Outcome of patients with severe alcoholic hepatitis after Model for End-Stage Liver Disease-based allocation system implementation in Korea.
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ABSTRACT: Background
The Model for End-Stage Liver Disease (MELD)-based allocation system was implemented in Korea in July 2016 without a mandatory abstinence period for liver transplantation (LT) listing. However, the impact of the allocation policy has not been evaluated in patients with severe alcoholic hepatitis (AH).Methods
A total of 81 consecutive patients with severe AH between January 2014 and December 2018 were analyzed. The clinical course of patients before and after the implementation of the MELD-based allocation system was assessed.Results
More patients received LT (25%-65%) after the MELD allocation system was implemented. The increase in patients receiving deceased donor LT was dramatic (17%-51%, P=0.001) compared to patients receiving living donor LT (7%-14%, P=0.30). The overall survival was better for those who received LT (88% vs. 44% at 1 year, P<0.001), and after the MELD era (1-year survival rate 80% vs. 50%, P=0.005). Post-LT mortality was observed in six patients, with one case of mortality related to recidivism. Baseline MELD and steroid response were factors associated with transplant-free survival.Conclusions
After implementation of the MELD-based allocation system, deceased donor LT dramatically increased in patients with severe AH. This translated into increased overall survival, but at a cost of mortality due to recidivism. Urgent evaluation is warranted to identify criteria to justify the use of precious liver grafts from deceased donors for severe AH patients in Korea.
SUBMITTER: Kwon TJ
PROVIDER: S-EPMC9235328 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND & AIMS:Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables. METHODS:We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2). RESULTS:We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001). CONCLUSIONS:We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.
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Project description:The severity of alcoholic hepatitis (AH) which may coexist with cirrhosis varies greatly, from asymptomatic forms which are detected in alcoholic patients without any sign of liver disease, except laboratory abnormalities, to severe forms characterised by deep jaundice, ascites, hepatic encephalopathy and low prothrombin index. In hospitalized patients the mortality could be as high as 75%. The elevated number of therapeutic proposals reported for more than forty years reveals the lack of efficacy of a particular modality. Even in the most favorable trials, the survival is already very poor and in some cases related to the development of renal failure or hepatorenal syndrome. There are some motivating reports concerning albumin dialysis as a support treatment in patients with severe AH, either alone or in combination with other pharmacological therapies. The favorable effects of albumin dialysis in patients with severe AH suggest that the procedure used alone or in combination with other therapies may have a role in this clinical condition. This will be particularly relevant to offer an alternative therapy in these patients, thus being a potential bridge to recovery or to be listed for liver transplantation.
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Project description:Background & aimsThe American Consortium of Early Liver Transplantation for Alcoholic Hepatitis comprises 12 centers from 8 United Network for Organ Sharing regions studying early liver transplantation (LT) (without mandated period of sobriety) for patients with severe alcoholic hepatitis (AH). We analyzed the outcomes of these patients.MethodsWe performed a retrospective study of consecutive patients with a diagnosis of severe AH and no prior diagnosis of liver disease or episodes of AH, who underwent LT before 6 months of abstinence from 2006 through 2017 at 12 centers. We collected data on baseline characteristics, psychosocial profiles, level of alcohol consumption before LT, disease course and treatment, and outcomes of LT. The interval of alcohol abstinence was defined as the time between last drink and the date of LT. The primary outcomes were survival and alcohol use after LT, defined as slip or sustained.ResultsAmong 147 patients with AH who received liver transplants, the median duration of abstinence before LT was 55 days; 54% received corticosteroids for AH and the patients had a median Lille score of 0.82 and a median Sodium Model for End-Stage Liver Disease score of 39. Cumulative patient survival percentages after LT were 94% at 1 year (95% confidence interval [CI], 89%-97%) and 84% at 3 years (95% CI, 75%-90%). Following hospital discharge after LT, 72% were abstinent, 18% had slips, and 11% had sustained alcohol use. The cumulative incidence of any alcohol use was 25% at 1 year (95% CI, 18%-34%) and 34% at 3 years (95% CI, 25%-44%) after LT. The cumulative incidence of sustained alcohol use was 10% at 1 year (95% CI, 6%-18%) and 17% at 3 years (95% CI, 10%-27%) after LT. In multivariable analysis, only younger age was associated with alcohol following LT (P = .01). Sustained alcohol use after LT was associated with increased risk of death (hazard ratio, 4.59; P = .01).ConclusionsIn a retrospective analysis of 147 patients who underwent early LT (before 6 months of abstinence) for severe AH, we found that most patients survive for 1 year (94%) and 3 years (84%), similar to patients receiving liver transplants for other indications. Sustained alcohol use after LT was infrequent but associated with increased mortality. Our findings support the selective use of LT as a treatment for severe AH. Prospective studies are needed to optimize selection criteria, management of patients after LT, and long-term outcomes.
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Project description:Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver-specific enzyme, inhibits oxidation of phospholipids and prevents lipid-mediated oxidative damage. However, its functional contribution in macrophage-mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku-Hospital-Pediatrics-1 (THP1)-derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up-regulated and 176 down-regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r2 > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut-off, <18 μg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low-density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate-binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28-day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.
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Project description:Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N-acetyl cysteine. At present, only short-term increases in survival can be expected-no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited.
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Project description:BACKGROUND & AIM:The goal of organ allocation is to distribute a scarce resource equitably to the sickest patients. In the United States, the Model for End-stage Liver Disease (MELD) is used to allocate livers for transplantation. Patients with greater MELD scores are at greater risk of death on the waitlist and are prioritized for liver transplant (LT). The MELD is capped at 40 however, and patients with calculated MELD scores >40 are not prioritized despite increased mortality. We aimed to evaluate waitlist and post-transplant survival stratified by MELD to determine outcomes in patients with MELD >40. METHODS:Using United Network for Organ Sharing data, we identified patients listed for LT from February 2002 through to December 2012. Waitlist candidates with MELD ?40 were followed for 30days or until the earliest occurrence of death or transplant. RESULTS:Of 65,776 waitlisted patients, 3.3% had MELD ?40 at registration, and an additional 7.3% had MELD scores increase to ?40 after waitlist registration. A total of 30,369 (46.2%) underwent LT, of which 2,615 (8.6%) had MELD ?40 at transplant. Compared to MELD 40, the hazard ratio of death within 30days of registration was 1.4 (95% CI 1.2-1.6) for patients with MELD 41-44, 2.6 (95% CI 2.1-3.1) for MELD 45-49, and 5.0 (95% CI 4.1-6.1) for MELD ?50. There was no difference in 1- and 3-year survival for patients transplanted with MELD >40 compared to MELD=40. A survival benefit associated with LT was seen as MELD increased above 40. CONCLUSIONS:Patients with MELD >40 have significantly greater waitlist mortality but comparable post-transplant outcomes to patients with MELD=40 and, therefore, should be given priority for LT. Uncapping the MELD will allow more equitable organ distribution aligned with the principle of prioritizing patients most in need. Lay summary: In the United States (US), organs for liver transplantation are allocated by an objective scoring system called the Model for End-stage Liver Disease (MELD), which aims to prioritize the sickest patients for transplant. The greater the MELD score, the greater the mortality without liver transplant. The MELD score, however, is artificially capped at 40 and thus actually disadvantages the sickest patients with end-stage liver disease. Analysis of the data advocates uncapping the MELD score to appropriately prioritize the patients most in need of a liver transplant.
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Project description:Offer acceptance practices may cause geographic variability in allocation Model for End-Stage Liver Disease (aMELD) score at transplant and could magnify the effect of donor supply and demand on aMELD variability. To evaluate these issues, offer acceptance practices of liver transplant programs and donation service areas (DSAs) were estimated using offers of livers from donors recovered between January 1, 2016, and December 31, 2016. Offer acceptance practices were compared with liver yield, local placement of transplanted livers, donor supply and demand, and aMELD at transplant. Offer acceptance was associated with liver yield (odds ratio, 1.32; P < 0.001), local placement of transplanted livers (odds ratio, 1.34; P < 0.001), and aMELD at transplant (average aMELD difference, -1.62; P < 0.001). However, the ratio of donated livers to listed candidates in a DSA (ie, donor-to-candidate ratio) was associated with median aMELD at transplant (r = -0.45; P < 0.001), but not with offer acceptance (r = 0.09; P = 0.50). Additionally, the association between DSA-level donor-to-candidate ratios and aMELD at transplant did not change after adjustment for offer acceptance. The average squared difference in median aMELD at transplant across DSAs was 24.6; removing the effect of donor-to-candidate ratios reduced the average squared differences more than removing the effect of program-level offer acceptance (33% and 15% reduction, respectively). Offer acceptance practices and donor-to-candidate ratios independently contributed to geographic variability in aMELD at transplant. Thus, neither offer acceptance nor donor-to-candidate ratios can explain all of the geographic variability in aMELD at transplant. Liver Transplantation 24 478-487 2018 AASLD.
| S-EPMC5869092 | biostudies-literature
Project description:BackgroundIn the appropriate candidate, liver transplantation (LT) is a viable treatment for alcoholic hepatitis (AH). We compared the waitlisting trends and outcomes of AH patients in the context of others with high Model for End-stage Liver Disease (MELD) score.MethodsLT listings for AH between January 1, 2008, and June 12, 2020 were identified in the United Network for Organ Sharing database. Temporal trends in listings for AH were assessed. Covariate adjusted competing risks models evaluated waitlist mortality and LT rates between AH candidates and others with listing native MELD ≥30.ResultsBetween 2008 and 2019, waitlist additions for AH increased 6.5-fold. Waiting time for AH candidates was short (median 10 d). Delisting for clinical improvement was infrequent in AH, albeit higher than MELD ≥30 patients (3.3% versus 0.8%; P < 0.001). Among 99 centers with ≥1 AH listing, AH patients accounted for 0.2%-18.2% of all alcohol-related listings and 0.6%-25.0% of those with native listing MELD ≥30. Overall listing volume was larger at these 99 centers than the 40 with no AH listings (P < 0.001). AH candidates in 2014-2020 experienced improved waitlist survival (adjusted subhazard ratio, 0.67; 95% confidence interval, 0.52-0.86; P = 0.002) and higher transplant rates (adjusted subhazard ratio, 1.14; 95% confidence interval, 1.04-1.25; P = 0.006) versus other MELD ≥30 candidates.ConclusionsThere has been a rising trend in waitlisting patients with AH and high MELD score. Liver disease causes influence waitlist outcomes and those of AH candidates are more favorable. Further research and allocation adjustments may be needed to ensure equitable organ allocation, based on liver disease cause, for those on the LT waitlist.
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Project description:Severe alcoholic hepatitis (SAH) has a high mortality rate, and corticosteroid therapy is effective in 60% patients. This study aimed to investigate a baseline metabolic phenotype that could help stratify patients not likely to respond to steroid therapy and to have an unfavorable outcome. Baseline urine metabolome was studied in patients with SAH using ultra-high performance liquid chromatography and high-resolution mass spectrometry. Patients were categorized as responders (Rs, n = 52) and nonresponders (NRs, n = 8) at day 7 according to the Lille score. Multivariate projection analysis identified metabolites in the discovery cohort (n = 60) and assessed these in a validation cohort of 80 patients (60 Rs, 20 NRs). A total of 212 features were annotated by using metabolomic/biochemical/spectral databases for metabolite identification. After a stringent selection procedure, a total of nine urinary metabolites linked to mitochondrial functions significantly discriminated nonresponders, most importantly by increased acetyl-L-carnitine (12-fold), octanoylcarnitine (4-fold), decanoylcarnitine (4-fold), and alpha-ketoglutaric acid (2-fold) levels. Additionally, urinary acetyl-L-carnitine and 3-hydroxysebasic acid discriminated nonsurvivors (P < 0.01). These urinary metabolites significantly correlated to severity indices and mortality (r > 0.3; P < 0.01) and were associated with nonresponse (odds ratio >3.0; P < 0.001). In the validation cohort, baseline urinary acetyl-L-carnitine documented an area under the receiver operating curve of 0.96 (0.85-0.99) for nonresponse prediction and a hazard ratio of 3.5 (1.5-8.3) for the prediction of mortality in patients with SAH. Acetyl-L-carnitine at a level of >2,500 ng/mL reliably segregated survivors from nonsurvivors (P < 0.01, log-rank test) in our study cohort. Conclusion: Urinary metabolome signatures related to mitochondrial functions can predict pretherapy steroid response and disease outcome in patients with SAH. (Hepatology Communications 2018;2:628-643).
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Project description:Severe alcoholic hepatitis (AH) is an acute and often devastating form of alcohol-associated liver disease. Clinically, AH is characterized by elevated bilirubin, model for end stage liver disease scores >20, and nonspecific symptoms that are caused by underlying inflammation, hepatocyte injury, and impaired intestinal barrier function. Compromised immune defense in AH contributes to infections, sepsis and organ failure. To date, corticosteroids are the only recommended treatment for severe AH, however it does not provide survival benefits beyond 1 month. Recent preclinical and early clinical studies in AH aided understanding of the disease and presented opportunities for new therapeutic options targeting inflammation, oxidative stress, liver regeneration and modification of intestinal microbiota. In this comprehensive review, we discuss promising preclinical results and ongoing clinical trials evaluating novel therapeutic agents for the treatment of severe AH.
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