A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

Group 2 innate lymphoid cells exhibit progressively higher levels of activation during worsening of liver fibrosis.

INTRODUCTION: The interleukin-33/interleukin-13 pathway is involved in the immunopathology of liver fibrosis and recently characterized group 2 innate lymphoid cells (ILC2) were identified as profibrotic immune cells in the liver of mouse models. Our aim was to elucidate whether ILC2 might be present in human liver tissue and whether ILC2 contribute to liver fibrosis. MATERIALS AND METHODS: To identify ILC2 in liver tissue and blood, we purified mononuclear immune cells from needle biopsies, cirrhotic explant specimen, and paired peripheral blood samples. Cell suspensions were incubated with specific markers for ILC2 and analyzed by flow cytometry. The CD69 marker was included to assess the activation level of ILC2. In addition, we determined the IL-33 plasma level. RESULTS: Results were correlated with the METAVIR fibrotic score of patients enrolled in this study. We detected ILC2 in a higher percentage of CD45+ cells in liver tissue than in paired peripheral blood. The number of ILC2 was significantly increased in fibrotic tissue, but only slightly increased in paired peripheral blood. A higher percentage of CD69+ ILC2 was observed in fibrotic tissue, and this increase correlates positively with aggravation of liver fibrosis measured by fibrotic METAVIR score. A higher level of plasma IL-33 was only detected in samples obtained from cirrhotic patients. CONCLUSION: Our study indicates that ILC2 are present in the human liver and are activated in tissue contributing to the immunopathology of human liver fibrosis, independently of the etiology; which might be a potential new therapeutic target.

Liver transplantation in adults with acute liver failure: Outcomes from the Argentinean Transplant Registry.

INTRODUCTION AND AIM: Liver transplantation (LT) for acute liver failure (ALF) still has a high early mortality. We aimed to evaluate changes occurring in recent years and identify risk factors for poor outcomes. MATERIAL AND METHODS: Data were retrospectively obtained from the Argentinean Transplant Registry from two time periods (1998-2005 and 2006-2016). We used survival analysis to evaluate risk of death. RESULTS: A total of 561 patients were listed for LT (69% female, mean age 39.5±16.4 years). Between early and later periods there was a reduction in wait-list mortality from 27% to 19% (p<0.02) and 1-month post-LT survival rates improved from 70% to 82% (p<0.01). Overall, 61% of the patients underwent LT and 22% died on the waiting list. Among those undergoing LT, Cox regression analysis identified prolonged cold ischemia time (HR 1.18 [1.02-1.36] and serum creatinine (HR 1.31 [1.01-1.71]) as independent risk factors of death post-LT. Etiologies of ALF were only available in the later period (N=363) with indeterminate and autoimmune hepatitis accounting for 28% and 26% of the cases, respectively. After adjusting for age, gender, private/public hospital, INR, creatinine and bilirubin, and considering LT as the competing event, indeterminate etiology was significantly associated with death (SHR 1.63 [1.06-2.51] and autoimmune hepatitis presented a trend to improved survival (SHR 0.61 [0.36-1.05]). CONCLUSIONS: Survival of patients with ALF on the waiting list and after LT has significantly improved in recent years. Indeterminate cause and autoimmune hepatitis were the most frequent etiologies of ALF in Argentina and were associated with mortality.

Changing etiologies and outcomes of acute liver failure: perspectives from 6 transplant centers in Argentina.

There is significant geographic variation in the etiologies and prognoses of acute liver failure (ALF). The aims of the present study were to determine the causes and short-term outcomes of ALF in Argentina, to evaluate the performance of prognostic criteria, and to identify clinical prognostic factors of death. We performed a retrospective analysis of 154 adult patients with ALF who were admitted to 6 liver transplantation (LT) programs between June 2005 and December 2011. The most frequent causes of ALF were viral hepatitis B (46 patients or 30%), autoimmune hepatitis (AIH; 40 patients or 26%), and indeterminate causes (40 patients or 26%). No acetaminophen (ACM) overdose was reported. One hundred and twenty one patients (78%) were included on the waiting list, and LT was performed for 83 patients (54%). Overall survival rate is now corected to 73%. Multivariate logistic regression identified 2 independent variables associated with adverse outcomes on admission: a Model for End-Stage Liver Disease (MELD) score ≥ 29 and an encephalopathy grade ≥ 3. In a direct comparison using a receiving operating characteristic curve analysis, the MELD score [C statistic = 0.830, 95% confidence interval (CI) = 0.73-0.93] had better prognostic accuracy for predicting outcomes than the Clichy criteria (C statistic = 0.719, 95% CI = 0.58-0.85) or the King's College criteria (C statistic = 0.631, 95% CI = 0.49-0.77). In conclusion, hepatitis B and AIH were the most frequent causes of fulminant hepatic failure in our series, and no cases of ACM overdosing were identified. A MELD score ≥ 29 and an encephalopathy grade ≥ 3 at admission were associated with death. The MELD score at admission showed the highest prognostic accuracy.

Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors.

BACKGROUND & AIMS: Robust clinical data evaluating fibrosis progression in hepatitis C virus (HCV) liver transplant patients receiving an mTOR inhibitor vs. calcineurin inhibitor (CNI) are lacking. To evaluate fibrosis progression in maintenance liver transplant patients receiving everolimus- or CNI-based immunosuppression. METHODS: In a randomised, multicentre, open-label study, 43 maintenance liver transplant patients with recurrent HCV infection were randomised to continue CNI-based immunosuppression or switch to everolimus. RESULTS: For patients with biopsy data at month 12, mean Ishak-Knodell fibrosis score at baseline was 2.6 ± 0.9 (n = 14) with everolimus vs. 1.9 ± 1.1 (n = 18) with CNI (P = 0.043), and 1.9 ± 1.2 vs. 2.2 ± 1.3 at month 12. Ishak-Knodell fibrosis score decreased from baseline to month 12 by a mean of -0.7 ± 1.1 with everolimus, but increased by 0.2 ± 1.2 with CNI (P = 0.046). No acute rejection or graft losses occurred up to month 12. Estimated GFR at month 12 was 65.6 ml/min/1.73 m² with everolimus and 62.2 ml/min/1.73 m² with CNI [mean difference 3.4 ml/min/1.73 m² compared to CNI control group, 95% CI -4.9, 11.8 ml/min/1.73 m², P = 0.411 (analysis of covariance adjusting for baseline GFR)]. Adverse events occurred in 95.5% of everolimus patients and 71.4% of CNI patients (serious adverse events 31.8% and 0.0%, respectively). Adverse events led to everolimus discontinuation in five patients (22.7%). CONCLUSIONS: This exploratory study suggests that conversion from CNI to everolimus reduces progression of liver fibrosis, and preserves renal function without jeopardising efficacy in liver transplant recipients with recurrent HCV, but is associated with a higher incidence of adverse events and serious adverse events. These preliminary findings merit examination in a larger trial.

[Hepatocellular carcinoma within Milan criteria and beyond: outcomes of liver transplantation in a single Argentinian institution]. / Hepatocarcinoma dentro y fuera de los criterios de Milán: resultados de un centro de trasplante hepático en la Argentina.

Hepatocellular carcinoma (HCC) recurrence following liver transplantation is associated to bad prognosis. We retrospectively analyzed the data of 95 patients who underwent liver transplantation for HCC. Recurrence rate and variables associated with recurrence were reviewed. According to the findings on the explanted livers they were divided in two groups: Milan (M) 67% and non-Milan (NM) 33%. Global recurrence rate, and M-group and NM-group recurrence rates were 19%; 12% and 32%, respectively (P = 0.001). Although in the univariate analysis we found some factors associated to recurrence (hemocromathosis, year of transplant, bilobar distribution, vascular invasion and previous chemoembolization), they were not independent predictors of recurrence in the multivariate analysis. Actuarial survival in cirrhotic patients with and without HCC at 1, 3 and 5 years was 86% and 91% (NS), 77% and 88% (NS), and 67% and 86% (P = 0.002), respectively; whereas actuarial survival of the M and NM groups was 86% and 71%; 82% and 61%, and 78% and 58%, respectively (P = 0.02). We had a satisfactory five-year global survival in our series even though one third of our patients grafted for HCC were outside Milan criteria.

[Hepatitis E: an infrequent virus or an unfrecuently investigated agent?]. / Hepatitis E: un virus infrecuente o un agente infrecuentemente pensado?

Two cases of hepatitis E that were assisted in our Unit of Hepatology and Liver Transplantation are described in this article. The first patient had prior hepatic involvement and therefore a more severe course, whereas the second case, with normal liver function, only developed a self-limited acute hepatitis.

A Novel Surgical Technique to Assure Donor and Recipient Safety: Pyloric to Segment 4 Arterial Reconstruction.

BACKGROUND: Strategies to extend the pool of organs include and promote the use of segmental liver grafts. While performing a living donor left lateral segment (LLS) liver transplant and in split procedures, the hepatic artery´s division becomes critical when a dominant segment 4 artery (S4A) emerges from the left hepatic artery (LHA). We aim to describe a novel technique that consists of performing microsurgical reconstruction from the pyloric artery (PA) to S4A. CASE REPORTS: A 45-y-old living donor was evaluated to use his LLS as a graft for a pediatric recipient. During the procedure, a dominant S4A born from the LHA was dissected. To obtain an appropriate LHA length and diameter for the recipient, it was necessary to transect it. An extended right lobe split graft was used in a 61-y-old patient. The S4A born from LHA had to be sectioned during the split procedure. In both cases, segment 4 remained incompletely perfused. The PA was dissected with enough length to be rotated, to perform a microsurgical anastomosis to the S4A, recovering parenchyma's color and Doppler signal while vascular permeability was demonstrated using CT scan. There was no biliary or cut surface complication. CONCLUSIONS: PA to S4A reconstruction is a simple and novel technique that can be used for LLS and extended right lobe split graft and might contribute to increase donor selection and reduce living donor and recipient S4A-related complications.

Fulminant presentation of autoimmune hepatitis: clinical features and early predictors of corticosteroid treatment failure.

BACKGROUND AND AIMS: Classical features of autoimmune hepatitis (AIH) may be altered during the abrupt onset of the disease. Corticosteroid therapy can be life-saving, but its use in the fulminant presentation of AIH (F-AIH) remains controversial. We aimed to assess the clinical features of patients with F-AIH and to describe the role of corticosteroids in this population. PATIENTS AND METHODS: We retrospectively analyzed 154 adult patients with fulminant hepatic failure who were admitted to six liver transplantation (LT) programs. The AIH simplified criteria were used to identify patients with F-AIH. RESULTS: We identified 40 (26%) patients with F-AIH. Compared with other etiologies, patients with F-AIH presented a longer interval from jaundice to encephalopathy (26 vs. 16 days, P=0.02) and a lower Model for End-Stage Liver Disease (MELD) score on admission (29 vs. 33, P=0.002). Overall, 25 (62%) patients with F-AIH underwent LT, eight (20%) patients survived, and seven (18%) died without LT. Seventeen patients received corticosteroids therapy, of whom seven (41%) survived without LT. Among the treated patients, higher MELD score and encephalopathy grade of 3 or more were associated significantly with corticosteroid failure. CONCLUSION: Patients with F-AIH have a more indolent presentation compared with the non-F-AIH population. Altogether, only eight (20%) patients presenting with F-AIH survived without LT. A subset of patients with F-AIH and an initial MELD score less than 27 and low-grade hepatic encephalopathy might benefit from administration of corticosteroids.

MELD is superior to King's college and Clichy's criteria to assess prognosis in fulminant hepatic failure.

Assessment of prognosis in fulminant hepatic failure (FHF) is essential for the need and appropriate timing of orthotopic liver transplantation (OLT). In this study we investigated the prognostic efficacy of King's College criteria, Clichy's criteria, Model for End-Stage Liver Disease (MELD), and Pediatric End-Stage Liver Disease (PELD) in 120 consecutive patients with FHF. Survival with medical therapy (18%), death without OLT (15%), and receipt of a liver transplant were similar in adults (n = 64) and children (n = 56). MELD scores were significantly higher in patients who died compared to those who survived without OLT, both in adults (38 +/- 7 vs. 26 +/- 7, P = 0.0003) and children (39 +/- 7 vs. 23 +/- 6, P = 0.0004). Using logistic regression analysis in this cohort of patients, concordance statistics were significantly higher for MELD (0.95) and PELD (0.99) when compared to King's College (0.74) and Clichy's criteria (0.68). When data was analyzed in a Cox model including patients receiving transplants and censoring the time from admission, the concordance statistic for MELD (0.77) and PELD (0.79) remained significantly higher than that of King's College criteria but not higher than that of Clichy's criteria. In conclusion, this study is the first to show that MELD and PELD are superior to King's College and Clichy's criteria to assess prognosis in FHF. However, because data was generated from a single center and included a rather low number of patients who survived or died without OLT, further confirmation of our findings is required.

How common is delayed cyclosporine absorption following liver transplantation?

The mean time to peak absorption of cyclosporine (CsA) in liver transplant patients is approximately 2 hours, but in some patients the peak occurs later. The goal of this study was, therefore, to investigate the incidence of delayed absorption in 27 de novo liver transplant recipients receiving CsA > or =10 mg/kg/day (C(2) monitoring) and in 15 maintenance patients. Patients were categorized as 'normal' absorbers (C(2) exceeding C(4) and C(6)) or 'delayed' absorbers (C(4) or C(6) exceeding C(2)), and as 'good' (>800 ng/mL at C(0), C(2), C(4), or C(6)) or 'poor' absorbers (C(0), C(2), C(4) and C(6) <800 ng/mL) on the day of study. Among de novo patients, 15 (56%) had 'normal' CsA absorption and 12 (44%) 'delayed' absorption. Good CsA absorption occurred in 16 patients (59%) and poor absorption in 11 (41%). The proportion of poor absorbers was similar in patients with normal (6/15, 40%) or delayed (5/12, 42%) absorption. Among the 12 delayed absorbers, 11 had peak CsA concentration at C(4). Mean C(0) level was significantly higher in delayed absorbers (282 +/- 96 ng/mL) than in normal absorbers (185 +/- 88 ng/mL; P = .01). Delayed absorbers reverted to normal absorption (C(2) > C(4)) after a median of 6 days from the day of study, and no cases of delayed absorption were found among maintenance patients. In conclusion, almost 50% of the patients had delayed CsA absorption early posttransplant; around half of these exhibited normal CsA exposure. Measurement of C(4) in addition to C(2) differentiates effectively between delayed and poor absorbers of CsA such that over- or underimmunosuppression can be avoided.

Hepatocarcinoma dentro y fuera de los criterios de Milán: resultados de un centro de trasplante hepático en la Argentina / [Hepatocellular carcinoma within Milan criteria and beyond: outcomes of liver transplantation in a single Argentinian institution].

Hepatocellular carcinoma (HCC) recurrence following liver transplantation is associated to bad prognosis. We retrospectively analyzed the data of 95 patients who underwent liver transplantation for HCC. Recurrence rate and variables associated with recurrence were reviewed. According to the findings on the explanted livers they were divided in two groups: Milan (M) 67

. Global recurrence rate, and M-group and NM-group recurrence rates were 19

, respectively (P = 0.001). Although in the univariate analysis we found some factors associated to recurrence (hemocromathosis, year of transplant, bilobar distribution, vascular invasion and previous chemoembolization), they were not independent predictors of recurrence in the multivariate analysis. Actuarial survival in cirrhotic patients with and without HCC at 1, 3 and 5 years was 86

(NS), and 67

(P = 0.002), respectively; whereas actuarial survival of the M and NM groups was 86

, and 78

, respectively (P = 0.02). We had a satisfactory five-year global survival in our series even though one third of our patients grafted for HCC were outside Milan criteria.

Hepatitis E: un virus infrecuente o un agente infrecuentemente pensado? / [Hepatitis E: an infrequent virus or an unfrecuently investigated agent?].

Two cases of hepatitis E that were assisted in our Unit of Hepatology and Liver Transplantation are described in this article. The first patient had prior hepatic involvement and therefore a more severe course, whereas the second case, with normal liver function, only developed a self-limited acute hepatitis.