Not All Cellular Rejections Are the Same: Differences in Early and Late Hepatic Allograft Rejection.

T cell-mediated rejection (TCMR) is common after liver transplantation (LT), and it is often thought to have a minimum impact on outcomes. Because alloimmune response changes over time, we investigated the role of the timing of TCMR on patient and allograft survival and examined the risk factors for early and late TCMR. We reviewed protocol liver biopsies for 787 consecutive LT recipients with an 8.6-year follow-up. The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic steatohepatitis patients having the lowest incidence. Younger recipient age (P < 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use of deceased donor allografts (P = 0.01) were associated with increased risk of early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI, 0.79-1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78-1.34; P = 0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was associated with different risk factors. The majority of late TCMR (56.2%) episodes had no antecedent early TCMR, although moderate-to-severe early TCMR (HR, 2.85; 95% CI, 1.55-5.23; P < 0.01) and steroid resistance (HR, 3.62; 95% CI, 1.87-6.99; P < 0.01) were associated with late TCMR. Late TCMR increased risk of mortality (HR, 1.89; 95% CI, 1.35-2.65; P = 0.001) and graft loss (HR, 1.71; 95% CI, 1.23-2.37; P = 0.001). Thus, these data suggest that the timing and histologic grade of TCMR determine its impact on patient and allograft survival. Early mild TCMR episodes after LT do not adversely impact patient or allograft survival provided that they are adequately treated. The occurrence of late TCMR carries deleterious effects with increased longterm risk of graft loss and decreased survival. Patients with moderate-to-severe early TCMR are at an increased risk for late TCMR and warrant closer clinical follow-up.

Hepatocellular Carcinoma Is the Most Common Indication for Liver Transplantation and Placement on the Waitlist in the United States.

BACKGROUND & AIMS: Management strategies for patients with hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) have changed, along with liver allocation policies based on model for end-stage liver disease score. We investigated etiologic-specific trends in liver transplantation in the United States during different time periods. METHODS: We performed a retrospective study, using the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry data, to identify all adult patients registered for liver transplantation in the United States from January 1, 2004, through December 31, 2015. For subjects listed with multiple diagnoses, HCC was considered the primary listing diagnosis. To determine whether availability of direct-acting antiviral agents, which began in 2011, affected pretransplant (death or drop-out) and post-transplant outcomes for patients with HCV infection, we compared data from the time periods of 2004 to 2010 and 2011 to 2014. We used competing-risk analysis to compare differences in end points between these periods. Differences between periods in pretransplantation and post-transplantation outcomes were estimated using Kaplan-Maier analysis and compared using the log-rank test. Associations between year of listing and pre-liver transplant outcome, and year of liver transplant and survival after transplant, were examined using the log-rank test. Proportional hazard regression was used to evaluate the reliability of the time period effect with potential confounders. RESULTS: Among 109,018 registrants, 18.5% were registered for liver transplantation because of HCC. In 2015, HCC was the leading diagnosis among registrants (23.9% of registrations) and recipients (27.2% of recipients). Between 2004 and 2015, the ratio of registrants with vs without HCC increased 5.6-fold for patients with HCV infection, 1.9-fold for patients with hepatitis B virus (HBV) infection, 2.7-fold for patients with alcohol abuse, and 10.2-fold for patients with nonalcoholic steatohepatitis. After adjusting for covariates, we associated the period of 2011 to 2014 with a decreased probability that HCC registrants would undergo liver transplantation (hazard ratio [HR], 0.62; P < .0001). The period of 2011 to 2014 also was associated with a decreased probability of drop-out owing to deterioration or death from HCV-induced (HR, 0.90; P = .0003), HBV-induced (HR, 0.71; P = .002), or alcohol-induced (HR, 0.90; P = .01) liver disease, and an increased probability of delisting as a result of clinical improvement in patients with HCV infection (HR, 3.4; P < .0001), HBV infection (HR, 2.3; P = .004), or alcohol abuse (HR, 2.2; P < .0001). The period of 2011 to 2014 was associated with a decreased risk of graft loss or death, with the largest effect seen in HCV-infected recipients (HR, 0.76; P < .0001). CONCLUSIONS: HCC was the leading indication for liver transplantation in the United States in 2015. Despite this, the probability of liver transplantation decreased the most in registrants with HCC. Pretransplantation and post-transplantation outcomes have improved, particularly in patients with HCV infection.

Primary biliary cirrhosis has high wait-list mortality among patients listed for liver transplantation.

Patients with primary sclerosing cholangitis (PSC) have frequent episodes of cholangitis with potential for high mortality while waiting for liver transplantation. However, data on wait-list mortality specific to liver disease etiology are limited. Using United Network for Organ Sharing (UNOS) database (2002-2013), of 81 592 listed patients, 11 284 (13.8%) died while waiting for transplant. Primary biliary cirrhosis (PBC) patients (N = 3491) compared to PSC (N = 4905) differed with age (56 vs. 47 years), female gender (88% vs. 33%), black race (6% vs. 13%), and BMI (25 vs. 27), P < 0.0001 for all. A total of 993 (11.8%) patients died while waiting for the transplant list. Using competing risk analysis controlling for baseline recipient factors and accounting for receipt of liver transplantation (LT), PBC compared to patients with PSC had higher overall and 3-month wait-list mortality (21.6% vs. 12.7% and 5.0% vs. 2.9%, respectively, Gray's test P < 0.001), [1.25 (1.07-1.47)]. Repeat analysis including all etiologies showed higher wait-list mortality for PBC compared to most etiologies, except for patients listed for diagnosis of alcoholic liver disease (ALD) + hepatitis C virus (HCV). Patients with PBC have high mortality while waiting for liver transplantation. These novel findings suggest that patients with PBC listed for LT may be considered for model for end-stage disease (MELD) exception points.

Embolization of portosystemic shunts for treatment of medically refractory hepatic encephalopathy.

Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003-2015). Patient data collected included the type of HE, medications, Model for End-Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1-4 months), and longer-term (6-12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty-five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1-4 and 6-12 months, respectively. The majority (67%; 8/12) were free from HE-related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. Liver Transplantation 22 723-731 2016 AASLD.

Impact of fibrosis progression on clinical outcome in patients treated for post-transplant hepatitis C recurrence.

BACKGROUND & AIMS: Patients who achieve sustained virological response (SVR) following the treatment of post-liver transplant (LT) recurrence of hepatitis C virus (HCV) infection have improved outcomes. The full impact of eradication of HCV on allograft histology is, however, not clearly known. METHODS: We studied allograft histology in protocol-based paired liver biopsies in consecutive LT recipients who underwent post-LT treatment of recurrence of HCV. RESULTS: A total of 116 patients were treated with interferon-based therapy for recurrent HCV. Paired pre-treatment baseline biopsies and post-treatment biopsies were available in 83.2% of patients. SVR was achieved in 37.9% of patients. Among the patients who achieved SVR, 20.5% had progression of fibrosis on post-treatment biopsies vs. 65.5% of patients with non-response/relapse (P < 0.001). The impact of virological response on fibrosis progression was sustained and a similar outcome was observed in the subset of patients who had 4-5 year post-treatment biopsies available. In the SVR group, 12.8% progressed to fibrosis stage ≥3 on post-treatment biopsies vs. 37.9% in the non-response/relapse group (P = 0.001). The 5-year survival in patients with progression of fibrosis 86% vs. 98% among patients who had improvement/stable fibrosis [P = 0.003; HR 3.8 (1.2-11.8)]. A small subset of patients who achieve SVR unfortunately still experience progression of fibrosis, most commonly associated with plasma cell hepatitis. CONCLUSIONS: In post-transplant patients treated for HCV, SVR is associated with improved graft survival and also with sustained and significant improvement in histological outcome. Importantly, progression of fibrosis still occurred in a small subset of patients who achieved SVR.

Hepatopulmonary syndrome: favorable outcomes in the MELD exception era.

UNLABELLED: Hepatopulmonary syndrome (HPS) is a pulmonary vascular disorder occurring as a consequence of advanced liver disease, characterized by hypoxemia due to intrapulmonary vascular dilatations. HPS independently increases mortality, regardless of the cause or severity of liver disease. Liver transplantation (LT) improves survival in HPS. We present the largest consecutive series of HPS patients specifically addressing long-term survival relative to the degree of hypoxemia and the era in which LT was conducted. We evaluated 106 HPS patients at the Mayo Clinic from 1986 through 2010. Survival was assessed using Kaplan-Meier methodology. LT was accomplished in 49 HPS patients. Post-LT survival (1, 3, 5, and 10 years) did not differ between groups based on baseline partial pressure of arterial oxygen (PaO2 ) obtained at the time of HPS diagnosis. Improvements in overall survival at 1, 3, and 5 years post-LT in those HPS patients transplanted after January 1 2002 (n = 28) (92%, 88%, and 88%, respectively) as compared with those transplanted prior to that time (n = 21) (71%, 67%, and 67%, respectively) did not reach statistical significance (5-year P = 0.09). Model for Endstage Liver Disease (MELD) exception to facilitate LT was granted to 21 patients since January 1 2002 with post-LT survival of 19/21 patients and one wait-list death. CONCLUSION: Long-term outcome after LT in HPS is favorable, with a trend towards improved survival in the MELD exception era since 2002 as compared to earlier HPS transplants. Survival after LT was not associated with PaO2 levels at the time of HPS diagnosis. (HEPATOLOGY 2012).

Pulmonary contraindications, indications and MELD exceptions for liver transplantation: a contemporary view and look forward.

Pulmonary concerns in liver transplant candidates have intraoperative and outcome implications. Evolving MELD exception policies address transplant priority for problems such as hepatopulmonary syndrome, portopulmonary hypertension, and hemorrhagic hereditary telangiectasia. Other pulmonary issues such as refractory hepatic hydrothorax, advanced chronic obstructive lung disease (including alpha-1 antitrypsin deficiency) and indeterminate pulmonary nodules may affect liver transplant consideration. Herein, we discuss current pulmonary-related contraindications, indications and MELD exception policies for liver transplantation, suggesting future considerations.

The use of sirolimus should be restricted in liver transplantation.

Sirolimus and mTOR inhibitors are important additions to the therapeutic armamentarium to prevent allograft rejection, but their role in liver transplantation is evolving. De novo use of Sirolimus in the early post-transplant period has undoubtedly been influenced by the high incidence of hepatic artery thrombosis and decreased patient and graft survival leading to a black box warning. The jury remains undecided on the role of conversion from CNIs to mTOR inhibitors in those developing renal insufficiency and it must be noted that a second warning was issued by the FDA because of decreased survival in those conversion studies. Finally, the anti-atherogenic, antiviral, and anti-neoplastic effects associated with Sirolimus, which might favor their use in certain liver transplant patients, need further evaluation before firm recommendations can be made.

Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation.

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.

Hyponatremia and mortality among patients on the liver-transplant waiting list.

BACKGROUND: Under the current liver-transplantation policy, donor organs are offered to patients with the highest risk of death. METHODS: Using data derived from all adult candidates for primary liver transplantation who were registered with the Organ Procurement and Transplantation Network in 2005 and 2006, we developed and validated a multivariable survival model to predict mortality at 90 days after registration. The predictor variable was the Model for End-Stage Liver Disease (MELD) score with and without the addition of the serum sodium concentration. The MELD score (on a scale of 6 to 40, with higher values indicating more severe disease) is calculated on the basis of the serum bilirubin and creatinine concentrations and the international normalized ratio for the prothrombin time. RESULTS: In 2005, there were 6769 registrants, including 1781 who underwent liver transplantation and 422 who died within 90 days after registration on the waiting list. Both the MELD score and the serum sodium concentration were significantly associated with mortality (hazard ratio for death, 1.21 per MELD point and 1.05 per 1-unit decrease in the serum sodium concentration for values between 125 and 140 mmol per liter; P<0.001 for both variables). Furthermore, a significant interaction was found between the MELD score and the serum sodium concentration, indicating that the effect of the serum sodium concentration was greater in patients with a low MELD score. When applied to the data from 2006, when 477 patients died within 3 months after registration on the waiting list, the combination of the MELD score and the serum sodium concentration was considerably higher than the MELD score alone in 32 patients who died (7%). Thus, assignment of priority according to the MELD score combined with the serum sodium concentration might have resulted in transplantation and prevented death. CONCLUSIONS: This population-wide study shows that the MELD score and the serum sodium concentration are important predictors of survival among candidates for liver transplantation.

Present state of immunosuppressive therapy in liver transplant recipients.

KEY POINTS: 1. Our increasing understanding of the signaling pathways and cellular interactions in transplant immunobiology has facilitated targeted strategies using novel immunosuppressive agents. 2. The pattern of immunosuppressive drug use in the United States continues to change, and the changes include the use of antibody induction therapy and the agents used in maintenance therapy. 3. The driving forces behind the development of new immunosuppressive regimens are the long-term complications of current immunosuppressive regimens (particularly renal dysfunction and metabolic disturbances).

Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis.

UNLABELLED: Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)-associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinine level ≥ 1.5 mg/dL]. We performed a search of all major databases, conference proceedings, and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was used to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus-based therapy at 1 year. Eleven studies (three randomized controlled trials and eight observational studies) met the final inclusion criteria. A nonsignificant improvement of 3.38 mL/minute [95% confidence interval (CI) = -2.93 to 9.69] was observed in methodologically sound observational studies and controlled trials reporting the primary outcome. In controlled trials, baseline GFR >50 mL/min sirolimus use was associated with an improvement of 10.35 mL/minute (95% CI = 3.98-16.77) in GFR or creatinine clearance. Sirolimus was not significantly associated with death [relative risk (RR) = 1.12, 95% CI = 0.66-1.88] or graft failure (RR = 0.80, 95% CI = 0.45-1.41), although reporting was incomplete. It was associated with a statistically significant risk of infection (RR = 2.47, 95% CI = 1.14-5.36), rash (RR = 7.57, 95% CI = 1.75-32.70), ulcers (RR = 7.44, 95% CI = 2.03-27.28), and discontinuation of therapy (RR = 3.61, 95% CI = 1.32-9.89). CONCLUSION: Conversion to sirolimus from CNIs is associated with a nonsignificant improvement in renal function in LT recipients with renal insufficiency, although the results are limited by heterogeneity, a risk of bias, and a lack of standardized reporting.

Impact of depressive symptoms and their treatment on completing antiviral treatment in patients with chronic hepatitis C.

BACKGROUND/GOALS: Interferon-induced depression affects 20% to 40% of patients treated for chronic hepatitis C virus (HCV). The aim of our study was to examine the influence of antidepressant treatment and whether this improves the likelihood of completing therapy. METHODS: One hundred randomly selected patients with chronic HCV undergoing antiviral therapy at a single center were identified. Patients were categorized as Group 1 (no depressive symptoms during treatment), Group 2 (depressive symptoms without antidepressant therapy), Group 3 (preexisting or prophylactic antidepressants before therapy), and Group 4 (on-demand antidepressant therapy for depressive symptoms). RESULTS: Mean age was 49 years with 72% men. Genotype 1 infection was noted in 65% of patients, and the mean pretreatment HCV RNA level was 1,419,919 IU. Patients without earlier depression receiving on-demand therapy (Group 4) had a significantly higher rate of antiviral treatment completion compared with Group 3 (92% vs. 52%; P=0.01). Patients in groups 1 and 4 with no baseline history of depression had similar treatment completion rates. No significant relationship between the use of antidepressant therapy, SVR or premature cessation of therapy was observed. CONCLUSIONS: Preexisting depression was associated with lower antiviral treatment completion rates despite the use of prophylactic antidepressant therapy. In patients without preexisting depression, however, on-demand antidepressant therapy for depressive symptoms was strongly associated with the highest treatment completion rates in the cohort. Antidepressant therapy for new or worsening depressive symptoms independent of baseline depression status did not affect the probability of achieving SVR or stopping treatment prematurely.

Long-term outcome of human leukocyte antigen mismatching in liver transplantation: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.

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.

Celiac disease autoantibodies in severe autoimmune liver disease and the effect of liver transplantation.

BACKGROUND/AIMS: Celiac disease (CD) is associated with primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. We investigated the following: (i) the prevalence of tissue transglutaminase antibodies (tTGAs) and endomysial antibodies (EMAs) in end-stage autoimmune liver disease (ESALD), (ii) the correlation among auto-antibodies and the human leucocyte antigen (HLA) haplotype, and (iii) the effect of liver transplantation on antibody kinetics. METHODS: Pretransplantation sera from 488 patients (310 with ESALD, and 178 with non-autoimmune disease) were tested for tTGAs. Positive samples were also tested for EMAs, and retested 6-12 and > or = 24 months post-transplantation. Results were correlated with the HLA type of the recipient. RESULTS: Serological evidence of CD was found in 3% (ESALD) vs. 0.6% (non-autoimmune) of the patients (five-fold increased risk in ESALD). The prevalence of tTGAs (14.2 vs. 5.4%, P=0.0001) and EMAs (4.3 vs. 0.78%, P=0.01) was significantly higher in patients with the HLA-DQ2 or HLA-DQ8 haplotypes. tTGAs and EMAs normalized in 94 and 100%, respectively, without gluten exclusion post-transplantation. Post-transplantation, of the five patients with symptoms of 'classical' CD, three improved. Intestinal lymphoma was diagnosed in another two cases with clinically 'silent' CD. CONCLUSIONS: Patients with ESALD, especially those who are HLA-DQ2 or HLA-DQ8 positive had a high prevalence of CD-associated antibodies. Both tTGAs and EMAs decreased post-transplantation without gluten withdrawal. Immunosuppression may improve symptoms of CD, but might not prevent progression to intestinal lymphoma.