P. Ichai

Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis

Immunosuppressive therapy, and particularly corticosteroids with or without azathioprine, can achieve a remission in more than 80% of patients with autoimmune hepatitis (AIH). By contrast, the usefulness of corticosteroid therapy in severe forms of AIH remains a subject of debate. Between 1986 and 2005, 16 patients (14 females, 2 males; mean age: 36.6 ± 13.1 yr) presenting with acute, severe, or fulminant disease due to type 1 AIH (n = 13) or type 2 AIH (n = 3) were admitted to our liver intensive care unit. At admission, 10 of 16 (62.5%) patients presented with encephalopathy. Median international normalized ratio (INR), bilirubin, alanine aminotransferase (ALT), and creatinine values were 5.36 (range, 1.7‐12.2), 425 μmol/L (range, 278‐850), 678 IU/L (range, 60‐2867), and 72 μmol/L (range, 52‐133), respectively. A total of 12 patients received corticosteroid therapy: 8 had started in the referring center a median of 2.5 days (range, 1‐89) previously, and this therapy was initiated in 4 patients at their admission to our unit (median: 2 days; range: 0‐5). Four patients were not treated because of a rapid deterioration in their AIH. Before treatment, 4 of 12 patients had been suffering from encephalopathy. The median duration of corticosteroid therapy was 7 days (range: 2‐135). Of 16 patients, 13 underwent liver transplantation (LT) (81%), at which time all were encephalopathic. Median values for INR, total bilirubin, and ALT were 7.2 (range: 3.3‐15.9), 400 μmol/L (range: 301‐550), and 706 IU/L (range: 69‐1,932), respectively, at the time of transplantation. All patients treated with corticosteroids had experienced a clinical (encephalopathy) and biochemical (Model for End‐Stage Liver Disease [MELD] score) deterioration at the time of transplantation. Histological findings did not reveal any features of underlying chronic liver disease. Of the 13 patients undergoing transplantation, 10 had received prior corticosteroid therapy. Of the 2 nontransplanted patients treated with corticosteroids, a clinical improvement was observed in only 1 patient. Severe septic complications occurred in 3 patients under corticosteroid therapy (gram‐negative septicemia n = 2; disseminated aspergillus n = 1). Nine of the treated patients are still alive; 1 died after liver transplantation (LT) (recurrence of AIH, acute pancreatitis, sepsis), 1 survived without LT, and 1 died without LT. Among the untreated patients, 3 survived after LT and 1 died without LT. In conclusion, corticosteroid therapy is of little benefit in severe and fulminant forms of AIH; it may favor septic complications and should not delay LT. Liver Transpl, 2007.

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

BACKGROUND/AIMS After liver transplantation for autoimmune hepatitis, the long-term results and the incidence of recurrence of primary disease are unknown. METHODS In 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). RESULTS The 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. CONCLUSIONS Patients 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.)

Hépatite fulminante et sub-fulminante : étiologie et traitement

Fulminant hepatitis is an emergency because within a few hours, the physician must find the cause of the hepatitis (not identified in 15 to 20% of cases), rule out any contraindication to liver transplantation, verify that it is indicated, and prevent and/or treat the complications associated with liver failure. Viruses (especially hepatitis viruses A and B), drugs, and toxic agents are the most common causes of fulminant hepatitis, with the proportions varying between countries. Hepatitis viruses, the leading cause through 1995-1996, have fallen behind drugs and in particular paracetamol, which is now the leading cause of this disease in Europe and in the United States. There are also other rarer causes: other viruses (e.g., herpes virus HSV1 or 2, hepatitis virus E, parvovirus B19, and chickenpox-herpes zoster), Wilson Disease, acute Budd-Chiari and Reyes syndromes, autoimmune hepatitis, neoplastic infiltration of the liver, hypoxic hepatitis, heatstroke, acute pregnancy-related steatosis, and the HELLP syndrome. Prognosis is essentially determined by neurological status, but is also affected very rapidly by damage to other organs. Liver transplantation has revolutionized the prognosis of fulminant hepatitis, causing survival to increase from 10-20% (all causes combined) to 75-80% at 1 year and 70% at 5 years. These patients can be treated only in specialized centers with access to liver transplantation and to different modern means of liver resuscitation (hypothermia, artificial liver support, albumin dialysis, monitoring intracranial pressure and cerebral perfusion, etc.) -all from the onset of the disease.

Repeat liver retransplantation: rationale and outcomes.

Liver retransplantation remains the only option for recurrent graft failure. The aim of our study is to identify predictive factors involved in patients and graft survival for patients undergoing repeat retransplantation (RRT).

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.

Augmentation de la perméabilité à long terme des anastomoses porto-caves par voie transjugulaire (TIPS) chez 218 patients cirrhotiques, grâce à un suivi strict

Resume Objectif Mesurer l’impact d’un suivi strict sur la permeabilite a long terme d’une anastomose porto-cave par voie transjugulaire (TIPS). Methodes De novembre 1991 a decembre 2002, 208 patients (152 hommes et 66 femmes) pris en charge pour la mise en place d’un TIPS pour echec de sclerotherapie ou ascite refractaire ont ete inclus. La permeabilite de la prothese a ete controlee sur la piece apres transplantation. La revision du TIPS etait effectuee durant le meme temps que le diagnostic de l’obstruction par angiographie trans-jugulaire. La permeabilite des TIPS a ete classee en 3 categories : la permeabilite primaire (duree de permeabilite constatee jusqu’a n’importe quelle intervention) ; la permeabilite primaire assistee (duree de permeabilite continue avec ou sans intervention percutanee) ; la permeabilite secondaire (duree de permeabilite totale avec ou sans occlusion traitee). Resultats Sur les 218 patients de l’etude, 108 ont eu un recul du TIPS inferieur a 1 an (49,5 %), 29 un recul compris entre 1 et 2 ans (13,5 %), 27 entre 2 et 3 ans (12,5 %), 16 entre 3 et 4 ans (7,5 %), 15 entre 4 et 5 ans (7 %) et 23 de plus de 5 ans (10 %). Le suivi moyen a ete de 24,1 ± 27,2 mois (mediane 13,7). La survie actuarielle de ces patients etait de 81,2 ± 2,9 % a 1 an, 62,9 ± 4,2 % a 3 ans et 52 ± 4,9 % a 5 ans. Trente-quatre patients ont ete perdus de vue (16 %), apres un suivi moyen de 22,9 ± 26,7 mois (mediane 9,7). Tous ces patients avaient un TIPS permeable lors de leur dernier controle. Cent trente-cinq patients (62 %) n’ont jamais eu d’episode d’obstruction du TIPS, avec un suivi moyen de 19,5 ± 26,2 mois (mediane 7,4) ; 83 patients (38 %) ont eu 117 episodes d’obstruction ; 24 deux episodes, 7 trois et 3 plus de trois ; 4 ont eu une thrombose provoquee pour une encephalopathie invalidante avec une contre-indication a une transplantation, dont 2 apres un premier episode de thrombose. Les permeabilites actuarielles primaires, primaire assistee et secondaire etaient, respectivement, de 67,7 ± 3 % et 51,4 ± 3,7 %, de 79,9 p 2,3 % et 69,3 ± 3,4 %, de 94,4 ± 1,8 % et 91 ± 2,6 % a 1 an et 3 ans (p = 0,0001, Log Rank = 65,3). Une analyse univariee a mis en evidence une relation entre la survenue d’un episode d’obstruction precoce ou tardif pour l’âge du patient au moment de la pose du TIPS, le score de Child avant, le gradient preoperatoire et le gradient postoperatoire. En analyse multivariee, aucun de ces elements n’etait significatif. Conclusion Bien que l’utilisation du TIPS dans le traitement de l’hypertension portale suive l’evolution de toute la chirurgie vers des methodes mini invasives, il est important de ne pas le considerer comme une derivation portale chirurgicale ou comme un traitement definitif : la permeabilite a long terme n’est obtenue qu’au prix d’un suivi regulier et de la possibilite d’une intervention rapide de desobstruction.

Long-Term Results of Transplantation for Hepatocellular Carcinoma With or Without Cirrhosis: 15 Years’-Experience at Paul Brousse Hospital

Hepatocellular carcinoma (HCC) still remains a controversial indication for liver transplantation (LT). An evaluation of long-term results is mandatory to define the patients who are likely to benefit from cadaveric or living-related LT. During 15 years’ experience, 220 LTs were performed consecutively at a single institution for HCC in patients with or without underlying cirrhosis (195 and 25 cases, respectively). The patients were younger and the proportion of females was higher in the noncirrhotic group (P < 0.001). Perioperative mortality (≤2 months) was 4% in cirrhotic and 0% in non cirrhotic patients. In spite of a higher incidence of recurrence related to more extensive tumors in HCC without cirrhosis (54% vs. 20%, P < 0.001), survival after transplantation was similar: 60% and 48% at 5 and 10 years, respectively, for patients without cirrhosis, and 73% and 39%, respectively, for patients with underlying cirrhosis (P not significant). While the combination of size and number of tumors was highly predictive of recurrence and survival in the cirrhotic group, this was not the case for non-cirrhotic patients. However, portal invasion was poorly associated with survival in both groups. HCC with and without underlying cirrhosis represents two separate entities with different patterns of evolution. The criteria of selection for transplantation should follow different policies in these two groups of patients.

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.

221 OUTCOME OF CIRRHOTIC PATIENTS ADMITTED TO THE LIVER ICU AND PREDICTIVE FACTORS OF MORTALITY: RESULTS OF A RECENT COHORT OF 308 PATIENTS

(p = 0.006), inotropic support (p = 0.006) and the absence of transplantation (p = 0.002) were significantly predictive of mortality. In the multivariate analysis, MELD score and need for inotropic support were major significant predictors of death while transplant free survival was significantly related to a MELD score <40 (OR:7.6; 95%CI: 2.2−26.2; p = 0.001), high fibrinogen level (OR: 3.2; 95%CI: 1.3−8.2; p = 0.01) and 3 MARS® treatments (OR: 6.3; 95%CI: 1.4−27.4; p = 0.01). Conclusion: In patients with fulminant hepatic failure awaiting liver transplantation, MELD score, inotropic support, fibrinogen and subsequent albumin dialysis therapy, outweighing liver transplantation, are major predictors of survival.