Metabolism
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Hyperammonaemic coma due to liver failure
Key points from this exercise:
Dead and dying cells release enzymes into the bloodstream, and measurement of these enzymes in plasma can be useful diagnostically, although they have no function in the bloodstream.
In order to measure the activity of an enzyme in the bloodstream, the limiting factor in the formation of product must be the amount of enzyme, not the amount of substrate. In order to ensure that the enzyme is saturated with substrate and acting at Vmax, the concentration of substrate needs to be 10 - 20x higher than the Km of the enzyme
Bilirubin is synthesised in macrophages by oxidation of the haem from old red blood cells, and is conjugated with glucuronic acid in the liver, then excreted in the bile. In obstructive jaundice, when the bile duct is blocked, liver function is normal, and conjugated bilirubin accumulates in the bloodstream. In liver failure, bilirubin cannot be conjugated adequately, and unconjugated bilirubin accumulates in the bloodstream.
Hepatocytes in the periportal region of the liver have a different complement of enzymes from those in the periportal region. In alcoholic liver disease it is mainly cells around the hepatic portal vein that are damaged, while in non-alcoholic liver disease cells are damaged in both regions.
The direction of the reaction of glutamate dehydrogenase is dependent on the amount of ammonium available; even a moderate increase in [plasma and tissue ammonium will lead to formation of glutamate from alpha-ketoglutarate. This depletes the tissue pool of alpha-ketoglutarate and slows the rate of citric acid cycle activity, leading to impaired formation of ATP. In the brain this leads to failure of ion transport across membranes, and loss of consciousness.
Although most ammonia in the bloodstream is as ammonium ions (NH4+), this is in equilibrium with a small amount of ammonia (NH3). Ammonia is lipid soluble, and can diffuse across cell membranes, whereas ammonium cannot. Lactulose is fermented by intestinal bacteria to form lactate and hydrogen ions. This acidifies the intestinal contents and traps ammonia that diffuses into the gut as ammonium. Ammonia continues to diffuse into the gut down a concentration gradient, so lowering blood ammonia + ammonium.