Evaluation of a gene expression biomarker to identify operationally tolerant liver transplant recipients: the LITMUS trial.

LITMUS was a single-centre, Phase 2a study designed to investigate whether the gene biomarker FGL2/IFNG previously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. Multiplex RT-PCR was used to amplify eight immunoregulatory genes in peripheral blood mononuclear cells (PBMC) from 69 adult liver transplant recipients. Patients with PBMC FGL2/IFNG ≥ 1 and a normal liver biopsy underwent immunosuppression (IS) withdrawal. The primary end point was the development of operational tolerance. Secondary end points included correlation of tolerance with allograft gene expression and immune cell markers. Twenty-eight of 69 patients (38%) were positive for the PBMC tolerance biomarker and 23 proceeded to IS withdrawal. Nine of the 23 patients had abnormal baseline liver biopsies and were excluded. Of the 14 patients with normal biopsies, eight (57%) have achieved operational tolerance and are off IS (range 12-57 months). Additional studies revealed that all of the tolerant patients and only one non-tolerant patient had a liver gene ratio of FOXP3/IFNG ≥ 1 prior to IS withdrawal. Increased CD4+ T regulatory T cells were detected both in PBMC and livers of tolerant patients following IS withdrawal. Higher expression of SELE (gene for E-selectin) and lower expression of genes associated with inflammatory responses (GZMB, CIITA, UBD, LSP1, and CXCL9) were observed in the pre-withdrawal liver biopsies of tolerant patients by RNA sequencing. These results suggest that measurement of PBMC FGL2/IFNG may enrich for the identification of operationally tolerant liver transplant patients, especially when combined with intragraft measurement of FOXP3/IFNG. Clinical Trial Registration: ClinicalTrials.gov (LITMUS: NCT02541916).

Long-term Outcomes of Pediatric Living Versus Deceased Donor Liver Transplantation Recipients: A Systematic Review and Meta-analysis.

Living donor liver transplantation (LDLT) emerged in the 1980s as a viable alternative to scarce cadaveric organs for pediatric patients. However, pediatric waitlist mortality remains high. Long-term outcomes of living and deceased donor liver transplantation (DDLT) are inconsistently described in the literature. Our aim was to systematically review the safety and efficacy of LDLT after 1 year of transplantation among pediatric patients with all causes of liver failure. We searched the MEDLINE, Medline-in-Process, MEDLINE Epub Ahead of Print, Embase + Embase Classic (OvidSP), and Cochrane (Wiley) from February 1, 1947 to February 26, 2020, without language restrictions. The primary outcomes were patient and graft survival beyond 1 year following transplantation. A meta-analysis of unadjusted and adjusted odds and hazard ratios was performed using a random-effects model. A total of 24 studies with 3677 patients who underwent LDLT and 9098 patients who underwent DDLT were included for analysis. In patients with chronic or combined chronic liver failure and acute liver failure (ALF), 1-year (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.53-0.88), 3-year (OR, 0.73; 95% CI, 0.61-0.89), 5-year (OR, 0.71; 95% CI, 0.57-0.89), and 10-year (OR, 0.42; 95% CI, 0.18-1.00) patient and 1-year (OR, 0.50; 95% CI, 0.35-0.70), 3-year (OR, 0.55; 95% CI, 0.37-0.83), 5-year (OR, 0.5; 95% CI, 0.32-0.76), and 10-year (OR, 0.26; 95% CI, 0.14-0.49) graft survival were consistently better in LDLT recipients compared with those in DDLT recipients. In patients with ALF, no difference was seen between the 2 groups except for 5-year patient survival (OR, 0.60; 95% CI, 0.38-0.95), which favored LDLT. Sensitivity analysis by era showed improved survival in the most recent cohort of patients, consistent with the well-described learning curve for the LDLT technique. LDLT provides superior patient and graft survival outcomes relative to DDLT in pediatric patients with chronic liver failure and ALF. More resources may be needed to develop infrastructures and health care systems to support living liver donation.

Outcomes of radiofrequency ablation as first-line therapy for hepatocellular carcinoma less than 3 cm in potentially transplantable patients.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is an effective treatment for single hepatocellular carcinoma (HCC) ≤3 cm. Disease recurrence is common, and in some patients will occur outside transplant criteria. We aimed to assess the incidence and risk factors for recurrence beyond Milan criteria in potentially transplantable patients treated with RFA as first-line therapy. METHODS: We performed a retrospective cohort study of potentially transplantable patients with new diagnoses of unifocal HCC ≤3 cm that underwent RFA as first-line therapy between 2000-2015. We defined potentially transplantable patients as those aged <70 years without any comorbidities that would preclude transplant surgery. Incidence of recurrence beyond Milan criteria was compared across 2 groups according to HCC diameter at the time of ablation: (HCC ≤2 cm vs. HCC >2 cm). Competing risks Cox regression was used to identify predictors of recurrence beyond Milan criteria. RESULTS: We included 301 patients (167 HCC ≤2 cm and 134 HCC >2 cm). Recurrence beyond Milan criteria occurred in 36 (21.6%) and 47 (35.1%) patients in the HCC ≤2 cm and the HCC >2 cm groups, respectively (p = 0.01). The 1-, 3- and 5-year actuarial survival rates after RFA were 98.2%, 86.2% and 79.0% in the HCC ≤2 cm group vs. 93.3%, 77.6% and 70.9% in the HCC >2 cm group (p = 0.01). Tumor size >2 cm (hazard ratio 1.94; 95%CI 1.25-3.02) and alpha-fetoprotein levels at the time of ablation (100-1,000 ng/ml: hazard ratio 2.05; 95%CI 1.10-3.83) were found to be predictors of post-RFA recurrence outside Milan criteria. CONCLUSION: RFA for single HCC ≤3 cm provides excellent short- to medium-term survival. However, we identified patients at higher risk of recurrence beyond Milan criteria. For these patients, liver transplantation should be considered immediately after the first HCC recurrence following RFA. LAY SUMMARY: Radiofrequency ablation and liver transplantation are treatment options for early stages of hepatocellular carcinoma (HCC). After ablation some patients will experience recurrence or metastatic spread of the initial tumor or may develop new tumors within the liver. Despite close follow-up, these recurrences can progress rapidly and exceed transplant criteria, preventing the patient from receiving a transplant. We identified that patients with HCC >2 cm and higher serum alpha-fetoprotein are at greater risk of recurrence beyond the transplant criteria. These data suggest that liver transplantation should be considered immediately after the first HCC recurrence for these patients.

Choosing Wisely Canada-Top Five List in Hepatology: Official Position Statement of the Canadian Association for the Study of the Liver (CASL) and Choosing Wisely Canada (CWC).

INTRODUCTION AND AIM: The prevalence and incidence of chronic liver disease is increasing resulting, in substantial direct and indirect medical costs. Overuse of investigations, treatments and procedures contribute to rising health care costs and can expose patients to unnecessary harm and delay in receiving care. The Choosing Wisely Canada (CWC) campaign has encouraged professional societies to develop statements that are directly actionable by their members in an effort to promote higher-value health care that will lead to downstream effect on how other practitioners make decisions. MATERIAL AND METHODS: The Canadian Association for the Study of the Liver (CASL) established its Choosing Wisely top five list of recommendations using the framework put forward by CWC. CASL convened a task force that developed a list of draft recommendations and shared this with CASL membership electronically with eventual ranking of the top five recommendations by consensus at Canadian Digestives Disease Week (CDDW) 2017. Following revisions, the CASL Executive Committee endorsed the final list, which was disseminated online by CWC (July 2017). RESULTS: The top five recommendations physicians and patients should question include: 1) Don't order serum ammonia to diagnose or manage hepatic encephalopathy (HE). 2) Don't routinely transfuse fresh frozen plasma, vitamin K, or platelets to reverse abnormal tests of coagulation in patients with cirrhosis prior to abdominal paracentesis, endoscopic variceal band ligation, or any other minor invasive procedures. 3) Don't order HFE genotyping based on serum ferritin values alone to diagnose hereditary hemochromatosis. 4) Don't perform computed tomography (CT) or magnetic resonance imaging (MRI) routinely to monitor benign focal liver lesions. 5) Don't repeat hepatitis C viral load testing in an individual who has established chronic infection, outside of anti-viral treatment. CONCLUSION: The Choosing Wisely recommendations will foster patient-physician discussions, reduce unnecessary treatment and testing, avert adverse effects from testing and treatment along with reducing medical expenditure in hepatology.

The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study.

The selection of liver transplant candidates with hepatocellular carcinoma (HCC) relies mostly on tumor size and number. Instead of relying on these factors, we used poor tumor differentiation and cancer-related symptoms to exclude patients likely to have advanced HCC with aggressive biology. We initially reported similar 5-year survival for patients whose tumors exceeded (M+ group) and were within (M group) the Milan criteria. Herein, we validate our original data with a new prospective cohort and report the long-term follow-up (10-years) using an intention-to-treat analysis. The previously published study (cohort 1) included 362 listed (294 transplanted) patients from January 1996 to August 2008. The validation cohort (cohort 2) includes 243 listed (105 M+ group, 76 beyond University of California San Francisco criteria; 210 transplanted) patients from September 2008 to December 2012. Median follow-up from listing was 59.7 (26.8-103) months. For the validation cohort 2, the actuarial survival from transplant for the M+ group was similar to that of the M group at 1 year, 3 years, and 5 years: 94%, 76%, and 69% versus 95%, 82%, and 78% (P = 0.3). For the combined cohorts 1 and 2, there were no significant differences in the 10-year actuarial survival from transplant between groups. On an intention-to-treat basis, the dropout rate was higher in the M+ group and the 5-year and 10-year survival rates from listing were decreased in the M+ group. An alpha-fetoprotein level >500 ng/mL predicted poorer outcomes for both the M and M+ groups. CONCLUSION: Tumor differentiation and cancer-related symptoms of HCC can be used to select patients with advanced HCC who are appropriate candidates for liver transplantation; alpha-fetoprotein level limitations should be incorporated in the listing criteria for patients within or beyond the Milan criteria. (Hepatology 2016;64:2077-2088).

Liver Transplantation is a Preferable Alternative to Palliative Therapy for Selected Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) beyond the traditional criteria (advanced HCC) are typically offered palliation, which is associated with a 3-year survival rate lower than 30%. This study aimed to describe the outcomes for a subset of patients with advanced HCC who satisfied the Extended Toronto Criteria (ETC) and were listed for liver transplantation (LT). METHODS: All patients listed in the Toronto liver transplantation program with HCC beyond both the Milan and University of California, San Francisco criteria were included in this study. Data were extracted from the prospectively collected electronic database. All radiologic images were reviewed by two independent radiologists. The primary end point was patient survival. RESULTS: Between January 1999 and August 2014, 96 patients with advanced HCC were listed for LT, and 62 (65%) of these patients received bridging therapy while on the waiting list. Bridging therapy led to a significant reduction in tumor progression (p = 0.02) and tumor burden (p < 0.001). The majority of those listed underwent LT (n = 69, 72%). Both tumor progression on waiting list (hazard ratio [HR] 4.973; range1.599-15.464; p = 0.006) and peak alpha-fetoprotein (AFP) at 400 ng/ml or higher (HR, 4.604; range 1.660-12.768; p = 0.003) were independently associated with waiting list dropout. Post-LT HCC recurrence occurred in 35% of the patients (n = 24). Among those with HCC recurrence, survival was significantly better for those who received curative treatment (p = 0.004). The overall actuarial survival rates from the listing were 76% at 1 year, 56% at 3 years, and 47% at 5 years, and the corresponding rates from LT were 93, 71, and 66%. CONCLUSION: Liver transplantation provides significantly better survival rates than palliation for patients with selected advanced HCC.

Characteristics of liver transplant candidates delisted following recompensation and predictors of such delisting in alcohol-related liver disease: a case-control study.

Whether and when recovery beyond the need for transplant may occur in patients listed for decompensation remains unclear. This study aimed to investigate the characteristics of patients delisted following recompensation. Seventy-seven patients who were listed between 2005 and 2015 for decompensation, but later delisted following recompensation were included. Alcohol-related liver disease (ALD) was the underlying etiology in the majority (n = 47, 61%). Listing characteristics of these patients were compared with those of decompensated ALD patients who either underwent deceased donor liver transplantation or died on the waiting list. The model for end-stage liver disease (MELD) score <20 and serum albumin ≥32 g/l at listing were the only independent predictors of recompensation/delisting in ALD. The probability of recompensation was 70% when both factors were present at listing. Interestingly, about a tenth of decompensated ALD patients who died on the waiting list (median duration on waiting list 11 months) and a quarter of decompensated ALD patients who underwent living donor liver transplantation (median duration on waiting list 2 months) also had both factors at listing. In conclusion, ALD seems to be the most favorable etiology for recompensation beyond the need for transplantation. Both MELD and serum albumin at listing independently predict recompensation/delisting in ALD. It seems advisable to implement a period of observation for ALD patients with both favorable factors, before embarking on living donor liver transplantation.

The effect of different immunoprophylaxis regimens on post-transplant cytomegalovirus (CMV) infection in CMV-seropositive liver transplant recipients.

BACKGROUND: The effects of different immunoprophylaxis regimens on cytomegalovirus (CMV) infection in liver transplant recipients (LTRs) have not been compared. METHODS: In a cohort, we studied 343 CMV-seropositive recipient (R+) and 83 seronegative donor/recipient (D-/R-) consecutive LTRs from 2004 to 2007. Immunoprophylaxis regimens included steroid-only, steroids plus rabbit anti-thymocyte globulin (rATG), and steroids plus basiliximab. Logistic regression analysis, Cox proportional hazards regression model, and log-rank test were performed for multivariate analysis as appropriate. RESULTS: In total, 164 (39%), 69 (16%), and 193 (45%) patients received steroid-only, basiliximab, and rATG immunoprophylaxis, respectively. CMV infection rates were 15.7% (54/343) in CMV R+ LTRs and 2.4% (2/83) in CMV R- LTRs. Among CMV R+ LTRs who received rATG, the use of at least 6 weeks of CMV prophylaxis reduced the rate of CMV infection from 24.4% (19/78) to 11.7% (9/77). In multivariate analysis, CMV R+ vs D-/R- (odds ratio [OR]=13.1, 95% confidence interval [CI]: 1.8-97.2), rATG >3 mg/kg vs steroid-only induction (OR=1.6, 95% CI: 1.1-2.3), and CMV prophylaxis <6 weeks vs ≥6 weeks (OR=2.7, 95% CI: 1.2-6.4) were independently associated with CMV infection. Subgroup analysis in CMV D-/R+ group who received rATG showed that ≥6 weeks of CMV prophylaxis significantly decreased the risk of CMV infection (OR=1.9, 95% CI: 1.1-3.9; P=.03). CONCLUSION: The use of rATG immunoprophylaxis increases the risk of CMV infection in CMV-seropositive LTRs, specifically in the CMV D-/R+ group. Prophylaxis with valganciclovir in this group for at least 6 weeks decreases the risk of CMV infection.

Wait Time for Curative Intent Radio Frequency Ablation is Associated with Increased Mortality in Patients with Early Stage Hepatocellular Carcinoma.

INTRODUCTION: Radiofrequency ablation (RFA) is a recommended curative intent treatment option for patients with early stage hepatocellular carcinoma (HCC). We investigated if wait times for RFA were associated with residual tumor, tumor recurrence, need for liver transplantation, or death. MATERIAL AND METHODS: We conducted a retrospective study of patients diagnosed with HCC between January 2010 and December 2013 presenting to University Health Network (UHN) in Toronto, Canada. All patients receiving curative intent RFA for HCC were included. Multivariable Cox regression was used to determine if wait times were associated with clinical outcomes. RESULTS: 219 patients were included in the study. 72.6% were male and the median age was 62.7 years (IQR 55.6-71). Median tumor size at diagnosis was 21.5 mm (IQR 17-26); median MELD was 8.7 (IQR 7.2-11.4) and 57.1% were Barcelona stage 0. The cause of liver disease was viral hepatitis in 73.5% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 96 days (IQR 75-139). In multivariate analysis, wait time was not associated with requiring liver transplant or tumor recurrence, however, each incremental 30-day wait time was associated with an increased risk of residual tumor (HR = 1.09; 95% CI 1.01-1.19; p = 0.033) as well as death (HR = 1.23; 95% CI 1.11-1.36; p ≤ 0.001). CONCLUSION: Incremental 30-day wait times are associated with a 9% increased risk of residual tumor and a 23% increased risk of death. We have identified system gaps where quality improvement measures can be implemented to reduce wait times and allocate resources for future RFA treatment, which may improve both quality and efficiency of HCC care.

Live Donor Liver Transplantation With Older (≥50 Years) Versus Younger (<50 Years) Donors: Does Age Matter?

OBJECTIVE: To compare the outcome of adult live donor liver transplantation (LDLT) with grafts from older versus younger donors. INTRODUCTION: Using older donor grafts for adult LDLT may help expand the donor pool. However, the risks of LDLT with older donors remain controversial, and many centers are reluctant to use live donors aged 45 years or older for adult LDLT. METHODS: Outcomes of patients receiving a LDLT graft from donors aged 50 years or older (n = 91) were compared with those receiving a live donor graft from donors younger than 50 years (n = 378). RESULTS: Incidences of biliary (LDLT <50: 24% vs LDLT ≥50: 23%; P = 0.89) and major complications (LDLT <50: 24% vs LDLT ≥50: 24%; P = 1) were similar between both groups of recipients. No difference was observed in 30-day recipient mortality (LDLT <50: 3% vs LDLT ≥50: 0%; P = 0.13). The 1- (90% vs 90%), 5- (82% vs 73%), and 10- (71% vs 58%) year graft survival was statistically similar between both groups (P = 0.075). Likewise, patient survival after 1- (92% vs 96%), 5- (83% vs 79%), and 10- (76% vs 69%) years was also similar (P = 0.686). Overall, donors rate of major complications (Dindo-Clavien ≥3b) within 30 days was low (n = 2.3%) and not different in older versus younger donors (P = 1). Donor median hospital stay in both groups was identical [LDLT <50: 6 (4-17) vs LDLT ≥50: 6 (4-14) days; P = 0.65]. No donor death occurred and all donors had full recovery and returned to baseline activity. CONCLUSIONS: Right lobe LDLT with donors aged 50 years or older results in acceptable recipient outcome without increased donor morbidity or mortality. Potential live donors should not be declined on the basis of age alone.

Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results.

The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non-US Food and Drug Administration-approved, bovine-derived, gelatin-based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin-based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340-580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56-1.74 mmol/L) and produced bile (61 mL; 14-146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP-preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1-3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1-1.56] versus 1.1 [1-1.3]; P = 0.5) and bilirubin (1.5; 1-7.7 mg/dL versus 2.78; 0.4-15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0-8 versus 0-23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8-17 versus 7-89 days; P = 0.23). Major complications (Dindo-Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration-approved Steen solution will avoid a potential regulatory barrier in North America. Liver Transplantation 22 1501-1508 2016 AASLD.

Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.

Hepatorenal syndrome type 1 (HRS1) is acute renal failure in the setting of advanced cirrhosis, and it results from hemodynamic derangements, which should be fully reversible after liver transplantation. However, the rate of hepatorenal syndrome (HRS) reversal and factors predicting renal outcomes after transplantation have not been fully elucidated. The aim of this study was to assess outcomes of HRS1 patients after liver transplantation and factors predicting HRS reversal. A chart review of all liver transplant patients with HRS1 (according to International Ascites Club criteria) at Toronto General Hospital from 2001 to 2010 was conducted. Patient demographic data, pretransplant and posttransplant laboratory data, and the presence of and time to posttransplant HRS reversal (serum creatinine < 1.5 mg/dL) were extracted from the center's transplant electronic database. Patients were followed until death or the end of the 2011 calendar year. Sixty-two patients (mean age, 54.7 ± 1.2 years; mean Model for End-Stage Liver Disease score, 35 ± 1) with HRS1 (serum creatinine, 3.37 ± 0.13 mg/dL) at liver transplant were enrolled. Thirty-eight patients received midodrine, octreotide, and albumin without success and subsequently received renal dialysis. One further patient received dialysis without pharmacotherapy. After liver transplantation, HRS1 resolved in 47 of 62 patients (75.8%) at a mean time of 13 ± 2 days. Patients without HRS reversal had significantly higher pretransplant serum creatinine levels (3.81 ± 0.34 versus 3.23 ± 0.14 mg/dL, P = 0.06), a longer duration of HRS1 {25 days [95% confidence interval (CI), 16-42 days] versus 10 days (95% CI, 10-18 days), P = 0.02}, a longer duration of pretransplant dialysis [27 days (95% CI, 13-41 days) versus 10 days (95% CI, 6-14 days), P = 0.01], and increased posttransplant mortality (P = 0.0045) in comparison with those whose renal function recovered. The only predictor of HRS1 nonreversal was the duration of pretransplant dialysis with a 6% increased risk of nonreversal with each additional day of dialysis. In conclusion, our study suggests that patients with HRS1 should receive a timely liver transplant to improve their outcome.

Liver transplantation in patients with end-stage liver disease requiring intensive care unit admission and intubation.

Data regarding transplantation outcomes in ventilated intensive care unit (ICU)-dependent patients with end-stage liver disease (ESLD) are conflicting. This single-center cohort study investigated the outcomes of patients with ESLD who were intubated with mechanical support before liver transplantation (LT). The ICU plus intubation group consisted of 42 patients with decompensated cirrhosis and mechanical ventilation before transplantation. LT was considered for intubated ICU patients if the fraction of inspired oxygen was ≤40% with a positive end-expiratory pressure ≤ 10, low pressor requirements, and the absence of an active infection. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and to 126 matched non-ICU-bound patients. Patients requiring ICU care with intubation and ICU care alone had more severe postoperative complications than non-ICU-bound patients. Intubation before transplantation was associated with more postoperative pneumonias (15% in intubated ICU transplant candidates, 5% in ICU-bound but not intubated patients, and 3% in control group patients; P = 0.02). Parameters of reperfusion injury and renal function on postoperative day (POD) 2 and POD 7 were similar in all groups. Bilirubin levels were higher in the ICU plus intubation group at POD 2 and POD 7 after transplantation but were normalized in all groups within 3 months. The ICU plus intubation group versus the ICU-only group and the non-ICU group had decreased 1-, 3-, and 5-year graft survival (81% versus 84% versus 92%, 76% versus 78% versus 87%, and 71% versus 77% versus 84%, respectively; P = 0.19), but statistical significance was not reached. A Glasgow coma scale score of <7 versus >7 before transplantation was associated with high postoperative mortality in ICU-bound patients requiring intubation (38% versus 23%; P = 0.01). In conclusion, ICU admission and mechanical ventilation should not be considered contraindications for LT. With careful patient selection, acceptable long-term outcomes can be achieved despite increased postoperative complications.

Recipient factors associated with having a potential living donor for liver transplantation.

Because of a persistent discrepancy between the demand for liver transplantation (LT) and the supply of deceased donor organs, there is an interest in increasing living donation rates at centers trained in this method of transplantation. We examined a large socioeconomically heterogeneous cohort of patients listed for LT to identify recipient factors associated with living donation. We retrospectively reviewed 491 consecutive patients who were listed for LT at our center over a 24-month period. Demographic, medical, and socioeconomic data were extracted from electronic records and compared between those who had a potential living donor (LD) volunteer for assessment and those who did not; 245 patients (50%) had at least 1 potential LD volunteer for assessment. Multivariate logistic regression analysis identified that patients with a LD were more likely to have Child-Pugh C disease (odds ratio [OR], 2.44; P = 0.02), and less likely to be older (OR, 0.96; P = 0.002), single (OR, 0.34; P = 0.006), divorced (OR, 0.53; P = 0.03), immigrants (OR, 0.38; P = 0.049), or from the lowest income quintile (OR, 0.44; P = 0.02). In conclusion, this analysis has identified several factors associated with access to living donation. More research is warranted to define and overcome barriers to living donor liver transplantation through targeted interventions in underrepresented populations.

Long-term follow-up of biliary complications after adult right-lobe living donor liver transplantation.

INTRODUCTION: Long-term biliary complications after living donor liver transplantation (LDLT) are not well described in the literature. This study was undertaken to determine the long-term impact of biliary complications after adult right-lobe LDLT. METHODS: This retrospective review analyzed an 11-yr experience of 344 consecutive right-lobe LDLTs with at least two yr of follow-up. RESULTS: Biliary leaks occurred in 50 patients (14.5%), and strictures occurred in 67 patients (19.5%). Cumulative biliary complication rates at 1, 2, 5, and 10 yr were 29%, 32%, 36%, and 37%, respectively. Most early biliary leaks were treated with surgical drainage (N = 29, 62%). Most biliary strictures were treated first with endoscopic retrograde cholangiography (42%). There was no association between biliary strictures and the number of ducts (hazard ratio [HR] 1.017 [0.65-1.592], p = 0.94), but freedom from biliary stricture was associated with a more recent era (2006-2010) (HR 0.457 [0.247-0.845], p = 0.01). Long-term graft survival did not differ between those who had or did not have biliary complications (66% vs. 67% at 10 yr). CONCLUSIONS: Biliary strictures are common after LDLT but may decline with a center's experience. With careful follow-up, they can be successfully treated, with excellent long-term graft survival rates.

The Negative Prognostic Impact of a First Ever Episode of Spontaneous Bacterial Peritonitis in Cirrhosis and Ascites.

BACKGROUND: The prognostic impact of the first ever episode of spontaneous bacterial peritonitis (SBP) on patient outcomes is not well described. Our aim was to compare the clinical outcomes of cirrhotic patients with ascites, and with or without a first episode of SBP. METHODS: Consecutive patients with cirrhosis and ascites were prospectively enrolled. Demographics, liver and renal function, and hemodynamics were documented at baseline, at resolution of SBP, and thereafter at 4 monthly intervals for 12 months. Complications of cirrhosis and survival were noted. RESULTS: Twenty-nine cirrhotic patients with a first ever episode of SBP (group A) and 123 control patients slightly younger but similar in gender who never had SBP (group B) were enrolled. At SBP diagnosis, group A had worse liver and renal function (Model of End-Stage Liver Disease : 21.1±10.6 vs. 14.4±5.0), lower serum sodium concentrations, and a more hyperdynamic circulation compared with group B (all P<0.001). SBP resolution resulted in improvement in all measures to baseline levels. During follow-up, group A required more frequent hospital admissions than group B (58% vs. 43%), developed more cirrhotic complications, including further SBP (31% vs. 3%*), hyponatremia (12% vs. 0.8%*), acute kidney injury (50% vs. 23%*), hepatorenal syndrome type 1 (46% vs. 7%*), liver transplantation (62% vs. 30%*), and had a worse overall 1-year survival (38% vs. 70%*) (*P<0.05). CONCLUSIONS: A first SBP episode is commonly followed by multiple complications, and overall worse prognosis. Consideration should be given to assess cirrhotic patients for liver transplant after the first episode of SBP.

High preoperative bilirubin values protect against reperfusion injury after live donor liver transplantation.

Heme Oxygenase-1 and its product biliverdin/bilirubin have been demonstrated to protect against ischemia/reperfusion injury (IRI). We investigated whether increased preoperative bilirubin values of transplant recipients decrease IRI. Preoperative bilirubin levels of live donor liver recipients were correlated to postoperative liver transaminase as a marker of IRI. Additionally, two recipient groups with pretransplant bilirubin levels >24 µmol/l (n = 348) and ≤24 µmol/l (n = 118) were compared. Post-transplant liver function, complications, length of hospital stay, and patient and graft survival were assessed. Preoperative bilirubin levels were negatively correlated to the postoperative increase in transaminases suggesting a protective effect against IRI. The maximal rise of ALT after transplantation in high versus low bilirubin patients was 288 (-210-2457) U/l vs. 375 (-11-2102) U/l, P = 0.006. Bilirubin remained a significant determining factor in a multivariate linear regression analysis. The MELD score and its individual components as a marker of severity of chronic liver disease were significantly higher in the high versus low bilirubin group (P < 0.001). Despite this, overall complication rate (21.0% vs. 21.2%, P = 0.88), hospital stay [13 (4-260) vs. 14 (6-313) days, P = 0.93), and 1-year graft survival (90.8% vs. 89.0%, P = 0.62) were similar in both groups. High bilirubin levels of liver recipients before live donor transplantation is associated with decreased postoperative IRI.

Health-related quality of life in long-term survivors of paediatric liver transplantation.

BACKGROUND: Long-term survival after paediatric liver transplantation is now the rule rather than the exception. Improving long-term outcomes after transplantation must consider not only the quantity but also the quality of life years restored. OBJECTIVES: To characterize health-related quality of life (HRQOL) of LT recipients ≥15 years after paediatric LT. METHODS: Recipients of a paediatric LT performed before December 1996 in a single institution with continuous follow-up at either the paediatric or adult partner centre were identified. Patients with severe developmental or neurological impairment were excluded. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0, the Medical Outcomes Study Short Form-36 version 2 and the Pediatric Liver Transplant Quality of Life Tool. RESULTS: A total of 27 (67% male) subjects (mean age 24.3±6.7 years [median 23.2 years; range 16.6 to 40.3 years]) participated. The median age at transplant was 1.7 years (range 0.5 to 17.0 years). Seven (26%) participants underwent retransplantation. Seventeen (63%) participants were engaged in full-time work/study. Mean Short Form-36 version 2 scores included physical (49.6±11.1) and mental (45.3±12.5) subscale scores. The mean score for the disease-specific quality of life tool for paediatric liver transplant recipients (the Pediatric Liver Transplant Quality of Life Tool) was 64.70±15.2. The physical health of the young adults strongly correlated with level of involvement in work/study (r=0.803; P<0.05). CONCLUSIONS: The self-reported HRQOL of participants <18 years of age was comparable with a standardized healthy population. In contrast, participants between 18 and 25 years of age had HRQOL scores that were more similar to a group with chronic illness. Participants engaged in full-time work/study experienced enhanced physical health.

HISTORIQUE: La survie à long terme après une transplantation du foie (TF) en pédiatrie est maintenant la règle plutôt que l'exception. Il faut tenir compte à la fois de la quantité et de la qualité des années de vie récupérées dans l'amélioration des résultats après la TF. OBJECTIFS: Caractériser la qualité de vie liée à la santé (QdVLS) des greffés du foie de 15 ans et plus après une TF en pédiatrie. MÉTHODOLOGIE: Les chercheurs ont dépisté des greffés du foie opérés avant décembre 1996 dans un seul établissement et recevant un suivi continu au centre pédiatrique ou au centre partenaire pour adultes. Les patients ayant une grave atteinte développementale et neurologique étaient exclus. La QdVLS était évaluée au moyen de l'inventaire de la qualité de vie en pédiatrie 4.0, de la version 2 du formulaire court sur les résultats médicaux en 36 questions et de l'outil sur la qualité de vie des greffés du foie en pédiatrie. RÉSULTATS: Au total, 27 sujets (67 % d'hommes, âge moyen de 24,3±6,7 ans [médiane de 23,2 ans; plage de 16,6 à 40,3 ans]) ont participé. Ils avaient un âge médian de 1,7 an au moment de la transplantation (plage de 0,5 à 17,0 ans). Sept participants (26 %) ont dû subir une autre transplantation. Dix-sept participants (63 %) travaillaient ou étudiaient à temps plein. La version 2 du formulaire court en 36 questions incluait des scores de sous-échelle physique (49,6±11,1) et mentale (45,3±12,5). Le score moyen pour l'outil de qualité de vie propre à la maladie (outil de qualité de vie des greffés du foie en pédiatrie) était de 64,70±15,2. La santé physique des jeunes adultes était fortement corrélée avec le taux d'investissement dans le travail ou l'étude (r=0,803, P<0,05). CONCLUSIONS: La QdVLS autodéclarée des participants de moins de 18 ans était comparable à celle d'une population en santé standardisée. En revanche, les participants de 18 à 25 ans avaient un score de QdVLS qui ressemblait davantage à celui d'un groupe ayant une maladie chronique. Les participants qui s'investissaient dans un emploi ou des études à temps plein présentaient une meilleure santé physique.

Protease inhibitor-based triple therapy is highly effective for hepatitis C recurrence after liver transplant: a multicenter experience.

INTRODUCTION: Hepatitis C (HCV) continues to be the leading indication for liver transplantation (LT). Sustained virological response (SVR) rates to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy for recurrent HCV in Genotype 1 (G1) LT recipients have been disappointing (30-40%). Experience with triple therapy using protease inhibitors (PI) boceprevir (BOC), telaprevir (TVR) in these patients has been limited. MATERIAL AND METHODS: This national multicenter retrospective study included 76 patients (64 male, mean age 57 ± 6 years), treated for G1 HCV recurrence with either BOC (n = 41) or TVR (n = 35), who were non-responders or relapsers (n = 54), treatment naïve (n = 22) or had fibrosing cholestatic HCV (n = 3). 53 patients were on cyclosporine, 22 on tacrolimus and one patient on prednisone alone. RESULTS: On treatment virologic response was observed in 84% (64/76), 83% in BOC and 85% in TVR group. A higher week 4 response after starting triple therapy (RVR) was noted in TVR group 25/35 (81%) as compared to BOC group 26/41 (63%); p value = 0.02. The end of treatment response was 78% and 75% in BOC and TVR group, respectively. SVR 12 weeks after treatment discontinuation was observed in 59.5% (22/37); 58.3% in the BOC group and 61.5% in TVR group. Treatment was discontinued early in 23 patients (serious adverse effects n = 19, treatment failure n = 4). Infections occurred in 5 patients with 2 deaths (all in BOC). Anemia was the most common side effect (n = 55, 72%) requiring erythropoietin and RBV dose reduction. In the BOC group, cyclosporine dose reduction was 2.2 ± 1.0 fold and 8.6 ± 2.4 fold with tacrolimus. In TVR group, dose reduction was 3.0 ± 1.4 with cyclosporine and 12 ± 5.7 fold with tacrolimus. CONCLUSIONS: PI-based triple therapy appears more effective in producing HCV-RNA clearance than dual therapy. Tolerability is a serious issue and drug-drug interactions are manageable with close monitoring.

Identifying patients with diagnosed cirrhosis in administrative health databases: a validation study.

Objectives: Case ascertainment algorithms were developed and validated to identify people living with cirrhosis in administrative health data in Manitoba, Canada using primary care electronic medical records (EMR) to define the reference standards. Methods: We linked provincial administrative health data to primary care EMR data. The validation cohort included 116,675 Manitobans aged >18 years with at least one primary care visit between April 1998 and March 2015. Hospital records, physician billing claims, vital statistics, and prescription drug data were used to develop and test 93 case-finding algorithms. A validated case definition for primary care EMR data was the reference standard. We estimated sensitivity, specificity, positive and negative predictive values (PPV, NPV), Youden's index, area under the receiver operative curve, and their 95% confidence intervals (CIs). Results: A total of 116,675 people were in the validation cohort. The prevalence of cirrhosis was 1.4% (n = 1593). Algorithm sensitivity estimates ranged from 32.5% (95% CI 32.2-32.8) to 68.3% (95% CI 68.0-68.9) and PPV from 17.4% (95% CI 17.1-17.6) to 23.4% (95% CI 23.1-23.6). Specificity (95.5-98.2) and NPV (approximately 99%) were high for all algorithms. The algorithms had slightly higher sensitivity estimates among men compared with women, and individuals aged ≥45 years compared to those aged 18-44 years. Conclusion: Cirrhosis algorithms applied to administrative health data had moderate validity when a validated case definition for primary care EMRs was the reference standard. This study provides algorithms for identifying diagnosed cirrhosis cases for population-based research and surveillance studies.