Proton Pump Inhibitor in Liver Cirrhosis Tradition vs Evidence-Based Practice.
Proton pump inhibitor in liver cirrhosis:
Tradition vs. Evidence based practice
I Dewa Nyoman Wibawa
Div.Gastroentero-hepatology, Dept.of Internal Medicine,
Udayana Univ., School of Medicine/Sanglah Gen. Hospital.
Introduction
The recommendation on the saftey use of most drugs in cirrhosis based largerly on
experiences and/or expert opinion because most drugs have not been well studied in cirrhosis
with dosing recommendations often based on pharmacokinetic changes. Most drugs can be used
safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced
dosing frequency is often recommended.
Proton pump inhibitors (PPI) have been related to an increased risk of infection in
cirrhosis including spontaneous bacterial peritonitis (SBP) and should be used with care.
PPIs, which reduce acid secretion, could increase the risk of gastrointestinal (GI)
infections by raising the pH of the stomach and making it more prone to colonization by various
pathogenic bacteria. The PPIs can disrupt the gut microbiota too, they change the bacterial
growth, including abnormal bacterial counts and overt small intestinal bacterial overgrowth
(SIBO). Moreover, gastric acid influences not only the upper gut flora, but also lower intestinal
microbiota. The number of bacteria in small and large bowel increases as a result of gastric
hypochlorhydric conditions. Previous case control studies have found an increased risk of GI
infections in patients taking PPIs. Increased ammonia-producing enteric bacteria in patients with
cirrhosis is also shown to be a risk factor for hepatic encephalopathy (HE).
Moreover there are convincing papers suggesting that acid secretion is reduced in patients
with liver cirrhosis.
Proton pump inhibitor in liver cirrhosis
PPIs or Acid-suppressant medications are prescribed quite frequently in patients with
cirrhosis. Indeed, PPIs were the most frequently prescribed class of medication prescribed to
cirrhotics (given to approximately 40% of 400 patients). Lucena et al. reported that nearly onefourth of the 568 patients in their series were prescribed these medications on admission and
35% on discharge. Ulcer-healing drugs accounted for 12% (n = 2377) of all medications
prescribed, with both PPIs and H2 blockers being utilized chronically.
Acid-suppressive therapy, including H2-blockers and PPIs, besides has a potential risk
factor for both spontaneous bacterial peritonitis (SBP) and infection with Clostridium difficile,
but also has other serious risk of infections in patients with cirrhosis. The odds ratios for the
various infectious associations range from about 1.5 to 3 for PPIs and somewhat less for H2
blockers. While the precise mechanism by which acid suppression increases the risk of infection
in this setting is uncertain, these agents are known to facilitate enteric bacterial colonization,
overgrowth and gut translocation, possibly through changes in intestinal permeability. The
studies on which these associations of an increased risk of SBP, etc are based, have been
retrospective and observational in nature, and also have been criticized for other methodological
reasons, including the large number of SBP patients excluded or invalidated, and the fact that
many SBP patients were already receiving antibiotics when admitted, making the analysis even
more challenging. For example, in the study by Goel et al. from the Cleveland Clinic, Terg notes
1
that only about 10% of more than 1309 patients were eligible for analysis, most of whom had
inadequate records and medicationsto lists to review. Moreover, the risk was apparentonly for
those patients taking PPIs in the previous 7 days, and why the investigators included patients
already on antibiotics was not clearly stated. Terg also mentions that the data on the association
of PPIs and bacterial overgrowth have been conflicting.
Although daily fluoroquinolone use as primary prophylaxis to high-risk patients with
cirrhosis has been shown to substantially reduce the risk of SBP as reported in various metaanalyses, it is unknown whether or not the use of a fluoroquinolone (or other antibiotic) in this
setting would mitigate the SBP risk associated with acid suppression in the same population.
Since about two-thirds of cirrhotics were found to have no documented indication for the use of a
PPI, we join the recommendation by Terg that acid-suppressive medications be used only when
clinically indicated in the cirrhotic patient at high risk for SBP and other infections (especially
those with ascites). While the riskof SPB was significantly lower in those taking PPIs formore
than 90 days, the risk may not be completely eliminated in such patients, and the safety of
chronic useof PPIs and H2 blockers in cirrhosis deserves additional study, both in terms of
design and duration.
Tradition
PPI are very effective in inhibiting acid secretion and are extensively used in many acid
related diseases. They are also often used in patients with cirrhosis sometimes in the absence of a
specific acid related disease, with the aim of preventing peptic complications in patients with
variceal or hypertensive gastropathic bleeding receiving multidrug treatment. Contradicting
reports support their use in cirrhosis and evidence of their efficacy in this condition is poor. In a
minority of patients, PPIs may be prescribed without clear indications or because of their
propensity to develop upper gastrointestinal symptoms.
Evidence –based practice
One study reported patients with SBP had a significantly higher rate of pre-hospital PPI
use (60.8%) compared with cirrhotic patients without SBP (42.2%; P=0.03). On multivariate
analysis, PPI use was the only factor independently associated with SBP (OR 2.09 [95% CI 1.04
to 4.23]; P=0.04). Thirty-five (35%) patients in both groups had no documented indication for
PPI use in their charts. Forty-five percent of the remaining cirrhotic patients with SBP had an
inappropriate indication, as defined in the protocol, for PPI use compared with 25% of controls.
Cirrhotic patients with SBP were twice as likely to have taken PPIs than patients without
SBP. These findings reinforce the association between PPI use and SBP observed in other
studies. A high percentage of cirrhotic patients were taking a PPI without any documented
indication.
Dultz et al on their study published this year, 2015, reported that PPI treatment is
associated with the severity of liver disease and increased mortality in patients with cirrhosis. A
total of 272 patients were included and 213 individuals (78.3%) were on PPI treatment. In
multivariate logistic regression analysis, PPI treatment was associated with higher MELD scores
(P = 0.027) and ascites (P = 0.039). In a multivariate Cox regression model, PPI use was an
independent predictor of mortality (hazard ratio 2.330, 95% confidence interval1.264–4.296, P =
0.007) in addition to the model of end-stage liver disease (MELD) score, hepatocellular
carcinoma and hepatic decompensation. Their concluded that PPI use is an independent risk
factor for mortality in patients with cirrhosis. Although a causative role for increased mortality in
2
patients taking PPI is still missing, the prescription of PPI in cirrhotics should be considered
carefully taking into account its potential adverse effects.
Summary
We need more paper provides further evidence that PPIs are associated with a worse
outcome in cirrhotic patients. More studies are required to clarify the mechanisms of increased
mortality in this patient group and at what stage (and for what indication) the risks may outweigh
benefits in cirrhosis. In the meantime, it is essential that clinicians are aware of the potential
deleterious effects of PPIs in cirrhotic patients. The use of this class of drugs seems more habit
related than evidence based eventually leading to an increase in health costs.
Further Readings
1. Dultz G, Piiper A, Zeuzem S, Kronenberger B, Waidmann O. Proton pump inhibitor
treatment is associated with the severity of liver disease and increased mortality in
patients with cirrhosis. Aliment PharmacolTher 2015; 41: 459–466.
2. Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis – a
practical guide. Aliment PharmacolTher 2013; 37: 1132–1156.
3. Deshpande A, Pasupuleti V, Thota. Acid suppressive therapy associated with
spontaneous bacterial peritonitis in cirrhotic patients – a meta-analysis. J Gastroenterol
Hepatol 2013; 28: 235–42.
4. Lewis SJ, Franco S, Young G, O'Keefe SJ. Altered bowel function and duodenal bacterial
overgrowth in patients treated withomeprazole. Aliment PharmacolTher.
1996;10(4):557–61.
5. Kanno T, Matsuki T, Oka M, Utsunomiya H, Inada K, Magari H, etal. Gastric acid
reduction leads to an alteration in lower intestinalmicroflora. BiochemBiophys Res
Commun. 2009;381(4):666–70.
6. Goel GA, Deshpande A, Loper R. Increased rate of spontaneous bacterial peritonitis
among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol
Hepatol 2012; 10: 422–7.
7. Trikudanathan G, Israel J, Cappa J. Association between proton pump inhibitors and
spontaneous bacterial peritonitis in cirrhotic patients: a systematic review and metaanalysis. Int J ClinPract 2011; 65: 674–8.
8. Deshpande A, Pant C, Pasupuleti V. Association between proton pump inhibitor therapy
and Clostridium difficile infection in a meta-analysis. Clin Gastroenterol Hepatol 2012;
10: 225–33.
9. Bajaj JS, Ratliff SM, Heuman DM. Proton pump inhibitors are associated with a high rate
of serious infection in veterans with decompensated cirrhosis. Aliment Pharmacol Ther
2012; 36: 866–74.
10. M Ratelle, S Perreault, J-P Villeneuve, L Tremblay. Association between proton pump
inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Can J
Gastroenterol Hepatol 2014;28(6):330-334.
11. vanVlerken LG, Huisman EJ, vanHoek B. Bacterial infections in cirrhosis: role of proton
pump inhibitors and intestinal permeability. Eur J Clin Invest 2012; 42: 760–7.
12. Terg R. Comment. Spontaneous bacterial peritonitis and pharmacologic acid suppression
in patients with cirrhosis. Hepatology 2013; 57: 411–3.
13. Loomba R, Wesley R, Bain A, CsakoG, Pucino F. Role of fluoroquinolones in the
3
14.
15.
16.
17.
18.
19.
primary prophylaxis ofs pontaneous bacterial peritonitis: meta-analysis. Clin
Gastroenterol Hepatol 2009; 7: 487–93.
Saab S, Hernandez JC, Chi AC, TongMJ. Oral antibiotic prophylaxis reduces
spontaneous bacterial peritonitis occurrence and improves short-term survival in
cirrhosis: ameta-analysis. Am J Gastroenterol 2009; 104: 993–1001.
Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated
diarrhea and proton pump inhibitor therapy: ameta-analysis. Am J Gastroenterol.
2012;107(7):1001–10.
Siple JF, Morey JM, Gutman TE, Weinberg KL, Collins PD. Protonpump inhibitor use
and association with spontaneous bacterialperitonitis in patients with cirrhosis and
ascites. Ann Pharmacother.2012;46(10):1413–8.
Lodato F, Azzaroli F, Di Girolamo M, Feletti V, Cecinato P, Lisotti A, et al. Proton pump
inhibitors in cirrhosis: Tradition or evidence based practice? World J Gastroenterol 2008;
14(19): 2980-2985.
Bajaj JS, Zadvornova Y, Heuman DM, Hafeezullah M, HoffmannRG, Sanyal AJ, et al.
Association of proton pump inhibitor therapywith spontaneous bacterial peritonitis in
cirrhotic patientswith ascites.Am J Gastroenterol. 2009;104(5):1130–4.
Blei AT, Cordoba J, Practice Parameters Committee of the American College of G.
Hepatic Encephalopathy. Am J Gastroenterol 2001;96(7):1968–76.
4
Tradition vs. Evidence based practice
I Dewa Nyoman Wibawa
Div.Gastroentero-hepatology, Dept.of Internal Medicine,
Udayana Univ., School of Medicine/Sanglah Gen. Hospital.
Introduction
The recommendation on the saftey use of most drugs in cirrhosis based largerly on
experiences and/or expert opinion because most drugs have not been well studied in cirrhosis
with dosing recommendations often based on pharmacokinetic changes. Most drugs can be used
safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced
dosing frequency is often recommended.
Proton pump inhibitors (PPI) have been related to an increased risk of infection in
cirrhosis including spontaneous bacterial peritonitis (SBP) and should be used with care.
PPIs, which reduce acid secretion, could increase the risk of gastrointestinal (GI)
infections by raising the pH of the stomach and making it more prone to colonization by various
pathogenic bacteria. The PPIs can disrupt the gut microbiota too, they change the bacterial
growth, including abnormal bacterial counts and overt small intestinal bacterial overgrowth
(SIBO). Moreover, gastric acid influences not only the upper gut flora, but also lower intestinal
microbiota. The number of bacteria in small and large bowel increases as a result of gastric
hypochlorhydric conditions. Previous case control studies have found an increased risk of GI
infections in patients taking PPIs. Increased ammonia-producing enteric bacteria in patients with
cirrhosis is also shown to be a risk factor for hepatic encephalopathy (HE).
Moreover there are convincing papers suggesting that acid secretion is reduced in patients
with liver cirrhosis.
Proton pump inhibitor in liver cirrhosis
PPIs or Acid-suppressant medications are prescribed quite frequently in patients with
cirrhosis. Indeed, PPIs were the most frequently prescribed class of medication prescribed to
cirrhotics (given to approximately 40% of 400 patients). Lucena et al. reported that nearly onefourth of the 568 patients in their series were prescribed these medications on admission and
35% on discharge. Ulcer-healing drugs accounted for 12% (n = 2377) of all medications
prescribed, with both PPIs and H2 blockers being utilized chronically.
Acid-suppressive therapy, including H2-blockers and PPIs, besides has a potential risk
factor for both spontaneous bacterial peritonitis (SBP) and infection with Clostridium difficile,
but also has other serious risk of infections in patients with cirrhosis. The odds ratios for the
various infectious associations range from about 1.5 to 3 for PPIs and somewhat less for H2
blockers. While the precise mechanism by which acid suppression increases the risk of infection
in this setting is uncertain, these agents are known to facilitate enteric bacterial colonization,
overgrowth and gut translocation, possibly through changes in intestinal permeability. The
studies on which these associations of an increased risk of SBP, etc are based, have been
retrospective and observational in nature, and also have been criticized for other methodological
reasons, including the large number of SBP patients excluded or invalidated, and the fact that
many SBP patients were already receiving antibiotics when admitted, making the analysis even
more challenging. For example, in the study by Goel et al. from the Cleveland Clinic, Terg notes
1
that only about 10% of more than 1309 patients were eligible for analysis, most of whom had
inadequate records and medicationsto lists to review. Moreover, the risk was apparentonly for
those patients taking PPIs in the previous 7 days, and why the investigators included patients
already on antibiotics was not clearly stated. Terg also mentions that the data on the association
of PPIs and bacterial overgrowth have been conflicting.
Although daily fluoroquinolone use as primary prophylaxis to high-risk patients with
cirrhosis has been shown to substantially reduce the risk of SBP as reported in various metaanalyses, it is unknown whether or not the use of a fluoroquinolone (or other antibiotic) in this
setting would mitigate the SBP risk associated with acid suppression in the same population.
Since about two-thirds of cirrhotics were found to have no documented indication for the use of a
PPI, we join the recommendation by Terg that acid-suppressive medications be used only when
clinically indicated in the cirrhotic patient at high risk for SBP and other infections (especially
those with ascites). While the riskof SPB was significantly lower in those taking PPIs formore
than 90 days, the risk may not be completely eliminated in such patients, and the safety of
chronic useof PPIs and H2 blockers in cirrhosis deserves additional study, both in terms of
design and duration.
Tradition
PPI are very effective in inhibiting acid secretion and are extensively used in many acid
related diseases. They are also often used in patients with cirrhosis sometimes in the absence of a
specific acid related disease, with the aim of preventing peptic complications in patients with
variceal or hypertensive gastropathic bleeding receiving multidrug treatment. Contradicting
reports support their use in cirrhosis and evidence of their efficacy in this condition is poor. In a
minority of patients, PPIs may be prescribed without clear indications or because of their
propensity to develop upper gastrointestinal symptoms.
Evidence –based practice
One study reported patients with SBP had a significantly higher rate of pre-hospital PPI
use (60.8%) compared with cirrhotic patients without SBP (42.2%; P=0.03). On multivariate
analysis, PPI use was the only factor independently associated with SBP (OR 2.09 [95% CI 1.04
to 4.23]; P=0.04). Thirty-five (35%) patients in both groups had no documented indication for
PPI use in their charts. Forty-five percent of the remaining cirrhotic patients with SBP had an
inappropriate indication, as defined in the protocol, for PPI use compared with 25% of controls.
Cirrhotic patients with SBP were twice as likely to have taken PPIs than patients without
SBP. These findings reinforce the association between PPI use and SBP observed in other
studies. A high percentage of cirrhotic patients were taking a PPI without any documented
indication.
Dultz et al on their study published this year, 2015, reported that PPI treatment is
associated with the severity of liver disease and increased mortality in patients with cirrhosis. A
total of 272 patients were included and 213 individuals (78.3%) were on PPI treatment. In
multivariate logistic regression analysis, PPI treatment was associated with higher MELD scores
(P = 0.027) and ascites (P = 0.039). In a multivariate Cox regression model, PPI use was an
independent predictor of mortality (hazard ratio 2.330, 95% confidence interval1.264–4.296, P =
0.007) in addition to the model of end-stage liver disease (MELD) score, hepatocellular
carcinoma and hepatic decompensation. Their concluded that PPI use is an independent risk
factor for mortality in patients with cirrhosis. Although a causative role for increased mortality in
2
patients taking PPI is still missing, the prescription of PPI in cirrhotics should be considered
carefully taking into account its potential adverse effects.
Summary
We need more paper provides further evidence that PPIs are associated with a worse
outcome in cirrhotic patients. More studies are required to clarify the mechanisms of increased
mortality in this patient group and at what stage (and for what indication) the risks may outweigh
benefits in cirrhosis. In the meantime, it is essential that clinicians are aware of the potential
deleterious effects of PPIs in cirrhotic patients. The use of this class of drugs seems more habit
related than evidence based eventually leading to an increase in health costs.
Further Readings
1. Dultz G, Piiper A, Zeuzem S, Kronenberger B, Waidmann O. Proton pump inhibitor
treatment is associated with the severity of liver disease and increased mortality in
patients with cirrhosis. Aliment PharmacolTher 2015; 41: 459–466.
2. Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis – a
practical guide. Aliment PharmacolTher 2013; 37: 1132–1156.
3. Deshpande A, Pasupuleti V, Thota. Acid suppressive therapy associated with
spontaneous bacterial peritonitis in cirrhotic patients – a meta-analysis. J Gastroenterol
Hepatol 2013; 28: 235–42.
4. Lewis SJ, Franco S, Young G, O'Keefe SJ. Altered bowel function and duodenal bacterial
overgrowth in patients treated withomeprazole. Aliment PharmacolTher.
1996;10(4):557–61.
5. Kanno T, Matsuki T, Oka M, Utsunomiya H, Inada K, Magari H, etal. Gastric acid
reduction leads to an alteration in lower intestinalmicroflora. BiochemBiophys Res
Commun. 2009;381(4):666–70.
6. Goel GA, Deshpande A, Loper R. Increased rate of spontaneous bacterial peritonitis
among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol
Hepatol 2012; 10: 422–7.
7. Trikudanathan G, Israel J, Cappa J. Association between proton pump inhibitors and
spontaneous bacterial peritonitis in cirrhotic patients: a systematic review and metaanalysis. Int J ClinPract 2011; 65: 674–8.
8. Deshpande A, Pant C, Pasupuleti V. Association between proton pump inhibitor therapy
and Clostridium difficile infection in a meta-analysis. Clin Gastroenterol Hepatol 2012;
10: 225–33.
9. Bajaj JS, Ratliff SM, Heuman DM. Proton pump inhibitors are associated with a high rate
of serious infection in veterans with decompensated cirrhosis. Aliment Pharmacol Ther
2012; 36: 866–74.
10. M Ratelle, S Perreault, J-P Villeneuve, L Tremblay. Association between proton pump
inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Can J
Gastroenterol Hepatol 2014;28(6):330-334.
11. vanVlerken LG, Huisman EJ, vanHoek B. Bacterial infections in cirrhosis: role of proton
pump inhibitors and intestinal permeability. Eur J Clin Invest 2012; 42: 760–7.
12. Terg R. Comment. Spontaneous bacterial peritonitis and pharmacologic acid suppression
in patients with cirrhosis. Hepatology 2013; 57: 411–3.
13. Loomba R, Wesley R, Bain A, CsakoG, Pucino F. Role of fluoroquinolones in the
3
14.
15.
16.
17.
18.
19.
primary prophylaxis ofs pontaneous bacterial peritonitis: meta-analysis. Clin
Gastroenterol Hepatol 2009; 7: 487–93.
Saab S, Hernandez JC, Chi AC, TongMJ. Oral antibiotic prophylaxis reduces
spontaneous bacterial peritonitis occurrence and improves short-term survival in
cirrhosis: ameta-analysis. Am J Gastroenterol 2009; 104: 993–1001.
Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated
diarrhea and proton pump inhibitor therapy: ameta-analysis. Am J Gastroenterol.
2012;107(7):1001–10.
Siple JF, Morey JM, Gutman TE, Weinberg KL, Collins PD. Protonpump inhibitor use
and association with spontaneous bacterialperitonitis in patients with cirrhosis and
ascites. Ann Pharmacother.2012;46(10):1413–8.
Lodato F, Azzaroli F, Di Girolamo M, Feletti V, Cecinato P, Lisotti A, et al. Proton pump
inhibitors in cirrhosis: Tradition or evidence based practice? World J Gastroenterol 2008;
14(19): 2980-2985.
Bajaj JS, Zadvornova Y, Heuman DM, Hafeezullah M, HoffmannRG, Sanyal AJ, et al.
Association of proton pump inhibitor therapywith spontaneous bacterial peritonitis in
cirrhotic patientswith ascites.Am J Gastroenterol. 2009;104(5):1130–4.
Blei AT, Cordoba J, Practice Parameters Committee of the American College of G.
Hepatic Encephalopathy. Am J Gastroenterol 2001;96(7):1968–76.
4