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Jiao J, Zhang X. Steatotic Liver Disease: Navigating Pathologic Features, Diagnostic Challenges, and Emerging Insights. Adv Anat Pathol 2025:00125480-990000000-00135. [PMID: 39895389 DOI: 10.1097/pap.0000000000000483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Steatotic liver disease (SLD) is now used as an overarching category encompassing five subcategories: metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol related/associated liver disease (MetALD), alcohol-related/associated liver disease (ALD), SLD with specific etiology, and cryptogenic SLD. This review summarizes foundational and recent advances in the histologic evaluation of SLD, including common pathologic features across all subcategories, distinctions associated with different etiologies, scoring and grading systems, and the evolution of digital pathology techniques for SLD assessment.
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Affiliation(s)
- Jingjing Jiao
- Department of Pathology, Yale University School of Medicine, New Haven, CT
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Li C, Wang Y, Bai R, Zhao Z, Li W, Zhang Q, Zhang C, Yang W, Liu Q, Su N, Lu Y, Yin X, Wang F, Gu C, Yang A, Luo B, Zhou M, Shen L, Pan C, Wang Z, Wu Q, Yin J, Hou Y, Shi Y. Development of fully automated models for staging liver fibrosis using non-contrast MRI and artificial intelligence: a retrospective multicenter study. EClinicalMedicine 2024; 77:102881. [PMID: 39498462 PMCID: PMC11532432 DOI: 10.1016/j.eclinm.2024.102881] [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: 06/22/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 11/07/2024] Open
Abstract
Background Accurate staging of liver fibrosis (LF) is essential for clinical management in chronic liver disease. While non-contrast MRI (NC-MRI) yields valuable information for liver assessment, its effectiveness in predicting LF remains underexplored. This study aimed to develop and validate artificial intelligence (AI)-powered models utilizing NC-MRI for staging LF. Methods A total of 1726 patients from Shengjing Hospital of China Medical University, registered between October 2003 and October 2022, were retrospectively collected, and divided into development (n = 1208) and internal test (n = 518) cohorts. An external test cohort consisting of 337 individuals from six centers, registered between June 2015 and November 2022, were also included. All participants underwent NC-MRI (T1-weighted imaging, T1WI; and T2-fat-suppressed imaging, T2FS) and liver biopsies. Two classification models (CMs), named T1 and T2FS, were trained on respective image types using 3D contextual transformer networks and evaluated on both test cohorts. Additionally, three CMs-Clinic, Image, and Fusion-were developed using clinical features, T1 and T2FS scores, and their integration via logistic regression. Classification effectiveness of CMs was assessed using the area under the receiver operating characteristic curve (AUC). A comparison was conducted between the optimal models (OMs) with highest AUC and other methods (transient elastography, five serum biomarkers, and six radiologists). Findings Fusion models (i.e., OM) yielded the highest AUC among the CMs, achieving AUCs of 0.810 for significant fibrosis, 0.881 for advanced fibrosis, and 0.918 for cirrhosis in the internal test cohort, and 0.808, 0.868, and 0.925, respectively, in the external test cohort. The OMs demonstrated superior performance in AUC, significantly surpassing transient elastography (only for staging ≥ F2 and ≥ F3 grades), serum biomarkers, and three junior radiologists for staging LF. Radiologists, with the aid of the OMs, can achieve a higher AUC in LF assessment. Interpretation AI-powered models utilizing NC-MRI, including T1WI and T2FS, accurately stage LF. Funding National Natural Science Foundation of China (No. 82071885); General Program of the Liaoning Provincial Department of Education (LJKMZ20221160); Liaoning Province Science and Technology Joint Plan (2023JH2/101700127); the Leading Young Talent Program of Xingliao Yingcai in Liaoning Province (XLYC2203037).
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Affiliation(s)
- Chunli Li
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuan Wang
- Department of Radiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Ruobing Bai
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhiyong Zhao
- Department of Medical Imaging, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Wenjuan Li
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
| | - Qianqian Zhang
- Department of Radiology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
| | - Chaoya Zhang
- Department of Radiology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Yang
- Department of Radiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Qi Liu
- Department of Radiology, The Second Affiliated Hospital of Baotou Medical College, Baotou, Neimenggu, China
| | - Na Su
- Department of Radiology, The Sixth People's Hospital of Shenyang, Shenyang, Liaoning, China
| | - Yueyue Lu
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaoli Yin
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fan Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chengli Gu
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Aoran Yang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Baihe Luo
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Minghui Zhou
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Liuhanxu Shen
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chen Pan
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhiying Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qijun Wu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jiandong Yin
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yang Hou
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Shi
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Bae J, Han E, Lee HW, Park CY, Chung CH, Lee DH, Cho EH, Rhee EJ, Yu JH, Park JH, Bae JC, Park JH, Choi KM, Kim KS, Seo MH, Lee M, Kim NH, Kim SH, Lee WY, Lee WJ, Choi YK, Lee YH, Hwang YC, Lyu YS, Lee BW, Cha BS, on Behalf of the Fatty Liver Research Group of the Korean Diabetes Association. Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 2 Diabetes Mellitus: A Review and Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association. Diabetes Metab J 2024; 48:1015-1028. [PMID: 39610131 PMCID: PMC11621661 DOI: 10.4093/dmj.2024.0541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 10/23/2024] [Indexed: 11/30/2024] Open
Abstract
Since the role of the liver in metabolic dysfunction, including type 2 diabetes mellitus, was demonstrated, studies on non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) have shown associations between fatty liver disease and other metabolic diseases. Unlike the exclusionary diagnostic criteria of NAFLD, MAFLD diagnosis is based on the presence of metabolic dysregulation in fatty liver disease. Renaming NAFLD as MAFLD also introduced simpler diagnostic criteria. In 2023, a new nomenclature, steatotic liver disease (SLD), was proposed. Similar to MAFLD, SLD diagnosis is based on the presence of hepatic steatosis with at least one cardiometabolic dysfunction. SLD is categorized into metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related/-associated liver disease, alcoholrelated liver disease, specific etiology SLD, and cryptogenic SLD. The term MASLD has been adopted by a number of leading national and international societies due to its concise diagnostic criteria, exclusion of other concomitant liver diseases, and lack of stigmatizing terms. This article reviews the diagnostic criteria, clinical relevance, and differences among NAFLD, MAFLD, and MASLD from a diabetologist's perspective and provides a rationale for adopting SLD/MASLD in the Fatty Liver Research Group of the Korean Diabetes Association.
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Affiliation(s)
- Jaehyun Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
| | - Eugene Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Hye Won Lee
- Department of Pathology, Keimyung University School of Medicine, Daegu, Korea
| | - Cheol-Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Choon Hee Chung
- Department of Internal Medicine and Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Dae Ho Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Eun-Hee Cho
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Eun-Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Hee Yu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ji Hyun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Korea
| | - Ji-Cheol Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Jung Hwan Park
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kyung-Soo Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Mi Hae Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Soonchunhyang University College of Medicine, Gumi, Korea
| | - Minyoung Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Nan-Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - So Hun Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Won-Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woo Je Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yeon-Kyung Choi
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yong-ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - You-Cheol Hwang
- Division of Endocrinology and Metabolism, Department of Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Young Sang Lyu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University Hospital, Chosun University College of Medicine, Gwangju, Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Bong-Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - on Behalf of the Fatty Liver Research Group of the Korean Diabetes Association
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Department of Pathology, Keimyung University School of Medicine, Daegu, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Internal Medicine and Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Soonchunhyang University College of Medicine, Gumi, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
- Division of Endocrinology and Metabolism, Department of Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University Hospital, Chosun University College of Medicine, Gwangju, Korea
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Wang CJ, Hu YX, Bai TY, Li J, Wang H, Lv XL, Zhang MD, Chang FH. Identification of disease-specific genes related to immune infiltration in nonalcoholic steatohepatitis using machine learning algorithms. Medicine (Baltimore) 2024; 103:e38001. [PMID: 38758850 PMCID: PMC11098182 DOI: 10.1097/md.0000000000038001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/03/2024] [Indexed: 05/19/2024] Open
Abstract
To identify disease signature genes associated with immune infiltration in nonalcoholic steatohepatitis (NASH), we downloaded 2 publicly available gene expression profiles, GSE164760 and GSE37031, from the gene expression omnibus database. These profiles represent human NASH and control samples and were used for differential genes (DEGs) expression screening. Two machine learning methods, the Least Absolute Shrinkage and Selection Operator regression model and Support Vector Machine Recursive Feature Elimination, were used to identify candidate disease signature genes. The CIBERSORT deconvolution algorithm was employed to analyze the infiltration of 22 immune cell types in NASH. Additionally, we constructed a NASH cell model using HepG2 cells treated with oleic acid and free fatty acids. The construction of the cell model was verified using oil red O staining, and Western blotting was used to detect the protein expression of the disease signature genes in both control and model groups. As a result, a total of 262 DEGs were identified. These DEGs were primarily associated with metal ion transmembrane transporter activity, sodium ion transmembrane transporter protein activity, calcium ion, and neuroactive ligand-receptor interactions. FOS, IGFBP2, dual-specificity phosphatase 1 (DUSP1), and IKZF3 were identified as disease signature genes of NASH by the least absolute shrinkage and selection operator and Support Vector Machine Recursive Feature Elimination algorithms for DEGs analysis. The receiver operating characteristic curves showed that FOS, IGFBP2, DUSP1, and IKZF3 had good diagnostic value (area under receiver operating characteristic curve > 0.8). These findings were validated in the GSE89632 dataset and through cellular assays. Immunocyte infiltration analysis revealed that NASH was associated with CD8 T cells, CD4 T cells, follicular helper T cells, resting NK cells, eosinophils, regulatory T cells, and γδ T cells. The FOS, IGFBP2, DUSP1, and IKZF3 genes were specifically associated with follicular helper T cells. Lipid droplet aggregation significantly increased in HepG2 cells treated with oleic acid and free fatty acids, indicating successful construction of the cell model. In this model, the expression of FOS, IGFBP2, and DUSP1 was significantly decreased, while that of IKZF3 was significantly elevated (P < .01, P < .001) compared with the control group. Therefore, FOS, IGFBP2, DUSP1, and IKZF3 can be considered as disease signature genes associated with immune infiltration in NASH.
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Affiliation(s)
- Chao-Jie Wang
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
| | - Yu-Xia Hu
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
| | - Tu-Ya Bai
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
| | - Jun Li
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
| | - Han Wang
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
| | - Xiao-Li Lv
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
| | - Meng-Di Zhang
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
| | - Fu-Hou Chang
- School of Pharmacy, Inner Mongolia Medical University, Huhhot, China
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Xu J, Jiang W, Hu T, Long Y, Shen Y. NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases. Biomolecules 2024; 14:577. [PMID: 38785984 PMCID: PMC11117611 DOI: 10.3390/biom14050577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 05/09/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding of ubiquitin (Ub) to the protein substrate and influences substrate specificity. In recent years, the relationship between the subfamily of neuron-expressed developmental downregulation 4 (NEDD4), which belongs to the E3 ligase system, and digestive diseases has drawn widespread attention. Numerous studies have shown that NEDD4 and NEDD4L of the NEDD4 family can regulate the digestive function, as well as a series of related physiological and pathological processes, by controlling the subsequent degradation of proteins such as PTEN, c-Myc, and P21, along with substrate ubiquitination. In this article, we reviewed the appropriate functions of NEDD4 and NEDD4L in digestive diseases including cell proliferation, invasion, metastasis, chemotherapeutic drug resistance, and multiple signaling pathways, based on the currently available research evidence for the purpose of providing new ideas for the prevention and treatment of digestive diseases.
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Affiliation(s)
| | | | | | | | - Yueming Shen
- Department of Digestive Diseases, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, 161 Shaoshan Road, Changsha 410000, China; (J.X.); (W.J.); (T.H.); (Y.L.)
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Greco S, Campigotto M, D’Amuri A, Fabbri N, Passaro A. Dyslipidemia, Cholangitis and Fatty Liver Disease: The Close Underexplored Relationship: A Narrative Review. J Clin Med 2024; 13:2714. [PMID: 38731243 PMCID: PMC11084647 DOI: 10.3390/jcm13092714] [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: 04/10/2024] [Revised: 04/25/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
In assessing individual cardiovascular risk, dyslipidemia is known for emerging as a pivotal factor significantly contributing to major cardiovascular events. However, dyslipidemic patients frequently present with concurrent medical conditions, each with varying frequencies of occurrence; cholangitis, whether acute or chronic, and hepatic steatosis, along with associated conditions, are strongly associated with specific forms of dyslipidemia, and these associations are reasonably well elucidated. Conversely, evidence linking biliary disease to hepatic steatosis is comparatively scant. This narrative review aims to bridge this gap in knowledge concerning the interplay between dyslipidemia, cholangitis, and hepatic steatosis. By addressing this gap, clinicians can better identify patients at heightened risk of future major cardiovascular events, facilitating more targeted interventions and management strategies. The review delves into the intricate relationships between dyslipidemia and these hepatic and biliary clinical conditions, shedding light on potential mechanisms underlying their associations. Understanding these complex interactions is crucial for optimizing cardiovascular risk assessment as well and devising tailored treatment approaches for patients with dyslipidemia and associated hepatic disorders. Moreover, elucidating these connections empowers clinicians with the knowledge needed to navigate the multifaceted landscape of cardiovascular risk assessment and management effectively. By exploring the intricate relationships between dyslipidemia, cholangitis, and hepatic steatosis (without forgetting the possible clinical consequences of hepatic steatosis itself), this review not only contributes to the existing body of knowledge but also offers insights into potential avenues for further research and clinical practice. Thus, it serves as a valuable resource for healthcare professionals striving to enhance patient care and outcomes in the context of cardiovascular disease and associated hepatic conditions.
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Affiliation(s)
- Salvatore Greco
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, FE, Italy;
- Department of Internal Medicine, Ospedale del Delta, Via Valle Oppio 2, 44023 Lagosanto, FE, Italy
| | - Michele Campigotto
- Gastroenterology and Digestive Endoscopy Unit, ASUGI, Cattinara University Hospital, Strada di Fiume 447, 34149 Trieste, TS, Italy;
| | - Andrea D’Amuri
- General Medicine Unit, Medical Department, ASST Mantova, Ospedale Carlo Poma, Strada Lago Paiolo 10, 46100 Mantova, MN, Italy;
| | - Nicolò Fabbri
- Department of General Surgery, Ospedale del Delta, Via Valle Oppio 2, 44023 Lagosanto, FE, Italy;
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, FE, Italy;
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Wang YF, Zhang WL, Li ZX, Liu Y, Tan J, Yin HZ, Zhang ZC, Piao XJ, Ruan MH, Dai ZH, Wang SJ, Mu CY, Yuan JH, Sun SH, Liu H, Yang F. METTL14 downregulation drives S100A4 + monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression. Signal Transduct Target Ther 2024; 9:91. [PMID: 38627387 PMCID: PMC11021505 DOI: 10.1038/s41392-024-01797-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 04/19/2024] Open
Abstract
Without intervention, a considerable proportion of patients with metabolism-associated fatty liver disease (MAFLD) will progress from simple steatosis to metabolism-associated steatohepatitis (MASH), liver fibrosis, and even hepatocellular carcinoma. However, the molecular mechanisms that control progressive MAFLD have yet to be fully determined. Here, we unraveled that the expression of the N6-methyladenosine (m6A) methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD, whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation, liver injury, and fibrosis. Conversely, hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet (HFD). Notably, in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner, which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1+Ccr2+ monocyte-derived macrophages (Mo-macs). In detail, Cx3cr1+Ccr2+ Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells (HSCs) to promote liver fibrosis. Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1+Ccr2+ Mo-macs. Restoration of METTL14 or GLS2, or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and fibrosis. Taken together, these findings indicate potential therapies for the treatment of MAFLD progression.
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Affiliation(s)
- Yue-Fan Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Wen-Li Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Zhi-Xuan Li
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, 100048, Beijing, China
| | - Yue Liu
- The Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, 200433, Shanghai, China
| | - Jian Tan
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Hao-Zan Yin
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Zhi-Chao Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Xian-Jie Piao
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Min-Hao Ruan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Zhi-Hui Dai
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Si-Jie Wang
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Chen-Yang Mu
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Ji-Hang Yuan
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Shu-Han Sun
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China.
| | - Fu Yang
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China.
- Key Laboratory of Biosafety Defense, Ministry of Education, 200433, Shanghai, China.
- Shanghai Key Laboratory of Medical Biodefense, 200433, Shanghai, China.
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Chen Q, Luo Y, Shen Y, Li X, Yang H, Li J, Wang J, Xiao Y. Fructose corn syrup induces inflammatory injury and obesity by altering gut microbiota and gut microbiota-related arachidonic acid metabolism. J Nutr Biochem 2024; 124:109527. [PMID: 37979711 DOI: 10.1016/j.jnutbio.2023.109527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/27/2023] [Accepted: 11/07/2023] [Indexed: 11/20/2023]
Abstract
Excessive fructose corn syrup (FCS) intake brings a series of health problems. The aim of the present study was to explore the mechanism of FCS-induced metabolic disorders from the perspective of gut microbiota. Mice were fed for 16 weeks with normal or 30% FCS drinking water. Compared to the control group, FCS caused significantly higher fat deposition, hepatic steatosis, liver and intestinal inflammatory damages (P<.05). FCS increased the abundance of Muribaculaceae in vivo and in vitro, which was positively correlated with the indices of metabolic disorders (P<.05). In vivo and in vitro data indicated that FCS enhanced the microbial function involved in pentose phosphate pathway and arachidonic acid metabolism, metabolomics further demonstrated that FCS led to an increase in prostaglandins (the catabolites of arachidonic acid) (P<.05). Our study confirmed that FCS can directly promote gut microbiota to synthesize inflammatory factor prostaglandins, which provides new insights and directions for the treatment of FCS-induced metabolic disorders and inflammation.
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Affiliation(s)
- Qu Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Yinmei Luo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Yu Shen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Xiaoqiong Li
- Institute of Food Sciences, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Hua Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Jinjun Li
- Institute of Food Sciences, Zhejiang Academy of Agricultural Sciences, Hangzhou, China.
| | | | - Yingping Xiao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, China.
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9
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Chen YC, Chen HH, Lin HJ, Huang CC, Chen KF, Peng YP, Tsang YF, Chen YH, Lin KYA, Lin CH. Hepatotoxicity evaluations of different surface charged carbon quantum dots in vivo and in vitro. Colloids Surf B Biointerfaces 2024; 234:113760. [PMID: 38244484 DOI: 10.1016/j.colsurfb.2024.113760] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/28/2023] [Accepted: 01/14/2024] [Indexed: 01/22/2024]
Abstract
Recently, carbon quantum dots (CQDs) have become popular because of their simple synthesis and potential applications. Although CQDs have high biocompatibility, their biotoxicity must be verified to reduce the possible risks associated with large-scale application. In this study, the hepatotoxicity of three CQD types, namely diammonium citrate (AC)-based (CQDs-AC), spermidine trihydrochloride (Spd)-based (CQDs-Spd), and AC- and Spd-based CQDs (CQDs-AC/Spd), were evaluated in vivo and in vitro. It was observed in vivo that CQDs-Spd and CQDs-AC/Spd, but not CQDs-AC, caused histopathological damage, including liver steatosis and mild mixed inflammatory cell infiltration; however, reduced liver function was only observed in CQD-Spd-treated mice. The in vitro results revealed that only CQDs-Spd significantly decreased the number of viable HepG2 cells (NADH depletion) and induced oxidative stress (heme oxygenase-1 activation) after 24 h of exposure, which promoted inflammatory factor secretion (NF-κB activation). Additionally, decreasing zonula occludens-2 and α1-antitrypsin protein expression in HepG2 cells suggested that CQD-Spd exposure increases the risk of liver diseases. Our results revealed that CQDs-Spd had greater hepatotoxic potential than CQDs-AC and CQDs-AC/Spd, which might be attributable to their high positive surface charge. Overall, the risk of CQD-induced hepatotoxic risk must be considered when applying positively charged CQDs.
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Affiliation(s)
- Yi-Chun Chen
- Department of Civil Engineering, National Taipei University of Technology, Taipei City 106, Taiwan; Department of Biotechnology, National Formosa University, Yunlin 63208, Taiwan
| | - Hung-Hsiang Chen
- Department of Biotechnology, National Formosa University, Yunlin 63208, Taiwan
| | - Han-Jia Lin
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan
| | - Chih-Ching Huang
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan
| | - Ku-Fan Chen
- Department of Civil Engineering, National Chi Nan University, Nantou, Taiwan
| | - Yen-Ping Peng
- Institute of Environmental Engineering, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Yiu Fai Tsang
- Department of Science and Environment Studies and State Key Laboratory in Marine Pollution, The Education University of Hong Kong, Tai Po, New Territories 999077, Hong Kong; Centre for Environment and Sustainable Development (CESD), The Education University of Hong Kong, Tai Po, New Territories 999077, Hong Kong
| | - Yan-Hua Chen
- Department of Biotechnology, National Formosa University, Yunlin 63208, Taiwan
| | - Kun-Yi Andrew Lin
- Department of Environmental Engineering, National Chung Hsing University, Taichung 40227, Taiwan; Institute of Analytical and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
| | - Chia-Hua Lin
- Department of Biotechnology, National Formosa University, Yunlin 63208, Taiwan.
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10
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Eurich D, Schlickeiser S, Ossami Saidy RR, Uluk D, Rossner F, Postel M, Schoening W, Oellinger R, Lurje G, Pratschke J, Reinke P, Gruen N. How to Estimate the Probability of Tolerance Long-Term in Liver Transplant Recipients. J Clin Med 2023; 12:6546. [PMID: 37892685 PMCID: PMC10607917 DOI: 10.3390/jcm12206546] [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: 09/03/2023] [Revised: 09/29/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Operational tolerance as the ability to accept the liver transplant without pharmacological immunosuppression is a common phenomenon in the long-term course. However, it is currently underutilized due to a lack of simple diagnostic support and fear of rejection despite its recognized benefits. In the present work, we present a simple score based on clinical parameters to estimate the probability of tolerance. PATIENTS AND METHODS In order to estimate the probability of tolerance, clinical parameters from 82 patients after LT who underwent weaning from the IS for various reasons at our transplant center were extracted from a prospectively organized database and analyzed retrospectively. Univariate testing as well as multivariable logistic regression analysis were performed to assess the association of clinical variables with tolerance in the real-world setting. RESULTS The most important factors associated with tolerance after multivariable logistic regression were IS monotherapy, male sex, history of hepatocellular carcinoma pretransplant, time since LT, and lack of rejection. These five predictors were retained in an approximate model that could be presented as a simple scoring system to estimate the clinical probability of tolerance or IS dispensability with good predictive performance (AUC = 0.89). CONCLUSION In parallel with the existence of a tremendous need for further research on tolerance mechanisms, the presented score, after validation in a larger collective preferably in a multicenter setting, could be easily and safely applied in the real world and already now address all three levels of prevention in LT patients over the long-term course.
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Affiliation(s)
- Dennis Eurich
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Stephan Schlickeiser
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.S.); (P.R.)
| | - Ramin Raul Ossami Saidy
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Deniz Uluk
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Florian Rossner
- Department of Pathology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany;
- Max Delbrueck Center for Molecular Medicine, Helmholtz Association, 13125 Berlin, Germany
| | - Maximilian Postel
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Wenzel Schoening
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Robert Oellinger
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Georg Lurje
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Johann Pratschke
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Petra Reinke
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.S.); (P.R.)
- Berlin Center for Advanced Therapies (BeCAT), Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitaetsmedizin Berlin, 13353 Berlin, Germany;
| | - Natalie Gruen
- Berlin Center for Advanced Therapies (BeCAT), Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitaetsmedizin Berlin, 13353 Berlin, Germany;
- Department of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
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11
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Gyorfi N, Gal AR, Fincsur A, Kalmar-Nagy K, Mintal K, Hormay E, Miseta A, Tornoczky T, Nemeth AK, Bogner P, Kiss T, Helyes Z, Sari Z, Klincsik M, Tadic V, Lenard L, Vereczkei A, Karadi Z, Vizvari Z, Toth A. Novel Noninvasive Paraclinical Study Method for Investigation of Liver Diseases. Biomedicines 2023; 11:2449. [PMID: 37760890 PMCID: PMC10525796 DOI: 10.3390/biomedicines11092449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/28/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Based on a prior university patent, the authors developed a novel type of bioimpedance-based test method to noninvasively detect nonalcoholic fatty liver disease (NAFLD). The development of a new potential NAFLD diagnostic procedure may help to understand the underlying mechanisms between NAFLD and severe liver diseases with a painless and easy-to-use paraclinical examination method, including the additional function to detect even the earlier stages of liver disease. The aim of this study is to present new results and the experiences gathered in relation to NAFLD progress during animal model and human clinical trials.
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Affiliation(s)
- Nina Gyorfi
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Institute of Physiology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Adrian Robert Gal
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Department of Medical Biology and Central Electron Microscopic Laboratory, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Andras Fincsur
- Department of Pathology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Karoly Kalmar-Nagy
- Department of Surgery, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Kitti Mintal
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Institute of Physiology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Edina Hormay
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Institute of Physiology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Attila Miseta
- Department of Laboratory Medicine, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Tamas Tornoczky
- Department of Pathology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Anita Katalin Nemeth
- Department of Medical Imaging, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Peter Bogner
- Department of Medical Imaging, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Tamas Kiss
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
- Eötvös Loránd Research Network, Chronic Pain Research Group, University of Pecs, H-7624 Pecs, Hungary
- National Laboratory for Drug Research and Development, Magyar Tudósok Krt. 2, H-1117 Budapest, Hungary
| | - Zoltan Sari
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Symbolic Methods in Material Analysis and Tomography Research Group, Faculty of Engineering and Information Technology, University of Pecs, Boszorkany Str. 6, H-7624 Pecs, Hungary
- Department of Technical Informatics, Faculty of Engineering and Information Technology, University of Pecs, Boszorkany Str. 2, H-7624 Pecs, Hungary
| | - Mihaly Klincsik
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Symbolic Methods in Material Analysis and Tomography Research Group, Faculty of Engineering and Information Technology, University of Pecs, Boszorkany Str. 6, H-7624 Pecs, Hungary
- Department of Technical Informatics, Faculty of Engineering and Information Technology, University of Pecs, Boszorkany Str. 2, H-7624 Pecs, Hungary
| | - Vladimir Tadic
- Symbolic Methods in Material Analysis and Tomography Research Group, Faculty of Engineering and Information Technology, University of Pecs, Boszorkany Str. 6, H-7624 Pecs, Hungary
- Institute of Information Technology, University of Dunaujvaros, Tancsics M. Str. 1/A, H-2401 Dunaujvaros, Hungary
- John von Neumann Faculty of Informatics, University of Obuda, Becsi Str. 96/B, H-1034 Budapest, Hungary
| | - Laszlo Lenard
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Institute of Physiology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Andras Vereczkei
- Department of Surgery, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Zoltan Karadi
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Institute of Physiology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
| | - Zoltan Vizvari
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Symbolic Methods in Material Analysis and Tomography Research Group, Faculty of Engineering and Information Technology, University of Pecs, Boszorkany Str. 6, H-7624 Pecs, Hungary
- John von Neumann Faculty of Informatics, University of Obuda, Becsi Str. 96/B, H-1034 Budapest, Hungary
- Department of Environmental Engineering, Faculty of Engineering and Information Technology, University of Pecs, Boszorkany Str. 2, H-7624 Pecs, Hungary
| | - Attila Toth
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentagothai Research Centre, University of Pecs, Ifjusag Str. 20, H-7624 Pecs, Hungary
- Institute of Physiology, Medical School, University of Pecs, Szigeti Str. 12, H-7624 Pecs, Hungary
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12
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Mishima M, Takeda S, Nagane M, Suzuki T, Ogata M, Shima A, Aihara N, Kamiie J, Suzuki R, Mizugaki H, Okamatsu-Ogura Y, Satoh T, Yamashita T. Prebiotic effect of poly-D-3-hydroxybutyrate prevents dyslipidemia in obese mice. FASEB J 2023; 37:e23121. [PMID: 37548278 DOI: 10.1096/fj.202301191r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/16/2023] [Accepted: 07/20/2023] [Indexed: 08/08/2023]
Abstract
Obesity is a global health problem caused by genetic, environmental, and psychological factors and is associated with various health disorders. As such, there is a growing focus on the prevention of obesity and related diseases. The gut microbiota plays a crucial role in these diseases and has become a therapeutic target. Prebiotics, such as poly-d-3-hydroxybutyric acid (PHB), have gained attention for their potential to alter the gut microbiota, promote beneficial bacterial growth, and alleviate obesity. In this study, we examined the prebiotic effects of PHB in obese mice. We found that, in C57BL/6N mice, PHB reduced blood lipid levels. Analysis of the intestinal microflora also revealed an increase in short-chain fatty acid-producing bacteria. When PHB was administered to obese mice, subcutaneous fat and dyslipidemia were reduced, and the number of beneficial bacteria in the intestinal microflora increased. Furthermore, fatty degradation and oxidative stress were suppressed in the liver. PHB regulates gut bacterial changes related to obesity and effectively inhibits dyslipidemia, suggesting that it could be a prebiotic agent for curing various obesity-related diseases. In summary, PHB increases the beneficial gut microbiota, leading to an alleviation of obesity-associated dyslipidemia.
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Affiliation(s)
- Mayuko Mishima
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | - Shiro Takeda
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
- Center for Human and Animal Symbiosis Science, Azabu University, Sagamihara, Japan
| | - Masaki Nagane
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
- Center for Human and Animal Symbiosis Science, Azabu University, Sagamihara, Japan
| | - Takehito Suzuki
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
- Center for Human and Animal Symbiosis Science, Azabu University, Sagamihara, Japan
| | - Masaya Ogata
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | - Ayaka Shima
- Anicom Specialty Medical Institute Inc., Tokyo, Japan
| | - Naoyuki Aihara
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | - Junichi Kamiie
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | - Rimina Suzuki
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | - Hinano Mizugaki
- School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | | | - Takumi Satoh
- Department of Antiaging Food Research, School of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Japan
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13
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Han S, Kwon JH, Lee KW, Lee S, Choi GS, Kim JM, Ko JS, Gwak MS, Kim GS, Ha SY, Joh JW. Abrogation of greater graft failure risk of female-to-male liver transplantation with donors older than 40 years or graft macrosteatosis greater than 5. Sci Rep 2023; 13:12914. [PMID: 37558742 PMCID: PMC10412610 DOI: 10.1038/s41598-023-38113-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 07/03/2023] [Indexed: 08/11/2023] Open
Abstract
Greater graft-failure-risk of female-to-male liver transplantation (LT) is thought to be due to acute decrease in hepatic-estrogen-signaling. Our previous research found evidence that female hepatic-estrogen-signaling decreases after 40 years or with macrosteatosis. Thus, we hypothesized that inferiority of female-to-male LT changes according to donor-age and macrosteatosis. We stratified 780 recipients of grafts from living-donors into four subgroups by donor-age and macrosteatosis and compared graft-failure-risk between female-to-male LT and other LTs within each subgroup using Cox model. In recipients with ≤ 40 years non-macrosteatotic donors, graft-failure-risk was significantly greater in female-to-male LT than others (HR 2.03 [1.18-3.49], P = 0.011). Within the subgroup of recipients without hepatocellular carcinoma, the inferiority of female-to-male LT became greater (HR 4.75 [2.02-11.21], P < 0.001). Despite good graft quality, 1y-graft-failure-probability was 37.9% (23.1%-57.9%) in female-to-male LT within this subgroup while such exceptionally high probability was not shown in any other subgroups even with worse graft quality. When donor was > 40 years or macrosteatotic, graft-failure-risk was not significantly different between female-to-male LT and others (P > 0.60). These results were in agreement with the estrogen receptor immunohistochemistry evaluation of donor liver. In conclusion, we found that the inferiority of female-to-male LT was only found when donor was ≤ 40 years and non-macrosteatotic. Abrogation of the inferiority when donor was > 40 years or macrosteatotic suggests the presence of dominant contributors for post-transplant graft-failure other than graft quality/quantity and supports the role of hepatic-estrogen-signaling mismatch on graft-failure after female-to-male LT.
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Affiliation(s)
- Sangbin Han
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Ji Hye Kwon
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyo Won Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sanghoon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gyu Sung Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Justin Sangwook Ko
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mi Sook Gwak
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gaab Soo Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Changwon, Korea.
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14
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Hsu CL, Wang Y, Duan Y, Chu H, Hartmann P, Llorente C, Zhou R, Schnabl B. Differences in Bacterial Translocation and Liver Injury in Ethanol Versus Diet-Induced Liver Disease. Dig Dis Sci 2023; 68:3059-3069. [PMID: 36807831 PMCID: PMC10313731 DOI: 10.1007/s10620-023-07860-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 01/30/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND Alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are two of the most common etiologies of chronic liver disease worldwide. Changes in intestinal permeability and increased gut microbial translocation have been posited as important contributors to inflammation in both ALD and NAFLD. However, gut microbial translocation has not been compared between the two etiologies and can lead to better understanding of the differences in their pathogenesis to liver disease. METHODS We compared serum and liver markers in the following five models of liver disease to understand the differences in the role of gut microbial translocation on liver disease progression caused by ethanol versus Western diet: (1) 8-week chronic ethanol feeding model. (2) 2-week chronic-plus-binge (National Institute on Alcohol Abuse and Alcoholism (NIAAA)) ethanol feeding model. (3) 2-week chronic-plus-binge (NIAAA) ethanol feeding model in microbiota-humanized gnotobiotic mice colonized with stool from patients with alcohol-associated hepatitis. (4) 20-week Western-diet-feeding model of NASH. (5) 20-week Western-diet-feeding model in microbiota-humanized gnotobiotic mice colonized with stool from NASH patients. RESULTS Translocation of bacterial lipopolysaccharide to the peripheral circulation was seen in both ethanol-induced and diet-induced liver disease, but translocation of bacteria itself was restricted to only ethanol-induced liver disease. Moreover, the diet-induced steatohepatitis models developed more significant liver injury, inflammation, and fibrosis compared with ethanol-induced liver disease models, and this positively correlated with the level of lipopolysaccharide translocation. CONCLUSIONS More significant liver injury, inflammation, and fibrosis are seen in diet-induced steatohepatitis, which positively correlates with translocation of bacterial components, but not intact bacteria.
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Affiliation(s)
- Cynthia L Hsu
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA
| | - Yanhan Wang
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Yi Duan
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Huikuan Chu
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children's Hospital San Diego, San Diego, CA, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA
| | - Rongrong Zhou
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, MC0063, USA.
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
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15
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Liu J, Gao S, Zhou W, Chen Y, Wang Z, Zeng Z, Zhou H, Lin T. Dihydrotrichodimerol Purified from the Marine Fungus Acremonium citrinum Prevents NAFLD by Targeting PPARα. JOURNAL OF NATURAL PRODUCTS 2023; 86:1189-1201. [PMID: 37083418 DOI: 10.1021/acs.jnatprod.2c00990] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is closely linked to the imbalance of lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPARs) play essential roles. The clinical trials have shown the beneficial effects of the PPARs' ligands on NAFLD. In this study, we screen the extracts from the marine fungus Acremonium citrinum and identify the natural compounds dihydrotrichodimerol (L1A) and trichodimerol (L1B) as the ligands of PPARs, of which L1A is a dual PPARα/γ agonist, whereas L1B is a selective PPARγ agonist. L1A but not L1B significantly prevents hepatic lipid accumulation in an oleic acid-induced NAFLD cell model as well as in a high-fat-diet-induced NAFLD mouse model. Moreover, L1A potently inhibits hepatic steatosis in a PPARα-dependent manner in another NAFLD mouse model constructed by using a choline-deficient and amino acid-defined diet. Mechanistically, L1A transcriptionally up-regulates the expression of SIRT1 in a PPARα-dependent manner, followed by the activation of AMPK and inactivation of ACC, resulting in the inhibition of lipid anabolism and the increase of lipid catabolism. Taken together, our study reveals a dual ligand of PPARα/γ with a distinct structure and therapeutic effect on NAFLD, providing a potential drug candidate bridging the currently urgent need for the management of NAFLD.
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Affiliation(s)
- Jie Liu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Shuo Gao
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Wanxuan Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Yongyan Chen
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
| | - Zhenwu Wang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
- High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian 361102, China
| | - Zhiping Zeng
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
- High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian 361102, China
| | - Hu Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
- High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian 361102, China
| | - Ting Lin
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen, Fujian 361102, China
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16
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Schelbert S, Schindeldecker M, Drebber U, Witzel HR, Weinmann A, Dries V, Schirmacher P, Roth W, Straub BK. Lipid Droplet-Associated Proteins Perilipin 1 and 2: Molecular Markers of Steatosis and Microvesicular Steatotic Foci in Chronic Hepatitis C. Int J Mol Sci 2022; 23:ijms232415456. [PMID: 36555099 PMCID: PMC9778710 DOI: 10.3390/ijms232415456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.
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Affiliation(s)
- Selina Schelbert
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Institute of Pathology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | | | - Uta Drebber
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Hagen Roland Witzel
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, University Medical Center, 55131 Mainz, Germany
| | - Volker Dries
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Medical Center Heidelberg, 69120 Heidelberg, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Beate Katharina Straub
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Correspondence: ; Tel.: +49-6131-17-7307
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17
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Chen L, Liu Y, Tang Z, Song Z, Cao F, Shi X, Xie P, Wei P, Li M. Radix Angelica dahuricae extract ameliorates oestrogen deficiency-induced dyslipidaemia in ovariectomized (OVX) rats by modulating the gut microbiota and bile acid signalling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 107:154440. [PMID: 36162241 DOI: 10.1016/j.phymed.2022.154440] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 06/23/2022] [Accepted: 09/04/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Radix Angelica dahuricae (RAD), a well-known traditional Chinese medicine, displays a promising effect on alleviating lipid metabolism. However, the improvement of RAD on oestrogen deficiency-induced dyslipidaemia and the underlying mechanism are unclear. PURPOSE The aim of this study was to study the effect of RAD on oestrogen deficiency-induced dyslipidaemia in ovariectomized (OVX) rats and investigate the involvement of the gut microbiota and bile acid signalling in the protective effects. METHODS Bilateral ovariectomy was executed to establish an oestrogen deficiency model. Serum biochemical indexes, liver lipids, inflammatory cytokines and histomorphology were evaluated. Gut microbes were analysed via 16S rRNA sequencing. Faecal short-chain fatty acids (SCFAs) and serum bile acids were quantified by gas chromatography-flame ionization detection (GC-FID) and ultra-high-performance chromatography-tandem mass spectrometry (UPLC-MS/MS), respectively. The expression of genes related to bile acid synthesis, metabolism and enterohepatic circulation in the liver and caecum was measured by real-time PCR. RESULTS The results displayed that RAD administration markedly decreased body weight, TC and TG levels in the serum and liver, and hepatic steatosis and inflammation in OVX rats. RAD administration could significantly regulate the gut microbial composition, increasing the abundance of Lactobacillus, increasing the content of bile salt hydrolase (BSH), and reestablishing the SCFA profile and bile acid metabolism profile in OVX rats. RAD administration could increase the gene expression of HMG-CoA reductase (HMGCR) and cytochrome P450 7A1(CYP7A1) and regulate the gene expression of the related receptors as well as proteins in enterohepatic circulation. CONCLUSIONS RAD alleviated oestrogen deficiency-induced dyslipidaemia in OVX rats. Modulation of the gut microbiota composition and bile acid signalling may be the underlying mechanism.
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Affiliation(s)
- Lin Chen
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712083, P R China.
| | - Yanru Liu
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712083, P R China.
| | - Zhishu Tang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712083, P R China; China Academy of Chinese Medical Sciences, Beijing 100700, P R China.
| | - Zhongxing Song
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712083, P R China
| | - Fan Cao
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi 712046, P R China
| | - Xinbo Shi
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712083, P R China
| | - Pei Xie
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712083, P R China
| | - Peifeng Wei
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi 712046, P R China
| | - Min Li
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi 712046, P R China
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18
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Kim RG, Chu JN, Vittinghoff E, Deng J, Reaso JN, Grenert JP, Khalili M. Racial/ethnic differences in fibrosis prevalence and progression in biopsy-proven steatosis: A focus on the Asian American population. Hepatol Commun 2022; 6:3024-3035. [PMID: 36087033 PMCID: PMC9592793 DOI: 10.1002/hep4.2078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/10/2022] [Accepted: 08/01/2022] [Indexed: 12/14/2022] Open
Abstract
Fatty liver disease (FLD) is a leading cause of chronic liver disease (CLD) globally, and vulnerable populations are disproportionately affected. Prior studies have suggested racial/ethnic differences in FLD prevalence and severity; however, these studies often excluded Asian Americans. This study aims to evaluate racial/ethnic differences in the prevalence of, and predictors associated with steatohepatitis, advanced fibrosis, and fibrosis progression over time within a diverse population. Using descriptive analyses and multivariable modeling, we performed a longitudinal evaluation of 648 patients with histologic evidence of FLD (steatosis or steatohepatitis) from August 2009 to February 2020 within San Francisco's safety-net health care system. Overall demographics were median age of 53 years, 54% male, and 38% Asian (40% Hispanic, 14% White). On histology, 61% had steatohepatitis and 30% had advanced fibrosis (≥F3). The comparison between steatosis and steatohepatitis groups showed differences in sex, race/ethnicity, metabolic risk factors, and co-existing CLD (predominantly viral hepatitis); patients with steatosis were more likely to be Asian (50%), and those with steatohepatitis were more likely to be Hispanic (51%). On multivariable modeling, while Asian race (vs. non-Asian) was not associated with steatohepatitis or advanced fibrosis when models included all relevant clinical predictors, Asian race was associated with higher relative risk of fibrosis progression as defined by change in Fibrosis-4 category over time (relative risk ratio = 1.9; p = 0.047). Conclusion: In this vulnerable population with a large proportion of Asian Americans, Asian race was associated with progression of fibrosis. Given the relative paucity of data in this high-risk group, future studies should confirm these findings.
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Affiliation(s)
- Rebecca G. Kim
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Division of Gastroenterology and HepatologyZuckerberg San Francisco GeneralSan FranciscoCaliforniaUSA
| | - Janet N. Chu
- Division of General Internal MedicineDepartment of MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Eric Vittinghoff
- Department of Epidemiology and BiostatisticsUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Jasmine Deng
- David Geffen School of Medicine at University of California, Los AngelesLos AngelesCaliforniaUSA
| | - Jewel N. Reaso
- Division of Gastroenterology and HepatologyZuckerberg San Francisco GeneralSan FranciscoCaliforniaUSA
| | - James P. Grenert
- Division of Surgical PathologyDepartment of Pathology and Laboratory MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Liver CenterUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Mandana Khalili
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Division of Gastroenterology and HepatologyZuckerberg San Francisco GeneralSan FranciscoCaliforniaUSA
- Liver CenterUniversity of California San FranciscoSan FranciscoCaliforniaUSA
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19
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Shi H, Qiao F, Huang K, Lu W, Zhang X, Ke Z, Wu Y, Cao L, Chen Y. Exploring therapeutic mechanisms of San-Huang-Tang in nonalcoholic fatty liver disease through network pharmacology and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2022; 296:115477. [PMID: 35764198 DOI: 10.1016/j.jep.2022.115477] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 04/10/2022] [Accepted: 06/14/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE San-Huang-Tang (SHT), a traditional Chinese medicine (TCM) formula, has been clinically used to treat obesity and type 2 diabetes mellitus. Recently it has proved that SHT have a good effect on non-alcoholic fatty liver disease (NAFLD). AIM OF THE STUDY Our study was designed to investigate the therapeutic mechanisms of the SHT against NAFLD. The data of SHT were obtained through network pharmacology platform and validated experimentally in vivo and in vitro. MATERIALS AND METHODS The candidate targets of SHT were predicted by network pharmacological analysis and crucial targets were chosen by the protein-protein interaction (PPI) network. Furthermore, Gene Ontology (GO) and Kyoto encyclopedia of genes and Genomes (KEGG) were applied to analyze the NAFLD-related signaling pathways affected by SHT, and then the analysis results were verified with molecular biological experiments in vivo and in vitro. RESULTS Molecules were screened with network pharmacological analysis, and then the improvement of insulin resistance of NAFLD mice was measured by IPITTs and IPGTTs. Through series of molecular experiments, it is revealed that SHT could increase the transcription of insulin receptor (INSR) and insulin receptor substrate (IRS1), and enhance the phosphorylation of both threonine protein kinase (AKT) and forkhead box O1 (FoxO1). CONCLUSIONS Screened by bioinformatics and verified by experiments in vivo and in vitro, SHT could contribute to NAFLD by affecting insulin resistance via activating INSR/IRS1/AKT/FoxO1 pathway. Our research findings provide not only an experimental basis for the therapeutic effect of SHT but also a new target against NAFLD.
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Affiliation(s)
- Huilian Shi
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Fei Qiao
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Kaiyue Huang
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Weiting Lu
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Xinzhuang Zhang
- State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co.,Ltd, Lianyungang, Jiangsu, PR China
| | - Zhipeng Ke
- State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co.,Ltd, Lianyungang, Jiangsu, PR China
| | - Yanchi Wu
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Liang Cao
- State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co.,Ltd, Lianyungang, Jiangsu, PR China; Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China.
| | - Yuanyuan Chen
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, PR China.
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20
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Tu T, Alba MM, Datta AA, Hong H, Hua B, Jia Y, Khan J, Nguyen P, Niu X, Pammidimukkala P, Slarve I, Tang Q, Xu C, Zhou Y, Stiles BL. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis. Front Oncol 2022; 12:958696. [PMID: 36276076 PMCID: PMC9581256 DOI: 10.3389/fonc.2022.958696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
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Affiliation(s)
- Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Aditi A. Datta
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jared Khan
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Xiatoeng Niu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Pranav Pammidimukkala
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Chenxi Xu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Bangyan L. Stiles,
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21
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Jung HJ, Cho K, Kim SY, Seong JK, Oh SH. Ethanol extract of Pharbitis nil ameliorates liver fibrosis through regulation of the TGFβ1-SMAD2/3 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115370. [PMID: 35568114 DOI: 10.1016/j.jep.2022.115370] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/22/2022] [Accepted: 05/07/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pharbitis nil (L.) Choisy is a medicinal herb, and herbal remedies based on its seeds have been used to treat of obesity and liver diseases, including fatty liver and liver cirrhosis in East Asia. AIM OF THE STUDY Liver fibrosis is a major cause of morbidity and mortality in patients with chronic liver inflammation such as that caused by non-alcoholic steatohepatitis. However, no effective pharmaceutical treatment for liver fibrosis has been approved. In this study, we aimed to investigate that ethanol extract of pharbitis nil (PNE) alleviates the liver fibrosis. MATERIALS AND METHODS We studied the effects of PNE on two preclinical models. Six-week-old male C57BL/6 mice were intraperitoneally injected with CCl4 twice weekly for 6 weeks and then treated with 5 or 10 mg/kg PNE daily from week 3 for weeks. Secondly, mice were fed HFD for 41 weeks and at 35 weeks treated with 5 mg/kg PNE daily for the remaining 6 weeks. In addition, we examined the antifibrotic effects of PNE in primary mouse hepatic stellate cells and LX-2 cells. RESULTS PNE treatment ameliorated hepatocyte necrosis, inflammation, and liver fibrosis in CCl4-treated mice and inhibited the progression of liver fibrosis in mice with HFD-induced fibrosis. PNE reduced the expressions of fibrosis markers and SMAD2/3 activations in mouse livers and in TGFβ1-treated primary mouse hepatic stellate and LX-2 cells CONCLUSIONS: This study demonstrates that PNE attenuates liver fibrosis by downregulating TGFβ1-induced SMAD2/3 activation.
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Affiliation(s)
- Hyun Jin Jung
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
| | - Kyohee Cho
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
| | - Sun Yeou Kim
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea; Laboratory of Developmental Biology and Genomics, Research Institute of Veterinary Science, BK21 Plus Program for Veterinary Science, Seoul National University, Seoul, 08826, South Korea.
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea.
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22
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Nickel S, Christ M, Schmidt S, Kosacka J, Kühne H, Roderfeld M, Longerich T, Tietze L, Bosse I, Hsu MJ, Stock P, Roeb E, Christ B. Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation. Cells 2022; 11:cells11111829. [PMID: 35681524 PMCID: PMC9180625 DOI: 10.3390/cells11111829] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/31/2022] [Accepted: 05/31/2022] [Indexed: 11/27/2022] Open
Abstract
Mesenchymal stromal cells (MSC) increasingly emerge as an option to ameliorate non-alcoholic steatohepatitis (NASH), a serious disease, which untreated may progress to liver cirrhosis and cancer. Before clinical translation, the mode of action of MSC needs to be established. Here, we established NASH in an immune-deficient mouse model by feeding a high fat diet. Human bone-marrow-derived MSC were delivered to the liver via intrasplenic transplantation. As verified by biochemical and image analyses, human mesenchymal stromal cells improved high-fat-diet-induced NASH in the mouse liver by decreasing hepatic lipid content and inflammation, as well as by restoring tissue homeostasis. MSC-mediated changes in gene expression indicated the switch from lipid storage to lipid utilization. It was obvious that host mouse hepatocytes harbored human mitochondria. Thus, it is feasible that resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes. Therefore, human MSC might provide oxidative capacity for lipid breakdown followed by restoration of metabolic and tissue homeostasis.
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Affiliation(s)
- Sandra Nickel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
- Division of General, Visceral and Vascular Surgery, University Hospital Jena, 07747 Jena, Germany
| | - Madlen Christ
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Sandra Schmidt
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Joanna Kosacka
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Hagen Kühne
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Martin Roderfeld
- Department of Gastroenterology, Justus-Liebig-University, 35392 Giessen, Germany; (M.R.); (E.R.)
| | - Thomas Longerich
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany;
| | - Lysann Tietze
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Ina Bosse
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Mei-Ju Hsu
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Peggy Stock
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
| | - Elke Roeb
- Department of Gastroenterology, Justus-Liebig-University, 35392 Giessen, Germany; (M.R.); (E.R.)
| | - Bruno Christ
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany; (S.N.); (M.C.); (S.S.); (J.K.); (H.K.); (L.T.); (I.B.); (M.-J.H.); (P.S.)
- Correspondence: ; Tel.: +49-(0)341-9713552
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Dionysopoulos G, Kalopitas G, Vadarlis A, Bakaloudi DR, Gkiourtzis N, Karanika E, Tsekitsidi E, Chourdakis M. Can omega-3 fatty acids be beneficial in pediatric NAFLD? A systematic review and meta-analysis. Crit Rev Food Sci Nutr 2022; 63:8545-8553. [PMID: 35400251 DOI: 10.1080/10408398.2022.2062589] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and no medications or supplements are currently recommended. The role of omega-3 (n-3) fatty acids has been investigated in clinical trials with promising results. The aim of this study is to provide a detailed summary of the evidence about the efficacy of n-3 in the treatment of pediatric NAFLD. A systematic literature search was performed through major electronic databases up to September 20, 2021 for randomized placebo-controlled trials, investigating the efficacy of n-3 fatty acids in children with NAFLD. The primary outcomes were changes in serum transaminases concentration, Body Mass Index (BMI) and improvement of ultrasonographic liver steatosis. The secondary outcomes were changes in the patients' serum lipid profile, γ-glutamyl transferase (GGT), fasting blood glucose (FBG), homeostatic model assessment of insulin resistance (ΗΟΜΑ-ΙR) and waist circumference (WC). Results were expressed as mean differences for continuous outcomes and odds ratios for dichotomous outcomes with 95% confidence intervals. Six RCTs (n = 378 patients) were included. Treatment with n-3, compared to placebo, resulted in a statistically significant reduction in transaminases concentration. In addition, a significant improvement in liver steatosis assessed by ultrasonography and a decrease in BMI were observed. N-3 fatty acids supplementation seems to be an effective alternative treatment in pediatric NAFLD by improving liver biochemistry, ultrasonographic steatosis and BMI. Further research is required concerning the effect of n-3 fatty acids in liver histology.
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Affiliation(s)
- Georgios Dionysopoulos
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios Kalopitas
- Division of Gastroenterology and Hepatology, 1st Department of Internal Medicine, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Vadarlis
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Department of Gastroenterology and Hepatology, General Hospital of Thessaloniki "G. Papanikolaou,"Thessaloniki, Greece
| | - Dimitra Rafailia Bakaloudi
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Gkiourtzis
- 4th Department of Paediatrics, Papageorgiou University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelia Karanika
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eirini Tsekitsidi
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Michail Chourdakis
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
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24
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Hliwa A, Mika A, Sledzinski M, Laski D, Ramos-Molina B, Sledzinski T. Changes in the Serum Fatty Acid Profile After Anhepatic Phase of Orthotopic Liver Transplantation Procedure. Front Physiol 2022; 13:817987. [PMID: 35422709 PMCID: PMC9004627 DOI: 10.3389/fphys.2022.817987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
During orthotopic liver transplantation (OLT), the patients’ body remains deprived of this organ for some time, which could cause critical changes in the levels of various metabolites in the circulation, including fatty acids. Thus, the aim of this study was to determine whether the liver transplantation procedure leads to significant changes in the FA profile in serum lipids after the anhepatic phase. Our gas chromatography–mass spectrometry analysis revealed that after transplantation, serum levels of myristic and palmitic acids significantly decreased, whereas serum levels of very long-chain FAs containing 20 or more carbons in their chains were increased. These results indicate that the anhepatic phase during liver transplantation produces significant changes in serum fatty acid levels, and emphasizes the role of the liver in the metabolism of very long-chain fatty acids.
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Affiliation(s)
- Aleksandra Hliwa
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
| | - Adriana Mika
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
- *Correspondence: Adriana Mika,
| | - Maciej Sledzinski
- Department of General, Endocrine and Transplant Surgery, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Dariusz Laski
- Department of General, Endocrine and Transplant Surgery, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Bruno Ramos-Molina
- Obesity and Metabolism Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
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25
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Abedin N, Tannapfel A, Wild PJ, Tischoff I. [Histopathological evaluation of nonalcoholic fatty liver disease : Automated evaluation of liver biopsies]. DER PATHOLOGE 2022; 43:157-166. [PMID: 35171314 DOI: 10.1007/s00292-022-01052-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 06/14/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent chronic liver diseases with a rising incidence in industrial countries. This is accompanied by an increased prevalence for NAFLD-associated liver cirrhosis and an increased risk for developing hepatocellular carcinoma. The current gold standard in the diagnostics is a liver biopsy. The histopathological evaluation is performed through semiquantitative scoring. To optimize the standardization and quantification of the existing scoring systems, in the coming years procedures with artificial intelligence, such as deep learning models could be used. Fields of application could be the supplementation of conventional histopathological diagnostics, the identification of new predictive parameters for estimating the prognosis and the prediction of a possible response to treatment.
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Affiliation(s)
- Nada Abedin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland.
| | - Andrea Tannapfel
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - Peter J Wild
- Dr. Senckenbergisches Institut für Pathologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main, Deutschland
| | - Iris Tischoff
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
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26
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Wu H, Xu X, Zheng A, Wang W, Mei L, Chen Y, Sun S, Jiang L, Wu Y, Zhou Y, Zheng M, Chen Q. TNF-α-Induce Protein 8-Like 1 Inhibits Hepatic Steatosis, Inflammation, and Fibrosis by Suppressing Polyubiquitination of Apoptosis Signal-Regulating Kinase 1. Hepatology 2021; 74:1251-1270. [PMID: 33713358 DOI: 10.1002/hep.31801] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/26/2021] [Accepted: 02/08/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Characterized by hepatocyte steatosis, inflammation, and fibrosis, NASH is a complicated process that contributes to end-stage liver disease and, eventually, HCC. TNF-α-induced protein 8-like 1 (TIPE1), a new member of the TNF-α-induced protein 8 family, has been explored in immunology and oncology research; but little is known about its role in metabolic diseases. APPROACH AND RESULTS Here, we show that hepatocyte-specific deletion of TIPE1 exacerbated diet-induced hepatic steatosis, inflammation, and fibrosis as well as systemic metabolic disorders during NASH pathogenesis. Conversely, hepatocyte-specific overexpression of TIPE1 dramatically prevented the progression of these abnormalities. Mechanically, TIPE1 directly interacted with apoptosis signal-regulating kinase 1 (ASK1) to suppress its TNF receptor-associated factor 6 (TRAF6)-catalyzed polyubiquitination activation upon metabolic challenge, thereby inhibiting the downstream c-Jun N-terminal kinase and p38 signaling pathway. Importantly, dramatically reduced TIPE1 expression was observed in the livers of patients with NAFLD, suggesting that TIPE1 might be a promising therapeutic target for NAFLD and related metabolic diseases. CONCLUSIONS TIPE1 protects against hepatic steatosis, inflammation, and fibrosis through directly binding ASK1 and restraining its TRAF6-catalyzed polyubiquitination during the development of NASH. Therefore, targeting TIPE1 could be a promising therapeutic approach for NAFLD treatment.
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Affiliation(s)
- Hong Wu
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaolei Xu
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ancheng Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weina Wang
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Li Mei
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yue Chen
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shasha Sun
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liujun Jiang
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yutao Wu
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yijiang Zhou
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Qishan Chen
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Pereira ENGDS, Paula DP, Araujo BPD, Fonseca MDJMD, Diniz MDFHS, Daliry A, Griep RH. Advanced glycation end product: A potential biomarker for risk stratification of non-alcoholic fatty liver disease in ELSA-Brasil study. World J Gastroenterol 2021; 27:4913-4928. [PMID: 34447235 PMCID: PMC8371502 DOI: 10.3748/wjg.v27.i29.4913] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/18/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver diseases are associated with the excess formation of advanced glycation end products (AGEs), which induce tissue inflammation and oxidative damage. However, the trend of oxidative marker levels according to the steatosis grade in non-alcoholic fatty liver disease (NAFLD) is unclear.
AIM To compare serum AGE levels between participants with NAFLD accordingly to steatosis severity in the baseline ELSA-Brasil population.
METHODS In 305 individuals at baseline ELSA-Brasil, NAFLD-associated steatosis was classified by ultrasound hepatic attenuation. The participants were grouped according to the severity of steatosis: mild and moderate/severe pooled. The measurement of serum fluorescent AGE concentrations was based on spectrofluorimetric detection. Serum AGE content and clinical and laboratory characteristics of the participants were compared between groups. The correlation between serum AGE levels and the grade of steatosis was analyzed. Logistic regression analysis was used to investigate the relationship between serum AGE levels and steatosis severity. A P value < 0.05 was considered statistically significant.
RESULTS According to the steatosis severity spectrum in NAFLD, from mild to moderate/severe, individuals with the most severe steatosis grade had a higher incidence of metabolic syndrome (63% vs 34%, P ≤ 0.001), diabetes mellitus (37% vs 14%, P ≤ 0.001), and high cholesterol levels (51% vs 33%, P < 0.001). Moreover, individuals with increasing severity of steatosis presented increasing waist circumference, body mass index, systolic and diastolic blood pressure, fasting blood glucose, glycated hemoglobin, insulin, triglycerides, alanine aminotransferase, gamma-glutamyl transferase, C-reactive protein, and uric acid levels and lower high-density lipoprotein. Higher serum AGE content was present in the moderate/severe group of individuals than in the mild group (P = 0.008). In addition, the serum AGE levels were correlated with the steatosis grade in the overall sample (rho = 0.146, P = 0.010). Logistic regression analysis, after adjusting for confounding variables, showed that subjects with higher serum AGE content had a 4.6-fold increased chance of having moderate or severe steatosis when compared to low levels of serum AGEs. According to the results of the receiver operator characteristic curves analyses (areas under the curve, AUC = 0.83), AGEs could be a good marker of steatosis severity in patients with NAFLD and might be a potential biomarker in predicting NAFLD progression, strengthening the involvement of AGE in NAFLD pathogenesis.
CONCLUSION NAFLD-associated steatosis was associated with serum AGE levels; therefore, plasmatic fluorescent AGE quantification by spectroscopy could be a promising alternative method to monitor progression from mild to severe NAFLD accordingly to steatosis grade.
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Affiliation(s)
| | - Daniela Polessa Paula
- National School of Statistical Sciences, Brazilian Institute of Geography and Statistics, Rio de Janeiro 20231-050, Brazil
| | - Beatriz Peres de Araujo
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
| | | | | | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
| | - Rosane Harter Griep
- Laboratory of Health and Environment Education, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
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Arab JP, Arrese M, Singal AK. Diagnosis of Alcohol-Associated Hepatitis: When Is Liver Biopsy Required? Clin Liver Dis 2021; 25:571-584. [PMID: 34229840 DOI: 10.1016/j.cld.2021.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcohol-associated hepatitis (AH) is a unique clinical syndrome in patients with excessive and prolonged alcohol consumption, and negatively impacts the patient outcomes. Among patients with asymptomatic alcohol-associated liver disease with elevated liver enzymes and/or steatosis, liver biopsy is required to diagnose AH. Noninvasive assessment should be performed in these patients to determine risk of advanced fibrosis. In symptomatic patients with jaundice, liver biopsy is required when the clinical diagnosis is uncertain. Liver biopsy is not recommended to determine prognosis of patients with AH. Noninvasive biomarkers are emerging for diagnosis of and determining prognosis of patients with AH.
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Affiliation(s)
- Juan Pablo Arab
- Department of Gastroenterology and Hepatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Av Libertador Bernardo O'Higgins 340, Santiago, Región Metropolitana, Chile; Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Department of Gastroenterology and Hepatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Av Libertador Bernardo O'Higgins 340, Santiago, Región Metropolitana, Chile; Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ashwani K Singal
- University of South Dakota Sanford School of Medicine, McKennan University Hospital Transplant Institute, Cliff Ave., Sioux Falls, SD 57105, USA.
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Abstract
IMPORTANCE Alcohol-associated liver disease results in cirrhosis in approximately 10% to 20% of patients. In 2017, more than 2 million people had alcohol-associated cirrhosis in the US. Alcohol-associated liver disease is the primary cause of liver-related mortality and the leading indication for liver transplant, representing 40% to 50% of all liver transplant in high-income countries. OBSERVATIONS Steatosis, alcoholic hepatitis, and fibrosis are the 3 pathologic findings that are associated with progression to cirrhosis, with highest risk in patients with alcoholic hepatitis. The amount and duration of alcohol consumption, female sex, obesity, and specific genetic polymorphisms such as patatin-like phospholipase domain protein 3, membrane bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes are risk factors for alcohol-associated liver disease progression. Ten-year survival of patients with alcohol-associated liver disease is 88% among those who are abstinent and 73% for those who relapse to alcohol consumption. Symptomatic alcoholic hepatitis is characterized by rapid onset of jaundice and a 30% risk of mortality 1 year after diagnosis. Severe alcoholic hepatitis, defined as a modified discriminant function score greater than or equal to 32 or Model for End-Stage Liver Disease score (starts at 6 and capped at 40; worst = 40) greater than 20, is associated with the development of acute-on-chronic liver failure and multiorgan failure. Corticosteroid therapy is associated with improved 1-month survival from 65% in untreated patients to 80% in treated patients. Early liver transplant may be appropriate in highly select patients with severe alcoholic hepatitis who do not respond to medical therapy. In patients with decompensated cirrhosis, liver transplant should be considered if the Model for End-Stage Liver Disease score remains greater than 17 after 3 months of alcohol abstinence. Between 2014 and 2019, the proportion of patients waiting for liver transplantation who had alcohol-associated liver disease increased from 22% to 40%. Alcohol-associated cirrhosis accounted for approximately 27% of 1.32 million deaths worldwide related to cirrhosis in 2017. CONCLUSIONS AND RELEVANCE Alcohol-associated liver disease is among the most common liver diseases and more than 2 million people in the US in 2017 had alcohol-associated cirrhosis. Corticosteroid therapy improves survival in select patients with severe alcoholic hepatitis. Liver transplantation is the most effective therapy in patients with decompensated liver disease.
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Affiliation(s)
- Ashwani K Singal
- University of South Dakota Sanford School of Medicine, Sioux Falls
- Avera Transplant Institute, Sioux Falls, South Dakota
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Esmail M, Anwar S, Kandeil M, El-Zanaty AM, Abdel-Gabbar M. Effect of Nigella sativa, atorvastatin, or L-Carnitine on high fat diet-induced obesity in adult male Albino rats. Biomed Pharmacother 2021; 141:111818. [PMID: 34126354 DOI: 10.1016/j.biopha.2021.111818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 06/01/2021] [Accepted: 06/07/2021] [Indexed: 12/19/2022] Open
Abstract
Obesity is increasing rapidly across the globe. It is widely accepted that natural products with a long safety background may modulate obesity. The current work aimed to investigate the effect of Nigella sativa, atorvastatin, or L-Carnitine on high-fat diet-induced obesity in white male albino rats. A regular basal diet was fed to 7 rats, and a high-fat diet (HFD) was fed to 24 rats throughout the study for 12 weeks. The HFD group was split equally into four subgroups, each containing six rats. The first group fed on HFD with no medication, the second group received HFD+ Nigella sativa, the third group received HFD+ atorvastatin, and the fourth group received HFD+L-carnitine. At the beginning of the seventh week (the start of the treatment regimen), Nigella sativa, atorvastatin, or L-Carnitine were administered for six weeks. Glucose, body weight, serum atherogenic index (AI), ALT, and AST activities were analyzed. The pathological alterations in the hepatic tissues were examined microscopically and scored. The results revealed that the HFD diet significantly increased the final body weight, serum AI, and serum levels of liver enzymes. Treatment with L-carnitine or Nigella sativa significantly normalized the lipid profile and decreased the final body weight, serum AI, and Serum ALT. Histopathological examination of the liver of HFD received rats showed features of steatosis, which were mitigated by the administration of Nigella sativa or L-Carnitine, while atorvastatin had no significant effect on the improvement of hepatic lesions. Collectively, study findings showed that Nigella sativa or L-Carnitine has mitigated effects on metabolic and histopathological changes in the liver tissues of rats fed with HFD.
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Affiliation(s)
- Mohammed Esmail
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Shehata Anwar
- Pathology Department, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62511, Beni-Suef, Egypt.
| | - Mohammed Kandeil
- Biochemistry Department, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62511, Beni-Suef, Egypt
| | - Ali Mahmoud El-Zanaty
- Chemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Mohammed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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Amzolini AM, Forţofoiu MC, Barău Abu-Alhija A, Vladu IM, Clenciu D, Mitrea A, Forţofoiu M, Matei D, Enăchescu V, Predescu OI, Micu ES. Triglyceride and glucose index: a useful tool for non-alcoholic liver disease assessed by liver biopsy in patients with metabolic syndrome? ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2021; 62:475-480. [PMID: 35024735 PMCID: PMC8848285 DOI: 10.47162/rjme.62.2.13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is associated with metabolic impairments, being a component of metabolic syndrome. Considering the involvement of fat accumulation and insulin resistance in NAFLD, triglyceride and glucose (TyG) index was proposed as a marker of NAFLD progression. The "gold standard" for the evaluation of liver lesions characteristic for NAFLD remains the liver biopsy. The aim of this study was to establish the links between TyG index, assessing insulin resistance, and histopathological lesions of liver samples obtained by liver biopsy in patients with metabolic syndrome. PATIENTS, MATERIALS AND METHODS We conducted a study over a period of three years, including 113 adult patients with metabolic syndrome in whom hepatic disorders were assessed by liver biopsy and insulin resistance was evaluated by TyG index. RESULTS AND DISCUSSIONS In our study, steatosis had a frequency of 92.03%, being identified 26 cases with mild steatosis, 48 with moderate steatosis and 31 with severe steatosis. Regarding non-alcoholic steatohepatitis (NASH), the frequency of this disorder in our study group was 29.2% in the subjects with liver steatosis, while liver fibrosis had a frequency of 53.09%. When we analyzed the relationships between TyG index and the presence of each type of lesion necessary for NASH diagnosis, we obtained statistically significant differences for the presence of hepatocyte ballooning (p=0.01) and a high statistically significance for the NAFLD activity score (NAS) (p<0.0001). CONCLUSIONS TyG index is a facile tool that can be used to identify patients at risk for advanced NAFLD lesions evaluated by liver biopsy.
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Affiliation(s)
- Anca Maria Amzolini
- Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy of Craiova, Romania; , ; Department of Nursing, Faculty of Nursing, Târgu Jiu Subsidiary, Titu Maiorescu University, Bucharest, Romania;
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Roeb E. Non-alcoholic fatty liver diseases: current challenges and future directions. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:726. [PMID: 33987424 PMCID: PMC8106107 DOI: 10.21037/atm-20-3760] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver diseases (NAFLD) is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries within the next years. This review focusses on the definition of NAFLD and NASH, possible screening mechanisms and the question who should be screened. Still there is a need for non-invasive diagnostic tools and biomarkers for NASH that can quickly and easily diagnose the severity of NAFLD, monitor liver changes, and identify high risk patients. In addition, treatment strategies are discussed as well as the clientele, who should be treated. There are currently no drugs approved for NAFLD. Successful clinical studies with e.g., obeticholic acid and new substances (e.g., cenicriviroc with anti-inflammatory activity) have already been published. If weight-reducing diets and a change in lifestyle fail in the case of severe obesity, bariatric surgery (e.g., gastric bypass or stomach reduction) should be considered. In the case of manifest type 2 diabetes, metformin can be used as an oral antidiabetic of first choice, and GLP-1 agonists have shown beneficial effects on NAFLD. However, up to now the prevention of overweight and lack of exercise targets the most important risk factors. This review aims to identify therapy relevant risk factors, management strategies, and open questions concerning NAFLD patients.
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Affiliation(s)
- Elke Roeb
- Justus-Liebig-University Giessen, University Hospital UKGM, Giessen, Germany
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Sex difference in the tolerance of hepatic ischemia-reperfusion injury and hepatic estrogen receptor expression according to age and macrosteatosis in healthy living liver donors. Transplantation 2021; 106:337-347. [PMID: 33982906 DOI: 10.1097/tp.0000000000003705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hepatic estrogen signaling, which is important in liver injury/recovery, is determined by the level of systemic estrogen and hepatic estrogen receptor. We aimed to evaluate whether female's advantage in the tolerance of hepatic ischemia-reperfusion injury decreases according to the age of 40 y (systemic estrogen decrease) and macrosteatosis (hepatic estrogen receptor decrease). METHODS We included 358 living liver donors (128 females and 230 males). The tolerance of hepatic ischemia-reperfusion injury was determined by the slope of the linear regression line modeling the relationship between the duration of intraoperative hepatic ischemia and the peak postoperative transaminase level. Estrogen receptor content was measured in the biopsied liver samples using immunohistochemistry. RESULTS In the whole cohort, the regression slope for aspartate transaminase was comparable between females and males (P=0.940). Within the subgroup of ≤40 y donors, the regression slope was significantly smaller in females (P=0.031), whereas it was comparable within >40 y donors (P=0.867). Within the subgroup of ≤40 y non-macrosteatotic donors, the regression slope was significantly smaller in females in univariable (P=0.002) and multivariable analysis (P=0.006), whereas the sex difference was not found within ≤40 y macrosteatotic donors (P=0.685). Estrogen receptor content was significantly greater in females within ≤40 y non-macrosteatotic donors (P=0.021), whereas it was not different in others of >40 y or with macrosteatosis (P=0.450). CONCLUSIONS The tolerance of hepatic ischemia-reperfusion injury was greater in females than in males only when they were <40 y and without macrosteatosis. The results were in agreement with hepatic estrogen receptor immunohistochemistry study.
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Rashu EB, Werge MP, Hetland LE, Junker AE, Jensen MK, Gluud LL. Referral Patterns for Patients with Nonalcoholic Fatty Liver Disease. J Clin Med 2021; 10:jcm10030404. [PMID: 33494361 PMCID: PMC7866077 DOI: 10.3390/jcm10030404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/14/2021] [Accepted: 01/17/2021] [Indexed: 11/16/2022] Open
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing. This study evaluates the referral pattern of patients with NAFLD. A cohort study evaluating all patients with NAFLD referred to a single Gastroenterology Department from January 2017 to June 2020. Electronic patient referral letters were reviewed, and patients with NAFLD were diagnosed using standardized tests as part of a prospective cohort study. Predictors of nonalcoholic steatohepatitis (NASH) with significant (≥F2) fibrosis were evaluated in logistic regression analyses. In total, 323 (18.6%) of 1735 patients referred to the Gastro Unit during the study period were diagnosed with NAFLD. Patients were referred from general practitioners (62.5%) or other hospital departments (37.5%). Most referral letters included information suggesting a possible diagnosis of NAFLD (patient history, blood tests, or diagnostic imaging) or used the nonspecific general diagnosis suspected disease (Z.038). Out of 110 patients referred for a liver biopsy, 71 (22%) had NASH with significant fibrosis (F2 n = 39, F3 n = 19, F4 n = 13). Thirty-nine of these patients were referred from the primary sector. A logistic regression analysis (adjusted for age and gender) including all 323 patients showed that type 2 diabetes was the only significant independent predictor of NASH with fibrosis.
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Affiliation(s)
- Elias Badal Rashu
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; (E.B.R.); (M.P.W.); (L.E.H.); (A.E.J.)
| | - Mikkel Parsberg Werge
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; (E.B.R.); (M.P.W.); (L.E.H.); (A.E.J.)
| | - Liv Eline Hetland
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; (E.B.R.); (M.P.W.); (L.E.H.); (A.E.J.)
| | - Anders Ellekaer Junker
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; (E.B.R.); (M.P.W.); (L.E.H.); (A.E.J.)
| | - Majken Karoline Jensen
- Section of Epidemiology, Department of Public Health, University of Copenhagen, 1356 Copenhagen, Denmark;
| | - Lise Lotte Gluud
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; (E.B.R.); (M.P.W.); (L.E.H.); (A.E.J.)
- Correspondence: ; Tel.: +45-3862-1964
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Salehi E, Mashayekh M, Taheri F, Gholami M, Motaghinejad M, Safari S, Sepehr A. Curcumin Can be Acts as Effective agent for Prevent or Treatment of Alcohol-induced Toxicity in Hepatocytes: An Illustrated Mechanistic Review. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:418-436. [PMID: 34400970 PMCID: PMC8170768 DOI: 10.22037/ijpr.2020.112852.13985] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Previous studies have shown that alcohol abuse can cause serious liver damage and cirrhosis. The main pathway for these types of hepatocellular cell neurodegeneration is mitochondrial dysfunction, which causes lipid peroxidation and dysfunction of the glutathione ring and the defect of antioxidant enzymes in alcoholic hepatic cells. Alcohol can also initiate malicious inflammatory pathways and trigger the initiation and activation of intestinal and extrinsic apoptosis pathways in hepatocellular tissues that lead to cirrhosis. Previous studies have shown that curcumin may inhibit lipid peroxidation, glutathione dysfunction and restore antioxidant enzymes. Curcumin also modulates inflammation and the production of alcohol-induced biomarkers. Curcumin has been shown to play a critical role in the survival of alcoholic hepatocellular tissue. It has been shown that curcumin can induce and trigger mitochondrial biogenesis and, by this mechanism, prevent the occurrence of both intrinsic and extrinsic apoptosis pathways in liver cells that have been impaired by alcohol. According to this mechanism, curcumin may protect hepatocellular tissue from alcohol-induced cell degeneration and may therefore survive alcoholic hepatocellular tissue. . Based on these mechanisms, the protective functions of curcumin against alcohol-induced cell degeneration due to oxidative stress, inflammation, and apoptosis events in hepatocellular tissue have been recorded. Hence, in this research, we have attempted to evaluate and analyze the main contribution mechanism of curcumin cell defense properties against alcohol-induced hepatocellular damage, according to previous experimental and clinical studies, and in this way we report findings from major studies.
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Affiliation(s)
- Elham Salehi
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University (IUAPS), Tehran, Iran.
| | - Mohammad Mashayekh
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University (IUAPS), Tehran, Iran.
| | - Fereshteh Taheri
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Mina Gholami
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Majid Motaghinejad
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Sepideh Safari
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Afrah Sepehr
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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[Histopathological diagnosis and differential diagnosis of nonalcoholic fatty liver disease]. DER PATHOLOGE 2020; 41:434-443. [PMID: 32533233 DOI: 10.1007/s00292-020-00800-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Fatty liver disease is a rising problem worldwide, particularly due to metabolic syndrome. The current prevalence is 20-30%, but a further increase is expected whereby children will also be increasingly affected. The presence of fat in hepatocytes is known as steatosis or, in the case of nonalcoholic origin, nonalcoholic fatty liver (NAFL). It is basically reversible, but can progress to steatohepatitis (NASH) as an active and progressive form of fatty liver disease due to continuous cell damage. This leads to progressive liver fibrosis up to end-stage liver cirrhosis. The gold standard of diagnosis is liver biopsy, in which obesity, inflammation, and hepatocellular damage (hepatocellular ballooning) are assessed for the distinction between NAFL and NASH. The extent of fibrosis indicates the progress of the disease. Childhood and adult fatty liver diseases differ morphologically, particularly in the location and amount of fat, inflammation, and fibrosis. Alcoholic and nonalcoholic fatty liver disease/steatohepatitis cannot be reliably differentiated by histology. Clinical parameters must also be taken into consideration for the differential diagnosis of other diseases associated with fatty liver. The main therapeutic goal is to reduce insulin resistance, which can be achieved through weight loss and lifestyle changes. Recently, however, drug therapies have also become available as a promising therapeutic option.
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Kim YS, Kim SG. Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases. Clin Mol Hepatol 2020; 26:715-727. [PMID: 32951410 PMCID: PMC7641579 DOI: 10.3350/cmh.2020.0173] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/31/2020] [Indexed: 12/15/2022] Open
Abstract
Alcoholic and non-alcoholic liver diseases begin from an imbalance in lipid metabolism in hepatocytes as the earliest response. Both liver diseases share common disease features and stages (i.e., steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma). However, the two diseases have differential pathogenesis and clinical symptoms. Studies have elucidated the molecular basis underlying similarities and differences in the pathogenesis of the diseases; the factors contributing to the progression of liver diseases include depletion of sulfhydryl pools, enhanced levels of reactive oxygen and nitrogen intermediates, increased sensitivity of hepatocytes to toxic cytokines, mitochondrial dysfunction, and insulin resistance. Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins and calcium depletion, contributes to the pathogenesis, often causing catastrophic cell death. Several studies have demonstrated a mechanism by which ER stress triggers liver disease progression. Autophagy is an evolutionarily conserved process that regulates organelle turnover and cellular energy balance through decomposing damaged organelles including mitochondria, misfolded proteins, and lipid droplets. Autophagy dysregulation also exacerbates liver diseases. Thus, autophagy-related molecules can be potential therapeutic targets for liver diseases. Since ER stress and autophagy are closely linked to each other, an understanding of the molecules, gene clusters, and networks engaged in these processes would be of help to find new remedies for alcoholic and non-alcoholic liver diseases. In this review, we summarize the recent findings and perspectives in the context of the molecular pathogenesis of the liver diseases.
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Affiliation(s)
- Yun Seok Kim
- College of Pharmacy, Seoul National University, Seoul, Korea
| | - Sang Geon Kim
- College of Pharmacy, Seoul National University, Seoul, Korea.,College of Pharmacy, Dongguk University, Goyang, Korea
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Endocan: A Biomarker for Hepatosteatosis in Patients with Metabolic Syndrome. Mediators Inflamm 2020; 2020:3534042. [PMID: 32317862 PMCID: PMC7152978 DOI: 10.1155/2020/3534042] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 02/19/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, which has recently been mentioned as an independent cardiovascular risk factor. Objectives Endocan is a novel molecule of endothelial dysfunction. We aimed to evaluate the associations of serum endocan levels with the hepatic steatosis index (HSI), fatty liver index (FLI), and degrees of hepatosteatosis in patients with metabolic syndrome with NAFLD. Design and Setting. This cross-sectional prospective study was performed in the outpatient clinic of an internal medicine department. Methods The study included 40 patients with metabolic syndrome with NAFLD as noted using hepatic ultrasound and 20 healthy controls. Secondary causes of fatty liver were excluded. FLI and HSI calculations were recorded. Serum endocan level values were obtained after overnight fasting. Results Higher values of HSI and FLI were found in the NAFLD groups than in the control groups (p < 0.001). Five (12.5%) of 20 patients with liver steatosis had grade 1 liver steatosis, 15 (37.5%) patients had grade 2 liver steatosis, and 20 (50%) patients had grade 3 liver steatosis. Serum endocan levels were lower in patients with NAFLD compared with the healthy controls (146.56 ± 133.29 pg/mL vs. 433.71 ± 298.01 pg/mL, p < 0.001). ROC curve analysis suggested that the optimum endocan value cutoff point for NAFLD was 122.583 pg/mL (sensitivity: 71.79%, specificity: 90%, PPV: 93.3%, and NPV: 62.1%). Conclusion Serum endocan concentrations are low in patients with NAFLD, and the optimum cutoff point is 122.583 pg/mL. HSI and FLI were higher in patients with NAFLD; however, there was no correlation with serum endocan.
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Roeb E. Das klinische Bild der nichtalkoholischen Fettlebererkrankung. DER GASTROENTEROLOGE 2020; 15:78-87. [DOI: 10.1007/s11377-020-00425-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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40
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Kumar R, Goh BBG, Kam JW, Chang PE, Tan CK. Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma. Clin Mol Hepatol 2020; 26:196-208. [PMID: 31914720 PMCID: PMC7160352 DOI: 10.3350/cmh.2019.0012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 07/29/2019] [Indexed: 12/11/2022] Open
Abstract
Background/Aims Non-alcoholic liver disease and alcoholic liver disease begin as simple steatosis that may progress to steatohepatitis and ensuing liver-related complications such as cirrhosis and hepatocellular carcinoma (HCC). We explored differences in characteristics between non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis-related (ASH) HCC.
Methods NASH and ASH patients were identified from our department’s prospective HCC database. A total of 54 and 45 patients met predefined inclusion and exclusion criteria for the NASH-HCC and ASH-HCC groups, respectively. Clinical, biochemical and tumor characteristics were studied.
Results NASH-HCC patients were older compared to ASH-HCC patients (72±9 vs. 66±9 years, P<0.001) and less male predominant (65% vs. 98%, P<0.001). Prevalence of diabetes mellitus (78% vs. 36%, P<0.001) and hypertension (80% vs. 58%, P<0.001) were significantly higher in the NASH-HCC group. Liver function tests and Child-Pugh scores were similar. There were no differences in alpha-fetoprotein level, lesions found at diagnosis (unifocal/multifocal) or prevalence of portal vein invasion. In both groups, almost half of the patients were in TNM stage 4 at the time of diagnosis and more than 50% of patients were not suitable for any therapy. Median survival in the NASH-HCC and ASH-HCC groups were 13 and 7 months respectively (P=0.113).
Conclusions Despite significant differences in demography of the NASH-HCC and ASH-HCC groups, liver and tumor characteristics were comparable. Most patients were diagnosed late and were not amenable to curative or locoregional therapies. Better characterization of patients with NASH and ASH at risk of HCC is necessary to optimize screening, surveillance, and management strategies.
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Affiliation(s)
- Rahul Kumar
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Boon-Bee George Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Jia-Wen Kam
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Pik-Eu Chang
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Chee-Kiat Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
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Samji NS, Verma R, Keri KC, Singal AK, Ahmed A, Rinella M, Bernstein D, Abdelmalek MF, Satapathy SK. Liver Transplantation for Nonalcoholic Steatohepatitis: Pathophysiology of Recurrence and Clinical Challenges. Dig Dis Sci 2019; 64:3413-3430. [PMID: 31312990 DOI: 10.1007/s10620-019-05716-1] [Citation(s) in RCA: 6] [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: 01/06/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023]
Abstract
Nonalcoholic steatohepatitis is the fastest-growing indication for the liver transplant and a leading cause of hepatocellular carcinoma among patients listed for liver transplantation in the USA. Post-transplant nonalcoholic hepatic steatosis and steatohepatitis are frequent complications of liver transplantation. Nonalcoholic steatohepatitis poses a significant challenge in both pre- and post-transplant period due to its association with metabolic syndrome, coronary artery disease, chronic kidney disease, and obstructive sleep apnea. While optimal therapy is not yet available in the post-liver transplant setting, lifestyle interventions continue to remain as the mainstay of therapy for post-transplant nonalcoholic steatohepatitis. Early recognition with protocol biopsies and noninvasive modalities, along with modification of known risk factors, are the most effective methods to curtail the progression of nonalcoholic steatohepatitis in the absence of FDA-approved pharmacologic therapy.
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Affiliation(s)
- Naga Swetha Samji
- Tennova Cleveland Hospital, 2305 Chambliss Ave NW, Cleveland, TN, 37311, USA
| | - Rajanshu Verma
- Division of Transplant Surgery, Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | | | - Ashwani K Singal
- University of South Dakota Sanford School of Medicine, Avera Transplant Institute, S. Cliff Ave, Sioux Falls, SD, 57105, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Mary Rinella
- Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - David Bernstein
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology/Hepatology, Duke University, 40 Duke Medicine Cir, Durham, NC, USA
| | - Sanjaya K Satapathy
- Division of Hepatology at Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Manhasset, NY, 11030, USA.
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Beck JR, Cabral F, Rasineni K, Casey CA, Harris EN, Stains CI. A Panel of Protein Kinase Chemosensors Distinguishes Different Types of Fatty Liver Disease. Biochemistry 2019; 58:3911-3917. [PMID: 31433166 DOI: 10.1021/acs.biochem.9b00547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The worldwide incidence of fatty liver disease continues to rise, which may account for concurrent increases in the frequencies of more aggressive liver ailments. Given the existence of histologically identical fatty liver disease subtypes, there is a critical need for the identification of methods that can classify disease and potentially predict progression. Herein, we show that a panel of protein kinase chemosensors can distinguish fatty liver disease subtypes. These direct activity measurements highlight distinct differences between histologically identical fatty liver diseases arising from diets rich in fat versus alcohol and identify a previously unreported decrease in p38α activity associated with a high-fat diet. In addition, we have profiled kinase activities in both benign (diet-induced) and progressive (STAM) disease models. These experiments provide temporal insights into kinase activity during disease development and progression. Altogether, this work provides the basis for the future development of clinical diagnostics and potential treatment strategies.
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Affiliation(s)
- Jon R Beck
- Department of Chemistry , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States
| | - Fatima Cabral
- Department of Biochemistry , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States
| | - Karuna Rasineni
- Division of Gastroenterology-Hepatology , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States.,Research Service, Veterans' Affairs , Nebraska-Western Iowa Health Care System , Omaha , Nebraska 68105 , United States
| | - Carol A Casey
- Division of Gastroenterology-Hepatology , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States.,Research Service, Veterans' Affairs , Nebraska-Western Iowa Health Care System , Omaha , Nebraska 68105 , United States.,Nebraska Center for Integrated Biomolecular Communication , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States
| | - Edward N Harris
- Department of Biochemistry , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States.,Nebraska Center for Integrated Biomolecular Communication , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States.,Cancer Genes and Molecular Regulation Program, Fred & Pamela Buffet Cancer Center , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Cliff I Stains
- Department of Chemistry , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States.,Nebraska Center for Integrated Biomolecular Communication , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States.,Cancer Genes and Molecular Regulation Program, Fred & Pamela Buffet Cancer Center , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States.,Department of Chemistry , University of Virginia , Charlottesville , Virginia 22904 , United States
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Chan SMH, Selemidis S, Bozinovski S, Vlahos R. Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies. Pharmacol Ther 2019; 198:160-188. [PMID: 30822464 PMCID: PMC7112632 DOI: 10.1016/j.pharmthera.2019.02.013] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and is currently the 4th largest cause of death in the world. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities (e.g. skeletal muscle wasting, ischemic heart disease, cognitive dysfunction) and infective viral and bacterial acute exacerbations (AECOPD). Current pharmacological treatments for COPD are relatively ineffective and the development of effective therapies has been severely hampered by the lack of understanding of the mechanisms and mediators underlying COPD. Since comorbidities have a tremendous impact on the prognosis and severity of COPD, the 2015 American Thoracic Society/European Respiratory Society (ATS/ERS) Research Statement on COPD urgently called for studies to elucidate the pathobiological mechanisms linking COPD to its comorbidities. It is now emerging that up to 50% of COPD patients have metabolic syndrome (MetS) as a comorbidity. It is currently not clear whether metabolic syndrome is an independent co-existing condition or a direct consequence of the progressive lung pathology in COPD patients. As MetS has important clinical implications on COPD outcomes, identification of disease mechanisms linking COPD to MetS is the key to effective therapy. In this comprehensive review, we discuss the potential mechanisms linking MetS to COPD and hence plausible therapeutic strategies to treat this debilitating comorbidity of COPD.
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Affiliation(s)
- Stanley M H Chan
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Stavros Selemidis
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Steven Bozinovski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Ross Vlahos
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
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Liu Z, Jia J, Ning H, Que S, Zhou L, Zheng S. Systematic Evaluation of the Safety Threshold for Allograft Macrovesicular Steatosis in Cadaveric Liver Transplantation. Front Physiol 2019; 10:429. [PMID: 31105577 PMCID: PMC6494939 DOI: 10.3389/fphys.2019.00429] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/28/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Currently, 30% macrovesicular steatosis (MaS) content is usually assigned empirically as the boundary between “use” and “refuse” a donor liver for liver transplantation (LT); however, this cut-off is questionable due to the lack of systemic evidence of the efficiency relative to prognosis prediction. Clinicians have tried to identify the threshold for optimized utilization of marginal steatotic allografts, but controversy exists among different studies. Aim: Our study aimed to systematically determine an acceptable donor MaS content cut-off without incurring extra risk in liver transplantation, using meta-analysis. Methods: The relevant literature reporting the relationship between MaS content and post-transplant mortality/morbidity was searched and retrieved in Pubmed, Embase, and ISI Web of Science. Results: Nine studies were enrolled into the final analysis. A categorical comparison revealed that patients who received allografts with moderate steatosis (MaS content >30%) had significantly higher risks of graft failure/dysfunction, but not of mortality. Dose-response analysis showed that donor MaS content affected the graft failure/dysfunction in a non-linear relationship. Risks associated with MaS content in terms of poorer outcomes were independent of other risk covariates for liver transplantation. A non-significant increase in risk of inferior post-transplant outcomes was observed in patients who received allografts with a MaS content <35%. The risks of post-transplant graft failure and dysfunction increased with severe donor MaS content infiltration, without a consistent relationship. Conclusions: The threshold of allograft MaS content can be safely extended to 35% without additional risk burden on post-transplant inferior outcomes. Clarification on “the effects of stratification” for MaS content can provide theoretical evidence for further optimal utilization of marginal steatotic allografts in liver transplantation.
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Affiliation(s)
- Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Huaijun Ning
- Department of Pediatrics, Women and Children's Hospital of Guangxi, Nanning, China
| | - Shuping Que
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lin Zhou
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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The Relevance of Toxic AGEs (TAGE) Cytotoxicity to NASH Pathogenesis: A Mini-Review. Nutrients 2019; 11:nu11020462. [PMID: 30813302 PMCID: PMC6412438 DOI: 10.3390/nu11020462] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/18/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most common feature of chronic liver disease. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD, and one of its risk factors is hyperglycemia. The chronic ingestion of excessive amounts of high-fructose corn syrup is associated with an increased prevalence of fatty liver. Under hyperglycemic conditions, advanced glycation end-products (AGEs) are generated through a non-enzymatic glycation reaction between the ketone or aldehyde groups of sugars and amino groups of proteins. Glyceraldehyde (GA) is a metabolic intermediate of sugars, and GA-derived AGEs (known as toxic AGEs (TAGE)) have been implicated in the development of NASH. TAGE accumulates more in serum or liver tissue in NASH patients than in healthy controls or patients with simple steatosis. Furthermore, the TAGE precursor, GA, causes cell damage through protein dysfunctions by TAGE modifications and induces necrotic-type hepatocyte death. Intracellular TAGE may leak outside of necrotic-type cells. Extracellular TAGE then induce inflammatory or fibrotic responses related to the pathology of NASH in surrounding cells, including hepatocytes and hepatic stellate cells. This review focuses on the contribution of TAGE to the pathology of NASH, particularly hepatic cell death related to NASH.
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Elias E, Uhanova J, Li Q, Zhang M, Minuk G. Serum immunoglobulin A levels and non-alcoholic fatty liver disease. CANADIAN LIVER JOURNAL 2018; 1:248-255. [PMID: 35992620 PMCID: PMC9202761 DOI: 10.3138/canlivj.2018-0005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 04/21/2018] [Indexed: 11/29/2024]
Abstract
BACKGROUND Intestinal immunity, and immunoglobulin A (IgA) in particular, may play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to document the prevalence of elevated serum IgA levels in NAFLD patients and determine whether the severity and course of NAFLD differs in those with elevated (E-IgA) versus normal (N-IgA) levels. METHODS A retrospective review of a clinical database containing demographic, laboratory, and histologic findings of adult NAFLD patients was undertaken. Liver biochemistry, model for end stage-liver disease (MELD) and Fib-4 scores served to document disease severity and progression. RESULTS Of 941 NAFLD study subjects, 254 (27%) had E-IgA at presentation. E-IgA patients were older, and had lower serum albumin levels and higher MELD scores than N-IgA patients. The percent of E-IgA patients with Fib-4 scores >3.25 (suggestive of cirrhosis) was also higher (25% vs. 5.5%, p<0.001). E-IgA patients had higher METIVIR fibrosis scores (2.2 ± 1.4 vs. 1.0 ± 1.2, p<0.0001) than N-IgA patients. After mean follow-ups of 47 (E-IgA) and 41 (N-IgA) months, serum albumin levels remained lower, INR values were now more prolonged and MELD scores higher in E-IgA patients. Of the non-cirrhotic patients at baseline, a larger percent of E-IgA patients developed cirrhosis by Fib-4 testing at last visit (11% vs. 2.9%, p<0.001). CONCLUSIONS Elevated serum IgA levels are common in NAFLD patients and when present, are associated with more advanced disease. Patients with elevated serum IgA levels are also more likely to progress to cirrhosis than those with normal levels.
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Affiliation(s)
- Evan Elias
- Section of Hepatology, Department of Medicine and 2 Department of Pharmacology and Therapeutics, University of Manitoba, John Buhler Research Centre, Winnipeg, Manitoba
| | - Julia Uhanova
- Section of Hepatology, Department of Medicine and 2 Department of Pharmacology and Therapeutics, University of Manitoba, John Buhler Research Centre, Winnipeg, Manitoba
| | - Qian Li
- Section of Hepatology, Department of Medicine and 2 Department of Pharmacology and Therapeutics, University of Manitoba, John Buhler Research Centre, Winnipeg, Manitoba
| | - Manna Zhang
- Section of Hepatology, Department of Medicine and 2 Department of Pharmacology and Therapeutics, University of Manitoba, John Buhler Research Centre, Winnipeg, Manitoba
| | - Gerald Minuk
- Section of Hepatology, Department of Medicine and 2 Department of Pharmacology and Therapeutics, University of Manitoba, John Buhler Research Centre, Winnipeg, Manitoba
- University of Manitoba, College of Medicine, Winnipeg, Manitoba
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Braun HA, Faasse SA, Vos MB. Advances in Pediatric Fatty Liver Disease: Pathogenesis, Diagnosis, and Treatment. Gastroenterol Clin North Am 2018; 47:949-968. [PMID: 30337043 DOI: 10.1016/j.gtc.2018.07.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Pediatric nonalcoholic fatty liver disease is an increasingly prevalent disease, but its pathophysiology is not fully elucidated, diagnosis is difficult and invasive, and therapeutic options are limited. This article addresses the recent advancements made in understanding the pathophysiology of nonalcoholic fatty liver disease, the development of less invasive diagnostic modalities, and emerging therapeutic options, including ongoing clinical trials in children.
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Affiliation(s)
- Hayley A Braun
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive North East, Atlanta, GA 30322, USA.
| | - Sarah A Faasse
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive North East, Atlanta, GA 30322, USA; Division of Gastroenterology, Hepatology, and Nutrition, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA 30329, USA
| | - Miriam B Vos
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive North East, Atlanta, GA 30322, USA; Division of Gastroenterology, Hepatology, and Nutrition, Children's Healthcare of Atlanta, 1405 Clifton Road, Atlanta, GA 30329, USA
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Balzano T, Forteza J, Borreda I, Molina P, Giner J, Leone P, Urios A, Montoliu C, Felipo V. Histological Features of Cerebellar Neuropathology in Patients With Alcoholic and Nonalcoholic Steatohepatitis. J Neuropathol Exp Neurol 2018; 77:837-845. [PMID: 30016459 DOI: 10.1093/jnen/nly061] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) affect 29 million people in the European Union. Patients with ASH and NASH may exhibit cognitive impairment, reducing their quality of life. Steatohepatitis induces cerebral alterations. It is not known if histological analysis could allow distinguishing ASH, NASH, and/or cirrhosis neuropathology and other entities. The aim of this work was to analyze a set of histopathological features characterizing the brain lesions due to ASH, NASH, and cirrhosis. We performed a histological study using hematoxylin and eosin staining and immunohistochemical techniques in cerebellum of 31 subjects who died with healthy liver (n = 6), NASH (n = 14), ASH (n = 3), nonalcoholic cirrhosis (n = 4), and alcoholic cirrhosis (n = 4). We analyzed in cerebellum, as an early marker for brain injury: 1) vascular damage; 2) cerebellar atrophy and neurodegeneration in Purkinje layer; and 3) microglia and astrocytes activation in white matter and molecular layer. Patients with steatohepatitis have increased number of microtrombi in cerebellar parenchyma, neuronal loss in Purkinje layer and microglial and astrocyte activation in white matter and molecular layer. These alterations are stronger in patients with ASH than in those with NASH. These results provide a set of histopathological features in brain that may allow differentiation of steatohepatitis from other conditions.
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Affiliation(s)
- Tiziano Balzano
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Spain
| | - Jerónimo Forteza
- Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular. Centro Investigación Príncipe Felipe/Universidad Católica, Valencia, Spain
| | - Irene Borreda
- Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular. Centro Investigación Príncipe Felipe/Universidad Católica, Valencia, Spain
| | - Pilar Molina
- Instituto de Medicina Legal y Ciencias Forenses, Valencia, Spain
- Departamento de Patología, Facultad de Medicina, Universidad de Valencia, Spain
| | - Juan Giner
- Instituto de Medicina Legal y Ciencias Forenses, Valencia, Spain
| | - Paola Leone
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Spain
| | - Amparo Urios
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Spain
| | - Carmina Montoliu
- Departamento de Patología, Facultad de Medicina, Universidad de Valencia, Spain
- Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Spain
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Milroy CM. Fatty Liver and the Forensic Pathologist. Acad Forensic Pathol 2018; 8:296-310. [PMID: 31240043 PMCID: PMC6490134 DOI: 10.1177/1925362118782061] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 04/23/2018] [Indexed: 12/13/2022]
Abstract
Fatty liver is a common finding in clinical practice and at autopsy. It is most commonly seen associated with alcohol abuse and in non-alcoholic fatty liver disease (NAFLD). It may also be seen in many other conditions in both adults and children. It is now recognized that NAFLD, like alcoholic liver disease, may lead to end stage liver disease. Nonalcoholic fatty liver disease is associated with increased mortality from other disorders, particularly cardiovascular diseases. Fatty liver may be seen in many conditions that concern autopsy pathologists, including drug toxicity, anorexia, hepatic ischemia, and heatstroke. In infants, steatosis is common in sudden unexpected deaths. Fatty liver has been associated with sudden death and this review examines the pathology and role of fatty liver in sudden death. Acad Forensic Pathol. 2018 8(2): 296-310.
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Dumitrascu DL, Neuman MG. Non-alcoholic fatty liver disease: an update on diagnosis. CLUJUL MEDICAL (1957) 2018; 91:147-150. [PMID: 29785151 PMCID: PMC5958978 DOI: 10.15386/cjmed-993] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 01/17/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM The non-alcoholic fatty liver disease (NAFLD) and its sub-entity, the non-alcoholic steatohepatitis (NASH) represent a field of a tremendous progress in recent years. Clinicians need to remain updated with new data on pathogenesis and therapy. The present mini review aims to present some new scientific reports on the diagnosis of NAFLD and NASH for clinical practitioners. METHODS A systematic literature search of the main international databases was performed. We looked for seminal and innovative papers published in main international languages. A narrative review of the topic was consequently written. RESULTS This review describes new data on the diagnosis of NAFLD including NASH. Liver punction biopsy remains the gold standard. However many patients and clinicians prefer to use noninvasive methods. We present the serological tests and the imaging methods used to diagnose inflammation and fibrosis occurring in NAFLD and NASH. CONCLUSIONS NAFLD-NASH are multifaceted entities that have to be diagnosed and treated by skilled and informed practitioners.
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Affiliation(s)
- Dan L Dumitrascu
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Manuela G Neuman
- In Vitro Drug Safety and Biotechnology; Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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