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Background and Aims: Acute liver failure (ALF) is a serious condition, typically in individuals without prior liver disease. Drug-induced ALF (DIALF) constitutes a major portion of ALF cases. Our research aimed to identify potential genetic predispositions to DIALF., Methods: We analysed the potential genetic variants associated with DIALF using the whole exome sequencing data from 75 cases, including 40 non-Finnish European cases in the pilot study. Chi-square tests were performed for case-control analysis against the 1000 genomes project as the control. A replication study of 44 DIALF cases that included 24 non-Finnish Europeans was conducted to validate candidate variants. The association between clinical phenotype and genotypes was analysed using one-way analysis of variance., Results: Eight variants (rs561037, rs561042, rs608339, rs655260, rs1142886, rs1142888, rs1142889 and rs1142890) in the guanylate binding protein 4 (GBP4) were significantly associated with DIALF in non-Finnish Europeans in the pilot study and confirmed in the replication study. Rs561037 and rs561042 were highly significant with the lowest allele frequencies in both pilot and replication studies. An association was also found between these variants and milder clinical outcomes, indicated by lower peak levels of ALT, AST and higher Karnofsky performance scores., Conclusion: Our study identified eight GBP4 missense variants linked to a lower risk of DIALF in the non-Finnish European population. The GBP4 protein, activated by interferon-gamma, plays a critical role in innate immunity. These findings suggest that GBP4 variants might influence immune and inflammatory responses in DIALF, though further studies are needed to elucidate the underlying mechanisms., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis., Methods: Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication., Results: With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role., Conclusions: Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the etiology remains unknown and is categorized as indeterminate ALF (IND-ALF). In this study, we summarize findings from patients with IND-ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND-ALF., Methods: Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21-day transplant-free survival (TFS)., Results: Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n = 114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients with true-IND ALF versus patients with indeterminable ALF (29.8% vs. 27.2%), with almost half of the patients requiring liver transplant (42.1% vs. 45.7%)., Conclusion: We illustrate the poor prognoses that true-IND-ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Autoimmune hepatitis is a common cause of acute liver failure. Treatment includes steroids for acute liver injury and liver transplantation in those who fail to respond or develop acute liver failure. The aim of this study is to further characterize acute liver failure secondary to autoimmune hepatitis and identify variables that predict 21-day transplant-free survival. This study included adults hospitalized with acute liver failure enrolled in the Acute Liver Failure Study Group Registry between 1998 and 2019 from 32 centers within the US. The etiology of all cases was reviewed by the Adjudication Committee, and all cases identified as autoimmune hepatitis were included. Acute liver injury was defined as an INR ≥2.0 without encephalopathy and acute liver failure as INR ≥ 1.5 with encephalopathy. Laboratory and clinical data were reviewed. Variables significantly associated with 21-day transplant-free survival were used to develop a multivariable logistic regression model.  A total of 193 cases of acute liver failure secondary to autoimmune hepatitis were identified and reviewed. There were 161 patients (83.4%) diagnosed with acute liver failure on enrollment, and 32 (16.6%) developed acute liver failure during hospitalization. At 21 days, 115 (59.6%) underwent liver transplantation, 28 (14.5%) had transplant-free survival, and 46 (23.8%) died before liver transplantation. Higher admission values of bilirubin, INR, and coma grade were associated with worse outcomes. A prognostic index incorporating bilirubin, INR, coma grade, and platelet count had a concordance statistic of 0.84. Acute liver failure secondary to autoimmune hepatitis is associated with a high short-term mortality. We developed a model specifically for autoimmune hepatitis that may be helpful in predicting 21-day transplant-free survival and early identification of patients in need of expedited liver transplant evaluation., (Copyright © 2023 American Association for the Study of Liver Diseases.)

There has been a growing interest in identifying prognostic biomarkers that alone or with available prognostic models (King's College Criteria, KCC; MELD and ALFSG Prognostic Index) would improve prognosis in acute liver failure (ALF) patients being assessed for liver transplantation. The Acute Liver Failure Study Group (ALFSG) has evaluated 15 potential prognostic biomarkers: serum AFP; apoptosis-associated proteins; serum actin-free Gc-globulin; serum glycodeoxycholic acid; sRAGE/RAGE ligands; plasma osteopontin; circulating MBL, M-, L-, H-ficolin and CL-1; plasma galectin-9; serum FABP1; serum Lct2; miRNAs; factor V; thrombocytopenia, and sCD163. The ALFSG also has reported on 4 susceptibility biomarkers: keratins 8 and 18 (K8/K18) gene variants; polymorphisms of genes encoding putative APAP-metabolizing enzymes ( UGT1A1 , UGT 1A0 , UGT 2B15 , SULT1A1 , CYP2E1 , and CYP3A5 ) as well as CD44 and BHMT1 ; single nucleotide polymorphisms (SNPs) of genes associated with human behavior, rs2282018 in the arginine vasopressin ( AVP ) gene and rs11174811 in the AVP receptor 1A gene. Finally, rs2277680 of the CSCL16 gene in HBV-ALF patients. In conclusion, we have reviewed the prognostic and susceptibility biomarkers studied by the ALFSG. We suggest that a better approach to predicting the clinical outcome of an ALF patient will require a combination of biomarkers of pathogenic processes such as cell death, hepatic regeneration, and degree of inflammation that could be incorporated into prognostic models such as KCC, MELD or ALFSG PI., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Liver transplantation (LT) is a life-saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long-term outcomes after LT for ALF. We combined prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT. Cohort analysis of detailed pretransplantation data for patients listed for LT for ALF in the ALFSG Registry between January 1998 and October 2018 matched with transplantation-related data from the SRTR. Primary outcomes were 1- and 3-year post-LT patient survival. Secondary outcome was receipt of LT; independent associations with successful receipt of LT were determined using multivariable logistic regression. Of 624 patients with ALF listed for LT, 398 (64%) underwent LT, 100 (16%) died without LT, and 126 (20%) recovered spontaneously. Among LT recipients, etiologies included seronegative/indeterminate (22%), drug-induced liver injury (18%), acetaminophen overdose (APAP; 16%), and viral hepatitis (15%). The 1- and 3-year post-LT patient survival rates were 91% and 90%, respectively. Comparing those dying on the waiting list versus with those who received LT, the former had more severe multiorgan failure, reflected by increased vasopressor use (65% vs. 22%), mechanical ventilation (84% vs. 57%), and renal replacement therapy (57% vs. 30%; p  < 0.0001 for all). After adjusting for relevant covariates, age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00-1.04), APAP etiology (aOR 2.72, 95% CI 1.42-5.23), requirement for vasopressors (aOR 4.19, 95% CI 2.44-7.20), Grade III/IV hepatic encephalopathy (aOR 2.47, 95% CI 1.29-4.72), and Model for End-Stage Liver Disease (MELD) scores (aOR 1.05, 95% CI 1.02-1.09; p  < 0.05 for all) were independently associated with death without receipt of LT. Post-LT outcomes for ALF are excellent in this cohort of very ill patients. The development of multiorgan failure while on the transplantation list and APAP ALF etiology were associated with a lower likelihood of successful receipt of LT., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Introduction: Indeterminate acute liver failure (IND-ALF) is a rare clinical syndrome with a high mortality rate. Lacking a known etiology makes rapid evaluation and treatment difficult, with liver transplantation often considered as the only therapeutic option. Our aim was to identify genetic variants from whole exome sequencing data that might be associated with IND-ALF clinical outcomes., Methods: Bioinformatics analysis was performed on whole exome sequencing data for 22 patients with IND-ALF. A 2-tier approach was used to identify significant single-nucleotide polymorphisms (SNPs) associated with IND-ALF clinical outcomes. Tier 1 identified the SNPs with a higher relative risk in the IND-ALF population compared with those identified in control populations. Tier 2 determined the SNPs connected to transplant-free survival and associated with model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores., Results: Thirty-one SNPs were found associated with a higher relative risk in the IND-ALF population compared with those in controls, of which 11 belong to the human leukocyte antigen (HLA) class II genes but none for the class I. Further analysis showed that 5 SNPs: rs796202376, rs139189937, and rs113473719 of HLA-DRB5; rs9272712 of HLA-DQA1; and rs747397929 of IDO1 were associated with a higher probability of IND-ALF transplant-free survival. Using 3 selected SNPs, a model for the polygenic risk score was developed to predict IND-ALF prognoses, which are comparable with those by model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores., Discussion: Certain gene variants in HLA-DRB5, HLA-DQA1, and IDO1 were found associated with IND-ALF transplant-free survival. Once validated, these identified SNPs may help elucidate the mechanism of IND-ALF and assist in its diagnosis and management., (Copyright © 2022 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

One promising goal for utilizing the molecular information circulating in biofluids is the discovery of clinically useful biomarkers. Extracellular RNAs (exRNAs) are one of the most diverse classes of molecular cargo, easily assayed by sequencing and with expressions that rapidly change in response to subject status. Despite diverse exRNA cargo, most evaluations from biofluids have focused on small RNA sequencing and analysis, specifically on microRNAs (miRNAs). Another goal of characterizing circulating molecular information, is to correlate expression to injuries associated with specific tissues of origin. Biomarker candidates are often described as being specific, enriched in a particular tissue or associated with a disease process. Likewise, miRNA data is often reported to be specific, enriched for a tissue, without rigorous testing to support the claim. Here we provide a tissue atlas of small RNAs from 30 different tissues and three different blood cell types. We analyzed the tissues for enrichment of small RNA sequences and assessed their expression in biofluids: plasma, cerebrospinal fluid, urine, and saliva. We employed published data sets representing physiological (resting vs. acute exercise) and pathologic states (early- vs. late-stage liver fibrosis, and differential subtypes of stroke) to determine differential tissue-enriched small RNAs. We also developed an online tool that provides information about exRNA sequences found in different biofluids and tissues. The data can be used to better understand the various types of small RNA sequences in different tissues as well as their potential release into biofluids, which should help in the validation or design of biomarker studies., Competing Interests: KV and SD are members of the scientific advisory board at Dyrnamix. Their involvement in this company had no bearing on the work performed in this manuscript. KV is on the scientific advisory board of HTG. Her involvement has no bearing on this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alsop, Meechoovet, Kitchen, Sweeney, Beach, Serrano, Hutchins, Ghiran, Reiman, Syring, Hsieh, Courtright-Lim, Valkov, Whitsett, Rakela, Pockros, Rozowsky, Gallego, Huentelman, Shah, Nakaji, Kalani, Laurent, Das and Van Keuren-Jensen.)

Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R 2  = 0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Spontaneous portosystemic shunts (SPSSs) have been associated with worse clinical outcomes in the pre-liver transplantation (LT) setting, but little is known about their post-LT impacts. Our aim was to compare LT candidates with and without SPSSs and assess the impact of SPSSs on patient mortality and graft survival in the post-LT setting. Patients 18 years or older with abdominal imaging done prior to LT were included. Exclusion criteria were the presence of pre-LT surgical shunts, LT indications other than cirrhosis, and combined solid organ transplantations. SPSSs were classified as absent, small, or large according to their maximum diameter (8 mm). Multiple variables that could influence the post-LT course were extracted for analysis. Patient and graft survival were estimated using the Kaplan-Meier method and were compared between groups using a log-rank test. The project received institutional review board approval. We extracted data from 326 patients. After comparing patients without SPSS or with small or large SPSSs, no statistical difference was found for overall patient survival: no SPSS (n = 8/63), reference; small SPSS (n = 18/150), hazard ratio (HR), 1.05 (95% confidence interval [CI], 0.45-2.46); and large SPSS (n = 6/113), HR, 0.60 (95% CI, 0.20-1.78); P = 0.20. Also, no difference was found for graft survival: no SPSS (n = 11/63), reference; small SPSS (n = 21/150), HR, 0.80 (95% CI, 0.38-1.70); large SPSS (n = 11/113), HR, 0.59 (95% CI, 0.25-1.40); P = 0.48. Similarly, no statistical significance was found for these variables when comparing if the graft used was procured from a donation after circulatory death donor versus a donation after brain death donor. In conclusion, the previously described association between SPSSs and worse clinical outcomes in pre-LT patients seems not to persist once patients undergo LT. This study suggests that no steps to correct SPSS intraoperatively are necessary., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Introduction: The etiology of acute liver failure (ALF) remains an important prognostic factor. The Acute Liver Failure Study Group recently reported that 150 of 2,718 adult patients with ALF (5.5%) had an indeterminate etiology. Our aim was to use whole exome sequencing to identify genetic variants associated with phenotypic, biochemical, and histologic features among patients with indeterminate ALF., Methods: This effort has defined a cohort of well-pedigreed patients with indeterminate ALF; DNA samples extracted from whole blood samples were obtained from 26 respective patients with indeterminate ALF. These samples were kept at the Acute Liver Failure Study Group repository at the NIDDK, Bethesda. Whole exome sequencing and bioinformatics analysis were performed at the Mayo Clinic Center of Individualized Medicine in Rochester, MN., Results: Of the 26 patients, 8 survived spontaneously, 6 died, and 12 underwent a liver transplantation; all those transplanted were alive at 21 days after enrollment in the study. Twenty-two of the 26 patients presented as ALF. We found 12 variants associated with 11 genes. The most common variant was rs4940595 in the SERPINB11 gene which was found in 23 of the 26 patients. This variant had a stop codon; no reports of disorders have been associated with this variant. The next most commonly found variant was rs1135840 in the CYP2D6 gene; this mutation is a missense&#95;variant and has been reported to be associated with hepatotoxicity of antituberculous therapy. None of our patients were receiving this therapy. We also found a significant asymmetric distribution of rs1800754 of the CYP2D7 gene and rs1135840 of the CYP2D6 gene between patients who survived spontaneously (75%) and those who died or underwent liver transplantation (30.5% and 25%, respectively)., Discussion: We found 12 variants of 11 genes significantly associated with ALF among adults with indeterminate etiology. We also found a significant asymmetric distribution of 2 variants belonging to the CYP2D7 and CYP2D6 genes, respectively, between those who survived spontaneously and those who died or underwent liver transplantation. The 2 most common variants, rs4940595 and rs1135840, of the SERPINB11 and CYP2D6 genes, respectively, found in our patients with ALF have been described as potentially important in the adaptive response combating the emergence of infectious diseases and associated with hepatotoxicity of antituberculous therapy, respectively. Our findings need to be expanded to include more patients with indeterminate ALF as well as viral, drug toxicity, and autoimmune etiologies to determine whether our findings are associated with the specific etiology, indeterminate, or with the overall ALF syndrome itself.

Background: Patients with solid organ transplants (SOTs) have been excluded from programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor clinical trials due to concern for allograft rejection. The use of immune checkpoint inhibitor therapy remains controversial in transplant patients., Methods: A retrospective pilot evaluation was conducted to assess the safety and efficacy of PD-1 inhibitors in patients with liver transplantation (LT). The primary endpoint was the rate of allograft rejection. Secondary endpoints included overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Translational objectives included evaluation of tumor PD-L1, tumor infiltrating lymphocytes (TILs) and allograft PD-L1 expression., Results: Seven metastatic cancer patients with a history of LT who received PD-1 inhibitor therapy were included [hepatocellular carcinoma (HCC), n=5; melanoma, n=2]. Rejection was observed in 2 of 7 patients. When rejection occurs it appears to be an early event with a median time to rejection of 24 days in our cohort. One patient achieved a complete response (CR), 3 patients had progressive disease (PD) and 3 patients discontinued therapy prior to restaging assessments. Two of five patients with available tissue had PD-L1 expression in the allograft and both developed rejection. One of five evaluable patients had abundant TILs. Two of five evaluable patients had PD-L1 tumor staining. The single patient with both abundant TILs and PD-L1 staining obtained a response. The median OS and PFS were 1.1 (0.3-21.1) and 1.8 (0.7-21.1) months, respectively., Conclusions: In this pilot evaluation both preliminary efficacy (1 of 4) and allograft rejection (2 of 7) were exhibited in evaluable patients. Larger, prospective trials are needed to elucidate optimal patient selection., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objectives: In the United States, the Acute Liver Failure Study Group (ALFSG) registry lists approximately 11% of cases as of indeterminate etiology (IND-ALF) as determined by the respective local site principal investigator (PI). Traditionally, IND-ALF has prompted concern that other viruses or toxins might be implicated. We hypothesized that many IND- ALF cases would have an identifiable etiology upon further investigation. Improving the identification process should reduce the number of truly indeterminate cases., Methods: Specific definitions for each etiology ("etiology-specific algorithms") were developed by a Causality Adjudication Committee that included six reviewers (each with 20 or more years of experience). Of 2718 patients with ALF, 303 initially deemed IND-ALF by site PIs underwent committee review guided by the algorithms. Acetaminophen (APAP) protein adducts were measured in sera when available, additional HEV testing was performed, and viral sequences sought by microarray analysis and metagenomic next-generation sequencing (mNGS). Study sites were asked to provide liver biopsy and/or explant reports and to update serological findings not reported previously., Results: Nearly half (142, 46.9%) of the 303 IND-ALF cases could be reassigned to a single, defined etiology and rated as highly likely or probable; 11 additional cases, upon review, did not meet ALF criteria. Amongst reassigned etiologies, 45 were previously unrecognized APAP, 34 autoimmune hepatitis (AIH), 24 drug-induced liver injury (DILI), 13 various viral causes, 12 ischemia, and 14 miscellaneous other etiologies. The remaining 150, deemed true IND-ALF, represented just 5.5%., Conclusions: The indeterminate etiology in ALF includes patients with a diagnosis that is discernible after closer examination. Revision of etiologic diagnoses of indeterminate cases using added testing and expert opinion is useful in understanding all aspects of ALF.

Thrombocytopenia has previously been reported after right lobe resection for organ donation. The mechanism(s) of low platelets after right hepatectomy is unclear and several hypotheses have been proposed including a decrease in thrombopoietin, and hepatic insufficiency resulting in relative portal hypertension following hepatic resection. However, there has previously not been any comparison between patients who undergo hepatic resection for neoplasia vs. for living organ donation. We compared platelet values in the postoperative period of patients who underwent right hepatectomy for living donation (n = 93) to those who underwent hepatectomy for neoplasia (n = 21). There was no significant difference in platelet values between the two groups at one month (291.2 ± 100 vs. 285.73 ± 159, p = NS), three months (223.8 ± 61 vs. 185.27 ± 80, p = NS) and at 12 months (212 ± 44 vs. 191 ± 60, p = NS). We conclude that thrombocytopenia is not uncommon following hepatic lobe resection, and is unaffected by the indication for hepatectomy.

Objectives: The increasing use of complementary and alternative medicines (CAMs) has been associated with a rising incidence of CAM-induced drug-induced liver injury (DILI). The aim of this study was to examine the clinical features and outcomes among patients with acute liver failure (ALF) and acute liver injury (ALI) enrolled in the Acute Liver Failure Study Group database, comparing CAM-induced with prescription medicine (PM)-induced DILI., Methods: A total of 2,626 hospitalized patients with ALF/ALI of any etiology were prospectively enrolled between 1998 and 2015 from 32 academic transplant centers. Only those with CAM or PM-induced ALI/ALF were selected for analysis., Results: A total of 253 (9.6%) subjects were found to have idiosyncratic DILI, of which 41 (16.3%) were from CAM and 210 (83.7%) were due to PM. The fraction of DILI-ALF/ALI cases due to CAM increased from 1998-2007 to 2007-2015 (12.4 vs. 21.1%, P=0.047). There was no difference in the type of liver injury-hepatocellular, cholestatic, or mixed-between groups as determined by R score (P=0.26). PM-induced DILI showed higher serum alkaline phosphatase levels compared with the CAM group (median IU/L, 171 vs. 125, P=0.003). The CAM population had fewer comorbid conditions (1.0 vs. 2.0, P<0.005), higher transplantation rates (56 vs. 32%, P<0.005), and a lower ALF-specific 21-day transplant-free survival (17 vs. 34%, P=0.044)., Conclusions: CAM-induced DILI is at least as severe in presentation as that observed due to PM with higher rates of transplantation and lower transplant-free survival in those who progress to ALF. This study highlights the increasing incidence of CAM-induced liver injury and emphasizes the importance of early referral and evaluation for liver transplantation when CAM-induced liver injury is suspected.

Hepatocellular carcinoma (HCC) is a common, increasingly prevalent malignancy. For all but the smallest lesions, surgical removal of cancer via resection or liver transplantation (LT) is considered the most feasible pathway to cure. Resection - even with favorable survival - is associated with a fairly high rate of recurrence, perhaps since most HCCs occur in the setting of cirrhosis. LT offers the advantage of removing not only the cancer but the diseased liver from which the cancer has arisen, and LT outperforms resection for survival with selected patients. Since time waiting for LT is time during which HCC can progress, loco-regional therapy (LRT) is widely employed by transplant centers. The purpose of LRT is either to bridge patients to LT by preventing progression and waitlist dropout, or to downstage patients who slightly exceed standard eligibility criteria initially but can fall within it after treatment. Transarterial chemoembolization and radiofrequency ablation have been the most widely utilized LRTs to date, with favorable efficacy and safety as a bridge to LT (and for the former, as a downstaging modality). The list of potentially effective LRTs has expanded in recent years, and includes transarterial chemoembolization with drug-eluting beads, radioembolization and novel forms of extracorporal therapy. Herein we appraise the various LRT modalities for HCC, and their potential roles in specific clinical scenarios in patients awaiting LT.

Background & Aims: Accumulating evidence indicates that microRNAs play a role in a number of disease processes including the pathogenesis of liver fibrosis in hepatitis C infection. Our goal is to add to the accruing information regarding microRNA deregulation in liver fibrosis to increase our understanding of the underlying mechanisms of pathology and progression., Methods: We used next generation sequencing to profile all detectable microRNAs in liver tissue and serum from patients with hepatitis C, stages F1-F4 of fibrosis., Results: We found altered expression of several microRNAs, in particular, miR-182, miR199a-5p, miR-200a-5p and miR-183 were found to be significantly upregulated in tissue from liver biopsies of hepatitis C patients with advanced fibrosis, stage F3 and F4, when compared with liver biopsies from patients with early fibrosis, stages F1 and F2. We also found miR-148-5p, miR-1260b, miR-122-3p and miR-378i among the microRNAs most significantly down-regulated from early to advanced fibrosis of the liver. We also sequenced the serum microRNAs; however, we were not able to detect significant changes in circulating microRNAs associated with fibrosis stage after adjusting for multiple tests., Conclusions: Adding measurements of tissue microRNAs acquired during routine biopsies will continue to increase our knowledge of underlying mechanisms of fibrosis. Our goal is that these data, in combination with studies from other researchers and future long-term studies, could be used to enhance the staging accuracy of liver biopsies and expand the surveillance of patients at increased risk for cancer and progression to advanced fibrosis., (© 2015 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Background: Acute hepatitis E virus (HEV) infection in solid organ transplant recipients is rare, but can cause severe hepatic and extrahepatic complications. We sought to identify the pretransplant prevalence of HEV infection in heart and kidney candidates and any associated risk factors for infection., Material and Methods: Stored frozen serum from patients undergoing evaluation for transplant was tested for HEV immunoglobulin G (IgG) antibodies and HEV RNA. All patients were seen at Mayo Clinic Hospital, Phoenix, Arizona, with 333 patients evaluated for heart (n = 132) or kidney (n = 201) transplant. HEV IgG antibodies (anti-HEV IgG) were measured by enzyme-linked immunosorbent assay, and HEV RNA by a noncommercial nucleic acid amplification assay., Results: The prevalence of anti-HEV IgG was 11.4% (15/132) for heart transplant candidates and 8.5% (17/201) for kidney transplant candidates, with an overall seroprevalence of 9.6% (32/333). None of the patients tested positive for HEV RNA in the serum. On multivariable analysis, age older than 60 years was associated with HEV infection (adjusted odds ratio, 3.34; 95% CI, 1.54-7.24; P = 0.002)., Conclusions: We conclude that there was no evidence of acute HEV infection in this pretransplant population and that older age seems to be associated with positive anti-HEV IgG.

Millions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed.

Background & Aims: In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes., Methods: Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the 'up-to-7 rule' [7=sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome., Results: At a median follow-up of 88months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR)=2.95, p<0.001], along with tumor size (HR=3.37, p=0.023) and presence of satellites (HR=2.98, p=0.001). S2 subclass signature was independently associated with poor OS (HR=3.18, p=0.001), along with tumor size (HR=5.06, p<0.001) and up-to-7 rule (HR=2.50, p=0.002). Using the presence of progenitor cell markers (either CK19 or S2 signatures) patients were classified into poor prognosis (n=58; 5-year recurrence 53%, survival 45%) and good prognosis (n=74; 5-year recurrence 19%, survival 67%) (HR=3.16, p<0.001 for recurrence, and HR=1.72, p=0.04 for OS)., Conclusions: HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to define liver shear stiffness by magnetic resonance elastography (MRE) that distinguishes normal from abnormal liver biopsy, especially when steatosis ≥20%, among potential live liver donors., Methods: Baseline clinical, laboratory, imaging, MRE, and liver biopsy results were recorded. Using MRE, hepatic shear stiffness in kilopascals (kPa) was measured and compared to liver biopsy. Comparison between groups was done using χ(2) or Fisher's exact test for categorical variables and Wilcoxon test for continuous variables. Receiver operating characteristic (ROC) curve was calculated to assess diagnostic accuracy. Statistical significance was set at p < 0.05., Results: 38 healthy adults were included. Liver biopsy was normal in 27 and abnormal in 11. ROC curve for MRE defined optimal cutoff at 2.6 kPa (sensitivity 0.72, specificity 0.85, AUC 0.81) to distinguish these 2 groups. Hepatic steatosis ≥20% on biopsy is a contraindication for liver donation in our center. We evaluated the ability of MRE to distinguish this degree of steatosis: 8 persons had steatosis ≥20% and were excluded from donation. ROC curve for MRE defined optimal cutoff at 2.82 kPa (sensitivity 0.88, specificity 1, AUC 0.98) to identify this group., Conclusions: Liver stiffness measured by MRE, even in the absence of liver fibrosis, can be useful in differentiating normal from abnormal liver histology, and most importantly in patients under evaluation for live liver donation, can very accurately distinguish those with complicated hepatic steatosis ≥20%, our cutoff for donation. In the future, MRE might provide supplementary information to make liver biopsy unnecessary in the donor evaluation process.

Sarcopenia, or loss of skeletal muscle mass, is associated with increased mortality and morbidity in liver transplant (LT) candidates. Six-minute walk distance (6MWD) and health-related quality of life (HRQOL) as assessed by short form 36 scores (SF-36) also impact clinical outcomes in these patients. This study explored the relationship between the sarcopenia, 6MWD, and HRQOL in LT candidates. Sarcopenia was evaluated based on skeletal muscle mass index (SMI) quantified from abdominal computed tomography. Patients were followed until death, removal from the wait list or the end of the study period. Two hundred and thirteen patients listed for LT were included. The mean SMI, 6MWD and mean gait speed were 54.3 ± 9.7, 370.5 m and 1 m/s, respectively. Sarcopenia was noted in 22.2% of LT candidates. There was no correlation between sarcopenia, 6MWD, and SF-36 scores. The 6MWD, but not sarcopenia, was an independent predictor of mortality (hazard ratio = 2.1 [0.9-4.7]). In summary, sarcopenia did not emerge as a significant predictor of waitlist mortality and also failed to correlate with either functional capacity or HRQOL in LT candidates. In patients with ESLD awaiting LT, 6MWD appears to be a more useful prognostic indicator than the presence of sarcopenia., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although herbs and botanicals have been available for thousands of years, detailed scientific research regarding the potential health benefits and risks of dietary supplements has been conducted only for the past 15-20 years. Millions of Americans use herbal supplements regularly, but many are not aware of the possible hidden dangers. Organ transplant recipients and patients with end-stage organ failure awaiting transplantation are at particularly high risk for potential complications due to herbal supplement use. This review provides background information regarding complementary and alternative medicine (CAM) use in the United States, regulatory history of dietary supplements in the United States, and concerns and special considerations regarding the risks associated with dietary/herbal supplement use in pretransplant and posttransplant patients.

Unlabelled: Vitamin D deficiency is common among patients with end-stage liver disease (ESLD). The primary aim of our study was to assess the prevalence of vitamin D deficiency, secondary hyperparathyroidism, and bone disease in patients with ESLD awaiting LT., Methods: We retrospectively studied 190 patients at our center. Serum total 25-hydroxyvitamin D (25-OH D), parathyroid hormone (PTH), calcium, and bone mineral analysis (BMA) were recorded. Standard World Health Organization (WHO) criteria were used to diagnose osteopenia/osteoporosis. Only patients with normal serum creatinine were analyzed., Results: Thirty-two of 190 patients were excluded from the final analysis (missing serum total 25-OH D levels in three patients and elevated serum creatinine, 29 patients). 105 of 158 (66.4%) evaluable patients had 25-OH D levels <25 ng/mL. Patients included in the analysis (n = 158) were divided according to serum total 25-OH D levels: 0-10 ng/mL (n = 23), 11-20 ng/mL (n = 64), and >20 ng/mL (n = 71). There were no significant differences in mean serum PTH and corrected calcium levels among the three subgroups. Only three patients had elevated serum PTH. Patients with total 25-OH D ≤ 10 ng/mL had higher model for end-stage liver disease (MELD) scores vs. those with 25-OH D > 20 ng/mL (13.3 ± 3, range 8-21, vs. 11.9 ± 3.4, range 6-29, p = 0.004). Irrespective of vitamin D status, bone disease was present in 64.6% of patients., Conclusion: Low vitamin D levels and bone disease are common among patients with ESLD awaiting LT. Despite a high prevalence of low serum total 25-OH D, our cohort maintained normal corrected calcium levels and did not develop secondary hyperparathyroidism. We propose that free serum 25-OH D and vitamin D-binding protein may be necessary to accurately establish the diagnosis of vitamin D deficiency in the setting of ESLD. Additional studies are needed to further define mechanisms of bone disease in patients with ESLD., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Regenerative medicine is energizing and empowering basic science and has the potential to dramatically transform health care in the future. Given the remarkable intrinsic regenerative properties of the liver, as well as widespread adoption of regenerative strategies for liver disease (eg, liver transplant, partial hepatectomy, living donor transplant), hepatology has always been at the forefront of clinical regenerative medicine. However, an expanding pool of patients awaiting liver transplant, a limited pool of donor organs, and finite applicability of the current surgical approaches have created a need for more refined and widely available regenerative medicine strategies. Although cell-based therapies have been used extensively for hematologic malignant diseases and other conditions, the potential application of cellular therapy for acute and chronic liver diseases has only more recently been explored. New understanding of the mechanisms of liver regeneration and repair, including activation of local stem/progenitor cells and contributions from circulating bone marrow-derived stem cells, provide the theoretical underpinnings for the rational use of cell-based therapies in clinical trials. In this review, we dissect the scientific rationale for various modalities of cell therapy for liver diseases being explored in animal models and review those tested in human clinical trials. We also attempt to clarify some of the important ongoing questions that need to be addressed in order to bring these powerful therapies to clinical translation. Discussions will cover transplant of hepatocytes and liver stem/progenitor cells as well as infusion or stimulation of bone marrow-derived stem cells. We also highlight tremendous scientific advances on the horizon, including the potential use of induced pluripotent stem cells and their derivatives as individualized regenerative therapy for liver disease., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Hepatitis E virus (HEV) infection (genotype 3) has been described in developed countries as a cause of chronic hepatitis in recipients of solid organ transplantation (SOT), with the first cases reported in 2008. Immunosuppression seems to play a major role in the pathogenesis of chronic infections. The current gold standard for the diagnosis of HEV infection is the detection of HEV RNA in serum, stools, or both. In liver transplant recipients, HEV infection is considered an uncommon disease; however, a high index of suspicion is needed for patients with graft hepatitis of an unclear etiology. Liver transplant recipients seem more likely to develop chronic HEV after an acute infection, and there is accelerated progression to advanced fibrosis and cirrhosis. A decrease in immunosuppression is considered the first line of treatment, and pegylated interferon can be considered the second line of treatment for liver transplant recipients. At the present time, there are not enough data to recommend treatment with ribavirin for adult liver transplant recipients, although this has been tried in other SOT populations.

Background: The prevalence of portal vein thrombosis (PVT) increases with the severity of liver disease. Development of PVT is often accompanied by increased rate of morbidity and mortality and may affect patient candidacy for liver transplant. There is limited data regarding the role of anticoagulation therapy in patients with PVT and liver cirrhosis., Objectives: The aims of this study were to describe the prevalence of hypercoagulable disorders in patients with liver cirrhosis and PVT, and to describe the outcome of anticoagulation in patients with liver cirrhosis and PVT., Methods: A retrospective chart review was conducted of patients with liver cirrhosis awaiting liver transplant who were diagnosed with PVT between January 2005 and November 2011., Results: During the study period, 537 patients were evaluated for liver transplant. Sixty-nine (13 %) patients were diagnosed with portal vein thrombosis. Chronic hepatitis C was the cause of liver disease in 24/69 (35 %) patients, and hepatocellular carcinoma was present in 39 % of patients. In 22 patients screened for hypercoagulable disorders, hypercoagulable disorder was diagnosed in one patient (5 %). Twenty-eight (28/69) patients were treated during the study period with warfarin: PVT resolved in 11/28 (39 %), no change in 5/28 (18 %), and 12/28 (43 %) patients showed partial resolution of thrombus. Eight patients received liver transplant while on anticoagulation, and operative notes confirmed patency of PV in all eight patients., Conclusions: PVT is frequently seen in patients with end stage liver disease with prevalence of 13 %. Hypercoagulable disorder was detected in 5 % of the patients screened. Careful use of anticoagulation is safe and effective in patients with PVT.

New onset diabetes after transplantation (NODAT) occurs less frequently in living donor liver transplant (LDLT) recipients than in deceased donor liver transplant (DDLT) recipients. The aim of this study was to compare the incidence and predictive factors for NODAT in LDLT versus DDLT recipients. The Organ Procurement and Transplant Network/United Network for Organ Sharing database was reviewed from 2004 to 2010, and 902 LDLT and 19,582 DDLT nondiabetic recipients were included. The overall incidence of NODAT was 12.2% at 1 year after liver transplantation. At 1, 3, and 5 years after transplant, the incidence of NODAT in LDLT recipients was 7.4, 2.1, and 2.6%, respectively, compared to 12.5, 3.4, and 1.9%, respectively, in DDLT recipients. LDLT recipients have a lower risk of NODAT compared to DDLT recipients (hazard ratio = 0.63 (0.52-0.75), P < 0.001). Predictors for NODAT in LDLT recipients were hepatitis C (HCV) and treated acute cellular rejection (ACR). Risk factors in DDLT recipients were recipient male gender, recipient age, body mass index, donor age, donor diabetes, HCV, and treated ACR. LDLT recipients have a lower incidence and fewer risk factors for NODAT compared to DDLT recipients. Early identification of risk factors will assist timely clinical interventions to prevent NODAT complications.

Introduction: Obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are both strongly associated with obesity. Whether OSA is an independent risk factor for liver injury is uncertain., Objective: To assess the hypothesis that OSA is associated with liver injury independent of obesity., Materials and Methods: We reviewed the histories of 73 consecutive patients referred to a hospital-based sleep lab because of suspected OSA. OSA was determined to be present if the apnea-hypopnea index was > 10. Obesity was defined as a BMI ≥ 30 kg/m 2 . Patients were included for analysis if they had aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels obtained within 60 days of sleep study. Patients with evidence of viral hepatitis, autoimmune-, metabolic- or established alcoholic-liver disease were excluded. Patients who reported alcohol intake equivalent to a dose ≥ 20 g/day were also excluded. 53 of 73 patients met study criteria. Patients were subdivided for analysis into groups meeting or not meeting OSA and obesity criteria, and having or not having elevated aminotransferase levels., Results: 35/53 patients (66%) had OSA. 31/53 (58%) patients were obese. 15 (28%) and 12 (23%) patients had elevated AST and ALT, respectively. Mean age, gender distribution, mean BMI and percentage with either diabetes or hyperlipidemia were not significantly different in those with or without OSA. Elevated ALT was found in 11/35 (31%) patients with OSA, compared to 1/18 patients without OSA (p = 0.041). Frequency of elevated AST [obese 11/31 (35%); non-obese 4/22 (18%)] or ALT [obese 10/31 (32%); non-obese 2/22 (9%)] was not significantly different in the obese and non-obese cohorts., Conclusions: OSA may be a risk factor for liver injury independent of obesity. The prevalence and nature of liver disease in the setting of OSA should be determined with larger, prospective studies. The impact of OSA treatment, if any, on liver injury should be similarly evaluated.

New-onset diabetes after transplantation (NODAT) is common after liver transplant and associated with poorer outcomes. The aim of this study was to identify risk factors for NODAT in liver transplant recipients off corticosteroids. In 225 adult nondiabetic liver transplant recipients, the mean age was 51.7 years, the majority were men (71%), and half had HCV (49%). The mean calculated MELD score at transplantation was 18.7, and 19% underwent living-donor transplant (LDLT). One year after transplantation, 17% developed NODAT, and an additional 16% had impaired fasting glucose. The incidence of NODAT in patients with HCV was 26%. In multivariate analysis, HCV, pretransplant FPG, and LDLT were significant. Each 10 mg/dL increase in pretransplant FPG was associated with a twofold increase in future development of NODAT. The incidence of NODAT after liver transplant in patients off corticosteroids is 17%. Risk factors for developing NODAT include HCV and pretransplant FPG; LDLT is protective.

A 44-year-old woman was found to have elevated aminotransferases, twice the upper limit of normal. Liver biopsy demonstrated a mixed inflammatory process suggestive of both primary biliary cirrhosis and autoimmune hepatitis (AIH). Prednisone and azathioprine were started, with normalization of aminotransferases. Six months later, she returned with worsening pruritus and re-evaluation demonstrated probable reactivation of AIH with acute elevation of liver injury tests. Repeat liver biopsy was suggestive of a flare of AIH which did not respond to prednisone, azathioprine, or mycophenolate mofetil. One month later the patient was hospitalized for sudden onset of anemia and thrombocytopenia, suggestive of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura consistent with Evans syndrome. Rituximab was initiated and mycophenolate mofetil discontinued. After one infusion of rituximab, liver injury tests significantly improved. Within four weeks of rituximab infusion (4 doses) the patient's Evans syndrome completely resolved with normal hemoglobin and platelet levels; aminotransferases also significantly improved to less than twice the upper limit of normal.

Background: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma or another plasma cell dyscrasia. Despite a high incidence in the general population and an increased relative risk for later malignancy, there are few reports about the clinical course of MGUS or risk profile in long-term immunosuppressed patients., Methods: We reviewed 1593 solid organ transplant patients and reported the frequency and outcomes of patients with MGUS identified pretransplant., Results: Polyclonal gammopathy pretransplant is common with 17% of all patients and as many as 75% of liver transplant candidates having increased globulins.However, a monoclonal immunoglobulin was identified in only 3% of all solid organ transplant patients pretransplant (n=34). Importantly, in these 34 patients, no cases of progression to multiple myeloma, amyloid, or lymphoma were observed during immune suppression, and there was no association between posttransplant lymphoproliferative disorders and pretransplant MGUS. Death in MGUS patients was not associated with progression of the monoclonal clone or development of posttransplant lymphoproliferative disorders or other malignancy., Conclusion: In conclusion, routine testing for MGUS before transplantation is not prognostic nor a contraindication to transplant, and therefore, it is not recommended.

The 6-minute walk distance (6MWD) is a simple test measuring global physical function. It is commonly used to predict mortality in patients with cardiac and pulmonary diseases, but it is also useful in assessing the functional status of patients with a variety of other medical conditions. We sought to determine (1) the characteristics of the 6MWD in patients listed for liver transplantation (LT), (2) the existence of a relationship between the 6MWD and the quality of life, and (3) the relationship between the 6MWD and survival in LT candidates. The 6MWD was prospectively measured in all patients listed for LT. The 6MWD was determined when the listed Model for End-Stage Liver Disease (MELD) score was ≥ 15. Patients were followed until LT, death, removal from the wait list, or the end of the study period. Quality of life was assessed with the Short Form 36 (SF-36). In 121 patients, the mean 6MWD was 369 ± 122 m; it was not related to age, height, weight, body mass index, albumin level, or etiology of liver disease and showed a moderate correlation with the physical component score (PCS) on the SF-36 (r = 0.4) and a moderate inverse correlation with the native MELD score (r = -0.61). In an unadjusted analysis, a high native MELD score, a low 6MWD, and a low PCS were associated with mortality, with only the 6MWD retaining significance after adjustment for covariates. Each 100-m increase in the 6MWD was significantly associated with increased survival (hazard ratio = 0.48, P = 0.0001), with 6MWD < 250 m being associated with an increased risk of death (P = 0.0001). In conclusion, the 6MWD is significantly reduced in patients awaiting LT and is inversely correlated with the native MELD score. A pretransplant 6MWD < 250 m is a risk for death on the wait list., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Gene therapy has reached the forefront of studies and research over the last 30 years because of its potential for curing, treating, and preventing diseases associated with DNA mutations. Type 1 and type 2 diabetes are two examples of very common polygenic and multifactorial diseases. The huge amount of scientific literature on this topic reflects a growing general interest in the possibilities of altering our genetic heritage and thus controlling the onset of diseases associated with mutations and relative risk factors. We have focussed on the new treatment opportunities and possibility of enhancing an individual's health, physical well-being, and even an individual's behaviour through technologies specially designed for therapeutic purposes, which have been presented in literature. This historical perspective shows how this type of research, however, was immediately subjected to an ethical evaluation, especially regarding the decoding of the human genome and the questions raised by the alteration of our genetic heritage through new biotechnologies. Moreover, understanding the limitations of gene therapy protocol experiments and the multifactorial nature of many diseases, which have a genetic base, also contributes to these considerations.

Background: There is no consensus on hepatitis C virus (HCV) treatment in patients with renal failure. Toxicity of pegylated interferon (PEG-IFN) and ribavirin limit options; hence the ideal approach for therapy in these patients deserves attention. We report the results of kidney transplantation (KTx) candidates infected with HCV treated with PEG-IFN monotherapy., Methods: KTx candidates with HCV infection treated with PEG-IFN monotherapy between January 2001 and February 2009 were included. Liver biopsies were performed before therapy. Response was assessed using accepted virological time points., Results: From 2636 patients listed for KTx, 60 patients were tested positive for anti-HCV. Twenty-two patients were eligible for treatment. All patients were HCV treatment naïve. One patient had biopsy-confirmed cirrhosis. Mean Ishak-Knodell fibrosis stage was 1.3. Ten patients (45%) achieved sustained viral response. In genotype 1 patients, there were no relapsers among early responders, despite the limited regimen. Nine patients (40%) in the cohort have had KTx. Of these, there were four responders and five nonresponders. None of the responders have had recurrence of their HCV after their KTx., Conclusions: End-stage renal disease patients with HCV can be treated successfully with PEG-IFN monotherapy. Our sustained viral response rate was 45% (10/22) in patients treated before KTx.

Toxicology studies were performed in rats and rhesus macaques to establish a safe starting dose for intratumoral injection of an oncolytic vesicular stomatitis virus expressing human interferon-beta (VSV-hIFNbeta) in patients with hepatocellular carcinoma (HCC). No adverse events were observed after administration of 7.59 x 10(9) TCID(50) (50% tissue culture infective dose) of VSV-hIFNbeta into the left lateral hepatic lobe of Harlan Sprague Dawley rats. Plasma alanine aminotransferase and alkaline phosphatase levels increased and platelet counts decreased in the virus-treated animals on days 1 and 2 but returned to pretreatment levels by day 4. VSV-hIFNbeta was also injected into normal livers or an intrahepatic McA-RH7777 HCC xenograft established in Buffalo rats. Buffalo rats were more sensitive to neurotoxic effects of VSV; the no observable adverse event level (NOAEL) of VSV-hIFNbeta in Buffalo rats was 10(7) TCID(50). Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared with VSV-hIFNbeta, toxicity of VSV-rIFNbeta (recombinant VSV expressing rat IFN-beta) was greatly diminished in Buffalo rats (NOAEL, >10(10) TCID(50)). Two groups of two adult male rhesus macaques received 10(9) or 10(10) TCID(50) of VSV-hIFNbeta injected directly into the left hepatic lobe under computed tomographic guidance. No neurological signs were observed at any time point. No abnormalities (hematology, clinical chemistry, body weights, behavior) were seen and all macaques developed neutralizing anti-VSV antibodies. Plasma interleukin-6, tumor necrosis factor-alpha, and hIFN-beta remained below detection levels by ELISA. On the basis of these studies, we will be proposing a cautious approach to dose escalation in a phase I clinical trial among patients with HCC.

Objectives. To determine the importance of acute cardiac events as a cause of mortality compared to non-cardiac events in the four month period following liver transplantation (LT) using current preoperative cardiac screening strategies. Patients and Methods. We retrospectively reviewed timing, type, and outcome of adverse cardiac events, and all cause mortality in the 4 month postoperative period in 393 consecutive LT patients from October 1999 to February 2008. Results. Of 30 total deaths (7.6% overall mortality rate), 27 (90%) were due to surgical or medical complications and 3 (10%) were primary cardiac deaths (0.8% cardiac mortality rate). Acute cardiac events occurred in 26 patients (6.6%), including 13 arrhythmias (50%), 7 new onset heart failures (27%), and 6 myocardial infarctions (23%). Twelve of 13 intraoperative events were arrhythmias (92%) including two of three cardiac deaths. Conclusions. Using current preoperative screening recommendations, deaths from primary cardiac events within four months of LT are very uncommon (0.8%), especially compared with deaths related to medical and surgical complications (6.9%).

Our aim was to assess long-term survival in patients transplanted for HCV-related end-stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV-related ESLD since the program's inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per-protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV-related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1-, 5-, and 7-year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI >or=6 and/or fibrosis >or=2) was present in 49%, "early recurrence" (within 1 year of LT) in 30.5% and biopsy-proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage >or=2 at 12-month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of "rapid fibrosers" may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV-positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV-positive recipients.

Unlabelled: A perfect or nearly perfect human leukocyte antigen (HLA) match has been associated with better immediate and long-term survival of diseased donor kidney transplants. However, the effect of HLA matching for hepatic allografts remains poorly defined. Using data from the National Institutes of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, we investigated the association between HLA mismatches and hepatic allograft survival, disease recurrence, and immunosuppression interactions. A, B, and DR loci were used to calculate total mismatch scores of 0 (no mismatches in any loci) to 6 (mismatches in all loci). Seven hundred ninety-nine adults (male, 55%; female, 45%) underwent 883 liver transplants. The 10-year graft survival according to total mismatch score was as follows: 0-2, 60%; 3-4, 54%; and 5-6, 57%. There was a negative effect of mismatching at the A locus on patient survival, with shorter survival for patients with 1 or 2 mismatches compared with 0 mismatches [P = 0.05, hazard ratio (HR) = 1.6]. Patients on tacrolimus with 1 or 2 mismatches at B or DR loci appeared to have increased rates of patient and graft survival compared to patients with 0 mismatches, with the appearance of a protective effect of tacrolimus (HR = 0.67). The effect of HLA mismatching was more pronounced on certain disease recurrences. DR-locus mismatch increased recurrence of autoimmune hepatitis (P = 0.01, HR = 4.2) and primary biliary cirrhosis (P = 0.04, HR = 2). Mismatch in the A locus was associated with more recurrence of hepatitis C virus (P = 0.01, HR = 1.6) and primary sclerosing cholangitis (P = 0.03, HR = 2.9)., Conclusion: Mismatching at the A locus decreases patient survival in liver transplant recipients, and mismatching at the DR and A loci affects recurrence of autoimmune liver diseases and hepatitis C, respectively.

The aim of this paper was to assess the persistence of hepatitis C virus (HCV) among patients successfully treated with peginterferon and ribavirin. The persistence of viral RNA was evaluated in the serum and peripheral blood mononuclear cells (PBMCs) of 25 chronic hepatitis C patients with sustained viral response to peginterferon and ribavirin treatment up to 56 months after the completion of therapy. Viral RNA was detected in the peripheral blood mononuclear cell cultures of five patients (20%), but none had detectable serum HCV RNA. At present, the clinical relevance of this finding is unclear. It is possible that viral persistence and, specifically, the presence of HCV RNA in PBMCs may lead to HCV reactivation under special circumstances, such as immunosuppression.

Objective To review all cases of drug-induced liver injury (DILI) requiring hospitalization at a single tertiary care center. Methods Patient records were identified by ICD-9 codes for inpatient visits from November 1998 through March 2006. Results Of a total 83,265 hospital admissions during the study period, 40 were for DILI (0.048%). Thirteen patients had non-acetaminophen DILI (NA-DILI); 27 had acetaminophen-related DILI (A-DILI). In the NA-DILI group, mean age was 59 +/- 17.9 years and liver injury was classified as hepatocellular (7), cholestatic (5), or mixed (1). A variety of medications were implicated with antimicrobials being the most common class. Resolution occurred in seven, two died of complications related to hepatotoxicity, one underwent liver transplantation, and the outcome was undetermined in three who were lost to follow-up. In the A-DILI group, mean age was 35 +/- 11.0 years. Eighteen involved intentional overdose of acetaminophen; nine were associated with chronic use. The pattern of injury was hepatocellular in all. Resolution occurred in 4 patients, death in 8, and improvement in 15. Conclusions DILI is a rare cause of inpatient admission but is associated with significant mortality. Spontaneous resolution occurs in most patients but return to normal liver function may take months. Antimicrobial agents account for the largest proportion of NA-DILI.

In the current Model for End-Stage Liver Disease system, patients with polycystic liver disease (PCLD) who have a poor quality of life secondary to their massive hepatomegaly are no longer competitive for a deceased donor liver transplant if their liver function is well preserved. Traditionally, a caval resection has been advocated in these patients because of the difficulty of the hepatectomy with hepatomegaly, which makes living donation impossible. This series looks at 3 patients who underwent a caval sparing hepatectomy and subsequent living donor liver transplantation (LDLT) for PCLD. Graft and patient survival was 100%, and there were few complications in either donors or recipients. LDLT is an ideal option for patients with PCLD and preserved liver function but poor quality of life.