Abstract
Patients with liver cirrhosis with normal neurological and mental status examination may present minimal forms of hepatic encephalopathy, showing intellectual function impairment that cannot be detected through general clinical examination but can be unveiled using specific neuropsychological or neurophysiological examination. Evaluation of minimal hepatic encephalopathy (MHE) in cirrhotic patients would have prognostic value. The psychometric hepatic encephalopathy score (PHES) has been recommended as the “gold standard” in the diagnosis of MHE. Altered modulation of cyclic GMP (cGMP) levels in the brain seems to be responsible for the impairment of some types of cognitive function in liver disease. In animal models of liver disease, some of the alterations in modulation of cGMP levels in the brain are reproduced in lymphocytes. The aim of the present work was to assess whether there is a correlation between the alterations in different parameters involved in modulation of cGMP levels and the presence of MHE in patients with liver disease. We studied in 46 patients with liver cirrhosis and 26 controls the performance in the PHES battery of psychometric tests and the critical flicker frequency (CFF), the concentration of cGMP in plasma and lymphocytes, activation of guanylate cyclase by nitric oxide (NO) in lymphocytes, and several parameters likely involved in altered cGMP homeostasis in liver disease such as ammonia, NO metabolites, and atrial natriuretic peptide (ANP). Activation of guanylate cyclase by NO in lymphocytes and cGMP in plasma were higher and CFF lower in patients with MHE than in patients without MHE. Ammonia, ANP, and metabolites of NO were higher in patients than in controls but were no different in patients with or without MHE. Alteration in activation of guanylate cyclase by NO in lymphocytes correlates with PHES performance, CFF, and ammonia levels. This suggests that altered modulation of guanylate cyclase by NO in lymphocytes would reflect a parallel alteration in the brain occurring in patients with MHE that would be involved in their cognitive impairment.
Similar content being viewed by others
Abbreviations
- ANP:
-
atrial natriuretic peptide
- CFF:
-
critical flicker frequency
- cGMP:
-
cyclic GMP
- DST:
-
the digit symbol test
- HE:
-
hepatic encephalopathy
- HEPES:
-
4-(2-hydroxyethyl)-1-piperazine-ethanosulfonic acid
- IBMX:
-
3-isobuthyl-1-methylxanthine
- LTT:
-
the line tracing test
- MHE:
-
minimal hepatic encephalopathy
- NCT-A:
-
the number connection test A
- NCT-B:
-
the number connection test B
- NO:
-
nitric oxide
- \({\text{NO}}^{ - }_{{\text{3}}} \) :
-
nitrate
- PHES:
-
psychometric hepatic encephalopathy score
- SD:
-
the serial dotting test
- PBS:
-
phosphate-buffered saline
- SNAP:
-
S-nitroso-N-acetylpenicillamine
- TCA:
-
trichloroacetic acid
References
Schomerus H, Hamster W (1998) Neuropsychological aspects of portal-systemic encephalopathy. Metab Brain Dis 13:361–377
Weissenborn K, Bokemeyer M, Krause J, Ennen J, Ahl B (2005) Neurological and neuropsychiatric syndromes associated with liver disease. AIDS 19(Suppl 3):S93–S98
Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodes J (1999) Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 30:890–895
Hui AY, Chan HL, Leung NW, Hung LC, Chan FK, Sung JJ (2002) Survival and prognostic indicators in patients with hepatitis B virus-related cirrhosis after onset of hepatic decompensation. J Clin Gastroenterol 34:569–572
Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 19:253–267
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT et al (2002) Hepatic encephalopathy—definition, nomenclature, diagnosis and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716–721
Romero-Gómez M, Boza F, Garcia Valdecasas MS, García E, Aguilar Reina J (2001) Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 96:2718–2723
Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR (2001) Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol 16:531–535
Häussinger D, Cordoba J, Kircheis G, Vilstrup H, Fleig WE, Jones EA, Schliess F, Blei AT (2006) Definition and assessment of low-grade hepatic encephalopathy. In: Häussinger D, Kircheis G, Schliess F (eds) Hepatic encephalopathy and nitrogen metabolism. Springer, Berlin Heidelberg New York
Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, Schalm SW (1998) Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 28:45–49
Wein C, Koch H, Popp B, Oehler G, Schauder P (2004) Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 39:739–745
Romero-Gomez M, Grande L, Camacho I (2004) Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy. Hepatology 39:939–943
Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D (2002) Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 35:357–366
Corbalán R, Chatauret N, Behrends S, Butterworth RF, Felipo V (2002) Region selective alterations of soluble guanylate cyclase content and modulation in brain of cirrhotic patients. Hepatology 36:1155–1162
Monfort P, Corbalán R, Martinez L, López-Talavera JC, Córdoba J, Felipo V (2001) Altered content and modulation of soluble guanylate cyclase in the cerebellum of rats with portacaval anastomosis. Neuroscience 104:1119–1125
Hermenegildo C, Montoliu C, Llansola M, Muñoz MD, Gaztelu JM, Miñana MD, Felipo V (1998) Chronic hyperammonemia impairs glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J Neurosci 10:3201–3209
Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V (2005) Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunt. Hepatology 45:2–10
Erceg S, Monfort P, Hernandez-Viadel M, Llansola M, Montoliu C, Felipo V (2005) Restoration of learning ability in hyperammonemic rats by increasing extracellular cGMP in brain. Brain Res 1036:115–121
Corbalán R, Miñana MD, Del Olmo JA, Serra MA, Rodrigo JM, Felipo V (2002) Altered cGMP content and soluble guanylate cyclase in lymphocytes from patients with liver disease. J Mol Med 80:117–123
Montoliu C, Kosenko E, Del Olmo JA, Serra MA, Rodrigo JM, Felipo V (2005) Correlation of nitric oxide and atrial natriuretic peptide changes with altered cGMP homeostasis in liver cirrhosis. Liver Int 25:787–795
Kimura M (1989) Metallothioneins of monocytes and lymphocytes. Methods Enzymol 205:291–302
Verdon CP, Burton BA, Prior RL (1995) Sample pretreatment with nitrate reductase and glucose-6-phosphate dehydrogenase quantitatively reduces nitrate while avoiding interference by NADP+ when the Griess reaction is used to assay for nitrite. Anal Biochem 224:502–508
Hermenegildo C, Monfort P, Felipo V (2000) Activation of N-methyl-d-aspartate receptors in rat brain in vivo following acute ammonia intoxication: characterization by in vivo brain microdialysis. Hepatology 31(3):709–715
Weissenborn K, Ennen JC, Schomerus H, Rückert N, Hecker H (2001) Neuropsychological characterization of hepatic encephalopathy. J Hepatol 34:768–773
Schomerus H, Weissenborn K, Hamster W, Rückert N, Hecker H (1999) PSE syndrome test manual. Swets Test Services, Frankfurt
Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40(2):247–254
Odeh M, Sabo E, Srugo I, Oliven A (2004) Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure. Liver Int 24(2):110–116
Odeh M, Sabo E, Srugo I, Oliven A (2005) Relationship between tumor necrosis factor-alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure. Ann Med 37(8):603–612
Rodrigo R, Erceg S, Felipo V (2005) Neurons exposed to ammonia reproduce the differential alteration in nitric oxide modulation of guanylate cyclase in cerebellum and cortex of patients with liver cirrhosis. Neurobiol Dis 19:150–161
Timmermann L, Butz M, Gross J, Kircheis G, Haussinger D, Schnitzler A (2005) Neural synchronization in hepatic encephalopathy. Metab Brain Dis 20:337–346
Zafiris O, Kircheis G, Rood HA, Boers F, Häussinger D, Zilles K (2004) NeuroImage 22:541–552
World Medical Organization (1996) Declaration of Helsinki. BMJ 313:1448–1449
Acknowledgements
This work was supported by grants from the Ministerio de Ciencia y Tecnología (SAF2002-00851 and SAF2005-06089) and from Ministerio de Sanidad (Red G03-155, PI050253 and FIS 02/0133) of Spain and by grants from Consellería de Empresa, Universidad y Ciencia, Generalitat Valenciana (Grupos03/001, GV04B-055, GV04B-012, ACOMP06/070 ACOMP06/080 and GVS05/082), and AP005/06 from Conselleria de Sanitat of Generalitat Valenciana.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Montoliu, C., Piedrafita, B., Serra, M.A. et al. Activation of soluble guanylate cyclase by nitric oxide in lymphocytes correlates with minimal hepatic encephalopathy in cirrhotic patients. J Mol Med 85, 237–245 (2007). https://doi.org/10.1007/s00109-006-0149-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-006-0149-y