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Hepatic encephalopathy in adults: Treatment

AUTHORS: Lorenzo Ridola, MD, PhD, Oliviero Riggio, MD
SECTION EDITOR: Elliot Tapper, MD
DEPUTY EDITOR: Kristen M Robson, MD, MBA, FACG

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2024.

This topic last updated: Sep 19, 2024.

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 5th to 6th grade reading
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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 10th to 12th 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.

Use of UpToDate is subject to the Terms of Use.

REFERENCES

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6. Mullen KD, Sanyal AJ, Bass NM, et al. Rifaximin is safe and well tolerated for long-term
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Topic 1255 Version 65.0
GRAPHICS

West Haven criteria for hepatic encephalopathy

WHC
Suggested
including ISHEN Description Comment
operative criteria
MHE

Unimpaired No encephalopathy at Tested and proved to be

all, no history of HE normal

Minimal Psychometric or Abnormal results of No universal criteria for

neuropsychological established diagnosis
alterations of tests psychometric or
Local standards and
exploring neuropsychological tests
expertise required
psychomotor without clinical
speed/executive manifestations
functions or
neurophysiological
alterations without
clinical evidence of
Covert mental change

Grade I Trivial lack of Despite oriented in time Clinical findings usually

awareness and space (see below), not reproducible
Euphoria or anxiety the patient appears to
have some
Shortened attention
cognitive/behavioral
span
decay with respect to his
Impairment of
or her standard on
addition or
clinical examination or to
subtraction
the caregivers
Altered sleep rhythm

Grade II Overt Lethargy or apathy Disoriented for time (at Clinical findings
Disorientation for least three of the variable, but
time following are wrong: day reproducible to some
of the month, day of the extent
Obvious personality
week, month, season, or
change
year) ± the other
Inappropriate
mentioned symptoms
behavior
Dyspraxia
Asterixis

Grade III Somnolence to Disoriented also for Clinical findings

semistupor space (at least three of reproducible to some
 Responsive to stimuli the following wrongly extent
Confused reported: country, state
Gross disorientation [or region], city, or place)
± the other mentioned
Bizarre behavior
symptoms

Grade IV Coma Does not respond even Comatose state usually

to painful stimuli reproducible

All conditions are required to be related to liver insufficiency and/or portosystemic shunting.

WHC: West Haven criteria; MHE: minimal hepatic encephalopathy; ISHEN: International Society for
Hepatic Encephalopathy and Nitrogen Metabolism; HE: hepatic encephalopathy.

From: Vilstrup H, Amodio P, Bajaj J, et al. Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the
American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 2014;
60:715. http://onlinelibrary.wiley.com/doi/10.1002/hep.27210/abstract. Copyright © 2014 American Association for the Study of
Liver Diseases. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley.
Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's
permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request
Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com).

Graphic 101898 Version 1.0

Clinical features of hepatic encephalopathy in adults

Diagram depicting the grade of hepatic encephalopathy in adults and the clinical features associated
with advancing stages.

Data from: Conn HO, Lieberthal MM. The hepatic coma syndromes and lactulose. Lippincott Williams & Wilkins, Baltimore 1979.

Graphic 70740 Version 6.0

Precipitants of hepatic encephalopathy in patients with cirrhosis

Drugs
Benzodiazepines

Nonbenzodiazepine hypnotics (eg, zolpidem)

Narcotics

Alcohol

Increased ammonia production, absorption or entry into the brain

Excess dietary intake of protein

Gastrointestinal bleeding

Infection

Electrolyte disturbances such as hypokalemia

Constipation

Metabolic alkalosis

Dehydration
Vomiting

Diarrhea

Hemorrhage

Diuretics

Large volume paracentesis

Portosystemic shunting
Radiographic or surgically placed shunts

Spontaneous shunts

Vascular occlusion
Hepatic vein thrombosis

Portal vein thrombosis

Primary hepatocellular carcinoma

Graphic 50440 Version 4.0

Inpatient management for adult patients with acute hepatic encephalopathy

Refer to UpToDate content on the management of hepatic encephalopathy for additional details.

* For patients who are being treated with systemic antibiotics, rifaximin is not added to the treatment
regimen.

¶ At the time of discharge, patients and their caregivers are provided with written instructions for dosing
and administration of drug therapy.

Graphic 131713 Version 3.0

Contributor Disclosures
Lorenzo Ridola, MD, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Oliviero Riggio, MD Consultant/Advisory Boards: Alfasigma [Complication of cirrhosis].
Speaker's Bureau: Alfasigma [Complication of cirrhosis]. All of the relevant financial relationships listed
have been mitigated. Elliot Tapper, MD Grant/Research/Clinical Trial Support: Madrigal [Non-alcoholic
steatohepatitis]; Salix [Hepatic encephalopathy]. Consultant/Advisory Boards: Iota [Liver failure / pre-
clinical device development]; Satellite Bio [Liver failure / pre-clinical device development]; Takeda [Non-
alcoholic steatohepatitis]. All of the relevant financial relationships listed have been mitigated. Kristen M
Robson, MD, MBA, FACG No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy