Case:
A 60 year-old-woman suffers 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?
a.Alpha ketoglutarate
b.Glutamine
c.Glutamate
d.Gamma amino butyric acid
e.Asparagine
A 60 year-old-woman suffers 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?
a.Alpha ketoglutarate
b.Glutamine
c.Glutamate
d.Gamma amino butyric acid
e.Asparagine
What is a cirrhosis ?
Cirrhosis is a type of disease which is caused by a scar tissue that replace a healthy liver tissue. This causes the liver to not be able to function properly. It is a condition in which liver slowly deteriorates and malfunctions due to chronic injury which causes the blocking flow of blood and lymph to the liver.
Cirrhosis is a type of disease which is caused by a scar tissue that replace a healthy liver tissue. This causes the liver to not be able to function properly. It is a condition in which liver slowly deteriorates and malfunctions due to chronic injury which causes the blocking flow of blood and lymph to the liver.
So basically, the liver detoxifies chemicals and metabolizes drugs. When cirrhosis occur which means damage occur on the liver, it will not be able to function properly.
WHAT IS THE RELATIONSHIP BETWEEN AMMONIA AND DAMAGED LIVER ?
Ammonia is a result from protein digestion, thus there is a high ammonium ion in the blood which then will affects the brain with a range of symptoms from mild confusion to possible brain damage and death. If the liver function in its proper way, ammonia in the blood will be send toward the liver to undergo chemical reactions. Ammonia is then turned into urea and become urine and is released from the body. BUT, if liver that function to remove toxic chemicals from blood are unable to removes these ammonium ion. Ammonia thats stays in the blood will causes toxicity.
WHAT IS THE MECHANISM OF AMMONIA DETOXIFICATION ?
FIRST LINE OF DEFENSE
Glutamate condense with ammonia to produce glutamine
Glutamate condense with ammonia to produce glutamine
- These reaction is catalyzed by Glutamine Synthethase.
- When glutamine is formed, it is then transported to liver
- Nitrogen of the glutamine is converted to urea in liver (see figure below)
- Hydrolytic of the amide in nitrogen of the glutamine is released as ammonia
- This reaction catalysed by Glutaminase in liver
- Ammonia that is release is the detoxified producing urea
SECOND LINE OF DEFENSE
This occur when there is an excess of ammonia released. This involves the formation of Glutamate from Alpha Ketoglutarate which is an intermediate of the TCA cycle that can used for Glutamine synthesis . Reaction is represents as the figure below:
- Figure above is the ammonia detoxification
- Glutamate dehydrogenase catalyze the first reaction which is reversible , but in the liver the reaction is directed towards Alpha Ketoglutarate formation and the released of ammonia is used for the synthesis of urea.
- Glutamate to Glutamine is an energy that requires and irreversible reaction catalyzed by Glutamine Synthethase
What is the implication of ammonia intoxification ?
- In the process of the detoxification of an ammonia, some of the compound are depleted whereas some are produced in a very high amount which can causes toxicity to occur.
- The final product if detoxification mentioned above is Glutamine which later be 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 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.
conclusion ?
- 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.