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Proton Pump Inhibitors and the Possible Development of Hepatic Encephalopathy in Cirrhotic Patients: True Association or Residual Confounding?

1 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 Dear Editors: In their recent study, Tsai et al evaluated a possible association between proton pump inhibitor (PPI) use and the development of hepatic encephalopathy (HE) in patients with cirrhosis. This is the second report of which we are aware that has examined this possible association. The first was a retrospective study by Dam et al that derived its population cohort from 3 separate clinical trials that were not designed to evaluate an association between PPI use and HE. They reported a hazard ratio of 1.36 (95% confidence interval, 1.01–1.84) after adjusting for multiple factors, all of which were significantly associated with HE, and also noted that only 66% of their patients had a valid indication for PPI use. In a retrospective case control study using Taiwan’s National Health Insurance database, Tsai et al have reported that 38% of patients with cirrhosis and HE had a history of PPI use before HE development. They also found some evidence for a dose–response relationship between PPI use and the risk of HE. However, the limitations of observational epidemiology should be considered before any suggestion of causality is entertained. In observational studies, odds ratios below 3 are more usually attributable to residual confounding rather than causality. In the study by Tsai et al, patients who developed HE were compared to patients who did not. Notably, those who developed HE had higher incidences of gastrointestinal bleeding, intra-abdominal infection and pneumonia in the preceding 3 months. It is, therefore, conceivable that those patients were placed on a PPI because of their comorbidity, thereby reflecting probable channeling bias. Furthermore, patients who developed HE were more likely to have had episodes of infection and were more likely to be on benzodiazepines or other psychoactive drugs, which are known precipitants of HE. The authors did not evaluate patients’ consumption of alcohol. The CANONIC study (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) found that alcohol was strongly related to the development of HE in patients with decompensated cirrhosis or acute-on-chronic liver failure. Similarly, hyponatremia was not evaluated; this can be a major confounding factor in the pathophysiology of HE in patients with acute-on-chronic liver failure and it may be very difficult to distinguish HE from hyponatremic encephalopathy. Diuretic-induced hypovolemia with resulting electrolyte disturbance, another recognized mechanism for the