Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1979 Mar;63(3):449–460. doi: 10.1172/JCI109322

The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia.

A H Lockwood, J M McDonald, R E Reiman, A S Gelbard, J S Laughlin, T E Duffy, F Plum
PMCID: PMC371973  PMID: 429564

Abstract

The cyclotron-produced radionuclide, 13N, was used to label ammonia and to study its metabolism in a group of 5 normal subjects and 17 patients with liver disease, including 5 with portacaval shunts and 11 with encephalopathy. Arterial ammonia levels were 52-264 micron. The rate of ammonia clearance from the vascular compartment (metabolism) was a linear function of its arterial concentration: mumol/min = 4.71 [NH3]a + 3.76, r = +0.85, P less than 0.005. Quantitative body scans showed that 7.4 +/- 0.3% of the isotope was metabolized by the brain. The brain ammonia utilization rate, calculated from brain and blood activities, was a function of the arterial ammonia concentration: mumol/min per whole brain = 0.375 [NH3]a - 3.6, r = +0.93, P less than 0.005. Assuming that cerebral blood flow and brain weights were normal, 47 +/- 3% of the ammonia was extracted from arterial blood during a single pass through the normal brains. Ammonia uptake was greatest in gray matter. The ammonia utilization reaction(s) appears to take place in a compartment, perhaps in astrocytes, that includes less than 20% of all brain ammonia. In the 11 nonencephalopathic subjects the [NH3]a was 100 +/- 8 micron and the brain ammonia utilization rate was 32 +/- 3 mumol/min per whole brain; in the 11 encephalopathic subjects these were respectively elevated to 149 +/- 18 micron (P less than 0.01), and 53 +/- 7 mumol/min per whole brain (P less than 0.01). In normal subjects, approximately equal to 50% of the arterial ammonia was metabolized by skeletal muscle. In patients with portal-systemic shunting, muscle may become the most important organ for ammonia detoxification. Muscle atrophy may thereby contribute to the development of hyperammonemic encephalopathy with an associated increase in the brain ammonia utilization rate.

Full text

PDF
449

Images in this article

454Image
on p.454
456Image
on p.456

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALMAN R. W., EHRMANTRAUT W. R., FAZEKAS J. F., TICKTIN H. E. Cerebral metabolism in hepatic insufficiency. Am J Med. 1956 Dec;21(6):843–849. doi: 10.1016/0002-9343(56)90098-5. [DOI] [PubMed] [Google Scholar]
  2. BERL S., TAKAGAKI G., CLARKE D. D., WAELSCH H. Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver. J Biol Chem. 1962 Aug;237:2562–2569. [PubMed] [Google Scholar]
  3. BESSMAN S. P., BRADLEY J. E. Uptake of ammonia by muscle; its implications in ammoniagenic coma. N Engl J Med. 1955 Dec 29;253(26):1143–1147. doi: 10.1056/NEJM195512292532602. [DOI] [PubMed] [Google Scholar]
  4. Brown T., Hug G., Lansky L., Bove K., Scheve A., Ryan M., Brown H., Schubert W. K., Partin J. C., Lloyd-Still J. Transiently reduced activity of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of children with Reye's syndrome. N Engl J Med. 1976 Apr 15;294(16):861–867. doi: 10.1056/NEJM197604152941602. [DOI] [PubMed] [Google Scholar]
  5. Clarke L. P., Laughlin J. S., Mayer K. Quantitative organ-uptake measurement. Radiology. 1972 Feb;102(2):375–382. doi: 10.1148/102.2.375. [DOI] [PubMed] [Google Scholar]
  6. Clarke L. P., Maugham E. Z., Laughlin J. S., Knapper W. H., Mayer K. Calibration methods for measuring splenic sequestration by external scanning. Med Phys. 1976 Sep-Oct;3(5):324–327. doi: 10.1118/1.594288. [DOI] [PubMed] [Google Scholar]
  7. DUDA G. D., HANDLER P. Kinetics of ammonia metabolism in vivo. J Biol Chem. 1958 May;232(1):303–314. [PubMed] [Google Scholar]
  8. Fischer J. E., Rosen H. M., Ebeid A. M., James J. H., Keane J. M., Soeters P. B. The effect of normalization of plasma amino acids on hepatic encephalopathy in man. Surgery. 1976 Jul;80(1):77–91. [PubMed] [Google Scholar]
  9. Folbergrová J., Passonneau J. V., Lowry O. H., Schulz D. W. Glycogen, ammonia and related metabolities in the brain during seizures evoked by methionine sulphoximine. J Neurochem. 1969 Feb;16(2):191–203. doi: 10.1111/j.1471-4159.1969.tb05937.x. [DOI] [PubMed] [Google Scholar]
  10. Ganda O. P., Ruderman N. B. Muscle nitrogen metabolism in chronic hepatic insufficiency. Metabolism. 1976 Apr;25(4):427–435. doi: 10.1016/0026-0495(76)90075-5. [DOI] [PubMed] [Google Scholar]
  11. Garber A. J., Karl I. E., Kipnis D. M. Alanine and glutamine synthesis and release from skeletal muscle. II. The precursor role of amino acids in alanine and glutamine synthesis. J Biol Chem. 1976 Feb 10;251(3):836–843. [PubMed] [Google Scholar]
  12. Gjedde A., Lockwood A. H., Duffy T. E., Plum F. Cerebral blood flow and metabolism in chronically hyperammonemic rats: effect of an acute ammonia challenge. Ann Neurol. 1978 Apr;3(4):325–330. doi: 10.1002/ana.410030409. [DOI] [PubMed] [Google Scholar]
  13. Grubb R. L., Jr, Raichle M. E., Eichling J. O., Ter-Pogossian M. M. The effects of changes in PaCO2 on cerebral blood volume, blood flow, and vascular mean transit time. Stroke. 1974 Sep-Oct;5(5):630–639. doi: 10.1161/01.str.5.5.630. [DOI] [PubMed] [Google Scholar]
  14. Hindfelt B., Plum F., Duffy T. E. Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J Clin Invest. 1977 Mar;59(3):386–396. doi: 10.1172/JCI108651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kuhl D. E., Edwards R. Q., Ricci A. R., Yacob R. J., Mich T. J., Alavi A. The Mark IV system for radionuclide computed tomography of the brain. Radiology. 1976 Nov;121(2):405–413. doi: 10.1148/121.2.405. [DOI] [PubMed] [Google Scholar]
  16. Lowenstein J. M. Ammonia production in muscle and other tissues: the purine nucleotide cycle. Physiol Rev. 1972 Apr;52(2):382–414. doi: 10.1152/physrev.1972.52.2.382. [DOI] [PubMed] [Google Scholar]
  17. Martinez-Hernandez A., Bell K. P., Norenberg M. D. Glutamine synthetase: glial localization in brain. Science. 1977 Mar 25;195(4284):1356–1358. doi: 10.1126/science.14400. [DOI] [PubMed] [Google Scholar]
  18. McDERMOTT W. V., Jr Metabolism and toxicity of ammonia. N Engl J Med. 1957 Nov 28;257(22):1076–1081. doi: 10.1056/NEJM195711282572205. [DOI] [PubMed] [Google Scholar]
  19. Orloff M. J., Charters A. C., 3rd, Chandler J. G., Condon J. K., Grambort D. E., Modafferi T. R., Levin S. E., Brown N. B., Sviokla S. C., Knox D. G. Portacaval shunt as emergency procedure in unselected patients with alcoholic cirrhosis. Surg Gynecol Obstet. 1975 Jul;141(1):59–68. [PubMed] [Google Scholar]
  20. POSNER J. B., PLUM F. The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy. J Clin Invest. 1960 Aug;39:1246–1258. doi: 10.1172/JCI104140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Phelps M. E., Hoffman E. J., Coleman R. E., Welch M. J., Raichle M. E., Weiss E. S., Sobel B. E., Ter-Pogossian M. M. Tomographic images of blood pool and perfusion in brain and heart. J Nucl Med. 1976 Jul;17(7):603–612. [PubMed] [Google Scholar]
  22. Rudman D., DiFulco T. J., Galambos J. T., Smith R. B., 3rd, Salam A. A., Warren W. D. Maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects. J Clin Invest. 1973 Sep;52(9):2241–2249. doi: 10.1172/JCI107410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schenker S., Breen K. J., Hoyumpa A. M., Jr Hepatic encephalopathy: current status. Gastroenterology. 1974 Jan;66(1):121–151. [PubMed] [Google Scholar]
  24. Stein T. P., Leskiw M. J., Wallace H. W. Metabolism of parenterally administered ammonia. J Surg Res. 1976 Jul;21(1):17–20. doi: 10.1016/0022-4804(76)90004-4. [DOI] [PubMed] [Google Scholar]
  25. WEBSTER L. T., Jr, GABUZDA G. J. Ammonium uptake by the extremities and brain in hepatic coma. J Clin Invest. 1958 Mar;37(3):414–424. doi: 10.1172/JCI103621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Walker C. O., Schenker S. Pathogenesis of hepatic encephalopathy--with special reference to the role of ammonia. Am J Clin Nutr. 1970 May;23(5):619–632. doi: 10.1093/ajcn/23.5.619. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES