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Kendall TJ, Chng E, Ren Y, Tai D, Ho G, Fallowfield JA. Outcome prediction in metabolic dysfunction-associated steatotic liver disease using stain-free digital pathological assessment. Liver Int 2024; 44:2511-2516. [PMID: 39109545 DOI: 10.1111/liv.16062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 10/10/2024]
Abstract
Computational quantification reduces observer-related variability in histological assessment of metabolic dysfunction-associated steatotic liver disease (MASLD). We undertook stain-free imaging using the SteatoSITE resource to generate tools directly predictive of clinical outcomes. Unstained liver biopsy sections (n = 452) were imaged using second-harmonic generation/two-photon excitation fluorescence (TPEF) microscopy, and all-cause mortality and hepatic decompensation indices constructed. The mortality index had greater predictive power for all-cause mortality (index >.14 vs. .31 vs.
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Affiliation(s)
- Timothy J Kendall
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
- Edinburgh Pathology, University of Edinburgh, Edinburgh, UK
| | | | - Yayun Ren
- HistoIndex Pte Ltd, Singapore, Singapore
| | - Dean Tai
- HistoIndex Pte Ltd, Singapore, Singapore
| | - Gideon Ho
- HistoIndex Pte Ltd, Singapore, Singapore
| | - Jonathan A Fallowfield
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
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Kim B, Jin HY, Yoon JS, Noh ES, Hwang IT. Triglyceride Glucose Index is Associated with Ultrasonographic Fatty Liver Indicator in Children and Adolescents with Non-alcoholic Fatty Liver Disease. J Clin Res Pediatr Endocrinol 2024; 16:306-313. [PMID: 38664989 PMCID: PMC11590764 DOI: 10.4274/jcrpe.galenos.2024.2024-2-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 03/25/2024] [Indexed: 09/06/2024] Open
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is defined as chronic hepatic steatosis and is becoming prevalent, along with the increasing trend for obesity in children and adolescents. A non-invasive and reliable tool is needed to differentiate non-alcoholic steatohepatitis from simple steatosis. This study evaluated the association between the triglyceride glucose (TyG) index and the ultrasonographic fatty liver indicator (US-FLI), and the possibility of using the TyG index for prediction of severity of pediatric NAFLD. Methods One hundred and twenty one patients who were diagnosed with NAFLD by ultrasonography were included. They were categorized into three groups according to body mass index (BMI). Ninety-two were obese, and 19 and 10 were overweight and normal weight, respectively. Results The homeostatic model assessment for insulin resistance (HOMA-IR) was highest in the group with obesity (p=0.044). The TyG index and US-FLI did not differ significantly among the three BMI groups (p=0.186). Fourteen (11.6%) of the 121 patients had US-FLI ≥6, in whom the BMI-SDS and TyG index were higher (p=0.017, p=0.004), whereas HOMA-IR did not differ significantly from the group with US-FLI <6 (p=0.366). US-FLI was associated with BMI-SDS and the TyG index. TyG index was significantly associated with US-FLI after adjustment for BMI-SDS. The cut-off value for the TyG index for predicting US-FLI ≥6 was 8.91, with an area under the curve of 0.785. Conclusion TyG index was associated with the degree of hepatic steatosis, suggesting that it might be a useful tool for predicting the severity of pediatric NAFLD.
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Affiliation(s)
- Bitgyeol Kim
- Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Clinic of Pediatrics, Seoul, Korea
| | - Hye Young Jin
- Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Clinic of Pediatrics, Seoul, Korea
| | - Jong Seo Yoon
- Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Clinic of Pediatrics, Seoul, Korea
| | - Eu Seon Noh
- Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Clinic of Pediatrics, Seoul, Korea
| | - Il Tae Hwang
- Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Clinic of Pediatrics, Seoul, Korea
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Oshida N, Oh S, Kim B, Miura I, Hasegawa N, Komine S, Isobe T, Shoda J. Muscle Quality as a Potential Diagnostic Marker of Advanced Liver Fibrosis in Patients with Non-alcoholic Fatty Liver Disease. J Obes Metab Syndr 2024; 33:143-154. [PMID: 38735655 PMCID: PMC11224921 DOI: 10.7570/jomes23072] [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: 10/29/2023] [Revised: 12/22/2023] [Accepted: 02/23/2024] [Indexed: 05/14/2024] Open
Abstract
Background Muscle-liver crosstalk plays an important role in the development and progression of non-alcoholic fatty liver disease (NAFLD). The measurement of muscle echo-intensity during ultrasonography is a real-time, non-invasive method of assessing muscle quality. In this retrospective study, we investigated the significance of poor muscle quality (namely, a greater mass of non-contractile tissue, including intramuscular fat) as a risk factor for advanced liver fibrosis and considered whether it may represent a useful tool for the diagnosis of advanced liver fibrosis. Methods We analyzed data from 307 patients with NAFLD (143 men and 164 women) who visited the University of Tsukuba Hospital between 2017 and 2022. The patients were stratified into the following tertiles of muscle quality according to their muscle echo-intensity on ultrasonography: modest (84.1 arbitrary units [A.U.]), intermediate (97.4 A.U.), and poor (113.6 A.U.). We then investigated the relationships between muscle quality and risk factors for advanced liver fibrosis and calculated appropriate cutoff values. Results Patients with poor muscle quality showed a significant, 7.6-fold greater risk of liver fibrosis compared to those with modest muscle quality. Receiver operating characteristic curve analysis showed that muscle quality assessment was as accurate as the fibrosis-4 index and NAFLD fibrosis score in screening for liver fibrosis and superior to the assessment of muscle quantity and strength, respectively. Importantly, a muscle echo-intensity of ≥92.4 A.U. may represent a useful marker of advanced liver fibrosis. Conclusion Muscle quality may represent a useful means of identifying advanced liver fibrosis, and its assessment may become a useful screening tool in daily practice.
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Affiliation(s)
- Natsumi Oshida
- Division of Laboratory Medicine, Tsukuba University Hospital, Tsukuba, Japan
| | - Sechang Oh
- Faculty of Rehabilitation, R Professional University of Rehabilitation, Tsuchiura, Japan
| | - Bokun Kim
- Future Convergence Research Institute, Changwon National University, Changwon, Korea
| | - Ikuru Miura
- Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
| | - Naoyuki Hasegawa
- Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Shoichi Komine
- Faculty of Human Care, Teikyo Heisei University, Tokyo, Japan
| | - Tomonori Isobe
- Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Junichi Shoda
- Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Curci R, Bianco A, Franco I, Bonfiglio C, Campanella A, Mirizzi A, Giannuzzi V, Cozzolongo R, Veronese N, Osella AR. Lifestyle Modification: Evaluation of the Effects of Physical Activity and Low-Glycemic-Index Mediterranean Diet on Fibrosis Score. Nutrients 2023; 15:3520. [PMID: 37630711 PMCID: PMC10459797 DOI: 10.3390/nu15163520] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/03/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Non-Alcoholic Fatty Liver Disease (NAFLD) is one the most prevalent causes of chronic liver disease worldwide. In the absence of an approved drug treatment, lifestyle modification is the first intervention strategy. This study aimed to estimate the main effect of two different physical activity (PA) programs, and a Low-Glycemic-Index Mediterranean Diet (LGIMD), or their combined effect on liver fibrosis parameters in subjects with NAFLD. METHODS Subjects with moderate or severe NAFLD grade of severity (n = 144) were randomly assigned to six intervention arms for three months: LGIMD, PA programs, and their combination. Data were collected at baseline, 45 days, and 90 days. Transient elastography was performed to assess the outcome. RESULTS at 90 days, a statistically significant reduction in kPa was found among subjects following LGMID (-2.85, 95% CI -5.24, -0.45) and those following an LGIMD plus PA1 (-2.37, 95% CI -4.39, -0.35) and LGIMD plus Pa2 (-2.21, 95% CI -4.10, -0.32). The contrast between time 2 and time 1 of the LGIMD plus PA2 treatment showed a statistically significant increase, and vice versa: the contrast between time 3 and time 2 of the same treatment showed a statistically significant reduction. The PA1 and PA2 arms also showed reduced kPa, although the results did not reach statistical significance. CONCLUSIONS The intervention arms, LGIMD, LGIMD+PA1, and LGIMD+PA2, reduced the fibrosis score.
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Affiliation(s)
- Ritanna Curci
- Laboratory of Epidemiology and Statistics, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (R.C.); (A.B.); (I.F.); (C.B.); (A.C.)
| | - Antonella Bianco
- Laboratory of Epidemiology and Statistics, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (R.C.); (A.B.); (I.F.); (C.B.); (A.C.)
| | - Isabella Franco
- Laboratory of Epidemiology and Statistics, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (R.C.); (A.B.); (I.F.); (C.B.); (A.C.)
| | - Caterina Bonfiglio
- Laboratory of Epidemiology and Statistics, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (R.C.); (A.B.); (I.F.); (C.B.); (A.C.)
| | - Angelo Campanella
- Laboratory of Epidemiology and Statistics, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (R.C.); (A.B.); (I.F.); (C.B.); (A.C.)
| | | | - Vito Giannuzzi
- Gastroenterology Unit, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (V.G.); (R.C.)
| | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (V.G.); (R.C.)
| | - Nicola Veronese
- Geriatric Unit, Department of Medicine, University of Palermo, 90100 Palermo, Italy;
| | - Alberto Ruben Osella
- Laboratory of Epidemiology and Statistics, National Institute of Gastroenterology—IRCCS “S. de Bellis”, Via Turi, 70013 Castellana Grotte, Italy; (R.C.); (A.B.); (I.F.); (C.B.); (A.C.)
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Caussy C, Telliam C, Al-Nuaimi B, Maynard-Muet M, Dumortier J, Zoulim F, Disse E, Colin C, Levrero M, Moulin P. Comparison of Pathway Referrals for Liver Fibrosis Risk Stratification Performed in Diabetology and Nutrition Clinics. Diabetes Metab Syndr Obes 2023; 16:1721-1729. [PMID: 37312899 PMCID: PMC10259533 DOI: 10.2147/dmso.s407511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/27/2023] [Indexed: 06/15/2023] Open
Abstract
Purpose A systematic screening for the presence of nonalcoholic fatty liver disease (NAFLD)-related advanced fibrosis is currently recommended in patients with type 2 diabetes mellitus (T2DM) and obesity. However, real-world data of such liver fibrosis risk stratification pathway from diabetology and nutrition clinics towards hepatology clinics are scarce. Therefore, we compared data from two pathways with or without transient elastography (TE) performed in diabetology and nutrition clinics. Patients and Methods This is a retrospective study comparing the proportion of patients with intermediate/high risk of advanced fibrosis (AF) as defined by a liver stiffness measurement (LSM) ≥8kPa, among patients referred in hepatology from two diabetology-nutrition departments at Lyon University Hospital, France between November 1st 2018 to December 31st 2019. Results Among the two diabetology and nutrition departments using TE or not, 27.5% (62/225) versus 44.2% (126/285) were referred to hepatology, respectively. The pathway using TE in diabetology and nutrition referred to hepatology a higher proportion of patients with intermediate/high risk of AF compared to the pathway without TE: 77.4% versus 30.9%, p<0.001. In the pathway with TE, the odds of patients with intermediate/high risk of AF referred to hepatology was significantly higher: OR: 7.7, 95% CI: 3.6-16.7, p<0.001 after adjustment for age, sex and presence of obesity and T2D compared to the pathway without TE in diabetology and nutrition clinics. However, among the patients not referred, 29.4% had an intermediate/high risk of AF. Conclusion A pathway-referral using TE performed in diabetology and nutrition clinics, significantly improves the liver fibrosis risk stratification and avoids over-referral. However, collaboration between diabetologist, nutritionists and hepatologists is needed to avoid under-referral.
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Affiliation(s)
- Cyrielle Caussy
- CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, 69495, France
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hopices Civils de Lyon, Pierre-Bénite, 69495, France
- Université de Lyon, Université Claude Bernard, Lyon, France
| | - Charlène Telliam
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hopices Civils de Lyon, Pierre-Bénite, 69495, France
- Département Endocrinologie, Diabète et Nutrition, Hôpital Cardiologique, Hospices Civils de Lyon, Bron, France
| | - Bader Al-Nuaimi
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hopices Civils de Lyon, Pierre-Bénite, 69495, France
| | - Marianne Maynard-Muet
- Service d’Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- Centre de Recherche sur le Cancer de Lyon, INSERM, Unité 1052, CNRS, UMR 5286, Lyon, France
| | - Jérôme Dumortier
- Université de Lyon, Université Claude Bernard, Lyon, France
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Fabien Zoulim
- Université de Lyon, Université Claude Bernard, Lyon, France
- Service d’Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- Centre de Recherche sur le Cancer de Lyon, INSERM, Unité 1052, CNRS, UMR 5286, Lyon, France
| | - Emmanuel Disse
- CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, 69495, France
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hopices Civils de Lyon, Pierre-Bénite, 69495, France
- Université de Lyon, Université Claude Bernard, Lyon, France
| | - Cyrille Colin
- Université de Lyon, Université Claude Bernard, Lyon, France
- Unité d’Evaluation Médico-Economique, Pôle Information Médicale Evaluation Recherche, Hospices Civils de Lyon, Lyon, France
| | - Massimo Levrero
- Université de Lyon, Université Claude Bernard, Lyon, France
- Service d’Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- Centre de Recherche sur le Cancer de Lyon, INSERM, Unité 1052, CNRS, UMR 5286, Lyon, France
| | - Philippe Moulin
- CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, 69495, France
- Université de Lyon, Université Claude Bernard, Lyon, France
- Département Endocrinologie, Diabète et Nutrition, Hôpital Cardiologique, Hospices Civils de Lyon, Bron, France
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Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, Kleiner DE, Loomba R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023; 77:1797-1835. [PMID: 36727674 PMCID: PMC10735173 DOI: 10.1097/hep.0000000000000323] [Citation(s) in RCA: 924] [Impact Index Per Article: 462.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 01/18/2023] [Indexed: 02/03/2023]
Affiliation(s)
- Mary E. Rinella
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA
| | | | | | | | - Stephen Caldwell
- School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Diana Barb
- University of Florida College of Medicine, Gainesville, Florida, USA
| | | | - Rohit Loomba
- University of California, San Diego, San Diego, California, USA
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Nogami A, Yoneda M, Iwaki M, Kobayashi T, Honda Y, Ogawa Y, Imajo K, Saito S, Nakajima A. Non-invasive imaging biomarkers for liver steatosis in non-alcoholic fatty liver disease: present and future. Clin Mol Hepatol 2023; 29:S123-S135. [PMID: 36503207 PMCID: PMC10029939 DOI: 10.3350/cmh.2022.0357] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease is currently the most common chronic liver disease, affecting up to 25% of the global population. Simple fatty liver, in which fat is deposited in the liver without fibrosis, has been regarded as a benign disease in the past, but it is now known to be prognostic. In the future, more emphasis should be placed on the quantification of liver fat. Traditionally, fatty liver has been assessed by histological evaluation, which requires an invasive examination; however, technological innovations have made it possible to evaluate fatty liver by non-invasive imaging methods, such as ultrasonography, computed tomography, and magnetic resonance imaging. In addition, quantitative as well as qualitative measurements for the detection of fatty liver have become available. In this review, we summarize the currently used qualitative evaluations of fatty liver and discuss quantitative evaluations that are expected to further develop in the future.
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Affiliation(s)
- Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
- Department of Gastroenterology, National Hospital Organization Yokohama Medical Center, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
- Department of Gastroenterology and Endoscopy, Shinyurigaoka General Hospital, Kawasaki, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate school of Medicine, Yokohama, Japan
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Bioelectrical Impedance Analysis Can Be an Effective Tool for Screening Fatty Liver in Patients with Suspected Liver Disease. Healthcare (Basel) 2022; 10:healthcare10112268. [PMID: 36421592 PMCID: PMC9690130 DOI: 10.3390/healthcare10112268] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/09/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Background and study aims: Although abdominal ultrasound (USG) or controlled attenuation parameter (CAP) score of transient elastography (TE) is recommended for the diagnosis of fatty liver, issues regarding cost and accessibility still exist. The aim of this study was to evaluate if bioelectrical impedance analysis (BIA) can be used as a reliable screening tool for fatty liver. Patients and methods: A total of 249 patients who underwent all three tests including TE, BIA, and USG were enrolled. The correlation between fat mass measured by BIA, CAP score of TE, and fatty liver grade measured by USG was analyzed. In addition, the cut-off value of BIA which can predict the fatty liver grade was calculated. Results: Fat mass index (FMI) assessed by BIA increased significantly along with the rise in fatty liver grade measured by USG (normal: 6.2 ± 2.4, Gr I: 8.0 ± 3.7, Gr II: 10.6 ± 3.5, Gr III: 10.7 ± 3.7 kg/m2, p < 0.001). In addition, a positive correlation was found between the CAP score of TE and the FMI of BIA. Additionally, a total body fat mass increase by 24.3% or 29.8% in men and 34.8% or 35.1% in women increased the possibility of developing any grade of fatty liver or significant fatty liver (≥Gr II fatty liver), respectively. Conclusion: The total fat or fat mass index of BIA was related to fatty liver as assessed by ultrasound or CAP score, and area under the receiver operating characteristic (AUROC) was about 0.8. Thus, BIA can be used as a screening tool for fatty liver in patients with suspected liver disease.
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Ijuin S, Oda K, Mawatari S, Taniyama O, Toyodome A, Sakae H, Tabu K, Kumagai K, Kanmura S, Tamai T, Moriuchi A, Uto H, Ido A. Serine palmitoyltransferase long chain subunit 3 is associated with hepatocellular carcinoma in patients with NAFLD. Mol Clin Oncol 2021; 16:55. [PMID: 35070304 PMCID: PMC8764653 DOI: 10.3892/mco.2021.2488] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 10/14/2021] [Indexed: 11/05/2022] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is continuously increasing, with the proportion of patients with liver carcinogenesis due to non-alcoholic steatohepatitis (NASH) rising accordingly. Although it is important to identify individuals with hepatic carcinogenesis among patients with NAFLD, useful biomarkers have not yet been established. Previously, in a mouse model of diabetes mellitus without genetic modifications, we reported that a high-fat diet increases serine palmitoyltransferase long chain subunit 3 (SPTLC3) expression in liver tissue, accompanied by high frequency of liver carcinogenesis. Serine palmitoyltransferase (SPT) catalyzes the metabolism of fatty acids, particularly sphingolipid synthesis, and SPTLC3 has been identified as its catalytic subunit, but its role in liver disease is unclear. In the present study, the importance of SPTLC3 in NAFLD development was investigated. SPTLC3 mRNA expression was observed in a liver cancer cell line and in liver tissues from patients with NAFLD and liver cancer. In total, 99 patients with NAFLD (66 without hepatocellular carcinoma (HCC) and 33 with HCC were recruited, having been diagnosed by liver biopsy or imaging, along with 6 healthy volunteers (HVs). Serum was collected from patients and HVs, and SPTLC3 level was assessed by ELISA. SPTLC3 expression was higher in non-cancerous compared with that in cancerous liver tissues. Serum SPTLC3 levels were negatively correlated with platelet count and positively correlated with hyaluronic acid levels, suggesting an association with liver fibrosis. Moreover, SPTLC3 levels were significantly higher in the HCC group than in the HV and NAFLD groups. Multivariate analysis of HCC-related factors identified platelets, alanine transferase, albumin and SPTLC3 as independent factors associated with HCC. Furthermore, in patients with other chronic liver diseases (hepatitis B and C, and alcoholic liver disease), no significant differences in serum SPTLC3 levels were observed between patients with or without HCC. Thus, SPTLC3 expression increases specifically with the progression of NAFLD. Overall, the present results indicate that SPTLC3 may be involved in the development of liver carcinogenesis during NAFLD.
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Affiliation(s)
- Sho Ijuin
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Kohei Oda
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Seiichi Mawatari
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Ohki Taniyama
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Ai Toyodome
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Haruka Sakae
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Kazuaki Tabu
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Tsutomu Tamai
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Kagoshima 890‑8760, Japan
| | - Akihiro Moriuchi
- Department of Gastroenterology, National Hospital Organization Kagoshima Medical Center, Kagoshima 892‑0853, Japan
| | - Hirofumi Uto
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, Miyazaki 880‑0003, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
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Marti-Aguado D, Fernández-Patón M, Alfaro-Cervello C, Mestre-Alagarda C, Bauza M, Gallen-Peris A, Merino V, Benlloch S, Pérez-Rojas J, Ferrández A, Puglia V, Gimeno-Torres M, Aguilera V, Monton C, Escudero-García D, Alberich-Bayarri Á, Serra MA, Marti-Bonmati L. Digital Pathology Enables Automated and Quantitative Assessment of Inflammatory Activity in Patients with Chronic Liver Disease. Biomolecules 2021; 11:1808. [PMID: 34944452 PMCID: PMC8699191 DOI: 10.3390/biom11121808] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/22/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Traditional histological evaluation for grading liver disease severity is based on subjective and semi-quantitative scores. We examined the relationship between digital pathology analysis and corresponding scoring systems for the assessment of hepatic necroinflammatory activity. A prospective, multicenter study including 156 patients with chronic liver disease (74% nonalcoholic fatty liver disease-NAFLD, 26% chronic hepatitis-CH etiologies) was performed. Inflammation was graded according to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network system and METAVIR score. Whole-slide digital image analysis based on quantitative (I-score: inflammation ratio) and morphometric (C-score: proportionate area of staining intensities clusters) measurements were independently performed. Our data show that I-scores and C-scores increase with inflammation grades (p < 0.001). High correlation was seen for CH (ρ = 0.85-0.88), but only moderate for NAFLD (ρ = 0.5-0.53). I-score (p = 0.008) and C-score (p = 0.002) were higher for CH than NAFLD. Our MATLAB algorithm performed better than QuPath software for the diagnosis of low-moderate inflammation (p < 0.05). C-score AUC for classifying NASH was 0.75 (95%CI, 0.65-0.84) and for moderate/severe CH was 0.99 (95%CI, 0.97-1.00). Digital pathology measurements increased with fibrosis stages (p < 0.001). In conclusion, quantitative and morphometric metrics of inflammatory burden obtained by digital pathology correlate well with pathologists' scores, showing a higher accuracy for the evaluation of CH than NAFLD.
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Affiliation(s)
- David Marti-Aguado
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
| | - Matías Fernández-Patón
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
| | - Clara Alfaro-Cervello
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (C.A.-C.); (C.M.-A.); (A.F.)
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Claudia Mestre-Alagarda
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (C.A.-C.); (C.M.-A.); (A.F.)
| | - Mónica Bauza
- Pathology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (M.B.); (J.P.-R.)
| | - Ana Gallen-Peris
- Digestive Disease Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain; (A.G.-P.); (S.B.)
| | - Víctor Merino
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
| | - Salvador Benlloch
- Digestive Disease Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain; (A.G.-P.); (S.B.)
- CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain;
| | - Judith Pérez-Rojas
- Pathology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (M.B.); (J.P.-R.)
| | - Antonio Ferrández
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (C.A.-C.); (C.M.-A.); (A.F.)
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Víctor Puglia
- Pathology Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain;
| | - Marta Gimeno-Torres
- Hepatology and Liver Transplantation Unit, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain;
| | - Victoria Aguilera
- CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Hepatology and Liver Transplantation Unit, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain;
| | - Cristina Monton
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
| | - Desamparados Escudero-García
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain; (V.M.); (C.M.); (D.E.-G.)
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Ángel Alberich-Bayarri
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
- Quantitative Imaging Biomarkers in Medicine, QUIBIM SL, 46021 Valencia, Spain
| | - Miguel A. Serra
- Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Luis Marti-Bonmati
- Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain; (M.F.-P.); (Á.A.-B.); (L.M.-B.)
- Radiology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain
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12
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Chen L, Wu N, Kennedy L, Francis H, Ceci L, Zhou T, Samala N, Kyritsi K, Wu C, Sybenga A, Ekser B, Dar W, Atkins C, Meadows V, Glaser S, Alpini G. Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes. Hepatology 2021; 74:1845-1863. [PMID: 33928675 PMCID: PMC8782246 DOI: 10.1002/hep.31871] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 04/11/2021] [Accepted: 04/20/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Human NAFLD is characterized at early stages by hepatic steatosis, which may progress to NASH when the liver displays microvesicular steatosis, lobular inflammation, and pericellular fibrosis. The secretin (SCT)/secretin receptor (SCTR) axis promotes biliary senescence and liver fibrosis in cholestatic models through down-regulation of miR-125b signaling. We aim to evaluate the effect of disrupting biliary SCT/SCTR/miR-125b signaling on hepatic steatosis, biliary senescence, and liver fibrosis in NAFLD/NASH. APPROACH AND RESULTS In vivo, 4-week-old male wild-type, Sct-/- and Sctr-/- mice were fed a control diet or high-fat diet (HFD) for 16 weeks. The expression of SCT/SCTR/miR-125b axis was measured in human NAFLD/NASH liver samples and HFD mouse livers by immunohistochemistry and quantitative PCR. Biliary/hepatocyte senescence, ductular reaction, and liver angiogenesis were evaluated in mouse liver and human NAFLD/NASH liver samples. miR-125b target lipogenesis genes in hepatocytes were screened and validated by custom RT2 Profiler PCR array and luciferase assay. Biliary SCT/SCTR expression was increased in human NAFLD/NASH samples and in livers of HFD mice, whereas the expression of miR-125b was decreased. Biliary/hepatocyte senescence, ductular reaction, and liver angiogenesis were observed in human NAFLD/NASH samples as well as HFD mice, which were decreased in Sct-/- and Sctr-/- HFD mice. Elovl1 is a lipogenesis gene targeted by miR-125b, and its expression was also decreased in HFD mouse hepatocytes following Sct or Sctr knockout. Bile acid profile in fecal samples have the greatest changes between wild-type mice and Sct-/- /Sctr-/- mice. CONCLUSION The biliary SCT/SCTR/miR-125b axis promotes liver steatosis by up-regulating lipid biosynthesis gene Elovl1. Targeting the biliary SCT/SCTR/miR-125b axis may be key for ameliorating phenotypes of human NAFLD/NASH.
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Affiliation(s)
- Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Niharika Samala
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX
| | - Amelia Sybenga
- Department of Pathology, Laboratory Medicine, University of Vermont Medical Center, Burlington, VT
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Wasim Dar
- Department of Surgery, Division of Acute Care Surgery, The University of Texas Health Sciences Center at Houston
| | - Constance Atkins
- Department of Anesthesiology, University of Texas Health Sciences Center at Houston
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, College of Medicine, Bryan, TX
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indianapolis, IN
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13
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Kulkarni S, Naz N, Gu H, Stoll JM, Thompson MD, DeBosch BJ. A clinical model to predict fibrosis on liver biopsy in paediatric subjects with nonalcoholic fatty liver disease. Clin Obes 2021; 11:e12472. [PMID: 34106515 PMCID: PMC8928096 DOI: 10.1111/cob.12472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/09/2021] [Accepted: 05/28/2021] [Indexed: 12/19/2022]
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) in children is rapidly increasing. Liver fibrosis is a poor prognostic feature that independently predicts cirrhosis. The time that intercedes the first medical encounter and biopsy is rate-limiting to multi-modal treatment. This study aimed to identify non-invasive parameters to predict advanced NAFLD and fibrosis. We conducted a single-center, retrospective 10-year analysis of 640 paediatric patients who underwent liver biopsy. 55 patients, age 3-21 years, had biopsy-confirmed NAFLD. We assessed primary outcomes, NAFLD activity score (NAS) and fibrosis scores, against non-invasive parameters by linear regression, by using binary cutoff values, and by a multivariate logistic regression fibrosis prediction model. NAS correlated with platelets and female sex. Fibrosis scores correlated with platelet counts, gamma glutamyl transferase (GGT), and ultrasound shear wave velocity. 25-hydroxy-vitamin D and GGT differentiated mild versus moderate-to-advanced fibrosis. Our multivariate logistical regression model-based scoring system predicted F2 or higher (parameters: BMI%, vitamin D, platelets, GGT), with sensitivity and specificity of 0.83 and 0.95 (area under the ROC curve, 0.944). We identify a clinical model to identify high-risk patients for expedited biopsy. Stratifying patients to abbreviate time-to-biopsy can attenuate delays in aggressive therapy for high-risk patients.
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Affiliation(s)
- Sakil Kulkarni
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Nadia Naz
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Hongjie Gu
- Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
| | - Janis M. Stoll
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Michael D. Thompson
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Digestive Diseases Research Center (DDRCC), Washington University School of Medicine, St. Louis, MO, USA
| | - Brian J. DeBosch
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Digestive Diseases Research Center (DDRCC), Washington University School of Medicine, St. Louis, MO, USA
- Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
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14
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Relationships of Dietary Habits and Physical Activity Status with Non-Alcoholic Fatty Liver Disease Featuring Advanced Fibrosis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18178918. [PMID: 34501508 PMCID: PMC8431170 DOI: 10.3390/ijerph18178918] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/20/2021] [Accepted: 08/22/2021] [Indexed: 11/29/2022]
Abstract
(1) Aim: Hepatic fibrosis is a prognostic factor for disease progression in non-alcoholic fatty liver disease (NAFLD). We aimed to determine the relationships between diet, physical activity, and the progression of liver fibrosis. (2) Methods: The 349 participants were categorized by their FibroScan-aspartate aminotransferase score, and they completed a questionnaire regarding their diet and physical activity. (3) Results: There were 233 patients in the negative-on-screening group, 78 in the gray zone group, and 38 in the positive-on-screening group. The frequencies of consumption of soybeans and soybean products and of light-colored vegetables were lower in the positive group; whereas the frequencies of consumption of snack food and fried sweets, jelly and pudding, fried food, and butter, lard, and beef tallow were higher. The odds ratios for the fibrosis progression in patients who consumed fried food ≥4 times/week was 2.21. The positive group also showed lower physical activity level (PAL) and exercise (Ex, metabolic equivalents for tasks (METs)/hour/week). The patients who undertook Ex at >7.5 had an odds ratio of 0.21 for the fibrosis progression. (4) Conclusion: High consumption of fried food and low Ex are risk factors for the fibrosis progression in NAFLD.
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15
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Park JH, Koo BK, Kim W, Kim WH. Histological severity of nonalcoholic fatty liver disease is associated with 10-year risk for atherosclerotic cardiovascular disease. Hepatol Int 2021; 15:1148-1159. [PMID: 34081289 DOI: 10.1007/s12072-021-10209-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 05/05/2021] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND AIM Nonalcoholic fatty liver disease (NAFLD) is associated with atherosclerotic cardiovascular disease (ASCVD). However, few studies have investigated the association between the histological severity of NAFLD and ASCVD. Therefore, we investigated whether the histological severity of NAFLD is associated with ASCVD risk. METHODS We performed cross-sectional analysis of prospectively enrolled, biopsy-proven NAFLD patients. The 10-year ASCVD risk was assessed using the Korean Risk Prediction Model. The histological spectrum of NAFLD was classified by the nonalcoholic steatohepatitis (NASH) clinical research network histological scoring system. The association between each histological subgroup and ASCVD risk was analyzed using logistic regression analysis. RESULTS This study included 398 Korean subjects (mean age, 57.9 years; male, 44.2%) with biopsy-proven NAFLD and 102 no-NALFD controls. Subjects with ASCVD risk ≥ 10% showed more severe grades of hepatocellular ballooning and more advanced stages of fibrosis when compared with subjects with ASCVD risk < 10% (p < 0.05 for each). The presence of NASH (odds ratio [OR] 4.07; 95% confidence interval [CI] 1.40-11.88) or advanced fibrosis (OR 8.11; 95% CI 1.83-35.98) was independently associated with a higher risk of ASCVD even after adjustment for age, sex, body mass index, blood pressure, lipids, liver enzymes, systemic inflammation, and insulin resistance. CONCLUSIONS Patients with NASH or advanced fibrosis are at an increased risk of developing ASCVD compared with no-NAFLD controls or subjects with NAFL, independent of conventional metabolic risk factors for CVD. Histological information on NAFLD may be helpful to promote our understanding of extrahepatic complications, such as ASCVD, resulting from NAFLD progression.
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Affiliation(s)
- Ji Hye Park
- Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Republic of Korea
| | - Bo Kyung Koo
- Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.,Innovative Target Exploration of NAFLD (ITEN) Consortium, Seoul, Republic of Korea
| | - Won Kim
- Innovative Target Exploration of NAFLD (ITEN) Consortium, Seoul, Republic of Korea. .,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Republic of Korea.
| | - Won-Ho Kim
- Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Republic of Korea.
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16
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Miura I, Komine S, Okada K, Wada S, Warabi E, Uchida F, Oh S, Suzuki H, Mizokami Y, Shoda J. Prevention of non-alcoholic steatohepatitis by long-term exercise via the induction of phenotypic changes in Kupffer cells of hyperphagic obese mice. Physiol Rep 2021; 9:e14859. [PMID: 33991461 PMCID: PMC8123550 DOI: 10.14814/phy2.14859] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/07/2021] [Accepted: 04/12/2021] [Indexed: 01/01/2023] Open
Abstract
Exercise ameliorates nonalcoholic fatty liver disease (NAFLD) by inducing phenotypic changes in Kupffer cells (KCs). p62/Sqstm1-knockout (p62-KO) mice develop NAFLD alongside hyperphagia-induced obesity. We evaluated (1) the effects of long-term exercise on the foreign-body phagocytic capacity of KCs, their surface marker expression, and the production of steroid hormones in p62-KO mice; and (2) whether long-term exercise prevented the development of non-alcoholic steatohepatitis (NASH) in p62-KO mice fed a high-fat diet (HFD). In experiment 1, 30-week-old male p62-KO mice were allocated to resting (p62-KO-Rest) or exercise (p62-KO-Ex) groups, and the latter performed long-term exercise over 4 weeks. Then, the phenotype of their KCs was compared to that of p62-KO-Rest and wild-type (WT) mice. In experiment 2, 5-week-old male p62-KO mice that were fed a HFD performed long-term exercise over 12 weeks. In experiment 1, the phagocytic capacity of KCs and the proportion of CD68-positive cells were lower in the p62-KO-Rest group than in the WT group, but they increased with long-term exercise. The percentage of CD11b-positive KCs was higher in the p62-KO-Rest group than in the WT group, but lower in the p62-KO-Ex group. The circulating dehydroepiandrosterone (DHEA) concentration was higher in p62-KO-Ex mice than in p62-KO-Rest mice. In experiment 2, the body mass and composition of the p62-KO-Rest and p62-KO-Ex groups were similar, but the hepatomegaly, hepatic inflammation, and fibrosis were less marked in p62-KO-Ex mice. The DHEA concentration was higher in p62-KO-Ex mice than in WT or p62-KO-Rest mice. Thus, long-term exercise restores the impaired phagocytic capacity of KCs in NAFLD obese mice, potentially through greater DHEA production, and prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis. These results suggest a molecular mechanism for the beneficial effect of exercise in the management of patients with NAFLD.
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Affiliation(s)
- Ikuru Miura
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Shoichi Komine
- Faculty of Human Care, Department of Acupuncture and Moxibustion, Teikyo Heisei University, Toshima-ku, Tokyo, Japan.,Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Kosuke Okada
- Tsukuba Preventive Medicine Research Center, University of Tsukuba Hospital, Tsukuba-shi, Ibaraki, Japan
| | - Shota Wada
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Eiji Warabi
- Division of Biomedical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Fumihiko Uchida
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Sechang Oh
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Hideo Suzuki
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.,Tsukuba Preventive Medicine Research Center, University of Tsukuba Hospital, Tsukuba-shi, Ibaraki, Japan
| | - Yuji Mizokami
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
| | - Junichi Shoda
- Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
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17
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Nikai H, Ishida K, Umemura A, Baba S, Nitta H, Sugai T, Sasaki A. Effects of Laparoscopic Sleeve Gastrectomy on Non-Alcoholic Steatohepatitis and Liver Fibrosis in Japanese Patients with Severe Obesity. Obes Surg 2021; 30:2579-2587. [PMID: 32124215 DOI: 10.1007/s11695-020-04515-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The prevalence of non-alcoholic steatohepatitis (NASH) in Japanese patients with severe obesity is extremely high. The aim of the present study was to evaluate the metabolic and histological effects of laparoscopic sleeve gastrectomy (LSG) on NASH and liver fibrosis in Japanese patients with severe obesity. METHODS Between June 2008 and March 2019, all 79 patients with severe obesity who underwent LSG were included in the study. Sixty-eight patients had an intraoperative liver biopsy performed at the time of LSG. Ultrasound-guided liver biopsies were performed in patients with fibrosis at 12 months after LSG. RESULTS NASH was present in 43 patients (63.2%), and 10 patients had a unique feature in which their fibrosis were observed without steatosis at the time of LSG. Of the 28 patients with NASH, 25 showed improvement and no longer met the diagnostic criteria of NASH at 12 months after LSG. Mean pericellular fibrosis scores showed significant improvement from 1.62 at baseline, to 1.50, 1.00, and 0.78, respectively (p < 0.001). Univariate analysis of the preoperative predictors in the improvement of fibrosis showed significant effects in preoperative weight (p = 0.037), HbA1c (p = 0.037), and serum insulin (p = 0.037). Multivariate analysis revealed HbA1c to be the only preoperative predictor of improvement in fibrosis (p = 0.004; odds ratio 0.440, 95% CI 0.229-0.842). CONCLUSIONS LSG has great potential as an effective treatment for patients with NASH.
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Affiliation(s)
- Haruka Nikai
- Department of Surgery, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, 028-3695, Japan
| | - Kazuyuki Ishida
- Department of Pathology, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, 028-3695, Japan
| | - Akira Umemura
- Department of Surgery, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, 028-3695, Japan
| | - Shigeaki Baba
- Department of Surgery, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, 028-3695, Japan
| | - Hiroyuki Nitta
- Department of Surgery, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, 028-3695, Japan
| | - Tamotsu Sugai
- Department of Pathology, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, 028-3695, Japan
| | - Akira Sasaki
- Department of Surgery, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, 028-3695, Japan.
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18
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Predictive scoring system for advanced liver fibrosis in Japanese patients with severe obesity. Surg Today 2021; 51:1513-1520. [PMID: 33829335 DOI: 10.1007/s00595-021-02266-w] [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: 11/27/2020] [Accepted: 01/11/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE The aim of this study was to examine the predictive scoring system of advanced liver fibrosis in severely obese Japanese patients. METHODS Seventy-two patients underwent laparoscopic sleeve gastrectomy and intraoperative liver biopsies. We classified these patients into two groups: Brunt stage ≥ 2 (advanced fibrosis) and 0/1 (none/mild fibrosis). A logistic regression analysis was performed to identify the predictors of advanced fibrosis. RESULTS Sixteen patients had advanced fibrosis, while 56 had no/mild fibrosis. The prevalence of type 2 diabetes mellitus (T2DM) in advanced fibrosis group was significantly higher than in none/mild fibrosis. An univariate analysis of the factors predicting advanced fibrosis showed significant differences in AST/ALT ratio, serum insulin levels, HOMA-IR, and type IV collagen 7S in the T2DM group. According to a multivariate analysis, type IV collagen 7S was an independent predictor and the cutoff value was 5.6 ng/mL. We created a flow chart; high risk (T2DM and type IV collagen 7S ≥ 5.6 ng/mL), moderate risk (T2DM and type IV collagen 7S < 5.6 ng/mL), and low risk (non-DM). For those at high risk, the sensitivity, specificity, positive predictive value, and negative predictive value were 56.2%, 94.4%, 75.0%, and 87.9%, respectively. CONCLUSION This classification system has the potential to accurately categorize the risk of liver fibrosis.
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19
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Evaluation of Nonalcoholic Fatty Liver Disease in Pediatric Patients With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2021; 72:574-578. [PMID: 33346578 DOI: 10.1097/mpg.0000000000003023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Adult studies demonstrate the co-existence of nonalcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) without traditional risk factors. Data in children with IBD are lacking. Here, we sought to establish the prevalence of NAFLD in a single-center pediatric IBD cohort, and identify potential risk factors. After institutional review board approval, we enrolled children with IBD who underwent routine abdominal magnetic resonance enterography. Proton density fat fraction (PDFF) was then estimated on magnetic resonance enterography. A total of 83 patients with IBD were identified and PDFF maps completed. Five (6%) were found to have PDFF >5%, meeting criteria for NAFLD. Compared to the patients with IBD without NAFLD, none of the evaluated risk factors including age, sex, diagnosis, time since diagnosis, medication, median alanine aminotransferase, and weight status were statistically significant. Our findings demonstrate the occult nature of NAFLD in pediatric IBD. The prevalence is not at variance with what is expected in general teenage populations.
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Tanshinone IIA Downregulates Lipogenic Gene Expression and Attenuates Lipid Accumulation through the Modulation of LXRα/SREBP1 Pathway in HepG2 Cells. Biomedicines 2021; 9:biomedicines9030326. [PMID: 33806955 PMCID: PMC8004631 DOI: 10.3390/biomedicines9030326] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/21/2021] [Accepted: 03/21/2021] [Indexed: 12/12/2022] Open
Abstract
Abnormal and excessive accumulation of lipid droplets within hepatic cells is the main feature of steatosis and nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). Dysregulation of lipogenesis contributes to hepatic steatosis and plays an essential role in the pathological progress of MAFLD. Tanshinone IIA is a bioactive phytochemical isolated from Salvia miltiorrhiza Bunge and exhibits anti-inflammatory, antiatherosclerotic and antihyperlipidemic effects. In this study, we aimed to investigate the lipid-lowering effects of tanshinone IIA on the regulation of lipogenesis, lipid accumulation, and the underlying mechanisms in hepatic cells. We demonstrated that tanshinone IIA can significantly inhibit the gene expression involved in de novo lipogenesis including FASN, ACC1, and SCD1, in HepG2 and Huh 7 cells. Tanshinone IIA could increase phosphorylation of ACC1 protein in HepG2 cells. We further demonstrated that tanshinone IIA also could suppress the fatty-acid-induced lipogenesis and TG accumulation in HepG2 cells. Furthermore, tanshinone IIA markedly downregulated the mRNA and protein expression of SREBP1, an essential transcription factor regulating lipogenesis in hepatic cells. Moreover, we found that tanshinone IIA attenuated liver X receptor α (LXRα)-mediated lipogenic gene expression and lipid droplet accumulation, but did not change the levels of LXRα mRNA or protein in HepG2 cells. The molecular docking data predicted tanshinone IIA binding to the ligand-binding domain of LXRα, which may result in the attenuation of LXRα-induced transcriptional activation. Our findings support the supposition that tanshinone IIA possesses a lipid-modulating effect that suppresses lipogenesis and attenuates lipid accumulation by modulating the LXRα/SREBP1 pathway in hepatic cells. Tanshinone IIA can be potentially used as a supplement or drug for the prevention or treatment of MAFLD.
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21
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Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, Bhandari BR, Gunn N, Caldwell SH, Goodman Z, Wapinski I, Resnick M, Beck AH, Ding D, Jia C, Chuang JC, Huss RS, Chung C, Subramanian GM, Myers RP, Patel K, Borg BB, Ghalib R, Kabler H, Poulos J, Younes Z, Elkhashab M, Hassanein T, Iyer R, Ruane P, Shiffman ML, Strasser S, Wong VWS, Alkhouri N. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology 2021; 73:625-643. [PMID: 33169409 DOI: 10.1002/hep.31622] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 10/19/2020] [Accepted: 10/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. APPROACH AND RESULTS In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. CONCLUSIONS In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.
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Affiliation(s)
- Rohit Loomba
- NAFLD Research CenterUniversity of California at San DiegoLa JollaCA
| | | | | | | | | | - Guy Neff
- Covenant Research, LLCSarasotaFL
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Reem Ghalib
- Texas Clinical Research InstituteArlingtonTX
| | | | - John Poulos
- Cumberland Research AssociatesFayettevilleNC
| | | | | | | | | | - Peter Ruane
- Ruane Medical and Liver Health InstituteLos AngelesCA
| | | | - Simone Strasser
- Royal Prince Alfred Hospital and The University of SydneyCamperdownNew South WalesAustralia
| | - Vincent Wai-Sun Wong
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongHong Kong
| | - Naim Alkhouri
- Texas Liver InstituteUT Health San AntonioSan AntonioTX
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22
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Tilg H, Adolph TE, Moschen AR. Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade. Hepatology 2021; 73:833-842. [PMID: 32780879 PMCID: PMC7898624 DOI: 10.1002/hep.31518] [Citation(s) in RCA: 231] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/20/2020] [Accepted: 07/27/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine IGastroenterologyHepatologyEndocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
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23
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Lee J, Vali Y, Boursier J, Spijker R, Anstee QM, Bossuyt PM, Zafarmand MH. Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: A systematic review. Liver Int 2021; 41:261-270. [PMID: 32946642 PMCID: PMC7898346 DOI: 10.1111/liv.14669] [Citation(s) in RCA: 210] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/27/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Fibrosis is the strongest predictor for long-term clinical outcomes among patients with non-alcoholic fatty liver disease (NAFLD). There is growing interest in employing non-invasive methods for risk stratification based on prognosis. FIB-4, NFS and APRI are models commonly used for detecting fibrosis among NAFLD patients. We aimed to synthesize existing literature on the ability of these models in prognosticating NAFLD-related events. METHODS A sensitive search was conducted in two medical databases to retrieve studies evaluating the prognostic accuracy of FIB-4, NFS and APRI among NAFLD patients. Target events were change in fibrosis, liver-related event and mortality. Two reviewers independently performed reference screening, data extraction and quality assessment (QUAPAS tool). RESULTS A total of 13 studies (FIB-4:12, NFS: 11, APRI: 10), published between 2013 and 2019, were retrieved. All studies were conducted in a secondary or tertiary care setting, with follow-up ranging from 1 to 20 years. All three markers showed consistently good prognostication of liver-related events (AUC from 0.69 to 0.92). For mortality, FIB-4 (AUC of 0.67-0.82) and NFS (AUC of 0.70-0.83) outperformed APRI (AUC of 0.52-0.73) in all studies. All markers had inconsistent performance for predicting change in fibrosis stage. CONCLUSIONS FIB-4, NFS, and APRI have demonstrated ability to risk stratify patients for liver-related morbidity and mortality, with comparable performance to a liver biopsy, although more head-to-head studies are needed to validate this. More refined models to prognosticate NAFLD-events may further enhance performance and clinical utility of non-invasive markers.
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Affiliation(s)
- Jenny Lee
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Yasaman Vali
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Jerome Boursier
- Hepato‐Gastroenterology DepartmentAngers University HospitalAngersFrance,HIFIH LaboratoryUPRES EA3859Angers UniversityAngersFrance
| | - Rene Spijker
- Medical LibraryAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands,Cochrane NetherlandsJulius Center for Health Sciences and Primary CareUniversity Medical Center UtrechtUtrecht UniversityUtrechtThe Netherlands
| | - Quentin M. Anstee
- The Newcastle Liver Research GroupFaculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK,Newcastle NIHR Biomedical Research CentreNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Patrick M. Bossuyt
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Mohammad H. Zafarmand
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
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24
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Bauvin P, Delacôte C, Lassailly G, Ntandja Wandji LC, Gnemmi V, Dautrecque F, Louvet A, Caiazzo R, Raverdy V, Leteurtre E, Pattou F, Deuffic-Burban S, Mathurin P. A tool to predict progression of non-alcoholic fatty liver disease in severely obese patients. Liver Int 2021; 41:91-100. [PMID: 32881244 DOI: 10.1111/liv.14650] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 08/13/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Severely obese patients are a growing population at risk of non-alcoholic fatty liver disease (NAFLD). Considering the increasing burden, a predictive tool of NAFLD progression would be of interest. Our objective was to provide a tool allowing general practitioners to identify and refer the patients most at risk, and specialists to estimate disease progression and adapt the therapeutic strategy. METHODS This predictive tool is based on a Markov model simulating steatosis, fibrosis and non-alcoholic steatohepatitis (NASH) evolution. This model was developped from data of 1801 severely obese, bariatric surgery candidates, with histological assessment, integrating duration of exposure to risk factors. It is then able to predict current disease severity in the absence of assessment, and future cirrhosis risk based on current stage. RESULTS The model quantifies the impact of sex, body-mass index at 20, diabetes, age of overweight onset, on progression. For example, for 40-year-old severely obese patients seen by the general practitioners: (a) non-diabetic woman overweight at 20, and (b) diabetic man overweight at 10, without disease assessment, the model predicts their current risk to have NASH or F3-F4: for (a) 5.7% and 0.6%, for (b) 16.1% and 10.0% respectively. If those patients have been diagnosed F2 by the specialist, the model predicts the 5-year cirrhosis risk: 1.8% in the absence of NASH and 6.0% in its presence for (a), 10.3% and 26.7% respectively, for (b). CONCLUSIONS This model provides a decision-making tool to predict the risk of liver disease that could help manage severely obese patients.
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Affiliation(s)
- Pierre Bauvin
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Claire Delacôte
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Guillaume Lassailly
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France.,Hôpital Claude Huriez, Services Maladies de l'Appareil Digestif, CHRU Lille, Lille, France
| | | | - Viviane Gnemmi
- Department of Pathology, Centre de Biologie Pathologie, Univ. Lille, CHU Lille, Inserm UMR-S 1172, Lille, France
| | - Flavien Dautrecque
- Hôpital Claude Huriez, Services Maladies de l'Appareil Digestif, CHRU Lille, Lille, France
| | - Alexandre Louvet
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France.,Hôpital Claude Huriez, Services Maladies de l'Appareil Digestif, CHRU Lille, Lille, France
| | - Robert Caiazzo
- Univ. Lille, Inserm, CHU Lille, U1190 - EGID, Lille, France
| | | | - Emmanuelle Leteurtre
- Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, Lille, France
| | | | - Sylvie Deuffic-Burban
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France.,Université de Paris, IAME, INSERM, Paris, France
| | - Philippe Mathurin
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France.,Hôpital Claude Huriez, Services Maladies de l'Appareil Digestif, CHRU Lille, Lille, France
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25
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Lee EH, Kim JY, Yang HR. Relationship Between Histological Features of Non-alcoholic Fatty Liver Disease and Ectopic Fat on Magnetic Resonance Imaging in Children and Adolescents. Front Pediatr 2021; 9:685795. [PMID: 34178902 PMCID: PMC8222518 DOI: 10.3389/fped.2021.685795] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/14/2021] [Indexed: 12/25/2022] Open
Abstract
Objectives: To investigate the association between ectopic fat content in the liver and pancreas, obesity-related metabolic components, and histological findings of non-alcoholic fatty liver disease (NAFLD) in children. Methods: This cross-sectional study investigated 63 children with biopsy-proven NAFLD who underwent magnetic resonance imaging (MRI), anthropometry, laboratory tests, and body composition analysis. Clinical and metabolic parameters, MRI-measured hepatic fat fraction (HFF) and pancreatic fat fraction (PFF), and histological findings were analyzed. Results: In a total of 63 children (48 boys, median age 12.6 years, median body mass index z-score 2.54), HFF was associated with histological steatosis [10.4, 23.7, and 31.1% in each steatosis grade, P < 0.001; Spearman's rho coefficient (rs) = 0.676; P < 0.001] and NAFLD activity score (rs = 0.470, P < 0.001), but not with lobular inflammation, hepatocyte ballooning, and hepatic fibrosis. PFF was not associated with any histological features of the liver. Waist circumference-to-height ratio and body fat percentage were associated with the steatosis grade (P = 0.006 and P = 0.004, respectively). Alanine aminotransferase was not associated with steatosis but was associated with lobular inflammation (P = 0.008). Lobular inflammation was also associated with high total cholesterol and low-density lipoprotein cholesterol and metabolic syndrome (P = 0.015, P = 0.036, and P = 0.038, respectively). Conclusions: Hepatic steatosis on MRI was only associated with the histological steatosis grade, while elevated serum levels of liver enzymes and lipids were related to the severity of lobular inflammation. Therefore, MRI should be interpreted in conjunction with the anthropometric and laboratory findings in pediatric patients.
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Affiliation(s)
- Eun Hye Lee
- Department of Pediatrics, Nowon Eulji Medical Center, Eulji University, Daejeon, South Korea
| | - Ji Young Kim
- Department of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, South Korea.,College of Medicine, Seoul National University, Seoul, South Korea
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26
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Lin CH, Kohli R. Emerging New Diagnostic Modalities and Therapies of Nonalcoholic Fatty Liver Disease. Curr Gastroenterol Rep 2020; 22:52. [PMID: 32814993 DOI: 10.1007/s11894-020-00786-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in both adults and children. In this article, we review recent developments in the screening, diagnosis, and treatment of pediatric NAFLD. RECENT FINDINGS Although alanine aminotransferase (ALT) remains the best screening test for NAFLD in children, and liver biopsy is still required for the diagnosis of nonalcoholic steatohepatitis (NASH), other noninvasive biomarker/imaging studies (MRI-PDFF and VCTE) have emerged as diagnostic methods for pediatric NAFLD. Two large clinical therapeutic trials testing vitamin E, metformin, and cysteamine in pediatric NAFLD yielded mostly inconclusive results. Bariatric surgery has begun to be used in adolescents with severe obesity. An adult phase 2 study using obeticholic acid (OCA) to treat NASH patients with fibrosis showed some positive results. As we continue to await the first FDA-approved therapeutic agent for NASH, lifestyle change remains the main modality of treatment. Newer diagnostic and treatment modalities for pediatric NAFLD continue to be in development under FDA guidance.
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Affiliation(s)
- Chuan-Hao Lin
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Los Angeles, and the Department of Pediatrics, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, Mail Stop 78, Los Angeles, CA, 90027, USA.
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Los Angeles, and the Department of Pediatrics, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, Mail Stop 78, Los Angeles, CA, 90027, USA
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27
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in childhood. There is an increase in disease prevalence and diagnoses as it is difficult to diagnose the problem. There are currently no effective medications. Management of NAFLD is a challenge for primary care clinicians and subspecialists. This paper provides guidelines for disease screening, diagnosis, management, and algorithm for subspecialty referral.
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Affiliation(s)
- Krista McNeice
- Department of Pediatric Gastroenterology, Dayton Children's Hospital, Dayton, OH 45404, United States.
| | - Kelly Sandberg
- Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
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28
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Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Animal Models of Fibrosis in Nonalcoholic Steatohepatitis: Do They Reflect Human Disease? Adv Nutr 2020; 11:1696-1711. [PMID: 33191435 PMCID: PMC7666900 DOI: 10.1093/advances/nmaa081] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/06/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases in the world, yet no pharmacotherapies are available. The lack of translational animal models is a major barrier impeding elucidation of disease mechanisms and drug development. Multiple preclinical models of NASH have been proposed and can broadly be characterized as diet-induced, deficiency-induced, toxin-induced, genetically induced, or a combination of these. However, very few models develop advanced fibrosis while still reflecting human disease etiology or pathology, which is problematic since fibrosis stage is considered the best prognostic marker in patients and an important endpoint in clinical trials of NASH. While mice and rats predominate the NASH research, several other species have emerged as promising models. This review critically evaluates animal models of NASH, focusing on their ability to develop advanced fibrosis while maintaining their relevance to the human condition.
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Affiliation(s)
- David H Ipsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
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29
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Geier A, Boursier J. Non-invasive diagnosis of patients with 'at-risk' NAFLD : only fibrosis counts? Gut 2020; 69:1164-1165. [PMID: 32220903 DOI: 10.1136/gutjnl-2020-320785] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/19/2020] [Accepted: 03/19/2020] [Indexed: 12/23/2022]
Affiliation(s)
- Andreas Geier
- Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Jerome Boursier
- Hepato-Gastroenterology, University Hospital, Angers, France
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30
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Performance of noninvasive scores for the diagnosis of advanced liver fibrosis in morbidly obese with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2020; 32:420-425. [PMID: 31464779 DOI: 10.1097/meg.0000000000001519] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Liver fibrosis is one of the most important predictors of mortality related to nonalcoholic fatty liver disease (NAFLD). The use of noninvasive markers has the advantage of a simple and low-cost evaluation. The aim of this study was to evaluate the performance of six noninvasive scores for the diagnosis of advanced liver fibrosis in morbidly obese patients. MATERIAL AND METHODS A retrospective study validation included 323 morbidly obese patients undergoing bariatric surgery. Advance fibrosis was defined as stage 3 and 4 (septal fibrosis or cirrhosis). Accuracy, sensitivity, specificity, positive (PPV) or negative (NPV) predictive value, and positive (PLR) or negative (NLR) likelihood ratio test of the following noninvasive liver fibrosis scores were evaluated: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR); AST to platelet ratio index (APRI); BARD; FIB4, NAFLD fibrosis score (NFS) and BAAT, which were compared with the histological findings of the intraoperative liver biopsy. The cutoff points established in the validation studies were used: AAR > 1; APRL > 0.98; BARD ≥ 2; FIB4 > 2.67; NFS > 0.676 and BAAT > 1. RESULTS Twenty-nine patients (8.97%) presented advanced fibrosis. APRI presented the higher specificity (99.61%), PPV (85.71%), PLR (62.5) and accuracy (0.93). FIB4 was the second test in accuracy (0.9) and in PLR (10.53). BAAT presented the highest sensitivity (73.08%) and NPV (94.78%); NFS the lowest sensitivity (12,5%), and BARD the lowest accuracy (0.44). CONCLUSION APRI and FIB-4 were the tests with best performance to predict advanced fibrosis.
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31
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Lin J, Zheng J, Lin X, Chen Y, Li Z. A Low Creatinine to Body Weight Ratio Predicts the Incident Nonalcoholic Fatty Liver Disease in Nonelderly Chinese without Obesity and Dyslipidemia: A Retrospective Study. Gastroenterol Res Pract 2020; 2020:4043871. [PMID: 32454814 PMCID: PMC7243030 DOI: 10.1155/2020/4043871] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
AIM A lower ratio of creatinine to body weight (Cr/BW) is considered the independent risk factor for incident nonalcoholic fatty liver disease (NAFLD). However, the relationship between the Cr/BW ratio and NAFLD among individuals without obesity and dyslipidemia and how this relationship is impacted by age are still ambiguous. Therefore, we explored the effect of the Cr/BW ratio on the incident NAFLD among Chinese without obesity and dyslipidemia of different age groups. METHODS A total of 9756 participants without NAFLD at baseline were included and grouped by the median value (1.32) of the Cr/BW ratio. Then, a further analysis was stratified by age (60 years old). The primary outcome was new-onset NAFLD. RESULTS After a median follow-up of 2.76 years, 844 (8.7%) participants developed NAFLD. The elderly had a higher person-years incidence rate and cumulative incidence rate than the nonelderly. A high Cr/BW ratio showed a lower cumulative incidence compared to a low Cr/BW ratio for the whole population (P = 0.039) and the nonelderly group (P = 0.008). After being adjusted for multivariate variables, the lower Cr/BW ratio was the independent risk factor for incident NAFLD in the nonelderly (HR 0.718, 95% CI 0.548-0.942), instead of the elderly. CONCLUSIONS The Cr/BW ratio has a negative relationship with incident NAFLD among nonobese Chinese without dyslipidemia before the age of 60.
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Affiliation(s)
- Jianxiong Lin
- Department of Hematology and Oncology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Jiehua Zheng
- Department of General Surgery, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Xiaoqing Lin
- Department of Ultrasound, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yexi Chen
- Department of General Surgery, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Zhiyang Li
- Department of General Surgery, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
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Lv Y, Patel N, Zhang HJ. The progress of non-alcoholic fatty liver disease as the risk of liver metastasis in colorectal cancer. Expert Rev Gastroenterol Hepatol 2019; 13:1169-1180. [PMID: 31774328 DOI: 10.1080/17474124.2019.1697231] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: The liver is the most common metastatic site of colorectal cancer (CRC), and the long-term survival rate of CRC patients who cannot resect liver metastatic lesions radically is extremely low. Early identification of risk factors for liver metastasis from CRC may be an effective strategy to reduce the incidence of liver metastasis. The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing in parallel with an increasing prevalence of obesity and metabolic syndrome (MS), which has become one of the main causes of chronic liver disease worldwide.Areas covered: An overview of the related research progress of the association between NAFLD and colorectal liver metastasis (CRLM).Expert opinion: Certain research proves that there is a close relationship between NAFLD and CRC, and the presence of NAFLD can promote the formation and development of CRC. Although the effect of liver diseases on the incidence of liver metastasis in CRC has been noted in recent years, the results are inconsistent and haven't reached a unified conclusion. Therefore, the association between liver metastasis and NAFLD remains the main focal point in the evolution of CRC.
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Affiliation(s)
- Yan Lv
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu, P.R. China
| | - Nishant Patel
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu, P.R. China
| | - Hai-Jun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu, P.R. China.,Precision Medicine Center, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu, P.R. China
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VOS MIRIAMB, Dimick-Santos L, Mehta R, Omokaro SO, Taminiau J, Schabel E, Kleiner DE, Szitanyi P, Socha P, Schwimmer JB, Noviello S, Silberg DG, Torstenson R, Miller V, Lavine JE, Baldyga W, Banerjee R, Behling C, Boulos S, Burgess G, Calboli D, Charles E, Christian R, Cohen-Bacrie C, Cosma-Roman D, Danzer CP, Delaet I, Delegge M, Dimick-Santos L, DiProspero N, Donohue K, Fischer L, Fitzpatrick E, Fried M, Hagerty D, Hale P, Hildick K, Hum D, Jamil K, Jiang L, Karpen S, Kelly M, Kleiner DE, Kohli R, Kordy K, Krieger N, Lavine J, Lee L, Lefebvre E, Lopez P, Lyons E, Malahias L, Megnien S, Mehta R, Mesenbrink P, Miller V, Minnick P, Murray C, Nghiem T, Nicholson N, Noviello S, Omokaro SO, Pang W, Percival L, Peres D, Powell M, Roman D, Root M, Sampson C, Sanyal A, Schabel E, Schwarz K, Schwimmer JB, Seyedkazemi S, Shapiro D, Shringarpure R, Silberg D, Smith E, Socha P, Squires R, Szitanyi P, Taminiau J, Torstenson R, Treem W, Vig P, Vos M, Yamashita M, Zemel M. Factors to Consider in Development of Drugs for Pediatric Nonalcoholic Fatty Liver Disease. Gastroenterology 2019; 157:1448-1456.e1. [PMID: 31520612 PMCID: PMC8996263 DOI: 10.1053/j.gastro.2019.08.048] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 08/13/2019] [Accepted: 08/17/2019] [Indexed: 02/07/2023]
Affiliation(s)
- MIRIAM B. VOS
- Emory University School of Medicine, Atlanta, Georgia
| | | | - Ruby Mehta
- US Food and Drug Administration, Bethesda, Maryland
| | | | | | - Elmer Schabel
- Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany
| | - David E Kleiner
- National Cancer Institute, Center for Cancer Research, Bethesda, Maryland
| | - Peter Szitanyi
- General University Hospital, Charles University, Prague, Czech Republic
| | - Piotr Socha
- Children's Memorial Health Institute, Warsaw, Poland
| | - Jeffrey B Schwimmer
- University of California, San Diego School of Medicine, La Jolla, California
| | | | | | | | | | - Joel E Lavine
- Columbia University Medical Center, New York, New York.
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Lackner C, Tiniakos D. Fibrosis and alcohol-related liver disease. J Hepatol 2019; 70:294-304. [PMID: 30658730 DOI: 10.1016/j.jhep.2018.12.003] [Citation(s) in RCA: 182] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/06/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023]
Abstract
Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.
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Affiliation(s)
- Carolin Lackner
- Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria.
| | - Dina Tiniakos
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Dept of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Vas. Sofias Avenue 76, Athens 11528, Greece
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Tanaka N, Kimura T, Fujimori N, Nagaya T, Komatsu M, Tanaka E. Current status, problems, and perspectives of non-alcoholic fatty liver disease research. World J Gastroenterol 2019; 25:163-177. [PMID: 30670907 PMCID: PMC6337019 DOI: 10.3748/wjg.v25.i2.163] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/24/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease that can lead to liver cirrhosis, liver cancer, and ultimately death. NAFLD is pathologically classified as non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) based on the existence of ballooned hepatocytes, although the states have been known to transform into each other. Moreover, since the detection of ballooned hepatocytes may be difficult with limited biopsied specimens, its clinical significance needs reconsideration. Repeated liver biopsy to assess histological NAFLD activity for therapeutic response is also impractical, creating the need for body fluid biomarkers and less invasive imaging modalities. Recent longitudinal observational studies have emphasized the importance of advanced fibrosis as a determinant of NAFLD outcome. Thus, identifying predictors of fibrosis progression and developing better screening methods will enable clinicians to isolate high-risk NAFLD patients requiring early intensive intervention. Despite the considerable heterogeneity of NAFLD with regard to underlying disease, patient age, and fibrosis stage, several clinical trials are underway to develop a first-in-class drug. In this review, we summarize the present status and future direction of NAFLD/NASH research towards solving unmet medical needs.
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Affiliation(s)
- Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- International Research Center for Agricultural Food Industry, Shinshu University, Matsumoto 390-8621, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoyuki Fujimori
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tadanobu Nagaya
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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Abstract
Pediatric nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in children. The spectrum of NAFLD ranges from steatosis to nonalcoholic steatohepatitis (NASH) to fibrosis. Obesity rates in children continue to rise and, as a result, NAFLD in children is becoming more prevalent. The pathophysiology, natural history, and progression of disease are still being elucidated but NAFLD/NASH in children may represent a more severe phenotype that will benefit from early identification and management.
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Affiliation(s)
- Sara Kathryn Smith
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California, San Francisco, 550 16th Street, 5th Floor, Mail Code 0136, San Francisco, CA 94143, USA.
| | - Emily R Perito
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California, San Francisco, 550 16th Street, 5th Floor, Mail Code 0136, San Francisco, CA 94143, USA
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Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 2018; 75:3313-3327. [PMID: 29936596 PMCID: PMC6105174 DOI: 10.1007/s00018-018-2860-6] [Citation(s) in RCA: 907] [Impact Index Per Article: 129.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/18/2018] [Accepted: 06/20/2018] [Indexed: 12/17/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the world's most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.
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Affiliation(s)
- David Højland Ipsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark.
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38
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Nascimbeni F, Ballestri S, Machado MV, Mantovani A, Cortez-Pinto H, Targher G, Lonardo A. Clinical relevance of liver histopathology and different histological classifications of NASH in adults. Expert Rev Gastroenterol Hepatol 2018; 12:351-367. [PMID: 29224471 DOI: 10.1080/17474124.2018.1415756] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses simple steatosis and steatohepatitis (NASH) with or without fibrosis/cirrhosis and hepatocellular carcinoma. NAFLD occurs epidemically in most areas of the world, contributes to cardiovascular events and liver-related mortality and therefore exacts a major economic toll. Areas covered: Here we summarize what clinicians should know about NAFLD histopathology in adults. We report on the individual histological features and scoring systems of NAFLD: the NAFLD activity score (NAS) introduced by the NASH-Clinical Research Network, the 'Fatty Liver Inhibition of Progression' algorithm and Steatosis, Activity, and Fibrosis (SAF) score. Pros and cons of histological classifications in NASH are discussed. Special emphasis is given to liver histopathology in some high-risk patient groups, such as those with severe obesity and type 2 diabetes. Moreover, we also examine the relationship between liver histopathology and clinical features, and the impact of liver histopathology on the long-term prognosis of NAFLD. Finally, we propose an integrated diagnostic approach which utilizes both non-invasive tools and liver biopsy in those individual patients with suspected NAFLD. Expert commentary: Based on expert opinions, we conclude with a research agenda on NAFLD which focuses on the most burning topics to be addressed over the next five years.
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Affiliation(s)
- Fabio Nascimbeni
- a Ospedale Civile di Baggiovara , Azienda Ospedaliero-Universitaria , Modena , Italy.,b Department of Biomedical, Metabolic and Neural Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | | | - Mariana Verdelho Machado
- d Departamento de Gastrenterologia e Hepatologia , Centro Hospitalar Lisboa Norte, Laboratório de Nutrição, Faculdade de Medicina de Lisboa , Lisboa , Portugal
| | - Alessandro Mantovani
- e Division of Endocrinology, Diabetes and Metabolism, Department of Medicine , University and Azienda Ospedaliera Universitaria Integrata of Verona , Verona , Italy
| | - Helena Cortez-Pinto
- d Departamento de Gastrenterologia e Hepatologia , Centro Hospitalar Lisboa Norte, Laboratório de Nutrição, Faculdade de Medicina de Lisboa , Lisboa , Portugal
| | - Giovanni Targher
- e Division of Endocrinology, Diabetes and Metabolism, Department of Medicine , University and Azienda Ospedaliera Universitaria Integrata of Verona , Verona , Italy
| | - Amedeo Lonardo
- a Ospedale Civile di Baggiovara , Azienda Ospedaliero-Universitaria , Modena , Italy
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Loomba R, Gindin Y, Jiang Z, Lawitz E, Caldwell S, Djedjos CS, Xu R, Chung C, Myers RP, Subramanian GM, Goodman Z, Charlton M, Afdhal NH, Diehl AM. DNA methylation signatures reflect aging in patients with nonalcoholic steatohepatitis. JCI Insight 2018; 3:96685. [PMID: 29367468 DOI: 10.1172/jci.insight.96685] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 11/21/2017] [Indexed: 01/04/2023] Open
Abstract
A DNA methylation (DNAm) signature (the "Horvath clock") has been proposed as a measure of human chronological and biological age. We determined peripheral blood DNAm in patients with nonalcoholic steatohepatitis (NASH) and assessed whether accelerated aging occurs in these patients. DNAm signatures were obtained in patients with biopsy-proven NASH and stage 2-3 fibrosis. The DNAm profile from one test and two validation cohorts served as controls. Age acceleration was calculated as the difference between DNAm age and the predicted age based on the linear model derived from controls. Hepatic collagen content was assessed by quantitative morphometry. The Horvath clock accurately predicts the chronological age of the entire cohort. Age acceleration was observed among NASH subjects compared with control data sets and our test controls. Age acceleration in NASH subjects did not differ by fibrosis stage but correlated with hepatic collagen content. A set of 152 differentially methylated CpG islands between NASH subjects and controls identified gene set enrichment for transcription factors and developmental pathways. Patients with NASH exhibit epigenetic age acceleration that correlates with hepatic collagen content.
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Affiliation(s)
- Rohit Loomba
- University of California, San Diego, La Jolla, California, USA
| | | | | | - Eric Lawitz
- Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA
| | | | | | - Ren Xu
- Gilead Sciences Inc., Foster City, California, USA
| | - Chuhan Chung
- Gilead Sciences Inc., Foster City, California, USA
| | | | | | | | | | - Nezam H Afdhal
- Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Anna Mae Diehl
- Duke Clinical Research Institute, Durham, North Carolina, USA
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41
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Wong VWS, Chan WK, Chitturi S, Chawla Y, Dan YY, Duseja A, Fan J, Goh KL, Hamaguchi M, Hashimoto E, Kim SU, Lesmana LA, Lin YC, Liu CJ, Ni YH, Sollano J, Wong SKH, Wong GLH, Chan HLY, Farrell G. Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 1: Definition, risk factors and assessment. J Gastroenterol Hepatol 2018; 33:70-85. [PMID: 28670712 DOI: 10.1111/jgh.13857] [Citation(s) in RCA: 344] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/30/2017] [Accepted: 06/25/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.,State Key Laboratory of Digestive Disease and Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Wah-Kheong Chan
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Shiv Chitturi
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Yogesh Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jiangao Fan
- Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Khean-Lee Goh
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Etsuko Hashimoto
- Departments of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Seung Up Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | | | - Yu-Cheng Lin
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Hepatitis Research Center and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | - Jose Sollano
- University of Santo Tomas, Manila, The Philippines
| | - Simon Kin-Hung Wong
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.,State Key Laboratory of Digestive Disease and Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.,State Key Laboratory of Digestive Disease and Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Geoff Farrell
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
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Management of Pediatric Nonalcoholic Fatty Liver Disease by Academic Hepatologists in Canada: A Nationwide Survey. J Pediatr Gastroenterol Nutr 2017; 65:380-383. [PMID: 28333768 DOI: 10.1097/mpg.0000000000001581] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The literature on the optimal clinical management of pediatric patients with nonalcoholic fatty liver disease (NAFLD) is limited. The objective of this study was to identify discrepancies in the care provided to patients with NAFLD by hepatologists practicing in academic centers across Canada. METHODS A nationwide survey was distributed electronically to all pediatric hepatologists practicing in university-affiliated hospitals using the infrastructure of the Canadian Pediatric Hepatology Research Group. The responses were anonymous. RESULTS The response rate to the survey was 79%. Everyone reported diagnosing NAFLD based on a combination of elevated transaminases and imaging suggestive of steatosis in the context of an otherwise negative workup for other liver diseases. Only 14% use liver biopsy to confirm the diagnosis. There are significant discrepancies in the frequency of screening for other comorbidities (eg, hypertension, sleep apnea, etc) and in the frequency of laboratory investigations (eg, lipid profile, transaminases, international normalized ratio, etc). Frequency of outpatient clinic follow-up varies significantly. Treatment is consistently based on lifestyle modifications; however, reported patient outcomes in terms of body mass index improvements are poor. CONCLUSIONS There are significant discrepancies in the care provided to children with NAFLD by hepatologists practicing in academic centers across Canada.
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Caussy C, Soni M, Cui J, Bettencourt R, Schork N, Chen CH, Ikhwan MA, Bassirian S, Cepin S, Gonzalez MP, Mendler M, Kono Y, Vodkin I, Mekeel K, Haldorson J, Hemming A, Andrews B, Salotti J, Richards L, Brenner DA, Sirlin CB, Loomba R. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J Clin Invest 2017. [PMID: 28628033 DOI: 10.1172/jci93465] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis. METHODS This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). RESULTS The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8-126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1-146.1, P = 0.0438). CONCLUSION Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. TRIAL REGISTRATION UCSD IRB 140084. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA.,Université Lyon 1, Hospices Civils de Lyon, Lyon, France
| | - Meera Soni
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA
| | - Jeffrey Cui
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA
| | - Ricki Bettencourt
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA.,Division of Epidemiology, Department of Family and Preventive Medicine, UCSD, La Jolla, California, USA
| | - Nicholas Schork
- Human Biology, J. Craig Venter Institute, La Jolla, California, USA
| | | | - Mahdi Al Ikhwan
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA
| | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA
| | - Sandra Cepin
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA
| | - Monica P Gonzalez
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA
| | | | - Yuko Kono
- Division of Gastroenterology, Department of Medicine
| | - Irine Vodkin
- Division of Gastroenterology, Department of Medicine
| | | | | | | | | | - Joanie Salotti
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA.,Division of Gastroenterology, Department of Medicine
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA.,Division of Gastroenterology, Department of Medicine
| | | | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, UCSD, La Jolla, California, USA
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, UCSD, La Jolla, California, USA.,Division of Epidemiology, Department of Family and Preventive Medicine, UCSD, La Jolla, California, USA.,Division of Gastroenterology, Department of Medicine
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Younossi ZM, Stepanova M, Rafiq N, Henry L, Loomba R, Makhlouf H, Goodman Z. Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease. Hepatol Commun 2017; 1:421-428. [PMID: 29404470 PMCID: PMC5721410 DOI: 10.1002/hep4.1054] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 04/16/2017] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD). The minimal pathologic criteria for NASH include hepatic steatosis, ballooning degeneration, and lobular inflammation. The resolution of NASH, which relies on the loss of ballooning degeneration, is subject to sampling and observer variability in pathologic interpretation. Ballooning is associated with advanced hepatic fibrosis in cross‐sectional studies but is not a predictor of mortality in NAFLD. Fibrosis staging, while still subject to some sampling variability, has less observer variability and is a robust predictor of liver‐related mortality in NAFLD. In this study, we hypothesize that, regardless of the diagnosis of NASH, the presence of steatofibrosis (steatosis accompanied by fibrosis) regardless of other pathologic features can also be a robust predictor of mortality in NAFLD. We used our previously reported cohort of patients with NAFLD with liver biopsies and long‐term mortality follow‐up. Cox proportional hazard models were used to determine the predictors of overall and liver‐related mortality. Of 209 enrolled NAFLD subjects, 97 can be classified as having steatofibrosis. During follow‐up (median 150 months), 64 (30.6%) patients died, with 18 (8.6%) from liver‐related causes. Adjusted for age, both diagnostic categories of NASH and steatofibrosis were significantly and similarly associated with liver‐related mortality (adjusted hazard ratio [aHR], 9.9; 95% confidence interval (CI), 1.3‐74.9; P = 0.027; aHR, 6.7; 95% CI, 1.5‐29.8; P = 0.013, respectively). However, only steatofibrosis showed independent association with overall mortality (aHR, 1.76; 95% CI, 1.02‐3.05; P = 0.043). Conclusion: Steatofibrosis and NASH are similarly associated with liver‐related mortality, but only steatofibrosis is associated with overall mortality in patients with NAFLD. Given the inherent observer variability in ballooning degeneration, a key diagnostic component of NASH, we suggest that steatofibrosis should be considered a viable diagnostic classification for NAFLD subjects at risk or adverse outcomes and provides a simpler endpoint for clinical trials of therapeutic agents. (Hepatology Communications 2017;1:421–428)
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Affiliation(s)
- Zobair M Younossi
- Center for Liver Diseases, Department of Medicine Inova Fairfax Hospital Falls Church VA.,Betty and Guy Beatty Center for Integrated Research Inova Health System Falls Church VA
| | - Maria Stepanova
- Center for Outcomes Research in Liver Diseases Washington DC.,Betty and Guy Beatty Center for Integrated Research Inova Health System Falls Church VA
| | - Nila Rafiq
- Center for Liver Diseases, Department of Medicine Inova Fairfax Hospital Falls Church VA.,Betty and Guy Beatty Center for Integrated Research Inova Health System Falls Church VA
| | - Linda Henry
- Center for Outcomes Research in Liver Diseases Washington DC.,Betty and Guy Beatty Center for Integrated Research Inova Health System Falls Church VA
| | - Rohit Loomba
- NAFLD Research Center University of California San Diego San Diego CA
| | - Hala Makhlouf
- Cancer Diagnosis Program, National Cancer Institute National Institutes of Health Bethesda MD
| | - Zachary Goodman
- Center for Liver Diseases, Department of Medicine Inova Fairfax Hospital Falls Church VA.,Betty and Guy Beatty Center for Integrated Research Inova Health System Falls Church VA
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Tanaka N, Aoyama T, Kimura S, Gonzalez FJ. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther 2017; 179:142-157. [PMID: 28546081 DOI: 10.1016/j.pharmthera.2017.05.011] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ligand-activated nuclear receptors, including peroxisome proliferator-activated receptor alpha (PPARα), pregnane X receptor, and constitutive androstane receptor, were first identified as key regulators of the responses against chemical toxicants. However, numerous studies using mouse disease models and human samples have revealed critical roles for these receptors and others, such as PPARβ/δ, PPARγ, farnesoid X receptor (FXR), and liver X receptor (LXR), in maintaining nutrient/energy homeostasis in part through modulation of the gut-liver-adipose axis. Recently, disorders associated with disrupted nutrient/energy homeostasis, e.g., obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), are increasing worldwide. Notably, in NAFLD, a progressive subtype exists, designated as non-alcoholic steatohepatitis (NASH) that is characterized by typical histological features resembling alcoholic steatohepatitis (ASH), and NASH/ASH are recognized as major causes of hepatitis virus-unrelated liver cirrhosis and hepatocellular carcinoma. Since hepatic steatosis is basically caused by an imbalance between fat/energy influx and utilization, abnormal signaling of these nuclear receptors contribute to the pathogenesis of fatty liver disease. Standard therapeutic interventions have not been fully established for fatty liver disease, but some new agents that activate or inhibit nuclear receptor signaling have shown promise as possible therapeutic targets. In this review, we summarize recent findings on the roles of nuclear receptors in fatty liver disease and discuss future perspectives to develop promising pharmacological strategies targeting nuclear receptors for NAFLD/NASH.
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Affiliation(s)
- Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
| | - Toshifumi Aoyama
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
| | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr 2017; 64:319-334. [PMID: 28107283 PMCID: PMC5413933 DOI: 10.1097/mpg.0000000000001482] [Citation(s) in RCA: 686] [Impact Index Per Article: 85.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs in the setting of insulin resistance and increased adiposity. It has rapidly evolved into the most common liver disease seen in the pediatric population and is a management challenge for general pediatric practitioners, subspecialists, and for health systems. In this guideline, the expert committee on NAFLD reviewed and summarized the available literature, formulating recommendations to guide screening and clinical care of children with NAFLD.
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Hannah WN, Harrison SA. Noninvasive imaging methods to determine severity of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2016; 64:2234-2243. [PMID: 27338123 DOI: 10.1002/hep.28699] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 06/16/2016] [Indexed: 12/21/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the most common form of liver disease in developed countries, with an estimated prevalence of 20%-30% and increasing to as high as 90% in diabetics. As the rates of NAFLD continue to rise in parallel with those of the obesity pandemic, it is increasingly important to differentiate those patients with the highest risk of progression to fibrosis and cirrhosis. In fact, those patients with nonalcoholic steatohepatitis (NASH) and fibrosis are at the greatest risk of progression to advanced disease, cirrhosis, and hepatocellular cancer and are more likely to develop liver-related mortality. Thus, it is critically important to distinguish between NASH and non-NASH NAFLD. Whereas liver biopsy remains the gold standard for staging of disease, complications of this procedure and other well-recognized limitations make it impractical for widespread use given the overall NAFLD disease burden. Noninvasive imaging modalities are increasingly being utilized to evaluate and stage NAFLD in patients with such a wide spectrum of disease. In this article, the role of these new and promising noninvasive imaging modalities to assess disease severity in NAFLD are reviewed. (Hepatology 2016;64:2234-2243).
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Affiliation(s)
- William N Hannah
- Department of Medicine, San Antonio Military Medical Center, JBSA-Fort Sam Houston, TX
| | - Stephen A Harrison
- Department of Medicine, San Antonio Military Medical Center, JBSA-Fort Sam Houston, TX
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Cui J, Chen CH, Lo MT, Schork N, Bettencourt R, Gonzalez MP, Bhatt A, Hooker J, Shaffer K, Nelson KE, Long MT, Brenner DA, Sirlin CB, Loomba R, for the Genetics of NAFLD in Twins. Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study. Hepatology 2016; 64:1547-1558. [PMID: 27315352 PMCID: PMC5090982 DOI: 10.1002/hep.28674] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 05/08/2016] [Accepted: 05/29/2016] [Indexed: 12/14/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging-proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m2 , respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging-proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716-1, P < 0.0001). CONCLUSIONS Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547-1558).
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Affiliation(s)
- Jeffrey Cui
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Chi-Hua Chen
- Department of Radiology, University of California at San Diego, La Jolla, CA, USA
| | - Min-Tzu Lo
- Department of Radiology, University of California at San Diego, La Jolla, CA, USA
| | | | - Ricki Bettencourt
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA
| | - Monica P Gonzalez
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Archana Bhatt
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA
| | - Katherine Shaffer
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA,Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA
| | | | - Michelle T Long
- Division of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, MA
| | - David A Brenner
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA. .,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA. .,Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA.
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Serum YKL-40 as a marker of liver fibrosis in patients with non-alcoholic fatty liver disease. Sci Rep 2016; 6:35282. [PMID: 27739482 PMCID: PMC5064386 DOI: 10.1038/srep35282] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/19/2016] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. YKL-40, chitinase-like protein expressed in multiple tissues including liver, is involved in cell proliferation, inflammation and remodeling of the extracellular matrix. The aim of this study was to assess whether serum YKL-40 levels are associated with liver fibrosis in NAFLD patients. Serum YKL-40 levels were quantified in 111 NAFLD patients and 23 HCC patients with NAFLD. To identify the source of YKL-40, immunofluorescence staining of liver specimens from NAFLD patients was performed. Serum YKL-40 levels in NAFLD patients increased in accordance with the progression of liver fibrosis. Multivariate analysis revealed that YKL-40 was one of the independent factors significantly associated with severe fibrosis (F3-4). We established a new predictive model for fibrosis of NAFLD, using logistic regression analysis: YKL-40 based fibrosis score = −0.0545 + type IV collagen 7s * 0.3456 + YKL-40 * 0.0024. Serum YKL-40 levels of HCC patients with non-cirrhotic NAFLD were significantly higher than those without HCC. Immunofluorescence staining showed that YKL-40 was expressed by macrophages in liver tissue of NAFLD patients. In conclusion, macrophage-derived YKL-40 is a feasible biomarker of liver fibrosis in NAFLD patients.
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Nonalcoholic fatty liver disease: one entity, multiple impacts on liver health. Cell Biol Toxicol 2016; 33:5-14. [PMID: 27680752 DOI: 10.1007/s10565-016-9361-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 09/04/2016] [Indexed: 12/20/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is very prevalent and now considered the most common cause of chronic liver disease. Staging the severity of liver damage is very important because the prognosis of NAFLD is highly variable. The long-term prognosis of patients with NAFLD remains incompletely elucidated. Even though the annual fibrosis progression rate is significantly higher in patients with nonalcoholic hepatitis (NASH), both types of NAFLD (nonalcoholic fatty liver and nonalcoholic steatohepatitis) can lead to fibrosis. The risk for progressive liver damage and poor outcomes is assessed by staging the severity of liver injury and liver fibrosis. Algorithms (scores) that incorporate various standard clinical and laboratory parameters alongside imaging-based approaches that assess liver stiffness are helpful in predicting advanced fibrosis.
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