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Static cold preservation remains the cornerstone for storing donor livers following procurement; however, the choice between University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK) remains controversial. Recent International Liver Transplantation Society (ILTS) guidelines have recommended avoiding HTK for donation after circulatory death (DCD) grafts based on older reports. We studied the latest US adult graft outcomes in three recent eras (2006-2010, 2011-2015, 2016-2020) comparing HTK and UW among 5956 DCD LTs: 3873 (65.0%) used UW and 1944 (32.7%) used HTK. In a total of 82,679 donation after brain death (DBD) liver transplantations (LTs), 63,511 (76.8%) used UW and 15,855 (19.2%) used HTK. The HTK group had higher 1-year and 5-year graft survival rates of 89.7% and 74.3%, respectively, compared with 85.9% and 70.8% in the UW group in the 2016-2020 era (p = 0.005). This difference remained when adjusted for important potential confounders (hazard ratio, 0.78; 95% confidence interval: 0.60, 0.99). There were no differences between groups among DCD LTs in the earlier eras or among DBD LTs in all eras (all p values > 0.05). The latest US data suggest that HTK is at least noninferior to UW for preserving DCD livers. These data support HTK use in DCD LT and contradict ILTS guidance., (© 2022 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Recent modifications in organ allocation policies and increases in chronic liver diseases may have resulted in important changes in living donor liver transplantation (LDLT) in the United States. We examined the trends, outcomes, and factors associated with outcomes in adult LDLT. United Network for Organ Sharing data on 2566 adult LDLT recipients who received transplants from January 1, 2010, through December 31, 2019, were analyzed. LDLT graft and patient survival rates were compared with propensity score-matched deceased donor liver transplantation recipients by the Kaplan-Meier curve estimator. The association between preceding LDLT frequency and subsequent outcomes were assessed by Cox proportional hazards mixed effects modeling. After a stable annual frequency of LDLTs from 2010 to 2014 (~200 per year), the number of LDLTs doubled to 440 in 2019. The 1-year and 5-year graft survival rates for LDLT recipients were 88.4% and 78.1%, respectively, compared with 92.5% and 80.7% in the propensity score-matched donation after brain death recipients (P = 0.005), respectively. Older donor age and recipient diabetes mellitus and life support requirement were significantly associated with graft failure among LDLT recipients (P values <0.05). Average preceding LDLT frequencies of <3 per year, 3 to 20 per year, and >20 per year resulted in 1-year graft survival rates of 82%, 88% to 89%, and 93%, respectively (P values <0.05). There were 3 living donor deaths (0.12%). The frequency of LDLTs has doubled during the past decade, with good outcomes and acceptable donor safety profiles. However, there appear to be varying threshold transplant frequencies (volume/unit time) associated with acceptable (88%-89%) and aspirational (93%) 1-year graft survival rates. These data should be reassuring and encourage LDLT practice as efforts continue to expand the donor pool., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

Currently, nonalcoholic steatohepatitis (NASH) is the second leading indication for liver transplantation (LT), behind alcohol-related liver disease. After transplant, both recurrent and de novo nonalcoholic fatty liver disease are common; however, recurrence rates of NASH and advanced fibrosis are low. Identification of high-risk groups and optimizing treatment of metabolic comorbidities both before and after LT is paramount to maintaining a healthy allograft, especially with the additional consequences of longterm immunosuppression. In addition, NASH LT recipients are at an increased risk of cardiovascular events and malignancy, and their condition warrants a tailored approach to management. The optimal approach to NASH LT recipients including metabolic comorbidities management, tailored immunosuppression, the role of bariatric surgery, and nutritional and pharmacotherapy of NASH are discussed in this review. Overall, aggressive management of metabolic syndrome after LT via medical and surgical modalities and a minimalist approach to immunosuppression is advised., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Highly effective direct-acting antiviral (DAA) therapy has transformed outcomes of liver transplantation in hepatitis C virus (HCV) patients. We examined longer-term outcomes in HCV-positive recipients in the DAA era and analyzed the Scientific Registry of Transplant Recipients for primary adult, single-organ, nonfulminant liver transplant recipients in the United States from January 1, 2008 to June 30, 2018. Graft loss was compared among HCV-positive liver transplant recipients who received either an HCV-negative or HCV-positive donor (donor [D]-/recipient [R]+; D+/R+) and HCV-negative liver transplant recipients who received a HCV-negative donor (D-/R-). The groups were further divided between the pre-DAA and DAA eras. There were 52,526 patients included: 31,193 were D-/R- patients; 18,746 were D-/R+ patients; and 2587 were D+/R+ patients. The number of D-/R+ transplants decreased from 2010 in 2008 to 1334 in 2017, with this decline particularly noticeable since 2015. D-/R+ patients in the DAA era (n = 7107) were older, had higher rates of hepatocellular carcinoma, and lower Model for End-Stage Liver Disease scores than those in the pre-DAA era. Graft survival improved for all recipients in the DAA era but improved most dramatically in HCV-positive recipients: D-/R+ 1-year survival was 92.4% versus 88.7% and 3-year survival was 83.7% versus 77.7% (DAA versus pre-DAA era, respectively) compared with D-/R- 1-year survival of 92.7% versus 91.0% and 3-year survival of 85.7% versus 84.0% (DAA versus pre-DAA era, respectively). The magnitude of improvement in 3-year graft survival was almost 4-fold greater for D-/R+ patients. The 3-year survival for D+/R+ patients was similar to HCV-negative patients. In conclusion, the number of liver transplants for HCV has decreased by more than one-third over the past decade. Graft survival among HCV-positive recipients has increased disproportionately in the DAA era with HCV-positive recipients now achieving similar outcomes to non-HCV recipients., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Growing evidence suggests that pretransplant alpha-fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-gamma-carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow-up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP-L3%, and DCP in a blinded fashion with the μTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9-6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4-5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3-12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4-4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0-24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8-18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility., (© 2015 American Association for the Study of Liver Diseases.)

Transarterial chemoembolization (TACE) is a common treatment for patients with hepatocellular carcinoma (HCC) who are awaiting liver transplantation (LT). The aim of this study was to assess the impact of multiple TACE treatments on tumor necrosis, tumor recurrence, and survival in these patients. A retrospective analysis was performed for 104 consecutive patients undergoing LT for HCC from January 2002 to December 2009 who were treated with TACE before LT. The number of TACE treatments was not associated with tumor necrosis in the explant. After a median follow-up of 69 months (range = 0-123 months), 14 of the 104 patients (13%) developed recurrent HCC after LT. Recurrence had a significant relationship with a short interval between the diagnosis of HCC and LT (≤6 months) in univariate and multivariate analyses [P = 0.029, odds ratio (OR) = 19.2]. Patients subjected to a single TACE treatment were more likely to experience recurrence, although this finding was not confirmed in the multivariate analysis. No significant relationship was observed between tumor necrosis in the explant and recurrence. The mean overall survival was 102.8 months (95% confidence interval = 94.9-110.8 months) with 1-, 3-, and 5-year survival rates of 91%, 89%, and 84% respectively. In the univariate survival analysis, the presence of ascites before TACE, a waiting time ≤ 9 months, and tumor characteristics at the pathological examination were statistically associated with shorter survival. In the multivariate analysis, only vascular invasion (P < 0.001, OR = 7.99) remained independently associated with shorter survival. The number of TACE treatments was not associated with survival. In conclusion, multiple TACE treatments were not associated with a higher risk of recurrence or shorter survival. Continued use of TACE should be considered as indicated if the patient and lesions are suitable for retreatment. A shorter waiting time before LT is related to an increased risk of recurrence and decreased survival after LT for HCC. These data could reflect the presence of more aggressive tumor biology and may be useful for guiding organ allocation policy to consider a minimum observation period before LT for regions with shorter wait times., (© 2014 American Association for the Study of Liver Diseases.)

In the nontransplant setting, aberrant serum adipokine levels are associated with cardiovascular (CV) disease. The effects of liver transplantation (LT) on serum adipokine levels and their association with post-LT CV disease have not been studied. A nested case-control study of 77 patients with major CV events more than 4 months after LT analyzed serum adiponectin, resistin, leptin, C-reactive protein, and apolipoprotein levels measured before transplantation and 4, 12, and 24 months after LT. Adiponectin and resistin levels decreased dramatically after LT in all patients. Recipients with CV disease had lower levels of adiponectin and higher levels of resistin, leptin, C-reactive protein, and apolipoprotein B100 than controls. The pre-LT adiponectin level was associated with a 16% increased risk for CV events for every 1 μg/mL decrease in adiponectin [hazard ratio (HR) = 0.84, P = 0.046]. Pre-LT C-reactive protein levels (HR = 1.03, P = 0.047) and 12-month C-reactive protein levels (HR = 1.03, P = 0.03) were associated with CV events after LT. Pre-LT Diabetes (HR = 2.14, P = 0.09), and post-LT resistin (HR = 1.07, P = 0.07), and apolipoprotein B (HR = 1.08, P = 0.08) were associated with a nonsignificantly increased risk of CV events in this small sample size. In conclusion, pre- and post-LT changes in serum adipokine and inflammatory markers may be signals of an increased risk of CV events after LT, but further study is needed., (© 2014 American Association for the Study of Liver Diseases.)

Chronic hepatitis C (CHC)-related cirrhosis is the leading indication for liver transplantation (LT). However, the recurrence of a hepatitis C virus (HCV) infection after transplantation is universal and is associated with worse outcomes. Fibrosing cholestatic hepatitis (FCH) is a particularly severe manifestation of a recurrent HCV infection and frequently results in graft failure and death. The identification of risk factors for FCH is important but has been limited by the low frequency of FCH. The interleukin-28B (IL-28B) genotype is important in an HCV infection: it is related to the clinical severity of an acute infection and may play a role in the development of FCH as well. Two hundred seventy-two consecutive LT cases for CHC were studied at a single institution. Consensus criteria were used to define an FCH cohort. The remainder of the study population served as a control group. The IL-28B genotype (at the rs12979860 locus) from both the donor and the recipient was determined, and other clinically relevant data were tabulated. A nonparametric statistical analysis was performed. Twelve cases of FCH were identified, and they were compared to a control group of 260 LT cases without FCH. A detailed analysis of clinical characteristics, including treatment responses and outcomes, was tabulated. FCH was associated with the earlier recurrence of HCV infections, higher HCV viral loads, and lower levels of immunosuppressive medications. There was a nonsignificant increase in recipient IL-28B non-CC genotypes in cases developing FCH. In conclusion, a high HCV viral load and earlier recurrence were identified as risk factors for FCH. It is still unclear what role immunosuppression plays in the pathogenesis of FCH and whether IL-28B polymorphisms constitute a risk factor. Collaborative studies with larger numbers of study subjects are needed in order to define these issues., (© 2013 American Association for the Study of Liver Diseases.)

For patients undergoing liver transplantation (LT) for hepatitis B virus (HBV)-related liver disease, the current standard of care for preventing reinfection of the allograft is nucleoside analogue therapy combined with hepatitis B immune globulin (HBIG). Entecavir has demonstrated high efficacy and a favorable safety profile for chronic hepatitis B (CHB) treatment, but data for patients undergoing HBV-related LT are limited. This study assessed the safety and efficacy of entecavir combined with various HBIG regimens after CHB-related LT. In this phase 3b, single-arm, open-label study, 65 patients undergoing LT for CHB-related liver disease with an HBV DNA load <172 IU/mL at LT received entecavir (1.0 mg daily) for 72 weeks after LT. The primary endpoint was the proportion of evaluable patients (treated for ≥4 weeks) with virological recurrence (HBV DNA level ≥50 IU/mL) through week 72. Concomitant HBIG therapy was received by 64 of the 65 enrolled patients, and 44% of these patients received high-dose HBIG (any HBIG dose in the specified interval ≥10,000 IU). Through week 72, all 61 patients evaluable for the efficacy analysis had undetectable HBV DNA. The Kaplan-Meier estimate of patients without hepatitis B surface antigen (HBsAg) recurrence at week 72 was 0.9655. Two patients experienced a reappearance of HBsAg, but both remained HBV DNA(-) until the last follow-up. The frequency and nature of adverse events were consistent with those expected for this patient population. Serum creatinine increments ≥0.3 mg/dL and ≥0.5 mg/dL occurred in 62% and 39% of the patients, respectively, and all of these patients received calcineurin inhibitor therapy. In conclusion, in this population of patients treated with entecavir after CHB-related LT, entecavir was well tolerated and effective in maintaining viral suppression, even in individuals who experienced a reappearance of HBsAg., (© 2013 American Association for the Study of Liver Diseases.)

The safety, efficacy, and effect on immunosuppression levels of telaprevir (TVR) or boceprevir (BOC) in combination with peginterferon (PEG-IFN) and ribavirin (RBV) in recipients of liver transplantation (LT) with hepatitis C virus (HCV) genotype 1 have not been defined. We report our 3 centers' preliminary experiences with administering triple antiviral treatment protocols containing PEG-IFN, RBV, and TVR or BOC. Patients with biopsy-proven HCV recurrence (METAVIR grade ≥ 3 and/or stage ≥ 2) received TVR with PEG-IFN/RBV for 12 weeks and then PEG-IFN/RBV for 36 weeks or BOC with PEG-IFN/RBV for 44 weeks after 4 weeks of lead-in PEG-IFN/RBV. Maintenance immunosuppression was changed to cyclosporine whenever possible, and the levels were followed closely. PEG-IFN/RBV dose adjustments were based on patients' tolerance. Sixty patients started triple antiviral treatment, and they were followed for up to 66 weeks (mean = 35 weeks); all were followed at least 12 weeks. Thirty of the 35 patients treated with TVR (86%) achieved undetectable HCV RNA levels after an average of 6 weeks, whereas 12 patients (48%) in the BOC-treated group achieved undetectable HCV RNA levels after a mean of 11 weeks. According to an intention-to-treat analysis, 14 of 21 TVR-treated patients (67%) and 10 of 22 patients who received BOC (45%) achieved undetectable HCV RNA levels at week 24 without viral breakthrough at the last follow-up. Cytopenias complicated both regimens; all patients required dose reductions of PEG-IFN and/or RBV or the administration of hematological growth factors. One death occurred in each group on triple antiviral treatment. In conclusion, TVR or BOC combined with PEG-IFN/RBV achieved on-treatment virological response rates of approximately 50% to 60% in patients with recurrent HCV after LT, but significant side effects were common., (Copyright © 2013 American Association for the Study of Liver Diseases.)

The discovery of interleukin-28B (IL-28B) single-nucleotide polymorphisms has opened an important new area of research in liver transplantation (LT) for hepatitis C virus (HCV). Both recipient- and donor-derived IL-28B genotypes affect the post-LT treatment response, with sustained virological response (SVR) rates oscillating from >50% in homozygotes for the favorable allele (up to 90% when this is present in both the recipient and the donor) to <15% in homozygotes for the unfavorable allele and from 30% to 50% in heterozygotes. Other key posttransplant outcomes affected by the IL-28B genotype are the time to histological recurrence, HCV RNA and alanine aminotransferase levels, histological variables (including the rate of fibrosis progression), and hepatocellular carcinoma. Interactions between donor and recipient IL-28B genotypes are complex and may affect outcomes not directly related to HCV infections, such as acute cellular rejection (ACR) and metabolic diseases. A preferential allocation system in which livers from donors homozygous for the favorable allele are given to HCV patients might be postulated to improve SVR rates and post-LT outcomes in recipients with HCV infections (a 25% increase in SVR and an 8% decrease in mortality at 5 years). Although negative effects from this are difficult to predict, they could include an accelerated progression of fibrosis in patients with failed HCV eradication and an increase in ACR in non-HCV patients. Our knowledge of the precise role of IL-28B genotypes in the course of post-LT HCV is evolving, but existing knowledge suggests the possibility of exploring strategies that use IL-28B genotyping to reduce the impact of post-LT adverse outcomes., (Copyright © 2012 American Association for the Study of Liver Diseases.)

By analyzing 26,414 patients [12,589 with hepatitis C virus (HCV)] in the Scientific Registry of Transplant Recipients Database, we sought to determine comparative risk factors (including primary immunosuppression) predictive of death and graft loss among patients with HCV and patients without HCV. Immunosuppression was examined at the baseline and as a time-dependent variable, and the results were stratified by the transplant center and were adjusted for variables well known to affect patient and graft survival. A multivariate analysis of patient mortality demonstrated that recipient age, donor age, hepatocellular carcinoma, diabetes, and creatinine were significantly associated with increased 3-year mortality for both groups. Tacrolimus-based immunosuppression was associated with superior survival in both groups. In contrast, the use of sirolimus was strongly associated with increased mortality in the HCV group, and cyclosporine was associated with increased mortality in the non-HCV group. Adjusting for known and unknown factors predictive of posttransplant outcomes, a propensity analysis confirmed the association of sirolimus use with an increased risk of death in HCV patients as well as the association of tacrolimus use with a decreased risk of death in all patients. In conclusion, this study suggests a novel association between sirolimus use and an increased risk of death and graft loss after liver transplantation in HCV patients that is not seen in patients without HCV. This study confirms the association of tacrolimus with superior outcomes. Sirolimus should be used sparingly in recipients with HCV infections., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Drug-induced liver injury (DILI) is increasingly being recognized as a common cause of acute hepatitis. The clinical impact of DILI after liver transplantation (LT) is not known. The aim of this study was to describe the frequency, clinical presentation, and outcomes of DILI in LT recipients. LT recipients with possible DILI were identified with electronic pathology records and clinical note database retrieval tools. Diagnostic criteria were applied to identify cases of DILI. Twenty-nine of 1689 LT recipients (1.7%) were identified with DILI. The mean age was 52 years, and 52% were women. The major indications for LT were primary sclerosing cholangitis (28%), cholangiocarcinoma (14%), and hepatocellular carcinoma (14%). The severity of DILI was mild or moderate in 92% of the cases. Nausea or diarrhea (31%), jaundice (24%), and pruritus (10%) were the most common symptoms at the time of diagnosis. The mean biochemistry values were as follows: alanine aminotransferase, 204 ± 263 U/L; aspartate aminotransferase, 108 ± 237 U/L; alkaline phosphatase, 469 ± 689 U/L; and total bilirubin, 1.9 ± 10.3 mg/dL. The median duration of medication use until the diagnosis of DILI was 57 days, and the major agent classes were antibiotics (48%), immunosuppressive agents (14%), and antihyperlipidemic drugs (7%). Trimethoprim-sulfamethoxazole was the most common implicated agent (n = 11). Serum liver enzymes improved within a median time of 34 days (range = 5-246 days) after drug withdrawal. Hepatic retransplantation or death did not occur. Among the 50 cases with possible DILI explained by other causes, 13 individuals (26%) had no alternative diagnosis despite histological findings compatible with DILI. In conclusion, DILI is a rare yet underrecognized event among LT recipients. The majority of cases are not clinically severe, and they resolve after drug cessation without hepatic retransplantation or death., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Ultrasound-based transient elastography (TE) is a promising noninvasive alternative to liver biopsy for the detection of hepatic fibrosis due to recurrent hepatitis C virus (HCV) after liver transplantation (LT). However, its overall test performance in various settings remains unknown. The aim of this study was to perform a systematic review and diagnostic accuracy meta-analysis of studies comparing ultrasound-based TE to liver biopsy for the detection of hepatic fibrosis due to a recurrent HCV infection after LT. Electronic and manual bibliographic searches (including scientific abstracts) were performed to identify potential studies. A meta-analysis was conducted to generate pooled estimates of the sensitivity values, specificity values, likelihood ratios, and diagnostic odds ratios of individual studies. The extent of the heterogeneity and the reasons for it were assessed. Six fully published studies were identified for analysis. Five studies that evaluated significant fibrosis were identified. Among these studies, the pooled estimates were 83% for sensitivity [95% confidence interval (CI) = 77%-88%], 83% for specificity (95% CI = 77%-88%), 4.95 for the positive likelihood ratio (95% CI = 3.4-7.2), 0.17 for the negative likelihood ratio (95% CI = 0.09-0.35), and 30.5 for the diagnostic odds ratio (95% CI = 12.8-72.4). For the 5 studies that assessed cirrhosis, the pooled estimates were 98% for sensitivity (95% CI = 90%-100%), 84% for specificity (95% CI = 80%-88%), 7 for the positive likelihood ratio (95% CI = 2.8-17.3), 0.06 for the negative likelihood ratio (95% CI = 0.02-0.19), and 130 for the diagnostic odds ratio (95% CI = 36.5-462.1). A diagnostic threshold (or cutoff value) bias was identified as an important cause of heterogeneity for the pooled results of both patient groups. In conclusion, ultrasound-based TE has excellent diagnostic accuracy for identifying cirrhosis due to a recurrent HCV infection after LT. The detection of significant fibrosis is more accurate for these patients versus patients whose native liver is chronically infected with HCV., (Copyright © 2012 American Association for the Study of Liver Diseases.)

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS., (Copyright © 2011 American Association for the Study of Liver Diseases.)

The diagnosis of acute cellular rejection (ACR) requires liver biopsy with its attendant expense and risk. Our first aim was to prospectively determine in an exploratory analysis whether there is a serum proteome signature associated with histologically confirmed ACR. Our second aim was to use simpler and faster enzyme-linked immunosorbent assay (ELISA)-based assays for proteins identified as differentially abundant in the proteomic analysis to identify patients with ACR in a separate validation cohort. We used sequential high-abundance protein depletion and isobaric tag for relative and absolute quantitation liquid chromatography-tandem mass spectrometry to characterize the serum proteome in serum samples of patients with or without ACR. Seven of the 41 proteins identified as differentially abundant [serum amyloid A, complement component 4 (C4), fibrinogen, complement component 1q (C1q), complement component 3, heat shock protein 60 (HSP60), and HSP70] could be measured with ELISA-based assays in a validation cohort consisting of patients with ACR (n = 25) and patients without ACR (n = 21). The mean alanine aminotransferase (ALT) levels in patients with ACR and in patients without ACR were 198 ± 27 and 153 ± 34 U/L, respectively. Among the 7 proteins for which ELISA assays were available, C4 and C1q were both independent predictors of ACR. C4 had the greatest predictivity for differentiating patients with or without ACR. A C4 level ≤ 0.31 g/L had a sensitivity of 97%, a specificity of 62%, a positive predictive value of 74%, and a negative predictive value of 94%. A C4 level ≤ 0.31 g/L and an ALT level ≥ 70 IU/mL together had a sensitivity of 96%, a specificity of 81%, a positive predictive value of 86%, and a negative predictive value of 94%. In summary, in this exploratory analysis, serum C4 and ALT levels were highly predictive of ACR in liver transplant recipients. Confirmation in a prospective, larger, and diverse population is needed., (Copyright © 2011 American Association for the Study of Liver Diseases.)

The efficacy, tolerability, and safety of the prophylactic treatment of hepatitis C virus (HCV) after liver transplantation (LT) with peginterferon alfa-2a and ribavirin are not known. LT recipients with HCV were randomized to peginterferon alfa-2a/ribavirin treatment or observation 10 to 26 weeks post-LT. Prophylaxis patients received peginterferon alfa-2a (135 μg/week for 4 weeks and then 180 μg/week for 44 weeks) plus ribavirin (the initial dose of 400 mg/day was escalated to 1200 mg/day). Observation patients received the same regimen only upon significant HCV recurrence (histological activity index ≥ 3 and/or fibrosis score ≥ 2). The primary endpoint was the proportion of patients with histological evidence of significant HCV recurrence 120 weeks after randomization. In all, 115 patients were randomized (prophylaxis arm, n = 55; observation arm, n = 60). Sustained virological response was achieved by 12 of 54 prophylaxis patients (22.2%) and by 3 of 14 observation patients who switched to treatment (21.4%). On an intent-to-treat basis, significant HCV recurrence at 120 weeks was similar in the prophylaxis (61.8%) and observation arms (65.0%, P = 0.725). The patient and graft survival rates and the rates of biopsy-proven acute cellular rejection were similar in the 2 study arms. Approximately 70% of the treated patients in both arms had at least one dose reduction for safety reasons. The most common adverse event leading to treatment withdrawal was anemia. Because of the safety profile of peginterferon alfa-2a/ribavirin and the lack of a clear benefit in terms of HCV recurrence and patient or graft survival, this study does not support the routine use of prophylactic antiviral therapy., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Cardiovascular complications are major causes of morbidity and mortality after liver transplantation. Identifying candidates at highest risk of postoperative complications is a cornerstone of optimizing outcomes and utility. Using traditional cardiac risk factors in addition to C-reactive protein (CRP) levels, troponin levels, and echocardiographic parameters before transplantation, we sought to define cardiac risk so that we could predict cardiovascular events after transplantation. From December 1998 to December 2001, 230 adult patients who underwent liver transplantation with a median follow-up of 8.2 years were studied. The risk factors for cardiac disease were as follows: male gender with a mean age of approximately 50 years (57%), smoking history (60%), diabetes (23%), hypertension (19%), elevated troponin (25%), elevated CRP (25%), and preexisting cardiac disease (16%). Fifty-nine cardiac events occurred over 8.2 years. Risk factors (univariate analysis) for first cardiac events included age in decades [hazard ratio (HR) = 1.31, P = 0.047], diabetes (HR = 2.20, P = 0.004), prior cardiovascular disease (HR = 4.77, P < 0.0001), a troponin I level > 0.07 ng/mL (HR = 2.00, P = 0.023), left ventricular hypertrophy (HR = 2.06, P = 0.047), stress wall abnormalities (HR = 2.25, P = 0.018), and ischemia on stress imaging (HR = 2.89, P = 0.015). Multivariate analysis confirmed age, diabetes, a troponin I level > 0.07, and prior cardiac disease as independent risk factors for posttransplant cardiac events. In conclusion, pretransplant elevated troponin levels, diabetes, and a history of cardiovascular disease, alone or in combination, are strongly associated with the occurrence of posttransplant cardiovascular events., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Optimizing the utility of liver transplantation requires the identification of factors that confer increased risk of posttransplant mortality. Elevated serum troponin (TN) levels are strongly predictive of posttransplant mortality after kidney transplantation. We sought to determine whether pretransplant TN levels were predictive of mortality and graft loss after liver transplantation in 236 liver transplant recipients from 1998 to 2001 with 8.2 years of follow-up. Elevated TN levels [hazard ratio (HR) = 2.19, P = 0.004] and a pretransplant history of cardiovascular disease (CVD; HR = 1.90, P = 0.031) were predictive of patient mortality. Elevated TN levels (HR = 2.44, P < 0.001), a history of CVD (HR = 1.83, P = 0.031), and a combination of elevated TN levels and CVD (HR = 2.75, P = 0.027) were associated with increased graft loss. Multivariate analysis confirmed TN and CVD as independent predictors of mortality and graft loss. CVD (HR = 2.39, P = 0.032) and a combination of elevated TN levels and a history of CVD (HR = 6.67, P < 0.001) were predictive of graft loss within 1 year. Age, smoking, diabetes, hypertension, obesity, creatinine levels, and Model for End-Stage Liver Disease scores were not predictive of posttransplant mortality or graft loss. In summary, elevated pretransplant serum TN levels are strongly predictive of mortality and graft loss after liver transplantation and may be helpful in risk stratification of potential liver transplant recipients., ((c) 2010 AASLD.)

1. Obesity is increasingly common among liver transplantation (LT) recipients and donors. Outcomes following LT for selected patients with class I-III obesity are similar to those for nonobese recipients. In patients who are otherwise satisfactory candidates for LT, a high body mass index, as long as it does not present a technical barrier, should not be considered to be an absolute contraindication to LT. 2. The most common causes of death beyond the first year of LT are, in descending order of frequency, graft failure (especially secondary to hepatitis C virus recurrence), malignancy, cardiovascular disease, infections, and renal failure. Metabolic syndrome is an important risk factor for each of these etiologies of posttransplant death. Posttransplant diabetes, posttransplant hypertension, and an original diagnosis of cryptogenic cirrhosis, which is commonly associated with metabolic syndrome, are all associated with an increased risk of post-LT mortality. Features of metabolic syndrome should be screened for and treated in LT recipients. 3. Because of the physiological mechanism of post-LT hypertension, which includes renal arteriolar constriction secondary to calcineurin inhibition, calcium channel blocking agents are a good pharmacological treatment modality and have been shown to be effective in renal protection in randomized controlled trials of posttransplant hypertension. 4. It is rare for dietary changes and weight reduction to result in normalization of the lipid profile. Statins should thus be initiated early in the course of management of post-LT dyslipidemia. Forty milligrams of simvastatin per day, 40 mg of atorvastatin per day, and 20 mg of pravastatin per day are reasonable starting doses for post-LT hypercholesterolemia. It is important to remember that the effects of statin therapy are additive to those of a controlled diet (eg, a Mediterranean diet rich in omega-3 fatty acids, fruits, vegetables, and dietary fiber). 5. Nonalcoholic steatohepatitis, an increasingly common etiology of cirrhosis and liver failure, recurs commonly after LT and may also arise de novo. Treatment should be directed at managing obesity and complications of metabolic syndrome. Optimal immunosuppression in patients with nonalcoholic steatohepatitis is still evolving but should include steroid minimization., ((c) 2009 AASLD.)

It is widely perceived that outcomes are relatively poor following retransplantation (reTX) for recurrent of hepatitis C virus (HCV) infection. Transplant centers debate the utility of offering another liver to these patients. A U.S. study group was formed to retrospectively compare survival after reTX in patients with recurrent HCV (histologically proven) and those transplanted for other indications greater than 90 days after first transplantation, from 1996 to 2004. Patients were divided into 3 groups; group 1: HCV reTX (n = 43), group 2: non-HCV reTX (n = 73), and group 3: recurrent HCV but no reTX (n = 156). They were predominantly male, Caucasian, with mean age of 47.2 yr. The commonest indications for non-HCV reTX were chronic rejection (36%), hepatic artery thrombosis (31%) and recurrent primary sclerosing cholangitis (17%). Duration of hospitalization, number of intensive care unit (ICU) days, and time interval from listing to transplantation or reTX were similar between reTX groups. The 1-yr and 3-yr survival rates after reTX were also similar for HCV reTX and non-HCV reTX groups (1 yr, 69% vs. 73%; 3 yr, 49% vs. 55%). Model for End-Stage Liver Disease (MELD) scores were not predictive of survival from reTX. However, with a MELD score of >30 in the non HCV group, survival was <50%. In the recurrent HCV not undergoing reTX group, 30% were reevaluated for reTX but only 15% were listed for reTX and the 3-yr survival was 47%. The most common reasons for not listing for reTX were recurrent HCV within 6 months (22%), fibrosing cholestatic hepatitis (19%), and renal dysfunction (9%). In conclusion, patients retransplanted for recurrent HCV had similar 1-yr and 3-yr survival when compared to patients undergoing reTX for other indications. MELD scores were not predictive of post-reTX survival. Survival was <50% in the non-HCV reTx group with MELD score of >30. Many patients with recurrent HCV are not considered for reTX and die from recurrent disease., (Copyright 2007 AASLD.)

A randomized, double-blind, dose-escalation study evaluated the safety and efficacy of hepatitis C virus (HCV)-Ab(XTL)68, a neutralizing, high-affinity, fully human, anti-E2 monoclonal antibody, in 24 HCV-positive patients undergoing liver transplantation. HCV-Ab(XTL)68 or placebo was administered at doses from 20-240 mg as 2-4 infusions during the first 24 hours after transplantation, followed by daily infusions for 6 days, weekly infusions for 3 weeks, and either 2 or 4 weekly infusions for 8 weeks. Serum concentrations of total anti-E2 obtained during daily infusions of 120-240 mg HCV-Ab(XTL)68 were 50-200 microg/mL above concentrations in the placebo group. Median serum concentration of HCV RNA dropped below baseline in all groups immediately after transplantation. On day 2, median change from baseline in HCV RNA was -1.8 and -2.4 log in the 120-mg and 240-mg groups, respectively, compared with -1.5 log with placebo. The difference was lost after day 7 when the dosing frequency was reduced. The coincidence of increases in anti-E2 with decreases in HCV RNA concentration indicate that the dose-related changes in HCV RNA concentration were a result of HCV-Ab(XTL)68 administration in the 120- and 240-mg groups. The overall incidence of nonfatal serious adverse events was higher with placebo (60%) vs. all active treatments combined (42%). In conclusion, HCV-Ab(XTL)68 may decrease serum concentrations of HCV RNA in patients after liver transplantation. Studies evaluating more frequent daily dosing at doses >120 mg are necessary to investigate sustained viral suppression in this population.

1. Hepatitis C-associated liver failure is the most common indication for liver transplantation, and approximately 10% of HCV-infected recipients will die or lose their allograft secondary to recurrent HCV infection. 2. Risk factors associated with histological recurrence of HCV include donor (age, fat content, ischemic time, and living donor), recipient (age and non-Caucasian race), clinical (rejection and CMV), and viral (viral load and quasispecies). 3. Treatment of recipients with histological recurrence is with pegylated IFN (+/- ribavirin). The role of hepatitis C immunoglobulin in the management of postransplant HCV is still evolving. (

Only a subset of hepatitis C virus (HCV)-infected patients develop progressive hepatic fibrosis after liver transplantation (LT). Hepatic stellate cell (HSC) activation is a pivotal step in hepatic fibrosis and precedes clinically apparent fibrosis. We determined whether early HSC activation, measured in 4-month protocol post-LT biopsies, is predictive of subsequent development of more histologically severe recurrence of HCV. Early (4 month) post-LT HSC activation, as measured by alpha-smooth muscle actin (alpha-SMA) staining, was determined in liver biopsies from recipients with severe (fibrosis score > or = 2, n = 13) and with mild (fibrosis score of 0, n = 13) recurrence of HCV at one-year post-LT. Immunohistochemical staining for alpha-smooth muscle actin (alpha-SMA) was used to generate HSC activation scores (regional and total). Total HSC activation scores at 4 months were similar in patients with severe and mild HCV recurrence (3.9 +/- 2.0 vs. 2.7 +/- 2.2, P = 0.2). Regional HSC activation, assessed as parenchymal (zones 1, 2, and 3) or mesenchymal (portal tracts and fibrous septa), was different between the study groups, with higher mesenchymal scores predictive of progression. No patients in the mild recurrence group had detectable mesenchymal alpha-SMA staining vs. 46% (6/13) of patients with severe recurrence (P < 0.01). Mesenchymal activation of HSC had a specificity and positive predictive value of 100% for development of progressive fibrosis in liver allografts of patients with hepatitis C. In conclusion, early activation of mesenchymal HSCs is a marker for progressive fibrosis in patients with hepatitis C post-LT and may help select patients who would benefit from HCV or HSC-targeted therapy.

Hepatitis C virus (HCV)-associated liver disease is the most common indication for liver transplantation (LT). There are, however, no long-term (>5 year) studies of comparative outcomes for recipients with HCV infection, and no models capable of identifying recipients with HCV infection at greatest risk for adverse outcomes. We prospectively determined: 1) long-term outcomes, and 2) whether pretransplant patient or donor variables can be used to predict death and/or graft loss in recipients with HCV infection. A total of 165 HCV-infected recipients were eligible for this study. Pretransplant donor and recipient characteristics and patient and graft survival data were prospectively collected. Model building for outcomes was carried out using logistic regression. Receiver operating characteristic curves for different models were created and compared. Median follow-up was 8.5 years. Adjusted 10 year graft survival was 64% for recipients with HCV infection and 51% for uninfected recipients. A model incorporating pretransplant HCV ribonucleic acid (RNA), cytomegalovirus immunoglobulin (CMV IgG) serostatus, creatinine, bilirubin, prothrombin time international ratio (INR), recipient age, and donor age was developed to identify recipients at greatest risk of short-term mortality or graft loss (area under receiver operating characteristic curve = .83) In conclusion, long-term outcomes following LT for recipients with HCV infection are comparable to those for recipients undergoing LT for other indications. HCV-infected recipients at greatest risk for short-term mortality and graft loss can be identified using several readily identifiable pretransplant variables. Long-term death and graft loss specifically secondary to recurrence of HCV appears, however, to be determined primarily by factors other than those included in this analysis.

1. Nearly all recipients who are chronically infected with hepatitis C virus (HCV) at the time of liver transplantation will have HCV RNA detectable postoperatively. 2. HCV replication can begin as early as the first postoperative week. 3. HCV levels fall significantly during the anhepatic phase of liver transplantation and continue to fall during the first 12-24 hours posttransplantation. 4. Serum HCV RNA levels typically increase rapidly from the second week posttransplantation and peak by the fourth postoperative month. HCV RNA levels at one year posttransplantation are 10-20 fold greater than pretransplant levels. 5. Corticosteroid treatment for acute cellular rejection is associated with large increases in HCV RNA levels. 6. HCV RNA levels do not appear to vary with choice of calcineurin inhibitor. 7. Early HCV RNA levels are predictive of subsequent histological severity of recurrence. 8. A correlation between early levels of viremia and subsequent allograft injury suggests that initiation of antiviral therapy early in the posttransplant course might be desirable.

Treatment of acute cellular rejection (ACR) is associated with increased viral load, more severe histologic recurrence, and diminished patient and graft survival after liver transplantation for hepatitis C virus (HCV). Recurrence of HCV may be difficult to distinguish histologically from ACR. Because the immunologic mechanisms of ACR and HCV recurrence are likely to differ, we hypothesized that ACR is associated with the expression of a specific subset of immune activation genes that may serve as a diagnostic indicator of ACR and provide mechanistic insight into the pathophysiology of ACR and recurrence of HCV. The goal of the study was to study intragraft gene expression patterns in ACR and during recurrence of HCV in HCV-infected recipients. High-density microarrays were used to determine relative intragraft gene expression in two groups of HCV-infected liver transplant recipients: four with steroid responsive ACR by Banff criteria and four age- and gender-matched HCV-infected recipients with similar necroinflammatory activity but without histological criteria for rejection (no cholangitis or endotheliitis). Immunosuppression was similar in both groups. Other etiologies of graft dysfunction were excluded by ultrasound, cholangiography, and cultures. High-quality total RNA was extracted from snap frozen liver biopsies, reverse transcribed, labeled with biotin, and fragmented according to established protocol. Twenty-five genes were relatively overexpressed, and 15 were relatively underexpressed by > or = twofold in the ACR when compared with the HCV group. ACR was most notably associated with the relative overexpression of genes associated with major histocompatibility complex I and II, insulin-like growth factor-1 expression, apoptosis induction, and T-cell activation. In HCV-infected liver transplant recipients, ACR is associated with an intragraft gene expression profile that is distinct from that seen during recurrence of HCV. These experiments provide evidence that alloimmunity, as indicated by expression of T-cell activation and apoptosis-inducing genes, is less important in recurrence of HCV than in ACR. Further studies are required to determine whether gene expression profiles, either intragraft or in serum, can be used for the diagnosis and differentiation of ACR from recurrence of HCV.

Recurrence of hepatitis C virus (HCV) infection after orthotopic liver transplantation is a major cause of graft failure. The aim of our study was to determine the safety, efficacy, and tolerability of combination therapy with interferon and ribavirin in the treatment of recurrent hepatitis after liver transplantation. Twenty-six patients (18 men) with histologically established HCV recurrence after liver transplantation for cirrhosis secondary to chronic HCV infection were treated with a combination of interferon alfa-2b (3 million units three times weekly) and ribavirin (800 to 1,000 mg/d). Dosage modifications were according to a standard protocol incorporating laboratory values and clinical side effects. Fifty percent of patients completed 1 year or more of therapy. On an intention-to-treat basis, nine patients (35%) showed an end-of-treatment virological response. Six of these nine patients completed greater than 6 additional months of follow-up, and all have had sustained virological responses. A histological response (decrease in histological activity index > or = 2) was seen in 75% of virological responders and 67% of nonresponders. Adverse events requiring dose modification or cessation of therapy occurred in 66% of patients. Adjuvant therapies used to support hemoglobin levels included erythropoietin and red blood cell transfusions. There were no independent pretreatment predictors of a virological response, perhaps because of the small sample size. Combination therapy with interferon and ribavirin may be beneficial in patients with recurrent HCV after liver transplantation. The majority of patients require dose modifications because of side effects. Histological response is common in virological nonresponders.

Recurrence of hepatitis C virus (HCV) infection after liver transplantation (LT) is almost universal. However, variables that hasten the progression of allograft injury have not been fully defined. Cytomegalovirus (CMV) is a common infection post-LT, and its impact on the course of post-LT HCV infection remains unclear. We investigated the impact of CMV infection on patient and graft outcomes in 93 consecutive HCV-infected liver transplant recipients. Data were collected prospectively, with surveillance cultures for CMV and protocol liver biopsies. CMV infection (defined as isolation of CMV from blood and treatment with ganciclovir) occurred in 25 patients (26.9%). Graft failure (defined as cirrhosis, relisting for LT, re-LT, or death) was significantly more common in CMV-positive compared with CMV-negative patients (52% v 19.1%; P =.002). Fibrosis stage 2 or greater on the 4-month liver biopsy specimen was more common in CMV-infected patients (45% v 16.4%; P =.01). Patients who underwent LT in more recent years had an increased risk for graft failure. Donor and recipient age, CMV infection, and mycophenolate mofetil use were significantly associated with graft failure in a stepwise multivariate analysis. CMV infection occurs in approximately one quarter of HCV-infected liver transplant recipients and is an independent risk factor for graft failure in these patients. Whether CMV mediates this by inducing increased immunosuppression or directly enhancing HCV replication requires further study.

Decompensated liver disease associated with chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation. It was shown previously that greater pretransplantation HCV titers are associated with relatively poor patient and graft survival. The tolerability and efficacy of antiviral therapy in patients with decompensated liver disease are not known. We conducted a pilot study to determine the likely tolerability and efficacy of pretransplantation antiviral therapy with interferon alfa-2b, with or without ribavirin. HCV RNA-positive patients at or near the top of their respective waiting lists were randomly assigned to one of three treatment regimens until the time of liver transplantation: (1) group A, interferon alfa-2b, 1 x 10(6) U/d; (2) group B, interferon alfa-2b, 3 x 10(6) U three times weekly; or (3) group C, interferon alfa-2b, 1 x 10(6) U/d, plus ribavirin, 400 mg twice daily. Less than half the patients screened met entry criteria, with thrombocytopenia and leukopenia the most common reasons for exclusion. Fifteen patients were administered antiviral therapy; three patients in group A and six patients each in groups B and C. Loss of detectable HCV RNA was seen in 33% of patients, whereas 55% had a decrease in viral titers on therapy. Twenty-three adverse events occurred, including 20 serious adverse events. Thrombocytopenia was the most common adverse event. Two infectious complications occurred; one of these had a fatal outcome. We conclude that although pretransplantation antiviral therapy may reduce HCV titers in a minority of patients who meet treatment initiation criteria, adverse events associated with therapy are frequent and often severe in patients with Child's class B and C cirrhosis.