Use of proton pump inhibitors in chronic liver diseases

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Abbreviations

EVL

endoscopic variceal ligation

GERD

gastroesophageal reflux disease

GI

gastrointestinal

NSAID

nonsteroidal anti‐inflammatory drug

PPI

proton pump inhibitor

SBP

spontaneous bacterial peritonitis

SIBO

small‐intestinal bacterial overgrowth

Proton pump inhibitors (PPIs) are among the most commonly prescribed classes of drugs among patients with cirrhosis.1, 2 In many cases, these drugs may be prescribed inappropriately without clear indications and lead to harm (Table 1). Overall, PPI treatment in patients with cirrhosis is likely driven by concern regarding the risk for bleeding in these patients and from ambiguity in guidance regarding the duration of PPI treatment after bleeding episodes. Although benefits of PPI treatment have clearly been demonstrated in the management of peptic ulcer disease in patients with cirrhosis and in the immediate postendoscopic banding period to prevent rebleeding, evidence for the use of PPIs outside of these indications is lacking.3 Though PPIs are frequently prescribed in practice, PPI treatment has been shown to be ineffective in the primary prevention of upper gastrointestinal (GI) bleeding in patients with cirrhosis, including those related to varices and portal hypertensive gastropathy.4

Table 1.

Prevalence of Proton Pump Inhibitor Use in Patients With Cirrhosis as Evidenced in Recent Studies Investigating the Association Between Proton Pump Inhibitors and Spontaneous Bacterial Peritonitis

Study	Sample Size, n	% on PPI	% on PPI Without Appropriate Indication	Indications
Bajaj et al.18	140	50% (70/140)	46% (32/70)	GERD, peptic ulcer disease, Barrett's esophagus, EVL, history of GI bleeding
Goel et al.19	130	56% (73/130)
de Vos et al.20	102	37% (38/102)	34% (13/38)	GERD, peptic ulcer disease, Barrett's esophagus, Helicobacter pylori eradication, NSAIDs
Ratelle et al.21	151	49% (74/151)
Mandorfer et al.22	607	86% (520/607)
Dultz et al.1	272	78% (213/272)	58% (124/213)	GERD, peptic ulcer disease, EVL, recent GI bleeding
Cole et al.23	206	55% (114/206)	74% (84/114)	GERD, peptic ulcer disease, Barrett's esophagus, esophagitis/gastritis/duodenitis

If assessed, the percentage of individuals who were on PPIs without an appropriate indication is reported.

Abbreviations: EVL, endoscopic variceal ligation; GERD, gastroesophageal reflux disease; NSAID, nonsteroidal anti‐inflammatory drug.

PPI Use and Spontaneous Bacterial Peritonitis

The prevalent use of PPIs in patients with cirrhosis has garnered increasing attention in recent years because of the increasing number of studies that have highlighted an association between PPI use and the development of spontaneous bacterial peritonitis (SBP). More than 20 studies have been published since 2008 that have investigated this association. Four meta‐analyses that have been published to date have each identified a statistically significant association between PPI use and increased risk for SBP in patients with cirrhosis.5, 6, 7, 8 However, most studies have been limited by retrospective or case–control design, as well as small sample size. To date, there has been one multicenter prospectively designed study investigating this question, and it did not show an increased association between SBP and PPI use.9 However, only half of PPI users in this study received acid‐suppressive therapy for more than 2 weeks, which leaves open the question whether the lack of association was the result of relatively short PPI exposure. Although long‐term acid suppression may lead to the development of SBP, a safe duration of therapy has not been established.

PPI Use and Hepatic Encephalopathy

PPI use in patients with cirrhosis has also been linked to the development of hepatic encephalopathy. A recent analysis of data from three large, multicenter, randomized trials originally investigating the use of satavaptan in patients with cirrhosis with ascites demonstrated an increased risk for hepatic encephalopathy associated with PPI exposure.10 This was further corroborated by a recent large, nested, case–control study in which PPI use was associated with a significant dose‐dependent risk for the development of hepatic encephalopathy after controlling for confounding effects including age, income, level of urbanization, medical comorbidities, and the use of psychotropic medications.11 However, it is unclear at this time whether there is a specific length of exposure that places patients at higher risk for development of hepatic encephalopathy.

Proposed Mechanisms for PPI‐Mediated Development of SBP and Hepatic Encephalopathy

The mechanisms by which PPI exposure predisposes patients with cirrhosis to the development of SBP and hepatic encephalopathy have not been fully elucidated but are thought to occur via increased pathogenic bacterial translocation. This may be mediated through several PPI‐dependent effects (Fig. 1). First, this may occur via direct effects of PPIs on the gut microbiome. Two recent studies have shown that administration of PPIs leads to significant alterations in the gut microbiota composition in healthy individuals.12, 13 These changes are likely due in part to reduced acidity of the upper GI tract because of PPI use, allowing for the distal colonization of microflora normally confined to the upper GI tract. Intriguingly, the microbiome of patients with cirrhosis show similar changes to that of the PPI‐treated microbiome.14 Indeed, dysbiosis itself has been increasingly linked with chronic intestinal inflammation, which leads to impaired gut barrier function and bacterial translocation.15 Second, PPIs may predispose patients to the development of small‐intestinal bacterial overgrowth (SIBO), which itself may increase pathogenic bacterial translocation. SIBO is thought to develop in response to PPI through a variety of mechanisms, including abrogation of the acidic host defense in the stomach, as well as delayed gastric motility or emptying. However, the published data regarding the association of PPIs and SIBO to date have been conflicting and require further investigation.16 Finally, impaired immunity may contribute to the development of SBP and hepatic encephalopathy in patients with cirrhosis. PPIs have been shown to directly reduce the function of neutrophils and monocytes by decreasing their oxidative burst.17 Thus, deficits in local and systemic immunity may also contribute to the development of increased pathogenic bacterial translocation.

Figure 1.

Putative mechanisms for PPI‐associated development of SBP and hepatic encephalopathy.

Conclusions

Given the potential deleterious impact of long‐term PPI use in cirrhotics, the use of PPIs in this group of patients needs to be carefully assessed. With the developing body of evidence suggesting an association between PPI use in patients with cirrhosis and the development of decompensation events including SBP and hepatic encephalopathy, well‐designed prospective trials evaluating the safety of long‐term PPI use in this population are needed. Until then, the use of PPIs in patients with cirrhosis should be carefully assessed for proper indication and, if used, should be limited to their lowest effective dose and time course.