Transamination collects it, glutamine transports it, the urea cycle removes it
Expansion
Three steps
- Transamination: amino groups are transferred to alpha-ketoglutarate to form glutamate, by aminotransferases using pyridoxal phosphate (vitamin B6). ALT and AST are these enzymes, which is why they are markers of hepatocyte damage
- Transport: glutamate accepts a second nitrogen to form glutamine, the non-toxic transport form carried in blood. Muscle also uses the alanine (Cahill) cycle
- Disposal: in the liver, glutamate is deaminated by glutamate dehydrogenase, releasing ammonia into the urea cycle
“Glutamate collects, glutamine carries, urea removes.”
Why ammonia is toxic: it depletes alpha-ketoglutarate as it is consumed forming glutamate, impairing the Krebs cycle, and glutamine accumulation in astrocytes draws in water, causing cerebral oedema.
Hepatic encephalopathy follows failure of step 3, from liver failure or portosystemic shunting. Precipitants include gastrointestinal bleeding (a protein load), constipation, infection, dehydration, hypokalaemia and sedatives.
Treatment targets the gut: lactulose acidifies the colon, trapping ammonia as ammonium and speeding transit, and rifaximin reduces ammonia producing bacteria.
Congenital hyperammonaemia from urea cycle defects, most often ornithine transcarbamylase deficiency, presents in the neonate with vomiting, lethargy and a respiratory alkalosis, with a raised orotic acid and a low urea.