Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting immune checkpoint molecules. ICIs are an immunotherapy for the treatment of many advanced malignancies. The advent of ICIs has ...been a major breakthrough in the field of oncology, a fact recognized by the 2018 Nobel Prize in Physiology or Medicine being awarded for the discovery. The Food and Drug Administration approved the first ICI, ipilimumab, in 2011 for the treatment of metastatic melanoma. Seven ICIs are now used in clinical practice, including nivolumab and pembrolizumab for treatment of advanced hepatocellular carcinoma. ICIs are increasingly used across the spectrum of hepatobiliary neoplasia. The utility of ICI therapy has been limited by immune‐related adverse reactions (irAEs) affecting multiple organ systems. Hepatotoxicity is an important irAE, occurring in up to 16% of patients receiving ICIs. Optimizing outcomes in patients receiving ICI therapy requires awareness of and familiarity with diagnosing and management of ICI‐induced immune‐mediated hepatotoxicity (IMH), including approaches to treatment and ICI dose management. The aim of this review article is to (1) provide a comprehensive, evidence‐based review of IMH; (2) perform a systematic review of the management of IMH; and (3) present algorithms for the diagnosis and management of IMH.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
More than 2,000,000 individuals worldwide have had coronavirus 2019 disease infection (COVID-19), yet there is no effective medical therapy. Multiple off-label and investigational drugs, such as ...chloroquine and hydroxychloroquine, have gained broad interest due to positive pre-clinical data and are currently used for treatment of COVID-19. However, some of these medications have potential cardiac adverse effects. This is important because up to one-third of patients with COVID-19 have cardiac injury, which can further increase the risk of cardiomyopathy and arrhythmias. Adverse effects of chloroquine and hydroxychloroquine on cardiac function and conduction are broad and can be fatal. Both drugs have an anti-arrhythmic property and are proarrhythmic. The American Heart Association has listed chloroquine and hydroxychloroquine as agents which can cause direct myocardial toxicity. Similarly, other investigational drugs such as favipiravir and lopinavir/ritonavir can prolong QT interval and cause Torsade de Pointes. Many antibiotics commonly used for the treatment of patients with COVID-19, for instance azithromycin, can also prolong QT interval. This review summarizes evidenced-based data regarding potential cardiac adverse effects due to off-label and investigational drugs including chloroquine and hydroxychloroquine, antiviral therapy, monoclonal antibodies, as well as common antibiotics used for the treatment of COVID-19. The article focuses on practical points and offers a point-of-care protocol for providers who are taking care of patients with COVID-19 in an inpatient and outpatient setting. The proposed protocol is taking into consideration that resources during the pandemic are limited.
Background and Aims
Hepatologists often determine whether transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) is preferred for patients with cirrhosis and severe ...aortic stenosis. The goal of this cohort study is to compare outcomes following TAVR and SAVR in patients with cirrhosis to inform the preferred intervention.
Approach and Results
Prospectively collected data on 105 consecutive patients with cirrhosis and aortic stenosis who underwent TAVR (n = 55) or SAVR (n = 50) between 2008 and 2016 were reviewed retrospectively. Two control groups were included: 2,680 patients without cirrhosis undergoing TAVR and SAVR and 17 patients with cirrhosis who received medical therapy alone. Among the 105 patients with cirrhosis, the median Society of Thoracic Surgeons score was 3.8% (1.5, 6.9), and the median Model for End‐Stage Liver Disease (MELD) score was 11.6 (9.4, 14.0). The TAVR group had similar in‐hospital (1.8% vs. 2.0%) and 30‐day mortality (3.6% vs. 4.2%) as the SAVR group. During the median follow‐up of 3.8 years (95% confidence interval, 3.0‐6.9), there were 63 (60%) deaths. MELD score (adjusted hazard ratio, 1.13; 95% confidence interval, 1.05‐1.21; P = 0.002) was an independent predictor of long‐term survival. In the subgroup of patients with MELD score <12, the TAVR group had reduced survival compared with the SAVR group (median survival of 2.8 vs. 4.4 years; P = 0.047). However, in those with MELD score ≥12, survival after TAVR, SAVR, and medical therapy was similar (1.3 vs. 2.1 vs. 1.6 years, respectively; P = 0.53).
Conclusion
In select patients with cirrhosis, both TAVR and SAVR have acceptable and comparable short‐term outcomes. MELD score, but not Society of Thoracic Surgeons score, independently predicts long‐term survival after TAVR and SAVR. For patients with MELD score <12, SAVR is a preferred procedure; however, neither procedure appears superior to medical therapy in patients with MELD score ≥12.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Patients admitted to the hospital for alcoholic hepatitis (AH) are at increased risk of readmission and death. We aimed to identify factors associated with readmission, alcohol relapse, and ...mortality.
We performed a retrospective analysis of consecutive patients admitted with AH to a tertiary care hospital from 1999 through 2016 (test cohort, n = 135). We validated our findings in a prospective analysis of patients in a multi-center AH research consortium from 2013 through 2017 (validation cohort, n = 159). Alcohol relapse was defined as any amount of alcohol consumption within 30 days after hospital discharge. Early alcohol rehabilitation was defined as residential or outpatient addiction treatment or mutual support group participation within 30 days after hospital discharge.
Thirty-day readmission rates were 30% in both cohorts. Alcohol relapse rates were 37% in the test and 34% in the validation cohort. Following hospital discharge, 27 patients (20%) in the test cohort and 19 patients (16%) in the validation cohort attended early alcohol rehabilitation. There were 53 deaths (39%) in a median follow-up time of 2.8 years and 42 deaths (26%) in a median follow-up time of 1.3 years, respectively. In the test cohort, early alcohol rehabilitation reduced odds for 30-day readmission (adjusted odds ratios AOR 0.16; 95% CI, 0.04-0.65; P = .01), 30-day alcohol relapse (AOR, 0.11; 95% CI, 0.02-0.53; P < .001), and death (adjusted hazard ratio AHR, 0.20; 95% CI, 0.05-0.56; P = .001). In the validation cohort early alcohol rehabilitation reduced odds for 30-day readmission (AOR, 0.30; 95% CI, 0.09-0.98; P = .04), 30-day alcohol relapse (AOR 0.09; 95% CI, 0.01-0.73; P = .02), and death (AHR, 0.20; 95% CI, 0.01-0.94; P = .04). A model combining alcohol rehabilitation and bilirubin identified patients with readmission to the hospital within 30 days with an area under the receiver operating characteristic curve of 0.73.
In an analysis from two cohorts of patients admitted with AH, early alcohol rehabilitation can reduce risk of hospital readmission, alcohol relapse, and death and should be considered as a quality indicator in AH hospitalization treatment.
To study the interaction of alcohol consumption with body mass index (BMI) in the development of hepatic steatosis and mortality.
We conducted a retrospective cohort study of 18,506 participants ...without fatty liver disease or cirrhosis at enrollment in the Mayo Clinic Biobank from April 9, 2009, through March 31, 2016. Participants were classified by self-reported alcohol consumption status (nondrinkers, moderate drinkers 0 to 2 drinks per day, and heavy drinkers >2 drinks per day). The primary outcome of interest was the incidence of hepatic steatosis, identified by International Classification of Diseases, Ninth Revision code and confirmed with imaging. The secondary outcome of interest was all-cause mortality. Multivariate Cox regression analysis determined the impact of alcohol consumption stratified by BMI on outcomes compared with nondrinkers.
The cohort (mean ± SD age, 55.8±16.9 years; 63.8% female; mean ± SD BMI, 28.8±6.1 kg/m
) of 18,506 participants included 3657 (19.8%) nondrinkers, 14,236 (76.9%) moderate drinkers, and 613 (3.3%) heavy drinkers at enrollment. After a median follow-up of 5.8 years (interquartile range, 3.8 to 7.2 years), 684 participants had development of hepatic steatosis and 968 died. In moderate drinkers, the risk of hepatic steatosis development was high in the obese group (adjusted hazard ratio AHR, 1.31; 95% CI, 1.03 to 1.67), insignificant in the overweight group (AHR, 0.86; 95% CI, 0.58 to 1.26), and decreased in the normal-BMI group (AHR, 0.48; 95% CI, 0.26 to 0.90). Heavy drinkers had an increased risk of hepatic steatosis irrespective of BMI. Moderate alcohol use was associated with decreased mortality in the normal-weight (AHR, 0.44; 95% CI, 0.34 to 0.58) and overweight (AHR, 0.70; 95% CI, 0.56 to 0.88) groups but not in the obese group (AHR, 0.80; 95% CI, 0.64 to 1.00).
In obese individuals, even moderate alcohol use is associated with the development of hepatic steatosis. Moderate alcohol consumption is associated with lower mortality in normal-BMI and overweight individuals but not in those who are obese.
To determine short-term outcomes of patients with alcohol-associated cirrhosis (ALC) admitted to the intensive care unit (ICU) compared with other etiologies of liver disease. In addition, we ...investigate whether quick sequential organ failure assessment accurately predicts presence of sepsis and in-hospital mortality in critically ill patients with various etiologies of cirrhosis.
A retrospective cohort of 1174 consecutive patients with cirrhosis admitted to the ICU between January of 2006 and December of 2015 was analyzed. Outcomes of interest included survival rates within the ICU, post-ICU in-hospital, or at 30 days post-ICU discharge.
Five hundred seventy-eight patients were found to have ALC with 596 in the non-ALC group. There was no significant difference in ICU mortality rates in ALC versus non-ALC cohorts (10.2% vs 11.7%, P=.40). However, patients with ALC had significantly higher post-ICU in-hospital death (10.0% vs 6.5%, P=.04) as well as higher mortality at 30-day post-ICU discharge (18.7% vs 11.2%, P<.001). Sustained alcohol abstinence did not offer survival advantage over nonabstinence. The predictive power for quick sequential organ failure assessment for sepsis and in-hospital mortality for patients with cirrhosis was limited.
Critically ill patients with ALC have decreased survival after ICU discharge compared with patients with other etiologies of cirrhosis, independent of alcohol abstinence.
Serum phosphatidylethanol (PEth) testing has emerged as a promising biomarker for assessing recent alcohol consumption, surpassing the limitations of self-reported data. Limited clinical data exists ...comparing PEth levels and patients' reported alcohol intake.
Compare PEth testing results with self-reported alcohol intake and assesses variables associated with underreporting.
Single-center retrospective cohort of patients with a diagnosis of chronic liver disease and serum PEth. A patient's first positive PEth (>/=10 ng/mL) and self-reported alcohol consumption was used. PEth results were categorized as mild (10–20), moderate (20–200), or heavy (>200). Severity measures between self-report and PEth were assessed using Bhapkar's test and Bonferroni-adjusted McNemar's tests. Demographic data was analyzed using Chi-Square tests.
279 patients were included. 94 (33.7%) patients had consistency with self-report, and 185 patients had inconsistencies in their report (66.3%, p < 0.001). Of 279 patients, 161 (57.7%) underreported their alcohol consumption, and 55 (19.7%) heavy PEth patients underreported alcohol consumption as light. 58% of alcohol-related and 56.4% of non-alcohol-related cirrhotic patients underreported their alcohol use.
In our cohort, only one third of self-reported alcohol consumption was consistent with the PEth level. Notably, 57.7% underreported alcohol intake. Our study reinforces the clinical importance of PEth testing as an objective clinical measure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Peeraphatdit et al explore new treatment paradigms for alcoholic hepatitis by extrapolating from NASH and cholestasis. They relate the study by Brandl et al which evaluates the relationship between ...bile acids, FGF19 and clinical outcomes in patients with AH compared to patients with alcohol use disorder and controls without known liver disease. Although this study provides insights on the interaction of bile acids and FGF19 in patients with AH, many questions still remain. First, it is unclear whether FGF19 has a protective effect on AH or it simply represents a marker of severity. Second, the main source of FGF19 in patients with AH is still unknown. While an increase in hepatic FGF19 expression was observed in this study, the expression of FCF19 in the ileum was not assessed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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