Abstract
Background/Aims
Studies in acute liver failure show correlation between evidence of a systemic inflammatory
response syndrome (SIRS) and progression of hepatic encephalopathy (HE). We tested
the hypothesis that SIRS mediators, such as nitric oxide and proinflammatory cytokines,
may exacerbate the neuropsychological effects of hyperammonemia in cirrhosis.
Methods
Ten patients with cirrhosis were studied, 24–36 h after admission with clinical evidence
of infection, and following its resolution. Hyperammonemia was induced by oral administration
of an amino-acid (aa) solution mimicking hemoglobin composition. Inflammatory mediators,
nitrate/nitrite, ammonia, aa profiles and a battery of neuropsychological tests were
measured.
Results
The hyperammonemia generated in response to the aa solution was similar prior to,
and after resolution, of the inflammation (P=0.77). With treatment of the infection there were significant reductions in white
blood cell count (WBC), C-reactive protein (CRP), nitrate/nitrite, interleukin-6,
interleukin-1β and tumour necrosis factor α. Induced hyperammonemia resulted in significant
worsening of the neuropsychological scores when patients showed evidence of SIRS but
not after its resolution.
Conclusions
The significant deterioration of neuropsychological test scores following induced
hyperammonemia during the inflammatory state, but not after its resolution, suggests
that the inflammation and its mediators may be important in modulating the cerebral
effect of ammonia in liver disease.
Keywords
Abbreviations:
aa (amino acid), BBB (blood–brain barrier), CNS (central nervous system), HE (hepatic encephalopathy), IL-6 (interleukin 6), IL-1β (interleukin 1 β), NO (nitric oxide), TNF-α (tumour necrosis factor α), SIRS (systemic inflammatory response syndrome), UGIB (upper gastrointestinal bleed)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Hepatic encephalopathy—definition, nomenclature, diagnosis and quantification: Final Report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998.Hepatology. 2002; 35: 716-721
- Pathophysiology of hepatic encephalopathy: the ammonia hypothesis revisited.in: Bengtsson F. Jeppsson B. Almdal B. Hepatic encephalopathy and metabolic nitrogen exchange. CRC Press, Boca Raton, FL1993: 9-24
- Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?.J Hepatol. 2000; 32: 1035-1038
- The systemic inflammatory response syndrome in acute liver failure.Hepatology. 2000; 32: 734-739
- Pathways and mechanisms for cytokine signalling of the central nervous system.J Clin Invest. 1997; 100: 2941-2947
- The relative effects of enterically administered plasma and packed cells on circulating blood ammonia.Gastroenterology. 1963; 45: 368-373
- Effects of simulated upper gastrointestinal haemorrhage on ammonia and related amino acids in blood and brain of chronic portacaval-shunted rats.Metab Brain Dis. 1997; 12: 121-135
- Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver.Metab Brain Dis. 2003; 18: 37-49
- American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.Crit Care Med. 1992; 20: 864-874
- Correlation of serial cytokine levels with progression to coma (grade IV) in patients with acute liver failure.Hepatology. 1995; 22: 366A
- Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis.Hepatology. 2003; 37: 931-939
- The kidney plays a major role in the hyperammonemia seen after simulated or actual upper gastrointestinal bleeding in patients with cirrhosis.Hepatology. 2003; 37: 1277-1285
- Amino acid challenge in patients with cirrhosis: a model for the assessment of treatments for hepatic encephalopathy.J Hepatol. 2001; 34: 658-664
- Oral glutamine challenge in cirrhotics pre-and post-liver transplantation: a psychometric and analysed EEG study.Hepatology. 1997; 26: 870-876
- Effect of l-ornithine-l-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial.Gut. 2000; 47: 571-574
- Effect of blood ammonia elevation following oral glutamine load on the psychometric performance of cirrhotic patients.Metab Brain Dis. 2003; 18: 27-35
- The hepatic coma syndromes and lactulose.Williams and Wilkins, Baltimore, MD1979
- The structure of human hemoglobin.J Biol Chem. 1962; 237: 3151-3156
- The influence of age on trail making test performance.J Clin Psychol. 1968; 24: 96-98
- Psychomotor function and psychoactive drugs.Br J Clin Pharmacol. 1980; 10: 189-209
- A memory test for longitudinal measurement of mild to moderate defects.Clin Neuropsychol. 1980; II: 184-197
- Performance on psychological tests. Demographic and clinical correlates of the results of these tests.Br J Psychiatry Suppl. 1991; (see also pages 44–6): 26-29
- Determination of amino acid isotope enrichment using liquid chromatography–mass spectrometry.Anal Biochem. 1999; 271: 8-17
- Adaptation of the nitrate reductase and Griess reaction methods for the measurement of serum nitrate plus nitrite levels.Ann Clin Biochem. 1997; 34: 193-198
- The natural history of the systemic inflammatory response (SIRS). A prospective study.J Am Med Assoc. 1995; 273: 117-123
- Transection of the oesophagus for bleeding oesophageal varices.Br J Surg. 1973; 60: 646-649
- Chadwick J. Mann W.N. The medical works of hippocrates. 50. Blackwell, Oxford1950: 223
- Pathophysiology of septic encephalopathy: a review.Crit Care Med. 2000; 28: 3019-3024
- Amino acid derangements in patients with sepsis.Ann Surg. 1978; 188: 423-429
- Amino acid imbalance early in septic encephalopathy.Intensive Care Med. 2002; 28: 293-298
- Amino acid alterations and encephalopathy in the sepsis syndrome.Crit Care Med. 1991; 19: 753-757
- The l-arginine–nitric oxide pathway.N Engl J Med. 1993; 329: 2002-2012
- Bacterial infection in the pathogenesis of variceal bleeding.Lancet. 1999; 353: 139-142
- Cytokine effects on glutamate uptake by human astrocytes.Neuroimmunomodulation. 2000; 7: 153-159
- Interleukin 1 beta and tumour necrosis factor alpha increase peripheral-type benzodiazepine binding sites in cultured polygonal astrocytes.J Neurochem. 1992; 58: 2131-2138
- Cerebral blood flow and oxidative metabolism during human endotoxemia.J Cereb Blood Flow Metab. 2002; 22: 1262-1270
- Effects of tumour necrosis factor alpha and interleukin 6 on fluid phase permeability and ammonia diffusion in CNS-derived endothelial cells.J Invest Med. 1996; 44: 474-482
- Relative contributions of peripheral and central sources to levels of IL-1α in the cerebral cortex of mice: assessment with species-specific enzyme immunoassays.J Neuroimmunol. 1997; 79: 22-28
- Cytokine to brain communication: a review and analysis of alternative mechanisms.Life Sci. 1995; 57: 1011-1026
- Roles of IL-1 and TNF-alpha in endotoxin-induced activation of nitric oxide synthase in cultured rat brain cells.Am J Physiol. 1996; 270: R326-R332
- Inducible nitric oxide synthase gene expression in the brain during systemic inflammation.Nat Med. 1996; 2: 581-584
Article info
Publication history
Accepted:
October 22,
2003
Received in revised form:
October 22,
2003
Received:
May 8,
2003
See Editorial, pages 327–330Footnotes
☆This paper was presented in part as an abstract at the British Society of Gastroenterology Annual Meeting in Birmingham, UK, 23–26 March 2003.
Identification
Copyright
© 2003 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
