Ammonia Production in the Body
Ammonia is produced through four primary mechanisms: amino acid catabolism, bacterial breakdown of proteins and urea in the gastrointestinal tract, glutamine dehydrogenase activity in multiple organs, and deamination of AMP during exercise. 1
Primary Sites and Mechanisms of Ammonia Production
Gastrointestinal Tract (Primary Source)
The gastrointestinal system is the dominant source of systemic ammonia, with portal vein ammonia concentrations approximately three times higher than systemic blood levels. 2 Three mechanisms drive gut ammonia production in order of quantitative importance:
- Bacterial urease hydrolysis of urea is the most significant contributor to gut ammonia production 2
- Bacterial protein deamination represents the second major mechanism 2
- Intestinal mucosal glutamine metabolism contributes as the third mechanism 2
Importantly, ammonia production occurs throughout the entire gastrointestinal tract, not just the colon as conventionally assumed. The stomach (via Helicobacter pylori metabolism) and small intestine may actually be more important than the colon. 2 In the post-absorptive state, the small and large bowel produce equal amounts of ammonia, with small intestinal synthesis related to amino acid breakdown and large bowel production caused by bacterial breakdown of amino acids and urea. 3
Hepatic Amino Acid Metabolism
The liver produces enormous amounts of ammonia during normal amino acid metabolism, particularly through the activity of glutamate dehydrogenase (GDH), which converts glutamate to α-ketoglutarate while releasing ammonia. 4 However, in healthy individuals, this hepatically-produced ammonia is completely captured by the urea cycle and does not contribute to blood ammonia levels. 2
Altered protein metabolism, particularly of branched-chain amino acids (BCAAs) that support glutamine synthesis and extrahepatic ammonia detoxification, can lead to accelerated protein breakdown and increased ammonia production. 5
Renal Production
The kidneys produce ammonia as part of normal metabolism, though they have the adaptive capacity to switch from net ammonia production to net ammonia excretion during hyperammonemic states. 3 This renal flexibility is beneficial for patients with elevated ammonia levels. 3
Muscle Metabolism
Muscle tissue produces ammonia through deamination of AMP during exercise and can contribute to systemic ammonia levels. 1 While muscle ammonia production is normally a minor contributor, muscle plays a major role in temporarily detoxifying ammonia to glutamine during hyperammonemic states. 3
Other Organs
Glutamine dehydrogenase activity in the liver, kidney, pancreas, and brain contributes to ammonia production across multiple organ systems. 1
Normal Ammonia Processing and Detoxification
Under physiological conditions, ammonia is processed through two primary pathways:
- The urea cycle in hepatocytes converts ammonia to urea for urinary excretion 1
- Conversion to glutamine provides an alternative detoxification pathway, with partial excretion by the kidneys 1
Normal blood ammonia concentrations are ≤35 μmol/L (≤60 μg/dL). 1
Pathological Ammonia Accumulation
When ammonia clearance mechanisms fail, hyperammonemia develops. This occurs through:
- Impaired hepatic ammonia clearance from loss of metabolic capacity combined with increased portosystemic shunting, which increases systemic ammonia concentration 5
- Loss of first-pass metabolism due to portal collateral circulation in chronic liver disease, which can account for hyperammonemia without necessarily implicating hepatocyte malfunction 2
- Damaged hepatocytes in acute hepatic necrosis, which directly impairs ammonia processing 2
The contribution of the gut to hyperammonemia during liver failure is mainly due to portosystemic shunting rather than changes in gut ammonia metabolism itself. 3