Observational Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jan 27, 2018; 10(1): 124-133
Published online Jan 27, 2018. doi: 10.4254/wjh.v10.i1.124
Toll-like receptor 4 polymorphisms and bacterial infections in patients with cirrhosis and ascites
Edilmar Alvarado-Tapias, Carlos Guarner-Argente, Elida Oblitas, Elisabet Sánchez, Silvia Vidal, Eva Román, Mar Concepción, Maria Poca, Cristina Gely, Oana Pavel, Juan Camilo Nieto, Cándido Juárez, Carlos Guarner, Germán Soriano
Edilmar Alvarado-Tapias, Carlos Guarner-Argente, Elida Oblitas, Elisabet Sánchez, Eva Román, Mar Concepción, Maria Poca, Cristina Gely, Oana Pavel, Carlos Guarner, Germán Soriano, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Edilmar Alvarado-Tapias, Elisabet Sánchez, Silvia Vidal, Cristina Gely, Juan Camilo Nieto, Carlos Guarner, Germán Soriano, Instituto de Salud Carlos III, Institut de Recerca IIB-Sant Pau, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès) 08193, Spain
Edilmar Alvarado-Tapias, Elisabet Sánchez, Eva Román, Maria Poca, Carlos Guarner, Germán Soriano, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid 28029, Spain
Silvia Vidal, Juan Camilo Nieto, Cándido Juárez, Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Eva Román, Escola Universitària d’Infermeria EUI-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Author contributions: Alvarado-Tapias E, Guarner-Argente C and Soriano G contributed to study concept and design; Alvarado-Tapias E, Poca M, Concepción M, Román E, Pavel O, Guarner-Argente C, Oblitas E, Sánchez E, Vidal S, Nieto JC and Juarez C contributed to acquisition of data; Alvarado-Tapias E, Soriano G and Vidal S contributed to analysis and interpretation of data; Alvarado-Tapias E and Soriano G contributed to drafting of the manuscript; Soriano G, Vidal S, Guarner C and Juarez C contributed to critical revision of the manuscript for important intellectual content; Alvarado-Tapias E, Soriano G and Vidal S contributed to statistical analysis; Soriano G contributed to study supervision.
Supported by (partially) from the Instituto de Salud Carlos III, Madrid, Spain, No. PI0900357; and cofinanced by Fondos FEDER (Fondo Europeo de Desarrollo Regional), “Una manera de hacer Europa”, European Union, and CERCA Programme, Generalitat de Catalunya; Silvia Vidal was supported by Fondo de Investigaciones Sanitarias (FIS) and is a participant in the Program for Stabilization of Investigators of the Direcció d’Estrategia i Coordinació del Departament de Salut, Generalitat de Catalunya; Edilmar Alvarado-Tapias is a recipient of a “Río Hortega” fellowship grant from the Instituto de Salud Carlos III, No. CM16/00133.
Institutional review board statement: This study was approved by the Ethics Committee of Hospital de la Santa Creu i Sant Pau. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
Informed consent statement: All study participants provided written informed consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Edilmar Alvarado-Tapias, MD, Research Fellow, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Mas Casanovas 90, Barcelona 08025, Spain. ealvaradot@santpau.cat
Telephone: +34-93-5565920 Fax: +34-93-5565608
Received: November 16, 2017
Peer-review started: November 17, 2017
First decision: December 1, 2017
Revised: December 16, 2017
Accepted: December 29, 2017
Article in press: December 29, 2017
Published online: January 27, 2018
Abstract
AIM

To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites.

METHODS

We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan’s criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed.

RESULTS

We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group (P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group (P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up.

CONCLUSION

Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.

Keywords: Cirrhosis, Genetic polymorphisms, Toll-like receptor 4, Bacterial infections, Ascites

Core tip: Patients with cirrhosis present a high incidence of bacterial infections. Toll-like receptor (TLR) 4 genetic polymorphisms, particularly D299G, have been previously associated with an increased predisposition to infection in several populations. In the present study, genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition to develop bacterial infections or in the prognosis of cirrhotic patients with ascites. Age, serum creatinine, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy and the presence of hepatocellular carcinoma were independent predictive factors of mortality during follow-up.