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Ge M, Zou H, Chen J, Zhang Q, Li C, Yang J, Wu J, Xie X, Liu J, Lei L, Peng S, Nie H. Cellular fibronectin-targeted fluorescent aptamer probes for early detection and staging of liver fibrosis. Acta Biomater 2024:S1742-7061(24)00614-7. [PMID: 39433198 DOI: 10.1016/j.actbio.2024.10.022] [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: 07/04/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/23/2024]
Abstract
Liver fibrosis is a key process in the progression of chronic liver disease to cirrhosis. Currently, early diagnosis and precise staging of liver fibrosis remain great challenges. Extracellular matrix (ECM) molecules expressed specifically during liver fibrosis are ideal targets for bioimaging and detection of liver fibrosis. Here, we report that fluorescent probes based on a nucleic acid aptamer (ZY-1) targeting cellular fibronectin (cFN), a critical ECM molecule significantly accumulating during liver fibrosis, are promising bioimaging agents for the staging of liver fibrosis. In the work, the outstanding binding affinity of ZY-1 to cFN was validated through an in vitro model of human-derived hepatic stellate cells (HSCs). Subsequently, we constructed different ZY-1-based fluorescent probes and explored the real-time imaging performance of these fluorescent probes in CCl4-induced mouse models of different liver fibrosis stages. The ZY-1-based fluorescent probes, for the first time, effectively identified and distinguished early-stage liver fibrosis (stage 3 of Ishak 6) from advanced liver fibrosis (stage 5 of Ishak 6). The proof-of-concept study provides compelling evidences that ZY-1-based probes are a promising tool for the early diagnosis and staging of liver fibrosis and paves the way for further development of clinical-related diagnosis strategies for fibrotic diseases of the liver and other organs. STATEMENT OF SIGNIFICANCE: Currently, early diagnosis and accurate staging of liver fibrosis continue to present significant challenges. This study demonstrates that fluorescent probes based on the nucleic acid aptamer ZY-1, which targets cellular fibronectin (cFN)-a crucial extracellular matrix (ECM) molecule that significantly accumulates during liver fibrosis-are promising bioimaging agents for staging liver fibrosis. The ZY-1-based fluorescent probes effectively identified and differentiated early-stage liver fibrosis from advanced liver fibrosis. This proof-of-concept study not only provides compelling evidence that ZY-1-based probes show promise for the early diagnosis and staging of liver fibrosis but also paves the way for further investigations into the use of ZY-1 in detecting other diseases associated with cFN.
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Affiliation(s)
- Mengjun Ge
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China
| | - Haitao Zou
- National Supercomputing Center in Changsha, College of Computer Science and Electronic Engineering, Hunan University, Changsha, China
| | - Jiahao Chen
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China
| | - Qinyao Zhang
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Chang Li
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiaxing Yang
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China
| | - Jiumei Wu
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Xing Xie
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Jun Liu
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lei Lei
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China.
| | - Shaoliang Peng
- National Supercomputing Center in Changsha, College of Computer Science and Electronic Engineering, Hunan University, Changsha, China
| | - Hemin Nie
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China.
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Long C, Ma Q, Huang L, Lin W. A near-infrared fluorescent probe for differentiating cancer cells from normal cells and early diagnosis of liver cirrhosis. Anal Chim Acta 2024; 1316:342802. [PMID: 38969400 DOI: 10.1016/j.aca.2024.342802] [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: 04/14/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 07/07/2024]
Abstract
BACKGROUND Cirrhosis represents the terminal stage of liver disease progression and timely intervention in a diseased liver can enhance the likelihood of recovery. Viscosity, a crucial parameter of the cellular microenvironment, is intricately linked to the advancement of cirrhosis. However, viscosity monitoring still faces significant challenges in achieving non-invasive and rapid early diagnosis of cirrhosis. Near-infrared (NIR) fluorescence imaging has the advantages of high sensitivity, non-destructive detection, and ignoring background fluorescence interference, plays an important role in diagnosing and treating various biological diseases. Hence, monitoring cellular viscosity changes with NIR fluorescence probe holds great significance in the early diagnosis of cirrhosis. RESULTS In this study, the NIR fluorescence probe based on the intramolecular charge transfer (TICT) mechanism was developed for imaging applications in mouse model of liver cirrhosis. A molecular rotor-type viscosity-responsive probe was synthesized by linking dioxanthracene groups via carbon-carbon double bonds. The probe demonstrated remarkable sensitivity, high selectivity and photostability, with its responsiveness to viscosity largely unaffected by factors such as polarity, pH, and interfering ions. The probe could effectively detect various drug-induced changes in cellular viscosity, enabling the differentiation between normal cells and cancerous cells. Furthermore, the enhanced tissue penetration capabilities of probe facilitated its successful application in mouse model of liver cirrhosis, allowing for the assessment of liver disease severity based on fluorescence intensity and providing a powerful tool for early diagnosis of cirrhosis. SIGNIFICANCE A NIR viscosity-sensitive fluorescent probe was specifically designed to effectively monitor alterations in cellular and organ viscosity, which could advance the understanding of the biological characteristics of cancer and provide theoretical support for the early diagnosis of cirrhosis. Overall, this probe held immense potential in monitoring viscosity-related conditions, expanding the range of biomedical tools available.
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Affiliation(s)
- Chenyuan Long
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, 530004, PR China
| | - Qingqing Ma
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, 530004, PR China
| | - Ling Huang
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, 530004, PR China
| | - Weiying Lin
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, 530004, PR China.
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Caon E, Forlano R, Mullish BH, Manousou P, Rombouts K. Liver sinusoidal cells in the diagnosis and treatment of liver diseases: Role of hepatic stellate cells. SINUSOIDAL CELLS IN LIVER DISEASES 2024:513-532. [DOI: 10.1016/b978-0-323-95262-0.00025-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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6
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Krassenburg LAP, Maan R, Puenpatom A, Erler NS, Welsch C, van Hees S, Cerrhoci O, Vermehren J, de Knegt RJ, Hansen BE, Zeuzem S, Vanwolleghem T, Janssen HLA, de Man RA, Feld JJ, van der Meer AJ. Progression of the FIB-4 index among patients with chronic HCV infection and early liver disease. BMJ Open Gastroenterol 2023; 10:e001209. [PMID: 38637963 PMCID: PMC10711888 DOI: 10.1136/bmjgast-2023-001209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 11/03/2023] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND AND AIMS Historical paired liver biopsy studies are likely to underestimate current progression of disease in patients with chronic hepatitis C virus (HCV) infection. We aimed to assess liver disease progression according to the non-invasive Fibrosis-4 (FIB-4) index in patients with chronic HCV and early disease. METHODS AND RESULTS Patients diagnosed with chronic HCV and FIB-4 <3.25 from four international liver clinics were included in a retrospective cohort study. Follow-up ended at start of antiviral therapy resulting in sustained virological response, at time of liver transplantation or death. Primary outcome of advanced liver disease was defined as FIB-4 >3.25 during follow-up. Survival analyses were used to assess time to FIB-4 >3.25.In total, 4286 patients were followed for a median of 5.0 (IQR 1.7-9.4) years, during which 41 071 FIB-4 measurements were collected. At baseline, median age was 47 (IQR 39-55) years, 2529 (59.0%) were male, and 2787 (65.0%) patients had a FIB-4 <1.45. Advanced liver disease developed in 821 patients. Overall, 10-year cumulative incidence of advanced disease was 32.1% (95% CI 29.9% to 34.3%). Patients who developed advanced disease showed an exponential FIB-4 increase. Among patients with a presumed date of HCV infection, cumulative incidence of advanced disease increased 7.7-fold from 20 to 40 years as opposed to the first 20 years after HCV infection. CONCLUSIONS The rate of advanced liver disease is high among chronic HCV-infected patients with early disease at time of diagnosis, among whom liver disease progression accelerated over time. These results emphasise the need to overcome any limitations with respect to diagnosing and treating all patients with chronic HCV across the globe.
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Affiliation(s)
- Lisette A P Krassenburg
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
- Francis Family Liver Clinic, Toronto Centre for Liver Disease, Toronto, Ontario, Canada
| | - Raoel Maan
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Nicole S Erler
- Department of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Christoph Welsch
- Department of Internal Medicine 1, Frankfurt Hospital Consortium, Frankfurt am Main, Germany
| | - Stijn van Hees
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Edegem, Belgium
| | - Orlando Cerrhoci
- Francis Family Liver Clinic, Toronto Centre for Liver Disease, Toronto, Ontario, Canada
| | - Johannes Vermehren
- Department of Internal Medicine 1, Frankfurt Hospital Consortium, Frankfurt am Main, Germany
| | - Robert J de Knegt
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
- Francis Family Liver Clinic, Toronto Centre for Liver Disease, Toronto, Ontario, Canada
| | - Stefan Zeuzem
- Department of Internal Medicine 1, Frankfurt Hospital Consortium, Frankfurt am Main, Germany
| | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Edegem, Belgium
| | - Harry L A Janssen
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
- Francis Family Liver Clinic, Toronto Centre for Liver Disease, Toronto, Ontario, Canada
| | - Robert A de Man
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Jordan J Feld
- Francis Family Liver Clinic, Toronto Centre for Liver Disease, Toronto, Ontario, Canada
| | - Adriaan J van der Meer
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
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Brennan PN, Elsharkawy AM, Kendall TJ, Loomba R, Mann DA, Fallowfield JA. Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach. Nat Rev Gastroenterol Hepatol 2023; 20:679-688. [PMID: 37268740 PMCID: PMC10236408 DOI: 10.1038/s41575-023-00796-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/09/2023] [Indexed: 06/04/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity is the only histological predictor of liver-related morbidity and mortality in NASH identified to date. Moreover, fibrosis regression is associated with improved clinical outcomes. However, despite numerous clinical trials of plausible drug candidates, an approved antifibrotic therapy remains elusive. Increased understanding of NASH susceptibility and pathogenesis, emerging human multiomics profiling, integration of electronic health record data and modern pharmacology techniques hold enormous promise in delivering a paradigm shift in antifibrotic drug development in NASH. There is a strong rationale for drug combinations to boost efficacy, and precision medicine strategies targeting key genetic modifiers of NASH are emerging. In this Perspective, we discuss why antifibrotic effects observed in NASH pharmacotherapy trials have been underwhelming and outline potential approaches to improve the likelihood of future clinical success.
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Affiliation(s)
- Paul N Brennan
- Institute for Regeneration & Repair, University of Edinburgh, Edinburgh, UK
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
| | - Ahmed M Elsharkawy
- Liver Unit and NIHR Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Timothy J Kendall
- Institute for Regeneration & Repair, University of Edinburgh, Edinburgh, UK
- Edinburgh Pathology, University of Edinburgh, Edinburgh, UK
| | - Rohit Loomba
- NAFLD Research Centre, Division of Gastroenterology and Hepatology, UC San Diego School of Medicine, La Jolla, CA, USA
| | - Derek A Mann
- Fibrosis Research Group, Newcastle University, Newcastle, UK.
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
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Aoyagi H, Iijima H, Gaber ES, Zaitsu T, Matsuda M, Wakae K, Watashi K, Suzuki R, Masaki T, Kahn J, Saito T, El-Kassas M, Shimada N, Kato K, Enomoto M, Hayashi K, Tsubota A, Mimata A, Sakamaki Y, Ichinose S, Muramatsu M, Wake K, Wakita T, Aizaki H. Hepatocellular organellar abnormalities following elimination of hepatitis C virus. Liver Int 2023; 43:1677-1690. [PMID: 37312620 DOI: 10.1111/liv.15624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 04/14/2023] [Accepted: 05/14/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND AIMS The future development of hepatocellular carcinoma (HCC) in patients after sustained virologic response (SVR) is an important issue. The purposes of this study were to investigate pathological alterations in organelle of the liver of SVR patients and to characterize organelle abnormalities that may be related to carcinogenesis after SVR. METHODS The ultrastructure of liver biopsy specimens from patients with chronic hepatitis C (CHC) and SVR were compared to cell and mouse models and assessed semi-quantitatively using transmission electron microscopy. RESULTS Hepatocytes in patients with CHC showed abnormalities in the nucleus, mitochondria, endoplasmic reticulum, lipid droplet, and pericellular fibrosis, comparable to those seen in hepatitis C virus (HCV)-infected mice and cells. DAA treatment significantly reduced organelle abnormalities such as the nucleus, mitochondria, and lipid droplet in the hepatocytes of patients and mice after SVR, and cured cells, but it did not change dilated/degranulated endoplasmic reticulum and pericellular fibrosis in patients and mice after SVR. Further, samples from patients with a post-SVR period of >1 year had significantly larger numbers of abnormalities in the mitochondria and endoplasmic reticulum than those of <1 year. A possible cause of organelle abnormalities in patients after SVR could be oxidative stress of the endoplasmic reticulum and mitochondria associated with abnormalities of the vascular system due to fibrosis. Interestingly, abnormal endoplasmic reticulum was associated with patients with HCC for >1 year after SVR. CONCLUSIONS These results indicate that patients with SVR exhibit a persistent disease state and require long-term follow-up to detect early signs of carcinogenesis.
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Affiliation(s)
- Haruyo Aoyagi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroko Iijima
- Department of Internal Medicine, Division of Hepatobiliary and Pancreatic Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Eman S Gaber
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takuma Zaitsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Mami Matsuda
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kosho Wakae
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takahiro Masaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Jeffrey Kahn
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Takeshi Saito
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Chiba, Japan
| | - Keizo Kato
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka Metropolitan University, Osaka, Japan
| | - Kazuhiko Hayashi
- Division of Gastroenterology and Hepatology, Meijo Hospital, Nagoya, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Ayako Mimata
- Research Core, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuriko Sakamaki
- Research Core, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shizuko Ichinose
- Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kenjiro Wake
- Liver Research Unit, Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
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Tomah S, Salah T, Al-Badri M, Dhaver S, Gardner H, Tasabehji MW, Hamdy O. Multidisciplinary intensive lifestyle intervention improves markers of nonalcoholic fatty liver disease (NAFLD) in patients with type 1 diabetes and obesity: a retrospective matched-cohort study. Clin Diabetes Endocrinol 2023; 9:3. [PMID: 37046323 PMCID: PMC10091669 DOI: 10.1186/s40842-023-00150-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 04/03/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing among patients with type 1 diabetes (T1D) paralleling the increasing prevalence of obesity among this population. However, little is known about the impact of intensive lifestyle intervention (ILI) on NAFLD in patients with T1D. METHODS Using Hepatic Steatosis Index (HSI), a noninvasive surrogate predictor of NAFLD, we retrospectively evaluated 88 adult patients with T1D and obesity after one year of participating in a 12-week ILI program in real-world clinical practice. Using the NAFLD guidelines of the American Association for the Study of Liver Diseases (AASLD), we excluded 11 participants. We matched the remaining ILI cohort (age 43 ± 12 years, females 65%, diabetes duration 22 ± 9 years, A1C 8.2 ± 0.9%, body weight 101 ± 17 kg, BMI 35.3 ± 4.9 kg/m2) in 1:1 ratio with a similar cohort of patients with T1D and obesity who received standard diabetes care (SC) at the same practice and during the same period. Matching criteria included: sex, age, BMI, A1C and duration of T1D. HSI [8 + ALT/AST + BMI (+ 2 if female, + 2 if T2D)] was calculated at baseline and after 12 months of intervention. RESULTS At baseline, HSI was similar between the two cohorts (46.2 ± 6.1 in the ILI cohort and 44.9 ± 5.7 in the SC cohort). After 12 months, the ILI group lost an average of 5.6 ± 2.7 kg (5.8%, p < 0.05) while the SC group maintained their baseline body weight (p < 0.001 between groups). HSI decreased significantly from baseline in the ILI group (-2.7 ± 1.1, p = 0.01), but did not change in the SC group (0.6 ± 0.9, p = 0.53, p < 0.001 between groups). Percentage of patients with high likelihood of NAFLD diagnosis decreased from 100% at baseline to 88.3% in the ILI group, and was 10.4% less compared to SC (p < 0.01). Total daily insulin dose decreased in the ILI cohort compared to the SC cohort (-6.1 ± 4.2 versus 1.34 ± 4.3 units/day, p < 0.01). CONCLUSIONS Twelve weeks of ILI improved HSI and decreased total daily insulin requirements in patients with T1D and obesity at one year. Short-term ILI should be implemented in the management of NAFLD for obese patients with type 1 diabetes.
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Affiliation(s)
- Shaheen Tomah
- Joslin Diabetes Center, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, 02215, USA
| | - Tareq Salah
- Joslin Diabetes Center, Boston, MA, 02215, USA.
- Harvard Medical School, Boston, MA, 02215, USA.
| | - Marwa Al-Badri
- Joslin Diabetes Center, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, 02215, USA
| | | | | | - Mhd Wael Tasabehji
- Joslin Diabetes Center, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, 02215, USA
| | - Osama Hamdy
- Joslin Diabetes Center, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, 02215, USA
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Desregulación inmunológica y fisiopatología del consumo de alcohol y la enfermedad hepática alcohólica. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2023; 88:136-154. [DOI: 10.1016/j.rgmx.2023.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Immune dysregulation and pathophysiology of alcohol consumption and alcoholic liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2023; 88:136-154. [PMID: 36973122 DOI: 10.1016/j.rgmxen.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 01/13/2023] [Indexed: 03/28/2023] Open
Abstract
Alcoholic liver disease (ALD) is a clinical-pathologic entity caused by the chronic excessive consumption of alcohol. The disease includes a broad spectrum of anomalies at the cellular and tissual level that can cause acute-on-chronic (alcoholic hepatitis) or chronic (fibrosis, cirrhosis, hepatocellular cancer) injury, having a great impact on morbidity and mortality worldwide. Alcohol is metabolized mainly in the liver. During alcohol metabolism, toxic metabolites, such as acetaldehyde and oxygen reactive species, are produced. At the intestinal level, alcohol consumption can cause dysbiosis and alter intestinal permeability, promoting the translocation of bacterial products and causing the production of inflammatory cytokines in the liver, perpetuating local inflammation during the progression of ALD. Different study groups have reported systemic inflammatory response disturbances, but reports containing a compendium of the cytokines and cells involved in the pathophysiology of the disease, from the early stages, are difficult to find. In the present review article, the role of the inflammatory mediators involved in ALD progression are described, from risky patterns of alcohol consumption to advanced stages of the disease, with the aim of understanding the involvement of immune dysregulation in the pathophysiology of ALD.
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Genetic Polymorphism in Angiotensinogen and Its Association with Cardiometabolic Diseases. Metabolites 2022; 12:metabo12121291. [PMID: 36557328 PMCID: PMC9785123 DOI: 10.3390/metabo12121291] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/30/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Angiotensinogen (AGT) is one of the most significant enzymes of the renin-angiotensin-aldosterone system (RAAS) which is involved in the regulation and maintenance of blood pressure. AGT is involved in the production of angiotensin I which is then converted into angiotensin II that leads to renal homeostasis. However, various genetic polymorphisms in AGT have been discovered in recent times which have shown an association with various diseases. Genetic polymorphism increases the level of circulating AGT in blood which exaggerates the effects produced by AGT. The associated diseases occur due to various effects produced by increased AGT levels. Several cardiovascular diseases including myocardial infarction, coronary heart disease, heart failure, hypertrophy, etc. are associated with AGT polymorphism. Other diseases such as depression, obesity, diabetic nephropathy, pre-eclampsia, and liver injury are also associated with some variants of AGT gene. The most common variants of AGT polymorphism are M235T and T174M. The two variants are associated with many diseases. Some other variants such as G-217A, A-6G, A-20C and G-152A, are also present but they are not as significant as that of M235T and T174M variants. These variants increase the level of circulating AGT and are associated with prevalence of different diseases. These diseases occur through various pathological pathways, but the initial reason remains the same, i.e., increased level of AGT in the blood. In this article, we have majorly focused on how genetic polymorphism of different variants of AGT gene is associated with the prevalence of different diseases.
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Soares GA, Pereira GM, Romualdo GR, Biasotti GGA, Stoppa EG, Bakuzis AF, Baffa O, Barbisan LF, Miranda JRA. Biodistribution Profile of Magnetic Nanoparticles in Cirrhosis-Associated Hepatocarcinogenesis in Rats by AC Biosusceptometry. Pharmaceutics 2022; 14:pharmaceutics14091907. [PMID: 36145654 PMCID: PMC9504370 DOI: 10.3390/pharmaceutics14091907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/30/2022] [Accepted: 08/31/2022] [Indexed: 11/20/2022] Open
Abstract
Since magnetic nanoparticles (MNPs) have been used as multifunctional probes to diagnose and treat liver diseases in recent years, this study aimed to assess how the condition of cirrhosis-associated hepatocarcinogenesis alters the biodistribution of hepatic MNPs. Using a real-time image acquisition approach, the distribution profile of MNPs after intravenous administration was monitored using an AC biosusceptometry (ACB) assay. We assessed the biodistribution profile based on the ACB images obtained through selected regions of interest (ROIs) in the heart and liver position according to the anatomical references previously selected. The signals obtained allowed for the quantification of pharmacokinetic parameters, indicating that the uptake of hepatic MNPs is compromised during liver cirrhosis, since scar tissue reduces blood flow through the liver and slows its processing function. Since liver monocytes/macrophages remained constant during the cirrhotic stage, the increased intrahepatic vascular resistance associated with impaired hepatic sinusoidal circulation was considered the potential reason for the change in the distribution of MNPs.
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Affiliation(s)
- Guilherme A. Soares
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
- Correspondence:
| | - Gabriele M. Pereira
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Guilherme R. Romualdo
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
- Department of Strucutral and Functional Biology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Gabriel G. A. Biasotti
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Erick G. Stoppa
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Andris F. Bakuzis
- Institute of Physics, Federal University of Goiás, Goiânia 74690-900, GO, Brazil
| | - Oswaldo Baffa
- Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-900, SP, Brazil
| | - Luis F. Barbisan
- Department of Strucutral and Functional Biology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
| | - Jose R. A. Miranda
- Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University—UNESP, Botucatu 18618-689, SP, Brazil
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14
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Dezső K, Paku S, Kóbori L, Thorgeirsson SS, Nagy P. What Makes Cirrhosis Irreversible?-Consideration on Structural Changes. Front Med (Lausanne) 2022; 9:876293. [PMID: 35572980 PMCID: PMC9091510 DOI: 10.3389/fmed.2022.876293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/04/2022] [Indexed: 11/17/2022] Open
Abstract
Several studies have shown that liver fibrosis, and even cirrhosis can be reversed, disproving the old “dogma” that cirrhosis is irreversible. In addition to scaring, vascular alterations appear to be critically important in the progression of chronic liver diseases. To overcome the “tipping-point” of cirrhosis, we need to understand in depth what might make it irreversible in some cases. Morphologically, the initial, as well as the advanced stages of cirrhosis are characterized by specific structural changes. The hallmark of the initial stage is the division of the original liver parenchyma by centro-central or porto-portal septa. No significant vascular changes are observed in this stage. The advanced stage is characterized by several morphological alterations: (i) The main feature is the parenchymal extinction, with intact portal vein branches, hepatic artery branches, and biliary ductules; (ii) In the extinct areas we observed numerous loops in the ductular network, indicating the disruption of the hepato-biliary junctions; (iii) Although the ductular progenitor cells are able to generate hepatocytes via the budding process, the newly formed hepatocyte nodules cannot re-establish the original lobular architecture due to their disorganized growth. In conclusion, this regenerative process characteristic for the advanced stage, contributes to circulatory disorders, perpetuates parenchymal injury and may lead to the irreversibility of cirrhosis.
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Affiliation(s)
- Katalin Dezső
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Paku
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - László Kóbori
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Snorri S Thorgeirsson
- Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute, National Institute of Health (NIH), Bethesda, MD, United States
| | - Péter Nagy
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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15
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Colombatto P, Coco B, Bonino F, Brunetto MR. Management and Treatment of Patients with Chronic Hepatitis B: Towards Personalized Medicine. Viruses 2022; 14:701. [PMID: 35458431 PMCID: PMC9027850 DOI: 10.3390/v14040701] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/07/2023] Open
Abstract
The currently available antiviral treatments (Peg-Interferon-α and Nucleos(t)ide Analogues, NA) for chronic hepatitis B (CHB) achieve a functional cure (serum HBsAg and HDV-DNA clearance) of HBV infection in a limited number of patients. Nevertheless, the continuous pharmacological suppression of viral replication by NA halts liver disease progression lowering the risk of HCC development and improving the survival. In the near future, to fully exploit the potential of old and new drugs for HBV treatment a personalized approach to the patients will be required according to an accurate definition of their virologic, immunologic and clinical profile.
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Affiliation(s)
- Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Ferruccio Bonino
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
| | - Maurizia R. Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56127 Pisa, Italy
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16
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Lv W, Jian J, Liu J, Zhao X, Xin X, Hu C. Use of the volume-averaged Murray's deviation method for the characterization of branching geometry in liver fibrosis: a preliminary study on vascular circulation. Quant Imaging Med Surg 2022; 12:979-991. [PMID: 35111599 DOI: 10.21037/qims-21-47] [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: 01/12/2021] [Accepted: 09/24/2021] [Indexed: 11/06/2022]
Abstract
Background Vascular changes in liver fibrosis can result in increased intrahepatic vascular resistance and impaired blood circulation. This can hinder the recovery from fibrosis and may eventually lead to portal hypertension, a major cirrhosis complication. This report proposed a volume-averaged Murray's deviation method to characterize intrahepatic circulation in the liver during fibrosis and its subsequent regression via X-ray phase-contrast computed tomography (PCCT). Methods Liver fibrosis was induced in 24 Sprague-Dawley rats by exposure to carbon tetrachloride (CCl4) for up to 10 weeks, after which, spontaneous regression commenced and continued until week 30. High-resolution three-dimensional (3D) imaging of the livers was performed with PCCT. The values of Murray's deviation based on the volume-averaged and the conventional diameter-based methods were compared. After that, the intrahepatic circulation at different stages of fibrosis was evaluated using the volume-averaged method. The increase in collagen during liver fibrosis was assessed by pathological analyses. Results A comparison of the 2 methods showed that with an increase in the number of diameter measurements, the value of Murrary's deviation obtained using the diameter-based method gradually approaches those of the volume-averaged method, with minimal variations. The value of Murray's deviation increased with the development of fibrosis. After reversal, the value rapidly decreased and approached that of the normal state in both the main branches (1.05±0.17, 1.17±0.21, 1.34±0.18, and 1.17±0.19 in the normal, moderate, severe, and regressive groups, respectively; P<0.05 between the severe group and other groups) and the small branches (1.05±0.09, 1.42±0.48, 1.79±0.57, and 1.18±0.28 in the normal, moderate, severe, and regressive group, respectively; P<0.05 between adjacent groups). An analysis of Murray's deviation and the pathological results showed that the vascular circulation in this disease model was consistent with the progression and recovery from fibrosis. Conclusions This study showed the validity of the volume-averaged method for calculating Murray's deviation and demonstrated that it could accurately evaluate the blood circulation state of the liver during fibrosis and its subsequent regression. Thus, the volume-averaged method of calculating Murray's deviation may be an objective and valuable staging criterion to evaluate intrahepatic circulation during liver fibrosis.
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Affiliation(s)
- Wenjuan Lv
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
| | - Jianbo Jian
- Department of Radiation Oncology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jingyi Liu
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xiaohong Xin
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
| | - Chunhong Hu
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
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17
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Zuñiga-Aguilar E, Ramírez-Fernández O. Fibrosis and hepatic regeneration mechanism. Transl Gastroenterol Hepatol 2022; 7:9. [PMID: 35243118 PMCID: PMC8826211 DOI: 10.21037/tgh.2020.02.21] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 02/10/2020] [Indexed: 11/26/2023] Open
Abstract
Liver cirrhosis is the final stage of continuous hepatic inflammatory activity derived by viral, metabolic or autoimmune origin. In the last years, cirrhosis was considered a unique and static condition; recently was accepted some patients subgroups with different liver injury degrees that coexist under the same diagnosis, with implications about the natural disease history. The liver growth factor (LGF) is a potent in vivo and in vitro mitogenic agent and an inducer of hepatic regeneration (HR) through the hepatocytes DNA synthesis. The clinical implications of the LGF levels in cirrhosis, are not clear and even with having a fundamental role in the liver regeneration processes, the studies suggest that it could be a cirrhosis severity marker, in acute liver failure and in chronic hepatitis. Its role as predictor of mortality in fulminant hepatic insufficiency patients has been suggested. HR is one of the most enigmatic and fascinating biological phenomena. The rapid volume and liver function restoration after a major hepatectomy (>70%) or severe hepatocellular damage and its strict regulation of tissue damage response after the cessation, is an exclusive property of the liver. HR is the clinical applications fundament, such as extensive hepatic resections (>70% of the liver parenchyma), segmental transplantation or living donor transplantation, sequential hepatectomies, isolated portal embolization or associated with in situ hepatic transection, temporary artificial support in acute liver failure and the possible cell therapy clinical applications.
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Affiliation(s)
- Esmeralda Zuñiga-Aguilar
- Universidad Autonoma de Ciudad Juárez, Depto de Ingeniería Eléctrica y Computación, Ciudad Juárez, Chih., México
| | - Odin Ramírez-Fernández
- Tecnologico Nacional de Mexico, Depto. De Ciencias Basicas, Tlalnepantla de Baz, Mexico
- Facultad de Medicina, HIPAM, Universidad Nacional Autonoma de Mexico, Ciudad de México, Mexico
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18
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Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells 2021; 10:cells10102759. [PMID: 34685739 PMCID: PMC8534788 DOI: 10.3390/cells10102759] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
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19
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Taurine ameliorates thioacetamide induced liver fibrosis in rats via modulation of toll like receptor 4/nuclear factor kappa B signaling pathway. Sci Rep 2021; 11:12296. [PMID: 34112866 PMCID: PMC8192756 DOI: 10.1038/s41598-021-91666-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a significant health problem that can cause serious illness and death. Unfortunately, a standard treatment for liver fibrosis has not been approved yet due to its complicated pathogenesis. The current study aimed at assessing the anti-fibrotic effect of taurine against thioacetamide induced liver fibrosis in rats through the modulation of toll like receptor 4/nuclear factor kappa B signaling pathway. Both concomitant and late taurine treatment (100 mg/kg, IP, daily) significantly reduced the rise in serum ALT and AST activities and significantly reversed the decrease in serum albumin and total protein. These results were confirmed by histopathological examinations and immunehistochemical inspection of α-SMA, caspase-3 and NF-κB. The antioxidant potential of taurine was verified by a marked increase of GSH content and a reduction of MDA level in liver tissue. The anti-fibrotic effects of taurine were evaluated by investigating the expression of TLR4, NF-κB. The protein levels of IL-6, LPS, MyD88, MD2, CD14, TGF-β1 and TNF-α were determined. Docking studies were carried out to understand how taurine interacts inside TLR4-MD2 complex and it showed good binding with the hydrophobic binding site of MD2. We concluded that the anti-fibrotic effect of taurine was attributable to the modulation of the TLR4/NF-κB signaling.
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20
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Henz AC, Marroni CA, Silva DMD, Teixeira JM, Silveira TT, Ferreira S, Silveira AT, Schmidt NP, Stein JT, Rayn RG, Fernandes SA. Resting energy expenditure in cirrhotic patients with and without hepatocellular carcinoma. World J Gastrointest Pharmacol Ther 2021; 12:1-12. [PMID: 33564492 PMCID: PMC7844573 DOI: 10.4292/wjgpt.v12.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/26/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The diagnosis of malnutrition in patients with independent hepatocellular carcinoma (HCC) varies from 20% to 50%, is related to important complications and has a direct impact on the prognosis. Determination of the resting energy expenditure (REE) has become an important parameter in this population, as it allows therapeutic adjustments to recover their nutritional status. The REE in cirrhosis, with and without HCC, is not clearly defined, and requires the identification and definition of the best nutritional approach. AIM To evaluate the REE of patients with cirrhosis, with and without HCC. METHODS This is a prospective observational study evaluating the REE of 118 patients, 33 with cirrhosis and hepatocellular carcinoma and a control group of 85 patients with cirrhosis without HCC, using indirect calorimetry (IC), bioimpedance, and predictive formulas. RESULTS The REE determined by IC in cirrhotic patients with HCC was 1643 ± 364 and in those without HCC was 1526 ± 277 (P = 0.064). The REE value as assessed by bioimpedance was 1529 ± 501 for those with HCC and 1660 ± 385 for those without HCC (P = 0.136). When comparing the values of REE determined by IC and predictive formulas in cirrhotics with HCC, it was observed that only the formulas of the Food and Agriculture Organization (FAO)/World Health Organization (WHO) (1985) and Cunningham (1980) presented values similar to those determined by IC. When comparing the REE values determined by IC and predictive formulas in cirrhotics without HCC, it was observed that the formulas of Schofield (1985), FAO/WHO (1985), WHO (2000), Institute of Medicine (IOM) (2005) and Katch and McArdie (1996) presented values similar to those determined by IC. CONCLUSION The FAO/WHO formula (1985) could be used for cirrhotic patients with or without HCC; as it is the one with the values closest to those obtained by IC in these cirrhotic patients.
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Affiliation(s)
- Ana Cristhina Henz
- Department of Nutrition, Centro Universitário Metodista (IPA), Porto Alegre 90420-060, RS, Brazil
| | - Claudio Augusto Marroni
- Department of Gastroenterology and Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 91760470, RS, Brazil
| | - Daniella Miranda da Silva
- Postgraduate Program in Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Joise Munari Teixeira
- Postgraduate Program in Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Thiago Thomé Silveira
- Hepatology Graduate Program, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Shaiane Ferreira
- Hepatology Graduate Program, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Andresa Thomé Silveira
- Hepatology Graduate Program, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Natalia Perin Schmidt
- Hepatology Graduate Program, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Jessica Taina Stein
- Hepatology Graduate Program, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Roberta Goulart Rayn
- Hepatology Graduate Program, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050170, RS, Brazil
| | - Sabrina Alves Fernandes
- Department of Nutrition, Centro Universitário Metodista (IPA), Porto Alegre 90420-060, RS, Brazil
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21
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Shahin AE, Alshmmary SN, Aljabarah NS, Alshammari AM, Alshammari KM, Alabedah RS, Almudayni HK, Alquwaiay DAS, Alghaithi AM. An Overview on Non-invasive Assessment of Cirrhosis. ARCHIVES OF PHARMACY PRACTICE 2021. [DOI: 10.51847/zpadewrmgx] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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22
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Contractor J, Patel V, Vaniya VH. Harbin's index: Morphological evaluation of caudate-to-right lobe ratio in human cadaveric liver. J ANAT SOC INDIA 2021. [DOI: 10.4103/jasi.jasi_25_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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23
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Wu B, Yeh MM. Pathology of Hepatitis B Virus (HBV) Infection and HBV-Related Hepatocellular Carcinoma. HEPATITIS B VIRUS AND LIVER DISEASE 2021:99-122. [DOI: 10.1007/978-981-16-3615-8_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Gardner H, Hamdy O. Oral GLP1 Analog: Where Does the Tide Go? Clin Med Insights Endocrinol Diabetes 2020; 13:1179551420984130. [PMID: 33447122 PMCID: PMC7780176 DOI: 10.1177/1179551420984130] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Abstract
T2D is a potentially preventable disease that has been ranked the seventh leading cause of mortality in the United States. There is strong evidence demonstrating that preventing type 2 diabetes is, in many cases, attainable through lifestyle intervention. Unfortunately, prediabetes is mostly overlooked and awareness with diabetes prevention tools is lacking among primary care physicians. Nationally, efforts were not successful in reversing this epidemic even with an array of diabetes medications. Among the most effective medications for T2D are glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have been shown to reduce both A1C and body weight. Dulaglutide, liraglutide and injectable semaglutide also reduced cardiovascular events and cardiovascular mortality in patients with established cardiovascular disease or multiple cardiovascular risk factors. In this review, we will examine the first FDA approved oral GLP-1 RA; semaglutide. Moreover, this review will discuss the potential impact oral semaglutide may have on glycemic control, weight loss and cardiovascular comorbidities. It also examines the factors that may impact patient compliance, including cost, side effects and clinical issues. Finally, it deliberates the optimism surrounding the development of oral semaglutide in the treatment of diabetes as well as related conditions, such as obesity and non-alcoholic fatty liver disease (NAFLD).
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25
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Quantitative HBcrAg and HBcAb versus HBsAg and HBV DNA in predicting liver fibrosis levels of chronic hepatitis B patients. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:526-536. [PMID: 32921478 DOI: 10.1016/j.gastrohep.2020.03.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 03/10/2020] [Accepted: 03/31/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To evaluate the performance of the quantitative markers of hepatitis B core-related antigen (HBcrAg) and anti-hepatitis B core antigen antibodies HbcAb versus hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA (HBV DNA) in predicting liver fibrosis levels in chronic hepatitis B patients. METHODS Two hundred and fifty hepatitis B e antigen (HBeAg)-positive and 245 HBeAg-negative patients were enrolled. With reference to the Scheuer standard, stage 2 or higher and stage 4 liver disease were defined as significant fibrosis and cirrhosis, respectively. A receiver operating characteristic (ROC) curve was used to evaluate the performance of the HBV markers investigated. RESULTS The areas under the ROC curves (AUCs) of HBcrAg in predicting significant fibrosis and cirrhosis in HBeAg-positive patients (0.577 and 0.700) were both close to those of HBsAg (0.617 and 0.762) (both P> 0.05). In HBeAg-negative patients (0.797 and 0.837), they were both significantly greater than those of HBV DNA (0.723 and 0.738) (P=0.0090 and P=0.0079). The AUCs of HBcAb in predicting significant fibrosis and cirrhosis in HBeAg-positive patients (0.640 and 0.665) were both close to those of HBsAg. In HBeAg-negative patients (0.570 and 0.621), they were both significantly less than those of HBcrAg (P <0.0001 and P=0.0001). Specificity in predicting significant fibrosis and sensitivity in predicting cirrhosis in HBeAg-positive patients, using a single cut-off of HBsAg ≤5,000 IU/ml, were 76.5% and 72.7%, respectively. In HBeAg-negative patients, using a single cut-off of HBcrAg>80kU/ml, they were 85.9% and 81.3%, respectively. CONCLUSIONS HBsAg has good performance in predicting liver fibrosis levels in HBeAg-positive and HBeAg-negative patients, and HBcrAg has very good performance in predicting liver fibrosis levels in HBeAg-negative patients.
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Bardou-Jacquet E, Morandeau E, Anderson GJ, Ramm GA, Ramm LE, Morcet J, Bouzille G, Dixon J, Clouston AD, Lainé F, Turlin B, Powell LW, Deugnier YM. Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE. Clin Gastroenterol Hepatol 2020; 18:1851-1857. [PMID: 31622736 DOI: 10.1016/j.cgh.2019.10.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/20/2019] [Accepted: 10/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Fibrosis stage can decrease following treatment in patients with hemochromatosis caused by mutations in the homeostatic iron regulator gene (HFE), but the effects on cirrhosis are not clear. We assessed regression of severe fibrosis and the ensuing risk of liver cancer after treatment. METHODS We performed a retrospective analysis of data from 106 patients in France or Australia who were homozygous for the C282Y mutation in HFE with F3 fibrosis (n = 40) or F4 fibrosis (n = 66) at diagnosis and from whom at least 1 liver biopsy was collected during follow up. We collected data from the time of first biopsy and during follow-up period on patient demographics, treatment, smoking habits, alcohol consumption, infection with hepatitis B or C viruses, and other diseases. The median time between first and last liver biopsy was 9.5 years (range, 3.5-15.6 years). We collected results of tests for liver function, markers of iron stores, and platelet levels. Patients were followed for a median 17.6 years (range, 9.8-24.1 years) for development of liver cancer occurrence. RESULTS At last liver biopsy, 41 patients (38.6%) had fibrosis scores of F2 or less. Liver cancer occurred in 34 patients (52.3%) with F3 or F4 fibrosis at last liver biopsy vs 2 patients (4.8%) with fibrosis scores of F2 or less at last liver biopsy (P < .001). Liver cancer incidences were 32.8 per 1000 person-years (95% CI, 22.7-45.9 per 1000 person-years) in patients with F3 or F4 fibrosis and 2.3 per 1000 person-years (95% CI, 0.2-8.6 per 1000 person-years) in patients with fibrosis scores of F2 or less (P < .001). In multivariate analysis, male sex (hazard ratio [HR], 6.09; 95% CI, 1.21-30.4), age at diagnosis (HR, 1.16; 95% CI, 1.09-1.25), presence of diabetes (HR, 3.07; 95% CI, 1.35-6.97), excess alcohol consumption (HR, 3.1; 95% CI, 1.47-6.35), serum level of ferritin at diagnosis (P < .01), and regression to fibrosis scores of F2 or less (HR, 0.08; 95% CI, 0.01-0.62) were significantly associated with risk of liver cancer. CONCLUSIONS In a retrospective analysis of patients with hemochromatosis caused by the C282Y mutation in HFE, we found that severe liver fibrosis can regress with treatment. In patients with fibrosis regression to a stage F2 or less, the long-term risk for liver cancer is significantly reduced.
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Affiliation(s)
- Edouard Bardou-Jacquet
- University of Rennes, CHU Rennes, INSERM, CIC 1414, Liver Disease Department, French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France.
| | | | - Gregory J Anderson
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Louise E Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | | | | | - Jeannette Dixon
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Andrew D Clouston
- Faculty of Health Sciences, University of Queensland, Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Fabrice Lainé
- CHU Rennes, INSERM, Liver Disease Department, CIC 1414, Rennes, France
| | - Bruno Turlin
- University of Rennes, CHU Rennes, INSERM, Pathology Department, French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France
| | - Lawrie W Powell
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Yves M Deugnier
- University of Rennes, CHU Rennes, INSERM, CIC 1414, Liver Disease Department, French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France
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Mihai F, Trifan A, Stanciu C, Singeap AM, Cucuteanu B, Lupascu Ursulescu C, Pop C, Girleanu I, Cuciureanu T, Negru D, Cojocariu C. Liver Remodeling on CT Examination in Patients with HCV Compensated Cirrhosis Who Achieved Sustained Virological Response after Direct-Acting Antivirals Treatment. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:171. [PMID: 32290305 PMCID: PMC7231305 DOI: 10.3390/medicina56040171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 03/27/2020] [Accepted: 04/06/2020] [Indexed: 02/05/2023]
Abstract
Aims: The purpose of this study was to assess the changes in hepatic morphology evaluated by computed tomography (CT) examination in patients with hepatitis C virus (HCV)-related compensated cirrhosis who achieved sustained virologic response (SVR) after direct-acting antivirals (DAAs) treatment. Methods: CT examination was performed in 56 patients with HCV-related compensated cirrhosis before and within 6-18 months after the treatment with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir. The liver CT changes were assessed by measuring liver volume, caudate-right lobe ratio (C/RL), hepatic vessels diameters, periportal widening space, and right posterior notch. Portal trunk, splenic and superior mesenteric vein diameters, as well as spleen volume were assessed as part of portal hypertension. Results: Right hepatic vein diameter was significantly wider after treatment (median: 8.12 mm; IQR: 4.20) than before treatment (median: 6.36 mm; IQR: 3.94) z = -3.894; p < 0.001. The liver volume was significantly higher prior to the treatment (median: 1786.77 mm3; IQR: 879.23) than after treatment (median: 1716.44 mm3; IQR: 840.50), z = -1.970; p = 0.049. Splenic volume was considerably higher before treatment (median: 564.79 mm3; IQR: 342.54) than after (median: 474.45 mm3; IQR: 330.00), z = -2.500; p = 0.012. The other parameters, such as C/RL, periportal space widening, and right hepatic notch showed no significant changes. Conclusions: SVR in patients with HCV-related compensated cirrhosis treated with DAAs is associated with some improvements of hepatic morphology detectable by CT, the most constant being the increase of right hepatic vein diameter.
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Affiliation(s)
- Florin Mihai
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Department of Radiology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania
| | - Anca Trifan
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania;
| | - Carol Stanciu
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania;
| | - Ana Maria Singeap
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania;
| | - Bogdan Cucuteanu
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Department of Radiology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania
| | - Corina Lupascu Ursulescu
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Department of Radiology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania
| | - Corina Pop
- Gastroenterology Department, Emergency University Hospital, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Irina Girleanu
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania;
| | - Tudor Cuciureanu
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
| | - Dragos Negru
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Department of Radiology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania
| | - Camelia Cojocariu
- “Grigore T. Popa”, University of Medicine and Pharmacy, 700115 Iasi, Romania; (F.M.); (B.C.); (C.L.U.); (I.G.); (T.C.); (D.N.); (C.C.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Emergency Hospital, 700111 Iasi, Romania;
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Stasi C, Gragnani L, Zignego AL. Fibrosis Assessment in Patients with HCV or HBV Chronic Infection. LIVER ELASTOGRAPHY 2020:113-121. [DOI: 10.1007/978-3-030-40542-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Shiha G, Mousa N. Noninvasive Biomarkers for Liver Fibrosis. LIVER DISEASES 2020:427-441. [DOI: 10.1007/978-3-030-24432-3_36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
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Dhar D, Baglieri J, Kisseleva T, Brenner DA. Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood) 2020; 245:96-108. [PMID: 31924111 PMCID: PMC7016420 DOI: 10.1177/1535370219898141] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma.
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Affiliation(s)
- Debanjan Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Jacopo Baglieri
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA
| | - David A Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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Quantitative Anti-HBc in Liver Pathological States in Patients with Chronic Hepatitis B Virus Infection. CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY 2019; 2019:6545642. [PMID: 31949546 PMCID: PMC6948315 DOI: 10.1155/2019/6545642] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023]
Abstract
Background Changes of hepatitis B core antigen antibody (anti-HBc) in liver pathological involvement in patients with chronic hepatitis B virus (HBV) infection have not been investigated in detail. This study aimed to explore evolving patterns of anti-HBc following liver pathological states and to investigate validities of anti-HBc for predicting liver pathological states. Methods 254 HBeAg-positive and 237 HBeAg-negative patients with chronic HBV infection were enrolled. Liver pathological diagnoses referred to Scheuer standard, and anti-HBc was measured using chemiluminescence microparticle immunoassay. Results Anti-HBc was significantly positively correlated with pathological grades and stages in both HBeAg-positive (rs = 0.312, P < 0.0001, and rs = 0.268, P < 0.0001) and HBeAg-negative (rs = 0.270, P < 0.0001, and rs = 0.147, P=0.0237) patients. The medians of anti-HBc in pathological grades of G1, G2, and G3 and stages of S1, S2, S3, and S4 in HBeAg-positive patients were all significantly lower than those in HBeAg-negative patients (all P < 0.005). The areas under receiver-operating characteristic curves (95% confidence interval) of anti-HBc for predicting pathological grades ≥G2 and ≥G3, and stages ≥S2 and =S4 in HBeAg-positive patients were 0.683 (0.622–0.740) and 0.662 (0.601–0.720), and 0.627 (0.564–0.687) and 0.683 (0.622–0.740), respectively, and in HBeAg-negative patients were 0.681 (0.618–0.740) and 0.702 (0.639–0.760), and 0.569 (0.503–0.633) and 0.630 (0.565–0.691), respectively. Conclusion Following hepatic aggravation of necroinflammation and progression of fibrosis, anti-HBc increases gradually in HBeAg-positive patients and continues to increase gradually in HBeAg-negative patients, which is a useful but unsatisfactory marker for monitoring pathological states.
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Fuzhenghuayu Decoction ameliorates hepatic fibrosis by attenuating experimental sinusoidal capillarization and liver angiogenesis. Sci Rep 2019; 9:18719. [PMID: 31822697 PMCID: PMC6904731 DOI: 10.1038/s41598-019-54663-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 07/08/2019] [Indexed: 12/13/2022] Open
Abstract
Fuzhenghuayu (FZHY) is a compound extracted from natural plants. Its anti-fibrotic effect has been confirmed in experimental and clinical studies. However, precise effects and underlying mechanisms of FZHY in liver angiogenesis largely remain understood. In this study, we investigated the effects of FZHY on sinusoidal capillarization and angiogenesis with mice challenged for Carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN), in vitro human hepatic sinusoidal endothelial cells (HHSEC) and Human Umbilical Vein Endothelial Cell (HUVEC) 3D fibrin gel model. Besides its anti-fibrotic effect, FZHY ameliorated CCl4 and DMN-induced sinusoidal capillarization, angiogenesis and expression of angiogenesis-associated factors, i.e. CD31, VEGF, VEGF receptor II, phosphor-ERK and HIF-1α. Consistent with the findings based on animal models, inhibitory effects of FZHY on capillarization and angiogenesis were further confirmed in HHSEC and the HUVEC 3D fibrin gel model, respectively. These data suggest that FZHY ameliorates not only liver fibrosis but also vessel remodeling in experimental models. Therefore, FZHY might be a potentially useful drug to treat liver cirrhosis in clinical practice.
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Czechowska G, Celiński K, Wójcicka G. Liver fibrosis mechanisms – the role of stellate cells, oxidative and nitrosative stress. POSTEP HIG MED DOSW 2019. [DOI: 10.5604/01.3001.0013.1974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis is a chronic and complex pathological process, occuring in patients with chronic liver diseases. The most common cause of liver fibrosis is the alcoholic liver disease, viral hepatitis type B, C and D, as well as autoimmune diseases. Other causes include metabolic dysfunctions like hemachromatosis and Wilson’s disease, biliary duct disorders, damaging effects of medicine and parasite infections. Fibrosis’ dynamics and progres speed depend on the nature of underlying mechanisms and are characterized by accumulation of ECM elements. They vary from patient to patient and are directly correlated to aberrations of homeostasis degradation and production of liver connective tissue.
In liver fibrosis the main source of ECM are hepatic stellate cells (HSCS), although other cells are also able to produce ECM such as: portal fibroblasts, narrow-derived cells, biliary duct epithelial cells and epithelial mesenchymal transition hepatocytes. The HSCS activity is stimulated by proinflammatory cytokines, oxidative and nitrosative stress which lead to different pathologies such as: inflammation, steatosis, fibrosis, cirrhosis, liver-cell cancer. Alcohol, the main fibrotic agents is metabolized almost entirely in the liver, so the organ is extremely sensitive to its negative intermediate and mediate influence. Factors influencing alcoholic liver failure are not only oxidative and nitrosative stress and proinflammatory cytokines activity, but also reductive stress, hepatocytes; hypoxia, mucous membranę dysfunction and intestine flora influence, as well as genetic and immunological factors. Though in last several yers there has been a great advancement in our knowledge of liver fibrosis mechanisms, it remains tough to diagnose the proces in its early stages and consequently apply an efficient therapy. The challenge for the futur is finding useful biomarkers and new therapeutic goals.
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Affiliation(s)
- Grażyna Czechowska
- Katedra i Klinika Gastroenterologii z Pracownią Endoskopową, Uniwersytet Medyczny w Lublinie
| | - Krzysztof Celiński
- Katedra i Klinika Gastroenterologii z Pracownią Endoskopową, Uniwersytet Medyczny w Lublinie
| | - Grażyna Wójcicka
- Katedra i Zakład Patofizjologii, Uniwersytet Medyczny w Lublinie
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Sarin SK, Choudhury A, Sharma MK, Maiwall R, Al Mahtab M, Rahman S, Saigal S, Saraf N, Soin AS, Devarbhavi H, Kim DJ, Dhiman RK, Duseja A, Taneja S, Eapen CE, Goel A, Ning Q, Chen T, Ma K, Duan Z, Yu C, Treeprasertsuk S, Hamid SS, Butt AS, Jafri W, Shukla A, Saraswat V, Tan SS, Sood A, Midha V, Goyal O, Ghazinyan H, Arora A, Hu J, Sahu M, Rao PN, Lee GH, Lim SG, Lesmana LA, Lesmana CR, Shah S, Prasad VGM, Payawal DA, Abbas Z, Dokmeci AK, Sollano JD, Carpio G, Shresta A, Lau GK, Fazal Karim M, Shiha G, Gani R, Kalista KF, Yuen MF, Alam S, Khanna R, Sood V, Lal BB, Pamecha V, Jindal A, Rajan V, Arora V, Yokosuka O, Niriella MA, Li H, Qi X, Tanaka A, Mochida S, Chaudhuri DR, Gane E, Win KM, Chen WT, Rela M, Kapoor D, Rastogi A, Kale P, Rastogi A, Sharma CB, Bajpai M, Singh V, Premkumar M, Maharashi S, Olithselvan A, Philips CA, Srivastava A, Yachha SK, Wani ZA, Thapa BR, Saraya A, Shalimar, Kumar A, Wadhawan M, Gupta S, Madan K, Sakhuja P, Vij V, Sharma BC, Garg H, Garg V, Kalal C, et alSarin SK, Choudhury A, Sharma MK, Maiwall R, Al Mahtab M, Rahman S, Saigal S, Saraf N, Soin AS, Devarbhavi H, Kim DJ, Dhiman RK, Duseja A, Taneja S, Eapen CE, Goel A, Ning Q, Chen T, Ma K, Duan Z, Yu C, Treeprasertsuk S, Hamid SS, Butt AS, Jafri W, Shukla A, Saraswat V, Tan SS, Sood A, Midha V, Goyal O, Ghazinyan H, Arora A, Hu J, Sahu M, Rao PN, Lee GH, Lim SG, Lesmana LA, Lesmana CR, Shah S, Prasad VGM, Payawal DA, Abbas Z, Dokmeci AK, Sollano JD, Carpio G, Shresta A, Lau GK, Fazal Karim M, Shiha G, Gani R, Kalista KF, Yuen MF, Alam S, Khanna R, Sood V, Lal BB, Pamecha V, Jindal A, Rajan V, Arora V, Yokosuka O, Niriella MA, Li H, Qi X, Tanaka A, Mochida S, Chaudhuri DR, Gane E, Win KM, Chen WT, Rela M, Kapoor D, Rastogi A, Kale P, Rastogi A, Sharma CB, Bajpai M, Singh V, Premkumar M, Maharashi S, Olithselvan A, Philips CA, Srivastava A, Yachha SK, Wani ZA, Thapa BR, Saraya A, Shalimar, Kumar A, Wadhawan M, Gupta S, Madan K, Sakhuja P, Vij V, Sharma BC, Garg H, Garg V, Kalal C, Anand L, Vyas T, Mathur RP, Kumar G, Jain P, Pasupuleti SSR, Chawla YK, Chowdhury A, Alam S, Song DS, Yang JM, Yoon EL. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatol Int 2019; 13:353-390. [PMID: 31172417 PMCID: PMC6728300 DOI: 10.1007/s12072-019-09946-3] [Show More Authors] [Citation(s) in RCA: 558] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 04/03/2019] [Indexed: 02/07/2023]
Abstract
The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the "APASL ACLF Research Consortium (AARC)" was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the 'Golden Therapeutic Window', extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.
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Affiliation(s)
- Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India.
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Manoj K Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Salimur Rahman
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Sanjiv Saigal
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | - Neeraj Saraf
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | - A S Soin
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | | | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea
| | - R K Dhiman
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, PGIMER, Chandigarh, India
| | - C E Eapen
- Department of Hepatology, CMC, Vellore, India
| | - Ashish Goel
- Department of Hepatology, CMC, Vellore, India
| | - Q Ning
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Chen
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital, Beijing, China
| | - Ke Ma
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Z Duan
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital, Beijing, China
| | - Chen Yu
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital, Beijing, China
| | | | - S S Hamid
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Amna S Butt
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Wasim Jafri
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Akash Shukla
- Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Sion, Mumbai, India
| | | | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Bata Caves, Selangor, Malaysia
| | - Ajit Sood
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Vandana Midha
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Omesh Goyal
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Hasmik Ghazinyan
- Department of Hepatology, Nork Clinical Hospital of Infectious Disease, Yerevan, Armenia
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital and GRIPMER, New Delhi, Delhi, India
| | - Jinhua Hu
- Department of Medicine, 302 Millitary Hospital, Beijing, China
| | - Manoj Sahu
- Department of Gastroenterology and Hepatology Sciences, IMS & SUM Hospital, Bhubaneswar, Odisha, India
| | - P N Rao
- Asian Institute of Gastroenterology, Hyderabad, India
| | - Guan H Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Seng G Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | | | | | - Samir Shah
- Department of Hepatology, Global Hospitals, Mumbai, India
| | | | - Diana A Payawal
- Fatima University Medical Center Manila, Manila, Philippines
| | - Zaigham Abbas
- Department of Medicine, Ziauddin University Hospital, Karachi, Pakistan
| | - A Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Jose D Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Gian Carpio
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Ananta Shresta
- Department of Hepatology, Foundation Nepal Sitapaila Height, Kathmandu, Nepal
| | - G K Lau
- Department of Medicine, Humanity and Health Medical Group, New Kowloon, Hong Kong, China
| | - Md Fazal Karim
- Department of Hepatology, Sir Salimullah Medical College, Dhaka, Bangladesh
| | - Gamal Shiha
- Egyptian Liver Research Institute And Hospital, Cairo, Egypt
| | - Rino Gani
- Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Kemal Fariz Kalista
- Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital Hong Kong, The University of Hong Kong, Hong Kong, China
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Viniyendra Pamecha
- Department of Hepatobilliary Pancreatic Surgery and Liver Transplant, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - V Rajan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | - Hai Li
- Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaolong Qi
- CHESS Frontier Center, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Atsushi Tanaka
- Department of Medicine, Tokyo University School of Medicine, Tokyo, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | | | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland Hospital, Auckland, New Zealand
| | | | - Wei Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Mohd Rela
- Department of Liver Transplant Surgery, Dr. Rela Institute and Medical Centre, Chennai, India
| | | | - Amit Rastogi
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | - Pratibha Kale
- Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Chhagan Bihari Sharma
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Meenu Bajpai
- Department of Immunohematology and Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | | | | | | | - A Olithselvan
- Division of Liver Transplantation and Hepatology, Manipal Hospitals, Bangalore, India
| | - Cyriac Abby Philips
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, SGPGIMS, Lucknow, India
| | | | | | - B R Thapa
- Department of Gastroenterology and Pediatric Gastroenterology, PGIMER, Chandigarh, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, AIIMS, New Delhi, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, AIIMS, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital and GRIPMER, New Delhi, Delhi, India
| | - Manav Wadhawan
- Department of Gastroenterology, Hepatology and Liver Transplant, B L K Hospital, New Delhi, India
| | - Subash Gupta
- Centre for Liver and Biliary Science, Max Hospital, New Delhi, India
| | - Kaushal Madan
- Department of Gastroenterology, Hepatology and Liver Transplant, Max Hospital, New Delhi, India
| | - Puja Sakhuja
- Department of Pathology, GB Pant Hospital, New Delhi, India
| | - Vivek Vij
- Department of Liver Transplant and Hepatobilliary Surgery, Fortis Hospital, New Delhi, India
| | - Barjesh C Sharma
- Department of Gastroenterology, GB Pant Hospital, New Delhi, India
| | - Hitendra Garg
- Department of Gastroenterology, Hepatology and Liver Transplant, Apollo Hospital, New Delhi, India
| | - Vishal Garg
- Department of Gastroenterology, Hepatology and Liver Transplant, Apollo Hospital, New Delhi, India
| | - Chetan Kalal
- Department of Hepatology, Sir H N Reliance Hospital and Research Centre, Mumbai, India
| | - Lovkesh Anand
- Department of Gastroenterology and Hepatology, Narayana Hospital, Gurugram, India
| | - Tanmay Vyas
- Department of Hepatology, Parimal Multi-Speciality Hospital, Ahmedabad, India
| | - Rajan P Mathur
- Department of Nephrology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Statistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Priyanka Jain
- Department of Statistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Samba Siva Rao Pasupuleti
- Department of Statistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Yogesh K Chawla
- Department of Hepatology and Gastroenterology, Kalinga Institute of Med Sciences, KIIT University, Bhubaneswar, India
| | - Abhijit Chowdhury
- Department of Hepatology, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Shahinul Alam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Do Seon Song
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Eileen L Yoon
- Department Of Internal Medicine, Inje University College of Medicine, Busan, South Korea
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35
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Van Haele M, Snoeck J, Roskams T. Human Liver Regeneration: An Etiology Dependent Process. Int J Mol Sci 2019; 20:ijms20092332. [PMID: 31083462 PMCID: PMC6539121 DOI: 10.3390/ijms20092332] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/06/2019] [Accepted: 05/09/2019] [Indexed: 02/07/2023] Open
Abstract
Regeneration of the liver has been an interesting and well-investigated topic for many decades. This etiology and time-dependent mechanism has proven to be extremely challenging to investigate, certainly in human diseases. A reason for this challenge is found in the numerous interactions of different cell components, of which some are even only temporarily present (e.g., inflammatory cells). To orchestrate regeneration of the epithelial cells, their interaction with the non-epithelial components is of utmost importance. Hepatocytes, cholangiocytes, liver progenitor cells, and peribiliary glands have proven to be compartments of regeneration. The ductular reaction is a common denominator in virtually all liver diseases; however, it is predominantly found in late-stage hepatic and biliary diseases. Ductular reaction is an intriguing example of interplay between epithelial and non-epithelial cells and encompasses bipotential liver progenitor cells which are able to compensate for the loss of the exhausted hepatocytes and cholangiocytes in biliary and hepatocytic liver diseases. In this manuscript, we focus on the etiology-specific damage that is observed in different human diseases and how the liver regulates the regenerative response in an acute and chronic setting. Furthermore, we describe the importance of morphological keynotes in different etiologies and how spatial information is of relevance for every basic and translational research of liver regeneration.
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Affiliation(s)
- Matthias Van Haele
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, 3000 Leuven, Belgium.
| | - Janne Snoeck
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, 3000 Leuven, Belgium.
| | - Tania Roskams
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, 3000 Leuven, Belgium.
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36
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Lackner C, Tiniakos D. Fibrosis and alcohol-related liver disease. J Hepatol 2019; 70:294-304. [PMID: 30658730 DOI: 10.1016/j.jhep.2018.12.003] [Citation(s) in RCA: 185] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/06/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023]
Abstract
Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.
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Affiliation(s)
- Carolin Lackner
- Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria.
| | - Dina Tiniakos
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Dept of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Vas. Sofias Avenue 76, Athens 11528, Greece
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37
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Bradley C, Scott RA, Cox E, Palaniyappan N, Thomson BJ, Ryder SD, Irving WL, Aithal GP, Guha IN, Francis S. Short-term changes observed in multiparametric liver MRI following therapy with direct-acting antivirals in chronic hepatitis C virus patients. Eur Radiol 2018; 29:3100-3107. [PMID: 30506214 PMCID: PMC6510871 DOI: 10.1007/s00330-018-5788-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/04/2018] [Accepted: 09/21/2018] [Indexed: 12/11/2022]
Abstract
Methods We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed). Results We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35 ± 4 ms), transverse relaxation time (T2, 2.5 ± 0.8 ms; T2* 3.0 ± 0.7 ms), and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow. Conclusion For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms. Key Points • DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis. • Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance. • The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms.
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Affiliation(s)
- C Bradley
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - R A Scott
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - E Cox
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - N Palaniyappan
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - B J Thomson
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - S D Ryder
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - W L Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - G P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, School of Medicine, the University Of Nottingham, Nottingham, UK
| | - I N Guha
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, School of Medicine, the University Of Nottingham, Nottingham, UK
| | - S Francis
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, UK. .,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
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38
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Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin P, Mueller S, Szabo G, Tsukamoto H. Alcoholic liver disease. Nat Rev Dis Primers 2018; 4:16. [PMID: 30115921 DOI: 10.1038/s41572-018-0014-7] [Citation(s) in RCA: 778] [Impact Index Per Article: 111.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by hepatic inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis and in some cases hepatocellular cancer (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical presentation of ALD that is associated with liver failure and high mortality. Most individuals consuming >40 g of alcohol per day develop AFL; however, only a subset of individuals will develop more advanced disease. Genetic, epigenetic and non-genetic factors might explain the considerable interindividual variation in ALD phenotype. The pathogenesis of ALD includes hepatic steatosis, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. The degree of AFL and liver fibrosis can be determined by ultrasonography, transient elastography, MRI, measurement of serum biomarkers and liver biopsy histology. Alcohol abstinence achieved by psychosomatic intervention is the best treatment for all stages of ALD. In the case of advanced disease such as cirrhosis or HCC, liver transplantation may be required. Thus, new therapies are urgently needed.
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Affiliation(s)
- Helmut K Seitz
- Centre of Alcohol Research (CAR),, University of Heidelberg, Heidelberg and Department of Medicine, Salem Medical Center, Heidelberg, Germany.
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Helena Cortez-Pinto
- Departmento de Gastroenterologia, CHLN, Laboratorio de Nutricão, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Antoni Gual
- Addiction Unit, Neuroscience Institute Hospital Clinic, IDIBAPS, Barcelona, Spain
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, Universite Lille 2 and INSERM U795, Lille, France
| | - Sebastian Mueller
- Centre of Alcohol Research (CAR),, University of Heidelberg, Heidelberg and Department of Medicine, Salem Medical Center, Heidelberg, Germany
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Hidekazu Tsukamoto
- University of Southern California Keck School of Medicine and Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA
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Liu D, Li J, Lu W, Wang Y, Zhou X, Huang D, Li X, Ding R, Zhang Z. Gamma-glutamyl transpeptidase to cholinesterase and platelet ratio in predicting significant liver fibrosis and cirrhosis of chronic hepatitis B. Clin Microbiol Infect 2018; 25:514.e1-514.e8. [PMID: 29906588 DOI: 10.1016/j.cmi.2018.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 05/28/2018] [Accepted: 06/02/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To evaluate the performance of a new mathematical model γ-glutamyl transpeptidase to cholinesterase and platelet ratio (GCPR) versus γ-glutamyl transpeptidase to platelet ratio (GPR) in predicting significant fibrosis and cirrhosis of chronic hepatitis B. METHODS A complete cohort of 2343 patients was divided into early and late cohort depending on the time of liver biopsy. With reference to the Scheuer standard, liver pathologic stage 2 or higher and stage 4 or higher were defined as significant fibrosis and cirrhosis, respectively. Receiver operating characteristic (ROC) curve was used to evaluate the performance of investigated models. RESULTS In the early cohort, the areas under ROC curves (AUROCs) of GCPR in predicting significant fibrosis of hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients (0.782 and 0.775) were both significantly greater than those of GPR (0.748 and 0.747) (Z = 8.198 and Z = 6.023, both p <0.0001); the AUROCs of GCPR in predicting cirrhosis of HBeAg-positive and HBeAg-negative patients (0.842 and 0.861) were both significantly greater than those of GPR (0.802 and 0.823) (Z = 6.686 and Z = 6.116, both p <0.0001). In early, late and complete cohorts, using a single cutoff of GCPR > 0.080, the specificities of GCPR in predicting significant fibrosis of HBeAg-positive patients were 83.3%, 88.2% and 85.0% and of HBeAg-negative patients were 87.6%, 87.4% and 87.6%, respectively; and the sensitivities of GCPR in predicting cirrhosis of HBeAg-positive patients were 81.9%, 88.7% and 84.2% and of HBeAg-negative patients were 83.1%, 82.1% and 82.7%, respectively. CONCLUSIONS GCPR has higher performance than GPR in predicting significant fibrosis and cirrhosis of chronic hepatitis B.
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Affiliation(s)
- D Liu
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - J Li
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Department of Infectology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - W Lu
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Y Wang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - X Zhou
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - D Huang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - X Li
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - R Ding
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Z Zhang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Department of Infectology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
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40
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Talal AH, Venuto CS, Younis I. Assessment of Hepatic Impairment and Implications for Pharmacokinetics of Substance Use Treatment. Clin Pharmacol Drug Dev 2018; 6:206-212. [PMID: 28263464 DOI: 10.1002/cpdd.336] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 12/30/2016] [Indexed: 12/12/2022]
Abstract
Although the liver is the primary site of metabolism and biliary excretion for many medications, data are limited on the liver's pharmacokinetic abilities in cirrhosis. Cirrhosis develops through collagen deposition, eventually culminating in end-stage liver disease that compromises hepatic drug metabolism. Consequently, the US Food and Drug Administration (FDA) recommends evaluating the pharmacokinetics of medications in subjects with hepatic impairment if hepatic metabolism constitutes more than 20% of their elimination or if they have a narrow therapeutic range. A variety of noninvasive indices and radiologic procedures can be employed to assess hepatic drug metabolism and excretion. The Child-Pugh score is the most commonly used scale for assessing hepatic impairment among drugs submitted for US FDA approval. The score, originally developed to guide operative mortality in patients undergoing hepatic resection, has not been modified since its inception 5 decades ago. Furthermore, the score was not originally intended to be a guide for potential dose modification in patients with hepatic impairment. These reasons, in combination with the availability of a variety of new imaging modalities and an enhanced understanding of hepatic biology, should foster the development of novel methods to assess the effect of hepatic impairment on liver drug metabolism.
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Affiliation(s)
- Andrew H Talal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Charles S Venuto
- Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY, USA.,AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Islam Younis
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
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41
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Liu DP, Lu W, Zhang ZQ, Wang YB, Ding RR, Zhou XL, Huang D, Li XF. Comparative evaluation of GPR versus APRI and FIB-4 in predicting different levels of liver fibrosis of chronic hepatitis B. J Viral Hepat 2018; 25:581-589. [PMID: 29230907 DOI: 10.1111/jvh.12842] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 10/25/2017] [Indexed: 12/11/2022]
Abstract
It is of great significance to develop and evaluate noninvasive indexes predicting the level of liver fibrosis. The aim of this study was to comparatively evaluate gamma-glutamyl transpeptidase-to-platelet ratio (GPR) versus aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on 4 factors (FIB-4) in predicting different levels of liver fibrosis of chronic hepatitis B (CHB) within the framework of HBeAg-positive and HBeAg-negative patients. A total of 1157 HBeAg-positive and 859 HBeAg-negative CHB patients were enrolled, among whom the pathological stage ≥S2, ≥S3, ≥S4 were defined as significant fibrosis, extensive fibrosis and cirrhosis, respectively. Receiver operating characteristic (ROC) curves were used to evaluate the performance of GPR, APRI and FIB-4 in predicting different levels of liver fibrosis. In HBeAg-positive patients, the area under ROC curves (AUROCs) of GPR in predicting extensive fibrosis and cirrhosis were both significantly larger than those of APRI (P = .0001 and P < .0001). In HBeAg-negative patients, the AUROCs of GPR in predicting significant fibrosis and cirrhosis were significantly larger than those of FIB-4 (P = .0006 and P = .0041). The AUROC of GPR in predicting extensive fibrosis was significantly larger than that of APRI and FIB-4 (P = .0320 and P = .0018). Using a cut-off of GPR > 0.500 as standard, the sensitivities and specificities of GPR in predicting significant fibrosis in HBeAg-positive patients were 59.6% and 81.2%, and for cirrhosis 80.9% and 63.8%, respectively; and those of HBeAg-negative patients were 60.3% and 78.3%, 84.5% and 66.1%, respectively. Regardless of HBeAg-positive or HBeAg-negative status, GPR had the best performance in predicting different levels of liver fibrosis.
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Affiliation(s)
- D-P Liu
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - W Lu
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Z-Q Zhang
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Y-B Wang
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - R-R Ding
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - X-L Zhou
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - D Huang
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - X-F Li
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
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42
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Garcia-Tsao G. Regression of HCV cirrhosis: Time will tell. Hepatology 2018; 67:1651-1653. [PMID: 29222930 PMCID: PMC6016365 DOI: 10.1002/hep.29720] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 11/22/2017] [Accepted: 12/06/2017] [Indexed: 12/21/2022]
Affiliation(s)
- Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA,Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT, USA
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43
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Feng R, Yuan X, Shao C, Ding H, Liebe R, Weng HL. Are we any closer to treating liver fibrosis (and if no, why not)? J Dig Dis 2018; 19:118-126. [PMID: 29389083 DOI: 10.1111/1751-2980.12584] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/26/2018] [Indexed: 12/11/2022]
Abstract
This review provides a personal view on anti-fibrosis therapy in the liver. The worst clinical consequence of liver fibrosis is the development of liver cirrhosis and portal hypertension. Etiology is a decisive factor which determines patterns of fibrous septa and subsequent vascular remodeling, which is essential for the development of portal hypertension. Removing or controlling the disease-causing agent, i.e. anti-viral treatment for hepatitis, is the essential first step for treating chronic liver diseases and can reverse fibrosis in some settings. However, removing etiology is not always sufficient to prevent fibrosis from progressing towards cirrhosis and portal hypertension. In liver diseases such as severe alcoholic hepatitis and massive parenchymal loss, the formation of vascular anastomoses between portal to central veins based on bridging fibrosis results in cirrhosis and portal hypertension. For these patients, anti-fibrotic treatment is crucial and urgent. Unfortunately, a lack of understanding how fibrosis contributes to vascular remodeling caused by and combined with a lack of suitable experimental models that recapitulate human liver diseases, has hampered the development of successful anti-fibrotic drugs for clinical use to date.
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Affiliation(s)
- Rilu Feng
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Xiaodong Yuan
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Chen Shao
- Department of Pathology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Roman Liebe
- Department of Medicine II, Saarland University Medical Center, Homburg/Saar, Germany
| | - Hong-Lei Weng
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Cordero-Espinoza L, Huch M. The balancing act of the liver: tissue regeneration versus fibrosis. J Clin Invest 2018; 128:85-96. [PMID: 29293095 PMCID: PMC5749503 DOI: 10.1172/jci93562] [Citation(s) in RCA: 156] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epithelial cell loss alters a tissue's optimal function and awakens evolutionarily adapted healing mechanisms to reestablish homeostasis. Although adult mammalian organs have a limited regeneration potential, the liver stands out as one remarkable exception. Following injury, the liver mounts a dynamic multicellular response wherein stromal cells are activated in situ and/or recruited from the bloodstream, the extracellular matrix (ECM) is remodeled, and epithelial cells expand to replenish their lost numbers. Chronic damage makes this response persistent instead of transient, tipping the system into an abnormal steady state known as fibrosis, in which ECM accumulates excessively and tissue function degenerates. Here we explore the cellular and molecular switches that balance hepatic regeneration and fibrosis, with a focus on uncovering avenues of disease modeling and therapeutic intervention.
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Salgado AA, Barbosa PRB, Ferreira AG, Reis CADSS, Terra C. Prognostic Value of a New Marker of Ventricular Repolarization in Cirrhotic Patients. Arq Bras Cardiol 2017; 107:523-531. [PMID: 28558079 PMCID: PMC5210456 DOI: 10.5935/abc.20160181] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 06/08/2016] [Indexed: 01/06/2023] Open
Abstract
Background There is still debate about the relationship between changes in ventricular
repolarization on the surface electrocardiogram and cirrhosis severity. Objective To study the relationship between variables related to ventricular
repolarization and the clinical severity of the cirrhotic disease. Methods We selected 79 individuals with hepatic cirrhosis, classified according to
the Child-Pugh-Turcotte criteria (Child A, B, and C). We measured the QT and
corrected QT (QTc) intervals, and the interval between the peak and the end
of the T wave (TpTe), and we identified their minimum, maximum, and mean
values in the 12-lead electrocardiogram. We also calculated the dispersion
of the QT (DQT) and QTc (DQTc) intervals. Results In 12 months of clinical follow-up, nine subjects underwent hepatic
transplantation (Child A: 0 [0%]; Child B: 6 [23.1%]; Child C: 3 [18.8%]; p
= 0.04) and 12 died (Child A: 3 [12.0%]; Child B: 4 [15.4%]; Child C: 5
[31.3%]; p = 0.002). No significant differences were observed between the
cirrhotic groups related to the minimum, maximum, and mean values for the
QT, QTc, TpTe, DQT, and DQTc intervals. A minimum TpTe interval ≤ 50
ms was a predictor for the composite endpoints of death or liver
transplantation with a sensitivity of 90% and a specificity of 57% (p =
0.005). In the Cox multivariate analysis, the Child groups and a minimum
TpTe of ≤ 50 ms were independent predictors of the composite
endpoints. Conclusion The intervals QT, QTc, DQT, DQTc, and TpTe have similar distributions between
different severity stages in cirrhotic disease. The TpTe interval proved to
be a prognostic marker in subjects with cirrhosis, regardless of disease
severity (NCT01433848).
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Affiliation(s)
- Angelo Antunes Salgado
- Hospital Universitário Pedro Ernesto, Universidade Estadual do Rio de Janeiro, RJ, Brazil
| | | | | | | | - Carlos Terra
- Hospital Universitário Pedro Ernesto, Universidade Estadual do Rio de Janeiro, RJ, Brazil
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Zhou Z, Park S, Kim JW, Zhao J, Lee MY, Choi KC, Lim CW, Kim B. Detrimental effects of nicotine on thioacetamide-induced liver injury in mice. Toxicol Mech Methods 2017; 27:501-510. [PMID: 28440100 DOI: 10.1080/15376516.2017.1323256] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
AIM Nicotine exerts a number of physiological effects. The purpose of this study was to determine the effects of nicotine on thioacetamide (TAA)-induced liver fibrosis in mice. MATERIALS AND METHODS For in vivo experiments, hepatic fibrosis was induced by TAA (0.25 g/kg, i.p.) three times a week for 6 weeks. Mice of TAA treated groups were administered daily with distilled water and nicotine (50 or 100 μg/mL) via gastrogavage throughout the experimental period. For in vitro experiments, HepG2 (human liver cancer cell line) and LX-2 (human hepatic stellate cell line) were used to determine oxidative stress and fibrosis, respectively. RESULTS Compared to control groups, TAA treated groups had significantly differences in serum alanine transferase and aspartate aminotransferase levels and nicotine accentuated liver injury. Moreover, nicotine increased the mRNA levels of TAA-induced transforming growth factor-β (TGF-β) and collagen type I alpha 1 in the liver. Nicotine also increased TAA-induced oxidative stress. Histological examination confirmed that nicotine aggravated the degree of fibrosis caused by TAA treatment. Additionally, nicotine enhanced hepatic stellate cell activation via promoting the expression of α-smooth muscle actin. CONCLUSIONS Oral administration of nicotine significantly aggravated TAA-induced hepatic fibrosis in mice through enhancing TGF-β secretion and TAA-induced oxidative stress. The increase in TGF-β levels might be associated with the strengthening of oxidative processes, subsequently leading to increased hepatic stellate cell activation and extracellular matrix deposition. These results suggest that patients with liver disease should be advised to abandon smoking since nicotine may exacerbate hepatic fibrosis.
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Affiliation(s)
- Zixiong Zhou
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea
| | - Surim Park
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea
| | - Jong Won Kim
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea
| | - Jing Zhao
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea
| | - Moo-Yeol Lee
- College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do, Republic of Korea
| | - Kyung Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Chae Woong Lim
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea
| | - Bumseok Kim
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea
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Ramachandran P, Henderson NC. Antifibrotics in chronic liver disease: tractable targets and translational challenges. Lancet Gastroenterol Hepatol 2016; 1:328-340. [PMID: 28404203 DOI: 10.1016/s2468-1253(16)30110-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/22/2016] [Accepted: 07/26/2016] [Indexed: 12/30/2022]
Abstract
Chronic liver disease prevalence is increasing globally. Iterative liver damage, secondary to any cause of liver injury, results in progressive fibrosis, disrupted hepatic architecture, and aberrant regeneration, which are defining characteristics of liver cirrhosis. Liver transplantation is an effective treatment for end-stage liver disease; however, demand greatly outweighs donor organ supply, and in many parts of the world liver transplantation is unavailable. Hence, effective antifibrotic therapies are urgently required. In the past decade, rapid progress has been made in our understanding of the pathophysiology of liver fibrosis and a large number of potential cellular and molecular antifibrotic targets have been identified. This has led to numerous clinical trials of antifibrotic agents in patients with chronic liver disease. However, none of these have resulted in a robust and reproducible effect on fibrosis. It is therefore imperative that the ongoing translational challenges are addressed, to convert scientific discoveries into potent antifibrotics and enable bridging of the translational gap between putative therapeutic targets and effective treatments for patients with chronic liver disease.
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Affiliation(s)
- Prakash Ramachandran
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neil C Henderson
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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Zhou L, Wang LY, Zhang XM, Zeng NL, Chen TW, Li R, Huang YC, Tang YL. Semi-quantitative assessment of the presence and Child-Pugh class of hepatitis B related cirrhosis by using liver lobe-based dynamic contrast-enhanced MRI. Clin Radiol 2016; 71:1289-1295. [PMID: 27633724 DOI: 10.1016/j.crad.2016.07.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 07/21/2016] [Accepted: 07/26/2016] [Indexed: 12/31/2022]
Abstract
AIM To determine whether liver lobe-based DCE-MRI can be used to detect the presence and Child-Pugh class of hepatitis B-related cirrhosis. MATERIALS AND METHODS Fifty-six cirrhotic patients with hepatitis B and 20 healthy participants underwent liver DCE-MRI, and the positive enhancement integral (PEI), time to peak (TTP), maximum slope of increase (MSI) and maximum slope of decrease (MSD) of the left lateral liver lobe (LLL), left medial liver lobe (LML), right liver lobe (RL), and caudate lobe (CL) were measured and analysed statistically to evaluate cirrhosis. RESULTS TTP values of the LLL, LML, RL and CL were positively correlated with the Child-Pugh class of cirrhosis (r=0.452 to 0.55, all p<0.05). PEI values of the LLL, LML, RL and CL, as well as the MSI of the CL and the MSD of the RL, were inversely correlated with the Child-Pugh class (r=-0.349 to -0.72, all p<0.05). PEI values of the LLL and CL, or TTP values of the RL had the most area under receiver operating characteristic curve (AUC) of 0.99 for identifying the presence of liver cirrhosis. The PEI of the RL had the largest AUC of 0.975 and 0.78 for distinguishing the Child-Pugh class A of cirrhosis from class B-C and class A-B of cirrhosis from class C, respectively. CONCLUSION Liver lobe-based DCE-MRI parameters are associated with the presence and Child-Pugh class of hepatitis B-related cirrhosis.
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Affiliation(s)
- L Zhou
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63(#) Wenhua Road, Shunqing District, Nanchong 637000, Sichuan Province, China; Department of Radiology, Affiliated Xi'an Gaoxin Hospital of Xi'an Jiaotong University, Xi'an 710075, Shanxi Province, China
| | - L-Y Wang
- Department of Imaging Centre, Central Hospital of Changsha, Changsha 430100, Hunan Province, China
| | - X-M Zhang
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63(#) Wenhua Road, Shunqing District, Nanchong 637000, Sichuan Province, China
| | - N-L Zeng
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63(#) Wenhua Road, Shunqing District, Nanchong 637000, Sichuan Province, China
| | - T-W Chen
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63(#) Wenhua Road, Shunqing District, Nanchong 637000, Sichuan Province, China.
| | - R Li
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63(#) Wenhua Road, Shunqing District, Nanchong 637000, Sichuan Province, China
| | - Y-C Huang
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63(#) Wenhua Road, Shunqing District, Nanchong 637000, Sichuan Province, China
| | - Y-L Tang
- Sichuan Key Laboratory of Medical Imaging and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63(#) Wenhua Road, Shunqing District, Nanchong 637000, Sichuan Province, China
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