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.

Factors Influencing Surveillance for Hepatocellular Carcinoma in Patients with Liver Cirrhosis.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide, and a rising cause of cancer mortality in the U.S. Liver cirrhosis is the major risk factor for HCC. Surveillance of persons with cirrhosis facilitates early detection and improves outcomes. We assessed the surveillance rate for HCC within a major academic health system and identified factors influencing surveillance. PATIENTS AND METHODS: We examined the surveillance rate for HCC using liver ultrasound, CT, or MRI, and factors influencing surveillance in a cohort of 369 Minnesota residents with cirrhosis seen at the Mayo Clinic between 2007 and 2009. RESULTS: Ninety-three percent of cirrhosis patients received at least one surveillance study, but only 14% received the recommended uninterrupted semiannual surveillance. Thirty percent received ≥75% of recommended surveillance, and 59% received ≥50% of recommended surveillance. Factors increasing surveillance included gastroenterology or hepatology specialist visits (p < 0.0001), advanced liver disease as assessed by hepatic encephalopathy (p = 0.0008), and comorbid illness as assessed by diabetes mellitus (p = 0.02). Age, sex, race, residence, cirrhosis etiology, or number of primary care visits did not significantly affect the rate of surveillance. CONCLUSIONS: While the rate of surveillance in a major academic health system was higher than reported in other studies, surveillance was heavily dependent on visits to a subspecialist. This suggests a major and urgent national need to improve identification of individuals at risk for HCC in the primary care setting and the initiation and maintenance of surveillance by primary care practitioners.

Risk Factors and Outcomes of De Novo Cancers (Excluding Nonmelanoma Skin Cancer) After Liver Transplantation for Primary Sclerosing Cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) may be at higher risk of malignancy after liver transplantation (LT) compared to other LT recipients. We aimed to determine the cumulative incidence of/risk factors for long-term cancer-related mortality in patients with PSC after LT. METHODS: All adult patients underwent LT for PSC without cholangiocarcinoma from 1984 to 2012, with follow-up through June 2015. We estimated cumulative incidence, risk factors, and mortality from de novo malignancies after LT. RESULTS: Two hundred ninety-three patients were identified (mean [SD] age, 47 [12] years; 63.3% males; 2.4% smoking at LT). Over a median of 11.5 years (range, 6.4-18.6 years), 64 patients (21.8%) developed 73 nonskin cancers, including 46 solid-organ cancers (renal, 11; colorectal, 11; prostate, 7; breast, 5; pancreas, 5; ovarian/endometrial/vulvar cancers, 3; and de novo cholangiocarcinoma, 4). Twenty-two patients developed hematologic malignancies (posttransplant lymphoproliferative diseases, 18; Hodgkin disease, 2; and myelodysplastic syndrome, 2). Five patients developed melanoma. The 1-, 5-, 10-, and 20-year cumulative incidences of cancer were 2.1%, 8.6%, 18.7%, and 27%, respectively. Mortality of patients with PSC who developed cancer was higher than that of patients with PSC without cancer (hazard ratio, 2.2; P < 0.01). On multivariate analysis, recipient's age and elevated pre-LT international normalized ratio were associated with increased risk of de novo (nonskin) malignancy. CONCLUSION: The 10-year cumulative risk of cancer after LT for advanced-stage PSC was 18.7%, with posttransplant lymphoproliferative diseases, colorectal cancer, and renal cell cancer being the most common. Post-LT de novo nonskin cancer decreased overall posttransplant survival. Only recipient's age and elevated international normalized ratio at LT were associated with increased nonskin cancer risk.

Charcoal hemoperfusion in the treatment of medically refractory pruritus in cholestatic liver disease.

BACKGROUND: Pruritus is a distressing symptom in a considerable proportion of cholestatic patients and a few of them do not respond to conventional treatment. Charcoal hemoperfusion (CH) is an extracorporeal technique that is effective in eliminating protein-bound substances which may have accumulated during cholestasis. Several case reports have shown significant reduction of bilirubin in mechanical jaundice and neonatal hemolytic jaundice. However, the published data of CH for the treatment of refractory pruritus in cholestatic patients are scarce. METHODS: Procedure code "Charcoal hemoperfusion" (90997) was used to identify patients who received CH at Mayo Clinic, Rochester, from 1 January 2000 to 5 January 2015. Patients who received CH for refractory cholestatic pruritus were retrospectively reviewed. RESULTS: Thirteen patients were identified. A median of 5 (range 1-18) sessions for a total of 20 (1-72) h were performed. CH resulted in a significant decrease of pruritus in nine patients (69%). Two patients did not have significant relief and two patients did not pursue further treatments after having adverse reactions during the first session. Median pruritus numerical rating scale significantly decreased from 9/10 (9-10) to 4/10 (0-9) post-treatment (p = 0.004). Duration of symptom-free periods ranged from 8 to 90 days (median 18 days) in six patients who returned for follow-up. Most common adverse reactions were pain, bleeding from the catheter site and fever. CONCLUSION: CH temporarily improves the severity of medically refractory cholestatic pruritus in some patients. However, the improvement is not sustained and the short duration of benefit should be balanced with the invasive nature of the therapy and the relatively common adverse reactions.

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.

Outcomes of liver transplantation alone after listing for simultaneous kidney: comparison to simultaneous liver kidney transplantation.

BACKGROUND: Data on patient and liver graft survival comparing liver transplantation alone after listing for kidney with simultaneous liver kidney (SLK) transplantation are scanty. METHODS: United Network Organ Sharing network database (1994-2011) queried for liver transplantation alone after being listed for kidney and SLK transplants. RESULTS: Of 65,206 first liver transplants, 3549 were listed for simultaneous kidney. Of these, 422 (12%) received only liver (LIST) and differed from SLK recipients for the white race (64% vs. 57%; 0.005), diabetes (27% vs. 37%; P = 0.02), model for end-stage liver disease era (68% vs. 82%; P = 0.0001), serum creatinine (2.9±1.9 vs. 4.3±2.5; P < 0.0001), dialysis (35% vs. 64%; P < 0.0001), and donor risk index (1.6±0.4 vs. 1.5±0.3; P < 0.0001). Overall survival was poorer in the LIST group (55% vs. 76%; P < 0.0001). A higher proportion of patients died within 2 days of transplantation in LIST group (11% vs. 0.5%; P < 0.0001), mostly from cardiovascular causes. After excluding these patients, odds of patient mortality and liver graft loss were about 1.2-fold and twofold higher in the LIST group. A total of 103 (24%) patients needed a renal transplantation in the LIST group with 16 (4%) receiving kidney within first year after transplantation. After excluding patients receiving kidney within first year, about 33% recovered renal function to above estimated GFR of greater than 60 mL per min. CONCLUSION: Guidelines are needed for patient selection to list for and receipt of simultaneous liver kidney transplantation.

Evolving trends in liver transplantation: listing and liver donor allocation.

The success of liver transplantation in the past three decades as a life-saving procedure for patients with end-stage liver disease has led to the ever-increasing disparity between the demands for liver transplantation and the supply of donor liver organs. Donor allocation and distribution remains a challenge and a moral issue as to how these organs can be equitably distributed. This article reviews the evolution of the liver allocation policy and discusses in detail the challenges clinicians face today in this area of medicine.

Evolving frequency and outcomes of simultaneous liver kidney transplants based on liver disease etiology.

BACKGROUND: The frequency of simultaneous liver kidney (SLK) transplantation is increasing. Data are scanty on outcomes of SLK transplants for liver disease etiology. METHODS: Outcomes for liver and kidney grafts and patients survival at 5 years were compared for liver disease etiology among adults receiving SLK during 2002 and 2011 in the United States. Cox regression analysis models were built to determine the independent impact of liver disease etiology on outcomes. RESULTS: A total of 2,606 patients (mean age 53 years, 69% males, 55% Caucasians) received SLK for primary biliary cirrhosis (PBC, n=76), primary sclerosing cholangitis (n=81), hepatitis C virus (HCV) (n=945), alcoholic liver disease (n=495), alcohol and HCV (n=152), cryptogenic cirrhosis (CC, n=289), nonalcoholic steatohepatitis (NASH) (n=221), hepatitis B virus (HBV) (n=98), and hepatocellular carcinoma (HCC) (n=249). HCV and NASH+CC contributed to about 44% and 9%, respectively, of all SLK transplants in 2002. Corresponding figures in 2011 were 34% and 22%, respectively. Compared to PBC, 5-year outcomes were worse for NASH, HCV, and HCC for liver graft (72%, 66%, and 72% vs. 82%; hazard ratio, HR: 2.5-3.1), kidney graft (71%, 65%, and 71% vs. 80%; HR: 2.3-2.8), and patient survival (74%, 69%, and 69% vs. 82%; HR: 2.4-2.7). Follow-up renal function assessed at 1, 3, and 5 years showed poor renal function among patients receiving SLK for HCV, NASH, CC, and HBV. CONCLUSIONS: Frequency of SLK transplants is increasing among NASH patients. Overall graft and patient outcomes are good. However, SLK for NASH, HCV, and HCC do worse. Strategies are needed to improve outcomes for SLK in HCV and NASH patients.

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.

Evolving frequency and outcomes of liver transplantation based on etiology of liver disease.

BACKGROUND: In the background of availability of better treatments for specific liver diseases and listing of nonalcoholic steatohepatitis (NASH) as an etiology for liver transplantation (LT), data are unclear on the impact of disease etiology on the frequency of LT and liver posttransplantation outcomes. METHODS: The United Network for Organ Sharing database (1994-2009) was queried for adults receiving first LT for primary biliary cirrhosis (PBC; n=3052), primary sclerosing cholangitis (PSC; n=3854), hepatitis C virus (HCV; n=15,147), alcoholic cirrhosis (AC; n=8940), HCV+alcohol (n=6066), NASH (n=1368), cryptogenic cirrhosis (CC; n=5856), hepatitis B virus (HBV; n=1816), and hepatocellular carcinoma (HCC; n=8588). Graft and patient survival were compared and Cox models were built to determine independent prediction of outcomes by disease etiology. RESULTS: The frequency of LT increased for NASH, HCC, and HCV+alcohol, remained stable for AC, and decreased for PBC, PSC, HCV, CC, and HBV. The proportion of simultaneous liver-kidney transplants increased from approximately 3% in 2001 to 10% in 2009. Compared with PBC, 5-year graft and patient survival were (a) similar for PSC, NASH, and HBV (80-85%), (b) poorer for AC and CC (hazard ratio, 1-1.5), and (c) worst for HCV, HCV+alcohol, and HCC (hazard ratio, 1.5-2.4). Five-year outcomes for HCV-associated HCC were poorer compared with HCC due to other etiologies. CONCLUSIONS: LT performed for NASH and HCC are increasing. Potent treatment options resulted in a decrease in number of transplants for HBV, HCV, and PBC. Better treatment modalities for HCV are expected to further reduce the number of LT for HCV. Excellent posttransplantation outcomes for NASH and AC are encouraging, resulting in wider acceptance of transplants for these etiologies.

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).

Immunomodulating therapy in liver transplantation: principles and practice.

Liver transplantation has enjoyed dramatic success as a treatment option for patients suffering from chronic end-stage liver diseases. It also serves as a definitive treatment for certain genetic conditions such as familial amyloidosis and primary oxalosis, and as a potential curative therapy in selected cases of primary liver cancer. Currently, over 50,000 patients are alive with functioning liver transplants. Liver transplantation owes its success to advances in surgical technique, improvements in anesthesia and critical care, and advances in treatment of post-transplant complications including improved therapies for cytomegalovirus infections. But perhaps the most important advances in liver transplantation arise in the context of improvements in our understanding of the molecular biology of transplant immunology and the development of new agents that allow for manipulation of immunological signaling pathways. These improvements in immunosuppressive therapy have dramatically increased both graft and patient survival.

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.

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.