Xifaxan (Rifaximin) in the Treatment of Hepatic Encephalopathy: Mechanism and Pathophysiology

Introduction

Hepatic encephalopathy (HE) is a spectrum of neuropsychiatric disturbances due to severe liver dysfunction and/or portosystemic shunting. Traditional therapy centers on ammonia reduction with agents such as lactulose. Xifaxan (rifaximin), a gut-selective antibiotic, is increasingly used to reduce HE recurrence and hospitalizations as an adjunct to standard care.

Pathophysiology of Hepatic Encephalopathy

Impaired hepatic detoxification permits accumulation of neurotoxic metabolites—most notably ammonia—leading to altered neurotransmission and cognitive dysfunction [1]. Contributions from the gut–liver axis (dysbiosis, bacterial translocation, inflammation) amplify this process and worsen neurologic symptoms [4].

Xifaxan: Overview

Rifaximin is a minimally absorbed, gut-targeted antibiotic used for GI indications and—importantly—HE prevention and treatment. Its benefit in HE is largely tied to reducing intestinal production of ammonia and other gut-derived toxins [2][3].

Mechanism of Action

Antibiotic Effect

Rifaximin suppresses ammonia-producing gut bacteria, lowering intestinal ammonia generation and systemic absorption [3].

Anti-inflammatory & Barrier Effects

By modulating the microbiome and bacterial translocation, rifaximin may reduce mucosal inflammation and systemic inflammatory signaling, supporting neurologic improvement in HE [4].

Clinical Evidence

Randomized trials and follow-up studies report reduced HE recurrence and fewer hospitalizations with rifaximin therapy, with durable benefit in maintenance settings [5].

Safety & Tolerability

Rifaximin is generally well tolerated with low systemic absorption; reported adverse effects are often mild, and the risk of systemic antimicrobial resistance appears low in available studies [6].

Conclusion

By targeting gut flora and inflammatory drivers, rifaximin offers a complementary strategy to ammonia-lowering therapies in HE. Its efficacy and tolerability profile support its use—typically in combination with lactulose—to help prevent recurrence and improve quality of life.

References

1. Häussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut. 2008;57(8):1156-1165.
2. Mas A. Rifaximin as therapy in HE. Hepatology. 2010;52(4):1484-1486.
3. Gatta A, Verardo A, Bolognesi M. Gut–liver axis in HE. Ann Gastroenterol. 2014;27(1):7-13.
4. Shawcross D, Jalan R. Ammonia & inflammation in HE. Cell Mol Life Sci. 2005;62(19-20):2295-2304.
5. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin for HE. N Engl J Med. 2010;362(12):1071-1081.
6. Neff GW, Jones EB, Rifkin SI. Safety/efficacy of rifaximin in HE. Aliment Pharmacol Ther. 2012;35(7):799-805.

References provided for educational context; consult current guidelines for treatment decisions.