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Smirne C, Crobu MG, Landi I, Vercellino N, Apostolo D, Pinato DJ, Vincenzi F, Minisini R, Tonello S, D’Onghia D, Ottobrelli A, Martini S, Bracco C, Fenoglio LM, Campanini M, Berton AM, Ciancio A, Pirisi M. Chronic Hepatitis C Infection Treated with Direct-Acting Antiviral Agents and Occurrence/Recurrence of Hepatocellular Carcinoma: Does It Still Matter? Viruses 2024; 16:1899. [PMID: 39772206 PMCID: PMC11680226 DOI: 10.3390/v16121899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 01/03/2025] Open
Abstract
Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Maria Grazia Crobu
- Laboratory of Molecular Virology, Maggiore della Carità Hospital, 28100 Novara, Italy;
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, 10126 Turin, Italy
| | - Irene Landi
- Emergency Medicine Department, Michele e Pietro Ferrero Hospital, 12060 Verduno, Italy;
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Daria Apostolo
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - David James Pinato
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London SW7 2AZ, UK
| | - Federica Vincenzi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Stelvio Tonello
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Davide D’Onghia
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Antonio Ottobrelli
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
| | - Silvia Martini
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
| | - Christian Bracco
- Department of Internal Medicine, Santa Croce e Carle Hospital, 12100 Cuneo, Italy; (C.B.); (L.M.F.)
| | - Luigi Maria Fenoglio
- Department of Internal Medicine, Santa Croce e Carle Hospital, 12100 Cuneo, Italy; (C.B.); (L.M.F.)
| | - Mauro Campanini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Alessandro Maria Berton
- Division of Endocrinology, Diabetes and Metabolism, City of Health and Science University Hospital, 10126 Turin, Italy;
| | - Alessia Ciancio
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
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Xu D, Sheng JQ, Hu PJH, Huang TS, Lee WC. Predicting hepatocellular carcinoma recurrences: A data-driven multiclass classification method incorporating latent variables. J Biomed Inform 2019; 96:103237. [PMID: 31238108 DOI: 10.1016/j.jbi.2019.103237] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 03/30/2019] [Accepted: 06/18/2019] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC), a malignant form of cancer, is frequently treated with surgical resections, which have relatively high recurrence rates. Effective recurrence predictions enable physicians' timely detections and adequate therapeutic measures that can greatly improve patient care and outcomes. Toward that end, predictions of early versus late HCC recurrences should be considered separately to reflect their distinct onset time horizons, clinical causes, underlying clinical etiology, and pathogenesis. We propose a novel Bayesian network-based method to predict different HCC recurrence outcomes by considering the respective recurrence evolution paths. Typical patient information obtained in early stages is insufficiently informative to predict recurrence outcomes accurately, due to the lack of subsequent patient progression information. Our method alleviates such information deficiency constraints by incorporating an independent latent variable, dominant recurrence type, to regulate recurrence outcome predictions (early, late, or no recurrence). We use a real-world HCC data set to evaluate the proposed method, relative to three prevalent benchmark techniques. Overall, the results show that our method consistently and significantly outperforms all the benchmark techniques in terms of accuracy, precision, recall, and F-measures. For increased robustness, we use another data set to perform an out-of-sample evaluation and obtain similar results. This study thus contributes to HCC recurrence research and offers several implications for clinical practice.
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Affiliation(s)
- Da Xu
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, USA.
| | - Jessica Qiuhua Sheng
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, USA.
| | - Paul Jen-Hwa Hu
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, USA.
| | - Ting Shuo Huang
- Department of General Surgery, Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC; Department of Chinese Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC.
| | - Wei-Chen Lee
- Department of Liver and Transplantation Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC; Department of Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan,Taiwan, ROC.
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Shiani A, Narayanan S, Pena L, Friedman M. The Role of Diagnosis and Treatment of Underlying Liver Disease for the Prognosis of Primary Liver Cancer. Cancer Control 2018; 24:1073274817729240. [PMID: 28975833 PMCID: PMC5937237 DOI: 10.1177/1073274817729240] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related
deaths worldwide. Underlying chronic liver disease has been associated with an
increased risk of developing HCC. This study is a review of the current
literature regarding the diagnosis, prognostic significance, and role of
treating underlying liver disease in patients who are at risk of primary liver
cancer. Relevant peer review of the English literature between 1980 and 2017
within PubMed and the Cochrane library was conducted for scientific content on
current advances in managing chronic liver diseases and the development of
hepatocellular carcinoma. Hepatitis C virus, hepatitis B virus (HBV),
nonalcoholic steatohepatitis, autoimmune hepatitis, hereditary hemochromatosis,
Wilson disease, primary biliary cirrhosis, α 1-antitrypsin deficiency, and
certain drugs lead to an increased risk of developing HCC. Patients with
underlying liver disease have an increased incidence of HCC. Hepatitis C virus,
HBV, and hemochromatosis can directly lead to HCC without the presence of
cirrhosis, while HCC related to other underlying liver diseases occurs in
patients with cirrhosis. Treating the underlying liver disease and reducing the
progression to cirrhosis should lead to a decreased incidence of HCC.
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Affiliation(s)
- Ashok Shiani
- 1 Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Shreya Narayanan
- 1 Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Luis Pena
- 2 Department of Gastroenterology, Gastrointestinal Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Mark Friedman
- 2 Department of Gastroenterology, Gastrointestinal Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Abstract
This article alludes to the findings of Tomasetti and Vogelstein and argues that for clinicians and scientists no matter how difficult understanding the pathogenesis of cancer may be, they remain the only hope for patients suffering from the disease. Data citing wide differences in cancer incidence in different parts of the world is presented to drive home the point that 'Bad luck' is not a good enough explanation for cancer pathogenesis. There remains a lot to be uncovered in cancer and clinicians and scientists should strive to this end.
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Affiliation(s)
- Savio George Barreto
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity, Gurgaon, Haryana, India
| | - Merlyn Barreto
- Consultant Obstetrician and Gynaecologist, Gurgaon, Haryana, India
| | - Rohan Chaubal
- The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, India
| | - Amit Dutt
- The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, India
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Antonelli A, Ferrari SM, Giuggioli D, Di Domenicantonio A, Ruffilli I, Corrado A, Fabiani S, Marchi S, Ferri C, Ferrannini E, Fallahi P. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes 2014; 5:586-600. [PMID: 25317237 PMCID: PMC4138583 DOI: 10.4239/wjd.v5.i5.586] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/10/2014] [Accepted: 07/12/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.
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Arase Y, Kobayashi M, Kawamura Y, Suzuki F, Suzuki Y, Akuta N, Kobayashi M, Sezaki H, Saito S, Hosaka T, Ikeda K, Kumada H, Kobayashi T. Impact of virus clearance for the development of hemorrhagic stroke in chronic hepatitis C. J Med Virol 2013; 86:169-75. [DOI: 10.1002/jmv.23777] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2013] [Indexed: 01/05/2023]
Affiliation(s)
- Yasuji Arase
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
- Department of Health Management Center; Toranomon Hospital; Tokyo Japan
- Department of Third Internal Medicine; University of Yamanashi; Yamanashi Japan
| | - Mariko Kobayashi
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Yusuke Kawamura
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Fumitaka Suzuki
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Norio Akuta
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Masahiro Kobayashi
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Hitomi Sezaki
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Satoshi Saito
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Tetsuya Hosaka
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Kenji Ikeda
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Hiromitsu Kumada
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Tetsuro Kobayashi
- Department of Third Internal Medicine; University of Yamanashi; Yamanashi Japan
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Ogura S, Saitoh S, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Suzuki F, Suzuki Y, Arase Y, Ikeda K, Kumada H. Magnetic resonance laparoscopy: A new non-invasive technique for the assessment of chronic viral liver disease. Hepatol Res 2013; 43:836-45. [PMID: 23445460 DOI: 10.1111/hepr.12025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Revised: 11/01/2012] [Accepted: 11/11/2012] [Indexed: 02/08/2023]
Abstract
AIM Laparoscopy-guided liver biopsy is the most accurate method for assessing liver fibrosis but have several limitations. We designed a non-invasive method, called magnetic resonance laparoscopy (MRL), based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, to assess liver fibrosis in patients with chronic hepatitis B and C virus. METHODS We prospectively analyzed 49 patients with normal liver and 353 patients with chronic viral hepatitis, laparoscopic liver biopsy was performed on 109 patients and 244 patients were diagnosed as having liver cirrhosis clinically. The MRL findings of the liver surface were classified into three categories: (i) smooth (essentially smooth surface of the entire liver or with limited areas of depression); (ii) partially irregular (several interconnected depressions on the surface mainly in the left lobe of the liver); and (iii) diffusely irregular (nodules present on the liver surface). Patients with diffusely irregular liver surface was diagnosed as liver cirrhosis. RESULTS The liver surface changed with the progression of liver fibrosis from smooth, partially irregular to diffusely irregular, irrespective of viral type. The sensitivity, specificity, positive and negative predictive values for the diagnosis of cirrhosis according to the surface findings on MRL were 96%, 100%, 95% and 95%, respectively. The cirrhotic liver showed: (i) disappearance of impression of the right ribs; (ii) enlargement of the lateral segment; and (iii) atrophy of the right lobe according to Child-Pugh classification. CONCLUSION Our data indicated that MRL is a potentially useful non-invasive examination for evaluation of liver fibrosis associated with viral hepatitis.
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Affiliation(s)
- Suguru Ogura
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
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Arase Y, Kobayashi M, Suzuki F, Suzuki Y, Kawamura Y, Akuta N, Kobayashi M, Sezaki H, Saito S, Hosaka T, Ikeda K, Kumada H, Kobayashi T. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology 2013; 57:964-73. [PMID: 22991257 DOI: 10.1002/hep.26087] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Accepted: 09/07/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors for malignancies after the termination of interferon (IFN) therapy in Japanese patients for hepatitis C virus (HCV). A total of 4,302 HCV-positive patients treated with IFN were enrolled. The mean observation period was 8.1 years. The primary outcome was the first onset of malignancies. Evaluation was performed using the Kaplan-Meier method and Cox proportional hazard analysis. A total of 606 patients developed malignancies: 393 developed hepatocellular carcinoma (HCC) and 213 developed malignancies other than HCC. The cumulative development rate of HCC was 4.3% at 5 years, 10.5% at 10 years, and 19.7% at 15 years. HCC occurred significantly (P<0.05) when the following characteristics were present: advanced histological staging, sustained virological response not achieved, male sex, advanced age of ≥50 years, total alcohol intake of ≥200 kg, and presence of type 2 diabetes (T2DM). T2DM caused a 1.73-fold enhancement in HCC development. In patients with T2DM, HCC decreased when patients had a mean hemoglobin A1c (HbA1c) level of <7.0% during follow-up (hazard ratio, 0.56; 95% confidence interval, 0.33-0.89; P=0.015). The cumulative development rate of malignancy other than HCC was 2.4% at 5 years, 5.1% at 10 years, and 9.8% at 15 years. Malignancies other than HCC occurred significantly when patients were of advanced age of ≤50 years, smoking index (package per day×year) was ≥20, and T2DM was present. T2DM caused a 1.70-fold enhancement in the development of malignancies other than HCC. CONCLUSION T2DM causes an approximately 1.7-fold enhancement in the development of HCC and malignancies other than HCC in HCV-positive patients treated with IFN. In T2DM patients, maintaining a mean HbA1c level of <7.0% reduces the development of HCC.
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Affiliation(s)
- Yasuji Arase
- Department of Hepatology and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan.
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Hagiwara S, Sakurai T, Takita M, Ueshima K, Minami Y, Inoue T, Yada N, Kitai S, Nagai T, Hayaishi S, Arizumi T, Nishida N, Kudo M. Risk of hepatocellular carcinoma development in cases of hepatitis C treated by long-term, low-dose PEG-IFNα-2a. Dig Dis 2012; 30:561-7. [PMID: 23258095 DOI: 10.1159/000343065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Increasing evidence suggests the efficacy of maintenance therapy with interferon (IFN) for chronic hepatitis C (CHC) in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to determine clinical characteristics on the risk of occurrence of HCC in CHC patients receiving maintenance IFN therapy. METHODS A total of 55 patients were treated in a single center with PEG-IFNα-2a monotherapy for CHC and evaluated for variables predictive of the occurrence of HCC. RESULTS The cumulative incidences of HCC were 0.092, 0.117 and 0.161 at 3, 5 and 7 years, respectively. Serum ALT level (>40 IU/l) in the 6th month after commencement of IFN therapy and BMI >25 were associated with shorter time-to-HCC emergence using multivariate analysis (relative risk 16.034, p = 0.01 for ALT >40 IU/l; relative risk 6.020, p = 0.026 for BMI >25, respectively). The IL28B SNP was extracted as a significant factor for the occurrence of HCC. CONCLUSIONS Maintenance therapy with the use of long-term low-dose PEG-IFNα-2a is effective for preventing HCC occurrence irrespective of the IL28B SNP, at least for a subset of CHC patients. The initial response of serum ALT levels and BMI provides a prognostic value for determining the risk of developing HCC later in life.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, Japan
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Matsumoto N, Arase Y, Seko Y, Imai N, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Kobayashi M, Suzuki Y, Saito S, Suzuki F, Ikeda K, Kumada H, Aida K, Kobayashi T. Prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhosis with fasting plasma glucose level of <126 mg/dL. Hepatol Res 2012; 42:558-63. [PMID: 22236146 DOI: 10.1111/j.1872-034x.2011.00957.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIM The aim of this study was to evaluate the prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhotic patients with fasting plasma glucose (FPG) level of <126 mg/dL. METHODS A total of 263 patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) positive liver cirrhosis, FPG level of <126 mg/dL, and had diabetes status evaluated by the use of 75-g oral glucose tolerance test (OGTT), were enrolled in this study. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading. Diabetes was defined as a 2-h post-load glucose on the OGTT of ≥200 mg/dL. The prevalence of diabetes by use of OGTT and predictive factors for diabetes were evaluated by the use of the Mann-Whitney U-test, Fisher's exact probability test or multivariate analysis by logistic regression. Hypoalbuminemia was defined as serum albumin level of <3.9 g/dL. Elevated indocyanine green retention rate at 15 min (ICG( R) 15) was regarded as ≥ 25%. RESULTS Out of 263 patients, 44 (16.7%) were diagnosed as having diabetes. Multivariate analysis showed that diabetes occurred when patients had hypoalbuminemia of <3.9 g/dL (odds ratio [OR] 2.33; 95% confidential interval [CI] = 1.04-5.24; P = 0.040) and ICG( R) 15 of <25% (OR 2.36; 95%CI = 1.01-5.58). CONCLUSIONS Hypoalbuminemia and elevated ICG( R) 15 in hepatitis virus related cirrhotic patients with FPG level of <126 mg/day enhance diabetes pattern after OGTT with significant difference.
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Affiliation(s)
- Naoki Matsumoto
- Department of Hepatology and Okinaka Memorial Institute for Medical Research Department of Health Management Center, Toranomon Hospital, Tokyo Department of Third Internal Medicine (Metabolism), University of Yamanashi, Yamanashi, Japan
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Osaki Y, Ueda Y, Marusawa H, Nakajima J, Kimura T, Kita R, Nishikawa H, Saito S, Henmi S, Sakamoto A, Eso Y, Chiba T. Decrease in alpha-fetoprotein levels predicts reduced incidence of hepatocellular carcinoma in patients with hepatitis C virus infection receiving interferon therapy: a single center study. J Gastroenterol 2012; 47:444-51. [PMID: 22105231 DOI: 10.1007/s00535-011-0505-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 10/24/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Increasing evidence suggests the efficacy of interferon therapy for hepatitis C in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to identify predictive markers for the risk of HCC incidence in chronic hepatitis C patients receiving interferon therapy. METHODS A total of 382 patients were treated with standard interferon or pegylated interferon in combination with ribavirin for chronic hepatitis C in a single center and evaluated for variables predictive of HCC incidence. RESULTS Incidence rates of HCC after interferon therapy were 6.6% at 5 years and 13.4% at 8 years. Non-sustained virological response (non-SVR) to antiviral therapy was an independent predictor for incidence of HCC in the total study population. Among 197 non-SVR patients, independent predictive factors were an average alpha-fetoprotein (AFP) integration value ≥10 ng/mL and male gender. Even in patients whose AFP levels before interferon therapy were ≥10 ng/mL, reduction of average AFP integration value to <10 ng/mL by treatment was strongly associated with a reduced incidence of HCC. This was significant compared to patients with average AFP integration values of ≥10 ng/mL (P = 0.009). CONCLUSIONS Achieving sustained virological response (SVR) by interferon therapy reduces the incidence of HCC in hepatitis C patients treated with interferon. Among non-SVR patients, a decrease in the AFP integration value by interferon therapy closely correlates with reduced risk of HCC incidence after treatment.
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Affiliation(s)
- Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, 5-53 Fudegasaki-cho, Tennoji-ku, Osaka 543-8555, Japan
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Arase Y, Suzuki F, Kawamura Y, Suzuki Y, Kobayashi M, Matsumoto N, Akuta N, Sezaki H, Hosaka T, Ogawa K, Imai N, Seko Y, Saito S, Ikeda K, Kobayashi M, Kumada H. Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy. Hepatol Res 2011; 41:946-54. [PMID: 21883737 DOI: 10.1111/j.1872-034x.2011.00845.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The aim of this retrospective cohort study is to assess the development incidence and predictive factors for chronic kidney disease (CKD) after the termination of interferon therapy in hepatitis C virus (HCV) positive Japanese patients with liver cirrhosis. METHODS A total of 650 HCV positive, liver cirrhotic patients who were treated with interferon and showed an estimated glomerular filtration rate (eGFR) of ≥60 mL/min per 1.73 m(2) after the termination of interferon therapy were enrolled. CKD was defined as an eGFR of <60 mL/min per 1.73 m(2) . End-stage-CKD was defined as an eGFR of <15 mL/min/1.73 m(2) . The primary goal is the new development of CKD and end-stage-CKD. RESULTS Eighty-five patients developed CKD, and six patients progressed to end-stage-CKD. The development rate of CKD was 5.2% at the 5th year, 14.5% at the 10th year and 30.6% at the 15th year. Multivariate Cox proportional hazards analysis showed that CKD occurred when patients had age increments of 10 years (hazard ratio: 2.32; 95% confidence interval [CI] 1.61-3.35; P < 0.001), eGFR decrements of 10 mL/min per 1.73 m(2) (hazard ratio: 1.66; 95% CI 1.27-2.16; P < 0.001), hypertension (hazard ratio: 2.00; 95% CI 1.13-3.53; P = 0.017), diabetes (hazard ratio: 1.79; 95% CI 1.02-3.14; P = 0.042), and non-clearance of HCV (hazard ratio: 2.67; 95% CI 1.34-5.32; P = 0.005). The development rate of end-stage-CKD was 0.4% at the 5th year, 1.6% at the 10th year and 2.8% at the 15th year. CONCLUSIONS The annual incidence for CKD among cirrhotic patients with HCV was determined to be about 1.0-1.5%. In addition, the annual incidence for end-stage-CKD is one order of magnitude lower than that of CKD.
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Affiliation(s)
- Yasuji Arase
- Department of Hepatology and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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13
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Arase Y, Suzuki F, Kobayashi M, Suzuki Y, Kawamura Y, Matsumoto N, Akuta N, Imai N, Kobayashi M, Sezaki H, Saito S, Hosaka T, Ikeda K, Kumada H, Ohmoto Y, Amakawa K, Tsuji H, Hsieh SD, Kobayashi T. Efficacy and safety in sitagliptin therapy for diabetes complicated by chronic liver disease caused by hepatitis C virus. Hepatol Res 2011; 41:524-9. [PMID: 21435130 DOI: 10.1111/j.1872-034x.2011.00798.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
AIM Diabetes is present in patients with chronic liver disease caused by hepatitis C virus (HCV). The aim of this case-control study is to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with chronic liver disease caused by HCV. METHODS Sixteen HCV positive patients with T2DM treated by sitagliptin were retrospectively enrolled. These patients were given sitagliptin between December 2009 and January 2010. Another 16 HCV patients with T2DM treated only with diet and excise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. RESULTS In the sitagliptin group, the average HbA1C level decreased approximately 0.8% at 48 weeks after the initiation of sitagliptin. Next, the average FPG level decreased approximately 20 mg/dL during follow up after the initiation of sitagliptin. All the patients were able to take sitagliptin of 50 mg/day without reduction because of sitagliptin-related side-effects. On the other hand, in the control group, the average HbA1C and FPG level did not change with statistical significance during follow up of 48 weeks. Regarding aminotransferase, there were no significant changes of average AST and ALT level during follow up of 48 weeks in both the sitagliptin group and control group. CONCLUSION Our results indicate that sitagliptin is effective and safe for the treatment of T2DM complicated with HCV positive chronic liver disease.
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Affiliation(s)
- Yasuji Arase
- Department of Hepatology and Okinaka Memorial Institute for Medical Research Department of Health Management Center, Toranomon Hospital, Tokyo Department of Third Internal Medicine (Metabolism), University of Yamanashi, Yamanashi, Japan
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Ripoli M, Barbano R, Balsamo T, Piccoli C, Brunetti V, Coco M, Mazzoccoli G, Vinciguerra M, Pazienza V. Hypermethylated levels of E-cadherin promoter in Huh-7 cells expressing the HCV core protein. Virus Res 2011; 160:74-81. [PMID: 21640770 DOI: 10.1016/j.virusres.2011.05.014] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Revised: 05/16/2011] [Accepted: 05/16/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The mechanisms of hepatocarcinogenesis induced by hepatitis C virus remain unclear. Our aim was to investigate the effect of the HCV core protein on the promoter methylation status of selected genes potentially involved in the hepatocellular carcinoma (HCC). MATERIALS AND METHODS We evaluated the promoter methylation levels of the E-cadherin (CDH1), the glutathione S-transferase p1 (GSTP1), adenomatosis polyposis coli (APC), tissue inhibitor of metalloproteinase 3 (TIMP3), catenin (cadherin-associated protein) beta 1 (CNNTB1) genes by a quantitative methylation-specific polymerase chain reaction (QMSP) in the in vitro model of Huh-7 cells expressing the HCV core protein of genotype 1b. RESULTS We found that CDH1 promoter was hypermethylated in genotype 1b HCV core protein-positive cells as compared to control cells expressing the GFP protein alone (HCV core 1b vs GFP p=0.00; HCV core 1b vs Huh-7 p=0.03). This resulted in reduced levels of CDH1 protein as evaluated by immunoblot and by immunofluorescence. On the other hand no significant changes were observed for the other genes investigated. Furthermore, we present evidence that genotype 1b HCV core protein expression induces SIRT1 upregulation and that treatment with SIRT1 inhibitor sirtinol decreases the methylation levels of CDH1 promoter (1b+sirtinol vs 1b p=0.05; 1b+sirtinol vs GFP+sirtinol p=NS) resulting in 1.7-fold increased CDH1 mRNA expression (1b+sirtinol vs 1b p=0.05). CONCLUSIONS Our findings suggest that HCV core protein could play a role in HCC at least in part by altering the methylation status of CDH1 promoter. These findings could also suggest a novel therapeutic approach for HCC.
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Affiliation(s)
- Maria Ripoli
- Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza Hospital, viale dei Cappuccini n.1, 71013 San Giovanni Rotondo (FG), Italy
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15
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Kawamura Y, Arase Y, Ikeda K, Hirakawa M, Hosaka T, Kobayashi M, Saitoh S, Yatsuji H, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Kumada H. Diabetes enhances hepatocarcinogenesis in noncirrhotic, interferon-treated hepatitis C patients. Am J Med 2010; 123:951-956.e1. [PMID: 20920698 DOI: 10.1016/j.amjmed.2010.05.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2009] [Revised: 03/31/2010] [Accepted: 05/05/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND This retrospective cohort study assessed the impact of diabetes mellitus on hepatocarcinogenesis and determined the predictors of hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus infection. METHODS A total of 2058 hepatitis C virus-positive, noncirrhotic patients treated with interferon were enrolled. The median follow-up period was 6.7 years. The primary end point was the onset of hepatocellular carcinoma. The cumulative rate of new hepatocellular carcinoma cases was computed by the Kaplan-Meier method and Cox proportional hazard analysis according to diabetic state and response to interferon therapy. RESULTS The cumulative rates of hepatocellular carcinoma in diabetic patients (3.2% at 4 years, 8.5% at 8 years, and 24.4% at 12 years) were significantly higher than those of nondiabetic patients (1.3% at 4 years, 2.2% at 8 years, and 5.6% at 12 years, P<.001). In patients with a sustained virologic response, diabetes had no significant effect on the rate of hepatocarcinogenesis. In contrast, the rate in patients with a nonsustained virologic response was significantly higher in diabetic than in nondiabetic patients. Multivariate analysis identified lack of sustained virologic response (hazard ratio [HR] 7.28; 95% confidence interval [CI], 3.28-16.15; P<.001) and diabetes as independent risk factors for hepatocarcinogenesis (HR 2.00; 95% CI, 1.05-3.84; P=.036). CONCLUSIONS Our results highlight the enhancing effect of diabetes mellitus on hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus. The sustained virologic response induced by interferon therapy eliminates the influence of diabetes and markedly reduces the rate of hepatocarcinogenesis in such patients.
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Affiliation(s)
- Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, Minato-ku, Tokyo, Japan.
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Tamura Y, Yamagiwa S, Aoki Y, Kurita S, Suda T, Ohkoshi S, Nomoto M, Aoyagi Y. Serum alpha-fetoprotein levels during and after interferon therapy and the development of hepatocellular carcinoma in patients with chronic hepatitis C. Dig Dis Sci 2009; 54:2530-2537. [PMID: 19093203 DOI: 10.1007/s10620-008-0642-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Accepted: 11/12/2008] [Indexed: 02/07/2023]
Abstract
The association between serum alpha-fetoprotein (AFP) levels during and after interferon (IFN) therapy and the development of hepatocellular carcinoma (HCC) was evaluated in patients with chronic hepatitis C (CHC). A total of 263 patients treated by IFN with or without ribavirin were enrolled in the study. Serum AFP levels during and after IFN therapy were investigated retrospectively, and statistical analysis was performed to identify the factors associated with HCC development. During IFN therapy, serum AFP levels significantly decreased, regardless of virologic response to treatment. Increased serum AFP levels (>or=10 ng/ml) at the end of IFN therapy (EOT) was a close-to-significant variable affecting the development of HCC (P = 0.057), and a significantly higher cumulative incidence of HCC was seen in patients with increased serum AFP levels at EOT (P = 0.021). Serum AFP level at EOT is a possible predictor of HCC in CHC patients after IFN therapy.
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Affiliation(s)
- Yasushi Tamura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
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Arase Y, Suzuki F, Suzuki Y, Akuta N, Kobayashi M, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Hirakawa M, Ikeda K, Kumada H. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology 2009; 49:739-44. [PMID: 19127513 DOI: 10.1002/hep.22703] [Citation(s) in RCA: 200] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED Diabetes is present in patients with chronic hepatitis C virus infection. The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors for type 2 diabetes after the termination of interferon therapy in Japanese patients positive for hepatitis C virus (HCV). A total of 2,842 HCV-positive patients treated with interferon (IFN) monotherapy or combination therapy with IFN and ribavirin were enrolled. The mean observation period was 6.4 years. An overnight (12-hour) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal was the onset of type 2 diabetes. Evaluation was performed by using the Kaplan-Meier method and Cox proportional hazard analysis. Of 2,842 HCV patients, 143 patients developed type 2 diabetes. The cumulative development rate of type 2 diabetes was 3.6% at 5 years, 8.0% at 10 years, and 17.0% at 15 years. Multivariate Cox proportional hazard analysis revealed that type 2 diabetes development after the termination of IFN therapy occurred when histological staging was advanced (hazard ratio 3.30; 95% confidence interval [CI] 2.06-5.28; P < 0.001), sustained virological response was not achieved (hazard ratio 2.73; 95% CI 1.77-4.20; P < 0.001), the patient had pre-diabetes (hazard ratio 2.19; 95% CI 1.43-3.37; P < 0.001), and age was >or=50 years (hazard ratio 2.10; 95% CI 1.38-3.18; P < 0.001). CONCLUSION Our results indicate sustained virological response causes a two-thirds reduction in the risk of type 2 diabetes development in HCV-positive patients treated with IFN.
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Affiliation(s)
- Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
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18
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Clinicopathological features of elderly patients with hepatitis C virus-related hepatocellular carcinoma. J Gastroenterol 2008; 43:550-7. [PMID: 18648742 DOI: 10.1007/s00535-008-2194-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2007] [Accepted: 03/20/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND It is well known that the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) correlates with progression of liver fibrosis. However, there is little information on the impact of aging on hepatocarcinogenesis. The aim of this study was to elucidate the clinicopathological features of elderly patients with HCV-related HCC. METHODS The study subjects were 693 consecutive patients newly diagnosed with HCC with anti-HCV. First, we divided them into a younger group (<70 years) and an elderly group (> or =70 years) and compared clinicopathological features between the two groups. Next, we selected pure HCV-related HCC patients by excluding the patients with other probable factors for hepatocarcinogenesis (anti-HBc, interferon therapy, and alcohol) and compared the two groups again. RESULTS Higher platelet count, lower male/female ratio, lower rate of habitual alcohol consumption, and better Child-Pugh class were recognized in the elderly group thant the younger group, statistically. In 133 cases of hepatic resection, fibrosis stage was lower in the elderly than the younger group. After selection of pure HCV-related HCC patients, in a stepwise multi variate analysis, male sex and platelet count <10 x 10(4)/mm3 were significant variables associated with age <70. Regarding the latency period to HCC development, the patients who received a blood transfusion at an older age developed HCC sooner despite their lower grade of fibrosis. CONCLUSIONS The elderly patients developed HCC more often, despite their lower grade of fibrosis, compared with the younger patients. In addition to fibrosis, aging could be a factor affecting HCV-related hepatocarcinogenesis.
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Arase Y, Suzuki F, Suzuki Y, Akuta N, Kobayashi M, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Hirakawa M, Saito S, Ikeda K, Kumada H. Hepatitis C virus enhances incidence of idiopathic pulmonary fibrosis. World J Gastroenterol 2008; 14:5880-6. [PMID: 18855988 PMCID: PMC2751899 DOI: 10.3748/wjg.14.5880] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the cumulative development incidence and predictive factors for idiopathic pulmonary fibrosis in hepatitis C virus (HCV) positive patients.
METHODS: We studied 6150 HCV infected patients who were between 40-70 years old (HCV-group). Another 2050 patients with hepatitis B virus (HBV) were selected as control (HBV-group). The mean observation period was 8.0 ± 5.9 years in HCV-group and 6.3 ± 5.5 years in HBV-group. The primary goal is the development of idiopathic pulmonary fibrosis (IPF) in both groups. The cumulative appearance rate of IPF and independent factors associated with the incidence rate of IPF were calculated using the Kaplan-Meier method and the Cox proportional hazard model. All of the studies were performed retrospectively by collecting and analyzing data from the patient records in our hospital.
RESULTS: Fifteen patients in HCV-group developed IPF. On the other hand, none of the patients developed IPF in HBV-group. In HCV-group, the cumulative rates of IPF development were 0.3% at 10th year and 0.9% at 20th year. The IPF development rate in HCV-group was higher than that in HBV-group (P = 0.021). The IPF development rate in patients with HCV or HBV was high with statistical significance in the following cases: (1) patients ≥ 55 years (P < 0.001); (2) patients who had smoking index (package per day × year) of ≥ 20 (P = 0.002); (3) patients with liver cirrhosis (P = 0.042).
CONCLUSION: Our results indicate that age, smoking and liver cirrhosis enhance the development of IPF in HCV positive patients.
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Arase Y, Suzuki F, Suzuki Y, Akuta N, Sezaki H, Kobayashi M, Kawamura Y, Yatsuji H, Hosaka T, Saito S, Ikeda K, Kumada H. Potential of laparoscopy in chronic liver disease with hepatitis B and C viruses. Hepatol Res 2008; 38:877-85. [PMID: 18507692 DOI: 10.1111/j.1872-034x.2008.00343.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIM The definitive diagnosis of chronic liver disease is made either by a histological examination of a biopsy specimen or upon visualization of the liver surface at laparoscopy. The aim of this retrospective cohort study is to assess whether histological or laparoscopic findings are associated with hepatocellular carcinoma (HCC) development. METHODS A retrospective review of paired laparoscopy and histology reports was performed on 4124 hepatitis virus-positive patients who underwent laparoscopy: 2804 patients had hepatitis C virus (HCV group) and 1320 patients had hepatitis B virus (HBV group). Based on the irregularities of the liver surface, the laparoscopic findings were classified into three groups in progression order: smooth, irregular, or nodular. The histological findings were classified according to the extent of fibrosis into four stages (stages 1-4) in progression order. RESULTS The number of patients with HCC development was 565 in the HCV group and 115 in the HBV group. The Coxregression hazard model showed that HCC appearance in the HCV group was independently associated with laparoscopic findings (relative risk based on every progression of one rank [RR], RR = 4.31, P < 0.0001) and histological findings (RR = 2.56, P < 0.0001). In the HBV group, however, HCC appearance in was mainly associated with laparoscopic findings (RR = 2.12, P < 0.0001) compared to histological findings (RR = 1.13, P = 0.403). CONCLUSION Our data indicate that laparoscopic findings of the liver are dominant predictors for HCC development compared with histological findings in patients with HBV.
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Affiliation(s)
- Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
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21
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Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. Am J Med 2008; 121:525-31. [PMID: 18501235 DOI: 10.1016/j.amjmed.2008.03.005] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2008] [Revised: 02/22/2008] [Accepted: 03/04/2008] [Indexed: 12/29/2022]
Abstract
BACKGROUND The increasing incidence of hepatocellular carcinoma coupled with this cancer's high mortality is a public health problem. Delineating high-risk populations and cancer patterns can provide valuable information. This is necessary to broaden screening and surveillance guidelines related to early detection and prevention. METHODS By using data collected by the Surveillance, Epidemiology, and End Results program, a population-based cancer registry in the United States, our retrospective cohort study evaluated sex-specific, race/ethnicity-specific, and age-specific variations in hepatocellular carcinoma incidence from 1992 to 2004. RESULTS With men and women combined, the incidence of hepatocellular carcinoma among Asians was the highest, nearly double that of white Hispanics (11.0 vs 6.8 per 100,000/y), and more than 4 times higher than that of Caucasians (11.0 vs 2.6 per 100,000/y). Although male subjects demonstrated a doubling of cancer rates every 10 years from 30 to 50 years of age, female subjects reached male-comparable rates of cancer 10 to 15 years later and peaked at significantly lower values for all race and ethnic groups. CONCLUSION Marked differences in the incidence rates of hepatocellular carcinoma by sex, ethnicity, and age of diagnosis likely represent variations in risk factor distributions (eg, viral hepatitis) and possibly in host genetics or other environmental factors. An individualized approach tailored to specific risk profiles may more effectively identify treatable tumors than more general guidelines.
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Kawamura Y, Ikeda K, Arase Y, Yatsuji H, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Suzuki F, Suzuki Y, Kumada H. Viral elimination reduces incidence of malignant lymphoma in patients with hepatitis C. Am J Med 2007; 120:1034-41. [PMID: 18060923 DOI: 10.1016/j.amjmed.2007.06.022] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2007] [Revised: 06/03/2007] [Accepted: 06/18/2007] [Indexed: 12/17/2022]
Abstract
PURPOSE A high prevalence of malignant lymphoma among patients with hepatitis C virus (HCV) infection has been reported. The aim of this retrospective study was to determine the incidence of malignant lymphoma and the relationship between malignant lymphoma and viral elimination in patients with HCV. METHOD We studied 501 consecutive HCV-infected patients who had never received interferon therapy and 2708 consecutive HCV-infected patients who received interferon therapy. RESULTS In the non-interferon group, the cumulative rates of malignant lymphoma development were 0.6% at the 5th year, 2.3% at the 10th year, and 2.6% at the 15th year. The cumulative rates of malignant lymphoma development in interferon-treated patients with sustained virologic response were 0% at the 5th year, 0% at the 10th year, and 0% at the 15th year. The cumulative rates of malignant lymphoma development with persistent infection were 0.4% at the 5th year, 1.5% at the 10th year, and 2.6% at the 15th year. The malignant lymphoma development rate was higher in patients with persistent infection than in patients with sustained virologic response (P=.0159). The hazard ratio of lymphomagenesis in 1048 patients with sustained virologic response was significantly lower than in patients with persistent infection (hazard ratio: 0.13; P=.049). CONCLUSION Our retrospective study is the first to determine the annual incidence of malignant lymphoma among patients with HCV at 0.23%. Our results indicate that sustained virologic response induced by interferon therapy protects against the development of malignant lymphoma in patients with chronic HCV.
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Li Q, Li H, Qin Y, Wang PP, Hao X. Comparison of surgical outcomes for small hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a Chinese experience. J Gastroenterol Hepatol 2007; 22:1936-41. [PMID: 17914973 DOI: 10.1111/j.1440-1746.2006.04619.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Although both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are well recognized risk factors for hepatocellular carcinoma (HCC), little is known with respect to how HBV and HCV infection affect HCC recurrence in postoperative HCC Chinese patients. The objective of this study was to determine if differences exist in preoperative characteristics and postoperative HCC recurrence in patients with different HBV and HCV infection status. METHODS The study population consisted of 413 patients undergoing a curative resection at Tianjin Cancer Hospital for small HCC (< or =3 cm) from January 1997 to December 2003. The patients were divided into four groups: HCV only (n = 75), HBV only (n = 251), HBV and HCV (n = 33), and neither HBV nor HCV (NBNC, n = 54). The preoperative status and postoperative HCC recurrence were recorded. Survival analyses were used to assess the impact of HBV/HCV status on HCC recurrence. RESULTS Patients with HCV had a significant association with older age, lower mean preoperative platelet counts and albumin levels, higher mean prothrombin time, alanine aminotransferase and total bilirubin levels and multinodular tumors during diagnosis. Patients with HCV also had significantly less differentiated tumors and a higher incidence of vascular invasion and cirrhosis when compared to the other groups. During the follow-up, the HCV group showed a higher incidence of intrahepatic recurrence and multiple recurrent lesions than the other patients. CONCLUSIONS Patients with HCV infection tended to be older, and were characterized by more severe cirrhosis and higher incidence of tumor multicentricity. The statistically significant determinants for reoccurrence in patients with small HCC were HCV infection, presence of vascular invasion and multiple tumors.
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Affiliation(s)
- Qiang Li
- Department of Hepatobiliary Surgery, Cancer Hospital of Tianjin Medical University, Tianjin, China.
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Ikeda K. Glycyrrhizin injection therapy prevents hepatocellular carcinogenesis in patients with interferon-resistant active chronic hepatitis C. Hepatol Res 2007; 37 Suppl 2:S287-93. [PMID: 17877497 DOI: 10.1111/j.1872-034x.2007.00199.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
AIM There is no useful and effective treatment for patients with non-sustained response to interferon, from the viewpoint of cancer prevention. Our aim was to elucidate the influence of a glycyrrhizin therapy on hepatocarcinogenesis rate in interferon-resistant hepatitis C Methods: We retrospectively analyzed 1249 patients with chronic hepatitis with or without cirrhosis. Among 346 patients with high alanine transaminase values of twice or more of the upper limit of normal, 244 patients received i.v. glycyrrhizin injection and 102 patients did not, after judgment of interferon resistance. RESULTS Crude carcinogenesis rates in the treated and untreated group were 13.3%, 26.0% at the fifth year, and 21.5% and 35.5% at the 10th year, respectively (P = 0.021). Proportional hazard analysis using time-dependent covariates disclosed that fibrotic stage, gender and glycyrrhizin treatmentwere significantly associated with future carcinogenesis. A long-term glycyrrhizin injection therapy decreased the hepatocarcinogenesis rate (hazard ratio, 0.49; 95% confidence interval, 0.27-0.86, P = 0.014) after adjusting the background features with significant covariates. Cancer preventive activity was also found in a subgroup of older patients of 60 years or more. CONCLUSIONS Glycyrrhizin injection therapy significantly decreased the incidence of hepatocellular carcinoma in patients with interferon-resistant active chronic hepatitis C, whose average aminotransferase value was twice or more of the upper limit of normal after interferon.
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Affiliation(s)
- Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
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Arrieta O, Cacho B, Morales-Espinosa D, Ruelas-Villavicencio A, Flores-Estrada D, Hernández-Pedro N. The progressive elevation of alpha fetoprotein for the diagnosis of hepatocellular carcinoma in patients with liver cirrhosis. BMC Cancer 2007; 7:28. [PMID: 17288606 PMCID: PMC1803796 DOI: 10.1186/1471-2407-7-28] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2006] [Accepted: 02/08/2007] [Indexed: 02/07/2023] Open
Abstract
Background Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the main causes of death in patients with liver cirrhosis. High Alpha fetoprotein serum levels have been found in 60–70% of patients with Hepatocellular carcinoma; nevertheless, there are other causes that increase this protein. Alpha fetoprotein levels ≥200 and 400 ng/mL in patients with an identifiable liver mass by imaging techniques are diagnostic of hepatocellular carcinoma with high specificity. Methods We analysed the sensitivity and specificity of the progressive increase of the levels of alpha fetoprotein for the detection of hepatocellular carcinoma in patients with liver cirrhosis. Seventy-four patients with cirrhosis without hepatocellular carcinoma and 193 with hepatic lesions diagnosed by biopsy and shown by image scans were included. Sensitivity and specificity of transversal determination of alpha fetoprotein ≥ 200 and 400 ng/mL and monthly progressive elevation of alpha fetoprotein were analysed. Areas under the ROC curves were compared. Positive and negative predictive values adjusted to a 5 and 10% prevalence were calculated. Results For an elevation of alpha fetoprotein ≥ 200 and 400 ng/mL the specificity is of 100% in both cases, with a sensitivity of 36.3 and 20.2%, respectively. For an alpha fetoprotein elevation rate ≥7 ng/mL/month, sensitivity was of 71.4% and specificity of 100%. The area under the ROC curve of the progressive elevation was significantly greater than that of the transversal determination of alpha fetoprotein. The positive and negative predictive values modified to a 10% prevalence are of: 98.8% and 96.92%, respectively; while for a prevalence of 5% they were of 97.4% and 98.52%, respectively. Conclusion The progressive elevation of alpha fetoprotein ≥7 ng/mL/month in patients with liver cirrhosis is useful for the diagnosis of hepatocellular carcinoma in patients that do not reach αFP levels ≥200 ng/mL. Prospective studies are required to confirm this observation.
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Affiliation(s)
- Oscar Arrieta
- Department of Medical Oncology, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
- Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Bernardo Cacho
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" (INCMNSZ), Mexico City, Mexico
| | | | - Ana Ruelas-Villavicencio
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" (INCMNSZ), Mexico City, Mexico
| | - Diana Flores-Estrada
- Department of Medical Oncology, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Norma Hernández-Pedro
- Department of Medical Oncology, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
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Arrieta O, Rodriguez-Diaz JL, Rosas-Camargo V, Morales-Espinosa D, Ponce de Leon S, Kershenobich D, Leon-Rodriguez E. Colchicine delays the development of hepatocellular carcinoma in patients with hepatitis virus-related liver cirrhosis. Cancer 2006; 107:1852-8. [PMID: 16967451 DOI: 10.1002/cncr.22198] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a malignant neoplasm associated with liver cirrhosis, with an annual incidence of 3% to 9%, which is one of the main causes of death in patients with cirrhosis. Viral hepatitis is associated with an increased risk of HCC, probably due to an inflammatory reaction. Colchicine is an antiinflammatory agent that inhibits the formation of intracellular microtubules, affecting mitosis and fibrogenesis. Diverse clinical studies have failed to demonstrate the benefit of colchicine over the progression of fibrosis in patients with liver cirrhosis; nevertheless, to the authors' knowledge there are no studies that evaluate its effect in the development of HCC. METHODS The effect of the administration of colchicine on the development of HCC was evaluated in 186 patients with hepatitis virus-related liver cirrhosis in a retrospective cohort study. The minimum follow-up time was 3 years (median, 84 months +/- 2.8 months). One hundred sixteen patients received treatment with colchicine. The characteristics of both groups were similar. RESULTS The percentage of patients who developed HCC was significantly smaller in the colchicine group when compared with the noncolchicine group (9% vs. 29%; P = .001). On multivariate analysis, an alpha-fetoprotein level > or = 5 ng/dL (P = .03), a platelet count < 100,000 at diagnosis (P = .05), alanine aminotransferase > or = 52 IU (P = .006), and a lack of treatment with colchicine (P = .0001) were found to be associated with an earlier development of HCC. The average time for the development of HCC was 222 months +/- 15 months and 150 months +/- 12 months in the patients who received and who did not receive colchicine, respectively. CONCLUSIONS The results suggest that treatment with colchicine prevents and delays the development of HCC in patients with hepatitis virus-related cirrhosis. The protective mechanisms of colchicine over the development of HCC could be related to antiinflammatory properties and inhibition of mitosis. Prospective studies to confirm this observation with a greater number of patients and long-term follow-up may be indicated.
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Affiliation(s)
- Oscar Arrieta
- Department of Medical Oncology, Instituto Nacional de Cancerologia, Tlalpan, Mexico.
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Ikeda K, Arase Y, Saitoh S, Kobayashi M, Someya T, Hosaka T, Akuta N, Suzuki Y, Suzuki F, Sezaki H, Kumada H, Tanaka A, Harada H. Prediction model of hepatocarcinogenesis for patients with hepatitis C virus-related cirrhosis. Validation with internal and external cohorts. J Hepatol 2006; 44:1089-97. [PMID: 16618514 DOI: 10.1016/j.jhep.2006.02.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2005] [Revised: 01/31/2006] [Accepted: 02/20/2006] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS To estimate hepatocarcinogenesis rates in patients with hepatitis C virus (HCV)-related cirrhosis, an accurate prediction table was created. METHODS A total of 183 patients between 1974 and 1990 were assessed for carcinogenesis rate and risk factors. Predicted carcinogenesis rates were validated using a cohort from the same hospital between 1991 and 2003 (n=302) and an external cohort from Tokyo National Hospital between 1975 and 2002 (n=205). RESULTS The carcinogenesis rates in the primary cohort were 28.9% at the 5th year and 54.0% at the 10th year. A proportional hazard model identified alpha-fetoprotein (>or=20 ng/ml, hazard ratio 2.30, 95% confidence interval 1.55-3.42), age (>or=55 years, 2.02, 95% CI 1.32-3.08), gender (male, 1.58, 95% CI 1.05-2.38), and platelet count (<100,000 counts/mm3, 1.54, 95% CI 1.04-2.28) as independently associated with carcinogenesis. When carcinogenesis rates were simulated in 16 conditions according to four binary variables, the 5th- and 10th-year rates varied from 9 to 64%, and 21-93%, respectively. Actual carcinogenesis rates in the internal and external validation cohorts were similar to those of the simulated curves. CONCLUSIONS Simulated carcinogenesis rates were applicable to patients with HCV-related cirrhosis. Since, hepatocarcinogenesis rates markedly varied among patients depending on background features, we should consider stratifying them for cancer screening and cancer prevention programs.
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Affiliation(s)
- Kenji Ikeda
- Department of Gastroenterology, Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo 105-8470, Japan.
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28
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Ikeda K, Arase Y, Kobayashi M, Saitoh S, Someya T, Hosaka T, Sezaki H, Akuta N, Suzuki Y, Suzuki F, Kumada H. A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients. Dig Dis Sci 2006; 51:603-9. [PMID: 16614974 DOI: 10.1007/s10620-006-3177-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2005] [Accepted: 07/12/2005] [Indexed: 12/17/2022]
Abstract
To elucidate the influence of a glycyrrhizin therapy on hepatocarcinogenesis rate in interferon (IFN)-resistant hepatitis C, we retrospectively analyzed 1249 patients with chronic hepatitis with or without cirrhosis. Among 346 patients with high alanine transaminase value (twice or more of upper limit of normal), 244 patients received intravenous glycyrrhizin injection and 102 patients did not, after judgment of IFN resistance. Crude carcinogenesis rates in the treated and untreated group were 13.3%, 26.0% at the 5th year, and 21.5% and 35.5% at the 10th year, respectively (P = .0210). Proportional hazard analysis using time-dependent covariates disclosed that glycyrrhizin treatment significantly decreased the hepatocarcinogenesis rate (hazard ratio 0.49, 95% confidence interval 0.27-0.86, P = .014) after adjusting the background features with significant covariates. Glycyrrhizin injection therapy significantly decreased the incidence of hepatocellular carcinoma in patients with IFN-resistant active chronic hepatitis C, whose average aminotransferase value was twice or more of upper limit of normal after interferon.
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Affiliation(s)
- Kenji Ikeda
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.
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Lee CM, Hung CH, Lu SN, Wang JH, Tung HD, Huang WS, Chen CL, Chen WJ, Changchien CS. Viral etiology of hepatocellular carcinoma and HCV genotypes in Taiwan. Intervirology 2005; 49:76-81. [PMID: 16166793 DOI: 10.1159/000087267] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas of the world. Hepatitis B virus infection is associated with HCC. However, hepatitis C virus (HCV) infection plays an increasingly more important role in the development of HCC and is associated with more than 30% of HCC in Taiwan. The prevalence of HCV infection and HCV genotypes vary in different geographic areas. The prevalence of HCV genotype 1b (HCV-1b) was around 50-70% in Taiwan and even varied in different townships. In addition to host factors, HCV genotypes may be associated with the development of HCC. In our study, the prevalence of HCV-1b in patients with HCC was significantly higher than in those with liver cirrhosis and chronic hepatitis; multivariate analysis revealed that the disease severity was significantly correlated with age and HCV-1b. Furthermore, HCV-1b was associated with a lower response rate to interferon (IFN) therapy than HCV-2. Our study has demonstrated that mutations in the IFN sensitivity-determining region, spanning nucleotides 2,209-2,248 in the NS5A region, correlate with the sustained virological response to combination therapy with IFN and ribavirin in patients with chronic HCV-1b infection in Taiwan. A third-generation enzyme immunoassay for antibody to HCV can be used to predict viremia and monitor the virological response.
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Affiliation(s)
- Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan (ROC).
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Hung CH, Lee CM, Wang JH, Tung HD, Chen CH, Lu SN. Antiviral therapy after non-surgical tumor ablation in patients with hepatocellular carcinoma associated with hepatitis C virus. J Gastroenterol Hepatol 2005; 20:1553-9. [PMID: 16174073 DOI: 10.1111/j.1440-1746.2005.03925.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Antiviral therapy for chronic hepatitis C virus (HCV) infection has led to a reduction in the incidence of hepatocellular carcinoma (HCC). The purpose of the present paper was to assess whether antiviral therapy might suppress tumor recurrence and influence overall survival in patients with HCV-related HCC who had complete ablation of nodules by non-surgical treatments. METHODS Twenty patients with three or fewer nodules of HCV-related HCC who were treated with percutaneous tumor ablation and/or transcatheter arterial embolization received combined interferon (IFN; 3 or 5 million units of IFN alpha-2b thrice weekly) plus ribavirin (1000-1200 mg per day) therapy for 24-48 weeks after complete ablation of lesions. During the same period, an additional 40 age- and sex-matched control patients with similar characteristics of tumors (sizes, numbers and treatment modalities) and severity of liver disease were recruited from the HCC database. Both recurrence-free survival and actuarial survival were evaluated. RESULTS Of the 20 patients, 16 completed therapy and 10 showed a sustained response with normalization of alanine aminotransferase and negative HCV-RNA at 6 months after therapy completion. Due to severe side-effects experienced by Child B patients, who mostly discontinued antiviral therapy, clinical outcome was analyzed in the Child A treated (n = 16) and control (n = 33) patients. There was no significant difference in the incidence of local recurrence in sustained responders compared with non-responders or control patients (P = 0.174, 0.1284, respectively); but the second recurrence-free interval in the sustained responders was significantly longer than that of non-responders and the control group (P = 0.0141, 0.0243, respectively). Survival in sustained responders was better than in non-responders and control patients (P = 0.0691, 0.0554, respectively). CONCLUSIONS These results indicate that successful antiviral therapy after non-surgical tumor ablation for HCV-related HCC may lower tumor recurrence rate and prolong survival.
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Affiliation(s)
- Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Filmus J, Capurro M. Glypican-3 and alphafetoprotein as diagnostic tests for hepatocellular carcinoma. ACTA ACUST UNITED AC 2005; 8:207-12. [PMID: 15887976 DOI: 10.1007/bf03260065] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumor. It is usually asymptomatic in the early stages and tends to be intravascularly and intrabiliary invasive. Therefore, most patients present with incurable disease at the time of detection and early diagnosis of HCC is critical for a good prognosis. The imaging-based diagnosis of small tumors is relatively inaccurate, as cirrhotic and dysplastic nodules mimic HCC radiologically. The availability of a suitable serological marker to distinguish between HCC and benign liver lesions would, therefore, be very useful for early diagnosis. The only serological marker currently widely used for the diagnosis of HCC is alphafetoprotein (AFP). However, the sensitivity of this marker is limited (41-65%). Given the high heterogeneity of HCC, it is currently thought that an optimal serological test for HCC will be based on the simultaneous measurement of two or three highly specific serological markers.Several laboratories have recently reported that glypican-3 (GPC3), a membrane-bound proteoglycan, is expressed by a large proportion of HCCs, but is undetectable in normal hepatocytes and non-malignant liver disease. Furthermore, various studies demonstrated that GPC3 could be used as a serological test for the diagnosis of patients with HCC. Although the specificity of the test was very high in the context of a population with chronic liver disease, the sensitivity was limited (within the same range as AFP). Interestingly, in most cases, elevated GPC3 values did not correlate with elevated AFP values. As a consequence, the serological level of at least one of the two markers was elevated in a large majority of HCC patients. These results suggest that the sensitivity of the diagnostic test can be significantly improved without compromising specificity with the simultaneous measurement of both GPC3 and AFP.
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Affiliation(s)
- Jorge Filmus
- Division of Molecular and Cell Biology, Sunnybrook & Women's College Health Sciences, Toronto, Ontario, Canada.
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Filmus J, Capurro M. Glypican-3 and alphafetoprotein as diagnostic tests for hepatocellular carcinoma. MOLECULAR DIAGNOSIS : A JOURNAL DEVOTED TO THE UNDERSTANDING OF HUMAN DISEASE THROUGH THE CLINICAL APPLICATION OF MOLECULAR BIOLOGY 2005. [PMID: 15887976 DOI: 10.2165/00066982-200408040-00002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumor. It is usually asymptomatic in the early stages and tends to be intravascularly and intrabiliary invasive. Therefore, most patients present with incurable disease at the time of detection and early diagnosis of HCC is critical for a good prognosis. The imaging-based diagnosis of small tumors is relatively inaccurate, as cirrhotic and dysplastic nodules mimic HCC radiologically. The availability of a suitable serological marker to distinguish between HCC and benign liver lesions would, therefore, be very useful for early diagnosis. The only serological marker currently widely used for the diagnosis of HCC is alphafetoprotein (AFP). However, the sensitivity of this marker is limited (41-65%). Given the high heterogeneity of HCC, it is currently thought that an optimal serological test for HCC will be based on the simultaneous measurement of two or three highly specific serological markers.Several laboratories have recently reported that glypican-3 (GPC3), a membrane-bound proteoglycan, is expressed by a large proportion of HCCs, but is undetectable in normal hepatocytes and non-malignant liver disease. Furthermore, various studies demonstrated that GPC3 could be used as a serological test for the diagnosis of patients with HCC. Although the specificity of the test was very high in the context of a population with chronic liver disease, the sensitivity was limited (within the same range as AFP). Interestingly, in most cases, elevated GPC3 values did not correlate with elevated AFP values. As a consequence, the serological level of at least one of the two markers was elevated in a large majority of HCC patients. These results suggest that the sensitivity of the diagnostic test can be significantly improved without compromising specificity with the simultaneous measurement of both GPC3 and AFP.
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Affiliation(s)
- Jorge Filmus
- Division of Molecular and Cell Biology, Sunnybrook & Women's College Health Sciences, Toronto, Ontario, Canada.
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Pudi R, Ramamurthy SS, Das S. A peptide derived from RNA recognition motif 2 of human la protein binds to hepatitis C virus internal ribosome entry site, prevents ribosomal assembly, and inhibits internal initiation of translation. J Virol 2005; 79:9842-53. [PMID: 16014945 PMCID: PMC1181605 DOI: 10.1128/jvi.79.15.9842-9853.2005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Human La protein is known to interact with hepatitis C virus (HCV) internal ribosome entry site (IRES) and stimulate translation. Previously, we demonstrated that mutations within HCV SL IV lead to reduced binding to La-RNA recognition motif 2 (RRM2) and drastically affect HCV IRES-mediated translation. Also, the binding of La protein to SL IV of HCV IRES was shown to impart conformational alterations within the RNA so as to facilitate the formation of functional initiation complex. Here, we report that a synthetic peptide, LaR2C, derived from the C terminus of La-RRM2 competes with the binding of cellular La protein to the HCV IRES and acts as a dominant negative inhibitor of internal initiation of translation of HCV RNA. The peptide binds to the HCV IRES and inhibits the functional initiation complex formation. An Huh7 cell line constitutively expressing a bicistronic RNA in which both cap-dependent and HCV IRES-mediated translation can be easily assayed has been developed. The addition of purified TAT-LaR2C recombinant polypeptide that allows direct delivery of the peptide into the cells showed reduced expression of HCV IRES activity in this cell line. The study reveals valuable insights into the role of La protein in ribosome assembly at the HCV IRES and also provides the basis for targeting ribosome-HCV IRES interaction to design potent antiviral therapy.
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Affiliation(s)
- Renuka Pudi
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and has a marked difference in geographic distribution. More than 80% of HCC cases occur in developing countries, especially the Far East and Southeast Asia. Although immunization has been successful against hepatitis B virus (HBV), a changing disease burden of HCC has been observed in many parts of the world because of the increasing prevalence and duration of hepatitis C virus (HCV) infection in these countries. In addition, the age-specific incidence of HCC has progressively shifted toward younger people. Hepatitis B genotypes B and C are prevalent in the Far East and Southeast Asia, and the clinical relevance of HBV genotypes has become increasingly recognized. Compared with genotype C, genotype B is associated with earlier hepatitis B e antigen seroconversion, slower progression to cirrhosis and less frequent development of HCC. By using periodic examinations of serum alfa-fetoprotein levels and abdominal ultrasonography, small HCC can be detected and treated earlier. However, prevention of HBV and HCV infections as well as effective treatment of the chronic viral infections with timely interventions are still needed for the global control of HCC, particularly in the Far East and Southeast Asia.
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MESH Headings
- Asia, Southeastern/epidemiology
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/etiology
- Early Diagnosis
- Asia, Eastern/epidemiology
- Female
- Hepatitis, Viral, Human/complications
- Hepatitis, Viral, Human/epidemiology
- Hepatitis, Viral, Human/prevention & control
- Humans
- Liver Neoplasms/epidemiology
- Liver Neoplasms/etiology
- Male
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Affiliation(s)
- Jia-Horng Kao
- Hepatitis Research Center, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Takami T, Terai S, Yokoyama Y, Tanimoto H, Tajima K, Uchida K, Yamasaki T, Sakaida I, Nishina H, Thorgeirsson SS, Okita K. Human homologue of maid is a useful marker protein in hepatocarcinogenesis. Gastroenterology 2005; 128:1369-80. [PMID: 15887118 DOI: 10.1053/j.gastro.2005.03.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Human homologue of maid (HHM) is a helix-loop-helix (HLH) transcriptional regulatory protein that is involved in the hepatic stem cell development and differentiation. We analyzed the potential involvement of HHM in hepatocarcinogenesis. METHODS We analyzed HHM expression in the choline-deficient L-amino acid defined (CDAA) diet model of rat hepatocarcinogenesis and in human adenomatous hyperplasia (AH) and hepatocellular carcinoma (HCC) biopsy samples. We assessed the effects of HHM on cell proliferation. We screened proteins that bind to HHM protein using a yeast 2-hybrid screen. RESULTS High HHM expression was seen in foci and HCC induced in the rat CDAA diet model. HHM protein was expressed in 23 of 32 AH samples (72%), 19 of 28 well-differentiated HCC samples (68%), and 9 of 18 poorly-moderately differentiated HCC samples (50%). Over-expressed HHM enhanced the S phase. HHM interference RNA significantly inhibited cell proliferation. A yeast 2-hybrid screen identified Jun activation domain-binding protein 1 (Jab1) as a binding partner for HHM. We confirmed HHM and Jab1 binding by immunoprecipitation and immunofluorescent histochemistry. The expression of Jab1 was found in human AH and HCC samples. We found an association between levels of expression of HHM and those of Jab1 in AH and HCC tissues examined (P = .027 by chi2 test). CONCLUSIONS High-level HHM expression was found from the very early stages of hepatocarcinogenesis, suggesting that HHM may be a useful marker protein to detect.
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Affiliation(s)
- Taro Takami
- Department of Molecular Science and Applied Medicine (Gastroenterology and Hepatology), Yamaguchi University School of Medicine, Ube, Japan
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Liu M, Liu Y, Cheng J, Zhang SL, Wang L, Shao Q, Zhang J, Yang Q. Transactivating effect of hepatitis C virus core protein: a suppression subtractive hybridization study. World J Gastroenterol 2004; 10:1746-9. [PMID: 15188498 PMCID: PMC4572261 DOI: 10.3748/wjg.v10.i12.1746] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2003] [Revised: 12/22/2003] [Accepted: 12/29/2003] [Indexed: 12/15/2022] Open
Abstract
AIM To investigate the transactivating effect of hepatitis C virus (HCV) core protein and to screen genes transactivated by HCV core protein. METHODS pcDNA3.1(-)-core containing full-length HCV core gene was constructed by insertion of HCV core gene into EcoRI/BamHI site. HepG2 cells were cotransfected with pcDNA3.1(-)-core and pSV-lacZ. After 48 h, cells were collected and detected for the expression of beta-gal by an enzyme-linked immunosorbent assay (ELISA) kit. HepG2 cells were transiently transfected with pcDNA3.1(-)-core using Lipofectamine reagent. Cells were collected and total mRNA was isolated. A subtracted cDNA library was generated and constructed into a pGEM-Teasy vector. The library was amplified with E. coli strain JM109. The cDNAs were sequenced and analyzed in GenBank with BLAST search after polymerase chain reaction (PCR). RESULTS The core mRNA and protein could be detected in HepG2 cell lysate which was transfected by the pcDNA3.1(-)-core. The activity of beta-galactosidase in HepG2 cells transfected by the pcDNA3.1(-)-core was 5.4 times higher than that of HepG2 cells transfected by control plasmid. The subtractive library of genes transactivated by HCV core protein was constructed successfully. The amplified library contained 233 positive clones. Colony PCR showed that 213 clones contained 100-1 000 bp inserts. Sequence analysis was performed in 63 clones. Six of the sequences were unknown genes. The full length sequences were obtained with bioinformatics method, accepted by GenBank. It was suggested that six novel cDNA sequences might be target genes transactivated by HCV core protein. CONCLUSION The core protein of HCV has transactivating effects on SV40 early promoter/enhancer. A total of 63 clones from cDNA library were randomly chosen and sequenced. Using the BLAST program at the National Center for Biotechnology Information, six of the sequences were unknown genes. The other 57 sequences were highly similar to known genes.
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Affiliation(s)
- Min Liu
- Department of Infectious Diseases, The First Hospital of Xi'an Jiaotong University, Shaanxi Province, China
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Legrand A, Vadrot N, Lardeux B, Bringuier AF, Guillot R, Feldmann G. Study of the effects of interferon a on several human hepatoma cell lines: analysis of the signalling pathway of the cytokine and of its effects on apoptosis and cell proliferation. Liver Int 2004; 24:149-60. [PMID: 15078480 DOI: 10.1111/j.1478-3231.2004.00899.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Interferon alpha (IFNalpha), currently used for the treatment of chronic viral hepatitis, is also known to prevent the development of hepatocellular carcinoma (HCC), the mechanism of this action being still debatable. AIMS To study thoroughly in human hepatoma cell lines (HHL)--Hep3B, HepG2, HuH7, SKHep1, and Chang-Liver--submitted to rhIFNalpha, the signalling pathway of IFNalpha, the binding activity of the cytokine on specific gamma-activated sequence (GAS) and interferon-stimulated regulatory element (ISRE) nuclear sequences, and its effects on apoptosis and cell proliferation. METHODS The behaviour of signal transducer and activator of transcription (STAT)1, STAT2, p48(IRF9) and the binding of nuclear proteins were investigated by immunoblot and electro-mobility shift assay. Expression of some IFNalpha-dependent proteins--p21/(WAF1), inducible nitric oxide synthase, IRF1 and 2--were studied by immunoblot. Apoptosis and the cell cycle were studied by morphological and biochemical methods. RESULTS Transduction of INFalpha was unaltered, although there were some variations in the different HHL. Nuclear protein binding to GAS or ISRE showed that ISRE was mainly involved. Apoptosis did not occur. The cell cycle was slightly modified in HuH7. Three GAS- and/or ISRE-dependent proteins increased, suggesting that IFNalpha may have some biological effects on HHL. CONCLUSIONS The IFNalpha signalling pathway is functional in several HHL, but the cytokine has no apoptotic effect and a moderate anti-proliferative effect. This suggests that the preventive role of IFNalpha on HCC cannot be explained by an apoptotic and/or an anti-proliferative effect, but possibly by its action on several specific nuclear sequences that protect liver cells from transformation.
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Affiliation(s)
- A Legrand
- Laboratoire de Biologie Cellulaire, Unité 481 INSERM, Faculté de Médecine Xavier Bichat, Université Paris 7, France
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Fontana RJ, Everson GT, Tuteja S, Vargas HE, Shiffman ML. Controversies in the management of hepatitis C patients with advanced fibrosis and cirrhosis. Clin Gastroenterol Hepatol 2004; 2:183-97. [PMID: 15017601 DOI: 10.1016/s1542-3565(04)00002-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
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van Dekken H, Wink J, Alers JC, de Man RA, IJzermans JN, Zondervan PE. Genetic evaluation of the dysplasia-carcinoma sequence in chronic viral liver disease: a detailed analysis of two cases and a review of the literature. Acta Histochem 2003; 105:29-41. [PMID: 12666986 DOI: 10.1078/0065-1281-00694] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies, especially in Asia and Africa, but also in the Western world its incidence is increasing. HCC is a complication of chronic liver disease with cirrhosis as the most important risk factor. Viral co-pathogenesis due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection seems to be an important factor in the development of HCC. Curative therapy is often not possible due to the late detection of HCC. Thus, it is attractive to find parameters which predict malignant transformation in HBV- and HCV-infected livers. In the past decade, preneoplastic lesions, i.e. dysplastic foci or nodules, have gained interest as possible markers for imminent malignancy. Noteworthy, dysplastic liver lesions are increasingly detected by imaging techniques. We describe here two cases of chronic viral liver disease, one HBV-and one HCV-related, in which dysplastic lesions were present adjacent to HCC. In the HBV case, a (smaller) satellite of HCC was present as well. The neoplastic specimens were investigated by comparative genomic hybridization (CGH) and in situ hybridization (ISH). Both methods revealed multiple genetic alterations in the HCCs. The genetic patterns of the HBV-related HCC and the satellite tumor showed many shared alterations suggesting a clonal relationship. A subset of genetic changes were already present in dysplasias illustrating their preneoplastic nature. Surrounding liver cirrhosis samples did not display chromosomal aberrations. A literature survey illustrates the relative paucity of information concerning genetic alterations in preneoplastic liver lesions. However, all the data strongly suggests a role for liver cell dysplasia as a precursor condition of liver cell cancer.
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Affiliation(s)
- Herman van Dekken
- Department of Pathology, Erasmus MC, Rotterdam University Medical Center, Rotterdam, The Netherlands.
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Di Bisceglie AM, Lyra AC, Schwartz M, Reddy RK, Martin P, Gores G, Lok ASF, Hussain KB, Gish R, Van Thiel DH, Younossi Z, Tong M, Hassanein T, Balart L, Fleckenstein J, Flamm S, Blei A, Befeler AS. Hepatitis C-related hepatocellular carcinoma in the United States: influence of ethnic status. Am J Gastroenterol 2003; 98:2060-3. [PMID: 14499788 DOI: 10.1111/j.1572-0241.2003.t01-1-07641.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The incidence of hepatocellular carcinoma (HCC) seems to be rising in the United States (US), and considerable variability in the incidence and etiology of HCC has been noted among different racial and ethnic groups in this country. The aim of this study was to evaluate the influence of racial and ethnic status in the viral etiology of HCC in the US. METHODS Retrospective surveys were conducted at liver transplantation centers in the US. Respondents were asked to review the charts of all patients with HCC seen at their institution for the 2-yr period between July, 1997, and June, 1999, and provide information about the racial and ethnic distribution of cases and their serological status with regard to hepatitis B and C markers. RESULTS Complete information was available on 691 patients who formed the basis of this study, comprising 59% whites, 14% blacks, 16% Asians, and 11% other racial groups. Of the patients, 107 patients (15.4%) were positive for hepatitis B surface antigen (HBsAg), 322 had antibodies to hepatitis C virus (anti-HCV) (46.5%), 33 (4.7%) had both HBsAg and anti-HCV), and 229 (33.1%) had neither marker present. Clear differences were seen among racial groups. Anti-HCV positivity was the most frequent risk factor in both blacks and whites, whereas HBsAg positivity was the most frequent etiological factor in Asians with HCC. CONCLUSIONS HCV infection seems to be the major risk factor for HCC in the US, particularly among individuals of white and black ethnicity, whereas hepatitis B remains the main risk factor among patients of Asian ethnicity. These preliminary findings indicate the need for a more detailed study of ethnic variability in the pathogenesis of HCC.
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Affiliation(s)
- Adrian M Di Bisceglie
- Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63110, USA
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41
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Miyaji K, Nakagawa Y, Matsumoto K, Yoshida H, Morikawa H, Hongou Y, Arisaka Y, Kojima H, Inoue T, Hirata I, Katsu K, Akao Y. Overexpression of a DEAD box/RNA helicase protein, rck/p54, in human hepatocytes from patients with hepatitis C virus-related chronic hepatitis and its implication in hepatocellular carcinogenesis. J Viral Hepat 2003; 10:241-8. [PMID: 12823589 DOI: 10.1046/j.1365-2893.2003.00447.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Hepatitis C virus (HCV) infection is the most common cause of chronic hepatitis, which frequently progresses to hepatocellular carcinoma. The pathogenesis of its persistent infection and tumour progression has not been fully characterized yet. The RCK gene was previously cloned at the breakpoint of the t(11;14)(q23;q32) chromosome translocation observed in human B-cell lymphoma cell line RC-K8. The RCK protein, rck/p54, which is a 54-kDa cytoplasmic protein belonging to the DEAD box/RNA helicase family, is considered to facilitate the translation of mRNA(s) of genes for cell proliferation and malignant transformation not only in B-cell lymphomas having the t(11;14) translocation but also in other solid tumours. The aim of this work was to examine the involvement of rck/p54 in carcinogenesis of hepatocellular carcinoma from HCV-related chronic hepatitis. We examined the expression of rck/p54 in 29 cases of HCV-related chronic hepatitis and eight cases of hepatocellular carcinoma by immunohistochemistry and Western blot analysis. Twenty-six of 29 cases with HCV-related chronic hepatitis and all cases with hepatocellular carcinoma tested overexpressed rck/p54 protein. The expression of rck/p54 was lowered by treatment with IFN-alpha in two cases who showed the decrease in HCV RNA levels. These findings suggest that rck/p54 protein is possibly involved in the replication of HCV genomes in hepatocytes and in tumourigenesis of hepatocellular carcinomas.
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Affiliation(s)
- K Miyaji
- The Second Department of Internal Medicine, Daigaku-cho, Takatsuki, Osaka, Japan
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Velázquez RF, Rodríguez M, Navascués CA, Linares A, Pérez R, Sotorríos NG, Martínez I, Rodrigo L. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis. Hepatology 2003; 37:520-7. [PMID: 12601348 DOI: 10.1053/jhep.2003.50093] [Citation(s) in RCA: 305] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Better knowledge of the risk factors associated with the appearance of hepatocellular carcinoma (HCC) could improve the efficacy of surveillance programs. A total of 463 patients aged 40 to 65 years with liver cirrhosis in Child-Pugh class A or B were included in a program of early diagnosis. The predictive value of different risk factors was evaluated using the Kaplan-Meier method and Cox regression model. Thirty-eight patients developed HCC. In the multivariate analysis, 4 variables showed an independent predictive value for the development of HCC: age 55 years or older, antibody to hepatitis C virus (anti-HCV) positivity, prothrombin activity 75% or less, and platelet count less than 75 x 10(3)/mm(3). According to the contribution of each of these factors to the final model, a score ranging between 0 and 4.71 points was constructed to allow the division of patients into 2 different risk groups. The low-risk group included those with a score of 2.33 points or less (n = 270; 4 with HCC; cumulative incidence of HCC at 4 years, 2.3%), and the high-risk group included those with a score greater than 2.33 (n = 193; 34 with HCC; cumulative incidence of HCC at 4 years, 30.1%) (P =.0001). In conclusion, a simple score made up of 4 clinical and biological variables allowed us to distinguish 2 groups of cirrhotic patients at high and low risk for the development of HCC. We believe this score can be useful in establishing a subset of cirrhotic patients in whom a surveillance program for early detection of HCC could be unjustified.
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Affiliation(s)
- Rosario F Velázquez
- Department of Gastroenterology, Hospital Central de Asturias, Oviedo, Spain. Department of Gastroenterology, Hospital de Cabueñes, Gijón, Spain
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Ciorlia LADS, Zanetta DMT. Hepatite C em profissionais da saúde: risco de exposição e infecção. REVISTA BRASILEIRA DE SAÚDE OCUPACIONAL 2003. [DOI: 10.1590/s0303-76572003000200008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Este artigo de revisão discute aspectos da hepatite C em profissionais da saúde e seu risco de exposição e infecção. Foram abordados temas como associação entre patógenos veiculados ao sangue e profissionais da saúde, hepatite C (epidemiologia, diagnóstico e prevenção), comunicação e registro de acidentes do trabalho com material biológico (sangue e fluidos corpóreos), e relação entre extensão e conseqüências dos acidentes com objetos perfurocortantes e exposição mucocutânea e a hepatite C.
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Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, Lai KM, Ji J, Dudoit S, Ng IOL, Van De Rijn M, Botstein D, Brown PO. Gene expression patterns in human liver cancers. Mol Biol Cell 2002. [PMID: 12058060 DOI: 10.1091/mbc.02-02-0023.] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression patterns intrinsic to each tumor were sufficiently distinctive that multiple tumor nodules from the same patient could usually be recognized and distinguished from all the others in the large sample set on the basis of their gene expression patterns alone. The distinctive gene expression patterns are characteristic of the tumors and not the patient; the expression programs seen in clonally independent tumor nodules in the same patient were no more similar than those in tumors from different patients. Moreover, clonally related tumor masses that showed distinct expression profiles were also distinguished by genotypic differences. Some features of the gene expression patterns were associated with specific phenotypic and genotypic characteristics of the tumors, including growth rate, vascular invasion, and p53 overexpression.
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Affiliation(s)
- Xin Chen
- Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA
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Abstract
Chronic infection with hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC). In general, HCC develops only after 2 or more decades of HCV infection and the increased risk is restricted largely to patients with cirrhosis or advanced fibrosis. Factors that predispose to HCC among HCV-infected persons include male sex, older age, hepatitis B virus (HBV) coinfection, heavy alcohol intake, and possibly diabetes and a transfusion-related source of HCV infection. Viral factors play a minor role. The likelihood of development of HCC among HCV-infected persons is difficult to determine because of the paucity of adequate long-term cohort studies; the best estimate is 1% to 3% after 30 years. Once cirrhosis is established, however, HCC develops at an annual rate of 1% to 4%. Successful antiviral therapy of patients with HCV-related cirrhosis may reduce the future risk for HCC. The incidence of and mortality caused by all HCC has doubled in the United States over the past 25 years, an increase that has affected all ethnic groups, both sexes, and younger age groups. Given the current prevalence of HCV infection among persons 30 to 50 years of age, the incidence and mortality rates of HCC are likely to double in the United States over the next 10 to 20 years. Future research should focus on improving understanding of the incidence and risk factors for HCC, causes of HCV-related carcinogenesis, means of early detection, and better treatment for HCC.
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Affiliation(s)
- Hashem B El-Serag
- Sections of Gastroenterology and Health Services Research at the Houston Department of Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, 77030, USA.
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Abstract
Chronic infection with hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC). In general, HCC develops only after 2 or more decades of HCV infection and the increased risk is restricted largely to patients with cirrhosis or advanced fibrosis. Factors that predispose to HCC among HCV-infected persons include male sex, older age, hepatitis B virus (HBV) coinfection, heavy alcohol intake, and possibly diabetes and a transfusion-related source of HCV infection. Viral factors play a minor role. The likelihood of development of HCC among HCV-infected persons is difficult to determine because of the paucity of adequate long-term cohort studies; the best estimate is 1% to 3% after 30 years. Once cirrhosis is established, however, HCC develops at an annual rate of 1% to 4%. Successful antiviral therapy of patients with HCV-related cirrhosis may reduce the future risk for HCC. The incidence of and mortality caused by all HCC has doubled in the United States over the past 25 years, an increase that has affected all ethnic groups, both sexes, and younger age groups. Given the current prevalence of HCV infection among persons 30 to 50 years of age, the incidence and mortality rates of HCC are likely to double in the United States over the next 10 to 20 years. Future research should focus on improving understanding of the incidence and risk factors for HCC, causes of HCV-related carcinogenesis, means of early detection, and better treatment for HCC.
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Affiliation(s)
- Hashem B El-Serag
- Sections of Gastroenterology and Health Services Research at the Houston Department of Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, 77030, USA.
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Higashi Y, Tada S, Miyase S, Hirota K, Imamura H, Kamio T, Suko H. Correlation of clinical characteristics with detection of hepatitis B virus X gene in liver tissue in HBsAg-negative, and HCV-negative hepatocellular carcinoma patients. LIVER 2002; 22:374-9. [PMID: 12390472 DOI: 10.1034/j.1600-0676.2002.01645.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE We studied the clinical features and the etiology of hepatitis B virus surface antigen (HBsAg)-negative and antibody to hepatitis C virus (anti-HCV) negative patients with hepatocellular carcinoma. METHODS A total of 550 patients, hospitalized with an initial diagnosis of HCC were retrospectively studied. Eighty-one of these patients were HBsAg-positive (HB group), 404 patients were anti-HCV positive (HC group). The other 65 patients were negative for both HBsAg and for anti-HCV (NBNC group). We purified HBV-X gene from HCC or non-tumorous liver tissue of 23 NBNC patients using PCR. RESULTS Clinical features of NBNC as compared with HB and HC patients were as follows, respectively: non-cirrhosis rate (%): 57,37,15 (P = 0.02 for HB, P < 0.00001 for HC), the proportion of patients with normal ALT concentrations (%): 59,28,10 (P = 0.0002 for HB, P < 0.00001 for HC). Forty of 59 NBNC patients (68%) had anti-HBs and/or anti-HBc (healthy controls: 29%, P < 0.00001) and two of 56 had serum HBV DNA. Twelve of 23 NBNC patients had HBV-X gene in HCC and/or non-cancerous liver tissues (52%). None of 52 had serum HCV RNA. CONCLUSIONS The NBNC patients with HCC had a higher frequency of non-cirrhotic liver without liver injury. The presence of the HBV-X gene in HCC suggests a possible role of past HBV infection in the development of HCC. About half of NBNC HCC is associated with seronegativity for HBsAg and positivity for the HBV-X gene in liver tissue.
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Affiliation(s)
- Yoichiro Higashi
- Department of Gastroenterology, Saiseikai Kumamoto Hospital, Kumamoto City, 861-4193, Japan.
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Abstract
To determine the role of screening and to screen in a cost-effective manner, it is important to define the high-risk patient population that is most likely to benefit from screening and to identify a readily available diagnostic modality that is sensitive, specific, and inexpensive. Moreover, to have a major effect on the outcome of hepatocellular carcinoma, the test should be applicable in the majority of high-risk subjects. Herein, we identify the high-risk patient population, discuss various diagnostic modalities, and recommend a practical and cost-effective strategy for screening.
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Affiliation(s)
- Ayman Koteish
- Department of Medicine, Johns Hopkins University School of Medicine, 1830 Monument Street, Room 429, Building 1830, Baltimore, MD 21025, USA
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49
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Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, Lai KM, Ji J, Dudoit S, Ng IOL, Van De Rijn M, Botstein D, Brown PO. Gene expression patterns in human liver cancers. Mol Biol Cell 2002; 13:1929-39. [PMID: 12058060 PMCID: PMC117615 DOI: 10.1091/mbc.02-02-0023] [Citation(s) in RCA: 655] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression patterns intrinsic to each tumor were sufficiently distinctive that multiple tumor nodules from the same patient could usually be recognized and distinguished from all the others in the large sample set on the basis of their gene expression patterns alone. The distinctive gene expression patterns are characteristic of the tumors and not the patient; the expression programs seen in clonally independent tumor nodules in the same patient were no more similar than those in tumors from different patients. Moreover, clonally related tumor masses that showed distinct expression profiles were also distinguished by genotypic differences. Some features of the gene expression patterns were associated with specific phenotypic and genotypic characteristics of the tumors, including growth rate, vascular invasion, and p53 overexpression.
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Affiliation(s)
- Xin Chen
- Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA
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Shiffman ML, Brown RS, Olthoff KM, Everson G, Miller C, Siegler M, Hoofnagle JH. Living donor liver transplantation: summary of a conference at The National Institutes of Health. Liver Transpl 2002; 8:174-88. [PMID: 11862598 DOI: 10.1053/jlts.2002.30981] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Living donor liver transplantation for adults was developed only recently in an attempt to increase the pool of donor organs; to reduce morbidity and mortality; and to improve the long-term survival of patients in need of liver transplant. Within a few brief years, this procedure has gained widespread support by both the public and transplant community. The procedure will soon be performed by nearly 80% of all liver transplant programs in the United States. Unfortunately, the long-term risks of the procedure to the recipient and especially the donor remain undefined. In response to the rapid growth and enthusiasm for this procedure, the National Institutes of Health sponsored a workshop, the goals of which were to review the scientific, medical, and nonmedical issues associated with living donor liver transplantation, and to define questions for future basic and clinical investigations which could improve the success and applicability of this procedure.
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Affiliation(s)
- Mitchell L Shiffman
- Hepatology Section, Virginia Commonwealth University Health System, Richmond, VA, USA.
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