|
1
|
Maya-Miles D, Ampuero J, Gallego-Durán R, Dingianna P, Romero-Gómez M. Management of NAFLD patients with advanced fibrosis. Liver Int 2021; 41 Suppl 1:95-104. [PMID: 34155801 DOI: 10.1111/liv.14847] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022]
Abstract
The prevalence of non alcoholic fatty liver disease (NAFLD) has increased to 25% in the general population and could double by 2030. Liver fibrosis is the main indicator of morbidity and mortality and recent estimations suggest a substantial number of individuals with undiagnosed advanced liver disease. Strategies to monitor advanced fibrosis are essential for early detection, referral, diagnosis and treatment in primary care and endocrine units, where NAFLD and consequently liver fibrosis are more prevalent. Blood-based non-invasive methods could be used to stratify patients according to the risk of the progression of fibrosis and combined with imaging techniques to improve stratification. Powerful new diagnostic tools such as MRE and PDFF are emerging and might prevent the need for liver biopsy in the near future. The current therapeutic landscape of NAFLD is rapidly evolving with an increasing number of molecules that treat key factors involved in its progression, but that still have a limited or no ability to effectively reverse fibrosis. Management of this disease will probably require a combination of sequential and personalized treatments as a result of its complex and dynamic pathophysiology. Lifestyle interventions are still the most effective therapeutic option and should be better integrated into patient management together with specific programs of bariatric endoscopy/surgery for morbidly obese patients.
Collapse
Affiliation(s)
- Douglas Maya-Miles
- Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain.,UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain.,CIBER Hepatic and Digestive Diseases (CIBERehd), Seville, Spain
| | - Javier Ampuero
- Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain.,UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain.,CIBER Hepatic and Digestive Diseases (CIBERehd), Seville, Spain.,University of Seville, Seville, Spain
| | - Rocío Gallego-Durán
- Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain.,UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain.,CIBER Hepatic and Digestive Diseases (CIBERehd), Seville, Spain
| | - Paola Dingianna
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Manuel Romero-Gómez
- Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain.,UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain.,CIBER Hepatic and Digestive Diseases (CIBERehd), Seville, Spain.,University of Seville, Seville, Spain
| |
Collapse
|
|
2
|
Rockey DC, Friedman SL. Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside. Gastroenterology 2021; 160:1502-1520.e1. [PMID: 33529675 PMCID: PMC8601597 DOI: 10.1053/j.gastro.2020.09.065] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/01/2020] [Accepted: 09/06/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection and its complications have been the major cause of cirrhosis and its complications for several decades in the Western world. Until recently, treatment for HCV with interferon-based regimens was associated with moderate success but was difficult to tolerate. More recently, however, an arsenal of novel and highly effective direct-acting antiviral (DAA) drugs has transformed the landscape by curing HCV in a broad range of patients, including those with established advanced fibrosis, cirrhosis, comorbidities, and even those with complications of cirrhosis. Fibrosis is a dynamic process comprising both extracellular matrix deposition, as well as its degradation. With almost universal sustained virologic response (SVR) (ie, elimination of HCV), it is timely to explore whether HCV eradication can reverse fibrosis and cirrhosis. Indeed, fibrosis in several types of liver disease is reversible, including HCV. However, we do not know with certainty in whom fibrosis regression can be expected after HCV elimination, how quickly it occurs, and whether antifibrotic therapies will be indicated in those with persistent cirrhosis. This review summarizes the evidence for reversibility of fibrosis and cirrhosis after HCV eradication, its impact on clinical outcomes, and therapeutic prospects for directly promoting fibrosis regression in patients whose fibrosis persists after SVR.
Collapse
Affiliation(s)
- Don C Rockey
- The Medical University of South Carolina, Charleston, South Carolina.
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
| |
Collapse
|
|
3
|
A novel classification via clustering algorithm for fibrosis assessment in liver biopsies. HEALTH AND TECHNOLOGY 2020. [DOI: 10.1007/s12553-019-00405-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
|
|
4
|
Leite C, Starosta RT, Trindade EN, Trindade MRM, Álvares-da-Silva MR, Cerski CTS. Corrected integrated density: a novel method for liver elastic fibers quantification in chronic hepatitis C. SURGICAL AND EXPERIMENTAL PATHOLOGY 2020. [DOI: 10.1186/s42047-020-0055-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Background
Elastic fibers deposition is triggered during liver fibrosis and is related to worse clinical prognosis in chronic hepatitis C patients. This study aimed to verify if a new method for elastic fiber quantification can be used to discriminate between different degrees of fibrosis in liver biopsies of patients with hepatitis C.
Methods
Individuals presenting with different degrees of fibrosis in liver biopsy were included. Slides of liver samples were stained with orcein with and without prior oxidation. Morphometric analysis was proceeded, and quantification accomplished by corrected integrated density.
Results
Twenty-seven patients, mean age 52 years-old, 59% women, were included. Elastic fibers density was higher in advanced fibrosis patients and there was a positive correlation with Metavir score (Spearman r = 0.609, p < 0.001), as well as with the noninvasive scores Fib-4 (Pearson r = 0.46, p = 0.029) and APRI (r = 0.52, p = 0.01).
Conclusion
Morphometric analysis by corrected integrated density demonstrates that elastic fibers abundance is higher in advanced stage of fibrosis in patients with hepatitis C.
Collapse
|
|
5
|
Moon AM, Green PK, Rockey DC, Berry K, Ioannou GN. Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding. Aliment Pharmacol Ther 2020; 51:364-373. [PMID: 31773763 PMCID: PMC7416556 DOI: 10.1111/apt.15586] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/03/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The real-world, long-term benefits of sustained virologic response (SVR) on the risk of variceal bleeding remain unclear. AIM To assess the association between DAA-induced SVR and post-treatment variceal bleeding METHODS: We identified patients who initiated DAA-only anti-viral treatments in the United States Veterans Affairs healthcare system from 2013 to 2015. We followed patients until 1 January 2019 for the development of gastro-oesophageal variceal bleeding defined by diagnostic codes. We used multivariable Cox proportional hazards regression to assess the association between SVR and development of variceal bleeding, adjusting for potential confounders. RESULTS Among 33 582 DAA-treated patients, 549 (1.6%) developed variceal bleeding after treatment (mean follow-up 3.1 years). Compared to no SVR, SVR was associated with a significantly lower incidence of variceal bleeding among all patients (0.46 vs 1.26 per 100 patient-years, adjusted hazard ratio [AHR] 0.66, 95% CI 0.52-0.83), among patients with pre-treatment cirrhosis (1.55 vs 2.96 per 100 patient-years, AHR 0.73, 95% CI 0.57-0.93) and among patients without pre-treatment cirrhosis (0.07 vs 0.29 per 100 patient-years, AHR 0.33, 95% CI 0.17-0.65). The risk of variceal bleeding after treatment was lower in those who achieved SVR vs no SVR among patients who had non-bleeding varices (3.5 vs 4.9 per 100 patient-years) or bleeding varices (12.9 vs 16.4 per 100 patient-years) diagnosed before treatment, but these differences were not statistically significant in adjusted analyses. CONCLUSION DAA-induced SVR is independently associated with a lower risk of variceal bleeding during long-term follow-up in patients with and without pre-treatment cirrhosis. These findings demonstrate an important real-world benefit of DAA treatment.
Collapse
Affiliation(s)
- Andrew M. Moon
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - Pamela K. Green
- Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, WA
| | - Don C. Rockey
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Kristin Berry
- Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, WA
| | - George N. Ioannou
- Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, WA.,Division of Gastroenterology, Department of Medicine Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, WA
| |
Collapse
|
|
6
|
Patel K, Sebastiani G. Limitations of non-invasive tests for assessment of liver fibrosis. JHEP Rep 2020; 2:100067. [PMID: 32118201 PMCID: PMC7047178 DOI: 10.1016/j.jhepr.2020.100067] [Citation(s) in RCA: 160] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/05/2020] [Accepted: 01/08/2020] [Indexed: 02/07/2023] Open
Abstract
The diagnostic assessment of liver injury is an important step in the management of patients with chronic liver disease (CLD). Although liver biopsy is the reference standard for the assessment of necroinflammation and fibrosis, the inherent limitations of an invasive procedure, and need for repeat sampling, have led to the development of several non-invasive tests (NITs) as alternatives to liver biopsy. Such non-invasive approaches mostly include biological (serum biomarker algorithms) or physical (imaging assessment of tissue stiffness) assessments. However, currently available NITs have several limitations, such as variability, inadequate accuracy and risk factors for error, while the development of a newer generation of biomarkers for fibrosis may be limited by the sampling error inherent to the reference standard. Many of the current NITs were initially developed to diagnose significant fibrosis in chronic hepatitis C, subsequently refined for the diagnosis of advanced fibrosis in patients with non-alcoholic fatty liver disease, and further adapted for prognostication in CLD. An important consideration is that despite their increased use in clinical practice, these NITs were not designed to reflect the dynamic process of fibrogenesis, differentiate between adjacent disease stages, diagnose non-alcoholic steatohepatitis, or follow longitudinal changes in fibrosis or disease activity caused by natural history or therapeutic intervention. Understanding the strengths and limitations of these NITs will allow for more judicious interpretation in the clinical context, where NITs should be viewed as complementary to, rather than as a replacement for, liver biopsy.
Collapse
Key Words
- AGA, American Gastroenterology Association
- ALT, alanine aminotransferase
- APRI, AST-platelet ratio index
- AST, aspartate aminotransferase
- AUC, area under the curve
- BMI, body mass index
- Biomarkers
- CAP, controlled attenuation parameter
- CHB, chronic hepatitis B
- CHC, chronic hepatitis C
- CLD, chronic liver disease
- CPA, collagen proportionate area
- DAA, direct-acting antiviral
- ELF, enhanced liver fibrosis
- Elastography
- FIB-4, fibrosis-4
- FLIP, fatty liver inhibition of progression
- HCC, hepatocellular carcinoma
- IFN, interferon
- LSM, liver stiffness measure
- Liver biopsy
- MR, magnetic resonance
- MRE, magnetic resonance elastography
- NAFLD, non-alcoholic fatty liver disease
- NFS, NAFLD fibrosis score
- NITs, non-invasive tests
- Non-alcoholic fatty liver disease
- SVR, sustained virologic response
- US, ultrasound
- VCTE, vibration-controlled transient elastography
- Viral hepatitis
Collapse
Affiliation(s)
- Keyur Patel
- Division of Gastroenterology, University Health Network Toronto, Toronto General Hospital, Toronto, ON, Canada
- Corresponding author. Address: Division of Gastroenterology, University of Toronto Health Network, Toronto General Hospital, 200 Elizabeth Street, 9EN, Toronto, ON M5G 2C4.
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology, McGill University Health Center, Montreal, QC, Canada
| |
Collapse
|
|
7
|
Abstract
PURPOSE OF REVIEW Hepatitis C virus (HCV) infection has been the leading cause of cirrhosis in the United States now for the last several decades. With the introduction of highly effective direct acting antiviral (DAA) drugs, cure rates are now almost 100%. With this explosion of effective therapy, it is possible that many patients with HCV may have reversion in fibrosis. The purpose of this review is, therefore, to report on recent findings in this field. RECENT FINDINGS Older data that examined the effect of interferon-based HCV therapy indicate that fibrosis reverses after HCV eradication. More recent work in the DAA era similarly indicates that fibrosis is reversible. A caveat is that DAA therapy causes rapid viral clearance, and appears to lead to rapid reductions in inflammation. Some tools (such as transient elastography), which may also reflect the inflammatory response, and thus may 'overestimate' of fibrosis reversal. However, emerging data suggesting improved outcomes in patients with cirrhosis after HCV clearance support the concept that even cirrhosis reverses in some patients. SUMMARY Fibrosis (and cirrhosis) reversion, to some extent, occurs after HCV clearance. This topic is vitally important and information continues to emerge; more data on this subject are expected and needed.
Collapse
|
|
8
|
Wang B, Sun Y, Zhou J, Wu X, Chen S, Wu S, Liu H, Wang T, Ou X, Jia J, You H. Advanced septa size quantitation determines the evaluation of histological fibrosis outcome in chronic hepatitis B patients. Mod Pathol 2018; 31:1567-1577. [PMID: 29785021 DOI: 10.1038/s41379-018-0059-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 03/08/2018] [Accepted: 03/09/2018] [Indexed: 02/08/2023]
Abstract
Hepatitis B (HBV)-related fibrosis can be reversed after effective antiviral therapy. However, detailed changes of collagen characteristics during fibrosis regression remain unclear. Paired biopsy samples obtained from chronic hepatitis B patients were imaged with second harmonic generation/two photon excitation fluorescence (SHG/TPEF)-based microscopy to identify and quantify collagen features in portal, septal, and fibrillar areas. According to the changes of Ishak stage and qFibrosis score, a total of 117 patients with paired liver biopsy appeared to have four different outcomes after 78-week antiviral therapy: fast reverse (9%), reverse (63%), stable (15%), or progress (13%) on fibrosis. Among 71 collagen features identified by SHG/TPEF analysis, the most prominent fibrosis reversion occurred in the "septal" area, followed by the "fibrillar" area, but not in the "portal" area (P < 0.001). Further analysis of 1060 individual septa identified four parameters that correlated with fibrosis reversion: average width, maximum width, number of fibers, and number of cross-link fibers (P < 0.001). Average septal width was independently associated with regressive septa (odds ratio (OR) = 5.22, 95% confidence interval (CI): 4.17-6.53; P < 0.001), with an AUROC of 0.96 (95% CI: 0.95-0.97). The threshold used to discriminate reversal of fibrosis was 30 μm. In conclusion, septal collagen was determined to be the most useful histological feature for evaluation of dynamic changes in liver fibrosis. Septal width was the most predictive indicator of prognosis in liver fibrosis.
Collapse
Affiliation(s)
- Bingqiong Wang
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yameng Sun
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jialing Zhou
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaoning Wu
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shuyan Chen
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shanshan Wu
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hui Liu
- Department Pathology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tailing Wang
- Department Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
9
|
Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, Lawitz EJ, Rockey DC, Schall RA, Jia C, McColgan BJ, McHutchison JG, Subramanian GM, Myers RP, Younossi Z, Ratziu V, Muir AJ, Afdhal NH, Goodman Z, Bosch J, Sanyal AJ. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology 2018; 155:1140-1153. [PMID: 29990488 DOI: 10.1053/j.gastro.2018.07.006] [Citation(s) in RCA: 272] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 06/12/2018] [Accepted: 07/01/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis. METHODS We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96. RESULTS The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis-including those given placebo-had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (-0.2%, 95% confidence interval [CI] -1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (-0.4%, 95% CI -1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI -1.2 to 1.5, P = .84 for 200 mg; 95% CI -1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups. CONCLUSION In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.govNCT01672866 and NCT01672879.
Collapse
Affiliation(s)
| | | | | | | | - Anna Mae Diehl
- Duke Clinical Research Institute, Durham, North Carolina
| | - Reem Ghalib
- Texas Clinical Research Institute, Arlington, Texas
| | - Eric J Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, Texas
| | - Don C Rockey
- Medical University of South Carolina, Charleston, South Carolina
| | | | | | | | | | | | | | | | - Vlad Ratziu
- Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Andrew J Muir
- Duke Clinical Research Institute, Durham, North Carolina
| | | | | | - Jaime Bosch
- Inselspital, Bern University, Switzerland; IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Arun J Sanyal
- Virginia Commonwealth University, Richmond, Virginia
| | | |
Collapse
|
|
10
|
Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Chalasani NP, Anstee QM, Kowdley KV, George J, Goodman ZD, Lindor K. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018; 68:361-371. [PMID: 29222911 PMCID: PMC6508084 DOI: 10.1002/hep.29724] [Citation(s) in RCA: 267] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/17/2017] [Accepted: 12/06/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, several important secondary endpoints, including noninvasive biomarkers, long-term outcomes, and patient-reported outcomes must be considered. In 2018, a few phase 3 clinical trials for the treatment of NASH have been initiated. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies. CONCLUSION Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD. (Hepatology 2018;68:361-371).
Collapse
Affiliation(s)
- Zobair M. Younossi
- Department of Medicine and Betty and Guy Beatty Center for Integrated Research, Claude Moore, Inova Health Systems, Falls Church, VA
| | - Rohit Loomba
- Department of Gastroenterology, University of California at San Diego, La Jolla, CA
| | - Mary E. Rinella
- Department of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | | | | | | | - Francesco Negro
- Department of Gastroenterology, University Hospitals of Geneva, Geneva, Switzerland
| | - Stephen H. Caldwell
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA
| | - Vlad Ratziu
- Institute of Cardiometabolism and Nutrition and Hospital Pitié Salpêtrière, de L’Hopital, Paris, France
| | - Kathleen E. Corey
- Division of Gastroenterology, Massachusetts General Hospital, Cambridge, MA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | | | - Arun J. Sanyal
- Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA
| | - Joel E. Lavine
- Department of Pediatrics, Columbia College of Physicians and Surgeons, New York, NY
| | | | | | - Naga P. Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
| | - Quentin M. Anstee
- Institute of Cellular Medicine, Newcastle University, New Castle, UK
| | - Kris V. Kowdley
- Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA
| | - Jacob George
- Department of Gastroenterology & Hepatology, Westmead Hospital and Sydney West Local Health District, Sydney, Australia
| | - Zachary D. Goodman
- Department of Medicine and Betty and Guy Beatty Center for Integrated Research, Claude Moore, Inova Health Systems, Falls Church, VA
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ
| |
Collapse
|
|
11
|
Horowitz JM, Venkatesh SK, Ehman RL, Jhaveri K, Kamath P, Ohliger MA, Samir AE, Silva AC, Taouli B, Torbenson MS, Wells ML, Yeh B, Miller FH. Evaluation of hepatic fibrosis: a review from the society of abdominal radiology disease focus panel. Abdom Radiol (NY) 2017. [PMID: 28624924 DOI: 10.1007/s00261-017-1211-7] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatic fibrosis is potentially reversible; however early diagnosis is necessary for treatment in order to halt progression to cirrhosis and development of complications including portal hypertension and hepatocellular carcinoma. Morphologic signs of cirrhosis on ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) alone are unreliable and are seen with more advanced disease. Newer imaging techniques to diagnose liver fibrosis are reliable and accurate, and include magnetic resonance elastography and US elastography (one-dimensional transient elastography and point shear wave elastography or acoustic radiation force impulse imaging). Research is ongoing with multiple other techniques for the noninvasive diagnosis of hepatic fibrosis, including MRI with diffusion-weighted imaging, hepatobiliary contrast enhancement, and perfusion; CT using perfusion, fractional extracellular space techniques, and dual-energy, contrast-enhanced US, texture analysis in multiple modalities, quantitative mapping, and direct molecular imaging probes. Efforts to advance the noninvasive imaging assessment of hepatic fibrosis will facilitate earlier diagnosis and improve patient monitoring with the goal of preventing the progression to cirrhosis and its complications.
Collapse
Affiliation(s)
- Jeanne M Horowitz
- Department of Radiology, Feinberg School of Medicine, Northwestern University, 676 St. Clair St, Suite 800, Chicago, IL, 60611, USA.
| | - Sudhakar K Venkatesh
- Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Richard L Ehman
- Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Kartik Jhaveri
- Division of Abdominal Imaging, Joint Department of Medical Imaging, University Health Network, Mt. Sinai Hospital & Women's College Hospital, University of Toronto, 610 University Ave, Toronto, ON, M5G 2M9, Canada
| | - Patrick Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Michael A Ohliger
- Department of Radiology and Biomedical Imaging, UCSF School of Medicine, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA, 94110, USA
| | - Anthony E Samir
- Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA
| | - Alvin C Silva
- Department of Radiology, Mayo Clinic in Arizona, 13400 E. Shea Blvd., Scottsdale, AZ, 85259, USA
| | - Bachir Taouli
- Department of Radiology and Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, Box 1234, New York, NY, 10029, USA
| | - Michael S Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Michael L Wells
- Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Benjamin Yeh
- Department of Radiology and Biomedical Imaging, UCSF School of Medicine, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA, 94110, USA
| | - Frank H Miller
- Department of Radiology, Feinberg School of Medicine, Northwestern University, 676 St. Clair St, Suite 800, Chicago, IL, 60611, USA
| |
Collapse
|
|
12
|
Abdel-hameed EA, Rouster SD, Zhang X, Chen J, Medvedovic M, Goodman ZD, Sherman KE. Characterization of HCV NS3 Protease Variants in HCV/HIV-Coinfected Patients by Ultra-Deep Sequence Analysis: Relationship with Hepatic Fibrosis. J Acquir Immune Defic Syndr 2017; 74:353-358. [PMID: 27898525 PMCID: PMC5303138 DOI: 10.1097/qai.0000000000001256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Treatment of HCV/HIV coinfection is now largely based on utilization of direct acting agents. Pretreatment viral resistant-associated variants (RAVs) and host liver condition may affect the sustained virological response. In this study, we explored relative prevalence of protease resistance-associated mutations, the evolution of those RAVs after 12 weeks of pegylated interferon alfa exposure, and the role hepatic fibrosis might have on RAV display. METHODS Thirty nonresponder HCV/HIV-coinfected subjects were evaluated before and after 12 weeks of PegIFN treatment. Ultra-deep sequence analysis of NS3 RAVs was performed. Hepatic fibrosis was determined by sensitive computer-assisted histomorphometry determination. RESULTS At baseline, protease inhibitor RAVs were present in 73.3% of patients and expanded to 83.3% of patients after 12 weeks of PegIFN exposure. Q80K showed the highest prevalence before and after treatment at 46.7% and 56.7%, respectively. The presence of Q80K is positively correlated with percent collagen content of the liver tissue. CONCLUSIONS Key RAVs for HCV protease inhibitors are present in a major portion of the HCV/HIV-coinfected population before therapy. Some variants get selected after exposure. Correlation of Q80K with collagen content of the liver suggests that compartmentalization within the liver may contribute to persistence of mutations less fit than wildtype.
Collapse
Affiliation(s)
| | - Susan D. Rouster
- University of Cincinnati College of Medicine, Cincinnati, OH
45267
| | - Xiang Zhang
- University of Cincinnati, Department of Environmental Health,
Cincinnati, OH 45267
| | - Jing Chen
- University of Cincinnati, Department of Environmental Health,
Cincinnati, OH 45267
| | - Mario Medvedovic
- University of Cincinnati, Department of Environmental Health,
Cincinnati, OH 45267
| | - Zachary D. Goodman
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA
22042
| | | |
Collapse
|
|
13
|
Shiha G, Ibrahim A, Helmy A, Sarin SK, Omata M, Kumar A, Bernstien D, Maruyama H, Saraswat V, Chawla Y, Hamid S, Abbas Z, Bedossa P, Sakhuja P, Elmahatab M, Lim SG, Lesmana L, Sollano J, Jia JD, Abbas B, Omar A, Sharma B, Payawal D, Abdallah A, Serwah A, Hamed A, Elsayed A, AbdelMaqsod A, Hassanein T, Ihab A, GHaziuan H, Zein N, Kumar M. Asian-Pacific Association for the Study of the Liver (APASL) consensus guidelines on invasive and non-invasive assessment of hepatic fibrosis: a 2016 update. Hepatol Int 2017; 11:1-30. [PMID: 27714681 DOI: 10.1007/s12072-016-9760-3] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 08/13/2016] [Indexed: 12/14/2022]
Abstract
Hepatic fibrosis is a common pathway leading to liver cirrhosis, which is the end result of any injury to the liver. Accurate assessment of the degree of fibrosis is important clinically, especially when treatments aimed at reversing fibrosis are being evolved. Despite the fact that liver biopsy (LB) has been considered the "gold standard" of assessment of hepatic fibrosis, LB is not favored by patients or physicians owing to its invasiveness, limitations, sampling errors, etc. Therefore, many alternative approaches to assess liver fibrosis are gaining more popularity and have assumed great importance, and many data on such approaches are being generated. The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on liver fibrosis in 2007, with a mandate to develop consensus guidelines on various aspects of liver fibrosis relevant to disease patterns and clinical practice in the Asia-Pacific region. The first consensus guidelines of the APASL recommendations on hepatic fibrosis were published in 2009. Due to advances in the field, we present herein the APASL 2016 updated version on invasive and non-invasive assessment of hepatic fibrosis. The process for the development of these consensus guidelines involved review of all available published literature by a core group of experts who subsequently proposed consensus statements followed by discussion of the contentious issues and unanimous approval of the consensus statements. The Oxford System of the evidence-based approach was adopted for developing the consensus statements using the level of evidence from one (highest) to five (lowest) and grade of recommendation from A (strongest) to D (weakest). The topics covered in the guidelines include invasive methods (LB and hepatic venous pressure gradient measurements), blood tests, conventional radiological methods, elastography techniques and cost-effectiveness of hepatic fibrosis assessment methods, in addition to fibrosis assessment in special and rare situations.
Collapse
Affiliation(s)
- Gamal Shiha
- Internal Medicine Department, El-Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.
- Egyptian Liver Research Institute And Hospital (ELRIAH), Mansoura, Egypt.
| | - Alaa Ibrahim
- Department of Internal medicine, University of Benha, Benha, Egypt
| | - Ahmed Helmy
- Department of Tropical Medicine & Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, University of Tokyo, Tokyo, Japan
| | - Ashish Kumar
- Department of Gastroenterology & Hepatology, Ganga Ram Institute for Postgraduate Medical Education & Research of Sir Ganga Ram Hospital, New Delhi, India
| | - David Bernstien
- Division of Hepatology, North Shore University Hospital and Long Island Jewish Medical Center, New Hyde Park, New York, USA
| | - Hitushi Maruyama
- Department of Gastroenterology, Chiba University Graduate School of Medicine, Chiba, Chiba Prefecture, Japan
| | - Vivek Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Yogesh Chawla
- Post Graduate Institute of Medial Education & Research, Chandigarh, India
| | - Saeed Hamid
- Department of Medicine, The Aga Khan University & Hospital, Stadium Road, Karachi, Pakistan
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Pierre Bedossa
- Department of Pathology, Physiology and Imaging, University Paris Diderot, Paris, France
| | - Puja Sakhuja
- Govind Ballabh Pant Hospital, Maulana Azad Medical College, New Delhi, India
| | - Mamun Elmahatab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Jose Sollano
- University of Santo Tomas, España Blvd, Manila, Philippines
| | - Ji-Dong Jia
- Liver Research Centre at the Beijing Friendship Hospital, Capital University in Beijing, Beijing, China
| | - Bahaa Abbas
- Department of Internal Medicine, Military Medical Academy, Cairo, Egypt
| | - Ashraf Omar
- Tropical Medicine Department, Cairo Medical School, Cairo, Egypt
| | - Barjesh Sharma
- Department of Gastroenterology, GB Pant Hospital, New Delhi, India
| | - Diana Payawal
- Section of Gastroenterology, Cardinal Santos Medical Center, San Juan City, Metro Manila, Philippines
| | - Ahmed Abdallah
- Pediatric Hospital, Mansoura University, Mansoura, Egypt
| | | | - Abdelkhalek Hamed
- Hepatology and Diabetes Unit, Military Medical Academy, Cairo, Egypt
| | - Aly Elsayed
- Hepatology & GIT Department, AHF Center Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amany AbdelMaqsod
- Internal Medicine Department, Faculty of Medicine Cairo University, Liver Transplant Unit Manial Hospital and Liver ICU French Hospital, Cairo University, Cairo, Egypt
| | | | - Ahmed Ihab
- Molecular Pathology Unit & Research Group, German University in Cairo, Cairo, Egypt
| | - Hamsik GHaziuan
- Department of Hepatology, Nork Clinical Hospital of Infectious Diseases, Yerevan, Armenia
| | - Nizar Zein
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, USA
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| |
Collapse
|
|
14
|
Behairy BES, Sira MM, Zalata KR, Salama ESE, Abd-Allah MA. Transient elastography compared to liver biopsy and morphometry for predicting fibrosis in pediatric chronic liver disease: Does etiology matter? World J Gastroenterol 2016; 22:4238-4249. [PMID: 27122674 PMCID: PMC4837441 DOI: 10.3748/wjg.v22.i16.4238] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 03/04/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate transient elastography (TE) as a noninvasive tool in staging liver fibrosis compared with liver biopsy and morphometry in children with different chronic liver diseases. METHODS A total of 90 children [50 with chronic hepatitis C virus (HCV), 20 with autoimmune hepatitis (AIH) and 20 with Wilson disease] were included in the study and underwent liver stiffness measurement (LSM) using TE. Liver biopsies were evaluated for fibrosis, qualitatively, by Ishak score and quantitatively by fibrosis area fraction (FAF) using digital image analysis (morphometry). LSM was correlated with fibrosis and other studied variables using spearman correlation. A stepwise multiple regression analysis was also performed to examine independent factors associated with LSM. Different cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. Cut-off values with optimal clinical performance (optimal sensitivity and specificity simultaneously) were selected. RESULTS The majority of HCV group had minimal activity (80%) and no/mild fibrosis (72%). On the other hand, the majority of AIH group had mild to moderate activity (70%) and moderate to severe fibrosis (95%) and all Wilson disease group had mild to moderate activity (100%) and moderate to severe fibrosis (100%). LSM correlated significantly with both FAF and Ishak scores and the correlation appeared better with the latter (r = 0.839 vs 0.879, P < 0.0001 for both). LSM discriminated individual stages of fibrosis with high performance. Sensitivity ranged from 81.4% to 100% and specificity ranged from 75.0% to 97.2%. When we compared LSM values for the same stage of fibrosis, they varied according to the different etiologies. Higher values were in AIH (16.15 ± 7.23 kPa) compared to Wilson disease (8.30 ± 0.84 kPa) and HCV groups (7.43 ± 1.73 kPa). Multiple regression analysis revealed that Ishak fibrosis stage was the only independent variable associated with higher LSM (P < 0.0001). CONCLUSION TE appears reliable in distinguishing different stages of liver fibrosis in children. However, its values vary according to the disease type. For that, a disease-specific estimation of cut-off values for fibrosis staging is worthy.
Collapse
|
|
15
|
Wang M, Devarajan K, Singal AG, Marrero JA, Dai J, Feng Z, Rinaudo JAS, Srivastava S, Evans A, Hann HW, Lai Y, Yang H, Block TM, Mehta A. The Doylestown Algorithm: A Test to Improve the Performance of AFP in the Detection of Hepatocellular Carcinoma. Cancer Prev Res (Phila) 2016; 9:172-179. [PMID: 26712941 PMCID: PMC4740237 DOI: 10.1158/1940-6207.capr-15-0186] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023]
Abstract
Biomarkers for the early diagnosis of hepatocellular carcinoma (HCC) are needed to decrease mortality from this cancer. However, as new biomarkers have been slow to be brought to clinical practice, we have developed a diagnostic algorithm that utilizes commonly used clinical measurements in those at risk of developing HCC. Briefly, as α-fetoprotein (AFP) is routinely used, an algorithm that incorporated AFP values along with four other clinical factors was developed. Discovery analysis was performed on electronic data from patients who had liver disease (cirrhosis) alone or HCC in the background of cirrhosis. The discovery set consisted of 360 patients from two independent locations. A logistic regression algorithm was developed that incorporated log-transformed AFP values with age, gender, alkaline phosphatase, and alanine aminotransferase levels. We define this as the Doylestown algorithm. In the discovery set, the Doylestown algorithm improved the overall performance of AFP by 10%. In subsequent external validation in over 2,700 patients from three independent sites, the Doylestown algorithm improved detection of HCC as compared with AFP alone by 4% to 20%. In addition, at a fixed specificity of 95%, the Doylestown algorithm improved the detection of HCC as compared with AFP alone by 2% to 20%. In conclusion, the Doylestown algorithm consolidates clinical laboratory values, with age and gender, which are each individually associated with HCC risk, into a single value that can be used for HCC risk assessment. As such, it should be applicable and useful to the medical community that manages those at risk for developing HCC.
Collapse
Affiliation(s)
- Mengjun Wang
- Drexel University College of Medicine, Philadelphia, Pennsylvania. 19102
| | | | - Amit G Singal
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas
| | - Jorge A Marrero
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas
| | - Jianliang Dai
- Department of Biostatistics, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ziding Feng
- Department of Biostatistics, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jo Ann S Rinaudo
- Cancer Biomarkers Research Group, Division of Cancer Prevention, NCI, Bethesda, Maryland
| | - Sudhir Srivastava
- Cancer Biomarkers Research Group, Division of Cancer Prevention, NCI, Bethesda, Maryland
| | - Alison Evans
- Drexel University School of Public Health, Philadelphia, Pennsylvania
| | - Hie-Won Hann
- Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Yinzhi Lai
- Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Hushan Yang
- Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - Anand Mehta
- Drexel University College of Medicine, Philadelphia, Pennsylvania. 19102.
| |
Collapse
|
|
16
|
Patel K, Tillmann HL, Matta B, Sheridan MJ, Gardner SD, Shackel NA, McHutchison JG, Goodman ZD. Longitudinal assessment of hepatitis C fibrosis progression by collagen and smooth muscle actin morphometry in comparison to serum markers. Aliment Pharmacol Ther 2016; 43:356-63. [PMID: 26560052 DOI: 10.1111/apt.13471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/21/2015] [Accepted: 10/21/2015] [Indexed: 01/14/2023]
Abstract
BACKGROUND Assessment of fibrosis progression in chronic liver disease relies upon non-invasive tools and changes in semi-quantitative histopathology scores that may not be reliable. AIM To assess the diagnostic performance of the FibroSURE (FS) index and collagen/alpha smooth muscle actin (α-SMA) morphometry in relation to longitudinal changes in fibrosis on paired biopsies. METHODS The study cohort included 201 chronic hepatitis C (CHC) nonresponders enrolled in a prior phase II anti-fibrotic study. Serum FS and paired biopsies, with both collagen and α-SMA morphometry, were evaluated at baseline and week 52. RESULTS Study patients were mostly male (67%) and Caucasian (77%), with Ishak stages 2 (n = 79), 3 (n = 88) and 4 (n = 30), excluded (n = 4 stage 1 or 5). Mean biopsy length was 22.9 mm. For baseline Ishak 2/3 vs. 4, there were no significant differences in AUROCs for collagen (0.71), SMA (0.66) or FS (0.70). At week 52, 62% of patients had no change in Ishak stage, but collagen/α-SMA increased by 34-51% (P < 0.0001), and FS decreased by 5% (P = 0.008). Among the 33% of patients with +/-1 Ishak stage change, FS changes were not significant, but α-SMA increased 29-72%, and collagen increased by 12-38% (P = 0.01 for +1 only). CONCLUSIONS Longitudinal changes in collagen and α-SMA morphometry are apparent prior to change in histological stage or FibroSURE in CHC nonresponders with intermediate fibrosis. This likely reflects quantitative morphological differences that are not detected by routine histological staging or serum markers such as FibroSURE.
Collapse
Affiliation(s)
- K Patel
- Duke Clinical Research Institute, Durham, NC, USA.,Duke University Medical Center, Durham, NC, USA.,Liver Cell Biology, Centenary Institute, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - H L Tillmann
- Duke Clinical Research Institute, Durham, NC, USA.,Duke University Medical Center, Durham, NC, USA
| | - B Matta
- Duke University Medical Center, Durham, NC, USA
| | - M J Sheridan
- Inova Research Center, Inova Fairfax Medical Campus, Falls Church, VA, USA
| | - S D Gardner
- Infectious Diseases Therapeutic Area Unit, GlaxoSmithKline, Research Triangle Park, NC, USA
| | - N A Shackel
- Liver Cell Biology, Centenary Institute, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | | | - Z D Goodman
- Hepatic Pathology Consultation and Research, Inova Fairfax Hospital, Falls Church, VA, USA
| |
Collapse
|
|
17
|
Wang Y, Hou JL. Fibrosis assessment: impact on current management of chronic liver disease and application of quantitative invasive tools. Hepatol Int 2016; 10:448-61. [DOI: 10.1007/s12072-015-9695-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 12/07/2015] [Indexed: 12/15/2022]
|
|
18
|
Halász T, Horváth G, Kiss A, Pár G, Szombati A, Gelley F, Nemes B, Kenessey I, Piurkó V, Schaff Z. Evaluation of Histological and non-Invasive Methods for the Detection of Liver Fibrosis: The Values of Histological and Digital Morphometric Analysis, Liver Stiffness Measurement and APRI Score. Pathol Oncol Res 2016; 22:1-6. [PMID: 26189126 DOI: 10.1007/s12253-015-9964-1] [Citation(s) in RCA: 8] [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] [Received: 04/22/2015] [Accepted: 07/09/2015] [Indexed: 12/16/2022]
Abstract
Prognosis and treatment of liver diseases mainly depend on the precise evaluation of the fibrosis. Comparisons were made between the results of Metavir fibrosis scores and digital morphometric analyses (DMA), liver stiffness (LS) values and aminotransferase-platelet ratio (APRI) scores, respectively. Liver biopsy specimens stained with Sirius red and analysed by morphometry, LS and APRI measurements were taken from 96 patients with chronic liver diseases (56 cases of viral hepatitis, 22 cases of autoimmune- and 18 of mixed origin). The strongest correlation was observed between Metavir score and DMA (r = 0.75 p < 0.05), followed in decreasing order by LS and Metavir (r = 0.61), LS and DMA (r = 0.47) LS and APRI (r = 0.35) and Metavir and APRI (r = 0.24), respectively. DMA is a helpful additional tool for the histopathological evaluation of fibrosis, even when the sample size is small and especially in case of advanced fibrosis. The non-invasive methods showed good correlation with the histopathological methods; LS proved to be more accurate than APRI. The stronger correlation between LS values and Metavir scores, as well as the results of DMA in case of appropriate sample size were remarkable.
Collapse
Affiliation(s)
- Tünde Halász
- Second Department of Pathology, Semmelweis University, Ulloi str 93, 1091, Budapest, Hungary
- Department of Pathology, Military Hospital, Budapest, Hungary
| | | | - András Kiss
- Second Department of Pathology, Semmelweis University, Ulloi str 93, 1091, Budapest, Hungary
| | - Gabriella Pár
- First Department of Medicine, Medical University of Pécs, Pécs, Hungary
| | | | - Fanni Gelley
- Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
| | - Balázs Nemes
- Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
| | - István Kenessey
- Second Department of Pathology, Semmelweis University, Ulloi str 93, 1091, Budapest, Hungary
| | - Violetta Piurkó
- Second Department of Pathology, Semmelweis University, Ulloi str 93, 1091, Budapest, Hungary
| | - Zsuzsa Schaff
- Second Department of Pathology, Semmelweis University, Ulloi str 93, 1091, Budapest, Hungary.
- MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
| |
Collapse
|
|
19
|
Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut 2015; 64:830-41. [PMID: 25681399 PMCID: PMC4477794 DOI: 10.1136/gutjnl-2014-306842] [Citation(s) in RCA: 682] [Impact Index Per Article: 68.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 01/07/2015] [Indexed: 12/12/2022]
Abstract
Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through 'activation', and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the 'ductular reaction' as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.
Collapse
Affiliation(s)
- Youngmin A Lee
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michael C Wallace
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
20
|
Abstract
PURPOSE OF REVIEW It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high-affinity hepatic transporters exhibit high 'first-pass' hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways. RECENT FINDINGS We highlight one quantitative liver function test, the dual cholate test, and introduce the concept of a disease severity index linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting. SUMMARY It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy.
Collapse
|
|
21
|
Zou X, Chi X, Pan Y, Du D, Sun H, Matsuda A, Li W, Kuno A, Zhang X, Narimatsu H, Niu J, Zhang Y. LecT-Hepa facilitates estimating treatment outcome during interferon therapy in chronic hepatitis C patients. Clin Proteomics 2014; 11:44. [PMID: 25593566 PMCID: PMC4276098 DOI: 10.1186/1559-0275-11-44] [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] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 11/25/2014] [Indexed: 02/07/2023] Open
Abstract
Background A combination treatment of interferon and ribavirin is the standard and the commonly used treatment for chronic hepatitis C (CHC). Developing noninvasive tests like serum indicators that can predict treatment outcome at an early stage of therapy is beneficial for individualized treatment and management of CHC. A glyco-indicator based on the glyco-alteration of serum α1-acid glycoprotein, LecT-Hepa, was discovered by glycomics technologies as a robust indicator of liver fibrosis. Here, we investigated the clinical utility of LecT-Hepa for evaluation of treatment outcome. Results Firstly, ninety-seven patients with CHC were used for comparison of LecT-Hepa in serum and plasma. We found no significant difference in the concentrations of LecT-Hepa in serum and plasma. And then, 213 serum specimens from 45 patients who received 48 weeks of treatment with interferon and ribavirin were followed up for 96 weeks, and were used for evaluation of the role of LecT-Hepa. We found that LecT-Hepa might reflect the change in fibrosis regression during the treatment process. Moreover, the change of LecT-Hepa at the first 12 weeks of treatment could already predict the antiviral treatment response, which was more superior to FIB-4 index and aspartate aminotransferase-to-platelet ratio index (APRI) in this study. Conclusions These results provide a new perspective that serum glycoprotein could be used as a joint diagnosis indicator for estimation treatment outcome of viral hepatitis at earlier stage of therapy. Electronic supplementary material The online version of this article (doi:10.1186/1559-0275-11-44) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Xia Zou
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025 China
| | - Xiumei Chi
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Yu Pan
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Dongning Du
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Haibo Sun
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Atsushi Matsuda
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Wei Li
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Atsushi Kuno
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Xinxin Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025 China
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568 Japan.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| | - Junqi Niu
- Department of Hepatology, First Hospital, Jilin University, Changchun, 130021 China
| | - Yan Zhang
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Minhang Shanghai, 200240 China.,SCSB (China) - AIST (Japan) Joint Medical Glycomics Laboratory, 800 Dong Chuan Road, Minhang Shanghai, 200240 China
| |
Collapse
|
|
22
|
Abstract
Magnetic resonance elastography (MRE) assesses tissue stiffness in vivo by imaging propagating shear waves through the tissues and processing the wave information. MRE is a robust technology with excellent technical success; is applicable in almost all patients and body habitus; and has excellent reproducibility, repeatability, and interobserver agreement for assessing liver stiffness. It is currently the most accurate noninvasive technique for detection and staging of liver fibrosis and has the potential to replace liver biopsy. This article describes the principles and technique of MRE, current clinical applications, and emerging clinical indications.
Collapse
Affiliation(s)
- Sudhakar Kundapur Venkatesh
- Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
| | - Richard L Ehman
- Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| |
Collapse
|
|
23
|
qFibrosis: a fully-quantitative innovative method incorporating histological features to facilitate accurate fibrosis scoring in animal model and chronic hepatitis B patients. J Hepatol 2014; 61:260-269. [PMID: 24583249 PMCID: PMC4278959 DOI: 10.1016/j.jhep.2014.02.015] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Revised: 02/18/2014] [Accepted: 02/18/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is increasing need for accurate assessment of liver fibrosis/cirrhosis. We aimed to develop qFibrosis, a fully-automated assessment method combining quantification of histopathological architectural features, to address unmet needs in core biopsy evaluation of fibrosis in chronic hepatitis B (CHB) patients. METHODS qFibrosis was established as a combined index based on 87 parameters of architectural features. Images acquired from 25 Thioacetamide-treated rat samples and 162 CHB core biopsies were used to train and test qFibrosis and to demonstrate its reproducibility. qFibrosis scoring was analyzed employing Metavir and Ishak fibrosis staging as standard references, and collagen proportionate area (CPA) measurement for comparison. RESULTS qFibrosis faithfully and reliably recapitulates Metavir fibrosis scores, as it can identify differences between all stages in both animal samples (p<0.001) and human biopsies (p<0.05). It is robust to sampling size, allowing for discrimination of different stages in samples of different sizes (area under the curve (AUC): 0.93-0.99 for animal samples: 1-16 mm(2); AUC: 0.84-0.97 for biopsies: 10-44 mm in length). qFibrosis can significantly predict staging underestimation in suboptimal biopsies (<15 mm) and under- and over-scoring by different pathologists (p<0.001). qFibrosis can also differentiate between Ishak stages 5 and 6 (AUC: 0.73, p=0.008), suggesting the possibility of monitoring intra-stage cirrhosis changes. Best of all, qFibrosis demonstrates superior performance to CPA on all counts. CONCLUSIONS qFibrosis can improve fibrosis scoring accuracy and throughput, thus allowing for reproducible and reliable analysis of efficacies of anti-fibrotic therapies in clinical research and practice.
Collapse
|
|
24
|
Snow KK, Bell MC, Stoddard AM, Curto TM, Wright EC, Dienstag JL. Processes to manage analyses and publications in a phase III multicenter randomized clinical trial. Trials 2014; 15:159. [PMID: 24886378 PMCID: PMC4040510 DOI: 10.1186/1745-6215-15-159] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 04/24/2014] [Indexed: 02/07/2023] Open
Abstract
Background The timely publication of findings in peer-reviewed journals is a primary goal of clinical research. In clinical trials, the processes leading to publication can be complex from choice and prioritization of analytic topics through to journal submission and revisions. As little literature exists on the publication process for multicenter trials, we describe the development, implementation, and effectiveness of such a process in a multicenter trial. Methods The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial included a data coordinating center (DCC) and clinical centers that recruited and followed more than 1,000 patients. Publication guidelines were approved by the steering committee, and the publications committee monitored the publication process from selection of topics to publication. Results A total of 73 manuscripts were published in 23 peer-reviewed journals. When manuscripts were closely tracked, the median time for analyses and drafting of manuscripts was 8 months. The median time for data analyses was 5 months and the median time for manuscript drafting was 3 months. The median time for publications committee review, submission, and journal acceptance was 7 months, and the median time from analytic start to journal acceptance was 18 months. Conclusions Effective publication guidelines must be comprehensive, implemented early in a trial, and require active management by study investigators. Successful collaboration, such as in the HALT-C trial, can serve as a model for others involved in multidisciplinary and multicenter research programs. Trial registration The HALT-C Trial was registered with clinicaltrials.gov (NCT00006164).
Collapse
Affiliation(s)
| | | | | | - Teresa M Curto
- New England Research Institutes, 9 Galen Street, Watertown, MA 02472, USA.
| | | | | |
Collapse
|
|
25
|
Baran B, Gulluoglu M, Soyer OM, Ormeci AC, Gokturk S, Evirgen S, Yesil S, Akyuz F, Karaca C, Demir K, Kaymakoglu S, Besisik F. Treatment failure may lead to accelerated fibrosis progression in patients with chronic hepatitis C. J Viral Hepat 2014; 21:111-20. [PMID: 24383924 DOI: 10.1111/jvh.12127] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Accepted: 05/01/2013] [Indexed: 01/16/2023]
Abstract
Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥ 2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01-1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81-19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.
Collapse
Affiliation(s)
- B Baran
- Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Murakami Y, Abe T, Hashiguchi A, Yamaguchi M, Saito A, Sakamoto M. Color correction for automatic fibrosis quantification in liver biopsy specimens. J Pathol Inform 2013; 4:36. [PMID: 24524002 PMCID: PMC3908497 DOI: 10.4103/2153-3539.124009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 11/04/2013] [Indexed: 12/31/2022] Open
Abstract
Context: For a precise and objective quantification of liver fibrosis, quantitative evaluations through image analysis have been utilized. However, manual operations are required in most cases for extracting fiber areas because of color variation included in digital pathology images. Aims: The purpose of this research is to propose a color correction method for whole slide images (WSIs) of Elastica van Gieson (EVG) stained liver biopsy tissue specimens and to realize automated operation of image analysis for fibrosis quantification. Materials and Methods: Our experimental dataset consisted of 38 WSIs of liver biopsy specimens collected from 38 chronic viral hepatitis patients from multiple medical facilities, stained with EVG and scanned at ×20 using a Nano Zoomer 2.0 HT (Hamamatsu Photonics K.K., Hamamatsu, Japan). Color correction was performed by modifying the color distribution of a target WSI so as to fit to the reference, where the color distribution was modeled by a set of two triangle pyramids. Using color corrected WSIs; fibrosis quantification was performed based on tissue classification analysis. Statistical Analysis Used: Spearman's rank correlation coefficients were calculated between liver stiffness measured by transient elastography and median area ratio of collagen fibers calculated based on tissue classification results. Results: Statistical analysis results showed a significant correlation r = 0.61-0.68 even when tissue classifiers were trained by using a subset of WSIs, while the correlation coefficients were reduced to r = 0.40-0.50 without color correction. Conclusions: Fibrosis quantification accompanied with the proposed color correction method could provide an objective evaluation tool for liver fibrosis, which complements semi-quantitative histologic evaluation systems.
Collapse
Affiliation(s)
- Yuri Murakami
- Global Scientific Information and Computing Center, Tokyo Institute of Technology, Meguro-ku, Tokyo, Japan
| | - Tokiya Abe
- Department of Pathology, School of Medicine, Keio University, Shinjyuku-ku, Tokyo, Japan
| | - Akinori Hashiguchi
- Department of Pathology, School of Medicine, Keio University, Shinjyuku-ku, Tokyo, Japan
| | - Masahiro Yamaguchi
- Global Scientific Information and Computing Center, Tokyo Institute of Technology, Meguro-ku, Tokyo, Japan
| | - Akira Saito
- Medical Solutions Division, BioMedical Imaging and Informatics Group, NEC Corporation, Minato-ku, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, School of Medicine, Keio University, Shinjyuku-ku, Tokyo, Japan
| |
Collapse
|
|
27
|
Venkatesh SK, Xu S, Tai D, Yu H, Wee A. Correlation of MR elastography with morphometric quantification of liver fibrosis (Fibro-C-Index) in chronic hepatitis B. Magn Reson Med 2013; 72:1123-9. [PMID: 24166665 DOI: 10.1002/mrm.25002] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 09/06/2013] [Accepted: 09/25/2013] [Indexed: 12/11/2022]
Abstract
PURPOSE We evaluated the correlation of MR Elastography (MRE) with morphometric assessment of liver fibrosis in chronic hepatitis B (CHB). METHODS Thirty-two patients with CHB underwent both MRE and a liver biopsy within a 6-month interval. MRE was performed using standard MRE sequence on a 1.5 Tesla clinical scanner. The liver stiffness (LS) was measured on automatically generated stiffness maps. Morphometric quantification of fibrosis of liver biopsies was performed using a semi-automated image analysis program and expressed as percentage area (Fibro-C-Index). Correlations between MRE, Fibro-C-Index, and histologic fibrosis stages were evaluated. Receiver operating curve (ROC) analysis of MRE and Fibro-C-index for differentiating fibrosis (≥F1), significant fibrosis (≥F2), advanced fibrosis (≥F3), and cirrhosis (F4) was performed. RESULTS MRE showed excellent correlation with both Fibro-C-Index (r = 0.78, 95% confidence interval [CI], 0.59-0.88, P < 0.001) and histologic staging (rho = 0.87, 95% CI, 0.72-0.94, P < 0.0001). Significant differences in MRE (P = 0.0001) and Fibro-C-Index (P = 0.003) among different stages of liver fibrosis was found. MRE and Fibro-C-Index had similar accuracies for differentiating fibrosis stages: ≥F1 (0.87 versus 0.81, P = 0.6), ≥F2 (0.95 versus 0.94, P = 0.78), ≥F3 (0.98 versus 0.96, P = 0.76), and F4 (1.00 versus 0.92, P = 0.10). CONCLUSION MRE is an excellent noninvasive indicator of liver fibrosis burden in CHB.
Collapse
|
|
28
|
Rosselli M, MacNaughtan J, Jalan R, Pinzani M. Beyond scoring: a modern interpretation of disease progression in chronic liver disease. Gut 2013; 62:1234-41. [PMID: 23645629 DOI: 10.1136/gutjnl-2012-302826] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Matteo Rosselli
- Division of Medicine, University College London, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | | | | | | |
Collapse
|
|
29
|
Alfaleh FZ, Alswat K, Helmy A, Al-hamoudi W, El-sharkawy M, Omar M, Shalaby A, Bedewi MA, Hadad Q, Ali SM, Alfaleh A, Abdo AA. The natural history and long-term outcomes in patients with chronic hepatitis C genotype 4 after interferon-based therapy. Liver Int 2013; 33:871-83. [PMID: 23490034 DOI: 10.1111/liv.12127] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Accepted: 01/16/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) genotype 4 (G4) infection is common in the Middle East. Post-treatment long-term outcomes have not been reported in these patients. This study evaluates these outcomes in patients after interferon-based therapy. PATIENTS AND METHODS A total of 157 patients were followed from June 2001 to February 2012. Descriptive and analytical statistics, cumulative outcomes and the independent predictors of disease progression were calculated. RESULTS The overall age was 48.0 ± 11.8 years, 75 (47.8%) were males and 53 (70.7%) of 75 who were genotyped had G4. The follow-up period was 63.8 ± 32.8 months. Sustained virological response (SVR) was achieved in 62 (39.5%) and 24 (45.3%) patients in the whole group and the G4 subgroup respectively. Among the whole cohort and the G4 subgroup, disease progressed in 59 (37.6%) and 21 (39.6%), respectively, with less progression in the SVR groups; 15/62 (24.2%) and 3/24 (12.5%) compared with non-responders; 44 (46.3%) and 18 (62.1%) with P = 0.01 and 0.001 respectively. Multivariate logistic regression analysis showed that having diabetes mellitus (P = 0.03), higher baseline APRI score (P = 0.00) and non-SVR (P = 0.00) were independent predictors of disease progression. G4 patients showed similar results, but 'non-SVR' (P = 0.00) was the only independent predictor of progression. Eight patients died and four developed HCC all among the non-SVR group only. CONCLUSIONS This study describes, for the first time, the natural history and demonstrates the beneficial long-term effects of interferon-based therapy in HCV G4 patients.
Collapse
Affiliation(s)
- Faleh Z Alfaleh
- Gastroenterology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Abe T, Hashiguchi A, Yamazaki K, Ebinuma H, Saito H, Kumada H, Izumi N, Masaki N, Sakamoto M. Quantification of collagen and elastic fibers using whole-slide images of liver biopsy specimens. Pathol Int 2013; 63:305-310. [PMID: 23782332 DOI: 10.1111/pin.12064] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 05/02/2013] [Indexed: 12/19/2022]
Abstract
Histological evaluation of fibrosis after a liver biopsy is crucial for evaluating the pathology of patients with chronic liver disease. Previous studies have reported quantitative analyses of fibrosis using images of collagen-stained sections. However, analysis of these studies requires manual selection of the region of interest. In addition, the quantification of elastic fibers is not considered. The present study was conducted in order to measure both the collagen and elastic fiber area ratios using Elastica van Gieson-stained whole-slide images (WSIs) of liver biopsy specimens. High-resolution WSIs provide precise color classification, enabling accurate detection of even fine collagen and elastic fibers. To minimize the influence of pre-existing fibrous tissue, median area ratios of the collagen and elastic fibers were independently calculated from the image tiles of the WSIs. These median area ratios were highly concordant with area ratios after the pre-existing fibrous tissues were manually trimmed from the WSI. Further, these median area ratios were correlated with liver stiffness as measured by transient elastography (collagen: r = 0.73 [P < 0.01], elastic: r = 0.53 [P < 0.01]). Our approach to quantifying liver fibrosis will serve as an effective tool to evaluate liver diseases in routine practice.
Collapse
Affiliation(s)
- Tokiya Abe
- Department of Pathology, School of Medicine, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
The end point of liver fibrosis in almost all chronic liver diseases is cirrhosis. Progression to cirrhosis is accompanied by vascular remodeling and regeneration with important functional and hemodynamic consequences that include development of portal hypertension and eventually decompensation and death. Fibrosis can regress following successful treatment of the underlying disease. However, most common fibrosis scoring systems are not equipped for assessing this aspect. Nodule size, septal width and fibrosis area seem to correlate with disease severity and progression in cirrhosis. Classification systems based on nodule size, septal width, and fibrosis area need to be further validated.
Collapse
Affiliation(s)
- Pierre Bedossa
- Department of Pathology, Beaujon Hospital and Clichy, University Denis Diderot, Clichy, Paris 7, France.
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA
| |
Collapse
|
|
32
|
Cozen ML, Ryan JC, Shen H, Lerrigo R, Yee RM, Sheen E, Wu R, Monto A. Nonresponse to interferon-α based treatment for chronic hepatitis C infection is associated with increased hazard of cirrhosis. PLoS One 2013; 8:e61568. [PMID: 23637856 PMCID: PMC3636226 DOI: 10.1371/journal.pone.0061568] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 03/08/2013] [Indexed: 12/17/2022] Open
Abstract
Background The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored. Methods and Findings We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18–4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50–23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients. Conclusion These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients.
Collapse
Affiliation(s)
- Myrna L Cozen
- Department of Medicine, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for Fibrotic Diseases: Nearing the Starting Line. Sci Transl Med 2013; 5:167sr1. [DOI: 10.1126/scitranslmed.3004700] [Citation(s) in RCA: 480] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
|
|
34
|
Calès P, Zarski JP, Chapplain JM, Bertrais S, Sturm N, Michelet C, Babany G, Chaigneau J, Eddine Charaf M. Fibrosis progression under maintenance interferon in hepatitis C is better detected by blood test than liver morphometry. J Viral Hepat 2012; 19:e143-53. [PMID: 22239512 DOI: 10.1111/j.1365-2893.2011.01531.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
We evaluated whether quantitative measurements of liver fibrosis with recently developed diagnostics outperform histological staging in detecting natural or interferon-induced changes. We compared Metavir staging, morphometry (area and fractal dimension) and six blood tests in 157 patients with chronic hepatitis C from two trials testing maintenance interferon for 96 weeks. Paired liver biopsies and blood tests were available for 101 patients, and there was a significant improvement in Metavir activity and a significant increase in blood tests reflecting fibrosis quantity in patients treated with interferon when compared with controls - all per cent changes in histological fibrosis measures were significantly increased in F1 vs F2-4 stages only in the interferon group. For the whole population studied between weeks 0 and 96, there was significant progression only in the area of fibrosis (AOF) (P = 0.026), FibroMeter (P = 0.020) and CirrhoMeter (P = 0.003). With regards to dynamic reproducibility, agreement was good (r(ic) ≥ 0.72) only for Metavir fibrosis score, FibroMeter and CirrhoMeter. The per cent change in AOF was significantly higher than that of fractal dimension (P = 0.003) or Metavir fibrosis score (P = 0.015). CirrhoMeter was the only blood test with a change significantly higher than that of AOF (P = 0.039). AOF and two blood tests, reflecting fibrosis quantity, have high sensitivity and/or reproducibility permitting the detection of a small progression in liver fibrosis over two years. A blood test reflecting fibrosis quantity is more sensitive and reproducible than morphometry. The study also shows that maintenance interferon does not improve fibrosis, whatever its stage.
Collapse
Affiliation(s)
- P Calès
- Liver-Gastroenterology Department, University Hospital, Angers, France.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Ishibashi H, Maruyama H, Takahashi M, Shimada T, Kamesaki H, Fujiwara K, Imazeki F, Yokosuka O. Demonstration of intrahepatic accumulated microbubble on ultrasound represents the grade of hepatic fibrosis. Eur Radiol 2011; 22:1083-90. [PMID: 22207268 PMCID: PMC3321145 DOI: 10.1007/s00330-011-2346-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Revised: 10/30/2011] [Accepted: 11/09/2011] [Indexed: 11/12/2022]
Abstract
Objectives To examine the feasibility of perflubutane-based ultrasound for grading hepatic fibrosis. Methods This prospective study included 202 subjects; main study (controls:33, F0–1:35, F2:26, F3:23, cirrhosis:29) and subsequent study (controls:16, F0–1:7, F2:20, F3:7, cirrhosis:6). Diagnostic abilities for assessing fibrosis grade were compared between contrast findings and FIB4 (age × AST/[platelet count × ALT0.5]). Results High-power emission produced an intrahepatic band-like structure, and the three-layer appearance was less frequent and monolayer appearance was more frequent in cirrhosis than controls/chronic hepatitis (P < 0.0001). Intensity difference at 15-min phase showed most significant correlation with fibrosis grade (ρ = 0.79, P < 0.0001), and the best areas under the receiver operating characteristic curves are 0.88 for marked fibrosis, 0.95 for advanced fibrosis and 0.97 for cirrhosis, which were significantly higher than those of FIB4, 0.85 for marked fibrosis, 0.89 for advanced fibrosis and 0.90 for cirrhosis. Sensitivity, specificity and efficiency of the intensity difference were 88%, 72% and 81% for marked fibrosis, 85%, 91% and 89% for advanced fibrosis and 97%, 90% and 91% for cirrhosis, respectively. The subsequent study validated the main study results; significant correlation between the intensity difference and the fibrosis grade (ρ = 0.73–0.77, P < 0.0001). Conclusions Perflubutane-based ultrasound accurately predicts the grade of hepatic fibrosis. Key Points • The behaviour of intrahepatic microbubbles depends on the severity of hepatic fibrosis. • Layer enhancement pattern simply represents the degree of chronic liver disease. • Parenchymal intensity change due to high-power emission predicts the hepatic fibrosis grade.
Collapse
Affiliation(s)
- Hiroyuki Ishibashi
- Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba 260-8670, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
A case-control histological study on the effects of phlebotomy in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2011; 23:1178-84. [PMID: 22002003 DOI: 10.1097/meg.0b013e328349923c] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE The aim of this study was to assess the actual effectiveness of long-term phlebotomy by comparing histological improvement (HI) in 69 Caucasian HCV-RNA-positive CHC patients undergoing phlebotomy or receiving an interferon-based therapy without virological response [nonresponders to interferon therapy(IBT-NR)]. METHODS HI was defined by at least one point reduction of the staging score or, in the case of unchanged stage, by at least two points reduction of the grading score (Knodel's Activity Index) and was retrospectively evaluated by comparing two consecutive (56 ± 28 months apart) liver biopsies from 30 phlebotomized and 39 IBT-NR patients. RESULTS HI was observed in 15 of 30 (50%) patients treated with phlebotomy and in six of 39 (15%) IBT-NR subjects (P=0.002). Furthermore, AST, ALT, and GGT serum levels were significantly reduced only in phlebotomized patients (P ≤ 0.003) at the time of the second biopsy. Univariate and multivariate analysis showed that histological grading score before therapy (P=0.001) and phlebotomy (P=0.002) were independently predictors of HI. CONCLUSION HI induced by long-term phlebotomy effectively exceeds that spontaneously occurring in patients IBT-NR confirming the efficacy of iron depletion in attenuating CHC progression when other therapies have failed.
Collapse
|
|
37
|
Guha IN, Myers RP, Patel K, Talwalkar JA. Biomarkers of liver fibrosis: what lies beneath the receiver operating characteristic curve? Hepatology 2011; 54:1454-62. [PMID: 21725995 DOI: 10.1002/hep.24515] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 06/17/2011] [Indexed: 12/19/2022]
Abstract
Noninvasive biomarkers of liver fibrosis represent an intense area of research with the goals of improving patient care, disease stratification, and aiding the development of future antifibrotic therapies. Despite the rapid progress in recent years, there remain questions about how diagnostic studies are designed, statistical methods to account for spectrum bias, clinically relevant thresholds of fibrosis that should be delineated, how diagnostics can be improved, and strengthening the reference test to judge emerging biomarkers. This review discusses the current methods to address these issues and where further progress is needed.
Collapse
Affiliation(s)
- Indra Neil Guha
- Liver Unit, University of Nottingham, NIHR NDDC BRU, Nottingham, UK.
| | | | | | | |
Collapse
|
|
38
|
Hoefs JC, Shiffman ML, Goodman ZD, Kleiner DE, Dienstag JL, Stoddard AM. Rate of progression of hepatic fibrosis in patients with chronic hepatitis C: results from the HALT-C Trial. Gastroenterology 2011; 141:900-908.e1-2. [PMID: 21699796 PMCID: PMC3773843 DOI: 10.1053/j.gastro.2011.06.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 05/13/2011] [Accepted: 06/03/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS The gradual accumulation of hepatic fibrosis in chronic liver disease results in clinical complications. The rate of hepatic fibrosis score progression (RFSP) in predicting clinical outcomes was assessed by extending the 4-year Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial to include preenrollment liver biopsies. METHODS The RFSP was calculated from the linear regression slope of Ishak fibrosis score vs time in 457 patients with liver biopsies (≥10-mm length) prior to the HALT-C Trial (575 biopsies) plus 1101 on-study biopsies (total 1676 biopsies). Individual slopes were calculated if duration from first to last biopsy was > 4 years. RESULTS The RFSP as average fibrosis score vs average time in intervals (0-3 and >3 years prestudy, screening, month 24 and 48 on-study) in 455 patients in cohorts of baseline Ishak score ranged from 0.005 with Ishak score 2 to 0.124 with Ishak 6. The RFSP in individual patients (-0.35 to +0.97 Ishak units/year) had a mean of 0.12 ± 0.23 in 344 patients with prestudy and on-study biopsies (group A) and only 0.17 ± 0.22 in 169 with prestudy and screening biopsies (group B). Group A patients with RFSP slope ≥ 0.2 (95 patients, 27.6%) had higher 7-year cumulative rates of non-hepatocellular carcinoma outcomes (46% vs 8%, respectively) and with a hepatocellular carcinoma (10% vs 3%, respectively) than RFSP slope < 02 (249 patients, 72.4%) (P < .0001). RFSP and screening Ishak score correlated independently (P <.0001) with clinical outcomes in multivariate analysis. CONCLUSIONS Rapid RFSP (>0.2), which occurred in 26.7% of HALT-C Trial patients, correlated strongly with clinical outcomes.
Collapse
Affiliation(s)
- John C. Hoefs
- Division of Gastroenterology, University of California - Irvine, Irvine, CA
| | | | | | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
| | - Jules L. Dienstag
- Gastrointestinal Unit (Medical Services), Massachusetts General Hospital, Boston, MA and the Department of Medicine, Harvard Medical School, Boston, MA
| | | | | |
Collapse
|
|
39
|
Krawczyk M, Grünhage F, Zimmer V, Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease. J Hepatol 2011; 55:299-306. [PMID: 21168459 DOI: 10.1016/j.jhep.2010.10.042] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2010] [Revised: 10/17/2010] [Accepted: 10/25/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Recent genome-wide association studies have identified the variant p.I148M of the adiponutrin gene PNPLA3 as a risk factor for developing severe forms of non-alcoholic and alcoholic liver diseases. The risk allele confers an increased risk for fatty liver disease and elevated serum aminotransferase activities reflecting liver injury. In the current elastography-based study, we investigate variant adiponutrin as genetic determinant of liver fibrosis, the hallmark of all chronic liver diseases. METHODS In this observational cross-sectional study, we staged 899 patients with different chronic liver diseases non-invasively by transient elastography (Fibroscan) and genotyped them for variant adiponutrin (rs738409) by PCR-based assays. A subgroup of 229 patients consented to percutaneous liver biopsy, validating the accuracy of elastography in staging fibrosis (ρ=0.743, p<0.01). RESULTS Carriers of distinct p.I148M adiponutrin genotypes display significant (p=0.017) differences in liver stiffness determined by elastography. In particular, individuals carrying the allele [G] are at higher risk of developing liver cirrhosis defined by stiffness values ≥13.0kPa (OR=1.56, p=0.005). Of note, the PNPLA3 risk variant advances fibrosis in the total cohort as well as in the subgroups of patients with viral hepatitis and non-viral liver diseases and contributes 16% of the total cirrhosis risk. CONCLUSIONS The adiponutrin risk variant is a common genetic determinant of progressive liver fibrosis. Our results underpin non-invasive follow-up for individuals with chronic liver disease at-risk for developing advanced fibrosis and cirrhosis.
Collapse
Affiliation(s)
- Marcin Krawczyk
- Department of Medicine II, Saarland University Hospital, Homburg, Germany
| | | | | | | |
Collapse
|
|
40
|
Comparison of noninvasive models of fibrosis in chronic hepatitis B. Hepatol Int 2011; 6:457-67. [DOI: 10.1007/s12072-011-9296-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2011] [Accepted: 06/22/2011] [Indexed: 12/19/2022]
|
|
41
|
Abstract
Chronic liver injuries of different etiologies eventually lead to fibrosis, a scarring process associated with increased and altered deposition of extracellular matrix in the liver. Progression of fibrosis has a major worldwide clinical impact due to the high number of patients affected by chronic liver disease which can lead to severe complications, expensive treatment, a possible need for liver transplantation, and death. Liver fibrogenesis is characterized by activation of hepatic stellate cells and other extracellular matrix producing cells. Liver fibrosis may regress following specific therapeutic interventions. Other than removing agents causing chronic liver damage, no antifibrotic drug is currently available in clinical practice. The extent of liver fibrosis is variable between individuals, even after controlling for exogenous factors. Thus, host genetic factors are considered to play an important role in the process of liver scarring. Until recently it was believed that this process was irreversible. However, emerging experimental and clinical evidence is starting to show that even cirrhosis in its early stages is potentially reversible.
Collapse
Affiliation(s)
- Mona H Ismail
- Department of Internal Medicine, Division of Gastroenterology, King Fahad University Hospital, Al-Khobar, Saudi Arabia
| | - Massimo Pinzani
- Dipartimento di Medicina Interna Center for Research, High Education and Transfer, Università degli Studi di Firenze, Florence, Italy
| |
Collapse
|
|
42
|
Ismail MH, Pinzani M. Reversal of hepatic fibrosis: pathophysiological basis of antifibrotic therapies. HEPATIC MEDICINE : EVIDENCE AND RESEARCH 2011. [PMID: 24367223 DOI: 10.2147/hmer.s905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Chronic liver injuries of different etiologies eventually lead to fibrosis, a scarring process associated with increased and altered deposition of extracellular matrix in the liver. Progression of fibrosis has a major worldwide clinical impact due to the high number of patients affected by chronic liver disease which can lead to severe complications, expensive treatment, a possible need for liver transplantation, and death. Liver fibrogenesis is characterized by activation of hepatic stellate cells and other extracellular matrix producing cells. Liver fibrosis may regress following specific therapeutic interventions. Other than removing agents causing chronic liver damage, no antifibrotic drug is currently available in clinical practice. The extent of liver fibrosis is variable between individuals, even after controlling for exogenous factors. Thus, host genetic factors are considered to play an important role in the process of liver scarring. Until recently it was believed that this process was irreversible. However, emerging experimental and clinical evidence is starting to show that even cirrhosis in its early stages is potentially reversible.
Collapse
Affiliation(s)
- Mona H Ismail
- Department of Internal Medicine, Division of Gastroenterology, King Fahad University Hospital, Al-Khobar, Saudi Arabia
| | - Massimo Pinzani
- Dipartimento di Medicina Interna Center for Research, High Education and Transfer, Università degli Studi di Firenze, Florence, Italy
| |
Collapse
|
|
43
|
Manousou P, Dhillon AP, Isgro G, Calvaruso V, Luong TV, Tsochatzis E, Xirouchakis E, Kalambokis G, Cross TJ, Rolando N, O'Beirne J, Patch D, Thornburn D, Burroughs AK. Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation. Liver Transpl 2011; 17:178-88. [PMID: 21280191 DOI: 10.1002/lt.22209] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Clinical outcomes of recurrent hepatitis C virus after liver transplantation are difficult to predict. We evaluated collagen proportionate area (CPA), a quantitative histological index, at 1 year with respect to the first episode of clinical decompensation. Patients with biopsies at 1 year after liver transplantation were evaluated by Ishak stage/grade, and biopsy samples stained with Sirius red for digital image analysis were evaluated for CPA. Cox regression was used to evaluate variables associated with first appearance of clinical decompensation. Receiver operating characteristic (ROC) curves were also used. A total of 135 patients with median follow-up of 76 months were evaluated. At 1 year, median CPA was 4.6% (0.2%-36%) and Ishak stage was 0-2 in 101 patients, 3-4 in 23 patients, and 5-6 in 11 patients. Decompensation occurred in 26 (19.3%) at a median of 61 months (15-138). Univariately, CPA, tacrolimus monotherapy, and Ishak stage/grade at 1 year were associated with decompensation; upon multivariate analysis, only CPA was associated with decompensation (P = 0.010; Exp(B) = 1.169; 95%CI, 1.037-1.317). Area under the ROC curve was 0.97 (95%CI, 0.94-0.99). A cutoff value of 6% of CPA had 82% sensitivity and 95% specificity for decompensation. In the 89 patients with hepatic venous pressure gradient (HVPG) measurement, similar results were obtained. When both cutoffs of CPA > 6% and HVPG ≥ 6 mm Hg were used, all patients decompensated. Thus, CPA at 1-year biopsy after liver transplantation was highly predictive of clinical outcome in patients infected with hepatitis C virus who underwent transplantation, better than Ishak stage or HVPG.
Collapse
Affiliation(s)
- Pinelopi Manousou
- The Royal Free Sheila Sherlock Liver Centre and Division of Surgery and Interventional Sciences, University College London, London, UK
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Freedman ND, Curto TM, Morishima C, Seeff LB, Goodman ZD, Wright EC, Sinha R, Everhart JE. Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther 2011; 33:127-37. [PMID: 21083592 PMCID: PMC3490214 DOI: 10.1111/j.1365-2036.2010.04503.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear. AIM To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment. METHODS Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes. RESULTS At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33-1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes. CONCLUSIONS Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Collapse
Affiliation(s)
- N D Freedman
- Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Abstract
Histologic evaluation of the liver is a major component in the medical management and treatment algorithm of patients with chronic hepatitis B (HBV) and chronic hepatitis C (HCV). Liver biopsy in these patients remains the gold standard, and decisions on treatment are often predicated on the degree of damage and stage of fibrosis. This article outlines the clinical course and serologic diagnosis of HBV and HCV for the clinician and the pathologist, who together have a close working relationship in managing patients with acute and chronic liver disease. The salient histologic features are elucidated in an attempt to provide the clinician with an understanding of the basic histopathology underlying chronic HCV and HBV.
Collapse
Affiliation(s)
- M Isabel Fiel
- The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, Mount Sinai School of Medicine, Box 1194, 1468 Madison Avenue, New York, NY 10029, USA.
| |
Collapse
|
|
46
|
Ge F, Lobdell H, Zhou S, Hu C, Berk PD. Digital analysis of hepatic sections in mice accurately quantitates triglycerides and selected properties of lipid droplets. Exp Biol Med (Maywood) 2010; 235:1282-6. [PMID: 20975077 DOI: 10.1258/ebm.2010.010095] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
We describe a method for the histologic evaluation of lipid accumulation in the livers of various mouse models of hepatic steatosis based on quantitative digital analysis of Oil Red O (ORO) accumulation in fresh-frozen hepatic sections. The process involves two principal steps: identification and digital photographic imaging of areas appropriate for analysis, followed by digital determination of the fraction of the identified area (Area Fraction) exhibiting ORO staining. The Area Fraction, designated the Digital Steatosis Score, is a valuable aspect of the histologic assessment of the liver, especially in various forms of alcoholic and non-alcoholic liver diseases. The method is rapid, requiring ∼3 min per specimen, and highly reproducible, avoiding the inevitably subjective, semi-quantitative evaluation of lipid content inherent in visual steatosis scoring systems. In normal mice and in six different mouse models of fatty liver, the Area Fraction was highly correlated with hepatic triglyceride content (P < 0.01). The coefficient of variation of repeated determinations of the Area Fraction by two different observers was ±6.4%. If made available in clinical settings, rapid, accurate quantitation of liver triglycerides by this method could be very useful in specific conditions such as assessment of donor livers for transplantation.
Collapse
Affiliation(s)
- Fengxia Ge
- The Department of Medicine, Divisions of Digestive & Liver Disease, Columbia University Medical Center, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
| | | | | | | | | |
Collapse
|
|
47
|
Abstract
Continued elucidation of the mechanisms of hepatic fibrosis has yielded a comprehensive and nuanced portrait of fibrosis progression and regression. The paradigm of hepatic stellate cell (HSC) activation remains the foundation for defining events in hepatic fibrosis and has been complemented by progress in a number of new areas. Cellular sources of extracellular matrix beyond HSCs have been identified. In addition, the role of chemokine, adipokine, neuroendocrine, angiogenic and NAPDH oxidase signaling in the pathogenesis of hepatic fibrosis has been uncovered, as has the contribution of extracellular matrix stiffness to fibrogenesis. There is also increased awareness of the contribution of innate immunity and greater understanding of the complexity of gene regulation in HSCs and myofibroblasts. Finally, both apoptosis and senescence have been recognized as orchestrated programs that eliminate fibrogenic cells during resolution of liver fibrosis. Ironically, the progress that has been made has highlighted the growing disparity between advances in the experimental setting and their translation into new diagnostic tools and treatments. As a result, focus is shifting towards overcoming key translational challenges in order to accelerate the development of new therapies for patients with chronic liver disease.
Collapse
|
|
48
|
Abstract
PURPOSE OF REVIEW Improved understanding of the pathophysiology of fibrosis and recent technological advances have resulted in the development of several serum biomarkers and imaging tools as noninvasive alternatives to biopsy. This review highlights some of the recent advances and potential application of these tools in clinical practice. RECENT FINDINGS Several newer approaches have been used to improve the semiquantitative histological assessment of fibrosis in relation to biomarker development. These include statistical considerations, smooth muscle actin morphometry, and emerging microscopy techniques to quantify fibrillar collagen. Serum marker panels, initially developed for determining disease stage in chronic hepatitis C infection, have now been adapted for use in nonalcoholic fatty liver disease. Genetic markers of disease progression have been validated, and newer proteomic technologies are increasingly being applied towards biomarker discovery. A sequential approach or the combination of serum markers and transient elastography is able to significantly reduce the need for biopsy for the diagnosis of cirrhosis. Serum markers also appear to provide useful prognostic information in end-stage liver disease. Newer imaging methods and breath tests require further validation, but appear promising adjunctive techniques for prediction of advanced stage fibrosis and providing functional assessment. SUMMARY Current noninvasive tools have potential diagnostic and prognostic utility for end-stage liver disease. Adapting these methods into clinical practice remains a challenge.
Collapse
|