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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 774-778

Relationship between proton-pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites


1 Department of Internal Medicine, ElMahalla General Hospital, ElMahalla, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission06-Mar-2020
Date of Decision18-Apr-2020
Date of Acceptance25-Apr-2020
Date of Web Publication18-Oct-2021

Correspondence Address:
Mostafa M Farrag
Department of Internal Medicine, ElMahalla General Hospital, 31951 ElMahalla
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_48_20

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  Abstract 


Objective
The aim of this study was to assess the occurrence of spontaneous bacterial peritonitis in cirrhotic patients with ascites and is relationship to proton-pump inhibitor (PPI) use.
Background
Gastric acid plays an important role in resisting intestinal pathogens. Changes in gastric pH induced by antacids may damage the gastric protective barrier.
Patients and methods
This prospective cohort study was conducted on 100 patients of 18 years old or more, both sexes with liver cirrhosis and ascites. Patients were divided into two groups (50 patients in each); group (PPI use positive) with a history of PPIs use in the last 15 days at a dose of more than 20 mg and group (PPI use negative) without a history of PPI use.
Results
White blood cells in the blood and in the ascitic fluid showed significant increase in the PPI group than in the second group. Cultures of ascitic fluid were positive in 28 (56%) patients with PPI use, and 15 patients in the negative PPI use group and comparison showed significant increase in the positive PPI use group. The hazardous ratio of developing positive cultures in the PPI group is 1.687 times than the second group (95% confidence interval: 1.1–2.502).
Conclusion
The use of PPIs in cirrhotic patients who have ascites has a risk for developing spontaneous bacterial peritonitis; therefore, it is recommended to avoid their use in this category of patients.

Keywords: ascites, cirrhosis, proton-pump inhibitor, spontaneous bacterial peritonitis


How to cite this article:
Farrag MM, Bahnacy AA, Dela AG, Badr MH, Montaser BA. Relationship between proton-pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Menoufia Med J 2021;34:774-8

How to cite this URL:
Farrag MM, Bahnacy AA, Dela AG, Badr MH, Montaser BA. Relationship between proton-pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:774-8. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/774/328339




  Introduction Top


The incidence of spontaneous bacterial peritonitis (SBP) caused by bacterial infections in cirrhotic patients is 10–30% [1]. Although the pathogenesis of SBP is not clear, studies have shown overgrowth and colonization of gastrointestinal bacteria in cirrhotic patients induced by intestinal activity reduction, intestinal permeability enhancement, and application of acid inhibitor drugs [2].

Proton-pump inhibitor (PPI) is the most widely used antacid [3] and its inhibition of gastric acid secretion is by blocking parietal cells H+/K+-ATP enzyme [4].

Gastric acid can purify stomach and proximal small intestine and plays an important role in resisting intestinal pathogens. However, changes in gastric pH induced by antacids may damage the gastric protective barrier [5].

Few studies have shown the risk of SBP occurrence after PPI therapy in cirrhotic patients and the relationship has been assessed in a small sample [6]. However, controversial results have been obtained in the last decades [5].

The aim of this study was to assess the occurrence of SBP in cirrhotic patients with ascites and its relationship to PPI use.


  Patients and methods Top


This prospective cohort study was conducted on 100 patients, 18 years old or more, of both sexes, who had established diagnosis of liver cirrhosis and clinically detectable ascites from November 2019 to October 2019 after approval of the Ethics and Medical Committee of Menoufia University Hospital and a written informed consent was obtained from all participants in this research. A code number for each patient was used, symbols to the name and address that were kept in a special file, we hide the patients' names when we use the research, and we used the results of the research only for scientific purpose.

Exclusion criteria were: active gastrointestinal bleeding, hepatocellular carcinoma, other causes of ascites (tuberculous peritonitis, malignant ascites, myxedema, nephrotic syndrome, constrictive pericarditis, and congestive heart failure) and intra-abdominal sepsis.

Patients were divided into two groups (50 patients in each); group (PPI use positive) cirrhotic patients with ascites and a history of PPIs use in the last 15 days at a dose more than 20 mg and group (PPI use negative) cirrhotic patients with ascites without a history of PPI use.

Diagnosis of cirrhosis [based on clinical, biochemical, and radiological criteria by US (coarse echogenic pattern, bulky caudate lobe, attenuated hepatic veins with or without liver biopsy)]. Diagnosis of SBP was by the following criteria (an ascitic fluid absolute polymorphonuclear leukocyte count of at least 250 cells/mm3 and a positive ascitic fluid bacterial culture without an intra-abdominal surgically treatable source of infection).

All patients were subjected to history taking: focus on PPI use at a dose of more than 20 mg/day in the previous 2 weeks, clinical examination, laboratory investigation (complete blood count, liver function tests: alanine transferase, aspartate transaminase, serum albumin, alpha fetoprotein, hepatitis C virus antibody, and HBsAg), specific investigations [ascitic fluid analysis (polymorphonuclear leukocytes count, culture], serum-ascites albumin gradient), and abdominal ultrasonography.

Statistical analysis

The primary outcome was the incidence of SBP and secondary outcomes were the difference in white blood cells in the blood and ascitic fluid.

Sample size calculation was done by Minitab 17.1.0 (Minitab Inc., State College, Pennsylvania, USA). The sample size was calculated as N ≥39 based on the following considerations: 95% confidence limit, 85% power of the study, group ratio 1: 1, and the incidence of SBP (was 38% with PPI use and 13.6% in non-PPI according to a previous study [7]). We added more cases to overcome dropout.

Statistical analysis was done by SPSS version 25 (IBM, Chicago, Illinois, USA). Quantitative data (e.g., age) were presented as mean and SD and were compared by unpaired Student's t-test. Qualitative data (e.g., sex) were presented as number and percent and were compared by the χ2 or Fisher's exact test when appropriate. A P value less than 0.05 was considered statistically significant.


  Results Top


As regards age and gender, hemoglobin, platelet, alanine transferase, aspartate transaminase, serum albumin, α-fetoprotein, serum-ascites albumin gradient ratio in ascitic fluid, and hepatitis C virus antibody showed insignificant difference between the two groups [Table 1] and [Table 2].
Table 1: Patient characteristics and laboratory data of both groups

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Table 2: Ascitic fluid analysis of both groups

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White blood cells in the blood and in ascitic fluid showed significant increase in the PPI group than the second one [Table 2].

As regards portal and splenic vein diameter, there was significant increase in the PPI group than the second one. But right lobe diameter comparison showed insignificant difference [Table 3].
Table 3: Radiological data of both groups

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Culture of ascitic fluid was positive in 28 (56%) patients with PPI use, and 15 patients in the negative PPI use group and comparison showed significant increase in the positive PPI use group [Table 2] and [Table 4]. The hazardous ratio of developing positive cultures in the PPI group is 1.687 times than the second group [95% confidence interval (CI): 1.138–2.502].
Table 4: Culture fluid in both groups

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  Discussion Top


Since the introduction of PPIs to the market in the late 1980s, they had a tremendous impact on patient care, clinical practice, and research development. Compared with other antacid drugs, PPIs were initially thought to have an excellent safety profile, resulting in their widespread use in both inpatient and ambulatory settings [8].

After more than 25 years of clinical postmarketing experience, improved reporting, and closer scrutiny, several serious adverse effects associated with the long-term use of PPIs have emerged. These include increased risks of falls and fractures in postmenopausal women [9], a reduction of renal and liver function, and an increased risk of community-acquired and nosocomial pneumonia [10]. PPIs are also found to be an independent risk factor for Clostridium difficile infection even with a very short-term use of 2 days in the intensive care setting [11]. Nevertheless, there is some controversy regarding the role of PPIs in SBP [7].

All the following studies were in agreement with our results

Elzouki et al. [7] concluded that PPI use, as well as older age (>60 years), was an independent predictive factor for the development of overall infection and SBP in hospitalized cirrhotic patients.

Also, Sy et al. [12] meta-analysis was in accordance with our results. A total of 21 studies: 10 case–control, 10 cohorts, and one randomized controlled trial, involving 13 862 patients were analyzed. The overall results showed a significant association between SBP and PPI use [pooled odds ratio (OR): 2.02; 95% CI: 1.51–2.69]. This meta-analysis showed that there is a weak association, although significant, between SBP and PPI use.

Also, Dam et al. [13] concluded that PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing hepatic encephalopathy (HE) and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of the gut bacteria.

Also, Deshpande et al. [14] reviewed all observational studies that investigated the risk of SBP associated with PPI/H(2)-receptor antagonists (H2RA) therapy and utilized SBP as an endpoint. Eight studies (n = 3815 patients) met the inclusion criteria. The risk of hospitalized cirrhotic patients developing SBP increased when using acid-suppressive therapy. The risk was greater with PPI therapy (n = 3815; OR 3.15; 95% CI: 2.09–4.74) as compared with those on H2RA therapy (n = 562; OR: 1.71; 95% CI: 0.97–3.01). Cirrhotic patients receiving a PPI have approximately three times the risk of developing SBP compared with those not receiving this medication.

All the following studies were in disagreement with our results

The Miozzo et al. [15] cohort study was carried out in 258 cirrhotic outpatients with ascites. The primary outcome was defined as development of SBP during the study period. SBP was diagnosed based on ascitic fluid polymorphonuclear cell count greater than or equal to 250 cells/mm ≥ without evidence of an intra-abdominal, surgically treatable source of infection. Of 258 patients with ascites, 151 used PPIs, and 34 developed SBP (22.5%). Among 107 nonusers of PPIs, 23 developed SBP (21.5%) (hazard ratio = 1.44; 95% CI: 0.85–2.47; P = 0.176). Univariate analysis of the risk factors associated with the development of SBP showed a significant association of SPB with the severity of liver disease according to the Child–Turcotte–Pugh score. Multivariate analysis confirmed that Child–Turcotte–Pugh score was the only independent variable influencing the occurrence of SBP. In conclusion, the rate of SBP was not significantly different in users or nonusers of PPIs in this cohort of cirrhotic patients with ascites.

In the Yu et al. [16] meta-analysis of 10 case–control and six cohort studies involving 8145 patients, the overall analysis indicated that PPI use was associated with SBP (OR = 2.11; 95% CI: 1.46–3.06). The association was limited in case–control studies (OR = 2.97; 95% CI: 2.06–4.26) but not in cohort studies (OR = 1.18; 95% CI: 0.99–1.14). PPI therapy was not associated with mortality during hospitalization or within 30 days after SBP (OR = 1.54; 95% CI: 0.92–2.59). They could not establish causality that PPI use increases the incidence or mortality of SBP.

Moreover, Terg et al. [17] studied 519 patients with decompensated cirrhosis in 23 hospitals; 226 patients (43.5%) had received PPI therapy within the last 3 months. In 135 patients, PPIs were administered for longer than 2 weeks. A bacterial infection was shown in 255 (49.1%) patients. SBP was diagnosed in 95 (24.7%) patients out of 394 patients with ascites. There was no significant difference in the rate of PPI consumption between the infected and the noninfected patients (44.3 vs 42.8%) or between SBP patients and patients with ascites without SBP (46 vs 42%). In SBP patients, the duration of PPI administration did not influence the rate of SBP occurrence. The type of bacteria and the origin of SBP infection were similar in patients with and without PPI. In this large, multicenter, prospective study, PPI therapy, specifically evaluated at admission of consecutive cirrhotic patients, was not associated with a higher risk of SBP.

Also, Mandorfer et al. [18] undertook a retrospective analysis of follow-up data from 607 consecutive patients with cirrhosis undergoing their first paracentesis at a tertiary center; 86% patients were receiving PPIs. After adjusting for potential confounding factors, PPI intake was neither associated with increased SBP prevalence at the first paracentesis (OR: 1.11; 95% CI: 0.6–2.06; P=0.731) nor cumulative incidence of SBP (subdistribution hazard ratio: 1.38; 95% CI: 0.63–3.01; P=0.42) and SBP or other infections (subdistribution hazard ratio: 1.71; 95% CI: 0.85–3.44; P=0.13) during the follow-up. They concluded that the proportion of cirrhotic patients with PPI intake was higher than in previous reports, suggesting that PPI indications were interpreted liberally. They observed no association between PPIs and SBP or other infections, as well as mortality.


  Conclusion Top


The use of PPIs in cirrhotic patients who have ascites is a risk for developing SBP; therefore, it is recommended to avoid their use in this category of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Sundaram V, Manne V, Al-Osaimi AM. Ascites and spontaneous bacterial peritonitis: recommendations from two United States centers. Saudi J Gastroenterol 2014; 20:279–287.  Back to cited text no. 1
    
2.
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Dong H, Luo S, Dong Y, Feng W, Wei Y. The use of PPI is associated with spontaneous bacterial peritonitis in cirrhotic patients of different ethnic groups: a meta-analysis. Int J Clin Exp Med 2016; 9:1227–1235.  Back to cited text no. 5
    
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Elzouki AN, Neffati N, Rasoul FA, Abdallah A, Othman M, Waness A. Increased risk of spontaneous bacterial peritonitis in cirrhotic patients using proton pump inhibitors. GE Port J Gastroenterol 2019; 26:83–89.  Back to cited text no. 7
    
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Durand C, Willett KC, Desilets AR. Proton pump inhibitor use in hospitalized patients: is overutilization becoming a problem? Clin Med Insights Gastroenterol 2012; 5:65–76.  Back to cited text no. 8
    
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Lewis JR, Barre D, Zhu K, Ivey KL, Lim EM, Hughes J, et al. Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res 2014; 29:2489–2497.  Back to cited text no. 9
    
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Thomson AB, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol 2010; 16:2323–2330.  Back to cited text no. 10
    
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Barletta JF, Sclar DA. Proton pump inhibitors increase the risk for hospital-acquired Clostridium difficile infection in critically ill patients. Crit Care 2014; 18:714.  Back to cited text no. 11
    
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Sy M, Janairo J, Gopez-Cervantes J, Cua I. Risk of spontaneous bacterial peritonitis with use of proton pump inhibitors – a systemic review and meta-analysis. Gut 2019; 68(Suppl 1):50–56.  Back to cited text no. 12
    
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Dam G, Vilstrup H, Watson H, Jepsen P. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology 2016; 64:1265–1272.  Back to cited text no. 13
    
14.
Deshpande A, Pasupuleti V, Thota P, Pant C, Mapara S, Hassan S, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol 2013; 28:235–242.  Back to cited text no. 14
    
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Miozzo SAS, John JA, Appel-da-Silva MC, Dossin IA, Tovo CV, Mattos AA. Influence of proton pump inhibitors in the development of spontaneous bacterial peritonitis. World J Hepatol 2017; 9:1278–1285.  Back to cited text no. 15
    
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Yu T, Tang Y, Jiang L, Zheng Y, Xiong W, Lin L. Proton pump inhibitor therapy and its association with spontaneous bacterial peritonitis incidence and mortality: a meta-analysis. Dig Liver Dis 2016; 48:353–359.  Back to cited text no. 16
    
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Mandorfer M, Bota S, Schwabl P, Bucsics T, Pfisterer N, Summereder C, et al. Proton pump inhibitor intake neither predisposes to spontaneous bacterial peritonitis or other infections nor increases mortality in patients with cirrhosis and ascites. PLoS One 2014; 9:e110503–e110503.  Back to cited text no. 18
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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