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Xiong Z, Shu K, Jiang Y. Investigation of the Pathogenesis of Liver Fibrosis Associated with Type 2 Diabetes Mellitus via Bioinformatic Analysis. Biomedicines 2025; 13:840. [PMID: 40299397 PMCID: PMC12024958 DOI: 10.3390/biomedicines13040840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/19/2025] [Accepted: 03/30/2025] [Indexed: 04/30/2025] Open
Abstract
Background: The global prevalence of type 2 diabetes mellitus (T2DM) with liver fibrosis is rising, with T2DM identified as an independent risk factor and key prognostic factor for liver fibrosis. However, the underlying mechanisms remain unclear. Methods: To explore the shared pathogenesis of liver fibrosis and T2DM, we analyzed gene expression profiles from the GEO database. The co-differentially expressed genes (co-DEGs) were identified and subsequently analyzed through functional enrichment, protein-protein interaction (PPI) network construction, transcription factor prediction, and drug prediction. Machine learning algorithms were then applied to identify key genes. Results: A total of 175 co-DEGs were identified. Functional enrichment analysis indicated their involvement in extracellular matrix (ECM) remodeling, inflammation, and the PI3K/Akt signaling pathway. Through PPI network analysis and four algorithms, eight hub genes were identified, including SPARC, COL4A2, THBS1, LUM, TIMP3, COL3A1, IGFBP7, and FSTL1, with THBS1 being recognized as a key gene by machine learning. The upregulation of THBS1 was observed in both diseases, and it is closely related to the progression of liver fibrosis and T2DM. Transcription factor analysis detected 29 regulators of these hub genes. Drug prediction analysis suggested that retinoic acid may serve as a potential therapeutic agent. Conclusions: This study provides novel insights into the shared pathogenesis of liver fibrosis and T2DM and offer potential targets for clinical intervention.
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Affiliation(s)
| | | | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China; (Z.X.); (K.S.)
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Liu CH, Cheng PN, Fang YJ, Chen CY, Kao WY, Lin CL, Yang SS, Shih YL, Peng CY, Chang YP, Huang SC, Su TH, Tseng TC, Liu CJ, Chen PJ, Kao JH. Risk of de novo HCC in patients with MASLD following direct-acting antiviral-induced cure of HCV infection. J Hepatol 2025; 82:582-593. [PMID: 39368711 DOI: 10.1016/j.jhep.2024.09.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 09/12/2024] [Accepted: 09/20/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND & AIMS Data are limited on the risk of de novo hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) who have achieved sustained virologic response at off-treatment week 12 (SVR12) using direct-acting antivirals (DAAs) for HCV. METHODS A total of 1,598 eligible patients received biannual alpha-fetoprotein (AFP) and liver imaging surveillance to detect de novo HCC after achieving SVR12. MASLD was defined as presence of controlled attenuation parameter (CAP) ≥248 dB/m and ≥1 cardiometabolic risk factor (CMRF). Cumulative HCC incidence was compared between patients with/without MASLD. We built univariable and multivariable Cox proportional hazards models to evaluate factors associated with HCC. Sensitivity analysis was performed using the Fine-Gray subdistribution hazards model. Additionally, we evaluated the mediation effect of MASLD on CMRFs and of CMRFs on MASLD for HCC using mediation analysis with bootstrapping. RESULTS The incidence rate of HCC was 1.44 per 100 person-years of follow-up (95% CI 1.19-1.74). Patients with MASLD had a higher cumulative HCC incidence than those without MASLD (log-rank test, p <0.001). Multivariable Cox regression analysis revealed that in addition to age, sex, liver stiffness measurement, platelet count, and AFP, MASLD (adjusted hazard ratio 2.07; 95% CI 1.36-3.16; p <0.001) was independently associated with HCC. This finding was confirmed by the Fine-Gray model, which showed a subdistribution hazard ratio of 2.07 (95% CI 1.34-3.19, p <0.001) for MASLD. MASLD significantly mediated CMRFs for HCC development. CONCLUSION After achieving SVR12, patients with MASLD exhibited an increased HCC risk compared to those without MASLD. Vigilant HCC surveillance and control of CMRFs to mitigate the effect of MASLD on HCC remain crucial for this population. IMPACT AND IMPLICATIONS The risk of de novo hepatocellular carcinoma (HCC) among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) who have attained a sustained virologic response to direct-acting antivirals remains to be confirmed. In this study, recruiting 1,598 patients in Taiwan, individuals with MASLD had an approximately two-fold increased risk of de novo HCC compared to those without MASLD after achieving a sustained virologic response. MASLD significantly mediated cardiometabolic risk factors for HCC development. Our findings underscore the critical importance of pharmacological interventions and proactive lifestyle modifications to control cardiometabolic risk factors in patients with MASLD, as well as the need for vigilant HCC surveillance to ensure favorable outcomes following HCV eradication.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yu-Jen Fang
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Chi-Yi Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Wei-Yu Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Ping Chang
- Department of Internal Medicine, National Taiwan University Biomedical Park Hospital, Hsin-Chu, Taiwan
| | - Shang-Chin Huang
- Department of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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Jiao J, Zhang X. Steatotic Liver Disease: Navigating Pathologic Features, Diagnostic Challenges, and Emerging Insights. Adv Anat Pathol 2025:00125480-990000000-00135. [PMID: 39895389 DOI: 10.1097/pap.0000000000000483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Steatotic liver disease (SLD) is now used as an overarching category encompassing five subcategories: metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol related/associated liver disease (MetALD), alcohol-related/associated liver disease (ALD), SLD with specific etiology, and cryptogenic SLD. This review summarizes foundational and recent advances in the histologic evaluation of SLD, including common pathologic features across all subcategories, distinctions associated with different etiologies, scoring and grading systems, and the evolution of digital pathology techniques for SLD assessment.
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Affiliation(s)
- Jingjing Jiao
- Department of Pathology, Yale University School of Medicine, New Haven, CT
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Liu CH, Chang YP, Fang YJ, Cheng PN, Chen CY, Kao WY, Lin CL, Yang SS, Shih YL, Peng CY, Tsai MC, Huang SC, Su TH, Tseng TC, Liu CJ, Chen PJ, Kao JH. Dynamic change of metabolic dysfunction-associated steatotic liver disease in patients with hepatitis C virus infection after achieving sustained virologic response with direct-acting antivirals. J Gastroenterol 2024; 59:609-620. [PMID: 38613690 DOI: 10.1007/s00535-024-02101-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/28/2024] [Indexed: 04/15/2024]
Abstract
BACKGROUND Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited. METHODS We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD. RESULTS The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13-2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11-2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03-2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51-22.56, p = 0.011). CONCLUSIONS The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Yu-Ping Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Jen Fang
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Chi-Yi Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Wei-Yu Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Ming-Chang Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shang-Chin Huang
- Department of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, 10002, Taiwan.
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Vitale E, Rizzo A, Santa K, Jirillo E. Associations between "Cancer Risk", "Inflammation" and "Metabolic Syndrome": A Scoping Review. BIOLOGY 2024; 13:352. [PMID: 38785834 PMCID: PMC11117847 DOI: 10.3390/biology13050352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/08/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Individuals with metabolic syndrome exhibit simultaneously pro-thrombotic and pro-inflammatory conditions which more probably can lead to cardiovascular diseases progression, type 2 diabetes mellitus, and some types of cancer. The present scoping review is aimed at highlighting the association between cancer risk, inflammation, and metabolic syndrome. METHODS A search strategy was performed, mixing keywords and MeSH terms, such as "Cancer Risk", "Inflammation", "Metabolic Syndrome", "Oncogenesis", and "Oxidative Stress", and matching them through Boolean operators. A total of 20 manuscripts were screened for the present study. Among the selected papers, we identified some associations with breast cancer, colorectal cancer, esophageal adenocarcinoma, hepatocellular carcinoma (HCC), and cancer in general. CONCLUSIONS Cancer and its related progression may also depend also on a latent chronic inflammatory condition associated with other concomitant conditions, including type 2 diabetes mellitus, metabolic syndrome, and obesity. Therefore, prevention may potentially help individuals to protect themselves from cancer.
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Affiliation(s)
- Elsa Vitale
- Scientific Directorate, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Alessandro Rizzo
- Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy;
| | - Kazuki Santa
- Faculty of Medical Science, Juntendo University, 6-8-1 Hinode, Urayasu 279-0013, Chiba, Japan;
| | - Emilio Jirillo
- Scuola di Medicina, University of Bari, 70121 Bari, Italy;
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Nakatsuka T, Tateishi R. Development and prognosis of hepatocellular carcinoma in patients with diabetes. Clin Mol Hepatol 2023; 29:51-64. [PMID: 35903020 PMCID: PMC9845683 DOI: 10.3350/cmh.2022.0095] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/03/2022] [Indexed: 02/02/2023] Open
Abstract
The incidence of diabetes mellitus and hepatocellular carcinoma (HCC) has been increasing worldwide during the last few decades, in the context of an increasing prevalence of obesity and non-alcoholic fatty liver disease (NAFLD). Epidemiologic studies have revealed that patients with diabetes have a 2- to 3-fold increased risk of developing HCC, independent of the severity and cause of the underlying liver disease. A bidirectional relationship exists between diabetes and liver disease: advanced liver disease promotes the onset of diabetes, and HCC is an important cause of death in patients with diabetes; conversely, diabetes is a risk factor for liver fibrosis progression and HCC development, and may worsen the long-term prognosis of patients with HCC. The existence of close interconnections among diabetes, obesity, and NAFLD causes insulin resistance-related hyperinsulinemia, increased oxidative stress, and chronic inflammation, which are assumed to be the underlying causes of hepatocarcinogenesis in patients with diabetes. No appropriate surveillance methods for HCC development in patients with diabetes have been established, and liver diseases, including HCC, are often overlooked as complications of diabetes. Although some antidiabetic drugs are expected to prevent HCC development, further research on the optimal use of antidiabetic drugs aimed at hepatoprotection is warranted. Given the increasing medical and socioeconomic impact of diabetes on HCC development, diabetologists and hepatologists need to work together to develop strategies to address this emerging health issue. This article reviews the current knowledge on the impact of diabetes on the development and progression of HCC.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,Corresponding author : Ryosuke Tateishi Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Tel: +81-3-3815-5411, Fax: +81-3-3814-0021, E-mail:
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Chang SS, Hu HY, Chen YC, Yen YF, Huang N. Late hepatitis C virus diagnosis among patients with newly diagnosed hepatocellular carcinoma: a case–control study. BMC Gastroenterol 2022; 22:425. [PMID: 36115934 PMCID: PMC9482748 DOI: 10.1186/s12876-022-02504-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/13/2022] [Indexed: 12/09/2022] Open
Abstract
Abstract
Background
New direct-acting antiviral therapies have revolutionized hepatitis C virus (HCV) infection therapy. Nonetheless, once liver cirrhosis is established, the risk of hepatocellular carcinoma (HCC) still exists despite virus eradication. Late HCV diagnosis hinders timely access to HCV treatment. Thus, we determined trends and risk factors associated with late HCV among patients with a diagnosis of HCC in Taiwan.
Methods
We conducted a population-based unmatched case–control study. 2008–2018 Claims data were derived from the Taiwan National Health Insurance Research Database. Individuals with an initial occurrence of liver cancer between 2012 and 2018 were included. The late HCV group were referred as individuals who were diagnosed with HCC within 3 years after HCV diagnosis. The control group were referred as individuals who were diagnosed more than 3 years after the index date. We used multivariable logistic models to explore individual- and provider-level risk factors associated with a late HCV diagnosis.
Results
A decreasing trend was observed in the prevalence of late HCV-related HCC diagnosis between 2012 and 2018 in Taiwan. On an individual level, male, elderly patients, patients with diabetes mellitus (DM), and patients with alcohol-related disease had significantly higher risks of late HCV-related HCC diagnosis. On a provider level, patients who were mainly cared for by male physicians, internists and family medicine physicians had a significantly lower risk of late diagnosis.
Conclusions
Elderly and patients who have DM and alcohol related disease should receive early HCV screening. In addition to comorbidities, physician factors also matter. HCV screening strategies shall take these higher risk patients and physician factors into consideration to avoid missing opportunities for early intervention.
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Abstract
Hepatitis B and hepatitis C are a global burden and underscore the impact of preventable acute and chronic diseases on personal as well as population level health. Caring for pediatric patients with hepatitis B and C requires a deep understanding of the pathophysiology of viral processes. Insight into the epidemiology, transmission, and surveillance of these infections is critical to prevention and therapy. Extensive research in recent years has created a growing number of treatments, changing the landscape of the medical field's approach to the viral hepatitis pandemic.
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Nakatsuka T, Tateishi R, Koike K. Changing clinical management of NAFLD in Asia. Liver Int 2022; 42:1955-1968. [PMID: 34459096 DOI: 10.1111/liv.15046] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/30/2021] [Accepted: 08/21/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%-20% of non-obese Asians with body mass indexes of less than 25 kg/m2 are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver-specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
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Yang C, Wan M, Lu Y, Yang X, Yang L, Wang S, Sun G. Associations between diabetes mellitus and the risk of hepatocellular carcinoma in Asian individuals with hepatitis B and C infection: systematic review and a meta-analysis of cohort studies. Eur J Cancer Prev 2022; 31:107-116. [PMID: 35103624 DOI: 10.1097/cej.0000000000000669] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
We aim to further analyze and compare associations between diabetes mellitus and the risk of hepatocellular carcinoma (HCC) in Asian individuals with hepatitis B or C virus infection by conducting an updated meta-analysis of cohort studies. Literature search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library from the beginning of indexing for each database to January 1, 2020. A total of 22 articles met the inclusion criteria, in which 18 were cohort studies and 4 were case-control studies. We identified eight cohort studies and three case-control studies that presented results on diabetes mellitus and the risk of HCC in Asian subjects with hepatitis B virus (HBV) infection: the cumulative relative risk (RR) with 95% confidence interval (CI) was 1.37 (95% CI: 1.24 to 1.51; I2 = 27.8%) for cohort studies and cumulative odds ratio (OR) with 95% CI was 1.99 (95% CI: 0.73 to 5.48; I2 = 88.4%) for case-control studies. Thirteen cohort studies and two case-control studies presented results on the association between diabetes mellitus and the risk of HCC in Asian subjects with hepatitis C virus (HCV) infection: the RR with 95% CI was 1.76 (95% CI: 1.42 to 2.17; I2 = 62.8%) for cohort studies and OR with 95% CI was 1.77 (95% CI: 1.18 to 2.64; I2 = 0.0%) for case-control studies. In summary, our meta-analysis strongly supports the association between coexistent HCV and diabetes with the increasing risk of HCC; although the results equally support diabetes mellitus being significantly associated with increased risk of HCC among patients with HBV infection, this correlation is weaker than the former.
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Affiliation(s)
- Chao Yang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, P.R. China
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Valenti L, Pelusi S, Aghemo A, Gritti S, Pasulo L, Bianco C, Iegri C, Cologni G, Degasperi E, D'Ambrosio R, Del Poggio P, Soria A, Puoti M, Carderi I, Pigozzi MG, Carriero C, Spinetti A, Zuccaro V, Memoli M, Giorgini A, Viganò M, Rumi MG, Re T, Spinelli O, Colombo MC, Quirino T, Menzaghi B, Lorini G, Pan A, D'Arminio Monforte A, Buscarini E, Autolitano A, Bonfanti P, Terreni N, Aimo G, Mendeni M, Prati D, Lampertico P, Colombo M, Fagiuoli S. Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study. Hepatol Commun 2021; 6:867-877. [PMID: 34811949 PMCID: PMC8948549 DOI: 10.1002/hep4.1851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real‐life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE‐Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow‐up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03‐1.09) and diabetes (OR 2.01 [1.65‐2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35‐0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20‐3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16‐6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11‐0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi‐disciplinary management approach may improve cardiovascular and possibly liver‐related outcomes.
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Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Serena Pelusi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Alessio Aghemo
- Department of Internal Medicine and Hepatology, Humanitas University and Research Hospital, Rozzano, Italy
| | - Sara Gritti
- Fondazione Ricerca Ospedale di Bergamo, Papa Giovanni Hospital, Bergamo, Italy
| | - Luisa Pasulo
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
| | - Cristiana Bianco
- Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Claudia Iegri
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
| | - Giuliana Cologni
- Department of Internal Medicine, Papa Giovanni Hospital, Bergamo, Italy
| | - Elisabetta Degasperi
- Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Roberta D'Ambrosio
- Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Paolo Del Poggio
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Zingonia, Italy
| | - Alessandro Soria
- Division of Infectious Diseases, San Gerardo Hospital-ASST Monza, Monza, Italy
| | - Massimo Puoti
- Department of Infectious Diseases, Hepatitis Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | | | | | - Canio Carriero
- Department of Infectious Diseases, Spedali Civili Hospital-ASST Brescia, Brescia, Italy
| | - Angiola Spinetti
- Department of Infectious Diseases, Spedali Civili Hospital-ASST Brescia, Brescia, Italy
| | - Valentina Zuccaro
- Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia, Italy
| | - Massimo Memoli
- Liver Center, San Raffaele Scientific Institute IRCCS, Milano, Italy
| | - Alessia Giorgini
- Department of Gastroenterology and Hepatology, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Mauro Viganò
- Department of Gastroenterology and Hepatology, San Giuseppe Hospital, Milan, Italy
| | - Maria Grazia Rumi
- Department of Gastroenterology and Hepatology, San Giuseppe Hospital, Milan, Italy
| | - Tiziana Re
- Department of Gastroenterology and Hepatology, Legnano Hospital-ASST Milano Ovest, Milan, Italy
| | - Ombretta Spinelli
- Department of Gastroenterology and Hepatology, Lariana Como Hospital, Milan, Italy
| | - Maria Chiara Colombo
- Department of Gastroenterology and Hepatology, Lariana Como Hospital, Milan, Italy
| | - Tiziana Quirino
- Department of Gastroenterology and Hepatology, Busto Arsizio Hospital ASST Valle Olona, Milan, Italy
| | - Barbara Menzaghi
- Department of Gastroenterology and Hepatology, Busto Arsizio Hospital ASST Valle Olona, Milan, Italy
| | - Gianpaolo Lorini
- Department of Gastroenterology and Hepatology, ASST Franciacorta, Milan, Italy
| | - Angelo Pan
- Department of Internal Medicine, Ospedale di Cremona, Cremona, Italy
| | | | | | | | - Paolo Bonfanti
- Division of Infectious Diseases, ASST Lecco, Lecco, Italy
| | | | | | | | - Daniele Prati
- Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Pietro Lampertico
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy.,CRC "AM. and A. Migliavacca" Center for Liver Disease, Università degli Studi di Milano, Milano, Italy
| | - Massimo Colombo
- Liver Center, San Raffaele Scientific Institute IRCCS, Milano, Italy
| | - Stefano Fagiuoli
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
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12
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Ding Y, Li G, Zhou Z, Deng T. Molecular mechanisms underlying hepatitis C virus infection-related diabetes. Metabolism 2021; 121:154802. [PMID: 34090869 DOI: 10.1016/j.metabol.2021.154802] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022]
Abstract
Diabetes is a noncommunicable widespread disease that poses the risk of severe complications in patients, with certain complications being life-threatening. Hepatitis C is an infectious disease that mainly causes liver damage, which is also a profound threat to human health. Hepatitis C virus (HCV) infection has many extrahepatic manifestations, including diabetes. Multiple mechanisms facilitate the strong association between HCV and diabetes. HCV infection can affect the insulin signaling pathway in liver and pancreatic tissue and change the profiles of circulating microRNAs, which may further influence the occurrence and development of diabetes. This review describes how HCV infection causes diabetes and discusses the current research progress with respect to HCV infection-related diabetes.
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Affiliation(s)
- Yujin Ding
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Guangdi Li
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410011, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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13
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Fouad Y, Lazarus JV, Negro F, Peck-Radosavljevic M, Sarin SK, Ferenci P, Esmat G, Ghazinian H, Nakajima A, Silva M, Lee S, Colombo M. MAFLD considerations as a part of the global hepatitis C elimination effort: an international perspective. Aliment Pharmacol Ther 2021; 53:1080-1089. [PMID: 33751604 DOI: 10.1111/apt.16346] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/17/2021] [Accepted: 03/09/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND The World Health Organization (WHO) set a goal to eliminate hepatitis C (HCV) infection globally by 2030, with specific targets to reduce new viral hepatitis infections by 80% and reduce related deaths by 65%. However, an overlooked aspect that may hinder these efforts is the impact other liver diseases could have by continuing to drive liver disease progression and offset the beneficial impact of DAAs on end-stage liver disease and hepatocellular carcinoma (HCC). In particular, the decrease in HCV prevalence has been countered by a marked increase in the prevalence of metabolic-associated fatty liver disease (MAFLD). AIMS To review the potential interaction of HCV and MAFLD. METHODS We have reviewed the literature relating to an arrange of interaction of HCV, metabolic dysfunction and MAFLD. RESULTS In this viewpoint, international experts suggest a holistic and multidisciplinary approach for the management of the growing number of treated HCV patients who achieved SVR, taking into consideration the overlooked impact of MAFLD for reducing morbidity and mortality in people who have had HCV. CONCLUSIONS This will strengthen and improve the continuum of care cascade for patients with liver disease(s) and holds the potential to alleviate the cost burden of disease; and increase quality of life for patients following DAAs treatment.
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Chaudhari R, Fouda S, Sainu A, Pappachan JM. Metabolic complications of hepatitis C virus infection. World J Gastroenterol 2021; 27:1267-1282. [PMID: 33833481 PMCID: PMC8015302 DOI: 10.3748/wjg.v27.i13.1267] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/10/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a systemic disease that is implicated in multiple extrahepatic organ dysfunction contributing to its protean manifestations. HCV is associated with diverse extrahepatic disorders including atherosclerosis, glucose and lipid metabolic disturbances, alterations in the iron metabolic pathways, and lymphoproliferative diseases over and above the traditional liver manifestations of cirrhosis and hepatocellular carcinoma. The orchestration between HCV major proteins and the liver-muscle-adipose axis, poses a major burden on the global health of human body organs, if not adequately addressed. The close and inseparable associations between chronic HCV infection, metabolic disease, and cardiovascular disorders are specifically important considering the increasing prevalence of obesity and metabolic syndrome, and their economic burden to patients, the healthcare systems, and society. Cellular and molecular mechanisms governing the interplay of these organs and tissues in health and disease are therefore of significant interest. The coexistence of metabolic disorders and chronic hepatitis C infection also enhances the progression to liver fibrosis and hepatocellular carcinoma. The presence of metabolic disorders is believed to influence the chronicity and virulence of HCV leading to liver disease progression. This comprehensive review highlights current knowledge on the metabolic manifestations of hepatitis C and the potential pathways in which these metabolic changes can influence the natural history of the disease.
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Affiliation(s)
- Rahul Chaudhari
- Department of Medicine, Pennsylvania Hospital of the University of Pennsylvania, Pennsylvania, PA 19104, United States
| | - Sherouk Fouda
- School of Health and Biomedical Sciences, RMIT University, Melbourne VIC 3000, Australia
| | - Ashik Sainu
- Department of Gastroenterology and Hepatology, Aster Oman Hospital, Al Ghubra, Muscat OM 133, Oman
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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15
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Sirli R, Sporea I. Controlled Attenuation Parameter for Quantification of Steatosis: Which Cut-Offs to Use? Can J Gastroenterol Hepatol 2021; 2021:6662760. [PMID: 33834008 PMCID: PMC8018863 DOI: 10.1155/2021/6662760] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 03/13/2021] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic liver diseases (CLDs) are a public health problem, even if frequently they are underdiagnosed. Hepatic steatosis (HS), encountered not only in nonalcoholic fatty liver disease (NAFLD) but also in chronic viral hepatitis, alcoholic liver disease, etc., plays an important role in fibrosis progression, regardless of CLD etiology; thus, detection and quantification of HS are imperative. Controlled attenuation parameter (CAP) feature, implemented in the FibroScan® device, measures the attenuation of the US beam as it passes through the liver. It is a noninvasive technique, feasible and well accepted by patients, with lower costs than other diagnostic techniques, with acceptable accuracy for HS quantification. Multiple studies have been published regarding CAP performance to quantify steatosis, but due to the heterogeneity of CLD etiologies, of steatosis prevalence, etc., it had widely variable calculated cut-off values, which in turn limited the day-to-day utility of CAP measurements in clinical practice. This paper reviews published studies trying to suggest cut-off values usable in clinical practice.
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Affiliation(s)
- Roxana Sirli
- Department of Gastroenterology and Hepatology, Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babeş” University of Medicine and Pharmacy, 156, Liviu Rebreanu Bv., Timişoara 300723, Romania
| | - Ioan Sporea
- Department of Gastroenterology and Hepatology, Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babeş” University of Medicine and Pharmacy, 156, Liviu Rebreanu Bv., Timişoara 300723, Romania
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16
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Impact of visceral fat accumulation on the prognosis of patients with cirrhosis. Clin Nutr ESPEN 2021; 42:354-360. [PMID: 33745605 DOI: 10.1016/j.clnesp.2021.01.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 01/04/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS The impact of obesity, evaluated using body mass index (BMI), on mortality in patients with cirrhosis is controversial. The prognostic impact of visceral fat accumulation, which is recommended as an indicator of obesity-related mortality, is still unknown. This study aimed to clarify the impact of visceral fat accumulation on mortality in patients with cirrhosis. METHODS A total of 335 cirrhotic patients without hepatocellular carcinoma were retrospectively evaluated. The impact of obesity, defined as a visceral fat area ≥100 cm2 at the umbilical level or BMI ≥25 kg/m2 on mortality, was evaluated using competing risk analysis. RESULTS Of 355 patients, visceral fat accumulation was seen in 147 patients. During the observation period (1340 ± 980 days), 84 patients died, and 17 received liver transplantation. Visceral fat accumulation was not found to be associated with mortality (hazard ratio [HR] 1.423, P = 0.180) in any of the patients. After stratification of the patients, visceral fat accumulation was observed to be associated with a poor prognosis in patients with skeletal muscle depletion (HR 3.804, P = 0.003), but not in those without (HR 1.147, P = 0.660). On the other hand, obesity defined by BMI ≥25 kg/m2 was not found to be associated with mortality in patients with (HR 0.341, P = 0.390) or without skeletal muscle depletion (HR 1.227, P = 0.500). CONCLUSIONS Visceral fat accumulation is a useful index for evaluating obesity and aggravates mortality in cirrhotic patients with skeletal muscle depletion, but not in those without.
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17
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Impaired insulin exocytosis in chronic hepatitis C infection: contributory role of p38δ MAPK-protein kinase D-golgi complex axis. Clin Sci (Lond) 2020; 134:1449-1456. [PMID: 32556178 DOI: 10.1042/cs20200686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 05/31/2020] [Accepted: 06/03/2020] [Indexed: 11/17/2022]
Abstract
Hepatitis C virus (HCV) infection and chronic hepatitis C (CHC) are associated with a measurable risk of insulin resistance (IR)/impaired glucose tolerance (IGT)/diabetes mellitus (DM). While loss of hepatic endocrine function contributes to liver cirrhosis in diabetic patients, onset and progression of IR/IGT to diabetes and exacerbation of incident hyperglycemia are ostensibly linked with chronic HCV infection. In this regard, the study by Chen J et al. appearing in Clinical Science (2020) (134(5) https://doi.org/10.1042/CS20190900) attempts to understand the mechanisms underlying the savaging effects of chronic HCV infection on insulin-producing pancreatic β-cells and hence diabetic onset. The study investigated the role of mitogen-activated protein kinase (MAPK) p38δ-protein kinase D (PKD)-golgi complex axis in impacting insulin exocytosis. It was inferred that an insulin secretory defect of pancreatic β-cells, owing to disrupted insulin exocytosis, to an extent explains β-cell dysfunction in HCV-infected or CHC milieu. HCV infection negatively regulates first-phase and second-phase insulin secretion by impinging on PKD-dependent insulin secretory granule fission at trans-golgi network and insulin secretory vesicle membrane fusion events. This commentary highlights the study in question, that deciphered the contribution of p38δ MAPK-PKD-golgi complex axis to β-cell dysfunction in CHC milieu. This pivotal axis proffers a formidable therapeutic opportunity for alleviation of double burden of glucose abnormalities/DM and CHC.
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Hepatitis C in 2020: A North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper. J Pediatr Gastroenterol Nutr 2020; 71:407-417. [PMID: 32826718 DOI: 10.1097/mpg.0000000000002814] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In 1989, a collaboration between the Centers for Disease Control (CDC) and a California biotechnology company identified the hepatitis C virus (HCV, formerly known as non-A, non-B hepatitis virus) as the causative agent in the epidemic of silent posttransfusion hepatitis resulting in cirrhosis. We now know that, the HCV genome is a 9.6 kb positive, single-stranded RNA. A single open reading frame encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield 10 individual gene products, consisting of 3 structural proteins (core and envelope glycoproteins E1 and E2) and 7 nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which participate in posttranslational proteolytic processing and replication of HCV genetic material. Less than 25 years later, a new class of medications, known as direct-acting antivirals (DAAs) which target these proteins, were introduced to treat HCV infection. These highly effective antiviral agents are now approved for use in children as young as 3 years of age and have demonstrated sustained virologic responses exceeding 90% in most genotypes. Although tremendous scientific progress has been made, the incidence of acute HCV infections has increased by 4-fold since 2005, compounded in the last decade by a surge in opioid and intravenous drug use. Unfortunately, awareness of this deadly hepatotropic virus among members of the lay public remains limited. Patient education, advocacy, and counseling must, therefore, complement the availability of curative treatments against HCV infection if this virus is to be eradicated.
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Jing W, Liu J, Liu M. Global Trends and Regional Differences in Hepatitis C Virus Infection Prevalence and Implications for Prevention - Worldwide, 1990-2017. China CDC Wkly 2020; 2:564-569. [PMID: 34594709 PMCID: PMC8422239 DOI: 10.46234/ccdcw2020.151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 07/16/2020] [Indexed: 11/29/2022] Open
Abstract
WHAT IS ALREADY KNOWN ON THIS TOPIC? The global prevalence of hepatitis C virus (HCV) infection in 2015 has been modeled to assess the disease burden in 21 Global Burden of Disease (GBD) regions. However, there is no study to clarify the global long-term trends and regional differences in HCV infection prevalence. WHAT IS ADDED BY THIS REPORT? This report clarified the global temporal trends and regional differences in HCV infection prevalence. Global HCV infection age-standardized prevalence rate (ASR) gradually decreased from 1990 to 2017 except in Eastern Europe, and liver cancer due to hepatitis C ASR increased worldwide with drastic shifts in low-middle Socio-Demographic Index (SDI) regions in the last decade. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE? HCV is still prevalent worldwide despite the development of highly effective direct-acting antivirals (DAAs) and showed a reemergence concurrent with the opioid crisis. HCV infection prevention might involve at least 3 aspects: first, prohibiting HCV widespread transmission among general populations; second, increasing global DAAs coverage; and third, continuously investing in the development of the HCV vaccine.
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Affiliation(s)
- Wenzhan Jing
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jue Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Min Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
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Kierepa A, Witkowska A, Kaczmarek M, Książek K, Mikuła-Pietrasik J, Żeromski J, Kowala-Piaskowska A, Mozer-Lisewska I. Impact of chronic HCV treatment on quality of life of patients with metabolic disorders in context of immunological disturbances. Sci Rep 2020; 10:10388. [PMID: 32587314 PMCID: PMC7316785 DOI: 10.1038/s41598-020-67296-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 04/20/2020] [Indexed: 12/20/2022] Open
Abstract
Chronic viral hepatitis C (CHC) and its complications have a negative effect on patient's quality of life. We evaluated the impact of a successful interferon-free treatment on the quality of life of patients with obesity and metabolic disorders in the context of immunological disturbances. Twenty overweight or obese (BMI > 25) patients with CHC were tested before the therapy and after a successful treatment regimen. After the therapy, patient's emotional well-being improved (p = 0.02), while physical well-being remained unchanged. There was a decrease of patient's liver fibrosis and an increase of steatosis along with body mass. Among HCV-infected individuals, the expression of toll-like receptor 3 (TLR3) on lymphocytes was higher than in the control group (p = 0.03), but it decreased (p = 0.001) after the treatment. There was also a decrease of the intensity of immunofluorescence of FoxP3+ after the treatment (p = 0.04). Our study showed an improvement in mental aspects of patient's quality of life after the treatment. Unfortunately, probably due to rapid immunological changes, patient's BMI, serum cholesterol levels and hepatic steatosis have a tendency to increase and may lead to cardiovascular and other complications, like hepatocellular carcinoma.
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Affiliation(s)
- Agata Kierepa
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznań, Poland.
| | - Aleksandra Witkowska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznań, Poland
| | - Mariusz Kaczmarek
- Chair of Clinical Immunology, Karol Marcinkowski University of Medical Sciences, Poznań, Poland
| | - Krzysztof Książek
- Department of Hypertensiology, Angiology and Internal Medicine, Karol Marcinkowski University of Medical Sciences, Poznań, Poland
| | - Justyna Mikuła-Pietrasik
- Department of Hypertensiology, Angiology and Internal Medicine, Karol Marcinkowski University of Medical Sciences, Poznań, Poland
| | - Jan Żeromski
- Chair of Clinical Immunology, Karol Marcinkowski University of Medical Sciences, Poznań, Poland
| | - Arleta Kowala-Piaskowska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznań, Poland
| | - Iwona Mozer-Lisewska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznań, Poland
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Sustained Improvements in Markers of Liver Disease Severity After Hepatitis C Treatment. J Clin Exp Hepatol 2020; 10:114-123. [PMID: 32189926 PMCID: PMC7068013 DOI: 10.1016/j.jceh.2019.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 09/15/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND & AIMS Although serological markers of disease severity improve after hepatitis C virus (HCV) treatment, it is unclear if all patients experience sustained improvement. We aim to evaluate longitudinal changes in aspartate (AST), alanine (ALT) aminotransferase, platelet count (PLT), and fibrosis-4 (FIB-4) after HCV treatment. METHODS All adult chronic HCV patients who received antiviral therapy from January 2011 to February 2017 at four large urban hospital systems were evaluated to assess changes in AST, ALT, PLT, and FIB-4 from pre-treatment to post-treatment annually up to 4 years after HCV therapy. Comparisons used Student's t-test and analysis of variance, and were stratified by sex, race, ethnicity, age, body mass index (BMI), and diabetes mellitus. RESULTS Among 2691 patients (62.2% men, 76.9% aged 45-65 years, 56.5% white), all markers of disease severity demonstrated sustained improvements from pre-treatment to 4 years post-treatment (AST 53 U/L to 27.5 U/L, ALT 53 U/L to 29 U/L, PLT 168 × 103 to 176 × 103, FIB-4 2.51 to 1.68). However, Hispanics and patients with BMI >30 kg/m2 experienced rebound increases in AST, ALT, and FIB-4 at 4 years post-treatment after experiencing initial improvements in these serological markers in the first-year post-treatment. Sustained improvements in PLT were observed in all groups, including Hispanics and patients with BMI >30 kg/m2. CONCLUSION HCV treatment in a large community-based cohort demonstrated sustained improvements in AST, ALT, PLT, and FIB-4. Rebound increases in AST, ALT, and FIB-4 observed in Hispanics and those with BMI >30 kg/m2 may reflect persisting nonalcoholic fatty liver disease.
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Shen F, Mi YQ, Xu L, Liu YG, Wang XY, Pan Q, Zhang RN, Hu XQ, Xu LM, Fan JG. Moderate to severe hepatic steatosis leads to overestimation of liver stiffness measurement in chronic hepatitis B patients without significant fibrosis. Aliment Pharmacol Ther 2019; 50:93-102. [PMID: 31094016 DOI: 10.1111/apt.15298] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 11/29/2018] [Accepted: 04/19/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Liver stiffness measurement (LSM) by transient elastography is a noninvasive method for the diagnosis of hepatic fibrosis. The impact of hepatic steatosis on LSM remains to be explored. AIM To determine whether LSM is affected by hepatic steatosis in patients with chronic hepatitis B (CHB). METHODS Consecutive patients with biopsy-proven CHB were prospectively enrolled. Hepatic steatosis was classified by pathology as none (S0, <5%), mild (S1, 5%-33%), and moderate-severe (S2-3, >33%), and quantitatively by controlled attenuation parameter (CAP) as CAP S0 (≤247 dB/m), CAP S1 (248-267 dB/m) and CAP S2-3 (≥268 dB/m). Liver fibrosis was assessed by METAVIR classification and noninvasively by LSM. RESULTS The prevalence of non-alcoholic fatty liver disease (n = 223) in CHB patients (n = 593) was 37.6%. Forty-eight belonged to S2-3 and 127 belonged to CAP S2-3. In patients without significant fibrosis (F0-1), the median LSM (kPa) was 7.4 in S2-3 and 7.1 in CAP S2-3, which was significantly higher than that in S0/S1 (P = 0.005) and CAP S0/S1 (P = 0.003). No significant difference was found in significant fibrosis (F2-4). For LSM identifying significant fibrosis (F2-4), the negative predictive value was higher in CHB patients with CAP ≥ 268 compared to those with CAP < 268 (0.81 vs 0.73); the positive predictive value was lower in CAP ≥ 268 than its counterpart (0.65 vs 0.76). CONCLUSIONS Moderate-severe steatosis increased the LSM value in CHB patients without significant fibrosis. A CAP ≥ 268 did not affect LSM for ruling out, but it slightly affected LSM for ruling in significant fibrosis. TRIAL REGISTRATION ChiCTR-DDT-13003983.
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Affiliation(s)
- Feng Shen
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu-Qiang Mi
- Research Institute of Liver Diseases, Tianjin Second People's Hospital, Tianjin, China
| | - Liang Xu
- Research Institute of Liver Diseases, Tianjin Second People's Hospital, Tianjin, China
| | - Yong-Gang Liu
- Research Institute of Liver Diseases, Tianjin Second People's Hospital, Tianjin, China
| | - Xiao-Ying Wang
- Department of Pathology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qin Pan
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rui-Nan Zhang
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xi-Qi Hu
- Department of Pathology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Lei-Ming Xu
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
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23
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019. [PMID: 30889843 DOI: 10.3390/ijms] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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24
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019; 20:ijms20061358. [PMID: 30889843 PMCID: PMC6470669 DOI: 10.3390/ijms20061358] [Citation(s) in RCA: 190] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/23/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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25
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Yen YH, Kuo FY, Kee KM, Chang KC, Tsai MC, Hu TH, Lu SN, Wang JH, Hung CH, Chen CH. Diabetes is associated with advanced fibrosis and fibrosis progression in non-genotype 3 chronic hepatitis C patients. Dig Liver Dis 2019; 51:142-148. [PMID: 30076015 DOI: 10.1016/j.dld.2018.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 07/01/2018] [Accepted: 07/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diabetes is a risk factor of fibrosis progression in chronic hepatitis C (CHC). However, only one longitudinal study exploring whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in CHC patients has been conducted. AIMS We investigated whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients. METHODS A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC was studied. After excluding patients with biopsy-proven or ultrasound-identified cirrhosis, there were 684 patients without cirrhosis. All 684 patients underwent hepatocellular carcinoma surveillance using ultrasound every 6 months, with a median duration of follow-up evaluation of 102.4 months. During the follow-up period, 60 patients developed cirrhosis according to ultrasound findings. RESULTS For the subgroup of 684 patients without cirrhosis, Kaplan-Meier survival analyses showed no significantly different cumulative incidences of cirrhosis (log-rank test; P = 0.71) among the patients with diabetes as compared to those without. However, after making adjustments for age, gender, fibrosis, steatosis, sustained virological response status, and obesity using Cox's proportional hazard model, diabetes was found to be an independent predictor for cirrhosis (HR = 1.9; 95% CI = 1.05-3.43, P = 0.03). CONCLUSIONS Diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients.
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Affiliation(s)
- Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Fang-Ying Kuo
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kwong-Ming Kee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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26
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González-Aldaco K, Torres-Reyes LA, Ojeda-Granados C, José-Ábrego A, Fierro NA, Román S. Immunometabolic Effect of Cholesterol in Hepatitis C Infection: Implications in Clinical Management and Antiviral Therapy. Ann Hepatol 2018; 17:908-919. [PMID: 30600305 DOI: 10.5604/01.3001.0012.7191] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a lipid-enveloped virion particle that causes infection to the liver, and as part of its life cycle, it disrupts the host lipid metabolic machinery, particularly the cholesterol synthesis pathway. The innate immune response generated by liver resident immune cells is responsible for successful viral eradication. Unfortunately, most patients fail to eliminate HCV and progress to chronic infection. Chronic infection is associated with hepatic fat accumulation and inflammation that triggers fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Despite that the current direct-acting antiviral agents have increased the cure rate of HCV infection, viral genotype and the host genetic background influence both the immune response and lipid metabolism. In this context, recent evidence has shown that cholesterol and its derivatives such as oxysterols might modulate and potentialize the hepatic innate immune response generated against HCV. The impairment of the HCV life cycle modulated by serum cholesterol could be relevant for the clinical management of HCV-infected patients before and after treatment. Alongside, cholesterol levels are modulated either by genetic variations in IL28B, ApoE, and LDLR or by dietary components. Indeed, some nutrients such as unsaturated fatty acids have demonstrated to be effective against HCV replication. Thus, cholesterol modifications may be considered as a new adjuvant strategy for HCV infection therapy by providing a biochemical tool that guides treatment decisions, an improved treatment response and favoring viral clearance. Herein, the mechanisms by which cholesterol contributes to the immune response against HCV infection and how genetic and environmental factors may affect this role are reviewed.
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Affiliation(s)
- Karina González-Aldaco
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Luis A Torres-Reyes
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Claudia Ojeda-Granados
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Alexis José-Ábrego
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Nora A Fierro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sonia Román
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, "Fray Antonio Alcalde" and Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
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27
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Wendum D, Layese R, Ganne-Carrié N, Bourcier V, Merabtene F, Cagnot C, Sauce E, Barget N, Bedossa P, Terris B, Selves J, Bioulac-Sage P, Sturm N, Sattonnet C, Nahon P, Roudot-Thoraval F, Ziol M. Influence of Progenitor-Derived Regeneration Markers on Hepatitis C Virus-Related Cirrhosis Outcome (ANRS CO12 CirVir Cohort). Hepatology 2018; 68:1534-1548. [PMID: 29637581 DOI: 10.1002/hep.29927] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 08/22/2016] [Accepted: 10/31/2016] [Indexed: 12/20/2022]
Abstract
UNLABELLED Progenitor-derived regeneration gives rise to the aberrant expression of biliary markers such as cytokeratin 7 (K7) and epithelial cell adhesion molecule (EpCAM) in hepatocytes. We aimed to describe the expression of these molecules in patients with compensated hepatitis C virus (HCV)-related cirrhosis and to investigate its potential influence on cirrhosis complications. Among patients with Child-Pugh A uncomplicated HCV-related cirrhosis enrolled in the prospective ANRS CO12 CirVir cohort, we selected individuals with a liver biopsy collected within 2 years before inclusion in the study. K7 and EpCAM immunostaining identified intermediate hepatobiliary cells. The influence of biliary marker expres-sion in hepatocytes on decompensation events and the occurrence of hepatocellular carcinoma (HCC) was studied using a multivariate Cox proportional hazards regression model. Among the 337 patients eligible for the study (men, 67%; median age, 52 years), 198 (58.8%) had biopsies with K7-positive hepatocytes including extensive staining in 40 (11.9%) and 203 had EpCAM-positive hepatocytes (60.6%). During follow-up (median, 54.2 months), 47 patients (14%) experienced a decompensation event, and HCC was diagnosed in 37 patients (11%). Extensive K7 staining was independently associated with the occurrence of a decompensation event (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.30-6.89; P = 0.010). EpCAM expression was independently associated with HCC occurrence (HR, 2.37; 95% CI, 1.07-5.23; P =0.033) along with age and a low prothrombin ratio. CONCLUSION Progenitor-derived regeneration depicted by K7 and EpCAM immunostaining of hepatocytes in liver biopsies of patients with compensated HCV-related cirrhosis marks a cirrhosis stage more prone to develop complications. (HEPATOLOGY 2018; 68:1534-1548).
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Affiliation(s)
- Dominique Wendum
- APHP, Hôpital St. Antoine, Anatomie Pathologiques.,Sorbonne Universités, UPMC Université Paris 06, INSERM UMRS_938 Centre de Recherche St. Antoine (CRSA), Paris, France
| | - Richard Layese
- APHP, Hôpital Henri Mondor, Unité de recherche clinique (URC-Mondor), Service de Santé Publique, AP-HP, Hôpital Henri-Mondor, Créteil, France.,Université Paris Est (UPEC), IMRB, A-TVB DHU, CEpiA EA 7376 (Clinical Epidemiology and Ageing Unit), Créteil, France
| | - Nathalie Ganne-Carrié
- APHP, Hôpital Jean Verdier, Service d'hépatologie, Bondy, France.,Université Paris 13, Sorbonne Paris-Cité, Bobigny, France.,INSERM UMR 1162, Génomique fonctionnelle des tumeurs solides, Université Paris Descartes, Université Paris Diderot, France
| | - Valérie Bourcier
- APHP, Hôpital Jean Verdier, Service d'hépatologie, Bondy, France
| | - Fatiha Merabtene
- Sorbonne Universités, UPMC Université Paris 06, INSERM UMRS_938 Centre de Recherche St. Antoine (CRSA), Paris, France.,Sorbonne Universités, UMS 30 LUMIC plateforme d'histomorphologie St. Antoine
| | | | - Emmanuel Sauce
- APHP, Hôpital Jean Verdier, Anatomie Pathologique et CRB BB-0033-00027, Bondy, France
| | - Nathalie Barget
- APHP, Hôpital Jean Verdier, Anatomie Pathologique et CRB BB-0033-00027, Bondy, France
| | - Pierre Bedossa
- APHP, Hôpital Beaujon, Département de Pathologie, Clichy, France
| | - Benoit Terris
- APHP, Hôpital Cochin, Anatomie Pathologique, Paris, France
| | - Janick Selves
- IUCT-Oncopole Toulouse, Departement d'Anatomie Pathologique, Toulouse, France
| | - Paulette Bioulac-Sage
- Pathology Department, Pellegrin Hospital, CHU Bordeaux.,Inserm, UMR1053 Bordeaux Research in Translational Oncology BaRITOn.,Université Bordeaux, UMR1053 Bordeaux Research in Translational Oncology BaRITOn, Bordeaux, France
| | - Nathalie Sturm
- CHU Grenoble, Département de Pathologie, Grenoble, France
| | | | - Pierre Nahon
- APHP, Hôpital Jean Verdier, Service d'hépatologie, Bondy, France.,Université Paris 13, Sorbonne Paris-Cité, Bobigny, France.,INSERM UMR 1162, Génomique fonctionnelle des tumeurs solides, Université Paris Descartes, Université Paris Diderot, France
| | - Françoise Roudot-Thoraval
- APHP, Hôpital Henri Mondor, Unité de recherche clinique (URC-Mondor), Service de Santé Publique, AP-HP, Hôpital Henri-Mondor, Créteil, France.,Université Paris Est (UPEC), IMRB, A-TVB DHU, CEpiA EA 7376 (Clinical Epidemiology and Ageing Unit), Créteil, France
| | - Marianne Ziol
- Université Paris 13, Sorbonne Paris-Cité, Bobigny, France.,INSERM UMR 1162, Génomique fonctionnelle des tumeurs solides, Université Paris Descartes, Université Paris Diderot, France.,APHP, Hôpital Jean Verdier, Anatomie Pathologique et CRB BB-0033-00027, Bondy, France
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28
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Huynh T, Zhang J, Hu KQ. Hepatitis C Virus Clearance by Direct-acting Antiviral Results in Rapid Resolution of Hepatocytic Injury as Indicated by Both Alanine Aminotransferase and Aspartate Aminotransferase Normalization. J Clin Transl Hepatol 2018; 6:258-263. [PMID: 30271737 PMCID: PMC6160300 DOI: 10.14218/jcth.2018.00014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 07/01/2018] [Accepted: 08/23/2018] [Indexed: 12/20/2022] Open
Abstract
Background and Aims: Hepatitis C virus (HCV) infection results in hepatocytic injury with elevation of both alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It remains to be determined if direct-acting antiviral treatment can terminate hepatocytic injury following virologic response. To this end, we evaluated the pattern and predicting factors of ALT and AST normalization during and after direct-acting antiviral treatment with sustained virologic response at 12 weeks (SVR12). Methods: Single-center retrospective study on 115 HCV-infected patients who achieved SVR12 was performed. Results: At treatment week 2, 100% and 45.9% showed decline in HCV RNA to <700 IU/mL and undetectable levels, respectively, and this was associated with 85.5%, 83.9% and 77.4% ALT normalization, AST normalization and ALT and AST normalization. At end of treatment, 85.6% of patients with baseline elevation of both ALT and AST had normalization of both ALT and AST. At posttreatment weeks 12 and 24, 90.8% and 94.8% had normalization of both ALT and AST. HCV clearance also resulted in further decline of both ALT and AST in those with baseline <40 IU. Univariate analysis showed baseline Child-Pugh score of <6, model for end-stage liver disease score of <10, HCV genotype 1, and HCV RNA of <500 IU/mL at treatment week 2 were associated with sustained normalization of both ALT and AST at posttreatment week 12. On multivariate analysis, baseline model for end-stage liver disease score of <10 was significantly associated with normalization of both ALT and AST at posttreatment week 12, independent of baseline Child-Pugh score <6, HCV genotype 1, and HCV RNA of <500 IU/mL at treatment week 2. Conclusions: During direct-acting antiviral therapy, 85.5% and 83.9% had normalization of both ALT and AST as early as in week 2, providing biochemical evidence of hepatocytic injury resolution. Sustained normalization of both ALT and AST was seen in 90.8% at posttreatment weeks 12, and was independently associated with baseline model for end-stage liver disease score of <10.
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Affiliation(s)
- Tung Huynh
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Orange, CA, USA
| | - Johnathan Zhang
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Orange, CA, USA
| | - Ke-Qin Hu
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Orange, CA, USA
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29
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Ukawa S, Tamakoshi A, Murakami Y, Kiyohara Y, Yamada M, Nagai M, Satoh A, Miura K, Ueshima H, Okamura T, EPOCH-JAPAN Research Group. Pooled Analysis of the Associations between Body Mass Index, Total Cholesterol, and Liver Cancer-related Mortality in Japan. Asian Pac J Cancer Prev 2018; 19:2089-2095. [PMID: 30139206 PMCID: PMC6171377 DOI: 10.22034/apjcp.2018.19.8.2089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective: We employed a large-scale pooled analysis to investigate the association of liver cancer-related
mortality with being overweight/obese and total cholesterol (TC) levels, since limited and inconsistent data on these
associations exist in Japan. Methods: A total of 59,332 participants (23,853 men and 35,479 women) from 12 cohorts
without a history of cancer who were followed for a median of 14.3 years were analyzed. A sex-specific stratified
Cox proportional hazards model adjusted for age and other potential confounders was used to calculate hazard ratios
(HRs) and 95% confidence intervals (CI) for liver cancer-related mortality. Results: A total of 447 participants
(266 men and 181 women) died of liver cancer within the follow-up period. Individuals classified as having a high
BMI (≥25.0 kg/m2) and low TC levels (<160 mg/dL) had a significantly increased risk for liver cancer-related
mortality (HR 7.05, 95% CI 4.41–11.26 in men; HR 8.07, 95% CI 4.76–13.67 in women) when compared with those
in the intermediate BMI (18.5–24.9 kg/m2) and TC (160–219 mg/dL) categories. These associations remained after
limiting the follow-up duration to >5 years. Conclusion: Being overweight/obese, combined with low TC levels, was
strongly associated with liver cancer-related mortality in the EPOCH-JAPAN.
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Affiliation(s)
- Shigekazu Ukawa
- Department of Public Health, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.,Research Unit of Advanced Interdisciplinary Care Science, Osaka City University Graduate School of Human Life Science, Osaka, Japan.
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30
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Yen YH, Lin MT, Kuo FY, Chang KC, Tsai MC, Tseng PL, Wu CK, Lin JT, Hu TH, Lu SN, Wang JH, Hung CH, Chen CH. The association between steatosis and diabetes with hepatocellular carcinoma in non-genotype 3 chronic hepatitis C patients. Liver Int 2018; 38:1064-1073. [PMID: 29164767 DOI: 10.1111/liv.13633] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 11/13/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Diabetes mellitus (DM) has been found to be strongly associated with an increased risk of hepatocellular carcinoma (HCC) among chronic hepatitis C (CHC) patients. Several studies have also found an association between metabolic steatosis and the risk of HCC in CHC patients, whether this latter association has been accounted for by the known relationship between DM and HCC is still unknown. METHODS A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC and treated with interferon and ribavirin was studied. Cumulative incidence and HCC risk were analysed using the Kaplan-Meier method and Cox proportional hazard analysis. RESULTS Hepatocellular carcinoma developed in 140 subjects over a median follow-up period of 97.3 months, while 699 patients achieved sustained virological response (SVR). According to multivariate analyses, age ≥ 60 years, advanced fibrosis and genotype 1 were identified as independent factors significantly associated with HCC development in SVR patients. Furthermore, using the absence of steatosis and absence of DM as references, the presence of steatosis without DM (HR = 2.09, 95% CI = 1.12-3.9, P = .021), the presence of DM without steatosis (HR = 2.78, 95% CI = 1.3-5.92, P = .008) and the combined presence of steatosis and DM (HR = 3.25, 95% CI = 1.44-7.33, P = .004) were identified as independent factors significantly associated with HCC development in the SVR patients. In contrast, steatosis alone, DM alone and the combined presence of steatosis and DM were not associated with HCC development in non-SVR patients. CONCLUSIONS Steatosis and DM may be associated with HCC development in non-genotype 3 CHC patients with SVR.
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Affiliation(s)
- Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Fang-Ying Kuo
- Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jung-Ting Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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31
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Impact of Alcohol and Coffee Intake on the Risk of Advanced Liver Fibrosis: A Longitudinal Analysis in HIV-HCV Coinfected Patients (ANRS HEPAVIH CO-13 Cohort). Nutrients 2018; 10:nu10060705. [PMID: 29857547 PMCID: PMC6024311 DOI: 10.3390/nu10060705] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 05/26/2018] [Accepted: 05/29/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Coffee intake has been shown to modulate both the effect of ethanol on serum GGT activities in some alcohol consumers and the risk of alcoholic cirrhosis in some patients with chronic diseases. This study aimed to analyze the impact of coffee intake and alcohol consumption on advanced liver fibrosis (ALF) in HIV-HCV co-infected patients. Methods: ANRS CO13-HEPAVIH is a French, nationwide, multicenter cohort of HIV-HCV-co-infected patients. Sociodemographic, behavioral, and clinical data including alcohol and coffee consumption were prospectively collected using annual self-administered questionnaires during five years of follow-up. Mixed logistic regression models were performed, relating coffee intake and alcohol consumption to ALF. Results: 1019 patients were included. At the last available visit, 5.8% reported high-risk alcohol consumption, 27.4% reported high coffee intake and 14.5% had ALF. Compared with patients with low coffee intake and high-risk alcohol consumption, patients with low coffee intake and low-risk alcohol consumption had a lower risk of ALF (aOR (95% CI) 0.24 (0.12–0.50)). In addition, patients with high coffee intake had a lower risk of ALF than the reference group (0.14 (0.03–0.64) in high-risk alcohol drinkers and 0.11 (0.05–0.25) in low-risk alcohol drinkers). Conclusions: High coffee intake was associated with a low risk of liver fibrosis even in HIV-HCV co-infected patients with high-risk alcohol consumption.
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Chitturi S, Wong VWS, Chan WK, Wong GLH, Wong SKH, Sollano J, Ni YH, Liu CJ, Lin YC, Lesmana LA, Kim SU, Hashimoto E, Hamaguchi M, Goh KL, Fan J, Duseja A, Dan YY, Chawla Y, Farrell G, Chan HLY. The Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 2: Management and special groups. J Gastroenterol Hepatol 2018; 33:86-98. [PMID: 28692197 DOI: 10.1111/jgh.13856] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/31/2017] [Accepted: 06/25/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Shiv Chitturi
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Wah-Kheong Chan
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Simon Kin-Hung Wong
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | | | - Yen-Hsuan Ni
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Hepatitis Research Center, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yu-Cheng Lin
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | | | - Seung Up Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Khean-Lee Goh
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jiangao Fan
- Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yogesh Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Geoff Farrell
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
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Banks DE, Bogler Y, Bhuket T, Liu B, Wong RJ. Significant disparities in risks of diabetes mellitus and metabolic syndrome among chronic hepatitis C virus patients in the U.S. Diabetes Metab Syndr 2017; 11 Suppl 1:S153-S158. [PMID: 27989517 DOI: 10.1016/j.dsx.2016.12.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 12/12/2016] [Indexed: 12/15/2022]
Abstract
AIM Diabetes mellitus (DM) and metabolic syndrome (MetSyn) among chronic hepatitis C virus (HCV) patients increases risks for nonalcoholic fatty liver disease (NAFLD) and more rapid progression to hepatocellular carcinoma (HCC). We aim to evaluate the prevalence of DM and MetSyn among HCV patients, focusing on age-specific and race/ethnicity-specific disparities. METHODS We retrospectively evaluated 2003-2012 National Health and Nutrition Examination Survey (NHANES) data for age and race disparities in concurrent DM and MetSyn among HCV patients. Multivariate logistic regression models evaluated for independent predictors of DM and MetSyn among HCV patients. RESULTS Overall U.S. prevalence of HCV was 1.29% from 2003 to 2012 and prevalence of DM and MetSyn among HCV patients was 17.5% and 35.0%, respectively. Higher rates of DM (36.9% vs. 3.3%, p<0.001) and MetSyn (50.5% vs. 11.7%, p<0.001) were seen among HCV patients ≥60 compared to <40years. The highest rates of DM and MetSyn were seen among African Americans (AA) (DM: 39.1%, MetSyn: 29.2%) and the lowest in non-Hispanic whites (DM: 9.4%, MetSyn: 33.0%). On multivariate regression, patients ≥60 were significantly more likely to have DM compared to patients <40 years (OR 11.90, 95% CI 2.73-52.60, p=0.001); AA were significantly more likely to have DM compared to non-Hispanic whites (OR 2.82, 95% CI 1.53-5.20, p=0.001). CONCLUSION Among chronic HCV patients, the highest risk of DM and MetSyn was seen among older patients, African Americans, and women. These groups are at higher risk of cirrhosis and HCC due to concurrent NAFLD.
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Affiliation(s)
- Darnna E Banks
- Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital, Oakland, CA, United States
| | - Yael Bogler
- Department of Medicine, Alameda Health System-Highland Hospital, Oakland, CA, United States
| | - Taft Bhuket
- Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital, Oakland, CA, United States
| | - Benny Liu
- Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital, Oakland, CA, United States
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital, Oakland, CA, United States.
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Dultz G, Graubard BI, Martin P, Welker MW, Vermehren J, Zeuzem S, McGlynn KA, Welzel TM. Liver transplantation for chronic hepatitis C virus infection in the United States 2002-2014: An analysis of the UNOS/OPTN registry. PLoS One 2017; 12:e0186898. [PMID: 29088255 PMCID: PMC5663425 DOI: 10.1371/journal.pone.0186898] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 09/20/2017] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.
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Affiliation(s)
- Georg Dultz
- University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Barry I. Graubard
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
| | - Paul Martin
- Hepatology Division, University of Miami, Miami, FL, United States of America
| | | | | | - Stefan Zeuzem
- University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Katherine A. McGlynn
- HREB, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
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Rao H, Wu E, Fu S, Yang M, Feng B, Lin A, Fei R, Fontana RJ, Lok AS, Wei L. The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease. Aliment Pharmacol Ther 2017; 46:731-740. [PMID: 28833342 DOI: 10.1111/apt.14273] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 05/03/2017] [Accepted: 07/27/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China. AIM To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage. METHODS Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre-defined criteria. RESULTS One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis. CONCLUSIONS HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes.
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Affiliation(s)
- H Rao
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - E Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - S Fu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - M Yang
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - B Feng
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - A Lin
- The Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - R Fei
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - R J Fontana
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - A S Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - L Wei
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
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Rinninella E, Cerrito L, Spinelli I, Cintoni M, Mele MC, Pompili M, Gasbarrini A. Chemotherapy for Hepatocellular Carcinoma: Current Evidence and Future Perspectives. J Clin Transl Hepatol 2017; 5:235-248. [PMID: 28936405 PMCID: PMC5606970 DOI: 10.14218/jcth.2017.00002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 04/29/2017] [Accepted: 04/29/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocarcinogenesis is a multistep process, heralded by abnormalities in cell differentiation and proliferation and sustained by an aberrant neoangiogenesis. Understanding the underlying molecular pathogenesis leading to hepatocellular carcinoma is a prerequisite to develop new drugs that will hamper or block the steps of these pathways. As hepatocellular carcinoma has higher arterial vascularization than normal liver, this could be a good target for novel molecular therapies. Introduction of the antiangiogenic drug sorafenib into clinical practice since 2008 has led to new perspectives in the management of this tumor. The importance of this drug lies not only in the modest gain of patients' survival, but in having opened a roadmap towards the development of new molecules and targets. Unfortunately, after the introduction of sorafenib, during the last years, a wide number of clinical trials on antiangiogenic therapies failed in achieving significant results. However, many of these trials are still ongoing and promise to improve overall survival and progression-free survival. A recent clinical trial has proven regorafenib effective in patients showing tumor progression under sorafenib, thus opening new interesting therapeutic perspectives. Many other expectations have been borne from the discovery of the immune checkpoint blockade, already known in other solid malignancies. Furthermore, a potential role in hepatocellular carcinoma therapy may derive from the use of branched-chain amino acids and of nutritional support. This review analyses the biomolecular pathways of hepatocellular carcinoma and the ongoing studies, the actual evidence and the future perspectives concerning drug therapy in this open field.
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Affiliation(s)
- Emanuele Rinninella
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Lucia Cerrito
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Irene Spinelli
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Marco Cintoni
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Maria Cristina Mele
- Clinical Nutrition Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Unit, Gastroenterology Area, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome, Italy
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Silva LD, Bering T, Rocha GA. The impact of nutrition on quality of life of patients with hepatitis C. Curr Opin Clin Nutr Metab Care 2017; 20:420-425. [PMID: 28617708 DOI: 10.1097/mco.0000000000000396] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The aim of this study was to review the most recent aspects of nutrition and its impact on health-related quality of life (HRQOL) in patients with chronic hepatitis C (CHC). RECENT FINDINGS Low HRQOL scores have been found in all stages of hepatitis C virus (HCV) infection. Of the factors linked to HRQOL, three aspects should be emphasized, nutritional status, physical activity and mental health status. Regarding the nutrition and metabolic conditions, a broad spectrum of nutritional disorders may impact on HRQOL of patients with CHC. SUMMARY Malnutrition, which is a significant comorbidity in end-stage of all chronic liver diseases, has been recognized as a significant factor related to poor HRQOL. Of note, in individuals chronically infected with HCV, low muscle skeletal mass, an early indicator of undernourishment, precedes the development of cirrhosis. Because of the strict linkage between HRQOL, nutrition and physical activity, the assessment of the musculoskeletal system abnormalities in every patient with CHC, independently of the stage of the liver disease, is of utmost relevance. Maintenance of healthy skeletal muscle is essential to reduce the negative effects of sarcopenia on HRQOL. Otherwise, overweight/obesity and chronic HCV infection can cause insulin resistance, which has been associated with HRQOL impairment.
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Affiliation(s)
- Luciana D Silva
- aDepartment of Internal Medicine, Medical School bAmbulatory of Viral Hepatitis, Alfa Institute of Gastroenterology, Medical School cLaboratory of Research in Bacteriology, Medical School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Xu L, Lu W, Li P, Shen F, Mi YQ, Fan JG. A comparison of hepatic steatosis index, controlled attenuation parameter and ultrasound as noninvasive diagnostic tools for steatosis in chronic hepatitis B. Dig Liver Dis 2017; 49:910-917. [PMID: 28433586 DOI: 10.1016/j.dld.2017.03.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 03/18/2017] [Accepted: 03/21/2017] [Indexed: 12/11/2022]
Abstract
AIMS To evaluate the value of noninvasive tools for diagnosis of hepatic steatosis in patients with chronic hepatitis B (CHB). METHODS Consecutive treatment-naïve patients with CHB with body mass index less than 30kg/m2 who underwent liver biopsy, ultrasound and FibroScan® were enrolled. The diagnostic performance of controlled attenuation parameter (CAP), hepatic steatosis index (HSI) and ultrasound for hepatic steatosis compared with liver biopsy was assessed. The areas under receiver operating characteristics curves (AUROCs) were calculated to determine the diagnostic efficacy, with comparisons using the DeLong test. RESULTS CAP and HSI accuracies were significantly higher than that of ultrasound to detect patients with biopsy-proven mild steatosis (S1, 65.3%, 56.5%, respectively, vs. 17.7%, χ2=46.305, 31.736, both P<0.05)and moderate-severe (S2-3) steatosis (92.3%, 100%, respectively, vs. 53.8%, χ2=4.887, 7.800, P=0.037, 0.007, respectively). Both CAP and HSI had lower underestimation rates of steatosis grade than ultrasound (12%, 14.8%, respectively, vs. 29.5%, χ2=9.765, 6.452; P<0.05 for both), but they exhibited higher overestimation rates (30.5%, 38.2%, respectively, vs. 12.4%, χ2=39.222, 70.986; both P<0.05). The AUROCs of CAP and HSI were 0.780 (95% confidence intervals [CIs] 0.735-0.822) and 0.655 (95%CI 0.604-0.704) for S ≥1, 0.932 (95%CI 0.902-0.956) and 0.755 (95%CI 0.707-0.799) for S ≥2, 0.990 (95%CI 0.974-0.998) and 0.786 (95% CI 0.740-0.827) for S3, respectively. CONCLUSION CAP might be more accurate for detecting hepatic steatosis than HSI and ultrasound in patients with CHB, but further studies are needed to reduce the overestimation rates.
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Affiliation(s)
- Liang Xu
- First Center for Clinical College, Tianjin Medical University, Tianjin, China; Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China; Tianjin Research Institute of Liver Diseases, Tianjin, China
| | - Wei Lu
- First Center for Clinical College, Tianjin Medical University, Tianjin, China; Tianjin First Center Hospital, Tianjin, China; Tianjin Research Institute of Liver Diseases, Tianjin, China.
| | - Ping Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China; Tianjin Research Institute of Liver Diseases, Tianjin, China
| | - Feng Shen
- Department of Gastroenterology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu-Qiang Mi
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China; Tianjin Research Institute of Liver Diseases, Tianjin, China.
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Wong RJ, Saab S, Ahmed A. Extrahepatic Manifestations of Hepatitis C Virus After Liver Transplantation. Clin Liver Dis 2017; 21:595-606. [PMID: 28689596 DOI: 10.1016/j.cld.2017.03.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic hepatitis C virus (HCV) infection remains a leading cause of chronic liver disease in the United States. Although the hepatic impact of chronic HCV leading to cirrhosis and the need for liver transplantation is paramount, the extrahepatic manifestations of chronic HCV infection are equally important. In particular, a better understanding of the prevalence and impact of extrahepatic manifestations of chronic HCV infection in the post-liver transplant setting relies on understanding the interplay between the effects of chronic HCV infection in a posttransplant environment characterized by strong immunosuppression and the associated risks of this milieu.
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Affiliation(s)
- Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, 1411 East 31st Street, Highland Hospital - Highland Care Pavilion 5th Floor, Oakland, CA 94602, USA.
| | - Sammy Saab
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 200 UCLA Medical Plaza, Suite 214, Los Angeles, CA 90095, USA; Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, 200 UCLA Medical Plaza, Suite 214, Los Angeles, CA 90095, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 750 Welch Road, Suite # 210, Palo Alto, CA 94304, USA
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Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Lédinghen V, Kumar M, Lupsor-Platon M, Han KH, Cardoso AC, Ferraioli G, Chan WK, Wong VWS, Myers RP, Chayama K, Friedrich-Rust M, Beaugrand M, Shen F, Hiriart JB, Sarin SK, Badea R, Jung KS, Marcellin P, Filice C, Mahadeva S, Wong GLH, Crotty P, Masaki K, Bojunga J, Bedossa P, Keim V, Wiegand J. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol 2017; 66:1022-1030. [PMID: 28039099 DOI: 10.1016/j.jhep.2016.12.022] [Citation(s) in RCA: 805] [Impact Index Per Article: 100.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 12/13/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The prevalence of fatty liver underscores the need for non-invasive characterization of steatosis, such as the ultrasound based controlled attenuation parameter (CAP). Despite good diagnostic accuracy, clinical use of CAP is limited due to uncertainty regarding optimal cut-offs and the influence of covariates. We therefore conducted an individual patient data meta-analysis. METHODS A review of the literature identified studies containing histology verified CAP data (M probe, vibration controlled transient elastography with FibroScan®) for grading of steatosis (S0-S3). Receiver operating characteristic analysis after correcting for center effects was used as well as mixed models to test the impact of covariates on CAP. The primary outcome was establishing CAP cut-offs for distinguishing steatosis grades. RESULTS Data from 19/21 eligible papers were provided, comprising 3830/3968 (97%) of patients. Considering data overlap and exclusion criteria, 2735 patients were included in the final analysis (37% hepatitis B, 36% hepatitis C, 20% NAFLD/NASH, 7% other). Steatosis distribution was 51%/27%/16%/6% for S0/S1/S2/S3. CAP values in dB/m (95% CI) were influenced by several covariates with an estimated shift of 10 (4.5-17) for NAFLD/NASH patients, 10 (3.5-16) for diabetics and 4.4 (3.8-5.0) per BMI unit. Areas under the curves were 0.823 (0.809-0.837) and 0.865 (0.850-0.880) respectively. Optimal cut-offs were 248 (237-261) and 268 (257-284) for those above S0 and S1 respectively. CONCLUSIONS CAP provides a standardized non-invasive measure of hepatic steatosis. Prevalence, etiology, diabetes, and BMI deserve consideration when interpreting CAP. Longitudinal data are needed to demonstrate how CAP relates to clinical outcomes. LAY SUMMARY There is an increase in fatty liver for patients with chronic liver disease, linked to the epidemic of the obesity. Invasive liver biopsies are considered the best means of diagnosing fatty liver. The ultrasound based controlled attenuation parameter (CAP) can be used instead, but factors such as the underlying disease, BMI and diabetes must be taken into account. Registration: Prospero CRD42015027238.
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Affiliation(s)
- Thomas Karlas
- Division of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - David Petroff
- Clinical Trial Centre, University of Leipzig, Leipzig, Germany; IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany
| | | | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, XinHua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu-Qiang Mi
- Research Institute of Liver Diseases, Tianjin Second People's Hospital, Tianjin, China
| | - Victor de Lédinghen
- Centre d'Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalo-Universitaire de Bordeaux, Pessac, France
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Monica Lupsor-Platon
- Department of Medical Imaging, Iuliu Hatieganu University of Medicine and Pharmacy, Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ana C Cardoso
- Department of Hepatology and INSERM U773-CRB3, Hôpital Beaujon, APHP, University of Paris 7, Clichy, France
| | - Giovanna Ferraioli
- Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Medical School University of Pavia, Pavia, Italy
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Gastrointestinal Endoscopy Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Robert P Myers
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Kazuaki Chayama
- Departments of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Mireen Friedrich-Rust
- Department of Internal Medicine, J.W. Goethe-University Hospital, Frankfurt, Germany
| | | | - Feng Shen
- Center for Fatty Liver, Department of Gastroenterology, XinHua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jean-Baptiste Hiriart
- Centre d'Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalo-Universitaire de Bordeaux, Pessac, France
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Radu Badea
- Department of Medical Imaging, Iuliu Hatieganu University of Medicine and Pharmacy, Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania
| | - Kyu Sik Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Patrick Marcellin
- Department of Hepatology and INSERM U773-CRB3, Hôpital Beaujon, APHP, University of Paris 7, Clichy, France
| | - Carlo Filice
- Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Medical School University of Pavia, Pavia, Italy
| | - Sanjiv Mahadeva
- Gastroenterology and Hepatology Unit, Gastrointestinal Endoscopy Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Pam Crotty
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keiichi Masaki
- Departments of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Joerg Bojunga
- Department of Internal Medicine, J.W. Goethe-University Hospital, Frankfurt, Germany
| | - Pierre Bedossa
- Department of Pathology, Physiology and Imaging, University Paris Diderot, Paris, France
| | - Volker Keim
- Division of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Johannes Wiegand
- Division of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
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Abstract
OPINION STATEMENT The long-term survival in liver transplant recipients (LTRs) is currently at an historical high level stemming from improvement in perioperative care, infection control, and immunosuppression medications. However, compared to the general population, LTRs have decreased survival. Metabolic diseases like hypertension, dyslipidemia, type 2 diabetes, and obesity are key determinants of long-term mortality in LTRs. The incidence and prevalence of these metabolic comorbidities is considerably higher in LTRs and likely results from a combination of factors including exposure to chronic immunosuppression, weight gain, and recurrence of chronic liver disease after liver transplantation (LT). Although there is currently little guidance in managing these metabolic conditions post-LT, recommendations are often extrapolated from non-transplant cohorts. In the current review, we explore the relationship between metabolic syndrome and its comorbidities in LTRs.
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Durier N, Yunihastuti E, Ruxrungtham K, Van Kinh N, Kamarulzaman A, Boettiger D, Widhani A, Avihingsanon A, Huy BV, Omar SFBS, Sanityoso A, Chittmittrapap S, Dung NTH, Pillai V, Suwan-Ampai T, Law M, Sohn AH, Matthews G. Chronic hepatitis C infection and liver disease in HIV-coinfected patients in Asia. J Viral Hepat 2017; 24:187-196. [PMID: 27917597 PMCID: PMC5272750 DOI: 10.1111/jvh.12630] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 10/05/2016] [Indexed: 12/14/2022]
Abstract
Data on markers of hepatitis C virus (HCV) disease in HIV-HCV-coinfected patients in resource-limited settings are scarce. We assessed HCV RNA, HCV genotype (GT), IL28B GT and liver fibrosis (FibroScan® ) in 480 HIV-infected patients with positive HCV antibody in four HIV treatment centres in South-East Asia. We enrolled 165 (34.4%) patients in Jakarta, 158 (32.9%) in Bangkok, 110 (22.9%) in Hanoi and 47 (9.8%) in Kuala Lumpur. Overall, 426 (88.8%) were male, the median (IQR) age was 38.1 (34.7-42.5) years, 365 (76.0%) reported HCV exposure through injecting drug use, and 453 (94.4%) were on combination antiretroviral therapy. The median (IQR) CD4 count was 446 (325-614) cells/mm3 and 208 (94.1%) of 221 patients tested had HIV-1 RNA <400 copies/mL. A total of 412 (85.8%) had detectable HCV RNA, at a median (IQR) of 6.2 (5.4-6.6) log10 IU/mL. Among 380 patients with HCV GT, 223 (58.7%) had GT1, 97 (25.5%) had GT3, 43 (11.3%) had GT6, eight (2.1%) had GT4, two (0.5%) had GT2, and seven (1.8%) had indeterminate GT. Of 222 patients with IL28B testing, 189 (85.1%) had rs12979860 CC genotype, and 199 (89.6%) had rs8099917 TT genotype. Of 380 patients with FibroScan® , 143 (37.6%) had no/mild liver fibrosis (F0-F1), 83 (21.8%) had moderate fibrosis (F2), 74 (19.5%) had severe fibrosis (F3), and 79 (20.8%) had cirrhosis (F4). One patient (0.3%) had FibroScan® failure. In conclusion, a high proportion of HIV-HCV-coinfected patients had chronic HCV infection. HCV GT1 was predominant, and 62% of patients had liver disease warranting prompt treatment (≥F2).
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Affiliation(s)
- Nicolas Durier
- TREAT Asia, amfAR - The Foundation for AIDS Research, Bangkok, Thailand
| | - Evy Yunihastuti
- Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
- Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Kiat Ruxrungtham
- HIVNAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand
- Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | | | - David Boettiger
- The Kirby Institute, UNSW Australia, Sydney NSW 2052, Australia
| | - Alvina Widhani
- Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
- Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Anchalee Avihingsanon
- HIVNAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand
- Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Bui Vu Huy
- National Hospital of Tropical Diseases, Hanoi, Vietnam
| | | | - Andri Sanityoso
- Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
- Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | | | | | - Veena Pillai
- Centre of Excellence for Research in AIDS (CERiA), Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Matthew Law
- The Kirby Institute, UNSW Australia, Sydney NSW 2052, Australia
| | - Annette H. Sohn
- TREAT Asia, amfAR - The Foundation for AIDS Research, Bangkok, Thailand
| | - Gail Matthews
- The Kirby Institute, UNSW Australia, Sydney NSW 2052, Australia
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43
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Weiler-Normann C, Lohse AW. Nonalcoholic Fatty Liver Disease in Patients with Autoimmune Hepatitis: Further Reason for Teeth GNASHing? Dig Dis Sci 2016; 61:2462-4. [PMID: 27468739 DOI: 10.1007/s10620-016-4258-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Christina Weiler-Normann
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
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44
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Poorly Controlled HIV Infection: An Independent Risk Factor for Liver Fibrosis. J Acquir Immune Defic Syndr 2016; 72:437-43. [DOI: 10.1097/qai.0000000000000992] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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45
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Aguilar M, Liu B, Holt EW, Bhuket T, Wong RJ. Impact of obesity and diabetes on waitlist survival, probability of liver transplantation and post-transplant survival among chronic hepatitis C virus patients. Liver Int 2016; 36:1167-75. [PMID: 26858016 DOI: 10.1111/liv.13091] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 02/02/2016] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS The rising prevalence of obesity and diabetes mellitus (DM) among hepatitis C virus (HCV) patients contributes to concurrent nonalcoholic fatty liver disease (NAFLD). We aim to evaluate the impact of concurrent obesity or DM on waitlist survival and probability of liver transplantation (LT) among adults with chronic HCV awaiting LT. METHODS Using 2003-2013 United Network for Organ Sharing data, we evaluated the impact of obesity and DM among adults with chronic HCV awaiting LT: non-obese, non-DM vs. obese, non-DM (obese) vs. non-obese, DM (DM) vs. obese and DM. Overall, LT waitlist survival and probability of receiving LT were evaluated using Kaplan-Meier and multivariate logistic regression models. RESULTS From 2003-2013, there were 43 478 new LT waitlist registrants with chronic HCV (21.0% with HCC, 79% without HCC). Obesity was associated with lower probability of receiving LT (OR, 0.91; 95% CI, 0.85-0.97; P < 0.01), and lower probability of waitlist mortality (OR, 0.80; 95% CI, 0.72-0.89; P < 0.001) when compared to non-obese patients. DM among HCV patients did not impact probability of waitlist survival or receiving LT. When evaluating post-LT survival, compared to non-obese, non-DM patients, obese HCV patients had significantly lower post-LT mortality (HR 0.86; 95%CI, 0.81-0.92; P < 0.001); whereas, HCV patients with DM had significantly higher post-LT mortality (HR, 1.22; 95% CI, 1.12-1.33; P < 0.001). CONCLUSION Among adults with chronic HCV awaiting LT in the US, obesity is associated with lower probability of receiving LT, but did not impact waitlist survival. DM among chronic HCV patients did not impact waitlist survival or probability of LT.
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Affiliation(s)
- Maria Aguilar
- Department of Medicine, Alameda Health System - Highland Hospital, Oakland, CA, USA
| | - Benny Liu
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Oakland, CA, USA
| | - Edward W Holt
- Department of Transplantation, Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA
| | - Taft Bhuket
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Oakland, CA, USA
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Oakland, CA, USA
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46
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HCV-Induced Oxidative Stress: Battlefield-Winning Strategy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:7425628. [PMID: 27293514 PMCID: PMC4880679 DOI: 10.1155/2016/7425628] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 04/21/2016] [Accepted: 04/26/2016] [Indexed: 02/08/2023]
Abstract
About 150 million people worldwide are chronically infected with hepatitis C virus (HCV). The persistence of the infection is controlled by several mechanisms including the induction of oxidative stress. HCV relies on this strategy to redirect lipid metabolism machinery and escape immune response. The 3β-hydroxysterol Δ24-reductase (DHCR24) is one of the newly discovered host markers of oxidative stress. This protein, as HCV-induced oxidative stress responsive protein, may play a critical role in the pathogenesis of HCV chronic infection and associated liver diseases, when aberrantly expressed. The sustained expression of DHCR24 in response to HCV-induced oxidative stress results in suppression of nuclear p53 activity by blocking its acetylation and increasing its interaction with MDM2 in the cytoplasm leading to its degradation, which may induce hepatocarcinogenesis.
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47
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Allison RD, Hale SA, Harvey BJ, Hudson TML, Livingston CJ, Sherin KM, Uduhiri KA, Niebuhr DW. The American College of Preventive Medicine Position Statement on Hepatitis C Virus Infection. Am J Prev Med 2016; 50:419-426. [PMID: 26897344 DOI: 10.1016/j.amepre.2015.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 12/01/2015] [Accepted: 12/02/2015] [Indexed: 01/25/2023]
Abstract
The American College of Preventive Medicine Prevention Practice Committee contributes to policy guidelines and recommendations on preventive health topics for clinicians and public health decision makers. After review of the currently available evidence, the College is providing a consensus-based set of recommendations designed to increase screening for and prevention of hepatitis C virus infection, increase linkage to care, improve access to treatment, and encourage development of hepatitis C virus-related quality measures.
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Affiliation(s)
- Robert D Allison
- Department of Preventive Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Steven A Hale
- Department of Family Medicine & Rural Health, University of Central Florida College of Medicine, Orlando, Florida; Florida Department of Health in Orange County, Orlando, Florida
| | - Bart J Harvey
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | | | | | - Kevin M Sherin
- Department of Family Medicine & Rural Health, University of Central Florida College of Medicine, Orlando, Florida; Florida Department of Health in Orange County, Orlando, Florida; Florida State University College of Medicine, Tallahassee, Florida
| | - Kelechi A Uduhiri
- Department of Family Medicine, Providence Hospital, Washington, District of Columbia
| | - David W Niebuhr
- Department of Preventive Medicine and Biostatistics, Uniformed Services University of Health Sciences, Bethesda, Maryland.
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Cheng PN, Chiu YC, Chiu HC, Chien SC. The Application of Liver Stiffness Measurement in Residents Without Overt Liver Diseases Through a Community-Based Screening Program. Medicine (Baltimore) 2016; 95:e3193. [PMID: 27015215 PMCID: PMC4998410 DOI: 10.1097/md.0000000000003193] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The application of liver stiffness measurement (LSM) by transient elastography (TE) in general population remains to clarify. This cohort study aimed to examine the usefulness of TE and to identify factors associated with significant liver fibrosis in community-based population.We conducted a hepatitis screening program in 2 remote villages of Southern Taiwan. All residents participated voluntarily and received questionnaire evaluation, blood tests, abdominal sonography, and LSM by TE. Residents with any one of following criteria including hepatitis B virus infection, hepatitis C virus infection, more than moderate alcohol drinking, and failure to obtain valid or reliable LSM were excluded.There were 831 residents participated in program. The valid and reliable LSM were obtained in 98.3% and 96.3% of residents, respectively. Finally, a total of 559 residents including 283 residents with nonalcoholic steatotic fatty liver disease (NAFLD) were enrolled for analysis. The mean liver stiffness was 4.9 ± 1.9 kPa. The liver stiffness increased in residents with diabetes mellitus (DM), higher body mass index (BMI), hypertension, abnormal waist-hip circumference ration (WHR), higher waist circumference (WC), and presence of fatty liver. Higher body weight, higher BMI, higher WC, abnormal WHR, abnormal aspartate aminotransferase (AST), abnormal alanine aminotransferase (ALT), and DM were the factors associated with significant fibrosis (liver stiffness ≥7 kPa) in either all participants or NAFLD residents. As determined by multivariate analysis, abnormal AST values and DM were the 2 independent factors in all participants (abnormal AST: OR 3.648, 95% CI 1.134-11.740, P = 0.03; DM: OR 2.882, 95% CI 1.282-6.478, P = 0.01) and in residents with NAFLD (abnormal AST: OR 4.197, 95% CI 1.154-15.262, P = 0.03; DM: OR 3.254, 95% CI 1.258-8.413, P = 0.02).LSM by TE is a useful screening tool in community. In residents, who were absence of chronic hepatitis virus infection or consumed less than moderate alcohol drinking, exhibited DM or abnormal AST values may consider a substantial group with significant fibrosis in community.
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Affiliation(s)
- Pin-Nan Cheng
- From the Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Dyal HK, Aguilar M, Bartos G, Holt EW, Bhuket T, Liu B, Cheung R, Wong RJ. Diabetes Mellitus Increases Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients: A Systematic Review. Dig Dis Sci 2016; 61:636-45. [PMID: 26703125 DOI: 10.1007/s10620-015-3983-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 11/26/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Rising rates of obesity, diabetes mellitus (DM), and nonalcoholic fatty liver disease (NAFLD) among chronic hepatitis C (HCV) patients may contribute to higher hepatocellular carcinoma (HCC) risk. AIM To perform a systematic review evaluating the impact of DM, body mass index (BMI), or steatosis on HCC risk among chronic HCV patients. METHODS A structured keyword search of PubMed from January 1, 2001, to July 1, 2014, was performed to identify original articles evaluating the association of DM, BMI, or steatosis with HCC among adults with chronic HCV. Studies involving HCV patients co-infected with human immunodeficiency virus, hepatitis B virus, or other chronic liver diseases with the exception of NAFLD were excluded. Quality assessment utilized the Newcastle-Ottawa scale. RESULTS Nine studies (seven cohorts, two case-controls) met inclusion criteria for the final analysis. Five of seven studies analyzing DM demonstrated significantly increased HCC risk associated with concurrent DM with effect sizes ranging from HR 1.73 (95 % CI 1.30-2.30) to RR 3.52 (95 % CI 1.29-9.24). One of three studies analyzing BMI demonstrated a significant association with HCC risk (BMI ≥ 30.0 vs. BMI < 23: RR 4.13, 95 % CI 1.38-12.40). Two of the three studies analyzing steatosis demonstrated significantly higher risk of HCC associated with steatosis ranging from RR 2.81 (95 % CI 1.49-4.41) to OR 6.39 (95 % CI 1.04-39.35). CONCLUSIONS Concurrent DM is associated with increased HCC risk among chronic HCV patients. BMI and steatosis may also increase HCC risk, but the limitations of the current studies do not allow us to draw strong conclusions.
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Affiliation(s)
- Harleen K Dyal
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
| | - Maria Aguilar
- Department of Medicine, Alameda Health System - Highland Hospital, 1411 East 31st Street, Oakland, CA, USA.
| | - Gabriella Bartos
- Department of Medicine, Alameda Health System - Highland Hospital, 1411 East 31st Street, Oakland, CA, USA.
| | - Edward W Holt
- Division of Hepatology, Department of Transplantation, California Pacific Medical Center, 2340 Clay Street, 3rd Floor, San Francisco, CA, 94115, USA.
| | - Taft Bhuket
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
| | - Benny Liu
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 750 Welch Road, Stanford, CA, 94305, USA.
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
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50
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Calvaruso V, Craxì A. Why do I treat my patients with mild hepatitis C? Liver Int 2016; 36 Suppl 1:7-12. [PMID: 26725891 DOI: 10.1111/liv.13011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 10/29/2015] [Indexed: 12/12/2022]
Abstract
The major advances achieved in the treatment of HCV by the development of new direct-acting antiviral agents (DAAs) allow treatment of almost the entire spectrum of patients with chornic infection. As a result of the exceedingly high cost of DAAs in many countries, IFN-free DAA regimens are mostly reserved to patients with advanced fibrosis or cirrhosis. Hence, treatment of patients with milder liver disease is often deferred. This could ultimately result in an increased burden of advanced liver disease and in increased long-term costs of management. Moreover, studies performed during the 'interferon era' and the early data on interferon-free regimens show that patients without severe fibrosis achieve higher rates of sustained virological response with less treatment-related adverse events. Unfortunately, there is no univocal way to predict the progression of liver fibrosis and therefore to identify the patients with early disease who would require urgent HCV treatment. Many studies have also demonstrated that treatment-induced HCV clearance reduces all-cause mortality regardless of the stage of liver fibrosis, pointing to an effect on extrahepatic manifestations of HCV infection. Last but not least, pharmacoeconomic studies show that DAA treatment of patients with mild HCV disease is cost-effective even at high prices of drugs, thus suggesting the opprtunity to treat regardless of the stage of liver disease.
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Affiliation(s)
- Vincenza Calvaruso
- Sezione di Gastroenterologia & Epatologia, DIBIMIS, Università di Palermo, Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia & Epatologia, DIBIMIS, Università di Palermo, Palermo, Italy
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