Abstract
Background and objective
Treatment with proton pump inhibitors (PPIs) has been associated with development of hepatic encephalopathy (HE). As development of HE is a major complication after implantation of a transjugular intrahepatic portosystemic shunt (TIPS), we hypothesized that PPI treatment may be associated with a higher risk of post-TIPS HE.
Methods
We analyzed data of 397 patients with liver cirrhosis who received de novo TIPS implantation at the University Medical Center Freiburg, Germany. We assessed whether PPI medication and other patient characteristics are predictive factors for the development of post-TIPS HE.
Results
Patients with PPI treatment at the time of TIPS implantation showed significantly higher rates of post-TIPS HE than those without PPI medication (30.4% vs 11.7%, p < 0.001). The rate of post-TIPS HE increased in a dose-dependent manner. However, PPI medication did not directly affect transplant-free survival. Remarkably, in 59.1% of patients who received PPIs there was no clear indication.
Conclusions
PPI treatment may be an independent risk factor for the development of post-TIPS HE and the risk increases with PPI dose. Indication for PPI treatment should be assessed carefully prior to TIPS implantation in patients with liver cirrhosis.
Keywords: Hepatic encephalopathy, PPI, proton pump inhibitors, transjugular intrahepatic portosystemic shunt, TIPS
Key summary
Summarize the established knowledge on this subject
Treatment with proton pump inhibitors (PPIs) is associated with the occurrence of complications of liver cirrhosis and portal hypertension (e.g. spontaneous bacterial peritonitis and development of hepatic encephalopathy (HE) outside the transjugular intrahepatic portosystemic shunt (TIPS) setting).
To date it is unknown whether treatment with PPIs may facilitate the development of post-TIPS HE.
What are the significant and /or new findings of this study?
A total of 59.1% of patients receiving transjugular intrahepatic portosystemic shunt (TIPS) implantation have no clear indication for treatment with proton pump inhibitors (PPIs).
Patients who have been treated with PPIs show a significantly higher rate of post-TIPS hepatic encephalopathy (HE) compared to patients without PPI treatment. The effect of PPI treatment on the development of post-TIPS HE is dose dependent.
Introduction
Liver cirrhosis occurs with a prevalence of up to 1% of people worldwide.1 A common complication of liver cirrhosis is the development of portal hypertension. Clinical manifestations of portal hypertension are variceal bleeding, ascites and hepatorenal syndrome, which are major causes of increased morbidity and mortality in these patients.2 Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) has become a well-established, effective and safe therapeutic option for prophylaxis and treatment of endoscopically unmanageable variceal bleeding and treatment-refractory ascites.3,4 A common risk of TIPS implantation, however, is the development of post-TIPS hepatic encephalopathy (HE) due to the increase of portosystemic blood flow.5 Importantly, in that setting HE is associated with increased morbidity and mortality.6,7 Hence it is important to carefully evaluate patients with liver cirrhosis for risk factors for the development of HE prior to TIPS implantation. Several risk factors have been described, e.g. former episodes of HE or reduced liver function.8 Nevertheless, many potential influencing factors remain to be investigated.
Proton pump inhibitors (PPIs) are widely used in clinical practice, e.g. in the treatment of gastritis or gastric ulcer disease. There is growing evidence that PPI treatment is associated with the occurrence of complications of liver cirrhosis and portal hypertension. For instance, PPI treatment has been found to be associated with an increased risk of spontaneous bacterial peritonitis as well as an increased risk of HE outside the TIPS setting.9–11 Importantly, there are no studies focusing on a possible effect of PPIs on HE in the context of TIPS implantation. Therefore, the aim of our study was to analyze the effect of PPI treatment on the development of post-TIPS HE.
Patients and methods
Patient selection and follow-up
Between January 2004 and September 2016 de novo TIPS implantation was performed at the University Medical Center Freiburg, Germany, in 489 patients. Patients with acute or chronic Budd-Chiari syndrome (n = 30), noncirrhotic portal vein thrombosis (n = 16) and hepatocellular carcinoma patients (n = 46) were excluded. Allocation of the patients was consecutive and ultimately 397 patients were included in our study. Patients were recruited during routine clinical care and were not participating in clinical trials.
In all patients, indication for TIPS implantation was clinical manifestation of portal hypertension due to liver cirrhosis. Diagnosis of liver cirrhosis was based on imaging studies, clinical findings and laboratory tests. The indication for TIPS treatment was defined according to the recommendations of the Baveno consensus conference and the German guidelines for the treatment of ascites.12,13 These guidelines do not recommend large-volume paracentesis in patients with diuretics-refractory ascites but suggest TIPS implantation. According to the Baveno consensus conference, early TIPS implantation within 72 hours (“emergency TIPS”) is recommended in patients with variceal bleeding and a high risk of treatment failure after initial pharmacological and endoscopic therapy.12
Demographic, interventional data and laboratory parameters including liver function tests were reviewed in the medical records. Liver function was assessed using the Child-Pugh score and the model for end-stage liver disease (MELD) score. Patients’ medication during the hospital stay for TIPS implantation was assessed retrospectively and determined by reviewing the medical charts of the patients with a special focus on PPI treatment. Medication was assessed the day before TIPS implantation and followed during the hospital stay for TIPS implantation. The indication for treatment with PPIs was included in the analyses. Further, we assessed the kind of PPI (pantoprazole, omeprazole, esomeprazole) and the dose of PPI. We calculated dose equivalents with pantoprazole being the reference (20 mg omeprazole or esomeprazole is equal to 40 mg pantoprazole, 40 mg omeprazole or esomeprazole is equal to 80 mg pantoprazole).
Further, patients’ comedication for HE prevention that was given after TIPS implantation including lactulose and/or l-ornithine-aspartate and/or rifaximin was determined from the patients’ charts. Peri-interventional antibiotic treatment also was assessed.
Ethics approval
Written informed consent for TIPS implantation and for data collection was obtained from all patients. The study was approved by the local ethics committee of the Medical Center University of Freiburg (no. EK 428/14; September 4, 2014) and is in accordance with the Declaration of Helsinki.
Statistical analyses
The present study was a retrospective observational study. Patients were analyzed from the day of TIPS implantation and followed-up until death, liver transplantation (n = 5) or last contact. Follow-up visits were performed one and three months after TIPS implantation and thereafter every six months if no complications occurred. In this retrospective study, follow-up for the development of post-TIPS HE was six months after TIPS implantation. The primary endpoint was development of post-TIPS HE according to the West Haven criteria within six months after TIPS implantation.14 The secondary endpoint was transplant-free survival (TFS) starting from the day of TIPS implantation. The cutoff point for survival data was December 15, 2017. TFS was calculated according to the Kaplan-Meier method with death and liver transplantation being recorded as events. Differences in survival were assessed using log-rank tests.
Continuous variables are expressed as mean with standard deviation whereas categorical variables are reported as frequencies and percentages.
For continuous variables differences were determined using Wilcoxon-Mann-Whitney and Kruskal-Wallis tests as there was no Gaussian distribution of the data, confirmed by the Kolmogorov-Smirnov test. χ2 tests or Fisher exact tests were used for categorical variables. P values < 0.05 were considered to be significant.
Time to development of post-TIPS HE within six months after TIPS implantation was assessed and Kaplan-Meier curves were plotted to describe the time-dependent development of post-TIPS HE stratified to different PPI doses.
Predictive factors for the development of post-TIPS HE were assessed by using uni- and multivariable logistic regression models. Age,8 etiology of liver disease (viral vs nonviral liver disease),15–17 TIPS indication (ascites vs varices),8 acute variceal bleeding with early TIPS implantation (within 72 hours after the bleeding episode),8 covering of the stent graft,18 portosystemic gradient before and after TIPS,19–21 HE before TIPS,8 MELD score,8 HE medication (lactulose and/or l-ornithine-aspartate and/or rifaximin), peri-interventional antibiotic treatment and the dose of PPI (no PPI vs 20 mg per day vs 40 mg per day vs 80 mg per day) were analyzed in a univariable model as possible factors with an impact on post-TIPS HE. These factors were chosen as they have been associated with higher risk of post-TIPS HE in previous studies and a meta-analysis.8 First, univariable analyses of these possible factors were performed. Afterward, all factors were included in a multivariable model and significant predictive factors were assessed by using the forward selection method. Statistical analyses were performed with SPSS (version 20.0, IBM, NY, USA) and GraphPad Prism (version 5, GraphPad Software, San Diego, CA, USA).
Results
Patient characteristics
Table 1 summarizes the baseline characteristics of the included study participants, stratified according to PPI medication. Before and after TIPS implantation 303 out of 397 patients (76.3%) received PPIs. Of those 30 patients (9.9%) took a daily dose of 20 mg, 210 patients (69.3%) 40 mg per day and 63 patients (20.8%) 80 mg per day, respectively. A total of 291 patients received pantoprazole (96.0%), two patients were treated with omeprazole (0.7%) and 10 patients received esomeprazole (3.3%). For patients with omeprazole and esomeprazole the dose equivalents for pantoprazole were calculated and reported. Remarkably, in 179 patients (59.1%) the indication for treatment with PPIs remained unclear. In the remaining patients, indications for PPI treatment were gastric ulcer disease (28 patients, 9.2%), gastroesophageal reflux disease (28 patients, 9.2%) and acute variceal bleeding (66 patients, 21.8%). Two patients (0.7%) received PPIs for prevention of gastric ulcers under long-term medication with nonsteroidal anti-inflammatory drugs. In none of the patients PPI administration was stopped during the hospital stay for TIPS implantation. Further, none of the patients without PPI treatment before TIPS implantation received newly prescribed PPI therapy during the index hospital stay.
Table 1.
Baseline characteristics of study patients.
| Characteristics | No proton pump inhibitor treatment n = 94 | Proton pump inhibitor treatment n = 303 | p value |
|---|---|---|---|
| Gender | 0.802 | ||
| Male | 65 (69.1) | 205 (67.7) | |
| Female | 29 (30.9) | 98 (32.3) | |
| Age | 59.7 ± 10.2 | 59.2 ± 11.7 | 0.763 |
| < 60 years | 44 (46.8) | 135 (44.6) | 0.723 |
| ≥ 60 years | 50 (53.2) | 168 (55.4) | |
| Etiology of liver disease | |||
| Viral liver disease | 15 (16.0) | 49 (16.2) | 0.999 |
| HCV | 12 (12.8) | 38 (12.5) | 0.999 |
| HBV | 3 (3.2) | 11 (3.6) | 0.999 |
| Nonviral liver disease | 79 (84.0) | 254 (83.8) | 0.999 |
| Alcoholic | 53 (56.4) | 185 (61.1) | 0.470 |
| NAFLD | 0 | 2 (0.7) | 0.989 |
| Others | 26 (27.7) | 67 (22.1) | 0.329 |
| Indication for TIPS implantation | |||
| Ascites | 46 (48.9) | 142 (46.7) | 0.813 |
| Varices (secondary prophylaxis) | 48 (51.1) | 161 (53.1) | |
| Variceal bleeding before TIPS and emergency TIPS implantation | 11 (11.7) | 33 (10.9) | 0.851 |
| HE before TIPS | 12 (12.8) | 41 (13.5) | 0.866 |
| Grade I | 6 (6.4) | 32 (10.6) | 0.315 |
| Grade II | 5 (5.3) | 9 (3.0) | 0.335 |
| Grade III | 0 | 0 | – |
| Grade IV | 1 (1.1)a | 0 | 0.237 |
| Child-Pugh score | 8 ± 2 | 8 ± 2 | 0.745 |
| A | 16 (17.0) | 42 (13.9) | 0.504 |
| B | 61 (64.9) | 202 (66.7) | 0.803 |
| C | 17 (18.) | 59 (19.5) | 0.881 |
| MELD score | 12 ± 6 | 13 ± 6 | 0.370 |
| Technical data of TIPS implantation | |||
| PSG before TIPS (mmHg) | 21.6 ± 5.4 | 21.2 ± 5.5 | 0.578 |
| PSG after TIPS (mmHg) | 9.3 ± 3.5 | 9.2 ± 3.3 | 0.682 |
| Covered stent graft | 55 (58.5) | 133 843.9) | 0.018 |
| Dilated diameter of stent (mm) | 9 ± 1 | 9 ± 1 | 0.337 |
| Laboratory | |||
| Platelets (106/µl) | 141 ± 83 | 140 ± 77 | 0.882 |
| INR | 1.2 ± 0.2 | 1.2 ± 0.2 | 0.870 |
| Creatinine (mg/dl) | 1.5 ± 0.8 | 1.7 ± 0.2 | 0.399 |
| Bilirubin (mg/dl) | 1.6 ± 0.9 | 1.6 ± 1.3 | 0.405 |
| Albumin (g/dl) | 3.1 ± 0.7 | 3.1 ± 0.7 | 0.502 |
| AST (u/l) | 65 ± 84 | 54 ± 40 | 0.820 |
| ALT (U/l) | 34 ± 39 | 30 ± 20 | 0.451 |
| Proton pump inhibitor treatment | |||
| Kind of proton pump inhibitor | |||
| Pantoprazole | 291 (96.0) | ||
| Omeprazole | 2 (0.7)d | ||
| Esomeprazole | 10 (3.3)e | ||
| Dose of proton pump inhibitorb | |||
| 20 mg/day | 30 (9.9) | ||
| 40 mg/day | 210 (69.3) | ||
| 80 mg/day | 63 (20.8) | ||
| Indication for proton pump inhibitor treatment | |||
| Gastric ulcer | 28 (9.2) | ||
| GERD | 28 (9.2) | ||
| Variceal hemorrhage | 66 (21.8) | ||
| NSAID comedication | 2 (0.7) | ||
| Unknown | 179 (59.1) | ||
| HE medication c | 40 (42.6) | 181 (59.7) | 0.004 |
| Lactulose | 35 (37.2) | 167 (55.1) | 0.003 |
| L-ornithine-aspartate | 17 (17.5) | 60 (19.8) | 0.767 |
| Rifaximin | 2 (2.1%) | 9 (2.9) | 0.744 |
| Peri-interventional antibiotic treatment | 14 (14.9) | 63 (20.8) | 0.234 |
| Post-TIPS HE | 11 (11.7) | 93 (30.7) | <0.001 |
| Grade I | 11 (11.7) | 83 (27.4) | 0.002 |
| Grade II | 0 | 7 (2.3) | 0.206 |
| Grade III | 0 | 1 (0.3) | 0.999 |
| Grade IV | 0 | 0 | – |
| Follow-up time (days) | 135 ± 65 | 116 ± 74 | 0.058 |
ALT: alanine aminotransferase; AST: aspartate aminotransferase; HBV: hepatitis B virus; HCV: hepatitis C virus; GERD: gastroesophageal reflux disease; HE: hepatic encephalopathy; INR: international normalized ratio; MELD: model for end-stage liver disease; NAFLD: nonalcoholic fatty liver disease; NSAID: nonsteroidal anti-inflammatory drug; PSG: portosystemic gradient; TIPS: transjugular intrahepatic portosystemic shunt.
Individual decision for TIPS implantation due to variceal bleeding that could not be controlled endoscopically.
In patients with esomperazole or omeprazole the dose equivalent for pantoprazole was calculated and all doses refer to pantoprazole.
Some patients received a combination of different HE medications. HE medication indicates treatment with lactulose and/or l-ornithine-aspartate and/or rifaximin.
Two patients were treated with omeprazole at a dose of 40 mg/day, which is the equivalent dose of 80 mg pantoprazole.
Ten patients were treated with esomeprazole. Four of 10 patients received a dose of 20 mg/day (equal to 40 mg pantoprazole) and 6/10 patients received a dose of 40 mg/day (equal to 80 mg pantoprazole).
A total of 181 PPI-treated patients (59.7%) received medication for HE prophylaxis after TIPS implantation compared to 40 patients without PPI treatment (42.6, p = 0.004) with lactulose being the most commonly used therapy (55.1% and 37.2%, respectively).
Moreover, 28.0% of PPI-treated patients compared to 14.6% of patients without PPI treatment had peri-interventional antibiotic treatment (p = 0.234).
Indication for TIPS implantation was comparable in patients with and without PPI treatment (refractory ascites: 48.9% vs 46.7%, varices: 51.1% vs 53.1%). Both patient groups presented with comparable liver function, with most patients being classified as Child B (64.9% vs 66.7%). There were no differences with respect to age, gender, etiology of liver disease and technical data of TIPS implantation. There was also no significant difference concerning the incidence of prior HE episodes (13.5% vs 12.8%; p = 0.866).
Dose-dependent development of post-TIPS HE in patients with PPI treatment
The rate of post-TIPS HE was significantly higher in patients treated with PPIs than in patients without PPI treatment (92 of 303 patients (30.4%) vs 11 of 94 patients (11.7%); p < 0.001; odds ratio 3.29 (1.86–6.46)). Furthermore, there was a dose-dependent effect of PPI treatment on post-TIPS HE rates. Patients receiving 40 mg per day showed significantly higher rates of post-TIPS HE compared to patients receiving 20 mg per day (65 out of 210 patients (30.9%) vs four out of 30 patients (10.0%), p = 0.028). In patients receiving 80 mg per day higher HE rates were observed compared to patients receiving 40 mg per day, although the difference was not statistically significant (24 of 63 patients (38.1%) vs 65 of 210 patients (30.9%), p = 0.858; Figure 1(a)). There was no significant difference in the development of post-TIPS HE in patients treated with a dose of 20 mg PPI per day compared to patients without PPI treatment (10.0% vs 11.7%, p = 0.999). Further, we included the time to development of post-TIPS HE in the analyses by using Kaplan-Meier methods and we were also able to confirm a dose-dependent increase of post-TIPS HE. Importantly, also in these analyses there were no significant differences between 20 mg and no PPI treatment and no significant differences between a PPI dose of 40 and 80 mg per day (Figure 1(b)).
Figure 1.
Dose-dependent increase of post-transjugular intrahepatic portosystemic shunt (TIPS) hepatic encephalopathy (HE) in patients treated with proton pump inhibitors (PPIs).
To determine the independent predictive effect of PPI treatment on the development of post-TIPS HE, we performed multivariable logistic regression models (Table 2). After adjusting for other known predictive factors, PPI treatment emerged as a significant independent predictive factor for post-TIPS HE. We were also able to confirm a dose-dependent increase for the risk of development of post-TIPS HE. As expected, HE before TIPS was also a strong predictive factor for the development of post-TIPS HE. Since previous studies have reported an association between PPI treatment and HE, we performed sensitivity analyses by focusing on patients without past HE episodes. In these patients PPI treatment was also associated with higher rates of post-TIPS HE compared to patients without PPI treatment (76 of 262 patients (29.0%) vs six of 82 patients (7.3%), p < 0.001). In this subgroup, we were able to confirm the dose-dependent increase of the rate of post-TIPS HE in a univariable as well as a multivariable logistic regression model (supplementary Figure 1, supplementary Table 1).
Table 2.
Predictive factors for development of post-TIPS HE. Uni- and multivariable logistic regression model showed that PPI treatment is significantly associated with the development of post-TIPS HE in a dose-dependent manner.
| Univariable |
Multivariable |
|||||
|---|---|---|---|---|---|---|
| Parameters | OR1 | 95% CI2 | p | OR | 95% CI | p |
| Age (<60 vs ≥60 years) | 1.76 | 1.11–2.81 | 0.017 | 1.76 | 1.08–2.89 | 0.024 |
| Viral liver disease | 1.04 | 0.57–1.91 | 0.902 | |||
| TIPS indication (ascites vs varices) | 1.22 | 0.78–1.92 | 0.387 | |||
| Covered TIPS | 0.82 | 0.52–1.29 | 0.397 | |||
| PSG before TIPS | 1.06 | 1.02–1.11 | 0.004 | 1.07 | 1.02–1.12 | 0.004 |
| PSG after TIPS | 1.07 | 0.99–1.14 | 0.057 | |||
| HE before TIPS | 2.30 | 1.26–4.20 | 0.006 | 2.81 | 1.46–5.42 | 0.002 |
| MELD score | 1.04 | 0.99–1.08 | 0.060 | |||
| HE medication | 1.43 | 0.90–2.27 | 0.126 | |||
| Peri-interventional antibiotic treatment | 0.64 | 0-34–1.18 | 0.052 | 0.44 | 0.22–0.86 | 0.016 |
| Variceal bleeding (early TIPS) | 1.38 | 0.70–2.73 | 0.347 | |||
| PPI treatment | <0.001 | <0.001 | ||||
| No PPI treatment | 1 | 1 | ||||
| PPI 20 mg/day | 0.84 | 0.22–3.23 | 0.798 | 0.86 | 0.22–3.41 | 0.833 |
| PPI 40 mg/day | 3.38 | 1.69–6.78 | 0.001 | 3.96 | 1.93–8.12 | <0.001 |
| PPI 80 mg/day | 4.64 | 2.07–10.43 | <0.001 | 5.12 | 2.21–11.85 | <0.001 |
CI: confidence interval; HE: hepatic encephalopathy; MELD: model for end-stage liver disease; OR: odds ratio; PPI: proton pump inhibitor; PSG: portosystemic gradient; TIPS: transjugular intrahepatic portosystemic shunt.
PPI treatment does not affect TFS after TIPS implantation
At the end of the observation period 287 of the 397 patients (72.3%) had died or had been transplanted (n = 5). Patients with PPI treatment showed a lower median TFS of 26.0 (15.5–36.5) months compared to 34.0 (25.7–42.3) months in patients without PPI treatment. However, the observed difference was not statistically significant (p = 0.944; Figure 2(a)). Still, development of post-TIPS HE was associated with reduced TFS compared to patients without HE after TIPS implantation (16.0 (10.8–21.2) vs 34.0 (27.5–40.5) months, p = 0.048; Figure 2(b)).
Figure 2.
Transplant-free survival (TFS) (a) in patients with and without proton pump inhibitor (PPI) treatment and (b) in patients with and without development of post-transjugular intrahepatic portosystemic shunt (TIPS) hepatic encephalopathy (HE). (a) Patients treated with PPIs showed a median TFS of 26.0 (15.5–36.5) months compared to 34.0 (25.7–42.3) months (p = 0.944). (b) Development of post-TIPS HE was associated with reduced TFS.
Subgroup analyses
To analyze the effect of PPI on the development of post-TIPS HE in different settings of TIPS implantation, we performed subgroup analyses focusing on patients with early TIPS implantation (“emergency TIPS”) and patients with treatment-refractory ascites and secondary prophylaxis of variceal bleeding. In all subgroups we were able to reproduce a dose-dependent increase of post-TIPS HE in PPI-treated patients. Importantly, in patients with early TIPS implantation TFS was 53 (4.3–101.7) months compared to 34 (0–76.1) months (p = 0.049). In patients with nonemergency TIPS implantation and in patients with TIPS implantation with treatment-refractory ascites or for secondary prophylaxis of variceal bleeding, there was no difference in TFS (Figure 3).
Figure 3.
Dose-dependent development of post-transjugular intrahepatic portosystemic shunt (TIPS) hepatic encephalopathy (HE) and transplant-free survival in the subgroups of patients with (a) early TIPS implantation, (b) nonemergency TIPS implantation: (ascites and varices), (c) treatment-refractory ascites and (d) secondary prophylaxis of variceal bleeding.
Discussion
TIPS implantation is a safe and effective treatment of complications related to portal hypertension. The most important drawback of TIPS implantation is the development of post-TIPS HE, which is associated with significant morbidity and mortality. Despite new options in medical treatment of HE, such as rifaximin, and improvements in technical aspects of TIPS implantation, such as generally using small-diameter shunts, post-TIPS HE still affects approximately one-third of TIPS patients.4,22,23 In some patients post-TIPS HE is refractory to medical treatment and interventional shunt reduction has to be performed, leading to possible reoccurrence of complications of portal hypertension.24 Thus, the identification of risk factors for the development of post-TIPS HE is of high clinical importance.
Outside the TIPS setting HE is an indicator of reduced liver function and a hallmark of decompensated liver cirrhosis. In recent years gastric acid suppression by PPIs has been associated with complications of liver cirrhosis, especially with the development of HE.10,11 In this study we set out to address the hypothesis that PPI treatment may increase the risk of post-TIPS HE. Indeed, in our cohort of patients with de novo TIPS implantation, we observed a significantly higher rate of post-TIPS HE in patients receiving PPIs. Multivariable logistic regression models showed that PPI treatment is an independent risk factor for the development of post-TIPS HE. Although prior studies have reported PPI medication as a risk factor for the development of HE outside the TIPS-setting, to our knowledge our study is the first to show an effect of PPI treatment on post-TIPS HE.10,11
A central pathomechanism responsible for the development of HE is hyperammonemia with the main source of blood ammonium being protein metabolism by gut bacteria.25 PPIs are known to affect the composition of intestinal microbiota, leading to a decrease in diversity and shifts in bacterial taxonomy.26 Therefore, dysbiosis caused by PPI treatment could be a decisive factor in the pathogenesis of HE in general and after TIPS implantation in particular.
Our results suggest a PPI-dose–dependent risk for the occurrence of post-TIPS HE. Interestingly, medication of only 20 mg per day was not associated with a higher rate of post-TIPS HE. A possible explanation for this observation may be that a certain “threshold” PPI dosage is required to have a relevant impact on the composition of the intestinal microbiota and thus on the development of HE. On the other hand, a PPI dose of 80 mg per day was still associated with a higher rate of post-TIPS HE compared to a dose of 40 mg per day, although the increase was not significant. This could point to a “ceiling effect” of the impact of PPIs on the intestinal flora and subsequent risk of development of post-TIPS HE. While duration of PPI treatment was shown to be associated with increased rates of HE in patients with liver cirrhosis in general, no studies have previously reported an association with the daily dose of PPIs.11 However, the dose-dependent effects of PPIs on the intestinal microbiota have not been analyzed so far. Thus, one can only speculate about the significance of the dose-dependency we observed.
We did not find a significant reduction of TFS in patients treated with PPIs. The development of post-TIPS HE, however, was associated with a significantly reduced TFS. Therefore, because of the association between PPI treatment and an increased rate of post-TIPS HE, an indirect effect of PPI treatment on TFS may be suggested. In the subgroup of patients with early TIPS implantation for variceal bleeding, we also observed a higher rate of post-TIPS-HE in PPI-treated patients, but further, only in this subgroup we observe an improved TFS for PPI-treated patients. However, this subgroup has been too small for multivariable logistic regression models to determine an independent effect of PPI treatment on post-TIPS HE as several confounding factors have to be considered in these critically ill patients. Therefore, further well-powered studies are necessary to focus on the net benefit of PPI treatment in these patients considering the risk of HE development and the effect on TFS.
PPIs are among the most widely prescribed drugs worldwide.27 However, especially long-term treatment with PPIs can lead to severe adverse effects.28 As mentioned previously, negative effects of PPI treatment have also been reported in patients with liver cirrhosis. There is growing concern about an overprescription of PPIs, with many patients receiving—some permanently—medication with PPIs without a clear indication.29 This is also supported by our findings, which showed that a great majority of patients (76.3%) received PPIs. Remarkably, in 59.1% of those there was no clear indication for PPI treatment. Another 21.8% of patients were treated with PPIs for variceal bleeding. Current guidelines, however, do not recommend the use of PPIs in the treatment or prevention of variceal bleeding.30
In conclusion, the indication for PPI treatment should be checked carefully and reassessed regularly, especially in critically ill patients, e.g. patients with liver cirrhosis, and prior to TIPS implantation.
The main limitation of our study is the retrospective design, which implies the risk of patient selection bias. Arguably, patients with PPI treatment form a cohort with more or more severe preexisting conditions that may have a higher risk of developing complications like HE following TIPS implantation. Yet, as mentioned previously, patients with and without PPI treatment showed similar liver function and no significant difference with respect to the rate of past HE episodes, which accounts for comparable medical starting situations prior to TIPS implantation.
Our primary endpoint was the initial diagnosis of HE within six months after TIPS implantation. Although psychophysiological tests like the critical flicker frequency test or instrumental diagnostics like electroencephalography can be applied, HE usually is a clinical diagnosis.14 This bears the risk of detection bias since diagnosis and grading of HE is investigator dependent. Also, HE can be confused with other neuropsychiatric disorders, such as forms of deliria.
Another limitation is that we were only able to review whether patients received PPI treatment for the time of their hospital stay for TIPS implantation. It therefore remains unclear for how long patients had received PPIs before and after discharge from the hospital and whether this might be an unrecognized effector of the risk of post-TIPS HE or TFS.
With these limitations in mind, however, this study provides the rationale for designing prospective studies further investigating the effects of PPI medication on the risk of post-TIPS HE and other complications in patients with liver cirrhosis.
Acknowledgments
Author contributions are as follows: L.S.: study concept and design, acquisition of data, analysis and interpretation of data, statistical analyses, and drafting of the manuscript; D.B.: study concept and design, acquisition of data, analysis and interpretation of data, statistical analyses, and drafting of the manuscript; M.G.: acquisition of data and analysis and interpretation of data; T.B.: critical revision of the manuscript for important intellectual content; A.S.: critical revision of the manuscript for important intellectual content; N.B.: critical revision of the manuscript for important intellectual content; R.T.: critical revision of the manuscript for important intellectual content; and M.S.: interpretation of the data and supervision. All authors approved the final version of the article, including the authorship.
Declaration of conflicting interests
D.B. is supported by the Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg. The other authors have nothing to declare.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Informed consent
Written informed consent for TIPS implantation and for data collection was obtained from all patients.
Ethics approval
The study was approved by the local ethics committee of the Medical Center University of Freiburg (no. EK 428/14; September 4, 2014) and is in accordance with the Declaration of Helsinki.
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