Abstract
Ammonia is thought to be central in the pathogenesis of hepatic encephalopathy and has been of importance to generations dating back to the early Egyptians. Hippocrates 2500 years ago described ‘encephalopathy’ simply translated as ‘inside head suffering.’ Over 1500 papers have been written on hepatic encephalopathy since 1966, but only a minority of these actually refer to the original observation of hepatic encephalopathy and the link with ammonia made by Marcel Nencki and Ivan Pavlov in 1893 with very little acknowledgement being made to the early landmark studies which described the importance of the muscle and kidneys in maintaining ammonia homeostasis as well as the liver and gut. Furthermore, infection was recognized as being an important modulator of brain function by the ancient Greek physicians and philosophers. This review focuses upon the original experiments of Nencki and Pavlov and describes how they fit into what we understand about the pathophysiology and treatment of hepatic encephalopathy today.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- HE:
-
hepatic encephalopathy
- PCS:
-
portacaval shunt
References
Balata, S., Olde Damink, S., Ferguson, K., Marshall, I., Hayes, P., Deutz, N., Williams, R., Wardlaw, J., and Jalan, R. (2003). Changes in neuropsychology, magnetic resonance spectroscopy and magnetization transfer following induced hyperammonemia. Hepatology 37:931–939.
Budge, E. (1985). Gods of the Egyptians, Dover, New York.
Chadwick, J., and Mann, W. (1950). The Medical Works of Hippocrates, Blackwell, Oxford, pp. 50, 223.
Clemmesen, J., Larsen, F., Kondrup, J., Hansen, B., and Ott, P. (1999). Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653.
Cordoba, J., Alonso, J., Rovira, A., Jacas, C., Sanpedro, F., Castells, L., Vargas, V., Maragrit, C., Kullsevsky, J., Esteban, R., Guardia, J. (2001). The development of low-grade cerebral oedema in cirrhosis is supported by the evolution of 1H-magnetic resonance abnormalities after liver transplantation. Journal of Hepatology 35:598–604.
Dejong, C., Deutz, N., and Soeters, P. (1993). Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat. J. Clin. Invest. 92:2834–2840.
Floch, M., Katz, J., and Conn, H. (1970). Qualitative and quantitative relationships of the faecal flora in cirrhotic patients with portal systemic encephalopathy and following portacaval anastomosis. Gastroenterology 59: 70–75.
Hagen, S., Wu, H., and Morrison, S. (2000). NH(4)Cl inhibition of acid secretion: Possible involvement of an apical (+) channel in bullfrog oxyntic cells. Am. J. Physiol. Gastrointest. Liver Physiol. 279:G400– G410.
Hahn, M., Massen, O., Nencki, M., and Pavlov, I. (1893). Die Eck’sche fistel zwischen der unteren hohlvene und der pfortader und ihre folgen fur den organismus. Arch. Exp. Pathol. Pharm. 32:161–210.
Jalan, R., Olde Damink, S.W.M., Hayes, P.C., Deutz, N.E.P., and Lee, A. (2004). Pathogenesis of intracranial hypertension in acute liver failure: Inflammation, ammonia and cerebral blood flow. J. Hepatol. 41:613–620.
Jalan, R., Olde Damink, S.W.M., Deutz, N.E.P., and Lee, A., and Hayes, P.C. (1999). Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 354:1164–1168.
Lockwood, A., McDonald, J., Reiman, R., Gelbard, A., Laughlin, J., Duffy, T., et al. (1979). The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J. Clin. Invest. 63:449– 460.
Lockwood, A., Yap, E., and Wong, W. (1991). Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J. Cerebr. Blood Flow Metab. 11:337–341.
Marcaida, G., Felipo, V., Hermenegildo, C., Minana, M.D., and Grisolia, S. (1992). Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett 296:67–68.
Master, S., Gottstein, J., and Blei, A. (1999). Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 30:876–880.
Mendez, M. (1996). Delirium. In (W. Bradley, R. Daroff, and G. Fenichel, eds), Neurology in Clinical Practice, Butterworth-Heinemann, Boston, pp. 29–38.
Nance, F., Kayfman, H., and Kline, D. (1974). Role of urea in the hyperammonemia of germ-free Eck fistula dogs. Gastroenterology 66:108–112.
Neiger, R., and Simpson, K. (2000). Helicobacter infection in dogs and cats: Facts and fiction. J. Vet. Int. Med. 14:125–133.
Nencki, M., Pawlow, J., and Zaleski, J. (1896). Ueber den ammoniakgehalt des blutes under der organe und die harnstoffbildung bei den saugethieren. Arch. Exp. Pathol. Pharmakol. 37:26–51.
Nencki, M., and Zaleski, J. (1895). Ueber die Bestimmung des Ammoniaks in Thierischen Fluessigkeiten und Geweben. Arch. Exp. Pathol. Pharmakol. 36:385–396.
Olde Damink, S., Deutz, N., Dejong, C., Soeters, P., and Jalan, R. (2002a). Interorgan ammonia metabolism in liver failure. Neurochem. Int. 41:177–188.
Olde Damink, S., Jalan, R., Hayes, P., Redhead, D., Deutz, N., and Soeters, P. (2002b). Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology 36:1163–1171.
Osler, W. (1892). The Principles and Practice of Medicine, Appleton, New York, pp. 114–118.
Owen, E., Mozzoli, M., Reichle, F., Kreulen, T., Owen, R., Boden, G., et al. (1985). Hepatic and renal metabolism before and after portosystemic shunts in patients with cirrhosis. J. Clin. Invest. 76:1209–1217.
Owen, E., Tyor, M., Flanagan, J., and Berry, J. (1960). The kidney as a source of blood ammonia in patients with liver disease: The effect of acetazolamaide. J. Clin. Invest. 39:288–294.
Phillips, G., Schwartz, R., Gabuzda, G., and Davidson, C. (1952). The syndrome of impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances. New Engl. J. Med. 247:239–246.
Pickett, J., et al. (2000). The American Heritage Dictionary of the English Language, Houghton Mifflin, Boston.
Rao, K.V., and Norenberg, M.D. (2001). Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab. Brain Dis. 16:67–78.
Rolando, N., Wade, J., Davalos, M., Wendon, J., Philpott-Howard, J., and Williams, R. (2000). The systemic inflammatory response syndrome in acute liver failure. Hepatology 32:734–739.
Schalm, S., and van der Mey, T. (1979). Hyperammonemia coma after hepatectomy in germ-free rats. Gastroenterology 77:231–234.
Shawcross, D., Davies, N., Williams, R., and Jalan, R. (2004). Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J. Hepatol. 40:247–254.
Tan, K.H., Harrington, S., Purcell, W.M., and Hurst, R.D. (2004). Peroxynitrite mediates nitric oxide-induced blood-brain barrier damage. Neurochem. Res. 29:579–587.
Todes, D. (2002). Pavlov’s Physiology Factory: Experiment, Interpretation, Laboratory Enterprise, The John Hopkins University Press, Baltimore.
Traber, P., Dalcanto, M., Ganger, D., Blei, A.T. (1989). Effect of body temperature on brain aedema and encephalopathy in the rat after hepatic devascularisation. Gastroenterology 96:885–891.
Vasconez, C., Ignasi Elizalde, J., Llach, J., Gines, A., de la Rosa, C., Fernadez, R., Mas, A., Santamaria, J., Bordas, J., Pique, J., and Teres, J. (1999). Helicobacter pylori, hyperammonemia and subclinical portosystemic encephalopathy: Effects of eradication. J. Hepatol. 30:260–264.
Weber, F.J., and Veach, G. (1979). The importance of the small intestine in gut ammonium production in the fasting dog. Gastroenterology 77:235–240.
Webster, L., and Gabuzda, G. (1958). Ammonium uptake by the extremities and brain in hepatic coma. J. Clin. Invest. 37:414–424.
Windmueller, H. (1982). Glutamine utilization by the small intestine. Adv. Enzyme Regul. 53:210–237.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shawcross, D.L., Damink, S.W.M.O., Butterworth, R.F. et al. Ammonia and Hepatic Encephalopathy: The More Things Change, the More They Remain the Same. Metab Brain Dis 20, 169–179 (2005). https://doi.org/10.1007/s11011-005-7205-0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11011-005-7205-0