Background for FF #188     Hepatic encephalopathy (HE) is a syndrome of brain dysfunction caused by liver insufficiency or portosystemic shunting. It manifests as a wide spectrum of fluctuating neurologic and psychiatric abnormalities that can range from subtle personality or sleep disturbances to severe HE (grade III or IV) which is defined by gross disorientation, bizarre behavior, stupor, or coma (1,2). Without transplantation, severe HE signifies a poor prognosis (58% 1-year and 77% 3-year mortality) (3).  HE can be deadly even for those awaiting transplantation, as 15% die before receiving liver transplantation (4,5).

Etiology     The cause of HE is likely multifactorial. Blood-derived factors present in chronic liver disease can alter the integrity and permeability of the blood-brain barrier. Compounds enter the brain more freely like ammonia which is metabolized by glutamine synthetase in astrocytes to generate glutamine.  Glutamine makes astrocytes hypertonic resulting in cell swelling and brain edema, which compromises neuronal communication (1). There is also increased GABA-ergic tone in the brains of patients with HE.

Evaluation     HE can be diagnosed in patients with advanced liver disease or portosystemic shunting who present with neurologic or psychiatric symptoms that include personality changes (apathy, irritability, disinhibition), sleep-wake disturbances, disorientation, stupor, or coma.  Asterixis or “flapping tremor” is a common sign, as is hyperreflexia. The West Haven Criteria is a useful tool grade HE severity (6). HE may be precipitated by medical factors, and in one study, 80% of cases were associated with an identifiable secondary cause such as gastrointestinal bleeding, infection (including spontaneous bacterial peritonitis), renal failure, diuretic overdose or electrolyte disorders, constipation, alcohol intoxication or withdrawal, excessive dietary protein, or medications (e.g., benzodiazepines and opioids) (7).  Brain imaging or electroencephalography do not diagnose HE and are mostly useful in refractory HE or in select cases to rule out intracranial pathology, such as stroke or hemorrhage, or non-convulsive epilepsy. Wernicke encephalopathy, Korsakoff psychosis, and dementia should be considered in the differential diagnosis.

Management of HE begins with correction of the underlying causes if this is consistent with the goals of care.  Depending upon goals of care, referral to a liver transplant center should be considered in patients with recurrent or refractory HE. Specific therapy of HE is aimed at limiting production of and increasing excretion of intestinally derived toxins, particularly ammonia. 

• Nonabsorbable disaccharides such as lactulose and lactitol are the mainstay of treatment (8,9). These agents decrease GI transit time to reduce absorption of gut-derived toxins. Additionally, they promote bacterial fermentation, which acidify the colonic environment, thus converting neutral ammonia into the charged ammonium form that remains trapped in the GI tract. The daily dose of lactulose should be titrated to result in 2-3 soft daily stools. For most patients the daily dose is between 30 and 60 grams.  Side effects include gastrointestinal cramping, diarrhea, and flatulence.
• Nonabsorbable antibiotic:  Rifaximin is a nonabsorbable derivative of rifampin. It reduces ammonia-producing enteric bacteria in patients with HE.  Rifaximin is indicated as an adjunct to lactulose in patients with recurrent HE (9,10). Rifaximin is administered at a dose of 550 mg twice daily.
• Reassess the dose of opioids and benzodiazepines:  since HE often can manifest as sedation, clinicians should reevaluate the dose of opioids/benzodiazepines necessary to provide comfort.
• Embolization of large portosystemic shunts, if present may be considered in select patients with refractory HE and relatively intact liver function (9,11). These procedures usually require referral to an interventional radiology team.
• Other medical therapies have unproven efficacy in treating HE and should not be routinely given.  These include branched chain amino acids (12), the benzodiazepine antagonist flumazenil (13), zinc, l-ornithine–l-aspartate and limitation of dietary protein (14).

Advance care planning    The patient’s values, goals of care, and treatment options should be discussed in the context of HE’s poor prognosis and increased risk for caregiver burden, mental distress, and financial challenges.  A health care proxy should be established in patients with cirrhosis before cognitive impairment ensues.

Supportive care    The patient and family must be educated to recognize HE’s symptoms, understand its fluctuating course, and its precipitating factors. This includes counseling on how HE can impair driving skills and may lead to motor vehicle accidents. There are no clear guidelines for defining driving fitness among patients with HE (15). Patients who are confused should be reoriented and measures should be taken to prevent falls, skin breakdown, and aspiration. Intravenous fluids, nasogastric feeding, and airway protection are sometimes appropriate. Dose-adjusted acetaminophen (<2 gm/day) is the first line analgesic. While opioids and benzodiazepines can worsen HE, sometimes they are necessary (16).

References  

1. Rose CF, Amodio P, Bajaj JS, et al. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J Hepatol 2020;73(6):1526-47.
2. Blei AT, Cordoba J.  Practice guidelines: Hepatic encephalopathy.  Am J Gastroenterology. 2001; 96(7):1968-1976.
3. Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999; 30:890–895.
4. Russo MW, LaPointe-Rudow D, Kinkhabwaa M, Emond J, Brown RS.  Impact of adult living donor liver transplantation on waiting time survival in candidates listed for liver transplantation. Am J Transplantation. 2004; 4(3):427–431.
5. Kwong AJ, Ebel NH, Kim WR, et al. OPTN/SRTR 2021 Annual Data Report: Liver. Am J Transplant. 2023;23(2 Suppl 1):S178-63.
6. Vilstrup H, Piero A, 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(2):715-35.
7. Fessel JM, Conn HO.  An analysis of the causes and prevention of hepatic coma. Gastroenterology. 1972; 62:191.
8. Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Systems Rev. 2016;2016(5):CD003044.
9. Montages S, et al. EASL Clinical Practice Guidelines on the management of hepatic encephalopathy. J Hepatol. 2022;77(3):807-24.
10. Kimer N, Krag A, Møller S, et al. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther. 2014; 40:123-132.
11. Laleman W, Simon-Talero M, Maleux G, et al. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology 2013;57(6):2448-57.
12. Als-Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched-chain amino acids for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939. DOI: 10.1002/14651858.CD001939.
13. Als-Nielsen B, Gluud LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD002798. DOI: 10.1002/14651858.CD002798.pub2.
14. Cordoba J, Lopez-Hellin J and Planas M, et al.  Normal protein diet for episodic hepatic encephalopathy. J Hepatol. 2004; 41:38–43.
15. Cohen SM, Kim A, Metropoulos M, Ahn J. Legal Ramifications for Physicians of Patients Who Drive With Hepatic Encephalopathy. Clin Gastroenterol Hepatol 2011;9:156-160.
16. Larson AM and Curtis JR.  Integrating palliative care for liver transplant candidates:  “Too well for transplant, too sick for life”.  JAMA. 2006; 295(18):2168-76.

Version History:  Originally published September 2007; 2nd Edition in May 2009; 3rd Edition in July 2015; 4th Edition February 2025.
Conflicts of Interest: None to report.