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Sadeghi A, Amiri R, Akbarpour E, Mirminachi B, Sharifi AH, Merat S. Changes in liver fibrosis in patients with chronic hepatitis C after successful direct-acting antiviral therapy. Int J Clin Pract 2021; 75:e14145. [PMID: 33709413 DOI: 10.1111/ijcp.14145] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/09/2021] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION AND OBJECTIVES After successful treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs), the stage of liver fibrosis decreases over time. Here, we aimed to assess the changes in the liver fibrosis stage using transient elastography (TE) after successful DAA therapy in HCV-infected cirrhotic patients who were referred to Shariati hospital from 2016 to 2017. MATERIAL AND METHODS In this observational cohort, all HCV-infected cirrhotic patients who were treated with a combination of sofosbuvir/daclatasvir, had sustained virologic response (SVR), and had undergone pre- and post-treatment TE, were enrolled. The primary outcome was the changes in TE parameters six months after the end of treatment compared with baseline. RESULTS A total of 442 eligible subjects received DAA therapy. Overall, the SVR rate was 96.6%. Of these, 149 patients had completed the protocol and were enrolled. The mean age of patients was 56.1 ± 10.3 years and the predominant sex was male (77.9%). The median (Q1 -Q3 ) liver stiffness (LS) value at baseline was 26.3 kPa (18.1-38 kPa), which significantly decreased to 20.9 kPa (12-29.7 kPa) [z = -8.45, P-value < .001]. Also, the liver steatosis of patients with baseline CAP ≥ 220 dB/m had a significant response to treatment [z = -2.3, P-value = .023]. Based on multivariate analysis, a higher baseline liver fibrosis stage was the only determinant of LS values improvement in our study. CONCLUSION Successful HCV eradication in patients with liver fibrosis results in significant improvement in LS, even in cirrhotic patients.
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Affiliation(s)
- Anahita Sadeghi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roya Amiri
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Akbarpour
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Mirminachi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir-Houshang Sharifi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahin Merat
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Wang H, Yan W, Feng Z, Gao Y, Zhang L, Feng X, Tian D. Plasma proteomic analysis of autoimmune hepatitis in an improved AIH mouse model. J Transl Med 2020; 18:3. [PMID: 31906950 PMCID: PMC6943959 DOI: 10.1186/s12967-019-02180-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/13/2019] [Indexed: 12/28/2022] Open
Abstract
Background The prevalence of autoimmune hepatitis (AIH) is increasing, and its early clinical diagnosis is difficult. The pathogenesis of AIH remains unclear, and AIH-related studies are largely limited because of lack of suitable mouse models. Methods To obtain a good tool for research on AIH, we first established an improved immune-mediated mouse model that can mimic the pathological process of AIH as in the human body, through repeated injections of human cytochrome P450 2D6 (CYP2D6) plasmid. Next, a proteomic analysis based on isobaric tag (IBT) technology was performed to detect the differentially expressed proteins (DEPs), and related biological functions and pathways in the plasma of AIH and normal mice. Finally, we performed enzyme-linked immunosorbent assay (ELISA) to further confirm the most abundant DEP in the plasma of patients with AIH. Results Autoantibodies and the characteristic pathology of AIH were observed in our mouse model. Inflammatory infiltration also increased in the livers of AIH mice over time and plateaued by day 42 post the first injection. Chronic hepatitis was most severe on day 35 with the development of fibrosis as well, and the plasma of AIH mice were collected for proteomic analysis. A total of 176 DEPs were found in this experiment, of which 148 DEPs were up-regulated and 28 DEPs were down-regulated. Thirty significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (P < 0.05) were detected. Arginine biosynthesis was found to be the most significant pathway involved in the AIH process. During the Gene Ontology (GO) analysis, most DEPs were found to be involved in the binding, cellular, and metabolic processes. Using ELISA, the most overexpressed DEP, serum amyloid A 1 (SAA1), was confirmed to be increased specifically in the plasma of patients with AIH compared to other chronic hepatitis. Different plasma levels of SAA1 were also found related to different grades of inflammation and stages of fibrosis in the liver of patients with AIH. Conclusions Our study is the first to describe the proteomics analysis of a true sense of AIH mouse model, which is beneficial for a better understanding of AIH pathogenesis and identifying potential biomarkers for its clinical diagnosis.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China
| | - Zuohua Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yuan Gao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Liu Zhang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China.
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, People's Republic of China.
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Minghui Z, Kunhua H, Yunwen B, Hongmei L, Jing L, Shaowen W, Longqiaozi S, Chaohui D. Analysis of Differentially Expressed Proteins Involved in Autoimmune Cirrhosis and Normal Serum by iTRAQ Proteomics. Proteomics Clin Appl 2018; 13:e1700153. [PMID: 29999587 PMCID: PMC6585725 DOI: 10.1002/prca.201700153] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 04/20/2018] [Indexed: 12/15/2022]
Abstract
PURPOSE In order to study the candidate biomarkers in autoimmune cirrhosis (AIC). EXPERIMENTAL DESIGN Isobaric tags are first implemented for relative and absolute quantitation technology on proteins prepared from serum obtained from AIC and normal controls. Proteins found to be differentially expressed are identified with liquid chromatography electrospray ionization tandem mass spectrometry by using a Q Exactive classic ion trap mass spectrometer. RESULTS 108 proteins (32 upregulated and 76 downregulated proteins) are identified from AIC samples, compared with the normal controls. Gene Ontology enrichment analysis, KEGG pathway analysis, and protein-protein interaction map by STRING show that they associate with multiple functional groups, including ion binding activity, peptidase activity, and enzyme regulator activity. Finally, the von Willebrand factor, insulin-like growth factor-binding protein complex acid labile subunit, transthyretin, adiponectin proteins are identified with western blot as candidate biomarkers for AIC. CONCLUSIONS AND CLINICAL RELEVANCE These findings offer a comprehensive profile of the AIC proteome about candidate biomarkers and provide a useful basis for further analysis of the pathogenic mechanism of AIC.
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Affiliation(s)
- Zheng Minghui
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Hu Kunhua
- Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Bao Yunwen
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Lu Hongmei
- The Second Clinical Medical College, Guangdong Medical University, Dongguan, 523808, China
| | - Li Jing
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Wu Shaowen
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Sun Longqiaozi
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Duan Chaohui
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
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Ebrahimi H, Naderian M, Sohrabpour AA. New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article. Middle East J Dig Dis 2018; 10:133-148. [PMID: 30186577 PMCID: PMC6119836 DOI: 10.15171/mejdd.2018.103] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
Currently, liver fibrosis and its complications are regarded as critical health problems.
With the studies showing the reversible nature of liver fibrogenesis, scientists have focused
on understanding the underlying mechanism of this condition in order to develop new
therapeutic strategies. Although hepatic stellate cells are known as the primary cells
responsible for liver fibrogenesis, studies have shown contributing roles for other cells,
pathways, and molecules in the development of fibrosis depending on the etiology of
liver fibrosis. Hence, interventions could be directed in the proper way for each type of
liver diseases to better address this complication. There are two main approaches in clinical
reversion of liver fibrosis; eliminating the underlying insult and targeting the fibrosis
process, which have variable clinical importance in the treatment of this disease. In this
review, we present recent concepts in molecular pathways of liver fibrosis reversibility
and their clinical implications.
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Affiliation(s)
- Hedyeh Ebrahimi
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Naderian
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Sohrabpour
- Associate Professor, The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Verloh N, Utpatel K, Haimerl M, Zeman F, Fellner C, Dahlke M, Renner P, Seyfried T, Müller M, Stroszczynski C, Evert M, Wiggermann P. DWI - histology: a possible means of determining degree of liver fibrosis? Oncotarget 2018; 9:20112-20118. [PMID: 29732007 PMCID: PMC5929450 DOI: 10.18632/oncotarget.24981] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 03/12/2018] [Indexed: 01/05/2023] Open
Abstract
Objectives The aim of this study was to determine the diagnostic value of diffusion-weighted MRI of the liver at 3T to classify liver fibrosis/cirrhosis. Methods 62 patients who underwent both histopathological examination and diffusion-weighted imaging of the liver via 3T MRI within a period of 3 months were included in the study. The Ishak score (1-6) was used to determine the degree of fibrosis: No liver fibrosis (NLF; Ishak 0, n = 16), mild liver fibrosis (MLF; Ishak 1-2, n = 23), advanced liver fibrosis (ALF; Ishak 3-5, n = 12), and liver cirrhosis (LC; Ishak 6, n = 11). Results The corresponding ADC values for the individual patient groups were as follows: NLF: 1123 (SD 95.8); MLF: 1032 (SD 77.6); ALF: 962 (SD 68.8); LC: 1015 (SD 60.2) mm2/s. There is a significant difference between NLF and MLF (p = 0.004) and between MLF and ALF (p = 0.022). A significant difference between patients with ALF and LC (p = 0.117) could not be found. Conclusion Liver fibrosis/cirrhosis lowers the ADC values of the liver parenchyma in 3T MRI. However, the degree of fibrosis can only be conditionally determined on the basis of ADC values.
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Affiliation(s)
- Niklas Verloh
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Kirsten Utpatel
- Department of Pathology, University Regensburg, Regensburg, Germany
| | - Michael Haimerl
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Florian Zeman
- Center for Clinical Trials, University Hospital Regensburg, Regensburg, Germany
| | - Claudia Fellner
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - Marc Dahlke
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Philipp Renner
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Timo Seyfried
- Department of Anaesthesia, University Hospital Regensburg, Regensburg, Germany
| | - Martina Müller
- Department of Gastroenterology, University Hospital Regensburg, Regensburg, Germany
| | | | - Matthias Evert
- Department of Pathology, University Regensburg, Regensburg, Germany
| | - Philipp Wiggermann
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
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Liu H, Dong F, Li G, Niu M, Zhang C, Han Y, He L, Yin P, Wang B, Sang X, Li R, Wang J, Bai Z, Xiao X. Liuweiwuling tablets attenuate BDL-induced hepatic fibrosis via modulation of TGF-β/Smad and NF-κB signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2018; 210:232-241. [PMID: 28864168 DOI: 10.1016/j.jep.2017.08.029] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 08/22/2017] [Accepted: 08/23/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liuweiwuling (LWWL) tablets contain a six-herb Chinese formula and are commonly prescribed to facilitate nourishment of the liver and kidneys, clear away toxic materials and activate blood circulation. Administration of LWWL is well known for its protective effects on the liver and its capacity to confer long-term stability in patients exhibiting reduced transaminase levels. Clinical studies have reported that LWWL can also be used for the treatment of liver fibrosis with associated treatment regimens resulting in a concomitant reduction in transforming growth factor β1 (TGF-β1) levels in the serum of patients with hepatic fibrosis. TGF-β1 plays a prominent role in stimulating liver fibrogenesis and this effect is mediated by myofibroblasts (MFB) derived from hepatic stellate cells (HSCs). It is likely that this phenomenon underpins the antifibrotic effects associated with LWWL. AIM The purpose of this study was to investigate the antifibrotic effects and mechanisms pertaining to LWWL. METHODS Hepatic fibrosis was induced in rats following bile duct ligation (BDL). Rats that underwent BDL received daily gavage administration of colchicine (0.2mg/kg per day), LWWL (0.4, 1.6, 6.4g/kg per day) or PBS (for the control group). Pathological changes in hepatic tissue were examined using hematoxylin and eosin (HE) and sirius red staining. Immunohistochemical analysis was performed to monitor α-SMA and type I collagen (Collagen I) protein expression. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot analyses were used to monitor the expression of genes and proteins in the TGF-β/Smad signaling pathway, including TGF-β1, bone morphogenic protein and activin membrane-bound inhibitor (Bambi), Smad3, phosphorylated Smad3 (p-Smad3) and Smad7. We also monitored the expression of genes and proteins in the nuclear factor-κB (NF-κB) signaling pathway, including NF-κB p65, IκBα and phosphorylation of IκBα (p-IκBα), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β). RESULTS LWWL dose-dependently inhibited BDL-induced liver injury and hepatic fibrosis in rats. Furthermore, LWWL reduced liver tissue collagen deposition, hydroxyproline content, liver dysfunction and α-SMA expression in BDL-induced hepatic fibrosis rats. Moreover, LWWL markedly prevented activation of the TGF-β/Smad signaling pathway by inhibiting expression of Smad2/3 and phosphorylation of Smad3, and upregulating the expression of Bambi and Smad7. In addition, LWWL regulated the expression of the inflammatory cytokines IL-1β, TNF-α and IL-6 by inhibiting the activation of NF-κB p65 and the phosphorylation of IκBα, and increasing the expression of IκBα. CONCLUSIONS LWWL can attenuate BDL-induced hepatic fibrosis in rats, and this effect may be due to modulation of the NF-κB-dependent inflammatory response and activation of HSC and TGF-β/Smad-mediated synthesis and degradation of Collagen I.
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Affiliation(s)
- Huimin Liu
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China; Chengde Medical University Chengde, Hebei, People's Republic of China.
| | - Fang Dong
- Department of Health Statistics, Taishan Medical University, Taian, Shandong, People's Republic of China
| | - Guangquan Li
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Ming Niu
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Congen Zhang
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Yanzhong Han
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Lanzhi He
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Ping Yin
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Bin Wang
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Xiuxiu Sang
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China; Chengde Medical University Chengde, Hebei, People's Republic of China
| | - Ruishen Li
- Animal Laboratory Center, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Jiabo Wang
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Zhaofang Bai
- Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Xiaohe Xiao
- China Military Institute of Chinese Medicine, 302 Hospital of People's Liberation Army, Beijing, People's Republic of China
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Saberifiroozi M. Improving Quality of Care in Patients with Liver Cirrhosis. Middle East J Dig Dis 2017; 9:189-200. [PMID: 29255576 PMCID: PMC5726331 DOI: 10.15171/mejdd.2017.73] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 09/19/2017] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a major chronic disease in the field of digestive diseases. It causes more than one million deaths per year. Despite established evidence based guidelines, the adherence to standard of care or quality indicators are variable. Complete adherence to the recommendations of guidelines is less than 50%. To improve the quality of care in patients with cirrhosis, we need a more holistic view. Because of high rate of death due to cardiovascular disease and neoplasms, the care of comorbid conditions and risk factors such as smoking, hypertension, high blood sugar or cholesterol, would be important in addition to the management of primary liver disease. Despite a holistic multidisciplinary approach for this goal, the management of such patients should be patient centered and individualized. The diagnosis of underlying etiology and its appropriate treatment is the most important step. Definition and customizing the quality indicators for quality measure in patients are needed. Because most suggested quality indicators are designed for measuring the quality of care in decompensated liver cirrhosis, we need special quality indicators for compensated and milder forms of chronic liver disease as well. Training the patients for participation in their own management, design of special clinics with dedicated health professionals in a form of chronic disease model, is suggested for improvement of quality of care in this group of patients. Special day care centers by a dedicated gastroenterologist and a trained nurse may be a practical model for better management of such patients.
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Affiliation(s)
- Mehdi Saberifiroozi
- Professor of Internal Medicine and Gastroenterology, Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences
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Zizzo AN, Valentino PL, Shah PS, Kamath BM. Second-line Agents in Pediatric Patients With Autoimmune Hepatitis: A Systematic Review and Meta-analysis. J Pediatr Gastroenterol Nutr 2017; 65:6-15. [PMID: 28644343 DOI: 10.1097/mpg.0000000000001530] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Ten percent to 20% of children with autoimmune hepatitis (AIH) require second-line therapy to achieve remission. Although current guidelines exist on first-line management, evidence for second-line therapy in treatment-refractory patients is lacking. Our aim was to perform a systematic review and meta-analysis of the efficacy and safety of second-line treatments used in this population. METHODS Electronic and manual searches were used to identify potential studies for inclusion. Studies were selected based on reported response rates to second-line therapies in children who failed response to prednisone and azathioprine. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Meta-analysis using weighted estimate of response rates at 6 months was performed for each treatment option. Heterogeneity was assessed. RESULTS Fifteen studies of 76 pediatric patients with AIH were included in the review. Overall response rates at 6 months were estimated as 36% for mycophenolate mofetil (MMF) (N = 34, 95% confidence interval [CI] (16-57)), and 50% for tacrolimus (N = 4, 95% CI (0-100%)) and 83% for cyclosporine (N = 15, 95% CI (66%-100%)). Adverse effects were most frequent with cyclosporine (64% experiencing at least 1 adverse effect) followed by tacrolimus (54%) and MMF (48%). Pooled estimates of adverse events were 78% for cyclosporine (95% CI (54%-100%)), 42% for tacrolimus (95% CI (0%-85%)) and 45% for MMF (95% CI (25%-68%)). Sensitivity analyses were not performed due to small sample size. CONCLUSIONS Cyclosporine had the highest response rate at 6 months in children with standard-treatment-refractory AIH; however, it also had the highest rate of adverse events. MMF was the second most efficacious option with a low adverse effect rate.
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Affiliation(s)
- Andréanne N Zizzo
- *The Hospital for Sick Children †University of Toronto, Toronto, Ontario, Canada ‡Yale University School of Medicine, New Haven, CT §Mount Sinai Hospital, Toronto ||London Health Sciences Centre, Western University, London, Ontario, Canada
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Kim KE, Park MS, Chung S, An C, Axel L, Ergashovna RG. Magnetization-tagged MRI is a simple method for predicting liver fibrosis. Clin Mol Hepatol 2016; 22:140-5. [PMID: 27044764 PMCID: PMC4825163 DOI: 10.3350/cmh.2016.22.1.140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 01/18/2016] [Accepted: 01/25/2016] [Indexed: 01/06/2023] Open
Abstract
Background/Aims: To assess the usefulness of magnetization-tagged magnetic resonance imaging (MRI) in quantifying cardiac-induced liver motion and deformation in order to predict liver fibrosis. Methods: This retrospective study included 85 patients who underwent liver MRI including magnetization-tagged sequences from April 2010 to August 2010. Tagged images were acquired in three coronal and three sagittal planes encompassing both the liver and heart. A Gabor filter bank was used to measure the maximum value of displacement (MaxDisp) and the maximum and minimum values of principal strains (MaxP1 and MinP2, respectively). Patients were divided into three groups (no fibrosis, mild-to-moderate fibrosis, and significant fibrosis) based on their aspartate-aminotransferase-to-platelet ratio index (APRI) score. Group comparisons were made using ANOVA tests. Results: The patients were divided into three groups according to APRI scores: no fibrosis (≤0.5; n=41), moderate fibrosis (0.5–1.5; n=23), and significant fibrosis (>1.5; n=21). The values of MaxDisp were 2.9±0.9 (mean±SD), 2.3±0.7, and 2.1±0.6 in the no fibrosis, moderate fibrosis, and significant fibrosis groups, respectively (P<0.001); the corresponding values of MaxP1 were 0.05±0.2, 0.04±0.02, and 0.03±0.01, respectively (P=0.002), while those of MinP2 were –0.07±0.02, –0.05±0.02, and –0.04±0.01, respectively (P<0.001). Conclusions: Tagged MRI to quantify cardiac-induced liver motion can be easily incorporated in routine liver MRI and may represent a helpful complementary tool in the diagnosis of early liver fibrosis.
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Affiliation(s)
- Kyung-Eun Kim
- Department of Radiology and Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea
| | - Mi-Suk Park
- Department of Radiology and Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea
| | - Sohae Chung
- Center for Biomedical Imaging, Department of Radiology, New York University Langone Medical Center, New York, USA
| | - Chansik An
- Department of Radiology and Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea
| | - Leon Axel
- Center for Biomedical Imaging, Department of Radiology, New York University Langone Medical Center, New York, USA
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EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015; 63:237-64. [PMID: 25911335 DOI: 10.1016/j.jhep.2015.04.006] [Citation(s) in RCA: 1307] [Impact Index Per Article: 130.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023]
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Hu G, Chan Q, Quan X, Zhang X, Li Y, Zhong X, Lin X. Intravoxel incoherent motion MRI evaluation for the staging of liver fibrosis in a rat model. J Magn Reson Imaging 2014; 42:331-9. [PMID: 25384923 DOI: 10.1002/jmri.24796] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 10/23/2014] [Indexed: 01/12/2023] Open
Abstract
PURPOSE To explore the characteristics of intravoxel incoherent motion (IVIM) in various stages of liver fibrosis, and their relationships with fibrotic stages in rats. MATERIALS AND METHODS Fifty rats were given various doses of carbon tetrachloride (CCl4 ) to induce various fibrotic stages in rats; 15 untreated rats served as controls. Diffusion-weighted magnetic resonance imaging (MRI) was performed and eight b-values (0-800 s/mm(2) ) were applied to obtain IVIM parameters (D, pure molecular diffusion; f, perfusion fraction; D*, pseudodiffusion). The stages of liver fibrosis (stages F0-F4) were evaluated histologically using METAVIR scores. Fifty-seven rats (15 controls and 42 with fibrosis) were analyzed by nonparametric methods and receiver operating characteristic curves to determine diagnostic accuracy. RESULTS Significant differences (P < 0.001) were found between stages (stages F0-F4) by D, f, D*, and apparent diffusion coefficient (ADC). There were inverse correlations between fibrosis stages and D, f, D*, ADC (r = -0.657, r = -0.631, r = -0.711 r = -0.719, respectively). Multivariate analysis showed that the combination models (D, f, D*) were better than the individual parameter (ADC) for the evaluation fibrosis stages (area under the curve [AUC]: 0.821-1.000 vs. AUC: 0.753-0.918) CONCLUSION: IVIM-derived parameters showed significant correlations with stages of liver fibrosis in a rat model.
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Affiliation(s)
- Genwen Hu
- Department of Medical Image Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, P.R. China.,Department of Medical Image Center, Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen, Guangdong Province, P.R. China
| | | | - Xianyue Quan
- Department of Medical Image Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, P.R. China
| | - Xuhui Zhang
- Department of Medical Image Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, P.R. China
| | - Yufa Li
- Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, P.R. China
| | - Xing Zhong
- Department of Medical Image Center, First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, P.R. China
| | - Xiaoying Lin
- Department of Medical Image Center, Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen, Guangdong Province, P.R. China
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Abstract
INTRODUCTION Cirrhosis is a major milestone in patients with chronic liver disease because of its impact on patient morbidity and mortality. Chronic hepatitis B (CHB) and hepatitis C (CHC) are important causes of cirrhosis. This systematic review examines the relevant literature and evidence to assess whether cirrhosis can be reversible in patients with cirrhosis from viral hepatitis through long viral suppression. METHODS A MEDLINE and Cochrane Library search was conducted to identify all articles pertinent to the subject matter. Fourteen publications were included in the final analysis: 4 hepatitis B studies and 10 hepatitis C studies. Data abstracted from individual studies included patient demographics, antiviral therapy used, length of treatment, liver biopsy scoring system, length of biopsy, and time between biopsies. RESULTS In CHB, the 7 studies reviewed included a total of 463 cirrhotic patients. Regression of cirrhosis was noted in a median of 70% (range, 33% to 80%) of patients. In CHC, the 13 studies reviewed included a total of 58 cirrhotic patients. Regression of cirrhosis was seen in a median of 64% (range, 33% to 100%) of patients with sustained viral response. CONCLUSIONS The results of our review suggest that viral suppression in CHB and sustained virologic response in CHC can be associated with histologic regression of cirrhosis in select patients.
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13
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Li H, Chen TW, Zhang XM, Li ZL, Zhang JL, Wang D, Li T, Wu JL, Guo X, Chen XL, Li L, Xie XY, Zhang ZS. Liver lobe volumes and the ratios of liver lobe volumes to spleen volume on magnetic resonance imaging for staging liver fibrosis in a minipig model. PLoS One 2013; 8:e79681. [PMID: 24223184 PMCID: PMC3819276 DOI: 10.1371/journal.pone.0079681] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 09/23/2013] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To investigate liver lobe volumes and the ratios of liver lobe volumes to spleen volume measured with magnetic resonance imaging (MRI) for quantitatively monitoring and staging liver fibrosis. METHODS Animal study was approved by Institutional Animal Care and Use Committee. Sixteen minipigs were prospectively used to model liver fibrosis, and underwent abdominal gadolinium-enhanced MRI on 0, 5(th), 9(th), 16(th) and 21(st) weekend after modeling this disease staged by biopsy according to METAVIR classification system. On MRI, volume parameters including left lateral liver lobe volume (LLV), left medial liver lobe volume (LMV), right liver lobe volume (RV), caudate lobe volume (CV), and spleen volume (SV) were measured; and LLV/SV, LMV/SV, RV/SV and CV/SV were calculated. Statistical analyses were performed for staging this fibrosis. RESULTS LLV and CV increased with increasing stage of fibrosis (r = 0.711, 0.526, respectively; all P < 0.05). RV and LMV increased from stage 0 to 2 and decreased from 2 to 4; and RV/SV decreased from 0 to 1, increased from 1 to 2, and decreased from 3 to 4 (all P > 0.05). LLV/SV, LMV/SV and CV/SV decreased from stage 0 to 4 (r = -0.566, -0.748 and -0.620, respectively; all P < 0.05). LLV, CV, LLV/SV, LMV/SV, RV/SV, and CV/SV could distinguish stage 0-1 from 2-4 and 0-2 from 3-4 (all P < 0.05). Among these parameters, LLV and LMV/SV could best classify stage ≥2 and ≥3, respectively (area under receiver operating characteristic curve = 0.893 and 0.946, respectively). CONCLUSION LLV and LMV/SV complement each other in staging liver fibrosis, and both parameters should be used to stage this disease.
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Affiliation(s)
- Hang Li
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Department of Radiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Tian-wu Chen
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- * E-mail: ; (TC); (JW)
| | - Xiao-ming Zhang
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Zhen-lin Li
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- * E-mail: ; (TC); (JW)
| | - Jin-ling Zhang
- Department of Radiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Dan Wang
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Ting Li
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jian-lin Wu
- Department of Radiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
- * E-mail: ; (TC); (JW)
| | - Xing Guo
- Department of Ultrasonography, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xiao-li Chen
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Li Li
- Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xian-yong Xie
- Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Zi-shu Zhang
- Department of Radiology, University of Michigan Health System, Ann Arbor, Michigan, United States of America
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14
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201Tl Heart-Liver Radioactivity Uptake Ratio and Prediction of Decompensation in Patients With Cirrhosis. Clin Nucl Med 2013; 38:169-74. [DOI: 10.1097/rlu.0b013e31827087e3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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15
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Li H, Chen TW, Chen XL, Zhang XM, Li ZL, Zeng NL, Zhou L, Wang LY, Tang HJ, Li CP, Li L, Xie XY. Magnetic resonance-based total liver volume and magnetic resonance-diffusion weighted imaging for staging liver fibrosis in mini-pigs. World J Gastroenterol 2012; 18:7225-7233. [PMID: 23326127 PMCID: PMC3544024 DOI: 10.3748/wjg.v18.i48.7225] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 11/04/2012] [Accepted: 12/14/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether and how magnetic resonance imaging (MRI)-based total liver volume (TLV) and diffusion weighted imaging (DWI) could predict liver fibrosis.
METHODS: Sixteen experimental mature mini-pigs (6 males, 10 females), weighing between 20.0 and 24.0 kg were prospectively used to model liver fibrosis induced by intraperitoneal injection of 40% CCl4 dissolved in fat emulsion twice a week for 16 wk, and by feeding 40% CCl4 mixed with maize flour twice daily for the subsequent 5 wk. All the survival animals underwent percutaneous liver biopsy and DWI using b = 300, 500 and 800 s/mm2 followed by abdominal gadolinium-enhanced MRI at the 0, 5th, 9th, 16th and 21st weekend after beginning of the modeling. TLV was obtained on enhanced MRI, and apparent diffusion coefficient (ADC) was obtained on DWI. Hepatic tissue specimens were stained with hematoxylin and Masson’s trichrome staining for staging liver fibrosis. Pathological specimens were scored using the human METAVIR classification system. Statistical analyses were performed to determine whether and how the TLV and ADC could be used to predict the stage of liver fibrosis.
RESULTS: TLV increased from stage 0 to 2 and decreased from stage 3 (r = 0.211; P < 0.001). There was a difference in TLV between stage 0-1 and 2-4 (P = 0.03) whereas no difference between stage 0-2 and 3-4 (P = 0.71). TLV could predict stage ≥ 2 [area under receiver operating characteristic curve (AUC) = 0.682]. There was a decrease in ADC values with increasing stage of fibrosis for b = 300, 500 and 800 s/mm2 (r = -0.418, -0.535 and -0.622, respectively; all P < 0.001). Differences were found between stage 0-1 and 2-4 in ADC values for b = 300, 500 and 800 s/mm2, and between stage 0-2 and 3-4 for b = 500 or 800 s/mm2 (all P < 0.05). For predicting stage ≥ 2 and ≥ 3, AUC was 0.803 and 0.847 for b = 500 s/mm2, and 0.848 and 0.887 for b = 800 s/mm2, respectively.
CONCLUSION: ADC for b = 500 or 800 s/mm2 could be better than TLV and ADC for b = 300 s/mm2 to predict fibrosis stage ≥ 2 or ≥ 3.
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Sohrabpour AA, Mohamadnejad M, Malekzadeh R. Review article: the reversibility of cirrhosis. Aliment Pharmacol Ther 2012; 36:824-32. [PMID: 22966946 DOI: 10.1111/apt.12044] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 04/18/2012] [Accepted: 08/22/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cirrhosis is the end result of many types of chronic liver diseases. Recent developments in the understanding of the process of hepatic fibrogenesis have revealed that the process is a dynamic one and a capacity for recovery from any degree of fibrosis including those associated with cirrhosis is plausible. AIM To review current evidence of histopathological reversibility following drug therapy of more common aetiologies of cirrhosis. METHODS A PubMed search was performed and the evidence for histopathological regression of advanced fibrosis/cirrhosis following drug therapy was reviewed as of the end of February 2012. RESULTS There is abundant clinical evidence in support of the idea of the reversibility of cirrhosis in patients with different aetiologies of advanced hepatic disease including viral, autoimmune and metabolic/infiltrative liver disease. CONCLUSIONS The concept of cirrhosis has changed from being a form of static and irreversible entity to a dynamic and reversible diseases stage. Novel therapeutic strategies are under investigation to target specific steps in the process of fibrogenesis with the aim of reversing advanced fibrosis/cirrhosis.
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Affiliation(s)
- A A Sohrabpour
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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17
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Autoimmune Hepatitis in Iran: What We Know, What We Don’t Know and Requirements for Better Management. HEPATITIS MONTHLY 2012. [DOI: 10.5812/hepatmon.4847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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18
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Malekzadeh Z, Haghazali S, Sepanlou SG, Vahedi H, Merat S, Sotoudeh M, Nasseri-Moghaddam S, Malekzadeh R. Clinical features and long term outcome of 102 treated autoimmune hepatitis patients. HEPATITIS MONTHLY 2012. [PMID: 22509185 DOI: 10.5812/hepatmon.4906] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND There is limited data on the natural history of autoimmune hepatitis (AIH) and on the long-term follow-up of AIH patients who have been referred for regular medical attention. OBJECTIVES We evaluated the clinical presentation and natural history of AIH in a large cohort of type I AIH patients from Iran. PATIENTS AND METHODS Between 1997 and 2008, 102 patients were enrolled in the study. Patients were diagnosed using the International Autoimmune Hepatitis Group criteria and were followed up for an average of 60 months. Clinical and biochemical data were gathered from all the patients at both the beginning and the end of the follow-up period. Liver biopsy was performed in all patients before treatment, and the biopsies were performed in 28 patients after treatment. RESULTS Biochemical remission was achieved by 80 (79.4%) patients. Of these, 53 (66.5%) showed near-normal liver histology or liver function test results and sonogram. The remaining 27 (33.5%) patients also achieved clinical and biochemical remission, but developed compensated cirrhosis. After a period of remission, 24 patients (32.5%) relapsed. Among the 22 (21.6%) patients who showed ultimate treatment failure, 6 underwent orthotopic liver transplantation and 3 died of liver failure while awaiting a transplant. Sixteen (72.7%) of the 22 patients who did not respond to therapy were non-compliant with medications and had irregular follow-up. The overall 10-year survival rate in the cohort was 96%. CONCLUSIONS Long-term survival in AIH patients is very good. Prompt diagnosis and appropriate first-line and salvage therapy that includes close follow-up will make liver transplantation a rare necessity in the treatment of this disease.
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Affiliation(s)
- Zinab Malekzadeh
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
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19
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Malekzadeh Z, Haghazali S, Sepanlou SG, Vahedi H, Merat S, Sotoudeh M, Nasseri-Moghaddam S, Malekzadeh R. Clinical features and long term outcome of 102 treated autoimmune hepatitis patients. HEPATITIS MONTHLY 2012; 12:92-9. [PMID: 22509185 PMCID: PMC3321327 DOI: 10.5812/hepatmon.808] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Revised: 12/14/2011] [Accepted: 12/26/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND There is limited data on the natural history of autoimmune hepatitis (AIH) and on the long-term follow-up of AIH patients who have been referred for regular medical attention. OBJECTIVES We evaluated the clinical presentation and natural history of AIH in a large cohort of type I AIH patients from Iran. PATIENTS AND METHODS Between 1997 and 2008, 102 patients were enrolled in the study. Patients were diagnosed using the International Autoimmune Hepatitis Group criteria and were followed up for an average of 60 months. Clinical and biochemical data were gathered from all the patients at both the beginning and the end of the follow-up period. Liver biopsy was performed in all patients before treatment, and the biopsies were performed in 28 patients after treatment. RESULTS Biochemical remission was achieved by 80 (79.4%) patients. Of these, 53 (66.5%) showed near-normal liver histology or liver function test results and sonogram. The remaining 27 (33.5%) patients also achieved clinical and biochemical remission, but developed compensated cirrhosis. After a period of remission, 24 patients (32.5%) relapsed. Among the 22 (21.6%) patients who showed ultimate treatment failure, 6 underwent orthotopic liver transplantation and 3 died of liver failure while awaiting a transplant. Sixteen (72.7%) of the 22 patients who did not respond to therapy were non-compliant with medications and had irregular follow-up. The overall 10-year survival rate in the cohort was 96%. CONCLUSIONS Long-term survival in AIH patients is very good. Prompt diagnosis and appropriate first-line and salvage therapy that includes close follow-up will make liver transplantation a rare necessity in the treatment of this disease.
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Affiliation(s)
- Zinab Malekzadeh
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
- Sasan Alborz Biomedical Research Institute, Tehran, IR Iran
| | - Sepideh Haghazali
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Sadaf G. Sepanlou
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Homayoon Vahedi
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
- Sasan Alborz Biomedical Research Institute, Tehran, IR Iran
| | - Shahin Merat
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
- Sasan Alborz Biomedical Research Institute, Tehran, IR Iran
| | - Masoud Sotoudeh
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
- Sasan Alborz Biomedical Research Institute, Tehran, IR Iran
- Department of Pathology, Shariati Hospital, Tehran University of Medical sciences, Tehran, IR Iran
| | - Siavosh Nasseri-Moghaddam
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
- Sasan Alborz Biomedical Research Institute, Tehran, IR Iran
| | - Reza Malekzadeh
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
- Sasan Alborz Biomedical Research Institute, Tehran, IR Iran
- Corresponding author: Reza Malekzadeh, Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, North Kargar St., Zip code: 14117-13135, Tehran, IR Iran. Tel.: +98-2182415555, Fax: +98-2182415400, E-mail:
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Bakan AA, Inci E, Bakan S, Gokturk S, Cimilli T. Utility of diffusion-weighted imaging in the evaluation of liver fibrosis. Eur Radiol 2011; 22:682-7. [PMID: 21984447 DOI: 10.1007/s00330-011-2295-z] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Revised: 08/13/2011] [Accepted: 09/13/2011] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To evaluate the usefulness of diffusion- weighted MRI (DWI) in the detection and staging of liver fibrosis and inflammation. METHODS DWI was performed with b-factors of 0, 500 and 1000 s/mm². ADC values were obtained by placing circular regions of interest in four segments of the liver. Differences between the study (n = 34) and control groups' (n = 25) ADC values were examined. Further, this study investigated if and how ADC values were related to fibrosis stages and histological activity index (HAI) scores. RESULTS The mean ADC value of the liver was smaller in the study group compared with the control group (P < 0.001). Spearman rho correlation analyses showed lower ADC values were associated with higher fibrosis and HAI scores (P < 0.01). There were statistically significant differences in liver ADC values between each combination of fibrosis stages (e.g. stages 0 and 1, 0 and 2) except for stages 1 and 2. CONCLUSIONS ADC values prove to be a valuable technique for the diagnosis of liver fibrosis and inflammation. They can also be useful in fibrosis staging, particularly in distinguishing later stages of fibrosis from intermediate and early stages. KEY POINTS Diffusion Weighted MRI is a promising technique for diagnosis of liver fibrosis. Apparent Diffusion Coefficients provide valuable information for staging of liver fibrosis. DWI may offer alternative to biopsy for assessing liver fibrosis.
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Affiliation(s)
- Ayse Ahsen Bakan
- Department of Radiology, Istanbul Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
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21
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Fukuda S, Komori A, Itoh M, Mihara Y, Hashimoto S, Bae SK, Nagaoka S, Abiru S, Yatsuhashi H, Ishibashi H. Histological Remission during Corticosteroid Therapy of Overlapping Nonalcoholic Steatohepatitis and Autoimmune Hepatitis: Case Report and Literature Review. Case Rep Gastroenterol 2011; 5:553-7. [PMID: 22110414 PMCID: PMC3219477 DOI: 10.1159/000332152] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Concurrence of nonalcoholic steatohepatitis (NASH) with autoimmune hepatitis (AIH) is a rare condition that is challenging to diagnosis, due to the relatively high prevalence of autoantibodies in NASH. It is also difficult to determine the most effective treatment as corticosteroids are likely to worsen NASH despite being effective in the treatment of AIH. In this case report, we present a female diagnosed with NASH-AIH overlap with accompanying diabetes mellitus, who successfully achieved normalization of serum alanine aminotransferase levels following prednisolone therapy and weight loss. A follow-up liver biopsy performed 40 months after the initial diagnosis showed only minimal inflammatory infiltrates in the portal area without any NASH histology. Resolution of NASH, in conjunction with a reduction in hepatic fibrosis, might suggest that prednisolone itself does not aggravate steatohepatitis, but rather prevents disease progression. Appropriate immunosuppressive treatment may therefore be an important component of the optimum therapy for NASH-AIH overlap.
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Affiliation(s)
- Shinichiroh Fukuda
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
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Relationship between plasma cells and hepatic stellate cells in autoimmune hepatitis. Pathol Res Pract 2011; 206:800-4. [PMID: 20926203 DOI: 10.1016/j.prp.2010.08.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2009] [Revised: 07/13/2010] [Accepted: 08/11/2010] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis is an inflammatory chronic disease of the liver, which frequently results in cirrhosis. The present study aimed to verify the relationship between plasma cells and stellate cells in autoimmune hepatitis. Thirty-three pre-treatment, 11 post-treatment, and 10 normal liver biopsies were reviewed. Sirius Red staining (for semi-quantitative analysis of hepatic fibrosis) and immunohistochemistry were carried out: double staining for smooth muscle α-actin and plasma cell marker (for detection and localization of activated hepatic stellate cells and plasma cells, respectively); and single staining for glial fibrillary acid protein (for detection of hepatic stellate cells). We found an increase in the stellate cell population, mainly with an activated phenotype in autoimmune hepatitis, compared to the control group (liver specimens with no histological evidence of liver disease, obtained from patients undergoing hepatic resection for benign liver mass). A positive significant correlation was observed between stellate cells and scores of fibrosis (measured by Sirius Red) and the number of plasma cells. Additionally, there was a co-localization of plasma cells and activated stellate cells. We also observed a reduction in the number of plasma cells, hepatic stellate cells, and fibrosis in patients who had successfully been treated and had a second liver biopsy post-treatment. Our findings support that the number of plasma cells can be a surrogate marker for the severity of liver disease, reflecting the number of hepatic stellate cells and the amount of fibrosis. It remains to be seen if this is a result of a direct interaction between the plasma cells and hepatic stellate cells or the response to the same stimulus that affects both cellular types.
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Björnsson E, Talwalkar J, Treeprasertsuk S, Neuhauser M, Lindor K. Patients with typical laboratory features of autoimmune hepatitis rarely need a liver biopsy for diagnosis. Clin Gastroenterol Hepatol 2011; 9:57-63. [PMID: 20723617 DOI: 10.1016/j.cgh.2010.07.016] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Revised: 07/20/2010] [Accepted: 07/23/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The importance of histologic analysis of biopsy samples in the diagnosis and management of patients with autoimmune hepatitis (AIH) is unclear. METHODS Patients with AIH were identified from a 10-year database. Individuals with overlap syndromes and decompensated liver disease were excluded. The proportion of patients who fulfilled the new simplified criteria for AIH was calculated. RESULTS A total of 257 patients (203 female) with a median age of 52 years (interquartile range, 39-63 y) were diagnosed with AIH. Overall, 183 of 257 (71%) were positive for antinuclear antibodies, 116 (45%) had positive smooth muscle antibodies, and 29 of 257 (11%) were seronegative. A total of 250 (97%) patients had increased levels of autoantibodies and/or γ-globulins. In 95% (243 of 257 cases), the histology was compatible with AIH whereas 5% (14 cases) had atypical histology. Overall, 77% had a score of at least 6, indicating probable or definite AIH according to most recent criteria; 22% were diagnosed with AIH with less than 6 points and 1 patient had nonalcoholic steatohepatitis based on biopsy analysis. Immunosuppression occurred in 93% of patients. Patients with atypical versus compatible histology were similar in terms of seronegativity or γ-globulins; 86% (12 of 14) received immunosuppressive therapy despite atypical histology. CONCLUSIONS Most patients with features of AIH, based on laboratory analyses, are likely to have a compatible liver histology. Few patients have atypical histology and these findings have little impact on patient management. These findings indicate biopsy samples might not need to be collected from patients who meet other clinical criteria for AIH.
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Affiliation(s)
- Einar Björnsson
- Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
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Value of diffusion-weighted MRI for assessing liver fibrosis and cirrhosis. AJR Am J Roentgenol 2010; 193:1556-60. [PMID: 19933647 DOI: 10.2214/ajr.09.2436] [Citation(s) in RCA: 157] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The objective of our study was to determine the usefulness of the apparent diffusion coefficient (ADC) of liver parenchyma for determining the severity of liver fibrosis. MATERIALS AND METHODS This study investigated 78 patients who underwent diffusion-weighted imaging (DWI) with 1.5-T MRI and pathologic staging of liver fibrosis based on biopsy. DWI was performed with b values of 50 and 400 s/mm(2). ADCs of liver were measured using 2.0- to 3.0-cm(2) regions of interest in the right and left lobes of the liver; the mean ADC value was used for analysis. Pathologic METAVIR scores for liver fibrosis stage were used as a reference standard. RESULTS The mean ADC values for fibrosis pathologically staged using the METAVIR classification system as F0 (n = 11), F1 (n = 16), F2 (n = 10), F3 (n = 14), and F4 (n = 27) were 125.9, 105.0, 104.5, 103.2, and 99.1 x 10(-5) s/mm(2), respectively. The correlation between the ADC values and the degree of liver fibrosis was moderate (Spearman's test, rho = -0.36). There was a significant difference in ADC values between patients with nonfibrotic liver (F0) and those with cirrhotic liver (F4) (p = 0.008). The best cutoff ADC value to distinguish between these groups was 118 x 10(-5) s/mm(2). However, ADC values were not useful for differentiating viral hepatitis patients with F2 fibrosis or higher from those with a lower degree of fibrosis (area under the receiver operating characteristic curve [AUC] = 0.66) or for differentiating low-stage fibrosis in all patients from high-stage fibrosis in all patients (AUC = 0.54). CONCLUSION The ADCs in cirrhotic livers are significantly lower than those in nonfibrotic livers. However, ADC values measured using the current generation of scanners are not reliable enough to replace liver biopsy for staging hepatic fibrosis.
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Barrio J, Piqueras B, Rodrigo G, Rivero M. Epistaxis como forma de inicio de enfermedad hepática. An Pediatr (Barc) 2009; 70:599-601. [DOI: 10.1016/j.anpedi.2009.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2009] [Revised: 03/15/2009] [Accepted: 03/16/2009] [Indexed: 01/12/2023] Open
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Abstract
Some patients with ascites due to liver cirrhosis become no longer responsive to diuretics. Once other causes of ascites such as portal vein thrombosis, malignancy or infection and non-compliance with medications and low sodium diet have been excluded, the diagnosis of refractory ascites can be made based on strict criteria. Patients with refractory ascites have very poor prognosis and therefore referral for consideration for liver transplantation should be initiated. Search for reversible components of the underlying liver pathology should be undertaken and targeted therapy, when available, should be considered. Currently, serial large volume paracentesis (LVP) and transjugular intrahepatic portasystemic stent-shunt (TIPS) are the two mainstay treatment options for refractory ascites. Other treatment options are available but not widely used either because they carry high morbidity and mortality (most surgical options) rates, or are new interventions that have shown promise but still need further evaluation. In this comprehensive review, we describe the evaluation and management of patients with refractory ascites from the prospective of the practicing physician.
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Ustundag G, Kuloglu Z, Kirsaçlioğlu CT, Kansu A, Erden E, Girgin N. Complete regression of cirrhosis after immunosuppressive treatment in autoimmune hepatitis. Pediatr Int 2008; 50:711-3. [PMID: 19261129 DOI: 10.1111/j.1442-200x.2008.02714.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Gonca Ustundag
- Department of Pediatrics, Gastroenterology Unit, Ankara University School of Medicine, Ankara, Turkey.
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Watson MR, Wallace K, Gieling RG, Manas DM, Jaffray E, Hay RT, Mann DA, Oakley F. NF-kappaB is a critical regulator of the survival of rodent and human hepatic myofibroblasts. J Hepatol 2008; 48:589-97. [PMID: 18279996 DOI: 10.1016/j.jhep.2007.12.019] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2007] [Revised: 12/06/2007] [Accepted: 12/26/2007] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Hepatic myofibroblast activation during injury causes deposition of extracellular matrix within the liver and promotes development of fibrosis. Hepatic myofibroblast apoptosis is associated with remodelling of fibrotic extracellular matrix and regression of fibrosis. Previous work showed that inhibition of constitutive NF-kappaB signaling promotes hepatic myofibroblast apoptosis and resolution of fibrosis in rodent models. However, to date agents used to target constitutive NF-kappaB transcriptional activity in hepatic myofibroblasts have been relatively non-specific with potential for off-target effects that may complicate data interpretation. Likewise, rat chronic liver disease models may not accurately recapitulate the activation of human hepatic myofibroblasts. METHODS We used a mutant recombinant IkappaBalpha super-repressor fused to the HIV-TAT domain to specifically target NF-kappaB signaling in hepatic myofibroblasts. Inhibition of NF-kappaB activity was measured using reporter assay. Apoptosis of hepatic myofibroblasts was assessed by morphological changes, cleavage of the PARP-1 protein and Caspase 3 activation. RESULTS TAT-IkappaBalphaSR reduced NF-kappaB dependent transcription, Bcl-2 expression and promoted Jun-N-terminal kinase-dependent apoptosis in human and rat hepatic myofibroblasts. CONCLUSIONS These data highlight the conserved role of NF-kappaB during fibrogenesis. Our data validate the use of rodent models for pre-clinical testing of NF-kappaB inhibitors as anti-fibrotics and stimulators of fibrotic extracellular matrix remodelling.
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Affiliation(s)
- Martha R Watson
- Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK
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Serum proteomic-based analysis for the identification of a potential serological marker for autoimmune hepatitis. Biochem Biophys Res Commun 2008; 367:284-90. [DOI: 10.1016/j.bbrc.2007.12.075] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2007] [Accepted: 12/13/2007] [Indexed: 11/21/2022]
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Muddu AK, Guha IN, Elsharkawy AM, Mann DA. Resolving fibrosis in the diseased liver: translating the scientific promise to the clinic. Int J Biochem Cell Biol 2006; 39:695-714. [PMID: 17110155 DOI: 10.1016/j.biocel.2006.10.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2006] [Revised: 10/03/2006] [Accepted: 10/04/2006] [Indexed: 01/18/2023]
Abstract
Liver fibrosis and its end-stage disease cirrhosis are a major cause of mortality and morbidity throughout the world. Fibrosis is a response to chronic liver injury or infection that if unabated leads to the replacement of normal functional liver tissue with scar tissue. Basic research over the past decade has generated a vastly improved knowledge of the cell and molecular biology of liver fibrosis that provides a framework on which to design and develop therapeutics. The field has also witnessed a genuine paradigm shift from the original dogma that liver fibrosis is only ever a progressive process, to the new understanding that liver fibrosis even in an advanced stage can be reversible. There is therefore renewed optimism that liver fibrosis may be cured providing that we develop therapies that halt the fibrogenic process and encourage the natural regenerative properties of the liver. The key to the design of effective therapeutics will be to exploit the ongoing discoveries pertaining to the biology and function of fibrogenic hepatic myofibroblasts and their interplay with other liver cells and with the hepatic extracellular matrix. This review provides a critique of those discoveries in basic research that provide the most promise for translation to the clinic. In addition, we review the latest developments in the search for minimal invasive diagnostic tests for fibrosis that will be essential for determining the efficacy of anti-fibrotic drugs.
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Affiliation(s)
- Ajay K Muddu
- Liver Group, Division of Infection, Inflammation & Repair, University of Southampton, Southampton SO16 6YD, United Kingdom
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Falize L, Guillygomarc'h A, Perrin M, Lainé F, Guyader D, Brissot P, Turlin B, Deugnier Y. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 2006; 44:472-7. [PMID: 16871557 DOI: 10.1002/hep.21260] [Citation(s) in RCA: 182] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The current study was undertaken to assess whether fibrosis could regress under venesection therapy in patients with C282Y homozygous genetic hemochromatosis. The 36 patients studied were recruited from a subfile of our database consisting of 125 C282Y homozygotes with either severe fibrosis or cirrhosis (F3 or F4 fibrosis stage, respectively, according to the METAVIR grading system). The second liver biopsy was performed for management of liver cancer, extrahepatic surgery, or assessment of liver fibrosis. All paired biopsies were reviewed by two pathologists without knowledge of clinical data. Among the 13 patients who had F3 fibrosis on their initial liver biopsy, 3 had F0, 6 had F1, and 2 had F2 on their second liver biopsy. Among the 23 patients with cirrhosis on their initial liver biopsy, 1 had F0, 4 had F1, 3 had F2, and 2 had F3 on their second liver biopsy. When defining regression of fibrosis as a decrease of at least 2 METAVIR units, fibrosis regressed in 9 of 13 (69%) F3 and in 8 of 23 (35%) F4. When the ratio of gammaglobulins (g/L) to (platelets [n/mm(3)] x prothrombin activity [%]) was greater than 7.5, fibrosis never regressed. In conclusion, these data extend the concept of regression of fibrosis to patients with treated genetic hemochromatosis and suggest that some simple biochemical tests would be predictive of further regression of fibrosis as a result of venesection therapy. If confirmed on larger series, this could modify the ultrasound screening policy of hepatocellular carcinoma in genetic hemochromatosis.
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Affiliation(s)
- Ludivine Falize
- Service des Maladies du Foie, CHU Pontchaillou, Rennes, France.
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