Ammonia Metabolism and Transport

Ammonia Metabolism

• Ammonia is a byproduct of amino acid metabolism, transamination, and deamination, as well as other nitrogenous compounds like biogenic amines and nitrogenous bases in purines or pyrimidines.
• Intestinal bacteria, like urease, also produce ammonia from urea.
• Ammonia is toxic, particularly to the central nervous system (CNS).
• The liver converts ammonia to less toxic urea, and excretes it in urine.

Ammonia Transport

• Ammonia is transported in the blood in the form of ammonium ions (NH4+).
• The hepatic portal vein carries blood from the gastrointestinal tract to the liver, where high concentrations of ammonia are found compared to systemic blood.
• The liver quickly removes ammonia from the portal blood, making blood leaving the liver virtually ammonia-free.
• This detoxification process is critical as even small amounts of ammonia are toxic to the CNS.

Biogenic Amines

• Biogenic amines include dopamine, norepinephrine, epinephrine, histamine, and serotonin. These are important neurotransmitters.
• Catecholamines (dopamine, norepinephrine, and epinephrine) and histamine are other nitrogenous compounds metabolized by similar mechanisms.

Clinical Significance of Ammonia

• Severe liver impairment can cause collateral circulation in the liver, which bypasses the liver, leading to higher ammonia levels.
• Surgical procedures like Eck-fistula can also create alternative pathways for blood flow.
• Elevated ammonia levels (Hyperammonemia) is associated with neurological problems like coma and mental retardation.
• Elevated ammonia can cause a distinctive neurological tremor known as a flapping tremor.
• Increased ammonia levels impair neuronal function.

Hyperammonemia (Classification)

• Acquired hyperammonemia: Often due to cirrhosis of the liver or other liver diseases that impair the liver's ability to process ammonia.
• Inherited hyperammonemia: Resulting genetic defects in urea cycle enzymes, leading to impaired ammonia detoxification.

Glasgow Coma Scale (GCS)

• A scale used to assess the level of consciousness.
• A tool commonly used in medical settings, in particular in cases of trauma or neurological dysfunction, with scoring used to classify the severity.

Mechanism of Urea

• The urea cycle is a metabolic pathway for converting ammonia (toxic) into urea (less toxic).
• The urea cycle is critical, converting ammonia to less toxic substances that can be excreted by the body.
• The Urea cycle involves five sequential enzymatic reactions, with the first two in the mitochondria and the remaining in the cytoplasm.
• The cycle also involves several important intermediates like citrulline, argininosuccinate, and arginine.
• This cycle links with the citric acid cycle (TCA) through fumarate
• It is a five-step cyclic process, using five different enzymes.
• Urea is the end product of the protein metabolism, the excess nitrogen is converted to urea.
• Urea is excreted as part of urine.
• Urea accounts for 80-90% of nitrogen excretion.

Urea Cycle Enzymes

• Reaction 1: Synthesis of carbamoyl-phosphate (mitochondrial)

• Reaction 2: Synthesis of citrulline (mitochondrial).

• Reaction 3: Synthesis of argininosuccinate (cytosolic).

• Reaction 4: Cleavage of argininosuccinate (cytosolic).

• Reaction 5: Cleavage of arginine to form ornithine and urea (cytosolic)

• Ammonia and CO2 combine to produce carbamoyl phosphate.

• The enzyme arginase catalyzes hydrolysis and the guanidine group, releasing urea and regenerating ornithine.

• The cycle requires 3 ATP molecules for each cycle, with 2 spent for the creation of carbamoyl phosphate and 2 during production of Arginosuccinate.

Protein Turnover

• Humans constantly break down and synthesize proteins.
• Proteins are major nitrogenous sources in the body.
• Protein turnover plays a significant role in nitrogen metabolism and waste production.
• 1-2% of the total body protein is turned over daily, mostly in muscles.
• Protein breakdown produces amino acids, some of which will contribute to the production of nitrogenous wastes that need processing by the liver for detoxification.

Ammonia Toxicity

• High ammonia levels can increase glutamine formation and decrease the formation of GABA.
• This disruption can lead to neurological symptoms, including tremors.
• Flapping tremors are a common neurological sign associated with high ammonia levels.
• Disruptions to the TCA cycle and neurotransmitter function are consequences of high ammonia.

Clinical Importance of Blood Urea

• Normal blood urea levels range from 10-40 mg/dL.
• Higher protein intake can increase blood urea marginally.
• 15-30 grams of urea are typically excreted daily in the urine.
• Blood urea is a screening test to assess kidney function.
• Elevated blood urea levels, can be classified as pre-renal, renal and post-renal.

Pre-renal azotemia and elevation in blood urea

• Increased protein breakdown (after major surgery, prolonged fever, diabetic coma).
• Elevated in conditions like leukemia (anemia of blood).

Renal azotemia and elevation in blood urea

• Conditions like acute glomerulonephritis, chronic nephritis, nephrosclerosis, polycystic kidney disease.

Post-renal azotemia and elevation in blood urea

• Obstructions in the urinary tract (tumors, stones, or enlarged prostate).
• This causes increased reabsorption of urea in kidney tubules.

Explore the crucial processes of ammonia metabolism and transport in the body. This quiz covers ammonia's production as a byproduct, its toxic effects on the central nervous system, and the liver's detoxification mechanism. Test your knowledge on the role of biogenic amines and intestinal bacteria in this process.