Interaction between infection and hepatic encephalopathy

Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver DiseasesJournal of HepatologyVol. 61Issue 3PreviewThese recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) Policy on the Joint Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Full-Text PDF Open Access We read with interest "The Hepatic Encephalopathy Practice Guidelines" published in the September issue of the Journal of Hepatology [[1]American Association for the Study of Liver Diseases European Association for the Study of the Liver Hepatic Encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the study of Liver Diseases and the European Association for the Study of the Liver.J Hepatol. 2014; 61: 642-659Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar]. As underlined by the authors in Table 3, infections are extremely frequent as precipitating factors for overt hepatic encephalopathy (OHE). In our tertiary referral centre, with an ongoing project for the search of active infection at hospital admission, infection was the precipitating event in 56% of patients with OHE in a study performed in 2008 and 2009 [[2]Merli M. Lucidi C. Giannelli V. Giusto M. Riggio O. Falcone M. et al.Cirrhotic patients are at risk for health care: associated bacterial infections.Clin Gastroenterol Hepatol. 2010; 8: 979-985Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]. This prevalence has increased to 64% in 2012 (personal data). In the same article however, the authors claim that "patients with cirrhosis do not differ from patients without cirrhosis regarding their risk to develop brain dysfunction with sepsis". We disagree with this information. We have recently investigated the association between bacterial infections and cognitive dysfunction in 150 cirrhotic patients and 81 non-cirrhotic controls [[3]Merli M. Lucidi C. Pentassuglio I. Giannelli V. Giusto M. Gregorio V. et al.Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.J Hepatol. 2013; 59: 243-250Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Signs of neurocognitive impairment were systematically looked for by means of standardized clinical examination or by the application of psychometric tests in both groups. Following a diagnosis of sepsis, neurocognitive alterations were significantly more frequent in cirrhotic patients than in controls (90% vs. 39% cirrhotic patients vs. non-cirrhotic controls). In cirrhotic patients, the probability to find neurocognitive alterations increased from patients without infection (42%) to patients with infection and no systemic inflammatory response syndrome (SIRS) (79%) to those with sepsis (90%). Efficaciously treated patients, in whom the infection subsided, improved their neurological symptoms. Both overt and covert hepatic encephalopathy were influenced by the presence of infection and by its resolution. These results are in keeping with a role for inflammation in the pathogenesis of HE [[4]Shawcross D.L. Sharifi Y. Canavan J.B. Yeoman A.D. Abeles R.D. Taylor N.J. et al.Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.J Hepatol. 2011; 54: 640-649Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. Other authors have supported this hypothesis: the administration of LPS has been found to alter consciousness and to exacerbate brain oedema only in rats with liver damage [[5]Wright G. Davies N.A. Shawcross D.L. Hodges S.J. Zwingmann C. Brooks H.F. et al.Endotoxemia produces coma and brain swelling in bile duct ligated rats.Hepatology. 2007; 45: 1517-1526Crossref PubMed Scopus (161) Google Scholar]; and ibuprofen restored the learning ability of rats with portacaval shunts and cognitive impairment [[6]Cauli O. Rodrigo R. Piedrafita B. Boix J. Felipo V. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts.Hepatology. 2007; 46: 514-519Crossref PubMed Scopus (176) Google Scholar]. In cirrhotic patients, serum levels of TNF-alfa [[7]Odeh M. Sabo E. Srugo I. Oliven A. Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure.Liver Int. 2004; 24: 110-116Crossref PubMed Scopus (85) Google Scholar], as well as of IL-6 and IL-18 [8Montoliu C. Piedrafita B. Serra M.A. del Olmo J.A. Urios A. Rodrigo J.M. et al.IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy.J Clin Gastroenterol. 2009; 43: 272-279Crossref PubMed Scopus (133) Google Scholar, 9Luo M. Li L. Yang E.N. Dai C.Y. Liang S.R. Cao W.K. Correlation between Interleukin 6 and ammonia in patients with overt hepatic encephalopathy due to cirrhosis.Clin Res Hepatol Gastroenterol. 2013; 37: 384-390Crossref PubMed Scopus (20) Google Scholar] were associated with the presence and severity of overt and minimal HE. Indeed pro-inflammatory cytokines may contribute to HE in cirrhotic patients by acting synergically with hyperammonemia [[10]Shawcross D.L. Davies N.A. Williams R. Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.J Hepatol. 2004; 40: 247-254Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar]. Interestingly, in our study [[3]Merli M. Lucidi C. Pentassuglio I. Giannelli V. Giusto M. Gregorio V. et al.Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.J Hepatol. 2013; 59: 243-250Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar] the mean ammonia plasma levels associated with OHE were lower in patients with concomitant infection/inflammation than in those without infection. We would like to emphasize the importance of actively searching for infections, even if not clinically evident, in any cirrhotic patient with cognitive impairment. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.