María Trapero-Marugán

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents

Background  Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Unresectable disease patients have median survival of few months. There is a substantial need for novel treatments for patients with advanced HCC.

Angiogenesis: From Chronic Liver Inflammation to Hepatocellular Carcinoma

Recently, new information relating to the potential relevance of chronic hepatic inflammation to the development and progression of hepatocellular carcinoma (HCC) has been generated. Persistent hepatocellular injury alters the homeostatic balance within the liver; deregulation of the expression of factors involved in wound healing may lead to the evolution of dysplastic lesions into transformed nodules. Progression of such nodules depends directly on the development and organization of a vascular network, which provides the nutritional and oxygen requirements to an expanding nodular mass. Angiogenic stimulation promotes intense structural and functional changes in liver architecture and physiology, in particular, it facilitates transformation of dysplasia to nodular lesions with carcinogenic potential. HCC depends on the growth and spreading of vessels throughout the tumor. Because these vascular phenomena correlate with disease progression and prognosis, therapeutic strategies are being developed that focus on precluding vascular expansion in these tumors. Accordingly, an in-depth study of factors that promote and support pathological angiogenesis in chronic hepatic diseases may provide insights into methods of preventing the development of HCC and/or stimulating the regression of established HCC.

Long-term outcome of chronic hepatitis C patients with sustained virological response to peginterferon plus ribavirin.

AIM To assess the clinical, biochemical and virological long-term outcome in chronic hepatitis C (CHC) patients with a sustained virological response (SVR) after peginterferon (PEG-IFN) plus ribavirin combination therapy. METHODS One hundred and fifty three patients with a SVR after treatment with PEG-IFN plus ribavirin were included in a 5-year follow-up study in a single Spanish center, based on standard clinical practice. Clinical anamnesis, biochemical analysis, hepatitis C virus RNA and alpha-fetoprotein measurement, ultrasonography and transient elastography were performed annually. RESULTS The mean follow-up period of the 153 patients was 76 ± 13 mo after they obtained a SVR. Five patients (3.26%) presented with cirrhosis before treatment and 116 (75.8%) had genotype 1. No patient showed evidence of hepatic decompensation. One patient (0.65%) developed a hepatocellular carcinoma at month 30 after achieving SVR. There were no virological relapses during this follow-up period. Persistently elevated alanine aminotransferase was found in only one patient (0.65%). At the end of the 5-year follow-up, the mean value of transient elastography was 7 ± 4.3 kPa (F1). There were no deaths and no other tumors. CONCLUSION The long-term outcome of 153 CHC patients with SVR to PEG-IFN plus ribavirin was good. No evidence of a virological relapse was seen. One patient (0.65%) developed a hepatocellular carcinoma.

The molecular and pathophysiological implications of hepatitis B X antigen in chronic hepatitis B virus infection.

Hepatitis B virus is considered one of the most significant environmental carcinogens in humans. Because the mechanisms of HBV replication and the development of hepatocellular carcinoma (HCC) are partially known, HBV‐associated pathogenesis remains a challenge to increase its understanding. Evidence suggests that the regulatory protein hepatitis B virus X (HBx) mediates the establishment and maintenance of the chronic carrier state. HBx is a multifunctional and potentially oncogenic protein that is conserved among mammalian hepadnaviruses; it is produced very early after infection and throughout the chronic phase. HBx exerts its effects by interacting with cellular proteins and activating various signaling pathways. HBx stimulates the transcription of genes that regulate cell growth, apoptosis, and DNA repair. It also interacts with proteasome subunits and affects mitochondrial stability. Moreover, HBx participates in processes that are associated with the progression of chronic liver disease, including angiogenesis and fibrosis. This review discusses the function of HBx in the life cycle of HBV and its contribution to the pathogenesis of HCC. Copyright

Sustained virological response to peginterferon plus ribavirin in chronic hepatitis C genotype 1 patients is associated with a persistent Th1 immune response

An impairment of cellular immune response may contribute to the persistency of hepatitis C virus infection.

Evaluation of liver fibrosis by transient elastography in methotrexate treated patients.

BACKGROUND AND AIMS Methotrexate (MTX) safety is questioned by the risk of inducing liver fibrosis (LF). As transient elastography (FibroScan®) is an effective non-invasive technique to evaluate LF, our aims were to assess LF in MTX-treated patients, to evaluate LF regarding treatment duration and cumulative dose, and to determine differences depending on the underlying disease. PATIENTS AND METHODS Prospective study including patients with rheumatoid arthritis, inflammatory bowel disease, and psoriasis treated with MTX. Hepatic stiffness was determined by FibroScan®. The LF cut-off values were established using METAVIR score. RESULTS Of 53 patients, 22 were men (41.5%), mean age was 55 (15) years, 17 (32%) had rheumatoid arthritis, 18 (34%) inflammatory bowel disease, and 18 (34%) psoriasis. Mean MTX cumulative dose was 1,805 (1,560) mg, and mean treatment duration was 178 weeks. Mean hepatic stiffness was 6.19 (2.43) KPa. In 49 patients (92.5%), absence/mild LF was found (F ≤ 2), and 4 patients (7.5%) had advanced LF (F ≥ 3). Treatment duration or cumulative doses of MTX were not associated with LF. CONCLUSIONS Regarding LF development, MTX therapy is safe. FibroScan® is useful for monitoring LF in MTX-treated patients.

The colorectal carcinoma prognosis factors. Significance of diagnosis delay

INTRODUCTION detection of early-stage colorectal carcinoma (CRC)--( Dukes A or B)--provides better survival rates in these patients. Thus, the effectiveness of screening programs in asymptomatic patients or of early diagnosis in symptomatic individuals has been postulated. The aim of this study was to establish whether a delay in diagnosis or other factors are related to CRC stage. PATIENTS AND METHODS a retrospective study was performed on 96 patients with CRC. Age at diagnosis, gender distribution, intestinal disorders, diagnosis delay, primary sign and -regarding CRC- localization, stage (Dukes) and grade of differentiation (well differentiated; non-well differentiated; poorly differentiated) were recorded. RESULTS diagnosis delay was 185 +/- 190 days. Patients delay in obtaining a diagnosis was 119 +/- 158 days. In 40% of patients CRC was diagnosed at an early stage (Dukes A or B), and in 13% CRC was poorly differentiated. The only factor with an independent effect on Dukes stage was tumor differentiation (p: 0.0012). Distal location was associated with less advanced tumors without statistical significance (p: 0.156). CONCLUSION based on the presented data, a greater effort regarding screening programs for healthy people seems warranted, as improved survival has been demonstrated when diagnosis delay is reduced, particularly in patients with the highest mean delay.

Autoimmune Hepatitis After Long-Term Methotrexate Therapy for Rheumatoid Arthritis

Methotrexate (MTX) therapy may be effective in patients with rheumatoid arthritis (RA) or psoriasis due to its anti-inflammatory and immunosuppressive properties. Potential liver toxicity of MTX exists, but the incidence of MTX-specific lesions in liver biopsy of patients with RA and elevated serum transaminase levels is rare; however, severe hepatic damage may occurs unexpectedly in these patients. We describe the first documented case of an adult patient with RA who developed an acute flare of severe hepatitis after long-term therapy with MTX. Autoantibodies positivity, elevated serum IgG levels and compatible liver biopsy findings prompted us to diagnose autoimmune hepatitis, most probably triggered by a breakdown of immune tolerance induced by MTX. A complete remission was achieved in this patient with corticosteroids therapy.

Azathioprine plus ribavirin treatment and pancytopenia

SIRS, We read with interest the article by Peyrin-Biroulet et al. that aimed to underline the interaction of ribavirin, an ionosine monophosphate dehydrogenase (IMPDH) inhibitor, with azathioprine metabolism, potentially leading to myelotoxicity. They reported eight cases of severe pancytopenia in patients receiving azathioprine for inflammatory bowel disease and ribavirin plus peginterferon for chronic hepatitis C (CHC). Their thipurine methyltransferase (TPMT) genotype was normal. In all cases, blood tests returned to normal after drug withdrawal. In no patient, haematological toxicity occurred after reintroduction of azathioprine or CHC therapy alone. The authors prospectively monitored azathioprine metabolites in two of these patients and found a dramatic increase in methylated metabolite levels accompanying myelotoxicity. Recently, we admitted a 39-year-old man presented with pancytopenia. In June 2004, he had to undergo surgery for Crohn’s disease (CD) stenosis. Azathioprine was started at a dose of 2.5mg ⁄kg ⁄day after the surgery. His TPMT activity was normal. Peginterferon alfa-2b (1.5 lg ⁄kg ⁄week) plus ribavirin 800 mg daily was initiated in December 2008 for CHC (genotype 2, stiffness 27.7 KPa). Haematological counts were within the normal range before initiation of CHC therapy. Blood tests during CHC therapy revealed an abrupt decrease in neutrophil count (1.05 · 10 ⁄mm) with anaemia (6 g ⁄dL) occurring 12 weeks after starting the treatment and all returned to normal values 4 weeks after drug (peginterferon, ribavirin and azathioprine) discontinuation. In May 2009, peginterferon plus ribavirin without azathioprine was reintroduced uneventfully. Crohn’s disease patients have prevalence of CHC similar or slightly higher than that in general population. Anti-viral therapy has shown to be effective and safe in the majority of these patients. 4 However, our experience is in accord with that reported previously, 5, 6 suggesting that ribavirin interacts with azathioprine metabolism, increasing the risk of developing myelotoxicity. Taking into account these observations, treatment with IMPDH inhibitors and purine analogues should be individualized and patients closely monitored.