Liver physiology 4 Protein synthesis and the urea cycle in liver disease Flashcards
fed state on needing amino acid surplus
In the fed state, any amino acids surplus to requirement for protein synthesis can be metabolized to non-nitrogenous substances, such as glucose, glycogen or fatty acids, or they can be oxidised to generate ATP
fasting/ starvation and needing amino acid excess
catabolic wasting of muscle occurs, thereby yielding amino acids which are used for gluconeogenesis so as to maintain normoglycaemia. Because the ammonia derived from these amino acids is extremely toxic, it is converted to non-toxic urea for urinary excretion. Any ammonia which evades detoxification as urea can alternatively be incorporated into glutamine by glutamine synthetase
Glucose alanine cycle
In muscle, alanine is the principal ammonia scavenger and transporter. Glutamate collects the ammonia,
the enzyme alanine aminotransferase (ALT) transaminates the amino group from glutamate, forming α ketoglutarate, and the amino group gets attached to pyruvate, formed from glycolysis, making alanine. This gets transported in the blood, taken up by the liver where the reverse reaction occurs and the ammonia gets converted to urea. Pyruvate is recycled into glucose.
ornithine cycle of urea synthesis
- Arginine either from the diet or protein breakdown, is cleaved by arginase, generating urea and ornithine. In subsequent reactions a new urea is built on the ornithine (from ammonia and CO2 ) making citrulline. This, in turn, is reconfigured into arginine. The enzymes responsible for this are found partly in the mitochondria and partly in the cytosol (like glutaminase/glutamine synthase).
- The reactions of one turn of the cycle consume 3 ATP equivalents and a total of 4 high energy nucleotide PO4=. Urea is the only compound generated by the cycle: all other components are re-cycled. The energy consumed by urea production is generated in the production of the cycle intermediates.
control of ornithine cycle of urea synthesis
• Control of the cycle is via up or down regulation of the enzymes responsible for urea formation. So with long term changes in the quantity of dietary protein, upregulation in the order of 20 times has been demonstrated. This can be due to either increased intake as with body builders – high protein low fat diets - or in starvation because muscle proteins are being broken down with the amino acid carbon skeletons providing the energy. Thus the amount of ammonia that must be excreted increases
the Krebs bicycle
composed of the urea cycle on the right, which meshes with the aspartate-argininosuccinate shunt of the citric acid cycle on the left. Fumarate produced in the cytosol by argininosuccinate lyase of the urea cycle enters the citric acid cycle in the mitochondrion and is converted in several steps to oxaloacetate. Oxaloacetate accepts an amino group from glutamate by transamination, and the aspartate thus formed leaves the mitochondrion and donates its amino group to the urea cycle in the argininosuccinate synthetase reaction. Intermediates in the citric acid cycle are boxed
Neurotoxicity associated with ammonia
Elevated blood ammonia is seen in severe liver disease, whether it be as a result of liver failure due to infection, toxicity or substantial surgical resection. The blood doesn’t get exposed to enough liver parenchymal cells to have the ammonia removed. This can be due either to the fact that there simply aren’t enough living, metabolising cells because they’ve been killed off by the disease process be it viral or toxic. Or because, in cirrhosis for example, the resistance to blood flow through the liver is so great (because of fibrosis) that the blood by-passes the liver by flowing through large collateral veins. It therefore gets delivered to the brain directly.
Ammonia crosses the blood-brain barrier readily. Once inside it is converted to glutamate via glutamate dehydrogenase and so depletes the brain of α ketoglutarate. As ketoglutarate falls, so does oxaloacetate and ultimately citric acid cycle activity stops, leading to irreparable cell damage and neural cell death.
Glutamine hypothesis
Hyperammonaemia activates glutamine synthase in astrocytes, accumulation of glutamine, which acts as an osmolyte and causes astrocytic swelling, imapired astrocytic function and cerebral oedema.
OTC: recognition, investigation
late onset very variable:
• male, 16th birthday, vomiting, encephalopathy, diagnosed, died.
• male, 17, Scout camp, drowsy, vomiting, swollen brain, died.
• female, 51, protein avoidance, P2+1, ops, 6 admissions 2002-3.
triad: encephalopathy, resp. alkalosis, hyperammonaemia
plasma ammonia: heparin, EDTA, presto to Lab, +- ice
lethargy, somnolence, irritability, agitation, disorientation, confusion. Need to consider in any young male in AE, overlap with intoxications (alcohol, MDMA, ketamine).
Respiratory alkalosis early feature.
Cerebral oedema due to glutamine accumulation in astrocyte, astrocyte swelling
OTC treatment
- Avoidance of catabolism, glucose polymers when unwell
- Low dietary protein, arginine, benzoate, phenylbutyrate
- Haemofiltration
- Liver transplantation, umbilical vein hepatocyte transfusion
- Gene therapy: NIH NGVL UPenn trial stopped after death (adenovirus E1 E4 del., fever, multi-organ failure)
- 10% dextrose intravenous
major proteins produced by the liver
- Albumin
* Clotting factor
what is albumin?
- Single polypeptide protein MW 66000
- 9-12g produced by the liver each day
- Possible to increase this threefold
- Leaves circulation via interstitium
- Collected by lymphatics
- Returned via thoracic duct
- Rate known as the Transcapillary Escape Rate
Starling equation
NDP = Kf x [(Pc-Pi)-rc(pc-pi)]
why is albumin important?
- Binding and transport
- Maintenance of colloid osmotic pressure
- Free Radicals
- Anticoagulant effects
What causes albumin to decrease?
- Decreased synthesis
- Increased catabolism
- Increased loss
