Proton Pump Inhibitor Therapy Does Not Affect Prognosis of Cirrhosis Patients With Acute Decompensation and Acute-on-Chronic Liver Failure: A Single-Center Prospective Study

Background: The aim of this study was to investigate the impact of proton pump inhibitor (PPI) therapy on complications and prognosis in cirrhosis patients with and without acute-on-chronic liver failure (ACLF). Materials and Methods: Cirrhosis patients with acute decompensation (AD) (n = 489) admitted in our center were enrolled in this prospective observational cohort study. According to treatment received, patients were identified as users or nonusers of PPI. Clinical and laboratory data, complications during hospitalization, and overall survival were recorded in all the patients. Results: Of the 489 patients, 299 (61.1%) patients received PPI therapy. The logistic regression analysis showed that age, albumin, history of previous hepatic encephalopathy (HE), and the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score were independent risk factors for HE in patients with decompensated cirrhosis [odds ratio (OR) = 1.07, 95% CI: 1.03–1.12, p = 0.001; OR = 1.13, 95% CI: 1.04–1.24, p = 0.006; OR = 242.52, 95% CI: 40.17–1464.11, p < 0.001; and OR = 2.89, 95% CI: 2.11–3.96, p < 0.001, respectively]. Previous severe liver injury and previous bacterial infections were independent risk factors for spontaneous bacterial peritonitis (SBP) in patients with decompensated cirrhosis (OR = 3.43, 95% CI: 1.16–10.17, p = 0.026 and OR = 6.47, 95% CI: 2.29–18.29, p < 0.001, respectively). The multivariate Cox proportional hazards regression model showed that the type and dose of the PPI used were not related to 28-day and 90-day mortality in cirrhosis patients with AD or ACLF. Conclusion: PPI use does not appear to increase mortality or the risk of HE and SBP in the hospitalized cirrhosis patients with and without ACLF.


INTRODUCTION
Proton pump inhibitors (PPIs) are commonly used in cirrhosis patients to treat gastrointestinal disorders, especially gastrointestinal bleeding (1)(2)(3). Gastrointestinal hemorrhage may be due to bleeding varices or ulcers or portal hypertensive gastropathy and is one of the most serious complications seen in acute-on-chronic liver failure (ACLF) (4)(5)(6). While PPI is useful in these cases, the drug may alter the composition of the gut microbiota and increase the risk of spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), Clostridium difficile infection, and mortality (7)(8)(9)(10)(11)(12)(13)(14). Although some recent studies have indicated that PPI therapy does not increase the risk of SBP or mortality in cirrhosis, these studies did not include patients with ACLF (15)(16)(17)(18). The aim of this study was to assess whether PPI therapy increases the incidence of SBP and HE and decreases survival in cirrhosis patients with and without ACLF.

Patients
Patients diagnosed as cirrhosis with acute decompensation (AD) and hospitalized in the Department of Infectious Diseases at the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China, between February 2014 and March 2015 were eligible for inclusion in this study. Patients were excluded if they: (1) were < 18 years old; (2) were pregnant; (3) had evidence of infection with human immunodeficiency virus, Epstein-Barr virus, or human cytomegalovirus; (4) had aplastic anemia, myelodysplastic syndrome, thrombocytopenia, hemophilia, or disseminated intravascular coagulation; (5) were currently using immunosuppressant medications or adrenocortical hormones; (6) had hepatocellular carcinoma or other malignant tumors; (7) had chronic renal disease or other serious comorbidity; or (8) had history of liver transplantation (19,20). The diagnosis of liver cirrhosis was based on clinical evidence, endoscopic or radiologic examination, and liver biopsy (6,21). Cirrhosis patients were diagnosed with AD if they had more than one of the following major complications: ascites, encephalopathy, gastrointestinal hemorrhage, severe liver injury, and infection (20). Severe liver injury was diagnosed if alanine aminotransferase (ALT) was ≥ five times the normal upper limit or more than twice the baseline value along with elevation of serum bilirubin to ≥ 85 µmol/l and international normalized ratio (INR) to ≥ 1.5 at any time during the preceding 1 month (21). The chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score was used to diagnose organ failure (6). The diagnosis of ACLF was based on the criteria proposed by the Chinese Group on the Study of Severe Hepatitis B (COSSH) (22). The diagnosis of gastrointestinal bleeding and bacterial infections was made as previously described (1,23,24). PPI treatment was generally used in patients with gastrointestinal bleeding and gastric ulcer, but was extended in patients receiving endoscopic variceal ligation and those manifesting gastrointestinal disturbances such as hiccups, epigastric pain, nausea, or vomiting. For this study, "PPI use" was defined as intravenous administration of any PPI for at least 6 days with daily dose higher than that recommended by the WHO (13). Patients receiving lower doses were considered to be nonusers. PPI doses are classified according to the cumulative defined daily dose (cDDD) (25).
Informed consent for participation in this study was obtained from each participant or his or her legal surrogate. This study was approved by the Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China and all the procedures were in accordance with the latest version of the Declaration of Helsinki.

Data Collection
Demographic data, clinical history, reason for admission, physical examination findings, laboratory results, cirrhosis complications, events of organ failure, and prognosis were recorded. Potential precipitating factors for SBP and HE were noted. Survival at 28 days and 90 days following enrollment was recorded. Survival information was obtained by telephonic interview.

Statistical Analysis
The Statistical Package for the Social Sciences (SPSS) version 26.0 (IBM Corporation, Armonk, New York, USA) was used for the data analysis. Categorical variables were summarized as numbers and percentages and compared by using the chisquared test. Continuous variables were summarized as means ± SDs or medians (and interquartile ranges) and compared by using the Student's t-test or the Mann-Whitney U test. Variables found to be associated with SBP and HE on the univariate analysis (p < 0.10) were entered into the multivariate logistic regression analysis to identify the independent risk factors for SBP or HE. Baseline characteristics were compared between patients receiving and not receiving PPI therapy before and after propensity score matching (PSM). We performed PSM to adjust differences in baseline characteristics of decompensated cirrhosis and ACLF including gender, age, leukocyte count, platelet count, hemoglobin, serum bilirubin, albumin, aspartate aminotransferase (AST), ALT, INR, creatinine, serum sodium, the CLIF-SOFA score, and the model for end-stage liver disease (MELD) score by matching non-PPI users with comparable patients with PPI users in a ratio of 1:1 with a caliper of 0.1 of the SD. A standardized difference < 0.1 indicated a good balance between PPI and non-PPI groups. The multivariate Cox proportional hazards regression model was used to analyze the risk factors for 28-day and 90-day mortality. For the multivariate analysis, the probability for stepwise entry was at p = 0.05 and for removal at p = 0.10; only variables with p < 0.05 were retained in the final model. Statistical significance was at p ≤ 0.05.
Then, we matched 489 patients with acute decompensated cirrhosis with 1:1. After PSM, there are 182 patients in PPI user group and non-user group, respectively ( Table 1). Compared with the decompensated cirrhosis patients before PSM, some baseline characteristics have changed. PPI users were younger   22.5%, p = 0.043). In addition, PPI users had remarkably higher serum sodium level (p = 0.000), lower AST level, and the CLIF-SOFA score (p = 0.002 and p = 0.017). Other baseline characteristics did not change significantly. We also analyzed 80 patients with ACLF in detail and matched them by the same method as above ( Table 2). Among patients with ACLF, there were no significant differences between PPI users and non-users in mean age, gender composition, prevalence of hypertension, etiology of cirrhosis, incidence of previous decompensation, complications of cirrhosis during hospital stay, laboratory data, and scores of the MELD and the CLIF-SOFA. Similarly, PPI users and non-users had comparable 28-day mortality (27.8 vs. 45.9%, 0.482) and 90-day mortality rates (47.2 vs. 56.8%, 0.887). After PSM, other features did not change significantly, except for the lower prevalence of hypertension in PPI users (25.0 vs. 5.6%, p = 0.023).

Proton Pump Inhibitor Therapy and the Complications of Cirrhosis During Hospitalization
The proportion of patients developing HE during hospitalization was comparable between PPI users and nonusers before and after PSM (8.7 vs. 12.6%, p = 0.162; 8.8 vs. 11.0%, p = 0.483) ( Table 1).   Table 3).
The cDDD of PPI in patients with decompensated cirrhosis and ACLF is summarized in Figure 2. The cDDDs of PPI in patients with decompensated cirrhosis and ACLF were divided into four groups: 1-7, 8-14, 15-30, and >30 patients. Among all the patients with decompensated cirrhosis, 25.15% were not treated with PPI. Especially, among all the patients with ACLF, 26.25% were not treated with PPI. Before and after PSM, the group of cDDD 15-30 patients accounted for the highest proportion of PPI users in both the decompensated cirrhosis group and ACLF group. But, the proportion of patients with cDDD > 30 patients was the smallest.
Then, we further discussed the relationship between the patients with HE and SBP during hospitalization and the cDDD of PPI (Figure 3). Before PSM, cDDD of 32% patients with HE and cDDD of 29% patients with SBP in decompensated cirrhosis were 15-30 patients, which had the highest proportion. The PPI non-user and cDDD 15-30 patients complicated with HE accounted for a high proportion of 33% in ACLF. After PSM of patients with decompensated cirrhosis, the PPI non-users and cDDD 15-30 patients complicated with HE accounted for a high proportion of 31%, while cDDD 1-7 patients and cDDD 15-30 patients with SBP accounted for a high proportion of 28%. ACLF patients with SBP had the same proportion in the three cDDD groups (1-7, 8-14, and 15-30 patients). Meanwhile, the type and dose of the PPI used were not related to the risk of developing HE or SBP ( Table 3).
The multivariate Cox proportional hazards regression model did not show significant association between the type and dose of the PPI and 28-day and 90-day mortality (Table 4; Figures 4, 5).  The p-value of the cumulative incidence of mortality death between patients with decompensated liver cirrhosis and the dose of the PPI was 0.018 before PSM, but after PSM, there was no statistical significance. However, age, leukocyte count, and the high MELD score were independent predictors of 28-day and 90day mortality in cirrhosis patients with AD (Table 4). In addition, previous severe liver injury was an independent predictor of 28-day mortality ( Table 4).

DISCUSSION
This study aimed to investigate the impact of PPI therapy on complications and prognosis in cirrhosis patients with and without ACLF. PPI therapy is used in as much as 46-78% of cirrhosis patients (7). In this study, PPI was used in 61.1% of cirrhosis patients including 62.6% of patients without ACLF and 53.8% of patients with ACLF. Thus, consistent with previous studies, our results also demonstrate that PPI use is common in cirrhosis patients with and without ACLF (2). The proportions of patients with history of previous gastrointestinal bleeding and low hemoglobin were higher among PPI users than among nonusers. This is not surprising because PPIs are commonly used in cirrhosis patients with gastrointestinal bleeding (2,26). The type of PPI and the dose were not associated with the risk of HE and SBP. Previous reports have indicated that treatment with acid-suppressing drugs increase the incidence of SBP and HE (7,11,14). The explanation offered was that PPIs might promote small intestinal bacterial overgrowth with subsequent bacterial translocation (7,27). Another explanation was that PPIs may inhibit the functions of neutrophils and natural killer cells (28). However, the association between PPI and SBP has not been consistently demonstrated (15,21,29). In one prospective multicenter study of many cirrhosis patients with AD, PPI use did not increase the risk of SBP (17). Our result is in accordance with the conclusion of an earlier meta-analysis that did not support the association between PPI use and SBP or HE (18).
In this study, age, albumin, history of previous HE, and the CLIF-SOFA score were significantly associated with HE during hospitalization. In addition, previous severe liver injury and previous bacterial infections were shown to be independent risk FIGURE 4 | The relationship between the type and dose of the PPI therapy and 28-day and 90-day mortality (A) The relationship between the type and dose of the PPI therapy and 28-day mortality before PSM; (B) The relationship between the type and dose of the PPI therapy and 90-day mortality before PSM; (C) The relationship between the type and dose of the PPI therapy and 28-day mortality after PSM; (D) The relationship between the type and dose of the PPI therapy and 90-day mortality after PSM. cDDD, cumulative defined daily dose; PPI, proton pump inhibitor; ACLF, acute-on-chronic liver failure. The 28-day cumulative incidence of death of patients with ACLF with different doses or without PPI treatment before PSM; (D) The 90-day cumulative incidence of death of patients with ACLF with different doses or without PPI treatment before PSM; (E) The 28-day cumulative incidence of death of patients with decompensated cirrhosis with different doses or without PPI treatment after PSM; (F) The 90-day cumulative incidence of death of patients with decompensated cirrhosis with different doses or without PPI treatment after PSM; (G) The 28-day cumulative incidence of death of patients with ACLF with different doses or without PPI treatment after PSM; (H) The 90-day cumulative incidence of death of patients with ACLF with different doses or without PPI treatment after PSM. cDDD, cumulative defined daily dose; PPI, proton pump inhibitor; ACLF, acute-on-chronic liver failure.
factors for SBP in cirrhosis patients. A previous study has also shown that history of HE is associated with increased incidence of HE during hospitalization (30). This study found that older age, high leukocyte count, and the high MELD score independently predicted the 28-day and 90-day mortality in cirrhosis patients with AD. Previous studies have also found that age, leukocyte count, and the MELD score have to be independently associated with the risk of death in cirrhosis (31,32). In this study, PPI therapy was not associated with the 28-day and 90-day mortality in cirrhosis patients with AD or ACLF. Others have also reported that PPI use does not increase the mortality rate in cirrhosis patients with or without ACLF (16,18).
In conclusion, PPI therapy does not appear to increase the risk of HE or SBP or to shorten survival in cirrhosis patients with or without ACLF. Further prospective multicenter studies with large samples are necessary to confirm our findings and to clarify how PPI therapy is related to complications and disease progression in cirrhosis.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital, School of Medicine of Zhejiang University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.