Alimentary Pharmacology & Therapeutics | 2021
Editorial: proton pump inhibitor use in cirrhosis—a piece of the puzzle
Abstract
Patients with cirrhosis often require several medicines for the treatment of their primary disease, and its complications and comorbidities. Impaired liver function together with increased intestinal permeability, alterations of plasma protein binding and biliary excretion, and the presence of porto-systemic shunts influence drug pharmacokinetics and pharmacodynamics. Proton pump inhibitors (PPIs) represent the most frequently prescribed class of medication in patients with cirrhosis, (often without a clear clinical indication).1 The cytochrome P450 (CYP450) enzymes are involved in the metabolism of PPIs and in most approved drugs.2 Since the activity of CYP450 is reduced in cirrhosis, the use of multiple concomitant drugs increases the risk of drug-drug interactions (DDIs) and adverse drug reactions in these patients.3 Evidence from several meta-analyses suggest that PPIs could be a risk factor for Clostridioides difficile infection, spontaneous bacterial peritonitis (SBP) and severe infections in patients with cirrhosis.4–6 Moreover, PPIs have also been associated with minimal or overt hepatic encephalopathy (HE).7 PPIinduced gastric acid suppression may facilitate intestinal microbiota dysbiosis causing bacterial overgrowth.8 Despite these signal alarms observed in patients with cirrhosis, data on the effect of PPIs on CYP450 enzymes are lacking in this population. The study of Rocco et al9 is the first randomised controlled trial (RCT) to investigate the effect of different PPIs on the activity of CYP450 enzymes in 60 consecutive patients with well compensated HCV-related cirrhosis and gastro-oesophageal reflux disease. Patients were randomised to receive omeprazole 20 mg/day, esomeprazole 20 mg/day, lansoprazole 15 mg/day, pantoprazole 40 mg/ day or rabeprazole 20 mg/day for 2 weeks. CYP 450-dependent liver function was assessed by the 13C-aminopyrine breath test (13C-ABT) at baseline and at the end of PPI therapy. Treatment with omeprazole, esomeprazole and lansoprazole resulted in a significant reduction of CYP450 activity, while pantoprazole and rabeprazole did not. These results are novel, and improve our understanding of drug safety in patients with cirrhosis. Some points deserve further discussion. First, the study included only patients with well compensated cirrhosis (all due to HCV infection) limiting the generalisability of these results to patients with more advanced (Child-Pugh B and C) cirrhosis. Moreover, caution must be exercised when recommending pantoprazole or rabeprazole in patients with other aetiologies of liver disease, particularly those with metabolic-associated fatty liver disease who are exposed to multiple drugs and are at high risk for DDIs. Second, the short treatment duration and follow-up did not allow for assessment of the occurrence of adverse drug reactions and decompensating liver events. PPIs modulate the microbiota composition in patients with cirrhosis, which could favour bacterial overgrowth.8,10 Last but not least, the small sample size and the randomisation to five groups did not ensure that a full balance among groups was obtained. As suggested by the authors, further largescale multicentre RCTs with long-term follow-up, including patients with multiple aetiologies of liver disease, are important to substantiate the safety of PPIs in patients with cirrhosis.