Mechanism of hepatic encephalopathy

Several theories regarding the pathophysiology of hepatic encephalopathy (HE) exist. The leading driver of HE appears to be the excess buildup of nitrogenous waste products, especially ammonia, in the body. In patients with end stage liver disease (ESLD), ammonia produced by bacteria in the gastrointestinal tract is absorbed and not adequately metabolized and cleared by the failing liver. This results in buildup of ammonia and other nitrogenous waste products in the body. Ammonia can cross the blood-brain barrier and interacts with hydrogen ions and glutamate from the Krebs cycle to produce glutamine, which causes brain swelling and other negative side effects, ultimately resulting in confusion, motor dysfunction, brain cell apoptosis, coma and death.

In the prevention and management of HE, the mainstay treatment has been to reduce the burden of ammonia in the body. This can be done by giving broad spectrum antibiotics to reduce the bacterial population that produce ammonia from metabolism of proteins. Lactulose is given as a cathartic agent, which helps minimize the absorption of ammonia. Conversion of lactulose into lactic acid can inhibit bacterial growth as well as maintain the integrity of the gastrointestinal tract.

Prevention and management of hepatic encephalopathy

Currently, lactulose, with or without rifaximin, and PEG, are treatments that are commonly used in preventing and managing HE. Rifaximin has shown positive results in several trials. However, its effect without lactulose may in fact be minimal. Rifaximin can also be quite costly. Small trials have shown superiority of PEG over lactulose, however these trials have not yet resulted in widepread adoption of PEG in the treatment of acute HE.

Prevention of hepatic encephalopathy

  • Rifaximin 550 mg PO BID with or without lactulose reduces the risk of breakthrough episodes of hepatic encephalopathy (HE) in patients with prior episodes of HE
    • Occurrence of 22.1% in the rifaximin group versus 45.9% in the placebo group over 6 months (HR 0.42)
    • Hospitalization of 13.6% in the rifaximin group versus 22.6% in the placebo group over 6 months (HR 0.50)
    • More than 90% of patients in both the rifaximin and placebo group also received lactulose therapy

Management of acute hepatic encephalopathy

  • PEG 4L PO at the onset of acute HEis superior to lactulose in improving HESA score within 24 hours (91% response versus 52% response)
  • Rifaximin with lactulose is superior to lactulose alone in facilitating complete reversal of HE at 10 days (76% versus 44%), reducing in-hospital mortality (24% versus 49%), and reducing hospital length-of-stay (5.8 versus 8.2 days)
  • Another study found that the effectiveness of rifaximin was “equivalent to disaccharides or other oral antibiotics… but with a better safety profile”

References

Bass et al. Rifaximin treatment in hepatic encephalopathy. NEJM 362(12): 1071-1080 (2010)

Kowdley and Burman. Adding rifaximin to lactulose increased reversal and decreased mortality in hepatic encephalopathy. ACP Journal Club 159(8): JC8 (2013)

Eltawil et al. Rifaximin vs conventional oral therapy for hepatic encephalopathy: a meta-analysis. World Journal of Gastroenterology 18(8): 767-777 (2012)