Ammonia toxicity: from head to toe?

Abstract

Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction.

Keywords: Ammonia; Brain; Hepatic encephalopathy; Liver; Muscle; Toxicity.

Figure 1.. Effects of ammonia toxicity in brain.

Left, physiological ammonia handling in the brain. Right, some of the proposed neurotoxic effects of excess brain ammonia. Glutamate (Glu), glutamine synthetase (GS), glutamine (Gln), adenosine triphosphate (ATP), sodium-coupled neutral amino acid transporters (SNAT1/2 and 5), glutamate transporter 1 (GLT1), glutaminase (Glnase), glutamate and γ-aminobutyric acid (GABA), glutamate receptor (GluR), GABA receptor (GABAR), cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), cerebral metabolic rate of glucose (CMRGlc), GABA reversal potential (EGABA), cytokines (CK).

Figure 2. Skeletal muscle molecular perturbations induced by hyperammonemia.

Ammonia transcriptionally up-regulates TGFB superfamily member, myostatin, that inhibits critical regulatory signaling molecule, mTORC1 via AMPK with resultant impaired downstream signaling responses that in turn results in decreased protein synthesis and increased autophagy, both of which contribute to sarcopenia in liver disease. 4EBP1 4E binding protein; ActIIBr activin II b receptor (TGF beta receptor type 2); Akt/PKB protein kinase B;ALK4 activin like kinase 4 (TGFbeta receptor type 1); ALK5 activin like kinase 5 (TGF beta receptor type 1); IGF-1 insulin like growth factor 1, mTORC1 mammalian target of rapamycin 1; PI3K phosphoinositide 3kinase; RiboS6 ribosomal S6 protein, ROS reactive oxygen species, TSC tuberous sclerosis complex.