M. Sebagh

Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease

BACKGROUND/AIMSnAfter liver transplantation for autoimmune hepatitis, the long-term results and the incidence of recurrence of primary disease are unknown.nnnMETHODSnIn this retrospective study we reviewed the clinical course of 25 patients transplanted for autoimmune hepatitis and followed for a mean of 5.3 years (2-8.5 years).nnnRESULTSnThe actuarial 5-year patient and graft survival rates were 91% (+/-6%) and 83% (+/-8%). The actuarial 1-year rate of acute rejection was 50% (+/-10.2%), which was comparable to that of patients transplanted for primary biliary cirrhosis and primary sclerosing cholangitis. Autoantibodies persisted in 77% of patients, at a lower titer than before liver transplantation. Ten patients were excluded from the study of autoimmune hepatitis recurrence, one because of an early postoperative death and nine because of hepatitis C virus infection acquired before or after liver transplantation. In the remaining 15 patients, who were free of hepatitis C virus infection, 5-year patient and graft survivals were 100% and 87%, respectively. Despite triple immunosuppressive therapy, three patients (20%) developed chronic hepatitis with histological and serological features of autoimmune hepatitis in the absence of any other identifiable cause. The disease was severe in two patients, leading to graft failure and asymptomatic in another, despite marked histological abnormalities. In one of these three patients, autoimmune hepatitis recurred on the second liver graft as well.nnnCONCLUSIONSnPatients undergoing liver transplantation for autoimmune hepatitis have an excellent survival rate although severe primary disease may recur, suggesting the need for stronger post-operative immunosuppressive therapy.

Herpes simplex virus-associated acute liver failure : A difficult diagnosis with a poor prognosis

We report 5 cases of acute liver failure related to herpes simplex (HSV) infection in 1 immunocompetent and 4 immunosuppressed patients. One patient was too ill for liver transplantation indication. Three patients, among the 4 listed, underwent liver transplantation. Three patients died 11 days to 1 year after transplantation and 2 patients died 2 to 3 days after admission. All presented with fever and none with skin lesions. The diagnosis of HSV‐related hepatitis was made antemortem in only 2 patients on the basis of positive blood cultures and/or immunohistochemic findings. In the remaining patients, HSV diagnosis was made retrospectively on further histologic and virologic investigations. Primary HSV infection was certain or likely in all cases, including an HSV2 superinfection of an anti‐HSV1‐positive patient and two HSV superinfections of hepatitis B virus (HBV)‐related chronic liver disease. In these latter patients, HSV diagnosis was totally unsuspected, despite fever. HSV superinfection has significantly contributed to liver dysfunction aggravation and death. In conclusion, the diagnosis of HSV hepatitis is difficult to establish in the absence of specific clinical signs. This may suggest the need for early administration of acyclovir in patients with suspected HSV hepatitis, without waiting for virologic confirmation. Diagnosis methods providing fast results (real‐time polymerase chain reaction [PCR]) should be implemented. (Liver Transpl 2005;11:1550–1555.)

Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes

Whether ischemic preconditioning (IP) reduces ischemia/reperfusion (I/R) injury in human normal and fatty livers remains controversial. We compared two independent groups of liver donor transplants with versus without steatosis to evaluate IP consequences. Liver donors with (n=22) or without (n=28) steatosis either did or did not undergo IP before graft retrieval. Clinical data from the recipients, as well as histological and immunohistological characteristics of post-reperfusion biopsies were analyzed. Incidence of post-reperfusion necrosis was increased (10/10 versus 9/14, respectively; P<0.05) and the clinical outcome of recipients was worse for non-IP steatotic liver grafts compared with non-IP non-steatotic grafts. IP significantly lowered the transaminase values only in patients receiving a non-steatotic liver. An increased expression of beclin-1 and LC3, two pro-autophagic proteins, tended to decrease the incidence of necrosis (P=0.067) in IP steatotic livers compared with non-IP steatotic group. IP decreased the incidence of acute and chronic rejection episodes in steatotic livers (2/12 versus 6/10; P=0.07 and 2/12 versus 7/10; P<0.05, respectively), but not in non-steatotic livers. Thus, IP may induce autophagy in human steatotic liver grafts and reduce rejection in their recipients.

Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy

BACKGROUND/AIMSnLiver pathology induced by chemotherapy (steatosis or vascular injury) is known to increase the livers sensitivity to ischemia/ reperfusion (I/R) injury, thereby increasing morbidity and mortality after liver resection. Our aim was to assess whether ischemic preconditioning (IP) reduces I/R injury to livers with chemotherapy-induced pathology.nnnMETHODSnWe analyzed a series of livers from patients treated with chemotherapy for colorectal cancer who underwent IP (n=30) or not (n=31) before hepatectomy. All but one of the livers exhibited chemotherapy-induced steatosis and/ or peliosis before the I/R insult.nnnRESULTSnNecrosis was less frequent (p=0.038) in livers with IP than in the others. IP had no influence on apoptosis as assessed by terminal transferase uridyl nick-end labeling (TUNEL) assay or caspase-3, -8 and -9 expression. IP induced a twofold increase in B-cell leukemia/ lymphoma 2 (Bcl-2; p<0.05), which was localized to hepatocytes of centrolobular and peliotic areas and colocalized with the autophagy protein beclin-1 in livers with IP, suggesting their coordinated role in autophagy. Increased expression of the phosphorylated Bcl-2 was observed in preconditioned livers and was associated with a decreased immunoprecipitation of beclin-1 and the increased expression of light chain 3 type II (LC3-II). The increased number of autophagic vacuoles seen by electron microscopy confirmed an association of autophagy in chemotherapy-injured livers following IP. However, the differences in protein expression were not reflected in postresection liver-injury tests or measure of patient morbidity.nnnCONCLUSIONSnIP is associated with a reduction in necrosis of hepatocytes already damaged by chemotherapy and an activation of autophagy. Bcl-2 and beclin-1 could be major targets in the regulation of cell death during I/R injury.

The Postresection Alpha-Fetoprotein in Cirrhotic Patients with Hepatocellular Carcinoma. An Independent Predictor of Outcome

BackgroundThe postresection alpha-fetoprotein (AFP) in cirrhotic patients with hepatocellular carcinoma (HCC) may predict overall survival (OS) and recurrence beyond Milan criteria (MC) among the subgroup of initially transplantable patients.MethodsAll patients with cirrhosis resected for HCC between January 1990 and December 2010 in a single institution and presenting a serum AFP valueu2009>u200915xa0ng/ml at diagnosis were included. The postresection AFP was analyzed as a dichotomized variable: normalization (norm + group) or not (norm − group) within the 90-day postresection period.ResultsAmong 271 resected patients, 141 patients (52xa0%) had a level of serum AFPu2009≥u200915xa0ng/ml at diagnosis. Five-year OS and median survival were 42xa0% and 52xa0months in group norm + versus 20xa0% and 23xa0months in the group norm − (Pu2009=u20090.009). On multivariate analysis, the absence of AFP normalization was an independent factor of poor OS as well as microvascular invasion, and satellites nodules. Among theoretically transplantable patients, independent predictors of recurrence beyond MC were the absence of AFP normalization (risk ratio (RR) 5.02 [1.53–16.34]) and microvascular invasion (RR 4.76 [1.42–15.34]).ConclusionThe postresection AFP has an independent prognostic value. Transplantable patients resected for HCC without 90-day AFP normalization should be discussed for early liver transplantation.

Gallbladder adenomyomatosis: Diagnosis and management

Gallbladder (GB) adenomyomatosis (ADM) is a benign, acquired anomaly, characterized by hypertrophy of the mucosal epithelium that invaginates into the interstices of a thickened muscularis forming so-called Rokitansky-Aschoff sinuses. There are three forms of ADM: segmental, fundal and more rarely, diffuse. Etiology and pathogenesis are not well understood but chronic inflammation of the GB is a necessary precursor. Prevalence of ADM in cholecystectomy specimens is estimated between 1% and 9% with a balanced sex ratio; the incidence increases after the age of 50. ADM, although usually asymptomatic, can manifest as abdominal pain or hepatic colic, even in the absence of associated gallstones (50% to 90% of cases). ADM can also be revealed by an attack of acalculous cholecystitis. Pre-operative diagnosis is based mainly on ultrasound (US), which identifies intra-parietal pseudo-cystic images and comet tail artifacts. MRI with MRI cholangiography sequences is the reference examination with characteristic pearl necklace images. Symptomatic ADM is an indication for cholecystectomy, which results in complete disappearance of symptoms. Asymptomatic ADM is not an indication for surgery, but the radiological diagnosis must be beyond any doubt. If there is any diagnostic doubt about the possibility of GB cancer, a cholecystectomy is justified. The discovery of ADM in a cholecystectomy specimen does not require special surveillance.

823 INDETERMINATE CAUSES OF ACUTE LIVER FAILURE: INCIDENCE AND PREDICTIVE FACTORS OF SPONTANEOUS SURVIVAL AND AFTER LIVER TRANSPLANTATION (LT)

Methods: A retrospective study of patients with ALF admitted to a tertiary liver centre from 2001 to 2009 was done. We looked at the demographic data, clinical features, prognostic markers – King’s College Hospital (KCH) criteria and Model for End-Stage Liver Disease (MELD) score, and the outcome of these patients. Data was analysed using SPSS. Results: A total of 155 cases were reviewed. 63.9% were females and the mean age was 36.7±15.9 years. The causes of ALF include hepatitis B-related (23.2%), indeterminate (20.0%), nonparacetamol drug-induced liver injury (DILI) (18.7%), autoimmune liver disease (7.7%), acute paracetamol toxicity (7.1%), acute fatty liver of pregnancy (6.5%), dengue-related (5.2%), Wilson’s disease (4.7%), acute hepatitis A (1.3%), hepatitis C (1.9%) and acute Budd Chiari (1.9%). The overall survival rate was 27.1%. Even though 57.2% of the patients satisfied the KCH criteria, only 2 patients were transplanted with one survived. The spontaneous survival rate in patients who satisfied the KCH was 8.3% while in the group who did not satisfy the KCH, the survival rate was 52.9%. In the group where KCH was not applicable, the survival rate was 53.3%. The mean MELD score for patients who died was 30±7, while for patients who survived the score was 22±7. Multivariable logistic regression showed for any one point increase in MELD score, ORadj1.22 (CI 95%: 1.12, 1.32) for mortality. Conclusion: ALF patients with poor prognostic criteria had a high mortality in the absence of liver transplant. The three main causes of ALF in Malaysia were viral hepatitis B, indeterminate and nonparacetamol DILI.

Large hepatocellular carcinoma: Does fibrosis really impact prognosis after resection?

BACKGROUNDnHepatectomy remains the standard treatment for large hepatocellular carcinoma (LHCC) ≥5cm. Fibrosis may constitute a contraindication for resection because of high risk of post-hepatectomy liver failure, but its impact on patient outcome and cancer recurrence remains ill defined. Our aim was to compare predictors of survival in patients with and without cirrhosis following hepatectomy for LHCC.nnnMETHODSnThe data on consecutive patients undergoing hepatectomy for LHCC in two tertiary centres between 2012 and 2016 were reviewed. The outcomes of cirrhotic (F4) and non-cirrhotic (F0-F3) patients were compared. Patients with perioperative medical (sorafenib) or radiological (transarterial chemoembolization, radiofrequency) treatments were excluded.nnnRESULTSnSixty patients were included. Preoperative and intraoperative features were identical between both groups. Cirrhotics (n=15) presented more satellite nodules on specimens (73% vs. 44%; P=0.073) but better differentiated lesions than non-cirrhotics (P=0.041). The median overall survival of cirrhotics was 34 vs. 29months for non-cirrhotics (P=0.8), and their disease-free survival was 14 versus 18 months (P=0.9). Fibrosis stage did not impact overall (P=0.2) nor disease-free survivals (P=0.6).nnnCONCLUSIONnHepatectomy for LHCC in cirrhotics can achieve acceptable oncological results when compared to non-cirrhotic patients. Curative resection of LHCC should be attempted if liver function is acceptable, whatever the fibrosis stage.

190 DE NOVO AUTO-IMMUNE HEPATITIS AND HCV RECURRENCE AFTER LIVER TRANSPLANTATION: A CHALLENGING DIAGNOSIS AND POOR PROGNOSIS

190 DE NOVO AUTO-IMMUNE HEPATITIS AND HCV RECURRENCE AFTER LIVER TRANSPLANTATION: A CHALLENGING DIAGNOSIS AND POOR PROGNOSIS E. De Martin, A. Coilly, M. Guido, C. Mescoli, M. Sebagh, A.C. Frigo, M. Rugge, D. Samuel, J.-C. Duclos-Vallee, P. Burra. Centre Hepato-Biliaire, AP-HP – Hopital Paul Brousse, Villejuif, France; Dept of Surgical and Gastroenterological Sciences, University Hospital of Padua, Padova, Italy; Faculte de Medecine, Univ Paris-Sud, Le Kremlin-Bicetre, France; Dept of Diagnostic Medical Sciences & Special Therapies, University Hospital of Padua, Padova, Italy; Laboratoire Anatomie Pathologique, AP-HP – Hopital Paul Brousse, Unit 785, INSERM, Villejuif, France; Department of Environmental Medicine and Public Health, University of Padova, Padova, Italy E-mail: audreycoilly@gmail.com

493 RESULTS OF LIVER RETRANSPLANTATION IN A MONOCENTRIC COHORT OF HCV INFECTED PATIENTS

quartile of LDLR mRNA expression in the PI biopsy survived with a significantly (Log-Rank test P < 0.05) better survival than those in the three lowest quartiles. Surviving graft (n = 34, median followup 44.8 months, range 8.6–72.3) had significantly higher LDLR (P < 0.01) and NPC1L1 (P < 0.05) mRNA expression in the PI biopsy and HMGCR (P < 0.05) mRNA expression in the PR biopsy than lost grafts (n = 13, median follow-up 6.0 months, range 0.03–43.7). Conclusions: In the settings of human liver transplantation: 1. hepatic LDLR mRNA is overexpressed immediately after graft reperfusion, suggesting an increased hepatocyte cholesterol uptake from blood; 2. hepatic upregulation of genes involved in cholesterol recruitment and synthesis is inversely related to the severity of IRI and is associated with better graft survival.