The Dark Side of the Long-Term Use of Proton Pump Inhibitors in Chronic Liver Disease

Proton pump inhibitors (PPIs) are among the most widely prescribed drugs in the world today. Accepted indications include an array of acid-related disorders such as peptic ulcer disease and gastroesophageal reflux, and the prevention of non-steroid anti-inflammatory drug (NSAID)-induced ulcers. Despite little evidence of efficacy, PPIs are also frequently prescribed for other indications including functional dyspepsia and for the prevention of gastroduodenal side effects of polypharmacy. Alarmingly, up to two-thirds of PPI prescriptions in ambulatory patients may be inadequate [1–3]. In recent years, several observational studies have raised concern regarding the potential long-term side effects of PPIs, including acute and chronic kidney disease, hypomagnesemia, cardiovascular events, bone fractures, dementia, and infections such as Clostridium difficile colitis, bacterial pneumonia, and spontaneous bacterial peritonitis (SBP) [4, 5]. SBP is a well-known complication in patients with cirrhosis and ascites. Despite improvements in medical care with timely diagnosis and treatment with antibiotics, short-term mortality of SBP amounts to about 30% and increases to over 65% at 1 year without liver transplantation [6]. Therefore, means of reducing the rates of SBP in patients with cirrhosis are welcomed. SBP is thought to result from bacterial translocation across the intestinal wall leading to infection of the ascitic fluid. Proliferation of bacteria in the ascitic fluid is favored in patients with cirrhosis by a dysfunctional immune system with low levels of immunoglobulins, opsonizing proteins, and complement [7]. Hypothetically, by increasing intragastric pH, PPIs facilitate proliferation of intestinal bacteria (i.e., bacterial overgrowth). Abnormal gastrointestinal motility is also common in patients with cirrhosis and may further be worsened by PPIs [8, 9]. Even more preoccupying is the fact that over 63% of prescriptions of PPIs in patients with cirrhosis may be inadequate [10]. At a time of growing concern over rising health care costs, substantial cost savings can be achieved by limiting inappropriate prescribing of PPIs according to the clinical guidelines [11].