STUDY CASE:
DETOXIFICATION OF AMMONIA
A 60-year old woman suffer from cirrhosis of liver.. Toxins such as ammonia are not properly metabolized by the liver and can damage brain. Which of the following compounds should be in highest concentration in brain as result of detoxification of ammonia?
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BASIC KNOWLEDGE ON CIRRHOSIS AND THE EFFECTS
CIRRHOSIS
AMMONIA AND LIVER DAMAGE
PROTEIN METABOLISM
- Cirrhosis is a slow progressing disease in which healthy liver tissue is replaced with scar tissue, eventually preventing the liver from functioning properly.
- The scar tissue blocks the flow of blood through the liver and slows the processing of nutrients, hormones, drugs and naturally produced toxins.
- It also shows the production of proteins and other substances made by the liver.
AMMONIA AND LIVER DAMAGE
- The liver removes toxic chemicals from the blood.
- When the liver is damaged from disease and injury, the cells of the liver are unable to function properly.
- They become unable to remove byproducts of metabolism such as ammonia resulting from protein digestion.
- High amounts of ammonium ion in the blood affects the brain with a range of symptoms from mild confusion to possible brain damage and death.
PROTEIN METABOLISM
- Bacteria living in the digestive tract break down proteins for absorption into the body used to repair cells.
- Protein breaks down into nitrogen compounds including ammonia in intestine.
- The bloodstream absorbs this ammonia and takes it first to the liver processing through chemical reactions.
- Ammonia is turned into urea and released from the body in the urine.
- If the liver is damaged and the cells cannot remove ammonia from the blood, the ammonia stays in the blood and enter general circulation resulting in toxicity.
BASIC CONCEPT
- Ammonia is produced as a result of various metabolic activities.
- It has to be detoxified immediately else can prove toxic to the brain cells and other tissues.
MECHANISM OF AMMONIA DETOXIFICATION
FIRST LINE OF DEFENSEGlutamate condenses with ammonia to produce glutamine.
Glutamine is transported to liver. The nitrogen of glutamine can be converted to urea in the liver.
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SECOND LINE OF DEFENSEIn conditions of excess ammonia release the second line of defense involves the formation of glutamate from alpha-ketoglutarate (intermediate if TCA cycle) that can be subsequently used for glutamine synthesis as explained in the first line of defense.
AMMONIA DETOXIFICATION
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IMPLICATION OF AMMONIA INTOXICATION
- In the process of detoxification of ammonia, some of the biologically important compounds are depleted whereas some are produced in highly excess amounts to cause toxicity.
- Glutamine is the final product of detoxification which is transported out of the brain cells in exchange with tryptophan.
- Tryptophan is a precursor of serotonin, the excess of which causes a state of hyper excitation.
- Glutamate and alpha-ketoglutarate are depleted in this process of ammonia detoxification.
- Decreased glutamate, produces less gamma amino butyric acid (GABA), which is an inhibitory transmitter, thus again the result is a state of hyper excitation.
* Glutamate is decarboxylated to produce GABA.
* The reaction is catalyzed by glutamate decarboxylase, that requires the presence of Vitamin B6.
* The reaction is catalyzed by glutamate decarboxylase, that requires the presence of Vitamin B6.
- The second compound that decreased is alpha-ketoglutarate, an intermediate of TCA cycle and the depletion of which causes overall suppression of TCA cycle resulting in a state of energy depletion.
SYMPTOMS OF AMMONIA INTOXICATION
- Slurring of speech
- Blurring of vision
- Tremors
- Convulsions
- Coma
- Death
- The biochemical basis of such symptoms is energy depletion and hyper excitation due to excess serotonin formation and decreased GABA synthesis.
- In cirrhosis of liver, the conversion of ammonia to urea is impaired, the resulting hyperammonemia, proves toxic to brain.
- In severe liver disorders, blood and CSF glutamine levels are increased. (a diagnostic feature of hepatic encephalopathy)
Therefore,
- Alpha-ketoglutarate = Its concentration is DECREASED
- Glutamine = Its concentration is INCREASED
- Glutamate = Its concentration is DECREASED
- GABA = Levels are DECREASED
- Asparagine = Levels are not much affected in ammonia intoxication
CONCLUSION: Glutamine has the highest concentration in brain as result of detoxification of ammonia.