Incidence of and Risk Factors for Hepatic Encephalopathy in a Population‐Based Cohort of Americans With Cirrhosis

Abstract

Hepatic encephalopathy (HE) is a devastating complication of cirrhosis. Data are limited regarding the incidence of and risk factors for HE among contemporary patients in the context of the shifting epidemiology of cirrhosis. We examined a 20% random sample of U.S. Medicare enrollees with cirrhosis and Part D prescription coverage from 2008 to 2014. We modelled incident HE using demographic, clinical, and pharmacologic data. Risk factors for HE were evaluated, including demographics/socioeconomics, cirrhosis etiology, severity of liver disease, and pharmacotherapy, along with gastroenterology consultation, as time‐varying covariates. Among 166,192 Medicare enrollees with cirrhosis followed for 5.25 (interquartile range [IQR], 2.00‐7.00) years, the overall incidence of HE was 11.6 per 100 patient‐years. The cohort's median age was 65 years (IQR, 57‐72), 31% had alcohol‐related cirrhosis, and 49% had likely nonalcoholic fatty liver disease cirrhosis. The two strongest associations with HE were alcohol‐related cirrhosis (adjusted hazard ratio [AHR], 1.44; 95% confidence interval [CI], 1.40, 1.47, relative to nonalcoholic nonviral cirrhosis) and the presence of portal hypertension (AHR, 3.42; 95% CI, 3.34, 3.50). Adjusting for confounders, benzodiazepines (AHR, 1.24; 95% CI, 1.21, 1.27), gamma aminobutyric acid (GABA)ergics (AHR, 1.17; 95% CI, 1.14, 1.21), opioids (AHR, 1.24; 95% CI, 1.21, 1.27), and proton pump inhibitors (PPIs) (AHR, 1.41; 95% CI, 1.38, 1.45) were all associated with incident HE. Only benzodiazepines, however, were associated with the risk of hospitalization with HE (incidence‐rate ratio, 1.23; 95% CI, 1.20, 1.26). Conclusion: Novel data regarding the risk of HE for contemporary patients with cirrhosis are provided. The incidence of HE in an older population of Americans with cirrhosis is high, particularly among those with alcohol‐related cirrhosis and portal hypertension. Several medication classes, namely PPIs, opiates, GABAergics, and benzodiazepines, represent potentially modifiable risk factors for HE.

Opioid prescriptions are associated with hepatic encephalopathy in a national cohort of patients with compensated cirrhosis

“…For instance, it may be that opioid‐induced altered mental status is being misdiagnosed as HE. However, the annual incidence of HE and other decompensation events are comparable to what has been published in the literature, providing external validity to our results . In addition, any event prompting a billing code for HE or the initiation of lactulose/rifaximin is likely to be clinically important.…”

“…Our findings add to the data from Medicare demonstrating that opioids are associated with an increased risk of HE . This Medicare study included a much older population than our current study and did not limit their population to those with well‐compensated cirrhosis.…”

“…Studies examining the association between opioids and HE have been conflicting and there have been no studies demonstrating an association between opioids and HE in younger patients with well‐compensated cirrhosis. A study within the United States Medicare population demonstrated that opioid prescriptions were associated with increased incidence of HE . However, given the data source, this population was older and may have been more susceptible to centrally acting medications due to decreased baseline cognitive reserve.…”

In inpatients with cirrhosis opioid use is common and associated with length of stay and persistent use post-discharge

“…This demonstrates the considerable risk of chronic opioid use among patients newly discharged on opioid therapy after hospitalization. Opioid use in patients with cirrhosis has also been associated with an increased risk of hepatic encephalopathy [27,28], health care utilization [5], hospital readmissions [6], respiratory depression or overdose [29], and decreased health-related quality of life [30].…”

Letter: are opioid prescriptions associated with hepatic encephalopathy in patients with compensated cirrhosis? Authors' reply

“…3,4 We found that opioid prescriptions are independently associated with incident HE in younger patients with well compensated cirrhosis, 2 validating similar findings from the US Medicare population. 5 This adds to many other potential harms of opioids in cirrhosis, including hospital readmissions, 6 overdose 7 and decreased health-related quality of life. 8 Furthermore, in a recent randomized trial of treatments for osteoarthritis and back pain, patients receiving opioids reported increased pain compared to the non-opioid group 9 and, in cirrhosis, opioid use is associated with greater pain-related disability, even when adjusting for the severity of pain.…”