Although HCC is the third-leading cause of cancer-related deaths worldwide, there is only an elemental understanding of its molecular pathogenesis. In western countries, HCV infection is the main etiology underlying this cancer's accelerating incidence. To characterize the molecular events of the hepatocarcinogenic process, and to identify new biomarkers for early HCC, the gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC, including 4 neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. We identified gene signatures that accurately reflect the pathological progression of disease at each stage. Eight genes distinguish between control and cirrhosis, 24 between cirrhosis and dysplasia, 93 between dysplasia and early HCC, and 9 between early and advanced HCC. Using quantitative real-time reverse-transcription PCR, we validated several novel molecular tissue markers for early HCC diagnosis, specifically induction of abnormal spindle-like, microcephaly-associated protein, hyaluronan-mediated motility receptor, primase 1, erythropoietin, and neuregulin 1. In addition, pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then upregulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages. Conclusion: These findings provide a comprehensive molecular portrait of genomic changes in progressive HCV-related HCC. (HEPATOLOGY 2007;45:938-947.)

Recurrent infection with hepatitis C virus (HCV) is has become increasingly apparent that recurrent disalmost universal following orthotopic liver transplanta-ease can be progressive and may result in poorer long tion although clinical severity varies. Data on 135 pa-term survival. 7,8 tients who underwent transplantation for hepatitis C A severe form of fibrosing cholestatic hepatitis charcirrhosis were reviewed. We describe a progressive, se-acterized by rapidly progressive graft dysfunction has vere cholestatic form of hepatitis occurring in a sub-been described in patients who underwent transplantagroup of patients with recurrent hepatitis C. Ten pa-tion for hepatitis B.9 There have been very few reports tients with severe recurrent hepatitis C were identified; of progressive cholestatic liver disease from HCV lead-1 has died, 1 awaits retransplantation, and 8 have undering to subfulminant hepatic failure after orthotopic gone retransplantation. All 10 developed severe progresliver transplantation. We report here on 10 patients sive cholestatic hepatitis, with a mean rise in bilirubin to 24.7 mg/dL at the time of retransplantation. Histology who underwent transplantation for hepatitis C cirrhoat initial recurrence was of mild hepatitis without evi-sis who developed severe progressive cholestatic liver dence of rejection. The failed grafts showed either cir-disease leading to liver failure and/or retransplantarhosis or confluent hepatic necrosis. The onset of chole-tion. We describe the pathological, biochemical, and stasis preceded retransplantation by less than 5 months. clinical characteristics of these patients.Our study suggests that a minority of patients with recurrent hepatitis C after undergoing liver transplanta-PATIENTS AND METHODS tion develop a severe progressive cholestatic hepatitis and liver failure. (HEPATOLOGY 1996;23:971-976.)Patients. We reviewed data on 135 consecutive patients transplanted for hepatitis C at the Mount Sinai Medical Center, New York, NY, between September 1988 and December Hepatitis C is a well-known cause of end-stage liver 1993. Among this series of 135 patients, the first 100 cases disease leading to transplantation. After transplanta-formed the basis for an earlier report on the incidence of recurrent hepatitis C after undergoing transplantation. 10 We tion, recurrent infection (serum hepatitis C virus identified 56 of 135 patients with recurrent hepatitis C, de-[HCV]-RNA positive by polymerase chain reaction fined as elevated aminotransferase activities in the presence [PCR]) is almost universal. 1 Recurrent disease (histoof compatible liver biopsy findings. Twelve of these 56 palogical hepatitis) has been reported in 15% to 65% of tients had progressive cholestasis manifested biochemically patients who underwent transplantation for hepatitis by rising bilirubin levels disproportionate to the rise in ami-C, with most programs reporting rates of approxi-notransferase levels. In 2 of the 12 patients who underwent mately 45%. [1][2][3][4][5][6] Although the majority of ...

Publications about liver transplantation (LTX) for autoimmune hepatitis (AIH) have started to emerge, but many issues remain unresolved. We reviewed data on 32 patients transplanted for AIH to determine how pretransplantation and posttransplantation characteristics correlate with recipient outcome, including disease recurrence. Recipients were 37؎ 14 years old; 30 of 32 were women. Most had chronic disease (8 ؎ 6 years); 25% had fulminant failure. The majority had ascites (91%), jaundice (88%), elevated prothrombin time (18 ؎ 3 seconds), and hypoalbuminemia (2.7 ؎ 0.6 g/dL). All had hypergammaglobulinemia (3.0 ؎ 1.0 g/dL) and autoantibodies (72% antinuclear, 74% smooth muscle). Only one was HLA A1-B8-DR3 positive. Other autoimmune disorders affected 25% of patients; half improved after transplantation. Actuarial survival was 81% at 1 and 2 years posttransplantation. There was a high frequency of rejection (75% of recipients had 1.7 ؎ 0.8 episodes), and 39% of rejections required OKT3. Among 24 recipients with long-term follow-up (27 ؎ 14 months), histologically proven recurrent AIH occurred in 25%, 15 ؎ 2 months posttransplantation; half (3 patients) required retransplantation 11 ؎ 3 months after diagnosis. After retransplantation 2 of 3 patients had re-recurrence within 3 months; 1 received a third LTx. Recurrence occurred in 6 of 18 patients transplanted for chronic disease vs. 0 of 6 transplanted as fulminants (P ‫؍‬ not significant [NS] Until a short time ago the literature on LTX for AIH was sparse, including one publication that addressed the role of LTX for AIH, 2 and some reports about recurrence of AIH after LTX. [4][5][6][7] Recently, several retrospective reviews on LTX for AIH have emerged from various transplantation programs [8][9][10][11][12] as well as a few publications about rejection and immunosuppression after LTX for AIH. [13][14][15] In general there is consensus about the demographics of AIH patients that come to LTX. However, there are unresolved issues regarding the posttransplantation course of these patients. For example, there is controversy about the prevalence, risk factors, and outcome of recurrent AIH, and about appropriate posttransplantation immunosuppression strategies that take into account the increased immunoreactivity of these patients.To address some of these issues, we reviewed our data on 32 patients who underwent LTX for a primary indication of AIH and we sought to determine whether specific pretransplantation characteristics or various aspects of the postoperative course could be used to predict posttransplantation outcome, including disease recurrence. PATIENTS AND METHODSWe retrospectively reviewed our data on patients in whom a clinical and pathologic diagnosis of AIH had been made on the basis of the diagnostic criteria of the International Autoimmune Hepatitis Group 16 and who underwent transplantation at The Mount Sinai Medical Center (New York, NY) between September 1988 and January 1995. Patients with coexisting causes of hepatitis, such as viral or alcohol-ind...