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Introduction: Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis. Methods and patients: We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results. Results: Untreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naive. While the percentage of naive regulatory T cells (Tregs) (CD4(+)FOXP3(low)CD45RA(+)) and regulatory B cells (Bregs, CD20(+)CD24(+)CD38(+)) was similar, AIH patients had fewer activated Tregs (CD4(+)FOXP3(high)CD45RA(-)) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS, This project was funded by the Turkish Association for the Study of the Liver (TASL) charity, and seed funded by Koc University.

Objective: Hepcidin is a peptide that that functions as main iron regulatory hormone in the body and exhibits antimicrobial activity. The synthesis of hepcidin is stimulated during inflammation and this elevation can cause inflammation anemia. The aim of this study was to determine the role of (pro)hepcidin in anemia in inflammatory bowel disease (IBD) and any correla-tion with clinical and biochemical findings.Materials and Methods: A total of 61 patients without any inflammatory condition other than IBD were included in this observational and cross-sectional study. The hepcidin level and other biochemical parameters related to anemia were mea-sured. All of the statistical analyses were performed using IBM SPSS Statistics for Windows, Version 22.0 software (IBM Corp., Armonk, NY, USA).Results: In all, 61 patients, 19 (31.1%) of whom were diagnosed with Crohn's disease (CD), 42 (68.9%) with ulcerative coli-tis (UC), and a control group of 23 were enrolled. There was no significant difference in the hepcidin level between the CD and UC groups, and there was no significant difference in the hepcidin level between the IBD and control groups regarding hepcidin levels. As disease activity increased, the hepcidin level decreases with a probability of 83%.Conclusion: No statistically significant difference in the level of hepcidin was observed between the group with IBD and the control group., NA

Graft Versus Host Disease (GVHD) is a severe immunological-clincopathological condition mediated by healthy T-lymphocytes in donor tissue against the immunosuppressed host tissue and rarely seen after solid organ transplantation (SOT). A 72-year old male patient underwent cadaveric liver transplantation. On day 34 of the postoperative follow-up, the patient developed fever, generalized skin rash and hemorrhagic lesions in the oropharynx. Skin biopsy was consistent with GVHD. Despite high-dose corticosteroid treatment, he died on postoperative day 51. Although it is seen rarely after liver transplantation, GVHD is an important clinical entity for which early diagnosis is critical due to its high rates of mortality., NA

Background and aim: liver biopsy is the gold standard method for the diagnosis and treatment of liver diseases. In this study, we aimed to evaluate the results of liver biopsies performed in a year in our clinic. In addition, we also aimed if these liver biopsies could reveal the etiology of liver disease in patients with elevations of transaminases or/and alkaline phosphatase levels or liver masses. Materials and methods: patients who had liver biopsies for persistently elevated transaminases or/and alkaline phosphatase levels, protocol biopsies after liver transplantation, or liver masses in our hepatology clinic between 2011 and 2012 were included in the study. Liver biopsy decisions were made by experts during the hepatology council. Liver biopsies were previously performed using classical percutaneous liver biopsy or ultrasonography-guided Sonocan (R) liver biopsy sets. The pathology results of liver biopsies and clinical data of the matching patients were obtained from the liver biopsy record archives and patient files, respectively. Results: totally, 479 liver biopsy results (male=252, 52.6%, mean age 49 +/- 14.5 years) were evaluated in the study. Of these patients, 432 (male=228) underwent percutaneous liver biopsy and 47 (male=24) underwent Sonocan (R) needle biopsy. The most common histopathologic diagnoses in the percutaneous liver biopsy group were chronic hepatitis B (n=127, 29.4%), normal histopathological findings (n=50, 11.6% and 32 of them were protocol biopsies after liver transplantation), and nonalcoholic steatohepatitis (NASH, n=41, 9.5%). The most common histopathologic diagnoses in the Sonocan (R) group were 25 liver metastasis out of 29 liver tumors (n=25, 53.2% of all) chronic hepatitis B (n=5, 10.6%), and NASH (n=3, 6.4%). Conclusion: in this study, diversity in liver biopsy results indicates the importance of histopathological evaluation. The most prevalent pathology in the liver biopsies was chronic hepatitis B, which is the most common, NA

Background and aim: Hepatocellular carcinoma (HCC) is one of the most common and most lethal cancers worldwide. The objective of this study was to investigate the relationship between basal parameters and survival characteristics in patients with HCC. Materials and methods: the records of 1447 HCC patients of a tertiary center during the period 2000-2017 were screened retrospectively. The demographic details; basal clinical, laboratory, and radiological characteristics; treatments; and survival time were recorded and prognostic scores were calculated. Results: a total of 788 patients with HCC (male/female: 623/165; mean age: 60.5±10.9 years) were included in the study. The median length of survival was 26.3 months (95% confidence interval [CI], 22.3-30.4 months). The 5-year survival rate was 28.1%. The number and diameter of the tumors; platelet count; platelet-to-lymphocyte ratio; level of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase; portal and hepatic vein involvement; and an alpha-fetoprotein level of <9.6 ng/mL were found to be independently related to survival. Conclusion: the positive predictive value of the prognostic index derived from independent survival-related parameters for 5- and 10-year survival or overall survival was approximately 86%. Integration of this prognostic index to the criteria used in making treatment decisions for patients with HCC should be considered., NA

Hepatic myelopathy (HMy) is a rare neurological complication of liver cirrhosis that involves spastic paraplegia caused by lateral cord demyelination especially due to the accumulation of some metabolites such as ammonia and manganese. We report a young adult woman presenting with spasticity and paraparesis in extremities after intrahepatic portosystemic shunting (TIPS) application and underwent deceased liver transplantation (LT). A 39-year-old woman underwent deceased LT because of cryptogenic liver cirrhosis. She underwent a TIPS procedure 5 years ago. After that, hepatic encephalopathy and spasticity appeared. She was on the waiting list for 3 years. Neurological findings after LT significantly decreased, but did not return to normal. After the emergence of neurological findings, the earlier LT can provide improvement in neurological findings., NA

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including the microbiome. To decipher hepatic steatosis (HS) pathogenesis by excluding critical confounding factors including genetic variants and diabetes, 56 heterogenous MAFLD patients are characterized by generating multiomics data including oral and gut metagenomics as well as plasma metabolomics and inflammatory proteomics data. The dysbiosis in the oral and gut microbiome is explored and the host-microbiome interactions based on global metabolic and inflammatory processes are revealed. These multiomics data are integrated using the biological network and HS's key features are identified using multiomics data. HS is finally predicted using these key features and findings are validated in a follow-up cohort, where 22 subjects with varying degree of HS are characterized., Knut and Alice Wallenberg Foundation; ScandiBio Therapeutics; European Union (EU); Horizon 2020; PoLiMeR Innovative Training Network; Marie Sklodowska-Curie Grant; Research and Innovation Program; Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX)

Background: we investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods: data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results: we included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion: baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH., Italian Ministry of University and Research (MIUR) Department of Excellence; Project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic)

Background: data regarding outcome of Coronavirus disease 2019 (COVID-19) in patients with autoimmune hepatitis (AIH) are lacking. Patients and methods: we performed a retrospective study on AIH patients with COVID-19 from 34 centres in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity-score matched cohort of non-AIH patients with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase>2xupper limit of normal) during COVID-19 was also evaluated. Results: we included 110 AIH patients (80%,female) with a median age of 49 (range:18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (p=0.041; odds ratio (OR) 3.36[1.05-10.78]) while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (p=0.009; OR 0.26[0.09-0.71]). The rates of severe COVID-19 (15.5% vs 20.2% p=0.231) and all-cause mortality (10% vs 11.5%; p=0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (p<0.001; OR 17.46[4.22-72.13]). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19. Conclusions: this international, multi-center study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in AIH patients. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19, but did lower the risk for new-onset liver injury during COVID-19.

Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients., Knut and Alice Wallenberg Foundation; European Union (EU); Horizon 2020; PoLiMeR Innovative Training Network; Marie Sklodowska-Curie Grant; Research and Innovation Program

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., NA

Background/aims: sleep disorders (SDs) are frequently seen in patients with liver cirrhosis. Polysomnography (PSG), actigraphy, and electroencephalogram (EEG) are the common objective methods to diagnose SDs. The most commonly used subjective methods are the Pittsburgh sleep quality index (PSQI) and Epworth sleepiness scale (ESS). We aimed to evaluate the effect of liver transplantation (LTx) on SDs using a combination of objective (PSG and EEG) and subjective (PSQI and ESS) methods. Materials and methods: a total of 18 patients with cirrhosis on an LTx waiting list were included in this study. Patient clinical status and biochemical parameters were evaluated. All patients completed the validated Turkish forms of the PSQI and ESS before and 9 months after LTx. All patients underwent EEG and PSG before and 9 months after LTx. Results: in total, 18 patients with liver cirrhosis (men: 12; 66.7%, mean age: 53.22 +/- 10.43 years) were included in this study. Pretransplant mean PSQI and ESS scores were 8.4 +/- 3.11 and 7.28 +/- 3.89, respectively; 9-month posttransplant mean PSQI and ESS scores were 4.5 +/- 2.8 and 4.72 +/- 2.91 (p<0.01), respectively. Before transplantation, metabolic encephalopathy was detected in 6 patients by EEG, whereas metabolic encephalopathy was detected in only 1 patient posttransplant. Posttransplantation PSG sleep duration (all stages) increased relative to pretransplant PSG values. Sleep latency and rapid eye movement latency were found to be reduced compared to the pretransplant values. Conclusion: this pilot study compared SDs in patients with pre- and post-LTx by combining the subjective and objective methods. Significant SD improvements were found at the 9th month., NA

Background/aims: an increased post-operative mortality risk has been reported among patients who undergo living donor liver transplantation (LDLT) with higher model for end-stage liver disease (MELD) scores. In this study, we investigated the effect of MELD score reduction on post-operative outcomes in patients with a high MELD (>= 20) score by pre-transplant management. Materials and methods: we retrospectively analyzed 386 LDLT cases, and patients were divided into low-MELD (<20, n=293) vs. high-MELD (>= 20, n=93) groups according to their MELD score at the time of index hospitalization. Patients in the high-MELD group were managed specifically according to a treatment algorithm in an effort to decrease the MELD score. Patients in the high-MELD group were further divided into 2 subgroups: (1) responders (n=34) to pre-transplant treatment with subsequent reduction of the MELD score by a minimum of I point vs. (2) non-responders (n=59), whose MELD score remained unchanged or further increased on the day of LDLT. Responders vs. non-responders were compared according to etiology, demographics, and survival., NA

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., NA