Short-Term Proton Pump Inhibitor Use and Hepatic Encephalopathy Risk in Patients with Decompensated Cirrhosis
Abstract
:1. Introduction
2. Methods
2.1. Case-Crossover Design
2.2. Data Source and Study Population
2.3. Ethics Statement
2.4. Data Processing and Statistical Analysis
3. Results
4. Discussion
Author Contributions
Funding
Conflicts of Interest
References
- Flamm, S.L. Complications of Cirrhosis in Primary Care: Recognition and Management of Hepatic Encephalopathy. Am. J. Med. Sci. 2018, 356, 296–303. [Google Scholar] [CrossRef] [PubMed]
- Bustamante, J.; Rimola, A.; Ventura, P.J. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J. Hepatol. 1999, 30, 890–895. [Google Scholar] [CrossRef]
- Stewart, C.A.; Malinchoc, M.; Kim, W.R. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl. 2007, 13, 1366–1371. [Google Scholar] [CrossRef] [PubMed]
- Vilstrup, H.; Amodio, P.; Bajaj, J. 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. Hepatology 2014, 60, 715–735. [Google Scholar] [CrossRef] [PubMed]
- Pantham, G.; Post, A.; Venkat, D.; Einstadter, D.; Mullen, K.D. A New Look at Precipitants of Overt Hepatic Encephalopathy in Cirrhosis. Dig. Dis. Sci. 2017, 62, 2166–2173. [Google Scholar] [CrossRef] [PubMed]
- Strauss, E.; Costa, M.F. The importance of bacterial infections as precipating factors of chronic hepatic encephalopathy in cirrhosis. Hepato Gastroenterol. 1998, 45, 900–904. [Google Scholar]
- Mumtaz, K.; Ahmed, U.S.; Abid, S. Precipitating factors and the outcome of hepatic encephalopathy in liver cirrhosis. J. Coll. Physicians Surg. Pak. 2010, 20, 514–518. [Google Scholar]
- Maqsood, S.; Saleem, A.; Iqbal, A.; Butt, J.A. Precipitating factors of hepatic encephalopathy: Experience at Pakistan Institute of Medical Sciences Islamabad. J. Ayub Med. Coll. Abbottabad 2006, 18, 58–62. [Google Scholar]
- Lo, W.K.; Chan, W.W. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: A meta-analysis. Clin. Gastroenterol. Hepatol. 2013, 11, 483–490. [Google Scholar] [CrossRef]
- Rai, R.; Saraswat, V.A.; Dhiman, R.K. Gut microbiota: Its role in hepatic encephalopathy. J. Clin. Exp. Hepatol. 2015, 5, S29–S36. [Google Scholar] [CrossRef]
- Dam, G.; Vilstrup, H.; Watson, H. 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. [Google Scholar] [CrossRef] [PubMed]
- Tsai, C.F.; Chen, M.H.; Wang, Y.P. Proton Pump Inhibitors Increase Risk for Hepatic Encephalopathy in Patients with Cirrhosis in a Population Study. Gastroenterology 2017, 152, 134–141. [Google Scholar] [CrossRef] [PubMed]
- Sakamaki, A.; Yokoo, T.; Kamimura, K.; Farcomeni, A.; Merli, M.; Riggio, O. Proton pump inhibitors do not increase the incidence of hepatic encephalopathy: A multicenter retrospective study in niigata prefecture. Hepatology 2018, 68, 1173A. [Google Scholar]
- Zhu, J.; Qi, X.; Yu, H.; Li, J.; Han, D.; Guo, X. Association of proton pump inhibitors with the risk of hepatic encephalopathy during hospitalization for liver cirrhosis. United Eur. Gastroenterol. J. 2018, 6, 1179–1187. [Google Scholar] [CrossRef]
- Lin, Z.N.; Zuo, Y.Q.; Hu, P. Association of Proton Pump Inhibitor Therapy with Hepatic Encephalopathy in Hepatitis B Virus-related Acute-on-Chronic Liver Failure. Hepat. Mon. 2014, 14, e16258. [Google Scholar] [CrossRef] [Green Version]
- Teixeira, C.; Antunes, A.; Dantas, E. Proton pump inhibitors intake not associated with hepatic encephalopathy in cirrhotic patients. United Eur. Gastroenterol. J. 2017, 5, A628. [Google Scholar]
- Tapper, E.B.; Henderson, J.; Baki, J. Incidence and predictors of hepatic encephalopathy in a population-based cohort of older americans with cirrhosis: Role of opiates, benzodiazepines and proton-pump inhibitors (PPIs). Hepatology 2018, 68, 138A. [Google Scholar]
- Khan, M.A.; Cholankeril, G.; Howden, C.W. Proton Pump Inhibitors and the Possible Development of Hepatic Encephalopathy in Cirrhotic Patients: True Association or Residual Confounding? Gastroenterology 2017, 152, 2076. [Google Scholar] [CrossRef] [Green Version]
- Maclure, M. The case-crossover design: A method for studying transient effects on the risk of acute events. Am. J. Epidemiol. 1991, 133, 144–153. [Google Scholar] [CrossRef]
- Mehta, G.; Mookerjee, R.P.; Sharma, V.; Jalan, R. Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure. Liver Int. 2015, 35, 724–734. [Google Scholar] [CrossRef]
- Dasani, B.M.; Sigal, S.H.; Lieber, C.S. Analysis of risk factors for chronic hepatic encephalopathy: The role of Helicobacter pylori infection. Am. J. Gastroenterol. 1998, 93, 726–731. [Google Scholar] [CrossRef] [PubMed]
- Kirchheiner, J.; Glatt, S.; Fuhr, U.; Klotz, U.; Meineke, I.; Seufferlein, T.; Brockmöller, J. Relative potency of proton-pump inhibitors-comparison of effects on intragastric pH. Eur. J. Clin. Pharmacol. 2009, 65, 19–31. [Google Scholar] [CrossRef] [PubMed]
- Rojo, L.E.; Alzate-Morales, J.; Saavedra, I.N.; Davies, P.; Maccioni, R.B. Selective interaction of lansoprazole and astemizole with tau polymers: Potential new clinical use in diagnosis of Alzheimer’s disease. J. Alzheimers Dis. 2010, 19, 573–589. [Google Scholar] [CrossRef] [PubMed]
- Assaraf, J.; Weiss, N.; Thabut, D. Proton Pump Inhibitor Administration Triggers Encephalopathy in Cirrhotic Patients by Modulating Blood-Brain Barrier Drug Transport. Gastroenterology 2017, 152, 2077. [Google Scholar] [CrossRef] [PubMed]
- Gupta, A.; Dhiman, R.K.; Kumari, S.; Rana, S.; Agarwal, R.; Duseja, A.; Chawla, Y. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J. Hepatol. 2010, 53, 849–855. [Google Scholar] [CrossRef]
- Lunia, M.K.; Sharma, B.C.; Sachdeva, S. Small intestinal bacterial overgrowth and delayed orocecal transit time in patients with cirrhosis and low-grade hepatic encephalopathy. Hepatol. Int. 2013, 7, 268–273. [Google Scholar] [CrossRef] [PubMed]
- Sanaka, M.; Yamamoto, T.; Kuyama, Y. Effects of proton pump inhibitors on gastric emptying: A systematic review. Dig. Dis. Sci. 2010, 55, 2431–2440. [Google Scholar] [CrossRef]
- Yoshida, N.; Yoshikawa, T.; Tanaka, Y.; Fujita, N.; Kassai, K.; Naito, Y.; Kondo, M. A new mechanism for anti-inflammatory actions of proton pump inhibitors—Inhibitory effects on neutrophil-endothelial cell interactions. Aliment. Pharmacol. Ther. 2000, 14, 74–81. [Google Scholar] [CrossRef]
- Teltschik, Z.; Wiest, R.; Beisner, J.; Nuding, S.; Hofmann, C.; Schoelmerich, J.; Bevins, C.L.; Stange, E.F.; Wehkamp, J. Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense. Hepatology 2012, 55, 1154–1163. [Google Scholar] [CrossRef]
- Jackson, M.A.; Goodrich, J.K.; Maxan, M.E.; Ley, R.E.; Bell, J.T.; Spector, T.D.; Steves, C.J. Proton pump inhibitors alter the composition of the gut microbiota. Gut 2016, 65, 749–756. [Google Scholar] [CrossRef]
- Freedberg, D.E.; Toussaint, N.C.; Chen, S.P.; Ratner, A.J.; Whittier, S.; Wang, T.C.; Wang, H.H.; Abrams, J.A. Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial. Gastroenterology 2015, 149, 883–885. [Google Scholar] [CrossRef] [PubMed]
- Bajaj, J.S.; Heuman, D.M.; Hylemon, P.B. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J. Hepatol. 2014, 60, 940–947. [Google Scholar] [CrossRef] [PubMed]
- Shawcross, D.L.; Dunk, A.A.; Jalan, R.; Kircheis, G.; Knegt, R.J.; Laleman, W.; Ramage, J.K.; Wedemeyer, H.; Morgan, I.E. How to diagnose and manage hepatic encephalopathy: A consensus statement on roles and responsibilities beyond the liver specialist. Neurogastroenterol. Motil. 2016, 28, 146–152. [Google Scholar] [CrossRef] [PubMed]
Characteristic | Cases (N = 13,195) | |
---|---|---|
Mean | SD | |
Age (years) | 56.6 | 13.2 |
N | % | |
Gender | ||
Male | 9271 | 70.3 |
Female | 3924 | 29.7 |
Cirrhosis etiology | ||
HBV-related | 4702 | 35.6 |
HCV-related | 3982 | 30.2 |
Alcohol-related | 7351 | 55.7 |
Hepatic decompensation at enrollment | ||
Ascites | 7920 | 60.0 |
Varices or varices bleeding | 9284 | 70.4 |
Hepatorenal syndrome | 79 | 0.60 |
Charlson Comorbidity Index score | ||
0 | 315 | 2.39 |
1 | 3680 | 27.9 |
2 | 5709 | 43.3 |
3+ | 3491 | 26.5 |
Medical comorbidities in recent 3 months | ||
GI bleeding | 3151 | 23.9 |
Intra-abdominal infection | 955 | 7.24 |
Pneumonia | 271 | 2.05 |
Urinary tract infection | 275 | 2.08 |
Case N = 13,195 | Control N = 13,195 | Crude | Adjusted a | |||||
---|---|---|---|---|---|---|---|---|
OR | 95% CI | OR | 95% CI | |||||
7 day window Proton pump inhibitor | 1779 | 13.5% | 977 | 7.40% | 2.18 | 1.99–2.39 | 3.13 | 2.33–4.20 |
14 day window Proton pump inhibitor | 2459 | 18.6% | 1192 | 9.03% | 2.82 | 2.59–3.08 | 4.77 | 3.81–5.98 |
28 day window Proton pump inhibitor | 3155 | 23.9% | 1268 | 9.61% | 3.86 | 3.55–4.21 | 5.60 | 4.63–6.78 |
Case N = 13,195 | Control N = 13,195 | Crude | Adjusted a | |||||
---|---|---|---|---|---|---|---|---|
OR | 95% CI | OR | 95% CI | |||||
Pantoprazole | 299 | 2.27% | 178 | 1.35% | 1.92 | 1.55–2.37 | 1.36 | 0.72–2.58 |
Lansoprazole | 722 | 5.47% | 397 | 3.01% | 2.16 | 1.87–2.48 | 4.38 | 2.76–6.97 |
Omeprazole | 255 | 1.93% | 140 | 1.06% | 2.29 | 1.79–2.94 | 1.85 | 0.86–3.98 |
Esomeprazole | 374 | 2.83% | 195 | 1.48% | 2.30 | 1.88–2.81 | 5.14 | 2.30–11.5 |
Rabeprazole | 129 | 0.98% | 67 | 0.51% | 2.55 | 1.77–3.68 | 3.62 | 1.02–12.9 |
Case N = 13,195 | Control N = 13,195 | Crude | Adjusted a | |||
---|---|---|---|---|---|---|
OR | 95% CI | OR | 95% CI | |||
GI bleeding | ||||||
Yes | 605 | 247 | 2.91 | 2.35–3.61 | 2.71 | 2.10–3.49 |
No | 2550 | 1021 | 2.97 | 2.75–3.21 | 1.42 | 1.29–1.56 |
Intra-abdominal infection | ||||||
Yes | 183 | 60 | 3.86 | 2.52–5.90 | 3.93 | 2.32–6.65 |
No | 2972 | 1208 | 2.92 | 2.72–3.14 | 1.43 | 1.31–1.57 |
Pneumonia | ||||||
Yes | 50 | 20 | 1.96 | 0.96–3.99 | 1.63 | 0.69–3.85 |
No | 3105 | 1248 | 2.96 | 2.76–3.18 | 1.46 | 1.34–1.59 |
Urinary tract infection | ||||||
Yes | 26 | 8 | 4.62 | 1.72–12.4 | 10.8 | 2.58–45.6 |
No | 3129 | 1260 | 2.95 | 2.75–3.17 | 1.45 | 1.33–1.58 |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kuan, Y.-C.; Huang, K.-W.; Lin, C.-L.; Luo, J.-C.; Kao, C.-H. Short-Term Proton Pump Inhibitor Use and Hepatic Encephalopathy Risk in Patients with Decompensated Cirrhosis. J. Clin. Med. 2019, 8, 1108. https://doi.org/10.3390/jcm8081108
Kuan Y-C, Huang K-W, Lin C-L, Luo J-C, Kao C-H. Short-Term Proton Pump Inhibitor Use and Hepatic Encephalopathy Risk in Patients with Decompensated Cirrhosis. Journal of Clinical Medicine. 2019; 8(8):1108. https://doi.org/10.3390/jcm8081108
Chicago/Turabian StyleKuan, Yi-Chun, Kuang-Wei Huang, Cheng-Li Lin, Jiing-Chyuan Luo, and Chia-Hung Kao. 2019. "Short-Term Proton Pump Inhibitor Use and Hepatic Encephalopathy Risk in Patients with Decompensated Cirrhosis" Journal of Clinical Medicine 8, no. 8: 1108. https://doi.org/10.3390/jcm8081108