|
1
|
Calès P, Canivet CM, Costentin C, Lannes A, Oberti F, Fouchard I, Hunault G, de Lédinghen V, Boursier J. A new generation of non-invasive tests of liver fibrosis with improved accuracy in MASLD. J Hepatol 2025; 82:794-804. [PMID: 39674323 DOI: 10.1016/j.jhep.2024.11.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 09/23/2024] [Accepted: 11/18/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND & AIMS The accuracy of non-invasive tests (NITs) should be ≥80% (EASL recommendation). We aimed to compare the accuracies of the recommended NITs for advanced fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) and to develop NITs with improved accuracy. METHODS A total of 1,051 patients with MASLD were allocated to derivation (n = 637) and validation (n = 414) sets. The main outcome (Kleiner F3+F4) was primarily evaluated by accuracy. Recommended NITs included: FIB-4, Fibrotest, FibroMeter, liver stiffness measurement (LSM by Fibroscan), Elasto-FibroMeter (FibroMeter-LSM combination), and ELF (enhanced liver fibrosis) in 396 patients. We used machine learning-optimized multitargeting to develop new NITs: FIB-9 (including nine common biomarkers), FIB-11 (adding two specialized blood markers) and FIB-12 (adding LSM). RESULTS In the whole population, the accuracies of recommended NITs were insufficient: Fibrotest, 68.0%; FIB-4, 71.2%; FibroMeter, 75.1%; LSM, 75.9%; Elasto-FibroMeter, 78.6%. Therefore, new NITs (FIB-9, FIB-11, FIB-12) were developed in the derivation set. In the validation set, AUROCs were: FIB-4, 0.757; Fibrotest, 0.766; FibroMeter, 0.850; LSM, 0.852; FIB-9, 0.863; FIB-11, 0.880; Elasto-FibroMeter, 0.894; FIB-12, 0.912 (p <0.001). The FIB-12 AUROC was superior to the ELF AUROC (0.906 vs. 0.865, p = 0.039). Accuracies were: FIB-4, 68.8%; Fibrotest, 68.6%; LSM, 75.4%; FibroMeter, 76.3%; FIB-9, 78.7%; Elasto-FibroMeter, 79.7%; FIB-11, 80.2%; FIB-12, 83.3% (p <0.001 between all NITs). Scores were segmented by ≥90% sensitivity and specificity cut-offs or NIT match, which individualized subgroups with NIT accuracies ≥80%, e.g. for FIB-9: 85.8% in 68.1% of patients using two cut-offs and 83.2% in 71.7% of patients where FIB-9 agreed with FIB-4. CONCLUSIONS Recommended NITs had accuracies <80% for advanced fibrosis in MASLD. Several NIT segmentations individualized subgroups with accuracies ≥80%. New NITs further improved accuracy. The simple FIB-9 (available via a free calculator) provided accuracy equaling or surpassing recommended NITs. FIB-12 outperformed other NITs. IMPACT AND IMPLICATIONS Currently recommended non-invasive tests (NITs) have insufficient accuracy (<80%) for the diagnosis of advanced fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we developed three new NITs with new statistical techniques. Thus, FIB-9 (available via a free calculator), including nine common blood markers, equaled the performance of patented NITs. FIB-11, adding two specialized blood markers, and FIB-12, adding liver stiffness, had accuracy >80%. FIB-12 outperformed all other NITs. FIB-9 is suitable for screening and FIB-11 or FIB-12 for diagnosis.
Collapse
Affiliation(s)
- Paul Calès
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France; Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France.
| | - Clémence M Canivet
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France; Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France
| | - Charlotte Costentin
- Université de Grenoble Alpes, Institut des Biosciences avancées, CNRS UMR 5309-INSERM U1209; Service d'Hépato-Gastroentérologie et d'Oncologie Digestive, Centre Hospitalier Universitaire de Grenoble Alpes, Grenoble, France
| | - Adrien Lannes
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France; Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France
| | - Frédéric Oberti
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France; Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France
| | - Isabelle Fouchard
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France; Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France
| | - Gilles Hunault
- Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France
| | - Victor de Lédinghen
- Service d'Hépatologie, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, Pessac, France; INSERM U1312, Université de Bordeaux, Bordeaux, France
| | - Jérôme Boursier
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France; Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France
| |
Collapse
|
|
2
|
Cerban R, Iacob S, Ester C, Ghioca M, Chitul M, Iacob R, Gheorghe L. Liver Elastography Methods for Diagnosis of De Novo and Recurrent Hepatocellular Carcinoma. Diagnostics (Basel) 2025; 15:1087. [PMID: 40361905 PMCID: PMC12072106 DOI: 10.3390/diagnostics15091087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 05/15/2025] Open
Abstract
Hepatocellular carcinoma (HCC), a common consequence of chronic liver disease, ranks among the most prevalent cancers globally and contributes significantly to cancer-related mortality. Liver fibrosis is intimately associated with hepatic function and the likelihood of future HCC occurrence. Despite the fact that liver biopsy continues to be the gold standard for diagnosing fibrosis, its utility is hindered by cost and invasiveness, along with patient unease, procedural rejection, and potential adverse effects. Liver elastography has become a leading noninvasive means of assessing tissue stiffness with considerable diagnostic precision. Malignant tumors generally exhibit higher cellularity in comparison to benign ones, resulting in increased stiffness. Elastography techniques capitalize on alterations in tissue elasticity stemming from specific pathological or physiological processes. Technological innovations, such as advanced ultrasound imaging and artificial intelligence (AI)-integrated systems, are paving the way for enhanced diagnostic accuracy and risk prediction. Recent research underscores the potential of elastography in managing HCC patients, presenting novel clinical applications, including prediction of HCC development, differentiation between malignant and benign liver lesions, evaluating treatment response, and forecasting recurrence post-treatment, though certain findings remain contentious. Therefore, this review aims to sum up the latest advancements in liver elastography for HCC patients, outlining its applications while addressing existing limitations and avenues for future progress.
Collapse
Affiliation(s)
- Razvan Cerban
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.); (C.E.); (M.C.); (R.I.); (L.G.)
- Center for Digestive Diseases and Liver Transplant, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Speranta Iacob
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.); (C.E.); (M.C.); (R.I.); (L.G.)
- Center for Digestive Diseases and Liver Transplant, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Carmen Ester
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.); (C.E.); (M.C.); (R.I.); (L.G.)
- Center for Digestive Diseases and Liver Transplant, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Mihaela Ghioca
- Center for Digestive Diseases and Liver Transplant, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Mirela Chitul
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.); (C.E.); (M.C.); (R.I.); (L.G.)
| | - Razvan Iacob
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.); (C.E.); (M.C.); (R.I.); (L.G.)
- Center for Digestive Diseases and Liver Transplant, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Liana Gheorghe
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (R.C.); (C.E.); (M.C.); (R.I.); (L.G.)
- Center for Digestive Diseases and Liver Transplant, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| |
Collapse
|
|
3
|
Patel K, Asrani SK, Fiel MI, Levine D, Leung DH, Duarte-Rojo A, Dranoff JA, Nayfeh T, Hasan B, Taddei TH, Alsawaf Y, Saadi S, Majzoub AM, Manolopoulos A, Alzuabi M, Ding J, Sofiyeva N, Murad MH, Alsawas M, Rockey DC, Sterling RK. Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline. Hepatology 2025; 81:358-379. [PMID: 38489517 DOI: 10.1097/hep.0000000000000842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/19/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND AND AIMS Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. APPROACH AND RESULTS We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR-) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86, respectively; LR+ and LR- for NAFLD F2-4, F3-4, and F4 were 2.65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. CONCLUSIONS Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.
Collapse
Affiliation(s)
- Keyur Patel
- Department of Medcine, Division of Gastroenterology and Hepatology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Sumeet K Asrani
- Department of Medicine, Division of Hepatology, Baylor University Medical Center, Dallas, Texas, USA
| | - Maria Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Deborah Levine
- Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel H Leung
- Department of Pediatrics, Baylor College of Medicine and Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Houston, Texas, USA
| | - Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, Northwestern Medicine and Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jonathan A Dranoff
- Yale School of Medicine, Department of Internal Medicine, Section of Digestive Diseases, New Haven, Connecticut, USA
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Tarek Nayfeh
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Bashar Hasan
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Tamar H Taddei
- Yale School of Medicine, Department of Internal Medicine, Section of Digestive Diseases, New Haven, Connecticut, USA
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Yahya Alsawaf
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Samer Saadi
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Muayad Alzuabi
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Jingyi Ding
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Nigar Sofiyeva
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Mohammad H Murad
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Mouaz Alsawas
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
- Department of Medicine, Section of Hepatology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Don C Rockey
- Department of Medicine, Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Richard K Sterling
- Department of Medicine, Section of Hepatology, Virginia Commonwealth University, Richmond, Virginia, USA
| |
Collapse
|
|
4
|
Otero Sanchez L, Moreno C. Noninvasive Tests in Assessment of Patients with Alcohol-Associated Liver Disease. Clin Liver Dis 2024; 28:715-729. [PMID: 39362717 DOI: 10.1016/j.cld.2024.06.010] [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: 10/05/2024]
Abstract
Alcohol-associated liver disease (ALD) remains a significant public health concern, accounting for at least half of cirrhosis cases in Europe. Historically, liver biopsy has been considered the gold standard method for both diagnosing and staging ALD. However, in the past 3 decades, there has been a growing interest in developing noninvasive biomarkers for identifying high-risk patients prone to develop liver-related complications, including elastography methods or blood-based biomarkers. This review aims to summarize currently available noninvasive testing methods that are clinically available for assessing patients with ALD, including notably steatosis and fibrosis.
Collapse
Affiliation(s)
- Lukas Otero Sanchez
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, C.U.B. Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, C.U.B. Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
| |
Collapse
|
|
5
|
Kim MN, Han JW, An J, Kim BK, Jin YJ, Kim SS, Lee M, Lee HA, Cho Y, Kim HY, Shin YR, Yu JH, Kim MY, Choi Y, Chon YE, Cho EJ, Lee EJ, Kim SG, Kim W, Jun DW, Kim SU. KASL clinical practice guidelines for noninvasive tests to assess liver fibrosis in chronic liver disease. Clin Mol Hepatol 2024; 30:S5-S105. [PMID: 39159947 PMCID: PMC11493350 DOI: 10.3350/cmh.2024.0506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024] Open
Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Ji Won Han
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jihyun An
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Seung-seob Kim
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Minjong Lee
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
| | - Hee Yeon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yu Rim Shin
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jung Hwan Yu
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Young Eun Chon
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Joo Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - on behalf of The Korean Association for the Study of the Liver (KASL)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
| |
Collapse
|
|
6
|
Manea M, Mărunțelu I, Constantinescu I. A New Assessment of Two Transferase-Based Liver Enzymes in Low- and High-Fibrosis Patients Chronically Infected with Hepatitis B Virus: A Meta-Analysis and Pilot Study. J Clin Med 2024; 13:3903. [PMID: 38999469 PMCID: PMC11242663 DOI: 10.3390/jcm13133903] [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: 06/03/2024] [Revised: 06/23/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024] Open
Abstract
Background: The detection of fibrosis remains a necessity for the evaluation of hepatitis B virus (HBV)-infected patients, but the most accurate technique is invasive. Current studies aim to develop a novel noninvasive biomarker for fibrosis assessment, but no-one has found the ideal candidate. This study is a meta-analysis combined with a pilot study to investigate the connection between two transferase compounds and the levels of fibrosis. Methods: We studied data from PUBMED, Web of Science, and Scopus, retrieving 28,896 articles. Following PRISMA guidelines, we finally analyzed full-text articles written in English. The excluded items were duplicates, non-article entries, and irrelevant papers. We assessed the variations in alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels between patients with high and low levels of fibrosis. Joanna Briggs Institute tools were used to assess article quality. We used R 4.2.2 for statistics. The pilot study included 14 randomly chosen patients with different fibrosis levels. Results: We found significant differences in ALT and GGT levels between patients with high and low fibrosis. The GGT/ALT ratio correlated with the levels of fibrosis and the fibrosis-4 (FIB-4) score. Conclusions: This meta-analysis assessed ALT and GGT levels in chronic HBV patients with fibrosis. The pilot study identified the first association between fibrosis and the GGT/ALT ratio in a Romanian cohort of chronic patients. This brings new ideas for future research.
Collapse
Affiliation(s)
- Marina Manea
- Immunology and Transplant Immunology, University of Medicine and Pharmacy "Carol Davila", 020021 Bucharest, Romania
| | - Ion Mărunțelu
- Immunology and Transplant Immunology, University of Medicine and Pharmacy "Carol Davila", 020021 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Ileana Constantinescu
- Immunology and Transplant Immunology, University of Medicine and Pharmacy "Carol Davila", 020021 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| |
Collapse
|
|
7
|
Nakano M, Kuromatsu R, Kawaguchi T. Ultrasonographic Assessment of Tissue Stiffness: Recent Progress in Transient Elastography and Shear Wave Elastography in the Liver and Various Organs. Kurume Med J 2024; 70:1-10. [PMID: 38763738 DOI: 10.2739/kurumemedj.ms7012010] [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: 05/21/2024]
Abstract
Ultrasonography is a noninvasive and widely accessible modality in clinical practice. Recently, ultrasonography has been used to evaluate tissue stiffness; the two representative techniques are transient elastography (FibroScan®) and shear wave elastography. These modalities are now generally used for the assessment of liver fibrosis, the prediction of hepatocarcinogenesis, and determining prognosis. In addition, shear wave elastography is available, not only for the liver but also for various other organs, including the breast and brain. In the breast and brain, shear wave elastography distinguishes malignant lesions from benign ones. Moreover, shear wave elastography can be useful for differentiating between ischemic and hemorrhagic strokes. This review summarizes the recent progress in transient elastography and shear wave elastography of the liver and introduces the advantages of ultrasonographic assessment of tissue stiffness in various organs, including the breast, brain, kidney, heart, thyroid, pancreas, muscle, and bone.
Collapse
Affiliation(s)
- Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine
- Ultrasound Diagnostic Center, Kurume University Hospital
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine
| |
Collapse
|
|
8
|
Maroto-García J, Moreno Álvarez A, Sanz de Pedro MP, Buño-Soto A, González Á. Serum biomarkers for liver fibrosis assessment. ADVANCES IN LABORATORY MEDICINE 2024; 5:115-130. [PMID: 38939201 PMCID: PMC11206202 DOI: 10.1515/almed-2023-0081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
Liver fibrosis is the result of chronic liver injury of different etiologies produced by an imbalance between the synthesis and degeneration of the extracellular matrix and dysregulation of physiological mechanisms. Liver has a high regenerative capacity in the early stage of chronic diseases so a prompt liver fibrosis detection is important. Consequently, an easy and economic tool that could identify patients with liver fibrosis at the initial stages is needed. To achieve this, many non-invasive serum direct, such as hyaluronic acid or metalloproteases, and indirect biomarkers have been proposed to evaluate liver fibrosis. Also, there have been developed formulas that combine these biomarkers, some of them also introduce clinical and/or demographic parameters, like FIB-4, non-alcoholic fatty liver disease fibrosis score (NFS), enhance liver fibrosis (ELF) or Hepamet fibrosis score (HFS). In this manuscript we critically reviewed different serum biomarkers and formulas for their utility in the diagnosis and progression of liver fibrosis.
Collapse
Affiliation(s)
| | - Ana Moreno Álvarez
- Biochemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
| | | | - Antonio Buño-Soto
- Laboratory Medicine Department, Hospital Universitario La Paz, Madrid, Spain
- Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
| | - Álvaro González
- Biochemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| |
Collapse
|
|
9
|
Maroto-García J, Moreno-Álvarez A, Sanz de Pedro MP, Buño-Soto A, González Á. Biomarcadores séricos para la evaluación de la fibrosis hepática. ADVANCES IN LABORATORY MEDICINE 2024; 5:131-147. [PMID: 38939202 PMCID: PMC11206201 DOI: 10.1515/almed-2023-0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
La fibrosis hepática se desarrolla como respuesta a la presencia de daño hepático crónico de diferentes etiologías, provocando un desequilibrio entre la síntesis y degeneración de la matriz extracelular y la desregulación de diversos mecanismos fisiológicos. En los estadios iniciales de las patologías crónicas, el hígado posee una elevada capacidad de regeneración, por lo que la detección temprana de la fibrosis hepática resulta esencial. En este contexto, es preciso contar con herramientas sencillas y económicas que permitan detectar la fibrosis hepática en sus fases iniciales. Para evaluar la fibrosis hepática, se han propuesto multitud de biomarcadores séricos no invasivos, tanto directos, como el ácido hialurónico o las metaloproteasas, como indirectos. Así mismo, se han desarrollado diversas fórmulas que combinan dichos biomarcadores junto con parámetros demográficos, como el índice FIB-4, el índice de fibrosis en la enfermedad de hígado graso no alcohólico (NFS, por sus siglas en inglés), la prueba ELF o el score de fibrosis Hepamet (HFS, por sus siglas en inglés). En el presente manuscrito, realizamos una revisión crítica del valor diagnóstico y pronóstico de los diferentes biomarcadores séricos y fórmulas actualmente existentes.
Collapse
Affiliation(s)
- Julia Maroto-García
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
| | - Ana Moreno-Álvarez
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
| | | | - Antonio Buño-Soto
- Departamento de Análisis Clínicos, Hospital Universitario La Paz, Madrid, España
- Instituto de investigación en salud del Hospital La (IdiPaz), Madrid, España
| | - Álvaro González
- Departamento de Bioquímica, Clínica Universidad de Navarra, Pamplona, España
- Instituto Navarro de investigación en salud (IdiSNA), Pamplona, España
| |
Collapse
|
|
10
|
Ouzan D, Penaranda G, Jlaiel M, Joly H, Corneille J. Using the FIB-4, automatically calculated, followed by the ELF test in second line to screen primary care patients for liver disease. Sci Rep 2024; 14:12198. [PMID: 38806580 PMCID: PMC11133421 DOI: 10.1038/s41598-024-62549-3] [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: 12/11/2023] [Accepted: 05/17/2024] [Indexed: 05/30/2024] Open
Abstract
The objective of our work was to evaluate the screening of hepatic fibrosis in primary care using the FIB-4 score, automatically calculated. When the FIB-4 was ≥ 1.3, it was defined as positive, and ELF Test was performed. FIB-4 positivity was confirmed when ELF Test was ≥ 9.8 indicating an advanced fibrosis. Among the 3427 patients included, 869 (25%) had a positive FIB-4 score, 784 (22.5%) at intermediate (FIB-4: 1.3-2.67), and 85 (2.5%) at high risk of fibrosis (FIB-4 > 2.67). 509 (59%) of the FIB-4 positive were confirmed by the ELF Test. The percentage of confirmation was significantly higher in patients over 65 years (83 vs. 57%), with FIB-4 > 2.67 (80 vs. 56%), BMI > 25 (47 vs. 37%), and diabetes (24 vs. 14%), p = 0.001). In patients without known liver disease (92%), the practitioner identified a cause of disease in 27% of cases: mainly NAFLD and alcohol. Liver fibrosis was suspected on FIB-4 in 25% of patients in primary care. The ELF Test, performed as a second-line, improves the screening of liver fibrosis, particularly for FIB-4 intermediate results. A positive FIB-4 test allows physicians to recognize a liver disease, providing an opportunity for timely intervention.Clinical trial registration: Comité de protection des personnes du sud-ouest et outre-mer SI18.00832.201865-MS04-IDRCB 2018-A01571-54.
Collapse
Affiliation(s)
- Denis Ouzan
- Département d'Hépato-Gastroentérologie, Institut Arnault Tzanck, 06700, Saint-Laurent-du-Var, France.
- Réseau ville hôpital hépatite C Cote d'Azur (RHeCCA), Nice, France.
| | - G Penaranda
- Laboratoire Alphabio-Biogroup, Marseille, France
- Hôpital Européen, Marseille, France
| | - M Jlaiel
- Laboratoire Bioesterel-Biogroup, Mandelieu-la-Napoule, France
| | - H Joly
- Département d'Hépato-Gastroentérologie, Institut Arnault Tzanck, 06700, Saint-Laurent-du-Var, France
| | - J Corneille
- Laboratoire Bioesterel-Biogroup, Mougins, France
| |
Collapse
|
|
11
|
Makri E, Orfanidou M, Makri ES, Goulas A, Terpos E, Polyzos SA. Circulating Ferritin in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. J Clin Exp Hepatol 2024; 14:101353. [PMID: 38435724 PMCID: PMC10905002 DOI: 10.1016/j.jceh.2024.101353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 01/26/2024] [Indexed: 03/05/2024] Open
Abstract
Objectives To synthesize data on circulating ferritin between patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and non-NAFLD controls. Methods A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Library. Thirty-one studies comprising data on 5631 individuals (2929 biopsy-proven NAFLD patients and 2702 controls) were included in the meta-analysis. Results Higher circulating ferritin levels were observed in NAFLD patients than in controls [standardized mean difference (SMD) 1.14; 95% confidence interval (95% CI) 0.73-1.55], in patients with simple nonalcoholic fatty liver (NAFL) than in controls (SMD 0.57; 95% CI 0.34-0.80), in patients with nonalcoholic steatohepatitis (NASH) than in controls (SMD 0.95; 95% CI 0.69-1.22), and in NASH than in NAFL patients (SMD 0.62; 95% CI 0.25-0.99). There was moderate-to-high heterogeneity among studies in the above pairs of comparisons (I2 = 68-97%); no risk of publication bias was observed by Egger's test (P = 0.81, P = 0.72, P = 0.59, P = 0.42, respectively). The heterogeneity was reduced in the subgroup of biopsy-proven controls in all pairs of comparisons (I2 = 0-65%). The heterogeneity was also reduced after excluding studies with the Newcastle-Ottawa Scale (NOS) score <7 (n = 10) for the comparison of NAFLD patients vs. controls (I2 = 54%, P = 0.02). The meta-regression analysis revealed that the male ratio was positively associated with ferritin SMD in the comparison between NAFLD patients and controls and accounted for 32.7% (P = 0.002) of the heterogeneity in this pair of comparison. Conclusions Circulating ferritin was higher in NAFLD (or NAFL or NASH) patients compared with controls. Higher levels of circulating ferritin were also associated with the severity of the disease, which, however, should be cautiously interpreted.PROSPERO registration ID: CRD42022354025.
Collapse
Affiliation(s)
- Eleftheria Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Myrsini Orfanidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelia S. Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Stergios A. Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| |
Collapse
|
|
12
|
Gelu-Simeon M, Lafrance MJ, Michineau L, Saillard E, Thomé JP, Emond C, Samson M, Multigner L. Inverse association between plasma chlordecone concentrations and progression of alcoholic liver fibrosis: the role of liver metabolism. Environ Health 2024; 23:30. [PMID: 38504260 PMCID: PMC10953091 DOI: 10.1186/s12940-024-01054-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 01/10/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND AND AIMS Chlordecone is a persistent organochlorinated insecticide, extensively used in the French West Indies and has been contaminating the population for more than thirty years. Its potentiation effect on hepatotoxic agents has been demonstrated in animal models. We investigated the relationship between environmental exposure to chlordecone and the progression of liver fibrosis. METHODS This study included 182 consecutive patients with chronic alcoholic hepatitis whose liver fibrosis was assessed using non-invasive methods. Measured plasma chlordecone concentrations at inclusion were used as surrogate of long-term exposure under steady-state conditions. As the pharmacokinetic processing of chlordecone is largely determined by the liver, we used a human physiologically based pharmacokinetic model to predict plausible changes in the steady-state blood chlordecone concentrations induced by liver fibrosis. RESULTS With a median follow-up of 27.1 years after the onset of alcohol consumption, we found a significant decrease in the risk of advanced liver fibrosis with increasing plasma chlordecone concentration (adjusted hazard ratio = 0.56; 95% confidence interval: 0.34-0.95 for the highest vs. lowest tertile, p = 0.04). Changes induced by liver fibrosis influenced the pharmacokinetic processing of chlordecone, resulting in substantial modifications in its steady-state blood concentrations. CONCLUSION According to this human model of coexposure to alcohol, reverse causality is the most plausible explanation of this inverse association between plasma chlordecone concentrations and progression of liver fibrosis. This study underlines the importance of considering the pharmacokinetic of environmental contaminants in epidemiological studies when biomarkers of exposure are used to investigate their own impact on the liver. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03373396.
Collapse
Affiliation(s)
- Moana Gelu-Simeon
- CHU de la Guadeloupe, Univ Antilles, Inserm, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Route de Chauvel, Pointe-à-Pitre Cedex, Guadeloupe, 97159, France.
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Guadeloupe, Pointe à Pitre, Guadeloupe, France.
| | - Marie-Josée Lafrance
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Guadeloupe, Pointe à Pitre, Guadeloupe, France
| | - Leah Michineau
- Univ Rennes, Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Avenue du Professeur Léon Bernard, Rennes, F-35000, France
| | - Eric Saillard
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Guadeloupe, Pointe à Pitre, Guadeloupe, France
| | - Jean Pierre Thomé
- Université de Liège, LEAE -CART, Freshwater and Oceanic Sciences Unit of Research (FOCUS), B6C, Liège, 4000, Belgium
| | - Claude Emond
- PKSH Inc, Crabtree, QC, Canada
- École de Santé Publique, Département de Santé Environnementale et Santé au Travail (DSEST), Université de Montréal, Montreal, QC, Canada
| | - Michel Samson
- Univ Rennes, Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Avenue du Professeur Léon Bernard, Rennes, F-35000, France.
| | - Luc Multigner
- Univ Rennes, Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Avenue du Professeur Léon Bernard, Rennes, F-35000, France
| |
Collapse
|
|
13
|
Shree Harini K, Ezhilarasan D. Flavonoids-based nanomedicines for the treatment of liver fibrosis: A recent progress. J Drug Deliv Sci Technol 2024; 93:105467. [DOI: 10.1016/j.jddst.2024.105467] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
14
|
Kaya E, Yilmaz Y. Noninvasive, serum-based evaluation of liver fibrosis in metabolic (dysfunction)-associated fatty liver disease. METABOLIC STEATOTIC LIVER DISEASE 2024:137-150. [DOI: 10.1016/b978-0-323-99649-5.00012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
15
|
Yakut A, Aladag M. Noninvasive Tests to Assess Liver Stiffness in Patients with Chronic Hepatitis B: APRI, FIB‐4, and FIB‐5 Scores. Int J Clin Pract 2024; 2024. [DOI: 10.1155/2024/5540648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/27/2024] [Indexed: 09/10/2024] Open
Abstract
Background. Invasive percutaneous liver parenchymal biopsy is the best test used to evaluate liver stiffness and fibrosis in the follow‐up and treatment of chronic hepatitis B (CHB) patients. In this study, we aimed to indirectly evaluate the severity of liver parenchymal fibrosis with tests used in the laboratory. Methods. This retrospective study was conducted with 201 patients diagnosed with CHB who underwent liver biopsy between 2021 and 2022. Preprocedural examination information, laboratory tests, and histopathological data of the patients were taken from the hospital database and examined. “Aspartate aminotransferase (AST)‐platelet ratio index” (APRI), “4 factor‐based fibrosis index” (FIB‐4) score, and “5 factor‐based fibrosis index” (FIB‐5) score were calculated and compared with liver histopathological features. Results. Of the 201 CHB patients, 76 were females and 125 were males. The average age of the patients was 38.05 ± 12.63 years. A weak, statistically significant correlation was observed between FIB‐4 and APRI scores. The patients’ significant fibrosis scores were 31.3% and 33.8%, respectively (r = 0.313; r = 0.338; p = 0.001; p < 0.01). The very weak negative correlation of 17.4% between the patients’ FIB‐5 score and fibrosis score was statistically significant (r = −0.174; p = 0.014; p < 0.05). Conclusions. According to the data we obtained in our study, while the APRI score and FIB‐4 score can be used safely, more comprehensive studies are needed for the reliability of the FIB‐5 score.
Collapse
|
|
16
|
Suwała S, Białczyk A, Koperska K, Rajewska A, Krintus M, Junik R. Prevalence and Crucial Parameters in Diabesity-Related Liver Fibrosis: A Preliminary Study. J Clin Med 2023; 12:7760. [PMID: 38137829 PMCID: PMC10744287 DOI: 10.3390/jcm12247760] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/28/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023] Open
Abstract
Diabetes and obesity have been recognized as confirmed risk factors for the occurrence of liver fibrosis. Despite the long-standing acknowledgment of "diabesity", the simultaneous existence of diabetes and obesity, scholarly literature has shown limited attention to this topic. The aim of this pilot study was to assess the prevalence of liver fibrosis among individuals with diabetes (specifically those who are obese) in order to identify the key factors associated with hepatofibrosis and determine the most important associations and differences between patients with and without liver fibrosis. The research included a total of 164 participants (48.17% had comorbid obesity). Liver elastography (Fibroscan) was performed on these individuals in addition to laboratory tests. Liver fibrosis was found in 34.76% of type 2 diabetes patients; male gender almost doubled the risk of hepatofibrosis (RR 1.81) and diabesity nearly tripled this risk (RR 2.81; however, in degree III of obesity, the risk was elevated to 3.65 times higher). Anisocytosis, thrombocytopenia, or elevated liver enzymes raised the incidence of liver fibrosis by 1.78 to 2.47 times. In these individuals, liver stiffness was negatively correlated with MCV, platelet count, and albumin concentration; GGTP activity and HbA1c percentage were positively correlated. The regression analysis results suggest that the concentration of albumin and the activity of GGTP are likely to have a substantial influence on the future management of liver fibrosis in patients with diabesity. The findings of this study can serve as the basis for subsequent investigations and actions focused on identifying potential therapeutic and diagnostic avenues.
Collapse
Affiliation(s)
- Szymon Suwała
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
| | - Aleksandra Białczyk
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Kinga Koperska
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Alicja Rajewska
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Magdalena Krintus
- Department of Laboratory Medicine, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
| | - Roman Junik
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
| |
Collapse
|
|
17
|
Bojanic K, Bogojevic MS, Vukadin S, Sikora R, Ivanac G, Lucic NR, Smolic M, Tabll AA, Wu GY, Smolic R. Noninvasive Fibrosis Assessment in Chronic Hepatitis C Infection: An Update. J Clin Transl Hepatol 2023; 11:1228-1238. [PMID: 37577224 PMCID: PMC10412701 DOI: 10.14218/jcth.2022.00365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 11/04/2022] [Accepted: 02/27/2023] [Indexed: 07/03/2023] Open
Abstract
Liver biopsy is historically the gold standard for liver fibrosis assessment of chronic hepatitis C patients. However, with the introduction and validation of noninvasive tests (NITs) to evaluate advanced fibrosis, and the direct-acting antiviral agents for treatment of chronic hepatitis C virus (HCV), the role of NITs have become even more complex. There is now need for longitudinal monitoring and elucidation of cutoff values for prediction of liver-related complication after sustained virological response. The aim of this report is to provide a critical overview of the various NITs available for the assessment of liver fibrosis in HCV patients.
Collapse
Affiliation(s)
- Kristina Bojanic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Health Center Osijek-Baranja County, Osijek, Croatia
| | | | - Sonja Vukadin
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Renata Sikora
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Health Center Osijek-Baranja County, Osijek, Croatia
| | - Gordana Ivanac
- University Hospital Dubrava, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Nikola Raguz Lucic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Ashraf A. Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Center, Giza, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt
| | - George Y. Wu
- University of Connecticut Health Center, Farmington, CT, USA
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| |
Collapse
|
|
18
|
Albhaisi S, Sun J, Sanyal AJ. Fibrosis-4 index is associated with the risk of hepatocellular carcinoma in patients with cirrhosis and nonalcoholic steatohepatitis. Front Oncol 2023; 13:1198871. [PMID: 37675229 PMCID: PMC10477779 DOI: 10.3389/fonc.2023.1198871] [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: 04/02/2023] [Accepted: 08/04/2023] [Indexed: 09/08/2023] Open
Abstract
Background and aims Identification of high-risk patients for hepatocellular carcinoma (HCC) is essential for long term monitoring of nonalcoholic steatohepatitis (NASH) cirrhosis progression. We sought to evaluate the association between Fibrosis-4 (FIB-4) index and incidence of HCC risk among patients with NASH cirrhosis. Methods We conducted a retrospective cohort study of adult patients with NASH cirrhosis (n= 1,338) who were evaluated in a single medical center between 2005 and 2015. Those who developed HCC were identified through electronic medical records using International Classification of Diseases (ICD) 9 and 10 codes until the end of September 2021. Results During a median follow-up time of 3.7 years, 157 (11.7%) patients with NASH cirrhosis developed HCC. At index visit, the study population had a median age 57 years, 43% males, 78.8% White, and mean FIB-4 index 4.2. The final multivariable Cox regression model revealed that male sex, BMI 25-29.9 kg/m2, and hypertension were independent factors associated with development of HCC in patients with NASH cirrhosis. Compared to patients with FIB-4 ¾ 1.45, patients with FIB-4 between 1.45-3.25 had a similar hazard of HCC (Hazard Ratio [HR] 1.12, 95% CI: 0.67-1.86, p=0.670), whereas patients with FIB-4 >3.25 had a 1.93 (95% CI: 1.22-3.05, p=0.005) increased hazard of HCC. Conclusion FIB-4 > 3.25 was an independent factor associated with increased HCC risk among NASH cirrhosis patients. FIB-4 index is a promising tool for determining high-risk patients and may be used in routine clinical practice to monitor risk of HCC in patients with NASH cirrhosis.
Collapse
Affiliation(s)
- Somaya Albhaisi
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Jing Sun
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
| |
Collapse
|
|
19
|
Ruta S, Grecu L, Iacob D, Cernescu C, Sultana C. HIV-HBV Coinfection-Current Challenges for Virologic Monitoring. Biomedicines 2023; 11:1306. [PMID: 37238976 PMCID: PMC10215721 DOI: 10.3390/biomedicines11051306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
HIV-HBV coinfected patients have higher rates of liver-related morbidity, hospitalizations, and mortality compared to HBV or HIV mono-infected ones. Clinical studies have shown an accelerated progression of liver fibrosis and an increased incidence of HCC, resulting from the combined action of HBV replication, immune-mediated hepatocytolysis, and HIV-induced immunosuppression and immunosenescence. Antiviral therapy based on dually active antiretrovirals is highly efficient, but late initiation, global disparities in accessibility, suboptimal regimens, and adherence issues may limit its impact on the development of end-stage liver disease. In this paper, we review the mechanisms of liver injuries in HIV-HBV coinfected patients and the novel biomarkers that can be used for treatment monitoring in HIV-HBV coinfected persons: markers that assess viral suppression, markers for liver fibrosis evaluation, and predictors of oncogenesis.
Collapse
Affiliation(s)
- Simona Ruta
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Laura Grecu
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Diana Iacob
- Department for the Prevention and Control of Healthcare Associated Infections, Emergency University Hospital, 050098 Bucharest, Romania;
| | | | - Camelia Sultana
- Virology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| |
Collapse
|
|
20
|
Raahimi MM, Livesey A, Hamilton J, Shipman AR, Aspinall RJ. Liver fibrosis for the dermatologist: a review. Clin Exp Dermatol 2023; 48:303-309. [PMID: 36763770 DOI: 10.1093/ced/llac083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 10/28/2022] [Accepted: 11/14/2022] [Indexed: 01/09/2023]
Abstract
Methotrexate-induced liver fibrosis is not a well-defined pathology, and many of the reported cases can instead be classified as nonalcoholic fatty liver disease by current diagnostic criteria, which is particularly common in the psoriasis cohort. Liver fibrosis usually takes many years to progress; therefore, screening for liver fibrosis should be done no more regularly than annually at the very most in dermatology practice. An algorithm is presented about how to investigate abnormal liver blood tests and screening tools for liver fibrosis are compared.
Collapse
Affiliation(s)
- Mina M Raahimi
- Departments of Dermatology, Portsmouth Hospitals University NHS Trust, UK
| | - Amy Livesey
- Departments of Dermatology, Portsmouth Hospitals University NHS Trust, UK
| | - Jessica Hamilton
- Departments of Dermatology, Portsmouth Hospitals University NHS Trust, UK
| | - Alexa R Shipman
- Departments of Dermatology, Portsmouth Hospitals University NHS Trust, UK
| | - Richard J Aspinall
- Departments of Gastroenterology and Hepatology, Portsmouth Hospitals University NHS Trust, UK
| |
Collapse
|
|
21
|
Free TJ, Tucker RW, Simonson KM, Smith SA, Lindgren CM, Pitt WG, Bundy BC. Engineering At-Home Dilution and Filtration Methods to Enable Paper-Based Colorimetric Biosensing in Human Blood with Cell-Free Protein Synthesis. BIOSENSORS 2023; 13:104. [PMID: 36671942 PMCID: PMC9855769 DOI: 10.3390/bios13010104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 06/17/2023]
Abstract
Diagnostic blood tests can guide the administration of healthcare to save and improve lives. Most clinical biosensing blood tests require a trained technician and specialized equipment to process samples and interpret results, which greatly limits test accessibility. Colorimetric paper-based diagnostics have an equipment-free readout, but raw blood obscures a colorimetric response which has motivated diverse efforts to develop blood sample processing techniques. This work uses inexpensive readily-available materials to engineer user-friendly dilution and filtration methods for blood sample collection and processing to enable a proof-of-concept colorimetric biosensor that is responsive to glutamine in 50 µL blood drop samples in less than 30 min. Paper-based user-friendly blood sample collection and processing combined with CFPS biosensing technology represents important progress towards the development of at-home biosensors that could be broadly applicable to personalized healthcare.
Collapse
|
|
22
|
Hong Z, Zhang S, Li L, Li Y, Liu T, Guo S, Xu X, Yang Z, Zhang H, Xu J. A Nomogram for Predicting Prognosis of Advanced Schistosomiasis japonica in Dongzhi County-A Case Study. Trop Med Infect Dis 2023; 8:tropicalmed8010033. [PMID: 36668940 PMCID: PMC9866143 DOI: 10.3390/tropicalmed8010033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUNDS Advanced schistosomiasis is the late stage of schistosomiasis, seriously jeopardizing the quality of life or lifetime of infected people. This study aimed to develop a nomogram for predicting mortality of patients with advanced schistosomiasis japonica, taking Dongzhi County of China as a case study. METHOD Data of patients with advanced schistosomiasis japonica were collected from Dongzhi Schistosomiasis Hospital from January 2019 to July 2022. Data of patients were randomly divided into a training set and validation set with a ratio of 7:3. Candidate variables, including survival outcomes, demographics, clinical features, laboratory examinations, and ultrasound examinations, were analyzed and selected by LASSO logistic regression for the nomogram. The performance of the nomogram was assessed by concordance index (C-index), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The calibration of the nomogram was evaluated by the calibration plots, while clinical benefit was evaluated by decision curve and clinical impact curve analysis. RESULTS A total of 628 patients were included in the final analysis. Atrophy of the right liver, creatinine, ascites level III, N-terminal procollagen III peptide, and high-density lipoprotein were selected as parameters for the nomogram model. The C-index, sensitivity, specificity, PPV, and NPV of the nomogram were 0.97 (95% [CI]: [0.95-0.99]), 0.78 (95% [CI]: [0.64-0.87]), 0.97 (95% [CI]: [0.94-0.98]), 0.78 (95% [CI]: [0.64-0.87]), 0.97 (95% [CI]: [0.94-0.98]) in the training set; and 0.98 (95% [CI]: [0.94-0.99]), 0.86 (95% [CI]: [0.64-0.96]), 0.97 (95% [CI]: [0.93-0.99]), 0.79 (95% [CI]: [0.57-0.92]), 0.98 (95% [CI]: [0.94-0.99]) in the validation set, respectively. The calibration curves showed that the model fitted well between the prediction and actual observation in both the training set and validation set. The decision and the clinical impact curves showed that the nomogram had good clinical use for discriminating patients with high risk of death. CONCLUSIONS A nomogram was developed to predict prognosis of advanced schistosomiasis. It could guide clinical staff or policy makers to formulate intervention strategies or efficiently allocate resources against advanced schistosomiasis.
Collapse
Affiliation(s)
- Zhong Hong
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Shiqing Zhang
- Department of Schistosomiasis Control and Prevention, Anhui Institute of Parasitic Diseases, Hefei 230061, China
| | - Lu Li
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Yinlong Li
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Ting Liu
- Department of Schistosomiasis Control and Prevention, Anhui Institute of Parasitic Diseases, Hefei 230061, China
| | - Suying Guo
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Xiaojuan Xu
- Department of Schistosomiasis Control and Prevention, Anhui Institute of Parasitic Diseases, Hefei 230061, China
| | - Zhaoming Yang
- Department of Clinical Treatment, Dongzhi Schistosomiasis Hospital, Chizhou 247230, China
| | - Haoyi Zhang
- Department of Clinical Treatment, Dongzhi Schistosomiasis Hospital, Chizhou 247230, China
| | - Jing Xu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
- Correspondence:
| |
Collapse
|
|
23
|
Canivet CM, Boursier J. Screening for Liver Fibrosis in the General Population: Where Do We Stand in 2022? Diagnostics (Basel) 2022; 13:diagnostics13010091. [PMID: 36611384 PMCID: PMC9818643 DOI: 10.3390/diagnostics13010091] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/30/2022] Open
Abstract
Approximately 30% of the worldwide population has at least one risk factor for liver disease. Identifying advanced liver disease before the occurrence of complications remains a difficult challenge in clinical practice, where diagnosis comes too late for many patients, at the time of liver decompensation or palliative hepatocellular carcinoma, with poor short-term prognosis. Noninvasive, blood- or elastography-based tests of liver fibrosis (NITs) have been developed for the early diagnosis of advanced liver fibrosis. Recent population-based studies evaluating the screening of liver fibrosis with these NITs have provided important information on at-risk groups that should be targeted. New measures based on the sequential use of NITs help to better organize the referral of at-risk patients to the liver specialist. However, energizing these measures will require increased awareness of both chronic liver diseases and the use of NITs among non-specialists.
Collapse
Affiliation(s)
- Clémence M. Canivet
- Service d’Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d’Angers, 49100 Angers, France
- Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d’Angers, 49035 Angers, France
- Correspondence: ; Tel.: +33-241353410; Fax: +33-241354119
| | - Jérôme Boursier
- Service d’Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d’Angers, 49100 Angers, France
- Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d’Angers, 49035 Angers, France
| |
Collapse
|
|
24
|
Minami Y, Aoki T, Chishina H, Takita M, Hagiwara S, Ida H, Ueshima K, Nishida N, Kudo M. Prognostic Factors for Overall Survival in Patients with HCV-Related HCC Undergoing Molecular Targeted Therapies: Beyond a Sustained Virological Response. Cancers (Basel) 2022; 14:cancers14194850. [PMID: 36230773 PMCID: PMC9562238 DOI: 10.3390/cancers14194850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The treatment of the hepatitis C virus (HCV) has reduced the risk of hepatocellular carcinoma (HCC)-related mortality. Many patients with advanced HCC have achieved longer survival through systemic chemotherapy. However, survivors of HCC may develop liver cancer during and after treatment. Therefore, the present study investigated prognostic factors for survival in patients with HCV-related HCC in the new era of molecular targeted therapy. Methods: A total of 359 patients with HCV-related HCC treated with first-line chemotherapy were reviewed. A Cox proportional hazards model and Kaplan−Meier curve were used to identify prognostic factors associated with survival outcomes. Results: The median follow-up duration was 16.0 months (range, 1.0−115.7) and the median duration of first-line systemic therapy was 3.73 months (range, 0.7−86.9). The achievement of a sustained virological response (SVR) (p < 0.001), albumin−bilirubin (ALBI) grade II/III (p < 0.001), Barcelona Clinic Liver Cancer (BCLC) stage C (p = 0.005), extrahepatic spread (p < 0.001), baseline AFP (alpha-fetoprotein) level ≥ 90 (p = 0.038), baseline DCP (des-γ-carboxy prothrombin) level ≥ 500 (p < 0.001), and a fibrosis-4 (FIB-4) index ≥ 4 (p = 0.003) were identified as prognostic factors for overall survival. Conclusions: The achievement of SVR was most strongly associated with overall survival. Other factors, such as the BCLC stage, extrahepatic spread, baseline tumor marker (AFP/DCP) levels, ALBI grade, and FIB-4 index need to be considered in the management of patients with HCV-related HCC.
Collapse
Affiliation(s)
- Yasunori Minami
- Correspondence: ; Tel.: +81-72-366-0221 (ext. 3525); Fax: +81-72-367-2880
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
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.
Collapse
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.
| |
Collapse
|
|
26
|
Kechagias S, Ekstedt M, Simonsson C, Nasr P. Non-invasive diagnosis and staging of non-alcoholic fatty liver disease. Hormones (Athens) 2022; 21:349-368. [PMID: 35661987 PMCID: PMC9464753 DOI: 10.1007/s42000-022-00377-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/19/2022] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome and is characterized by ectopic accumulation of triglycerides in the cytoplasm of hepatocytes, i.e., steatosis. NAFLD has become the most common chronic liver disease, with an estimated global prevalence of 25%. Although the majority of NAFLD patients will never experience liver-related complications, the progressive potential of NAFLD is indisputable, with 5-10% of subjects progressing to cirrhosis, end-stage liver disease, or hepatocellular carcinoma. NAFLD patients with advanced fibrosis are at the highest risk of developing cardiovascular and cirrhosis-related complications. Liver biopsy has hitherto been considered the reference method for evaluation of hepatic steatosis and fibrosis stage. Given the limitations of biopsy for widescale screening, non-invasive tests (NITs) for assessment of steatosis and fibrosis stage, including serum-based algorithms and ultrasound- and magnetic resonance-based methods, will play an increasing role in the management of NAFLD patients. This comprehensive review presents the advantages and limitations of NITs for identification of steatosis and advanced fibrosis in NAFLD. The clinical implications of using NITs to identify and manage NAFLD patients are also discussed.
Collapse
Affiliation(s)
- Stergios Kechagias
- Department of Gastroenterology and Hepatology, University Hospital, Linköping, Sweden.
- Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden.
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, University Hospital, Linköping, Sweden
- Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden
| | - Christian Simonsson
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden
| | - Patrik Nasr
- Department of Gastroenterology and Hepatology, University Hospital, Linköping, Sweden
- Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden
| |
Collapse
|
|
27
|
Louvet A, Trabut JB, Moreno C, Moirand R, Aubin HJ, Ntandja Wandji LC, Nourredine M, Ningarhari M, Ganne-Carrié N, Pageaux GP, Bailly F, Boursier J, Daeppen JB, Luquiens A, Nguyen-Khac E, Anty R, Orban T, Donnadieu-Rigole H, Mallat A, Bureau C, Pariente EA, Paupard T, Benyamina A, Perney P, Mathurin P, Rolland B. Management of alcohol-related liver disease: the French Association for the Study of the Liver and the French Alcohol Society clinical guidelines. Liver Int 2022; 42:1330-1343. [PMID: 35488390 DOI: 10.1111/liv.15221] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 12/15/2022]
Abstract
Excessive alcohol consumption is the leading cause of liver diseases in Western countries, especially in France. Alcohol-related liver disease (ARLD) is an extremely broad context and there remains much to accomplish in terms of identifying patients, improving prognosis and treatment, and standardising practices. The French Association for the Study of the Liver wished to organise guidelines together with the French Alcohol Society in order to summarise the best evidence available about several key clinical points in ARLD. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe how patients with ARLD should be managed nowadays and discuss the main unsettled issues in the field.
Collapse
Affiliation(s)
- Alexandre Louvet
- Service des Maladies de l'Appareil digestif, Hôpital Huriez, CHU, Lille, France
| | - Jean-Baptiste Trabut
- Groupe Hospitalier Cochin Saint-Vincent de Paul, Unité d'Hépatologie et d'Addictologie, Paris, France
| | | | - Romain Moirand
- Inserm, UMR 991, "Foie, Métabolismes et Cancer", Rennes, France.,Université de Rennes 1, Rennes, France
| | | | | | | | - Massih Ningarhari
- Service des Maladies de l'Appareil digestif, Hôpital Huriez, CHU, Lille, France
| | | | | | - François Bailly
- Service d'Hépato-Gastroentérologie, Hospices Civils de Lyon, Lyon, France
| | | | | | | | | | - Rodolphe Anty
- Service d'Hépato-Gastroentérologie, CHU de l'Archet 2, Nice, France
| | - Thomas Orban
- Société Scientifique de Médecine Générale, Brussels, Belgium
| | | | - Ariane Mallat
- Service d'Hépatologie, Hopital Henri-Mondor, Créteil, France
| | | | | | - Thierry Paupard
- Service d'Hépato-Gastroentérologie, Centre Hospitalier, Dunkerque, France
| | - Amine Benyamina
- Service d'Addictologie, Hôpital Paul-Brousse, Villejuif, France
| | | | - Philippe Mathurin
- Service des Maladies de l'Appareil digestif, Hôpital Huriez, CHU, Lille, France
| | - Benjamin Rolland
- Service Universitaire d'Addictologie de Lyon (SUAL), CH Le Vinatier, Université de Lyon, UCBL, Lyon, France
| | | |
Collapse
|
|
28
|
Martinou E, Pericleous M, Stefanova I, Kaur V, Angelidi AM. Diagnostic Modalities of Non-Alcoholic Fatty Liver Disease: From Biochemical Biomarkers to Multi-Omics Non-Invasive Approaches. Diagnostics (Basel) 2022; 12:407. [PMID: 35204498 PMCID: PMC8871470 DOI: 10.3390/diagnostics12020407] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 02/05/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and its prevalence is increasing globally. NAFLD is a multifaceted disorder, and its spectrum includes steatosis to steatohepatitis, which may evolve to advanced fibrosis and cirrhosis. In addition, the presence of NAFLD is independently associated with a higher cardiometabolic risk and increased mortality rates. Considering that the vast majority of individuals with NAFLD are mainly asymptomatic, early diagnosis of non-alcoholic steatohepatitis (NASH) and accurate staging of fibrosis risk is crucial for better stratification, monitoring and targeted management of patients at risk. To date, liver biopsy remains the gold standard procedure for the diagnosis of NASH and staging of NAFLD. However, due to its invasive nature, research on non-invasive tests is rapidly increasing with significant advances having been achieved during the last decades in the diagnostic field. New promising non-invasive biomarkers and techniques have been developed, evaluated and assessed, including biochemical markers, imaging modalities and the most recent multi-omics approaches. Our article provides a comprehensive review of the currently available and emerging non-invasive diagnostic tools used in assessing NAFLD, also highlighting the importance of accurate and validated diagnostic tools.
Collapse
Affiliation(s)
- Eirini Martinou
- Hepatobiliary and Pancreatic Surgery Department, Royal Surrey County Hospital, Guildford GU2 7XX, UK
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK;
| | - Marinos Pericleous
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK;
- Department of Gastroenterology and Hepatology, Royal Surrey County Hospital, Guildford GU2 7XX, UK
| | - Irena Stefanova
- Department of General Surgery, Frimley Health NHS Foundation Trust, Camberley GU16 7UJ, UK;
| | - Vasha Kaur
- Department of Upper Gastrointestinal and Bariatric Surgery, St George’s Hospital, London SW17 0QT, UK;
| | - Angeliki M. Angelidi
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| |
Collapse
|
|
29
|
Tokorodani R, Kume T, Daikoku K, Oka M. [Evaluation of the Validity of ROI Setting in CEI Used for the Assessment of Liver]. Nihon Hoshasen Gijutsu Gakkai Zasshi 2022; 78:44-52. [PMID: 35046221 DOI: 10.6009/jjrt.780105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE The enhancement effect ratio using ethoxybenzyl (EOB) contrast is useful in the assessment of liver fibrosis. Since the enhancement effect ratio is calculated by setting a region of interest (ROI) in the liver, the ROI setting method may affect the enhancement effect ratio. One of the methods of setting the ROI in liver fibrosis evaluation is by placing the ROI in each Quinault segment, but this method requires considerable time. Therefore, it is necessary to consider a reproducible ROI setting method in contrast to the method of placing ROIs in each Quinault segment. METHOD In contrast to the method of placing one ROI in each Quinault segment, we examined the method of setting four ROIs (two in the right lobe and two in the left lobe) and two ROIs (one in the right lobe and one in the left lobe). The size of the ROI was set to 1 cm2, 4 cm2, and the maximum area that fits within each placement area. CONCLUSION In the ROI setting method for CEI calculation, reproducibility can be maintained by setting the number of ROIs in four locations and by setting ROIs of 4 cm2 or more.
Collapse
Affiliation(s)
- Ryotaro Tokorodani
- Division of Radiology, Department of Medical Technology, Kochi Medical School Hospital
| | - Toshiaki Kume
- Department of Radiological Technology, Kochi Health Sciences Center
| | - Kazuki Daikoku
- Division of Radiology, Department of Medical Technology, Kochi Medical School Hospital
| | - Masaki Oka
- Department of Radiological Technology, Kochi Health Sciences Center
| |
Collapse
|
|
30
|
Kaya E, Yilmaz Y. Epidemiology, natural history, and diagnosis of metabolic dysfunction-associated fatty liver disease: a comparative review with nonalcoholic fatty liver disease. Ther Adv Endocrinol Metab 2022; 13:20420188221139650. [PMID: 36533185 PMCID: PMC9747887 DOI: 10.1177/20420188221139650] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide - with an estimated global prevalence of 37%. Different from nonalcoholic fatty liver disease (NAFLD), which is an exclusion diagnosis, MAFLD is defined by a set of positive criteria. This recent change in terminology is challenging because MAFLD and NAFLD denote two similar, albeit not identical, clinical populations. When the diagnostic criteria for MAFLD are applied, liver histology appears more severe and clinical outcomes are less favorable. However, the clinical management of MAFLD and NAFLD remains similar. While liver biopsy is still the reference standard for achieving a final diagnosis, noninvasive imaging- or biomarker-based diagnostic modalities are currently gaining momentum. However, liver biopsy should be recommended when diagnostic challenges exist. In this review, we compared the epidemiology, natural history, and diagnosis of MAFLD with respect to the traditional NAFLD definition.
Collapse
Affiliation(s)
- Eda Kaya
- Section of Gastroenterology and Hepatology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany
- Department of Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany
| | | |
Collapse
|
|
31
|
Prospective screening for significant liver fibrosis by fibrosis-4 in primary care patients without known liver disease. Eur J Gastroenterol Hepatol 2021; 33:e986-e991. [PMID: 34966134 PMCID: PMC8734630 DOI: 10.1097/meg.0000000000002340] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fibrosis-4 test (FIB-4) is one of the simplest, free of charge, noninvasive scoring tests. We aimed to prospectively measure the prevalence of liver fibrosis in adults with no previously known liver disease and who consulted a general practitioner by FIB-4 score; compare this test to an NAFLD Fibrosis Score (NFS) and Fibrometer (FM); explore the prevalence of risk factors (obesity, diabetes, alcohol, and hypertension) and reconsider a possible cause of liver disease in patients recognized as FIB-4-positive. METHODS Over a 6-month period, 40 general practitioners (GPs) offered all their consecutive adult primary care patients with no previously known liver pathology and a liver fibrosis screening via a blood test of three scores. RESULTS Among the consecutive 2121 patients included in the study, 39% had a BMI greater than 25 kg/m2, 13% had an alcohol consumption greater than 100 g/week, 10% had type 2 diabetes, and 29% had hypertension. The prevalence of significant liver fibrosis by FIB-4, according to age was 19.1% (95% confidence interval: 17.5-20.9%). By comparison, prevalence was 16.8% (15.0-18.5%) by the NFS and 8.2% (6.9-9.6%) by the FM. A significant relationship was observed between FIB-4 fibrosis risk stages and NFS and FM scores. GPs identified the cause of disease in 2/3 of FIB-4-positive cases, mainly nonalcoholic steatohepatitis. CONCLUSION Liver fibrosis was suspected by FIB-4 score in 19.1% of patients with no previously known liver disease. The detection of significant fibrosis by the FIB-4 allowed the GP to suspect liver disease. The FIB-4 score that can be automatically generated should allow earlier recognition of liver disease in the general population.
Collapse
|
|
32
|
[Delta hepatitis: Epidemiology, diagnostic, natural history and treatment]. Rev Med Interne 2021; 43:160-169. [PMID: 34799189 DOI: 10.1016/j.revmed.2021.10.329] [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: 05/17/2021] [Revised: 09/17/2021] [Accepted: 10/17/2021] [Indexed: 11/20/2022]
Abstract
Hepatitis B virus is a small enveloped RNA virus, which replicates independently but requires the hepatitis B virus (HBV) to provide the envelope proteins necessary for the assembly of its own viral particles. Approximately 5% of chronic hepatitis B virus carriers are infected with HDV. HBV vaccination remains the best preventive treatment for HDV. All HBV patients should be screened for HDV (anti-HDV serology). In case of positive HDV serology, HDV replication (HDV RNA) should be investigated using a sensitive and specific technique. Hepatitis Delta is often complicated by cirrhosis and hepatocellular carcinoma (HCC). For this reason, every patient with Delta cirrhosis should be screened for HCC by abdominal ultrasound every 6 months. The historical treatment was based on PEG-IFN with many side effects. A new treatment has been approved, Bulevirtide (Hepcludex®) an HDV/HBV entry inhibitor, for any patient with chronic hepatitis Delta infection (CHD) with active replication (except in decompensated cirrhosis), at a dose of 2mg/day by subcutaneous injection. The exact duration on-treatment is unknown, thus treatment should be continued if clinical benefit is observed.
Collapse
|
|
33
|
Alqahtani SA, Schattenberg JM. Nonalcoholic fatty liver disease: use of diagnostic biomarkers and modalities in clinical practice. Expert Rev Mol Diagn 2021; 21:1065-1078. [PMID: 34346799 DOI: 10.1080/14737159.2021.1964958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The global burden of liver disease is increasing, and nonalcoholic fatty liver disease (NAFLD) is among the most common chronic liver diseases in Asia, Europe, North and South America. The field of noninvasive diagnostic and their role in staging, but also predicting outcome is evolving rapidly. There is a high-unmet need to stage patients with NAFLD and to identify the subset of patients at risk of progression to end-stage liver disease. AREAS COVERED The review covers all established diagnostic blood-based and imaging biomarkers to stage and grade NAFLD. Noninvasive surrogate scores are put into perspective of the available evidence and recommended use. The outlook includes genetics, combined algorithms, and artificial intelligence that will allow clinicians to guide and support the management in both early and later disease stages. EXPERT OPINION In the future, these diagnostics tests will help clinicians to establish patient care pathways and support the identification of relevant subgroups for monitoring and pharmacotherapy. In addition, researchers will be guided to better understand available scores and support the development of future prediction systems. These will likely include multiparametric aspects of the disease and machine learning algorithms will refine their use and integration with large datasets.
Collapse
Affiliation(s)
- Saleh A Alqahtani
- Liver Transplantation Unit, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.,Division Of Gastroenterology And Hepatology, Johns Hopkins University, Baltimore, USA
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department Of Medicine, University Medical Center, Mainz, Germany
| |
Collapse
|
|
34
|
Nana J, Skaare K, Bosson JL, Leroy V, Asselah T, Adler M, Sturm N, Zarski JP. EASL-ALEH 2015 algorithm for the use of transient elastography in treatment-naive patients with hepatitis B: An independent validation. J Viral Hepat 2021; 28:1169-1176. [PMID: 34002927 DOI: 10.1111/jvh.13548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/28/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022]
Abstract
Various non-invasive methods have been evaluated in chronic hepatitis B, but none of them have been fully validated for the assessment of liver fibrosis. The issued EASL-ALEH 2015 guidelines provide detailed algorithms based on LSM and ALT serum levels. The aim of our study was to validate the diagnostic accuracy of this algorithm and to better understand discrepancies. Four hundred and thirteen patients from 3 centres were retrospectively included. All included patients were classified for fibrosis stage according to results of a liver biopsy. The overall diagnostic value was expressed with AUROCs given with 95% confidence intervals for the diagnostic targets. For each diagnostic target, optimal cut-offs were determined according to the Youden method. For the population of patients with ALT<N (n = 65), the AUROCs of TE were 0.75 (0.62-0.88) and 0.72 (0.56-0.88) for F ≥ 2 and F ≥ 3 diagnostic targets. Taking the EASL cut-offs, the prevalence of significant fibrosis was 8%, 38% and 67% when LSM was <6kPa, between 6 and 9 kPa or >9 kPa, respectively. For patients with ALT>N but ≤5N (n = 306), AUROCs of transient elastography were 0.79 (0.73-0.84) and 0.84 (0.75-0.92) for F ≥ 2 and F ≥ 3 diagnostic targets. The prevalence of significant fibrosis was, respectively, 15%, 52% and 85% when LSM was <6kPa, between 6 and 12 kPa or >12 kPa. Our study independently validates the EASL-ALEH algorithm based on ALT levels and LSM assessed by transient elastography.
Collapse
Affiliation(s)
- Jean Nana
- Clinique Universitaire d'Hépato-Gastroentérologie, Pôle DIGIDUNE, Centre Hospitalier Universitaire Grenoble Alpes Hôpital Michallon, La Tronche, France.,TIMC-IMAG UMR 5525, équipe ThEMAS (techniques pour l'évaluation et la modélisation des actions de santé), Université Grenoble-Alpes, La Tronche, France
| | - Kristina Skaare
- Pôle santé publique, Centre Hospitalier Universitaire Grenoble Alpes Hôpital Michallon, La Tronche, France
| | - Jean Luc Bosson
- TIMC-IMAG UMR 5525, équipe ThEMAS (techniques pour l'évaluation et la modélisation des actions de santé), Université Grenoble-Alpes, La Tronche, France.,Pôle santé publique, Centre Hospitalier Universitaire Grenoble Alpes Hôpital Michallon, La Tronche, France
| | - Vincent Leroy
- Clinique Universitaire d'Hépato-Gastroentérologie, Pôle DIGIDUNE, Centre Hospitalier Universitaire Grenoble Alpes Hôpital Michallon, La Tronche, France.,Unité INSERM/Université Grenoble Alpes U823, IAPC Institut Albert Bonniot, Grenoble, France
| | - Tarik Asselah
- Service d'Hépatologie, Hôpital Beaujon, Paris, France
| | - Michael Adler
- Service d'Hépato-Gastro-Entérologie, Hôpital Erasme, Cliniques Universitaires de Bruxelles, Bruxelles, Belgium
| | - Nathalie Sturm
- Département Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire Grenoble Alpes Hôpital Michallon, La Tronche, France
| | - Jean-Pierre Zarski
- Clinique Universitaire d'Hépato-Gastroentérologie, Pôle DIGIDUNE, Centre Hospitalier Universitaire Grenoble Alpes Hôpital Michallon, La Tronche, France.,Unité INSERM/Université Grenoble Alpes U823, IAPC Institut Albert Bonniot, Grenoble, France
| |
Collapse
|
|
35
|
Lanquetin A, Leclercq S, de Timary P, Segobin S, Naveau M, Coulbault L, Maccioni P, Lorrai I, Colombo G, Vivien D, Rubio M, Pitel AL. Role of inflammation in alcohol-related brain abnormalities: a translational study. Brain Commun 2021; 3:fcab154. [PMID: 34396111 PMCID: PMC8361421 DOI: 10.1093/braincomms/fcab154] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/30/2021] [Accepted: 05/24/2021] [Indexed: 12/19/2022] Open
Abstract
Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver–brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.
Collapse
Affiliation(s)
- Anastasia Lanquetin
- Normandie Univ, UNICAEN, INSERM, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, 14000 Caen, France
| | - Sophie Leclercq
- Institute of Neuroscience and Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Philippe de Timary
- Institute of Neuroscience and Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Shailendra Segobin
- Normandie Univ, UNICAEN, PSL Université Paris, EPHE, INSERM, U1077, CHU de Caen, GIP Cyceron, Neuropsychologie et Imagerie de la Mémoire Humaine, 14000 Caen, France
| | - Mikaël Naveau
- Normandie Univ UNICAEN, CNRS, UMS 3408, GIP Cyceron, Caen, France
| | - Laurent Coulbault
- Caen University Hospital, Biochemistry Department, Normandie University, UNICAEN, EA 4650, Caen, France
| | - Paola Maccioni
- Neuroscience Institute, Section of Cagliari, National Research Council of Italy, 09042 Monserrato, CA, Italy
| | - Irene Lorrai
- Neuroscience Institute, Section of Cagliari, National Research Council of Italy, 09042 Monserrato, CA, Italy
| | - Giancarlo Colombo
- Neuroscience Institute, Section of Cagliari, National Research Council of Italy, 09042 Monserrato, CA, Italy
| | - Denis Vivien
- Normandie Univ, UNICAEN, INSERM, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, 14000 Caen, France.,Department of Clinical Research, CHU Côte de Nacre, Caen 14000, France
| | - Marina Rubio
- Normandie Univ, UNICAEN, INSERM, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, 14000 Caen, France
| | - Anne-Lise Pitel
- Normandie Univ, UNICAEN, PSL Université Paris, EPHE, INSERM, U1077, CHU de Caen, GIP Cyceron, Neuropsychologie et Imagerie de la Mémoire Humaine, 14000 Caen, France.,Institut Universitaire de France (IUF), Paris 75231, France
| |
Collapse
|
|
36
|
Van Dijk AM, Vali Y, Mak AL, Lee J, Tushuizen ME, Zafarmand MH, Anstee QM, Brosnan MJ, Nieuwdorp M, Bossuyt PM, Holleboom AG. Systematic Review with Meta-Analyses: Diagnostic Accuracy of FibroMeter Tests in Patients with Non-Alcoholic Fatty Liver Disease. J Clin Med 2021; 10:jcm10132910. [PMID: 34209858 PMCID: PMC8269151 DOI: 10.3390/jcm10132910] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 12/14/2022] Open
Abstract
Early detection of liver fibrosis is crucial to select the correct care path for patients with non-alcoholic fatty liver disease (NAFLD). Here, we systematically review the evidence on the performance of FibroMeter versions in detecting different levels of fibrosis in patients with NAFLD. We searched four databases (Medline, Embase, the Cochrane library, and Web of Science) to find studies that included adults with NAFLD and biopsy-confirmed fibrosis (F1 to F4), compared with any version of FibroMeter. Two independent researchers screened the references, collected the data, and assessed the methodological quality of the included studies. We used a bivariate logit-normal random effects model to produce meta-analyses. From 273 references, 12 studies were eligible for inclusion, encompassing data from 3425 patients. Meta-analyses of the accuracy in detecting advanced fibrosis (F ≥ 3) were conducted for FibroMeter Virus second generation (V2G), NAFLD, and vibration controlled transient elaFS3stography (VCTE). FibroMeter VCTE showed the best diagnostic accuracy in detecting advanced fibrosis (sensitivity: 83.5% (95%CI 0.58–0.94); specificity: 91.1% (95%CI 0.89–0.93)), followed by FibroMeter V2G (sensitivity: 83.1% (95%CI 0.73–0.90); specificity: 84.4% (95%CI 0.62–0.95)) and FibroMeter NAFLD (sensitivity: 71.7% (95%CI 0.63–0.79); specificity: 82.8% (95%CI 0.71–0.91)). No statistically significant differences were found between the different FibroMeter versions. FibroMeter tests showed acceptable sensitivity and specificity in detecting advanced fibrosis in patients with NAFLD, but an urge to conduct head-to-head comparison studies in patients with NAFLD of the different FibroMeter tests remains.
Collapse
Affiliation(s)
- Anne-Marieke Van Dijk
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (A.L.M.); (M.N.); (A.G.H.)
- Correspondence: ; Tel.: +31-205665973
| | - Yasaman Vali
- Department of Epidemiology and Data Science, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (Y.V.); (J.L.); (M.H.Z.); (P.M.B.)
| | - Anne Linde Mak
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (A.L.M.); (M.N.); (A.G.H.)
| | - Jenny Lee
- Department of Epidemiology and Data Science, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (Y.V.); (J.L.); (M.H.Z.); (P.M.B.)
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, 2333ZA Leiden, The Netherlands;
| | - Mohammad Hadi Zafarmand
- Department of Epidemiology and Data Science, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (Y.V.); (J.L.); (M.H.Z.); (P.M.B.)
| | - Quentin M. Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK;
| | - M. Julia Brosnan
- Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA 02139, USA;
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (A.L.M.); (M.N.); (A.G.H.)
| | - Patrick M. Bossuyt
- Department of Epidemiology and Data Science, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (Y.V.); (J.L.); (M.H.Z.); (P.M.B.)
| | - Adriaan G. Holleboom
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centres, Location AMC, 1105AZ Amsterdam, The Netherlands; (A.L.M.); (M.N.); (A.G.H.)
| |
Collapse
|
|
37
|
Vali Y, Lee J, Boursier J, Spijker R, Verheij J, Brosnan MJ, Anstee QM, Bossuyt PM, Zafarmand MH. FibroTest for Evaluating Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review and Meta-Analysis. J Clin Med 2021; 10:jcm10112415. [PMID: 34072480 PMCID: PMC8198930 DOI: 10.3390/jcm10112415] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
(1) Background: FibroTest™ is a multi-marker panel, suggested by guidelines as one of the surrogate markers with acceptable performance for detecting fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). A number of studies evaluating this test have been published after publication of the guidelines. This study aims to produce summary estimates of FibroTest™ diagnostic accuracy. (2) Methods: Five databases were searched for studies that evaluated FibroTest™ against liver biopsy as the reference standard in NAFLD patients. Two authors independently screened the references, extracted data, and assessed the quality of included studies. Meta-analyses of the accuracy in detecting different levels of fibrosis were performed using the bivariate random-effects model and the linear mixed-effects multiple thresholds model. (3) Results: From ten included studies, seven were eligible for inclusion in our meta-analysis. Five studies were included in the meta-analysis of FibroTest™ in detecting advanced fibrosis and five in significant fibrosis, resulting in an AUC of 0.77 for both target conditions. The meta-analysis of three studies resulted in an AUC of 0.69 in detecting any fibrosis, while analysis of three other studies showed higher accuracy in cirrhosis (AUC: 0.92). (4) Conclusions: Our meta-analysis showed acceptable performance (AUC > 0.80) of FibroTest™ only in detecting cirrhosis. We observed more limited performance of the test in detecting significant and advanced fibrosis in NAFLD patients. Further primary studies with high methodological quality are required to validate the reliability of the test for detecting different fibrosis levels and to compare the performance of the test in different settings.
Collapse
Affiliation(s)
- Yasaman Vali
- Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.L.); (P.M.B.); (M.H.Z.)
- Correspondence: ; Tel.: +31-(0)20-5668520
| | - Jenny Lee
- Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.L.); (P.M.B.); (M.H.Z.)
| | - Jérôme Boursier
- Hepato-Gastroenterology Department, Angers University Hospital, 49933 Angers, France;
- HIFIH Laboratory, UPRES EA3859, Angers University, 49035 Angers, France
| | - René Spijker
- Medical Library AMC, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
- Cochrane Netherlands, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Joanne Verheij
- Department of Pathology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - M. Julia Brosnan
- Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA 02139, USA;
| | - Quentin M. Anstee
- The Newcastle Liver Research Group, Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK;
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 7RU, UK
| | - Patrick M. Bossuyt
- Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.L.); (P.M.B.); (M.H.Z.)
| | - Mohammad Hadi Zafarmand
- Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.L.); (P.M.B.); (M.H.Z.)
| | | |
Collapse
|
|
38
|
Guerra-Ruiz AR, Casals G, Iruzubieta P, Lalana M, Leis A, López RM, Crespo J, Morales-Ruiz M. Valoración bioquímica en la enfermedad hepática grasa asociada a la disfunción metabólica. ADVANCES IN LABORATORY MEDICINE 2021; 2:209-219. [PMCID: PMC10197419 DOI: 10.1515/almed-2020-0062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/18/2020] [Indexed: 11/15/2022]
Abstract
La enfermedad hepática grasa asociada a la disfunción metabólica (MAFLD) se define por el acúmulo de grasa en el hígado en presencia de alteraciones metabólicas. Suele cursar de forma asintomática y puede progresar a formas graves de enfermedad hepática, ligadas a la aparición de inflamación y/o fibrosis. Su prevalencia es muy elevada (26%), resultando en un alto número de pacientes con riesgo de presentar una enfermedad hepática avanzada. El presente documento describe los marcadores serológicos más relevantes en la caracterización y diagnóstico de la MAFLD, y se propone un ejemplo de su integración en un algoritmo diagnóstico en práctica clínica habitual. En la actualidad se dispone de índices serológicos útiles en el manejo de los pacientes con MAFLD, especialmente en la estratificación del riesgo de la presencia fibrosis. Una gran parte de la población está en riesgo de desarrollar enfermedad hepática grave. La integración de los marcadores serológicos no invasivos en la estratificación del riesgo de fibrosis hepática puede contribuir a un mejor control y manejo de los pacientes con MAFLD.
Collapse
Affiliation(s)
- Armando R. Guerra-Ruiz
- Grupo de trabajo de valoración bioquímica de la enfermedad hepática, Sociedad Española de Medicina de Laboratorio (SEQC-ML), Barcelona, España
- Servicio de Análisis Clínicos, Hospital Universitario Marqués de Valdecilla, Santander, España
| | - Gregori Casals
- Grupo de trabajo de valoración bioquímica de la enfermedad hepática, Sociedad Española de Medicina de Laboratorio (SEQC-ML), Barcelona, España
- Servicio de Bioquímica y Genética Molecular, CDB, Hospital Clínic de Barcelona, IDIBAPS, CIBEREHD, Barcelona, España
| | - Paula Iruzubieta
- Sociedad Española de Patología Digestiva (SEPD), Madrid, España
- Servicio Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, IDIVAL, Santander, España
| | - Marta Lalana
- Grupo de trabajo de valoración bioquímica de la enfermedad hepática, Sociedad Española de Medicina de Laboratorio (SEQC-ML), Barcelona, España
- Servicio de Análisis Clínicos, Hospital de Barbastro, Huesca, España
| | - Alba Leis
- Grupo de trabajo de valoración bioquímica de la enfermedad hepática, Sociedad Española de Medicina de Laboratorio (SEQC-ML), Barcelona, España
- Servicio de Análisis Clínicos y Bioquímica, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Badalona, España
| | - Rosa María López
- Grupo de trabajo de valoración bioquímica de la enfermedad hepática, Sociedad Española de Medicina de Laboratorio (SEQC-ML), Barcelona, España
- Unidad de Patología hepática, Departamentos de Bioquímica y Microbiología, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, España
| | - Javier Crespo
- Sociedad Española de Patología Digestiva (SEPD), Madrid, España
- Servicio Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, IDIVAL, Santander, España
| | - Manuel Morales-Ruiz
- Grupo de trabajo de valoración bioquímica de la enfermedad hepática, Sociedad Española de Medicina de Laboratorio (SEQC-ML), Barcelona, España
- Servicio de Bioquímica y Genética Molecular-Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Departamento de Biomedicina de la Facultad de Medicina y Ciencias de la Salud-Universidad de Barcelona, Barcelona, España
| |
Collapse
|
|
39
|
The FIB-4 Index Is a Useful Predictor for the Development of Hepatocellular Carcinoma in Patients with Coexisting Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B. Cancers (Basel) 2021; 13:cancers13102301. [PMID: 34064988 PMCID: PMC8151791 DOI: 10.3390/cancers13102301] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/03/2021] [Accepted: 05/05/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary This retrospective study analyzed 237 consecutive patients with coexisting nonalcoholic fatty liver disease and chronic hepatitis B (NAFLD-CHB) with long observation period (median follow-up duration, 13 years). The optimal cutoff for the FIB-4 index of 1.77 was calculated based on the maximum Youden index value, and the value was 1.77 with an AUC of 0.70. The significant higher risk of developing hepatocellular carcinoma (HCC) in patients with a high FIB-4 index (≥1.77) than the patients with a low FIB-4 index (<1.77) (adjusted hazard ratio, 4.35; 95% CI, 1.42–13.24; log-rank test, p = 0.006) were found among the NAFLD-CHB patients whose baseline characteristics were balanced by propensity score matching. The FIB-4 index might be a useful predictor of the development of HCC among NAFLD–CHB patients. Abstract Background: The FIB-4 index, a noninvasive tool (FIB-4 index = age × aspartate transaminase (AST)/(platelet count × √alanine aminotransferase (ALT)), is a useful assessment for liver fibrosis. Patients with a high FIB-4 index were reported to have a high risk of developing hepatocellular carcinoma (HCC). This study analyzed the clinical association of the FIB-4 index with HCC development in patients with coexisting nonalcoholic fatty liver disease and chronic hepatitis B (NAFLD–CHB). Methods: This retrospective study analyzed 237 consecutive patients with NAFLD–CHB between January 2006 and December 2010 at the National Police Hospital in Korea. Patients with HCC at baseline and those diagnosed with HCC within 6 months from baseline were excluded. Propensity score matching analysis (PSM) was adopted to balance the baseline characteristics between patients with low and high FIB-4 index values. The cumulative rates of HCC development were compared between the two groups using the Kaplan–Meier method in the matched population. Results: The median follow-up duration was 13 years (interquartile range, 8.2–15.7). The optimal cutoff for the FIB-4 index of 1.77 was calculated based on the maximum Youden index value, with an AUC of 0.70. Among a total of 237 patients with NAFLD–CHB, HCC developed in 20 patients (8.4%) (14 of the 90 patients with a high FIB-4 index vs. 6 of the 147 patients (4.1%) with a low FIB-4 index; log-rank p = 0.003). Patients with a high FIB-4 index had a significantly and independently higher risk of HCC than those with a low FIB-4 index (adjusted hazard ratio, 4.35; 95%; confidence interval, 1.42–13.24; log-rank test, p = 0.006). Conclusion: A high FIB-4 index (≥1.77) might be a useful marker for predicting the development of HCC in patients with NAFLD–CHB.
Collapse
|
|
40
|
Guerra-Ruiz AR, Casals G, Iruzubieta P, Lalana M, Leis A, López RM, Crespo J, Morales-Ruiz M. Biochemical assessment of metabolic associated fatty liver disease. ADVANCES IN LABORATORY MEDICINE 2021; 2:199-219. [PMID: 37363330 PMCID: PMC10197265 DOI: 10.1515/almed-2021-0009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/18/2020] [Indexed: 01/05/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is defined as fat accumulation in the liver in the presence of metabolic alterations. This disorder is generally asymptomatic and may progress to severe liver disease, which are linked to inflammation and/or fibrosis. MAFLD has a high prevalence (26%) and therefore a considerable number of patients are at high risk of having advanced liver disease. This document provides an overview of the most relevant serological markers in the characterization and diagnosis of MAFLD. An example is provided of a routine diagnostic algorithm that incorporates serological testing. A range of useful serological scores are currently available for the management of MAFLD patients, especially for the stratification of patients at risk of fibrosis. A large proportion of the population is at risk of developing severe liver disease. The integration of non-invasive serological markers in the stratification of patients at risk for liver fibrosis may contribute to improve the control and management of MAFLD patients.
Collapse
Affiliation(s)
- Armando R. Guerra-Ruiz
- Commission on Biochemistry of Liver Disease, Spanish Society of Laboratory Medicine (SEQC-ML), Barcelona, Spain
- Service of Clinical Analysis, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Gregori Casals
- Commission on Biochemistry of Liver Disease, Spanish Society of Laboratory Medicine (SEQC-ML), Barcelona, Spain
- Service of Biochemistry and Molecular Genetics, CDB, Hospital Clinic de Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
| | - Paula Iruzubieta
- Spanish Society of Digestive Pathology (SEPD), Madrid, Spain
- Service of Digestive System, Hospital Universitario Marqués de Valdecilla, Clinical and Traslational Research Group on Digestive Disorders, IDIVAL, Santander, Spain
| | - Marta Lalana
- Commission on Biochemistry of Liver Disease, Spanish Society of Laboratory Medicine (SEQC-ML), Barcelona, Spain
- Service of Clinical Analysis, Hospital de Barbastro, Huesca, Spain
| | - Alba Leis
- Commission on Biochemistry of Liver Disease, Spanish Society of Laboratory Medicine (SEQC-ML), Barcelona, Spain
- Service of Clinical Analysis and Biochemistry, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Rosa María López
- Commission on Biochemistry of Liver Disease, Spanish Society of Laboratory Medicine (SEQC-ML), Barcelona, Spain
- Departments of Biochemistry and Microbiology, Unit of Liver Disease, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Javier Crespo
- Spanish Society of Digestive Pathology (SEPD), Madrid, Spain
- Service of Digestive System, Hospital Universitario Marqués de Valdecilla, Clinical and Traslational Research Group on Digestive Disorders, IDIVAL, Santander, Spain
| | - Manuel Morales-Ruiz
- Commission on Biochemistry of Liver Disease, Spanish Society of Laboratory Medicine (SEQC-ML), Barcelona, Spain
- Department of Biomedicine of the Faculty of Medicine and Health Sciences, Service of Biochemistry and Molecular Genetics, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
41
|
Abd Alla MDA, Dawood RM, Rashed HAEH, Farrag G, Ammar IAE, Mahmoud MMAH, Salum GM, Altanbouly AMA, El Meguid MA, Awady MKE. Treatment of hepatitis C virus infection with direct-acting antivirals plus ribavirin eliminates viral RNA from peripheral blood mononuclear cells and reduces virologic relapse in diverse hepatic parenchymal changes. Arch Virol 2021; 166:1071-1081. [PMID: 33533976 DOI: 10.1007/s00705-021-04969-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 11/22/2020] [Indexed: 12/21/2022]
Abstract
Elimination of hepatitis C virus (HCV) may fail, leading to a non-response outcome because of inappropriate testing for viral RNA in peripheral blood mononuclear cells (PBMCs). Sequelae of HCV genotype 4 therapy with sofosbuvir and daclatasvir ± ribavirin were assessed in our study at the 12th week after end of treatment (EOT) by screening for viral genomic RNA in serum and PBMCs with correlation to hepatic parenchymal changes. We recruited 102 out of 2165 patients who had received sofosbuvir/daclatasvir, either alone (n = 1573) or together with ribavirin (n = 592). Subjects were classified into three groups based on testing by single-step reverse transcription PCR: group I, HCV negative in both serum and PBMCs (n = 25); group II, HCV positive in PBMCs only (n = 52); and group III, HCV positive in both serum and PBMCs (n = 25). Groups I and II (n = 77) were selected out of 2102 (every 27th subject), while group III (n = 25) were selected from every second or third serologic relapse (n = 63). The pre-sampling population (n = 2165) showed sustained virologic response (SVR) in 33.21%; serologic relapse in 2.91%; HCV RNA only in PBMCs (66.79%) compared to serologic relapses and potential cure (P < 0.0001); higher serologic (38 out of 63, P = 0.03210) and cellular (36 out of 52, P = 0.0002) relapses in dual therapy than in triple therapy. The post-sampling population (n = 102) showed more HCV relapses in dual (50 out of 60) than in triple (27 out of 42) therapy (P = 0.0351); increased HCV antisense RNA strand in relapses compared to positive-sense strands alone (P < 0.001); and significant SVR events in undetectable (15 out of 31) compared to early (10 out of 55, P = 0.0058) and cirrhotic liver tissue changes (0 out of 16, P = 0.0006). In summary, HCV treatment with sofosbuvir/daclatasvir is followed by higher rates of serologic and intracellular viral RNA relapse than treatment with sofosbuvir/daclatasvir plus ribavirin. Cellular and serum viral RNA relapses are accompanied by HCV-induced hepatic pathology. An increased SVR with no detectable liver tissue changes was observed after triple therapy due to elimination of HCV RNA from PBMCs.
Collapse
Affiliation(s)
- Mohamed Darwish Ahmed Abd Alla
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo, 11675, Egypt.
| | - Reham M Dawood
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| | - Hassan Abd El-Hafeth Rashed
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo, 11675, Egypt
| | - Galal Farrag
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo, 11675, Egypt
| | - Islam Abdelmawla Emran Ammar
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo, 11675, Egypt
| | - Mohamed Mahmoud Abdel-Halim Mahmoud
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo, 11675, Egypt
| | - Ghada M Salum
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| | - Ahmed Mohamed Abdulhamid Altanbouly
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo, 11675, Egypt
| | - Mai A El Meguid
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| |
Collapse
|
|
42
|
Calès P, Bertrais S, Boursier J, Fouchard I, Oberti F. Non-selective beta-blockers increase overall and liver mortality in alcoholic cirrhosis with MELD ≥ 12 over 5 years of follow-up. Liver Int 2021; 41:168-179. [PMID: 32979020 DOI: 10.1111/liv.14674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Non-cardioselective beta-blocker (NSBB) effects on mortality in cirrhosis are controversial. We evaluated the impact of NSBBs on mortality according to liver severity and mortality cause. METHODS Two hundred and fifty-eight patients with alcoholic cirrhosis were included in a retroprospective cohort: 129 NSBB-treated and 129 controls. The NSBB group had the following significant baseline differences: higher MELD, more frequent previous gastrointestinal bleeding, large oesophageal varices (OV) and lower heart rate. Propranolol dose was 160 mg/d in 81% of NSBB patients. RESULTS (i) Liver function: during 5.3 ± 2.6 years of follow-up, MELD progression was higher in NSBB patients: 1 (-1-4) than in controls: 0 (-1-1) (P = .017). (ii) Overall survival: no significant differences were observed between NSBBs and controls (Kaplan-Meier curves: P = .291). In multivariate Cox analysis, baseline MELD interacted with NSBB (P = .011). Thus, the NSBB hazard ratio (HR) was 0.99 (0.50-1.98) in MELD < 12 vs 3.17 (1.19-8.42) in MELD ≥ 12. (iii) Liver survival: NSBB decreased liver survival (Kaplan-Meier: P = .031). In multivariate Cox analysis, baseline MELD interacted with NSBB (P < .001). The NSBB HR was 0.81 (0.30-2.19) in MELD < 12 vs 6.23 (1.94-20.0) in MELD ≥ 12. In competing risk multivariate analysis for liver mortality, the MELD-NSBB interaction was significant (P < .001): the NSBB HR was 1.02 (0.36-2.91) in MELD < 12 vs 9.24 (3.18-26.9) in MELD ≥ 12. 4) Non-liver survival: contrastingly, non-liver survival was increased by NSBBs, especially in MELD ≥ 12 (competing Kaplan-Meier: P = .044). These results were confirmed in propensity risk score (PRS)-matched patients. CONCLUSION In alcoholic cirrhosis with rather high propranolol doses, overall and liver survival are significantly aggravated when MELD is ≥12.
Collapse
Affiliation(s)
- Paul Calès
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Sandrine Bertrais
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Jérôme Boursier
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Isabelle Fouchard
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Frédéric Oberti
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | | |
Collapse
|
|
43
|
Castera L. Assessment of Liver Disease Severity. HEPATITIS C: CARE AND TREATMENT 2021:1-20. [DOI: 10.1007/978-3-030-67762-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
44
|
Abbas SH, Pickett E, Lomas DA, Thorburn D, Gooptu B, Hurst JR, Marshall A. Non-invasive testing for liver pathology in alpha-1 antitrypsin deficiency. BMJ Open Respir Res 2020; 7:7/1/e000820. [PMID: 33323365 PMCID: PMC7745521 DOI: 10.1136/bmjresp-2020-000820] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/11/2022] Open
Abstract
Background Many patients with alpha-1 antitrypsin deficiency (A1ATD) receive care in respiratory clinics without access to specialist hepatology expertise. Liver disease can develop asymptomatically, and non-invasive markers of fibrosis may help identify patients who require definitive assessment with liver biopsy. We evaluated the utility of non-invasive markers of liver fibrosis in A1ATD to guide testing in settings without ready access to hepatology expertise. Methods Patients attending the London A1ATD service undergo assessment using blood tests to calculate the ‘APRI’ and ‘FIB-4’ score, liver ultrasound and Fibroscan. Liver biopsy is offered to patients who have abnormal liver function tests with abnormal liver ultrasound and/or liver stiffness >6 kPa on Fibroscan. Liver biopsies were assessed for the presence of A1AT, steatosis, fibrosis and inflammation. Results 75 patients with A1ATD had results for analysis, 56% were female, age 16–82 years. 75% of patients had Fibroscan <6 kPa, 19% had Fibroscan 6–7.9 kPa and 6%>8 kPa. There was a significant correlation between FIB-4 and Fibroscan (r=0.244, p=0.035). Fibroscan >6 kPa corresponded to a FIB-4 score of >1.26. However, FIB-4 >1.26 had poor sensitivity (47%), specificity (32%) and positive-predictive value (PPV; 36%) to identify Fibroscan >6 kPa. The negative-predictive value (NPV) was stronger at 81%. APRI data were similar. Twelve patients underwent liver biopsy, with 11 reports available for analysis. Six had FIB-4 scores<1.26 and five had Fibroscan of <6 kPa. A1AT was present in 64% of biopsies, steatosis in 82%, mild fibrosis in 36%, moderate fibrosis in 9% and severe fibrosis in 9%. Conclusion A combination of liver ultrasound and non-invasive fibrosis tests can help identify patients with A1ATD liver injury. However, APRI and FIB-4 scores alone had poor sensitivity and specificity to justify use as an independent tool for liver pathology in A1ATD.
Collapse
Affiliation(s)
| | - Elisha Pickett
- London Alpha-1 Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK
| | - David A Lomas
- UCL Medical School, London, UK.,London Alpha-1 Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK.,UCL Respiratory, University College London, London, UK
| | - Douglas Thorburn
- London Alpha-1 Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK.,Sheila Sherlock Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| | - Bibek Gooptu
- London Alpha-1 Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK.,NIHR Leicester BRC-Respiratory, Glenfield Hospital, University Hospitals of Leicester, Leicester, UK.,University of Leicester, Leicester, UK
| | - John R Hurst
- London Alpha-1 Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK .,Sheila Sherlock Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| | - Aileen Marshall
- London Alpha-1 Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK.,Sheila Sherlock Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| |
Collapse
|
|
45
|
Hernandez Roman J, Siddiqui MS. The role of noninvasive biomarkers in diagnosis and risk stratification in nonalcoholic fatty liver disease. Endocrinol Diabetes Metab 2020; 3:e00127. [PMID: 33102796 PMCID: PMC7576290 DOI: 10.1002/edm2.127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/28/2020] [Accepted: 02/29/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronically elevated liver enzymes. Diagnosis and risk stratification of NAFLD remains clinically challenge as patients with NAFLD are either asymptomatic or have nonspecific presenting complaints and may have normal liver enzymes. Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, is also difficult to differentiate noninvasively, and a liver biopsy is required to definitively diagnose NASH. Thus, the definitive diagnosis and risk stratification of NAFLD is embedded in histological assessment of the liver. Several clinical aides been investigated in an attempt to risk stratify and identify patients noninvasively as doing a liver biopsy in all patients with NAFLD are not feasible. Since these biomarkers are unable to differentiate NASH from non-NASH, they have leveraged biochemical changes within the liver as patients progress to varying degree of hepatic fibrosis to identify patients with moderate fibrosis (fibrosis stage 2 or greater) and advanced fibrosis (fibrosis stage 3 or greater) to help guide the need for additional and more definitive workup. These clinical aides span from by-products of apoptosis to statistical modelling of clinically available data to identify 'at-risk' patients with NAFLD. The current review will focus the diagnostic performance of these noninvasive serum-based biomarkers in NAFLD.
Collapse
Affiliation(s)
| | - Mohammad S. Siddiqui
- Division of Gastroenterology, Hepatology and NutritionDepartment of Internal MedicineVirginia Commonwealth University (VCU)RichmondVirginia
| |
Collapse
|
|
46
|
Zarski JP, David-Tchouda S, Trocme C, Margier J, Vilotitch A, Hilleret MN, Cagnot C, Boursier V, Ziol M, Sutton A, Layese R, Audureau E, Roudot-Thoraval F, Nahon P. Non-invasive fibrosis tests to predict complications in compensated post-hepatitis C cirrhosis. Clin Res Hepatol Gastroenterol 2020; 44:524-531. [PMID: 31839535 DOI: 10.1016/j.clinre.2019.11.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/08/2019] [Accepted: 11/14/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Markers predicting complications of post-hepatitis C cirrhosis are needed. We asked whether changes in noninvasive markers of fibrosis can predict liver-related complications. METHODS This was a case-controlled study using a prospective national cohort (ANRS-CO12-CIRVIR) of 1323 HCV-infected patients with compensated cirrhosis: 97 patients who developed liver-related complications such as hepatocellular carcinoma or hepatic decompensation (cases) matched in age, sex and follow-up duration were compared with 257 patients without complications (controls). Actitest/Fibrotest™, Inflameter/Fibrometer™, ELF™ and Fibroscan™ were performed at baseline and yearly. Samples based on Propensity score matching were built and mixed linear models performed. Outcomes in a sustained virological response (SVR) negative population and a SVR-positive population were also described. RESULTS At baseline, all characteristics of patients were similar between the groups. All fibrosis tests were statistically higher for cases compared to controls, Fibroscan™ excepted: Fibrotest™: 0.83±0.13 vs. 0.77±0.16; Fibrometer™: 0.93±0.07 vs. 0.90±0.11; ELF™: 11.4±1.0 vs. 11.0±1.2 (P<0.02). The mean follow-up was 5.7±1.9 years. Over a 3-year period, the significant difference in fibrosis marker values between cases and controls remained constant; with a trend toward a decrease in inflammation markers in controls, independent of SVR status. CONCLUSIONS Baseline noninvasive serum fibrosis and inflammation markers were significantly higher in patients developing a complication than in controls. During the follow-up only inflammatory markers decreased in controls, but not in cases, and thus could potentially be used to predict the occurrence of complications in cirrhotic patients.
Collapse
Affiliation(s)
- Jean-Pierre Zarski
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France.
| | - Sandra David-Tchouda
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Candice Trocme
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Jennifer Margier
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Antoine Vilotitch
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | | | - Carole Cagnot
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Valerie Boursier
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Marianne Ziol
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Angela Sutton
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Richard Layese
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | - Etienne Audureau
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| | | | - Pierre Nahon
- CHU de grenoble, gastroenterologie et hepatologie, CS 10217, 38043 Grenoble, France
| |
Collapse
|
|
47
|
Schulz M, Tacke F. Identifying High-Risk NASH Patients: What We Know so Far. ACTA ACUST UNITED AC 2020; 12:125-138. [PMID: 32982495 PMCID: PMC7493213 DOI: 10.2147/hmer.s265473] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022]
Abstract
Steatosis is a condition of hepatic fat overload that is associated with overweight and the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease with a global impact on healthcare. A proportion of NAFLD patients develops nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis or hepatocellular carcinoma (HCC). Identifying patients at risk for potentially life-threatening complications is crucial in their prevention, surveillance and treatment. In addition to hepatic disease progression (cirrhosis, portal hypertension, HCC), NAFLD patients are also at risk of cardiovascular and metabolic diseases as well as extrahepatic malignancies. Liver fibrosis is related to morbidity and mortality in NASH patients, and biomarkers, imaging techniques (ultrasound, elastography, MRI) as well as liver biopsy help in diagnosing fibrosis. In this review, we discuss the tools for identifying patients at risk and their reasonable application in clinical routine in order to stratify prevention and treatment of this emerging disease.
Collapse
Affiliation(s)
- Marten Schulz
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) Und Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) Und Campus Charité Mitte (CCM), Berlin, Germany
| |
Collapse
|
|
48
|
Albhaisi S, Sanyal AJ. Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date. Pharmaceut Med 2020; 33:451-463. [PMID: 31933238 DOI: 10.1007/s40290-019-00305-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has now become a worldwide health issue due to the obesity epidemic, affecting approximately 90% of the obese population and 15-40% of the general population. It is the most common form of chronic liver disease in the United States. NAFLD constitutes a spectrum of diseases ranging in severity from mild, such as fatty liver, progressing into nonalcoholic steatohepatitis (NASH), then fibrosis, and ending with cirrhosis. NASH and increasing fibrosis stage are associated with increased morbidity and mortality; the fibrosis stage is therefore a critical element of risk stratification needed to determine therapeutic approach and also the response to treatment. Liver biopsy is considered the 'gold standard' in the diagnosis of NAFLD. However, it is not practical for widespread clinical use because it is invasive, costly, and associated with complications including occasional death. These limitations have driven the development of noninvasive tests that can accurately predict the fibrosis stage in those with NAFLD. In this review, we provide a concise overview of different non-invasive measurements used for NAFLD/NASH.
Collapse
Affiliation(s)
- Somaya Albhaisi
- Department of Internal Medicine, Virginia Commonwealth University, Box 980102, Richmond, VA, 23298, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Box 980341, Richmond, VA, 23298, USA.
| |
Collapse
|
|
49
|
Abstract
Fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. Traditionally the gold standard for assessment of fibrosis is liver biopsy, but it suffers from various limitations including risk of patient injury and sampling error. As a result, noninvasive tests of hepatic fibrosis have been used in patients with chronic liver disease due to conditions such as hepatitis B and C, and alcoholic and non-alcoholic fatty liver disease. With the advent of new direct-acting antivirals, hepatic fibrosis staging is an important component of treatment decisions in the care of patients with chronic hepatitis C virus infection. Current limitations of the noninvasive biomarker models include a significant indeterminate range, and a predictive ability that is limited to only a few stages of fibrosis. However newer technologies and novel proteins identified by proteomics and genomics offer the possibility for further refinement and individualisation of biomarker fibrosis models in the future.
Collapse
|
|
50
|
Labarca G, Horta G. Obstructive sleep apnea and nonalcoholic fatty liver disease: do we need to consider this association in current clinical practice? Sleep Med 2020; 77:355-356. [PMID: 32564917 DOI: 10.1016/j.sleep.2020.05.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Gonzalo Labarca
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepcion, Concepcion, Chile.
| | - Gloria Horta
- Division of Gastroenterology, Hospital Regional Grant Benavente, Concepcion, Chile
| |
Collapse
|