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Evidence-Based Management Options for Hepatic Encephalopathy Explored in New Review


A review of 6 studies on treatment options for hepatic encephalopathy found that many require further research before they can be recommended.

While management of hepatic encephalopathy (HE) has greatly advanced since the condition was first discovered, there is still wide discrepancy in care delivery and patient outcomes, and knowledge on underlying pathophysiologic mechanisms is limited, according to an evidence review published in World Journal of Hepatology.

HE is an often-reversible neurological condition in which a damaged liver does not remove toxins from the blood and leads to impaired brain function. The condition represents one of the many complications of portal hypertension and decompensated liver disease.

Ammonia, a nitrogenous toxin derived from the gut and produced by the bacterial metabolism of urea from dietary proteins, is considered the primary pathophysiologic mechanism of HE. Other factors include inhibited neurotransmission in the central nervous system (CNS) via gamma-aminobutyric acid receptors and alteration in other CNS neurotransmitters and circulating amino acids.

Many therapeutic agents exist for the management of HE, and most focus on lowering the gut nitrogen load and, therefore, the serum ammonia level. To suggest updates to these conventional and emerging HE treatment options, the authors conducted a review of 6 studies.

They first looked at gut flora modifying agents, including nonabsorbable disaccharides, antibiotics, and probiotics.

Lactulose and lactitol are 2 nonabsorbable disaccharides that are the first-line treatments for HE and have been shown to significantly improve cognition and quality of life in patients with minimal HE (MHE). Lactitol has also been shown to lead to fewer adverse effects (AEs) compared with lactulose.

Antibiotics that target urease-producing gut bacteria have an ammonia-lowering effect. These include rifaximin, neomycin, vancomycin, and metronidazole.

Rifaximin is mostly used as a backup option to prevent HE recurrence when lactulose alone fails. However, based on more recent studies, combination therapy with lactulose may be more beneficial than rifaximin.

The 2014 American Association for the Study of Liver Diseases (AASLD) guidelines for HE management recommend neomycin as an alternative for the treatment of overt HE (OHE), but its significant AE profile—including ototoxicity, nephrotoxicity, and enterocolitis—warrants caution.

Vancomycin and metronidazole also had serious AEs—including bacterial resistance and neurotoxicity, respectively—and are not recommended for long-term use.

One review found probiotics may improve HE recovery and quality of life while reducing OHE recurrence and plasma ammonia concentrations compared with placebo. However, no effects on mortality or significant clinical outcomes were seen when probiotics were compared with lactulose, warranting further research before it can be recommended.

Additionally, studies on fecal microbiota transplant have shown promising results, including improved cognitive function and reduced serum ammonia levels—but these require larger trials to validate these results.

Regarding nutrition, dietary modification, and supplementation, all 3 treatments—zinc, branched-chain amino acids, and acetyl-L-carnitine—cannot yet be recommended due to lack of clear data. Branched-chain amino acids may be considered for treatment of patients who are severely protein intolerant, but no benefit was seen in patients who are protein tolerant.

CNS-acting agent flumazenil is not recommended for routine clinical use for HE, but the authors said it may be considered for certain patients who have received benzodiazepine therapy. Further, clinical data on the benefits of dopamine agonists are insufficient, but the authors said these may be helpful in patients with HE who do not respond to first-line therapies.

For ammonia-scavenging agents, L-ornithine L-aspartate—a combination of 2 endogenous amino acids—has been deemed safe, effective, and well tolerated for patients with HE and is routinely given to patients with HE outside of the United States.

Contradictory findings on the benefits of ornithine phenylacetate and limited data on phenylbutyrate make them unable to be recommended at this time, but sodium benzoate was found to be as safe and effective as lactulose.

Larger trials are also needed regarding spherical carbon microsphere adsorbent, polyethylene glycol 3350-electrolyte solution, and molecular absorbent recirculating system.

Finally, patients with refractory HE may experience large spontaneous portosystemic shunts (SPSS), a rare malformation of the vessels supplying the liver that can lead to sustained HE episodes. With some studies finding beneficial results of SPSS embolization in HE episodes, it may be a treatment option in certain patients with refractory HE.

“Although HE is not an indication for liver transplant, liver transplantation remains the definitive treatment for reversal of the complications related to cirrhosis,” the authors said. “Studies have shown that patients become free of HE following transplantation; follow-up studies have also shown that HE may become irreversible despite liver transplant.”


Hoilat GJ, Suhail FK, Adhami T, John S. Evidence-based approach to management of hepatic encephalopathy in adults. World J Hepatol. 2022;14(4):670-681. doi:10.4254/wjh.v14.i4.670

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