Adrian Reuben

Background & Aims: The long‐term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2‐year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrolment in the Acute Liver Failure Study Group (ALFSG).Methods: Outcomes in adult ALFSG patients that were enrolled between 1998 and 2010 were reviewed.Results: Two‐year patient survival was significantly higher in the 262 LT recipients (92.4%) compared to the 306 acetaminophen (APAP) spontaneous survivors (SS) (89.5%) and 200 non‐APAP SS (75.5%) (P < 0.0001). The causes of death were similar in the three groups but the time to death was significantly longer in the LT recipients (P < 0.0001). Independent predictors of 2‐year mortality in the APAP group were a high serum phosphate level and patient age (c‐statistic = 0.65 (0.54, 0.76)), patient age and days from jaundice to ALF onset in the non‐APAP group (c‐statistic = 0.69 (0.60, 0.78)), and patient age, days from jaundice, and higher coma grade in the LT recipients (c‐statistic = 0.74 (0.61, 0.87)). The LT recipients were significantly more likely to be employed and have a higher educational level (P < 0.05).Conclusions: Two‐year outcomes in initial survivors of ALF are generally good but non‐APAP patients have a significantly lower survival which may relate to pre‐existing medical comorbidities. Spontaneous survivors with APAP overdose experience substantial morbidity during follow‐up from ongoing psychiatric and substance abuse issues.

Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has pro-spectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overre-presentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, spe-cifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. Conclusion: DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival. (HEPATOLOGY 2010;52:2065-2076)

To update the reader with advances in epidemiology, genetics, detection, pathogenesis and therapy of alcohol-related liver disease. Ill-health due to alcohol abuse is improving in some nations but deteriorating in others. Oxidative and nitrosative stress are key to the pathogenesis of alcoholic liver disease, and there is now greater emphasis than previously on their development and role of cytochrome P450 2E1, on mitochondrial stress and disruption, (including elucidation of mitochondrial protection mechanisms) disturbance of signaling pathways and involvement of extrahepatic mediators like adiponectin. Treatment of alcoholic liver disease has stagnated, but transplantation is still favored and debated for end-stage cirrhosis. Basic and clinical research into the mechanisms of alcoholic liver disease is making headway, but has yet to produce safe and effective therapies for alcoholic hepatitis and for reversing cirrhosis.

Case series describing posttransplantation lymphoproliferative disorder (PTLD) after liver transplantation (LTx) have been limited in number because of the rarity of the disorder. The prevalence of Epstein-Barr virus (EBV) infection and its detection, the clinical and histological diversity of disease, and survival have varied. The aim of this study is to define the clinical and pathological spectrum of PTLD after LTx, and evaluate EBV prevalence, impact of infection, and patient survival. A retrospective analysis of all LTx recipients at our institution diagnosed with PTLD from January 1990 until May 2005, recording clinical presentations, times of presentation after transplantation, histological findings, results of EBV assessment, and survival, as well as the interrelationship of these variables. Among 621 LTx recipients were 22 cases of PTLD in 21 patients, of whom 5 were children and 16 were adults. Extranodal disease was present in 17 of 22 cases (77%) involving a wide variety of organ systems, while 5/22 (23%) had lymphadenopathy. The spectrum of PTLD histopathology was equally varied. In situ hybridization for EBV showed negativity in 8 of 13 (62%) and positivity in 5 of 13 (38%) cases tested. Neither time interval from transplantation to presentation (median 33 months) nor mortality (average 32%) was influenced by EBV status. In conclusion, PTLD in LTx recipients is predominantly extranodal and can involve a wide variety of organ systems, which may confound initial diagnosis. The lymphoproliferative histological spectrum is also diverse. Nowadays, PTLD is frequently EBV-negative, and EBV status does not appear to influence clinical or pathological presentation, or survival. Liver Transpl 13:904–912, 2007. © 2007 AASLD.

This review aims to acquaint the reader with advances in 2006 in the epidemiology, genetics, detection, pathogenesis and treatment of alcoholic liver disease. Important discoveries have been made in pathogenesis and mechanism of disease, with great emphasis on the many pathways leading to oxidative stress, and the novel mechanism of endoplasmic reticulum stress that is proving to be important in the pathogenesis of many liver diseases. The reliability of ethyl glucuronide and other biomarkers for the detection of alcohol abuse is being better established. There have been no treatment advances for alcoholic liver disease but, on balance, steroids are still favored for carefully selected patients with alcoholic hepatitis. Many compounds tested in rodents may now be available for consideration for clinical trials. Criteria for patient selection and refusal for liver transplantation are being established but the 6 months abstinence rule still holds. Insights are being made into the pathogenesis of alcoholic liver disease but safe and effective therapies for both alcoholic hepatitis and alcoholic cirrhosis have yet to be discovered.

To apprise the reader of advances in 2005 in the epidemiology, pathogenesis, prognosis and treatment of alcoholic liver disease. Alcohol use has declined in developed countries, but the opposite is true elsewhere; alcoholic liver disease is a considerable burden worldwide. Genetic mechanisms for alcoholic liver disease are being discovered in addition to aggravating cofactors, such as hepatitis C, obesity and iron overload, and ameliorating ones, like coffee and tea drinking. The involvement of the innate immune system and the mechanisms of apoptosis in alcoholic liver disease are better appreciated, especially the emerging role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Steroid use and nutrition for alcoholic hepatitis are being refined, and the validity of the model for end-stage liver disease (MELD) score in predicting the outcome of alcoholic liver disease is upheld. Recidivism after liver transplantation for alcoholic liver disease adversely impacts long-term survival. Inroads are being made into the genetics of alcoholic liver disease and new phenomena are being uncovered in its pathogenesis, but safe and effective therapies for both alcoholic hepatitis and alcoholic cirrhosis are still wanting.

Activation of hepatic stellate cells from quiescence to myofibroblast-like cells (MFBs) is a pivotal event in hepatic fibrogenesis. Plastic-cultured stellate cells (an established in vitro model of the activated phenotype) recultured on Matrigel^™ revert to quiescence. In the present study we analyzed the molecular mechanism underlying this process, focusing on the effect of collagen receptors α₂β₁ and α₁β₁ integrin signaling on the expression of Ets-1 transcription factor and its target gene MMP1 in cultured human MFBs. Cells grown in 3-dimensional (3D) substrates (Matrigel^™ or collagen type I gel) markedly upregulated Ets-1 and MMP1 messages, in comparison to cells cultured on plastic. A similar effect but less intense was mimicked by stimulation of α₂β₁ or blocking of α₁β₁ integrin in cells grown on plastic. We observed increased expression of MMP1 transcripts with parallel changes in MMP1 promoter activity, and in mRNA and protein levels of upstream transcription factors Ets-1 and c-Jun. Interference with α₂β₁ and α₁β₁ integrin function in cells cultured in a 3D collagen substrate resulted in an even greater effect. Morphologically, stimulation of α₂β₁ integrin resulted in formation of multicellular networks, probably by facilitation of cell migration. Thus, we report the novel observation that in cultured human MFBs reverting to quiescence, the expression of transcription factor Ets-1 and its downstream target MMP1 can be modulated by changes in the microenvironment, which are mediated, at least in part, by the balance between collagen receptor integrin α₂β₁ and α₁β₁ activities