The mechanisms leading to the toxicity of hyperammonemia have been long known to be complex. For a review of what was known in 2012, see this article:
Auron A, Brophy PD. Pediatr Nephrol. 2012 Feb;27(2):207-22. doi: 10.1007/s00467-011-1838-5. Epub 2011 Mar 23.
Hyperammonemia in review: pathophysiology, diagnosis, and treatment.
In this review, they discuss amino acid disturbances in the brain (glutamine and arginine), alterations in neurotransmission systems (Glutamatergic, Cholinergic, Serotonergic, Energy metabolism), and astrocytic swelling.
However, more recently, a new pathophysiological mechanism has been uncovered for the neurotoxicity of ammonia: neuronal disinhibition secondary to impairing astrocyte potassium buffering. this was described recently in the following paper:
Rangroo Thrane V1, Thrane AS, Wang F, Cotrina ML, Smith NA, Chen M, Xu Q, Kang N, Fujita T, Nagelhus EA, Nedergaard M. Nat Med. 2013 Dec;19(12):1643-8. doi: 10.1038/nm.3400.
Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering.
In that paper, they describe how ammonia compromises astroglial potassium buffering by competing for uptake. Lethal doses were required before astrocyte swelling was noted. The excess ammonia and potassium depolarized the neuronal GABA reversal potential via NKCC1. And finally, they showed that inhibiting the chloride channel NKCC1 with bumetanide attenuated cortical disinhibition and improved survival.
Perhaps a new therapy for hyperammonemia will be on the way…
Posted by Philippe Campeau, MD