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Sogabe M, Okahisa T, Kagawa M, Kashihara T, Shinomiya R, Miyake T, Kawaguchi T, Yokoyama R, Kagemoto K, Kida Y, Okada Y, Tomonari T, Kawano Y, Sato Y, Nakasono M, Takayama T. The association between alcohol consumption and cardiometabolic factors and liver fibrosis in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction and alcohol-associated liver disease. Aliment Pharmacol Ther 2024; 60:1587-1598. [PMID: 39310953 DOI: 10.1111/apt.18280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/27/2024] [Accepted: 09/02/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND The relationships between alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease and those with metabolic dysfunction and alcohol-associated liver disease remain unclear. AIMS To investigate the longitudinal associations among alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with these two liver diseases. METHODS This observational cohort study included 1866 patients with metabolic dysfunction-associated steatotic liver disease and 521 patients with metabolic dysfunction and alcohol-associated liver disease who underwent > two health checkups over >2 years. The associations of both liver diseases with worsening non-invasive liver fibrosis scores were assessed using the Cox regression analysis. RESULTS Both liver diseases independently worsened liver fibrosis in both sexes. However, the hazard ratio for worsening liver fibrosis in females was significantly higher with metabolic dysfunction and alcohol-associated liver disease than with metabolic dysfunction-associated steatotic liver disease. Worsening liver fibrosis was not associated with alcohol consumption. Among males with metabolic dysfunction-associated steatotic liver disease, the hazard ratio for worsening liver fibrosis was significantly higher in those with multiple cardiometabolic factors compared to those with a single cardiometabolic factor. CONCLUSIONS Although both metabolic steatotic liver disease and metabolic alcohol-associated liver disease were correlated with liver fibrosis progression in both sexes, the impact of alcohol consumption and cardiometabolic factors on fibrosis progression differed by sex. Cardiometabolic factors may have a stronger impact on liver fibrosis than alcohol consumption in males with metabolic dysfunction-associated steatotic liver disease.
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Affiliation(s)
- Masahiro Sogabe
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Internal Medicine, Shikoku Central Hospital of the Mutual Aid Association of Public School Teachers, Shikokuchuo City, Ehime, Japan
| | - Toshiya Okahisa
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Internal Medicine, Shikoku Central Hospital of the Mutual Aid Association of Public School Teachers, Shikokuchuo City, Ehime, Japan
| | - Miwako Kagawa
- Department of Internal Medicine, Shikoku Central Hospital of the Mutual Aid Association of Public School Teachers, Shikokuchuo City, Ehime, Japan
| | - Takanori Kashihara
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Internal Medicine, Shikoku Central Hospital of the Mutual Aid Association of Public School Teachers, Shikokuchuo City, Ehime, Japan
| | - Ryo Shinomiya
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Takanori Miyake
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tomoyuki Kawaguchi
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Reiko Yokoyama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Kaizo Kagemoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yoshifumi Kida
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yasuyuki Okada
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yutaka Kawano
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiko Nakasono
- Department of Internal Medicine, Tsurugi Municipal Handa Hospital, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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Ota T, Soga K, Hayakawa F, Yamaguchi M, Tamano M. Utility of pemafibrate in nonalcoholic steatohepatitis model mice induced by a choline-deficient, high-fat diet and dextran sulfate sodium. Biochem Biophys Rep 2024; 38:101724. [PMID: 38737727 PMCID: PMC11088230 DOI: 10.1016/j.bbrep.2024.101724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/22/2024] [Accepted: 04/26/2024] [Indexed: 05/14/2024] Open
Abstract
Aim The purpose of this study was to examine the effect of pemafibrate in a murine model of non-alcoholic steatohepatitis (NASH). Methods Forty-two, 19-week-old, male, C57BL/6J mice were divided into three groups: a Control group (n = 14), a dextran sulfate sodium (DSS) group (n = 14), and a DSS + PEM group (n = 14). All mice were given a standard rodent diet for the first week, followed by a choline-deficient, high-fat diet (CDHF) for the next 12 weeks. The 22nd day after the animals arrived was taken as Day 1 of the experiment. The Control group continued the CDHF diet and MilliQ water. The DSS group continued the CDHF diet, but starting on Day 1, the group received 0.8 % DSS to drink for 7 consecutive days, followed by MilliQ water for 10 days; this was taken as one course, and it was repeated on the same schedule until autopsy. The DSS + PEM group received the CDHF diet with PEM 0.1 mg/kg/day. Their drinking water was the same as that of the DSS group. On Seven animals from each group were autopsied on each of Day 50 and Day 120, and histopathological and immunohistochemical examinations, as well as quantitative RNA and cytokine measurements, of autopsied mice were performed. Results Pemafibrate improved hepatic steatosis (decreased steatosis area), improved liver inflammation enhanced by DSS (decreased aspartate transaminase and alanine aminotransferase), improved hepatic fibrosis promoted by DSS (decreased fibrotic areas and a marker of fibrosis), inhibited tumorigenesis, and decreased intestinal inflammation in the NASH model mice. Conclusions In a murine model of NASH, mixing PEM 0.1 mg/kg/day into the diet inhibited disease progression and tumor formation.
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Affiliation(s)
- Takahiro Ota
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya-shi, Saitama, 343-8555, Japan
| | - Koichi Soga
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya-shi, Saitama, 343-8555, Japan
| | - Fuki Hayakawa
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya-shi, Saitama, 343-8555, Japan
| | - Mayumi Yamaguchi
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya-shi, Saitama, 343-8555, Japan
| | - Masaya Tamano
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya-shi, Saitama, 343-8555, Japan
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Iwaki M, Yoneda M, Wada N, Otani T, Kobayashi T, Nogami A, Saito S, Nakajima A. Emerging drugs for the treatment of hepatic fibrosis on nonalcoholic steatohepatitis. Expert Opin Emerg Drugs 2024; 29:127-137. [PMID: 38469871 DOI: 10.1080/14728214.2024.2328036] [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: 09/30/2023] [Accepted: 03/05/2024] [Indexed: 03/13/2024]
Abstract
INTRODUCTION Approved drug therapies for nonalcoholic steatohepatitis (NASH) are lacking, for which various agents are currently being tested in clinical trials. Effective drugs for liver fibrosis, the factor most associated with prognosis in NASH, are important. AREAS COVERED This study reviewed the treatment of NASH with a focus on the effects of existing drugs and new drugs on liver fibrosis. EXPERT OPINION Considering the complex pathophysiology of fibrosis in NASH, drug therapy may target multiple pathways. The method of assessing fibrosis is important when considering treatment for liver fibrosis in NASH. The Food and Drug Administration considers an important fibrosis endpoint to be histological improvement in at least one fibrosis stage while preventing worsening of fatty hepatitis. To obtain approval as a drug for NASH, efficacy needs to be demonstrated on endpoints such as liver-related events and myocardial infarction. Among the current therapeutic agents for NASH, thiazolidinedione, sodium-glucose co-transporter 2, and selective peroxisome proliferator-activated receptors α modulator have been reported to be effective against fibrosis, although further evidence is required. The effects of pan-peroxisome proliferator-activated receptors, obeticholic acid, and fibroblast growth factor-21 analogs on liver fibrosis in the development stage therapeutics for NASH are of particular interest.
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Affiliation(s)
- Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Naohiro Wada
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiro Otani
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology, Sanno Hospital, Minato-Ku, Tokyo, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Katsuyama H, Hakoshima M, Kaji E, Mino M, Kakazu E, Iida S, Adachi H, Kanto T, Yanai H. Effects of Once-Weekly Semaglutide on Cardiovascular Risk Factors and Metabolic Dysfunction-Associated Steatotic Liver Disease in Japanese Patients with Type 2 Diabetes: A Retrospective Longitudinal Study Based on Real-World Data. Biomedicines 2024; 12:1001. [PMID: 38790963 PMCID: PMC11118092 DOI: 10.3390/biomedicines12051001] [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: 03/11/2024] [Revised: 04/28/2024] [Accepted: 04/30/2024] [Indexed: 05/26/2024] Open
Abstract
Once-weekly semaglutide is a widely used glucagon-like peptide-1 receptor agonist (GLP-1RA) used for the treatment of type 2 diabetes (T2D). In clinical trials, semaglutide improved glycemic control and obesity, and reduced major cardiovascular events. However, the reports are limited on its real-world efficacy relating to various metabolic factors such as dyslipidemia or metabolic dysfunction-associated steatotic liver disease (MASLD) in Asian patients with T2D. In our retrospective longitudinal study, we selected patients with T2D who were given once-weekly semaglutide and compared metabolic parameters before and after the start of semaglutide. Seventy-five patients were eligible. HbA1c decreased significantly, by 0.7-0.9%, and body weight by 1.4-1.7 kg during the semaglutide treatment. Non-HDL cholesterol decreased significantly at 3, 6 and 12 months after the initiation of semaglutide; LDL cholesterol decreased at 3 and 6 months; and HDL cholesterol increased at 12 months. The effects on body weight, HbA1c and lipid profile were pronounced in patients who were given semaglutide as a first GLP-1RA (GLP-1R naïve), whereas improvements in HbA1c were also observed in patients who were given semaglutide after being switched from other GLP-1RAs. During a 12-month semaglutide treatment, the hepatic steatosis index (HSI) tended to decrease. Moreover, a significant decrease in the AST-to-platelet ratio index (APRI) was observed in GLP-1RA naïve patients. Our real-world study confirmed the beneficial effects of once-weekly semaglutide, namely, improved body weight, glycemic control and atherogenic lipid profile. The beneficial effects on MASLD were also suggested.
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Affiliation(s)
- Hisayuki Katsuyama
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Mariko Hakoshima
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Emika Kaji
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Masaaki Mino
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.M.); (E.K.); (T.K.)
| | - Eiji Kakazu
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.M.); (E.K.); (T.K.)
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Sakura Iida
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Hiroki Adachi
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Tatsuya Kanto
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.M.); (E.K.); (T.K.)
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
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Yasin A, Nguyen M, Sidhu A, Majety P, Spitz J, Asgharpour A, Siddiqui MS, Sperling LS, Quyyumi AA, Mehta A. Liver and cardiovascular disease outcomes in metabolic syndrome and diabetic populations: Bi-directional opportunities to multiply preventive strategies. Diabetes Res Clin Pract 2024; 211:111650. [PMID: 38604447 DOI: 10.1016/j.diabres.2024.111650] [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: 08/09/2023] [Revised: 03/26/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024]
Abstract
The incidence and prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are rising globally. MetS and T2DM are associated with significant morbidity and mortality, which is partly related to liver and cardiovascular disease. Insulin resistance is central to MetS and T2DM pathophysiology, and drives ectopic fat deposition in the liver, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). MetS and T2DM are not only risk factors for developing MASLD but are also independently associated with disease progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In addition to the risk of liver disease, MetS and T2DM are independent risk factors for cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF). Importantly, there is a bidirectional relationship between liver and CVD due to shared disease pathophysiology in patients with MetS and T2DM. In this review, we have described studies exploring the relationship of MetS and T2DM with MASLD and CVD, independently. Following this we discuss studies evaluating the interplay between liver and cardiovascular risk as well as pragmatic risk mitigation strategies in this patient population.
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Affiliation(s)
| | | | - Angad Sidhu
- Virginia Commonwealth University, Richmond, VA, US
| | | | - Jared Spitz
- Inova Heart and Vascular Institute, Fairfax, VA, US
| | | | | | | | - Arshed A Quyyumi
- Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia
| | - Anurag Mehta
- Virginia Commonwealth University, Richmond, VA, US.
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Cao L, An Y, Liu H, Jiang J, Liu W, Zhou Y, Shi M, Dai W, Lv Y, Zhao Y, Lu Y, Chen L, Xia Y. Global epidemiology of type 2 diabetes in patients with NAFLD or MAFLD: a systematic review and meta-analysis. BMC Med 2024; 22:101. [PMID: 38448943 PMCID: PMC10919055 DOI: 10.1186/s12916-024-03315-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 02/23/2024] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) shares common pathophysiological mechanisms with type 2 diabetes, making them significant risk factors for type 2 diabetes. The present study aimed to assess the epidemiological feature of type 2 diabetes in patients with NAFLD or MAFLD at global levels. METHODS Published studies were searched for terms that included type 2 diabetes, and NAFLD or MAFLD using PubMed, EMBASE, MEDLINE, and Web of Science databases from their inception to December 2022. The pooled global and regional prevalence and incidence density of type 2 diabetes in patients with NAFLD or MAFLD were evaluated using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression. RESULTS A total of 395 studies (6,878,568 participants with NAFLD; 1,172,637 participants with MAFLD) from 40 countries or areas were included in the meta-analysis. The pooled prevalence of type 2 diabetes among NAFLD or MAFLD patients was 28.3% (95% confidence interval 25.2-31.6%) and 26.2% (23.9-28.6%) globally. The incidence density of type 2 diabetes in NAFLD or MAFLD patients was 24.6 per 1000-person year (20.7 to 29.2) and 26.9 per 1000-person year (7.3 to 44.4), respectively. CONCLUSIONS The present study describes the global prevalence and incidence of type 2 diabetes in patients with NAFLD or MAFLD. The study findings serve as a valuable resource to assess the global clinical and economic impact of type 2 diabetes in patients with NAFLD or MAFLD.
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Affiliation(s)
- Limin Cao
- The Third Central Hospital of Tianjin, Tianjin, China
| | - Yu An
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Huiyuan Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China
| | - Jinguo Jiang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China
| | - Wenqi Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China
| | - Yuhan Zhou
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China
| | - Mengyuan Shi
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China
| | - Wei Dai
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China
| | - Yanling Lv
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuhong Zhao
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China
| | - Yanhui Lu
- School of Nursing, Peking University, 38 Xueyuan Rd, Haidian District, Beijing, 100191, China.
| | - Liangkai Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Yang Xia
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, China.
- Liaoning Key Laboratory of Precision Medical Research On Major Chronic Disease, Liaoning Province, Shenyang, China.
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Doumas SA, Tripathi S, Kashikar A, Khuttan A, Kumar A, Singh H, Canakis JP, Ashish K, Dey D, Oppenheim I, Dey AK. Nonalcoholic Fatty Liver Disease (NAFLD) and Cardiovascular Risk: Is Imaging Helpful? Curr Probl Cardiol 2024; 49:102065. [PMID: 37652112 DOI: 10.1016/j.cpcardiol.2023.102065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 08/26/2023] [Indexed: 09/02/2023]
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is proving to be a globally prevalent condition. Moreover, NAFLD may be an independent risk factor associated with higher cardiovascular (CVD) morbidity and mortality. Further studies are needed to assess whether NAFLD needs to be included in the atherosclerotic risk score algorithms or whether patients with NAFLD need to be screened early on to assess their CVD risk especially since imaging such as positron emission tomography can be used to assess both NAFLD and CV disease at the same time. Therefore employing cardiovascular imaging modalities to investigate the incidence, extent, and nature of atherosclerotic lesions in NAFLD may be beneficial. Additionally, whether treating NAFLD halts the progression of CVD on imaging remains to be seen. Further research to delineate NAFLD and CVD associations, deciphering screening imaging modalities, and investigating targeted interventions could improve CVD morbidity and mortality in NAFLD.
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Affiliation(s)
| | | | - Aditi Kashikar
- The University of Texas Health Science Center, Houston, TX
| | | | - Ashwin Kumar
- Georgetown University Medical Center, Washington, DC
| | - Harjit Singh
- Georgetown University Medical Center, Washington, DC
| | | | | | - Debashish Dey
- Vidyasagar University, Midnapore, India; National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Ian Oppenheim
- Georgetown University Medical Center, Washington, DC
| | - Amit Kumar Dey
- Georgetown University Medical Center, Washington, DC; National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
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Lai RM, Yao LX, Lin S, Zhou JH, Liu BP, Liang ZY, Chen T, Jiang JJ, Zheng Q, Zhu Y. Influence of metabolic dysfunction-associated fatty liver disease on the prognosis of patients with HBV-related acute-on-chronic liver failure. Expert Rev Gastroenterol Hepatol 2024; 18:103-112. [PMID: 38164659 DOI: 10.1080/17474124.2023.2298261] [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: 09/10/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
OBJECTIVES Metabolic-associated fatty liver disease (MAFLD) has clinical relevance in patients with acute-on-chronic liver failure (ACLF). We investigated the association between MAFLD and prognosis in patients with ACLF. METHODS We included patients with ACLF with available clinical data who visited our hospital for nearly 9 years. We compared the prognosis of patients in the different subgroups of ACLF and predicted the incidence of adverse outcomes. Moreover, a new model based on MAFLD was established. RESULTS Among 339 participants, 75 had MAFLD. The prognosis of patients with ACLF was significantly correlated with MAFLD. Patients with ACLF with concomitant MAFLD tended to have a lower cumulative survival rate (p = 0.026) and a higher incidence of hepatorenal syndrome (9.33% versus 3.40%, p = 0.033) than those without MAFLD. We developed an TIM2 model and the area under the ROC curve of the new model for 30-day and 60-day mortality (0.759 and 0.748) was higher than other predictive methods. CONCLUSION The presence of MAFLD in patients with HBV-related ACLF was associated with an increased risk of in-hospital mortality. Moreover, The TIM2 model is a high-performance prognostic score for HBV-related ACLF.
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Affiliation(s)
- Rui-Min Lai
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hosptial, Fujian Medical University, Fuzhou, China
| | - Li-Xi Yao
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
| | - Shan Lin
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
| | - Jia-Hui Zhou
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
| | - Bing-Ping Liu
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
| | - Zhao-Yi Liang
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
| | - Tianbin Chen
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jia-Ji Jiang
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
| | - Qi Zheng
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
| | - Yueyong Zhu
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fujian Clinical Research Center for Hepatopathy and Intestinal Diseases, Fuzhou, Fujian Province, China
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9
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Pais R, Cariou B, Noureddin M, Francque S, Schattenberg JM, Abdelmalek MF, Lalazar G, Varma S, Dietrich J, Miller V, Sanyal A, Ratziu V. A proposal from the liver forum for the management of comorbidities in non-alcoholic steatohepatitis therapeutic trials. J Hepatol 2023; 79:829-841. [PMID: 37001695 DOI: 10.1016/j.jhep.2023.03.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 02/08/2023] [Accepted: 03/13/2023] [Indexed: 06/19/2023]
Abstract
The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.
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Affiliation(s)
- Raluca Pais
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000 Nantes, France
| | | | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Belgium
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Duke University, Durham, NC, USA
| | - Gadi Lalazar
- Liver Unit, Digestive Disease Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Sharat Varma
- Novo Nordisk A/S, Vandtårnsvej 108-110, 2860 Søborg Denmark
| | - Julie Dietrich
- GENFIT, Parc Eurasanté 885, Avenue Eugène Avinée, 59120, Loos, France
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C., USA
| | - Arun Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; INSERM UMRS 1138 CRC, Paris, France.
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10
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Ryaboshapkina M, Azzu V. Sample size calculation for a NanoString GeoMx spatial transcriptomics experiment to study predictors of fibrosis progression in non-alcoholic fatty liver disease. Sci Rep 2023; 13:8943. [PMID: 37268815 DOI: 10.1038/s41598-023-36187-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/29/2023] [Indexed: 06/04/2023] Open
Abstract
Sample size calculation for spatial transcriptomics is a novel and understudied research topic. Prior publications focused on powering spatial transcriptomics studies to detect specific cell populations or spatially variable expression patterns on tissue slides. However, power calculations for translational or clinical studies often relate to the difference between patient groups, and this is poorly described in the literature. Here, we present a stepwise process for sample size calculation to identify predictors of fibrosis progression in non-alcoholic fatty liver disease as a case study. We illustrate how to infer study hypothesis from prior bulk RNA-sequencing data, gather input requirements and perform a simulation study to estimate required sample size to evaluate gene expression differences between patients with stable fibrosis and fibrosis progressors with NanoString GeoMx Whole Transcriptome Atlas assay.
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Affiliation(s)
- Maria Ryaboshapkina
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
| | - Vian Azzu
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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11
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Sun DQ, Targher G, Byrne CD, Wheeler DC, Wong VWS, Fan JG, Tilg H, Yuan WJ, Wanner C, Gao X, Long MT, Kanbay M, Nguyen MH, Navaneethan SD, Yilmaz Y, Huang Y, Gani RA, Marzuillo P, Boursier J, Zhang H, Jung CY, Chai J, Valenti L, Papatheodoridis G, Musso G, Wong YJ, El-Kassas M, Méndez-Sánchez N, Sookoian S, Pavlides M, Duseja A, Holleboom AG, Shi J, Chan WK, Fouad Y, Yang J, Treeprasertsuk S, Cortez-Pinto H, Hamaguchi M, Romero-Gomez M, Al Mahtab M, Ocama P, Nakajima A, Dai C, Eslam M, Wei L, George J, Zheng MH. An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease. Hepatobiliary Surg Nutr 2023; 12:386-403. [PMID: 37351121 PMCID: PMC10282675 DOI: 10.21037/hbsn-22-421] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 02/01/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. METHODS AND RESULTS Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. CONCLUSIONS This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.
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Affiliation(s)
- Dan-Qin Sun
- Department of Nephrology, Jiangnan University Medical Center, Wuxi, China
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, and Southampton General Hospital, University of Southampton, Southampton, UK
| | - David C. Wheeler
- Department of Renal Medicine, University College London, London, UK
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Wei-Jie Yuan
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Christoph Wanner
- Division of Nephrology, Department of Medicine, Würzburg University Clinic, Würzburg, Germany
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Michelle T. Long
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine (M.K.), Koc University School of Medicine, Istanbul, Turkey
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA
- Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA
| | - Sankar D. Navaneethan
- Section of Nephrology and Institute of Clinical and Translational Research, Baylor College of Medicine, and Michael E. DeBakey VA Medical Center, Houston, TX, USA
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University, Foshan, China
| | - Rino A. Gani
- Division of Hepatobiliary, Department of Internal Medicine, Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | - Pierluigi Marzuillo
- Department of Woman, Child and of General and Specialized Surgery, Università della Campania “Luigi Vanvitelli”, Napoli, Italy
| | - Jérôme Boursier
- HIFIH Laboratory, UPRES EA3859, Angers University, Angers, France
- Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chan-Young Jung
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Jin Chai
- Cholestatic Liver Diseases Center, Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Università degli Studi di Milano, Milan, Italy
| | - George Papatheodoridis
- Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Giovanni Musso
- Emergency and Intensive Care Medicine, HUMANITAS Gradenigo Hospital;
| | - Yu-Jun Wong
- Department of Gastroenterology & Hepatology, Changi General Hospital, Singhealth, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Mohamed El-Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt
| | | | - Silvia Sookoian
- Clinical and Molecular Hepatology, Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Michael Pavlides
- Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Adriaan G. Holleboom
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Junping Shi
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Wah-Kheong Chan
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yasser Fouad
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Minia University, Minya, Egypt
| | - Junwei Yang
- Center for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | | | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Manuel Romero-Gomez
- UCM Digestive Diseases, University Hospital Virgen del Rocio, Institute of Biomedicine of Seville (CSIC/HUVR/US), Ciberehd, University of Seville, Sevilla, Spain
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Ponsiano Ocama
- Department of Medicine, Makerere University of College of Health Sciences, Kampala, Uganda
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Chunsun Dai
- Center for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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12
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Teng PC, Huang DQ, Lin TY, Noureddin M, Yang JD. Diabetes and Risk of Hepatocellular Carcinoma in Cirrhosis Patients with Nonalcoholic Fatty Liver Disease. Gut Liver 2023; 17:24-33. [PMID: 36530125 PMCID: PMC9840929 DOI: 10.5009/gnl220357] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/09/2022] [Accepted: 09/19/2022] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD is a hepatic manifestation of insulin resistance, the core pathophysiology of diabetes. Multiple clinical studies show that diabetes increases the risk of liver disease progression and cirrhosis development in patients with NAFLD. Diabetes has causal associations with many different cancers, including hepatocellular carcinoma (HCC). More recent studies demonstrate that diabetes increases the risk of HCC in patients with underlying NAFLD cirrhosis, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients. Diabetes promotes hepatocarcinogenesis via the activation of inflammatory cascades producing reactive oxygen species and proinflammatory cytokines, leading to genomic instability, cellular proliferation, and inhibition of apoptosis. Given the global increase in the burden of NAFLD and HCC, high-risk patients such as older diabetic individuals should be carefully monitored for HCC development. Future larger studies should explore whether the effect of diabetes on HCC risk in NAFLD cirrhosis is modifiable by the type of antidiabetic medication and the effectiveness of diabetes control.
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Affiliation(s)
- Pai-Chi Teng
- Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei, Taiwan,Department of Urology, National Taiwan University Hospital, Taipei, Taiwan,Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Daniel Q. Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore,Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Ting-Yi Lin
- Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ju Dong Yang
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Corresponding AuthorJu Dong Yang, ORCIDhttps://orcid.org/0000-0001-7834-9825, E-mail
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13
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Chew NW, Muthiah MD, Sanyal AJ. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: pathophysiology and implications for cardiovascular disease. CARDIOVASCULAR ENDOCRINOLOGY AND METABOLISM 2023:137-173. [DOI: 10.1016/b978-0-323-99991-5.00003-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Nababan SHH, Lesmana CRA. Portal Hypertension in Nonalcoholic Fatty Liver Disease: From Pathogenesis to Clinical Practice. J Clin Transl Hepatol 2022; 10:979-985. [PMID: 36304507 PMCID: PMC9547264 DOI: 10.14218/jcth.2021.00593] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/05/2022] [Accepted: 06/06/2022] [Indexed: 12/04/2022] Open
Abstract
Portal hypertension in nonalcoholic fatty liver disease (NAFLD) mostly occur in cirrhotic stage. However, several experimental and clinical studies showed evidence of portal hypertension in NAFLD without significant or advance fibrosis. This early development of portal hypertension in NAFLD is associated with liver sinusoidal contraction by hepatocellular lipid accumulation and ballooning, which is also accompanied by capillarization and dysfunction of liver sinusoidal endothelial cells. Both of these impaired mechanical and molecular components can cause an increase in intrahepatic vascular resistance which lead to the increase of portal pressure in the absence of significant liver fibrosis. Extrahepatic factors such as insulin resistance and gut dysbiosis may also contribute to liver sinusoidal endothelial dysfunction and early portal hypertension in NAFLD. The clinical impact of early portal hypertension in NAFLD is still unclear. However, clinical tools for diagnosis and monitoring of portal hypertension in NAFLD are being investigated to predict high-risk patients and to guide therapy.
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Affiliation(s)
- Saut Horas H. Nababan
- Hepatobiliary Division, Department of Internal Medicine, Dr Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Gastrointestinal Cancer Center, MRCCC Siloam Semanggi Hospital, Jakarta, Indonesia
| | - Cosmas Rinaldi Adithya Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Dr Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Gastrointestinal Cancer Center, MRCCC Siloam Semanggi Hospital, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
- Correspondence to: Cosmas Rinaldi Adithya Lesmana, Hepatobiliary Division, Department of Internal Medicine, Dr Cipto Mangunkusomo National General Hospital Medical Faculty Universitas Indonesia, Jl. Diponegoro No.71 Jakarta 10430, Indonesia. ORCID: https://orcid.org/0000-0001-9992-9968. Tel: +62-21-31900924, Fax: +62-21-3918842, E-mail: mailto:
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15
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Nagatomo A, Ninomiya K, Marumoto S, Sakai C, Watanabe S, Ishikawa W, Manse Y, Kikuchi T, Yamada T, Tanaka R, Muraoka O, Morikawa T. A Gedunin-Type Limonoid, 7-Deacetoxy-7-Oxogedunin, from Andiroba ( Carapa guianensis Aublet) Reduced Intracellular Triglyceride Content and Enhanced Autophagy in HepG2 Cells. Int J Mol Sci 2022; 23:13141. [PMID: 36361930 PMCID: PMC9655357 DOI: 10.3390/ijms232113141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 01/03/2025] Open
Abstract
The seed oil of Carapa guianensis Aublet (Andiroba) has been used in folk medicine for its insect-repelling, anti-inflammatory, and anti-malarial activities. This study aimed to examine the triglyceride (TG) reducing effects of C. guianensis-derived limonoids or other commercially available limonoids in human hepatoblastoma HepG2 cells and evaluate the expression of lipid metabolism or autophagy-related proteins by treatment with 7-deacetoxy-7-oxogedunin (DAOG; 1), a principal limonoid of C. guianensis. The gedunin-type limonoids, such as DAOG (% of control at 20 μM: 70.9 ± 0.9%), gedunin (2, 74.0 ± 1.1%), epoxyazadiradione (4, 73.4 ± 2.0%), 17β-hydroxyazadiradione (5, 79.9 ± 0.6%), 7-deacetoxy-7α-hydroxygedunin (6, 61.0 ± 1.2%), andirolide H (7, 87.4 ± 2.2%), and 6α-hydroxygedunin (8, 84.5 ± 1.1%), were observed to reduce the TG content at lower concentrations than berberine chloride (BBR, a positive control, 84.1 ± 0.3% at 30 μM) in HepG2 cells pretreated with high glucose and oleic acid. Andirobin-, obacunol-, nimbin-, and salannin-type limonoids showed no effect on the intracellular TG content in HepG2 cells. The TG-reducing effect of DAOG was attenuated by the concomitant use of compound C (dorsomorphin), an AMPK inhibitor. Further investigation on the detailed mechanism of action of DAOG at non-cytotoxic concentrations revealed that the expressions of autophagy-related proteins, LC3 and p62, were upregulated by treatment with DAOG. These findings suggested that gedunin-type limonoids from Andiroba could ameliorate fatty liver, and that the action of DAOG in particular is mediated by autophagy.
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Affiliation(s)
- Akifumi Nagatomo
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
| | - Kiyofumi Ninomiya
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
- School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Okayama, Japan
| | - Shinsuke Marumoto
- Joint Research Center, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
| | - Chie Sakai
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
| | - Shuta Watanabe
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
| | - Wakana Ishikawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
| | - Yoshiaki Manse
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
| | - Takashi Kikuchi
- Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan
- Faculty of Pharmacy, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Chiba, Japan
| | - Takeshi Yamada
- Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan
| | - Reiko Tanaka
- Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan
| | - Osamu Muraoka
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
| | - Toshio Morikawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Osaka, Japan
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16
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Association between arterial hypertension and liver outcomes using polygenic risk scores: a population-based study. Sci Rep 2022; 12:15581. [PMID: 36114231 PMCID: PMC9481629 DOI: 10.1038/s41598-022-20084-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 09/08/2022] [Indexed: 12/03/2022] Open
Abstract
Arterial hypertension (HTA) is associated with liver disease, but causality remains unclear. We investigated whether genetic predisposition to HTA is associated with liver disease in the population, and if antihypertensive medication modifies this association. Participants of the Finnish health-examination surveys, FINRISK 1992–2012 and Health 2000 (n = 33,770), were linked with national electronic healthcare registers for liver-related outcomes (K70-K77, C22.0) and with the drug reimbursement registry for new initiation of antihypertensive medication during follow-up. Genetic predisposition to HTA was defined by polygenic risk scores (PRSs). During a median 12.9-year follow-up (409,268.9 person-years), 441 liver-related outcomes occurred. In the fully-adjusted Cox-regression models, both measured systolic blood pressure and clinically defined HTA were associated with liver-related outcomes. PRSs for systolic and diastolic blood pressure were significantly associated with liver-related outcomes (HR/SD 1.19, 95% CI 1.01–1.24, and 1.12, 95% CI 1.01–1.25, respectively). In the highest quintile of the systolic blood pressure PRS, new initiation of antihypertensive medication was associated with reduced rates of liver-related outcomes (HR 0.55, 95% CI 0.31–0.97). HTA and a genetic predisposition for HTA are associated with liver-related outcomes in the population. New initiation of antihypertensive medication attenuates this association in persons with high genetic risk for HTA.
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Yokoyama K, Fukuda H, Yamauchi R, Higashi M, Miyayama T, Higashi T, Uchida Y, Shibata K, Tsuchiya N, Fukunaga A, Umeda K, Takata K, Tanaka T, Shakado S, Sakisaka S, Hirai F. Long-Term Effects of Rifaximin on Patients with Hepatic Encephalopathy: Its Possible Effects on the Improvement in the Blood Ammonia Concentration Levels, Hepatic Spare Ability and Refractory Ascites. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58091276. [PMID: 36143954 PMCID: PMC9501622 DOI: 10.3390/medicina58091276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/09/2022] [Accepted: 09/11/2022] [Indexed: 11/20/2022]
Abstract
Background and Objectives: To investigate the long-term efficacy of rifaximin (RFX) for hyperammonemia and efficacy for refractory ascites in patients with cirrhosis. Materials and Methods: We enrolled 112 patients with liver cirrhosis who were orally administered RFX in this study. Changes in the clinical data of patients were evaluated up to 36 months after RFX administration. The primary endpoint was a change in blood ammonia levels. Secondary endpoints included changes in clinical symptoms, Child−Pugh (CP) score, number of hospitalizations, degree of refractory ascites, adverse events, and the relationship between RFX administration and the renin-angiotensin-aldosterone system. Results: An improved rate of overt hepatic encephalopathy (HE) of 82.7% was observed 3 months after RFX administration, which significantly induced a progressive decrease in blood ammonia concentration and an improved CP score up to 36 months. No serious RFX treatment-related adverse events were observed. 36.5% in patients after RFX administration improved refractory ascites. After RFX administration, patients with satisfactory control of hepatic ascites without addition of diuretic had lower renin concentration than those with poor control (p < 0.01). At less than 41 pg/mL renin concentration, the control of refractory ascites was significantly satisfactory (p < 0.0001). Conclusions: RFX reduced blood ammonia concentration and improved hepatic spare ability and the quality of life of patients with long-term HE to up to 36 months. Our study revealed the effects of RFX against refractory ascites, suggesting that renin concentration may be a predictive marker for assessing ascites control.
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Affiliation(s)
- Keiji Yokoyama
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
- Correspondence: ; Tel.: +81-92-801-1011 (ext. 3355)
| | - Hiromi Fukuda
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Masashi Higashi
- Higashi Hospital, 593-1 Hirotsu, Yositomi-machi, Chikujo-gun 871-0811, Fukuoka, Japan
| | - Takashi Miyayama
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Tomotaka Higashi
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Yotaro Uchida
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kumiko Shibata
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Naoaki Tsuchiya
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Atsushi Fukunaga
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kaoru Umeda
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
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Han E, Kim MK, Im SS, Jang BK, Kim HS. Non-alcoholic fatty liver disease and sarcopenia is associated with the risk of albuminuria independent of insulin resistance, and obesity. J Diabetes Complications 2022; 36:108253. [PMID: 35817677 DOI: 10.1016/j.jdiacomp.2022.108253] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/21/2022] [Accepted: 06/28/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Although non-alcoholic fatty liver disease (NAFLD) is associated with metabolic disorders, its influence on albuminuria has not been determined. The aim of this study was to identify the relationship between NAFLD and albuminuria in the general Korean population. METHODS Data from the Korea National Health and Nutrition Examination Surveys (KNHANES) of 2008-2011 were analyzed (n = 1795). Albuminuria was defined as an albumin-to-creatinine ratio of ≥30 mg/g in random spot urine samples. NAFLD was defined as a fatty liver index (FLI) ≥60 or NAFLD liver fat score (LFS) > -0.64. RESULTS A total of 289 (16.1 %) subjects were classified as having albuminuria. Subjects with NAFLD exhibited a higher rate of albuminuria than subjects without NAFLD (crude odds ratios [ORs] = 2.60-2.95, all P < 0.001). Regardless of hypertension, insulin resistance, or obesity, the risk for albuminuria was higher in the NAFLD group than in the group without NAFLD (measured by either FLI or LFS; all P < 0.001). When subjects with NAFLD had sarcopenia, the risk of albuminuria further increased (OR = 4.33-4.64, all P < 0.001). Multiple logistic regression analyses also demonstrated that NAFLD was independently associated with albuminuria (OR = 2.58, 95 % confidence interval [CI] = 1.66-4.02, P < 0.001 for FLI, OR = 1.87, 95 % CI = 1.28-2.75, P = 0.001 for LFS). CONCLUSIONS NAFLD was associated with an increased risk of albuminuria in the general Korean population. This association was independent of hypertension, insulin resistance, chronic kidney disease, diabetes and obesity, and stronger in subjects with sarcopenia.
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Affiliation(s)
- Eugene Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Mi Kyung Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Seung-Soon Im
- Department of Physiology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hye Soon Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.
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19
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Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on ongoing hepatic fibrosis. Indian J Gastroenterol 2022; 41:169-180. [PMID: 35279807 DOI: 10.1007/s12664-021-01220-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/19/2021] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Nonalcoholic steatohepatitis (NASH) is difficult to diagnose in patients with no symptoms. We aimed to investigate the combined effect of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), and angiotensin II type 1 receptor blocker (ARB: losartan) on an ongoing hepatic fibrosis in a NASH rat model. METHODS Fischer 344 rats were fed with choline-deficient L-amino-acid-defined (CDAA) diet for 16 weeks. After 8-week administration of CDAA diet, OCA, losartan, or a combination of these drugs was administered at a dose of 30 mg/kg/day for 8 weeks by oral gavage. The in vivo and in vitro effects of OCA + losartan and liver fibrosis progression, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) regulatory cascade, and gut barrier function were evaluated. RESULTS OCA + losartan alleviated hepatic fibrosis progression by suppressing α-SMA expression. It inhibited the proliferation of activated hepatic stellate cell (Ac-HSC) and mRNA expression of hepatic transforming growth factor-β1 (TGF-β1), TLR4, and tissue inhibitor of metalloproteinase-1 (TIMP-1) and decreased the hydroxyproline levels. OCA increased the hepatic matrix metalloproteinase-2 (MMP-2) mRNA expression. OCA decreased the mRNA expression of hepatic LPS-binding protein and intestinal permeability by ameliorating the disruption of CDAA diet-induced zonula occludens-1. Losartan directly inhibited the proliferation of Ac-HSC. The in vitro suppressive effects of OCA + losartan on the mRNA expressions of TGF-β1 and α1(I)-procollagen, TLR4, and TIMP-1 in Ac-HSCs were almost in parallel. CONCLUSIONS OCA + losartan suppressed the ongoing hepatic fibrosis by attenuating gut barrier dysfunction and suppressing Ac-HSC proliferation. Combined therapy may be a promising novel approach for NASH with fibrosis.
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20
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Kuchay MS, Misra A. Role of diabetologists in the management of nonalcoholic fatty liver disease: Primary prevention and screening/management of fibrosis and cirrhosis. Diabetes Metab Syndr 2022; 16:102446. [PMID: 35259705 DOI: 10.1016/j.dsx.2022.102446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 02/24/2022] [Accepted: 02/26/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is a common condition, especially among individuals with type 2 diabetes (T2D). Presence of T2D increases the risk of progression of simple steatosis to more severe liver conditions, such as nonalcoholic steatohepatitis (NASH) and fibrosis (NASH-fibrosis). Since majority of patients with T2D are managed by diabetologists (including physicians and endocrinologists), their roles in the management of coexisting NAFLD are not well defined, partly due to lack of unambiguous guidelines. METHODS A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till January 2022, using relevant keywords (nonalcoholic fatty liver disease and diabetologist; screening of NASH; management of NASH) to extract relevant studies describing prevention and screening of NAFLD/NASH, especially in people with T2D. RESULTS Diabetologists have two main roles for the management of patients with T2D and coexisting NAFLD. The most important role is to prevent the development of NASH-fibrosis in patients with simple steatosis (primary prevention). This can be achieved by reinforcing the importance of lifestyle measures, and by early use of glucose-lowering agents with beneficial effects on the liver. The second important role of diabetologists is to screen all patients with T2D for liver fibrosis and compensated cirrhosis, and provide appropriate referral for timely management of complications (secondary prevention). CONCLUSION Diabetologists can play a central role in mitigating the epidemic of NAFLD in individuals with T2D. However, diabetologists need to be aware about their roles in NASH-fibrosis prevention and screening. Furthermore, longitudinal studies should explore the role of newer glucose-lowering drugs in the primary prevention of NASH-fibrosis in individuals with coexisting T2D and simple steatosis.
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Affiliation(s)
- Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta The Medicity Hospital, Gurugram, 122001, Haryana, India.
| | - Anoop Misra
- Fortis CDOC Hospital for Diabetes and Allied Sciences, New Delhi, India; National Diabetes Obesity and Cholesterol Foundation (NDOC) and Diabetes Foundation, India.
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21
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Song Q, Liu S, Ling QH, Gao QN, Yang RX, Chen SH, Wu S, Chen ML, Cai J. Severity of Nonalcoholic Fatty Liver Disease is Associated With Cardiovascular Outcomes in Patients With Prehypertension or Hypertension: A Community-Based Cohort Study. Front Endocrinol (Lausanne) 2022; 13:942647. [PMID: 36093080 PMCID: PMC9453754 DOI: 10.3389/fendo.2022.942647] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/15/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND It is unclear whether more severe non-alcoholic fatty liver disease (NAFLD) combined with prehypertension or hypertension is associated with a higher risk of cardiovascular events (CVEs). To evaluate the relationship between the severity of NAFLD and CVEs among patients with prehypertension or hypertension. METHODS In this prospective community-based Kailuan cohort, participants without cardiovascular disease and alcohol abuse, or other liver diseases were enrolled. NAFLD was diagnosed by abdominal ultrasonography. Prehypertension was defined as systolic blood pressure (BP) of 120-139 mmHg or diastolic BP of 80-89 mmHg. Participants with NAFLD were divided into mild, moderate, and severe subgroups. Follow-up for CVEs including myocardial infarction, hemorrhagic stroke, and ischemic stroke. The Cox proportional hazards model was used to estimate hazard ratios and 95% CIs of CVEs according to the severity of NAFLD and hypertensive statutes. The C-statistic was used to evaluate the efficiency of models. RESULTS A total of 71926 participants (mean [SD] age, 51.83 [12.72] years, 53794 [74.79%] men, and 18132 [25.21%] women) were enrolled in this study, 6,045 CVEs occurred during a median of 13.02 (0.65) years of follow-up. Compared with participants without NAFLD, the hazard ratios of CVEs for patients with mild, moderate, and severe NAFLD were 1.143 (95% CI 1.071-1.221, P < 0.001), 1.218 (95% CI 1.071-1.221, P < 0.001), and 1.367 (95% CI 1.172-1.595, P < 0.001), respectively. Moreover, participants with prehypertension plus moderate/severe NAFLD and those with hypertension plus moderate/severe NAFLD had 1.558-fold (95% CI 1.293-1.877, P < 0.001) and 2.357-fold (95% CI 2.063-2.691, P < 0.001) higher risks of CVEs, respectively, compared with those with normal BP and no NAFLD. Adding a combination of NAFLD and BP status to the crude Cox model increased the C-statistic by 0.0130 (0.0115-0.0158, P < 0.001). CONCLUSIONS Our findings indicated that the increased cardiovascular risk with elevated BP is largely driven by the coexistence of moderate/severe NAFLD, suggesting that the severity of NAFLD may help further stratify patients with prehypertension and hypertension.
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Affiliation(s)
- Qi–Rui Song
- State Key Laboratory of Cardiovascular Disease of China, Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuo–Lin Liu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
| | - Qian-Hui Ling
- State Key Laboratory of Cardiovascular Disease of China, Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian-Nan Gao
- State Key Laboratory of Cardiovascular Disease of China, Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui-Xue Yang
- State Key Laboratory of Cardiovascular Disease of China, Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuo-Hua Chen
- Department of Cardiology, Kailuan General Hospital, Tangshan, China
| | - Shou–Ling Wu
- Department of Cardiology, Kailuan General Hospital, Tangshan, China
- *Correspondence: Shou–Ling Wu, ; Mu-Lei Chen, ; Jun Cai,
| | - Mu-Lei Chen
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- *Correspondence: Shou–Ling Wu, ; Mu-Lei Chen, ; Jun Cai,
| | - Jun Cai
- State Key Laboratory of Cardiovascular Disease of China, Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Shou–Ling Wu, ; Mu-Lei Chen, ; Jun Cai,
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22
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Alexopoulos AS, Duffy R, Kobe EA, German J, Moylan CA, Soliman D, Jeffreys AS, Coffman CJ, Crowley MJ. Underrecognition of Nonalcoholic Fatty Liver Disease in Poorly Controlled Diabetes: A Call to Action in Diabetes Care. J Endocr Soc 2021; 5:bvab155. [PMID: 34755002 PMCID: PMC8570418 DOI: 10.1210/jendso/bvab155] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Indexed: 11/19/2022] Open
Abstract
Individuals with type 2 diabetes (T2DM) are at high risk for nonalcoholic fatty liver disease (NAFLD), and evidence suggests that poor glycemic control is linked to heightened risk of progressive NAFLD. We conducted an observational study based on data from a telehealth trial conducted in 2018-2020. Our objectives were to (1) characterize patterns of NAFLD testing/care in a cohort of individuals with poorly controlled T2DM; and (2) explore how laboratory based measures of NAFLD (eg, liver enzymes, fibrosis-4 [FIB-4]) vary by glycemic control. We included individuals with poorly controlled T2DM (n = 228), defined as hemoglobin A1c (HbA1c) ≥ 8.5% despite clinic-based care. Two groups of interest were (1) T2DM without known NAFLD; and (2) T2DM with known NAFLD. Demographics, medical history, medication use, glycemic control (HbA1c), and NAFLD testing/care patterns were obtained by chart review. Among those without known NAFLD (n = 213), most were male (78.4%) and self-identified as Black race (68.5%). Mean HbA1c was 9.8%. Most had liver enzymes (85.4%) and platelets (84.5%) ordered in the outpatient department over a 2-year period that would allow for FIB-4 calculation, yet only 2 individuals had FIB-4 documented in clinical notes. Approximately one-third had abnormal liver enzymes at least once over a 2-year period, yet only 7% had undergone liver ultrasound and 4.7% had referral to hepatology. Among those with known NAFLD (n = 15), mean HbA1c was 9.5%. Only 4 individuals had undergone transient elastography, half of whom had advanced fibrosis. NAFLD is underrecognized in poorly controlled T2DM, even though this is a high-risk group for NAFLD and its complications.
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Affiliation(s)
- Anastasia-Stefania Alexopoulos
- Durham Veterans Affairs Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham, NC 27705, USA.,Department of Medicine, Division of Endocrinology, Duke University, Durham NC 27710, USA
| | - Ryan Duffy
- Department of Medicine, Duke University Medical Center, Durham NC 27710, USA
| | - Elizabeth A Kobe
- Department of Medicine, Duke University Medical Center, Durham NC 27710, USA
| | - Jashalynn German
- Department of Medicine, Division of Endocrinology, Duke University, Durham NC 27710, USA
| | - Cynthia A Moylan
- Division of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, NC 27710, USA.,Department of Medicine, Division of Gastroenterology, Duke University, Durham NC 27710, USA
| | - Diana Soliman
- Department of Medicine, Division of Endocrinology, Duke University, Durham NC 27710, USA
| | - Amy S Jeffreys
- Durham Veterans Affairs Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham, NC 27705, USA
| | - Cynthia J Coffman
- Durham Veterans Affairs Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham, NC 27705, USA.,Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA
| | - Matthew J Crowley
- Durham Veterans Affairs Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham, NC 27705, USA.,Department of Medicine, Division of Endocrinology, Duke University, Durham NC 27710, USA
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23
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Hatanaka T, Kosone T, Saito N, Takakusagi S, Tojima H, Naganuma A, Takagi H, Uraoka T, Kakizaki S. Effect of 48-week pemafibrate on non-alcoholic fatty liver disease with hypertriglyceridemia, as evaluated by the FibroScan-aspartate aminotransferase score. JGH OPEN 2021; 5:1183-1189. [PMID: 34622006 PMCID: PMC8485409 DOI: 10.1002/jgh3.12650] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/04/2021] [Accepted: 08/21/2021] [Indexed: 12/30/2022]
Abstract
Background and Aim This retrospective study investigated the effect of 48‐week pemafibrate therapy in non‐alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia, as evaluated by the FibroScan‐aspartate aminotransferase (FAST) score. Methods A total of 31 NAFLD patients who were treated with pemafibrate in Gunma Saiseikai Maebashi Hospital and Kusunoki Hospital from September 2018 to April 2020 were included in the current study. We used the FAST score, which is a novel index of steatohepatitis that can be calculated based on the AST value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM), to evaluate the effect of pemafibrate treatment. Results The median age was 64.0 (interquartile range [IQR] 55.0–75.0) years and 14 patients (45.2%) were male. Median body mass index was 26.8 (IQR 23.8–28.8). Hypertension and diabetes mellitus were detected in 14 (45.2%) and five (16.1%) patients, respectively. Fasting triglyceride and high‐density lipoprotein cholesterol were significantly improved (P < 0.001 and 0.013, respectively) and the AST, alanine aminotransferase (ALT), alkaline phosphatase, and γ‐glutamyl transpeptidase values were significantly decreased during pemafibrate treatment (P = 0.041, <0.001, <0.001, and <0.001, respectively). While the LSM value and CAP value did not differ to a statistically significant extent (P = 0.19 and 0.140, respectively), the FAST score was significantly improved during pemafibrate treatment (P = 0.029). The delta FAST score was found to be correlated with the variations of ALT (r = 0.504, P = 0.005), which represents the effect of pemafibrate. Conclusions Pemafibrate improved the FAST score due to the hepatic anti‐inflammatory effect, indicating that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology Gunma Saiseikai Maebashi Hospital Maebashi Japan
| | - Takashi Kosone
- Department of Gastroenterology and Hepatology Kusunoki Hospital Fujioka Japan
| | - Naoto Saito
- Department of Gastroenterology Gunma Saiseikai Maebashi Hospital Maebashi Japan
| | - Satoshi Takakusagi
- Department of Gastroenterology and Hepatology Kusunoki Hospital Fujioka Japan
| | - Hiroki Tojima
- Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan
| | - Atsushi Naganuma
- Department of Gastroenterology National Hospital Organization Takasaki General Medical Center Takasaki Japan
| | - Hitoshi Takagi
- Department of Gastroenterology and Hepatology Kusunoki Hospital Fujioka Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan.,Department of Clinical Research National Hospital Organization Takasaki General Medical Center Takasaki Japan
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24
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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25
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Kumar V, Xin X, Ma J, Tan C, Osna N, Mahato RI. Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis. Adv Drug Deliv Rev 2021; 176:113888. [PMID: 34314787 PMCID: PMC8440458 DOI: 10.1016/j.addr.2021.113888] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/12/2021] [Accepted: 07/18/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress. Free fatty acid (FFA) accumulation in the liver exerts oxidative and endoplasmic reticulum (ER) stresses. Hepatocyte injury induces release of inflammatory cytokines from Kupffer cells (KCs), which are responsible for activating hepatic stellate cells (HSCs). In this review, we will discuss various molecular targets for treating chronic liver diseases, including homeostasis of FFA, lipid metabolism, and decrease in hepatocyte apoptosis, role of growth factors, and regulation of epithelial-to-mesenchymal transition (EMT) and HSC activation. This review will also critically assess different strategies to enhance drug delivery to different cell types. Targeting nanocarriers to specific liver cell types have the potential to increase efficacy and suppress off-target effects.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jingyi Ma
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
| | - Natalia Osna
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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26
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Seen TK, Sayed M, Bilal M, Reyes JV, Bhandari P, Lourdusamy V, Al-khazraji A, Syed U, Sattar Y, Bansal R. Clinical indicators for progression of nonalcoholic steatohepatitis to cirrhosis. World J Gastroenterol 2021; 27:3238-3248. [PMID: 34163108 PMCID: PMC8218360 DOI: 10.3748/wjg.v27.i23.3238] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 12/06/2020] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), is a disease spectrum characterized by fat accumulation in hepatocytes presenting as hepatic steatosis to advance disease with active hepatic inflammation, known as nonalcoholic steatohepatitis. Chronic steatohepatitis will lead to progressive hepatic fibrosis causing cirrhosis and increased risk for developing hepatocellular carcinoma (HCC). Fatty liver disease prevalence has increased at alarming rates alongside obesity, diabetes and metabolic syndrome to become the second most common cause of cirrhosis after alcohol related liver disease worldwide. Given this rise in prevalence, it is becoming increasingly more important to find non-invasive methods to diagnose disease early and stage hepatic fibrosis. Providing clinicians with the tools to diagnose and treat the full spectrum of NAFLD will help prevent known complications such as cirrhosis and HCC and improve quality of life for the patients suffering from this disease. This article discusses the utility of current non-invasive liver function testing in the clinical progression of fatty liver disease along with the imaging modalities that are available. Additionally, we summarize available treatment options including targeted medical therapy through four different pathways, surgical or endoscopic intervention.
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Affiliation(s)
- Tasur Kumar Seen
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Muntazir Sayed
- Division of Internal Medicine, R.C.S.M. Government College, Mahrashta 416013, India
| | - Muhammad Bilal
- Division of Gastroenterology, Hepatology and Endoscopy, Pakistan Institute of Medical Sciences, Islamabad 45710, Pakistan
| | - Jonathan Vincent Reyes
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Priyanka Bhandari
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Vennis Lourdusamy
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Ahmed Al-khazraji
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Umer Syed
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Yasar Sattar
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Raghav Bansal
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital, Elmhurst, NY 11375, United States
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27
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Mantovani A, Valenti L. A call to action for fatty liver disease. Liver Int 2021; 41:1182-1185. [PMID: 34002475 DOI: 10.1111/liv.14907] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 02/13/2023]
Affiliation(s)
- Alessandro Mantovani
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.,Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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28
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Dufour JF, Scherer R, Balp MM, McKenna SJ, Janssens N, Lopez P, Pedrosa M. The global epidemiology of nonalcoholic steatohepatitis (NASH) and associated risk factors–A targeted literature review. ENDOCRINE AND METABOLIC SCIENCE 2021. [DOI: 10.1016/j.endmts.2021.100089] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Ramadan MS, Russo V, Nigro G, Durante-Mangoni E, Zampino R. Interplay between Heart Disease and Metabolic Steatosis: A Contemporary Perspective. J Clin Med 2021; 10:jcm10081569. [PMID: 33917867 PMCID: PMC8068259 DOI: 10.3390/jcm10081569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/26/2021] [Accepted: 04/03/2021] [Indexed: 12/12/2022] Open
Abstract
The liver-heart axis is a growing field of interest owing to rising evidence of complex bidirectional interplay between the two organs. Recent data suggest non-alcoholic fatty liver disease (NAFLD) has a significant, independent association with a wide spectrum of structural and functional cardiac diseases, and seems to worsen cardiovascular disease (CVD) prognosis. Conversely, the effect of cardiac disease on NAFLD is not well studied and data are mostly limited to cardiogenic liver disease. We believe it is important to further investigate the heart-liver relationship because of the tremendous global health and economic burden the two diseases pose, and the impact of such investigations on clinical decision making and management guidelines for both diseases. In this review, we summarize the current knowledge on NAFLD diagnosis, its systemic manifestations, and associations with CVD. More specifically, we review the pathophysiological mechanisms that govern the interplay between NAFLD and CVD and evaluate the relationship between different CVD treatments and NAFLD progression.
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Affiliation(s)
- Mohammad Said Ramadan
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Vincenzo Russo
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Gerardo Nigro
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Correspondence:
| | - Rosa Zampino
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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30
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Petta S, Sebastiani G, Viganò M, Ampuero J, Wai-Sun Wong V, Boursier J, Berzigotti A, Bugianesi E, Fracanzani AL, Cammà C, Enea M, Grottes MD, Di Marco V, Younes R, Keyrouz A, Mazzola S, Mendoza Y, Pennisi G, Romero-Gomez M, Craxì A, de Ledinghen V. Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver Disease. Clin Gastroenterol Hepatol 2021; 19:806-815.e5. [PMID: 32621970 DOI: 10.1016/j.cgh.2020.06.045] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 06/13/2020] [Accepted: 06/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events. METHODS We performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3-F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19-63 months). RESULTS Based on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00-1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02-1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11-2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02). CONCLUSIONS In patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy.
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Mauro Viganò
- Hepatology Unit, Ospedale San Giuseppe, University of Milan, Milan, Italy
| | - Javier Ampuero
- Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Instituto de Biomedicina de Sevilla, University of Seville, Seville, Spain
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Jerome Boursier
- Hepato-Gastroenterology Department, Angers University Hospital, Angers, France
| | - Annalisa Berzigotti
- Hepatology Group, University Clinic for Visceral Surgery and Medicine, Inselspital, Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Elisabetta Bugianesi
- Division of Gastroenterology, Department of Medical Sciences, University of Torino, Turin, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Milan, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Marco Enea
- Dipartimento di Scienze Economiche, Aziendali e Statistiche, University of Palermo, Palermo, Italy
| | - Marraud des Grottes
- Centre d'Investigation de la Fibrose Hépatique, INSERM U1053, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Ramy Younes
- Division of Gastroenterology, Department of Medical Sciences, University of Torino, Turin, Italy
| | - Aline Keyrouz
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Sergio Mazzola
- Clinical Epidemiology and Cancer Registry Operative Unit, University Hospital Policlinico "Paolo Giaccone," Palermo, Italy
| | - Yuly Mendoza
- Hepatology Group, University Clinic for Visceral Surgery and Medicine, Inselspital, Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Grazia Pennisi
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Manuel Romero-Gomez
- Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Instituto de Biomedicina de Sevilla, University of Seville, Seville, Spain
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Victor de Ledinghen
- Centre d'Investigation de la Fibrose Hépatique, INSERM U1053, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
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Selicean S, Wang C, Guixé-Muntet S, Stefanescu H, Kawada N, Gracia-Sancho J. Regression of portal hypertension: underlying mechanisms and therapeutic strategies. Hepatol Int 2021; 15:36-50. [PMID: 33544313 PMCID: PMC7886770 DOI: 10.1007/s12072-021-10135-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
Abstract
Portal hypertension is the main non-neoplastic complication of chronic liver disease, being the cause of important life-threatening events including the development of ascites or variceal bleeding. The primary factor in the development of portal hypertension is a pathological increase in the intrahepatic vascular resistance, due to liver microcirculatory dysfunction, which is subsequently aggravated by extra-hepatic vascular disturbances including elevation of portal blood inflow. Evidence from pre-clinical models of cirrhosis has demonstrated that portal hypertension and chronic liver disease can be reversible if the injurious etiological agent is removed and can be further promoted using pharmacological therapy. These important observations have been partially demonstrated in clinical studies. This paper aims at providing an updated review of the currently available data regarding spontaneous and drug-promoted regression of portal hypertension, paying special attention to the clinical evidence. It also considers pathophysiological caveats that highlight the need for caution in establishing a new dogma that human chronic liver disease and portal hypertension is reversible.
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Affiliation(s)
- Sonia Selicean
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Cong Wang
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Sergi Guixé-Muntet
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Horia Stefanescu
- Department of Hepatology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Liver Research Club, Cluj-Napoca, Romania
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Jordi Gracia-Sancho
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland.
- Liver Vascular Biology Research Group, IDIBAPS Research Institute, CIBEREHD, Barcelona, Spain.
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32
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Campos-Murguía A, Ruiz-Margáin A, González-Regueiro JA, Macías-Rodríguez RU. Clinical assessment and management of liver fibrosis in non-alcoholic fatty liver disease. World J Gastroenterol 2020; 26:5919-5943. [PMID: 33132645 PMCID: PMC7584064 DOI: 10.3748/wjg.v26.i39.5919] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 05/24/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan′s nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.
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Affiliation(s)
- Alejandro Campos-Murguía
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - José A González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Ricardo U Macías-Rodríguez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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Meroni M, Longo M, Dongiovanni P. Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease. EXPLORATION OF MEDICINE 2020; 1:218-243. [DOI: 10.37349/emed.2020.00015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/20/2020] [Indexed: 01/04/2025] Open
Abstract
The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
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Mantovani A, Zusi C, Dalbeni A, Grani G, Buzzetti E. Risk of Kidney Dysfunction IN Nafld. Curr Pharm Des 2020; 26:1045-1061. [DOI: 10.2174/1381612825666191026113119] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/21/2019] [Indexed: 02/06/2023]
Abstract
Background:
The timely identification of traditional and non-traditional precursors and risk factors for
chronic kidney disease (CKD) (a common systemic disease defined as a decreased kidney function documented
by reduced glomerular filtration rate, or markers of kidney damage, or both) is relevant in clinical practice, as
CKD increases the risk of end-stage renal disease and other serious comorbidities. A possible relationship between
non-alcoholic fatty liver disease (NAFLD) (which is to date the most common chronic disease worldwide)
and CKD has recently gained significant attention of researchers.
Methods :
A systematic literature search using appropriate keywords was made in order to identify relevant articles
that have investigated the association between NAFLD and CKD.
Results:
Several observational studies and meta-analyses have reported the existence of an independent association
between NAFLD and risk of CKD in patients with and without diabetes. However, whilst the association
between NAFLD and risk of prevalent CKD is strong across various patient populations, whether NAFLD is
independently associated with the development and progression of CKD is still debatable. Moreover, emerging
evidence now suggests a potential association between patatin-like phospholipase domain-containing protein-3
(PNPLA3) rs738409 genotype (the most important genetic variant associated to NAFLD) and decreasing kidney
function, independent of NAFLD.
Conclusions :
Convincing evidence now indicates that CKD is increased among patients with NAFLD. For this
reason, patients with NAFLD should be regularly monitored for renal function and, on the other hand , NAFLD
should be considered in all patients with CKD, especially if they are obese or have type 2 diabetes.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Chiara Zusi
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Andrea Dalbeni
- Section of General Medicine, Hypertension and Liver Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Giorgio Grani
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Elena Buzzetti
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
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35
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Jarvis H, Craig D, Barker R, Spiers G, Stow D, Anstee QM, Hanratty B. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of population-based observational studies. PLoS Med 2020; 17:e1003100. [PMID: 32353039 PMCID: PMC7192386 DOI: 10.1371/journal.pmed.1003100] [Citation(s) in RCA: 248] [Impact Index Per Article: 49.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. Many individuals have risk factors associated with NAFLD, but the majority do not develop advanced liver disease: cirrhosis, hepatic decompensation, or hepatocellular carcinoma. Identifying people at high risk of experiencing these complications is important in order to prevent disease progression. This review synthesises the evidence on metabolic risk factors and their potential to predict liver disease outcomes in the general population at risk of NAFLD or with diagnosed NAFLD. METHODS AND FINDINGS We conducted a systematic review and meta-analysis of population-based cohort studies. Databases (including MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov) were searched up to 9 January 2020. Studies were included that reported severe liver disease outcomes (defined as liver cirrhosis, complications of cirrhosis, or liver-related death) or advanced fibrosis/non-alcoholic steatohepatitis (NASH) in adult individuals with metabolic risk factors, compared with individuals with no metabolic risk factors. Cohorts selected on the basis of a clinically indicated liver biopsy were excluded to better reflect general population risk. Risk of bias was assessed using the QUIPS tool. The results of similar studies were pooled, and overall estimates of hazard ratio (HR) were obtained using random-effects meta-analyses. Of 7,300 unique citations, 22 studies met the inclusion criteria and were of sufficient quality, with 18 studies contributing data suitable for pooling in 2 random-effects meta-analyses. Type 2 diabetes mellitus (T2DM) was associated with an increased risk of incident severe liver disease events (adjusted HR 2.25, 95% CI 1.83-2.76, p < 0.001, I2 99%). T2DM data were from 12 studies, with 22.8 million individuals followed up for a median of 10 years (IQR 6.4 to 16.9) experiencing 72,792 liver events. Fourteen studies were included in the meta-analysis of obesity (BMI > 30 kg/m2) as a prognostic factor, providing data on 19.3 million individuals followed up for a median of 13.8 years (IQR 9.0 to 19.8) experiencing 49,541 liver events. Obesity was associated with a modest increase in risk of incident severe liver disease outcomes (adjusted HR 1.20, 95% CI 1.12-1.28, p < 0.001, I2 87%). There was also evidence to suggest that lipid abnormalities (low high-density lipoprotein and high triglycerides) and hypertension were both independently associated with incident severe liver disease. Significant study heterogeneity observed in the meta-analyses and possible under-publishing of smaller negative studies are acknowledged to be limitations, as well as the potential effect of competing risks on outcome. CONCLUSIONS In this review, we observed that T2DM is associated with a greater than 2-fold increase in the risk of developing severe liver disease. As the incidence of diabetes and obesity continue to rise, using these findings to improve case finding for people at high risk of liver disease will allow for effective management to help address the increasing morbidity and mortality from liver disease. TRIAL REGISTRATION PROSPERO CRD42018115459.
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Affiliation(s)
- Helen Jarvis
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
- * E-mail:
| | - Dawn Craig
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Robert Barker
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Gemma Spiers
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Daniel Stow
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Quentin M. Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
- NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Barbara Hanratty
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
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Yang JD, Ahmed F, Mara KC, Addissie BD, Allen AM, Gores GJ, Roberts LR. Diabetes Is Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Cirrhosis From Nonalcoholic Fatty Liver Disease. Hepatology 2020; 71:907-916. [PMID: 31309602 PMCID: PMC6960360 DOI: 10.1002/hep.30858] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 07/16/2019] [Indexed: 12/13/2022]
Abstract
Diabetes increases the risk of liver disease progression and cirrhosis development in patients with nonalcoholic steatohepatitis (NASH). The association between diabetes and the risk of hepatocellular carcinoma (HCC) in NASH patients with cirrhosis is not well quantified. All patients with the diagnosis of NASH cirrhosis seen at Mayo Clinic Rochester between January 2006 and December 2015 were identified. All adult liver transplant registrants with NASH between 2004 and 2017 were identified using the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation registry for external validation. Cox proportional hazard analysis was performed to investigate the association between diabetes and HCC risk. Among 354 Mayo Clinic patients with NASH cirrhosis, 253 (71%) had diabetes and 145 (41%) were male. Mean age at cirrhosis evaluation was 62. During a median follow-up of 47 months, 30 patients developed HCC. Diabetes was associated with an increased risk of developing HCC in univariate (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 1.1-11.9; P = 0.04) and multivariable analysis (HR = 4.2; 95% CI = 1.2-14.2; P = 0.02). In addition, age (per decade, HR = 1.8; 95% CI = 1.2-2.6; P < 0.01) and low serum albumin (HR = 2.1; 95% CI = 1.5-2.9; P < 0.01) were significantly associated with an increased risk of developing HCC in multivariable analysis. Other metabolic risk factors, including body mass index, hyperlipidemia, and hypertension, were not associated with HCC risk. Among UNOS NASH registrants (N = 6,630), 58% had diabetes. Diabetes was associated with an increased risk of developing HCC in univariate (HR = 1.4; 95% CI = 1.1-1.8; P < 0.01) and multivariable (HR = 1.3; 95% CI = 1.0-1.7; P = 0.03) analysis. Conclusion: Diabetes is associated with an increased risk of HCC in patients with NASH cirrhosis.
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Affiliation(s)
- Ju Dong Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN,Division of Digestive and Liver Diseases, Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA,Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA,Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA
| | - Fowsiyo Ahmed
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Kristin C. Mara
- Department of Health Science Research, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Benyam D. Addissie
- Division of Gastroenterology and Hepatology, Geisinger Medical Center, Danville, PA
| | - Alina M. Allen
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
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Samji NS, Heda R, Satapathy SK. Peri-transplant management of nonalcoholic fatty liver disease in liver transplant candidates . Transl Gastroenterol Hepatol 2020; 5:10. [PMID: 32190778 DOI: 10.21037/tgh.2019.09.09] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 09/23/2019] [Indexed: 12/12/2022] Open
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly growing, affecting 25% of the world population. Non-alcoholic steatohepatitis (NASH) is the most severe form of NAFLD and affects 1.5% to 6.5% of the world population. Its rising incidence will make end-stage liver disease (ESLD) due to NASH the number one indication for liver transplantation (LT) in the next 10 to 20 years, overtaking Hepatitis C. Patients with NASH also have a high prevalence of associated comorbidities such as type 2 diabetes, obesity, metabolic syndrome, cardiovascular disease, and chronic kidney disease (CKD), which must be adequately managed during the peritransplant period for optimal post-transplant outcomes. The focus of this review article is to provide a comprehensive overview of the unique challenges these patients present in the peritransplant period, which comprises the pre-transplant, intraoperative, and immediate postoperative periods.
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Affiliation(s)
- Naga Swetha Samji
- Tennova Cleveland Hospital, 2305 Chambliss Ave NW, Cleveland, TN, USA
| | - Rajiv Heda
- University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA
| | - Sanjaya K Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY, USA
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Valenti L, Pelusi S. The Natural History of NAFLD: Environmental vs. Genetic Risk Factors. NON-ALCOHOLIC FATTY LIVER DISEASE 2020:129-145. [DOI: 10.1007/978-3-319-95828-6_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Cheung A, Neuschwander-Tetri BA, Kleiner DE, Schabel E, Rinella M, Harrison S, Ratziu V, Sanyal AJ, Loomba R, Jeannin Megnien S, Torstenson R, Miller V. Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum. Hepatology 2019; 70:1841-1855. [PMID: 31034092 DOI: 10.1002/hep.30672] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 04/16/2019] [Indexed: 12/20/2022]
Abstract
Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood-based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials.
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Affiliation(s)
- Amanda Cheung
- Stanford Hospital and Clinics, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA
| | | | | | - Elmer Schabel
- Gastroenterology & Hepatology Unit, Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany/European Medicines Agency, London, United Kingdom
| | - Mary Rinella
- Feinberg School of Medicine, Northwestern University, Chicago, IL
| | | | - Vlad Ratziu
- Department of Hepatology and Gastroenterology, Hôpital Pitié Salpêtrière et Université Pierre et Marie Curie, Paris, France
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA
| | - Rohit Loomba
- Division of Gastroenterology, University of California San Diego School of Medicine, San Diego, CA
| | | | | | - Veronica Miller
- Forum for Collaborative Research, University of California School of Public Health, Berkeley, CA
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Johansen ML, Schou M, Rossignol P, Holm MR, Rasmussen J, Brandt N, Frandsen M, Chabanova E, Dela F, Faber J, Kistorp C. Effect of the mineralocorticoid receptor antagonist eplerenone on liver fat and metabolism in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial (MIRAD trial). Diabetes Obes Metab 2019; 21:2305-2314. [PMID: 31183945 DOI: 10.1111/dom.13809] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/29/2019] [Accepted: 06/07/2019] [Indexed: 12/21/2022]
Abstract
AIM To investigate whether the mineralocorticoid receptor antagonist eplerenone has beneficial effects on liver fat and metabolism in patients with type 2 diabetes (T2D), the mineralocorticoid receptor antagonist in type 2 diabetes (MIRAD) trial. MATERIAL AND METHODS In this 26-week, double-blind, randomized, placebo-controlled trial, we enrolled 140 patients with T2D and high risk of cardiovascular disease. Patients were randomized 1:1 to either eplerenone with a target dose of 200 mg/day for patients with estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 or more and 100 mg/day for patients with eGFR between 41 and 59 mL/min per 1.73 m2 or placebo. The primary outcome measure was change in liver fat by proton magnetic resonance spectroscopy at week 26 from baseline; secondary outcomes were changes in metabolism, and safety by incident hyperkalaemia. RESULTS No changes in liver fat in the eplerenone group 0.91% (95% CI -0.57 to 2.39) or the placebo group -1.01% (-2.23 to 0.21) were found. The estimated absolute treatment difference was 1.92% (-3.81 to 0.01; P = 0.049). There was no beneficial impact on supporting secondary outcome variables of metabolism as fat mass distribution, lipid metabolism or insulin resistance. Despite a high dosage of eplerenone 164 versus 175 mg in patients treated with placebo (P = 0.228), the number of patients with incident hyperkalaemia (≥5.5 mmol/L) was low, with six in the eplerenone versus two in the placebo group (P = 0.276). CONCLUSION The addition of high doses of eplerenone to background antidiabetic and antihypertensive therapy does not show beneficial effects on liver fat and metabolism in patients with T2D.
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Affiliation(s)
- Marie L Johansen
- Department of Endocrinology-Internal Medicine, Copenhagen University Hospital, Herlev-Gentofte Hospital, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten Schou
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Copenhagen University Hospital, Herlev-Gentofte Hospital, Copenhagen, Denmark
| | - Patrick Rossignol
- Université de Lorraine, Inserm CIC Plurithémathique 1433, UMRS 1116 Inserm, CHRU Nancy, and FCRIN INI-CRCT, Nancy, France
| | - Maria R Holm
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jon Rasmussen
- Department of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Niels Brandt
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Mikkel Frandsen
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Elizaveta Chabanova
- Department of Radiology, Copenhagen University Hospital, Herlev-Gentofte Hospital, Copenhagen, Denmark
| | - Flemming Dela
- Faculty of Health and Medical Sciences, Department of Biomedical Sciences, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
- Department of Geriatrics, Copenhagen University Hospitals, Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Jens Faber
- Department of Endocrinology-Internal Medicine, Copenhagen University Hospital, Herlev-Gentofte Hospital, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Caroline Kistorp
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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Pelusi S, Cespiati A, Rametta R, Pennisi G, Mannisto V, Rosso C, Baselli G, Dongiovanni P, Fracanzani AL, Badiali S, Maggioni M, Craxi A, Fargion S, Prati D, Nobili V, Bugianesi E, Romeo S, Pihlajamaki J, Petta S, Valenti L. Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis. Clin Gastroenterol Hepatol 2019; 17:2310-2319.e6. [PMID: 30708111 DOI: 10.1016/j.cgh.2019.01.027] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 01/06/2019] [Accepted: 01/20/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis. METHODS We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy. RESULTS In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016). CONCLUSIONS In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis.
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Affiliation(s)
- Serena Pelusi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Annalisa Cespiati
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Raffaela Rametta
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Grazia Pennisi
- Section of Gastroenterology, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Ville Mannisto
- Department of Medicine, University of Eastern Finland and Kuopio, University Hospital, Kuopio, Finland
| | - Chiara Rosso
- Division of Gastroenterology, Department of Medical Sciences, University of Torino, Turin, Italy
| | - Guido Baselli
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Sara Badiali
- Surgery Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marco Maggioni
- Pathology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonio Craxi
- Section of Gastroenterology, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Prati
- Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Valerio Nobili
- Department of Gastroenterology, Ospedale Bambin Gesù, Roma, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology, Department of Medical Sciences, University of Torino, Turin, Italy
| | - Stefano Romeo
- Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Cardiology Department, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Jussi Pihlajamaki
- Department of Medicine, University of Eastern Finland and Kuopio, University Hospital, Kuopio, Finland
| | - Salvatore Petta
- Section of Gastroenterology, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
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Ismaiel A, Dumitraşcu DL. Cardiovascular Risk in Fatty Liver Disease: The Liver-Heart Axis-Literature Review. Front Med (Lausanne) 2019; 6:202. [PMID: 31616668 PMCID: PMC6763690 DOI: 10.3389/fmed.2019.00202] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 08/27/2019] [Indexed: 12/14/2022] Open
Abstract
According to the World Health Organization, cardiovascular disease (CVD) remains the leading cause of death worldwide, accounting for approximately 18 million deaths per year. Nevertheless, the worldwide prevalence of metabolic diseases, such as type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease (NAFLD), also known to be common risk factors for CVD, have dramatically increased over the last decades. Chronic alcohol consumption is a major cause of chronic liver diseases (CLD) as well as being a major health care cost expenditure accounting for the spending of tremendous amounts of money annually. NAFLD has become one of the major diseases plaguing the world while standing as the most common cause of liver disease in the Western countries by representing about 75% of all CLD. Currently, the most common cause of death in NAFLD remains to be CVD. Several mechanisms have been suggested to be responsible for associating FLD with CVD through several mechanisms including low-grade systemic inflammation, oxidative stress, adipokines, endoplasmic reticulum stress, lipotoxicity and microbiota dysbiosis which may also be influenced by other factors such as genetic and epigenetic variations. Despite of all this evidence, the exact mechanisms of how FLD can causally contribute to CVD are not fully elucidated and much remains unknown. Moreover, the current literature supports the increasing evidence associating FLD with several cardiovascular (CV) adverse events including coronary artery disease, increased subclinical atherosclerosis risk, structural alterations mainly left ventricular hypertrophy, increased epicardial fat thickness, valvular calcifications including aortic valve sclerosis and mitral annular calcification and functional cardiac modifications mainly diastolic dysfunction in addition to cardiac arrhythmias such as atrial fibrillation and ventricular arrythmias and conduction defects including atrioventricular blocks and bundle branch blocks. Patients with FLD should be evaluated and managed accordingly in order to prevent further complications. Possible management methods include non-pharmacological strategies including life style modifications, pharmacological therapies as well as surgical management. This review aims to summarize the current state of knowledge regarding the pathophysiological mechanisms linking FLD with an increased CV risk, in addition to associated CV adverse events and current management modalities.
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Affiliation(s)
- Abdulrahman Ismaiel
- Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,2nd Department of Internal Medicine, Cluj-Napoca, Romania
| | - Dan L Dumitraşcu
- Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,2nd Department of Internal Medicine, Cluj-Napoca, Romania
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Klein S, Kleine CE, Pieper A, Granzow M, Gautsch S, Himmit M, Kahrmann K, Schierwagen R, Uschner FE, Magdaleno F, Naoum ME, Kristiansen G, Walther T, Bader M, Sauerbruch T, Trebicka J. TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor. Sci Rep 2019; 9:11598. [PMID: 31406138 PMCID: PMC6690919 DOI: 10.1038/s41598-019-48024-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 07/29/2019] [Indexed: 12/14/2022] Open
Abstract
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
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Affiliation(s)
- Sabine Klein
- Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany
| | | | - Andrea Pieper
- House for Experimental Therapy, University of Bonn, Bonn, Germany
| | - Michaela Granzow
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Sebastian Gautsch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Mimoun Himmit
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | - Robert Schierwagen
- Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany
| | - Frank Erhard Uschner
- Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany
| | | | | | | | - Thomas Walther
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.,Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany
| | - Michael Bader
- Berlin Institute of Health (BIH), Berlin, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.,Institute for Biology, University of Lübeck, Lübeck, Germany.,Charité-University Medicine Berlin, Berlin, Germany.,Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany. .,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain. .,Institute for Bioengineering of Catalonia, Barcelona, Spain. .,Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
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44
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Chalasani N, Abdelmalek MF, Loomba R, Kowdley KV, McCullough AJ, Dasarathy S, Neuschwander-Tetri BA, Terrault N, Ferguson B, Shringarpure R, Shapiro D, Sanyal AJ. Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis. Liver Int 2019; 39:924-932. [PMID: 30253043 PMCID: PMC6433535 DOI: 10.1111/liv.13974] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 09/14/2018] [Accepted: 09/18/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. METHODS In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks. RESULTS In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)]. CONCLUSIONS Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.
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Affiliation(s)
- Naga Chalasani
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Rohit Loomba
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Kris V. Kowdley
- Organ Transplant Center, Swedish Medical Center, Seattle, Washington
| | - Arthur J. McCullough
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Srinivasan Dasarathy
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | | | - Norah Terrault
- Departments of Medicine and Surgery, University of California, San Francisco, San Francisco, California
| | | | | | - David Shapiro
- Intercept Pharmaceuticals, Inc., San Diego, California
| | - Arun J. Sanyal
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
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45
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Telmisartan and/or chlorogenic acid attenuates fructose-induced non-alcoholic fatty liver disease in rats: Implications of cross-talk between angiotensin, the sphingosine kinase/sphingoine-1-phosphate pathway, and TLR4 receptors. Biochem Pharmacol 2019; 164:252-262. [PMID: 31004566 DOI: 10.1016/j.bcp.2019.04.018] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 04/16/2019] [Indexed: 12/18/2022]
Abstract
Renin-angiotensin-aldosterone system (RAS) has been implicated in non-alcoholic fatty liver disease (NAFLD); the most common cause of chronic liver diseases. There is accumulating evidence that altered TLR4 and Sphingosine kinase 1(SphK1)/sphingosine1phosphate (S1P) signaling pathways are key players in the pathogenesis of NAFLD. Cross talk of the sphingosine signaling pathway, toll-4 (TLR4) receptors, and angiotensin II was reported in various tissues. Therefore, the aim of this study was to define the contribution of these two pathways to the hepatoprotective effects of telmisartan and/or chlorogenic acid (CGA) in NAFLD. CGA is a strong antioxidant that was previously reported to inhibit angiotensin converting enzyme. Male Wistar rats were treated with either high-fructose, with or without telmisartan, CGA, telmisartan + CGA for 8 weeks. Untreated NAFL rats showed characteristics of NAFLD, as evidenced by significant increase in the body weight, insulin resistance, and serum hepatotoxicity markers (Alanine and Aspartate transaminases) and lipids as compared to the negative control group, in addition to characteristic histopathological alterations. Treatment with either telmisartan and/or CGA improved aforementioned parameters, in addition to upregulation of antioxidant enzymes (Superoxide dismutase and Glutathione peroxidase). Effect of inhibiting RAS on both sphingosine pathway and TLR4 was evident by the suppressing effect of telmisartan and/or CGA on high fructose-induced upregulation of hepatic SPK1 and S1P, in addition to concomitant up-regulation of Sphingosine-1-Phosphate receptor (S1PR)3 protein level and increased expression of S1PR1 and TLR4. As TLR4 and SPK/S1P signaling pathways play important roles in the progression of liver inflammation, the effect on sphingosine pathway and TLR4 was associated with decreased concentrations of inflammatory markers, enzyme kB kinase (IKK), nuclear factor-kB and tumor necrosis factor-α as compared to untreated NAFL group. In conclusion, the present data strongly suggests the cross-talk between angiotensin, the Sphingosine SPK/S1P Axis and TLR4 Receptors, and their role in the pathogenesis of fructose-induced NAFLD, and the protection afforded by drugs inhibiting RAS.
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46
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Angiotensin II Type 1 Receptor rs5186 Gene Variant Predicts Incident NAFLD and Associated Hypertension: Role of Dietary Fat-Induced Pro-Inflammatory Cell Activation. Am J Gastroenterol 2019; 114:607-619. [PMID: 30920415 DOI: 10.14309/ajg.0000000000000154] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Hypertension has been linked to the presence and severity of nonalcoholic fatty liver disease (NAFLD) through unclear mechanisms. The gain-of-function rs5186 A1166C variant in angtiotensin receptor type 1 (AGTR1) gene has been linked to hypertension, cardiovascular disease and metabolic syndrome. We assessed the impact of AGTR1 A1166C variant on NAFLD incidence and severity and on glucose and lipid metabolism and explored the underlying mechanisms. METHODS We followed up 314 healthy nonobese, nondiabetic, nonhypertensive, insulin-sensitive participants in a population-based study, characterized for AGTR1 rs5186 A1166C variant, adipokine profile, inflammatory and endothelial dysfunction markers. An independent cohort of 78 biopsy-proven nondiabetic NAFLD patients and controls underwent an oral glucose tolerance test with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, calprotectin, and nuclear factor-κB activation in circulating mononuclear cells. RESULTS AGTR1 A1166C polymorphism predicted 9.8-year incident NAFLD (odds ratio: 1.67, 95% CI: 1.26-2.21) and hypertension (odds ratio: 1.49, 95% CI: 1.12-2.63) and 9-year increase in cardiovascular disease risk and endothelial dysfunction markers. In the cross-sectional cohort, AGTR1 C allele carriers had higher insulin resistance. Despite comparable fasting lipid profiles, AGTR1 C allele carriers showed postprandial triglyceride-rich and cholesterol-rich VLDL lipoprotein accumulation, higher resistin, MCP-1 and calprotectin responses and nuclear factor-κB activation in mononuclear cells, and a blunted postprandial adiponectin response to fat, which predicted liver histology, hepatocyte apoptosis activation, insulin resistance, and endothelial dysfunction. DISCUSSION AGTR1 A1166C variant affects liver disease, insulin resistance, and endothelial dysfunction in NAFLD, at least in part by modulating adipokine, chemokine, and pro-inflammatory cell activation in response to fat ingestion.
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47
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Lonardo A, Lugari S, Ballestri S, Nascimbeni F, Baldelli E, Maurantonio M. A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? Acta Diabetol 2019; 56:385-396. [PMID: 30519965 DOI: 10.1007/s00592-018-1266-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023]
Abstract
Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD.
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Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy.
| | - Simonetta Lugari
- Università di Modena e Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy
| | - Stefano Ballestri
- Azienda USL di Modena, Ospedale Di Pavullo, UO di Medicina, Pavullo (Mo), Italy
| | - Fabio Nascimbeni
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy
| | - Enrica Baldelli
- Università di Modena e Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy
| | - Mauro Maurantonio
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy
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Cavalla D. Using human experience to identify drug repurposing opportunities: theory and practice. Br J Clin Pharmacol 2019; 85:680-689. [PMID: 30648285 DOI: 10.1111/bcp.13851] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 12/07/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022] Open
Abstract
Retrospective evidence drawn from real-world experience of a medicine's use outside its labelled indication is one of a number of techniques used in drug repurposing (DRP). Relying as it does on large numbers of real incidences of human experience, rather than individual case reports with limited statistical support, preclinical experiments with poor translatability or in silico associations, which are early-stage hypotheses, it represents the best validated form of DRP. Cancer is the most frequent of such DRP examples (e.g. aspirin in pancreatic cancer, hazard ratio = 0.25). This approach can be combined with pathway analysis to provide first-in-class treatments for complex diseases. Alternatively, it can be combined with prospective preclinical studies to uncover a validated mechanism for a new indication, after which a repurposed molecule is chemically optimized.
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49
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Pelusi S, Valenti L. Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease. Liver Int 2019; 39:250-256. [PMID: 30248234 DOI: 10.1111/liv.13972] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 08/28/2018] [Accepted: 09/17/2018] [Indexed: 02/13/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of advanced liver disease in Western countries. NAFLD is defined in the presence of increased hepatic fat content, which is mainly stored under the form of neutral lipids within intracellular droplets and is not explained by at risk alcohol intake. In order to understand the pathogenesis, monitor the progression and find novel treatments for this condition, previous research efforts mainly addressed the role of inflammation. However, very recent data seem to suggest that hepatic lipid accumulation may be involved in NAFLD pathogenesis by driving secondary inflammation and fibrosis progression. Here, we will briefly review the novel results derived from natural history, genetics, imaging studies and therapeutic trials that support the notion that hepatic fat accumulation may represent a major clinical outcome and therapeutic target for NAFLD. Indeed, prospective and genetic data are consistent with hepatic fat being a driver of NAFLD progression. Furthermore, new technologies will render possible to monitor hepatic fat content without the need of invasive assessment, thereby allowing to identify patients at higher risk, and to monitor the response to drugs that act by decreasing hepatic lipid accumulation.
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Affiliation(s)
- Serena Pelusi
- Department of Pathophysiology and Transplantation, University of Milan, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, University of Milan, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
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50
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Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis 2019; 282:110-120. [PMID: 30731283 DOI: 10.1016/j.atherosclerosis.2019.01.029] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/22/2018] [Accepted: 01/18/2019] [Indexed: 12/15/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and includes a spectrum of abnormalities ranging from steatosis to cirrhosis. In this review, we address recent evidence and limitations of studies that evaluated the association of NAFLD with atherosclerotic cardiovascular disease. NAFLD is considered an ectopic fat deposit associated with metabolic (insulin resistance, hyperglycemia and dyslipidemia), inflammatory, coagulation and blood pressure disturbances. Prospective studies have associated NAFLD presence and severity, particularly steatohepatitis and fibrosis, with an increased risk of cardiovascular disease. However, these studies are limited by heterogeneity concerning NAFLD diagnostic criteria and disease severity stratification, as well as by the presence of confounding factors. In addition, genetic variants predisposing to NAFLD, such as the PNPLA3 I148M mutation, were not consistently associated with an increased risk of cardiovascular events. Therefore, currently, it is not possible to prove a causal relation between NAFLD and cardiovascular disease. Furthermore, there is presently no evidence that NAFLD diagnosis can be used as a tool to improve cardiovascular risk stratification and modify treatment. Specific treatments for NAFLD are being developed and must be tested prospectively in adequately designed trials to determine the potential of reducing both hepatic and cardiovascular diseases and to prove whether NAFLD is indeed a cause of atherosclerosis.
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Affiliation(s)
- Raul D Santos
- Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Lipid Clinic Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil.
| | - Luca Valenti
- Università Degli Studi Milano, Fondazione IRCCS Ca' Granda Pad Granelli, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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