The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.

INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

No country for old livers? Examining and optimizing the utilization of elderly liver grafts.

Of the 1.6 million patients >70 years of age who died of stroke since 2002, donor livers were retrieved from only 2402 (0.15% yield rate). Despite reports of successful liver transplantation (LT) with elderly grafts (EG), advanced donor age is considered a risk for poor outcomes. Centers for Medicare and Medicaid Services definitions of an "eligible death" for donation excludes patients >70 years of age, creating disincentives to donation. We investigated utilization and outcomes of recipients of donors >70 through analysis of a United Network for Organ Sharing Standard Transplant Analysis and Research-file of adult LTs from 2002 to 2014. Survival analysis was conducted using Kaplan-Meier curves, and Cox regression was used to identify factors influencing outcomes of EG recipients. Three thousand one hundred four livers from donors >70, ≈40% of which were used in 2 regions: 2 (520/3104) and 9 (666/3104). Unadjusted survival was significantly worse among recipients of EG compared to recipients of younger grafts (P < .0001). Eight independent negative predictors of survival in recipients of EG were identified on multivariable analysis. Survival of low-risk recipients who received EG was significantly better than survival of recipients of younger grafts (P = .04). Outcomes of recipients of EG can therefore be optimized to equal outcomes of younger grafts. Given the large number of stroke deaths in patients >70 years of age, the yield rate of EGs can be maximized and disincentives removed to help resolve the organ shortage crisis.

The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Hypothermic machine preservation facilitates successful transplantation of "orphan" extended criteria donor livers.

Hypothermic machine preservation (HMP) remains investigational in clinical liver transplantation. It is widely used to preserve kidneys for transplantation with improved results over static cold storage (SCS). At our center, we have used HMP in 31 adults receiving extended criteria donor (ECD) livers declined by the originating United Network for Organ Sharing region ("orphan livers"). These cases were compared to ECD SCS cases in a matched cohort study design. Livers were matched for donor age, recipient age, cold ischemic time, donor risk index and Model for End-Stage Liver Disease (MELD) score. HMP was performed for 3-7 h at 4-8 °C using our previously published protocol. Early allograft dysfunction rates were 19% in the HMP group versus 30% in the control group (p = 0.384). One-year patient survival was 84% in the HMP group versus 80% in the SCS group (p = NS). Post hoc analysis revealed significantly less biliary complications in the HMP group versus the SCS group (4 vs. 13, p = 0.016). Mean hospital stay was significantly shorter in the HMP group (13.64 ± 10.9 vs. 20.14 ± 11.12 days in the SCS group, p = 0.001). HMP provided safe and reliable preservation in orphan livers transplanted at our center.

Trends and Patterns in Reporting of Patient Safety Situations in Transplantation.

Analysis and dissemination of transplant patient safety data are essential to understanding key issues facing the transplant community and fostering a "culture of safety." The Organ Procurement and Transplantation Network's (OPTN) Operations and Safety Committee de-identified safety situations reported through several mechanisms, including the OPTN's online patient safety portal, through which the number of reported cases has risen sharply. From 2012 to 2013, 438 events were received through either the online portal or other reporting pathways, and about half were self-reports. Communication breakdowns (22.8%) and testing issues (16.0%) were the most common types. Events included preventable errors that led to organ discard as well as near misses. Among events reported by Organ Procurement Organization (OPOs), half came from just 10 of the 58 institutions, while half of events reported by transplant centers came from just 21 of 250 institutions. Thirteen (23%) OPOs and 155 (62%) transplant centers reported no events, suggesting substantial underreporting of safety-related errors to the national database. This is the first comprehensive, published report of the OPTN's safety efforts. Our goals are to raise awareness of safety data recently reported to the OPTN, encourage additional reporting, and spur systems improvements to mitigate future risk.

Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis.

Drug-induced gingival overgrowth (DIGO) is a disfiguring side effect of anti-convulsants, calcineurin inhibitors, and calcium channel blocking agents. A unifying hypothesis has been constructed which begins with cation flux inhibition induced by all three of these drug categories. Decreased cation influx of folic acid active transport within gingival fibroblasts leads to decreased cellular folate uptake, which in turn leads to changes in matrix metalloproteinases metabolism and the failure to activate collagenase. Decreased availability of activated collagenase results in decreased degradation of accumulated connective tissue which presents as DIGO. Studies supporting this hypothesis are discussed.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.

BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Multivisceral ex vivo surgery for tumors involving celiac and superior mesenteric arteries.

Abdominal tumors involving both roots of the celiac and superior mesenteric artery are deemed unresectable by conventional surgical methods. We performed three cases of multivisceral ex vivo surgery involving temporary removal of the entire abdominal viscera followed by vascular reconstruction, ex vivo tumor resection and autotransplantation of excised organs. We achieved a complete tumor resection with negative margins in all cases. All patients have survived with no tumor recurrence to date at 17-, 27- and 38-month follow-up. Postoperative complications included diarrhea, sphincter of Oddi dysfunction and arterial stenosis; all responded to directed treatments. Multivisceral ex vivo surgery applying techniques of deceased donor multivisceral transplantation is feasible in achieving local control of otherwise unresectable abdominal tumors. This surgery is best suitable for locally invasive tumors unresectable because of location and vascular involvement.

Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.

Standardization of terminology of virological response in the treatment of chronic hepatitis C: panel recommendations.

The treatment paradigm for hepatitis C virus (HCV) infection is at a critical point in its evolution. The addition of a protease inhibitor to peginterferon plus ribavirin has become the new standard-of-care treatment for most patients. Data from clinical trials of new antivirals have been difficult to interpret and compare, partly because of heterogeneity in trial design, and partly because of inconsistencies in terminology used to define viral responses and the populations evaluated. Present definitions of viral responses for treatment with peginterferon and ribavirin are insufficient for novel treatment paradigms. Further, categorization of prior patient treatment experience in clinical trials, particularly of nonresponders to prior therapy, is inconsistent. Existing terms and definitions must be updated, standardized and/or redefined for easier interpretation of data and effective communication among clinicians. A panel of experts in HCV infection treatment met on 3 December 2009. Goals of the panel were to evaluate terms and definitions used traditionally in treatment with peginterferon and ribavirin, to refine and clarify definitions of existing terms that have varying meanings and to propose new terms and definitions appropriate for novel treatment paradigms emerging with development of new agents. A number of recommendations were accepted unanimously by the panel. Adoption of these terms would improve communication among investigators, enhance comparability among clinical trials, facilitate development of therapeutic guidelines and provide a standardized terminology for use in clinical practice.

Impacts of COVID-19 lockdown on private domestic groundwater sample numbers, E. coli presence and E. coli concentration across Ontario, January 2020-March 2021: An interrupted time-series analysis.

Approximately 1.5 million individuals in Ontario are supplied by private water wells (private groundwater supplies). Unlike municipal supplies, private well water quality remains unregulated, with owners responsible for testing, treating, and maintaining their own water supplies. The COVID-19 global pandemic and associated non-pharmaceutical interventions (NPIs) have impacted many environmental (e.g., surface water and air quality) and human (e.g., healthcare, transportation) systems over the past 15-months (January 2020 to March 2021). To date, the impact of these interventions on private groundwater systems remains largely unknown. Accordingly, the current study aimed to investigate the impact of a province-wide COVID-19 lockdown (late-March 2020) on health behaviours (i.e., private domestic groundwater sampling) and groundwater quality (via Escherichia coli (E. coli) detection and concentration) in private well water in Ontario, using time-series analyses (seasonal decomposition, interrupted time-series) of a large-spatio-temporal dataset (January 2016 to March 2021; N = 743,200 samples). Findings indicate that lockdown concurred with an immediate (p = 0.015) and sustained (p < 0.001) decrease in sampling rates, equating to approximately 2200 fewer samples received per week post-interruption. Likewise, a slightly decreased E. coli detection rate was observed approximately one month after lockdowns began (p = 0.003), while the proportion of "highly contaminated" samples (i.e., E. coli > 10 CFU/100 mL) was shown to increase within one month (p = 0.02), followed by a sustained decrease for the remainder of the year (May 2020-December 2020). Analyses strongly suggest that COVID-19 interventions resulted in discernible impacts on both well user behaviours and hydrogeological mechanisms. Findings may be used as an evidence-base for assisting policy makers, public health practitioners and private well owners in developing recommendations and mitigation strategies to manage public health risks during extreme and/or unprecedented future events.

Differential changes in responses of hypothalamic and brainstem neuronal populations to prolactin during lactation in the mouse.

During lactation, there are numerous functional adaptations in the maternal brain. There is evidence that the high levels of circulating prolactin present during lactation might contribute to these adaptive changes. The present study aimed to investigate levels of functional prolactin-mediated signal transduction in the brain of lactating mice, using prolactin-induced phosphorylation of signal transducer and activator of transcription 5 (pSTAT5) as a marker, and compare these to the effect of exogenous prolactin during diestrus. On Day 7 of lactation, widespread induction of pSTAT5 was observed in numerous regions of the mouse forebrain and brainstem. In the medial preoptic nucleus, bed nuclei stria terminalis, paraventricular nucleus, and medial amygdala of the forebrain, and in the rostral periaqueductal gray, parabrachial nucleus, dorsal raphe, and the raphe obscurus nucleus of the brainstem, pSTAT5 expression was markedly increased during lactation compared with the response to exogenous prolactin during diestrus. In the anteroventral periventricular nucleus, arcuate nucleus, ventromedial nucleus, and dorsomedial nucleus, responses in lactation were comparable to diestrus. Conversely, in the area postrema of the brainstem, there was a reduction in response to prolactin, with a loss of pSTAT5 expression, during lactation. These differential responses following either acute or chronic elevations in prolactin were not accompanied by any changes in levels of prolactin receptor mRNA, when measured by in situ hybridization. These data are consistent with the hypothesis that prolactin might mediate widespread adaptive responses in the maternal brain.

Hypothermic machine preservation in human liver transplantation: the first clinical series.

Hypothermic machine perfusion (HMP) is widely used to preserve kidneys for transplantation with improved results over cold storage (CS). To date, successful transplantation of livers preserved with HMP has been reported only in animal models. In this, the first prospective liver HMP study, 20 adults received HMP-preserved livers and were compared to a matched group transplanted with CS livers. HMP was performed for 3-7 h using centrifugal perfusion with Vasosol solution at 4-6 degrees C. There were no cases of primary nonfunction in either group. Early allograft dysfunction rates were 5% in the HMP group versus 25% in controls (p = 0.08). At 12 months, there were two deaths in each group, all unrelated to preservation or graft function. There were no vascular complications in HMP livers. Two biliary complications were observed in HMP livers compared with four in the CS group. Serum injury markers were significantly lower in the HMP group. Mean hospital stay was shorter in the HMP group (10.9 +/- 4.7 days vs. 15.3 +/- 4.9 days in the CS group, p = 0.006). HMP of donor livers provided safe and reliable preservation in this pilot case-controlled series. Further multicenter HMP trials are now warranted.

Database comparison of the adult-to-adult living donor liver transplantation cohort study (A2ALL) and the SRTR U.S. Transplant Registry.

Data submitted by transplant programs to the Organ Procurement and Transplantation Network (OPTN) are used by the Scientific Registry of Transplant Recipients (SRTR) for policy development, performance evaluation and research. This study compared OPTN/SRTR data with data extracted from medical records by research coordinators from the nine-center A2ALL study. A2ALL data were collected independently of OPTN data submission (48 data elements among 785 liver transplant candidates/recipients; 12 data elements among 386 donors). At least 90% agreement occurred between OPTN/SRTR and A2ALL for 11/29 baseline recipient elements, 4/19 recipient transplant or follow-up elements and 6/12 donor elements. For the remaining recipient and donor elements, >10% of values were missing in OPTN/SRTR but present in A2ALL, confirming that missing data were largely avoidable. Other than variables required for allocation, the percentage missing varied widely by center. These findings support an expanded focus on data quality control by OPTN/SRTR for a broader variable set than those used for allocation. Center-specific monitoring of missing values could substantially improve the data.

Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation.

The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre-OLT and HBIG regimens post-OLT. Data from the NIH HBV-OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1-81) post-OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log(10) copies/mL, 74% were receiving antiviral therapy. Twenty-five patients experienced virologic breakthrough before OLT. Post-OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high-dose, IV low-dose, intramuscular low-dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre-OLT as long as rescue therapy is administered pre- and post-OLT.

The evolution and direction of OPTN oversight of live organ donation and transplantation in the United States.

For more than 20 years, the Organ Procurement and Transplantation Network (OPTN) has developed policies and bylaws relating to equitable allocation of deceased donor organs for transplantation. United Network for Organ Sharing (UNOS) operates the OPTN under contract with the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS). Until recent years, the OPTN had little defined authority regarding living donor organ for transplantation except for the collection of data relating to living donor transplants. Beginning with the implementation of the OPTN Final Rule in 2000, and continuing with more recent announcements, the OPTN's role in living donation has grown. Its responsibilities now include monitoring of living donor outcomes, promoting equity in nondirected living donor transplantation and ensuring that transplant programs have expertise and established protocols to promote the safety of living donors and recipients. The purpose of this article is to describe the evolving mandates for the OPTN in living donation, as well as the network's recent activities and ongoing efforts.

Resource utilization of living donor versus deceased donor liver transplantation is similar at an experienced transplant center.

Although living donor liver transplantation (LDLT) has been shown to decrease waiting-list mortality, little is known of its financial impact relative to deceased donor liver transplantation (DDLT). We performed a retrospective cohort study of the comprehensive resource utilization, using financial charges as a surrogate measure-from the pretransplant through the posttransplant periods-of 489 adult liver transplants (LDLT n = 86; DDLT n = 403) between January 1, 2000, through December 31, 2006, at a single center with substantial experience in LDLT. Baseline characteristics differed between LDLT versus DDLT with regards to age at transplantation (p = 0.02), male gender (p < 0.01), percentage Caucasians (p < 0.01) and transplant model for end-stage liver disease (MELD) score (p < 0.01). In univariate analysis, there was a trend toward decreased total transplant charges with LDLT (p = 0.06), despite increased surgical charges associated with LDLT (p < 0.01). After adjustment for the covariates that were associated with financial charges, there was no significant difference in total transplant charges (p = 0.82). MELD score at transplant was the strongest driver of resource utilization. We conclude that at an experienced transplant center, LDLT imposes a similar overall financial burden than DDLT, despite the increased complexity of living donor surgery and the addition of the costs of the living donor. We speculate that LDLT optimizes transplantation by transplanting healthier and younger recipients.

The impact of hepatitis C and biliary complications on patient and graft survival following liver transplantation.

Recurrent hepatitis C (HCV) and biliary complications (BC) are major causes of post liver transplant morbidity and mortality. The impact of these complications may be additive or synergistic. We performed a retrospective cohort study to analyze the effects of HCV and BC on all patients transplanted at two institutions over 6 years. BC was defined by imaging findings in the setting of abnormal liver function tests that required intervention. The primary outcomes were graft and patient survival over a mean 3.4 years. 709 patients (619 deceased, 90 living donor) were included, 337 with HCV and 372 without. BC was diagnosed more frequently in patients with HCV, 26% versus 18% (p = 0.008). One-year and overall patient and graft survival were significantly lower in patients with HCV, but BC impacted only 1-year graft survival. The combination of BC and HCV had no additional impact on survival or fibrosis rates on 1-year protocol biopsies. Multivariate analysis revealed HCV (HR 2.1) and HCC (HR 1.9) to be independent predictors of mortality. Since BC are diagnosed more frequently in HCV patients and only affect early graft loss, it is likely that recurrent HCV rather than BC accounts for the majority of adverse graft outcomes.