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1
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Lu Y, Tang W, Zhang H, Liu J, Zhong S. Effect of hepatocyte damage in hepatic fibrogenesis of patients infected with Schistosoma japonicum. Infect Immun 2024; 92:e0002624. [PMID: 38767360 PMCID: PMC11237810 DOI: 10.1128/iai.00026-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/22/2024] [Indexed: 05/22/2024] Open
Abstract
Schistosomiasis is a serious public health problem, and previous studies found that liver function and hepatic cells are damaged. To evaluate the serum parameters of liver function and fibrosis in schistosomiasis patients infected with Schistosoma japonicum (Schistosoma J.) and analyze the correlations between liver function and serum fibrosis markers in patients infected with Schistosoma J., this retrospective study enrolled 133 patients. The study population was divided into four groups: healthy people control group (n = 20), chronic schistosomiasis without liver cirrhosis (CS) group (n = 21), schistosomiasis cirrhosis without hypoalbuminemia (SC-HA) group (n = 68), and schistosomiasis cirrhosis with hypoalbuminemia (SC +HA) group (n = 24). Clinical and laboratory data were collected for analysis. In the multiple comparison of abnormal rates of aspartate aminotransferase (AST) and total bilirubin (TBIL), the abnormal rate of the SC +HA group was significantly higher than that of the other three groups (P < 0.05), and the abnormal rate of γ-GT in the SC +HA group was significantly higher than that in the control group (P < 0.05). Multiple comparison results of serum levels of fibrosis markers showed that the SC group had a significantly higher level of indexes than other groups (P < 0.05). The levels of TGF-β1 in the CS group, SC-HA group and SC +HA group were significantly higher than those in the control group (P < 0.001). Our study demonstrated that the liver function and hepatic cells were damaged with the progression of liver disease in patients infected with Schistosoma J., and they played an important role in the occurrence and development of liver fibrosis.
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Affiliation(s)
- Yaqi Lu
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wangxian Tang
- Institute of Liver Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Heng Zhang
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Liu
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shan Zhong
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, Hubei, China
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2
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Wuopio A, Baker BM, Koethe B, Goodman MD, Shin R, Bugaev N, Nepomnayshy D, Kim WC, Schnelldorfer T. Can Surgeons Reliably Identify Non-cirrhotic Liver Disease During Laparoscopic Bariatric Surgery? Obes Surg 2024; 34:769-777. [PMID: 38280161 DOI: 10.1007/s11695-024-07070-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 01/11/2024] [Accepted: 01/18/2024] [Indexed: 01/29/2024]
Abstract
INTRODUCTION Identification of liver disease during bariatric operations is an important task given the patients risk for occult fatty liver disease. Surgeon's accuracy of assessing for liver disease during an operation is poorly understood. The objective was to measure surgeons' performance on intra-operative visual assessment of the liver in a simulated environment. METHODS Liver images from 100 patients who underwent laparoscopic bariatric surgery and pre-operative ultrasound elastography between July 2020 and July 2021 were retrospectively evaluated. The perception of 15 surgeons regarding the degree of hepatic steatosis and fibrosis was collected in a simulated clinical environment by survey and compared to results determined by ultrasonographic exam. RESULTS The surgeons' ability to correctly identify the class of steatosis and fibrosis was poor (accuracy 61% and 59%, respectively) with a very weak correlation between the surgeon's predicted class and its true class (r = 0.17 and r = 0.12, respectively). When liver disease was present, surgeons completely missed its presence in 26% and 51% of steatosis and fibrosis, respectively. Digital image processing demonstrated that surgeons subjectively classified steatosis based on the "yellowness" of the liver and fibrosis based on texture of the liver, despite neither correlating with the true degree of liver disease. CONCLUSION Laparoscopic visual assessment of the liver surface for identification of non-cirrhotic liver disease was found to be an inaccurate method during laparoscopic bariatric surgery. While validation studies are needed, the results suggest the clinical need for alternative approaches.
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Affiliation(s)
- Alexandra Wuopio
- Department of Surgery, Lahey Hospital and Medical Center, Burlington, MA, 01805, USA
| | | | - Benjamin Koethe
- Tufts Clinical and Translational Science Institute, Tufts University, and Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, 02111, USA
| | - Martin D Goodman
- Department of Surgery, Tufts Medical Center, Boston, MA, 02111, USA
| | - Reuben Shin
- Department of Surgery, Lahey Hospital and Medical Center, Burlington, MA, 01805, USA
| | - Nikolay Bugaev
- Department of Surgery, Tufts Medical Center, Boston, MA, 02111, USA
| | - Dmitry Nepomnayshy
- Department of Surgery, Lahey Hospital and Medical Center, Burlington, MA, 01805, USA
| | - Woon Cho Kim
- Department of Surgery, Tufts Medical Center, Boston, MA, 02111, USA
| | - Thomas Schnelldorfer
- Department of Surgery, Tufts Medical Center, Boston, MA, 02111, USA.
- Department of Translational Research, Lahey Hospital and Medical Center, Burlington, MA, 01805, USA.
- Surgical Imaging Lab, Tufts Medical Center, Boston, MA, 02111, USA.
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3
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Abid F, Saleem M, Leghari T, Rafi I, Maqbool T, Fatima F, Arshad AM, Khurshid S, Naz S, Hadi F, Tahir M, Akhtar S, Yasir S, Mobashar A, Ashraf M. Evaluation of in vitro anticancer potential of pharmacological ethanolic plant extracts Acacia modesta and Opuntia monocantha against liver cancer cells. BRAZ J BIOL 2024; 84:e252526. [DOI: 10.1590/1519-6984.252526] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 11/27/2021] [Indexed: 12/30/2022] Open
Abstract
Abstract Acacia modesta (AM) and Opuntia monocantha (OM) are distributed in Pakistan, Afghanistan and India. Both of these plants have different pharmacological properties. This study was designed to evaluate anticancer potential of Acacia modesta (AM) and Opuntia monocantha (OM). Liver cancer cell line HepG2 was used for assessment of anticancer activity. For the evaluation of anti-proliferative effects, cell viability and cell death in all groups of cells were evaluated via MTT, crystal violet and trypan blue assays. For the evaluation of apoptosis ELISA of p53 performed. Furthermore, LDH assay to find out the ability of malignant cells to metabolize pyruvate to lactate and antioxidant enzymes activity (GSH, CAT and SOD) at the end HPLC was performed to find active compound of AM and OM. Cytotoxicity (MTT), Viability assays (trypan blue, crystal viability, MUSE analysis) showed more dead, less live cells in plant treated groups with increase of concentration. Scratch assay for the anti-migratory effect of these plants showed treated groups have not ability to heal scratch/wound. ELISA of p53 for cellular apoptosis showed more release of p53 in treated groups. Antioxidant assay via glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) showed less anti-oxidative potential in treated cancer groups. LDH assay showed more lactate dehydrogenase release in treated groups compared with untreated. HPLC analysis showed the presence of phytochemicals such as steroids, alkaloids, phenols, flavonoids, saponins, tannins, anthraquinone and amino acids in AM and OM plant extracts. Based on all these findings, it can be concluded that ethanolic extracts of Acacia modesta and Opuntia monocantha have promising anti-cancer potential.
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Affiliation(s)
- F. Abid
- Government College University Faisalabad, Pakistan; The University of Lahore, Pakistan
| | - M. Saleem
- Government College University Faisalabad, Pakistan; University of the Punjab, Pakistan
| | | | - I. Rafi
- University of Lahore, Pakistan
| | | | | | | | | | - S. Naz
- University of Lahore, Pakistan
| | - F. Hadi
- University of Lahore, Pakistan
| | | | - S. Akhtar
- University of Lahore, Pakistan; University of Bradford, United Kingdom
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Sanyal AJ, Jha P, Kleiner DE. Digital pathology for nonalcoholic steatohepatitis assessment. Nat Rev Gastroenterol Hepatol 2024; 21:57-69. [PMID: 37789057 DOI: 10.1038/s41575-023-00843-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/23/2023] [Indexed: 10/05/2023]
Abstract
Histological assessment of nonalcoholic fatty liver disease (NAFLD) has anchored knowledge development about the phenotypes of the condition, their natural history and their clinical course. This fact has led to the use of histological assessment as a reference standard for the evaluation of efficacy of drug interventions for nonalcoholic steatohepatitis (NASH) - the more histologically active form of NAFLD. However, certain limitations of conventional histological assessment systems pose challenges in drug development. These limitations have spurred intense scientific and commercial development of machine learning and digital approaches towards the assessment of liver histology in patients with NAFLD. This research field remains an area in rapid evolution. In this Perspective article, we summarize the current conventional assessment of NASH and its limitations, the use of specific digital approaches for histological assessment, and their application to the study of NASH and its response to therapy. Although this is not a comprehensive review, the leading tools currently used to assess therapeutic efficacy in drug development are specifically discussed. The potential translation of these approaches to support routine clinical assessment of NAFLD and an agenda for future research are also discussed.
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Affiliation(s)
- Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Prakash Jha
- Food and Drug Administration, Silver Spring, MD, USA
| | - David E Kleiner
- Post-Mortem Section Laboratory of Pathology Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Mohammed OS, Attia HG, Mohamed BMSA, Elbaset MA, Fayed HM. Current investigations for liver fibrosis treatment: between repurposing the FDA-approved drugs and the other emerging approaches. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2023; 26:11808. [PMID: 38022905 PMCID: PMC10662312 DOI: 10.3389/jpps.2023.11808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023]
Abstract
Long-term liver injuries lead to hepatic fibrosis, often progressing into cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. There is currently no effective therapy available for liver fibrosis. Thus, continuous investigations for anti-fibrotic therapy are ongoing. The main theme of anti-fibrotic investigation during recent years is the rationale-based selection of treatment molecules according to the current understanding of the pathology of the disease. The research efforts are mainly toward repurposing current FDA-approved drugs targeting etiological molecular factors involved in developing liver fibrosis. In parallel, investigations also focus on experimental small molecules with evidence to hinder or reverse the fibrosis. Natural compounds, immunological, and genetic approaches have shown significant encouraging effects. This review summarizes the efficacy and safety of current under-investigation antifibrosis medications targeting various molecular targets, as well as the properties of antifibrosis medications, mainly in phase II and III clinical trials.
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Affiliation(s)
- Omima S. Mohammed
- Department of Microbiology, College of Medicine, Najran University, Najran, Saudi Arabia
| | - Hany G. Attia
- Department of Pharmacognosy, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Bassim M. S. A. Mohamed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Marawan A. Elbaset
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Hany M. Fayed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
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6
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Christopher KL, Patnaik JL, Penland KJ, Pantcheva MB, Lynch AM, Ifantides C. Outcomes and Risk Factors for Complications in Cataract Patients with Hepatitis C Virus Infection. Ophthalmic Epidemiol 2023; 30:492-498. [PMID: 36196031 DOI: 10.1080/09286586.2022.2131836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 09/09/2022] [Accepted: 09/26/2022] [Indexed: 10/10/2022]
Abstract
PURPOSE To describe outcomes of patients with hepatitis C virus (HCV) seropositivity undergoing cataract surgery, as well as investigate risk factors for surgical complications. METHODS This is a retrospective cohort study of all consecutive patients who underwent cataract surgery at a tertiary care hospital in the United States between 2014 and 2019. The exposure of interest was HCV seropositivity and outcomes included surgical complications and associated risk factors, visual acuity, and post-operative complications. RESULTS A total of 11,276 eyes of 6,858 patients were included in the study, of which 122 patients (1.78%) and 210 eyes (1.86%) were HCV positive. Average age at surgery was 63.4 (8.4) years for HCV positive patients and 69.1 (10.6) years for HCV negative patients. Patients with HCV were more likely to suffer a complication during cataract surgery, 2.9% versus 1.2% (OR 2.27, 95% CI 1.03 to 5.01, p = .0415). Postoperative best corrected visual acuity was excellent: median and range 0.00 (-0.13, 3.00) logMAR for HCV positive eyes versus 0.00 (-0.30, 3.00) logMAR for HCV negative eyes. Among HCV positive patients, elevated alanine transaminase (>52 U/L) was associated with a higher intraoperative complication rate (10.0% vs 1.8%, OR 5.53, 95% CI 1.05 to 29.2, p = .044). CONCLUSION While patients with HCV are more likely to have complications during cataract surgery, final best corrected visual acuity was excellent regardless of HCV status. Patients with HCV are more likely to undergo cataract surgery at a younger age, and those with elevated alanine transaminase are at highest risk for complications.
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Affiliation(s)
- Karen L Christopher
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States
| | - Jennifer L Patnaik
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States
| | - Kylie J Penland
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States
| | - Mina B Pantcheva
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States
| | - Anne M Lynch
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States
| | - Cristos Ifantides
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States
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7
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Abouelezz HM, Shehatou GS, Shebl AM, Salem HA. A standardized pomegranate fruit extract ameliorates thioacetamide-induced liver fibrosis in rats via AGE-RAGE-ROS signaling. Heliyon 2023; 9:e14256. [PMID: 36938469 PMCID: PMC10015255 DOI: 10.1016/j.heliyon.2023.e14256] [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: 07/29/2022] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/07/2023] Open
Abstract
This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-β1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-β1, and TIMP-1.
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Affiliation(s)
- Hadeer M. Abouelezz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Corresponding author.
| | - George S.G. Shehatou
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City, Egypt
| | - Abdelhadi M. Shebl
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hatem A. Salem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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8
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Savedchuk S, Raslan R, Nystrom S, Sparks MA. Emerging Viral Infections and the Potential Impact on Hypertension, Cardiovascular Disease, and Kidney Disease. Circ Res 2022; 130:1618-1641. [PMID: 35549373 DOI: 10.1161/circresaha.122.320873] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world's population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.
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Affiliation(s)
- Solomiia Savedchuk
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
| | - Rasha Raslan
- Internal Medicine, Virginia Commonwealth University, Richmond (R.R.)
| | - Sarah Nystrom
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
- Renal Section, Durham VA Health Care System, NC (M.A.S.)
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9
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Marti-Aguado D, Fernández-Patón M, Alfaro-Cervello C, Mestre-Alagarda C, Bauza M, Gallen-Peris A, Merino V, Benlloch S, Pérez-Rojas J, Ferrández A, Puglia V, Gimeno-Torres M, Aguilera V, Monton C, Escudero-García D, Alberich-Bayarri Á, Serra MA, Marti-Bonmati L. Digital Pathology Enables Automated and Quantitative Assessment of Inflammatory Activity in Patients with Chronic Liver Disease. Biomolecules 2021; 11:1808. [PMID: 34944452 PMCID: PMC8699191 DOI: 10.3390/biom11121808] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/22/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Traditional histological evaluation for grading liver disease severity is based on subjective and semi-quantitative scores. We examined the relationship between digital pathology analysis and corresponding scoring systems for the assessment of hepatic necroinflammatory activity. A prospective, multicenter study including 156 patients with chronic liver disease (74% nonalcoholic fatty liver disease-NAFLD, 26% chronic hepatitis-CH etiologies) was performed. Inflammation was graded according to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network system and METAVIR score. Whole-slide digital image analysis based on quantitative (I-score: inflammation ratio) and morphometric (C-score: proportionate area of staining intensities clusters) measurements were independently performed. Our data show that I-scores and C-scores increase with inflammation grades (p < 0.001). High correlation was seen for CH (ρ = 0.85-0.88), but only moderate for NAFLD (ρ = 0.5-0.53). I-score (p = 0.008) and C-score (p = 0.002) were higher for CH than NAFLD. Our MATLAB algorithm performed better than QuPath software for the diagnosis of low-moderate inflammation (p < 0.05). C-score AUC for classifying NASH was 0.75 (95%CI, 0.65-0.84) and for moderate/severe CH was 0.99 (95%CI, 0.97-1.00). Digital pathology measurements increased with fibrosis stages (p < 0.001). In conclusion, quantitative and morphometric metrics of inflammatory burden obtained by digital pathology correlate well with pathologists' scores, showing a higher accuracy for the evaluation of CH than NAFLD.
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Affiliation(s)
- David Marti-Aguado
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
| | - Matías Fernández-Patón
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
| | - Clara Alfaro-Cervello
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (C.A.-C.); (C.M.-A.); (A.F.)
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Claudia Mestre-Alagarda
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (C.A.-C.); (C.M.-A.); (A.F.)
| | - Mónica Bauza
- Pathology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (M.B.); (J.P.-R.)
| | - Ana Gallen-Peris
- Digestive Disease Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain; (A.G.-P.); (S.B.)
| | - Víctor Merino
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
| | - Salvador Benlloch
- Digestive Disease Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain; (A.G.-P.); (S.B.)
- CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain;
| | - Judith Pérez-Rojas
- Pathology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (M.B.); (J.P.-R.)
| | - Antonio Ferrández
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (C.A.-C.); (C.M.-A.); (A.F.)
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Víctor Puglia
- Pathology Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain;
| | - Marta Gimeno-Torres
- Hepatology and Liver Transplantation Unit, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain;
| | - Victoria Aguilera
- CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Hepatology and Liver Transplantation Unit, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain;
| | - Cristina Monton
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
| | - Desamparados Escudero-García
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Ángel Alberich-Bayarri
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
- Quantitative Imaging Biomarkers in Medicine, QUIBIM SL, 46021 Valencia, Spain
| | - Miguel A. Serra
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Luis Marti-Bonmati
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
- Radiology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain
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10
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Effects of silybin supplementation on nutrient digestibility, hematological parameters, liver function indices, and liver-specific mi-RNA concentration in dogs. BMC Vet Res 2021; 17:228. [PMID: 34174886 PMCID: PMC8235871 DOI: 10.1186/s12917-021-02929-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 05/24/2021] [Indexed: 12/01/2022] Open
Abstract
Background Hepatopathies are an important group of disorders in dogs where proper nutritional care is crucial. Supplementation with a hepatoprotectant like silybin can improve liver function and should not interfere with nutrient digestibility. The purpose of this study was to investigate the effect of both pure silybin and commercial hepatoprotectant on nutrients digestibility, liver function indices and health status in healthy dogs (EXP1). Moreover, the second experiment (EXP2) investigated the effect of commercial hepatoprotectant on liver function tests and liver-associated miRNAs concentration in dogs with idiopathic liver disorder. Results Nutrient digestibility was not affected by treatment in EXP1. Supplementation did alter the serum fatty acid profile, with no clinical relevance. The levels of liver markers such as ALT, AST and GGT significantly decreased. In EXP2, supplementation with commercial hepatoprotectant containing silybin improved liver function tests. A decrease was observed in liver serum markers such as ALT, AST and miR122 concentration. Conclusions EXP1 confirmed that silybin (whether pure or as a commercial hepatoprotectant) does not interfere with digestion which subsequently exerts no detrimental effect on dogs’ health and metabolism. In EXP2, dietary supplementation with commercial hepatoprotectant containing silybin resulted in a decreased activity of serum liver markers, accompanied by a decrease in the concentration of liver-specific miRNA molecules. Liver function indices were consequently improved. Silybin supplementation can thus serve as an effective therapeutical tool in dogs with hepatopathies. Supplementary Information The online version contains supplementary material available at 10.1186/s12917-021-02929-3.
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Maqbool T, Hadi F, Razzaq S, Naz S, Aftab S, Khurshid S, Awan SJ, Nawaz A, Abid F, Malik A. Synergistic Effect of Barbadensis miller and Marsdenia Condurango Extracts Induces Apoptosis Promotes Oxidative Stress by Limiting Proliferation of Cervical Cancer and Liver Cancer Cells. Asian Pac J Cancer Prev 2021; 22:843-852. [PMID: 33773549 PMCID: PMC8286677 DOI: 10.31557/apjcp.2021.22.3.843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Indexed: 12/04/2022] Open
Abstract
Background: Drug synergy is the combine effect of drug efficacy. Synergistic combinations of active ingredients have proven to be highly effective and more useful in therapeutics. In contrast, the individual effect of drug is usually undesirable and mostly used for selecting drug-resistant mutations. Purpose of this study was to check synergistic effects of both plants (Barbadensis miller and Marsdenia condurango) against liver and cervical cancer. Methodology: Culturing of HeLa (cervical cancer cell line) and HepG2 (liver cancer cell line) cells, IC50 evaluation, viability assays (trypan blue, crystal violet), p53 ELISA and immunocytochemistry, MUSE analysis (count and viability), antioxidants (GSH, SOD, CAT), at the end RT-PCR was performed. Results: IC50 evaluation was done of each plant individually and with combination for synergistic effects, IC50 with plants combination (synergism) was applied on further viability assays (trypan blue, crystal violet, MUSE analysis via count and viability kit) p53 ELISA and immunocytochemistry for evaluation of cellular apoptosis, antioxidants assays (GSH, SOD, CAT), and RT-PCR with proliferative and apoptotic markers along with internal control. Conclusion: According to current study it was observed that synergistic effect of these plants has more anticancer properties with minimum effective dose. It was also observed that extracts possess the ability to induce apoptosis, restrict proliferation and enhanced oxidative stress.
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Affiliation(s)
- Tahir Maqbool
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Faheem Hadi
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Sehrish Razzaq
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Sadia Naz
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Saira Aftab
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Sameera Khurshid
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Sana Javaid Awan
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Aisha Nawaz
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Farah Abid
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
| | - Arif Malik
- Faculty of Pharmacy, University of Lahore, Defence Road, Lahore, Pakistan
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12
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Magri MC, Alvarez MSM, Iogi AA, Alves GM, Manchiero C, Dantas BP, Prata TVG, Nunes AKDS, Tengan FM. Study of CXCL9-11 gene polymorphisms in liver fibrosis among patients with chronic hepatitis C. Pathog Dis 2021; 79:6105222. [PMID: 33476381 DOI: 10.1093/femspd/ftab007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/19/2021] [Indexed: 01/10/2023] Open
Abstract
Several factors are associated with the progression of chronic hepatitis C: comorbidities, lifestyle, and pathogenic factors, including immune response, apoptosis and heredity. Single nucleotide polymorphisms (SNPs) in the PNPLA3 and TM6SF2 genes are more widely studied genetic risk factors, while CXCL9-11 chemokines produced by hepatocytes in the process of infection are less well studied. Our aim was to evaluate the influence of CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 in liver fibrosis when analysed together with PNPLA3 rs738409 and TM6SF2 rs58542926. The study included 219 patients with chronic hepatitis C. SNP genotyping was performed by real-time PCR. Univariate and multivariate analyses were used to detect the association between SNPs and advanced fibrosis in a recessive genetic model. All SNPs had a minimum allele frequency >5%, and CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 were in high linkage disequilibrium (D' ≥ 0.84). In the multivariate analysis, we observed that male gender (P = 0.000), older age (P = 0.025), moderate to intense inflammatory activity (P = 0.002), moderate to accentuated hepatic steatosis (P = 0.026) and the CT genotype of the TM6SF2 rs58542926 SNP (P = 0.014) presented significant associations with advanced fibrosis. Overall, the CXCL9 rs10336, CXCL10 rs3921, CXCL11 rs4619915 and PNPLA3 rs738409 SNPs did not influence liver fibrosis among patients with chronic hepatitis C.
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Affiliation(s)
- Mariana Cavalheiro Magri
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Maria Stella Montanha Alvarez
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Anny Ayumi Iogi
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Grayce Mendes Alves
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Caroline Manchiero
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Bianca Peixoto Dantas
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Thamiris Vaz Gago Prata
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Arielle Karen da Silva Nunes
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Fátima Mitiko Tengan
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.,Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255. Bairro Cerqueira Cesar. Sao Paulo, SP, Brazil. CEP 05403-000
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13
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Changes of Gut-Microbiota-Liver Axis in Hepatitis C Virus Infection. BIOLOGY 2021; 10:biology10010055. [PMID: 33451143 PMCID: PMC7828638 DOI: 10.3390/biology10010055] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/02/2021] [Accepted: 01/08/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary Gut microbiota alteration is linked to many health disorders including hepatitis C virus (HCV) infection. This dysbiosis in turn impacts the coordination between the gut and the liver that is known as the gut–liver-axis. Here, we discuss the latest findings regarding the changes in gut microbiota structure and functionality post HCV infection and its treatment regimens. In addition, we underline the contribution of the microbiota alterations to HCV associated liver complications. Abstract The gut–liver-axis is a bidirectional coordination between the gut, including microbial residents, the gut microbiota, from one side and the liver on the other side. Any disturbance in this crosstalk may lead to a disease status that impacts the functionality of both the gut and the liver. A major cause of liver disorders is hepatitis C virus (HCV) infection that has been illustrated to be associated with gut microbiota dysbiosis at different stages of the disease progression. This dysbiosis may start a cycle of inflammation and metabolic disturbance that impacts the gut and liver health and contributes to the disease progression. This review discusses the latest literature addressing this interplay between the gut microbiota and the liver in HCV infection from both directions. Additionally, we highlight the contribution of gut microbiota to the metabolism of antivirals used in HCV treatment regimens and the impact of these medications on the microbiota composition. This review sheds light on the potential of the gut microbiota manipulation as an alternative therapeutic approach to control the liver complications post HCV infection.
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Iqubal A, Syed MA, Ali J, Najmi AK, Haque MM, Haque SE. Nerolidol protects the liver against cyclophosphamide-induced hepatic inflammation, apoptosis, and fibrosis via modulation of Nrf2, NF-κB p65, and caspase-3 signaling molecules in Swiss albino mice. Biofactors 2020; 46:963-973. [PMID: 32941697 DOI: 10.1002/biof.1679] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 07/29/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022]
Abstract
Cyclophosphamide (CP)-induced hepatotoxic manifestations are major concern for patients undergoing chemotherapy, which often limit its therapeutic utility. Nerolidol (NER) is a natural bioactive molecule having potent gonadoprotective, neuroprotective, and cardioprotective properties but has not been explored for its hepatoprotective effect and underlying mechanism. Therefore, in the current study hepatoprotective potential of nerolidol was studied in CP-induced hepatic oxidative stress, inflammation, apoptosis, and fibrosis via modulation of Nrf2, NF-κB p65, caspase-3, TGF-β1, and associated biochemical status in Swiss albino mice. NER (200, 400 mg/kg, p.o) and fenofibrate (FF) 80 mg/kg, p.o. were administered from first to fourteenth day and CP was administered at the dose of 200 mg/kg, i.p on seventh day. On fifteenth day, animals were sacrificed and estimation of oxidative stress, inflammation, apoptosis, fibrosis, histopathology (H E and MT staining), and immunohistochemistry was performed in the liver tissue. Administration of NER effectively normalized the elevated level of hepatic injury markers (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), marker of oxidative stress that is, malondialdehyde, inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-10), NF-κB p65, apoptotic marker (cleaved caspase 3) and increased the level of Nrf2 and antioxidant enzymes (superoxide dismutase, CAT, and glutathione). Treatment with NER further reduced the structural damage of hepatocytes and markers of hepatic fibrosis such as TGF-β1, hyaluronic acid, 4-hydroxyproline and collagen-rich stained area, estimated by MT staining. Findings of the current study showed that nerolidol exhibited potent antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic potential and thus acted as hepatoprotective agent. Present study represents novel mechanism of nerolidol against CP-induced hepatotoxicity. However, further studies are needed to use nerolidol as an adjuvant in chemotherapeutically treated patients.
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Affiliation(s)
- Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Mansoor Ali Syed
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | | | - Syed Ehtaishamul Haque
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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15
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Graf C, Welzel T, Bogdanou D, Vermehren J, Beckel A, Bojunga J, Friedrich-Rust M, Dietz J, Kubesch A, Mondorf A, Fischer S, Lutz T, Stoffers P, Herrmann E, Poynard T, Zeuzem S, Dultz G, Mihm U. Hepatitis C Clearance by Direct-Acting Antivirals Impacts Glucose and Lipid Homeostasis. J Clin Med 2020; 9:E2702. [PMID: 32825571 PMCID: PMC7564474 DOI: 10.3390/jcm9092702] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. METHODS 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. RESULTS 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). CONCLUSION Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.
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Affiliation(s)
- Christiana Graf
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Tania Welzel
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Dimitra Bogdanou
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Johannes Vermehren
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Anita Beckel
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Jörg Bojunga
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Mireen Friedrich-Rust
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Julia Dietz
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Alica Kubesch
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Antonia Mondorf
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Sarah Fischer
- Infektiologikum, Center for Infectious Diseases, 60596 Frankfurt, Germany; (S.F.); (T.L.)
| | - Thomas Lutz
- Infektiologikum, Center for Infectious Diseases, 60596 Frankfurt, Germany; (S.F.); (T.L.)
| | - Philipp Stoffers
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, 60596 Frankfurt, Germany;
| | | | - Stefan Zeuzem
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Georg Dultz
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Ulrike Mihm
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
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New LncRNAs in Chronic Hepatitis C progression: from fibrosis to hepatocellular carcinoma. Sci Rep 2020; 10:9886. [PMID: 32555359 PMCID: PMC7303194 DOI: 10.1038/s41598-020-66881-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/28/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world, and about 80% of the cases are associated with hepatitis B or C. Genetic and epigenetic alterations are accumulated over decades of chronic injury and may affect the functioning of tumor suppressor genes and protooncogenes. Studies have evidenced the role of Long non-coding RNAs (LncRNA) with oncogenic or tumor suppressor activities, suggesting a great potential in the treatment, diagnosis or indicator of prognosis in cancer. In this context, the aim of this study was to evaluate the global expression profile lncRNA in hepatic tissue samples with different stages of fibrosis associated with chronic hepatitis C, HCC and normal liver, in order to identify new lncRNAs that could contribute to study the progression of hepatic fibrosis to HCC associated with chronic hepatitis C. RNA-Seq was performed on Illumina NextSeq platform to identify lncRNAs expressed differently in 15 patients with chronic hepatitis C, three patients with HCC and three normal liver specimens. When the pathological tissues (fibrosis and carcinoma) were compared to normal hepatic tissue, were identified 2, 6 e 34 differentially expressed lncRNAs in moderate fibrosis, advanced fibrosis and HCC, respectively. The carcinoma group had the highest proportion of differentially expressed lncRNA (34) and of these, 29 were exclusive in this type of tissue. A heat map of the deregulated lncRNA revealed different expression patterns along the progression of fibrosis to HCC. The results showed the deregulation of some lncRNA already classified as tumor suppressors in HCC and other cancers, as well as some unpublished lncRNA whose function is unknown. Some of these lncRNAs are dysregulated since the early stages of liver injury in patients with hepatitis C, others overexpressed only in tumor tissue, indicating themselves as candidates of markers of fibrosis progression or tumor, with potential clinical applications in prognosis as well as a therapeutic target. Although there are already studies on lncRNA in hepatocellular carcinoma, this is the first study conducted in samples exclusively of HCV-related liver and HCV HCC.
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Laursen TL, Sandahl TD, Kazankov K, George J, Grønbæk H. Liver-related effects of chronic hepatitis C antiviral treatment. World J Gastroenterol 2020; 26:2931-2947. [PMID: 32587440 PMCID: PMC7304101 DOI: 10.3748/wjg.v26.i22.2931] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
More than five years ago, the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral (DAA) drugs. They proved highly efficient in curing patients with chronic hepatitis C (CHC), including patients with cirrhosis. The new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis, but the exact cause of the expected benefit was unclear. Further, little was known about how the underlying liver disease would be affected during and after viral clearance. In this review, we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects, such as macrophage activation, and the time-dependent effects of therapy, with specific emphasis on inflammation, structural liver changes, and liver function, as these factors are all related to morbidity and mortality in CHC patients. It seems clear that antiviral therapy, especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or cirrhosis. There seems to be a time-dependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver lesions. These improvements lead to favorable effects on liver function, followed by an improvement in cognitive dysfunction and portal hypertension. Overall, the data provide knowledge on the several beneficial effects of DAA therapy on liver-related parameters in CHC patients suggesting short- and long-term improvements in the underlying disease with the promise of an improved long-term prognosis.
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Affiliation(s)
- Tea L Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Thomas D Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, Sydney NSW 2145, Australia
- University of Sydney, Sydney NSW 2145, Australia
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
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18
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Schwabe RF, Tabas I, Pajvani UB. Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology 2020; 158:1913-1928. [PMID: 32044315 PMCID: PMC7682538 DOI: 10.1053/j.gastro.2019.11.311] [Citation(s) in RCA: 402] [Impact Index Per Article: 80.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/18/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk. We discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages, including the reactivation of developmental pathways such as TAZ, Notch, and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single-cell RNA sequencing. Finally, we summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH.
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Affiliation(s)
- Robert F Schwabe
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York.
| | - Ira Tabas
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York; Department of Physiology and Cellular Biophysics, Columbia University, New York, New York
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York
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19
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Sojoodi M, Wei L, Erstad DJ, Yamada S, Fujii T, Hirschfield H, Kim RS, Lauwers GY, Lanuti M, Hoshida Y, Tanabe KK, Fuchs BC. Epigallocatechin Gallate Induces Hepatic Stellate Cell Senescence and Attenuates Development of Hepatocellular Carcinoma. Cancer Prev Res (Phila) 2020; 13:497-508. [PMID: 32253266 DOI: 10.1158/1940-6207.capr-19-0383] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/02/2020] [Accepted: 03/31/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly morbid condition with lack of effective treatment options. HCC arises from chronically inflamed and damaged liver tissue; therefore, chemoprevention may be a useful strategy to reduce HCC incidence. Several reports suggest that epigallocatechin gallate (EGCG), extracted from green tea, can suppress liver inflammation and fibrosis in animal models, but its role in HCC chemoprevention is not well established. In this study, male Wistar rats were injected with diethylnitrosamine at 50 mg/kg for 18 weeks to induce cirrhosis and HCC, and EGCG was given in drinking water at a concentration of 0.02%. Clinically achievable dosing of EGCG was well-tolerated in diethylnitrosamine-injured rats and was associated with improved serum liver markers including alanine transaminase, aspartate transaminase, and total bilirubin, and reduced HCC tumor formation. Transcriptomic analysis of diethylnitrosamine-injured hepatic tissue was notable for increased expression of genes associated with the Hoshida high risk HCC gene signature, which was prevented with EGCG treatment. EGCG treatment also inhibited fibrosis progression, which was associated with inactivation of hepatic stellate cells and induction of the senescence-associated secretory phenotype. In conclusion, EGCG administered at clinically safe doses exhibited both chemopreventive and antifibrotic effects in a rat diethylnitrosamine liver injury model.
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Affiliation(s)
- Mozhdeh Sojoodi
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
| | - Lan Wei
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Derek J Erstad
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Suguru Yamada
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Tsutomu Fujii
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Hadassa Hirschfield
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Rosa S Kim
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Gregory Y Lauwers
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Michael Lanuti
- Division of Thoracic Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kenneth K Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
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20
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Tabll AA, Afifi MS, El-Etrawy AAS, El-Kousy SM, Smolic M, El Abd YS. CXCL9 chemokine level is associated with spontaneous clearance and sustained virological response in Egyptian Chronic Hepatitis C patients receiving direct acting antivirals. Hum Antibodies 2020; 28:141-148. [PMID: 32675406 DOI: 10.3233/hab-190400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic Hepatitis C virus (HCV) infection is associated with progressive liver inflammation which in turn leads to cirrhosis and finally causes hepatocellular carcinoma (HCC). By different escape mechanisms, the virus succeeds to evade the innate and acquired immune responses to establish chronic infection. AIM This study aimed to evaluate the level of chemokine CXCL9 and its correlation with some biochemical parameters in different subjects of HCV patients. MATERIALS AND METHODS A total of 83 persons participated in this study including healthy subjects without both HCV antibodies and HCV RNA (22.9%), HCV treated responders accomplished SVR post treatment, with HCV antibodies and absence of HCV RNA (24.1%), spontaneous or natural clearance patients, with positive HCV antibodies and negative HCV RNA without treatment (26.5%) and chronic HCV-patients, with both positive HCV antibodies and HCV RNA with no treatment (26.5%). HCV RNA was quantitated by real time PCR and serum CXCL9 level was measured by ELISA commercial kit pre-coated with human MIG/CXCL9 antibody. Assessment of biochemical and hematological parameters was carried out. RESULTS Data showed that, the level of CXCL9 was significantly increased in chronic individuals (627.1 pg/ml) (P< 0.001) than spontaneous clearance (107.76 pg/ml) and responder subjects (117.28 pg/ml) (P⩽ 0.05). No correlation has been found between CXCL9 level and viral load. Furthermore, CXCL9 levels correlated variably with some biochemical and hematological parameters according to each subject. CONCLUSION Serum Chemokine CXCL9 level is associated with spontaneous clearance of HCV and response to HCV treatment, which may be identified as a predictive marker among HCV patients.
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Affiliation(s)
- Ashraf A Tabll
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division National Research Centre, Giza, Egypt
| | - Mamdouh S Afifi
- Chemistry Department, Faculty of Science, Menufia University, Menufia, Egypt
| | - Abd-Allah S El-Etrawy
- Chemistry Department, Basic Science Center and Pharmaceutical Organic Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th October City, Egypt
| | - Salah M El-Kousy
- Chemistry Department, Faculty of Science, Menufia University, Menufia, Egypt
| | - Martina Smolic
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Yasmine S El Abd
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division National Research Centre, Giza, Egypt
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21
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Khatun M, Ray RB. Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis. Cells 2019; 8:E1249. [PMID: 31615075 PMCID: PMC6829586 DOI: 10.3390/cells8101249] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/11/2019] [Accepted: 10/12/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.
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Affiliation(s)
- Mousumi Khatun
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
| | - Ratna B Ray
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
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22
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Diabetes Mellitus and Risk of Hepatic Fibrosis/Cirrhosis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5308308. [PMID: 31080822 PMCID: PMC6475555 DOI: 10.1155/2019/5308308] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Accepted: 03/27/2019] [Indexed: 02/06/2023]
Abstract
Development of cirrhosis is two- to threefold greater in patients with diabetes mellitus (DM), and in this setting, the prevalence of cirrhosis is surging worldwide. The present review served to examine clinical ties between DM and liver fibrosis and hepatic cirrhosis and explore related biologic mechanisms. Pathways contributing to various etiologies of cirrhosis in conjunction with DM were key investigative targets.
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23
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Circulating levels of CXCL11 and CXCL12 are biomarkers of cirrhosis in patients with chronic hepatitis C infection. Cytokine 2019; 117:72-78. [PMID: 30826602 DOI: 10.1016/j.cyto.2019.02.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/21/2019] [Accepted: 02/01/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS The chemokines CXCL10 (interferon ϒ-inducible protein 10 [IP-10]), CXCL11 (Human interferon inducible T cell alpha chemokine [I-TAC]), and CXCL12 (stromal cell derived factor 1 [SDF-1]) contribute to cell recruitment, migration, activation, and homing in liver diseases and their serum levels have been shown to be associated with the degree of liver inflammation or fibrosis in various etiologies. However, the data may be contradictory or insufficient, particularly for CXCL12, in the field of chronic HCV infection. Here, we aimed to provide evidence for these chemokines as biomarkers for chronic HCV infection. METHODS We analyzed the serum concentration of the three chemokines in healthy donors (n = 39) and patients (n = 87) with chronic HCV infection. Chemokine serum levels were compared to the stage of liver inflammation and fibrosis obtained from liver biopsies. RESULTS Serum CXCL10 and CXCL11 levels were higher at advanced stages of liver inflammation than at earlier stages, but the results were only of medium significance. Both serum CXCL11 and CXCL12 levels were significantly higher in cirrhotic patients than those with low or medium stages of fibrosis. The AUROCs were 0.8167 and 0.8574, respectively, for the diagnosis of cirrhotic patients. CONCLUSION These data provide evidence for the value of CXCL10, CXCL11, and CXCL12 as biomarkers of liver inflammation and fibrosis during chronic HCV infection. Serum CXCL10 and CXCL11 levels were associated with liver inflammation, but the level of significance was insufficient. However, serum CXCL11 and CXCL12 levels were elevated in cirrhotic patients, showing equivalent diagnostic accuracy as the existing established single serum fibrosis markers or algorithms.
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24
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Sølund C, Hallager S, Pedersen MS, Fahnøe U, Ernst A, Krarup HB, Røge BT, Christensen PB, Laursen AL, Gerstoft J, Bélard E, Madsen LG, Schønning K, Pedersen AG, Bukh J, Weis N. Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation. Scand J Gastroenterol 2018; 53:849-856. [PMID: 29720023 DOI: 10.1080/00365521.2018.1467963] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES We describe factors associated with and barriers to initiation of Direct Acting Antiviral (DAA) treatment in patients with chronic hepatitis C, who fulfill national fibrosis treatment guidelines in Denmark. MATERIALS AND METHODS In this nationwide cohort study, we included patients with chronic hepatitis C from The Danish Database for Hepatitis B and C (DANHEP) who fulfilled fibrosis treatment criteria. Factors associated with treatment initiation and treatment failure were determined by logistic regression analyses. Medical records were reviewed from patients who fulfilled fibrosis treatment criteria, but did not initiate DAA treatment to determine the cause. RESULTS In 344 (49%) of 700 patients, who fulfilled treatment criteria, factors associated with DAA treatment initiation were transmission by other routes than injecting drug use odds ratio (OR) 2.13 (CI: 1.38-3.28), previous treatment failure OR 2.58 (CI: 1.84-3.61) and ALT above upper limit of normal OR 1.60 (CI: 1.18-2.17). The most frequent reasons for not starting treatment among 356 (51%) patients were non-adherence to medical appointments (n = 107/30%) and ongoing substance use (n = 61/17%). Treatment failure with viral relapse occurred in 19 (5.5%) patients, who were more likely to have failed previous treatment OR 4.53 (CI: 1.59-12.91). CONCLUSIONS In this nationwide cohort study, we found non-adherence to medical appointments and active substance use to be major obstacles for DAA treatment initiation. Our findings highlight the need for interventions that can overcome these barriers and increase the number of patients who can initiate and benefit from curative DAA treatment.
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Affiliation(s)
- Christina Sølund
- a Department of Infectious Diseases , Copenhagen University Hospital , Hvidovre , Denmark.,b Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Sofie Hallager
- a Department of Infectious Diseases , Copenhagen University Hospital , Hvidovre , Denmark
| | - Martin S Pedersen
- b Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark.,c Department of Clinical Microbiology , Copenhagen University Hospital , Hvidovre , Denmark.,d Department of Science and Environment , Roskilde University , Roskilde , Denmark
| | - Ulrik Fahnøe
- b Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Anja Ernst
- e Department of Molecular Diagnostics , Aalborg University Hospital , Aalborg , Denmark
| | - Henrik B Krarup
- e Department of Molecular Diagnostics , Aalborg University Hospital , Aalborg , Denmark.,f Department of Medical Gastroenterology , Aalborg University Hospital , Aalborg , Denmark
| | - Birgit T Røge
- g Department of Medicine , Lillebaelt Hospital , Kolding , Denmark
| | - Peer B Christensen
- h Department of Infectious Diseases , Odense University Hospital , Odense , Denmark.,i Department of Clinical Research, Faculty of Health Sciences , University of Southern Denmark , Odense , Denmark
| | - Alex L Laursen
- j Department of Infectious Diseases , Aarhus University Hospital , Skejby , Denmark
| | - Jan Gerstoft
- k Department of Infectious Diseases , Copenhagen University Hospital, Rigshospitalet , Copenhagen , Denmark.,l Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Erika Bélard
- m Department of Gastroenterology , Copenhagen University Hospital , Herlev , Denmark
| | - Lone G Madsen
- l Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark.,n Department of Medical Gastroenterology , Zealand University Hospital , Køge , Denmark
| | - Kristian Schønning
- c Department of Clinical Microbiology , Copenhagen University Hospital , Hvidovre , Denmark.,l Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Anders G Pedersen
- o DTU Bioinformatics , Technical University of Denmark , Lyngby , Denmark
| | - Jens Bukh
- a Department of Infectious Diseases , Copenhagen University Hospital , Hvidovre , Denmark.,b Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Nina Weis
- a Department of Infectious Diseases , Copenhagen University Hospital , Hvidovre , Denmark.,l Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
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25
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Nguyen C, Schlesinger KJ, James TW, James KM, Sah RL, Masuda K, Carlson JM. Novel magnetic resonance technique for characterizing mesoscale structure of trabecular bone. ROYAL SOCIETY OPEN SCIENCE 2018; 5:180563. [PMID: 30225048 PMCID: PMC6124118 DOI: 10.1098/rsos.180563] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/25/2018] [Indexed: 06/08/2023]
Abstract
Osteoporosis, characterized by increased fracture risk and bone fragility, impacts millions of adults worldwide, but effective, non-invasive and easily accessible diagnostic tests of the disease remain elusive. We present a magnetic resonance (MR) technique that overcomes the motion limitations of traditional MR imaging to acquire high-resolution frequency-domain data to characterize the texture of biological tissues. This technique does not involve obtaining full two-dimensional or three-dimensional images, but can probe scales down to the order of 40 μm and in particular uncover structural information in trabecular bone. Using micro-computed tomography data of vertebral trabecular bone, we computationally validate this MR technique by simulating MR measurements of a 'ratio metric' determined from a few k-space values corresponding to trabecular thickness and spacing. We train a support vector machine classifier on ratio metric values determined from healthy and simulated osteoporotic bone data, which we use to accurately classify osteoporotic bone.
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Affiliation(s)
- Chantal Nguyen
- Department of Physics, University of California, Santa Barbara, UC Santa Barbara, Santa Barbara, CA 93106-9530, USA
| | - Kimberly J. Schlesinger
- Department of Physics, University of California, Santa Barbara, UC Santa Barbara, Santa Barbara, CA 93106-9530, USA
| | - Timothy W. James
- BioProtonics, LLC, 3090 Old Calzada Rd, Santa Ynez, CA 93460, USA
| | - Kristin M. James
- BioProtonics, LLC, 3090 Old Calzada Rd, Santa Ynez, CA 93460, USA
| | - Robert L. Sah
- Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
- Department of Orthopaedic Surgery, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
- Center for Musculoskeletal Research, Institute of Engineering in Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
| | - Koichi Masuda
- Department of Orthopaedic Surgery, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
| | - Jean M. Carlson
- Department of Physics, University of California, Santa Barbara, UC Santa Barbara, Santa Barbara, CA 93106-9530, USA
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26
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Jiménez-Sousa MÁ, Gómez-Moreno AZ, Pineda-Tenor D, Medrano LM, Sánchez-Ruano JJ, Fernández-Rodríguez A, Artaza-Varasa T, Saura-Montalbán J, Vázquez-Morón S, Ryan P, Resino S. The IL7RA rs6897932 polymorphism is associated with progression of liver fibrosis in patients with chronic hepatitis C: Repeated measurements design. PLoS One 2018; 13:e0197115. [PMID: 29742149 PMCID: PMC5942816 DOI: 10.1371/journal.pone.0197115] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/26/2018] [Indexed: 02/07/2023] Open
Abstract
The polymorphisms at the α-chain of the IL-7 receptor (IL7RA) have been related to T-cell homeostasis and development and may contribute to immune system deregulation. In the present study, we analyzed the association between IL7RA polymorphisms and the progression of liver fibrosis in patients infected with HCV. We carried out a retrospective study with a design consisting of repeated measurements in 187 HCV-infected patients, to study the risk prediction of liver fibrosis progression using genetic factors. We genotyped the rs6897932, rs987106 and rs3194051 IL7RA polymorphisms using the Agena Bioscience's MassARRAY. Transient elastography was used to measure liver stiffness. The used cut-offs were: <7.1 kPa (F0-F1), 7.1-9.4 kPa (F2; significant fibrosis), 9.5-12.4 kPa (F3; advanced fibrosis), and ≥12.5 kPa (F4; cirrhosis). All HCV genotypes were analyzed. The median of follow-up time was 47.9 months. Baseline liver stiffness measurement (LSM) values did not show significant statistical differences for IL7RA genotypes (p>0.05). In univariate analysis, the rs6897932 T allele had a positive relationship with an increase in LSM (arithmetic mean ratio (AMR) = 1.21 (95%CI = 1.08; 1.36); p = 0.001), progression to advanced fibrosis (F≥3) (odds ratio (OR) = 2.51 (95%CI = 1.29; 4.88); p = 0.006) and progression to cirrhosis (F4) (OR = 2.71 (95%CI = 0.94; 5.03); p = 0.069). In multivariable analysis, the rs6897932 T allele was related to a higher increase of LSM values during follow-up (adjusted AMR = 1.27 (95%CI = 1.13; 1.42); p<0.001) and higher odds of progression to advanced fibrosis [adjusted OR = 4.46 (95%CI = 1.87; 10.62); p = 0.001], and progression to cirrhosis [adjusted OR = 3.92 (95%CI = 1.30; 11.77); p = 0.015]. Regarding IL7RA rs987106 and rs3194051 polymorphisms, we did not find significant results except for the relationship between IL7RA rs987106 and the increase in LSM values [adjusted OR = 1.12 (95%CI = 1.02; 1.23); p = 0.015]. The IL7RA rs6897932 polymorphism seems to be related to increased risk of liver fibrosis progression in HCV-infected patients. Thus, the rs6897932 polymorphism could be related to the physiopathology of CHC and might be used to successfully stratify the risk of CHC progression.
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Affiliation(s)
- María Ángeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Spain
| | | | - Daniel Pineda-Tenor
- Servicio de Laboratorio Clínico, Hospital Universitario de Fuenlabrada, Madrid, Spain
| | - Luz Maria Medrano
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Spain
| | | | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Spain
| | | | | | - Sonia Vázquez-Morón
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Spain
| | - Pablo Ryan
- Servicio de Medicina Interna, Hospital Universitario Infanta Leonor, Madrid, Spain
- Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Spain
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27
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Hernandez C, Huebener P, Pradere JP, Antoine DJ, Friedman RA, Schwabe RF. HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J Clin Invest 2018; 128:2436-2451. [PMID: 29558367 DOI: 10.1172/jci91786] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/13/2018] [Indexed: 12/15/2022] Open
Abstract
Cell death is a key driver of disease progression and carcinogenesis in chronic liver disease (CLD), highlighted by the well-established clinical correlation between hepatocellular death and risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Moreover, hepatocellular death is sufficient to trigger fibrosis and HCC in mice. However, the pathways through which cell death drives CLD progression remain elusive. Here, we tested the hypothesis that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) with key roles in acute liver injury, may link cell death to injury responses and hepatocarcinogenesis in CLD. While liver-specific HMGB1 deficiency did not significantly affect chronic injury responses such as fibrosis, regeneration, and inflammation, it inhibited ductular/progenitor cell expansion and hepatocyte metaplasia. HMGB1 promoted ductular expansion independently of active secretion in a nonautonomous fashion, consistent with its role as a DAMP. Liver-specific HMGB1 deficiency reduced HCC development in 3 mouse models of chronic injury but not in a model lacking chronic liver injury. As with CLD, HMGB1 ablation reduced the expression of progenitor and oncofetal markers, a key determinant of HCC aggressiveness, in tumors. In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor signature, and hepatocarcinogenesis in CLD.
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Affiliation(s)
- Celine Hernandez
- Department of Medicine, Columbia University, New York, New York, USA
| | - Peter Huebener
- Department of Medicine, Columbia University, New York, New York, USA.,Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jean-Philippe Pradere
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France
| | - Daniel J Antoine
- MRC Centre for Inflammation Research, University of Edinburgh, United Kingdom
| | - Richard A Friedman
- Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University, New York, New York, USA
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, New York, USA
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28
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Iqbal MS, Ashfaq UA, Aslam S, Khaliq S, Ghani MU, Batool F. Analysis of polymorphism rs1990760 of IFIH1 gene and treatment outcomes in HCV infection. Future Virol 2018. [DOI: 10.2217/fvl-2017-0116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hepatitis C virus (HCV) is endemic in Pakistan, infecting approximately 12 million people and expected to increase in the coming decades. IFIH1 is a viral RNA sensor gene essential for the activation of innate immunity against RNA viruses. Aim: The aim of the study was to analyze the association of the polymorphism (rs1990760) in IFIH1 gene among HCV infected Pakistani patients and healthy controls. Materials & methods: Blood samples from 400 chronic HCV patients (including 323 responders and 77 nonresponders) and 100 healthy individuals were collected. Results: Frequencies of heterozygous computed tomography genotype significantly associated with decreased HCV risk (χ2 = 0.072; 95% Cl: 1.06; 0.68−1.65; p ≤ 0.788). Conclusion: No significant differences were observed in alleles and genotype frequencies of IFIH1 (rs1990760) in Pakistani HCV infected patients.
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Affiliation(s)
- Muhammad Sarfaraz Iqbal
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Pakistan
| | - Sadia Aslam
- Allama Iqbal Medical College, Lahore, Pakistan
| | - Saba Khaliq
- Department of Physiology, University of Health Sciences, Lahore, Pakistan
| | - Muhammad Usman Ghani
- Department of Bioinformatics & Biotechnology, Government College University Faisalabad, Pakistan
| | - Farzana Batool
- Department of Biochemistry, Government College University Faisalabad, Pakistan
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29
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Mizuochi T, Takano T, Yanagi T, Ushijima K, Suzuki M, Miyoshi Y, Ito Y, Inui A, Tajiri H. Epidemiologic features of 348 children with hepatitis C virus infection over a 30-year period: a nationwide survey in Japan. J Gastroenterol 2018; 53:419-426. [PMID: 28567493 DOI: 10.1007/s00535-017-1351-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 05/19/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Although the epidemiology of hepatitis C virus (HCV) infection among children may be rapidly changing, few reports have characterized large nationwide cohorts of children with HCV infection. We, therefore, sought to clarify the epidemiology and natural history of HCV infection in Japanese children born over the last three decades. METHODS Sixty-five pediatric centers retrospectively and prospectively recruited consecutive, otherwise-healthy HCV-infected children born during 1986 to 2015. RESULTS Entry criteria were met by 348 children. Age at initial diagnosis of infection has decreased significantly in recent years. Cirrhosis and hepatocellular carcinoma were not identified. Prevalence of spontaneous clearance and of interferon treatment with/without ribavirin were 9 and 54%, respectively. Maternal transmission has increased significantly, representing over 99% of cases in the last decade. No transfusion-related cases have been seen after 1994. HCV genotype 2 has increased to become the most prevalent in Japanese children. Histopathology examination of liver specimens showed no or mild fibrosis in most children with chronic hepatitis C; none showed cirrhosis. CONCLUSIONS This largest nationwide cohort study of Asian children with HCV infection spanned the last three decades. None of these Japanese children developed cirrhosis or hepatocellular carcinoma. Maternal transmission increased to account for 99% of cases during the last decade. Genotype 2 now is most prevalent in these children. Histopathologically, most children with chronic hepatitis C showed mild fibrosis or none.
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Affiliation(s)
- Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
| | - Tomoko Takano
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Tadahiro Yanagi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Kosuke Ushijima
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yoko Miyoshi
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshinori Ito
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Hitoshi Tajiri
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
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Page SJ, Rivera MM, Kleiner DE, Zhao X, Auh S, Remmers EF, Heller T. Three variants in the nicotinamide adenine dinucleotide phosphate oxidase complex are associated with HCV-related liver damage. Hepatol Commun 2018; 1:973-982. [PMID: 29404504 PMCID: PMC5721460 DOI: 10.1002/hep4.1103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 08/13/2017] [Accepted: 08/28/2017] [Indexed: 12/23/2022] Open
Abstract
Approximately 71 million people are chronically infected with the hepatitis C virus (HCV), a potentially lethal pathogen. HCV generates oxidative stress correlating with disease severity. HCV proteins increase reactive oxygen species production by stimulating nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity. Reactive oxygen species are necessary for host defense and cell signaling; however, elevated NOX activity contributes to cancer, and NOX overexpression is associated with hepatic fibrosis. Our aim was to investigate whether single nucleotide polymorphisms (SNPs) in NOX family members are associated with HCV-related liver damage. Three hundred and thirty-one individuals of European ancestry and 90 individuals of African ancestry, all diagnosed with HCV, were genotyped for 243 tagSNPs in NOX enzymes and their regulatory factors. Pathology scores were available for 288 Caucasians and 71 Africans, and mortality status was determined for all subjects. SNPs were tested for association with pathology scores and as predictors of mortality. In Africans, homozygosity for the A allele of rs12753665 (neutrophil cytosolic factor 2) and homozygosity for the T allele of rs760519 (neutrophil cytosolic factor 4) were associated with and predictive of higher rates of advanced fibrosis and cirrhosis compared to other genotypes after controlling for age and sex. In Caucasians, homozygosity for the T allele of rs2292464 (dual oxidase 1) was associated with and predictive of decreased periportal inflammation after controlling for age and sex. No SNPs were significant predictors of mortality. Conclusion: In this exploratory study, three NOX-related polymorphisms in two ethnic groups were significantly associated with hepatic inflammation and fibrosis. Future studies investigating these SNPs in larger cohorts of patients with HCV are warranted. (Hepatology Communications 2017;1:973-982).
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Affiliation(s)
- Sandra J Page
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda MD
| | - Maria M Rivera
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda MD
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health Bethesda MD
| | - Xiongce Zhao
- Center for Veterinary Medicine, U.S. Food and Drug Administration Rockville MD
| | - Sungyoung Auh
- Office of Clinical Director, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda MD
| | - Elaine F Remmers
- Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health Bethesda MD
| | - Theo Heller
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda MD
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31
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Jiao X, Fan Z, Chen H, He P, Li Y, Zhang Q, Ke C. Serum and exosomal miR-122 and miR-199a as a biomarker to predict therapeutic efficacy of hepatitis C patients. J Med Virol 2017; 89:1597-1605. [PMID: 28401565 DOI: 10.1002/jmv.24829] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 03/08/2017] [Indexed: 02/05/2023]
Abstract
MicroRNA (miRNA), which has been shown to correlate with liver functions, has been proposed as a new biomarker reflecting liver injury. The aim of the study was to investigate miRNA-122 (miR-122) and mir-RNA-199a (miR-199a) as a biomarker for predicting therapeutic efficacy in hepatitis C (HepC) patients. A total of 47 HepC 1b patients and 16 healthy subjects were enrolled in the study. Serum and exosomal mir-RNAs and other conventional biomarkers reflecting liver function were evaluated. The miR-122 levels in serum (miR-122ser ) and exosomes (miR-122exo ) were significantly lower in the Hepatitis C virus (HCV) genotype 1b patients than in the normal controls, but these levels were higher compared to the non-genotype 1b group. The mean miR-122ser level in the sustained virological response (SVR) group was significantly higher than that in the non-response (NR) group (P < 0.01), and the miR-122exo level in the SVR group was also higher than that in the NR group (P > 0.05), although this difference was not significant. miR-199a levels showed similar trends with the miR-122 levels in serum and exosomes. HCV RNAser was negatively correlated with the miR-122ser (r = -0.473, P = 0.004) and miR-122exo (r = -0.424, P = 0.009) levels. miR-122ser levels were positively associated with miR-199aser levels (r = 0.453, P = 0.002). Univariate and multivariate regression analyses reveal that the miR-122ser levels and ALT/AST ratio demonstrated a predictive value in evaluating patient outcomes. Serum miR-122 and miR-199a are potential biomarkers that reflect therapeutic efficacy.
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Affiliation(s)
- Xiaoyang Jiao
- Cell Biology and Genetics Department, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Zhicheng Fan
- Cell Biology and Genetics Department, Shantou University Medical College, Shantou, Guangdong, P.R. China
- Department of Clinical Laboratory, Henan Province Hospital of Traditional Chinese Medicine, Second Affiliated Hospital of Henan University of TCM, Henan, P.R. China
| | - Huanzhu Chen
- Cell Biology and Genetics Department, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Ping He
- Cell Biology and Genetics Department, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Yazhen Li
- Cell Biology and Genetics Department, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Qiaoxin Zhang
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Changwen Ke
- Cell Biology and Genetics Department, Shantou University Medical College, Shantou, Guangdong, P.R. China
- Center for Disease Control and Prevention of Guangdong Province, Guangzhou
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Jiménez-Sousa MÁ, Gómez-Moreno AZ, Pineda-Tenor D, Medrano LM, Sánchez-Ruano JJ, Fernández-Rodríguez A, Artaza-Varasa T, Saura-Montalban J, Vázquez-Morón S, Ryan P, Resino S. CXCL9-11 polymorphisms are associated with liver fibrosis in patients with chronic hepatitis C: a cross-sectional study. Clin Transl Med 2017; 6:26. [PMID: 28755163 PMCID: PMC5533694 DOI: 10.1186/s40169-017-0156-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 07/23/2017] [Indexed: 02/06/2023] Open
Abstract
Background and aims CXCL9-11 polymorphisms are related to various infectious diseases, including hepatitis C virus (HCV) infection. In this study, we analyzed the association between CXCL9-11 polymorphisms and liver fibrosis in HCV-infected patients. Methods We performed a cross-sectional study in 389 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using the Sequenom’s MassARRAY platform. The primary outcome variable was the liver stiffness measurement (LSM). We established three cut-offs of LSM: LSM ≥ 7.1 kPa (F ≥ 2—significant fibrosis), LSM ≥ 9.5 kPa (F ≥ 3—advanced fibrosis), and LSM ≥ 12.5 kPa (F4—cirrhosis). Results Recessive, overdominant and codominant models of inheritance showed significant values, but the overdominant model was the best fitting our data. In this case, CXCL9 rs10336 AG, CXCL10 rs3921 CG and CXCL11 rs4619915 AG were mainly associated with lower values of LSM [(adjusted GMR (aGMR) = 0.85 (p = 0.005), aGMR = 0.84 (p = 0.003), and aGMR = 0.84 (p = 0.003), respectively]. Patients with CXCL9 rs10336 AG genotype had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.59 (p = 0.016)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.54 (p = 0.010)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.56 (p = 0.043)]. Patients with CXCL10 rs3921 CG or CXCL11 rs4619915 AG genotypes had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.56 (p = 0.008)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.55 (p = 0.013)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.57 (p = 0.051)]. Additionally, CXCL9-11 polymorphisms were related to lower liver stiffness under a codominant model of inheritance, being the heterozygous genotypes also protective against hepatic fibrosis. In the recessive inheritance model, the CXCL9 rs10336 AA, CXCL10 rs3921 CC and CXCL11 rs4619915 AA were associated with higher LSM values [(adjusted GMR (aGMR) = 1.19 (p = 0.030), aGMR = 1.21 (p = 0.023), and aGMR = 1.21 (p = 0.023), respectively]. Moreover, patients with CXCL9 rs10336 AA genotype had higher odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 1.83 (p = 0.044)] and advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.85 (p = 0.045)]. Furthermore, patients with CXCL10 rs3921 CC or CXCL11 rs4619915 AA genotypes had higher odds of advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.89 (p = 0.038)]. Conclusions CXCL9-11 polymorphisms were related to likelihood of having liver fibrosis in HCV-infected patients. Our data suggest that CXCL9-11 polymorphisms may play a significant role against the progression of CHC and could help prioritize antiviral therapy.
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Affiliation(s)
- María Ángeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | | | - Daniel Pineda-Tenor
- Servicio de Laboratorio Clínico, Hospital Universitario de Fuenlabrada, Madrid, Spain
| | - Luz Maria Medrano
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | | | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | | | | | - Sonia Vázquez-Morón
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Pablo Ryan
- Servicio de Medicina Interna, Hospital Universitario Infanta Leonor, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Neesgaard B, Ruhwald M, Weis N. Inducible protein-10 as a predictive marker of antiviral hepatitis C treatment: A systematic review. World J Hepatol 2017; 9:677-688. [PMID: 28588752 PMCID: PMC5437612 DOI: 10.4254/wjh.v9.i14.677] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 12/30/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate interferon-γ-inducible protein-10’s (IP-10) potential to anticipate rapid (RVR)- and sustained virological responses (SVR) to chronic hepatitis C (CHC) treatment.
METHODS We included case series examining RVR or SVR in relation to 24 or 48 wk treatment for CHC, in patients treatment free for at least six months, with genotype 1 or 4, and in relation to 24 wk treatment for genotype 2 and 3, with pegylated interferon in combination with ribavirin. Patients had to have both a baseline IP-10 level as well as a hepatitis C virus (HCV)-RNA determination 4 wk after treatment initiation or 24 wk after end of treatment. Studies including patients with liver diseases other than CHC, human immunodeficiency virus-infection, treatment with immunosuppresents or cytostatica, alcohol dependency or active intravenous drug-use were excluded. We found 81 articles by searching the MEDLINE and EMBASE databases. Eight studies were eligible for inclusion. Their quality were assesed using an 18 point checklist for case series, developed using a modified Delphi technique. Information was extracted from the articles, and no raw data was requisitioned. The review protocol was registered at the International Prospective Register of Systematic Reviews (reg. number: CRD42014008736).
RESULTS Three studies reported on baseline IP-10 level in association with RVR. A signigficant association was found for HCV genotype 1 infection by two studies. Only two studies reported on HCV genotype 4 infected and genotype 2 and 3 infected patients, respectively. A trend was seen for an association between RVR and baseline IP-10 for genotype 4, while no association was found for genotype 2 and 3. Seven studies provided information regarding baseline IP-10 and SVR. Following the pattern regarding rapid virological response all five studies examining SVR in relation to baseline IP-10 levels for HCV, genotype 1 infected patients showed a significant association. Likewise a significant association was seen for HCV, genotype 4 infected, while no association was found for HCV, genotype 2 and 3 infected. Though only two studies examined the assosiation for HCV genotype 4 infected and HCV genotype 2 and 3 infected respectively.
CONCLUSION We found indications of a possible association between baseline IP-10 level and virological responses in patients with CHC genotype 1 and 4.
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Moqueet N, Kanagaratham C, Gill MJ, Hull M, Walmsley S, Radzioch D, Saeed S, Platt RW, Klein MB. A prognostic model for development of significant liver fibrosis in HIV-hepatitis C co-infection. PLoS One 2017; 12:e0176282. [PMID: 28467457 PMCID: PMC5415136 DOI: 10.1371/journal.pone.0176282] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 04/07/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Liver fibrosis progresses rapidly in HIV-Hepatitis C virus (HCV) co-infected individuals partially due to heightened inflammation. Immune markers targeting stages of fibrogenesis could aid in prognosis of fibrosis. METHODS A case-cohort study was nested in the prospective Canadian Co-infection Cohort (n = 1119). HCV RNA positive individuals without fibrosis, end-stage liver disease or chronic Hepatitis B at baseline (n = 679) were eligible. A random subcohort (n = 236) was selected from those eligible. Pro-fibrogenic markers and Interferon Lambda (IFNL) rs8099917 genotype were measured from first available sample in all fibrosis cases (APRI ≥ 1.5 during follow-up) and the subcohort. We used Cox proportional hazards and compared Model 1 (selected clinical predictors only) to Model 2 (Model 1 plus selected markers) for predicting 3-year risk of liver fibrosis using weighted Harrell's C and Net Reclassification Improvement indices. RESULTS 113 individuals developed significant liver fibrosis over 1300 person-years (8.63 per 100 person-years 95% CI: 7.08, 10.60). Model 1 (age, sex, current alcohol use, HIV RNA, baseline APRI, HCV genotype) was nested in model 2, which also included IFNL genotype and IL-8, sICAM-1, RANTES, hsCRP, and sCD14. The C indexes (95% CI) for model 1 vs. model 2 were 0.720 (0.649, 0.791) and 0.756 (0.688, 0.825), respectively. Model 2 classified risk more appropriately (overall net reclassification improvement, p<0.05). CONCLUSIONS Including IFNL genotype and inflammatory markers IL-8, sICAM-1, RANTES, hs-CRP, and sCD14 enabled better prediction of the 3-year risk of significant liver fibrosis over clinical predictors alone. Whether this modest improvement in prediction justifies their additional cost requires further cost-benefit analyses.
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Affiliation(s)
- Nasheed Moqueet
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
| | - Cynthia Kanagaratham
- Department of Medicine and Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - M. John Gill
- Southern Alberta HIV Clinic, Calgary, Alberta, Canada
| | - Mark Hull
- BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, BC, Canada
| | - Sharon Walmsley
- Toronto General Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Danuta Radzioch
- Department of Medicine and Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Sahar Saeed
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
| | - Robert W. Platt
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
| | - Marina B. Klein
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
- Division of Infectious Diseases and Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada
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Kleiner DE. On beyond staging and grading: Liver biopsy evaluation in a posttreatment world. Hepatology 2017; 65:1432-1434. [PMID: 28195336 PMCID: PMC5397352 DOI: 10.1002/hep.29111] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 02/08/2017] [Indexed: 01/22/2023]
Affiliation(s)
- David E. Kleiner
- Chief, Post-mortem Section, Laboratory of Pathology, National Cancer Institute
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Zaily DG, Marlen CF, Santiago DC, Gillian MD, Carmen VS, Zurina CE, Enrique R. AS, Liz AL, Lisset GF, Sacha LDV, Elena FB. Clinical Evaluation of Terap C Vaccine in Combined Treatment with Interferon and Ribavirin in Patients with Hepatitis C. CURRENT THERAPEUTIC RESEARCH 2017; 85:20-28. [PMID: 29158855 PMCID: PMC5681293 DOI: 10.1016/j.curtheres.2017.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 04/14/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND An estimated 170 million individuals worldwide are infected with the hepatitis C virus (HCV). Although treatment options using a combination of pegylated interferon and ribavirin (P-IFN/RBV) are available, sustained clearance of the virus is only achieved in approximately 40% of individuals infected with HCV genotype 1. Recent advances in the treatment of HCV using directly acting antiviral agents have been achieved; however, treatment can be very expensive and is associated with substantial side effects. The development of a new treatment modality is needed. One possible modality could be specific immunotherapy. Terap C is a therapeutic vaccine candidate composed of pIDKE2, a plasmid expressing HCV structural antigens, with a recombinant HCV core protein, Co.120. OBJECTIVE To assess the safety and efficacy of concomitant therapy with the candidate vaccine, Terap C, IFN α-2b and ribavirin in untreated individuals with HCV genotype 1 infection. METHODS This was a Phase II randomized, placebo-controlled, double-blind clinical trial evaluating the safety and efficacy of Terap C concomitant with IFN α-2b/RBV in 92 treatment-naïve patients with HCV genotype 1 infection. The study was conducted at the Gastroenterology Institute in Havana, Cuba. Patients were randomly assigned to 1 of 5 groups. The control group (Group 1) received IFN α-2b/RBV and placebo for 48 weeks. Groups 2 and 3 were administered Terap C 6 and 9 times, respectively, in addition to standard IFN α-2b/RBV treatment. In groups 4 and 5, Terap C was introduced 12 weeks after the initiation of IFN α-2b/RBV and administered 6 and 9 times, respectively, concomitant with IFN α-2b/RBV. RESULTS All patients showed some adverse events. Out of 3615 adverse events, only 18.8% were considered to be probably associated with administration of Terap C. Most events (47.4%) were considered to be improbably associated with of administration Terap C. Only 33.8% were considered possibly temporarily associated with Terap C, and can be explained by the use of conventional IFN α-2b + RBV or by HCV itself. The most common adverse events (≥65%) observed were pain at the injection site, headache, asthenia, psychiatric disturbances, fever, and gastrointestinal symptoms. Regarding sustained virological response, a 20% superiority was observed in the patients who received concomitant Terap C treatments from the beginning of the study compared with those who started after Week 12. CONCLUSIONS Vaccination with Terap C in patients with chronic HCV infection was safe and well tolerated. Clinical trial protocol code: IG/VHI/HC/0701; Public Register Code: RPCEC00000074.
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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.
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Liu Z, Wei X, Chen T, Huang C, Liu H, Wang Y. Characterization of fibrosis changes in chronic hepatitis C patients after virological cure: A systematic review with meta-analysis. J Gastroenterol Hepatol 2017; 32:548-557. [PMID: 27503423 DOI: 10.1111/jgh.13500] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/20/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Virological cure becomes available for most patients with chronic hepatitis C (CHC), but residual fibrosis can be an independent risk factor for liver-related complications. We aimed to characterize fibrosis change in CHC patients achieved virological cure. METHODS We did a systematic literature search for studies that had pre and post-treatment evaluations of histologic fibrosis in CHC patients with sustained virological response (SVR). We identified the association of SVR with the incidence, extent, and velocity of fibrosis change. RESULTS Overall, 3243 patients were included. Interferon-based regimens were used for all the patients, achieving a median SVR prevalence of 36.2%. Biopsy interval ranged from 1 to 10 years. Mean baseline fibrosis score (METAVIR) was 2.3 points. Compared with non-SVR patients, SVR patients could have higher incidence of fibrosis regression (35.1% vs 17.0%; OR: 3.3; P < 0.001), regardless of baseline fibrosis severity, way of biopsy evaluation, treatment regimen, or study design, and could have more extent of reduction (-0.31 points vs -0.00 points; P = 0.004). Baseline advanced fibrosis (F > 2) was associated with more rapid regression in both SVR and non-SVR patients (P < 0.05 for both). SVR patients could have lower incidence of fibrosis progression and maintenance than non-SVR patients by 4.8% versus 23.1% (OR: 0.20; P = 0.008) and 42.9% versus 55.2% (OR: 0.53; P < 0.001), respectively. CONCLUSIONS There could be a favorable characteristic of fibrosis regression in SVR patients. However, residential fibrosis may remain an issue because of a non-ignorable prevalence of fibrosis maintenance among these patients.
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Affiliation(s)
- Zhipeng Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Xuewu Wei
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Ting Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Chuhong Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Haiyan Liu
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Yan Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Southern Medical University Biomedical Research Center, Southern Medical University, Guangzhou, China
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Besheer T, El-Bendary M, Elalfy H, Abd El-Maksoud M, Salah M, Zalata K, Elkashef W, Elshahawy H, Raafat D, Elemshaty W, Almashad N, Zaghloul H, El-Gilany AH, Abdel Razek AAK, Abd Elwahab M. Prediction of Fibrosis Progression Rate in Patients with Chronic Hepatitis C Genotype 4: Role of Cirrhosis Risk Score and Host Factors. J Interferon Cytokine Res 2017; 37:97-102. [PMID: 28068153 DOI: 10.1089/jir.2016.0111] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The rate of liver fibrosis progression in chronic hepatitis C (CHC) patients is highly variable and affected by different factors. This study aimed to assess the role of cirrhosis risk score (CRS) based on 7 genetic variants (7 single-nucleotide polymorphisms [SNPs]) and host factors (age and sex) in the prediction of the rate of fibrosis progression in CHC. Duration of infection was determined in 115 patients. The fibrosis progression rate (FPR) per year was calculated as the ratio between fibrosis stage and the duration of infection. SNP genotyping were performed and CRS was determined based on it. FPR was significantly elevated in patients who acquired infection at age >40 years versus those who acquired infection at 30-40 years and those who acquired infection at <30 years. Median FPR was significantly higher in males than females (0.17 vs. 0.15) with P = 0.001. CRS value ≥0.8 is predictive of patients with high risk for cirrhosis, and CRS value <0.5 is predictive of patients with low risk for cirrhosis. There was significant positive correlation between CRS and FPR (P ≤ 0.001). CRS based on 7 SNPs at cutoff value ≥0.8, age at infection >40 years, and male sex are predictors of higher FPR.
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Affiliation(s)
- Tarek Besheer
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | - Mahmoud El-Bendary
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | - Hatem Elalfy
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | | | - Mohamed Salah
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | - Khaled Zalata
- 2 Department of Pathlogy, Mansoura University , Mansoura, Egypt
| | - Wagdi Elkashef
- 2 Department of Pathlogy, Mansoura University , Mansoura, Egypt
| | - Heba Elshahawy
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Doaa Raafat
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Wafaa Elemshaty
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Noha Almashad
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Hosam Zaghloul
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Abdel-Hady El-Gilany
- 4 Department of Public Health and Preventive Medicine, Mansoura University , Mansoura, Egypt
| | | | - Mohamed Abd Elwahab
- 6 Gastroenterology Surgical Center, Mansoura Faculty of Medicine, Mansoura University , Mansoura, Egypt
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Takyar V, Surana P, Kleiner DE, Wilkins K, Hoofnagle JH, Liang TJ, Heller T, Koh C. Noninvasive markers for staging fibrosis in chronic delta hepatitis. Aliment Pharmacol Ther 2017; 45:127-138. [PMID: 27813124 PMCID: PMC5135658 DOI: 10.1111/apt.13834] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 08/21/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Serum fibrosis markers are useful in staging chronic hepatitis B (HBV) and C (HCV) virus but have not been evaluated in chronic hepatitis D virus (HDV). AIM To evaluate the utility of serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, aspartate aminotransferase ratio (AAR), age-platelet index (API), AST-to-platelet-ratio-index (APRI) and Hui score] in HDV infection. METHODS Clinical and histologic laboratory data from HBV, HCV and HDV patients were evaluated and serum fibrosis markers were calculated. The ability of fibrosis markers to detect advanced fibrosis (Ishak ≥4) and cirrhosis (Ishak = 6) were evaluated and compared between viral infections. RESULTS A total of 1003 subjects (HCV = 701, HBV = 240 and HDV = 62) with mean age of 46 ± 11 and 66% male were evaluated. HDV subjects had higher ALT and AST than HCV and lower platelets than both HBV and HCV. Histologically, HDV had the greatest percentage of Ishak ≥4 and necroinflammation. FIB-4 performed best in detecting advanced fibrosis and cirrhosis in all viral cohorts. In HDV, area under the receiver operator curve (AUROC) 95% confidence intervals for detecting advanced fibrosis were: FIB-4 = 0.70 (0.55-0.84), API = 0.69 (0.55-0.82), APRI = 0.68 (0.54-0.82), Hui score = 0.63 (0.49-0.78), AAR = 0.63 (0.48-0.77). The AUROC for detecting cirrhosis in HDV were: FIB-4 = 0.83 (0.69-0.97), API = 0.80 (0.66-0.95), APRI = 0.75 (0.61-0.89), Hui score = 0.70 (0.49-0.91) and AAR = 0.70 (0.48-0.93). Adjustment of published cut-offs led to marginal improvements in FIB4 for advanced fibrosis and of APRI for cirrhosis in HDV. CONCLUSIONS Serum fibrosis markers have lower performance accuracy in chronic HDV infected patients compared to HBV and HCV patients. Other noninvasive fibrosis markers should be explored to assist in the management of these patients.
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Affiliation(s)
- Varun Takyar
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Pallavi Surana
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kenneth Wilkins
- Office of the Director, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jay H. Hoofnagle
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Clinical Advancements in the Targeted Therapies against Liver Fibrosis. Mediators Inflamm 2016; 2016:7629724. [PMID: 27999454 PMCID: PMC5143744 DOI: 10.1155/2016/7629724] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 10/11/2016] [Accepted: 10/19/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis.
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Zeremski M, Dimova RB, Pillardy J, de Jong YP, Jacobson IM, Talal AH. Fibrosis Progression in Patients With Chronic Hepatitis C Virus Infection. J Infect Dis 2016; 214:1164-70. [PMID: 27485356 PMCID: PMC6281340 DOI: 10.1093/infdis/jiw332] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 06/17/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Fibrosis progression varies markedly in hepatitis C virus (HCV)-infected individuals. We investigated factors that influence fibrosis progression in chronic HCV infection. METHODS HCV-infected patients who underwent at least 2 liver biopsies were included in this study. Associations between fibrosis progression and epidemiologic, virologic, and disease-associated factors were analyzed using logistic regression and multistate Markov modeling. RESULTS We analyzed 936 biopsy specimens obtained from 378 individuals. Mean age (±SD) at first biopsy was 48.3 ± 9.3 years, 59.3% of patients were male, 59.9% were white, and 86.7% were infected with HCV genotype 1. Fibrosis progression and cirrhosis occurred in 57.4% and 5.8%, respectively. Fibrosis progression between the first and last biopsies was associated with lower fibrosis in the first biopsy specimen (P < .001) and with the occurrence of at least 1 flare in the alanine aminotransferase (ALT) level (>200 U/L; P = .007). We found the highest fibrosis progression rate between stages 0 and 1 and the lowest between stages 2 and 3. Increased necroinflammation and higher ALT level were associated with faster progression. HCV genotype 3-infected patients were more likely to progress to cirrhosis (P < .001). CONCLUSIONS Fibrosis progression in HCV is not linear but varies according to stage, with the highest progression in patients with the lowest fibrosis severity. Patients who experience flares in the ALT level are also more likely to progress.
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Affiliation(s)
- Marija Zeremski
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College
| | - Rositsa B. Dimova
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine
- Department of Biostatistics, State University of New York, Buffalo
| | | | - Ype P. de Jong
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College
| | | | - Andrew H. Talal
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine
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Carmona I, Cordero P, Ampuero J, Rojas A, Romero-Gómez M. Role of assessing liver fibrosis in management of chronic hepatitis C virus infection. Clin Microbiol Infect 2016; 22:839-845. [PMID: 27677698 DOI: 10.1016/j.cmi.2016.09.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Revised: 08/25/2016] [Accepted: 09/20/2016] [Indexed: 12/16/2022]
Abstract
Fibrosis progression is common in hepatitis C. Both host and viral factors influence its natural history. Liver fibrosis is a key predictive factor for advanced disease including endpoints such as liver failure, cirrhosis and hepatocellular carcinoma (HCC). METAVIR fibrosis stages F3-F4 have been considered as the threshold for antiviral therapy. However, this aspect is controversial after the advent of new direct-acting antivirals (DAAs) because they show an excellent efficacy and safety profile. Moreover, in the DAA era, fibrosis stage seems not to be a predictive factor of a sustained virological response (SVR). Viral eradication decreases liver damage by improving the inflammation, as well as by regressing fibrosis irrespective of the treatment regimen. Non-invasive methods are useful in the assessment of liver fibrosis, replacing liver biopsy in clinical practice; but their usefulness for monitoring fibrosis after SVR needs to be demonstrated. Fibrosis regression has been demonstrated after the eradication of hepatitis C virus infection and is associated with a lower risk of hepatic cirrhosis and liver cancer. However, patients showing advanced fibrosis and cirrhosis must be followed-up after SVR, as risks of portal hypertension and HCC remain.
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Affiliation(s)
- I Carmona
- Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen del Rocio-Virgen Macarena University Hospitals, Sevilla, Spain
| | - P Cordero
- Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen del Rocio-Virgen Macarena University Hospitals, Sevilla, Spain
| | - J Ampuero
- Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen del Rocio-Virgen Macarena University Hospitals, Sevilla, Spain; Institute of Biomedicine of Seville, Sevilla, Spain
| | - A Rojas
- Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen del Rocio-Virgen Macarena University Hospitals, Sevilla, Spain; Institute of Biomedicine of Seville, Sevilla, Spain
| | - M Romero-Gómez
- Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen del Rocio-Virgen Macarena University Hospitals, Sevilla, Spain; Institute of Biomedicine of Seville, Sevilla, Spain.
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DebRoy S, Hiraga N, Imamura M, Hayes CN, Akamatsu S, Canini L, Perelson AS, Pohl RT, Persiani S, Uprichard SL, Tateno C, Dahari H, Chayama K. Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. J Viral Hepat 2016; 23:708-17. [PMID: 27272497 PMCID: PMC4974116 DOI: 10.1111/jvh.12551] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 04/04/2016] [Indexed: 12/15/2022]
Abstract
Legalon SIL (SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle (Silybum marianum) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus (HCV) in patients leading to viral clearance in combination with ribavirin. To elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA-SCID-chimeric mice with humanized livers. Chronically HCV-infected mice (n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albumin (hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated (r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. The results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes.
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Affiliation(s)
- Swati DebRoy
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA,Department of Mathematics and Computational Science, University of South Carolina-Beaufort, Bluffton, SC, USA
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C. Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Sakura Akamatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Laetitia Canini
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA,Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
| | - Alan S. Perelson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Ralf T. Pohl
- German Association of Phytotherapy, Nachtigallenweg 46, Speyer 67346, Germany
| | | | - Susan L. Uprichard
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | | | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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Hepatocarcinogenesis associated with hepatitis B, delta and C viruses. Curr Opin Virol 2016; 20:1-10. [PMID: 27504999 DOI: 10.1016/j.coviro.2016.07.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 07/20/2016] [Accepted: 07/20/2016] [Indexed: 12/13/2022]
Abstract
Globally, over half a billion people are persistently infected with hepatitis B (HBV) and/or hepatitis C viruses. Chronic HBV and HCV infection frequently lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Co-infections with hepatitis delta virus (HDV), a subviral satellite requiring HBV for its propagation, accelerates the progression of liver disease toward HCC. The mechanisms by which these viruses cause malignant transformation, culminating in HCC, remain incompletely understood, partially due to the lack of adequate experimental models for dissecting these complex disease processes in vivo.
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Elkrief L, Rautou PE, Sarin S, Valla D, Paradis V, Moreau R. Diabetes mellitus in patients with cirrhosis: clinical implications and management. Liver Int 2016; 36:936-48. [PMID: 26972930 DOI: 10.1111/liv.13115] [Citation(s) in RCA: 140] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 03/07/2016] [Indexed: 12/12/2022]
Abstract
Disorders of glucose metabolism, namely glucose intolerance and diabetes, are frequent in patients with chronic liver diseases. In patients with cirrhosis, diabetes can be either a classical type 2 diabetes mellitus or the so-called hepatogenous diabetes, i.e. a consequence of liver insufficiency and portal hypertension. This review article provides an overview of the possible pathophysiological mechanisms explaining diabetes in patients with cirrhosis. Cirrhosis is associated with portosystemic shunts as well as reduced hepatic mass, which can both impair insulin clearance by the liver, contributing to peripheral insulin resistance through insulin receptors down-regulation. Moreover, cirrhosis is associated with increased levels of advanced-glycation-end products and hypoxia-inducible-factors, which may play a role in the development of diabetes. This review also focuses on the clinical implications of diabetes in patients with cirrhosis. First, diabetes is an independent factor for poor prognosis in patients with cirrhosis. Specifically, diabetes is associated with the occurrence of major complications of cirrhosis, including ascites and renal dysfunction, hepatic encephalopathy and bacterial infections. Diabetes is also associated with an increased risk of hepatocellular carcinoma in patients with chronic liver diseases. Last, the management of patients with concurrent diabetes and liver disease is also addressed. Recent findings suggest a beneficial impact of metformin in patients with chronic liver diseases. Insulin is often required in patients with advanced cirrhosis. However, the favourable impact of controlling diabetes in patients with cirrhosis has not been demonstrated yet.
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Affiliation(s)
- Laure Elkrief
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
| | - Pierre-Emmanuel Rautou
- DHU UNITY, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France.,Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.,Inserm U970, Paris Research Cardiovascular Center, Paris, France
| | - Shiv Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dominique Valla
- DHU UNITY, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France.,Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.,Inserm U1149, Centre de Recherche sur l'Inflammation CRI, Clichy, France
| | - Valérie Paradis
- Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.,Inserm U1149, Centre de Recherche sur l'Inflammation CRI, Clichy, France.,DHU UNITY, Pathology Department, Hôpital Beaujon, APHP, Clichy, France
| | - Richard Moreau
- DHU UNITY, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France.,Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.,Inserm U1149, Centre de Recherche sur l'Inflammation CRI, Clichy, France
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Zhang JY, Qu F, Li JF, Liu M, Ren F, Zhang JY, Bian DD, Chen Y, Duan ZP, Zhang JL, Zheng SJ. Up-regulation of Plasma Hexosylceramide (d18: 1/18: 1) Contributes to Genotype 2 Virus Replication in Chronic Hepatitis C: A 20-Year Cohort Study. Medicine (Baltimore) 2016; 95:e3773. [PMID: 27281078 PMCID: PMC4907656 DOI: 10.1097/md.0000000000003773] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 04/25/2016] [Accepted: 04/30/2016] [Indexed: 12/14/2022] Open
Abstract
The aim of the present study was to explore the relationship between plasma sphingolipids and hepatitis C virus (HCV) replication in chronic hepatitis C (CHC) patients.A cohort of 120 treatment-naïve CHC patients was included. Liver biopsies and the Scheuer scoring system were used to assess hepatic inflammatory activity. Blood biochemical indicators, HCV-RNA load, and immunological markers were also measured. Forty-four plasma sphingolipids were identified and quantified using high-performance liquid chromatography-tandem mass spectrometry.The hexosylceramide (HexCer) (d18:1/18:1) level was significantly different between patients with a low HCV load (<10 IU/mL) and a high HCV load (≥10 IU/mL), and it was positively correlated with the HCV-RNA load (r = 0.337, P = 0.001) in CHC patients. Additionally, the plasma HexCer (d18:1/18:1) level (odds ratio 1.302, 95% confidence interval 1.129-1.502) was an independent factor for a high HCV-RNA load. For patients with hepatic inflammation grade ≤2 or HCV genotype 2, HexCer (d18:1/18:1) was independently related to a high HCV-RNA load.Plasma HexCer (d18:1/18:1) might be involved in the high viral replication level in chronic HCV infection, especially for CHC patients with genotype 2.
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Affiliation(s)
- Jin-Yan Zhang
- From the Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China (J-YZ, ML, FR, J-YZ, D-DB, YC, Z-PD, S-JZ); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medica Sciences & Peking Union Medical College, Beijing, China (FQ, J-LZ); and Institute of Infectious Diseases, Department of Infectious Diseases, the First Hospital of Lanzhou University, Lanzhou, China (J-FL)
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Abstract
With a worldwide prevalence of 6% to 40% among patients with end-stage renal disease, hepatitis C virus (HCV) infection is a significant cause of comorbidity in kidney transplant candidates and recipients alike. Hepatitis C infection negatively impacts patient and allograft outcomes, predisposes to progressive liver disease and increases the risks of glomerular disease as well as new onset diabetes after transplantation. Treatment options until now have revolved around interferon, limited in efficacy, restricted to pretransplant administration because of concerns related to allograft dysfunction and immune stimulation, and fraught with high rates of intolerance. Direct-acting antivirals therapies are now emerging, providing the opportunity to effectively cure chronic HCV infection and to reduce the burden of hepatic and extrahepatic complications of HCV that are observed in kidney recipients, thereby offering hope of improved patient outcomes. Against a description of the major outcomes and risks that HCV+ kidney candidates and recipients encounter, and a summary of the pertinent studies of interferon-based therapies in this population, this review discusses the potential role for emerging direct-acting antivirals, proposing treatment algorithms that should be considered in the management of these complex patients. Conundrums relating to the new treatment, including the potential impact on the utilization of kidneys from HCV-infected donors, are presented.
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49
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Moqueet N, Cooper C, Gill J, Hull M, Platt RW, Klein MB. Responder Interferon λ Genotypes Are Associated With Higher Risk of Liver Fibrosis in HIV-Hepatitis C Virus Coinfection. J Infect Dis 2016; 214:80-6. [PMID: 26984148 PMCID: PMC4907413 DOI: 10.1093/infdis/jiw088] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 02/25/2016] [Indexed: 02/07/2023] Open
Abstract
Background. Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon λ3 (IFN-λ3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-λ genotypes and significant liver fibrosis in HIV-HCV coinfection. Methods. From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA–positive participants in whom IFN-λ genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of ≥1.5) by IFN-λ genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4+ T-cell count, HCV genotype, γ-glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity. Results. A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58–9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94–2.02) for rs12979860CC, 1.34 (95% CI, .91–1.97) for rs8103142TT, and 1.79 (95% CI, 1.24–2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73–1.77]). Conclusions. IFN-λ SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-λ genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease.
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Affiliation(s)
- Nasheed Moqueet
- Epidemiology, Biostatistics, Occupational Health, McGill University
| | | | - John Gill
- Southern Alberta HIV Clinic, Calgary
| | - Mark Hull
- BC Centre for Excellence in HIV/AIDS, Vancouver, Canada
| | - Robert W Platt
- Epidemiology, Biostatistics, Occupational Health, McGill University
| | - Marina B Klein
- Epidemiology, Biostatistics, Occupational Health, McGill University Division of Infectious Diseases and Chronic Viral Illness Service, McGill University Health Centre, Montreal
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Costiniuk CT, Brunet L, Rollet-Kurhajec KC, Cooper CL, Walmsley SL, Gill MJ, Martel-Laferriere V, Klein MB. Tobacco Smoking Is Not Associated With Accelerated Liver Disease in Human Immunodeficiency Virus-Hepatitis C Coinfection: A Longitudinal Cohort Analysis. Open Forum Infect Dis 2016; 3:ofw050. [PMID: 27047987 PMCID: PMC4817089 DOI: 10.1093/ofid/ofw050] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 03/01/2016] [Indexed: 11/30/2022] Open
Abstract
Background. Tobacco smoking has been shown to be an independent risk factor for liver fibrosis in hepatitis C virus (HCV) infection in some cross-sectional studies. No longitudinal study has confirmed this relationship, and the effect of tobacco exposure on liver fibrosis in human immunodeficiency virus (HIV)-HCV coinfected individuals is unknown. Methods. The study population consisted of participants from the Canadian Co-infection Cohort study (CTN 222), a multicenter longitudinal study of HIV-HCV coinfected individuals from 2003 to 2014. Data were analyzed for all participants who did not have significant fibrosis or end-stage liver disease (ESLD) at baseline. The association between time-updated tobacco exposure (ever vs nonsmokers and pack-years) and progression to significant liver fibrosis (defined as an aspartate-to-platelet ratio index [APRI] ≥1.5) or ESLD was assessed by pooled logistic regression. Results. Of 1072 participants included in the study, 978 (91%) had ever smoked, 817 (76%) were current smokers, and 161 (15%) were previous smokers. Tobacco exposure was not associated with accelerated progression to significant liver fibrosis nor with ESLD when comparing ever vs never smokers (odds ratio [OR] = 1.06, 95% confidence interval [CI], 0.43–1.69 and OR = 1.20, 95% CI, 0.21–2.18, respectively) or increases in pack-years smoked (OR = 1.05, 95% CI, 0.97–1.14 and OR = 0.94, 95% CI, 0.83–1.05, respectively). Both time-updated alcohol use in the previous 6 months and presence of detectable HCV ribonucleic acid were associated with APRI score ≥1.5. Conclusions. Tobacco exposure does not appear to be associated with accelerated progression of liver disease in this prospective study of HIV-HCV coinfected individuals.
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Affiliation(s)
- Cecilia T Costiniuk
- Chronic Viral Illnesses Service , Division of Infectious Diseases and Research Institute of the McGill University Health Centre , Montreal
| | - Laurence Brunet
- Department of Epidemiology , Biostatistics and Occupational Health, McGill University , Montreal, Quebec
| | - Kathleen C Rollet-Kurhajec
- Chronic Viral Illnesses Service , Division of Infectious Diseases and Research Institute of the McGill University Health Centre , Montreal
| | - Curtis L Cooper
- Division of Infectious Diseases, The Ottawa Hospital, Ontario, Canada; Canadian HIV Trials Network, Vancouver, British Columbia
| | - Sharon L Walmsley
- Canadian HIV Trials Network, Vancouver, British Columbia; Division of Infectious Diseases, University Health Network, University of Toronto, Ontario
| | - M John Gill
- Canadian HIV Trials Network, Vancouver, British Columbia; Southern Alberta HIV Clinic, Calgary
| | | | - Marina B Klein
- Chronic Viral Illnesses Service, Division of Infectious Diseases and Research Institute of the McGill University Health Centre, Montreal; Canadian HIV Trials Network, Vancouver, British Columbia
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