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Ammonia and Urea Cycle

Ammonia (NH3) is a small metabolite that results predominantly from protein and amino acid degradation. It is highly membrane-permeant and readily crosses epithelial barriers in its nonionized form.

Ammonia does not have a physiologic function. However, it is important clinically because it is highly toxic to the nervous system. Because ammonia is being formed constantly from the deamination of amino acids derived from proteins, it is important that mechanisms exist to provide for the timely and efficient disposal fo this molecule. The liver is critical for ammonia catabolism because it is the only tissue in which all elements of the urea cycle, also known as the Krebs-Henseleit cycle, are expressed, providing for the conversion of ammonia to urea. Ammonia is also consumed in the synthesis of nonessential amino acids, and in various facets of intermediary metabolism.

Ammonia Formation and Disposition

Ammonia in the circulation originates in a number of different sites. A diagram showing the major contributors to ammonia levels is shown in 14-1. Note that the liver is efficient in taking up ammonia from the portal blood in health, leaving only approximately 15% to spill over into the systemic circulation.

Intestinal Production

The major contributor to plasma ammonia is the intestine, supplying about 50% of the plasma load. Intestinal ammonia is derived via two major mechanisms. First, ammonia is liberated from urea in the intestinal lumen by enzymes known as ureases. Ureases are not expressed by mammalian cells, but are products of many bacteria, and convert urea to ammonia and carbon dioxide. Indeed, this provides the basis for a common diagnostic test, since H. pylori, which colonizes the gastric lumen and has been identified as a cause of peptic ulcer disease, has a potent urease. Therefore, if patients are given a dose of urea labeled with carbon-13, rapid production of labeled carbon dioxide in the breath is suggestive of infection with this microorganism.

Second, after proteins are digested by either host or bacterial proteases, further breakdown of amino acids generates free ammonia. Ammonia in its unionized form crosses the intestinal epithelium freely, and enters the portal circulation to travel to the liver; however, depending on the pH of the colonic contents, a portion of the ammonia will be protonated to ammonium ion. Because the colonic pH is usually slightly acidic, secondary to the production of short-chain fatty acids, the ammonium is thereby trapped in the lumen and can be eliminated in the stool.

Extraintestinal Production

The second largest contributor to plasma ammonia levels is the kidney. Ammonia is also produced in the liver itself during the deamination of amino acids. Minor additional components of plasma ammonia derive from adenylic acid metabolism in muscle cells, as well as glutamine released from senescent red blood cells.

Urea Cycle

The most important site for ammonia catabolism is the liver, where the elements of the urea cycle are expressed in hepatocytes. Ammonia derived from the sources described earlier is converted in the mitochondria to carbamoyl phosphate, which in turn reacts with ornithine to generate citrulline. Citrulline, in turn, reacts in the cytosol with aspartate, produced by the deamination of glutarate, to yield sequentially arginine succinate then arginine itself. The enzyme arginase then dehydrates arginine to yield urea and ornithine, which returns to the mitochondria and can reenter the cycle to generate additional urea. The net reaction is the combination of two molecules of ammonia with one of carbon dioxide, yielding urea and water.

Urea Disposition

A “mass balance” for the disposition of ammonia and urea is presented in Figure 14-2. As a small molecule, urea can cross cell membranes readily. Likewise, it is filtered at the glomerulus and enters the urine. While urea can be passively reabsorbed across the renal tubule as the urine is concentrated, its permeability is less than that of water such that only approximately half of the filtered load can be reabsorbed. Because of this, the kidney serves as the site where the majority of the urea produced by the liver is excreted. However, some circulating urea may passively back diffuse into the gut, where it is acted on by bacterial ureases to again yield ammonia and (CO2?). Some of the ammonia generated is excreted in the form of ammonium ion; the remainder is again reabsorbed to the handled by the liver once more.

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