Low ascitic fluid protein does not indicate an increased risk for spontaneous bacterial peritonitis in current cohorts
Authors: Tony Bruns, Philipp Lutz, Andreas Stallmach, Hans Dieter Nischalke
Journal: Journal of Hepatology (2015)

Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: A multicenter prospective studyJournal of HepatologyVol. 62Issue 5PreviewRetrospective studies show an association between proton pump inhibitor (PPI) therapy and spontaneous bacterial peritonitis (SBP). We investigate the relationship between PPI and SBP in decompensated cirrhotic patients in a large nationwide prospective study. Full-Text PDF We read with interest the results of a large multicenter trial on risk factors for spontaneous bacterial peritonitis (SBP) by Terg et al. in the Journal of Hepatology [[1]Terg R. Casciato P. Garbe C. Cartier M. Stieben T. Mendizabal M. et al.Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study.J Hepatol. 2015; 62: 1056-1060Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. In their analysis including 95 patients with SBP, neither proton pump inhibitor use nor the concentration of ascitic fluid (AF) protein could be confirmed as a risk factor for SBP. Low AF protein has been reported to predispose to SBP in decompensated cirrhosis according to several studies [2Runyon B.A. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.Gastroenterology. 1986; 91: 1343-1346Abstract Full Text PDF PubMed Google Scholar, 3Titó L. Rimola A. Ginès P. Llach J. Arroyo V. Rodés J. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors.Hepatology. 1988; 8: 27-31Crossref PubMed Scopus (354) Google Scholar, 4Llach J. Rimola A. Navasa M. Ginès P. Salmerón J.M. Ginès A. et al.Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Scopus (180) Google Scholar, 5Andreu M. Sola R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. et al.Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites.Gastroenterology. 1993; 104: 1133-1138Abstract Full Text PDF PubMed Google Scholar] dating from 1986 to 1993. This association was attributed to a lack of opsonic factors, since AF protein correlates with peritoneal immunoglobulin concentration and complement activity [6Runyon B.A. Morrissey R.L. Hoefs J.C. Wyle F.A. Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis.Hepatology. 1985; 5: 634-637Crossref PubMed Scopus (158) Google Scholar, 7García-Díaz M. Alcalde M. de Sande F. Romero J. Sánchez-Risco P. Pijierro A. et al.Low protein concentration in cirrhotic ascites is related to low ascitic concentrations of immunoglobulins G and A.Eur J Gastroenterol Hepatol. 1995; 7: 963-969Crossref PubMed Scopus (4) Google Scholar]. During hospitalization, patients with AF protein ⩽10 g/L developed SBP ten times more often than patients with higher AF protein concentrations in an analysis including 17 patients with SBP [[2]Runyon B.A. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.Gastroenterology. 1986; 91: 1343-1346Abstract Full Text PDF PubMed Google Scholar]. Two prospective studies comprising 127 patients (13 with SBP) [[4]Llach J. Rimola A. Navasa M. Ginès P. Salmerón J.M. Ginès A. et al.Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Scopus (180) Google Scholar] and 110 patients (28 with SBP) [[5]Andreu M. Sola R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. et al.Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites.Gastroenterology. 1993; 104: 1133-1138Abstract Full Text PDF PubMed Google Scholar] confirmed low AF protein concentration as an independent predictor of SBP. In addition, AF protein ⩽10 g/L was shown to predict the recurrence of SBP [[3]Titó L. Rimola A. Ginès P. Llach J. Arroyo V. Rodés J. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors.Hepatology. 1988; 8: 27-31Crossref PubMed Scopus (354) Google Scholar]. Thus, current guidelines recommend the measurement of AF protein to identify patients at high risk for SBP [[8]Ginès P. Angeli P. Lenz K. Møller S. Moore K. Moreau R. et al.EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.J Hepatol. 2010; 53: 397-417Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar]. Given the discrepancies of available data, we here report the results of a post-hoc analysis from two prospectively collected registries of patients with cirrhosis and ascites undergoing paracentesis in two German tertiary centers comprising 683 patients, of whom 220 had SBP. Among 347 patients receiving paracentesis with AF protein measurement between 12/2007 and 07/2014 in the Jena University Hospital, 13 patients presented with a documented history of SBP more than 30 days before inclusion and 81 patients presented with SBP at baseline or during follow-up. In the Bonn University Hospital, 336 patients with liver cirrhosis received baseline paracentesis with AF protein measurement between 05/2006 and 09/2013. Of these patients, 51 had a history of SBP while 75 developed SBP at baseline paracentesis or during follow-up. In both cohorts, AF protein concentrations were similar for patients who never had SBP and patients who developed SBP (Table 1). When patients were stratified according to a cut-off of less than 10 g/L or less than 15 g/L AF total protein, frequencies were comparable between the SBP and non-SBP group.Table 1Baseline clinical and laboratory findings in cirrhotic patients of both cohorts stratified for the occurrence of SBP.Median/Interquartiles and frequency/percentage are shown.AF, ascitic fluid; MELD, model for end-stage liver disease; SBP, spontaneous bacterial peritonitis.ap values from Mann-Whitney U test or Fisher's exact test as appropriate. Open table in a new tab Median/Interquartiles and frequency/percentage are shown. AF, ascitic fluid; MELD, model for end-stage liver disease; SBP, spontaneous bacterial peritonitis. ap values from Mann-Whitney U test or Fisher's exact test as appropriate. In line with previous findings that AF protein does not change during and after SBP [[9]Runyon B.A. Hoefs J.C. Ascitic fluid chemical analysis before, during and after spontaneous bacterial peritonitis.Hepatology. 1985; 5: 257-259Crossref PubMed Scopus (51) Google Scholar], restricting the analysis to patients without a history of SBP did not alter the results. AF protein in patients with SBP at baseline (Jena: 15 g/L, interquartiles: 9–20, p = 0.33; Bonn: 11 g/L, 8–20, p = 0.86) and AF protein in patients with a first episode of SBP during follow-up (Jena: 12 g/L, 8–20, p = 0.93; Bonn: 12 g/L, 7–23, p = 0.54) did not differ from patients who never had SBP (Jena: 12 g/L, 8–20; Bonn: 11 g/L, 7–18). We can only speculate about the causes that underlie the failure to replicate the association between SBP and AF protein, which has been reported in several studies more than 20 years ago. Based on the data of the first report on low AF protein as a risk factor for SBP [[2]Runyon B.A. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.Gastroenterology. 1986; 91: 1343-1346Abstract Full Text PDF PubMed Google Scholar], the power to detect a significant difference between the groups exceeded 80% for each of our cohorts by far. It is probable that changed epidemiology and/or different treatments for cirrhosis play a major part. We can exclude the widespread use of antibiotic prophylaxis, since Terg et al. [[1]Terg R. Casciato P. Garbe C. Cartier M. Stieben T. Mendizabal M. et al.Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study.J Hepatol. 2015; 62: 1056-1060Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar] did not include patients receiving antibiotic prophylaxis, only 2.3% of the patients in the Jena cohort and 1.5% of the patients in the Bonn cohort received long-term primary prophylaxis with quinolones or cotrimoxazol. Changes in diuretic therapy may also account for the discrepancies. Diuretics have been shown to improve AF opsonic activity to a greater degree than the protein concentration [[10]Runyon B.A. Van Epps D.E. Diuresis of cirrhotic ascites increases its opsonic activity and may help prevent spontaneous bacterial peritonitis.Hepatology. 1986; 6: 396-399Crossref PubMed Scopus (55) Google Scholar], which may reduce the correlation of AF protein with opsonic activity and therefore diminish its role as a surrogate of peritoneal immune competence [[6]Runyon B.A. Morrissey R.L. Hoefs J.C. Wyle F.A. Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis.Hepatology. 1985; 5: 634-637Crossref PubMed Scopus (158) Google Scholar]. Indeed, in direct comparison, AF opsonic activity but not total AF protein was an independent predictor of SBP in a multivariate regression model [[5]Andreu M. Sola R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. et al.Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites.Gastroenterology. 1993; 104: 1133-1138Abstract Full Text PDF PubMed Google Scholar]. Since differential effects of diuretic treatment and/or albumin use on sequential changes in AF protein and opsonic activity were not systematically assessed in our data sets, this hypothesis remains to be proven. In summary, the study of Terg et al. [[1]Terg R. Casciato P. Garbe C. Cartier M. Stieben T. Mendizabal M. et al.Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study.J Hepatol. 2015; 62: 1056-1060Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar] and the data presented herein fail to replicate an association of SBP with low total AF protein concentration in three large cohorts of hospitalized patients with decompensated cirrhosis. Although the underlying mechanisms remain elusive, our data have implications on the design of clinical studies and the identification of patients at highest risk for SBP, who might benefit from primary prophylaxis. Large prospective studies are needed to clarify the prognostic significance of low AF protein on the occurrence of SBP. The authors who have taken part in this study declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.