| Course of LABORATORY MEDICINE Nitrogen balance Nitrogen is the second most abundant element in our diet after carbon: proteins contain an average 16% by weight of nitrogen and a diet of 1 g protein/kg body weight per day provides approximately 0.8-1 mol of N mainly absorbed in the form of aminoacids derived form the digestion of proteins. In an adult with neutral nitrogen balance, the same amount of nitrogen must be excreted, mainly via the urine. The most important organs involved in nitrogen balance are the liver and the kidney, but relevant roles are also played by the gut and muscle.
Dietary aminoacids are by far the most relevant component of N intake. Dietary proteins are digested by proteases in the stomach and small intestine and free aminoacids are absorbed and carried to the liver via the portal vein. In the liver they are either used to synthesize serum albumin, which the cells can uptake to digest it to aminoacids for protein synthesis, or metabolized via deamination and the urea cycle. Circulating aminoacids in the blood attain only low concentrations (< 1 mM). The urea cycle in the liver is very efficient and essentially all the ammonia produced by aminoacid deamination is converted to urea, with very little escape in the circulation. Urea is escreted in the urine by the kidney as the principal by-product of nitrogen. Ammonia and ammonium ion (NH3 and NH4+) are produced in the gut by bacterial catabolism of aminoacids and by bacterial urease. Part of the ammonia thus produced ends up in the feces, but part is absorbed in the blood and carried to the liver, where it is converted to urea; moreover, the liver and muscle can use ammonia to convert glutamic acid to glutamine, an important donor of ammonia for several biosynthetic pathways. The kidney possesses glutaminase and converts glutamine to ammonia and α-ketoglutarate in the process of urine acidification; however part of kidney produced ammonia is reabsorbed in the blood and carried to the liver for conversion to urea. The absorption of ammonia from the gut is dependent on the diet, but an average estimate is reported in Table 1. Nucleic acids present in the diet are digested by pancreatic nucleases and converted to nucleosides or free bases, which are absorbed and used for DNA and RNA biosynthesis, via the salvage pathway. If absorbed in excess nitrogenous bases are metabolized. Nitrogen from pyrimidine bases is released as ammonia, and converted to urea by the liver; nitrogen from purine bases is converted to urate / uric acid and excreted as such by the kidney. The dietary content of nucleic acids is variable, and cannot be reliably estimated from the daily excretion of uric acid because of the possible concomitance with de novo biosynthesis (see the lecture on nucleotide metabolism). Creatinine is a by-product of creatine, a high energy phosphate donor present in several tissues, most notably in the striated muscles. The biosynthetic pathway requires Gly and Arg, from which guanidineacetate and ornitine are produced by the enzyme aminidino transferase. Guanidineacetate is methylated to creatine by a specific methyltransferase that uses S-adenosylMet as a methyl donor. The conversion of creatine to creatinine is spontaneous and creatinine is released in the plasma ad excreted by the kidney.
Hyperammonemias and hepatic encephalopathy In the course of liver diseases or genetic defects of the urea cycle, biosynthesis of urea is impaired and the concentration of ammonia in the blood increases. Ammonia is toxic for several organs and in particular for the brain. Paradoxically, the main source of ammonia in hyperammonemia in chronic liver disease is not dietary aminoacids (which may contribute), but ammonia absorbed by the gut or produced by the kidney. The reason for this is that the loss of functional liver parenchima impairs both the urea cycle and the deamination of aminoacids; thus relatively little ammonia derives from the latter. Since aminoacid deamination and metabolism, as well as synthesis of serum albumin, are impaired, the patient may present aminoaciduria. Absorption of ammonia produced by intestinal bacteria amounts to some 80-90 mg/day, of which, under healthy conditions, up to 70% is removed and converted to urea during the first passage of portal blood through the liver; the remaining 30% is removed by other organs or by the liver. Additional ammonia is produced by the kidneys that convert glutamine to ammonium ion and excrete this anion in the urine as a mechanism of acid elimination. Part of the ammonia produced by the kidneys, however, is reabsorbed in the blood and carried to the liver. In the course of liver failure ammonia absorbed by the gut or produced by the kidney is only slowly converted to urea and accumulates in the blood leading to hyperammonemia and liver encephalopathy. Consistently, treatments aimed to replace the intestinal microbiota with species that do not produce urea are effective in reducing ammoniemia in patients suffering of chronic liver failure, whereas reducing dietary proteins has relatively minor effects on hyperammonemia, and may instead cause sarcopenia. The drugs used to control the intestinal bacterial flora are lactulose or lactitol (metabolized by many non-urease producing bacteria) and rifaximine (a non absorbed antibiotic). Further readings Levitt MD, Levitt DG. Use of quantitative modelling to elucidate the roles of liver, gut, kidney, and muscle in ammonia homeostasis ... Int. J. Gen. Med. 2019; 12: 367-380. Home of this course |
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