Eric S. Orman

Efficacy and durability of radiofrequency ablation for Barrett's Esophagus: systematic review and meta-analysis.

BACKGROUND & AIMS In patients with Barretts esophagus (BE), radiofrequency ablation (RFA) safely and effectively eradicates dysplasia and intestinal metaplasia. We aimed to determine the efficacy and durability of RFA for patients with dysplastic and nondysplastic BE. METHODS We performed a systematic review and meta-analysis of studies identified in PubMed and EMBASE that reported the proportion of patients treated with RFA who had complete eradication of dysplasia (CE-D) and intestinal metaplasia (CE-IM), and the proportion of patients with recurrent IM after successful treatment. Pooled estimates of CE-D, CE-IM, IM recurrence, and adverse events were calculated. RESULTS We identified 18 studies of 3802 patients reporting efficacy and 6 studies of 540 patients reporting durability. Ten were prospective cohort studies, 9 were retrospective cohort studies, and 1 was a randomized trial. CE-IM was achieved in 78% of patients (95% confidence interval [CI], 70%-86%) and CE-D was achieved in 91% (95% CI, 87%-95%). After eradication, IM recurred in 13% (95% CI, 9%-18%). Progression to cancer occurred in 0.2% of patients during treatment and in 0.7% of those after CE-IM. Esophageal stricture was the most common adverse event and was reported in 5% of patients (95% CI, 3%-7%). Confidence in most summary estimates was limited by a high degree of heterogeneity, which did not appear to be caused by single outlier studies. CONCLUSIONS Treatment of BE with RFA results in CE-D and CE-IM in a high proportion of patients, with few recurrences of IM after treatment and a low rate of adverse events. Despite the large amount of study heterogeneity, these data provide additional information for patients and providers to make informed treatment decisions.

Alcoholic liver disease: Pathogenesis, management, and novel targets for therapy

Alcohol use is a leading cause of preventable morbidity and mortality worldwide, with much of its negative impact as the result of alcoholic liver disease (ALD). ALD is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanisms underlying the development of these different disease stages are incompletely understood. Standard treatment of ALD, which includes abstinence, nutritional support, and corticosteroids, has not changed in the last 40 years despite continued poor outcomes. Novel therapies are therefore urgently needed. The development of such therapies has been hindered by inadequate resources for research and unsuitable animal models. However, recent developments in translational research have allowed for identification of new potential targets for therapy. These targets include: (i) CXC chemokines, (ii) IL-22/STAT3, (iii) TNF receptor superfamily, (iv) osteopontin, (v) gut microbiota and lipopolysaccharide (LPS), (vi) endocannabinoids, and (vii) inflammasomes. We review the natural history, risk factors, pathogenesis, and current treatments for ALD. We further discuss the findings of recent translational studies and potential therapeutic targets.

Intestinal metaplasia recurs infrequently in patients successfully treated for Barrett's esophagus with radiofrequency ablation.

OBJECTIVES:Radiofrequency ablation (RFA) of Barretts esophagus (BE) is safe and effective in eradicating dysplasia and intestinal metaplasia, and may reduce rates of esophageal adenocarcinoma (EAC). We assessed rates of and risk factors for disease recurrence after successful treatment of BE with RFA.METHODS:We performed a retrospective cohort study of patients who completed RFA for dysplastic BE or intramucosal carcinoma (IMC), achieved complete eradication of dysplasia (CE-D) or intestinal metaplasia (CE-IM), and underwent subsequent endoscopic surveillance at a single center. Rates of disease recurrence and progression were determined. Patients with and without recurrent disease were compared to determine risk factors for recurrence.RESULTS:Two hundred and sixty-two subjects underwent RFA during the study period. Of these, 119 and 112 patients were retained in endoscopic surveillance after CE-D and CE-IM, respectively. Median observation time was 397 days (range: 54–1,668 days). Eight patients (7% of those with CE-IM) had recurrent disease after a median of 235 days (range 55–1,124 days). Progression to IMC (n=1) or EAC (n=2) occurred in three of these eight patients, all of whom had pre-ablation high-grade dysplasia (HGD). Five patients had recurrence of non-dysplastic BE (n=3), low-grade dysplasia (n=1), and HGD (n=1). During 155 patient-years of observation, recurrence occurred in 5.2%/year, and progression occurred in 1.9%/year. No clinical characteristics were associated with disease recurrence.CONCLUSIONS:In patients with BE and dysplasia or early cancer who achieved CE-IM, BE recurred in ∼5%/year. Patient characteristics did not predict recurrence. Subjects undergoing RFA for dysplastic BE should be retained in endoscopic surveillance.

Declining liver utilization for transplantation in the United States and the impact of donation after cardiac death

Worsening donor liver quality resulting in decreased organ utilization may be contributing to the recent decline in liver transplants nationally. We sought to examine trends in donor liver utilization and the relationship between donor characteristics and nonuse. We used the United Network for Organ Sharing database to review all deceased adult organ donors in the United States from whom at least 1 solid organ was transplanted into a recipient. Trends in donor characteristics were examined. Multivariate logistic regression was used to evaluate the association between donor characteristics and liver nonuse between 2004 and 2010. Population attributable risk proportions were determined for donor factors associated with nonuse. We analyzed 107,259 organ donors. The number of unused livers decreased steadily from 1958 (66% of donors) in 1988 to 841 (15%) in 2004 but then gradually increased to 1345 (21%) in 2010. The donor age, the body mass index (BMI), and the prevalence of diabetes and donation after cardiac death (DCD) all increased over time, and all 4 factors were independently associated with liver nonuse. DCD had the highest adjusted odds ratio (OR) for nonuse, and the odds increased nearly 4‐fold between 2004 [OR = 5.53, 95% confidence interval (CI) = 4.57‐6.70] and 2010 (OR = 21.31, 95% CI = 18.30‐24.81). The proportion of nonuse attributable to DCD increased from 9% in 2004 to 28% in 2010. In conclusion, the proportion of donor livers not used has increased since 2004. Older donor age, greater BMI, diabetes, and DCD are all independently associated with nonuse and are on the rise nationally. Current trends may lead to significant declines in liver transplant availability. Liver Transpl 19:59–68, 2013.

Clinical and Histopathologic Features of Fluoroquinolone-Induced Liver Injury

BACKGROUND & AIMS Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatotoxicity from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features. METHODS We identified subjects with fluoroquinolone hepatotoxicity enrolled in the DILIN from September 2004 to January 2010. Demographic, clinical, and laboratory data were analyzed by descriptive statistical methods. RESULTS Of the 679 registrants in the DILIN prospective study, 12 had fluoroquinolone hepatotoxicity (6 ciprofloxacin, 4 moxifloxacin, 1 levofloxacin, and 1 gatifloxacin). Seven were women; median age was 57 years (range, 23-80 years), and median time from fluoroquinolone start to symptoms was only 4 days (range, 1-39 days). Nine patients developed symptoms on medication; 3 did so 2, 8, and 32 days after stopping the medication. Cases were equally distributed among hepatocellular injury (predominantly increased levels of alanine aminotransferase), cholestatic injury (predominantly increased levels of alkaline phosphatase), and both. Seven patients had immunoallergic features. Patients with mixed hepatocellular and cholestatic injury had mild disease without jaundice; all recovered. In contrast, 2 of 4 patients with hepatocellular injury and jaundice died, 1 of acute liver failure. One patient with cholestatic injury developed vanishing bile duct syndrome and required liver transplantation; another had a persistently increased serum level of alkaline phosphatase. CONCLUSIONS Fluoroquinolone liver injury is rapid in onset and often has immunoallergic features, indicating a hypersensitivity reaction. The pattern of injury can be hepatocellular, cholestatic, or mixed; mixed cases are the least severe. Acute and chronic liver failure can occur.

Declining liver graft quality threatens the future of liver transplantation in the United States

National liver transplantation (LT) volume has declined since 2006, in part because of worsening donor organ quality. Trends that degrade organ quality are expected to continue over the next 2 decades. We used the United Network for Organ Sharing (UNOS) database to inform a 20‐year discrete event simulation estimating LT volume from 2010 to 2030. Data to inform the model were obtained from deceased organ donors between 2000 and 2009. If donor liver utilization practices remain constant, utilization will fall from 78% to 44% by 2030, resulting in 2230 fewer LTs. If transplant centers increase their risk tolerance for marginal grafts, utilization would decrease to 48%. The institution of “opt‐out” organ donation policies to increase the donor pool would still result in 1380 to 1866 fewer transplants. Ex vivo perfusion techniques that increase the use of marginal donor livers may stabilize LT volume. Otherwise, the number of LTs in the United States will decrease substantially over the next 15 years. In conclusion, the transplant community will need to accept inferior grafts and potentially worse posttransplant outcomes and/or develop new strategies for increasing organ donation and utilization in order to maintain the number of LTs at the current level. Liver Transpl 21:1040‐1050, 2015.

Paracentesis Is Associated With Reduced Mortality in Patients Hospitalized With Cirrhosis and Ascites

BACKGROUND & AIMS Diagnostic paracentesis is recommended for patients with cirrhosis who are admitted to the hospital for ascites or encephalopathy. However, it is not known whether clinicians in the United States adhere to this recommendation; a relationship between paracentesis and clinical outcome has not been reported. We analyzed a U.S. database to determine the frequency of paracentesis and its association with mortality. METHODS The 2009 Nationwide Inpatient Sample (which contains data from approximately 8 million hospital discharges each year) was used to identify patients with cirrhosis and ascites who were admitted with a primary diagnosis of ascites or encephalopathy. In-hospital mortality, length of stay, and hospital charges were compared for those who did and did not undergo paracentesis. Outcomes were compared for those who received an early paracentesis (within 1 day of admission) and those who received one later. RESULTS Of 17,711 eligible admissions, only 61% underwent paracentesis. In-hospital mortality was reduced by 24% among patients who underwent paracentesis (6.5% vs 8.5%; adjusted odds ratio, 0.55; 95% confidence interval, 0.41-0.74). Most paracenteses (66%) occurred ≤1 day after admission. In-hospital mortality was lower among patients who received early paracentesis than those who received it later (5.7% vs 8.1%, P = .049), although this difference was not significant after adjustment for confounders (odds ratio, 1.26; 95% confidence interval, 0.78-2.02). Among patients who underwent paracentesis, the mean hospital stay was 14% longer and hospital charges were 29% greater than for patients who did not receive the procedure. CONCLUSIONS Paracentesis is underused for patients admitted to the hospital with ascites; the procedure is associated with increased short-term survival. These data support practice guidelines derived from expert opinion. Studies are needed to identify barriers to guideline adherence.

Impact of nighttime and weekend liver transplants on graft and patient outcomes

Safety concerns have been raised about nighttime and weekend patient care, but it is unknown whether these issues affect liver transplantation. We sought to identify the impact of nighttime and weekend liver transplants on graft and patient survival. We used the United Network for Organ Sharing database to review adult liver transplants from 1987 to 2010. Comparisons were made between nighttime and daytime operations and between weekday and weekend operations. Cox proportional hazard ratios (HRs) were determined 30, 90, and 365 days after transplantation after we controlled for relevant factors; 94,768 transplants were included in the analysis. The patient survival rates at 30, 90, and 365 days for nighttime operations were 96%, 93%, and 86%, respectively. The patient survival rates at 30, 90, and 365 days for weekend operations were 95%, 92%, and 86%, respectively. These rates did not significantly differ from those for daytime and weekday operations, respectively. The graft failure rate was unchanged at 30 and 90 days for weekend transplants but was modestly increased at 365 days [HR = 1.05 (95% confidence interval = 1.01‐1.11)]. Graft survival was unaffected by nighttime transplantation. Nighttime and weekend operations for liver transplantation do not affect patient or graft survival, and this testifies to the patient safety measures in place. Liver Transpl, 2012.

Poor Performance Status Is Associated With Increased Mortality in Patients With Cirrhosis

BACKGROUND & AIMS Functional status (a patients ability to perform activities that meet basic needs, fulfill usual roles, and maintain health and well-being) has been linked to outcomes in patients with cirrhosis and can be measured by the Karnofsky performance status (KPS) scale. We investigated the association between KPS score and mortality in patients with cirrhosis. METHODS We used the United Network for Organ Sharing database to perform a retrospective cohort study of patients listed for liver transplantation in the United States between 2005 and 2015. We used Cox proportional hazards and competing risk regression analyses to examine the association between KPS and mortality and transplantation. RESULTS Of 79,092 patients, 44% were in KPS category A (KPS, 80%-100%), 43% were in category B (KPS, 50%-70%), and 13% were in category C (KPS, 10%-40%). Between 2005 and 2015, the proportion of patients in category A decreased from 53% to 35%, whereas the proportions in categories B and C increased from 36% to 49% and from 11% to 16%, respectively. KPS was associated with mortality: compared with patients in KPS category A, the KPS B adjusted hazard ratio (HR) was 1.14 (95% confidence interval [CI], 1.11-1.18) and the KPS C adjusted HR was 1.63 (95% CI, 1.55-1.72). KPS was also associated with liver transplantation; compared with patients in KPS category A, the KPS B adjusted HR was 1.08 (95% CI, 1.06-1.11) and the KPS C adjusted HR was 1.35 (95% CI, 1.30-1.40). In competing risk analysis, only the relationship between KPS and mortality maintained significance and directionality. These relationships were most pronounced in patients without hepatocellular carcinoma. CONCLUSIONS Among patients with cirrhosis listed for liver transplantation, poor performance status, based on the KPS scale, is associated with increased mortality. In this population, performance status has decreased over time.

Predicting Liver Transplant Capacity Using Discrete Event Simulation.

The number of liver transplants (LTs) performed in the US increased until 2006 but has since declined despite an ongoing increase in demand. This decline may be due in part to decreased donor liver quality and increasing discard of poor-quality livers. We constructed a discrete event simulation (DES) model informed by current donor characteristics to predict future LT trends through the year 2030. The data source for our model is the United Network for Organ Sharing database, which contains patient-level information on all organ transplants performed in the US. Previous analysis showed that liver discard is increasing and that discarded organs are more often from donors who are older, are obese, have diabetes, and donated after cardiac death. Given that the prevalence of these factors is increasing, the DES model quantifies the reduction in the number of LTs performed through 2030. In addition, the model estimatesthe total number of future donors needed to maintain the current volume of LTs and the effect of a hypothetical scenario of improved reperfusion technology.We also forecast the number of patients on the waiting list and compare this with the estimated number of LTs to illustrate the impact that decreased LTs will have on patients needing transplants. By altering assumptions about the future donor pool, this model can be used to develop policy interventions to prevent a further decline in this lifesaving therapy. To our knowledge, there are no similar predictive models of future LT use based on epidemiological trends.