|
1
|
Yeung V, Boychev N, Kanu LN, Ng V, Ross AE, Hutcheon AEK, Ciolino JB. Proteomic Characterization of Corneal Epithelial and Stromal Cell-Derived Extracellular Vesicles. Int J Mol Sci 2024; 25:10338. [PMID: 39408670 PMCID: PMC11477500 DOI: 10.3390/ijms251910338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Communication between the different layers of the cornea (epithelium and stroma) is a complex, yet crucial element in the corneal healing process. Upon corneal injury, it has been reported that the bi-directional cross talk between the epithelium and stroma via the vesicular secretome, namely, extracellular vesicles (EVs), can lead to accelerated wound closure upon injury. However, the distinct protein markers of EVs derived from human corneal epithelial (HCE) cells, keratocytes (HCKs), fibroblasts (HCFs), and myofibroblasts (HCMs) remain poorly understood. All EVs were enriched for CD81 and showed increased expression levels of ITGAV and FN1 in HCM-EVs compared to HCE- and HCF-EVs. All EVs were negative for GM130 and showed minimal differences in biophysical properties (particle concentration, median particle size, and zeta potential). At the proteomic level, we show that HCM-EVs are enriched with proteins associated with fibrosis pathways, such as COL6A1, COL6A2, MMP1, MMP2, TIMP1, and TIMP2, compared to HCE-, HCK-, and HCF-EVs. Interestingly, HCE-EVs express proteins involved with the EIF-2 signaling pathway (stress-induced signals to regulate mRNA translation), such as RPS21, RALB, EIF3H, RALA, and others, compared to HCK-, HCF-, and HCM-EVs. In this study, we isolated EVs from cell-conditioned media from HCE, HCKs, HCFs, and HCMs and characterized their biophysical and protein composition by Western blot, nanoparticle tracking analysis, and proteomics. This study supports the view that EVs from the corneal epithelium and stroma have a distinct molecular composition and may provide novel protein markers to distinguish the difference between HCE-, HCK-, HCF-, and HCM-EVs.
Collapse
Affiliation(s)
- Vincent Yeung
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA; (N.B.); (L.N.K.); (V.N.); (A.E.R.); (A.E.K.H.); (J.B.C.)
| | | | | | | | | | | | | |
Collapse
|
|
2
|
Hu X, Liu W, Liu J, Wang B, Qin X. Research advances in serum chitinase-3-like protein 1 in liver fibrosis. Front Med (Lausanne) 2024; 11:1372434. [PMID: 38962736 PMCID: PMC11219575 DOI: 10.3389/fmed.2024.1372434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 05/31/2024] [Indexed: 07/05/2024] Open
Abstract
While liver fibrosis remains a serious, progressive, chronic liver disease, and factors causing damage persist, liver fibrosis may develop into cirrhosis and liver cancer. However, short-term liver fibrosis is reversible. Therefore, an early diagnosis of liver fibrosis in the reversible transition phase is important for effective treatment of liver diseases. Chitinase-3-like protein 1 (CHI3L1), an inflammatory response factor that participates in various biological processes and is abundant in liver tissue, holds promise as a potential biomarker for liver diseases. Here, we aimed to review research developments regarding serum CHI3L1 in relation to the pathophysiology and diagnosis of liver fibrosis of various etiologies, providing a reference for the diagnosis, treatment, and prognosis of liver diseases.
Collapse
Affiliation(s)
- Xingwei Hu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, China
| | - Wenhan Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, China
| | - Jianhua Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, China
| | - Bojian Wang
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, China
| | - Xiaosong Qin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, China
| |
Collapse
|
|
3
|
Liebold I, Al Jawazneh A, Casar C, Lanzloth C, Leyk S, Hamley M, Wong MN, Kylies D, Gräfe SK, Edenhofer I, Aranda-Pardos I, Kriwet M, Haas H, Krause J, Hadjilaou A, Schromm AB, Richardt U, Eggert P, Tappe D, Weidemann SA, Ghosh S, Krebs CF, A-Gonzalez N, Worthmann A, Lohse AW, Huber S, Rothlin CV, Puelles VG, Jacobs T, Gagliani N, Bosurgi L. Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages. Science 2024; 384:eabo7027. [PMID: 38574142 DOI: 10.1126/science.abo7027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 02/26/2024] [Indexed: 04/06/2024]
Abstract
Macrophages are functionally heterogeneous cells essential for apoptotic cell clearance. Apoptotic cells are defined by homogeneous characteristics, ignoring their original cell lineage identity. We found that in an interleukin-4 (IL-4)-enriched environment, the sensing of apoptotic neutrophils by macrophages triggered their tissue remodeling signature. Engulfment of apoptotic hepatocytes promoted a tolerogenic phenotype, whereas phagocytosis of T cells had little effect on IL-4-induced gene expression. In a mouse model of parasite-induced pathology, the transfer of macrophages conditioned with IL-4 and apoptotic neutrophils promoted parasitic egg clearance. Knockout of phagocytic receptors required for the uptake of apoptotic neutrophils and partially T cells, but not hepatocytes, exacerbated helminth infection. These findings suggest that the identity of apoptotic cells may contribute to the development of distinct IL-4-driven immune programs in macrophages.
Collapse
Affiliation(s)
- Imke Liebold
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Amirah Al Jawazneh
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Christian Casar
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Bioinformatics Core, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Clarissa Lanzloth
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Stephanie Leyk
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Madeleine Hamley
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Milagros N Wong
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Dominik Kylies
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefanie K Gräfe
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ilka Edenhofer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Marie Kriwet
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Jenny Krause
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandros Hadjilaou
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andra B Schromm
- Division of Immunobiophysics, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Ulricke Richardt
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Petra Eggert
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Dennis Tappe
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Sören A Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sourav Ghosh
- Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
| | - Christian F Krebs
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Anna Worthmann
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Carla V Rothlin
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Victor G Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas Jacobs
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Nicola Gagliani
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lidia Bosurgi
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
4
|
Kotani K, Kawada N. Recent Advances in the Pathogenesis and Clinical Evaluation of Portal Hypertension in Chronic Liver Disease. Gut Liver 2024; 18:27-39. [PMID: 37842727 PMCID: PMC10791512 DOI: 10.5009/gnl230072] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 06/16/2023] [Accepted: 06/25/2023] [Indexed: 10/17/2023] Open
Abstract
In chronic liver disease, hepatic stellate cell activation and degeneration of liver sinusoidal endothelial cells lead to structural changes, which are secondary to fibrosis and the presence of regenerative nodules in the sinusoids, and to functional changes, which are related to vasoconstriction. The combination of such changes increases intrahepatic vascular resistance and causes portal hypertension. The subsequent increase in splanchnic and systemic hyperdynamic circulation further increases the portal blood flow, thereby exacerbating portal hypertension. In clinical practice, the hepatic venous pressure gradient is the gold-standard measure of portal hypertension; a value of ≥10 mm Hg is defined as clinically significant portal hypertension, which is severe and is associated with the risk of liver-related events. Hepatic venous pressure gradient measurement is somewhat invasive, so evidence on the utility of risk stratification by elastography and serum biomarkers is needed. The various stages of cirrhosis are associated with different outcomes. In viral hepatitis-related cirrhosis, viral suppression or elimination by nucleos(t)ide analog or direct-acting antivirals results in recompensation of liver function and portal pressure. However, careful follow-up should be continued, because some cases have residual clinically significant portal hypertension even after achieving sustained virologic response. In this study, we reviewed the current and future prospects for portal hypertension.
Collapse
Affiliation(s)
- Kohei Kotani
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| |
Collapse
|
|
5
|
Ciardullo S, Perseghin G. Advances in fibrosis biomarkers in nonalcoholic fatty liver disease. Adv Clin Chem 2022; 106:33-65. [PMID: 35152974 DOI: 10.1016/bs.acc.2021.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult world population and the degree of liver fibrosis represents the best predictor of the development of liver-related outcomes. Easily applicable and well performing non-invasive fibrosis tests can overcome the limitations of liver biopsy and are of paramount importance to identify at-risk subjects in clinical practice. While tests with optimal performance and ease of use do not exist at this stage, available markers can be divided in three broad groups: simple serum tests, complex serum tests and elastographic methods. Simple scores (such as Fibrosis-4 and NAFLD Fibrosis Score) are based on readily available biochemical data and clinical features, while complex/proprietary tests (such as Fibrotest, Enhanced Liver Fibrosis and Hepascore) directly measure markers of fibrogenesis and fibrolysis, but have higher costs. Elastography techniques estimate the degree of fibrosis from liver stiffness and are based on either ultrasound or magnetic resonance (MR) imaging. MR elastography has better performance compared with sonographic techniques and is not affected by obesity and inflammation, but is highly costly and less available. In general, non-invasive tests are able to exclude the presence of fibrosis, but their positive predictive value is low to moderate and they lead to a high number of indeterminate results. In this context, a combination of different tests might increase accuracy while reducing gray-zone results. Their ability to predict future events and response to treatment is suboptimal and needs to be studied further. Finally, recent studies have tried different approaches, spanning from "omics" to the microbiome and micro-RNAs, with some promising results.
Collapse
Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Gianluca Perseghin
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy.
| |
Collapse
|
|
6
|
Proteomic Analysis of Human Serum for Patients at Different Pathological Stages of Hepatic Fibrosis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:3580090. [PMID: 34877354 PMCID: PMC8645358 DOI: 10.1155/2021/3580090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022]
Abstract
Background Hepatic fibrosis is a severe liver disease that has threatened human health for a long time. In order to undergo timely and adequate therapy, it is important for patients to obtain an accurate diagnosis of fibrosis. Laboratory inspection methods have been efficient in distinguishing between advanced hepatic fibrosis stages (F3, F4), but the identification of early stages of fibrosis has not been achieved. The development of proteomics may provide us with a new direction to identify the stages of fibrosis. Methods We established serum proteomic maps for patients with hepatic fibrosis at different stages and identified differential expression of proteins between fibrosis stages through ultra-high-performance liquid chromatography tandem mass spectrometry proteomic analysis. Results From the proteomic profiles of the serum of patients with different stages of liver fibrosis, a total of 1,338 proteins were identified. Among three early fibrosis stages (control, F1, and F2), 55 differential proteins were identified, but no proteins simultaneously exhibited differential expression between control, F1, and F2. Differential proteins were detected in the comparison between different fibrosis stages. Significant differences were found between advanced fibrosis stages (F2-vs.-F3 and F3-vs.-F4) through a series of statistical analysis, including hierarchical clustering, Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes pathway, and protein-protein interaction network analysis. The differential proteins identified by GO annotation were associated with biological processes (mainly platelet degranulation and cell adhesion), molecular functions, and cellular components. Conclusions All potential biomarkers identified between the stages of fibrosis could be key points in determining the fibrosis staging. The differences between early stages may provide a useful reference in addressing the challenge of early fibrosis staging.
Collapse
|
|
7
|
Kang Q, Xu J, Luo H, Tan N, Chen H, Cheng R, Pan J, Han Y, Yang Y, Liu D, Xi H, Yu M, Xu X. Direct antiviral agent treatment leads to rapid and significant fibrosis regression after HCV eradication. J Viral Hepat 2021; 28:1284-1292. [PMID: 34105867 DOI: 10.1111/jvh.13558] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/22/2021] [Accepted: 05/21/2021] [Indexed: 12/14/2022]
Abstract
Limited data are currently available regarding fibrosis progression after hepatitis C virus (HCV) eradication. The goal of the present study was to evaluate the effects of HCV eradication on liver stiffness measurements (LSMs), aspartate aminotransferase/platelet ratio index (APRI) scores, fibrosis-4(FIB-4) scores, chitinase-3-like protein 1 (CHI3L1) levels and Golgi protein 73 (GP73) levels in patients with chronic hepatitis C (CHC). One hundred and two patients who received direct antiviral agents (DAAs) therapy at Peking University First Hospital participated in the present study. Clinical information and serum samples were collected at baseline, at the end of treatment (EOT), and at the weeks 12, 24 and 48 after treatment (W12, W24 and W48, respectively). Of the 102 patients, 51 had mild-to-moderate fibrosis (F1/F2), and 51 had advanced fibrosis (F3/F4). The LSMs improved for all patients at the EOT, with observed changes of 2.85 kPa, and the decrease continued to W12. However, a more pronounced improvement was noted for the advanced fibrosis (F3/F4) patients, with a change of 3.6 kPa from baseline to the EOT. Significant decreases between the baseline and EOT measurements were observed in the APRI and FIB-4 scores [0.64 (0.39-1.21) vs. 0.35 (0.26-0.52), p<0.001; 2.53 (1.30-3.91) vs. 1.87 (0.89-2.5), p<0.001], after which the values decreased until W12, with no significant difference observed. Serum CHI3L1 and GP73 levels were profoundly decreased at the EOT compared with those at baseline [134.07 (154.49) vs. 103.75 (98.04), p=0.025; 98.24 (64.76) vs. 88.91 (50.89), p=0.002]. DAA treatments could significantly improve liver fibrosis of CHC patients as evidenced by decreased liver stiffness, APRI scores and FIB-4 scores. Improvements in liver fibrosis markers (especially serum CHI3L1 and GP73) were prominent in patients with advanced fibrosis, indicating that serum CHI3L1 and GP73 could be noninvasive markers for monitoring fibrosis in CHC patients. Significance Statement The prospective cohort evaluated the effect of direct antiviral agents (DAAs) on fibrosis regression after hepatitis C virus (HCV) eradication of Chinese people in the real-world study. This study highlighted that rapid and significant fibrosis regression rather than reduction in inflammation was achieved with DAA treatment, and this regression could be detected as early as the end of treatment. We found the serum CHI3L1 and GP73 levels can be used to monitor changes in fibrosis in CHC patients.
Collapse
Affiliation(s)
- Qian Kang
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Jinghang Xu
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Hao Luo
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Ning Tan
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Hongyu Chen
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Ran Cheng
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Jiali Pan
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Yifan Han
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Yuqing Yang
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Dan Liu
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Hongli Xi
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Min Yu
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| | - Xiaoyuan Xu
- Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China
| |
Collapse
|
|
8
|
Astbury S, Grove JI, Dorward DA, Guha IN, Fallowfield JA, Kendall TJ. Reliable computational quantification of liver fibrosis is compromised by inherent staining variation. J Pathol Clin Res 2021; 7:471-481. [PMID: 34076968 PMCID: PMC8363922 DOI: 10.1002/cjp2.227] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/31/2021] [Accepted: 05/06/2021] [Indexed: 12/22/2022]
Abstract
Biopsy remains the gold-standard measure for staging liver disease, both to inform prognosis and to assess the response to a given treatment. Semiquantitative scores such as the Ishak fibrosis score are used for evaluation. These scores are utilised in clinical trials, with the US Food and Drug Administration mandating particular scores as inclusion criteria for participants and using the change in score as evidence of treatment efficacy. There is an urgent need for improved, quantitative assessment of liver biopsies to detect small incremental changes in liver architecture over the course of a clinical trial. Artificial intelligence (AI) methods have been proposed as a way to increase the amount of information extracted from a biopsy and to potentially remove bias introduced by manual scoring. We have trained and evaluated an AI tool for measuring the amount of scarring in sections of picrosirius red-stained liver. The AI methodology was compared with both manual scoring and widely available colour space thresholding. Four sequential sections from each case were stained on two separate occasions by two independent clinical laboratories using routine protocols to study the effect of inter- and intra-laboratory staining variation on these tools. Finally, we compared these methods to second harmonic generation (SHG) imaging, a stain-free quantitative measure of collagen. Although AI methods provided a modest improvement over simpler computer-assisted measures, staining variation both within and between laboratories had a dramatic effect on quantitation, with manual assignment of scar proportion being the most consistent. Manual assessment also most strongly correlated with collagen measured by SHG. In conclusion, results suggest that computational measures of liver scarring from stained sections are compromised by inter- and intra-laboratory staining. Stain-free quantitative measurement using SHG avoids staining-related variation and may prove more accurate in detecting small changes in scarring that may occur in therapeutic trials.
Collapse
Affiliation(s)
- Stuart Astbury
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK
- Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
| | - Jane I Grove
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK
- Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
| | - David A Dorward
- University of Edinburgh Centre for Inflammation ResearchUniversity of EdinburghEdinburghUK
- Edinburgh PathologyUniversity of EdinburghEdinburghUK
| | - Indra N Guha
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK
- Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
| | - Jonathan A Fallowfield
- University of Edinburgh Centre for Inflammation ResearchUniversity of EdinburghEdinburghUK
| | - Timothy J Kendall
- University of Edinburgh Centre for Inflammation ResearchUniversity of EdinburghEdinburghUK
- Edinburgh PathologyUniversity of EdinburghEdinburghUK
| |
Collapse
|
|
9
|
Rewisha E, Salman T, Alhaddad O, Raia GA, Naguib M, Rashad S, Abdelfattah A, Metwally K, Abdelsameea E. Hyaluronic acid as a potential marker for assessment of fibrosis regression after direct acting antiviral drugs in chronic hepatitis C patients. Clin Exp Hepatol 2021; 7:320-327. [PMID: 34712835 PMCID: PMC8527342 DOI: 10.5114/ceh.2021.109293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/27/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Fibrosis is an inevitable complication of chronic hepatitis C virus (HCV) infection. Direct acting antivirals (DAAs) radically treated HCV and were suggested to ameliorate fibrosis. Silymarin (a natural herbal remedy) was proposed to further decrease hepatic inflammation and fibrosis. Consequently, serial monitoring of liver fibrosis status by different biomarkers is needed. AIM OF THE STUDY To assess hyaluronic acid (HA) as a potential marker of fibrosis regression after DAAs in chronic HCV patients; in addition, to evaluate silymarin as an agent that, beside DAAs, could further improve fibrosis. MATERIAL AND METHODS Two groups were included (150 patients each). Group 1 received DAAs only, while group 2 received DAAs followed by silymarin. Hyaluronic acid and FIB4 score were assessed at baseline before treatment and 1 year after inclusion in the study. RESULTS We found that DAA therapy alone or in combination with silymarin resulted in a significant reduction in serum HA level. However, the latter case showed a statistically significantly greater reduction (p = 0.034). Mean ±SD of serum HA level was 211.8 ±179.9 and 143.3 ±123.9 µg/l before and one year after inclusion respectively in group 1 (p = 0.001) and also, its level decreased significantly in group 2 from 188.3 ±211.8 µg/l before receiving DAAs to 126.4 ±136.9 µg/l at one year after inclusion (p = 0.001). There was no significant difference between the 2 studied groups as regards FIB-4 at 1 year after inclusion (p = 0.103). CONCLUSIONS Hyaluronic acid might be a sensitive marker for monitoring fibrosis regression in treated chronic HCV patients. Adding silymarin to treatment protocols could ameliorate the fibrosis status.
Collapse
Affiliation(s)
- Eman Rewisha
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Egypt
| | - Tary Salman
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Egypt
| | - Omkolsoum Alhaddad
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Egypt
| | - Gamal Abo Raia
- Clinical Pathology Department, National Liver Institute, Menoufia University, Egypt
| | - Mary Naguib
- Clinical Pathology Department, National Liver Institute, Menoufia University, Egypt
| | - Shymaa Rashad
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Egypt
| | - Ahmed Abdelfattah
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Egypt
| | - Khaled Metwally
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Egypt
| | - Eman Abdelsameea
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Egypt
| |
Collapse
|
|
10
|
Gu J, Zhang E, Liang B, Zhang Z, Chen X, Xiong M, Huang Z. Liver Collagen Contents Are Closely Associated with the Severity of Cirrhosis and Posthepatectomy Liver Failure in Patients with Hepatocellular Carcinoma and Child-Pugh Grade A Liver Function. Ann Surg Oncol 2021; 28:4227-4235. [PMID: 33452603 DOI: 10.1245/s10434-020-09557-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 12/23/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is usually accompanied by different severities of cirrhosis, which is a risk factor for posthepatectomy liver failure (PHLF). Collagen proportional area (CPA) measurements can quantitatively determine the collagen contents of liver tissue. This study explored the impact of CPA on PHLF, and further investigated the correlation between CPA and a non-invasive method, namely cirrhotic severity scoring (CSS), previously proposed by our team. METHODS A total of 224 HCC patients with Child-Pugh grade A liver function undergoing hepatectomy between 2017 and 2019 were retrospectively studied. Quantitative digital image analysis of resected liver tissues was used for the CPA measurement. Risk factors for PHLF were subjected to univariate and multivariate analyses, and the correlation between CPA and CSS was analyzed. RESULTS Overall, 28 (12.5%) patients experienced PHLF. Patients with PHLF had higher CPA values than those without PHLF (p < 0.001). Multivariate analysis showed CPA and extent of hepatectomy to be independent risk factors for PHLF. CPA values were divided into four stages based on their quartiles (C1: < 6.6%; C2: 6.6-10.7%; C3: 10.7-18.0%; C4: ≥ 18.0%). The incidence of PHLF increased with increasing CPA stages (p < 0.001). Furthermore, CSS was significantly correlated with CPA (r = 0.720; p < 0.001). The incidence of PHLF also increased with increasing severity of cirrhosis evaluated by CSS (p < 0.001). CONCLUSIONS In HCC patients with Child-Pugh grade A liver function, cirrhosis could be staged by liver collagen contents, which significantly influenced PHLF. Furthermore, CSS was useful in the preoperative evaluation of cirrhotic severity.
Collapse
Affiliation(s)
- Jin Gu
- Department of Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Erlei Zhang
- Department of Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binyong Liang
- Department of Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zunyi Zhang
- Department of Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Chen
- Department of Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Xiong
- Department of Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhiyong Huang
- Department of Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
11
|
Wei T, Hao W, Tang L, Wu H, Huang S, Yang Y, Qian N, Liu J, Yang W, Duan X. Comprehensive RNA-Seq Analysis of Potential Therapeutic Targets of Gan-Dou-Fu-Mu Decoction for Treatment of Wilson Disease Using a Toxic Milk Mouse Model. Front Pharmacol 2021; 12:622268. [PMID: 33935715 PMCID: PMC8082393 DOI: 10.3389/fphar.2021.622268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 03/19/2021] [Indexed: 12/20/2022] Open
Abstract
Background: Gan–Dou–Fu–Mu decoction (GDFMD) improves liver fibrosis in experimental and clinical studies including those on toxic mouse model of Wilson disease (Model). However, the mechanisms underlying the effect of GDFMD have not been characterized. Herein, we deciphered the potential therapeutic targets of GDFMD using transcriptome analysis. Methods: We constructed a tx-j Wilson disease (WD) mouse model, and assessed the effect of GDFMD on the liver of model mice by hematoxylin and eosin, Masson, and immunohistochemical staining. Subsequently, we identified differentially expressed genes (DEGs) that were upregulated in the Model (Model vs. control) and those that were downregulated upon GDFMD treatment (compared to the Model) using RNA-sequencing (RNA-Seq). Biological functions and signaling pathways in which the DEGs were involved were determined by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. A protein–protein interaction (PPI) network was constructed using the STRING database, and the modules were identified using MCODE plugin with the Cytoscape software. Several genes identified in the RNA-Seq analysis were validated by real-time quantitative PCR. Results: Total of 2124 DEGs were screened through the Model vs. control and Model vs. GDFMD comparisons, and dozens of GO and KEGG pathway terms modulated by GDFMD were identified. Dozens of pathways involved in metabolism (including metabolic processes for organic acids, carboxylic acids, monocarboxylic acids, lipids, fatty acids, cellular lipids, steroids, alcohols, eicosanoids, long-chain fatty acids), immune and inflammatory response (such as complement and coagulation cascades, cytokine–cytokine receptor interaction, inflammatory mediator regulation of TRP channels, antigen processing and presentation, T-cell receptor signaling pathway), liver fibrosis (such as ECM-receptor interactions), and cell death (PI3K-Akt signaling pathway, apoptosis, TGF-beta signaling pathway, etc.) were identified as potential targets of GDFMD in the Model. Some hub genes and four modules were identified in the PPI network. The results of real-time quantitative PCR analysis were consistent with those of RNA-Seq analysis. Conclusions: We performed gene expression profiling of GDFMD-treated WD model mice using RNA-Seq analysis and found the genes, pathways, and processes effected by the treatment. Our study provides a theoretical basis to prevent liver fibrosis resulting from WD using GDFMD.
Collapse
Affiliation(s)
- Taohua Wei
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Graduate School, Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'An Medicine, Ministry of Education, Hefei, China
| | - Wenjie Hao
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Graduate School, Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'An Medicine, Ministry of Education, Hefei, China
| | - Lulu Tang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'An Medicine, Ministry of Education, Hefei, China
| | - Huan Wu
- Scientific Research and Experiment Center, Anhui University of Chinese Medicine, Hefei, China
| | - Shi Huang
- Graduate School, Anhui University of Chinese Medicine, Hefei, China
| | - Yue Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Graduate School, Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'An Medicine, Ministry of Education, Hefei, China
| | - Nannan Qian
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Graduate School, Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'An Medicine, Ministry of Education, Hefei, China
| | - Jie Liu
- Institute for Medical Virology, Goethe University Frankfurt Am Main, Frankfurt, Germany
| | - Wenming Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,Graduate School, Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'An Medicine, Ministry of Education, Hefei, China
| | - Xianchun Duan
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| |
Collapse
|
|
12
|
Castera L. Assessment of Liver Disease Severity. HEPATITIS C: CARE AND TREATMENT 2021:1-20. [DOI: 10.1007/978-3-030-67762-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
13
|
Habib S. Portal Hypertensive Gastropathy. VARICEAL BLEEDING IN LIVER CIRRHOSIS 2021:123-140. [DOI: 10.1007/978-981-15-7249-4_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
14
|
Decrease in Chitinase 3-Like Protein 1 Levels Reflects Improvement in Liver Fibrosis after HCV Eradication. DISEASE MARKERS 2020; 2020:8539804. [PMID: 33082884 PMCID: PMC7556050 DOI: 10.1155/2020/8539804] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 08/20/2020] [Accepted: 09/05/2020] [Indexed: 12/13/2022]
Abstract
Aim The success of direct-acting antivirals (DAAs) against hepatitis C virus is a major breakthrough in hepatology. Previous studies have shown that chitinase 3-like protein 1 (CHI3L1) was a marker for staging of liver fibrosis caused by HCV. In this investigation, we used CHI3L1 as a surrogate marker to compare dynamic hepatic fibrosis variations following the elimination of HCV among cases receiving sofosbuvir (SOF)-based regimens and pegylated interferon/ribavirin (PR) treatments. Methods The study enrolled 105 patients, including 46 SOF-based regimens treated patients, 34 PR-experienced patients, and 25 untreated patients. Serum samples and clinical data were obtained at the baseline, the end of treatment, and at weeks 24 and 48 after treatments. Results First, we found that serum level of CHI3L1 correlated moderately but significantly with LSM (r = 0.615, P < 0.001) at the baseline, and diagnosed liver cirrhosis at baseline with high accuracy (AUC = 0.939) by ROC analysis. So we explored CHI3L1 as a sensitive biomarker to monitor the regression of liver fibrosis after HCV eradication. We found that the serum CHI3L1 level of CHC cases receiving SOF-based regimen treatments was markedly reduced immediately after treatment compared with that at the baseline (123.79 (118.55) vs. 118.20 (103.68), P = 0.001). For cases undergoing PR treatment, the serum CHI3L1 decreased significantly at week 24 posttreatment compared with that at the baseline (69.98 (51.44) vs 89.15 (110.59), P = 0.016). For the untreated cirrhotic patients, CHI3L1 levels increased at week 96 follow-up compared with that at the baseline (194.73 (172.46) vs. 89.50 (242.97), P = 0.048), reflecting continued worsening of liver fibrosis. Conclusion CHI3L1 is suggested to be the sensitive marker to monitor fibrosis variations in weeks during treatments and after achieving SVR. It has the potential to allow the identification of early treatment failure for a timely switch to alternative treatment and to allow monitoring progression of fibrosis as a risk factor for liver cirrhosis.
Collapse
|
|
15
|
Caussy C, Chuang JC, Billin A, Hu T, Wang Y, Subramanian GM, Djedjos CS, Myers RP, Dennis EA, Loomba R. Plasma eicosanoids as noninvasive biomarkers of liver fibrosis in patients with nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2020; 13:1756284820923904. [PMID: 32523627 PMCID: PMC7257854 DOI: 10.1177/1756284820923904] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 03/23/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Eicosanoid and related docosanoid polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives have been proposed as noninvasive lipidomic biomarkers of nonalcoholic steatohepatitis (NASH). Therefore, we investigated associations between plasma eicosanoids and liver fibrosis to evaluate their utility in diagnosing and monitoring NASH-related fibrosis. METHODS Our analysis used baseline eicosanoid data from 427 patients with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), and longitudinal measurements along with liver fibrosis staging from 63 patients with NASH and stage 2/3 fibrosis followed for 24 weeks in a phase II trial. RESULTS At baseline, four eicosanoids were significantly associated with liver fibrosis stage: 11,12-DIHETE, tetranor 12-HETE, adrenic acid, and 14, 15-DIHETE. Over 24 weeks of follow up, a combination of changes in seven eicosanoids [5-HETE, 7,17-DHDPA, adrenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), 16-HDOHE, and 9-HODE) had good diagnostic accuracy for the prediction of ⩾1 stage improvement in fibrosis (AUROC: 0.74; 95% CI: 0.62-0.87), and a combination of four eicosanoids (7,17-DHDPA, 14,15-DIHETRE, 9-HOTRE, and free adrenic acid) accurately predicted improvement in hepatic collagen content (AUROC: 0.72; 95% CI: 0.50-0.77). CONCLUSION This study provides preliminary evidence that plasma eicosanoids may serve as noninvasive biomarkers of liver fibrosis and may predict liver fibrosis improvement in NASH.
Collapse
Affiliation(s)
- Cyrielle Caussy
- Univ Lyon, CarMen Laboratory, INSERM, INRA, INSA
Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France,Hospices Civils de Lyon, Département
Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Pierre-Bénite,
France
| | | | | | - Tao Hu
- Gilead Sciences, Inc., Foster City, CA,
USA
| | - Ya Wang
- Gilead Sciences, Inc., Foster City, CA,
USA
| | | | | | | | - Edward A. Dennis
- Department of Pharmacology and Department of
Chemistry and Biochemistry, University of California San Diego, 9500 Gilman
Drive, MC 0601, La Jolla, CA 92093-0601, USA
| | | |
Collapse
|
|
16
|
Gawrieh S, Sethunath D, Cummings OW, Kleiner DE, Vuppalanchi R, Chalasani N, Tuceryan M. Automated quantification and architectural pattern detection of hepatic fibrosis in NAFLD. Ann Diagn Pathol 2020; 47:151518. [PMID: 32531442 DOI: 10.1016/j.anndiagpath.2020.151518] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/25/2020] [Accepted: 04/03/2020] [Indexed: 02/06/2023]
Abstract
Accurate detection and quantification of hepatic fibrosis remain essential for assessing the severity of non-alcoholic fatty liver disease (NAFLD) and its response to therapy in clinical practice and research studies. Our aim was to develop an integrated artificial intelligence-based automated tool to detect and quantify hepatic fibrosis and assess its architectural pattern in NAFLD liver biopsies. Digital images of the trichrome-stained slides of liver biopsies from patients with NAFLD and different severity of fibrosis were used. Two expert liver pathologists semi-quantitatively assessed the severity of fibrosis in these biopsies and using a web applet provided a total of 987 annotations of different fibrosis types for developing, training and testing supervised machine learning models to detect fibrosis. The collagen proportionate area (CPA) was measured and correlated with each of the pathologists semi-quantitative fibrosis scores. Models were created and tested to detect each of six potential fibrosis patterns. There was good to excellent correlation between CPA and the pathologist score of fibrosis stage. The coefficient of determination (R2) of automated CPA with the pathologist stages ranged from 0.60 to 0.86. There was considerable overlap in the calculated CPA across different fibrosis stages. For identification of fibrosis patterns, the models areas under the receiver operator curve were 78.6% for detection of periportal fibrosis, 83.3% for pericellular fibrosis, 86.4% for portal fibrosis and >90% for detection of normal fibrosis, bridging fibrosis, and presence of nodule/cirrhosis. In conclusion, an integrated automated tool could accurately quantify hepatic fibrosis and determine its architectural patterns in NAFLD liver biopsies.
Collapse
Affiliation(s)
- Samer Gawrieh
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
| | - Deepak Sethunath
- Department of Computer and Information Science, Indiana University Purdue University, Indianapolis, IN, United States of America
| | - Oscar W Cummings
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, United States of America
| | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Mihran Tuceryan
- Department of Computer and Information Science, Indiana University Purdue University, Indianapolis, IN, United States of America
| |
Collapse
|
|
17
|
Targeted delivery of hyaluronic acid nanomicelles to hepatic stellate cells in hepatic fibrosis rats. Acta Pharm Sin B 2020; 10:693-710. [PMID: 32322471 PMCID: PMC7161713 DOI: 10.1016/j.apsb.2019.07.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 07/01/2019] [Accepted: 07/02/2019] [Indexed: 12/21/2022] Open
Abstract
Hepatic fibrosis is one kind of liver diseases with a high mortality rate and incidence. The activation and proliferation of hepatic stellate cells (HSCs) is the most fundamental reason of hepatic fibrosis. There are no specific and effective drug delivery carriers for the treatment of hepatic fibrosis at present. We found that when hepatic fibrosis occurs, the expression of CD44 receptors on the surface of HSCs is significantly increased. Based on this finding, we designed silibinin-loaded hyaluronic acid (SLB-HA) micelles to achieve the treatment of hepatic fibrosis. Meanwhile, we constructed liver fibrosis rat model using Sprague–Dawley rats. We demonstrated that HA micelles had specific uptake to HSCs in vitro while avoiding the distribution in normal liver cells and the phagocytosis of macrophages. Importantly, HA micelles showed a significant liver targeting effect in vivo, especially in fibrotic liver which highly expressed CD44 receptors. In addition, SLB-HA micelles could selectively kill activated HSCs, having an excellent anti-hepatic fibrosis effect in vivo and a significant sustained release effect, and also had a good biological safety and biocompatibility. Overall, HA micelles represented a novel nanomicelle system which showed great potentiality in anti-hepatic fibrosis drugs delivery.
Collapse
|
|
18
|
Higashiyama M, Tomita K, Sugihara N, Nakashima H, Furuhashi H, Nishikawa M, Inaba K, Wada A, Horiuchi K, Hanawa Y, Shibuya N, Kurihara C, Okada Y, Nishii S, Mizoguchi A, Hozumi H, Watanabe C, Komoto S, Yamamoto J, Seki S, Miura S, Hokari R. Chitinase 3-like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis. Hepatol Res 2019; 49:1316-1328. [PMID: 31250532 PMCID: PMC6916176 DOI: 10.1111/hepr.13396] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/14/2019] [Accepted: 06/24/2019] [Indexed: 12/11/2022]
Abstract
AIM Chitinase 3-like 1 (CHI3L1), an 18-glycosyl hydrolase-related molecule, is a member of the enzymatically inactive chitinase-like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. METHODS Chitinase 3-like 1-deficient (Chi3l1-/- ) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline-deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. RESULTS In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1-/- mice compared to that in wild-type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1-/- mice compared to that in wild-type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1-/- mice. Chitinase 3-like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. CONCLUSIONS Chitinase 3-like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Masaaki Higashiyama
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Kengo Tomita
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Nao Sugihara
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | | | - Hirotaka Furuhashi
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Makoto Nishikawa
- Departments of SurgeryNational Defense Medical CollegeTokorozawa
| | - Kenichi Inaba
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Akinori Wada
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Kazuki Horiuchi
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Yoshinori Hanawa
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Naoki Shibuya
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Chie Kurihara
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Yoshikiyo Okada
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Shin Nishii
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Akinori Mizoguchi
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Hideaki Hozumi
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Chikako Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Shunsuke Komoto
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| | - Junji Yamamoto
- Departments of SurgeryNational Defense Medical CollegeTokorozawa
| | - Shuhji Seki
- Departments of Immunology and MicrobiologyTokorozawa
| | - Soichiro Miura
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
- International University of Health and Welfare Graduate SchoolTokyoJapan
| | - Ryota Hokari
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTokorozawa
| |
Collapse
|
|
19
|
Castera L. Noninvasive Tests of Liver Fibrosis. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 4E 2019:445-453. [DOI: 10.1002/9781119211419.ch30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
20
|
Do serum markers of liver fibrosis vary by HCV infection in patients with alcohol use disorder? Drug Alcohol Depend 2018; 188:180-186. [PMID: 29778771 DOI: 10.1016/j.drugalcdep.2018.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/06/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
INTRODUCTION HCV infection is frequent in patients with alcohol use disorder (AUD). Ethanol and hepatitis C have a synergistic effect that increases the risk of end-stage liver disease. We aimed to assess fibrosis of the liver in patients admitted to treatment of AUD. METHODS Data were collected in two hospital units between 2000 and 2014. Liver fibrosis was assessed by serum biomarkers APRI, FIB-4 and Forns, and Advanced Liver Fibrosis (ALF) was defined if APRI > 1.5, FIB-4 > 3.25 or Forns > 6.9. Correlations were analyzed by Pearson's coefficients and logistic regression models were used. RESULTS 1313 patients (80% M) had complete data; age at admission was 45 years (IQR: 39-52 yrs), age of initial regular alcohol consumption was 20 years (IQR: 17-26 yrs) and the amount of alcohol consumed preceding admission was 200 g/day (IQR: 120-270 g/day). Prevalence of HCV infection was 18%. Prevalence of ALF in HCV positive patients was 40.6% by APRI, 30.6% by FIB-4, and 43.3% by Forns. Correlations were high for APRI vs. FIB-4 r = 0.906, APRI vs. Forns r = 0.710, and, FIB-4 vs. Forns r = 0.825. There was no significant difference in the APRI/FIB-4 correlation by HCV status (z = 1.35, p = 0.177). However, the APRI/Forns correlation was significantly higher in HCV positive patients (p < 0.001). Patients with HCV infection were two times more likely to present with ALF at admission (OR = 2.1, 95%CI:1.5-3.1). CONCLUSIONS HCV infection is associated with severity of fibrosis in patients with excessive alcohol consumption. In this context, APRI and FIB-4 are highly correlated which facilitates the assessment of liver damage.
Collapse
|
|
21
|
|
|
22
|
Yan L, Deng Y, Zhou J, Zhao H, Wang G. Serum YKL-40 as a biomarker for liver fibrosis in chronic hepatitis B patients with normal and mildly elevated ALT. Infection 2018; 46:385-393. [PMID: 29600444 PMCID: PMC5976691 DOI: 10.1007/s15010-018-1136-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 03/22/2018] [Indexed: 12/19/2022]
Abstract
Purpose YKL-40 is a chitinase-like protein expressed in multiple tissues including liver and is reported as a fibrosis marker. This study aimed to determine whether YKL-40 could serve as a diagnostic marker for the assessment of liver fibrosis in chronic hepatitis B patients with normal and mildly elevated ALT. Methods Six hundred and eighty-five patients with chronic hepatitis B infection were enrolled in this study from October 2013 to March 2016. All patients underwent liver biopsy and then staged based on Ishak histological system. Serum YKL-40 levels were measured by Human Magnetic Luminex Assays. Results Among chronic hepatitis B patients with normal and mildly elevated ALT, almost more than 30% of patients have significant liver fibrosis. Serum YKL-40 levels increased significantly in parallel with the progression of fibrosis in patients with ALT less than two times the upper limit of normal range (P < 0.0001). Multivariate analysis revealed that serum YKL-40, hyaluronic acid, PLT, and AST were independently associated with significant fibrosis. We established a novel YKL-40-based fibrosis model for patients with ALT less than two times the upper limit of normal range (ULN). YKL-40 model was superior to APRI, FIB-4, Forns’ index, and Hui model for diagnosis of significant fibrosis in patients with ALT < 2ULN, with AUROCs of 0.786 [95% confidence interval (CI) 0.726–0.846] in the training group, 0.831 (95%CI 0.752–0.910) in the validation group and 0.801 (95%CI 0.753–0.849) in the entire cohort. Conclusion Serum YKL-40 is a feasible biomarker of liver fibrosis in chronic hepatitis B patients. YKL-40 model was superior to APRI, FIB-4, Forns’ index and Hui model for diagnosis of significant fibrosis in patients with normal and mildly elevated ALT. Electronic supplementary material The online version of this article (10.1007/s15010-018-1136-2) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Linlin Yan
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Yongqiong Deng
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China.,The Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jiyuan Zhou
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Hong Zhao
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Guiqiang Wang
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China. .,The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China. .,Peking University International Hospital, Beijing, China.
| | | |
Collapse
|
|
23
|
Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, Diehl AM, Djedjos CS, Han L, Myers RP, Subramanian GM, McHutchison JG, Goodman ZD, Afdhal NH, Charlton MR, for the GS‐US‐384‐1497 Investigators. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology 2018; 67:549-559. [PMID: 28892558 PMCID: PMC5814892 DOI: 10.1002/hep.29514] [Citation(s) in RCA: 432] [Impact Index Per Article: 61.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/28/2017] [Accepted: 09/06/2017] [Indexed: 12/12/2022]
Abstract
Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).
Collapse
Affiliation(s)
- Rohit Loomba
- University of California at San DiegoSan DiegoCA
| | - Eric Lawitz
- Texas Liver InstituteUniversity of Texas Health San AntonioSan AntonioTX
| | | | | | | | - Hays Arnold
- Gastroenterology Consultants of San AntonioSan AntonioTX
| | | | | | - Ling Han
- Gilead Sciences, Inc.Foster CityCA
| | | | | | | | | | - Nezam H. Afdhal
- Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMA
| | | | | |
Collapse
|
|
24
|
Tapper EB, Afdhal NH. Noninvasive Assessment of Disease Progression. ZAKIM AND BOYER'S HEPATOLOGY 2018:117-126.e3. [DOI: 10.1016/b978-0-323-37591-7.00008-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
25
|
Cano A, Mariño Z, Millet O, Martínez-Arranz I, Navasa M, Falcón-Pérez JM, Pérez-Cormenzana M, Caballería J, Embade N, Forns X, Bosch J, Castro A, Mato JM. A Metabolomics Signature Linked To Liver Fibrosis In The Serum Of Transplanted Hepatitis C Patients. Sci Rep 2017; 7:10497. [PMID: 28874799 PMCID: PMC5585246 DOI: 10.1038/s41598-017-10807-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 08/11/2017] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis must be evaluated in patients with hepatitis C virus (HCV) after liver transplantation because its severity affects their prognosis and the recurrence of HCV. Since invasive biopsy is still the gold standard to identify patients at risk of graft loss from rapid fibrosis progression, it becomes crucial the development of new accurate, non-invasive methods that allow repetitive examination of the patients. Therefore, we have developed a non-invasive, accurate model to distinguish those patients with different liver fibrosis stages. Two hundred and three patients with HCV were histologically classified (METAVIR) into five categories of fibrosis one year after liver transplantation. In this cross-sectional study, patients at fibrosis stages F0-F1 (n = 134) were categorised as “slow fibrosers” and F2-F4 (n = 69) as “rapid fibrosers”. Chloroform/methanol serum extracts were analysed by reverse ultra-high performance liquid chromatography coupled to mass spectrometry. A diagnostic model was built through linear discriminant analyses. An algorithm consisting of two sphingomyelins and two phosphatidylcholines accurately classifies rapid and slow fibrosers after transplantation. The proposed model yielded an AUROC of 0.92, 71% sensitivity, 85% specificity, and 84% accuracy. Moreover, specific bile acids and sphingomyelins increased notably along with liver fibrosis severity, differentiating between rapid and slow fibrosers.
Collapse
Affiliation(s)
- Ainara Cano
- OWL, Parque Tecnológico de Bizkaia, Derio, 48160, Bizkaia, Spain.
| | - Zoe Mariño
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Oscar Millet
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain.,Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain
| | | | - Miquel Navasa
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan Manuel Falcón-Pérez
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain.,Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain
| | | | - Joan Caballería
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Nieves Embade
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Jaume Bosch
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Azucena Castro
- OWL, Parque Tecnológico de Bizkaia, Derio, 48160, Bizkaia, Spain
| | - José María Mato
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain
| |
Collapse
|
|
26
|
Discher DE, Smith L, Cho S, Colasurdo M, García AJ, Safran S. Matrix Mechanosensing: From Scaling Concepts in 'Omics Data to Mechanisms in the Nucleus, Regeneration, and Cancer. Annu Rev Biophys 2017; 46:295-315. [PMID: 28532215 DOI: 10.1146/annurev-biophys-062215-011206] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Many of the most important molecules of life are polymers. In animals, the most abundant of the proteinaceous polymers are the collagens, which constitute the fibrous matrix outside cells and which can also self-assemble into gels. The physically measurable stiffness of gels, as well as tissues, increases with the amount of collagen, and cells seem to sense this stiffness. An understanding of this mechanosensing process in complex tissues, including fibrotic disease states with high collagen, is now utilizing 'omics data sets and is revealing polymer physics-type, nonlinear scaling relationships between concentrations of seemingly unrelated biopolymers. The nuclear structure protein lamin A provides one example, with protein and transcript levels increasing with collagen 1 and tissue stiffness, and with mechanisms rooted in protein stabilization induced by cytoskeletal stress. Physics-based models of fibrous matrix, cytoskeletal force dipoles, and the lamin A gene circuit illustrate the wide range of testable predictions emerging for tissues, cell cultures, and even stem cell-based tissue regeneration. Beyond the epigenetics of mechanosensing, the scaling in cancer of chromosome copy number variations and other mutations with tissue stiffness suggests that genomic changes are occurring by mechanogenomic processes that now require elucidation.
Collapse
Affiliation(s)
- Dennis E Discher
- Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, Pennsylvania 19104;
| | - Lucas Smith
- Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, Pennsylvania 19104;
| | - Sangkyun Cho
- Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, Pennsylvania 19104;
| | - Mark Colasurdo
- Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332
| | - Andrés J García
- Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332
| | - Sam Safran
- Department of Materials and Interfaces, Weizmann Institute of Science, Rehovet 76100, Israel
| |
Collapse
|
|
27
|
Wang Y, Huang W, Li R, Yun Z, Zhu Y, Yang J, Liu H, Liu Z, Feng Q, Hou J. Systematic quantification of histological patterns shows accuracy in reflecting cirrhotic remodeling. J Gastroenterol Hepatol 2017; 32:1631-1639. [PMID: 28068755 DOI: 10.1111/jgh.13722] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 12/06/2016] [Accepted: 01/04/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM There still lacks a tool for precisely evaluating cirrhotic remodeling. Histologic distortion characterized in cirrhosis (i.e. cirrhotic patterns) has a validated pathophysiological meaning and potential relevance to clinical complications. We aimed to establish a new tool to quantify the cirrhotic patterns and test it for reflecting the cirrhotic remodeling. METHODS We designed a computerized algorithm, named qCP, dedicated for the analysis of liver images acquired by second harmonic microscopy. We evaluated its measurement by using a cohort of 95 biopsies (Ishak staging F4/5/6 = 33/35/27) of chronic hepatitis B and a carbon tetrachloride-intoxicated rat model for simulating the bidirectional cirrhotic change. RESULTS QCP can characterize 14 histological cirrhosis parameters involving the nodules, septa, sinusoid, and vessels. For chronic hepatitis B biopsies, the mean overall intra-observer and inter-observer agreement was 0.94 ± 0.08 and 0.93 ± 0.09, respectively. The robustness in resisting sample adequacy-related scoring error was demonstrated. The proportionate areas of total (collagen proportionate area), septal (septal collagen proportionate area [SPA]), sinusoidal, and vessel collagen, nodule area, and nodule density (ND) were associated with Ishak staging (P < 0.01 for all). But only ND and SPA were independently associated (P ≤ 0.001 for both). A histological cirrhosis parameters-composed qCP-index demonstrated an excellent accuracy in quantitatively diagnosing evolving cirrhosis (areas under receiver operating characteristic curves 0.95-0.92; sensitivity 0.93-0.82; specificity 0.94-0.85). In the rat model, changes in collagen proportionate area, SPA, and ND had strong correlations with both cirrhosis progression and regression and faithfully characterized the histological evolution. CONCLUSIONS QCP preliminarily demonstrates potential for quantitating cirrhotic remodeling with high resolution and accuracy. Further validation with in-study cohorts and multiple-etiologies is warranted.
Collapse
Affiliation(s)
- Yan Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - Wei Huang
- School of Biomedical Engineering, Southern Medical University, Guangzhou, China
| | - Ruhua Li
- Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - Zhaoqiang Yun
- School of Biomedical Engineering, Southern Medical University, Guangzhou, China
| | - Youfu Zhu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlian Yang
- Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - Hailin Liu
- School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhipeng Liu
- School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qianjin Feng
- School of Biomedical Engineering, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
28
|
Affiliation(s)
- Elliot B Tapper
- From the Division of Gastroenterology and Hepatology and the Institute for Healthcare Policy and Innovation, University of Michigan (E.B.T., A.S.-F.L.), and the Veterans Affairs Hospital (E.B.T.) - both in Ann Arbor
| | - Anna S-F Lok
- From the Division of Gastroenterology and Hepatology and the Institute for Healthcare Policy and Innovation, University of Michigan (E.B.T., A.S.-F.L.), and the Veterans Affairs Hospital (E.B.T.) - both in Ann Arbor
| |
Collapse
|
|
29
|
Kjaergaard AD, Johansen JS, Bojesen SE, Nordestgaard BG. Role of inflammatory marker YKL-40 in the diagnosis, prognosis and cause of cardiovascular and liver diseases. Crit Rev Clin Lab Sci 2016; 53:396-408. [PMID: 27187575 DOI: 10.1080/10408363.2016.1190683] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This review summarizes present evidence for the role of YKL-40 in the diagnosis, prognosis and cause of cardiovascular and alcoholic liver disease. The question of whether YKL-40 is merely a marker or a causal factor in the development of cardiovascular and liver disease is addressed, with emphasis on the Mendelian randomization design. The Mendelian randomization approach uses genetic variants associated with lifelong high plasma YKL-40 levels that are largely unconfounded and not prone to reverse causation. Thus, the approach mimics a controlled double-blind randomized trial, but it uses genetic variants rather than a drug and placebo, and like a blinded trial, it allows inference about causality. Moreover, the review also covers background on the molecular biology and functions of YKL-40, YKL-40 levels in healthy individuals and reference range, and the role of YKL-40 as a biomarker of cardiovascular and alcoholic liver disease. YKL-40 is a plasma protein named after its three N-terminal amino acids, Y (tyrosine), K (lysine) and L (leucine), and its molecular weight of 40 kDa. It is produced by local inflammatory cells in inflamed tissues, such as lipid-laden macrophages inside the vessel wall and perhaps also hepatic stellate cells. Observational studies show that plasma YKL-40 levels are elevated in patients with cardiovascular and liver disease and are associated with disease severity and prognosis. Furthermore, elevated plasma YKL-40 levels in apparently healthy individuals are associated with a 2-fold increased risk of future ischemic stroke and venous thromboembolism, but not with myocardial infarction, suggesting that YKL-40 could play a role in the formation of embolisms rather than atherosclerosis per se. Further, elevated YKL-40 levels combined with excessive alcohol consumption are associated with 10-years risk of alcoholic liver cirrhosis of up to 7%, suggesting that YKL-40 can be used as a strong noninvasive marker of predicting alcoholic liver cirrhosis. Importantly, in Mendelian randomization studies, genetically elevated plasma YKL-40 levels were not associated with risk of cardiovascular and alcoholic liver disease, thus suggesting that plasma YKL-40 does not play a causal role in the development of these diseases. Despite this, plasma YKL-40 levels may play a role in disease progression after diagnosis, and inhibition of YKL-40 activity might be a novel therapy in some cardiovascular and liver diseases.
Collapse
Affiliation(s)
- A D Kjaergaard
- a Department of Clinical Biochemistry , Aarhus University Hospital , Aarhus , Denmark
| | - J S Johansen
- b Department of Medicine and Oncology , Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen , Copenhagen , Denmark .,c Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - S E Bojesen
- c Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark .,d Department of Clinical Biochemistry , Herlev and Gentofte Hospital, Copenhagen University Hospital , Herlev , Copenhagen , Denmark .,e The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen , Denmark , and.,f The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen , Denmark
| | - B G Nordestgaard
- c Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark .,d Department of Clinical Biochemistry , Herlev and Gentofte Hospital, Copenhagen University Hospital , Herlev , Copenhagen , Denmark .,e The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen , Denmark , and.,f The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen , Denmark
| |
Collapse
|
|
30
|
Yegin EG, Yegin K, Ozdogan OC. Digital image analysis in liver fibrosis: basic requirements and clinical implementation. BIOTECHNOL BIOTEC EQ 2016. [DOI: 10.1080/13102818.2016.1181989] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Ender Gunes Yegin
- Department of Gastroenterology, Bozyaka State Hospital, Izmir, Turkey
| | - Korkut Yegin
- Electrical and Electronics Engineering Department, Ege University, Izmir, Turkey
| | - Osman Cavit Ozdogan
- Faculty of Medicine, Department of Gastroenterology, Marmara University, Istanbul, Turkey
| |
Collapse
|
|
31
|
Babaei Z, Parsian H. Hyaluronic acid algorithm-based models for assessment of liver fibrosis: translation from basic science to clinical application. Hepatobiliary Pancreat Dis Int 2016; 15:131-40. [PMID: 27020628 DOI: 10.1016/s1499-3872(16)60062-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The estimation of liver fibrosis is usually dependent on liver biopsy evaluation. Because of its disadvantages and side effects, researchers try to find non-invasive methods for the assessment of liver injuries. Hyaluronic acid has been proposed as an index for scoring the severity of fibrosis, alone or in algorithm models. The algorithm model in which hyaluronic acid was used as a major constituent was more reliable and accurate in diagnosis than hyaluronic acid alone. This review described various hyaluronic acid algorithm-based models for assessing liver fibrosis. DATA SOURCE A PubMed database search was performed to identify the articles relevant to hyaluronic acid algorithm-based models for estimating liver fibrosis. RESULT The use of hyaluronic acid in an algorithm model is an extra and valuable tool for assessing liver fibrosis. CONCLUSIONS Although hyaluronic acid algorithm-based models have good diagnostic power in liver fibrosis assessment, they cannot render the need for liver biopsy obsolete and it is better to use them in parallel with liver biopsy. They can be used when frequent liver biopsy is not possible in situations such as highlighting the efficacy of treatment protocol for liver fibrosis.
Collapse
Affiliation(s)
- Zeinab Babaei
- Student Research Committee & Department of Biochemistry and Biophysics, and Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
| | | |
Collapse
|
|
32
|
Wu W, Zhang H, Xu X, Huang K, Fu J. Intrahepatic Fat Content and Markers of Hepatic Fibrosis in Obese Children. Int J Endocrinol 2016; 2016:4890974. [PMID: 26966436 PMCID: PMC4757713 DOI: 10.1155/2016/4890974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/03/2016] [Accepted: 01/06/2016] [Indexed: 11/17/2022] Open
Abstract
Aim. We evaluated both direct and indirect hepatic fibrosis markers in obese children and their relationship with intrahepatic fat (IHF) content. We also aimed to investigate the possible roles of IHF and fibrosis markers in metabolic syndrome (MS). Methods. 189 obese children were divided into simple obese (SOB), simple steatosis (SS), and nonalcoholic steatohepatitis (NASH) groups according to their IHF and blood alanine transaminase (ALT) levels. They were also scored for the MS components. IHF was assessed as a continuous variable by proton magnetic resonance spectroscopy (1H-MRS). In addition, 30 nonobese children were enrolled as controls and their direct hepatic fibrosis markers and IHF were assessed. Results. Age was related to IHF, NFS, and FIB-4. Both NFS and APRI were related to IHF more significantly than the direct markers. In the estimation of liver function impairment, indirect markers had greater AUROC than direct markers. In MS, IHF and all the fibrosis markers showed similar AUROC. Conclusions. Both direct and indirect markers played a valuable role in evaluating MS. Indirect markers were more effective in distinguishing fatty hepatitis. Age is an important factor underlying hepatic steatosis and fibrosis even in children.
Collapse
Affiliation(s)
- Wei Wu
- Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou, Zhejiang 310003, China
| | - Hongxi Zhang
- Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou, Zhejiang 310003, China
| | - Xiaoqin Xu
- Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou, Zhejiang 310003, China
| | - Ke Huang
- Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou, Zhejiang 310003, China
| | - Junfen Fu
- Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou, Zhejiang 310003, China
| |
Collapse
|
|
33
|
Schneider MD, Zeuzem S, Friedrich-Rust M. Leberzirrhose. DER GASTROENTEROLOGE 2016; 11:34-39. [DOI: 10.1007/s11377-015-0034-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
34
|
Valva P, Ríos DA, De Matteo E, Preciado MV. Chronic hepatitis C virus infection: Serum biomarkers in predicting liver damage. World J Gastroenterol 2016; 22:1367-1381. [PMID: 26819506 PMCID: PMC4721972 DOI: 10.3748/wjg.v22.i4.1367] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 08/04/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus (HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C (CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are (1) the physical ones based on imaging techniques; and (2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss: (1) class I serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes; (2) class II biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and (3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC.
Collapse
|
|
35
|
ORASAN OLGAHILDA, CIULEI GEORGE, COZMA ANGELA, SAVA MADALINA, DUMITRASCU DANLUCIAN. Hyaluronic acid as a biomarker of fibrosis in chronic liver diseases of different etiologies. CLUJUL MEDICAL (1957) 2016; 89:24-31. [PMID: 27004022 PMCID: PMC4777465 DOI: 10.15386/cjmed-554] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 09/17/2015] [Indexed: 12/27/2022]
Abstract
Chronic liver diseases represent a significant public health problem worldwide. The degree of liver fibrosis secondary to these diseases is important, because it is the main predictor of their evolution and prognosis. Hyaluronic acid is studied as a non-invasive marker of liver fibrosis in chronic liver diseases, in an attempt to avoid the complications of liver puncture biopsy, considered the gold standard in the evaluation of fibrosis. We review the advantages and limitations of hyaluronc acid, a biomarker, used to manage patients with chronic viral hepatitis B or C infection, non-alcoholic fatty liver disease, HIV-HCV coinfection, alcoholic liver disease, primary biliary cirrhosis, biliary atresia, hereditary hemochromatosis and cystic fibrosis.
Collapse
Affiliation(s)
- OLGA HILDA ORASAN
- 4th Medical Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - GEORGE CIULEI
- 4th Medical Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - ANGELA COZMA
- 4th Medical Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - MADALINA SAVA
- 4th Medical Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - DAN LUCIAN DUMITRASCU
- 2nd Medical Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| |
Collapse
|
|
36
|
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: 11] [Impact Index Per Article: 1.2] [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]
|
|
37
|
Suga T, Sato K, Yamazaki Y, Ohyama T, Horiguchi N, Kakizaki S, Kusano M, Yamada M. Probable case of drug reaction with eosinophilia and systemic symptom syndrome due to combination therapy with daclatasvir and asunaprevir. World J Clin Cases 2015; 3:1005-1010. [PMID: 26677451 PMCID: PMC4677081 DOI: 10.12998/wjcc.v3.i12.1005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 09/25/2015] [Accepted: 10/20/2015] [Indexed: 02/05/2023] Open
Abstract
A 66-year-old, interferon-ineligible, treatment-naive man who was diagnosed with chronic hepatitis C due to hepatitis C virus genotype 1b began combination therapy with daclatasvir and asunaprevir. On day 14 of treatment, hepatic reserve and renal function deterioration was observed, while his transaminase levels were normal. Both daclatasvir and asunaprevir were discontinued on day 18 of treatment, because the patient complained of dark urine and a rash on his trunk and four limbs. After discontinuing antiviral therapy, the abnormal laboratory finding and clinical manifestations gradually improved, without recurrence. Our case fulfilled the diagnostic criteria of probable drug reaction with eosinophilia and systemic symptom (DRESS) syndrome. Despite the 18-d treatment, sustained virological response 12 was achieved. Based on the clinical course, we concluded that there was a clear cause-and-effect relationship between the treatment and adverse events. To our knowledge, this patient represents the first case of probable DRESS syndrome that includes concomitant deterioration of hepatic reserve and renal function due to combination therapy with daclatasvir and asunaprevir, regardless of normalization of transaminase levels. Our case suggests that we should pay attention not only to the transaminase levels but also to allergic symptoms associated with organ involvement during combination therapy with daclatasvir and asunaprevir.
Collapse
|
|
38
|
Sevgi DY, Bayraktar B, Gündüz A, Özgüven BY, Togay A, Bulut E, Uzun N, Dökmetaş İ. Serum soluble urokinase-type plasminogen activator receptor and interferon-γ-induced protein 10 levels correlate with significant fibrosis in chronic hepatitis B. Wien Klin Wochenschr 2015; 128:28-33. [PMID: 26546355 DOI: 10.1007/s00508-015-0886-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 10/12/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) presents an important public health problem. Liver biopsy is currently the gold standard for assessing the degree of intrahepatic inflammation and for staging liver fibrosis. However, the value of liver biopsies is limited by sampling errors, understaging and interobserver variability in interpretation. There is, therefore, a need to identify novel, non-invasive serologic biomarkers for the development of new predictive models of fibrosis. METHODS We enrolled patients with chronic hepatitis B infection (CHB) and examined the relationships between serum soluble urokinase plasminogen activator receptor (suPAR) and interferon-induced protein-10 (IP-10), and the results of liver biopsies. Healthy volunteers with normal aminotransferase levels and negative serological results for HBV, hepatitis C virus and human immunodeficiency virus were recruited as controls. RESULTS Mean platelet volume, serum suPAR and IP-10 were significantly elevated in patients with CHB compared with controls. Median serum suPAR and IP-10 levels were significantly higher in patients with liver fibrosis compared with patients with mild fibrosis. There was no significant difference in mean platelet volume or aspartate aminotransferase-to-platelet ratio index scores between patients with mild and significant fibrosis. CONCLUSION suPAR and IP-10 were able to distinguish between significant and mild fibrosis with good sensitivity and specificity, and may thus represent useful biomarkers for identifying patients with significant fibrosis.
Collapse
Affiliation(s)
- Dilek Yıldız Sevgi
- Department of Infectious Diseases and Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey.
| | - Banu Bayraktar
- Department of Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Alper Gündüz
- Department of Infectious Diseases and Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Banu Yılmaz Özgüven
- Department of Pathology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Alper Togay
- Department of Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Emin Bulut
- Department of Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Nuray Uzun
- Department of Infectious Diseases and Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - İlyas Dökmetaş
- Department of Infectious Diseases and Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| |
Collapse
|
|
39
|
Abstract
BACKGROUND The prognosis and management of chronic liver diseases greatly depend on the amount and progression of liver fibrosis with the risk of developing cirrhosis. Liver biopsy, traditionally considered as the reference standard for the staging of fibrosis, has been challenged over the past decade by the development of novel noninvasive methodologies. Key Messages: Noninvasive methods rely on two different but complementary approaches: a 'biological' approach based on the dosage serum biomarkers, and a 'physical' approach based on the measurement of liver stiffness using transient elastography (TE). There are two clinically relevant endpoints for the staging of liver fibrosis: (1) significant fibrosis (indication for antiviral treatment in viral hepatitis B and C), and (2) cirrhosis (indication for screening of esophageal varices and hepatocellular carcinoma). TE (FibroScan®), FibroTest® and APRI have been the most extensively studied and validated methods, mainly in chronic hepatitis C. Combining two unrelated methods, such as TE and biomarkers, is an attractive approach that increases diagnostic performance and limits the drawback of both methodologies. TE appears to be an excellent tool for the early detection of cirrhosis with likely prognostic value in this setting. Thus far, however, it cannot replace upper endoscopy for screening of esophageal varices. The main limitation of TE in clinical practice is the impossibility of obtaining reliable liver stiffness measurements in around 20% of cases, mainly comprising obese patients. CONCLUSION An increasing number of reliable noninvasive methods are now available that are widely used in clinical practice, mostly in viral hepatitis, resulting in a significant decrease in the need for liver biopsy.
Collapse
Affiliation(s)
- Laurent Castera
- Service d'Hépatologie, INSERM U773, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Denis Diderot Paris 7, Clichy, France
| |
Collapse
|
|
40
|
EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015; 63:237-64. [PMID: 25911335 DOI: 10.1016/j.jhep.2015.04.006] [Citation(s) in RCA: 1320] [Impact Index Per Article: 132.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023]
|
|
41
|
Mansy SS, Nosseir MM, Zoheiry MA, Hassanein MH, Guda MF, Othman MM, AbuTalab H. Value of reelin for assessing hepatic fibrogenesis in a group of Egyptian HCV infected patients. Clin Chem Lab Med 2015; 52:1319-28. [PMID: 24803609 DOI: 10.1515/cclm-2014-0030] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 04/07/2014] [Indexed: 01/28/2023]
Abstract
BACKGROUND Development of non-invasive markers that can predict the stages of hepatic fibrosis without resorting to repeated liver biopsies is still an important goal to evaluate the effectiveness of antifibrotic treatment. The present work investigates the value of the assessment of peripheral circulating reelin, in which the liver represents its prime source, as a marker for monitoring hepatic fibrogenesis. METHODS Seventy-four cases with chronic hepatitis positive for serum HCV RNA and 15 healthy volunteers were enrolled in this study. Assessment of reelin in the harvested serum and in 64 corresponding liver biopsies using immunofluorescence technique was done. The results were evaluated in relation to the stages and quantitative morphometric analysis of hepatic fibrosis as well as the serum levels of the validated biomarker hyaluronic acid. RESULTS Significant correlation was detected between the levels of serum reelin and the semiquantitative assessment of reelin immunoreactivity in liver tissue, the stages of hepatic fibrosis, the morphometrically determined collagen and serum hyaluronic acid with a correlation coefficient of 0.675, 0.623, 0.479, 0.772, respectively with p<0.001. The sensitivity and the specificity of reelin for the determination of advanced (F2+F3) and significant fibrosis (F2-F4) were nearly comparable to the result of hyaluronic acid. In addition the area under curve (AUC) were 0.859, 0.871 for the reelin versus 0.878, and 0.891 for the hyaluronic acid. CONCLUSIONS In conclusion serum reelin may be considered an additional useful parameter for monitoring the progression of hepatic fibrosis in HCV-infected patients specially in those with active rheumatological conditions which result in an increase in serum hyaluronic acid.
Collapse
|
|
42
|
Fagan KJ, Pretorius CJ, Horsfall LU, Irvine KM, Wilgen U, Choi K, Fletcher LM, Tate J, Melino M, Nusrat S, Miller GC, Clouston AD, Ballard E, O'Rourke P, Lampe G, Ungerer JPJ, Powell EE. ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. Liver Int 2015; 35:1673-81. [PMID: 25495373 DOI: 10.1111/liv.12760] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 12/07/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS There is increasing need to identify individuals with advanced liver fibrosis, who are at risk of complications such as hepatocellular carcinoma. The commercially available enhanced liver fibrosis (ELF) test provides a non-invasive assessment of fibrosis severity. This study was designed to determine the diagnostic accuracy of the manufacturer's cut-off value (≥9.8) in identifying advanced fibrosis. METHODS The relationship between ELF score and fibrosis was examined using serum collected at time of liver biopsy for investigation of liver disease, particularly viral hepatitis. Fibrosis was staged using a modified METAVIR score. If available, liver tissue was recut and stained with Sirius red to determine collagen proportional area (CPA) and subsinusoidal fibrosis (SSF). RESULTS Enhanced liver fibrosis score ≥9.8 had a sensitivity of 74.4% and specificity 92.4% for detecting advanced fibrosis. In the whole cohort (n = 329), ELF score was more likely to incorrectly classify individuals if age was ≥45 years and METAVIR inflammatory grade was 2 or 3 (adjusted OR, odds ratio 3.71 and 2.62 respectively). In contrast, ELF score was less likely to misclassify individuals in the presence of steatosis (OR 0.37). Neither SSF nor CPA explained the discordance in ELF score for patients with or without advanced fibrosis. CONCLUSION Although ELF score ≥9.8 reliably identifies advanced fibrosis in patients with chronic liver disease, both age and inflammatory activity need to be considered when interpreting the result. Importantly, ELF score performed well in the presence of steatosis and could thus be helpful in the assessment of fatty liver disease.
Collapse
Affiliation(s)
- Kevin J Fagan
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Carel J Pretorius
- School of Medicine, The University of Queensland, Brisbane, Qld, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, Qld, Australia
| | - Leigh U Horsfall
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Katharine M Irvine
- Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Urs Wilgen
- School of Medicine, The University of Queensland, Brisbane, Qld, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, Qld, Australia
| | - Kihoon Choi
- Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Linda M Fletcher
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Jill Tate
- Department of Chemical Pathology, Pathology Queensland, Brisbane, Qld, Australia
| | - Michelle Melino
- Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Sharmin Nusrat
- Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Gregory C Miller
- Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Andrew D Clouston
- Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| | - Emma Ballard
- Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia
| | - Peter O'Rourke
- Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia
| | - Guy Lampe
- Pathology Queensland, Princess Alexandra Hospital, Brisbane, Qld, Australia
| | - Jacobus P J Ungerer
- Department of Chemical Pathology, Pathology Queensland, Brisbane, Qld, Australia
| | - Elizabeth E Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Qld, Australia
| |
Collapse
|
|
43
|
Ding H, Ma JJ, Wang WP, Zeng WJ, Jiang T, Huang BJ, Chen SY. Assessment of liver fibrosis: the relationship between point shear wave elastography and quantitative histological analysis. J Gastroenterol Hepatol 2015; 30:553-8. [PMID: 25250854 DOI: 10.1111/jgh.12789] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM Traditional pathological scoring systems for liver fibrosis progression are predominantly based on the description of architectural changes with no consideration of the amount of collagen fiber deposition. Our purpose was to explore a true histological standard in accordance with the liver stiffness measured by point shear wave elastography (PSWE) in patients with chronic hepatitis B. METHODS A total of 78 patients with liver neoplasms underwent liver stiffness measurements with PSWE as well as biochemical investigations within 3 days before partial hepatectomy. One tissue section of the liver specimens was stained with HE trichrome and evaluated traditionally with the Scheuer scoring system. The other tissue section was stained with picroSirius red and was evaluated according to the semiquantitative Chevallier et al. scoring system. In addition, this second tissue section was evaluated for the collagen proportionate area (CPA) with computer-assisted digital image analysis. The reproducibility of PSWE technology was explored through the intra-class correlation coefficient of a reliability analysis. RESULTS The PSWE technology revealed good reproducibility in liver stiffness measurements, and the PSWE values increased with the pathological severity of liver fibrosis on both the Scheuer scoring system and the semiquantitative Chevallier et al. scoring system. PSWE values exhibited more reasonable relationships with CPA (r = 0.628, P = 0.00 < 0.05) than with the Scheuer scoring system (r = 0.473, P = 0.00 < 0.05) or the Chevallier et al. semiquantitative scoring system (r = 0.487, P = 0.00 < 0.05). CONCLUSION CPA is a better pathological parameter than traditional semiquantitative scoring systems in accordance with liver stiffness measured by PSWE technology.
Collapse
Affiliation(s)
- Hong Ding
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Nielsen MJ, Veidal SS, Karsdal MA, Ørsnes-Leeming DJ, Vainer B, Gardner SD, Hamatake R, Goodman ZD, Schuppan D, Patel K. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int 2015; 35:429-37. [PMID: 25308921 DOI: 10.1111/liv.12700] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/06/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Fibrogenesis results in release of certain extracellular matrix protein fragments into the circulation. We evaluated the diagnostic and prognostic performance of two novel serological markers, the precisely cleaved N-terminal propeptide of type III collagen (Pro-C3) and a peptide of helical collagen type III degradation (C3M), in chronic hepatitis C (CHC) patients. METHOD Pro-C3 and C3M were measured by ELISA in plasma from CHC patients (n = 194) from a prior phase II antifibrotic trial (NCT00244751). Plasma samples and paired liver biopsies were obtained at baseline and after 1-year. Patients were stratified according to Ishak stages 2-4. Internal cross-validation was performed by bootstrap analysis. RESULTS Pro-C3 levels were significantly higher in CHC patients in Ishak stage 4 compared to stage 2 (P < 0.001) or 3 (P < 0.01). Pro-C3 could significantly distinguish moderate (stage 4) from mild fibrosis (stage 2/3) (AUC = 0.72, P < 0.001). Importantly, an overall significance in Pro-C3 (P = 0.007) levels was observed between the groups of -1, 0, +1 and +2 change in Ishak stage at 12 months. Pro-C3 was significantly increased in group +1 (P = 0.030) and +2 (P = 0.021) compared to group 0. No significant differences were observed for C3M. In multivariate analysis, only baseline Pro-C3, but not FibroTest, had an independent association with fibrosis progression. CONCLUSIONS Pro-C3 is a useful test to predict fibrogenesis and monitor disease progression. Moreover, it could differentiate mild from moderate disease. Pro-C3 may become a promising blood parameter be included in future studies for monitoring disease progression and eventually for evaluation of potential antifibrotic therapies.
Collapse
Affiliation(s)
- Mette J Nielsen
- Nordic Bioscience A/S, Herlev, Denmark; Faculty of Health Science, University of Southern Denmark, Odense, Denmark
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Crossan C, Tsochatzis EA, Longworth L, Gurusamy K, Davidson B, Rodríguez-Perálvarez M, Mantzoukis K, O'Brien J, Thalassinos E, Papastergiou V, Burroughs A. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess 2015; 19:1-vi. [PMID: 25633908 PMCID: PMC4781028 DOI: 10.3310/hta19090] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION This study is registered as PROSPERO CRD42011001561. FUNDING The National Institute for Health Research Health Technology Assessment programme.
Collapse
Affiliation(s)
- Catriona Crossan
- Health Economics Research Group, Brunel University London, Uxbridge, UK
| | - Emmanuel A Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Louise Longworth
- Health Economics Research Group, Brunel University London, Uxbridge, UK
| | | | | | - Manuel Rodríguez-Perálvarez
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Konstantinos Mantzoukis
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Julia O'Brien
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Evangelos Thalassinos
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Vassilios Papastergiou
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Andrew Burroughs
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| |
Collapse
|
|
46
|
de Sousa GA, do Céu Clara Costa I, de Souza DLB, de Andrade FB, Celani LMS, Pessoa RS, de Souza Filho MC, de Oliveira DFM, de Medeiros LL, de Oliveira LSD, Monteiro MF. Variables Associated with Cirrhosis Diagnosis in Patients with Chronic Hepatitis C: A Case-Control Study. Health (London) 2015. [DOI: 10.4236/health.2015.712176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
47
|
Soresi M, Giannitrapani L, Cervello M, Licata A, Montalto G. Non invasive tools for the diagnosis of liver cirrhosis. World J Gastroenterol 2014; 20:18131-18150. [PMID: 25561782 PMCID: PMC4277952 DOI: 10.3748/wjg.v20.i48.18131] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/22/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC), the end stage of many forms of chronic hepatitis of different etiologies is a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules surrounded by annular fibrosis. This chronic progressive clinical condition, leads to liver cell failure and portal hypertension, which can favour the onset of hepatocellular carcinoma. Defining the phase of the natural history is crucial for therapeutic choice and prognosis. Liver biopsy is currently considered the best available standard of reference but it has some limits, so alternative tools have been developed to substitute liver biopsy when assessing liver fibrosis. Serum markers offer a cost-effective alternative to liver biopsy being less invasive and theoretically without complications. They can be classified into direct and indirect markers which may be used alone or in combination to produce composite scores. Diagnostic imaging includes a number of instruments and techniques to estimate liver fibrosis and cirrhosis like ultrasound (US), US Doppler, contrast enhanced US and Elastography. US could be used for the diagnosis of advanced LC while is not able to evaluate progression of fibrosis, in this case Elastography is more reliable. This review aims to revise the most recent data from the literature about non invasive methods useful in defining liver fibrosis.
Collapse
|
|
48
|
Nøjgaard C, Johansen JS, Bjerregaard P, Bojesen SE, Becker U. Plasma YKL-40 in Inuit and Danes. Alcohol Alcohol 2014; 50:11-7. [PMID: 25332349 DOI: 10.1093/alcalc/agu072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIMS The aim of the present study was to investigate whether there are differences in plasma levels of YKL-40 between Inuit in Greenland and in Denmark and in Danes, as well as to study the relationship between alcohol intake, plasma YKL-40 and other factors in Inuit. METHODS Plasma YKL-40 levels were measured on 1645 people from The Greenland Population Study (a cross-sectional population study of Inuit from Denmark and West Greenland) and were compared with the plasma YKL-40 levels of 8899 people from The Copenhagen City Heart Study (a population-based, prospective study of the Danish general population). RESULTS The plasma concentrations of YKL-40 were significantly (P = 0.001) lower in Inuit living in Greenland (median 46 µg/l, range 10-2164, n = 1164) compared with the plasma YKL-40 levels of Inuit living in Denmark (median 63 µg/l, range 20-2827, n = 481) and of Danes living in Denmark (median 55 µg/l, range 10-2909, n = 8899). In Inuit, increased alcohol intake was significantly associated with increased plasma YKL-40 levels (P < 0.001), and high plasma YKL-40 levels were associated with high values of alkaline phosphatase and low values of albumin. Smoking, gender and bilirubin were not associated with the plasma YKL-40 level. High levels of YKL-40 and alcohol were associated with where people lived. CONCLUSION The plasma concentrations of YKL-40 are significantly lower in Inuit living in Greenland than Inuit and Danes living in Denmark. A number of factors, including different alcohol intake patterns, nutrition and genes may play a role in these findings.
Collapse
Affiliation(s)
- Camilla Nøjgaard
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Julia S Johansen
- Departments of Medicine and Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark
| | - Peter Bjerregaard
- National Institute of Public Health, University of Southern Denmark, Odense, Denmark
| | - Stig E Bojesen
- Department of Clinical Biochemistry, Copenhagen University Hospital Herlev, Herlev, Denmark The Copenhagen City Heart Study, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Ulrik Becker
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark National Institute of Public Health, University of Southern Denmark, Odense, Denmark
| |
Collapse
|
|
49
|
Impact of contacting study authors to obtain additional data for systematic reviews: diagnostic accuracy studies for hepatic fibrosis. Syst Rev 2014; 3:107. [PMID: 25239493 PMCID: PMC4185334 DOI: 10.1186/2046-4053-3-107] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/29/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Seventeen of 172 included studies in a recent systematic review of blood tests for hepatic fibrosis or cirrhosis reported diagnostic accuracy results discordant from 2 × 2 tables, and 60 studies reported inadequate data to construct 2 × 2 tables. This study explores the yield of contacting authors of diagnostic accuracy studies and impact on the systematic review findings. METHODS Sixty-six corresponding authors were sent letters requesting additional information or clarification of data from 77 studies. Data received from the authors were synthesized with data included in the previous review, and diagnostic accuracy sensitivities, specificities, and positive and likelihood ratios were recalculated. RESULTS Of the 66 authors, 68% were successfully contacted and 42% provided additional data for 29 out of 77 studies (38%). All authors who provided data at all did so by the third emailed request (ten authors provided data after one request). Authors of more recent studies were more likely to be located and provide data compared to authors of older studies. The effects of requests for additional data on the conclusions regarding the utility of blood tests to identify patients with clinically significant fibrosis or cirrhosis were generally small for ten out of 12 tests. Additional data resulted in reclassification (using median likelihood ratio estimates) from less useful to moderately useful or vice versa for the remaining two blood tests and enabled the calculation of an estimate for a third blood test for which previously the data had been insufficient to do so. We did not identify a clear pattern for the directional impact of additional data on estimates of diagnostic accuracy. CONCLUSIONS We successfully contacted and received results from 42% of authors who provided data for 38% of included studies. Contacting authors of studies evaluating the diagnostic accuracy of serum biomarkers for hepatic fibrosis and cirrhosis in hepatitis C patients impacted conclusions regarding diagnostic utility for two blood tests and enabled the calculation of an estimate for a third blood test. Despite relatively extensive efforts, we were unable to obtain data to resolve discrepancies or complete 2 × 2 tables for 62% of studies.
Collapse
|
|
50
|
Busk TM, Bendtsen F, Nielsen HJ, Jensen V, Brünner N, Møller S. TIMP-1 in patients with cirrhosis: relation to liver dysfunction, portal hypertension, and hemodynamic changes. Scand J Gastroenterol 2014; 49:1103-10. [PMID: 25048331 DOI: 10.3109/00365521.2014.934910] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Cirrhotic portal hypertensive patients often develop hemodynamic complications and the diagnosis is often based on liver biopsy and measurements of the hepatic venous pressure gradient (HVPG). Potential noninvasive biomarkers for the severity of cirrhosis are the matrix metalloproteinase and their specific inhibitors such as tissue inhibitor of metalloproteinases-1 (TIMP-1). The aim of the study was to investigate TIMP-1 levels in cirrhosis in relation to the degree of liver dysfunction, portal hypertension, and hemodynamic changes. MATERIALS AND METHODS We retrospectively studied 84 patients with cirrhosis and 14 controls without liver disease. All individuals underwent a liver vein catheterization with a hemodynamic assessment. TIMP-1 was determined in arterial and hepatic venous plasma using an MAC-15 TIMP-1 ELISA. RESULTS Hepatic venous concentrations of TIMP-1 were significantly increased in patients compared to controls: 336 (166) ng/ml versus 145 (100) (median/IQ range) (p < 0.001) with a progressive increase throughout the Child classes (p < 0.001). Circulating TIMP-1 correlated significantly with indocyanine green clearance (r = -0.44, p < 0.0001), Child Turcotte score (r = 0.50, p < 0.0001), HVPG (r = 0.40, p < 0.0001), mean arterial pressure (r = -0.29, p = 0.008), and systemic vascular resistance (r = -0.23, p = 0.03). Receiver operating characteristic curve analysis enabled us to establish cutoff values for TIMP-1 with regard to portal hypertension. CONCLUSIONS TIMP-1 is significantly increased in patients with cirrhosis and correlates with the severity of the disease, degree of portal hypertension, and vasodilatory state. TIMP-1 is therefore a promising new noninvasive marker to predict hemodynamic-related complications in cirrhosis.
Collapse
Affiliation(s)
- Troels M Busk
- Department of Clinical Physiology and Nuclear Medicine, Centre of Functional Imaging and Research, Copenhagen University Hospital Hvidovre , Copenhagen , Denmark
| | | | | | | | | | | |
Collapse
|