Review
Refining the Ammonia Hypothesis: A Physiology-Driven Approach to the Treatment of Hepatic Encephalopathy

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Abstract

Hepatic encephalopathy (HE) is one of the most important complications of cirrhosis and portal hypertension. Although the etiology is incompletely understood, it has been linked to ammonia directly and indirectly. Our goal is to review for the clinician the mechanisms behind hyperammonemia and the pathogenesis of HE to explain the rationale for its therapy. We reviewed articles collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar between October 1, 1948, and December 8, 2014, and by a manual search of citations within retrieved articles. Search terms included hepatic encephalopathy, ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic shunt, ammonia and lactulose, rifaximin, zinc, and nutrition. Ammonia homeostatsis is a multiorgan process involving the liver, brain, kidneys, and muscle as well as the gastrointestinal tract. Indeed, hyperammonemia may be the first clue to poor functional reserves, malnutrition, and impending multiorgan dysfunction. Furthermore, the neuropathology of ammonia is critically linked to states of systemic inflammation and endotoxemia. Given the complex interplay among ammonia, inflammation, and other factors, ammonia levels have questionable utility in the staging of HE. The use of nonabsorbable disaccharides, antibiotics, and probiotics reduces gut ammoniagenesis and, in the case of antibiotics and probiotics, systemic inflammation. Nutritional support preserves urea cycle function and prevents wasting of skeletal muscle, a significant site of ammonia metabolism. Correction of hypokalemia, hypovolemia, and acidosis further assists in the reduction of ammonia production in the kidney. Finally, early and aggressive treatment of infection, avoidance of sedatives, and modification of portosystemic shunts are also helpful in reducing the neurocognitive effects of hyperammonemia. Refining the ammonia hypothesis to account for these other factors instructs a solid foundation for the effective treatment and prevention of hepatic encephalopathy.

Section snippets

Methods

A search of the representative literature was performed. Articles were collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar and by a manual search of citations within retrieved articles. Search dates spanned October 1, 1948, to December 8, 2014. Search terms included hepatic encephalopathy [MeSH], ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic

Putting it All Together

By focusing on the determinants of ammonia metabolism and neurotoxicity, clinicians may develop an effective multimodal therapeutic strategy for their patients with HE. In patients with cirrhosis and portosystemic shunting, amino acid bypass of the liver in the postabsorptive state and loss of intrinsic hepatic function significantly raise the importance of alternative sites of ammonia metabolism. Namely, the muscle and kidney are critical for maintaining ammonia homeostasis (Figures 1 and 2).

Conclusion

In summary, the ideal therapeutic approach to patients with HE can be guided by a refined ammonia hypothesis. This refined and up-to-date view of the ammonia hypothesis is one that acknowledges the contribution of inflammation to the neurotoxicity of serum ammonia and underscores the importance of multiple organ systems, namely, the gut, kidney, and skeletal muscle, in achieving ammonia homeostasis.

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