Changing trends in the etiology of liver transplantation in Turkiye: A multicenter study.

Background and Aim: This study aimed to identify the indications for liver transplantation (LT) based on underlying etiology and to characterize the patients who underwent LT. Materials and Methods: We conducted a multicenter cross-sectional observational study across 11 tertiary centers in Turkiye from 2010 to 2020. The study included 5,080 adult patients. Results: The mean age of patients was 50.3±15.2 years, with a predominance of female patients (70%). Chronic viral hepatitis (46%) was the leading etiological factor, with Hepatitis B virus infection at 35%, followed by cryptogenic cirrhosis (24%), Hepatitis C virus infection (8%), and alcohol-related liver disease (ALD) (6%). Post-2015, there was a significant increase in both the number of liver transplants and the proportion of living donor liver transplants (p<0.001). A comparative analysis of patient characteristics before and after 2015 showed a significant decline in viral hepatitis-related LT (p<0.001), whereas fatty liver disease-related LT significantly increased (p<0.001). Conclusion: Chronic viral hepatitis continues to be the primary indication for LT in Turkiye. However, the proportions of non-alcoholic fatty liver disease (NAFLD) and ALD-related LT have seen an upward trend over the years.

Outcomes of Surgical Strategies for Living Donor Liver Transplantation in Patients With Portal Vein Thrombosis: A Cohort Study.

BACKGROUND: Adequate portal flow to the liver graft is the requirement of a successful liver transplant (LT). Historically, portal vein thrombosis (PVT) was a contraindication for LT, especially for living donor LT (LDLT), demanding technically more difficult operations and advanced technique. In this study, the outcomes of patients with and without PVT after LDLT were compared. METHODS: Adult LDLTs performed by 2 centers (n = 335) between 2013 and 2020 were included into this large cohort study. PVT was classified based on Yerdel classification grade 1 to 4. RESULTS: Sixty-two patients with PVT constituted 19% of the study cohort of 335 recipients. While mean platelet count was found to be lower (P = .011) in the PVT group, patient age (P = .035), operation duration (P = .001), and amount of intraoperative blood transfusion (P = .010) were found to be higher. Incidence of PVT was higher in female patients than males (22.7% vs 16.1%, P = .037). There was no significant difference in survival between patients with and without PVT on 30-day (P = .285), 90-day (P = .565), 1-year (P = .777), and overall survival (P = .917). Early thrombosis did not show a better survival rate than Grades 2, 3, or 4 PVT. Thrombosis limited to portal vein was not found to bring a survival advantage compared with Grade 3 and 4 thromboses. Eversion thrombectomy was the most common procedure (66%) to overcome PVT intraoperatively. CONCLUSION: Although technically more challenging, PVT is not a contraindication of LDLT. Similar outcomes can be achieved in LDLT in patients with PVT after proper restoration of portal flow, which eliminates the default survival disadvantage of patients with PVT.

Proceedings of the 26th Annual Virtual Congress of the International Liver Transplantation Society.

After a 1-y absence due to the coronavirus disease 2019 pandemic, the 26th Annual Congress of the International Liver Transplantation Society was held from May 15 to 18, 2021, in a virtual format. Clinicians and researchers from all over the world came together to share their knowledge on all the aspects of liver transplantation (LT). Apart from a focus on LT in times of coronavirus disease 2019, featured topics of this year's conference included infectious diseases in LT, living donation, machine perfusion, oncology, predictive scoring systems and updates in anesthesia/critical care, immunology, radiology, pathology, and pediatrics. This report presents highlights from invited lectures and a review of the select abstracts. The aim of this report, generated by the Vanguard Committee of International Liver Transplantation Society, is to provide a summary of the most recent developments in clinical practice and research in LT.

The role of preoperative psychosocial counseling on the improvement of the recipient compliance and speed of recovery after liver transplantation - A systematic review of the literature and expert panel recommendations.

BACKGROUND: Psychosocial disorders ranging from anxiety to severe psychiatric diseases and active alcohol/substance abuse are frequent in liver transplant candidates and potentially associated with worse post- transplant outcomes. Therefore, psychosocial evaluation is mandatory to optimize success after liver transplantation. However, how to carry out this evaluation, the type of intervention needed and its potential impact on patient outcome remain unclear. OBJECTIVES: To investigate whether psychosocial assessment may help in predicting risks of poor outcome; and to investigate whether psychosocial interventions may mitigate these risks and improve posttransplant outcomes, in particular compliance and speed of recovery. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. The protocol was registered on PROSPERO CRD42021238361. Main outcomes assessed were mortality, alcohol relapse, rejection, and medication compliance. RESULTS: Fifteen studies were analyzed including five observational comparative and ten observational noncomparative studies. Preoperative psychosocial evaluation of LT candidates was associated with higher concordance with the treatment plan (i.e., higher adherence to treatment and lower alcohol relapse) and lower rates of rejection. Psychosocial assessment tools were used in some studies to guide the evaluation, but their predictive ability remains debated, and they should not be used in isolation. Most of the interventions were studied in patients with alcohol related issues. In this context, support by specialized teams was associated with better posttransplant outcome, especially through a decrease in post-transplant alcohol relapse. CONCLUSIONS: Preoperative psychosocial assessment should be provided in order to detect patients at increased risk of poorer post-transplant outcome, in particular in terms of concordance to the treatment plan (Quality of Evidence; Low | Grade of Recommendation; Strong/For). The experts suggest that, when possible, provision of preoperative psychological assessment and concomitant interventions aimed at improving the concordance to treatment plans will positively impact the success of liver transplantation. (Quality of Evidence; Very Low | Grade of Recommendation; Strong/For].

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

BACKGROUND & AIMS: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival. METHODS: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis. RESULTS: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001). CONCLUSION: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH. LAY SUMMARY: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.

Recommendations for Hepatitis B Immunoglobulin and Antiviral Prophylaxis Against Hepatitis B Recurrence After Liver Transplantation.

The combination of hepatitis B immunoglobulin and potent nucleos(t)ide analogs after liver transplantation is considered as the standard of care for prophylaxis against hepatitis B virus recurrence. However, the recommended doses, route of administration, and duration of HBIG administration remain unclear. Moreover, hepatitis B immunoglobulin-free prophylaxis with potent nucleos(t)ide analogs has shown promising disease outcomes in preventing hepatitis B virus recurrence. The current recommendations, produced by the Turkish Association for the Study of the Liver, Acute Liver Failure and Liver Transplantation Special Interest Group, suggest a reduced need for hepatitis B immunoglobulin administration with effective long-term suppression of hepatitis B virus replication using potent nucleos(t) ide analogs after liver transplantation.

ATA Index: A novel score for predicting fibrosis stage in chronic viral hepatitis.

Background and Aim: This study was designed to predict the fibrosis stage with a clinical scoring system that may reduce the need for liver biopsy. Materials and Methods: The study cohort included the treatment of 430 chronic hepatitis B (CHB) and 170 chronic hepatitis C (CHC) of naive patients. The patients were divided into two groups as mild to moderate and severe fibrosis. After an index obtained in the study cohort, the index was tested in a validation cohort and compared with the FIB-4 Index. Results: The AUC of CHC index was found of 0.89 the sensitivity of 0.91 the specificity of 0.74, the positive predictive value (PPV) of 0.54 and the negative predictive value (NPV) of 0.96. The FIB-4 Index was applied to the CHC study cohort and the ATA Index Hepatitis C was found to be superior in terms of AUC (0.89-0.82), sensitivity (0.91-0.76) and NPV (0.96-0.86). The AUC of CHB Index was determined of 0.92, the sensitivity of 0.90, the specificity of 0.84, the PPV of 0.53 and the NPV of 0.98. Compared to the FIB-4 Index in CHB study cohort, the ATA Index Hepatitis B was predominant in terms of AUC (0.92-0.88), sensitivity (0.90-0.75), NPV (0.98-0.94) and PPV (0.53-0.49). Conclusion: ATA Indexes can predict the non-existence of severe fibrosis with an accuracy similar to FIB-4 Index and may reduce the need for liver biopsy.

Proceedings of the 25th Annual Congress of the International Liver Transplantation Society.

The 25th Annual Congress of the International Liver Transplantation Society was held in Toronto, Canada, from May 15 to 18, 2019. Surgeons, hepatologists, anesthesiologists, critical care intensivists, radiologists, pathologists, and research scientists from all over the world came together with the common aim of improving care and outcomes for liver transplant recipients and living donors. Some of the featured topics at this year's conference included multidisciplinary perioperative care in liver transplantation, worldwide approaches to organ allocation, donor steatosis, and updates in pediatrics, immunology, and radiology. This report presents excerpts and highlights from invited lectures and select abstracts, reviewed and compiled by the Vanguard Committee of International Liver Transplantation Society. This will hopefully contribute to further advances in clinical practice and research in liver transplantation.

The COVID-19 pandemic: Clinical practice advice for gastroenterologists, hepatologists, and liver transplant specialists.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a novel acute infectious disease that has rapidly reached staggering pandemic proportions. This review addresses gastroenterologists, hepatologists, liver transplant (LT) specialists, and health-care professionals working in the field of liver diseases and liver transplantation. It has been written based on a limited number of publications, recommendations of national and international liver and organ transplantation societies, and experiences of patients with COVID-19 around the world. The purpose of this review is to provide information addressing questions and concerns about COVID-19, to reveal the effects of the novel disease on patients with chronic liver disease and LT recipients, and to share information about ways in which this pandemic will affect clinical practices. We, the Turkish Association for the Study of the Liver (TASL), would like to remind you that this text is actually not a practical guide. It is imperative to act according to the standards set by health-care institutions and the Ministry of Health, Republic of Turkey.

Current status of liver transplantation in Europe.

Liver transplantation (LT) in Europe became an established life-saving treatment for patients with end-stage liver disease, hepatocellular carcinoma, and acute liver conditions with life-threatening hepatic dysfunction. Although there are substantial disparities in donation and transplant rates among European countries, LT can be offered to almost every European citizen today. In order to maximize the LT benefit beyond national levels, many countries cooperate within transnational organizations including Eurotransplant, Scandiatransplant, and Southern Alliance for Transplantation. In the majority of European countries, liver allocation is based on the Model for End-Stage Liver Disease (MELD). Similar to North America, the ongoing extinction of hepatitis C and increase of non-alcoholic steatohepatitis are also a hallmark of change in LT indications in Europe. Apart from Turkey, the organ pool for LT in European countries is mainly based on organs from donors after brain death, although some countries retrieve a substantial proportion of organs from donors after circulatory death. According to the 2018 report of the European Liver Transplant Registry, 146,762 LT have been performed in Europe until 2016. In the most recent period, LT in Europe achieved respectable 1- and 5-year overall survival rates of 86% and 74%.

The role of living donor liver transplantation for acute liver failure.

Acute liver failure (ALF) is a life-threatening illness that occurs in the absence of pre-existing liver disease. When symptoms seriously progress under continuous supportive medical care, liver transplantation becomes the only therapeutic strategy. However, the available sources of organs for liver transplantation differ worldwide. In regions in which organs from cadaveric donors are more common, deceased donor liver transplantation (DDLT) is performed in this urgent situation. Conversely, in countries where cadaveric donors are scarce, living donor liver transplantation (LDLT) is the only choice. Special considerations must be made for urgent LDLT for ALF, including the expedited evaluation of living donors, technical issues, and the limitations of ABO blood type combinations between recipients and donor candidates. In this review, we highlight the role of LDLT for ALF and the considerations that distinguish it from DDLT. LDLT is well-established as a life-saving procedure for ALF patients and there is often no alternative to LDLT, especially in countries where DDLT is not feasible. However, from a global perspective, an increase in the deceased donor pool might be an urgent and important necessity.

The natural course of non-alcoholic fatty liver disease.

Background and Aim: The present study aims to describe the characteristics and long-term clinical outcomes of patients with non-alcoholic fatty liver disease (NAFLD). Material and Methods: A total of 1308 individuals with NAFLD were seen in the Liver Diseases Outpatient Clinic. Diagnosis of NAFLD in each case was based on biochemical, radiological and histological criteria, when available. After diagnosis, all NAFLD patients were administered a conventional diet and exercise program. The median follow-up period was 55.3 months. Results: At the time of the diagnosis, the mean age was 50.8±11.3 years, and female gender was slightly predominant (51.4%). The median body mass index was 29.2±4.7 kg/m2: 39% were obese. Seventeen percent of the patients had diabetes mellitus, 53% insulin resistance, 60% hyperlipidemia, and 32% hypertension. Median serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase levels were 31 U/L (range: 10-248 U/L), 45 U/L (range: 10-285 U/L) and 41 (range: 8-1200 U/L), respectively. Liver biopsy was performed in 293 individuals. The median NAFLD activity score was 5.0, median hepatic steatosis 2, ballooning 1, lobular inflammation 1, portal inflammation 0, and fibrosis 0. Of note, 41.3% of the samples (121/293) revealed the presence of fibrosis and 31% of the samples (37/121) showed significant fibrosis. With multivariate analysis, diabetes and obesity were associated with the presence of significant fibrosis. Among them, 765 patients (M/F: 353/412, mean age: 51.0±10.9) had at least six months of follow-up. In this group, from baseline to the end of the follow-up period, a significant improvement in the serum AST and ALT levels was observed. Conclusion: NAFLD is a potentially progressive disease. Diabetes and obesity were associated with the presence of advanced fibrosis.

The role of PNPLA3 (rs738409) c>g variant on histological progression of non-alcoholic fatty liver disease.

Background and Aim: The present study aims to investigate the role of genetic variability of the PNPLA3 gene (adiponectin) in predisposition to non-alcoholic fatty liver disease (NAFLD) by comparing NAFLD patients to healthy controls and to investigate any impact of the PNPLA3 genetic variability on the natural course of the disease. Materials and Methods: This cohort consisted of 174 patients with biopsy-proven NAFLD and 151 healthy controls. DNA was extracted from peripheral blood and the rs738409 C>G single nucleotide polymorphism was assessed using PCR-DNA sequencing. Results: The frequency distribution of the GG genotype was significantly higher in NAFLD patients than in controls (p=0.01). In patients with NAFLD, the GG genotype was associated with lower platelet counts (p=0.001), the presence of steatohepatitis (p=0.04) and hepatic fibrosis (p=0.016). After adjustment for age, gender, obesity, and diabetes mellitus, the GG genotype was an independent predictor of significant hepatic fibrosis (adjusted odds ratio =3.031 p=0.012). From the baseline to sequential liver biopsies, the progression of NAS in NAFLD patients was slightly higher in the GG genotype than that of CC and GG genotypes (p=0.18). Conclusion: The PNPLA3 GG genotype is a predisposing factor for the development of hepatic steatosis in NAFLD patients and related to a more severe liver disease.

Report of the 24th Annual Congress of the International Liver Transplantation Society.

The 24th Joint Annual Congress of the International Liver Transplantation Society in association with European Liver and Intestine Transplant Association and Liver Intensive Care Group of Europe was held in Lisbon, Portugal from May 23 to 26, 2018. More than 1200 participants from over 60 countries including surgeons, hepatologists, anesthesiologists and critical care intensivists, radiologists, pathologists, organ procurement personnel, and research scientists came together with the common aim of improving care and outcomes for liver transplant recipients. Over 600 scientific abstracts were presented. The principal themes were living donation, use of marginal liver donors, machine preservation, disease-specific immunosuppressive regimen, malignancies, and advances in pediatric liver transplantation and liver transplant anesthesia. This report presents excerpts from invited lectures and select abstracts from scientific sessions, which add to current knowledge, and will drive clinical practice and future research.

Interferon Treatment Duration in Patients With Chronic Delta Hepatitis and its Effect on the Natural Course of the Disease.

Background: Interferon is the only treatment option in chronic delta hepatitis (CDH). A CDH database (333 patients, 161 with interferon treatment history) was analyzed for effects of treatment duration on virologic response and clinical outcomes. Methods: Ninety-nine CDH patients who received at least 6 months of interferon were selected. Maintained virologic response (MVR) was defined as hepatitis D virus RNA negative for 2 years after treatment discontinuation. Cumulative median interferon treatment duration was 24 months (range 6-126 months), with a median of 2 courses (range 1-8). Post-treatment median follow-up was 55 months (24-225 months). Results: Thirty-five patients achieved MVR. Cumulative probability of MVR increased with treatment duration and reached 50% at 5 years. Patients with MVR were less likely to die from liver disease or develop complications compared to patients without MVR (P = .032, P = .006, respectively). Cirrhosis at baseline and no response to therapy (odds ratio 16.1 and 5.23, respectively) predicted an adverse endpoint. Hepatitis B surface antigen clearance occurred in 37% of patients with MVR. Conclusion: Viral response to interferon increases with treatment duration and favorably affects the natural course of disease. Interferon treatment duration has to be individualized with careful post-treatment assessment.

Single-Center Experience in Pre-transplant Hepatitis C Virus (HCV) Treatment Among Living Donor Liver Transplant Candidates: Bridging the Direct-Acting Antivirals (DAA).

BACKGROUND Treatment with DAAs before deceased donor liver transplantation has been shown to be an effective strategy to prevent post-transplant HCV recurrence, with a 95% cure-rate among individuals who achieve undetectable HCV VL for ≥30 days pre- transplant. This strategy has not been evaluated in LDLT. MATERIAL AND METHODS We evaluated outcomes in LDLT recipients treated with DAAs pre-transplant and bridged with 4 weeks of post-transplant SOF. All cases of LDLT at Johns Hopkins (1/1/2014-3/1/15) were retrospectively reviewed. RESULTS There were 4 HCV+ LDLT cases treated with DAAs pre- and post-transplant. Pre-transplant DAA regimens included SOF plus SIM in 2 cases of HCC and SOF plus RBV in 2 cases of ESLD. All patients achieved negative VL by week 7 of treatment and all patients had at least 30 days of HCV RNA negativity at the time of LDLT. Patient 4 had a delay in LDLT due to uncontrolled pulmonary hypertension, and experienced viral breakthrough because of treatment interruption. Due to concerns for SOF resistance, a salvage regimen of LDV-SOF and SIM was used. Post-LDLT patients 1-3 received 4 weeks of SOF monotherapy and patient 4 received 14 weeks of LDV-SOF. Three patients achieved SVR12. One died from non-HCV related complications at 4 months post-LDLT. CONCLUSIONS Our preliminary experience suggests that bridging DAAs pre- and post-LDLT is an effective strategy to prevent HCV recurrence. With delays in transplant and prolonged use of SOF/RBV, there is a risk of viral breakthrough, but a salvage strategy of triple DAA therapy can be effective.

Pre- Versus Posttransplant Treatment of Hepatitis C Virus With Direct-Acting Antivirals in Liver Transplant Recipients: More Issues to be Solved.

OBJECTIVES: Our goal was to investigate wait times related to hepatitis C virus treatment with direct acting antivirals before versus after liver transplant at a single center as well as wait times for insurance approval for preemptive treatment with these agents after liver transplant. MATERIALS AND METHODS: We retrospectively evaluated hepatitis C virus infections in transplant recipients of deceased liver donations in 2014 and 2015. Demographics, hepatocellular carcinoma incidence, Model for End-Stage Liver Disease scores, and transplant wait times were compared between patients treated before or after liver transplant. Wait times to approval of direct-acting antiviral treatment were evaluated in those untreated before transplant. RESULTS: During our study period, of 67 deceased-donor liver transplants, 21 patients received hepatitis C virus treatment pretransplant (treated group) and 46 patients were not treated pretransplant (untreated group). Twenty-five patients in the untreated group received hepatitis C virus-positive donations, with all in this group treated with direct-acting antivirals. We found no statistically significant differences regarding age, sex, race, donation after cardiac death, or incidence of hepatocellular carcinoma between groups. The treated group had a longer median wait time (287 vs 172 days; P = .02). Twelve of the 46 untreated patients (26.1%) developed biopsy-proven hepatitis C virus-related relapse (median 87 days; range, 55-383 days). Preemptive direct-acting antiviral therapy was initiated at a median of 81 days in the untreated group. CONCLUSIONS: Although treatment of hepatitis C virus before liver transplant is an attractive option to eliminate the risk of complications, it can limit the donor pool for recipients to uninfected donors, significantly increasing wait times in regions with large hepatitis C virus-positive donor pools. Allocation of Model for End-Stage Liver Disease score was not different between the treated and untreated groups. Insurance companies should revise their policies for rapid approval of preemptive direct-acting antiviral treatment after liver transplant.

Discontinuation of lamivudine treatment in HBeAg-negative chronic hepatitis B: a pilot study with long-term follow-up.

BACKGROUND: Finite treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) with nucleoside/nucleotide analogues (NAs) is important in resource-limited countries. Outcome of treatment discontinuation in patients on long-term lamivudine (LVD) was assessed in a single centre observational pilot study in the current study. METHODS: Non-cirrhotic patients on LVD for at least 5 years with undetectable HBV DNA on at least two consecutive assessments were offered to stop treatment. Biochemical, serological and virological measures were determined at 3-6 month intervals after treatment discontinuation. Serum quantitative hepatitis B surface antigen (HBsAg) was determined at treatment discontinuation and 5-6 years thereafter. NA treatment was re-instituted in patients with confirmed viral rebound defined as HBV DNA >20,000 IU/ml. Relapser patients were no longer followed but were re-assessed 6 years after treatment cessation. RESULTS: LVD was discontinued in 23 patients. 8 patients relapsed within 1 year and NA treatment was restarted; 15 patients (65%) were non-relapsers. Thirteen of them were followed for at least 5 years. Two patients had undetectable HBV DNA throughout the follow-up period. In the rest, HBV DNA fluctuated at low levels. Two patients cleared HBsAg 24 and 36 months after stopping treatment. Quantitative HBsAg levels 5-7 years after treatment discontinuation were lower in non-relapser compared to relapser patients (1.21 IU/ml ±0.98 versus 2.71 ±0.76; P=0.002). Of 8 relapser patients 1 patient had HBsAg levels less than 100 IU/ml compared to 11 out of 13 non-relapser patients (P=0.0022). CONCLUSIONS: These data suggest that cessation of NA treatment is a viable option after a reasonable treatment duration in patients with HBeAg-negative CHB and that HBsAg clearance may become an achievable target in these patients.