Ammonia is a compound found within the human body. It is a major byproduct of protein catabolism and is required for the anabolism of certain essential cellular compounds. Extra amounts of ammonia are processed by the liver and kidneys in order to keep blood levels within a tightly controlled range. If levels build up and exceed this range then severe neurological damage and even death can occur.
Ammonia is a waste product produced by the body as a byproduct of metabolism. It is mainly produced within the digestive tract however it can also be produced wherever amino acid breakdown occurs within the body. The major areas in the body that produce ammonia are the intestines, skeletal muscle, liver, and kidneys. The body gains energy from proteins via the Kreb’s Cycle which occurs within the mitochondria of all cells. In this process some of the intermediary products produced within the cycle can be converted to glutamate if transaminated for other metabolic processes. It is the conversion of glutamate to α-ketoglutarate via the enzyme glutamate dehydrogenase that creates ammonia. Glutamate can also be produced from glutamine via a hydrolysis reaction; the addition of water and glutaminase produces the compound glutamate. Both of the aforementioned reactions are constantly in flux within the cells as needed producing ammonia as a waste product. In order to rid the body of excess ammonia the hepatocytes in the liver metabolize the ammonia into urea. This is accomplished via the Krebs-Henseleit urea cycle which is a combination of the Krebs and urea cycle that specifically processes ammonia. The urea is then excreted via the kidneys without harming the body. Some ammonia is also produced and excreted by the kidneys. This occurs within the renal tubular cells as they generate ammonia via the glutamate reaction. Because the tubular cells are selectively permeable the ammonia cannot get back through into the blood stream and is excreted directly into the urine. In the event that the liver or kidneys are not working properly urea and ammonia can back up into the system and these cycles will shut down causing toxic amounts of ammonia to build up in the blood stream.
It is normal to have low levels of ammonia in the blood stream as it is constantly being produced by the body, however high levels can hold much clinical significance for a physician. Normal ranges for ammonia can differ between labs. As a general rule patients less than 30 days old have an ammonia level around 64-107 umol/L, 1 month to 12 years old is around 29-57 umol/L, and greater than 12 years old is around 11-32 umol/L. While hyperammonemia has many different causes its overall effect on the body is expressed solely as neurological damage. Ammonia can cross the blood-brain barrier via passive diffusion. It needs to be able to do this because neurons need to use energy from the Kreb’s cycle just like all other cells in the body. The problem occurs when ammonia builds up to toxic levels in the cerebrospinal fluid. At this point all sorts of important brain functions begin to become inhibited causing brain swelling and alteration in cognition. If the situation is left unchecked eventually the body will fall into a coma and die.
Hyperammonemia can be caused by either an inherited disorder or it can be caused by an acquired illness. Inherited causes include inherited deficiencies of urea cycle enzymes such as lysine and ornithine. These disorders usually manifest in infancy however there are rare cases that manifest in adulthood. There are dozens of inherited disorders that affect enzymes related to ammonia metabolism the key is that the outcome is still the same if ammonia levels become toxic. The list of acquired causes of hyperammonemia is a bit more varied. The two big causes are liver and kidney failure. Severe liver failure directly impacts ammonia metabolism whereas kidney failure affects the body’s ability to excrete urea causing a backup of ammonia. A third cause is Reye’s syndrome which occurs in children. This occurs when a child has a viral infection and the liver becomes overloaded due to aspirin toxicity. Once the liver is overworked then the ammonia levels begin to back up to toxic levels and cause damage. Other drugs such as heparin and valproic acid will actually increase ammonia. Tetracycline and diphenhydramine will decrease ammonia. The key to finding the cause of hyperammonemia is determining at what point in the body the metabolic cycle is getting jammed up.
Treatment for hyperammonemia is relatively simple in concept; fix the metabolic cycle. For inherited enzyme deficiencies a change in diet is usually required. For patients with acquired causes of hyperammonemia treatment can be as simple as adhering to a low protein diet to something as drastic as undergoing a liver transplant. In general to treat acute hyperammonemia physicians can give a patient an intravenous solution of sodium benzoate and phenylacetate to remove excess nitrogen from the blood. Dialysis can also be performed if needed to remove excess toxins. These are quick fixes though, the main goal is to treat the underlying condition that created the environment of hyperammmonemia.
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* Glutamic Acid. (2009). Retrieved December 20, 2009 from http://en.wikipedia.org/wiki/Glutamic_acid