|
1
|
Yi H, Zhang Y, Zhou Z, Sun W, Wang Y, Tao W, Yu H, Yao L, Li J, Li L. Diagnostic performance of noninvasive tests for identifying advanced fibrosis in metabolic dysfunction-associated fatty liver disease with mixed etiologies. Endocr Pract 2025:S1530-891X(25)00140-5. [PMID: 40334939 DOI: 10.1016/j.eprac.2025.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/10/2025] [Accepted: 04/28/2025] [Indexed: 05/09/2025]
Abstract
OBJECTIVES To assess the performance of fibrosis-4 index (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS) and aspartate aminotransferase to platelet ratio index (APRI) for advanced fibrosis in metabolic dysfunction-associated fatty liver disease (MAFLD) subgroups categorized by concomitant liver conditions. METHODS We conducted a multicentered study comprising inpatients with type 2 diabetes mellitus (T2DM) and MAFLD. Participants were categorized into two groups: MAFLD with pure metabolic etiologies (MAFLD-P) and MAFLD with mixed etiologies (MAFLD-M). Diagnostic performance of FIB-4, NFS and APRI was assessed by area under receiver operating characteristic curve (AUC), sensitivity and specificity. RESULTS This study comprised a total of 1475 participants, with a mean (SD) age of 58.4 (13) years and 835 (56.6%) males. FIB-4 and APRI had higher AUCs for advanced fibrosis in the MAFLD-M group than in the MAFLD-P group (MAFLD-M vs MAFLD-P: FIB-4 0.680 vs 0.591, p = 0.0442; APRI 0.723 vs 0.631, p = 0.0363). No significant difference was observed in the AUC of NFS between the two subgroups (MAFLD-M 0.572 vs MAFLD-P 0.617; p = 0.3237). Besides, the sensitivity of FIB-4 (69.6% vs 54.0%; p = 0.019) and APRI (43.5% vs 26.1%; p = 0.005) was higher in the MAFLD-M group. However, no significant difference in sensitivity of NFS and specificity of FIB-4, NFS and APRI was observed between subgroups. CONCLUSIONS In this diagnostic study of the T2DM population, FIB-4 and APRI showed better performance for identifying advanced fibrosis in MAFLD with mixed etiologies.
Collapse
Affiliation(s)
- He Yi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, 210009, China
| | - Yan Zhang
- Department of Endocrinology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212000, China
| | - Ziwei Zhou
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, 210009, China
| | - Weixia Sun
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, 210009, China
| | - Yifan Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, 210009, China
| | - Wenxuan Tao
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, 210009, China
| | - Hekai Yu
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, 210009, China
| | - Liqin Yao
- Department of Endocrinology, Yixing Hospital of Traditional Chinese Medicine, Yixing, 214200, China.
| | - Jia Li
- Department of Ultrasound, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China; Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing, 210009, China.
| |
Collapse
|
|
2
|
McCary A, Sheu YS, Chesbrough K, Jonas MC. Improved Liver Fibrosis Regression After Direct-Acting Antiviral Therapy in Hepatitis C Patients: A Comparison of Patients With and Without MASLD. Clin Ther 2025:S0149-2918(25)00087-6. [PMID: 40287335 DOI: 10.1016/j.clinthera.2025.03.011] [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: 12/18/2024] [Revised: 03/12/2025] [Accepted: 03/23/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE Chronic Hepatitis C (CHC) often results in liver fibrosis. Therefore, an important benefit of CHC treatment with direct-acting antiviral (DAA) medication is liver fibrosis regression. However, it is unclear how concurrent liver steatosis affects fibrosis regression following DAA therapy. Recent guidelines have defined liver steatosis associated with metabolic syndrome as metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to examine the association of MASLD with the fibrosis regression benefits of DAA treatment for CHC. METHODS We conducted an observational retrospective analysis using electronic health records of patients aged 18-65 who completed DAA therapy for CHC from 2016 through 2022. FIB-4 scores were calculated during three time periods: just prior to DAA initiation, within 6 months post-DAA completion, and within 6-12 months post-DAA completion. These scores categorized liver fibrosis as high risk (>3.25), intermediate risk (1.45-3.25), or low risk (<1.45). An ordinal logistic regression model assessed the degree of fibrosis regression across these periods in CHC patients with and without MASLD. FINDINGS We identified 845 patients with CHC who received DAA therapy, of whom 225 met MASLD criteria. Both CHC patients with and without MASLD exhibited a decrease in FIB-4 category (coefficient = -0.361, P < 0.001) within the year following DAA therapy. The reduction in FIB-4 category post-treatment was more pronounced in the MASLD group compared to the non-MASLD group, as evidenced by a significant interaction between group and time period (coefficient = -0.439, P = 0.004). IMPLICATIONS In our cohort, MASLD was associated with greater liver fibrosis regression in the year following DAA therapy for CHC. This suggests that the concurrent presence of MASLD is not associated with diminished fibrosis regression from DAA therapy. Additional research is needed to determine the exact mechanism responsible for DAA-associated fibrosis regression in patients with MASLD.
Collapse
Affiliation(s)
- Alexis McCary
- Department of Gastroenterology, Mid-Atlantic Permanente Medical Group, Upper Marlboro, Maryland; Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia.
| | - Yi-Shin Sheu
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| | - Karen Chesbrough
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| | - M Cabell Jonas
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| |
Collapse
|
|
3
|
Ratziu V. Cirrhose métabolique : une entité en plein essor. BULLETIN DE L'ACADÉMIE NATIONALE DE MÉDECINE 2024. [DOI: 10.1016/j.banm.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
4
|
Fernandez CJ, Alkhalifah M, Afsar H, Pappachan JM. Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink. Pathogens 2024; 13:68. [PMID: 38251375 PMCID: PMC10821334 DOI: 10.3390/pathogens13010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
Collapse
Affiliation(s)
- Cornelius J. Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, UK;
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11411, Saudi Arabia
| | - Hafsa Afsar
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK
| |
Collapse
|
|
5
|
Tsai PS, Cheng YM, Wang CC, Kao JH. The impact of concomitant hepatitis C virus infection on liver and cardiovascular risks in patients with metabolic-associated fatty liver disease. Eur J Gastroenterol Hepatol 2023; 35:1278-1283. [PMID: 37773778 DOI: 10.1097/meg.0000000000002558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/01/2023]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV)-infected patients with hepatic steatosis are excluded from the diagnosis of nonalcoholic fatty liver disease (NAFLD). The new name and diagnostic criteria of metabolic-associated fatty liver disease (MAFLD) were proposed in 2020 to replace the original term NAFLD. The clinical outcome of MAFLD patients with concomitant chronic HCV infection requires further investigation. METHODS The participants from Taiwan bio-bank cohort were included. MAFLD is defined as the presence of fatty liver, plus any of the following three conditions: overweight/obesity, type 2 diabetes, or metabolic dysfunction. The patients with positive anti-HCV were considered chronic HCV infections. The severity of liver fibrosis was determined using the fibrosis-4 index and NAFLD fibrosis score (NFS). The risk of cardiovascular disease (CVD) was assessed using intima-media thickness (IMT) or plaques of carotid duplex ultrasound. RESULTS A total of 18 907 participants (age 55.79 ± 10.42; males 31.9%) were included for final analysis. The prevalence of MAFLD and chronic HCV infections were 39.2% and 2.6%, respectively. According to the status of MAFLD and chronic HCV infection, they were distributed to four groups: 'dual etiology group', 'MAFLD alone', 'HCV alone', and healthy controls. Compared with the 'MAFLD alone' group, the 'dual etiology' group had a lower frequency of the male sex, reduced levels of serum triglyceride, total cholesterol, and LDL; but overall older age, a higher percentage of hypertension history. In addition, they had higher levels of serum aspartate aminotransferase, fibrosis-4 index, and NFS; but no difference in levels of alanine aminotransferase, gamma-glutamyl transferase, fatty liver index, IMT, and the percentage of carotid plaques. Using binary logistic regression, chronic HCV infection was associated with more severe liver fibrosis, but not with carotid plaques in MAFLD patients. CONCLUSION MAFLD patients with concomitant HCV infection, a specific phenotype of MAFLD may include a higher risk of advanced liver fibrosis, but a similar risk of atherosclerotic cardiovascular disease compared to those without.
Collapse
Affiliation(s)
- Pei-Shan Tsai
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung's Taichung MetroHarbor Hospital, Taichung
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| |
Collapse
|
|
6
|
Popescu MS, Firu DM, Pădureanu V, Mărginean CM, Mitruț R, Arsene AL, Mărgăritescu DN, Calina D, Docea AO, Mitruț P. Effects of Achieving Sustained Virologic Response after Direct-Acting Antiviral Agents on Long-Term Liver Fibrosis in Diabetics vs. in Non-Diabetic Patients with Chronic Hepatitis C Infection. Biomedicines 2022; 10:2093. [PMID: 36140194 PMCID: PMC9495608 DOI: 10.3390/biomedicines10092093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 12/15/2022] Open
Abstract
Because of the prevalence of HCV worldwide as well as its undiagnosed population due to a lack of screening, HCV can be considered a modern pandemic disease. In 2016, the World Health Organization (WHO) set goals for HCV's elimination that included a 65 percent reduction in mortality and an 80 percent reduction in newly infected cases by 2030. This study is a follow-up evaluation of 80 patients who received interferon-free treatment with direct-acting agents (DAA) for chronic HCV infection between the second half of 2017 and the end of 2018. They were assessed using a FibroMax test prior to DAA administration. Two pills/day of Ombitasvir 12.5 mg/Paritaprevir 75 mg/Ritonavir 50 mg and two pills/day of Dasabuvir 250 mg were given to the patients for 8 weeks. After treatment, all 80 patients in this study achieved an SVR (sustained virologic response), and the FibroMax test was performed three years later. Our study found that successfully treating HCV infection can play a significant role in reducing fibrosis in T2DM patients. In comparison to those of ActiTest and SteatoTest, FibroMax scores showed a significantly greater reduction in T2DM patients than in treatment-naive patients.
Collapse
Affiliation(s)
- Marian-Sorin Popescu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan-Mihai Firu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Vlad Pădureanu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristina Maria Mărginean
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Radu Mitruț
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | - Andreea Letitia Arsene
- Department of Microbiology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitruț
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| |
Collapse
|
|
7
|
Wang X, Xie Q. Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) and Viral Hepatitis. J Clin Transl Hepatol 2022; 10:128-133. [PMID: 35233381 PMCID: PMC8845159 DOI: 10.14218/jcth.2021.00200] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 08/19/2021] [Accepted: 09/07/2021] [Indexed: 12/04/2022] Open
Abstract
A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in 2020. The change from nonalcoholic fatty liver disease (NAFLD) to MAFLD highlights the metabolic abnormalities that accompany fatty liver. The diagnosis of MAFLD does not require exclusion of secondary causes of liver diseases and alcohol consumption. Thus, MAFLD may coexist with other types of liver diseases, such as viral hepatitis, a disease that remains the most common cause of liver disease-related death. With the increasing prevalence of MAFLD, patients with coincidental MAFLD and viral hepatitis are frequently encountered in clinical practice. In this review, we mainly summarize the mutual relationship between hepatitis B/C and systematic metabolism dysfunction related to MAFLD. We discuss the impact of MAFLD on progression of viral hepatitis and the therapies. Some unaddressed clinical problems related to concomitant MAFLD and viral hepatitis are also identified.
Collapse
Affiliation(s)
- Xiaolin Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
8
|
Reza MI, Syed AA, Singh P, Husain A, Gayen JR. Pancreastatin induces hepatic steatosis in type 2 diabetes by impeding mitochondrial functioning. Life Sci 2021; 284:119905. [PMID: 34453940 DOI: 10.1016/j.lfs.2021.119905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/02/2021] [Accepted: 08/12/2021] [Indexed: 11/15/2022]
Abstract
AIMS Mitochondrial dysfunction is among the key factors for the advancement of hepatic steatosis to NAFLD and NASH. Pancreastatin (PST: human ChgA250-301) is a dysglycemic hormone, previously reported to promote steatosis and inflammation in various animal models of metabolic disorders. Recently, we observed PST deregulates energy expenditure and mitochondrial functioning in perimenopausal rats. In the current study, we aimed to decipher the role of PST instigated altered mitochondrial functioning in hepatic steatosis. MAIN METHODS The HepG2 cells were PST exposed and the Chga gene was knocked down using siRNA and lipofectamine. Parallelly, type 2 diabetes (T2D) was developed in C57BL/6 mice by HFD feeding and administered PST inhibitor (PSTi8). KEY FINDINGS The PST exposed cells and HFD fed mice depicted: enhanced CHGA expression detected by IF/IHC, WB, and ELISA; dysregulated cellular ROS, mitochondrial ROS, oxygen consumption rate, mitochondrial membrane potential, ATP level, and NADP/NADP ratio; enhanced apoptosis determined by MTT, TUNEL, Annexin-V FITC, and WB of Bax/bcl2 and caspase 3; hepatic lipid accumulation upon Nile Red, Oil Red O, H&E staining, and the expression of SREBP-1c, FAS, ACC, and SCD; inflammation based on expression and circulatory level of IL6, IL-1β, and TNF-α. However, Chga knocked down HepG2 cells and PSTi8 treated mice unveiled protection from all the above abnormalities. SIGNIFICANCE Collectively, the aforementioned data suggested the alteration in mitochondrial function induced by PST is responsible for hepatic steatosis in T2D.
Collapse
Affiliation(s)
- Mohammad Irshad Reza
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Anees A Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Pragati Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| |
Collapse
|
|
9
|
Saldarriaga OA, Dye B, Pham J, Wanninger TG, Millian D, Kueht M, Freiberg B, Utay N, Stevenson HL. Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome. Sci Rep 2021; 11:14506. [PMID: 34267267 PMCID: PMC8282660 DOI: 10.1038/s41598-021-93881-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.
Collapse
Affiliation(s)
- Omar A Saldarriaga
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Bradley Dye
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Judy Pham
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Timothy G Wanninger
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Daniel Millian
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Michael Kueht
- Dept. of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Benjamin Freiberg
- Digital Pathology, Araceli Biosciences, 7425 NE Evergreen Pkwy, Hillsboro, OR, 97124, USA
| | - Netanya Utay
- Department of Internal Medicine, University of Texas Health Science Center at Houston, 7000 Fannin St # 1200, Houston, TX, 77030, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA.
- Department of Pathology, The University of Texas Medical Branch, 712 Texas Avenue, Clinical Services Wing-Room 5.506Q, Galveston, TX, 77555-0416, USA.
| |
Collapse
|
|
10
|
Florea M, Serban T, Tirpe GR, Tirpe A, Lupsor-Platon M. Noninvasive Assessment of Hepatitis C Virus Infected Patients Using Vibration-Controlled Transient Elastography. J Clin Med 2021; 10:jcm10122575. [PMID: 34200885 PMCID: PMC8230562 DOI: 10.3390/jcm10122575] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/06/2021] [Accepted: 06/08/2021] [Indexed: 02/08/2023] Open
Abstract
Chronic infection with hepatitis C virus (HCV) is one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC). Surveillance of these patients is an essential strategy in the prevention chain, including in the pre/post-antiviral treatment states. Ultrasound elastography techniques are emerging as key methods in the assessment of liver diseases, with a number of advantages such as their rapid, noninvasive, and cost-effective characters. The present paper critically reviews the performance of vibration-controlled transient elastography (VCTE) in the assessment of HCV patients. VCTE measures liver stiffness (LS) and the ultrasonic attenuation through the embedded controlled attenuation parameter (CAP), providing the clinician with a tool for assessing fibrosis, cirrhosis, and steatosis in a noninvasive manner. Moreover, standardized LS values enable proper staging of the underlying fibrosis, leading to an accurate identification of a subset of HCV patients that present a high risk for complications. In addition, VCTE is a valuable technique in evaluating liver fibrosis prior to HCV therapy. However, its applicability in monitoring fibrosis regression after HCV eradication is currently limited and further studies should focus on extending the boundaries of VCTE in this context. From a different perspective, VCTE may be effective in identifying clinically significant portal hypertension (CSPH). An emerging prospect of clinical significance that warrants further study is the identification of esophageal varices. Our opinion is that the advantages of VCTE currently outweigh those of other surveillance methods.
Collapse
Affiliation(s)
- Mira Florea
- Community Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Teodora Serban
- Medical Imaging Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - George Razvan Tirpe
- Department of Radiology and Medical Imaging, County Emergency Hospital Cluj-Napoca, 3-5 Clinicilor Street, 400000 Cluj-Napoca, Romania;
| | - Alexandru Tirpe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania;
| | - Monica Lupsor-Platon
- Medical Imaging Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Medical Imaging Department, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- Correspondence:
| |
Collapse
|
|
11
|
Hong Y, Dufendach K, Wang Y, Thoma F, Kilic A. Impact of hepatic steatosis on outcomes after left ventricular assist device implantation. J Card Surg 2021; 36:2277-2283. [PMID: 33783048 DOI: 10.1111/jocs.15536] [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: 11/10/2020] [Revised: 03/07/2021] [Accepted: 03/18/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND This single-center, retrospective study evaluates the impact of hepatic steatosis on outcomes after continuous-flow left ventricular assist device (LVAD) implantation. METHODS Adults undergoing LVAD implantation between 2004 and 2018 with a preoperative noncontrast-enhanced chest and abdominal computed tomography scan were included in the study. Patients were stratified as with and without radiographic signs of hepatic steatosis. The primary outcome was survival, and secondary outcomes included rates of postimplant adverse events. RESULTS A total of 203 patients were included in the study. 27.6% (n = 56) had radiographic signs of hepatic steatosis. Hepatic steatosis group had a higher body mass index (30.1 vs. 27.0, p < .01), model for end-stage liver disease excluding international normalized ratio score (16.8 vs. 15.1, p = .05), and incidence of diabetes (53.6% vs. 35.4%, p = .02). The rates of postimplant adverse events, including bleeding, infection, reoperation, renal failure, hepatic dysfunction, stroke, and right ventricular failure, were similar between the groups (all, p > .05). Unadjusted survival was comparable between the groups at 30-days, 90-days, 1-year, and 2-year following LVAD implantation (all, p > .05). In addition, hepatic steatosis did not impact risk-adjusted overall mortality when modeled as a categorical variable (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.46-1.13; p = .15). CONCLUSIONS This study demonstrates that the presence of preoperative hepatic steatosis on imaging is not predictive of increased morbidity or mortality following LVAD implantation. Despite the association with obesity, metabolic diseases, and heart failure, hepatic steatosis on imaging appears to have a limited role in patient selection or prognostication in LVAD patients.
Collapse
Affiliation(s)
- Yeahwa Hong
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Keith Dufendach
- Division of Cardiac Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Yisi Wang
- Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Floyd Thoma
- Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Arman Kilic
- Division of Cardiac Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.,Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
12
|
Tanpowpong N, Panichyawat S. Comparison of sonographic hepatorenal ratio and the degree of hepatic steatosis in magnetic resonance imaging-proton density fat fraction. J Ultrason 2020; 20:e169-e175. [PMID: 33365152 PMCID: PMC7705486 DOI: 10.15557/jou.2020.0028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 07/13/2020] [Indexed: 12/21/2022] Open
Abstract
Objectives: Conventional ultrasonography can provide only semi-quantitative assessment of hepatic steatosis. The aim of this study was to assess sonographic hepatorenal ratio to quantify the severity of fatty liver. Methods: We performed a retrospective analysis of 179 patients with various liver diseases who underwent abdominal magnetic resonance imaging and ultrasonography on the same day. The hepatorenal ratio was calculated by the ratio between the mean echo intensity in regions of interests of the liver and regions of interests of the right renal cortex. Magnetic resonance imaging-proton density fat fraction was used as standard reference for steatosis grading. The effect of fibrosis measured by magnetic resonance elastography on the degree of correlation was also assessed. Results: The hepatorenal ratio was highly correlated with magnetic resonance imaging-proton density fat fraction (Spearman’s coefficient = 0.83) (p <0.001). High correlation of hepatorenal ratio with magnetic resonance imaging-proton density fat fraction was observed in patients with less than stage 2 fibrosis (p <0.001), whereas moderate correlation of hepatorenal ratio with magnetic resonance imaging-proton density fat fraction was found in patients with ≥ stage 2 fibrosis or higher (p <0.001). The hepatorenal ratio cutoff point for prediction of grade 1 hepatic steatosis was 1.18 with sensitivity of 90.0% and specificity of 80.0%. The hepatorenal ratio cutoff point for prediction of grade 2 and grade 3 hepatic steatosis was 1.55 and 1.60, respectively, with sensitivity greater than 90% and specificity greater than 80%. Conclusions: The hepatorenal ratio could become an effective quantitative tool for hepatic steatosis alternative to magnetic resonance imaging-proton density fat fraction. Application should be careful in the group of patients with stage 2 liver fibrosis or higher.
Collapse
Affiliation(s)
- Natthaporn Tanpowpong
- Diagnostic Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sineenart Panichyawat
- Diagnostic Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
13
|
Shabangu CS, Huang JF, Hsiao HH, Yu ML, Chuang WL, Wang SC. Liquid Biopsy for the Diagnosis of Viral Hepatitis, Fatty Liver Steatosis, and Alcoholic Liver Diseases. Int J Mol Sci 2020; 21:3732. [PMID: 32466319 PMCID: PMC7279404 DOI: 10.3390/ijms21103732] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/18/2020] [Accepted: 05/19/2020] [Indexed: 02/07/2023] Open
Abstract
During the progression from hepatitis to fibrosis, cirrhosis, and liver failure, the accumulation of stressed/damaged hepatocyte elements associated with liver inflammation is critical. The causes of hepatocyte injuries include viral hepatitis infections, alcoholic hepatitis, and non-alcoholic fatty liver disease. Hepatocyte-derived extracellular vesicles (Hep-EVs) released from stressed/damaged hepatocytes are partly responsible for liver disease progression and liver damage because they activate non-parenchymal cells and infiltrate inflammatory cells within the liver, which are in turn are an important source of EVs. This cell-to-cell signaling is prevalent during inflammation in many liver diseases. Accordingly, special emphasis should be placed on liquid biopsy methods for the long-term monitoring of chronic liver diseases. In the present review, we have highlighted various aspects of current liquid biopsy research into chronic liver diseases. We have also reviewed recent progress on liquid biopsies that focus on cell-free DNA (cfDNA), long non-coding RNA (lncRNA), and the proteins in EVs as potential diagnostic tools and novel therapeutic targets in patients with viral hepatitis, fatty liver steatosis, and alcoholic liver diseases.
Collapse
Affiliation(s)
- Ciniso Sylvester Shabangu
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (J.-F.H.); (M.-L.Y.)
| | - Jee-Fu Huang
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (J.-F.H.); (M.-L.Y.)
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hui-Hua Hsiao
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Ming-Lung Yu
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (J.-F.H.); (M.-L.Y.)
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (J.-F.H.); (M.-L.Y.)
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| |
Collapse
|
|
14
|
Morihara D, Ko YL, Shibata K, Yamauchi R, Fukuda H, Tsuchiya N, Fukunaga A, Kunimoto H, Iwashita H, Takata K, Tanaka T, Sakurai K, Inomata S, Yokoyama K, Nishizawa S, Takeyama Y, Irie M, Shakado S, Sohda T, Sakisaka S. IL28B gene polymorphism is correlated with changes in low-density lipoprotein cholesterol levels after clearance of hepatitis C virus using direct-acting antiviral treatment. J Gastroenterol Hepatol 2019; 34:2019-2027. [PMID: 31144350 DOI: 10.1111/jgh.14741] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/08/2019] [Accepted: 05/23/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment. METHODS A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2 years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥ 140 mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics. RESULTS A total of 63, 3, and 55 patients were administered daclatasvir + asunaprevir, ombitasvir + paritaprevir + ritonavir, and ledipasvir + sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3 ± 27.0 and 9.6 ± 27.3 mg/dL; P < 0.001). In addition, IL28B TG/GG was an independent risk factor for hyper-LDL cholesterolemia (odds ratio: 8.47; P < 0.001). CONCLUSIONS An IL28B polymorphism is associated with ΔLDL-C and hyper-LDL cholesterolemia after achieving SVR. Thus, lipid markers should be carefully monitored in patients who achieve SVR with DAA.
Collapse
Affiliation(s)
- Daisuke Morihara
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Yi-Ling Ko
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Kumiko Shibata
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hiromi Fukuda
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Naoaki Tsuchiya
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | | | - Hideo Kunimoto
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hideyuki Iwashita
- Department of Gastroenterology, Fukuoka University Nishijin Hospital, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | | | - Shinjiro Inomata
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Shinya Nishizawa
- Department of Hepatology, Japanese Red Cross Hospital, Fukuoka, Japan
| | - Yasuaki Takeyama
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Makoto Irie
- Department of Gastroenterology, Fukuoka University Nishijin Hospital, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Tetsuro Sohda
- Department of Hepatology, Japanese Red Cross Hospital, Fukuoka, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| |
Collapse
|
|
15
|
Rosso C, Caviglia GP, Ciruolo M, Ciancio A, Younes R, Olivero A, Giordanino C, Troshina G, Abate ML, Rizzetto M, Pellicano R, Saracco GM, Bugianesi E, Smedile A. Clinical outcomes in chronic hepatitis C long-term responders to pre-direct antiviral agents: a single-center retrospective study. Minerva Med 2019; 110:401-409. [PMID: 31081312 DOI: 10.23736/s0026-4806.19.06108-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Obesity, type 2 diabetes (T2D), dyslipidemia, arterial hypertension as well as hepatic steatosis (HS) are common conditions that can affect clinical outcomes of patients with chronic hepatitis C (CHC) who achieved sustained virologic response (SVR). The aim of this study was to assess the impact of metabolic cofactors on the occurrence of clinical events during follow-up (FU) in a group of CHC long-term responders (LTRs) to interferon- (IFN) based therapy. METHODS A total of 5172 medical records of CHC patients enrolled from 1990 to 2011 were examined; 1034 of 5172 (20%) patients were treated with IFN-based therapy and 382 of 1034 (37%) of them achieved SVR. A total of 188 (49%) LTRs underwent liver biopsy before antiviral treatment. Data on liver and cardiometabolic events such as cirrhosis and its complications, hepatocellular carcinoma, coronary artery disease, arterial hypertension, impaired fasting glucose (IFG)/type 2 diabetes (T2D) and dyslipidemia, were collected over time. RESULTS The mean age of the whole cohort was 46±12 years and 114/188 (61%) patients were males. HS was found in 82 of 188 (43.6%) patients and most of them were infected by HCV genotype 3a. The prevalence of obesity, IFG/T2D, dyslipidemia and arterial hypertension was 4.3%, 6.9%, 37.2%, and 5.9%, and was similarly distributed among patients with and without HS. Cirrhosis was histologically diagnosed in 18 of 188 (9.6%) patients. After a median follow-up of 11 years (range 3-21 years), the cumulative incidence of cardiovascular events, IFG/T2D and dyslipidemia was higher in CHC-LTRs who had HS at baseline compared to those without HS (1.2%, 2.3%, and 3.0% vs. 0.4%, 0.8%, and 2.5%, respectively). At multivariable Cox regression analysis, HS was significantly associated to the development of cardiovascular events and IFG/T2D (HR=5.2, 95% CI: 1.3-20.7, P=0.019, and HR=2.6, 95% CI: 1.1-6.2, P=0.027, respectively). CONCLUSIONS In CHC-LTRs, HS at baseline may predispose to the development of cardiovascular events and T2D during follow-up emphasizing the importance of an accurate counseling in order to prevent extra-hepatic complications.
Collapse
Affiliation(s)
- Chiara Rosso
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy -
| | - Gian Paolo Caviglia
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Michela Ciruolo
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alessia Ciancio
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Ramy Younes
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonella Olivero
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Giordanino
- Department of Gastro-Hepatology, Città della Salute e della Scienza University Hospital, Turin, Italy
| | - Giulia Troshina
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Maria Lorena Abate
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Mario Rizzetto
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Rinaldo Pellicano
- Department of Gastro-Hepatology, Città della Salute e della Scienza University Hospital, Turin, Italy
| | - Giorgio M Saracco
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonina Smedile
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| |
Collapse
|
|
16
|
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.
Collapse
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
| |
Collapse
|
|
17
|
Nordmann S, Vilotitch A, Roux P, Esterle L, Spire B, Marcellin F, Salmon-Ceron D, Dabis F, Chas J, Rey D, Wittkop L, Sogni P, Carrieri P. Daily cannabis and reduced risk of steatosis in human immunodeficiency virus and hepatitis C virus-co-infected patients (ANRS CO13-HEPAVIH). J Viral Hepat 2018; 25:171-179. [PMID: 28984055 DOI: 10.1111/jvh.12797] [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] [Received: 04/28/2017] [Accepted: 09/13/2017] [Indexed: 12/27/2022]
Abstract
Liver steatosis is common in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-co-infected patients. Some recent studies have found that cannabis use is negatively associated with insulin resistance in the general population and in HIV-HCV-co-infected patients. Given the causal link between insulin resistance and steatosis, we hypothesized that cannabis use has a positive impact on steatosis. Therefore, we aimed to study whether cannabis use in this population was associated with a reduced risk of steatosis, measured by ultrasound examination. ANRS CO13-HEPAVIH is a French nationwide multicentre cohort of HIV-HCV-co-infected patients. Medical and socio-behavioural data from clinical follow-up visits and annual self-administered questionnaires were prospectively collected. A cross-sectional analysis was conducted using data from the first visit where both ultrasound examination data for steatosis (positive or negative diagnosis) and data on cannabis use were available. A logistic regression model was used to evaluate the association between cannabis use and steatosis. Among study sample patients (n = 838), 40.1% had steatosis. Fourteen per cent reported daily cannabis use, 11.7% regular use and 74.7% no use or occasional use ("never or sometimes"). Daily cannabis use was independently associated with a reduced prevalence of steatosis (adjusted odds ratio [95% CI] = 0.64 [0.42;0.99]; P = .046), after adjusting for body mass index, hazardous alcohol consumption and current or lifetime use of lamivudine/zidovudine. Daily cannabis use may be a protective factor against steatosis in HIV-HCV-co-infected patients. These findings confirm the need for a clinical evaluation of cannabis-based pharmacotherapies in this population. Eudract.ema.europa.eu number, DGS050367.
Collapse
Affiliation(s)
- S Nordmann
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.,ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - A Vilotitch
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.,ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - P Roux
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.,ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - L Esterle
- Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, UMR 1219, Team MORPH3EUS, Bordeaux, France
| | - B Spire
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.,ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - F Marcellin
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.,ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - D Salmon-Ceron
- Université Paris-Sud et Université Paris Descartes, UMR-S0669, Paris, France.,Service Maladies infectieuses et tropicales, AP-HP, Hôpital Cochin Port-Royal, Paris, France
| | - F Dabis
- Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, UMR 1219, Team MORPH3EUS, Bordeaux, France.,CHU de Bordeaux, Pole de sante publique, Service d'Information Médicale, Bordeaux, France
| | - J Chas
- Infectious Diseases Department, Hopital Tenon-APHP, Paris, France
| | - D Rey
- Le Trait d'Union, centre de Soins de l'Infection par le VIH, VHC, CHU de Strasbourg, Strasbourg, France
| | - L Wittkop
- Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, UMR 1219, Team MORPH3EUS, Bordeaux, France.,CHU de Bordeaux, Pole de sante publique, Service d'Information Médicale, Bordeaux, France
| | - P Sogni
- Service Maladies infectieuses et tropicales, AP-HP, Hôpital Cochin Port-Royal, Paris, France.,INSERM U-1223-Institut Pasteur, Paris, France.,Université Paris Descartes, Paris, France.,Service Service d'Hépatologie, AP-HP, Hôpital Cochin, Paris, France
| | - P Carrieri
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.,ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | | |
Collapse
|
|
18
|
Rastogi A, Shasthry SM, Agarwal A, Bihari C, Jain P, Jindal A, Sarin S. Non-alcoholic fatty liver disease - histological scoring systems: a large cohort single-center, evaluation study. APMIS 2017; 125:962-973. [PMID: 29076589 DOI: 10.1111/apm.12742] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 06/19/2017] [Indexed: 12/20/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease. Till date, liver biopsy remains the gold standard for identification and quantification of the wide histological spectra of NAFLD. Histological scorings are very useful and widely applied for the diagnosis and management in clinical trials and follow-up studies of non-alcoholic steatohepatitis (NASH). However, in view of scarce published literature, there is a need to evaluate them in large cohort of NAFLD. This study was aimed to evaluate the two histological scoring systems (NAS-CRN, SAF) in the diagnosis of NAFLD and to assess the role of histological characteristics as injury markers in NAFLD. Retrospective histological study of liver biopsies of 1000 patients diagnosed as NAFLD, between 2010 and 2016, was conducted. Histopathologic evaluation and semiquantiative scoring based on NAS-CRN and SAF algorithm and their correlation with serum aminotransferase and fibrosis were performed. Liver biopsies were classified according to the NAS-CRN scoring, as NAS <3 (not NASH) in 72 (7.2%), NAS 3-4 (borderline NASH) in 310 (31%), and NAS ≥5 (definite NASH) in 618 (61.8%), and SAF classified 117 (11.7%) not NASH and 883 (88.3%) definite NASH. There was excellent concordance for definite NASH and not NASH; however, 88.06% of borderline NASH was classified as NASH by SAF. 76.39% by NAS and 78.63% by SAF algorithm who were diagnosed as not NASH showed the presence of fibrosis; however, higher stages of fibrosis were significantly more prevalent in definite NASH, excluding burnt-out cirrhosis. Serum ALT was significantly associated with increasing stages of fibrosis (p < 0.001) and the three categories (not NASH, borderline NASH, and definite NASH) when classified as with/without fibrosis (p < 0.001). Steatosis of higher grades, more ballooned cells, and more foci of Lobular Inflammation were found in significantly higher proportion of patients with NASH (p < 0.001), with higher fibrosis stages (p < 0.001) and higher serum ALT levels (p < 0.001). NAFLD classifications based on histological scoring NAS-CRN and SAF algorithm are concordant for the category of definite NASH and not NASH, while borderline NASH shows discrepant interpretation. There was highly significant correlation between the NAS and SAF categories with high grades of histological characteristics, with serum ALT and with higher stages of fibrosis. Exclusion of fibrosis is a limitation with both scores.
Collapse
Affiliation(s)
- Archana Rastogi
- Department of Pathology, Institute of Liver & Biliary Sciences, Delhi, India
| | | | - Ayushi Agarwal
- Department of PDCC-Pathology, Institute of Liver & Biliary Sciences, Delhi, India
| | - Chhagan Bihari
- Department of Pathology, Institute of Liver & Biliary Sciences, Delhi, India
| | - Priyanka Jain
- Department of Biostatistics, Institute of Liver & Biliary Sciences, Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver & Biliary Sciences, Delhi, India
| | - Shiv Sarin
- Department of Hepatology, Institute of Liver & Biliary Sciences, Delhi, India
| |
Collapse
|
|
19
|
Recent Advances in the Pathogenesis of Hepatitis C Virus-Related Non-Alcoholic Fatty Liver Disease and Its Impact on Patients Cured of Hepatitis C. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11901-017-0370-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
|
|
20
|
Hepatic Inflammation May Influence Liver Stiffness Measurements by Transient Elastography in Children and Young Adults. J Pediatr Gastroenterol Nutr 2017; 64:512-517. [PMID: 27540711 PMCID: PMC5316380 DOI: 10.1097/mpg.0000000000001376] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Transient elastography (TE) measures liver stiffness to assess fibrosis. Studies in adults have shown that inflammation increases stiffness, leading to an overestimation of fibrosis. We investigated the contribution of inflammation to liver stiffness measurements (LSMs) in children/young adults. METHODS This was a cohort analysis of children/young adults who underwent TE within 1 year of liver biopsy. Alanine aminotransferase (ALT) was obtained within 30 days of the biopsy and LSM. Fibrosis was assessed by METAVIR stage and inflammation by ALT and Ishak score. Data were stratified into METAVIR F0-F2 versus F3-F4. Change between ALT and LSM over time was also assessed. RESULTS A total of 154 patients (50% male patients) ages 3 weeks to 24 years (18% <3 years) were studied. Diagnoses included autoimmune (N = 38, 25%), viral (N = 25, 16%), cholestasis (N = 17, 11%), fatty liver (N = 9, 6%), biliary atresia (N = 8, 5%), metabolic (N = 5, 3%), allograft rejection (N = 4, 3%), and other (N = 48, 31%). Thirty-four percent of patients had F3-F4. In patients with F0-F2, the proportion of those with LSM >8.6 kPa increased with increasing ALT (P = 0.002). In patients with F3-F4, there was no association between ALT and LSM (P = 0.17). A correlation between change in ALT and LSM was observed in patients with no/minimal fibrosis and inflammatory liver diseases (r = 0.33). CONCLUSIONS In children with no/minimal hepatic fibrosis and inflammatory liver disease, high ALT values are associated with LSM in the range typical of advanced fibrosis. However, with more advanced fibrosis, inflammation does not appear to contribute to LSM. Caution must be taken when interpreting LSM for assessing fibrosis severity in the setting of inflammation.
Collapse
|
|
21
|
Shiffman ML, Gunn NT. Impact of hepatitis C virus therapy on metabolism and public health. Liver Int 2017; 37 Suppl 1:13-18. [PMID: 28052632 DOI: 10.1111/liv.13282] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 10/20/2016] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C virus (HCV) is associated with insulin resistance (IR) and leads to type 2 diabetes mellitus (T2DM) and hepatic steatosis in many patients. These metabolic complications of HCV have been shown to accelerate the progression of fibrosis to cirrhosis and increase the risk of hepatocellular carcinoma. The metabolic syndrome is a common disorder that also includes IR, T2DM and hepatic steatosis. Approximately 20%-30% of patients with chronic HCV also have co-existent metabolic syndrome. The cause of steatosis in patients with the features of both the metabolic syndrome and chronic HCV is sometime difficult to determine. Patients with metabolic syndrome and chronic HCV are also at risk of developing renal, cardiovascular and cerebrovascular disease. Recent data suggest that HCV is an independent risk factor for renal, coronary and cerebral vascular disease, and may increase mortality associated with these disorders. The treatment of HCV can now result in a sustained virological response and cure nearly all patients with chronic HCV. The eradication of HCV reduces the risk of developing IR and T2DM, improves IR and 2TDM, reduces the risk of developing chronic kidney disease, end-stage renal disease, acute cardiac syndrome and stroke in patients with 2TDM. Thus, treatment of chronic HCV can provide a significant public health benefit, but only if all patients with chronic HCV are identified and universally treated.
Collapse
Affiliation(s)
- Mitchell L Shiffman
- Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, VA, USA
| | - Nadege T Gunn
- Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, VA, USA
| |
Collapse
|
|
22
|
Cardoso AC, Beaugrand M, de Ledinghen V, Douvin C, Poupon R, Trinchet JC, Ziol M, Bedossa P, Marcellin P. Diagnostic performance of controlled attenuation parameter for predicting steatosis grade in chronic hepatitis B. Ann Hepatol 2016; 14:826-36. [PMID: 26436354 DOI: 10.5604/16652681.1171762] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND & AIMS A novel controlled attenuation parameter (CAP) using the signals acquired by the FibroScan® has been developed as a method for evaluating steatosis. The aim of this study is to assess the performance of the CAP for the detection and quantification of steatosis in patients with chronic hepatitis B (CHB). MATERIAL AND METHODS 136 subjects with CHB underwent liver biopsy and FibroScan® within 60 days. CAP was evaluated retrospectively using raw FibroScan® data. Steatosis was graded as follows: S0 (steatosis < 10% of hepatocytes), S1 (10 to < 30%), S2 (30 to < 60%) or S3 (≥ 60%). Performance was evaluated by area under the receiver operating characteristic (AUROC) curve. RESULTS Proportions of each steatosis grade (S0-S3) were 78, 10, 9 and 3%, respectively. Using univariate analysis, liver stiffness measurement (LMS) significantly correlated with fibrosis (τ = 0.43; P < 10-10), sex, necro-inflammatory activity, steatosis, age, NASH, and perisinusoidal fibrosis, and with liver fibrosis (P < 10-8) and perisinusoidal fibrosis (P = 0.008) using multivariate analysis. CAP correlated with steatosis (τ = 0.38, P < 10-7), body mass index, NASH, fibrosis and perisinusoidal fibrosis using univariate analysis, but only steatosis (P < 10-10) and perisinusoidal fibrosis (P = 0.002) using multivariate analysis. AUROCs for LSM were: 0.77 (0.69-0.85), 0.87 (0.80-0.95), and 0.93 (0.83-1.00), respectively, for fibrosis stages F ≥ 2, F ≥ 3 and F = 4. AUROCs for CAP were: 0.82 (0.73-0.92), 0.82 (0.69-0.95), and 0.97 (0.84-1.00) for ≥ S1, ≥ S2 and S3 steatosis, respectively. CONCLUSIONS In conclusión CAP is a novel, accurate non-invasive tool and may be suitable for detecting and quantifying steatosis in CHB patients.
Collapse
Affiliation(s)
- Ana C Cardoso
- Department of Hepatology and INSERM U773-CRB3, Hôpital Beaujon, APHP, University of Paris 7, Clichy, France
| | | | - Victor de Ledinghen
- Department of Hepatology, Hôpital Haut-Leveque, CHU Bordeaux Pessac, France and INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
| | | | - Raoul Poupon
- Department of Hepatology, Hôpital Saint Antoine, Paris, France
| | | | - Marianne Ziol
- Department of Anatomy and Pathology, Hospital Group Paris-Seine-Saint Denis, Hôpital Jean Verdier, AP-PH, Bondy, France and Paris 13 University, Sorbonne Paris Cité, UFR SMBH, Bobigny, France
| | - Pierre Bedossa
- Department of Anatomy Pathology and INSERM U773-CRB3, Hôpital Beaujon, Clichy, France
| | - Patrick Marcellin
- Department of Hepatology and INSERM U773-CRB3, Hôpital Beaujon, APHP, University of Paris 7, Clichy, France
| |
Collapse
|
|
23
|
Adinolfi LE, Rinaldi L, Guerrera B, Restivo L, Marrone A, Giordano M, Zampino R. NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations. Int J Mol Sci 2016; 17:ijms17060803. [PMID: 27231906 PMCID: PMC4926337 DOI: 10.3390/ijms17060803] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/15/2016] [Accepted: 05/19/2016] [Indexed: 02/06/2023] Open
Abstract
The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%–10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely “viral steatosis” and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host’s genetic background predisposes him or her to the development of steatosis. HCV’s impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related “metabolic steatosis” impairs the response rate to interferon-based treatment, whereas it seems that “viral steatosis” may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases.
Collapse
Affiliation(s)
- Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Barbara Guerrera
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Luciano Restivo
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Mauro Giordano
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| |
Collapse
|
|
24
|
Kralj D, Jukić LV, Stojsavljević S, Duvnjak M, Smolić M, Čurčić IB. Hepatitis C Virus, Insulin Resistance, and Steatosis. J Clin Transl Hepatol 2016; 4:66-75. [PMID: 27047774 PMCID: PMC4807145 DOI: 10.14218/jcth.2015.00051] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 02/15/2016] [Accepted: 02/16/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality.
Collapse
Affiliation(s)
- Dominik Kralj
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Lucija Virović Jukić
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Sanja Stojsavljević
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Marko Duvnjak
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Martina Smolić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Osijek, Croatia
| | - Ines Bilić Čurčić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Department of Endocrinology and metabolism disorders, University Hospital Center, Osijek, Osijek, Croatia
| |
Collapse
|
|
25
|
Petta S, Valenti L, Bugianesi E, Targher G, Bellentani S, Bonino F. A "systems medicine" approach to the study of non-alcoholic fatty liver disease. Dig Liver Dis 2016; 48:333-342. [PMID: 26698409 DOI: 10.1016/j.dld.2015.10.027] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Revised: 10/18/2015] [Accepted: 10/31/2015] [Indexed: 02/07/2023]
Abstract
The prevalence of fatty liver (steatosis) in the general population is rapidly increasing worldwide. The progress of knowledge in the physiopathology of fatty liver is based on the systems biology approach to studying the complex interactions among different physiological systems. Similarly, translational and clinical research should address the complex interplay between these systems impacting on fatty liver. The clinical needs drive the applications of systems medicine to re-define clinical phenotypes, assessing the multiple nature of disease susceptibility and progression (e.g. the definition of risk, prognosis, diagnosis criteria, and new endpoints of clinical trials). Based on this premise and in light of recent findings, the complex mechanisms involved in the pathology of fatty liver and their impact on the short- and long-term clinical outcomes of cardiovascular, metabolic liver diseases associated with steatosis are presented in this review using a new "systems medicine" approach. A new data set is proposed for studying the impairments of different physiological systems that have an impact on fatty liver in different subsets of subjects and patients.
Collapse
Affiliation(s)
- Salvatore Petta
- Section of Gastroenterology, Di.Bi.M.I.S Policlinico Paolo Giaccone Hospital, University of Palermo, Italy
| | - Luca Valenti
- Internal Medicine, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Italy
| | - Elisabetta Bugianesi
- Gastroenterology and Hepatology, Department of Medical Sciences, Città della Salute e della Scienza di Torino Hospital, University of Turin, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Italy
| | - Stefano Bellentani
- Shrewsbury and Telford NHS Trust, Department of Gastroenterology, Shrewsbury, UK; Fondazione Italiana Fegato, Bassovizza, Trieste, Italy
| | - Ferruccio Bonino
- General Medicine 2, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Italy.
| |
Collapse
|
|
26
|
Tamaki N, Kurosaki M, Higuchi M, Takada H, Nakakuki N, Yasui Y, Suzuki S, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Ogawa S, Tanaka Y, Asahina Y, Izumi N. Genetic Polymorphisms of IL28B and PNPLA3 Are Predictive for HCV Related Rapid Fibrosis Progression and Identify Patients Who Require Urgent Antiviral Treatment with New Regimens. PLoS One 2015; 10:e0137351. [PMID: 26352693 PMCID: PMC4564246 DOI: 10.1371/journal.pone.0137351] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 08/15/2015] [Indexed: 12/12/2022] Open
Abstract
The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment.
Collapse
Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Natsuko Nakakuki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shoko Suzuki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shintaro Ogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan
| | - Yasuhiro Asahina
- Department of Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| |
Collapse
|
|
27
|
Simon TG, Butt AA. Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes. World J Gastroenterol 2015; 21:8293-8303. [PMID: 26217081 PMCID: PMC4507099 DOI: 10.3748/wjg.v21.i27.8293] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 04/17/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.
Collapse
|
|
28
|
Uraki S, Tameda M, Sugimoto K, Shiraki K, Takei Y, Nobori T, Ito M. Substitution in Amino Acid 70 of Hepatitis C Virus Core Protein Changes the Adipokine Profile via Toll-Like Receptor 2/4 Signaling. PLoS One 2015; 10:e0131346. [PMID: 26121241 PMCID: PMC4487891 DOI: 10.1371/journal.pone.0131346] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 06/01/2015] [Indexed: 12/28/2022] Open
Abstract
Background & Aims It has been suggested that amino acid (aa) substitution at position 70 from arginine (70R) to glutamine (70Q) in the genotype 1b hepatitis C virus (HCV) core protein is associated with insulin resistance and worse prognosis. However, the precise mechanism is still unclear. The aim of this study was to investigate the impact of the substitution at position 70 in HCV core protein on adipokine production by murine and human adipocytes. Methods The influence of treatment with HCV core protein (70R or 70Q) on adipokine production by both 3T3-L1 and human adipocytes were examined with real-time PCR and enzyme-linked immunosorbent assay (ELISA), and triglyceride content was also analyzed. The effects of toll-like receptor (TLR)2/4 inhibition on IL-6 production by 3T3-L1 induced by HCV core protein were examined. Results IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes. IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%. Conclusions Our study suggests that extracellular HCV core protein with substitution at position 70 enhanced IL-6 production and reduced adiponectin production from visceral adipose tissue, which can cause insulin resistance, hepatic steatosis, and ultimately development of HCC.
Collapse
Affiliation(s)
- Satoko Uraki
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan
| | - Masahiko Tameda
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan
- Department of Molecular and Laboratory Medicine, Mie University School of Medicine, 2–174 Edobashi, Tsu, Mie, 514–8507, Japan
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Japan
| | - Kazushi Sugimoto
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan
- Department of Molecular and Laboratory Medicine, Mie University School of Medicine, 2–174 Edobashi, Tsu, Mie, 514–8507, Japan
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Japan
- * E-mail:
| | - Katsuya Shiraki
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Japan
| | - Tsutomu Nobori
- Department of Molecular and Laboratory Medicine, Mie University School of Medicine, 2–174 Edobashi, Tsu, Mie, 514–8507, Japan
| | - Masaaki Ito
- First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan
| |
Collapse
|
|
29
|
Diagnostic value of MRI proton density fat fraction for assessing liver steatosis in chronic viral C hepatitis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:758164. [PMID: 25866807 PMCID: PMC4383409 DOI: 10.1155/2015/758164] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 10/08/2014] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To assess the diagnostic performance of a T1-independent, T2*-corrected multiecho magnetic resonance imaging (MRI) technique for the quantification of hepatic steatosis in a cohort of patients affected by chronic viral C hepatitis, using liver biopsy as gold standard. METHODS Eighty-one untreated patients with chronic viral C hepatitis were prospectively enrolled. All included patients underwent MRI, transient elastography, and liver biopsy within a time interval <10 days. RESULTS Our cohort of 77 patients included 43/77 (55.8%) males and 34/77 (44.2%) females with a mean age of 51.31 ± 11.27 (18-81) years. The median MRI PDFF showed a strong correlation with the histological fat fraction (FF) (r = 0.754, 95% CI 0.637 to 0.836, P < 0.0001), and the correlation was influenced by neither the liver stiffness nor the T2* decay. The median MRI PDFF result was significantly lower in the F4 subgroup (P < 0.05). The diagnostic accuracy of MRI PDFF evaluated by AUC-ROC analysis was 0.926 (95% CI 0.843 to 0.973) for S ≥ 1 and 0.929 (95% CI 0.847 to 0.975) for S = 2. CONCLUSIONS Our MRI technique of PDFF estimation allowed discriminating with a good diagnostic accuracy between different grades of hepatic steatosis.
Collapse
|
|
30
|
Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol 2014; 61:S69-78. [PMID: 25443347 DOI: 10.1016/j.jhep.2014.08.003] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/16/2014] [Accepted: 08/01/2014] [Indexed: 12/16/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed.
Collapse
Affiliation(s)
- Francesco Negro
- Divisions of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
| |
Collapse
|
|
31
|
Konerman MA, Yapali S, Lok AS. Systematic review: identifying patients with chronic hepatitis C in need of early treatment and intensive monitoring--predictors and predictive models of disease progression. Aliment Pharmacol Ther 2014; 40:863-79. [PMID: 25164152 PMCID: PMC4167918 DOI: 10.1111/apt.12921] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2014] [Revised: 07/07/2014] [Accepted: 07/26/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Advances in hepatitis C therapies have led to increasing numbers of patients seeking treatment. As a result, logistical and financial concerns regarding how treatment can be provided to all patients with chronic hepatitis C (CHC) have emerged. AIM To evaluate predictors and predictive models of histological progression and clinical outcomes for patients with CHC. METHODS MEDLINE via PubMed, EMBASE, Web of Science and Scopus were searched for studies published between January 2003 and June 2014. Two authors independently reviewed articles to select eligible studies and performed data abstraction. RESULTS Twenty-nine studies representing 5817 patients from 20 unique cohorts were included. The outcome incidence rates were widely variable: 16-61% during median follow-up of 2.5-10 years for fibrosis progression; 13-40% over 2.3-14.4 years for hepatic decompensation and 8-47% over 3.9-14.4 years for overall mortality. Multivariate analyses showed that baseline steatosis and baseline fibrosis score were the most consistent predictors of fibrosis progression (significant in 6/21 and 5/21, studies, respectively) while baseline platelet count (significant in 6/13 studies), aspartate and alanine aminotransferase (AST/ALT) ratio, albumin, bilirubin and age (each significant in 4/13 studies) were the most consistent predictors of clinical outcomes. Five studies developed predictive models but none were externally validated. CONCLUSIONS Our review identified the variables that most consistently predict outcomes of patients with chronic hepatitis C allowing the application of risk based approaches to identify patients in need of early treatment and intensive monitoring. This approach maximises effective use of resources and costly new direct-acting anti-viral agents.
Collapse
Affiliation(s)
- M A Konerman
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | | | | |
Collapse
|
|
32
|
Li JF, Qu F, Zheng SJ, Wu HL, Liu M, Liu S, Ren Y, Ren F, Chen Y, Duan ZP, Zhang JL. Elevated plasma sphingomyelin (d18:1/22:0) is closely related to hepatic steatosis in patients with chronic hepatitis C virus infection. Eur J Clin Microbiol Infect Dis 2014; 33:1725-1732. [PMID: 24810965 DOI: 10.1007/s10096-014-2123-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 04/09/2014] [Indexed: 12/20/2022]
Abstract
Hepatic steatosis affects disease progression in patients with chronic hepatitis C virus (HCV) infection. We investigated the plasma sphingolipid profile in patients with chronic hepatitis C (CHC) and whether there was an association between HCV-related steatosis and plasma sphingolipids. We used high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze plasma sphingolipids in 120 interferon-naïve, non-diabetic, and non-obese CHC patients. Hepatic steatosis was defined as ≥5 % hepatocytes with fat based on histopathological analysis. Blood biochemical indicators and HCV load and genotype were also determined. Thirty-six (30.0 %) of 120 patients presented with hepatic steatosis Grades 1-3. Forty-four plasma sphingolipids were detected. Plasma sphingomyelin (SM) (d18:1/22:0) and ceramide (Cer) (d18:1/24:0)-1-P correlated with steatosis grade (r = 0.22, p = 0.015; r = -0.23, p = 0.012, respectively). SM (d18:1/22:0) [odds ratio (OR) = 1.12] and Cer (d18:1/24:0)-1-P (OR = 0.88) were independent factors for the presence of hepatic steatosis in CHC patients. The area under the curve (AUC) of SM (d18:1/22:0) and Cer (d18:1/24:0)-1-P was 0.637 and 0.638, respectively, to identify the presence of steatosis. Further analysis for genotype 2 CHC showed that only SM (d18:1/22:0) was independently linked to steatosis (OR = 1.21). The AUC of SM (d18:1/22:0) to identify hepatic steatosis in genotype 2 CHC was 0.726. Its sensitivity and negative predictive value reached 0.813 and 0.886, respectively. This study suggested that altered plasma SM (d18:1/22:0) was closely related to hepatic steatosis in chronic HCV infection, especially with genotype 2. Experimental studies are needed to determine further the underlying mechanisms responsible for these associations.
Collapse
Affiliation(s)
- J-F Li
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, 8 Xitoutiao, Youwai Street, Beijing, 100069, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Flores-Contreras L, Sandoval-Rodríguez AS, Mena-Enriquez MG, Lucano-Landeros S, Arellano-Olivera I, Álvarez-Álvarez A, Sanchez-Parada MG, Armendáriz-Borunda J. Treatment with pirfenidone for two years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C. BMC Gastroenterol 2014; 14:131. [PMID: 25064094 PMCID: PMC4236537 DOI: 10.1186/1471-230x-14-131] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 07/14/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The aim of this study was to assess whether two-years treatment with Pirfenidone influences necroinflammation, fibrosis and steatosis, serum levels of TGF-β1, IL-6, TNF-α and CB1 and CB2 gene expression, in patients with chronic hepatitis C (CHC). METHODS Twenty-eight patients out of 34 with CHC virus infection were enrolled in the study and received Pirfenidone (1200 mg/day) for 24 months. Six patients dropped out after 12 months of PFD. Liver biopsies and serum samples were obtained at the beginning and end of treatment. Modified HAI was calculated. CB1 and CB2 gene expression was correlated with fibrosis progression alongside with necroinflammation and steatosis. TGF-β1, IL-6, TNF-α and liver transaminases were measured in serum at two-months intervals. HCV genotype and viral load were also assessed. Quality of life was evaluated by SF36 questionnaires and the prognosis of disease was assessed with Child-Pugh score. The Wilcoxon test matched-pair signed ranks were used to analyze the outcomes. RESULTS Intention to treat analyses were performed for biochemistry and clinical parameters. At the end of treatment, necroinflammation grading was reduced in an average of 3.2 points in 82% of patients (p < 0.05) and Ishak's fibrosis stage decreased 2-points average in 67% of patients (p < 0.05). Steatosis decreased in 61% of patients. IL-6 and TGF-β1 serum levels decreased significantly in 93% and 67% of patients (p < 0.05), respectively, while TNF-α diminished in 47% of patients. ALT and AST tended to normalize in 81% of patients; CB2 mRNA levels increased in 86% and CB1 expression diminished in 29% of patients. Both, quality of life and Child-Pugh score improvements were reported in all patients. CONCLUSIONS Pirfenidone for two years benefits CHC patients and improves inflammation, fibrosis and steatosis in higher number of patients as previously shown for 12-months treatment with PFD. Additionally, PFD improved TGFβ1 and IL-6 levels and diminished liver expression of anti-fibrogenic receptor CB2. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02161952. Protocol Registration Date: 06/11/2014.
Collapse
Affiliation(s)
- Lucia Flores-Contreras
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Ana S Sandoval-Rodríguez
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Mayra G Mena-Enriquez
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Silvia Lucano-Landeros
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Inmaculada Arellano-Olivera
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
- Unidad Médica de Alta Especialidad, Hospital de Especialidades Centro Medico Nacional de Occidente, Guadalajara, Jalisco, Mexico
| | - Arnulfo Álvarez-Álvarez
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - M Guadalupe Sanchez-Parada
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Juan Armendáriz-Borunda
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
- INNOVARE, Guadalajara, Jalisco, Mexico
| |
Collapse
|
|
34
|
The prevalence of bright liver echo pattern in patients with chronic hepatitis C: correlation with steatosis and fibrosis. J Ultrasound 2014; 19:91-8. [PMID: 27298639 DOI: 10.1007/s40477-014-0114-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 06/11/2014] [Indexed: 12/17/2022] Open
Abstract
PURPOSE To evaluate the prevalence of bright liver echo pattern (BLP) on ultrasonography and its correlation with liver steatosis (LS), and fibrosis in patients with chronic hepatitis C. The usefulness of detecting skip areas for steatosis diagnosis has also been evaluated. METHODS The study included 88 patients with chronic hepatitis C (55 men, 33 women, average age 45.7 ± 11.2 years). Ultrasound examination was performed in all patients before liver biopsy. The presence of BLP was assessed and graded from 1 to 3. Hypoechogenic areas (skip areas) around the gallbladder or near the portal vein were also evaluated. Hepatic fibrosis was assessed using the Ishak fibrosis score. Steatosis was graded as follows: 1, 2, 3 (<30, 30-70, >70 % of hepatocytes affected, respectively). RESULTS Fifty-three of the 88 patients (60 %) showed BLP (40 grade 1, 13 grades 2 or 3). Skip areas were found in 14 patients (16 %). Histological steatosis was observed in 40 patients (45 %) and in 10 of them (25 %) was grades 2 and 3 (4 and 6 patients, respectively). As regards fibrosis, 2 patients showed F0, 34 F1, 28 F2, 20 F3, 4 F4, none of them F5 and F6. BLP of grades 2 or 3 and presence of skip areas were strongly correlated with LS (P = 0.00007 and P = 0.00003, respectively). No correlation was found between BLP and fibrosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of BLP for LS were 75, 50, 56, 68 and 61 %, respectively. When BLP of grades 2 and 3 and LS of 30 % or more were correlated, the sensitivity, specificity, PPV, NPV and accuracy of BLP were 72, 96, 61, 96 and 90 %, respectively. As regards skip areas the sensitivity, specificity, PPV, NPV and accuracy for LS were 35, 100, 100, 64 and 70 %, respectively. CONCLUSIONS In a well-defined group of patients with chronic hepatitis C, the detection of BLP grades 2 and 3 has a good sensitivity and high specificity for high grades of steatosis. A high specificity but low sensitivity for liver steatosis was also found for skip areas, whereas mild fibrosis does not seem to correlate with the hyperechogenicity of the liver.
Collapse
|
|
35
|
Salmon-Ceron D, Arvieux C, Bourlière M, Cacoub P, Halfon P, Lacombe K, Pageaux GP, Pialoux G, Piroth L, Poizot-Martin I, Rosenthal E, Pol S. Use of first-generation HCV protease inhibitors in patients coinfected by HIV and HCV genotype 1. Liver Int 2014; 34:869-89. [PMID: 24138548 DOI: 10.1111/liv.12363] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 10/13/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND In HCV genotype 1-infected patients with HIV co-infection, tritherapy [HCV protease inhibitors (PIs) plus peg-interferon and ribavirin] has been shown to have an increased rate of sustained virological response. However, complex drug-to-drug interactions and tolerability issues remain a concern. METHODS Under the auspices of four French scientific societies of medicine, a committee was charged of establishing guidelines on the use of first-generation HCV PIs in these patients. This scientific committee based its work on preliminary results from tritherapy clinical trials in co-infected patients and, since data on these patients are still scarce, on the statements already made by the French Association for the Study of the Liver (AFEF) on the use of tritherapy in HCV mono-infected patients, written in May 2011 and updated in 2012. Each AFEF guideline concerning HCV monoinfection was examined to determine whether it could be used in the context of HIV/HCV coinfection. RESULTS These guidelines are addressed for the treatment of coinfected patients with various profiles, including treatment-naïve or patients with failure to previous bitherapy and mention those patients for whom tritherapy should start or those for whom it should be delayed. Preliminary results of triple therapy as well as factors associated to virological response are also discussed. Other issues include virological monitoring, clinical and virological criteria to stop therapy, practical treatment management, treatment adherence and the management of side effects and interactions with antiretroviral drugs. These guidelines were submitted for critical review to independent experts.
Collapse
Affiliation(s)
- Dominique Salmon-Ceron
- Paris Descartes University, Paris, France; APHP, Department of Internal Medicine, Infectious Diseases Unit, Cochin Hospital, Paris, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Lonardo A, Adinolfi LE, Restivo L, Ballestri S, Romagnoli D, Baldelli E, Nascimbeni F, Loria P. Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen. World J Gastroenterol 2014; 20:7089-7103. [PMID: 24966582 PMCID: PMC4064057 DOI: 10.3748/wjg.v20.i23.7089] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/17/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a successful pathogen on the grounds that it exploits its host's metabolism to build up viral particles; moreover it favours its own survival by inducing chronic disease and the development of specific anatomic changes in the infected organ. Steatosis, therefore, is associated with HCV infection by necessity rather than by chance alone. Approximately 6% of HCV patients have steatohepatitis. Interestingly, HCV steatosis occurs in the setting of multiple metabolic abnormalities (hyperuricemia, reversible hypocholesterolemia, insulin resistance, arterial hypertension and expansion of visceral adipose tissue) collectively referred to as "hepatitis C-associated dysmetabolic syndrome" (HCADS). General, nonalcoholic fatty liver disease (NAFLD)-like, mechanisms of steatogenesis (including increased availability of lipogenic substrates and de novo lipogenesis; decreased oxidation of fatty substrates and export of fatty substrates) are shared by all HCV genotypes. However, genotype 3 seemingly amplifies such steatogenic molecular mechanisms reported to occur in NAFLD via more profound changes in microsomal triglyceride transfer protein; peroxisome proliferator-activated receptor alpha; sterol regulatory element-binding proteins and phosphatase and tensin homologue. HCV steatosis has a remarkable clinical impact in as much as it is an acknowledged risk factor for accelerated fibrogenesis; for impaired treatment response to interferon and ribavirin; and development of hepatocellular carcinoma. Recent data, moreover, suggest that HCV-steatosis contributes to premature atherogenesis via both direct and indirect mechanisms. In conclusion, HCV steatosis fulfills all expected requirements necessary to perpetuate the HCV life cycle. A better understanding of the physiology of HCADS will likely result in a more successful handling of disease with improved antiviral success rates.
Collapse
|
|
37
|
Macaluso FS, Maida M, Cammà C, Cabibi D, Alessi N, Cabibbo G, Di Marco V, Craxì A, Petta S. Body mass index and liver stiffness affect accuracy of ultrasonography in detecting steatosis in patients with chronic hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 2014; 12:878-884.e1. [PMID: 24112998 DOI: 10.1016/j.cgh.2013.09.059] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 09/16/2013] [Accepted: 09/22/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Few studies have evaluated the accuracy of ultrasonography in detecting steatosis in patients with chronic hepatitis C. We assessed its accuracy in detecting steatosis and factors that affect its diagnostic performance in consecutive patients with chronic hepatitis C virus genotype 1 infection. METHODS We analyzed data from 515 patients with chronic hepatitis C, confirmed by liver biopsy, assessing anthropometric, biochemical, metabolic, virologic, and ultrasonography features. Transient elastography was performed to measure liver stiffness. Steatosis was identified with ultrasonography based on detection of a bright liver echo pattern. RESULTS Ultrasonography identified steatosis in 5% or more of parenchyma of the liver with 63.6% sensitivity, 90.4% specificity, an 87.5% positive predictive value (PPV), and a 70.3% negative predictive value (NPV). The higher the degree of steatosis (based on histology analysis), the higher the sensitivity values and NPVs (up to values of 75.3% and 93.8%, respectively, for steatosis in ≥30% of liver), and the lower the specificity values and PPVs (down to values of 69.8% and 31.7% for steatosis in ≥30% of liver, respectively). Body mass index of 30 kg/m(2) or greater (odds ratio, 2.761; 95% confidence interval, 1.156-6.595; P = .02) and liver stiffness measurements of 8.9 kPa or higher (odds ratio, 3.128; 95% confidence interval, 1.715-5.706; P < .001) were independent risk factors for false-negative results from ultrasonography when there was 5% or more steatosis, as well as when there was 10% or more, 20% or more, or 30% or more steatosis. CONCLUSIONS Ultrasonography detects steatosis with low levels of accuracy in patients with chronic hepatitis C virus genotype 1 infection; it has low NPVs for amounts of steatosis of 5% or more and low PPVs for livers with moderate-severe amounts. Higher body mass indexes and liver stiffness measurements are associated with false-negative results in steatosis detection by ultrasonography.
Collapse
Affiliation(s)
- Fabio Salvatore Macaluso
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy.
| | - Marcello Maida
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Daniela Cabibi
- Cattedra di Anatomia Patologica, University of Palermo, Palermo, Italy
| | - Nicola Alessi
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Salvatore Petta
- Sezione di Gastroenterologia, Dipartimento Biochimico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| |
Collapse
|
|
38
|
Mera K, Uto H, Mawatari S, Ido A, Yoshimine Y, Nosaki T, Oda K, Tabu K, Kumagai K, Tamai T, Moriuchi A, Oketani M, Shimada Y, Hidaka M, Eguchi S, Tsubouchi H. Serum levels of apoptosis inhibitor of macrophage are associated with hepatic fibrosis in patients with chronic hepatitis C. BMC Gastroenterol 2014; 14:27. [PMID: 24524410 PMCID: PMC3937012 DOI: 10.1186/1471-230x-14-27] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 02/05/2014] [Indexed: 12/18/2022] Open
Abstract
Background Apoptosis inhibitor of macrophage (AIM) and adipocytokines are involved in the metabolic syndrome, which has been putatively associated with the progression of chronic hepatitis C (CHC). However, the association between these cytokines and CHC is not fully elucidated. The aim of this study is to test whether serum levels of AIM and adipocytokines are associated with histological features, homeostasis model assessment-insulin resistance index (HOMA-IR), or whole body insulin sensitivity index (WBISI) in CHC patients. Methods Serum samples were obtained from 77 patients with biopsy-proven CHC. In 39 patients without overt diabetes mellitus, a 75 g oral glucose tolerance test (OGTT) was performed and HOMA-IR and WBISI were calculated. Results A serum AIM level of ≥1.2 μg/ml was independently associated with advanced hepatic fibrosis (F2 or F3) (odds ratio [OR], 5.612; 95% confidence interval [CI], 1.103–28.563; P = 0.038) based on a multivariate analysis, but there was no significant association between AIM and hepatic steatosis or inflammation. Furthermore, a serum leptin level of ≥8.6 ng/ml was independently associated with the presence of hepatic steatosis (≥5%) (OR, 6.195; 95% CI, 1.409–27.240; P = 0.016), but not hepatic fibrosis or inflammation. No relationship was observed between levels of adiponectin or resistin and hepatic histological parameters based on a multivariate analysis. Although serum levels of leptin, resistin, and adiponectin were significantly correlated with HOMA-IR and WBISI, there was no significant relationship between serum AIM levels and HOMA-IR or WBISI, respectively. Conclusion High serum levels of AIM in CHC patients are potentially related to advanced hepatic fibrosis. AIM and adipocytokines are possibly associated with pathological changes via a different mechanism.
Collapse
Affiliation(s)
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Cheng FKF, Torres DM, Harrison SA. Hepatitis C and lipid metabolism, hepatic steatosis, and NAFLD: still important in the era of direct acting antiviral therapy? J Viral Hepat 2014; 21:1-8. [PMID: 24329852 DOI: 10.1111/jvh.12172] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) have an individual prevalence of 1.8-3% and at least 30%, respectively, in the United States. It is therefore not surprising that there is overlap between these two common chronic liver diseases, although the relationship appears to go beyond isolated co-existence. Hepatic steatosis is a common feature of CHC infection and can be related to both metabolic and viral specific factors. Steatosis in the setting of nongenotype 3 CHC has been predictive of response to therapy prior to the advent of the direct acting antiviral medications (DAAs). Similarly, lipid metabolism appears important in response to CHC treatment. The pathways for both lipid homeostasis and NAFLD as it pertains to CHC infection as well as the utilization of statin therapy in CHC infection will be reviewed with a focus on the relevance of these topics in the era of DAA therapy.
Collapse
Affiliation(s)
- F-K F Cheng
- Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Washington, DC, USA
| | | | | |
Collapse
|
|
40
|
Qi Y, Xiang Y, Wang J, Qi Y, Li J, Niu J, Zhong J. Inhibition of hepatitis C virus infection by polyoxometalates. Antiviral Res 2013; 100:392-8. [PMID: 24025401 DOI: 10.1016/j.antiviral.2013.08.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 08/16/2013] [Accepted: 08/30/2013] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus (HCV) infects about 2% of the world population. The standard treatment of chronic HCV infection is still discontented because of the low sustained virological response rate. The development of new HCV antivirals is a healthcare imperative. We explored the potentials of polyoxometalates to inhibit HCV infection using newly developed HCVcc cell culture system. We found one polyoxometalate compound (named POM-12) can inhibit HCV infection at the nanomolar range while displayed little cytotoxicity. We showed that POM-12 inhibited pseudotyped HCV infection but had no effect on HCV RNA replication. Furthermore, we showed that POM-12 was virucidal and can disrupt HCV particles. Finally we demonstrated that POM-12 had no effect on the vesicular stomatitis virus infection while had weak inhibitory activity against the influenza virus infection. In conclusion, we identified a potent anti-HCV compound which may provide an attractive drug candidate to cure HCV infection.
Collapse
Affiliation(s)
- Yue Qi
- Department of Hepatology, First Hospital, Jilin University, Changchun, Jilin 130021, China
| | | | | | | | | | | | | |
Collapse
|
|
41
|
Mangia A, Ripoli M. Insulin resistance, steatosis and hepatitis C virus. Hepatol Int 2013; 7 Suppl 2:782-9. [PMID: 24587848 PMCID: PMC3918408 DOI: 10.1007/s12072-013-9460-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 06/30/2013] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have shown an increased occurrence of metabolic disorders such as insulin resistance (IR) and steatosis in patients with hepatitis C virus (HCV) infection. IR is believed to represent one of the central clinical features of the "metabolic syndrome" and the major pathogenetic factor for type 2 diabetes mellitus. In patients with chronic HCV hepatitis, IR may have several dangerous consequences such as accelerated progression of liver fibrosis, resistance to antiviral therapy and development of hepatocellular carcinoma. According to recent evidence, the global epidemic of metabolic disorders related to incorrect diets will lead physicians to deal with 1.2 billion patients with diabetes in the world in 2025. Given the high prevalence of HCV infection in several countries, metabolic manifestations will contribute to increasing morbidity and mortality in patients with HCV chronic infection in the near future. HCV treatment, shown able to decrease both the occurrence of HCV-related IR and diabetes, may reduce the risk of the associated morbidities.
Collapse
Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Maria Ripoli
- Liver Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| |
Collapse
|
|
42
|
Macaluso FS, Maida M, Minissale MG, Li Vigni T, Attardo S, Orlando E, Petta S. Metabolic factors and chronic hepatitis C: a complex interplay. BIOMED RESEARCH INTERNATIONAL 2013; 2013:564645. [PMID: 23956991 PMCID: PMC3730187 DOI: 10.1155/2013/564645] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/29/2013] [Indexed: 12/15/2022]
Abstract
In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.
Collapse
Affiliation(s)
- Fabio Salvatore Macaluso
- Section of Gastroenterology, DiBiMIS, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Sato C, Saito T, Misawa K, Katsumi T, Tomita K, Ishii R, Haga H, Okumoto K, Nishise Y, Watanabe H, Ueno Y, Kawata S. Impaired mitochondrial β-oxidation in patients with chronic hepatitis C: relation with viral load and insulin resistance. BMC Gastroenterol 2013; 13:112. [PMID: 23841691 PMCID: PMC3711919 DOI: 10.1186/1471-230x-13-112] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 07/08/2013] [Indexed: 12/20/2022] Open
Abstract
Background Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting. Methods This study consisted of thirty patients with CH-C. Serum levels of insulin and hepatitis C virus (HCV) core protein were measured by chemiluminescence enzyme immunoassay. The subjects were then fasted, and venous blood samples were drawn 12 h and 15 h after the start of fasting. The levels of blood ketone bodies were measured by an enzymatic cycling method. The rate of change in total ketone body concentration was compared with that in eight healthy volunteers. Results The rate of change in total ketone body concentration between 12 h and 15 h after the start of fasting was significantly lower in CH-C patients than in healthy volunteers (129.9% (8.5-577.3%) vs. 321.6% (139.6-405.4%); P <0.01). The rate of change in total ketone body concentration in patients with a serum level of HCV core protein of 10000 fmol/L or higher was significantly lower than in patients with a level of less than 10000 fmol/L (54.8% (8.5-304.3%) vs. 153.6% (17.1-577.3%); P <0.05). The rate of change in total ketone body concentration in patients with a homeostasis model assessment of insulin resistance (HOMA-IR) of 2.5 or higher was significantly lower than in patients with a HOMA-IR of less than 2.5 (56.7% (8.5-186.7%) vs. 156.4% (33.3-577.3%); P <0.01). Conclusions These results suggest that mitochondrial β-oxidation is impaired, possibly due to HCV infection in patients with CH-C.
Collapse
Affiliation(s)
- Chikako Sato
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Monjardim RDF, Costa DMC, Romano RFT, Salvadori PS, Santos JDVCD, Atzingen ACV, Shigueoka DC, D'Ippolito G. Diagnosis of hepatic steatosis by contrast-enhanced abdominal computed tomography. Radiol Bras 2013. [DOI: 10.1590/s0100-39842013000300005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Objective To evaluate the diagnostic capacity of abdominal computed tomography in the assessment of hepatic steatosis using the portal phase with a simplified calculation method as compared with the non-contrast-enhanced phase. Materials and Methods In the present study, 150 patients were retrospectively evaluated by means of non-contrast-enhanced and contrast-enhanced computed tomography. One hundred patients had hepatic steatosis and 50 were control subjects. For the diagnosis of hepatic steatosis in the portal phase, the authors considered a result of < 104 HU calculated by the formula [L - 0.3 × (0.75 × P + 0.25 × A)] / 0.7, where L, P and A represent the attenuation of the liver, of the main portal vein and abdominal aorta, respectively. Sensitivity, specificity, positive and negative predictive values were calculated, using non-contrast-enhanced computed tomography as the reference standard. Results The simplified calculation method with portal phase for the diagnosis of hepatic steatosis showed 100% sensitivity, 36% specificity, negative predictive value of 100% and positive predictive value of 75.8%. The rate of false positive results was 64%. False negative results were not observed. Conclusion The portal phase presents an excellent sensitivity in the diagnosis of hepatic steatosis, as compared with the non-contrast-enhanced phase of abdominal computed tomography. However, the method has low specificity.
Collapse
|
|
45
|
Adinolfi LE, Restivo L, Marrone A. The predictive value of steatosis in hepatitis C virus infection. Expert Rev Gastroenterol Hepatol 2013; 7:205-13. [PMID: 23445230 DOI: 10.1586/egh.13.7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Steatosis is a complication of hepatitis C virus (HCV) infection and the mechanisms of its development are complex, involving viral and host factors. Steatosis that is prevalently viral is associated with HCV genotype 3, and steatosis that is prevalently metabolic is associated with non-3 genotypes. Viral steatosis is correlated with the level of HCV replication, whereas metabolic steatosis is related to insulin resistance. The two types of steatosis have a different impact on HCV disease and may have an additive effect. HCV infection is a multifaceted disease with hepatic and extrahepatic manifestations. There is a body of evidence indicating that HCV-related steatosis plays a role in many HCV manifestations and, thus, the presence of steatosis is a predictive factor for the development of such events. The current data show that HCV-related steatosis predicts an advanced liver disease and a more rapid progression of fibrosis, as well as an increased risk of development of hepatocellular carcinoma. Moreover, the presence of steatosis in a HCV patient has a high predictive value that the subject may have or may develop insulin resistance, diabetes and metabolic syndrome. Recently, a strict association between HCV-related steatosis and development of atherosclerosis has been demonstrated. In addition, steatosis negatively impacts response rate to interferon-based treatment, even in HCV genotype-3 infection. Therapeutic strategies to improve steatosis and, consequently, response to standard antiviral therapy and outcome of disease are wanted. The authors summarize current knowledge of impact of steatosis on the above reported clinical conditions associated with HCV infection.
Collapse
Affiliation(s)
- Luigi E Adinolfi
- Department of Medicine, Surgery, Neurology, Geriatric & Metabolic Disease, Second University of Naples, Internal Medicine of Clinic Hospital of Marcianise, ASL Caserta, Italy.
| | | | | |
Collapse
|
|
46
|
Leroy V, Serfaty L, Bourlière M, Bronowicki JP, Delasalle P, Pariente A, Pol S, Zoulim F, Pageaux GP. Protease inhibitor-based triple therapy in chronic hepatitis C: guidelines by the French Association for the Study of the Liver. Liver Int 2012; 32:1477-92. [PMID: 22891751 DOI: 10.1111/j.1478-3231.2012.02856.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 07/02/2012] [Indexed: 12/13/2022]
Abstract
The recent marketing authorizations and hence availability of the new protease inhibitors, telaprevir and boceprevir, have profoundly changed the management of chronic hepatitis C patients. Guidelines for the use of these new drugs as part of a triple therapy, in combination with the standard therapy of peginterferon plus ribavirin, are proposed. The guidelines have been drawn up and evaluated by a meeting of the French Association for the Study of the Liver, posted online for comments, and extensively reviewed by international experts. The current published data on the various treatment strategies are reviewed. The guidelines address the majority of patient profiles including treatment-naïve patients and patients with failure of previous treatment. They recommend which patients should be treated with triple therapy and consider the results of triple therapy including the factors that are predictive of response. They consider the circumstances in which the length of triple therapy can be shortened and the advantages of a peginterferon plus ribavirin lead-in phase. Virological monitoring, stopping criteria, the evaluation of resistance to protease inhibitors, practical treatment management, treatment adherence and the management of side effects are discussed and simple guidelines proposed.
Collapse
Affiliation(s)
- Vincent Leroy
- Centre de Recherche INSERM-UJF U823, Institut Albert Bonniot et Clinique Universitaire d'Hépato-Gastroentérologie, Pôle Digidune, CHU, Grenoble, France
| | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Aghemo A. Understanding the role of PNPLA3 genetic variants in patients with chronic hepatitis C infection. Dig Dis Sci 2012; 57:1977-9. [PMID: 22736017 DOI: 10.1007/s10620-012-2277-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 06/05/2012] [Indexed: 12/09/2022]
|
|
48
|
Insulin resistance and diabetes mellitus in patients with chronic hepatitis C: spectators or actors? Dig Liver Dis 2012; 44:359-60. [PMID: 22418268 DOI: 10.1016/j.dld.2012.02.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 02/03/2012] [Indexed: 12/11/2022]
|
|
49
|
Sasso M, Tengher-Barna I, Ziol M, Miette V, Fournier C, Sandrin L, Poupon R, Cardoso AC, Marcellin P, Douvin C, de Ledinghen V, Trinchet JC, Beaugrand M. Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan(®): validation in chronic hepatitis C. J Viral Hepat 2012; 19:244-53. [PMID: 22404722 DOI: 10.1111/j.1365-2893.2011.01534.x] [Citation(s) in RCA: 150] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A novel controlled attenuation parameter (CAP) has been developed for Fibroscan(®) to assess liver steatosis, simultaneously with liver stiffness measurement (LSM). We assessed CAP diagnostic accuracy in a large cohort of patients with chronic hepatitis C (CHC) virus. A total of 615 patients with CHC, who underwent both Fibroscan(®) and liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assessment as S(0) : steatosis in <10% of hepatocytes, S(1) : 11-33%, S(2) : 34-66% and S(3) : 67-100%. Performances of CAP and liver stiffness were determined using receiver operating characteristic (ROC) curve analysis and cross-validated using the bootstrap method. The Obuchowski measure was used to assess overall accuracy of CAP and to differentiate between steatosis grades. In multivariate analysis, CAP was related to steatosis (P < 10(-15) ) independently of fibrosis stage (which was related to LSM). The areas under ROC curves using CAP to detect steatosis were 0.80 (95% CI, 0.75-0.84) for S ≥ S(1) , 0.86 (0.81-0.92) for S ≥ S(2) and 0.88 (0.73-1) S = S(3) . CAP exhibited a good ability to differentiate steatosis grades (Obuchowski measure = 0.92). Performance of LSM for fibrosis assessment confirmed results from previous studies. CAP is a novel tool to assess the degree of steatosis and both fibrosis and steatosis can be evaluated noninvasively during the same procedure using Fibroscan(®) , in patients with CHC.
Collapse
Affiliation(s)
- M Sasso
- R&D Department, Echosens, Paris, France.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Vescovo T, Romagnoli A, Perdomo AB, Corazzari M, Ciccosanti F, Alonzi T, Nardacci R, Ippolito G, Tripodi M, Garcia-Monzon C, Lo Iacono O, Piacentini M, Fimia GM. Autophagy protects cells from HCV-induced defects in lipid metabolism. Gastroenterology 2012; 142:644-653.e3. [PMID: 22155365 DOI: 10.1053/j.gastro.2011.11.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Revised: 11/15/2011] [Accepted: 11/19/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Autophagy is a lysosome-mediated catabolic process that mediates degradation and recycling of all major components of eukaryotic cells. Different stresses, including viral and bacterial infection, induce autophagy, which can promote cell survival by removing the stress inducer or by attenuating its dangerous effects. High levels of autophagy occur during infection of cells with hepatitis C virus (HCV), but the clinical relevance of this process is not clear. METHODS Levels of autophagy were analyzed in liver biopsy samples from 22 patients with HCV infection using microtubule-associated protein-1 light chain 3 immunoblotting; associations with histological and metabolic parameters were evaluated by Pearson correlation analysis. We investigated the role of HCV-induced autophagy in lipid degradation in cells infected with the virus or replicons, and analyzed autophagosome contents by confocal microscopy and by measuring lipid levels after inhibition of autophagy by Beclin 1 knockdown or lysosome inhibitors. RESULTS In liver biopsy samples from patients with HCV, there was an inverse correlation between microvesicular steatosis and level of autophagy (r = -0.617; P = .002). HCV selectively induced autophagy of lipids in virus-infected and replicon cells. In each system, autophagosomes frequently colocalized with lipid deposits, mainly formed by unesterified cholesterol. Inhibition of the autophagic process in these cells significantly increased the induction of cholesterol accumulation by HCV. CONCLUSIONS Autophagy counteracts the alterations in lipid metabolism induced by HCV. Disruption of the autophagic process might contribute to development of steatosis in patients with HCV.
Collapse
Affiliation(s)
- Tiziana Vescovo
- National Institute for Infectious Diseases IRCCS L. Spallanzani, Rome, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|