Background & aims: Diabetes mellitus is a major risk factor for fatty liver disease development and progression. A novel machine learning method identified five clusters of patients with diabetes, with different characteristics and risk of diabetic complications using six clinical and biological variables. We evaluated whether this new classification could identify individuals with an increased risk of liver-related complications. Methods: We used a prospective cohort of patients with a diagnosis of type 1 or type 2 diabetes without evidence of advanced fibrosis at baseline recruited between 2000 and 2020. We assessed the risk of each diabetic cluster of developing liver-related complications (i.e. ascites, encephalopathy, variceal haemorrhage, hepatocellular carcinoma), using competing risk analyses. Results: We included 1,068 patients, of whom 162 (15.2%) were determined to be in the severe autoimmune diabetes subgroup, 266 (24.9%) had severe insulin-deficient diabetes, 95 (8.9%) had severe insulin-resistant diabetes (SIRD), 359 (33.6%) had mild obesity-related diabetes, and 186 (17.4%) were in the mild age-related diabetes subgroup. In multivariable analysis, patients in the SIRD cluster and those with excessive alcohol consumption at baseline had the highest risk for liver-related events. The SIRD cluster, excessive alcohol consumption, and hypertension were independently associated with clinically significant fibrosis, evaluated by liver biopsy or transient elastography. Using a simplified classification, patients assigned to the severe and mild insulin-resistant groups had a three- and twofold greater risk, respectively, of developing significant fibrosis compared with those in the insulin-deficient group. Conclusions: A novel clustering classification adequately stratifies the risk of liver-related events in a population with diabetes. Our results also underline the impact of the severity of insulin resistance and alcohol consumption as key prognostic risk factors for liver-related complications. Impact and implications: Diabetes represents a major risk factor for NAFLD development and progression. This study examined the ability of a novel machine-learning approach to identify at-risk diabetes subtypes for liver-related complications. Our results suggest that patients that had severe insulin resistance had the highest risk of liver-related outcomes and fibrosis progression. Moreover, excessive alcohol consumption at the diagnosis of diabetes was the strongest risk factor for developing liver-related events.

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder that may develop in association with portal hypertension [1] (porto-pulmonary hypertension, PoPH). When liver transplantation (LT) is performed in patients with PoPH, the risks of cardiogenic shock and death during and early after the surgery [1,2] are increased, as a consequence of abrupt haemodynamic changes occurring during the procedure. Indeed, these risks could be higher in patients with multi-organ failure (MOF).

Background: Ciliopathies are rare diseases causing renal and extrarenal manifestations. Here, we report the case of a ciliopathy induced by a homozygous pathogenic variant in the TTC21B gene. Case Description: A 47-year-old patient started hemodialysis for chronic kidney disease (CKD) of unknown origin. She presented with early onset of hypertension, pre-eclampsia, myopia and cirrhosis. Renal biopsy showed mild interstitial fibrosis, tubular atrophy, and moderate arteriosclerosis while liver pathology demonstrates grade B biliary cirrhosis. Family history revealed several cases of early-onset severe hypertension and one case of end-stage renal disease (ESRD) needing kidney transplantation at twenty years of age. Clinical exome sequencing showed homozygosis for the pathogenic variant c.626C>T (p.Pro209Leu) in the TTC21B gene. The patient underwent combined liver-renal transplantation with an excellent renal and hepatic graft outcome. Conclusions:TTC21B gene mutations can lead heterogeneous to clinical manifestations and represent an underappreciated cause of ESRD. The paradigm in diagnosis of CKD of early onset and/or of unknown origin is changing and genetic counseling should be performed in all patients and families that meet those criteria. Renal or combined liver-renal transplantation represents the best option for patients suffering from those diseases in terms of prognosis and quality of life.

Background and Aim The aim of this study is to describe the cholangiographic features and endoscopic management of biliary cast syndrome (BCS), a rare specific ischemic cholangiopathy following liver transplantation. Methods Patients with biliary complications were identified from prospectively collected database records of patients who underwent liver transplantation at the Erasme Hospital from January 2005 to December 2014. After excluding patients with hepatico-jejunostomy or no suspicion of stricture, cholangiograms obtained during endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance imaging were systematically reviewed. Biliary complications were categorized as anastomotic (AS) and non-AS strictures, and patients with BCS were identified. Clinical, radiological, and endoscopic data were reviewed. Results Out of 311 liver transplantations, 14 cases were identified with BCS (4.5%) and treated with ERCP. Intraductal hyperintense signal on T1-weighted magnetic resonance and a "duct-in-a-duct" image were the most frequent features of BCS on magnetic resonance imaging. On initial ERCP, 57% of patients had no stricture. Complete cast extraction was achieved in 12/14, and one of these had cast recurrence. On follow-up, 85% of the patients developed biliary strictures that were treated with multiple plastic stents reaching 60% complete stricture resolution, but 40% of them had recurrence. After a median follow-up of 58 months, BCS patients had lower overall and graft survival (42.9% and 42.9%) compared with non-AS (68.8% and 56.3%) and AS (83.3% and 80.6%), respectively. Conclusions Particular magnetic resonance-cholangiographic and ERCP-cholangiographic features of BCS have been identified. Outcomes for BCS are characterized by high complete cast extraction rates, high incidence of secondary strictures, and poorer prognosis.

Background: Preservation solutions used for organ procurement and transportation before liver transplantation (LT) differ in their electrolytes content and density. The influence of the solution type on liver function recovery and postoperative complications after LT still remains controversial. We aimed to compare the outcomes of patients after LT according to the type of preservation solution. Methods: All patients undergoing LT at our institution were retrospectively reviewed from a prospectively maintained database. Early allograft dysfunction was assessed according to Olthoff's, Dhillon's and MEAF's scores. Postoperative and long-term outcomes were compared between grafts preserved with UW, HTK or IGL-1 solutions. Results: Between 2007 and 2018, 432 LT were performed on 403 patients, divided into IGL-1 (n=111), HTK (n=186) and UW (n=135) groups. The median recipient age at LT was 56 years old and sex ratio 2.1 (291 men, 141 women). No difference was observed between groups according to sex, age, BMI and Child-Pugh scores. The postoperative mortality was similar between groups, such as the rate of biliary fistula and retransplantation for primary non function. Less early allograft dysfunction were observed in IGL-1 compared to HTK and UW groups according to Olthoff's definition (51% vs. 69% and 72%, p<=0.005), and compared to only HTK group according to MEAF score (12% vs. 21%, p=0.044). After a median follow-up of 35 months (shorter in IGL-1 compared to HTK and UW groups: 20 vs. 48 and 92 months, p<0.001), biliary stricture was less frequent in IGL-1 compared to HTK and UW groups (14% vs. 33% and 31%, p<0.005); the median delay for developing biliary stricture was similar between groups, ranging from 4 to 5 months. Conclusions: IGL-1 solution seems to have some benefits on liver function recovery and could reduce the incidence of biliary stricture after LT, compared to HTK solution.

Background and aim Insulin resistance plays an important role in chronic liver disease, where it has been associated with the progression of fibrosis and correlated with portal hypertension in cirrhotic patients with mixed etiology. However, the impact of insulin resistance in alcoholic liver disease remains mostly unknown. The aim of this study was to evaluate the association between insulin resistance, portal hypertension, severity of liver disease, and mortality in patients with alcoholic cirrhosis. Patients and methods A total of 106 consecutive alcoholic cirrhotic patients undergoing hepatic venous pressure gradient measurement at Erasme Hospital were included. Insulin resistance was estimated using the homeostatic model assessment-2 index. Results The median model for end-stage liver disease (MELD) score was 15 (9–21) and the mean hepatic venous pressure gradient was16.3±6 mmHg. Twenty-six percent of the patients had compensated cirrhosis. Insulin resistance was significantly associated with portal hypertension in compensated cirrhotic patients and with the presence of esophageal varices, but was not associated with the MELD score and mortality. MELD score was the only independent covariate associated with mortality at 6 (P<0.001) and 12 months (P<0.001). Conclusion Insulin resistance is associated with the presence of esophageal varices, suggesting that the presence of insulin resistance could be harmful to alcoholic liver disease patients.

BACKGROUND:We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin. METHODS:LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells. RESULTS:Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (Vβ/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells. CONCLUSION:High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-γ and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.

The treatment of hepatocellular carcinoma (HCC) in cirrhotic patients is challenging: the incidence is increasing, the cirrhosis dramatically limits the tolerance to treatment possibilities, there are many therapeutic modalities but resources are limited, namely in the context of organ shortage for transplantation. Liver transplantation (LT) is the optimal treatment as it combines the largest tumor resection possible and the correction of the underlying liver disease. Due to organ shortage however, LT is reserved for early-stages HCC. Surgical resection and radiofrequency destruction represent potentially curative options in highly selected patients. Arterial embolizations, chemo- or radio-embolizations, allow local tumor control but are not curative. These techniques could be performed before surgical resection or LT, to downstage the tumor and/or to control tumor progression while waiting for a graft. Finally, sorafenib is the only systemic treatment which has shown a survival benefit in advanced HCC. The benefit of combination of sorafenib and surgical treatments remains undetermined. The challenge in the management of HCC in cirrhotic patients is to integrate both individual (age, comorbidities, cirrhosis stage, tumor stage, specific contraindications to LT, etc.) and collective variables (expected waiting time before LT) to determine the best therapeutic option for each patient. In this process, multidisciplinarity is a key for success.

We designed a pilot trial in cadaveric liver transplantation to determine whether induction with antithymocyte globulins (ATG) and sirolimus would allow immunosuppression withdrawal. Patients received ATG 3.75 mg/kg per day from day 1 to 5 after transplantation followed by sirolimus for 4 to 6 months. We monitored interleukin (IL)-7 serum levels, interferon (IFN)-γ, and IL-2 mRNA accumulation in mixed leukocyte reaction and intragraft IFN-γ mRNA expression. In the first three patients, immunosuppression discontinuation was followed by reversible acute rejection occurring on days 280, 246, and 163 posttransplantation, corresponding to days 140, 40, and 39 after drug withdrawal, respectively. At the time of rejection, blood CD8+ T-cells counts had returned to or above pretransplant levels in two of three patients, whereas CD4+ T-cell count remained low. IL-7 serum levels rose in all three patients in the first months after transplantation and IFN-γ mRNA accumulated in mixed leukocyte reaction between recipient T cells and donor spleen cells at the time of rejection. High levels of IFN-γ mRNA were consistently detected in liver biopsy performed at the time of rejection. In conclusion, lymphopenia-induced IL-7 production after induction with ATG and sirolimus might lead to emergence of IFN-γ-secreting CD8+ T-cells responsible for acute rejection after immunosuppression withdrawal.

Donckier, V; Buggenhout, A; Troisi, R; Lucidi, V; Rogiers, X; Nagy, N; Craciun, L; Bourgeois, N; de Hemptinne, B; Goldman, M Author Information

Better tools for predicting the risk of death while awaiting transplantation are urgently needed because organ shortage is increasing the numbers on transplantation waiting lists. The aminopyrine breath test (ABT), model for end-stage liver disease (MELD), and Child-Pugh (C-P) score were compared as predictors of this risk in 137 cirrhotic candidates for liver transplantation. Eighty-three were transplanted within 3 months of registration, 35 others survived, 13 died before transplantation, and 6 were removed from the list. By univariate analysis, the continuous variables significantly associated with death while awaiting transplantation were: history of infected ascites, C-P score, ABT, and international normalized ratio or prothrombin time. Receiver operating characteristic curves for quantitative variables showed that the area under the curve was greatest for ABT (0.858 +/- 0.067). By Youden curve analysis, the best cut-off points for identifying cirrhotic patients at high risk of death while on the waiting list were: > 10, > 16, and < 0.7% for the C-P score, MELD score, and ABT, respectively. These results show that ABT is as good as the MELD and C-P scores, or better, as a predictor of death among cirrhotic patients awaiting liver transplantation.