24 versus 49 percent). A meta-analysis of 19 trials showed that rifaximin has a beneficial effect on hepatic encephalopathy and may reduce mortality [35].

Rifaximin plays a role in gut barrier repair, and this function may ameliorate bacterial translocation and systemic endotoxemia in patients with cirrhosis [36].

Neomycin had been used to treat hepatic encephalopathy but studies reached variable conclusions regarding its efficacy, and there is concern over its association with ototoxicity and kidney toxicity if used long-term. An early study found neomycin to be as effective as lactulose in 33 patients [14], and a subsequent randomized trial that compared neomycin with rifaximin in 49 patients with cirrhosis found that both treatments were similarly effective at reducing the neuropsychiatric signs of hepatic encephalopathy and blood ammonia levels [37]. On the other hand, a randomized trial of 39 patients comparing neomycin at a dose of 6 grams per day with placebo reported no difference in outcomes between the two treatment groups [38].

Other antibiotics, such as metronidazole and oral vancomycin, were effective for treating hepatic encephalopathy in limited clinical trials and are not associated with the same toxicities as neomycin [39,40]. However, metronidazole is associated with neurotoxicity and there are concerns about bacterial resistance in patients receiving vancomycin. As a result, neither is used commonly.

L-ornithine-L-aspartate — Oral L-ornithine-L-aspartate (LOLA) is frequently given to patients with hepatic encephalopathy outside of the United States [41]. Treatment with LOLA has shown benefit compared with placebo, although trials comparing LOLA with standard therapy (ie, lactulose or lactitol) are needed [41-44]. LOLA improves health-related quality and is well tolerated [45].

In a meta-analysis of four trials, patients with overt hepatic encephalopathy who received LOLA were more likely to improve clinically compared with those receiving placebo (OR 3.71, 95% CI 1.98-6.98) [43].

In trial of 40 patients who underwent transjugular intrahepatic portosystemic shunt placement, prophylactic use of LOLA infusion was safe and effective in reducing post-prandial increases in venous ammonia concentration [46]. (See "Transjugular intrahepatic portosystemic shunts: Postprocedure care and complications", section on 'Issues related to portosystemic shunting'.)

LOLA does not appear to be effective for patients with hepatic encephalopathy in the setting of acute liver failure [47]. (See "Acute liver failure in adults: Management and prognosis", section on 'Hepatic encephalopathy'.)

LOLA lowers plasma ammonia concentrations by enhancing the metabolism of ammonia to glutamine. Ammonia is removed from the body by formation of urea in periportal hepatocytes and/or by synthesis of glutamine from glutamate in perivenous hepatocytes. In patients with cirrhosis, the activities of carbamyl phosphate synthetase and of glutamine synthetase (the key enzymes for urea and glutamine synthesis) are impaired and the glutaminase flux is increased in a compensatory fashion, resulting in hyperammonemia. Ornithine serves both as an activator of carbamyl phosphate synthetase and ornithine-carbamyl transferase in periportal hepatocytes and as a substrate for ureagenesis. Ornithine (via alpha-ketoglutarate) and aspartate increase ammonia removal by these cells via stimulation of glutamine synthesis.

Other therapies — Other therapies that have been studied for treating hepatic encephalopathy include:

●Branched-chain amino acids — Increases in the ratio of plasma aromatic amino acids (AAA) to branched-chain amino acids (BCAA) because of liver disease could contribute to encephalopathy. The altered ratio could then increase brain levels of AAA precursors for monoamine neurotransmitters and contribute to altered neuronal excitability. As a result, several studies have evaluated the effects of the provision of BCAA. The efficacy of BCAA was examined in a meta-analysis of 16 trials with 827 participants with hepatic encephalopathy [48]. Patients in the control groups received placebo/no intervention (2 trials), dietary interventions (10 trials), lactulose (2 trials), or neomycin (2 trials). Treatment with BCAA did not result in a benefit with regard to mortality (relative risk [RR] 0.8, 95% CI 0.7-1.1), but it did have a beneficial effect on hepatic encephalopathy (defined as improvement in the manifestations of hepatic encephalopathy; RR 0.7, 95% CI 0.6-0.9).

Dietary BCAA supplementation may have a role in treating selected patients (eg, those who are severely protein-intolerant). As an example, a randomized trial with 64 patients found that a low-protein diet supplemented with oral BCAA was more likely to improve mental performance at three months than supplementation with casein (80 versus 35 percent) [49]. In addition, some patients who did not improve on casein rapidly improved when switched to BCAA. Another trial evaluated 37 hospitalized patients with cirrhosis who were protein-intolerant [50]. The addition of BCAA to the diet enabled the daily protein intake to be increased up to 80 grams without worsening cerebral function; by comparison, many control patients (receiving casein as a protein source) deteriorated after increasing dietary protein intake. No benefit of BCAA supplementation was observed in protein-tolerant patients. A subsequent randomized trial of 116 patients who had a prior episode of hepatic encephalopathy found no benefit of BCAA on recurrent encephalopathy, although supplementation appeared to improve covert hepatic encephalopathy and muscle mass [51]. (See 'Nutritional support' above.)

●Polyethylene glycol — Polyethylene glycol (PEG) solution is a cathartic that may help treat hepatic encephalopathy by increasing excretion of ammonia in the stool. PEG was compared with lactulose in a trial that included patients with cirrhosis who were admitted to the hospital with hepatic encephalopathy [52]. Patients were randomly assigned to receive four liters of PEG over four hours or lactulose (three or more doses of 20 to 30 grams over 24 hours). After 24 hours, patients who received PEG had more improvement in the hepatic encephalopathy scoring algorithm (HESA) score compared with those who received lactulose (from a mean of 2.3 to 0.9 compared with 2.3 to 1.6). In addition, the median time to resolution of the hepatic encephalopathy was shorter with PEG (one versus two days).

PROGNOSIS AFTER RECOVERY — 

Patients with overt hepatic encephalopathy may have persistent and cumulative neurologic deficits despite an apparent normalization of mental status after treatment [53,54]. In a study that summarized the results of two cohorts of patients with cirrhosis, overt hepatic encephalopathy was associated with persistent deficits in working memory, response inhibition, and learning when assessed by psychometric testing [53]. The number of episodes of overt hepatic encephalopathy correlated with the severity of residual impairment.

CAPACITY TO DRIVE — 

Issues related to driving in patients with hepatic encephalopathy are discussed separately. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Capacity to drive'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cirrhosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Hepatic encephalopathy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overt hepatic encephalopathy

•General principles – Patients with overt hepatic encephalopathy have clinically apparent impairments in cognitive and neuromuscular function. Treatment includes determining the appropriate setting for care, correcting any precipitating conditions (table 2), and lowering ammonia production and absorption with medications such as lactulose (algorithm 1). We do not restrict dietary protein for most patients. (See 'Overt hepatic encephalopathy' above.)

Patients with mild hepatic encephalopathy (grade I) may be managed as outpatients, provided caregivers are available to look for signs of worsening hepatic encephalopathy and to bring the patient to the hospital if needed. Whether to admit a patient with grade II encephalopathy to the hospital will depend on the degree of lethargy and confusion. If there is any concern that a patient may not be able to adhere to treatment or if caregivers are not available who can monitor the patient, the patient should be admitted to the hospital for care. Patients with more severe hepatic encephalopathy (grades III to IV) require hospital admission for treatment. (See 'Patient triage' above and "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Categorization and grading'.)

•Supportive measures – General supportive care for patients with hepatic encephalopathy includes avoiding dehydration and electrolyte abnormalities, providing nutritional support, and providing a safe environment. Patients should not have their protein intake restricted unless they are severely protein-intolerant. Patients should be instructed to eat small meals throughout the day with a late-night snack of complex carbohydrates. Precautions to prevent falls should be instituted for patients who are disoriented. (See 'General supportive care' above and 'Nutritional support' above.)

•Drug therapy – For patients with acute, overt hepatic encephalopathy, we suggest initial treatment with lactulose or lactitol (where available) rather than a nonabsorbable antibiotic (Grade 2B). This recommendation is based primarily on cost; for patients for whom cost is not an important consideration, initial treatment with rifaximin is a reasonable alternative. The typical dose of lactulose (30 to 45 mL [20 to 30 grams] orally two to four times per day) should be titrated to achieve two to three soft stools per day. An equivalent dose of lactitol is approximately 30 to 60 grams (powder), diluted according to the label (eg, in 100 mL of water), given orally in two to four divided doses per day. Lactulose or lactitol enemas can be given if the patient cannot take a nonabsorbable disaccharide orally. (See 'Lactulose and lactitol' above and 'Oral antibiotics' above.)

For patients who have not improved within 48 hours of starting lactulose or lactitol or who cannot take lactulose or lactitol, we suggest rifaximin rather than an alternative nonabsorbable oral antibiotic (Grade 2C). The dose of rifaximin is 550 mg orally two times daily. As a general rule, antibiotics are added to, rather than substituted for, lactulose or lactitol. (See 'Oral antibiotics' above.)

In patients with recurrent encephalopathy, we suggest daily administration of lactulose or lactitol rather than waiting for episodes of overt hepatic encephalopathy to develop to initiate treatment (Grade 2B). Rifaximin can be added to lactulose or lactitol if needed. Polyethylene glycol (PEG) solution is an alternative to using lactulose for patients who do not tolerate or will not use lactulose. (See 'Chronic therapy' above.)

●Covert hepatic encephalopathy

•Patients with covert hepatic encephalopathy have signs and symptoms that are not clinically apparent but can be detected with psychometric testing. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

•Whether to treat patients with covert hepatic encephalopathy is unclear. For patients with covert hepatic encephalopathy that is impacting quality of life, we suggest treating with lactulose or lactitol rather than not treating (Grade 2C). We do not use pharmacologic treatment for patients with covert hepatic encephalopathy who do not have impaired quality of life attributable to the minimal hepatic encephalopathy or driving impairment. (See 'Patients with covert hepatic encephalopathy' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter Ferenci, MD, who contributed to earlier versions of this topic review.