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Huynh HH, Barahona-Carrillo L, Moncrieffe D, Cowan DA, Forrest K, Becker JO, Emrick MA, Thomas A, Thevis M, Eichner D, Byers PH, Miller GD, Hoofnagle AN. A Novel High-Throughput Immunoaffinity LC-MS/MS Assay for P-III-NP and Other Fragments of Type III Procollagen in Human Serum. Drug Test Anal 2024. [PMID: 39462787 DOI: 10.1002/dta.3814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/16/2024] [Accepted: 09/22/2024] [Indexed: 10/29/2024]
Abstract
The amino-terminal propeptide of type III procollagen (P-III-NP) is used with IGF-I to detect the illicit use of growth hormone and to monitor growth hormone therapy. However, the only currently available assays for P-III-NP are immunoassays, which are not well harmonized. In addition, other fragments of type III procollagen may better evaluate collagen turnover. We aimed to develop a high-throughput assay using immunoaffinity enrichment coupled to ultra-high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify peptides belonging to three different regions of type III procollagen in human serum simultaneously. To facilitate higher throughput, we transferred the assay from microcentrifuge tubes to a 96-well plate format with partially automated pipetting. The method was linear (Pearson's R ≥ 0.994) over an estimated concentration range of 1.35-13.3 nM, 0.04-2.28 nM, and 0.26-5.1 nM for each surrogate peptide of P-III-NP, collagen degradation products, and the carboxyl-terminal propeptide, respectively. Intra-day and inter-day imprecision were both < 13.6%, and the results of robustness testing were also encouraging. The method was successfully applied to capillary blood samples obtained using Tasso+ microsampling devices. Modest correlation of P-III-NP concentration was observed between our new method and a WADA-approved immunoassay (N = 40, Pearson's R = 0.789) with a significant bias of -87.8%. Our method simultaneously quantifies four peptides belonging to three regions of type III procollagen in human serum. High bias between assays highlights the need for common higher-order calibrators or reference materials to help improve the comparability of results across laboratories.
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Affiliation(s)
- Huu-Hien Huynh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Lili Barahona-Carrillo
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Danielle Moncrieffe
- Drug Control Centre, Department of Analytical, Environmental and Forensic Science, King's College London, London, UK
- Department of Analytical, Environmental & Forensic Sciences, King's College London, London, UK
| | - David A Cowan
- Drug Control Centre, Department of Analytical, Environmental and Forensic Science, King's College London, London, UK
| | - Katrina Forrest
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Jessica O Becker
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Michelle A Emrick
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Andreas Thomas
- Center for Preventive Doping Research (ZePraeDo), Institute of Biochemistry, German Sport University, Cologne, Germany
| | - Mario Thevis
- Center for Preventive Doping Research (ZePraeDo), Institute of Biochemistry, German Sport University, Cologne, Germany
| | - Daniel Eichner
- Sport Medicine Research and Testing Laboratory, Salt Lake City, Utah, USA
| | - Peter H Byers
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Geoffrey D Miller
- Sport Medicine Research and Testing Laboratory, Salt Lake City, Utah, USA
| | - Andrew N Hoofnagle
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washngton, USA
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Kaya S, Boydak M, Aydin M, Aras İ. Association between serum cytokeratin 18 and N-terminal procollagen III propeptide in patients with biopsy-proven nonalcoholic fatty liver disease. Biotech Histochem 2024; 99:313-319. [PMID: 39092622 DOI: 10.1080/10520295.2024.2385011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024] Open
Abstract
Liver biopsy is still the gold standard in the staging of nonalcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease worldwide. However, being an invasive method, liver biopsy has limited use in clinical practice. The aim of this study was to determine the relationship between serum levels of cytokeratin 18 (CK-M30) and N-terminal procollagen III propeptide (PIIINP) in patients with biopsy-proven NAFLD. The study was carried out on volunteers, including both healthy individuals and patients pre-diagnosed with NAFLD. The liver biopsies were re-assessed by applying the Steatosis, Activity, Fibrosis/Fatty Liver Inhibition of Progression (SAF/FLIP) algorithm. At the end of the study, frozen serum samples (-80 °C) were analyzed using commercial kits. CK18-M30 and PIIINP levels significantly differed in all study groups. There was no significant correlation between serum levels of CK18-M30 and PIIINP in healthy individuals but there was a significant positive correlation between CK18-M30 and PIIINP levels in NAFLD (NAFL-nonalcoholic steatohepatitis (NASH)) groups. CK18-M30 was better than PIIINP at distinguishing between NAFL and NASH. The results obtained for biopsy-proven NAFLD demonstrated that both PIIINP and CK18-M30 were partly associated with histological parameters and could aid in distinguishing between NASH and NAFL.
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Affiliation(s)
- Sercan Kaya
- Health Services Vocational School, Medical Laboratory Program, Batman University, Batman, Turkey
| | - Murat Boydak
- Faculty of Veterinary Medicine Faculty, Department of Histology and Embryology, Selçuk University, Konya, Turkey
| | - Mesut Aydin
- School of Medicine, Department of Gastroenterology, Van Yuzuncu Yil University, Van, Turkey
| | - İbrahim Aras
- School of Medicine, Department of Pathology, Van Yuzuncu Yil University, Van, Turkey
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Zeng Q, Liu CH, Ampuero J, Wu D, Jiang W, Zhou L, Li H, Bai L, Romero-Gómez M, Tang H. Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance. RNA Biol 2024; 21:1-15. [PMID: 38113132 PMCID: PMC10761141 DOI: 10.1080/15476286.2023.2290769] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2023] [Indexed: 12/21/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.
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Affiliation(s)
- Qingmin Zeng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Javier Ampuero
- Digestive Diseases Unit, Virgen del Rocío University Hospital. SeLiver group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US). University of Seville, Seville, Spain
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Manuel Romero-Gómez
- Digestive Diseases Unit, Virgen del Rocío University Hospital. SeLiver group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US). University of Seville, Seville, Spain
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
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Gowda D, Shekhar C, B. Gowda SG, Chen Y, Hui SP. Crosstalk between Lipids and Non-Alcoholic Fatty Liver Disease. LIVERS 2023; 3:687-708. [DOI: 10.3390/livers3040045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), a complex liver disorder that can result in non-alcoholic steatohepatitis, cirrhosis, and liver cancer, is the accumulation of fat in the liver seen in people due to metabolic dysfunction. The pathophysiology of NAFLD is influenced by several variables, such as metabolic dysregulation, oxidative stress, inflammation, and genetic susceptibility. This illness seriously threatens global health because of its link to obesity, insulin resistance, type 2 diabetes, and other metabolic disorders. In recent years, lipid–NAFLD crosstalk has drawn a lot of interest. Through numerous methods, lipids have been connected to the onset and advancement of the illness. The connection between lipids and NAFLD is the main topic of the current review, along with the various therapeutic targets and currently available drugs. The importance of hepatic lipid metabolism in the progression of NAFLD is summarized with the latest results in the field.
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Affiliation(s)
- Divyavani Gowda
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Chandra Shekhar
- Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Siddabasave Gowda B. Gowda
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
- Graduate School of Global Food Resources, Hokkaido University, Sapporo 060-0812, Japan
| | - Yifan Chen
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Shu-Ping Hui
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
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Terracciani F, Falcomatà A, Gallo P, Picardi A, Vespasiani-Gentilucci U. Prognostication in NAFLD: physiological bases, clinical indicators, and newer biomarkers. J Physiol Biochem 2023; 79:851-868. [PMID: 36472795 DOI: 10.1007/s13105-022-00934-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic in Western countries. Notably, while the majority of NAFLD patients will not evolve until advanced liver disease, a minority of them will progress towards liver-related events. Therefore, risk stratification and prognostication are emerging as fundamental in order to optimize human and economic resources for the care of these patients.Liver fibrosis has been clearly recognized as the main predictor of poor hepatic and extrahepatic outcomes. However, a prediction based only on the stage of fibrosis is near-sighted and static, as it does not capture the propensity of disease to further progress, the speed of progression and their changes over time. These determinants, which result from the interaction between genetic predisposition and acquired risk factors (obesity, diabetes, etc.), express themselves in disease activity, and can be synthesized by biomarkers of hepatic inflammation and fibrogenesis.In this review, we present the currently available clinical tools for risk stratification and prognostication in NAFLD specifically with respect to the risk of progression towards hard hepatic outcomes, i.e., liver-related events and death. We also discuss about the genetic and acquired drivers of disease progression, together with the physiopathological bases of their come into action. Finally, we introduce the most promising biomarkers in the direction of repeatedly assessing disease activity over time, mainly in response to future therapeutic interventions.
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Affiliation(s)
- Francesca Terracciani
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Andrea Falcomatà
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Paolo Gallo
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy.
| | - Antonio Picardi
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
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Nagai K, Nagai K, Iwaki M, Kobayashi T, Nogami A, Oka M, Saito S, Yoneda M. Frontiers of Collaboration between Primary Care and Specialists in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Review. Life (Basel) 2023; 13:2144. [PMID: 38004284 PMCID: PMC10672694 DOI: 10.3390/life13112144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/26/2023] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common liver disease. It has a rapidly growing patient population owing to the increasing prevalence of obesity and type 2 diabetes. Patients with MASLD are primarily treated by family physicians when fibrosis is absent or mild and by gastroenterologists/hepatologists when fibrosis is more advanced. It is imperative that a system for the appropriate treatment and surveillance of hepatocellular carcinoma be established in order to ensure that highly fibrotic cases are not overlooked among the large number of MASLD patients. Family physicians should check for viral hepatitis, autoimmune hepatitis, alcoholic liver disease, and drug-induced liver disease, and should evaluate fibrosis using NIT; gastroenterologists/hepatologists should perform liver biopsy, ultrasound elastography (260 units in Japan as of October 2023), and MR elastography (35 units in Japan as of October 2023). This review presents the latest findings in MASLD and the role, accuracy, and clinical use of NIT. It also describes the collaboration between Japanese primary care and gastroenterologists/hepatologists in Japan in the treatment of liver diseases, including MASLD.
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Affiliation(s)
- Koki Nagai
- Gastroenterology Division, National Hospital Organization Yokohama Medical Center, 3-60-2 Harajyuku, Totsuka-ku, Yokohama 245-8575, Japan;
| | - Kazuki Nagai
- Nagai Clinic, 1-7-25 Yokodai, Isogo-ku, Yokohama 235-0045, Japan;
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan; (M.I.); (T.K.); (A.N.)
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan; (M.I.); (T.K.); (A.N.)
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan; (M.I.); (T.K.); (A.N.)
| | - Masanao Oka
- OkaMedical, 1-19-18-3F Kamiookanishi, Kounan-ku, Yokohama 233-0002, Japan;
| | - Satoru Saito
- Sanno Hospital, 8-10-16 Akasaka, Minato-ku, Tokyo 107-0052, Japan;
| | - Masato Yoneda
- Gastroenterology Division, National Hospital Organization Yokohama Medical Center, 3-60-2 Harajyuku, Totsuka-ku, Yokohama 245-8575, Japan;
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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Lee J, Westphal M, Vali Y, Boursier J, Petta S, Ostroff R, Alexander L, Chen Y, Fournier C, Geier A, Francque S, Wonders K, Tiniakos D, Bedossa P, Allison M, Papatheodoridis G, Cortez-Pinto H, Pais R, Dufour JF, Leeming DJ, Harrison S, Cobbold J, Holleboom AG, Yki-Järvinen H, Crespo J, Ekstedt M, Aithal GP, Bugianesi E, Romero-Gomez M, Torstenson R, Karsdal M, Yunis C, Schattenberg JM, Schuppan D, Ratziu V, Brass C, Duffin K, Zwinderman K, Pavlides M, Anstee QM, Bossuyt PM. Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study. Hepatology 2023; 78:258-271. [PMID: 36994719 DOI: 10.1097/hep.0000000000000364] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 12/22/2022] [Indexed: 03/31/2023]
Abstract
BACKGROUND AND AIMS Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. APPROACH AND RESULTS Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). CONCLUSIONS Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.
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Affiliation(s)
- Jenny Lee
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
| | - Max Westphal
- Fraunhofer Institute for Digital Medicine MEVIS, Bremen, Germany
| | - Yasaman Vali
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
| | - Jerome Boursier
- Department of Hepatology, Angers University Hospital, Angers, France
| | - Salvatorre Petta
- Section of Gastroenterology and Hepatology, Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza, Department, University of Palermo, Palermo, Italy
| | | | | | - Yu Chen
- Lilly Research Laboratories, Eli Lilly and Company Ltd (LLY), Indianapolis, Indiana, USA
| | | | - Andreas Geier
- Division of Hepatology, Department of Medicine II, Wurzburg University Hospital, Wurzburg, Germany
| | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, and Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Belgium
| | - Kristy Wonders
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Department of Pathology, Aretaieion Hospital, national and Kapodistrian University of Athens, Athens, Greece
| | - Pierre Bedossa
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Mike Allison
- Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University NHS Foundation Trust, CB2 0QQ, Cambridge, UK
| | - Georgios Papatheodoridis
- Gastroenterology Department, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - Raluca Pais
- Assistance Publique-Hôpitaux de Paris, hôpital Pitié Salpêtrière, Sorbonne University, ICAN (Institute of Cardiometabolism and Nutrition), Paris, France
| | - Jean-Francois Dufour
- Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | | | - Stephen Harrison
- Department of Gastroenterology and Hepatology, Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
| | - Jeremy Cobbold
- Department of Gastroenterology and Hepatology, Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
| | - Adriaan G Holleboom
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centres, location AMC, Amsterdam, the Netherlands
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Javier Crespo
- Department of Gastroenterology and Hepatology, University Hospital Marques de Valdecilla. Research Institute Valdecilla-IDIVAL, Santander, Spain
| | - Mattias Ekstedt
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, School of Medicine, NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, UK
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Manuel Romero-Gomez
- UCM Digestive Diseases, ciberehd, Virgen del Rocio University Hospital. Institute of Biomedicine of Seville (CSIC/HUVR/US), Department of Medicine, University of Seville, Seville, Spain
| | - Richard Torstenson
- Cardiovascular, Renal and Metabolism Regulatory Affairs, AstraZeneca, Mölndal, Sweden
| | | | - Carla Yunis
- Internal Medicine and Hospital, Global Product Development, Pfizer, Inc, New York, New York, USA
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center Mainz, Mainz, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Vlad Ratziu
- Assistance Publique-Hôpitaux de Paris, hôpital Pitié Salpêtrière, Sorbonne University, ICAN (Institute of Cardiometabolism and Nutrition), Paris, France
| | - Clifford Brass
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | - Kevin Duffin
- Lilly Research Laboratories, Eli Lilly and Company Ltd (LLY), Indianapolis, Indiana, USA
| | - Koos Zwinderman
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
| | | | - Quentin M Anstee
- Department of Gastroenterology Hepatology, Antwerp University Hospital, and Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Belgium
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Patrick M Bossuyt
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
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9
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Jayasekera D, Hartmann P. Noninvasive biomarkers in pediatric nonalcoholic fatty liver disease. World J Hepatol 2023; 15:609-640. [PMID: 37305367 PMCID: PMC10251277 DOI: 10.4254/wjh.v15.i5.609] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/14/2023] [Accepted: 04/10/2023] [Indexed: 05/24/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide among children and adolescents. It encompasses a spectrum of disease, from its mildest form of isolated steatosis, to nonalcoholic steatohepatitis (NASH) to liver fibrosis and cirrhosis, or end-stage liver disease. The early diagnosis of pediatric NAFLD is crucial in preventing disease progression and in improving outcomes. Currently, liver biopsy is the gold standard for diagnosing NAFLD. However, given its invasive nature, there has been significant interest in developing noninvasive methods that can be used as accurate alternatives. Here, we review noninvasive biomarkers in pediatric NAFLD, focusing primarily on the diagnostic accuracy of various biomarkers as measured by their area under the receiver operating characteristic, sensitivity, and specificity. We examine two major approaches to noninvasive biomarkers in children with NAFLD. First, the biological approach that quantifies serological biomarkers. This includes the study of individual circulating molecules as biomarkers as well as the use of composite algorithms derived from combinations of biomarkers. The second is a more physical approach that examines data measured through imaging techniques as noninvasive biomarkers for pediatric NAFLD. Each of these approaches was applied to children with NAFLD, NASH, and NAFLD with fibrosis. Finally, we suggest possible areas for future research based on current gaps in knowledge.
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Affiliation(s)
- Dulshan Jayasekera
- Department of Internal Medicine and Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, United States
| | - Phillipp Hartmann
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California San Diego, La Jolla, CA 92093, United States.
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10
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Feng Y, Peng B, Li Y, Sun L, Sun Y. Letter to the editor: diagnosing fibrosis and cirrhosis in nonalcoholic fatty liver disease using machine learning models. Hepatology 2023; 77:E103-E104. [PMID: 36645222 DOI: 10.1097/hep.0000000000000209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 01/17/2023]
Affiliation(s)
- Yifei Feng
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
| | | | - Yanan Li
- Peking Union Medical College, Beijing, China
| | - Lejia Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
| | - Yueming Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
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11
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Shi YW, Fan JG. Surveillance of the progression and assessment of treatment endpoints for nonalcoholic steatohepatitis. Clin Mol Hepatol 2023; 29:S228-S243. [PMID: 36521452 PMCID: PMC10029951 DOI: 10.3350/cmh.2022.0401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease (NAFLD) characterized by steatosis-associated inflammation and liver injury. Without effective treatment or management, NASH can have life-threatening outcomes. Evaluation and identification of NASH patients at risk for adverse outcomes are therefore important. Key issues in screening NASH patients are the assessment of advanced fibrosis, differentiation of NASH from simple steatosis, and monitoring of dynamic changes during follow-up and treatment. Currently, NASH staging and evaluation of the effectiveness for drugs still rely on pathological diagnosis, despite sample error issues and the subjectivity associated with liver biopsy. Optimizing the pathological assessment of liver biopsy samples and developing noninvasive surrogate methods for accessible, accurate, and safe evaluation are therefore critical. Although noninvasive methods including elastography, serum soluble biomarkers, and combined models have been implemented in the last decade, noninvasive diagnostic measurements are not widely applied in clinical practice. More work remains to be done in establishing cost-effective strategies both for screening for at-risk NASH patients and identifying changes in disease severity. In this review, we summarize the current state of noninvasive methods for detecting steatosis, steatohepatitis, and fibrosis in patients with NASH, and discuss noninvasive assessments for screening at-risk patients with a focus on the characteristics that should be monitored at follow-up.
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Affiliation(s)
- Yi-Wen Shi
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
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12
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Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated. J Hepatol 2023; 78:989-997. [PMID: 36702175 DOI: 10.1016/j.jhep.2022.12.034] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 12/21/2022] [Accepted: 12/29/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers. METHOD Between 2014-2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. The MTX group included patients who received MTX for ≥6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements. RESULTS A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted odds ratio = 3.19; 95% CI 1.95-5.20; p <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (odds ratio = 1.76; 95% CI 1.20-2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis. CONCLUSION The risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX. IMPACT AND IMPLICATIONS Current guidelines recommend intensive (2-3 monthly) monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis. Evaluation of the association using two validated non-invasive markers of liver fibrosis, liver stiffness and enhanced liver fibrosis score, in a large cohort of patients with rheumatoid arthritis or psoriasis shows that the reported risk has previously been overestimated. The clinical focus should be to improve patients' metabolic risk factors, diabetes and BMI, that are independently associated with liver stiffness. There is a need to consider modifying current treatment monitoring guidelines for methotrexate.
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13
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Chen Z, Ma Y, Cai J, Sun M, Zeng L, Wu F, Zhang Y, Hu M. Serum biomarkers for liver fibrosis. Clin Chim Acta 2022; 537:16-25. [PMID: 36174721 DOI: 10.1016/j.cca.2022.09.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 11/03/2022]
Abstract
Liver fibrosis is a common pathway in most chronic liver diseases, characterized by excessive extracellular matrix accumulation. Without treatment, fibrosis will ultimately result in cirrhosis, portal hypertension, and even liver failure. It is considered that liver fibrosis is reversible while cirrhosis is not, making it significant to diagnose and evaluate liver fibrogenesis timely. As the gold standard, liver biopsy is imperfect due to its invasiveness and sampling error. Therefore, attempts at uncovering noninvasive tests have become a hot topic in liver fibrosis. Nowadays, as an important category of noninvasive tests, serum biomarkers, which are safer, convenient, repeatable, and more acceptable, are widely discussed and commonly used in clinical practice. Serum biomarkers of liver fibrosis can be divided into class I (direct) and classⅡ (indirect) markers. However, the diagnostic efficiency still varies among studies. This article summarizes the most established and newly discovered serum biomarkers for hepatic fibrogenesis.
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Affiliation(s)
- Zhiyang Chen
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yichen Ma
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jingyao Cai
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Mei Sun
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling Zeng
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Fengxi Wu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yiru Zhang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Min Hu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
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14
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Shrestha A, Pradhananga S. Holistic Approach in the Management of Nonalcoholic Fatty Liver Disease. Euroasian J Hepatogastroenterol 2022; 12:S51-S58. [DOI: 10.5005/jp-journals-10018-1359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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15
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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16
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Anstee QM, Castera L, Loomba R. Impact of non-invasive biomarkers on hepatology practice: Past, present and future. J Hepatol 2022; 76:1362-1378. [PMID: 35589256 DOI: 10.1016/j.jhep.2022.03.026] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 12/11/2022]
Abstract
Over the last two decades, there have been tremendous advances in the non-invasive diagnosis and risk stratification of chronic liver diseases (CLDs). Non-invasive approaches are based on the quantification of biomarkers in serum samples or on the measurement of liver stiffness, using either ultrasound- or magnetic resonance-based elastography techniques. The fibrosis-4 index (non-patented) and enhanced liver fibrosis test (patented) are the most widely adopted serum markers, whereas vibration-controlled transient elastography is the most widely adopted elastography technique. In this review, we discuss the role of non-invasive tests in the current era, as well as their accuracy and how their use in clinical practice has changed the practice of hepatology, including identification of early cirrhosis in patients with risk factors for CLD, diagnosis of portal hypertension, establishing prognosis in compensated cirrhosis, guiding antiviral treatment, and screening for fibrosis and cirrhosis in primary care.
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Affiliation(s)
- Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
| | - Laurent Castera
- Université de Paris, UMR1149 (CRI), Inserm, F-75018 Paris, France; Service d'Hépatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Beaujon, F-92110 Clichy-la-Garenne, France.
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, CA, United States; Herbert Wertheim School of Public Health, University of California at San Diego, La Jolla, CA, United States.
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17
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Marie S, Tripp DKK, Cherrington NJ. Strategies to Diagnose Nonalcoholic Steatohepatitis: A Novel Approach to Take Advantage of Pharmacokinetic Alterations. Drug Metab Dispos 2022; 50:492-499. [PMID: 34531312 PMCID: PMC9014462 DOI: 10.1124/dmd.121.000413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 09/13/2021] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and is diagnosed by a liver biopsy. Because of the invasiveness of a biopsy, the majority of patients with NASH are undiagnosed. Additionally, the prevalence of NAFLD and NASH creates the need for a simple screening method to differentiate patients with NAFLD versus NASH. Noninvasive strategies for diagnosing NAFLD versus NASH have been developed, typically relying on imaging techniques and endogenous biomarker panels. However, each technique has limitations, and none can accurately predict the associated functional impairment of drug metabolism and disposition. The function of several drug-metabolizing enzymes and drug transporters has been described in NASH that impacts drug pharmacokinetics. The aim of this review is to give an overview of the existing noninvasive strategies to diagnose NASH and to propose a novel strategy based on altered pharmacokinetics using an exogenous biomarker whose disposition and elimination pathways are directly impacted by disease progression. Altered disposition of safe and relatively inert exogenous compounds may provide the sensitivity and specificity needed to differentiate patients with NAFLD and NASH to facilitate a direct indication of hepatic impairment on drug metabolism and prevent subsequent adverse drug reactions. SIGNIFICANCE STATEMENT: This review provides an overview of the main noninvasive techniques (imaging and panels of biomarkers) used to diagnose NAFLD and NASH along with a biopsy. Pharmacokinetic changes have been identified in NASH, and this review proposes a new approach to predict NASH and the related risk of adverse drug reactions based on the assessment of drug elimination disruption using exogenous biomarkers.
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Affiliation(s)
- Solène Marie
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona
| | - David K K Tripp
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona
| | - Nathan J Cherrington
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona
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18
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Bel Lassen P, Nori N, Bedossa P, Genser L, Aron-Wisnewsky J, Poitou C, Surabattula R, Juul Nielsen M, Asser Karsdal M, Julie Leeming D, Schuppan D, Clément K. Fibrogenesis Marker PRO-C3 Is Higher in Advanced Liver Fibrosis and Improves in Patients Undergoing Bariatric Surgery. J Clin Endocrinol Metab 2022; 107:e1356-e1366. [PMID: 34905051 DOI: 10.1210/clinem/dgab897] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Serum propeptides of type III and type VI collagen (PRO-C3 and PRO-C6) are elevated in advanced nonalcoholic fatty liver disease (NAFLD), but their value in patients with severe obesity and their evolution after bariatric surgery (BS) is unknown. It is unclear if these markers of fibrogenesis are affected by adipose tissue fibrosis (ATF). OBJECTIVE We studied the association of PRO-C3 and PRO-C6 with liver fibrosis before BS, examined their evolution after BS, and evaluated how much patients' ATF contribute to their levels. METHODS Serum PRO-C3 and PRO-C6 were measured in 158 BS patients and compared with liver, subcutaneous, and omental adipose tissue histology obtained during surgery. PRO-C3 and PRO-C6 levels of 63 patients were determined in follow-up at 3 and 12 months post-BS. RESULTS Patients in the highest quartile of PRO-C3 had a higher risk of advanced liver fibrosis (stage F3-4; odds ratio 5.8; 95% CI [1.5-29.9]; P = 0.017) vs the lowest quartile (adjustment for age, gender, and BMI). PRO-C3 was positively correlated with markers of insulin resistance and liver enzymes. After BS, PRO-C3 levels decreased in patients with high baseline liver fibrosis. This decrease correlated with improvement of metabolic and liver parameters. PRO-C6 was not related to stage of liver fibrosis. ATF did not correlate with PRO-C3 or PRO-C6 levels at baseline or after BS. CONCLUSION PRO-C3 was associated with advanced liver fibrosis in patients with severe obesity, and decreased after BS, without being affected by ATF. These data suggest that BS prominently eliminates drivers of hepatic fibrogenesis in NAFLD.
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Affiliation(s)
- Pierre Bel Lassen
- Sorbonne Université, INSERM, Nutrition & Obesities: Systemic Approaches Research Group (NutriOmics), F-75013, Paris, France
- Assistance Publique Hôpitaux de Paris, Nutrition department, CRNH Ile-de-France, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Nicole Nori
- Sorbonne Université, INSERM, Nutrition & Obesities: Systemic Approaches Research Group (NutriOmics), F-75013, Paris, France
| | | | - Laurent Genser
- Sorbonne Université, INSERM, Nutrition & Obesities: Systemic Approaches Research Group (NutriOmics), F-75013, Paris, France
- Assistance Publique Hôpitaux de Paris, Department of Digestive Surgery, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Judith Aron-Wisnewsky
- Sorbonne Université, INSERM, Nutrition & Obesities: Systemic Approaches Research Group (NutriOmics), F-75013, Paris, France
- Assistance Publique Hôpitaux de Paris, Nutrition department, CRNH Ile-de-France, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Christine Poitou
- Sorbonne Université, INSERM, Nutrition & Obesities: Systemic Approaches Research Group (NutriOmics), F-75013, Paris, France
- Assistance Publique Hôpitaux de Paris, Nutrition department, CRNH Ile-de-France, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Rambabu Surabattula
- Institute of Translational Immunology and Research Center for Immune Therapy, Mainz University Medical Center, 55131 Mainz, Germany
| | | | | | | | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy, Mainz University Medical Center, 55131 Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Karine Clément
- Sorbonne Université, INSERM, Nutrition & Obesities: Systemic Approaches Research Group (NutriOmics), F-75013, Paris, France
- Assistance Publique Hôpitaux de Paris, Nutrition department, CRNH Ile-de-France, Pitié-Salpêtrière Hospital, 75013 Paris, France
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19
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Rinella ME, Dufour JF, Anstee QM, Goodman Z, Younossi Z, Harrison SA, Loomba R, Sanyal AJ, Bonacci M, Trylesinski A, Natha M, Shringarpure R, Granston T, Venugopal A, Ratziu V. Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study. J Hepatol 2022; 76:536-548. [PMID: 34793868 DOI: 10.1016/j.jhep.2021.10.029] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study. METHODS Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study. RESULTS Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable. CONCLUSIONS Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS. GOV NUMBER NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy.
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Affiliation(s)
- Mary E Rinella
- Department of Medicine, Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Jean-Francois Dufour
- University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland; Hepatology, Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Quentin M Anstee
- The Newcastle Liver Research Group, Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
| | - Zachary Goodman
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
| | - Zobair Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
| | | | - Rohit Loomba
- Division of Gastroenterology, University of California San Diego, San Diego, CA, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA
| | | | | | - Macky Natha
- Intercept Pharmaceuticals, San Diego, CA, USA
| | | | | | | | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié - Salpêtrière, Institute for Cardiometabolism and Nutrition, INSERM UMRS 1138 CRC, Paris, France.
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20
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Relationship of Enhanced Liver Fibrosis Score with Pediatric Nonalcoholic Fatty Liver Disease Histology and Response to Vitamin E or Metformin. J Pediatr 2021; 239:161-167.e5. [PMID: 34400208 PMCID: PMC8922020 DOI: 10.1016/j.jpeds.2021.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/02/2021] [Accepted: 08/09/2021] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To study the diagnostic performance of the enhanced liver fibrosis score (ELF) for detecting different stages of fibrosis and its usefulness in detecting histologic response to vitamin E or metformin in children with nonalcoholic fatty liver disease who participated in the Vitamin E or Metformin for the Treatment Of NAFLD In Children (TONIC) trial. STUDY DESIGN ELF was measured at baseline and weeks 24, 48, and 96 on sera from 166 TONIC participants. Associations between ELF with baseline and end of trial (EOT) fibrosis stages and other histologic features were assessed using χ2 tests and logistic regression models. RESULTS ELF was significantly associated with severity of fibrosis at baseline and EOT. ELF areas under the curve for discriminating patients with clinically significant and advanced fibrosis were 0.70 (95% CI, 0.60-0.80) and 0.79 (95% CI, 0.69-0.89), respectively. A 1-unit decrease in ELF at EOT was associated with overall histologic improvement (OR, 1.86; 95% CI, 1.11-3.14; P = .02), resolution of steatohepatitis (OR, 1.88; 95% CI, 1.09-3.25; P = .02), improvement in steatosis grade (OR, 1.76; 95% CI, 1.06-2.82; P = .03), and hepatocellular ballooning (OR, 1.79; 95% CI, 1.06-3.00; P = .03), but not with improvement in fibrosis stage (OR, 1.26; 95% CI, 0.78-2.03; P = .34). CONCLUSIONS ELF was associated with fibrosis stage in children who participated in TONIC. Although not associated with improvement in fibrosis, a decrease in ELF at EOT was associated with Nonalcoholic Steatohepatitis resolution and improvement in nonalcoholic fatty liver disease histology. ELF may be a useful noninvasive test to monitor treatment response in children with nonalcoholic fatty liver disease.
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21
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Stefano JT, Guedes LV, de Souza AAA, Vanni DS, Alves VAF, Carrilho FJ, Largura A, Arrese M, Oliveira CP. Usefulness of collagen type IV in the detection of significant liver fibrosis in nonalcoholic fatty liver disease. Ann Hepatol 2021; 20:100253. [PMID: 32949785 DOI: 10.1016/j.aohep.2020.08.070] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION/AIMS Liver fibrosis assessment is a key issue in the evaluation of nonalcoholic fatty liver disease (NAFLD) patients. In the present study, we aimed to validate a noninvasive marker panel to assess significant and advanced fibrosis in these patients. METHOD 126 biopsy-proven NAFLD patients were included. NAFLD diagnosis was based on histological criteria. Fibrosis stages were determined according to NASH-Clinical Research Network criteria. Clinical and laboratorial data were collected during the interval of three months before or after liver biopsy. Histological fibrosis stages were classified as significant fibrosis (F2-F4) and advanced fibrosis (F3-F4). Five serum biomarkers [hyaluronic acid (HA), collagen type IV (cIV), procollagen type III (PC III), laminin (LN) and cholylglycine (CG)] were assessed by chemiluminescence immunoassays. RESULTS Most patients were female (61.61%), mean age: 55.7 ± 9.13 years old and mean BMI was 32.1 ± 5.9 kg/m2. Prevalence of diabetes, dyslipidemia, arterial hypertension, and metabolic syndrome was 68.75%, 82.29%, 63.54% and 81.05%, respectively. Patients with cIV above 30 ng/mL had a 5.57-times (IC: 1.86-16.69) the chance of having significant fibrosis and 7.61-times (IC: 2.27-25.54) the chance of having advanced fibrosis versus patients with values below 30 ng/mL. HA, PC III, LN and CG did not detect the presence of significant and advanced fibrosis. The AUROC of clV for detection of significant (0.718) and advanced fibrosis (0.791) was better than that of other serum biomarkers. CONCLUSION Type 4 collagen could predict the presence of significant and advanced fibrosis in NAFLD patients and it would be a useful tool in routine clinical practice.
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Affiliation(s)
- José Tadeu Stefano
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Laura Vilar Guedes
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Arthur Alencar Arrais de Souza
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Denise Siqueira Vanni
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Flair José Carrilho
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Alvaro Largura
- Laboratório Biovel Análises e Pesquisas Clínicas, Cascavel, PR, Brazil; Hospital Universitário do Oeste do Parana (UNIOESTE), Cascavel, PR, Brazil
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile and Centro de Envejecimiento y Regeneracion (CARE), Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Claudia P Oliveira
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
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22
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Zhu B, Chan SL, Li J, Li K, Wu H, Cui K, Chen H. Non-alcoholic Steatohepatitis Pathogenesis, Diagnosis, and Treatment. Front Cardiovasc Med 2021; 8:742382. [PMID: 34557535 PMCID: PMC8452937 DOI: 10.3389/fcvm.2021.742382] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022] Open
Abstract
There has been a rise in the prevalence of non-alcohol fatty liver disease (NAFLD) due to the popularity of western diets and sedentary lifestyles. One quarter of NAFLD patients is diagnosed with non-alcoholic steatohepatitis (NASH), with histological evidence not only of fat accumulation in hepatocytes but also of liver cell injury and death due to long-term inflammation. Severe NASH patients have increased risks of cirrhosis and liver cancer. In this review, we discuss the pathogenesis and current methods of diagnosis for NASH, and current status of drug development for this life-threatening liver disease.
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Affiliation(s)
| | | | | | | | | | | | - Hong Chen
- Department of Surgery, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
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23
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Kawaguchi T, Ide T, Amano K, Arinaga-Hino T, Kuwahara R, Sano T, Miki S, Ono N, Torimura T. Enhanced liver fibrosis score as a predictive marker for hepatocellular carcinoma development after hepatitis C virus eradication. Mol Clin Oncol 2021; 15:215. [PMID: 34476099 PMCID: PMC8408682 DOI: 10.3892/mco.2021.2377] [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: 01/17/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Advanced liver fibrosis is the most important risk factor for hepatocellular carcinoma (HCC) development after achieving sustained virological response (SVR) by direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C. Wisteria floribunda agglutinin-positive Mac-2-binding protein (M2BPGi), enhanced liver fibrosis (ELF) score, type IV collagen and fibrosis-4 (FIB-4) index have been reported as non-invasive biomarkers for liver fibrosis. In the present study, the possibility of using fibrosis biomarkers and other parameters to predict the development of HCC was evaluated. A total of 743 patients infected with hepatitis C virus who achieved SVR by using DAA were retrospectively enrolled. Of these, 122 patients whose blood samples were stored were selected. The aforementioned four fibrosis biomarkers were analyzed at baseline, at the end of treatment (EOT) and at post-treatment week 24 (PTW24). Tumor markers and laboratory tests were also analyzed. The baseline/EOT/PTW24 values for each fibrosis biomarker were as follows: ELF score: 11.5±1.2/10.8±1.1/10.4±1.0; type IV collagen: 213±85/190±67/174±55 ng/ml; M2BPGi: 4.8±3.5/2.7±2.0/2.2±1.8; and FIB-4 index: 5.31±3.82/4.36± 2.79/4.24±3.09. Of the 122 patients, 23 developed HCC. A high baseline ELF score (P=0.0264), PTW24 ELF score (P=0.0003), PTW24 α-fetoprotein level (P=0.0133), baseline FIB-4 index (P=0.0451) and low baseline prothrombin time (P=0.0455) were risk factors for HCC development based on univariate analyses. Based on the multivariate analysis, a high PTW24 ELF score was the only risk factor for HCC development (P=0.0035). The ELF score after DAA therapy was strongly associated with HCC development; therefore, it may be a useful marker for predicting HCC.
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Affiliation(s)
- Toshihiro Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.,Social Insurance Tagawa Hospital, Tagawa, Fukuoka 826-0023, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Reiichiro Kuwahara
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Tomoya Sano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Shirachi Miki
- Chikugo City Hospital, Chikugo, Fukuoka 833-0041, Japan
| | - Naofumi Ono
- Yame General Hospital, Yame, Fukuoka 834-0034, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
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24
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Okanoue T, Sakamoto M, Harada K, Inagaki M, Totsuka N, Hashimoto G, Kumada H. Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: A randomized controlled study. Hepatol Res 2021; 51:943-956. [PMID: 34260795 DOI: 10.1111/hepr.13695] [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: 04/30/2021] [Revised: 06/24/2021] [Accepted: 07/01/2021] [Indexed: 12/30/2022]
Abstract
AIM To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH). METHODS In this multicenter, randomized, double-blind, placebo-controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end-point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end-points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated. RESULTS Forty-eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was -3.0% and -13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen-3 N-terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis-4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment. CONCLUSIONS In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti-inflammatory and antifibrotic effects of apararenone.
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Affiliation(s)
- Takeshi Okanoue
- Department of Gastroenterology, Saiseikai Suita Hospital, Osaka, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Masaya Inagaki
- Data Science Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Naoko Totsuka
- Clinical Research and Development II Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Gaia Hashimoto
- Clinical Research and Development II Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
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25
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Chang E, Chang JS, Kong ID, Baik SK, Kim MY, Park KS. Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease. Gut Liver 2021; 16:171-189. [PMID: 34420934 PMCID: PMC8924798 DOI: 10.5009/gnl210106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.
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Affiliation(s)
- Eunha Chang
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Seung Chang
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In Deok Kong
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
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26
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Gawrieh S, Wilson LA, Yates KP, Cummings OW, Vilar‐Gomez E, Ajmera V, Kowdley KV, Rosenberg WM, Tonascia J, Chalasani N. Relationship of ELF and PIIINP With Liver Histology and Response to Vitamin E or Pioglitazone in the PIVENS Trial. Hepatol Commun 2021; 5:786-797. [PMID: 34027269 PMCID: PMC8122381 DOI: 10.1002/hep4.1680] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 12/09/2020] [Accepted: 12/24/2020] [Indexed: 12/18/2022] Open
Abstract
Enhanced liver fibrosis score (ELF) and one of its components, amino-terminal propeptide of type III procollagen (PIIINP) are promising noninvasive biomarkers of liver histology in patients with nonalcoholic steatohepatitis (NASH). We evaluated the association of ELF and PIIINP with fibrosis stages at baseline and end of treatment (EOT) with vitamin E or pioglitazone in the PIVENS trial (Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients With NASH) and characterized ELF and PIIINP changes and their associations with changes in the histological endpoints. ELF and PIIINP were measured at baseline and weeks 16, 48, and 96 on sera from 243 PIVENS participants. Baseline and EOT ELF were significantly associated with fibrosis stage (P < 0.001). The area under the curve for ELF's detection of clinically significant and advanced fibrosis in baseline biopsies was 0.74 and 0.79, respectively (P < 0.001). There was a significant drop in ELF score at weeks 48 and 96 in patients who achieved the NAFLD activity score (NAS)-based primary end point (P = 0.007) but not in those who experienced NASH resolution (P = 0.24) or fibrosis improvement (P = 0.50). Change in PIIINP was significantly associated with NASH resolution and improvement in NAS-based histological endpoint and fibrosis (P < 0.05 for all). Over the study period, both ELF and PIIINP significantly decreased with vitamin E (P < 0.05), but only PIIINP decreased with pioglitazone (P < 0.001). Conclusion: ELF is significantly associated with clinically significant and advanced fibrosis in patients with NASH, but its longitudinal changes were not associated with improvement in fibrosis or NASH resolution. PIIINP, one of its components, appears promising for identifying longitudinal histologic changes in patients with NASH and is worthy of further investigation.
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Affiliation(s)
- Samer Gawrieh
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana UniversityIndianapolisINUSA
| | - Laura A. Wilson
- Department of EpidemiologyBloomberg School of Public HealthJohns Hopkins UniversityBaltimoreMDUSA
| | - Katherine P. Yates
- Department of EpidemiologyBloomberg School of Public HealthJohns Hopkins UniversityBaltimoreMDUSA
| | | | - Eduardo Vilar‐Gomez
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana UniversityIndianapolisINUSA
| | - Veeral Ajmera
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of California San DiegoSan DiegoCAUSA
| | | | | | - James Tonascia
- Department of EpidemiologyBloomberg School of Public HealthJohns Hopkins UniversityBaltimoreMDUSA
| | - Naga Chalasani
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana UniversityIndianapolisINUSA
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27
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Ding R, Zhou X, Huang D, Wang Y, Li X, Yan L, Lu W, Yang Z, Zhang Z. Nomogram for predicting advanced liver fibrosis and cirrhosis in patients with chronic liver disease. BMC Gastroenterol 2021; 21:190. [PMID: 33906623 PMCID: PMC8077956 DOI: 10.1186/s12876-021-01774-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 04/20/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND We aimed to formulate a novel predictive nomogram to discriminate liver fibrosis stage in patients with chronic liver disease. METHODS Nomograms were established based on the results of multivariate analysis. The predictive accuracy of the nomograms was assessed by ROC analysis and calibration. Decision curve analysis (DCA) was used to determine the clinical benefit of the nomograms. RESULTS INR, platelets, and N-terminal propeptide type III collagen (PIIINP) were independent predictors for advanced liver fibrosis (≥ S3) and cirrhosis (S4) in patients with chronic liver disease in the training cohort. In the training set, the areas under the ROCs (AUROCs) of nomogram S3S4, APRI, FIB-4, and GPR for stage ≥ S3 were 0.83, 0.71, 0.68, and 0.74, respectively; the AUROCs of nomogram S4, APRI, FIB-4, and GPR for stage S4 were 0.88, 0.74, 0.78, and 0.79, respectively. The calibrations showed optimal agreement between the prediction by the established nomograms and actual observation. In the validation set, the AUROCs of nomogram S3S4, APRI, FIB-4, and GPR for stage ≥ S3 were 0.86, 0.79, 0.78, and 0.81, respectively; the AUROCs of nomogram S4, APRI, FIB-4, and GPR for stage S4 were 0.88, 0.77, 0.81, and 0.83, respectively. Furthermore, the decision curve analysis suggested that the nomograms represent better clinical benefits in both independent cohorts than APRI, FIB-4, and GPR. CONCLUSION The constructed nomograms could be a superior tool for discriminating advanced fibrosis and cirrhosis in chronic liver disease.
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Affiliation(s)
- Rongrong Ding
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Xinlan Zhou
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Dan Huang
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Yanbing Wang
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Xiufen Li
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Li Yan
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Wei Lu
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Zongguo Yang
- grid.8547.e0000 0001 0125 2443Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
| | - Zhanqing Zhang
- grid.8547.e0000 0001 0125 2443Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai, 201508 China
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28
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Rosso N, Stephenson AM, Giraudi PJ, Tiribelli C. Diagnostic management of nonalcoholic fatty liver disease: a transformational period in the development of diagnostic and predictive tools-a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:727. [PMID: 33987425 PMCID: PMC8106012 DOI: 10.21037/atm-20-4723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
NAFLD is an emerging healthcare epidemic that is causing predictable adverse consequences for healthcare systems, societies and individuals. Whilst NAFLD is recognized as a multi-system disease with compound pathways that are both benign and pernicious in their unfolding; NASH is generally understood as a deleterious follow-on condition with path-specific tendencies that progress to cirrhosis, HCC and liver transplantation. Recent evidence is beginning to challenge this interpretation demanding more attention to the personalized nature of the disease and its pathogenesis across multiple different cohorts. This means that we need better diagnostic and prognostic tools not only to capture those 'at risk' disease phenotypes; but for better stratification and monitoring of patients according to their treatment strategies. With the advent of pipeline therapies for NASH underway, the medical profession looks to adopt more accurate non-invasive diagnostic tools that can help to delineate and eliminate NASH histology. This review looks at the search for the killer application revealing this particular moment in time as a transformational period; one that is pushing the boundaries of technology to integrate diverse panels of species through sensitive profiling and multi-omics approaches that cast wide, yet powerful diagnostic nets that have the potential to elucidate pathway specific biomarkers that are personalized and predictable.
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Affiliation(s)
- Natalia Rosso
- Fondazione Italiana Fegato, ONLUS Area Science Park Basovizza, Trieste, Italy
| | - Adam M Stephenson
- Helena Biosciences, Queensway South, Team Valley Trading Estate, Gateshead, UK
| | - Pablo J Giraudi
- Fondazione Italiana Fegato, ONLUS Area Science Park Basovizza, Trieste, Italy
| | - Claudio Tiribelli
- Fondazione Italiana Fegato, ONLUS Area Science Park Basovizza, Trieste, Italy
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29
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Kogachi S, Noureddin M. Noninvasive Evaluation for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clin Ther 2021; 43:455-472. [PMID: 33581876 DOI: 10.1016/j.clinthera.2021.01.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/26/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and has the potential risk for progressing to nonalcoholic steatohepatitis (NASH), which is associated with a greater risk for complications of chronic liver disease. Noninvasive testing has been evaluated for diagnosis, risk stratification, disease progression, and assessing response to therapy. The purpose of this narrative review was to outline the current noninvasive testing modalities for the diagnostic evaluation of NAFLD and NASH, while discussing possible markers that could be used for monitoring response to therapies. METHODS The PubMed and Cochrane databases were searched for relevant articles that evaluated the diagnosis of NAFLD/NASH with serum biomarkers and/or imaging. FINDINGS Serum biomarkers, imaging modalities, and combinations/serial algorithms involved in the diagnosis of NAFLD and NASH are outlined. In addition, noninvasive modalities that have been used for assessing response to therapies in clinical trials are discussed. IMPLICATIONS Liver biopsy currently remains the gold standard for diagnosis and is often used in clinical trials to assess treatment response. However, developing safe and accessible noninvasive modalities for diagnosis and monitoring will have greater impact and relevance, as biopsy may not always be feasible in all clinical settings.
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Affiliation(s)
- Shannon Kogachi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mazen Noureddin
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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30
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Tincopa MA. Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis. Endocrinol Diabetes Metab 2020; 3:e00177. [PMID: 33102798 PMCID: PMC7576258 DOI: 10.1002/edm2.177] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/17/2020] [Accepted: 07/18/2020] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION In the setting of the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent forms of chronic liver disease worldwide. Approximately 25% of adults globally have NAFLD which includes those with NAFL, or simple steatosis, and individuals with nonalcoholic steatohepatitis (NASH) where inflammation, hepatocyte injury and potentially hepatic fibrosis are found in conjunction with steatosis. Individuals with NASH, particularly those with hepatic fibrosis, have higher rates of liver-related and overall mortality, making this distinction of significant clinical importance. One of the core challenges in current clinical practice is identifying this subset of individuals with NASH without the use of liver biopsy, the gold standard for both diagnostics and staging disease severity. Identifying noninvasive biomarkers, an accurately measured and reproducible parameter, would aide in identifying patients eligible for NASH pharmacotherapy clinical trials and to help tailor intensity of monitoring required. METHODS RESULTS AND CONCLUSIONS In this review, we highlight both the currently available and novel diagnostic and interventional circulating biomarkers under investigation for NASH, underscoring their accuracy and limitations relevant to our patient population and current clinical practice.
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Affiliation(s)
- Monica A. Tincopa
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
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31
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Rosato V, Masarone M, Aglitti A, Persico M. The diagnostic conundrum in non-alcoholic fatty liver disease. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver alteration worldwide. It encompasses a spectrum of disorders that range from simple steatosis to a progressive form, defined non-alcoholic steatohepatitis (NASH), that can lead to advanced fibrosis and eventually cirrhosis and hepatocellular carcinoma. On liver histology, NASH is characterized by the concomitant presence of significant fat accumulation and inflammatory reaction with hepatocellular injury. Until now, liver biopsy is still required to differentiate simple steatosis from NASH and evaluate the degree of liver fibrosis. Unfortunately, this technique has well-known limitations, including invasiveness and expensiveness. Moreover, it may be biased by sampling error and intra- or inter-observed variability. Furthermore, due to the increasing prevalence of NAFLD worldwide, to program a systematic screening with liver biopsy is not imaginable. In recent years, different techniques were developed and validated with the aim of non-invasively identifying NASH and assess liver fibrosis degrees. The non-invasive tests range from simple blood-tests analyses to composite scores and complex imaging techniques. Nevertheless, even if they could represent cost-effective strategies for diagnosing NASH, advanced fibrosis and cirrhosis, their accuracy and consequent usefulness are to be discussed. With this aim, in this review the authors summarize the current state of non-invasive assessment of NAFLD. In particular, in addition to the well-established tests, the authors describe the future perspectives in this field, reporting the latest tests based on OMICS, gut-miocrobioma and micro-RNAs. Finally, the authors provide an accurate assessment of how these non-invasive tools perform in clinical practice depending on the clinical context, with the aim of giving the clinicians a useful tool to try to resolve the diagnostic conundrum of NAFLD.
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Affiliation(s)
- Valerio Rosato
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Andrea Aglitti
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
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32
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Inadomi C, Takahashi H, Ogawa Y, Oeda S, Imajo K, Kubotsu Y, Tanaka K, Kessoku T, Okada M, Isoda H, Akiyama T, Fukushima H, Yoneda M, Anzai K, Aishima S, Nakajima A, Eguchi Y. Accuracy of the Enhanced Liver Fibrosis test, and combination of the Enhanced Liver Fibrosis and non-invasive tests for the diagnosis of advanced liver fibrosis in patients with non-alcoholic fatty liver disease. Hepatol Res 2020; 50:682-692. [PMID: 32090397 DOI: 10.1111/hepr.13495] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 02/08/2023]
Abstract
AIM The Enhanced Liver Fibrosis (ELF) test comprises a logarithmic algorithm combining three serum markers of hepatic extracellular matrix metabolism. We aimed to evaluate the performance of ELF for the diagnosis of liver fibrosis and to compare it with that of liver stiffness measurement (LSM) by FibroScan in non-alcoholic fatty liver disease. METHODS ELF cut-off values for the diagnosis of advanced fibrosis were obtained using receiver operating characteristic analysis in patients with biopsy-confirmed non-alcoholic fatty liver disease (training set; n = 200). Diagnostic performance was analyzed in the training set and in a validation set (n = 166), and compared with that of LSM in the FibroScan cohort (n = 224). RESULTS The area under receiver operating characteristic curve was 0.81 for the diagnosis of advanced fibrosis, and the ELF cut-off values were 9.34 with 90.4% sensitivity and 10.83 with 90.6% specificity in the training set, and 89.8% sensitivity and 85.5% specificity in the validation set. There was no significant difference in the area under the receiver operating characteristic curve between ELF and LSM (0.812 and 0.839). A combination of ELF (cut-off 10.83) and LSM (cut-off 11.45) increased the specificity to 97.9% and the positive predictive value, versus ELF alone. Sequential use of the Fibrosis-4 index (cut-off 2.67) and ELF (cut-off 9.34) increased the sensitivity to 95.9%. CONCLUSIONS ELF can identify advanced liver fibrosis in non-alcoholic fatty liver disease, and its diagnostic accuracy is comparable to that of FibroScan. According to the clinical setting, combinations or sequential procedures using other non-invasive tests complement the diagnostic performance of ELF for the identification of advanced fibrosis.
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Affiliation(s)
- Chika Inadomi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Liver Center, Saga University Hospital, Saga, Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Liver Center, Saga University Hospital, Saga, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Satoshi Oeda
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Department of Clinical Laboratory Medicine, Saga University Hospital, Saga, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yoshihito Kubotsu
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Michiaki Okada
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | | | - Takumi Akiyama
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Hideaki Fukushima
- Diagnostics Business Area, Siemens Healthcare Diagnostics K.K., Tokyo, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Shinichi Aishima
- Department of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Piazzolla VA, Mangia A. Noninvasive Diagnosis of NAFLD and NASH. Cells 2020; 9:E1005. [PMID: 32316690 PMCID: PMC7226476 DOI: 10.3390/cells9041005] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/09/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
The aim of this review is to outline emerging biomarkers that can serve as early diagnostic tools to identify patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and, among them, the subgroup of best candidates for clinical trials on emerging compounds. Regarding possible predictors of NAFLD, a number of studies evaluated a combination of serum biomarkers either available in routine practice (or investigational) or proprietary and expensive. So far, magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) appears to be the most accurate for fatty liver diagnosis. In clinical practice, the main question is how to diagnose NASH early. There are new promising biomarkers that can help in diagnosing early stages of NASH, yet they include variables not routinely tested. In the setting of NASH, most studies confirm that, in spite of several well-known limitations, transient elastography or point shear wave elastography can help in enriching the pool of patients that should be screened for investigational treatments. Newer multiomics biomarkers including those focusing on microbiota can be useful but require methods to be standardized and implemented. To date, one biomarker alone is not able to non- or minimally invasively identify patients with NASH and mild to moderate fibrosis.
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Affiliation(s)
| | - Alessandra Mangia
- Liver Unit, Department of Medical Sciences, IRCCS Fondazione, “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy;
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34
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Challenges and opportunities in drug development for nonalcoholic steatohepatitis. Eur J Pharmacol 2020; 870:172913. [PMID: 31926994 DOI: 10.1016/j.ejphar.2020.172913] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/04/2019] [Accepted: 01/07/2020] [Indexed: 12/22/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered major global medical burdens with high prevalence and steeply rising incidence. Despite the characterization of numerous pathophysiologic pathways leading to metabolic disorder, lipid accumulation, inflammation, fibrosis, and ultimately end-stage liver disease or liver cancer formation, so far no causal pharmacological therapy is available. Drug development for NAFLD and NASH is limited by long disease duration and slow progression and the need for sequential biopsies to monitor the disease stage. Additional non-invasive biomarkers could therefore improve design and feasibility of such. Here, the current concepts on preclinical models, biomarkers and clinical endpoints and trial designs are briefly reviewed.
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35
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Singh SP, Barik RK. NonInvasive Biomarkers in Nonalcoholic Fatty Liver Disease: Are We There Yet? J Clin Exp Hepatol 2020; 10:88-98. [PMID: 32025168 PMCID: PMC6995889 DOI: 10.1016/j.jceh.2019.09.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 09/15/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD encompasses a spectrum of disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. However, despite the growing recognition of this important disease burden, there are significant challenges to accurately and noninvasively diagnose the various forms of NAFLD, especially to differentiate benign steatosis from the progressive NASH. This is of utmost importance because although liver biopsy is considered the current imperfect 'gold' standard for diagnosing NASH and staging fibrosis, it is an invasive procedure with significant limitations. Although, a number of noninvasive markers have been or are currently undergoing investigation, until date, no highly sensitive and specific tests are available to differentiate NASH from simple steatosis. At the moment, further investigations are needed before prediction models or blood-based biomarkers become available and acceptable for routine clinical care. There is a great need for developing inexpensive, easily accessible, highly sensitive and specific biomarkers that permit not only the identification of patients at high risk of adverse outcomes, but also the monitoring of disease progression and response after therapeutic interventions.
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Affiliation(s)
- Shivaram P. Singh
- Address for correspondence: Shivaram Prasad Singh, Professor, Dept. of Gastroenterology, S.C.B. Medical College, Cuttack, Odisha, 753007, India.
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36
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Aithal GP. Commentary: non-alcoholic steatohepatitis-finding and minding the fire behind the smoke. Aliment Pharmacol Ther 2020; 51:209-211. [PMID: 31850574 DOI: 10.1111/apt.15565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
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37
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Kuwashiro T, Takahashi H, Hyogo H, Ogawa Y, Imajo K, Yoneda M, Nakahara T, Oeda S, Tanaka K, Amano Y, Ogawa S, Kawaguchi A, Aishima S, Kage M, Chayama K, Nakajima A, Eguchi Y. Discordant pathological diagnosis of non-alcoholic fatty liver disease: A prospective multicenter study. JGH OPEN 2019; 4:497-502. [PMID: 32514460 PMCID: PMC7273711 DOI: 10.1002/jgh3.12289] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 11/06/2019] [Accepted: 11/10/2019] [Indexed: 12/25/2022]
Abstract
Background Liver biopsy has been the standard procedure for diagnosing and evaluating the severity of non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH); however, interobserver discordance remains a critical issue in its pathological diagnosis. Methods and Results We examined the concordance rates of pathological scoring and diagnosis between pathologists at individual institutions (local diagnosis) and two central pathologists specialized in liver pathology (central diagnosis). A total of 150 patients with NAFLD underwent prospective liver biopsies. NAFLD activity score (NAS) and fibrosis stage were evaluated, and NASH was determined according to Matteoni's classification. NAS, scores for all NAS components, and fibrosis stage were diagnosed at a lower degree by central compared with local diagnosis. NASH was diagnosed in 34% of the patients according to central pathologists compared with 54% according to local pathologists (P < 0.001). The concordance rates for NAS, steatosis, inflammation, ballooning, fibrosis, and NASH diagnosis were 26.7, 62.7, 51.3, 48.7, 43.3, and 50.7%, respectively. The correlation coefficient between local and central diagnoses was the lowest for the scoring of ballooning (ρ = 0.218). Conclusion Concordance rates among pathologists for the evaluation of NAFLD are currently poor, and simple and reliable diagnostic and evaluation criteria are urgently needed to improve the clinical management of NAFLD patients.
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Affiliation(s)
- Takuya Kuwashiro
- Liver Center Saga University Hospital Saga Japan.,Division of Metabolism and Endocrinology, Faculty of Medicine Saga University Saga Japan
| | - Hirokazu Takahashi
- Liver Center Saga University Hospital Saga Japan.,Division of Metabolism and Endocrinology, Faculty of Medicine Saga University Saga Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology JA Hiroshima General Hospital Hiroshima Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine Yokohama Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine Yokohama Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine Yokohama Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Satoshi Oeda
- Liver Center Saga University Hospital Saga Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine Saga University Saga Japan
| | - Yuichiro Amano
- Takeda Pharmaceutical Company, Ltd. Fujisawa Kanagawa Japan
| | - Shinji Ogawa
- Takeda Pharmaceutical Company, Ltd. Fujisawa Kanagawa Japan
| | - Atsushi Kawaguchi
- Section of Clinical Cooperation System, Center for Comprehensive Community Medicine, Faculty of Medicine Saga University Saga Japan
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine Saga University Saga Japan
| | - Masayoshi Kage
- Kurume University Research Center for Innovative Cancer Therapy Kurume Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology JA Hiroshima General Hospital Hiroshima Japan
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Mosca A, Comparcola D, Romito I, Mantovani A, Nobili V, Byrne CD, Alisi A, Targher G. Plasma N-terminal propeptide of type III procollagen accurately predicts liver fibrosis severity in children with non-alcoholic fatty liver disease. Liver Int 2019; 39:2317-2329. [PMID: 31436362 DOI: 10.1111/liv.14225] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS We examined the diagnostic performance of plasma N-terminal propeptide of type III procollagen (PIIINP) levels, aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for predicting non-alcoholic steatohepatitis (NASH) and liver fibrosis stage in children/adolescents with non-alcoholic fatty liver disease (NAFLD). METHODS We enrolled 204 children/adolescents with biopsy-proven NAFLD at the "Bambino Gesù" Children's Hospital. We measured plasma PIIINP levels using a commercially available enzyme-linked immunosorbent assay kit and calculated APRI and FIB-4 scores using standard methods. RESULTS Children with NASH had higher plasma PIIINP levels, APRI and FIB-4 scores compared with those without NASH (all P < .001). However, PIIINP levels had much better diagnostic performance and accuracy than APRI and FIB-4 scores for predicting liver fibrosis stage. PIIINP levels correlated with the total NAFLD activity score (NAS) and its constituent components (P < .0001). The risk of either NASH or F ≥ 2 fibrosis progressively increased with increasing PIIINP levels (P < .0001), independent of age, gender, adiposity measures, insulin resistance, NAS score and the patatin-like phospholipase domain-containing protein-3 rs738409 polymorphism. For every 3.6 ng/mL increase in PIIINP levels, the likelihood of having F ≥ 2 fibrosis increased by ~14-fold (adjusted-odds ratio 14.1, 95% CI 5.50-35.8, P < .0001) after adjustment for the aforementioned risk factors. The area under the receiver operating characteristics curve was 0.921 (95% CI 0.87-0.97) for F ≥ 2 fibrosis, and 0.993 (95% CI 0.98-1.0) for F3 fibrosis respectively. CONCLUSIONS Unlike APRI and FIB-4 scores, plasma PIIINP levels are a promising, non-invasive biomarker for diagnosing liver fibrosis stage in children/adolescents with biopsy-proven NAFLD.
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Affiliation(s)
- Antonella Mosca
- Hepatology Gastroenterology and Nutrition, Bambino Gesù Children's Hospital, Rome, Italy
| | - Donatella Comparcola
- Hepato-Metabolic Disease Unit, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy
| | - Ilaria Romito
- Research Unit of Molecular Genetics of Complex Phenotypes, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Valerio Nobili
- Hepatology Gastroenterology and Nutrition, Bambino Gesù Children's Hospital, Rome, Italy.,Department of Pediatrics, University La Sapienza, Rome, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital, University Hospital Southampton, Southampton, UK.,Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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39
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Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). Cells 2019; 8:cells8080845. [PMID: 31394730 PMCID: PMC6721710 DOI: 10.3390/cells8080845] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next 20 years. Typically, hepatic alterations start with simple steatosis, which easily progresses to more advanced stages such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. This course of disease finally leads to end-stage liver disease such as hepatocellular carcinoma, which is associated with increased morbidity and mortality. Although clinical trials show promising results, there is actually no pharmacological agent approved to treat NASH. Another important problem associated with NASH is that presently the liver biopsy is still the gold standard in diagnosis and for disease staging and grading. Because of its invasiveness, this technique is not well accepted by patients and the method is prone to sampling error. Therefore, an urgent need exists to find reliable, accurate and noninvasive biomarkers discriminating between different disease stages or to develop innovative imaging techniques to quantify steatosis.
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40
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Jennison E, Patel J, Scorletti E, Byrne CD. Diagnosis and management of non-alcoholic fatty liver disease. Postgrad Med J 2019; 95:314-322. [PMID: 31085617 DOI: 10.1136/postgradmedj-2018-136316] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/08/2019] [Accepted: 04/14/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western industrialised countries. The prevalence of NAFLD is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. NAFLD represents a spectrum of liver disease severity. NAFLD begins with accumulation of triacylglycerols in the liver (steatosis), and is defined by hepatic fatty infiltration amounting to greater than 5% by liver weight or the presence of over 5% of hepatocytes loaded with large fat vacuoles. In almost a quarter of affected individuals, steatosis progresses with the development of liver inflammation to non-alcoholic steatohepatitis (NASH). NASH is a potentially progressive liver condition and with ongoing liver injury and cell death can result in fibrosis. Progressive liver fibrosis may lead to the development of cirrhosis in a small proportion of patients. With the growing prevalence of NAFLD, there is an increasing need for a robust, accurate and non-invasive approach to diagnosing the different stages of this condition. This review will focus on (1) the biochemical tests and imaging techniques used to diagnose the different stages of NAFLD; and (2) a selection of the current management approaches focusing on lifestyle interventions and pharmacological therapies for NAFLD.
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Affiliation(s)
- Erica Jennison
- Chemical Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Janisha Patel
- Hepatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Eleonora Scorletti
- Human Development and Health, University of Southampton, Southampton, UK
| | - Christopher D Byrne
- The Institute of Developmental Sciences, University of Southampton, Southampton, UK
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasingly dominant cause of liver disease worldwide. The progressive subtype, nonalcoholic steatohepatitis, is a leading indication for liver transplantation and a noteworthy cause of hepatocellular carcinoma. The overall prevalence of NAFLD is on the rise, and even more concerning data modeling predicts that an increasing percentage of those with NAFLD will develop advanced disease. This increased volume of patients with advanced liver disease will impose a significant health care burden in terms of resources and cost. Thus, the identification of patients with established fibrosis or at high risk of developing advanced liver disease is critical to effectively intervene and prevent overall and liver-related morbidity and mortality. Herein, we provide a framework to consider for the identification of patients with NAFLD at high risk of nonalcoholic steatohepatitis with advanced fibrosis and provide a critical assessment of currently accessible diagnostic and treatment modalities.
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42
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Lin B, Ma Y, Wu S, Liu Y, Liu L, Wu L. Novel Serum Biomarkers for Noninvasive Diagnosis and Screening of Nonalcoholic Fatty Liver Disease-Related Hepatic Fibrosis. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 23:181-189. [PMID: 30932742 DOI: 10.1089/omi.2019.0035] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing global public health concern and becoming the leading cause of liver disease worldwide. The estimated global prevalence of NAFLD is ∼25% depending on the country and the assessment method used to establish the diagnosis. Meta-analyses suggest that the highest prevalence is in the Middle East (31.8%) and South America (30.4%), and the lowest in Africa (13.5%). In the United States, between 75 and 100 million individuals were estimated to have NAFLD. This important disease is associated with increased incidence of liver-related deaths, hepatocarcinoma, and overall mortality. Fibrosis stage, among other histological characteristics, is the most critical factor in predicting all-cause and disease-specific mortality in NAFLD. The ability to detect fibrosis early in NAFLD patients is critical in controlling mortality associated with this highly prevalent disease. We present here an expert review on recent advances in novel blood biomarkers, for example, the Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA+-M2BP), type IV collagen 7S, chitinase 3 like 1 (CHI3L1; YKL-40), and insulin-like growth factor-1 (IGF-1). Algorithms using multiple biomarkers such as alpha-2-macroglobulin, mir34a, YKL-40, and hemoglobin A1c (HbA1c; NIS4), enhanced liver fibrosis (ELF), Hepascore, FibroMeter, FibroTest, FIBROSpect, FIB-C3, and ADPAPT are highlighted. Novel technologies such as tandem mass spectrometry to directly measure protein turnover rate of the key proteins involved in hepatic fibrosis, as an indicator of fibrogenesis, are also discussed. In conclusion, NAFLD is a growing global health problem that warrants long-term funding, research, and training of scholars across the fields of public health diagnostics, systems sciences, nutrition, hepatology, and clinical oncology.
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Affiliation(s)
- Biaoyang Lin
- 1 Zhejiang-California International Nanosystems Institute (ZCNI), Proprium Research Center, Zhejiang University, Hangzhou, China.,2 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,3 Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - Yingying Ma
- 1 Zhejiang-California International Nanosystems Institute (ZCNI), Proprium Research Center, Zhejiang University, Hangzhou, China.,2 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Shengjun Wu
- 4 School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Yunhua Liu
- 5 Department of Liver Diseases, The Second Hospital of Yunnan Province, Kunming, China
| | - Longgen Liu
- 6 The Third People's Hospital of Changzhou, Changzhou, China
| | - Lihua Wu
- 7 State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The Research Center for Clinical Pharmacy, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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Daniels SJ, Leeming DJ, Eslam M, Hashem AM, Nielsen MJ, Krag A, Karsdal MA, Grove JI, Neil Guha I, Kawaguchi T, Torimura T, McLeod D, Akiba J, Kaye P, de Boer B, Aithal GP, Adams LA, George J. ADAPT: An Algorithm Incorporating PRO-C3 Accurately Identifies Patients With NAFLD and Advanced Fibrosis. Hepatology 2019; 69:1075-1086. [PMID: 30014517 DOI: 10.1002/hep.30163] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 07/03/2018] [Indexed: 12/14/2022]
Abstract
Given the high global prevalence of nonalcoholic fatty liver disease (NAFLD), the need for relevant noninvasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (≥ F3) is the most crucial, as these individuals have the greatest risk of adverse, long-term, liver-related outcomes. We aimed to investigate the role of PRO-C3 (a marker of type III collagen formation) as a biomarker for advanced fibrosis in NAFLD. We measured PRO-C3 by enzyme-linked immunosorbent assay in two large independent cohorts with extensive clinical phenotyping and liver biopsy: 150 in the derivation and 281 in the validation cohort. A PRO-C3-based fibrosis algorithm that included age, presence of diabetes, PRO-C3, and platelet count (ADAPT) was developed. PRO-C3 increased with fibrosis stage (Rho 0.50; P < 0.0001) and was independently associated with advanced fibrosis (odds ratio = 1.05; 95% confidence interval [CI] 1.02-1.08; P = 0.003). ADAPT showed areas under the receiver operating characteristics curve of 0.86 (95% CI 0.79-0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83-0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase to platelet ratio index (APRI), FIB-4, and NAFLD fibrosis score (NFS) in most comparisons. Conclusion: PRO-C3 is an independent predictor of fibrosis stage in NAFLD. A PRO-C3-based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB-4, and NFS.
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Affiliation(s)
- Samuel J Daniels
- Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark.,Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Diana J Leeming
- Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, Australia
| | - Ahmed M Hashem
- Department of Systems and Biomedical Engineering, Faculty of Engineering, Minia University, Minia, Egypt
| | - Mette J Nielsen
- Nordic Bioscience Biomarkers and Research A/S, Herlev, Denmark
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | | | - Jane I Grove
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, United Kingdom.,NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom.,Medical Research Council (MRC) Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, United Kingdom
| | - Indra Neil Guha
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, United Kingdom.,NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom.,Medical Research Council (MRC) Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, United Kingdom
| | - Takumi Kawaguchi
- Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia
| | - Jun Akiba
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan
| | - Philip Kaye
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, United Kingdom.,Medical Research Council (MRC) Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, United Kingdom
| | - Bastiaan de Boer
- Department of Anatomical Pathology, PathWest, Fiona Stanley Hospital, Murdoch, Australia
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, United Kingdom.,NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom.,Medical Research Council (MRC) Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, United Kingdom
| | - Leon A Adams
- Medical School, University of Western Australia, Nedlands, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, Australia
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44
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The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD). Metabolites 2019; 9:metabo9020025. [PMID: 30717274 PMCID: PMC6409793 DOI: 10.3390/metabo9020025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/26/2019] [Accepted: 01/30/2019] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.
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Bernal-Reyes R, Castro-Narro G, Malé-Velázquez R, Carmona-Sánchez R, González-Huezo M, García-Juárez I, Chávez-Tapia N, Aguilar-Salinas C, Aiza-Haddad I, Ballesteros-Amozurrutia M, Bosques-Padilla F, Castillo-Barradas M, Chávez-Barrera J, Cisneros-Garza L, Flores-Calderón J, García-Compeán D, Gutiérrez-Grobe Y, Higuera de la Tijera M, Kershenobich-Stalnikowitz D, Ladrón de Guevara-Cetina L, Lizardi-Cervera J, López-Cossio J, Martínez-Vázquez S, Márquez-Guillén E, Méndez-Sánchez N, Moreno-Alcantar R, Poo-Ramírez J, Ramos-Martínez P, Rodríguez-Hernández H, Sánchez-Ávila J, Stoopen-Rometti M, Torre-Delgadillo A, Torres-Villalobos G, Trejo-Estrada R, Uribe-Esquivel M, Velarde-Ruiz Velasco J. The Mexican consensus on nonalcoholic fatty liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2019. [DOI: 10.1016/j.rgmxen.2019.02.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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46
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Bernal-Reyes R, Castro-Narro G, Malé-Velázquez R, Carmona-Sánchez R, González-Huezo MS, García-Juárez I, Chávez-Tapia N, Aguilar-Salinas C, Aiza-Haddad I, Ballesteros-Amozurrutia MA, Bosques-Padilla F, Castillo-Barradas M, Chávez-Barrera JA, Cisneros-Garza L, Flores-Calderón J, García-Compeán D, Gutiérrez-Grobe Y, Higuera de la Tijera MF, Kershenobich-Stalnikowitz D, Ladrón de Guevara-Cetina L, Lizardi-Cervera J, López-Cossio JA, Martínez-Vázquez S, Márquez-Guillén E, Méndez-Sánchez N, Moreno-Alcantar R, Poo-Ramírez JL, Ramos-Martínez P, Rodríguez-Hernández H, Sánchez-Ávila JF, Stoopen-Rometti M, Torre-Delgadillo A, Torres-Villalobos G, Trejo-Estrada R, Uribe-Esquivel M, Velarde-Ruiz Velasco JA. The Mexican consensus on nonalcoholic fatty liver disease. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2019; 84:69-99. [PMID: 30711302 DOI: 10.1016/j.rgmx.2018.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 11/06/2018] [Accepted: 11/20/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak. This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease.
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Affiliation(s)
- R Bernal-Reyes
- Sociedad Española de Beneficencia, Pachuca, Hidalgo, México.
| | - G Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática SA de CV, Guadalajara, Jalisco, México
| | | | - M S González-Huezo
- Servicio de Gastroenterología y Endoscopia GI, ISSSEMYM, Metepec, Estado de México, México
| | - I García-Juárez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - N Chávez-Tapia
- Servicio de Gastroenterología, Fundación Clínica Médica Sur, Ciudad de México, México
| | - C Aguilar-Salinas
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - I Aiza-Haddad
- Clínica de enfermedades hepáticas, Hospital Ángeles Lómas, Ciudad de México, México
| | | | | | - M Castillo-Barradas
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico La Raza IMSS, Ciudad de México, México
| | - J A Chávez-Barrera
- Servicio de Gastroenterología Pediátrica, Hospital General, Centro Médico La Raza, IMSS, Ciudad de México, México
| | - L Cisneros-Garza
- Servicio de Gastroenterología, Hospital Universitario de la UANL, Monterrey, Nuevo León, México
| | - J Flores-Calderón
- Servicio de Gastroenterología, Hospital de Pediatría, Centro Médico Siglo XXI, IMSS, Ciudad de México, México
| | - D García-Compeán
- Servicio de Gastroenterología, Hospital Universitario de la UANL, Monterrey, Nuevo León, México
| | - Y Gutiérrez-Grobe
- Servicio de Gastroenterología, Fundación Clínica Médica Sur, Ciudad de México, México
| | | | | | | | - J Lizardi-Cervera
- Servicio de Gastroenterología, Fundación Clínica Médica Sur, Ciudad de México, México
| | - J A López-Cossio
- Servicio de Gastroenterología y Endoscopia GI, ISSSEMYM, Metepec, Estado de México, México
| | - S Martínez-Vázquez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - E Márquez-Guillén
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - N Méndez-Sánchez
- Servicio de Gastroenterología, Fundación Clínica Médica Sur, Ciudad de México, México
| | - R Moreno-Alcantar
- Servicio de Gastroenterología, Hospital de Especialidades Centro Médico Siglo XXI, IMSS, Ciudad de México, México
| | - J L Poo-Ramírez
- Centro de Innovación y Educación Ejecutiva, Tec de Monterrey, Ciudad de México, México
| | | | - H Rodríguez-Hernández
- Unidad de Investigación Biomédica AMCCI, Hospital de Especialidades, Durango, México
| | - J F Sánchez-Ávila
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey, Nuevo León, México
| | - M Stoopen-Rometti
- Centro de Diagnóstico CT-Scanner Lomas Altas, Ciudad de México, México
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - G Torres-Villalobos
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | - M Uribe-Esquivel
- Servicio de Gastroenterología, Fundación Clínica Médica Sur, Ciudad de México, México
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Rudolph B, Bjorklund N, Ovchinsky N, Kogan-Liberman D, Perez A, Liszewski M, Levin TL, Ewart M, Liu Q, Xue X, Viswanathan S, Strickler HD. Methods to improve the noninvasive diagnosis and assessment of disease severity in children with suspected nonalcoholic fatty liver disease (NAFLD): Study design. Contemp Clin Trials 2018; 75:51-58. [PMID: 30401631 PMCID: PMC6249118 DOI: 10.1016/j.cct.2018.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/18/2018] [Accepted: 10/25/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and is the most common liver disease in the developed world. In children with suspected NAFLD, present guidelines suggest consideration of alternative diagnoses via extensive blood testing, though the yield of this work up is unknown. Furthermore, the gold standard diagnostic test for NAFLD remains liver biopsy, making the development of non-invasive tests critically important. OBJECTIVES Our objectives are: 1) to determine the accuracy of elastography and multiple serum biomarkers - each assessed individually and as algorithms (including those previously tested in adults) - for the diagnosis of nonalcoholic steatohepatitis (NASH) and early fibrosis in children and (2) to examine the utility of extensive testing for rare alternative diagnoses in overweight or obese children with elevated alanine aminotransferase (ALT) suspected to have NAFLD. DESIGN This is an ongoing, cross-sectional study in children 2-18 years of age with up to 2 years of prospective follow up. Eligible patients are asymptomatic, overweight or obese, and have an ALT ≥35 U/L upon enrollment. Two forms of elastography are obtained serially along with anthropometric data and routine laboratory tests. Elastography and serum biomarkers are also performed immediately prior to any clinically-indicated biopsy. METHODS Between April 2015 and April 2018, 193 children have been enrolled in this ongoing study and 71 have undergone liver biopsy. Here we carefully report the rationale, methodology, and preliminary data for this study.
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Affiliation(s)
- Bryan Rudolph
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Nicole Bjorklund
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute of Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Nadia Ovchinsky
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Debora Kogan-Liberman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Adriana Perez
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Mark Liszewski
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Terry L Levin
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Michelle Ewart
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Qiang Liu
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Xiaonan Xue
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Shankar Viswanathan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Howard D Strickler
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
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48
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Ogawa Y, Honda Y, Kessoku T, Tomeno W, Imajo K, Yoneda M, Kawanaka M, Kirikoshi H, Ono M, Taguri M, Saito S, Yamanaka T, Wada K, Nakajima A. Wisteria floribunda agglutinin-positive Mac-2-binding protein and type 4 collagen 7S: useful markers for the diagnosis of significant fibrosis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2018; 33:1795-1803. [PMID: 29633352 DOI: 10.1111/jgh.14156] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/16/2018] [Accepted: 03/25/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The fibrosis stage of liver is associated with the long-term outcomes in patients with non-alcoholic fatty liver disease (NAFLD). However, significant fibrosis, defined as fibrosis stages 2-4, is associated with an elevated risk of progression to severe liver disease; there have been scant reports about diagnosing significant fibrosis. We compare the noninvasive method and aim to identify appropriate liver fibrosis markers for detecting significant fibrosis in NAFLD patients. METHODS We compared the usefulness of liver fibrosis markers (Wisteria floribunda agglutinin-positive Mac-2-binding protein [WFA+ -M2BP], type 4 collagen 7S, etc.), clinical scoring systems, and liver stiffness measurement obtained using vibration-controlled transient elastography and magnetic resonance imaging-based magnetic resonance elastography in the same individuals and identified the most appropriate noninvasive method for detecting significant fibrosis in 165 patients with liver biopsy-diagnosed NAFLD. RESULTS The area under the receiver operating characteristic curve based on the serum cutoff index values of WFA+ -M2BP/the serum levels of type IV collagen 7S for the diagnosis of significant fibrosis was 0.832 (95% confidence interval: 0.771-0.894)/0.837 (95% confidence interval: 0.778-0.898). "WFA+ -M2BP (cutoff index) ≥ 0.83 or type IV collagen 7S ≥ 5.2 ng/mL" showed a high sensitivity (91.4%) and negative predictive value (87.9%) for the diagnosis of significant fibrosis. CONCLUSIONS We showed that serum WFA+ -M2BP or type IV collagen 7S levels serve as useful independent markers for detecting significant fibrosis and that use of both WFA+ -M2BP and type IV collagen 7S together increased the sensitivity and negative predictive value for the diagnosis of liver fibrosis. These results need to be validated in larger populations from multiple clinical centers.
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Affiliation(s)
- Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Wataru Tomeno
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Hiroyuki Kirikoshi
- Clinical Laboratory Department, Yokohama City University Hospital, Yokohama, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Masataka Taguri
- Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Koichiro Wada
- Department of Pharmacology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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49
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Grove JI, Thiagarajan P, Astbury S, Harris R, Delahooke T, Guha IN, Aithal GP. Analysis of genotyping for predicting liver injury marker, procollagen III in persons at risk of non-alcoholic fatty liver disease. Liver Int 2018; 38:1832-1838. [PMID: 29493856 DOI: 10.1111/liv.13733] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 02/21/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We, therefore, evaluated variant alleles at loci associated with non-alcoholic fatty liver disease as genetic determinants of substantial liver injury in patients with disease risk factors. METHODS Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI > 27.3 (identified from registration with general practitioners) in this observational cross-sectional study. Patients were genotyped for characterised risk alleles in PNPLA3 (rs738409), GCKR (rs1260326) and TM6SF2 (rs58542926) and associations with PIIINP assessed. RESULTS The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP. The prevalence of possession of both PNPLA3 and GCKR variant alleles combined was significantly higher in at-risk patients with clinically significant liver disease indicated by serum PIIINP above 11 ng/mL (P = .014). CONCLUSIONS Genotyping, therefore, has limited value for predicting severe liver disease in at-risk individuals identified in a community setting.
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Affiliation(s)
- Jane I Grove
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Prarthana Thiagarajan
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Stuart Astbury
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Rebecca Harris
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Toby Delahooke
- Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - I Neil Guha
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
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50
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Luo Y, Oseini A, Gagnon R, Charles ED, Sidik K, Vincent R, Collen R, Idowu M, Contos MJ, Mirshahi F, Daita K, Asgharpour A, Siddiqui MS, Jarai G, Rosen G, Christian R, Sanyal AJ. An Evaluation of the Collagen Fragments Related to Fibrogenesis and Fibrolysis in Nonalcoholic Steatohepatitis. Sci Rep 2018; 8:12414. [PMID: 30120271 PMCID: PMC6098042 DOI: 10.1038/s41598-018-30457-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 07/31/2018] [Indexed: 02/07/2023] Open
Abstract
Fibrosis, resulted from the imbalance of fibrogenesis and fibrolysis, is a key readout of disease progression in nonalcoholic steatohepatitis (NASH) and reflects mortality risk. Non-invasive biomarkers capable of diagnosing fibrosis stages and monitoring fibrosis changes in NASH patients are urgently needed. This study is to evaluate collagen formation and degradation biomarkers, reflective of fibrogenesis or fibrolysis, in patients with biopsy proven NASH. Collagen formation biomarker PRO-C3 and PRO-C6 levels were significantly higher in patients with advanced fibrosis stage 3–4 than those with fibrosis stage 0–2. Elevated PRO-C3 levels were also associated with severe lobular inflammation and ballooning, but not with steatosis. Multivariate logistic regression analysis identified PRO-C3 and PRO-C6 to be independently related to fibrosis stage. PRO-C3 showed similar performance to identify patients with advanced fibrosis in discovery and validation cohorts. Furthermore, in a longitudinal study cohort with paired biopsies, mean PRO-C3 increased with worsening of fibrosis and decreased with fibrosis improvement. The results suggest that PRO-C3 may be a potentially useful biomarker in identifying patients with advanced fibrosis and active fibrogenesis, as well as in assessing changes in fibrosis over time. It is worthy of further evaluation to confirm its diagnostic value and clinical utility.
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Affiliation(s)
- Yi Luo
- Fibrosis Translational Research and Development, Bristol-Myers Squibb, Pennington, NJ, USA.
| | - Abdul Oseini
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Robert Gagnon
- Fibrosis Translational Research and Development, Bristol-Myers Squibb, Pennington, NJ, USA
| | - Edgar D Charles
- Fibrosis Translational Research and Development, Bristol-Myers Squibb, Pennington, NJ, USA
| | - Kurex Sidik
- Fibrosis Translational Research and Development, Bristol-Myers Squibb, Pennington, NJ, USA
| | - Robert Vincent
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Rebeca Collen
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Michael Idowu
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Melissa J Contos
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Faridoddin Mirshahi
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Kalyani Daita
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Amon Asgharpour
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Mohammed S Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA
| | - Gabor Jarai
- Fibrosis Translational Research and Development, Bristol-Myers Squibb, Pennington, NJ, USA
| | - Glenn Rosen
- Fibrosis Translational Research and Development, Bristol-Myers Squibb, Pennington, NJ, USA
| | - Rose Christian
- Fibrosis Translational Research and Development, Bristol-Myers Squibb, Pennington, NJ, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Common Wealth University, Richmond, VA, USA.
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