Metabolic encephalopathies comprise a spectrum of clinical disorders that cause a disruption of cerebral function, resulting in global brain dysfunction. At the root cause of these disorders are various metabolic, toxic, or systemic disturbances, each with the potential to impose dire physiological consequences if not rapidly identified.
Ammonia, by nature, is an inorganic compound consisting of nitrogen bonded with three atoms of hydrogen to form NH3. From a physiological standpoint, it is a naturally occurring compound mainly derived as a by-product of nitrogen metabolism. Its production is constantly occurring in all tissues with approximately 1000 mmol of ammonia produced daily. Despite this, however, it is highly recognized as neurotoxic and only a tiny fraction remains free in the systemic circulation due to various metabolic pathways either leading to degradation and/or excretion of ammonia.
Excessive serum ammonia levels do not necessarily correlate with severity of disease when dealing with the encephalopathic patient; however, alterations of its metabolism are highly considered to be a contributing factor. Although ammonia is primarily generated by colonic bacteria residing in the gut, there are five organs that each play a role in its overall metabolism: the gut, brain, muscle, kidney, and liver.
Ammonia is primarily a by-product of nitrogen metabolism and breakdown of amino acids by bacteria residing in the gut. Along the intestinal wall and primarily in the colon are urease-producing bacteria, among other bacterial species, that can also generate ammonia from the small amount of urea that re-enters the gut via the enterohepatic circulation. Muscle also has the capacity to produce ammonia at a magnitude that correlates with the duration and intensity of muscle work. In times of intense exercise or during seizures, the higher energy requirements of skeletal muscle drive the generation of ammonia via deamination of adenosine monophosphate in the purine nucleotide cycle along with breakdown of branched-chain amino acids.
Despite the constant production of ammonia by the tissues, its concentration in the systemic circulation is kept at a minimum primarily by the hepatocytes of the liver. These cells contain the enzymes that facilitate the urea cycle, a process by which ammonia is detoxified to urea, a much less toxic form. A large portion of the urea formed by the liver is taken up by the kidneys where it plays a vital role in renal handling and excretion of acid. The small portion that remains re-enters the enterohepatic circulation and is hydrolyzed to ammonia by urease-producing bacteria. Skeletal muscle has the capacity to provide some buffering capacity in situations where serum ammonia levels are high. It does this through conversion of ammonia to glutamine using the enzyme, glutamine synthetase. This enzyme is also present in the astrocytes of brain tissue and is used to provide a constant source of glutamine used in the synthesis of two important neurotransmitters: glutamate and GABA.
Mechanisms of Hyperammonemia
- Increased Ammonia Production
- Intense Exercise
- GI Hemorrhage
- Steroid administration
- Small Intestinal Bacterial Overgrowth
- Multiple Myeloma
- Total Parenteral Nutrition
- Impaired Ammonia Clearance
- Liver Failure (Acute/Chronic)
- Portosystemic Shunt (TIPSS)
- Drug Interference with the Urea Cycle
- Drugs that Cause Liver Failure
- Inborn Errors of Metabolism
- Ornithine Transcarbamylase Deficiency
- Carbamyl Synthetase Deficiency
- Argininosuccinate Lyase Deficiency
- Fatty Acid Oxidation Disorders
- Organic Aciduria
- Renal Tubular Acidosis (Type 1 – Distal)
Through our understanding of ammonia generation along with its various pathways of degradation, treatment strategies become more evident with a higher likelihood of success. In the following article in the series, different case scenarios will be highlighted.
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