Letter to the Editor: Proton Pump Inhibitors in Cirrhosis: A Marker of Morbid Conditions or a Cause of Mortality?

We read with interest the study by Nardelli et al., which adds to a growing literature on the potential ills of proton pump inhibitors (PPIs) in patients with cirrhosis. Their prospective design allowed for assessment of minimal hepatic encephalopathy (HE), and they reported that PPI use was independently associated with minimal HE, overt HE, and mortality. While we applaud the authors’ efforts, we are concerned about residual confounding that may have led to misinterpretation of mortality results

Immunosuppression in Autoimmune Hepatitis: Is There an End Game?

Autoimmune hepatitis (AIH) is a rare, chronic disease associated with the development of cirrhosis and premature mortality. Current guidelines state that patients with AIH should receive induction therapy with corticosteroids or the combination of corticosteroids/azathioprine, followed by maintenance therapy with lower doses of steroids and/or azathioprine (1–3). However, the optimal strategy for the ongoing treatment beyond this point remains unclear

COVID-19 and liver disease: mechanistic and clinical perspectives

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity. © 2021, Springer Nature Limited

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

Background Previous studies have demonstrated that opioids are often prescribed and associated with complications in outpatients with cirrhosis. Less is known about opioids among hospitalized patients with cirrhosis. We aimed to describe the patterns and complications of opioid use among inpatients with cirrhosis. Methods This retrospective cohort study included adult patients with cirrhosis admitted to a single hospital system from 4/4/2014 to 9/30/2015. We excluded hospitalizations with a surgery, invasive procedure, or palliative care/hospice consult in order to understand opioid use that may be avoidable. We determined the frequency, dosage, and type of opioids given during hospitalization. Using bivariable and multivariable analyses, we assessed length of stay, intensive care unit transfer, and in-hospital mortality by opioid use. Results Of 217 inpatients with cirrhosis, 118 (54.4%) received opioids during hospitalization, including 41.7% of patients without prior outpatient opioid prescriptions. Benzodiazepines or hypnotic sleep aids were given to 28.8% of opioid recipients. In the multivariable model, younger age and outpatient opioid prescription were associated with inpatient opioids. Hospitalization was longer among opioid recipients (median 3.9 vs 3.0 days, p = 0.002) and this difference remained after adjusting for age, cirrhosis severity, and medical comorbidities. There was no difference in intensive care unit transfers and no deaths occurred. At discharge, 22 patients were newly started on opioids of whom 10 (45.5%) had opioid prescriptions at 90 days post-discharge. Conclusion In non-surgical inpatients with cirrhosis, opioid prescribing was common and associated with prolonged length of stay. A high proportion of patients newly discharged with opioid prescriptions had ongoing prescriptions at 90 days post-discharge

A Quality Improvement Initiative Results in Improved Rates of Timely Postvariceal Bleeding Surveillance Endoscopy

OBJECTIVES: We performed a study to assess the effects of a quality improvement (QI) initiative on the rates of postvariceal bleeding surveillance upper endoscopy (EGD). METHODS: We identified patients with cirrhosis hospitalized with variceal bleeding and assessed the rates of timely (≤4 weeks) EGD before and after a QI initiative. RESULTS: Preintervention: 16% (5 of 32) of patients underwent timely surveillance EGD. We developed a standardized ordering template for gastroenterology fellows and reserved postvariceal EGD scheduling slots. Postintervention: 43% (12 of 28) of patients underwent timely surveillance EGD. DISCUSSION: A QI intervention was associated with a 27% absolute increase in timely surveillance EGDs

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

Background: Opioids are often prescribed for pain in cirrhosis and may increase the risk of hepatic encephalopathy (HE). Aim: To assess the association between opioids and HE in patients with well-compensated cirrhosis. Methods: We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18-64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1-89 days) and chronic (90-180 days). We assessed whether patients developed HE over the subsequent year (ie 6-18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and HE, adjusting for relevant confounders. Results: The cohort included 6451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short-term and chronic opioid prescriptions respectively. Over the subsequent year, HE occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short-term opioid prescriptions and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of HE was observed with short-term (adjusted hazard ratio, HR 1.44, 95% CI 1.07-1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07-3.12) compared to no opioid prescriptions. Conclusion: In this national cohort of privately insured patients with cirrhosis, opioid prescriptions were associated with the risk of incident HE. Opioid use should be minimised in those with cirrhosis and, when required, limited to short duration

Complications Associated With Anesthesia Services in Endoscopic Procedures Among Patients With Cirrhosis

Background and Aims: Anesthesia services for endoscopic procedures have proliferated with the promise of increased comfort and safety. Cirrhosis patients are higher risk for sedation, yet limited data are available describing anesthesia complications in this population. Approach and Results: This cross-sectional study utilized the National Anesthesia Clinical Outcomes Registry, a multicenter quality-improvement database from 2010 to 2015. Patients with cirrhosis undergoing an endoscopy were identified by International Classification of Diseases, Ninth Revision (ICD-9)/Current Procedures Terminology (CPT) codes. The outcome of interest was serious anesthesia-related complication defined as cardiovascular, respiratory, neurological, drug related, patient injury, death, or unexpected admission. A mixed-effects multivariate logistic regression model determined odds ratios (ORs) between variables and serious complications, adjusting for potential confounders. In total, 9,007 endoscopic procedures were performed among patients with cirrhosis; 92% were esophagogastroduodenoscopies. The majority (81%) were American Society of Anesthesiologists (ASA) class ≥3, and 72% had a history of hepatic encephalopathy, ascites, varices, hepatorenal syndrome, or spontaneous bacterial peritonitis identified by ICD-9/CPT codes. In total, 87 complications were reported, 33 of which were serious. Frequency of serious complications was 0.4% or 378.6 per 100,000 procedures (95% confidence interval [CI], 260.8, 531.3). The majority of serious complications were cardiovascular (21 of 33), including 15 cardiac arrests. Serious complications were significantly associated with ASA 4/5 (OR, 3.84; 95% CI, 1.09, 13.57) and general anesthesia (OR, 4.71; 95% CI, 1.20, 18.50), adjusting for age, sex, ASA class, anesthesia type, inpatient status, portal hypertension history, and variable complication reporting practices. Conclusions: Anesthesia complications among endoscopic procedures in cirrhosis are rare overall. Serious complications were predominantly cardiac and associated with sicker patients undergoing general anesthesia. The complexity of end-stage liver disease may warrant more intensive care during endoscopic procedures, including anesthesia monitoring

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

EDITORS, We appreciate the letter from Li et al about our recently pub-lished article on the association between opioids and hepatic en-cephalopathy (HE). The letter raises interesting points deserving additional clarification

Medicare/medicaid insurance, rurality, and black race associated with provision of hepatocellular carcinoma treatment and survival

Background: Early treatment of hepatocellular carcinoma (HCC) is associated with improved survival, but many patients with HCC do not receive therapy. We aimed to examine factors associated with HCC treatment and survival among incident patients with HCC in a statewide cancer registry. Materials and Methods: All patients with HCC from 2003 through 2013 were identified in the North Carolina cancer registry. These patients were linked to insurance claims from Medicare, Medicaid, and large private insurers in North Carolina. Associations between prespecified covariates and more advanced HCC stage at diagnosis (ie, multifocal cancer), care at a liver transplant center, and provision of HCC treatment were examined using multivariate logistic regression. A Cox proportional hazards model was developed to assess the association between these factors and survival. Results: Of 1,809 patients with HCC, 53% were seen at a transplant center,90 days from diagnosis, with lower odds among those who were Black (adjusted odds ratio [aOR], 0.54; 95% CI, 0.39-0.74), had Medicare insurance (aOR, 0.35; 95% CI, 0.21-0.59), had Medicaid insurance (aOR, 0.46; 95% CI, 0.28-0.77), and lived in a rural area; odds of transplant center visits were higher among those who had prediagnosis alpha fetoprotein screening (aOR, 1.74; 95% CI, 1.35-2.23) and PCP and gastroenterology care (aOR, 1.66; 95% CI, 1.27-2.18). Treatment was more likely among patients who had prediagnosis gastroenterology care (aOR, 1.68; 95% CI, 0.98-2.86) and transplant center visits (aOR, 2.42; 95% CI, 1.74-3.36). Survival was strongly associated with age, cancer stage, cirrhosis complications, and receipt of HCC treatment. Individuals with Medicare (adjusted hazard ratio [aHR], 1.58; 95% CI, 1.20-2.09) and Medicaid insurance (aHR, 1.55; 95% CI, 1.17-2.05) had shorter survival than those with private insurance. Conclusions: In this population-based cohort of patients with HCC, Medicare/Medicaid insurance, rural residence, and Black race were associated with lower provision of HCC treatment and poorer survival. Efforts should be made to improve access to care for these vulnerable populations

Newer second-line glucose-lowering drugs versus thiazolidinediones on cirrhosis risk among older US adult patients with type 2 diabetes

Aims: Type 2 diabetes (T2D) accelerates progression of chronic liver disease to cirrhosis, yet the effects of most glucose-lowering drugs (GLDs) on cirrhosis risk in T2D are unknown. To address this gap, we compared cirrhosis risk following initiation of newer second-line GLDs vs. thiazolidinediones (TZDs), which improve histology in non-alcoholic fatty liver disease. Materials and methods: Using the US Medicare Fee-for-Service database (2007–2015) and an active comparator, new-user design, we estimated crude incidence rates (IRs) and propensity-score adjusted hazard ratios (aHR) for incident cirrhosis, comparing newer GLDs (dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA), and sodium-glucose co-transporter 2 inhibitors (SGLT2i)) vs. TZDs. Results: Among 239,549 total initiators, we observed 318, 151, and < 30 cirrhosis events when comparing DPP4i vs. TZD, GLP1RA vs. TZD, and SGLT2i vs. TZD, respectively. IRs ranged from 1.7 [95% CI, 0.8–3.6] to 3.6 [2.5–5.2] events per 1000 person-years. Point aHR estimates for cirrhosis were elevated among newer GLD initiators vs. TZD (DPP4i: 1.15 [0.89–1.50]; GLP1RA: 1.34 [0.82–2.20]; SGLT2i: 1.16, [0.44–3.08]), although estimates were imprecise due to short durations of drug exposure. Conclusions: We observed mildly elevated cirrhosis risk with newer GLDs vs. TZD; however, uncertainty remains due to imprecise and statistically non-significant effect estimates