Association Between Proton Pump Inhibitor Therapy and Spontaneous Bacterial Peritonitis Occurrence in Cirrhotic Patients: A Clinical Review

Abstract

Spontaneous bacterial peritonitis (SBP) is one of the most common complications in patients with end-stage liver disease (ESLD), which increases the risk of short-term mortality. Proton pump inhibitors (PPIs) are frequently used in patients with ESLD, in which controversies about the risk of PPI treatment in the occurrence of SBP are largely raised and the pathogenic mechanism of PPI-associated SBP remains unclear. We conducted a systematic literature search through PubMed/MEDLINE for publications mainly from 1 January 2000 to 1 January 2021. Our narrative review summarized the adverse effect of specific PPI therapy on the occurrence and prognosis of SBP in cirrhotic patients, described the potential mechanisms by which PPI induces the development of SBP, and discussed the risk factors associated with the development of SBP and the strategy of PPI therapy in cirrhotic patients. Although controversy regarding the association between PPI use and the occurrence of SBP exists, PPIs use should be restricted to patients with clear benefit indications, and be cautious for elderly patients with severe liver damage.

Keywords

proton pump inhibitors / spontaneous bacterial peritonitis / cirrhosis / complication / side effect

References

[1] PangSH, GrahamDY. A clinical guide to using intravenous proton-pump inhibitors in reflux and peptic ulcers. Therap Adv Gastroenterol, 2010, 3(1): 11-22

[2] CorletoVD, FestaS, Di GiulioE, et al.. Proton pump inhibitor therapy and potential long-term harm. Curr Opin Endocrinol Diabetes Obes, 2014, 21(1): 3-8

[3] SinghA, CresciGA, KirbyDF. Proton Pump Inhibitors: Risks and Rewards and Emerging Consequences to the Gut Microbiome. Nutr Clin Pract, 2018, 33(5): 614-624

[4] YuT, TangY, JiangL, et al.. Proton pump inhibitor therapy and its association with spontaneous bacterial peritonitis incidence and mortality: A meta-analysis. Dig Liver Dis, 2016, 48(4): 353-359

[5] MandorferM, BotaS, SchwablP, 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(11): e110503

[6] TrikudanathanG, IsraelJ, CappaJ, et al.. Association between proton pump inhibitors and spontaneous bacterial peritonitis in cirrhotic patients — a systematic review and meta-analysis. Int J Clin Pract, 2011, 65(6): 674-678

[7] MinYW, LimKS, MinBH, et al.. Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study. Aliment Pharmacol Ther, 2014, 40(6): 695-704

[8] XuHB, WangHD, LiCH, et al.. Proton pump inhibitor use and risk of spontaneous bacterial peritonitis in cirrhotic patients: a systematic review and meta-analysis. Genet Mol Res, 2015, 14(3): 7490-7501

[9] DeverJB, SheikhMY. Review article: spontaneous bacterial peritonitis—bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther, 2015, 41(11): 1116-1131

[10] RunyonBA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology, 2013, 57(4): 1651-1653

[11] SchwablP, BucsicsT, SoucekK, et al.. Risk factors for development of spontaneous bacterial peritonitis and subsequent mortality in cirrhotic patients with ascites. Liver Int, 2015, 35(9): 2121-2128

[12] ChoiEJ, LeeHJ, KimKO, et al.. Association between acid suppressive therapy and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Scand J Gastroenterol, 2011, 46(5): 616-620

[13] BajajJS, ZadvornovaY, HeumanDM, et al.. Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites. Am J Gastroenterol, 2009, 104(5): 1130-1134

[14] TergR, CasciatoP, GarbeC, et al.. Study Group of Cirrhosis Complications of the Argentine Association for the Study of Liver Disease. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol, 2015, 62(5): 1056-1060

[15] DamG, VilstrupH, WatsonH, et al.. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology, 2016, 64(4): 1265-1272

[16] YamamotoK, IshigamiM, HondaT, et al.. Influence of proton pump inhibitors on microbiota in chronic liver disease patients. Hepatol Int, 2019, 13(2): 234-244

[17] YasutomiE, HoshiN, AdachiS, et al.. Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria. Dig Dis Sci, 2018, 63(4): 881-889

[18] MerliM, LucidiC, Di GregorioV, et al.. The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis. Liver Int, 2015, 35(2): 362-369

[19] BajajJS, RatliffSM, HeumanDM, et al.. Proton pump inhibitors are associated with a high rate of serious infections in veterans with decompensated cirrhosis. Aliment Pharmacol Ther, 2012, 36(9): 866-874

[20] MiuraK, TanakaA, YamamotoT, et al.. Proton pump inhibitor use is associated with spontaneous bacterial peritonitis in patients with liver cirrhosis. Intern Med, 2014, 53(10): 1037-1042

[21] HuangKW, KuanYC, LuoJC, et al.. Impact of long-term gastric acid suppression on spontaneous bacterial peritonitis in patients with advanced decompensated liver cirrhosis. Eur J Intern Med, 2016, 32: 91-95

[22] RatelleM, PerreaultS, VilleneuveJP, et al.. Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Can J Gastroenterol Hepatol, 2014, 28(6): 330-334

[23] GoelGA, DeshpandeA, LopezR, et al.. Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol Hepatol, 2012, 10(4): 422-427

[24] Lázaro-PachecoIB, Servín-CaamañoAI, Pérez-HernándezJL, et al.. Proton pump inhibitors increase the overall risk of developing bacterial infections in patients with cirrhosis. Arq Gastroenterol, 2018, 55(1): 28-32

[25] JamilS, AhmedS, MemonA, et al.. Factors predicting the recurrence of spontaneous bacterial peritonitis in patients with cirrhosis. J Coll Physicians Surg Pak, 2011, 21(7): 407-410

[26] ElzoukiAN, NeffatiN, RasoulFA, et al.. Increased Risk of Spontaneous Bacterial Peritonitis in Cirrhotic Patients Using Proton Pump Inhibitors. GE Port J Gastroenterol, 2019, 26(2): 83-89

[27] CampbellMS, ObsteinK, ReddyKR, et al.. Association between proton pump inhibitor use and spontaneous bacterial peritonitis. Dig Dis Sci, 2008, 53(2): 394-398

[28] MiozzoSAS, JohnJA, Appel-da-SilvaMC, et al.. Influence of proton pump inhibitors in the development of spontaneous bacterial peritonitis. World J Hepatol, 2017, 9(35): 1278-1285

[29] KwonJH, KohSJ, KimW, et al.. Mortality associated with proton pump inhibitors in cirrhotic patients with spontaneous bacterial peritonitis. J Gastroenterol Hepatol, 2014, 29(4): 775-781

[30] TriantosC, KalafateliM, SpantideaPI, et al.. Bacterial load and cytokine profile in patients with cirrhosis following therapy with proton pump inhibitors: a prospective cohort study. Ann Gastroenterol, 2017, 30(4): 450-456

[31] TergastTL, WrankeA, LaserH, et al.. Dose-dependent impact of proton pump inhibitors on the clinical course of spontaneous bacterial peritonitis. Liver Int, 2018, 38(9): 1602-1613

[32] ChangSS, LaiCC, LeeMG, et al.. Risk of spontaneous bacterial peritonitis associated with gastric Acid suppression. Medicine (Baltimore), 2015, 94(22): e944

[33] HungTH, TsengCW, LeeHF, et al.. Effect of Proton Pump Inhibitors on Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis. Ann Hepatol, 2018, 17(6): 933-939

[34] O’LearyJG, ReddyKR, WongF, et al.. North American Consortium for the Study of End-Stage Liver Disease. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clin Gastroenterol Hepatol, 2015, 13(4): 753-759

[35] KimJH, LimKS, MinYW, et al.. Proton pump inhibitors do not increase the risk for recurrent spontaneous bacterial peritonitis in patients with cirrhosis. J Gastroenterol Hepatol, 2017, 32(5): 1064-1070

[36] JankaT, TornaiT, BorbélyB, et al.. Deleterious effect of proton pump inhibitors on the disease course of cirrhosis. Eur J Gastroenterol Hepatol, 2020, 32(2): 257-264

[37] BajajJS, AcharyaC, FaganA, et al.. Proton Pump Inhibitor Initiation and Withdrawal Affects Gut Microbiota and Readmission Risk in Cirrhosis. Am J Gastroenterol, 2018, 113(8): 1177-1186

[38] de VosM, De VroeyB, GarciaBG, et al.. Role of proton pump inhibitors in the occurrence and the prognosis of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Liver Int, 2013, 33(9): 1316-1323

[39] MarcianoS, DíazJM, DirchwolfM, et al.. Spontaneous bacterial peritonitis in patients with cirrhosis: incidence, outcomes, and treatment strategies. Hepat Med, 2019, 11: 13-22

[40] LlachJ, RimolaA, NavasaM, 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(3): 724-727

[41] NischalkeHD, BergerC, AldenhoffK, et al.. Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis. J Hepatol, 2011, 55(5): 1010-1016

[42] AppenrodtB, GrünhageF, GentemannMG, et al.. Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology, 2010, 51(4): 1327-1333

[43] LeoneV, GibbonsSM, MartinezK, et al.. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe, 2015, 17(5): 681-689

[44] InoueT, NakayamaJ, MoriyaK, et al.. Gut dysbiosis associated with Hepatitis C virus infection. Clin Infect Dis, 2018, 67(6): 869-877

[45] KakiyamaG, PandakWM, GillevetPM, et al.. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol, 2013, 58(5): 949-955

[46] ZhangZ, ZhaiH, GengJ, et al.. Large-scale survey of gut microbiota associated with MHE Via 16S rRNA-based pyrosequencing. Am J Gastroenterol, 2013, 108(10): 1601-1611

[47] JacobsC, Coss AdameE, AttaluriA, et al.. Dysmotility and proton pump inhibitor use are independent risk factors for small intestinal bacterial and/or fungal overgrowth. Aliment Pharmacol Ther, 2013, 37(11): 1103-1111

[48] LombardoL, FotiM, RuggiaO, et al.. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol, 2010, 8(6): 504-508

[49] OkuraY, NamisakiT, SatoS, et al.. Proton pump inhibitor therapy does not increase serum endotoxin activity in patients with cirrhosis. Hepatol Res, 2019, 49(2): 232-238

[50] van VlerkenLG, HuismanEJ, van HoekB, et al.. Bacterial infections in cirrhosis: role of proton pump inhibitors and intestinal permeability. Eur J Clin Invest, 2012, 42(7): 760-767

[51] YoshidaN, YoshikawaT, TanakaY, et al.. A new mechanism for anti-inflammatory actions of proton pump inhibitors—inhibitory effects on neutrophil-endothelial cell interactions. Aliment Pharmacol Ther, 2000, 14(Suppl 1): 74-81

[52] FurusawaY, ObataY, FukudaS, et al.. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature, 2013, 504(7480): 446-450

[53] MurrayLJ, GabelloM, RudolphDS, et al.. Transmucosal gastric leak induced by proton pump inhibitors. Dig Dis Sci, 2009, 54(7): 1408-1417

[54] ChenY, LuQ, SchneebergerEE, et al.. Restoration of tight junction structure and barrier function by down-regulation of the mitogen-activated protein kinase pathway in ras-transformed Madin-Darby canine kidney cells. Mol Biol Cell, 2000, 11(3): 849-862

[55] SuzukiH, MasaokaT, MinegishiY, et al.. Lansoprazole promotes gastric mucosal cell proliferation and migration by activating p44/p42 mitogen-activated protein kinase. Wound Repair Regen, 2004, 12(1): 93-99

[56] ClarkeH, MaranoCW, Peralta SolerA, et al.. Modification of tight junction function by protein kinase C isoforms. Adv Drug Deliv Rev, 2000, 41(3): 283-301

[57] HessMW, de BaaijJH, GommersLM, et al.. Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice. PLoS One, 2015, 10(9): e0138881

[58] HorvathA, LeberB, SchmerboeckB, et al.. Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis. Aliment Pharmacol Ther, 2016, 44(9): 926-935

[59] ZhangS, WangW, RenW, et al.. Effects of lactulose on intestinal endotoxin and bacterial translocation in cirrhotic rats. Chin Med J (Engl), 2003, 116(5): 767-771