Hepatic encephalopathy (HE) may be precipitated by a variety of factors including infection, hypovolemia, electrolyte imbalance (eg, hyponatremia, hypokalemia), metabolic alkalosis, sedatives, and of course UGIB. ^1-3

Ammonia is often considered to play a central role in the the pathogenesis of HE, particularly when associated with UGIB. The ammoniagenic potential of UGIB is primarily attributed to the presence of hemoglobin protein in the intestinal tract. One-half of the ammoniagenesis originates from amino acid metabolism (mainly glutamine) in the mucosa of the small bowel, while the other half is due to the splitting of urea by the resident bacteria in the colon (eg, Proteus spp., Enterobacteriaceae, and anerobes).^1,2

A large protein load in the GI tract, as occurs in UGIB, may result in hyperammonemia in patients with cirrhosis due to the limited capacity of the liver to convert ammonia to urea through the urea cycle as well as by the shunting of blood around hepatic sinusoids. Recent studies, however, also implicate the kidneys as an important source of ammonia in this setting, further compounding HE.³

It’s important to stress that ammonia is not likely to be the only mediator of HE. Enhanced production of cytokines due to infection or other inflammatory states, neurosteroids, endogenous benzodiazepines, and other bacterial byproducts may also play an important role in precipitating HE.^2,4-6  So stay tuned!

Bonus pearl: Did you know that proinflammatory cytokines tumor necrosis factor-alpha and inerleukin-6 increase ammonia permeability across central nervous system-derived endothelial cells? ⁷

References

1. Olde Damink SWM, Jalan R, Deutz NEP, et al. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 2003;37:1277-85.
2. Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol 2011;7:222-233.
3. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90:646-58.
4. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254.
5. Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with grade ¾ hepatic encephalopathy, but not mortality in controls. J Hepatol 2011;54:640-49.
6. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci 2005;62:2295-2304.
7. Duchini A, Govindarajan S, Santucci M, et al. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 1996;44:474-82.

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