Approach

The primary objectives of treatment are to:[1][2][19]

  • Provide supportive care

  • Exclude other causes of altered mental status

  • Identify and correct precipitating factors

  • Reduce the nitrogenous load from the gut

  • Assess the need for long-term therapy.

Supportive care

This involves frequently monitoring the patient's neurologic and mental status. Comatose patients should be admitted to intensive care and their airway protected to avoid aspiration. Intracranial pressure monitoring may be needed for patients with significant intracerebral edema.

Excluding other causes of altered mental status

Patients with cirrhosis are also prone to altered mental status due to other causes, including medications (e.g., opioids, benzodiazepines, and proton-pump inhibitors), infections, altered electrolytes, alcohol, illicit drugs, and strokes. It is important to exclude these alternative or synergistic causes before assuming that all mental statue alteration in patients with cirrhosis is HE.[19]

Identifying and correcting precipitating factors

Precipitating factors should be actively sought and treated.[2][19] Nearly all cases of episodic HE are precipitated, and up to 90% of patients can be expected to recover from episodic overt HE by correction of one or more precipitating factors.[1][2]

Precipitating factors include hypovolemia, gastrointestinal bleeding, infections, electrolyte disturbances (hypokalemia, hyponatremia) and renal failure, sedative or opioid ingestion, diuretic overdose, hypoxia, hypoglycemia, excessive dietary protein intake, constipation, acute hepatic or portal vein thrombosis, and recent placement of a transjugular intrahepatic portosystemic shunt (TIPS).[1][16][17][18][19] Occasionally TIPS must be occluded if the condition cannot otherwise be managed.

Rapid resolution of constipation and rapid removal of blood from the gastrointestinal tract in the setting of a gastrointestinal bleed has been shown to improve recovery from an episode of HE.[2] Demonstrated or suspected vitamin or micronutrient deficiencies should be treated as they can compound HE. Patients with cirrhosis of any etiology are prone to deficiencies in water-soluble vitamins, especially thiamine.[2]

Reducing nitrogenous load

Diet

Decreasing the patient's protein intake has been hypothesized to reduce intestinal ammonia production, but it may also worsen pre-existing protein-caloric malnutrition in patients with cirrhosis. One randomized controlled trial (RCT) found no difference between moderate and aggressive protein restriction; another RCT found no increased risk of HE with a normal-protein diet, compared with a low-protein diet.[27][28]

Patients may require a short-term protein-restricted diet after HE is diagnosed but should not continue protein restriction indefinitely, because malnutrition and sarcopenia are risk factors for HE. The recommended daily protein intake is 1.2 to 1.5 g/kg/day.[1] There is no advantage to parenteral nutrition in patients with cirrhosis.

In patients with recurrent/persistent HE, replacement of animal protein with vegetable and dairy protein can be considered, provided that the overall protein intake is not compromised. There is little evidence to support this, however, and it should be performed by expert centers under close dietary monitoring (to avoid inducing weight loss and sarcopenia) and confined to patients in whom standard treatment has failed and who seem truly intolerant of animal protein.[2]

Nonabsorbable disaccharides

The nitrogenous load from the gut can be reduced by treatment with either nonabsorbable disaccharides (e.g., lactulose) or antibiotics. Colonic cleansing also helps to reduce gut ammonia and, subsequently, blood ammonia levels.

Although the mainstay of therapy, the exact mechanism of action of nonabsorbable disaccharides, such as lactulose (a laxative), is not clear. Lactulose is degraded by intestinal bacteria into lactic acid and other organic acids. Acidification of the gut lumen favors the conversion of ammonium ions to ammonia, aiding passage of ammonia from tissues to lumen. Acidification also inhibits ammonia-producing coliform bacteria. Side effects such as diarrhea, abdominal discomfort, and flatulence limit compliance.

Meta-analysis suggests a beneficial effect of nonabsorbable disaccharides on mortality compared with placebo or no intervention.[29] [ Cochrane Clinical Answers logo ] [Evidence B]​​ Lactulose is recommended first line for the management of episodic overt HE.[1][2]

Antibiotics

Rifaximin has a broad spectrum of antimicrobial activity, including gram-positive, gram-negative, and anaerobic enteric bacteria.[30] Very little is absorbed systemically following oral administration; most of the dose remains in the gastrointestinal tract. In HE, antibiotics are thought to reduce production of ammonia and other neurotoxins in the gastrointestinal tract.

Rifaximin should be considered in patients with persistent symptoms despite treatment with lactulose or those who cannot tolerate lactulose.[31] It is recommended as add-on therapy for episodic overt HE to prevent recurrences.[1] Rifaximin is typically added to, rather than substituted for, lactulose.

One systematic review and meta-analysis reported that rifaximin has a beneficial effect on mortality and full recovery from HE compared with placebo, nonabsorbable disaccharides, or other antibiotics.[32] Another meta-analysis found that the addition of rifaximin to lactulose decreases mortality and improves clinical efficacy compared with lactulose alone.[33]

Rifaximin is usually better tolerated than lactulose. In one retrospective study of 145 patients treated for HE, only 31% of patients reported taking more than 75% of their prescribed doses of lactulose, whereas 92% of patients reported taking more than 75% of their prescribed doses of rifaximin.[34]

Trials comparing rifaximin with neomycin reported that asterixis and ammonia levels improved more quickly with rifaximin. Both groups showed similar improvement in mental status.[30]

Long-term therapy

Care should be taken to help patients with chronic liver disease avoid recurrent events. Measures include:

  • Avoiding psychoactive medications where possible

  • Prophylaxis of spontaneous bacterial peritonitis if indicated

  • Avoiding constipation

  • Prophylaxis against gastrointestinal bleeding

  • Undertaking measures to control progression of the underlying liver disease.

Lactulose is recommended as secondary prophylaxis following a first episode of overt HE.[1][2][5]

Rifaximin effectively prevents recurrence of HE and is a recommended add-on therapy to lactulose for secondary prophylaxis following ≥1 episode of overt HE within 6 months of the first one.[2] In one RCT, a 6-month course of rifaximin decreased the risk of relapse and hospitalization due to HE in patients with recurrent HE.[35] One systematic review and meta-analysis found that rifaximin had a beneficial effect on secondary prevention of HE, full recovery from HE, and mortality.[32] Rifaximin can also be considered for prophylaxis of HE prior to non-urgent transjugular intrahepatic portosystemic shunt (TIPS) placement. TIPS is a treatment for portal hypertension-related complications but one of the drawbacks is the increased risk of HE, with 35% to 50% of patients experiencing an episode of overt HE after TIPS.[2]

There is no strong evidence to guide the decision as to if, or when, prophylactic treatment for HE should be discontinued. Guidelines recommend that if liver and nutritional status have improved, and precipitating factors have been controlled, discontinuation of HE treatment can be considered on an individual basis.[2]

Management of non-HE decompensations and attempts to prevent liver disease progression, such as cessation of alcohol misuse in patients with alcohol-related cirrhosis, is recommended, with the aim of improving prognosis. In patients presenting with gastrointestinal bleeding, rapid removal of blood from the gastrointestinal tract (using lactulose or mannitol by nasogastric tube or lactulose enemas) has been shown to prevent HE in the acute setting.[2]

Liver transplant

Appropriate candidates should be referred to liver transplant centers for evaluation after a first episode of HE, and those with end-stage liver disease and recurrent or persistent HE not responding to other treatments should be considered for transplantation.[2] The most commonly used prognostic model for estimating disease severity and listing for transplant is the Model for End-stage Liver Disease (MELD) score. A score of >15 is an appropriate indicator for referral for transplant evaluation.[36][37] The Child-Pugh score can also be used.[2] [ Child Pugh classification for severity of liver disease Opens in new window ]

Evaluation for portosystemic shunts that could be embolized

Obliteration of accessible portosystemic shunts in patients with cirrhosis with recurrent or persistent HE (despite adequate medical treatment) can be considered in stable patients with a low MELD score (<11) and no obvious contraindications.[2]

Up to one third of patients with cirrhosis have portosystemic shunts on imaging. Large spontaneous shunts may contribute to recurrent or persistent HE. Almost 50% of these are splenorenal shunts.[2]

Only two small retrospective cohort studies including a total of 58 patients have examined the utility of shunt obliteration by embolization.[38][39] In one European multicenter cohort study, shunt embolization in patients with recurrent or persistent HE who were diagnosed with a single large portosystemic shunt resulted in 59% of patients being free of HE at 100 days and 49% remaining free of HE for 2 years. Hospitalization rate and HE severity were also decreased.[38]

The success and safety of shunt embolization seems to be dependent on whether there is sufficient functional liver mass to accommodate redirected portal flow; hence the recommendation that patients should have a MELD score of <11. In patients with a MELD score of 11 or more, there is an increased risk of de novo development or aggravation of pre-existing varices, portal hypertensive gastropathy, or ascites.[2]

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