Daniele Nicolini

Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis.

Background/Aims: High‐fat dietary intake and low physical activity lead to insulin resistance, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent studies have shown an effect of glucagon‐like peptide‐1 (GLP‐1) on hepatic glucose metabolism, although GLP‐1 receptors (GLP‐1r) have not been found in human livers. The aim of this study was to investigate the presence of hepatic GLP‐1r and the effect of exenatide, a GLP‐1 analogue, on hepatic signalling.

Safety of Conversion From Twice-Daily Tacrolimus (Prograf) to Once-Daily Prolonged-Release Tacrolimus (Advagraf) in Stable Liver Transplant Recipients

Nonadherence to immunosuppressive regimens among solid organ transplantation to range has been estimated from 15% to 55%. This problem has been identified as a leading cause of preventable graft loss. Tacrolimus once daily Advagraf has been developed to provide a more convenient dosing regimen to improve adherence. The aim of this study was to analyze the safety of a 1:1 dose conversion from twice-daily tacrolimus (Prograf) to Advagraf in 36 stable liver transplant recipients. The tacrolimus whole blood trough level at T0 was 6.7 +/- 2.9 ng/mL with a daily dose of 3.7 +/- 1.8 mg. The mean tacrolimus blood trough levels at T1 (7 days) and T2 (14 days) were 5.8 +/- 2.5 and 5.8 +/- 1.8 ng/mL with mean daily doses of 3.9 +/- 1.9 and 4.1 +/- 1.8 mg, respectively. There was no significant difference between T0, T1, and T2, either for tacrolimus blood trough levels or for tacrolimus daily dosages. Liver and renal function tests remained stable; no episodes of acute rejection were encountered after the conversion. A switching policy using a dose ratio of 1:1 from twice-daily tacrolimus to once-daily prolonged-release tacrolimus was safely applied to stable liver transplant recipients.

ALPPS Procedure for Extended Liver Resections: A Single Centre Experience and a Systematic Review

Aim To report a single-centre experience with the novel Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) technique and systematically review the related literature. Methods Since January 2013, patients with extended primary or secondary liver tumors whose future liver remnant (FLR) was considered too small to allow hepatic resection were prospectively assessed for the ALPPS procedure. A systematic literature search was performed using PubMed, Scopus and the Cochrane Library Central. Results Until July 2014 ALPPS was completed in 9 patients whose mean age was 60±8 years. Indications for surgical resection were metastases from colorectal cancer in 3 cases, perihilar cholangiocarcinoma in 3 cases, intrahepatic cholangiocarcinoma in 2 cases and hepatocellular carcinoma without chronic liver disease in 1 case. The calculated FLR volume was 289±122 mL (21.1±5.5%) before ALPPS-1 and 528±121 mL (32.2±5.7%) before ALLPS-2 (p<0.001). The increase in FLR between the two procedures was 96±47% (range: 24–160%, p<0.001). Additional interventions were performed in 4 cases: 3 patients underwent Roux-en-Y hepaticojejunostomy, and one case underwent wedge resection of a residual tumor in the FLR. The average time between the first and second step of the procedure was 10.8±2.9 days. The average hospital stay was 24.1±13.3 days. There was 1 postoperative death due to hepatic failure in the oldest patient of this series who had a perihilar cholangiocarcinoma and concomitant liver fibrosis; 11 complications occurred in 6 patients, 4 of whom had grade III or above disease. After a mean follow-up of 17.1±8.5 months, the overall survival was 89% at 3–6 and 12 months. The recurrence-free survival was 100%, 87.5% and 75% at 3-6-12 months respectively. The literature search yielded 148 articles, of which 22 articles published between 2012 and 2015 were included in this systematic review. Conclusion The ALPPS technique effectively increased the resectability of otherwise inoperable liver tumors. The postoperative morbidity in our series was high in accordance with the data from the systematic review. Age, liver fibrosis and presence of biliary stenting were predisposing factors for postoperative morbidity and mortality.

A Novel Prognostic Index in Patients With Hepatocellular Cancer Waiting for Liver Transplantation: Time-Radiological-response-Alpha-fetoprotein-INflammation (TRAIN) Score.

Objective: A novel and easy prognostic score based on the combination of pre-operatively available variables in patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) has been developed from a long waiting time (WT) training set and then validated in a short-WT set. Summary of Background Data: The role of radiological response to loco-regional therapies, alpha-fetoprotein modification, inflammatory markers, and length of WT has been recently shown to be important selection criteria for the risk of intention-to-treat (ITT)-death and recurrence. Methods: The training set consisted of 179 HCC patients listed for LT during the period January 2000 to December 2012 from the UCL Brussels Transplant Centre; the validation set consisted of 110 patients listed during the period January 2005 to December 2014 from the Ancona Liver Centre. Results: The proposed Time–Radiological-response–Alpha-fetoprotein–INflammation (TRAIN) score was the best predictor of microvascular invasion. A TRAIN score ≥1.0 excellently stratified both the investigated populations in terms of ITT and recurrence survivals. When compared with Milan criteria, the proposed score allowed obtaining an increase of potentially transplantable patients (+8.9% in training set and 24.6% in validation set) without additive recurrence risks. Conclusions: The proposed TRAIN score is an easy selection tool based on variables available before LT. This score enables the selection process to be refined in the 2 different scenarios of long and short WT. In case of longer WT, the score is better at predicting risk of death during the WT; in case of short WT, the score is better at identifying risk of post-LT recurrence.

Predictive factors of short term outcome after liver transplantation: A review

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1(th) and the 5(th) day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function.

Elderly Versus Young Liver Transplant Recipients: Patient and Graft Survival

The indications for organ transplantation continue to broaden with advances in perioperative care and immunosuppression. The elderly have especially benefited from this progress; advanced age is no longer considered a contraindication to transplantation at most centers. Although numerous studies support the use of renal allografts in older patients, only a few centers have addressed this issue as it pertains to liver transplantation. Published studies have revealed that operative course, length of hospitalization, and incidence of perioperative complications among patients older than 60 years of age are comparable with their younger adult counterparts. In our study we analyzed the clinical experiences of two centers with primary cadaveric orthotopic liver transplantations comparing patients older than 63 with patients younger than 40 years of age, suggesting no difference in unadjusted survival with age stratification. Now age cannot be considered to be a contraindication to liver transplantation.

Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer

The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing to discriminate between “high‐” and “low‐benefit” patients. To do so, the concept of intention‐to‐treat (ITT) survival benefit of LT has been created. Data of 2,103 adult HCC patients consecutively enlisted during the period 1987‐2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non‐LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (Model for End‐Stage Liver Disease, alpha‐fetoprotein, Milan‐Criteria status, and radiological response) displayed a high effect in terms of delta benefit. According to these risk factors, four benefit groups were identified. Patients with three to four factors (“no‐benefit group”; n = 405 of 2,103; 19.2%) had no benefit of LT compared to alternative treatments. Conversely, patients without any risk factor (“large‐benefit group”; n = 108; 5.1%) yielded the highest benefit from LT reaching 60 months. Conclusion: The ITT transplant survival benefit presented here allows physicians to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equitable method of organ allocation. Patients without benefit should be de‐listed, whereas patients with large benefit ratio should be prioritized for LT. (Hepatology 2017;66:1910–1919)

Fast track program in liver resection: a PRISMA-compliant systematic review and meta-analysis.

Background: FT program (FT) is a multimodal approach used to enhance postoperative rehabilitation and accelerate recovery. It was 1st described in open heart surgery, then modified and applied successfully in colorectal surgery. FT program was described in liver resection for the 1st time in 2008. Although the program has become widely accepted, it has not yet been considered the standard of care in liver surgery. Objectives: we performed this systematic review and meta-analysis to evaluate the impact of using the FT program compared to the traditional care (TC), on the main clinical and surgical outcomes for patients who underwent elective liver resection. Methods: PubMed/Medline, Scopus, and Cochran databases were searched to identify eligible articles that compared FT with TC in elective liver resection to be included in this study. Subgroup meta-analysis between laparoscopic and open surgical approaches to liver resection was also conducted. Quality assessment was performed for all the included studies. Odds ratios (ORs) and mean differences (MDs) were considered as a summary measure of evaluating the association in this meta-analysis for dichotomous and continuous data, respectively. A 95% confidence interval (CI) was reported for both measures. I 2 was used to assess the heterogeneity across studies. Results: From 2008 to 2015, 3 randomized controlled trials (RCTs) and 5 cohort studies were identified, including 394 and 416 patients in the FT and TC groups, respectively. The length of hospital stay (LoS) was markedly shortened in both the open and laparoscopic approaches within the FT program (P < 0.00001). The reduced LoS was accompanied by accelerated functional recovery (P = 0.0008) and decreased hospital costs, with no increase in readmission, morbidity, or mortality rates. Moreover, significant results were found within the FT group such as reduced operative time (P = 0.03), lower intensive care unit admission rate (P < 0.00001), early bowel opening (P ⩽ 0.00001), and rapid normal diet restoration (P ⩽ 0.00001). Conclusion: FT program is safe, feasible, and can be applied successfully in liver resection. Future RCTs on controversial issues such as multimodal analgesia and adherence rate are needed. Specific FT guidelines should be developed for liver resection.

Immunological risk factors in biliary strictures after liver transplantation.

BACKGROUND The purpose of this study was to investigate immunological risk factors associated with BS (Biliary Strictures) after LT (Liver Transplantation). MATERIAL AND METHODS The study included 192 patients out of 273 adult liver transplantations performed from August 2005 to December 2012, with a radiological or surgically proven biliary stricture. About 35 potential risk factors for biliary strictures were studied. Results A biliary stricture was diagnosed in 22.9% of transplants; the anastomotic type and the non-anastomotic type complicated the transplantation in 18.2% and 7.8% of cases, respectively. Six patients (3.1%) presented both of forms. Univariate analysis using logistic regression showed that preoperative serum bilirubin level >2 mg/dl (P=0.040), donor age >46 years old (P=0.007), positive crossmatch (P=0.007), product of donor age and preoperative Model for End Stage Liver Disease (DMELD) >710 (P=0.011), occurrence of acute or chronic rejection (P=0.004; P=0.003), and biliary leak (P=0.002) were all significantly associated with the development of biliary stricture. At the multivariate analysis, Primary Biliary Cirrhosis (PBC) (P=0.019), donor age >46 years (P=0.008), crossmatch positivity (P=0.001), and acute or chronic rejection (P=0.005; P=0.043) appeared to be the only variables independently associated with the development of a biliary stricture. Conclusions Immunological risk factors (PBC, crossmatch positivity, acute and chronic rejection) emerged as being the most important variables associated to the development of biliary strictures after LT.

Liver Transplantation in Patients with Common Variable Immunodeficiency: A Report of Two Cases

BACKGROUND Common variable immunodeficiency (CVID) is the most common primary immunodeficiency disease and is a heterogeneous group of antibody deficiency syndromes characterized by hypogammaglobulinemia, recurrent bacterial infections, and frequent autoimmune manifestations. Liver transplantation (LT) is rarely performed in patients with CVID and associated end-stage liver disease. CASE REPORT We report the successful results of 2 patients who underwent LT with pre-existing diagnosis of CVID. Case 1: A 21-year-old man affected by CVID and HCV-related cirrhosis underwent LT in December 2010 with a 67-year-old deceased donor liver graft. At the time of LT, MELD score was 30. The early post-LT course was characterized by a biliary stricture treated with Roux-en-Y repackaging of the anastomosis. Neither main infections nor acute rejection were detected during the postoperative period. After 43 months follow-up, the patient is alive and well with a histological recurrence of hepatitis C grade 1 and stage 2 according to Metavir staging. Case 2. On March 2013, a 53-year-old woman developed HBV-related fulminant liver failure and underwent urgent LT utilizing a 21-year-old deceased donor liver graft. The postoperative course was characterized by relaparotomy for hemoperitoneum. CMV infection was diagnosed 5 months after LT and resolved after valganciclovir therapy. After 6 months, mild acute rejection was diagnosed and treated with steroids. The patient is currently alive and well. The immunosuppressive regimen was based on Advagraf and early steroids discontinuation in both patients. CONCLUSIONS LT should not be precluded to patients with CVID and end-stage liver diseases. Immunosuppression has a key role in this category of patients to balance the higher risk of rejection and serious infections.