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Hepatic encephalopathy - The mechanism of ammonia toxicity

A middle aged man, Mr. X, who was a chronic alcoholic was brought to the EMD by his relatives as they noticed a change in his behavior. He had irrelevant speech since morning. There was no history of head trauma, no history of binge drinking and his last alcohol intake was 12 hours ago. On examination, you find his vitals to be stable. Neurological examination revealed disorientation to time, place and person and mild asterexis. Pupillary reflexes were intact. As an intern, the first thing that would pop in your mind is hepatic encephalopathy. This is in fact, the most common cause of disorientation in middle aged men with history of alcoholism. So you have a diagnosis, but do you really understand it?

We all know that encephalopathy due to liver cirrhosis has got something to do with raised ammonia levels because we know that the liver is the one organ in our body that can take any insult thrown at it and turn that into something less noxious, more tolerable. If we dig deeper we might be able to recall how the liver is capable of making ammonia less toxic. You see, normally ammonia is converted into urea via the urea cycle in the liver and urea in turn is excreted by the kidney in the urine. The fundamental issue with alcoholics is that their livers are not functioning properly, and the ammonia is not getting converted completely to urea, which means that there is excess ammonia in the blood.

But so what? What if there's an excess of ammonia? Why is it so bad for us? Why did these NH3 molecules bring Mr. X to the EMD? Like many other things we don’t understand, we just take this fact for granted. We just convince ourselves:

Ammonia in blood = Bad stuff

But here is why it’s bad. 

It really is not as complex as it sounds. We just need to refresh some basic biochemistry knowledge and we are good to go. 

Essentially, all we need to recall, is this equation.

Ammonia (NH4+) is being sequentially added to alpha keto glutarate to form Glutamate and finally Glutamine. This is a transamination reaction.

As mentioned earlier, usually the ammonia that is formed in our body due to breakdown of proteins is converted into urea in the liver. But when the liver is not functioning to its optimum capabilities, the ammonia gets channelled into other pathways like the above said transamination reactions. Now this might seem like a fine alternative, but in the long run, it is a self destructive process. As more and more ammonia participates in the transamination reactions, more molecules of alpha ketoglutarate and glutamate get converted into glutamine. And that brings us to the next question. So what if our alpha ketoglutarate and glutamate stores get depleted? What could possibly be the effect of raised glutamine? Lets take one metabolite at a time.

1) Alpha ketoglutarate:

It is the most important intermediate in the citric acid cycle, a cycle responsible for producing 10 molecules of ATP from a single molecule of glucose.  So obviously when the fuel is missing, the machine will shut down and unfortunately the brain, which is mostly dependant on glucose for energy, is now starved. 

2) Glutamate :


Gamma ammino butyric acid (GABA) is an inhibitory neurotransmitter synthesised from glutamate. When glutamate is depleted, there is no other inhibitory neurotransmitter molecule to keep an eye on the neurons. Hence the neurons are in a perpetually excited state and that explains the tremors.

3) Finally, Glutamine :

This is the simplest mechanism of all. Glutamine is a hygroscopic molecule, i.e., it absorbs water. Hence increased level of glutamine within a cell causes the cell to swell up and that leads to brain edema. In fact, brain herniation is the most dreaded complication of hepatic encephalopathy, which is why intravenous mannitol has a role in the management of such patients. 

So, to summarise, a swollen up, starved brain and tremors... That's what brought Mr. X to the EMD that morning!

Now Harrison mentions that “the correlation between the severity of liver disease and height of ammonia levels is often poor”. But as long as this sequence helps us remember the pathophysiology better, why would Harrison mind? We don’t think so either.

Author: Soundarya V (Facebook)

Sources and citations

"Chapter - 28: Catabolism of Proteins and Amino Acid Nitrogen." Harper's Illustrated Biochemistry. 30th ed. 291-92.
"Chapter - 29: Catabolism of the Carbon Skeleton of Amino Acids." Harper's Illustrated Biochemistry. 30th ed. 299. Figure 29-2
"Chapter 365: Cirrhosis and Its Complications." Harrison's Principles of Internal Medicine. 19th ed. 2066-067.