NAFLD and liver transplantation: Current burden and expected challenges

Because of global epidemics of obesity and type 2 diabetes, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing both in Europe and the United States, becoming one of the most frequent causes of chronic liver disease and predictably, one of the leading causes of liver transplantation both for end-stage liver disease and hepatocellular carcinoma. For most transplant teams around the world this will raise many challenges in terms of preand post-transplant management. Here we review the multifaceted impact of NAFLD on liver transplantation and will discuss: (1) NAFLD as a frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease, and hepatocellular carcinoma; (2) prevalence of NAFLD as an indication for liver transplantation both in Europe and the United States; (3) the impact of NAFLD on the donor pool; (4) the access of NAFLD patients to liver transplantation and their management on the waiting list in regard to metabolic, renal and vascular comorbidities; (5) the prevalence and consequences of post-transplant metabolic syndrome, recurrent and de novo NAFLD; (6) the alternative management and therapeutic options to improve the long-term outcomes with particular emphasis on the correction and control of metabolic comorbidities

Diagnostic performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using the SAF score as histological reference

BACKGROUND: Blood tests of liver injury are less well validated in non‐alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. AIMS: To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. METHODS: We pre‐included new NAFLD patients with biopsy and blood tests from a single‐centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary‐ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. RESULTS: A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864–0.892) for FibroTest and fibrosis stages, 0.846 (0.830–0.862) for ActiTest and activity grades, and 0.822 (0.804–0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820–0.852; P = 0.0001), FIB4 (0.845; 0.829–0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850–0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). CONCLUSIONS: In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non‐invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis

Domino liver transplantation: the risk of disease recurrence

International audienc

Regression of Hypervascular Nodules in a Patient with Wilson's Disease Awaiting Liver Transplantation

This paper describes the regressive course over one year of hypervascular nodules in a patient with Wilson's disease. CT revealed multiple, enhancing nodules (up to 3 cm in diameter) detected in the liver in the early arterial phase after the administration of intravenous contrast material. Most of these nodules became isodense in the portal venous phase. After one year of efficient therapy combining d-penicillamine and zinc acetate, most of the nodules had disappeared, while the liver contours had become more regular. To our knowledge, the regression of large hypervascular nodules has not previously been reported in patients with Wilson's disease

Regulatory T cell therapy: An option to induce operational tolerance in liver transplantation.

Regulatory T cells (Treg) may play an important role in operational (clinical) tolerance (OT), a stable graft function without immunosuppression in an otherwise immunocompetent host, that is spontaneously observed in some patients many years after transplantation. Several ongoing clinical trials are currently testing the effects of donor-specific or non-specific Treg infusion with the goal to induce this state of OT a few months after liver transplantation (LT). The preliminary results of two of these trials have been recently published, and raise a number of comments and issues: (1) These two papers demonstrate that a 100 to 1000-fold ex-vivo expansion of Treg is possible in humans after 2 weeks of culture. The optimal human Treg dose is however not clearly established, and might be higher than the dose that would be expected from translating murine data. (2) A lot of concerns are remaining regarding the Treg purity before expansion, the Treg stability during in vitro culture and the in vivo fate of infused cells. A strict monitoring of Treg should thus be done at each step. (3) Since Treg may play a detrimental role in some conditions, such as viral diseases and cancer, potential LT recipients with such diseases should probably be excluded from the initial trials of Treg infusion. (4) The follow-up of tolerant liver recipients should include repeated liver biopsies and detection of autoantibodies and humoral response, in addition to conventional liver graft assessment, in order to prevent the development of immune complications related to immunosuppression withdrawal. (5) The final issue raised by Treg therapy in LT is the choice of the immunosuppressive regimen used before tapering or withdrawal, appropriate to preserve OT establishment

Outcome of orthotopic liver transplantation in autoimmune hepatitis according to subtypes

The relevance of autoimmune hepatitis (AIH) classification for clinical purposes is controversial. We analyzed the outcome after orthotopic liver transplantation (OLT) of nine type I and seven type II AIH patients. Type II patients had a significantly higher incidence of cirrhosis at the time of diagnosis, more resistance to steroid therapy, and a higher Child-Pugh score at the time of OLT. OLT was performed in emergency in three type II patients and electively in all type I patients. Four type II and one type I patients died in the postoperative period. There was no difference regarding the incidence of post-OLT infection and rejection between the two types. No recurrence of AIH was observed. The 6-year actuarial survival rates for type I and type II patients were 76% and 43%, respectively. Type II AIH patients who have a poor response to medical therapy should be considered for OLT with a shortened delay

Hepatitis C Virus Improves Human Tregs Suppressive Function and Promotes Their Recruitment to the Liver

International audienceBACKGROUND : The role of regulatory T cells (Tregs) is now well established in the progression of hepatocellular carcinoma (HCC) linked to Hepatitis C virus (HCV) infection. However, nothing is known about the potential interplay between Tregs and HCV. In this pilot study, we have investigated the ability of Tregs to hang HCV on and the subsequent effect on their suppressive function and phenotype. Moreover, we have evaluated how HCV could promote the recruitment of Tregs by infected primary human hepatocytes.METHODS : Tregs of healthy donors were incubated with JFH-1/HCVcc. Viral inoculation was assessed using adapted assays (RT-qPCR, Flow Citometry (FACS) and Western Blot (WB). Expression of Tregs phenotypic (CD4, CD25, CD127 and Foxp3) and functional (IL-10, GZMB, TGF-β1 and IL-2) markers was monitored by RT-qPCR, FACS and ELISA. Suppressive activity was validated by suppressive assays. Tregs recruitment by infected primary hepatic cells was evaluated using Boyden Chamber.RESULTS : Tregs express the classical HCV receptors (CD81, CLDN1 and LDLR) and some co-receptors (CD5). HCV inoculation significantly increases the suppressive phenotype and activity of Tregs, and raises their anergy by inducing an unexpected IL-2 production. Moreover, HCV infection induces the expression of chemokines (CCL17, CXCL16, and CCL20) by primary hepatic human hepatocytes and chemokine receptors (CCR4, CXCR6 and CCR6) by Tregs. Finally, infected hepatocytes have a significantly higher potential to recruit Tregs in a seemingly CCL20-dependent manner.CONCLUSIONS : Direct interaction between HCV and Tregs represents a newly defined mechanism that could potentiate HCV immune evasion and favor intratumoral recruitment contributing to HCC progression

CD49b, a Major Marker of Regulatory T-Cells Type 1, Predicts the Response to Antiviral Therapy of Recurrent Hepatitis C after Liver Transplantation

The TRANSPEG study was a prospective study to assess the efficacy of antiviral therapy in patients with a recurrent hepatitis C virus (HCV) after liver transplantation. The influence of regulatory T-cells (Tregs) on the response to antiviral therapy was analyzed. Patients were considered as a function of their sustained virological response (SVR) at 18 months after treatment initiation. A transcriptomic analysis was performed to assess Treg markers (Tr1 and FoxP3+) in serum, PBMC, and liver biopsies. 100 patients had been included in the TRANSPEG study. Data from 27 of these patients were available. The results showed that the expression of CD49b (a predominant marker of Tr1) before the introduction of antiviral therapy was significantly associated with SVR. Responders displayed lower serum levels of CD49b than nonresponders (P<0.02). These findings were confirmed in PBMC and liver biopsies even if in a nonsignificant manner for the limited number of samples. The assessment of CD49b levels is thus predictive of the response to antiviral therapy. This data suggests that CD49b may be a marker of the failure of the immune response and antiviral therapy during HCV recurrence. The assessment of CD49b could help to select patients who require earlier and more intensive antiviral therapy