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Activation of soluble guanylate cyclase by nitric oxide in lymphocytes correlates with minimal hepatic encephalopathy in cirrhotic patients

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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.

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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

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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.

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Correspondence to Vicente Felipo.

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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

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  • DOI: https://doi.org/10.1007/s00109-006-0149-y

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