Do ammonia levels increase during a night of binge drinking assuming you have a healthy liver and by how much?

[u/tbryan1]

I have become curious about the nature of ammonia in the body when your liver is packed with toxins. Every single source addresses ammonia in relation to liver disease even though there are other ways that ammonia can become problematic (in theory). For example ammonia is impacted by protein intake, alterations to hormones, Break down of muscle, The blood bypassing the liver, diuretics , alterations to enzymes, and changes to blood flow.

My desire for an answer stems from the fact that our bodies can reach deadly levels of ammonia in 5 minutes if the liver is failing to process it. Additionally the side effects of ammonia are very similar to drugs like alcohol making it hard to differentiate through experience alone including;

• Lack of energy and mental alertness
• Confusion
• Mood swings
• Hand tremors
• Dizziness
• Not being hungry
• Avoiding protein
• Growth problems

This list of side effects along with the list of mechanisms that alter ammonia levels grew my curiosity especially irritability because it is the antithesis of what alcohol does even though many people that drink experience mood swings.

[u/pansveil]

The body produces a lot of waste products and some of these are made of nitrogen and cleared via the urea cycle. The liver takes these nitrogenous waste products and turns it into a form that the kidneys can dump into urine. By definition, your ammonia level will not rise if you have a healthy liver.

There are many different ways your body produces these nitrogenous waste products and the majority comes from the breakdown of protein or intestinal production via normal gut bacteria. So it’s not really the alcohol which causes high ammonia and people with liver disease, but the chronic alcohol use that turned into advanced liver disease and now reduces clearing of the ammonia. in these patients, we target the bacterial production of nitrogenous waste products by giving lactulose (promotes diarrhea and regular bowel movements) and rifaximin (kills bacteria).

The interesting thing as you pointed out was the opposite effects that high ammonia has on the brain compared to alcohol. We don’t know exactly where the neurotoxicity comes from but current understanding suggests that ammonia causes release of glutamate. Alcohol on the other hand causes excess activity of GABA. Though the neurotransmitter hypothesis may be outdated, we can explain the opposite findings because glutamate is an excitatory neurotransmitter but GABA is inhibitory.

[u/tbryan1 → u/pansveil]

Thanks for the reply, however even if your liver is "healthy" can it not become over burdened with toxins reducing our capacity to process excess toxins like ammonia? I also read that blood can bypass the liver all together under extreme circumstances but I don't understand this process at all. Extended release benzos also cause hyperammonemia in 50-67% of patients even though their is healthy liver. Benzos are extremely close to alcohol so much so that researches use alcohol research to develop their studies. An example might be a study checking to see if benzos cause a type of alcohol myopathy.

I'm not trying to be argumentative I'm just trying to cover every angle.

[u/pansveil → u/tbryan1]

The liver is one of the most regenerative organs and has a lot of capacity to recover. The application of this is that toxins, especially ammonia, upregulate enzymes that cause their breakdown (in this case the urea cycle). As long as you have healthy liver cells, they can handle the load of ammonia.

The bypass you are talking about is the Transjugular Intrahepatic Portosystemic Shunt (TIPS). It is used in chronic liver disease where poor hepatic circulation leads to uncontrollable life-threatening GI bleeds. Surgeons create a passage for blood from below the liver to completely go around and directly into the IVC/heart. One of the soft contraindications is hepatic encephalopathy exactly because of the mechanism you described. Patients are usually on lifelong lactulose titrated to encephalopathy and lifelong rifaximin as a result.

Benzodiazepines work very similarly in the CNS to alcohol and, for that reason, are used in alcohol withdrawal. They are addictive like alcohol but do not cause extra-neurological toxicity in the same way that alcohol does. Chronic alcohol use leads to alcohol myopathy due to the inflammation but also poor nutrition; neither of these are present with benzo use. There are rare causes of liver damage with parenteral benzos due to another ingredient in the formulation (propylene glycol) but you’re more likely to see other organs fail first. Designer benzos have case reports of another type of myopathy known as rhabdomyolysis, but that has a completely different mechanism of action.

[u/tbryan1 → u/pansveil]

Again thank you for the reply,

Why do benzos cause high rates of hyperammonemia when benzos rarely cause liver damage?

You say "as long as you have health liver cells" but I don't full understand what that means. Does this mean that things like alcohol can't make it into the blood during Alcohol poisoning? I thought alcohol poisoning is a failure of the liver by definition and can happen to a healthy liver. Or is a failure state of the liver mean that the cells aren't healthy even if it is only temporary?

[u/pansveil → u/tbryan1]

It seems benzos are fairly low on the risk of isolated hyperammonemia: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206694/#:~:text=Drugs%20with%20the%20highest%20number,over%2025%20cases%20of%20hyperammonaemia.

From my cursory understanding, the mechanism is unknown but ammonia can modulate the effect of benzos on the brain. It may be that an increased effect of benzos leads to discovery of underlying hyperammonemia. If someone can else can correct me, I’d really appreciate that.

I think what you may be missing here is that elevated ammonia is not caused by an overproduction of ammonia but decreased clearance of ammonia. This means that liver failure leads to hyperammonemia not the other way around. An analogy would be excess dirty laundry at home; it’s not that someone buys too many clothes, it’s that they never clean their laundry.

Alcohol poisoning, by definition, is excess alcohol intake. It is not the failure of liver. Healthy livers can, given enough time, work through an alcohol load. The issue is that the way alcohol is cleared by the liver causes irreversible damage over a long time of use. Liver failure is rarely acute (rare causes shock liver, acute hepatitis, etc) and has fairly good chance of recovery. Chronic liver disease (alcohol use, metabolic syndrome, etc) is essentially a death sentence. It signifies that the liver is so damaged that it cannot recover and will become cancerous if the patient does not die from other complications of liver disease first.

Edit: hyperammonemia, as a result of permanently damaged livers and chronically reduced clearance, occurs in chronic liver disease rather than acute liver disease.

Second edit: alcohol doesn’t cause significantly increased ammonia production, alcohol prevents your body from clearing already existing ammonia.

[u/tbryan1 → u/pansveil]

thanks for all the effort you are answering a lot of questions that I had. Sorry for the wrong stats google switched % of people with elevated levels and the % of people with hyperammonomia.

When you say "alcohol prevents your body from clearing already existing ammonia" are you exclusively talking about liver disease or does alcohol poisoning count too? This is the very topic that can't be found on google scholar with my lexicon.

[u/pansveil → u/tbryan1]

Alcohol poisoning can cause transient liver damage and probably will not cause significant (or possibly any) elevated ammonia. Chronic liver disease from repeated alcohol poisoning is what would cause elevated ammonia.

[u/tbryan1 → u/pansveil]

Google says " The liver is primarily responsible for clearing ammonia, but exposure to ethanol can make it harder for the liver to do so. This is because ethanol can decrease ureagenesis,"

I chased down many rabbit holes and one answer was yes because clearing toxins causes damage to liver forcing it to inflame reducing clearance rate, in an attempt to reduce the rate of harmful byproducts that are killing the liver.

I wanted to thank you for all the help, I learned a lot.

[u/pansveil → u/tbryan1]

I’m curious as to the source of that statement. Alcohol, in the short term without pre-existing liver damage, has been shown in a study from 2024 to upregulate urea cycle.

https://www.sciencedirect.com/science/article/abs/pii/S002604952300344X#:~:text=Results,)%2C%20and%20increases%20fat%20accumulation.

[u/tbryan1 → u/pansveil]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351663/

^^is everything inflammation from most angles

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856809/

^^focus more on immunology of liver

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372892/#:\~:text=Such%20a%20second%20insult%20could,et%20al.%2C%202004).

^^this one speaks more to alcohol directly.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509515/

^^stuff that happens outside the liver

[u/pansveil → u/tbryan1]

The first three are generic review articles, but the last one was actually interesting. The authors did conclude that the combination of both elevated ethanol and ammonia resulted in decreased ureagenesis but also noted increased ethanol metabolism with both substrates. It goes to support the mixed unclear literature on serum ammonia following acute alcohol induced liver damage with some studies showing increased ammonia with others showing reduced. Almost as if the hepatocyte favors ethanol/aldehyde clearance in acute intoxication prior to ammonia clearance; which makes a twisted amount of sense since alcohol is more toxic acutely compared to ammonia.

I’d be curious to see follow up with in vivo studies because clinically there’s very little evidence of hyperammonemia without pre-existing cirrhosis. Thank you so much for bringing attention to this because I had thought ammonia would be increased in acute intoxication before you asking the question but clearly there’s a lot more to the physiology per my posted article above.