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Geng W, Liao W, Cao X, Yang Y. Therapeutic Targets and Approaches to Manage Inflammation of NAFLD. Biomedicines 2025; 13:393. [PMID: 40002806 PMCID: PMC11853636 DOI: 10.3390/biomedicines13020393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.
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Affiliation(s)
- Wanying Geng
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China;
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Wanying Liao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Xinyuan Cao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Yingyun Yang
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
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Sohn W, Lee YS, Kim SS, Kim JH, Jin YJ, Kim GA, Sung PS, Yoo JJ, Chang Y, Lee EJ, Lee HW, Choi M, Yu SJ, Jung YK, Jang BK. KASL clinical practice guidelines for the management of metabolic dysfunction-associated steatotic liver disease 2025. Clin Mol Hepatol 2025; 31:S1-S31. [PMID: 39967303 PMCID: PMC11925433 DOI: 10.3350/cmh.2025.0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/19/2025] [Indexed: 02/20/2025] Open
Affiliation(s)
- Won Sohn
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Soon Sun Kim
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Dongtan Sacred Heart Hospital, Hallym University School of Medicine, Hwaseong, Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Gi-Ae Kim
- Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, Korea
| | - Pil Soo Sung
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Chang
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Eun Joo Lee
- Department of Pediatrics, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- Clinical Evidence Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
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Sevilla-González M, González-Ortiz A, Landa-Anell MV, Melgarejo-Hernández MA, Arias-Marroquín AT, Del Razo-Olvera FM, Román-Calleja BM, Monreal-Lugo AV, Martin-Vences AJ, Haua-Navarro K, Espinosa-Cuevas A. Adaptation of the nutrition care process for metabolic diseases in the Mexican population. Front Nutr 2025; 12:1513747. [PMID: 39980684 PMCID: PMC11841437 DOI: 10.3389/fnut.2025.1513747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 01/08/2025] [Indexed: 02/22/2025] Open
Abstract
Background The Nutrition Care Process (NCP) is a systematic framework designed to enhance the quality of nutrition care. Given the high prevalence of metabolic diseases in Mexican population, there is a critical need for tailored nutrition care strategies. Objective We aim to describe the adaptation of the NCP to manage metabolic diseases in Mexican individuals. Methods Our adaptation included a comprehensive literature review of clinical nutrition guidelines, by a structured consultation with experts to ensure clinical setting-specific and culturally appropriate modifications. A team of registered dietitians from two tier 3 hospitals, each with over five years of experience in metabolic disease management, customized the NCP's four core steps-assessment, diagnosis, intervention, and monitoring-to meet the specific needs of the Mexican population. Results We adapted the NCP to manage five common metabolic disorders: obesity, type 2 diabetes, kidney disease, metabolic dysfunction-associated steatotic liver disease, and dyslipidemia. Each step of the NCP was complemented by the development of educational materials designed to (1) enhance awareness of disease risk, (2) broaden their knowledge of nutritional management, and (3) provide tailored strategies for developing personalized action plans. The adapted NCP was implemented in clinical and research settings and the materials were documented as an online publication to facilitate widespread dissemination. Conclusion Our adaptation represents a significant advancement in the use of structured tools for nutrition care in Mexican populations, who face disproportionately high rates of metabolic diseases. Further research is needed to assess the effectiveness of this approach in clinical settings.
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Affiliation(s)
- Magdalena Sevilla-González
- Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Ailema González-Ortiz
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Translational Research Center, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - María Victoria Landa-Anell
- Centro de Atención Integral del Paciente con Diabetes (CAIPaDi), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Marco A. Melgarejo-Hernández
- Centro de Atención Integral del Paciente con Diabetes (CAIPaDi), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Department of Endocrinology and Metabolism, Lipid Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Ana Teresa Arias-Marroquín
- Department of Epidemiological Surveillance, Dirección de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Fabiola Mabel Del Razo-Olvera
- Department of Endocrinology and Metabolism, Lipid Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Metabolic Diseases Research Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Ana Victoria Monreal-Lugo
- Metabolic Diseases Research Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - Angeles Espinosa-Cuevas
- Nephrology and Mineral Metabolism Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Patil PV, Julakanti S, Dhadve RU. Point Shear Wave Elastography for Assessment of Liver Stiffness in Normal Individuals and in Patients With Non-alcoholic Fatty Liver Disease. Cureus 2024; 16:e70711. [PMID: 39493184 PMCID: PMC11530260 DOI: 10.7759/cureus.70711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 10/02/2024] [Indexed: 11/05/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is an increasing health issue worldwide, driven by rising rates of diabetes, obesity, and hypertriglyceridemia. Often asymptomatic, NAFLD is diagnosed through blood tests, imaging, and sometimes liver biopsy. Some cases advance to non-alcoholic steatohepatitis (NASH), which can lead to complications like liver cirrhosis and liver failure. While liver biopsy is the standard test for diagnosis, non-invasive methods such as shear wave elastography (SWE) offer a simpler and more reproducible alternative for diagnosing NAFLD. This is crucial for early intervention and preventing the progression of liver damage. Objectives The objectives of the study were to measure and compare liver stiffness in healthy individuals and patients with NAFLD using point shear wave elastography (pSWE), as well as to correlate liver stiffness in NAFLD patients with the ultrasonographic grades of fatty liver. Materials and methods This observational study was carried out at Dr. D. Y. Patil Medical College, Hospital and Research Centre in Pune, India, from December 2022 to April 2024. The study involved 82 participants in total, with 41 patients diagnosed with NAFLD (cases) and 41 healthy individuals with a sonographically normal liver (controls). pSWE was performed on each participant to measure liver stiffness, with results expressed in kilopascals (kPa). The procedure was conducted using a Samsung HS70A ultrasound machine (Samsung Electronics Pvt. Ltd., Seoul, South Korea). Data analysis was performed using IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, USA). Non-parametric tests, such as the Mann-Whitney test and Kruskal-Wallis test, were used to evaluate the significance of differences. A p-value of less than 0.05 was considered statistically significant. Results The mean liver stiffness, measured in kilopascals (kPa), was higher in NAFLD patients (cases) (10±5.1 kPa) than in normal individuals (controls) (4.4±0.7 kPa). This difference was statistically significant, with a p-value of less than 0.001. A positive correlation (rho=0.848, p<0.001) was found between the ultrasonographic grade of fatty liver and liver stiffness in NAFLD patients. Conclusion Our study demonstrated that individuals with NAFLD exhibited significantly higher liver stiffness compared to healthy individuals, as measured by ultrasound SWE. These findings suggest that pSWE could serve as a valuable, non-invasive diagnostic tool for assessing liver stiffness in NAFLD patients. Additionally, pSWE holds the potential for evaluating and monitoring the progression of the disease. However, further research with larger sample sizes is necessary to determine the prognostic significance of liver stiffness in these patients.
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Affiliation(s)
- Parag V Patil
- Radiodiagnosis, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, IND
| | - Sravya Julakanti
- Radiodiagnosis, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, IND
| | - Rajshree U Dhadve
- Radiodiagnosis, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, IND
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Hosseeini SM, Jafari M, Tahmasebi M, Adibi P. Adaptation of Clinical Practice Guideline for Assessment of Liver Fibrosis in Patients with Non Alcoholic Fatty Liver Disease in Isfahan Province. Int J Prev Med 2024; 15:27. [PMID: 39239302 PMCID: PMC11376528 DOI: 10.4103/ijpvm.ijpvm_284_22] [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: 08/21/2022] [Accepted: 10/04/2023] [Indexed: 09/07/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis (accumulation of fat in the liver to over 5% of its weight) in the absence of secondary causes of fat accumulation in the liver such as excessive alcohol use. NAFLD is divided into two types: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Therefore, in this clinical guideline, we sought to determine general and important policies for this disease and modify its managment approaches. We adapted this guideline for the management of NAFLD in Isfahan Province. This guideline was developed by clinical appraisal and review of the evidence, available clinical guidelines, and in consultation with members of the Isfahan Chamber of the Iranian Association of Gastroenterology and Hepatology. Biopsy is recommended as the most reliable method (gold standard) to diagnose steatohepatitis and fibrosis in patients with NAFLD. NAFLD fibrosis score (NFS) and fibrosis-4 (FIB-4) are recommended as the test with the highest predictive value for advanced fibrosis in patients with NAFLD compared to other serologic tests. Among the noninvasive methods used to assess liver fibrosis, transient elastography (TE) is preferable to other methods.
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Affiliation(s)
- Sayed Mohammad Hosseeini
- Isfahan Gastroenterology and Hepatology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Jafari
- Isfahan Gastroenterology and Hepatology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Tahmasebi
- Clinical Informationist Research Group, Health Information Technology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Payman Adibi
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Erdogan BT, Tam AA, Baser H, Cuhaci Seyrek FN, Polat SB, Ersoy R, Topaloglu O, Cakir B. Relationship between fibrosis-4 score and microvascular complications in patients with type 2 diabetes mellitus. Arab J Gastroenterol 2024; 25:269-274. [PMID: 38719663 DOI: 10.1016/j.ajg.2024.04.001] [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: 04/08/2023] [Revised: 03/31/2024] [Accepted: 04/19/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND AND STUDY AIMS Nonalcoholic fatty liver disease is the most prevalent chronic liver disease globally and is linked to augmented susceptibility to type 2 diabetes mellitus (DM), cardiovascular disease, and microvascular complications inherent to DM, such as nephropathy, neuropathy, and retinopathy. The fibrosis-4 (FIB-4) scoring system, a noninvasive tool, is useful for predicting the extent of liver fibrosis across diverse pathologies. This study aimed to assess the potential predictive role of FIB-4 scores in microvascular complications associated with diabetes. PATIENTS AND METHODS The medical records of patients with type 2 DM admitted to our endocrinology clinic between February 2019 and December 2020 were retrospectively evaluated. Parameters including demographic attributes, fasting blood glucose, glycated hemoglobin, aspartate aminotransferase, alanine aminotransferase, thrombocyte levels, and microvascular complications were recorded. The FIB-4 score was computed, and patients were categorized based on these scores (<1.3 and ≥ 1.3). RESULTS The analysis included 312 patients with a median age of 60 (50-68 years); 39.7 % were men. The median duration of diabetes was 10 years (5-20 years), and the median FIB-4 score was 0.93 (0.63-1.34). Neuropathy, nephropathy, and retinopathy were observed in 50.6 %, 31.4 %, and 34 % of the patients, respectively. Although the FIB-4 score did not differ significantly between patients with and without neuropathy or retinopathy, patients with nephropathy exhibited higher FIB-4 scores. Notably, patients with FIB-4 scores ≥ 1.3 demonstrated a significantly higher prevalence of nephropathy. Logistic regression analysis demonstrated that higher FIB-4 scores were significantly associated with an increased risk of nephropathy. CONCLUSION The FIB-4 score is a cost-effective and straightforward tool with potential applicability in predicting nephropathy in individuals with type 2 DM.
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Affiliation(s)
- Beril Turan Erdogan
- University of Health Sciences, Ankara City Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey.
| | - Abbas Ali Tam
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Husniye Baser
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Fatma Neslihan Cuhaci Seyrek
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Sefika Burcak Polat
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Reyhan Ersoy
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Oya Topaloglu
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Bekir Cakir
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
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Liu H, Huang Y, Huang M, Wang M, Ming Y, Chen W, Chen Y, Tang Z, Jia B. From nitrate to NO: potential effects of nitrate-reducing bacteria on systemic health and disease. Eur J Med Res 2023; 28:425. [PMID: 37821966 PMCID: PMC10566198 DOI: 10.1186/s40001-023-01413-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 09/29/2023] [Indexed: 10/13/2023] Open
Abstract
Current research has described improving multisystem disease and organ function through dietary nitrate (DN) supplementation. They have provided some evidence that these floras with nitrate (NO3-) reductase are mediators of the underlying mechanism. Symbiotic bacteria with nitrate reductase activity (NRA) are found in the human digestive tract, including the mouth, esophagus and gastrointestinal tract (GT). Nitrate in food can be converted to nitrite under the tongue or in the stomach by these symbiotic bacteria. Then, nitrite is transformed to nitric oxide (NO) by non-enzymatic synthesis. NO is currently recognized as a potent bioactive agent with biological activities, such as vasodilation, regulation of cardiomyocyte function, neurotransmission, suppression of platelet agglutination, and prevention of vascular smooth muscle cell proliferation. NO also can be produced through the conventional L-arginine-NO synthase (L-NOS) pathway, whereas endogenous NO production by L-arginine is inhibited under hypoxia-ischemia or disease conditions. In contrast, exogenous NO3-/NO2-/NO activity is enhanced and becomes a practical supplemental pathway for NO in the body, playing an essential role in various physiological activities. Moreover, many diseases (such as metabolic or geriatric diseases) are primarily associated with disorders of endogenous NO synthesis, and NO generation from the exogenous NO3-/NO2-/NO route can partially alleviate the disease progression. The imbalance of NO in the body may be one of the potential mechanisms of disease development. Therefore, the impact of these floras with nitrate reductase on host systemic health through exogenous NO3-/NO2-/NO pathway production of NO or direct regulation of floras ecological balance is essential (e.g., regulation of body homeostasis, amelioration of diseases, etc.). This review summarizes the bacteria with nitrate reductase in humans, emphasizing the relationship between the metabolic processes of this microflora and host systemic health and disease. The potential effects of nitrate reduction bacteria on human health and disease were also highlighted in disease models from different human systems, including digestive, cardiovascular, endocrine, nervous, respiratory, and urinary systems, providing innovative ideas for future disease diagnosis and treatment based on nitrate reduction bacteria.
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Affiliation(s)
- Hongyu Liu
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yisheng Huang
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Mingshu Huang
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Min Wang
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yue Ming
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Weixing Chen
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yuanxin Chen
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Zhengming Tang
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Bo Jia
- Department of Oral Surgery, School of Stomatology, Southern Medical University, Guangzhou, China.
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Nagata T, Funakoshi S, Morihara D, Shakado S, Yokoyama K, Takata K, Tanaka T, Fukunaga A, Yamauchi R, Fukuda H, Matsuoka H, Imakiire S, Sakisaka H, Matsuoka S, Kuno N, Abe K, Ishibashi H, Ashizuka S, Hirai F. Malnutrition and inflammation status in nonobese patients with inflammatory bowel disease are associated with nonalcoholic fatty liver disease: a retrospective study. Intest Res 2023; 21:471-480. [PMID: 37559192 PMCID: PMC10626015 DOI: 10.5217/ir.2023.00035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/19/2023] [Accepted: 07/03/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND/AIMS The frequency and details of nonalcoholic fatty liver disease (NAFLD) complications in patients with inflammatory bowel disease (IBD) remain unclear. This study aimed to clarify characteristics of NAFLD in patients with IBD. METHODS We retrospectively identified and enrolled patients with IBD diagnosed with or without NAFLD by undergoing abdominal computed tomography (CT) at our institution between 2005 and 2020. The primary endpoint was the complication rate of NAFLD in patients with IBD. Secondary endpoints were the clinical characteristics of nonobese patients with IBD and comorbid NAFLD and their association with nutritional and inflammatory parameters. RESULTS Twenty-one (21.9%) of 96 eligible patients with IBD also had NAFLD. In nonobese patients (defined as patients with a body mass index <25 kg/m2), C-reactive protein (CRP; P<0.001) and alanine aminotransferase (P=0.018) levels were higher and the albumin level (P=0.005) and prognostic nutritional index (PNI; P=0.002) values were lower in patients with NAFLD than in those without NAFLD. The PNI value was positively correlated (P<0.001) and the CRP level was negatively correlated (P=0.001) with the hepatosplenic ratio. However, in the NAFLD combined group, PNI (P<0.05) and CRP values (P<0.001) were improved over time after CT imaging by continuing IBD treatment. CONCLUSIONS Worsening nutritional and inflammatory status in IBD patients is associated with complications of NAFLD. Diagnosis of NAFLD in IBD patients using CT imaging might be useful not only for early detection of NAFLD but also in assessing the need for therapeutic intervention for IBD.
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Affiliation(s)
- Takahiro Nagata
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Sadahiro Funakoshi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Daisuke Morihara
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Atsushi Fukunaga
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hiromi Fukuda
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hiroki Matsuoka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - So Imakiire
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hideto Sakisaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Satoshi Matsuoka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Nobuaki Kuno
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Koichi Abe
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hideki Ishibashi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Shinya Ashizuka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
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Izumi H, Yoshii H, Fujino R, Takeo S, Nomura E, Mukai M, Makuuchi H. Factors contributing to nonalcoholic fatty liver disease (NAFLD) and fat deposition after pancreaticoduodenectomy: A retrospective analysis. Ann Gastroenterol Surg 2023; 7:793-799. [PMID: 37663962 PMCID: PMC10472401 DOI: 10.1002/ags3.12673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/04/2023] [Accepted: 03/13/2023] [Indexed: 09/05/2023] Open
Abstract
Aim Nonalcoholic fatty liver disease (NAFLD) can occur due to various reasons after pancreaticoduodenectomy (PD). This study examined the risk and perioperative determinants of NAFLD and fat deposition after PD. Methods A total of 101 patients who had undergone computed tomography 6 months after PD were included. We compared perioperative factors between patients who developed NAFLD and those who developed fatty deposits after PD. Results In the NAFLD group, pancreatic cancer was significantly more prevalent among patients who developed postoperative NAFLD (p = 0.024) and had a lower postoperative body mass index (BMI; p = 0.008). Multivariate analysis revealed that pancreatic carcinoma (hazard ratio [HR] 4.42, 95% confidence interval [CI] 1.118-17.442, p = 0.034) and lower postoperative BMI (HR 0.51, 95% CI 0.274-0.954, p = 0.0355) were risk factors for fatty liver. Pancreatic leakage (p = 0.024) and postoperative BMI (p = 0.002) were significantly lower in the fat deposition group than those in the NAFLD group. Multivariate analysis also revealed that a lower postoperative BMI was a risk factor for fat deposition (HR 0.56, 95% CI 0.523-0.982, p = 0.042). Moreover, multivariate analysis revealed that the fat deposition group had significantly lower pancreatic leakage than the NAFLD group (HR 7.944, 95% CI 1.993-63.562, p = 0.049). Conclusion The findings of this study suggest that postoperative BMI and pancreatic cancer are associated with a higher risk of NAFLD after PD, possibly because of pancreatic exocrine insufficiency and impaired fat absorption.
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Affiliation(s)
- Hideki Izumi
- Department of Gastrointestinal SurgeryTokai University Hachioji HospitalHachioji, TokyoJapan
| | - Hisamichi Yoshii
- Department of Gastrointestinal SurgeryTokai University Hachioji HospitalHachioji, TokyoJapan
| | - Rika Fujino
- Department of Gastrointestinal SurgeryTokai University Hachioji HospitalHachioji, TokyoJapan
| | - Shigeya Takeo
- Department of Gastrointestinal SurgeryTokai University Hachioji HospitalHachioji, TokyoJapan
| | - Eiji Nomura
- Department of Gastrointestinal SurgeryTokai University Hachioji HospitalHachioji, TokyoJapan
| | - Masaya Mukai
- Department of Gastrointestinal SurgeryTokai University Hachioji HospitalHachioji, TokyoJapan
| | - Hiroyasu Makuuchi
- Department of Gastrointestinal SurgeryTokai University Hachioji HospitalHachioji, TokyoJapan
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Kogiso T, Ogasawara Y, Horiuchi K, Taniai M, Tokushige K. Analysis of genetic factors associated with fatty liver disease-related hepatocellular carcinoma. Cancer Med 2023; 12:17798-17807. [PMID: 37644826 PMCID: PMC10524060 DOI: 10.1002/cam4.6410] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/03/2023] [Accepted: 07/25/2023] [Indexed: 08/31/2023] Open
Abstract
AIM Single-nucleotide polymorphisms (SNPs) in PNPLA3 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) genes are associated with fatty liver disease (FLD) progression and carcinogenesis. In the present study, we evaluated the characteristics of Japanese FLD patients according to HSD17B13 polymorphisms. METHODS We enrolled 402 patients who were clinically and pathologically diagnosed with FLD (alcoholic: 63 cases, nonalcoholic: 339 cases) at our hospital in 1990-2018 (228 males; median age: 54.9 [14.6-83.6] years). FLD patients with HSD17B13 A/A (212 cases) and others (A/AA or AA/AA; 190 cases) were compared. RESULTS Compared to patients with HSD17B13 A/A and others, those with the A/A genotype showed increased incidence of hepatocellular carcinoma (HCC) (A/A vs. others; 18.4% vs. 9.5%, p = 0.01), cardiovascular diseases (14.2% vs. 4.2%, p < 0.01), and hypertension (56.6% vs. 47.4%, p = 0.06). In patients without A/A, the HCC incidence was significantly reduced in those with alcohol-related FLD, fibrosis-4 index <2.67, and the PNPLA3 CC genotype; however, there was no significant difference in nonalcoholic-FLD. Patients without HSD17B13 A/A showed severe steatosis (77% vs. 88.6%, p < 0.01). New HCC developed in 11 cases and the 5-year incidence rate of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 A/A, which was significantly higher than the rate for those with other SNP profiles (0.6%, p = 0.03). CONCLUSIONS Inhibiting HSD17B13 activity may prevent HCC development, particularly in alcohol-related FLD and low-risk patients. Therefore, combinations of SNPs and other risk factors can be used for screening FLD-HCC.
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Affiliation(s)
- Tomomi Kogiso
- Department of Internal MedicineInstitute of Gastroenterology, Tokyo Women's Medical UniversityTokyoJapan
| | - Yuri Ogasawara
- Department of Internal MedicineInstitute of Gastroenterology, Tokyo Women's Medical UniversityTokyoJapan
| | - Kentaro Horiuchi
- Department of Internal MedicineInstitute of Gastroenterology, Tokyo Women's Medical UniversityTokyoJapan
| | - Makiko Taniai
- Department of Internal MedicineInstitute of Gastroenterology, Tokyo Women's Medical UniversityTokyoJapan
| | - Katsutoshi Tokushige
- Department of Internal MedicineInstitute of Gastroenterology, Tokyo Women's Medical UniversityTokyoJapan
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11
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Rinaldi L, Giorgione C, Mormone A, Esposito F, Rinaldi M, Berretta M, Marfella R, Romano C. Non-Invasive Measurement of Hepatic Fibrosis by Transient Elastography: A Narrative Review. Viruses 2023; 15:1730. [PMID: 37632072 PMCID: PMC10459581 DOI: 10.3390/v15081730] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Transient elastography by FibroScan® (Echosens, Paris, France) is a non-invasive method that can provide a reliable measurement of liver fibrosis through the evaluation of liver stiffness. Despite its limitations and risks, liver biopsy has thus far been the only procedure able to provide data to quantify fibrosis. Scientific evidence and clinical practice have made it possible to use FibroScan® in the diagnostic work-up of several liver diseases to monitor patients' long-term treatment response and for complication prevention. For these reasons, this procedure is widely used in clinical practice and is still being investigated for further applications. The aim of this narrative review is to provide a comprehensive overview of the main applications of transient elastography in the current clinical practice.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Chiara Giorgione
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Andrea Mormone
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Francesca Esposito
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Michele Rinaldi
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, “Federico II” University of Naples, 80131 Naples, Italy;
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Ciro Romano
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
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12
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Miao X, Luo P, Liu J, Wang J, Chen Y. Dihydromyricetin ameliorated nonalcoholic steatohepatitis in mice by regulating the composition of serous lipids, bile acids and ileal microflora. Lipids Health Dis 2023; 22:112. [PMID: 37533083 PMCID: PMC10394885 DOI: 10.1186/s12944-023-01871-7] [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: 03/08/2023] [Accepted: 07/07/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Dihydromyricetin (DMY) is a natural flavonoid with anti-nonalcoholic steatohepatitis (NASH) activity. However, the effects of DMY on the composition of lipids and bile acids (BAs) in serum, and gut microbiota (GM) in ileum of mice with NASH are not clear. METHODS After male C57BL/6 mice was fed with methionine and choline deficiency (MCD) diet and simultaneously administered with DMY (300 mg/kg/day) by gavage for 8 weeks, the pathological changes of liver tissue were observed by Oil Red O, hematoxylin eosin and Masson staining, the levels of serum alaninea minotransferase, aspartate aminotransferase and liver triglyceride, malonic dialdehyde were detected by the detection kits, the composition and contents of serum lipids and BAs were detected by Liquid Chromatograph-Mass Spectrometry, the mRNA levels of hepatic BAs homeostasis-related genes were detected by RT-qPCR, and microbiological diversity in ileum was analyzed by 16S rDNA sequencing. RESULTS The results showed that the significant changes including 29 lipids, 4 BAs (23-nor-deoxycholic acid, ursodeoxycholic acid, 7-ketodeoxycholic acid and cholic acid), 2 BA transporters (Mrp2 and Oatp1b2) and 8 GMs between MCD and DMY groups. Among them, DMY treatment significantly down-regulated 21 lipids, 4 BAs mentioned above, the ratio of Firmicutes/Bacteroidota and the abundance of Erysipelotrichaceae, Faecalibacuium, significantly up-regulated 8 lipids and 5 GMs (Verrucomicrobiota, Bacteroidota, Actinobacteria, Akkermansiaceae and Akkermansia). CONCLUSIONS The results suggested that DMY may alleviate MCD diet-induced NASH through decreasing the serum levels of toxic BAs which regulated by liver Oatp1b2 and Mrp2, regulating the metabolism of related lipids, and up-regulating intestinal probiotics (Actinobacteria and Verrucomicrobiota at the phylum level; Akkermansiaceae at the family level; Akkermansiaat at the genus level) and inhibiting intestinal harmful bacteria (Firmicutes at the phylum level; Erysipelotrichaceae at the family level; Faecalibaculum at the genus level).
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Affiliation(s)
- Xiaolei Miao
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Ping Luo
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
| | - Jiao Liu
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
| | - Junjun Wang
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China.
| | - Yong Chen
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China.
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13
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Wakabayashi S, Joshita S, Kimura K, Motoki H, Okumura T, Kobayashi H, Yamashita Y, Sugiura A, Yamazaki T, Kimura T, Kuwahara K, Umemura T. Symptom-based portopulmonary hypertension screening questionnaire in Japanese patients with chronic liver disease. JGH Open 2023; 7:527-536. [PMID: 37649859 PMCID: PMC10463024 DOI: 10.1002/jgh3.12939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/21/2023] [Accepted: 06/29/2023] [Indexed: 09/01/2023]
Abstract
Background and Aim As the exact prevalence of portopulmonary hypertension (PoPH) and the etiology of chronic liver disease (CLD) remain unknown, the present study aimed to clarify these points in Japanese patients with CLD using symptom-based questionnaire screening. Methods Patients with CLD were asked to complete an eight-item written questionnaire on pulmonary hypertension (PH) symptoms. If at least one item response was "yes," the patient was offered ultrasonic echocardiography (UCG). Patients identified as having an intermediate or high risk of PH by UCG were referred to a cardiologist for further evaluation, whereby a definitive diagnosis of PoPH was made using right heart catheterization (RHC) findings. Results A total of 1111 patients with CLD completed the survey. Of the 566 symptomatic patients with at least one question answered as "yes," approximately half agreed to undergo UCG (n = 267). Compared with asymptomatic patients, symptomatic patients were significantly older, predominantly female, and more frequently exhibited cirrhosis. Based on UCG findings, 228, 12, and 8 patients had a low, intermediate, or high risk for PH, respectively. Intermediate-/high-risk patients showed significantly more advanced disease progression status than low-risk patients. The frequencies of answer to the eight questions were comparable. Ultimately, three patients were diagnosed as having PoPH (1.1% of UCG cases), one with underlying hepatitis C virus (HCV) infection and two with primary biliary cholangitis (PBC). Conclusion This symptom-based PoPH screening study clarified the prevalence of PoPH in CLD patients according to a PH symptom questionnaire, UCG, and RHC. Patients with HCV and PBC may have a higher risk of PoPH.
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Affiliation(s)
- Shun‐Ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
- Department of Health Promotion MedicineShinshu University School of MedicineMatsumotoJapan
| | - Kazuhiro Kimura
- Department of Cardiovascular MedicineShinshu University School of MedicineMatsumotoJapan
| | - Hirohiko Motoki
- Department of Cardiovascular MedicineShinshu University School of MedicineMatsumotoJapan
| | - Taiki Okumura
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
- Department of Health Promotion MedicineShinshu University School of MedicineMatsumotoJapan
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
- Department of Advanced Endoscopic TherapyShinshu University School of MedicineMatsumotoJapan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
| | - Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
- Consultation Center for Liver DiseasesShinshu University HospitalMatsumotoJapan
| | - Koichiro Kuwahara
- Department of Cardiovascular MedicineShinshu University School of MedicineMatsumotoJapan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and HepatologyShinshu University School of MedicineMatsumotoJapan
- Department of Health Promotion MedicineShinshu University School of MedicineMatsumotoJapan
- Department of Advanced Endoscopic TherapyShinshu University School of MedicineMatsumotoJapan
- Consultation Center for Liver DiseasesShinshu University HospitalMatsumotoJapan
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14
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Sato M, Akamatsu M, Shima T, Ikegami T, Yanase M, Mikami S, Imamura J, Nakatsuka T, Tateishi R, Yamauchi N, Ushiku T, Okanoue T, Fujishiro M, Hida E, Koike K. Impact of a Novel Digital Therapeutics System on Nonalcoholic Steatohepatitis: The NASH App Clinical Trial. Am J Gastroenterol 2023; 118:1365-1372. [PMID: 36656974 PMCID: PMC10392885 DOI: 10.14309/ajg.0000000000002143] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/29/2022] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Management of nonalcoholic steatohepatitis (NASH) is a currently unmet clinical need. Digital therapeutics (DTx) is an emerging class of medicine that delivers evidence-based therapeutic interventions. This study was aimed at investigating the efficacy of DTx in patients with NASH. METHODS We conducted a multicenter, single-arm, 48-week trial in 19 patients with biopsy-confirmed NASH. All patients received a DTx intervention with a newly developed smartphone application. The primary endpoint was change in the nonalcoholic fatty liver disease activity score (NAS) without worsening of liver fibrosis. The secondary endpoints included improvement of the NAS by ≥2 points without worsening of liver fibrosis, change in the body weight, and regression of fibrosis. RESULTS After the 48-week DTx intervention, improvement of the NAS was observed in 68.4% (13/19) of patients. The mean change in the NAS from baseline to the end of the intervention was -2.05 ± 1.96 ( P < 0.001 when compared with the threshold of -0.7). A decrease in the NAS by ≥ 2 points was achieved in 11 (57.9%). The average weight loss at the end of the intervention was 8.3% ( P < 0.001). Reduction of the fibrosis stage was observed in 58.3% when the analysis was limited to patients with stage F2/3 fibrosis. There were no serious adverse events that could be considered as being related to the DTx intervention. DISCUSSION DTx for NASH was found to be highly efficacious and well-tolerated. Further evaluation of the DTx intervention for NASH in a phase 3 trial is warranted.
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Affiliation(s)
- Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Toshihide Shima
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Mikio Yanase
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Shintaro Mikami
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Jun Imamura
- Department of Hepatology, Tokyo Metropolitan Cancer an Infectious Disease Center Komagome Hospital, Tokyo, Japan
| | - Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoko Yamauchi
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Eisuke Hida
- Department of Biostatics and Data Science, Osaka University Graduate School of Medicine, Osaka, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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15
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Chin Y, Lim J, Kong G, Ng CH, Goh R, Muthiah M, Mehta A, Chong B, Lin C, Chan KE, Kong W, Poh KK, Foo R, Chai P, Yeo TC, Low AF, Lee CH, Tan HC, Chan MYY, Richards AM, Loh PH, Chew NWS. Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long-term mortality in acute myocardial infarction. Diabetes Obes Metab 2023; 25:1032-1044. [PMID: 36546614 DOI: 10.1111/dom.14950] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/07/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
AIM To examine the prevalence and prognosis of hepatic steatosis and fibrosis in post-acute myocardial infarction (AMI) patients. METHODS Patients presenting with AMI to a tertiary hospital were examined from 2014 to 2021. Hepatic steatosis and advanced hepatic fibrosis were determined using the Hepatic Steatosis Index and fibrosis-4 index, respectively. The primary outcome was all-cause mortality. Cox regression models identified determinants of mortality after adjustments and Kaplan-Meier curves were constructed for all-cause mortality, stratified by hepatic steatosis and advanced fibrosis. RESULTS Of 5765 patients included, 24.8% had hepatic steatosis, of whom 41.7% were diagnosed with advanced fibrosis. The median follow-up duration was 2.7 years. Patients with hepatic steatosis tended to be younger, female, with elevated body mass index and an increased metabolic burden of diabetes, hypertension and hyperlipidaemia. Patients with hepatic steatosis (24.6% vs. 20.9% mortality, P < .001) and advanced fibrosis (45.6% vs. 32.9% mortality, P < .001) had higher all-cause mortality rates compared with their respective counterparts. Hepatic steatosis (adjusted hazard ratio 1.364, 95% CI 1.145-1.625, P = .001) was associated with all-cause mortality after adjustment for confounders. Survival curves showed excess mortality in patients with hepatic steatosis compared with those without (P = .002). CONCLUSIONS Hepatic steatosis and advanced fibrosis have a substantial prevalence among patients with AMI. Both are associated with mortality, with an incrementally higher risk when advanced fibrosis ensues. Hepatic steatosis and fibrosis could help risk stratification of AMI patients beyond conventional risk factors.
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Affiliation(s)
- YipHan Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jieyu Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Gwyneth Kong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rachel Goh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Anurag Mehta
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, VCU Health Pauley Heart Center, Richmond, Virginia, Richmond, USA
| | - Bryan Chong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chaoxing Lin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kai En Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - William Kong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Kian Keong Poh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Roger Foo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Ping Chai
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Tiong-Cheng Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Adrian F Low
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Chi Hang Lee
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Huay Cheem Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Mark Yan-Yee Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - A Mark Richards
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
- Christchurch Heart Institute, University of Otago, Dunedin, New Zealand
| | - Poay-Huan Loh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
- Division of Cardiology, Department of Medicine, Ng Teng Fong General Hospital, Singapore, Singapore
| | - Nicholas W S Chew
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
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Shinoda H, Watanabe Y, Fukai K, Kasuya K, Furuya Y, Nakazawa S, Honda T, Hayashi T, Nakagawa T, Tatemichi M, Korenaga M. Significance of Fib4 index as an indicator of alcoholic hepatotoxicity in health examinations among Japanese male workers: a cross-sectional and retrospectively longitudinal study. Eur J Med Res 2023; 28:31. [PMID: 36650608 PMCID: PMC9847145 DOI: 10.1186/s40001-022-00976-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/29/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Fib4 index (Fib4) is clinically used as a noninvasive marker of liver fibrosis. In this study, we aimed to preliminarily investigate whether Fib4 can be used to detect individuals who need assessment for alcoholic liver disease (ALD) in the general population by clarifying the detailed association of Fib4 with alcohol consumption and gamma-glutamyl transferase (GGT) among male workers. METHODS We analyzed data sets on the comprehensive medical examinations of male workers as cross-sectional and retrospectively longitudinal studies. We enrolled 10 782 males (mean age: 52.2 ± 10.2 years) in FY2019 and 7845 males (mean follow-up: 12.6 ± 6.7 years) who could be consecutively followed up for 20 years from FY2000 to FY2019. Data were evaluated using logistic regression and COX proportional analysis. RESULTS In the cross-sectional setting, the rate of Fib4 ≥ 2.67 in heavy drinkers (≥ 40 g of ethanol/day) was increased dose dependently in those over 65 years old, and that of body mass index ≥ 30 kg/m2 was increased in those over 60 years old, but not in those with fatty liver. The odds ratio (OR) (95% confidence interval [CI]) for heavy drinking was 4.30 (95% CI = 1.90-9.72), and GGT ≥ 200 IU/L was considerably high (OR = 29.05 [95% CI = 17.03-49.56]). In the longitudinal setting, heavy drinkers and those with GGT ≥ 200 IU/L at 10 years after the baseline showed an increased risk for Fib4 ≥ 2.67 (hazard ratio = 2.17 [95% CI = 1.58-2.98] and 7.65 [95% CI 5.26-11.12], respectively). CONCLUSIONS The development of Fib4 ≥ 2.67 after 10 years was associated with heavy alcohol drinking and GGT level ≥ 200 IU/L. Therefore, Fib4 combined with GGT could indicate high risk of ALD. However, clinical examinations and course observations are essentially needed.
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Affiliation(s)
- Hideki Shinoda
- grid.414178.f0000 0004 1776 0989Hitachi General Hospital, Hitachi, Japan
| | - Yuya Watanabe
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan.
| | - Kayoko Kasuya
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Yuko Furuya
- grid.265061.60000 0001 1516 6626Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Shoko Nakazawa
- grid.265061.60000 0001 1516 6626Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Toru Honda
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Takeshi Hayashi
- grid.417547.40000 0004 1763 9564Present Address: Occupational Hygiene and Promotion Center, Hitachi, Ltd, Tokyo, Japan
| | - Toru Nakagawa
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Masayuki Tatemichi
- grid.265061.60000 0001 1516 6626Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Masaaki Korenaga
- Hepatitis Information Centre, Research Centre for Hepatitis and Immunology, National Centre for Global Health and Medicine, Ichikawa, Japan
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17
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Kamada Y, Nakamura T, Isobe S, Hosono K, Suama Y, Ohtakaki Y, Nauchi A, Yasuda N, Mitsuta S, Miura K, Yamamoto T, Hosono T, Yoshida A, Kawanishi I, Fukushima H, Kinoshita M, Umeda A, Kinoshita Y, Fukami K, Miyawaki T, Fujii H, Yoshida Y, Kawanaka M, Hyogo H, Morishita A, Hayashi H, Tobita H, Tomita K, Ikegami T, Takahashi H, Yoneda M, Jun DW, Sumida Y, Okanoue T, Nakajima A. SWOT analysis of noninvasive tests for diagnosing NAFLD with severe fibrosis: an expert review by the JANIT Forum. J Gastroenterol 2023; 58:79-97. [PMID: 36469127 PMCID: PMC9735102 DOI: 10.1007/s00535-022-01932-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/12/2022] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions.
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Affiliation(s)
- Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Takahiro Nakamura
- Medicine Division, Nippon Boehringer Ingelheim Co., Ltd., 2-1-1, Osaki, Shinagawa-Ku, Tokyo, 141-6017 Japan
| | - Satoko Isobe
- FibroScan Division, Integral Corporation, 2-25-2, Kamiosaki, Shinagawa-Ku, Tokyo, 141-0021 Japan
| | - Kumiko Hosono
- Immunology, Hepatology & Dermatology Medical Franchise Dept., Medical Division, Novartis Pharma K.K., 1-23-1, Toranomon, Minato-Ku, Tokyo, 105-6333 Japan
| | - Yukiko Suama
- Medical Information Services, Institute of Immunology Co., Ltd., 1-1-10, Koraku, Bunkyo-Ku, Tokyo, 112-0004 Japan
| | - Yukie Ohtakaki
- Product Development 1St Group, Product Development Dept., Fujirebio Inc., 2-1-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 163-0410 Japan
| | - Arihito Nauchi
- Academic Department, GE Healthcare Japan, 4-7-127, Asahigaoka, Hino, Tokyo, 191-8503 Japan
| | - Naoto Yasuda
- Ultrasound Business Area, Siemens Healthcare KK, 1-11-1, Osaki, Shinagawa-Ku, Tokyo, 141-8644 Japan
| | - Soh Mitsuta
- FibroScan Division, Integral Corporation, 2-25-2, Kamiosaki, Shinagawa-Ku, Tokyo, 141-0021 Japan
| | - Kouichi Miura
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Takuma Yamamoto
- Cardiovascular and Diabetes, Product Marketing Department, Kowa Company, Ltd., 3-4-10, Nihonbashi Honcho, Chuo-Ku, Tokyo, 103-0023 Japan
| | - Tatsunori Hosono
- Clinical Development & Operations Japan, Nippon Boehringer Ingelheim Co., Ltd., 2-1-1, Osaki, Shinagawa-Ku, Tokyo, 141-6017 Japan
| | - Akihiro Yoshida
- Medical Affairs Department, Kowa Company, Ltd., 3-4-14, Nihonbashi Honcho, Chuo-Ku, Tokyo, 103-8433 Japan
| | - Ippei Kawanishi
- R&D Planning Department, EA Pharma Co., Ltd., 2-1-1, Irifune, Chuo-Ku, Tokyo, 104-0042 Japan
| | - Hideaki Fukushima
- Diagnostics Business Area, Siemens Healthcare Diagnostics KK, 1-11-1, Osaki, Shinagawa-Ku, Tokyo, 141-8673 Japan
| | - Masao Kinoshita
- Marketing Dep. H.U. Frontier, Inc., Shinjuku Mitsui Building, 2-1-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 163-0408 Japan
| | - Atsushi Umeda
- Clinical Development Dept, EA Pharma Co., Ltd., 2-1-1, Irifune, Chuo-Ku, Tokyo, 104-0042 Japan
| | - Yuichi Kinoshita
- Global Drug Development Division, Novartis Pharma KK, 1-23-1, Toranomon, Minato-Ku, Tokyo, 105-6333 Japan
| | - Kana Fukami
- 2Nd Product Planning Dept, 2Nd Product Planning Division, Fujirebio Inc, 2-1-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 163-0410 Japan
| | - Toshio Miyawaki
- Medical Information Services, Institute of Immunology Co., Ltd., 1-1-10, Koraku, Bunkyo-Ku, Tokyo, 112-0004 Japan
| | - Hideki Fujii
- Departments of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3, Asahi-Machi, Abeno-Ku, Osaka, Osaka 545-8585 Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, 5-7, Kishibe Shinmachi, Suita, Osaka 564-8567 Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine2, Kawasaki Medical School, Kawasaki Medical Center, 2-6-1, Nakasange, Kita-Ku, Okayama, Okayama 700-8505 Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima Kouseiren General Hospital, 1-3-3, Jigozen, Hatsukaichi, Hiroshima 738-8503 Japan ,Hyogo Life Care Clinic Hiroshima, 6-34-1, Enkobashi-Cho, Minami-Ku, Hiroshima, Hiroshima 732-0823 Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1, Oaza Ikenobe, Miki-Cho, Kita-Gun, Kagawa 761-0793 Japan
| | - Hideki Hayashi
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, 7-1, Kashima-Cho, Gifu, Gifu 500-8513 Japan
| | - Hiroshi Tobita
- Division of Hepatology, Shimane University Hospital, 89-1, Enya-Cho, Izumo, Shimane 693-8501 Japan
| | - Kengo Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513 Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, 3-20-1, Chuo, Ami-Machi, Inashiki-Gun, Ibaraki, 300-0395 Japan
| | - Hirokazu Takahashi
- Liver Center, Faculty of Medicine, Saga University Hospital, Saga University, 5-1-1, Nabeshima, Saga, Saga 849-8501 Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004 Japan
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, 04763 Korea
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, 21 Yazako Karimata, Nagakute, Aichi, 480-1195, Japan.
| | - Takeshi Okanoue
- Department of Gastroenterology & Hepatology, Saiseikai Suita Hospital, Osaka, 1-2, Kawazono-Cho, Suita, Osaka 564-0013 Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004 Japan
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Huiban L, Trifan A, Stanciu C. Nonalcoholic Fatty Liver Disease and Psoriasis. ESSENTIALS OF NON-ALCOHOLIC FATTY LIVER DISEASE 2023:229-241. [DOI: 10.1007/978-3-031-33548-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Seko Y, Kawanaka M, Fujii H, Iwaki M, Hayashi H, Toyoda H, Oeda S, Hyogo H, Morishita A, Munekage K, Kawata K, Yamamura S, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Tokushige A, Kamada Y, Takahashi H, Ueda S, Aishima S, Sumida Y, Okanoue T, Itoh Y, Nakajima A. Age-dependent effects of diabetes and obesity on liver-related events in non-alcoholic fatty liver disease: Subanalysis of CLIONE in Asia. J Gastroenterol Hepatol 2022; 37:2313-2320. [PMID: 36198983 DOI: 10.1111/jgh.16019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/25/2022] [Accepted: 09/19/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LREs). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with non-alcoholic fatty liver disease (NAFLD). METHODS We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1395 patients with biopsy-proven NAFLD. The median follow-up was 4.6 years. RESULTS The median age was 57 years, and 36.2% had T2DM. The median body mass index (BMI) was 27.4, and 28.5% were severely obese (BMI ≥ 30). During follow-up, 37 patients developed hepatocellular carcinoma (HCC), and 58 patients developed LRE. In patients younger than 65 years, advanced fibrosis (hazard ratio [HR] 7.69, P < 0.001) and T2DM (HR 3.37, P = 0.017) were HCC risk factors, and advanced fibrosis (HR 9.40, P < 0.001) and T2DM (HR 2.51, P = 0.016) were LRE risk factors. In patients 65 years and older, advanced fibrosis (HR 4.24, P = 0.010) and obesity (HR 4.60, P = 0.006) were HCC risk factors, and advanced fibrosis (HR 4.22, P = 0.002) and obesity (HR 4.22, P = 0.002) were LRE risk factors. CONCLUSION Type 2 diabetes mellitus and obesity contributed to LRE in younger and older patients, respectively, along with advanced fibrosis. Therefore, controlling T2DM in patients younger than 65 years and controlling weight in patients 65 years and older could prevent LRE. The development of age-dependent screening and management strategies is necessary for patients with NAFLD.
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Affiliation(s)
- Yuya Seko
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, Kawasaki Medical Center, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Hideki Fujii
- Department of Hepatology, Osaka Metropolitan University, Osaka, Japan
| | - Michihiro Iwaki
- Division of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hideki Hayashi
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Oeda
- Liver Center, Saga University Hospital, Saga, Japan.,Department of Laboratory Medicine, Saga University Hospital, Saga, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima Kouseiren General Hospital, Hatsukaichi, Hiroshima, Japan.,Life Care Clinic Hiroshima, Hiroshima, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Takamatsu, Kagawa, Japan
| | - Kensuke Munekage
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Sakura Yamamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Koji Sawada
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Tatsuji Maeshiro
- First Department of Internal Medicine, University of the Ryukyus Hospital, Nishihara, Okinawa, Japan
| | - Hiroshi Tobita
- Division of Pathology, Shimane University Hospital, Izumo, Shimane, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Suita, Osaka, Japan
| | - Masafumi Naito
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Suita, Osaka, Japan
| | - Asuka Araki
- Division of Pathology, Shimane University Hospital, Izumo, Shimane, Japan
| | - Shingo Arakaki
- First Department of Internal Medicine, University of the Ryukyus Hospital, Nishihara, Okinawa, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hidenao Noritake
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masafumi Ono
- Division of Innovative Medicine for Hepatobiliary and Pancreatology, Faculty of Medicine, Kagawa University, Takamatsu, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Takamatsu, Kagawa, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Eiichi Tomita
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
| | - Masato Yoneda
- Division of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Akihiro Tokushige
- Department of Cardiovascular Medicine and Hypertension, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | | | - Shinichiro Ueda
- Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Takeshi Okanoue
- Hepatology Center, Saiseikai Suita Hospital, Suita, Osaka, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Nakajima
- Division of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Yoshida N, Ishikawa H, Otani T, Goto C, Matsuda T, Takeuchi Y, Sano Y, Itoh Y, Suzuki S, Mutoh M. Aspirin-Mediated Prevention of Colorectal Adenomas Recurrence is Affected by Blood Biochemistry and Nutritional Intake. Cancer Prev Res (Phila) 2022; 15:837-846. [PMID: 36075073 DOI: 10.1158/1940-6207.capr-22-0144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/03/2022] [Accepted: 09/02/2022] [Indexed: 01/31/2023]
Abstract
Aspirin has been shown to prevent the onset of colorectal adenoma and cancer. This study aimed to identify patient characteristics and blood chemistry factors related to the effect of aspirin. A total of 231 men and 59 women who participated in our previous randomized clinical study in 2007-2009 using aspirin or placebo (J-CAPP study) were analyzed. Interaction of aspirin with age at entry, body mass index (BMI), alcohol intake, blood biochemistry, and nutrients calculated from a semiquantitative food frequency questionnaire were analyzed on the basis of the presence of adenomas 2 years later. Our study showed that suppression of adenoma by aspirin was not affected by age or BMI. Among men, significant suppression of adenoma by aspirin was seen with triglyceride (TG) <167 mg/dL (P = 0.02), total cholesterol (T-cho) ≥220 mg/dL (P = 0.01), high-density lipoprotein (HDL) ≥60 mg/dL (P < 0.01), and low-density lipoprotein (LDL) ≥140 mg/dL (P = 0.01), aspartate aminotransferase (AST) <30 IU/L (P = 0.01), alanine aminotransferase <30 IU/L (P = 0.04), and gamma-glutamyl transpeptidase <60 IU/L (P = 0.04). In addition, the interaction was significant with TG ≥/<167 mg/dL (P = 0.02), T-cho ≥/<220 mg/dL (P = 0.03), HDL ≥/<60 mg/dL (P = 0.02), LDL ≥/<140 mg/dL (P = 0.03), and AST ≥/<30 IU/L (P = 0.01). Daily nutrient intake associated with aspirin was <2,000 mg sodium (P = 0.06) and ≥850 μg retinol equivalent (P = 0.05) among men, indicating a marginal effect on adenoma suppression. No significant differences were detected among women due to the small sample size. In conclusion, lipid metabolism and liver function were correlated with the suppressive effect of aspirin on the recurrence of colorectal adenoma. PREVENTION RELEVANCE Aspirin has been shown to prevent the onset of colorectal adenoma and cancer, and its effect modifications have been analyzed. Lipid metabolism and liver function were correlated with the suppressive effect of aspirin on the recurrence of colorectal adenoma.
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Affiliation(s)
- Naohisa Yoshida
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takahiro Otani
- Department of Public Health, Graduate School of Medical Sciences, Nagoya City University, Aichi, Japan
| | - Chiho Goto
- Department of Health and Nutrition, Nagoya Bunri University, Aichi, Japan
| | - Takahisa Matsuda
- Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Yoji Takeuchi
- Department of Gastrointestinal Oncology and Department of Genetic Oncology, Division of Hereditary Tumors, Osaka International Cancer Institute, Osaka, Japan
| | - Yasushi Sano
- Gastrointestinal Center and Institute of Minimally Invasive Endoscopic Care (iMEC), Sano Hospital, Hyogo, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sadao Suzuki
- Department of Public Health, Graduate School of Medical Sciences, Nagoya City University, Aichi, Japan
| | - Michihiro Mutoh
- Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Sato S, Kawai H, Sato S, Iwasaki H, Omori M, Kita Y, Ikeda Y, Awatsu T, Murata A, Taniguchi G, Shimada Y, Genda T. Hypertension and diabetes mellitus are associated with high FIB-4 index in a health checkup examination cohort without known liver disease. BMC Gastroenterol 2022; 22:478. [PMID: 36411436 PMCID: PMC9677657 DOI: 10.1186/s12876-022-02575-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/11/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is usually asymptomatic and lacks a specific biomarker; therefore, many individuals might remain undiagnosed even with advanced liver fibrosis. The aim of this study was to clarify the prevalence and clinical features of subjects with a high risk of advanced liver fibrosis in the general population, using the Fibrosis-4 (FIB-4) index. METHODS We retrospectively investigated 6,087 subjects without known liver disease who had participated in an annual health checkup examination. We analyzed the factors associated with high FIB-4 index (≥ 2.67) using a logistic regression analysis. RESULTS Among the 6,087 subjects, 76 (1.2%) had high FIB-4 index. Multivariate analysis identified hypertension (odds ratio [OR]; 9.040; 95% confidence interval [CI], 4.081-20.024; P < 0.001) and diabetes mellitus (OR = 4.251; 95% CI, 1.773-10.193; P = 0.001) as important risk factors for high FIB-4 index. The rates of hypertension and diabetes mellitus in subjects with high FIB-4 index were 78.9% and 23.7%, respectively. No significant association was observed between obesity or large waist circumference and high FIB-4 index. A history of cardiovascular disease was significantly more common in subjects with high FIB-4 index. These results were also observed in subjects with normal liver function test. CONCLUSIONS The present study revealed that approximately 1% of the general Japanese population has a high risk of advanced liver fibrosis. Many of these patients had hypertension and/or diabetes mellitus. Our findings suggest that there are many undiagnosed patients NAFLD with risk of advanced liver fibrosis in the general population.
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Affiliation(s)
- Shunsuke Sato
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Hidehiko Kawai
- Fuji Town Medical Center, 12-12 Fujicho, Shizuoka, Fuji 416-0915 Japan
| | - Sho Sato
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Hirohiko Iwasaki
- Fuji Town Medical Center, 12-12 Fujicho, Shizuoka, Fuji 416-0915 Japan
| | - Masashi Omori
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Yuji Kita
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Yuji Ikeda
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Takahito Awatsu
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Ayato Murata
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Gentaro Taniguchi
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Yuji Shimada
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
| | - Takuya Genda
- grid.482667.9Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295 Japan
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22
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Kusano Y, Funada K, Yamaguchi M, Sugawara M, Tamano M. Dietary counseling based on artificial intelligence for patients with nonalcoholic fatty liver disease. Artif Intell Gastroenterol 2022; 3:105-116. [DOI: 10.35712/aig.v3.i4.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/13/2022] [Accepted: 10/27/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND About 25% of the general population in Japan are reported to have nonalcoholic fatty liver disease (NAFLD). NAFLD and nonalcoholic steatohepatitis carry a risk of progressing further to hepatocellular carcinoma. The primary treatment for NAFLD is dietary therapy. Dietary counseling plays an essential role in dietary therapy. Although artificial intelligence (AI)-based nutrition management software applications have been developed and put into practical use in recent years, the majority focus on weight loss or muscle strengthening, and no software has been developed for patient use in clinical practice.
AIM To examine whether effective dietary counseling is possible using AI-based nutrition management software.
METHODS NAFLD patients who had been assessed using an AI-based nutrition management software application (Calomeal) that automatically analyzed images of meals photographed by patients and agreed to receive dietary counseling were given dietary counseling. Blood biochemistry tests were performed before (baseline) and 6 mo after (6M follow-up) dietary counseling. After the dietary counseling, the patients were asked to complete a questionnaire survey.
RESULTS A total of 29 patients diagnosed with NAFLD between August 2020 and March 2022 were included. There were significant decreases in liver enzyme and triglyceride levels at the 6M follow-up compared to baseline. The food analysis capability of the AI used by Calomeal in this study was 75.1%. Patient satisfaction with the AI-based dietary counselling was high.
CONCLUSION AI-based nutrition management appeared to raise awareness of dietary habits among NAFLD patients. However, it did not directly alleviate the burden of registered dietitians, and improvements are much anticipated.
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Affiliation(s)
- Yumi Kusano
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, Koshigaya 343-8555, Saitama, Japan
| | - Kei Funada
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, Koshigaya 343-8555, Saitama, Japan
| | - Mayumi Yamaguchi
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, Koshigaya 343-8555, Saitama, Japan
| | - Miwa Sugawara
- Nutrition Unit, Dokkyo Medical University Saitama Medical Center, Koshigaya 343-8555, Saitama, Japan
| | - Masaya Tamano
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, Koshigaya 343-8555, Saitama, Japan
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Bartolini D, Marinelli R, Stabile AM, Frammartino T, Guerrini A, Garetto S, Lucci J, Migni A, Zatini L, Marcantonini G, Rende M, Galli F. Wheat germ oil vitamin E cytoprotective effect and its nutrigenomics signature in human hepatocyte lipotoxicity. Heliyon 2022; 8:e10748. [PMID: 36193535 PMCID: PMC9525900 DOI: 10.1016/j.heliyon.2022.e10748] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 05/06/2022] [Accepted: 09/19/2022] [Indexed: 11/29/2022] Open
Abstract
Wheat germ oil (WGO) is rich in α-tocopherol (vitamin E, VE), a vitamin that has long been suggested to exert hepatoprotective effects. In this study, this function of WGO-VE and its transcriptomics fingerprint were investigated in comparison with RRR-α-tocopherol and all-rac-α-tocopherol (nVE and sVE, respectively), in human liver cells treated with oleic acid (OA) to develop steatosis and lipotoxicity. Used in chemoprevention mode, all the VE formulations afforded significant reduction of the OA-induced steatosis and its consequent impact on lipotoxicity indicators, including ROS production and efflux (as H2O2), and apoptotic and necrotic cell death. A trend toward a better control of lipotoxicity was observed for WGO-VE and nVE compared to sVE. Gene microarray data demonstrated that these effects of VE formulations were associated with significantly different responses of the cellular transcriptome to compensate for the modifications of OA treatment, including the downregulation of cellular homeostasis genes and the induction of genes associated with defects of liver cell metabolism, fibrosis and inflammation, liver disease and cancer. Ingenuity Pathway Analysis data showed that WGO-VE modulated genes associated with liver carcinogenesis and steatosis, whereas nVE modulated genes involved in liver cell metabolism and viability biofunctions; sVE did not significantly modulate any gene dataset relevant to such biofunctions. In conclusion, WGO-VE prevents lipotoxicity in human liver cells modulating genes that differ from those affected by the natural or synthetic forms of pure VE. These differences can be captured by precision nutrition tools, reflecting the molecular complexity of this VE-rich extract and its potential in preventing specific cues of hepatocellular lipotoxicity.
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Affiliation(s)
- Desirée Bartolini
- Department of Pharmaceutical Sciences, Lipidomics and Micronutrient Vitamins Lab. and Human Anatomy Lab., University of Perugia, 06126 Perugia, Italy
| | - Rita Marinelli
- Department of Pharmaceutical Sciences, Lipidomics and Micronutrient Vitamins Lab. and Human Anatomy Lab., University of Perugia, 06126 Perugia, Italy
| | - Anna Maria Stabile
- Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy, University of Perugia, Perugia, Italy
| | - Tiziana Frammartino
- Natural Bio-Medicine SpA, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy.,Innovation and Medical Science Division, Aboca SpA Societa Agricola, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy
| | - Angela Guerrini
- Natural Bio-Medicine SpA, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy.,Innovation and Medical Science Division, Aboca SpA Societa Agricola, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy
| | - Stefano Garetto
- Natural Bio-Medicine SpA, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy.,Innovation and Medical Science Division, Aboca SpA Societa Agricola, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy
| | - Jacopo Lucci
- Natural Bio-Medicine SpA, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy.,Innovation and Medical Science Division, Aboca SpA Societa Agricola, Loc. Aboca 20, 52037 Sansepolcro, AR, Italy
| | - Anna Migni
- Department of Pharmaceutical Sciences, Lipidomics and Micronutrient Vitamins Lab. and Human Anatomy Lab., University of Perugia, 06126 Perugia, Italy
| | - Linda Zatini
- Department of Pharmaceutical Sciences, Lipidomics and Micronutrient Vitamins Lab. and Human Anatomy Lab., University of Perugia, 06126 Perugia, Italy
| | - Giada Marcantonini
- Department of Pharmaceutical Sciences, Lipidomics and Micronutrient Vitamins Lab. and Human Anatomy Lab., University of Perugia, 06126 Perugia, Italy
| | - Mario Rende
- Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy, University of Perugia, Perugia, Italy
| | - Francesco Galli
- Department of Pharmaceutical Sciences, Lipidomics and Micronutrient Vitamins Lab. and Human Anatomy Lab., University of Perugia, 06126 Perugia, Italy
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Takahashi Y, Konishi T, Nishimura M, Nishihira J. Dietary supplementation of deoxyribonucleic acid derived from chum salmon milt improves liver function in healthy Japanese individuals: a placebo-controlled, randomised, double-blind, parallel-group clinical trial. Food Funct 2022; 13:9383-9390. [PMID: 35959802 DOI: 10.1039/d2fo01149b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A placebo-controlled, randomised, double-blind, parallel-group comparative study was conducted to investigate the effect of continuous intake of salmon milt (SM) DNA for 12 weeks on the improvement of liver function in 50 healthy Japanese participants aged 30 to 70 years with alanine aminotransferase (ALT) levels of 25-87 U L-1 in men, 22-66 U L-1 in women, of BMI 22.1-29.4 kg m-2. Comparative analysis of hepatic functions and several other parameters, including anthropometric parameters in placebo and SM DNA administered groups, revealed no significant differences in serum ALT level. SM DNA significantly improved the liver-to-spleen (L/S) ratio, body weight, and BMI in the main group. In addition to these parameters, in the BMI < 25 kg m-2 subgroup, the leptin level was significantly reduced. No adverse reactions or abnormal changes, symptoms, or findings in the clinical examination after intake of the test food containing SM DNA were observed. Furthermore, no significant difference in uric acid levels between SM DNA and placebo groups indicated the safety of using SM DNA as a food supplement. These results demonstrated the potential fatty liver improvement and anti-obesity action of continuous intake of SM DNA for 12 weeks without any significant adverse effects.
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Affiliation(s)
- Yoshinori Takahashi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki, 300-4295, Japan.
| | - Tatsuya Konishi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki, 300-4295, Japan.
| | - Mie Nishimura
- Department of Medical Management and Informatics, Hokkaido Information University, 59-2, Nishi-nopporo, Ebetsu, Hokkaido, 069-8585, Japan.
| | - Jun Nishihira
- Department of Medical Management and Informatics, Hokkaido Information University, 59-2, Nishi-nopporo, Ebetsu, Hokkaido, 069-8585, Japan.
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25
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Takahashi Y, Konishi T, Nishimura M, Nishihira J. Evaluation of the efficacy and safety of chum salmon milt deoxyribonucleic acid for improvement of hepatic functions: a placebo-controlled, randomised, double-blind, and parallel-group, pilot clinical trial. Food Funct 2022; 13:9372-9382. [PMID: 35959845 DOI: 10.1039/d2fo01145j] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The increased prevalence of nonalcoholic fatty liver disease (NAFLD) is a critical public health concern. Deoxyribonucleic acid (DNA) from chum salmon (Oncorhynchus keta) milt (salmon milt DNA; SM DNA), a by-product obtained during industrial processing of the pharmaceutical raw material protamine, ameliorates hepatosteatosis in animals. This randomised, double-blind, parallel-group comparative study evaluated the effects of SM DNA on hepatic function in healthy Japanese participants with slightly decreased liver function and high alanine aminotransferase level and body mass index. Fifty participants were included in the study. The participants were divided into the placebo (n = 24) and SM DNA (n = 26) groups and administered equal doses of placebo (dextrin) and SM DNA (530 mg day-1), respectively. No significant alleviating effects of SM DNA were observed on the primary (hepatic functions and liver-to-spleen ratio), and secondary (NAFLD fibrosis score, serum protein levels, blood glucose, blood lipids, inflammatory markers, adipokines, cytokines, fatigue scoring, and skin conditions) endpoints. Subsequently, a sex-based subgroup analysis revealed a significant improvement in the primary and secondary outcomes in males ingesting SM DNA compared with those in males who were administered placebo. However, no such effect was observed in females. Overall, this clinical study demonstrated the anti-obesity potential of SM DNA and suggested that SM DNA can benefit hepatic function in males.
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Affiliation(s)
- Yoshinori Takahashi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki, 300-4295, Japan.
| | - Tatsuya Konishi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki, 300-4295, Japan.
| | - Mie Nishimura
- Department of Medical Management and Informatics, Hokkaido Information University, 59-2, Nishi-nopporo, Ebetsu Hokkaido, 069-8585, Japan.
| | - Jun Nishihira
- Department of Medical Management and Informatics, Hokkaido Information University, 59-2, Nishi-nopporo, Ebetsu Hokkaido, 069-8585, Japan.
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26
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Wada N, Fujita N, Ishimatsu K, Takao S, Yoshizumi T, Miyazaki Y, Oda Y, Nishie A, Ishigami K, Ushijima Y. A novel fast kilovoltage switching dual-energy computed tomography technique with deep learning: Utility for non-invasive assessments of liver fibrosis. Eur J Radiol 2022; 155:110461. [DOI: 10.1016/j.ejrad.2022.110461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/22/2022] [Accepted: 08/03/2022] [Indexed: 11/26/2022]
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27
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Nakatsuka T, Tateishi R, Koike K. Changing clinical management of NAFLD in Asia. Liver Int 2022; 42:1955-1968. [PMID: 34459096 DOI: 10.1111/liv.15046] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/30/2021] [Accepted: 08/21/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%-20% of non-obese Asians with body mass indexes of less than 25 kg/m2 are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver-specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
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28
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Trends in drug prescriptions for type 2 diabetes, hypertension, and dyslipidemia among adults with non-alcoholic fatty liver disease. Ann Hepatol 2022; 27:100699. [PMID: 35278680 DOI: 10.1016/j.aohep.2022.100699] [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: 01/06/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Clinical guidelines recommend specific drugs for type 2 diabetes (T2D), hypertension, and dyslipidemia in patients with non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH). We aimed to investigate the differences in prescription trends of antidiabetic, antihypertensive, and lipid-lowering drugs among adult patients according to the presence of comorbid NAFLD and/or NASH. METHODS We conducted a cross-sectional analysis using a large claims database from January 2013 to December 2020. RESULTS Among 7,716,908 people, 47,157 patients with T2D, 180,050 with hypertension, and 191,348 with dyslipidemia were identified. A total of 8,897, 16,451, and 24,762 patients with NAFLD, as well as 435, 523, and 1033 patients with NASH, had T2D, hypertension, and dyslipidemia, respectively. Among antidiabetic drugs, sodium-glucose cotransporter-2 inhibitors (SGLT2is) and thiazolidine were more frequently prescribed to patients with NAFLD than to those without NAFLD (non-NAFLD) (thiazolidine: 1.4% and 2.8% and SGLT2is: 17.8% and 25.9% for non-NAFLD and NAFLD, respectively [2019-2020]). Among antihypertensive drugs, angiotensin II receptor antagonists exhibited a slightly higher prescription ratio in patients with NAFLD (33.6% vs. 39.0%). Regarding lipid-lowering drugs, fibrates were more frequently prescribed to patients with NAFLD (10.3% vs. 18.4%). CONCLUSIONS Specific drugs tended to be prescribed to patients with NAFLD. However, the differences in prescription ratios were not considerable. Further investigation is required to confirm the effects of drugs on the prognosis of patients with NAFLD or NASH.
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29
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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30
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Morita S, Sakamaki A, Koyama K, Shibata O, Owaki T, Oda C, Kimura A, Nakaya T, Ohbuchi K, Nahata M, Fujitsuka N, Sakai N, Abe H, Kamimura K, Terai S. Daisaikoto improves fatty liver and obesity in melanocortin-4 receptor gene-deficient mice via the activation of brown adipose tissue. Sci Rep 2022; 12:10105. [PMID: 35710868 PMCID: PMC9203505 DOI: 10.1038/s41598-022-14371-y] [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: 11/21/2021] [Accepted: 06/06/2022] [Indexed: 11/09/2022] Open
Abstract
Melanocortin 4 receptor gene-knockout (MC4R-KO) mice are known to develop obesity with a high-fat diet. Meanwhile, daisaikoto, one of Kampo medicines, is a drug that is expected to have therapeutic effects on obesity. Here, we report the efficacy of daisaikoto in MC4R-KO mice. Eight-week-old MC4R-KO male mice (n = 12) were divided into three groups as follows: the SD group, which is fed with a standard diet; the HFD group, fed a high-fat diet; and the DSK group, fed with a high-fat diet containing 10% of daisaikoto. After the four-week observation period, mice in each group were sacrificed and samples were collected. The body weights at 12 weeks were significantly higher in the HFD group than in the other groups, indicating that daisaikoto significantly reduced body weight gain and fat deposition of the liver. The metabolome analysis indicated that degradation of triglycerides and fatty acid oxidation in the liver were enhanced by daisaikoto administration. In MC4R-KO mice, the cytoplasm and uncoupling protein 1 expression of brown adipose tissue was decreased; however, it was reversed in the DSK group. In conclusion, daisaikoto has potentially improved fatty liver and obesity, making it a useful therapeutic agent for obesity and fatty liver.
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Affiliation(s)
- Shinichi Morita
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
| | - Kyutaro Koyama
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Osamu Shibata
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Takashi Owaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Chiyumi Oda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Atsushi Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Taiki Nakaya
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., 3586, Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan
| | - Katsuya Ohbuchi
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., 3586, Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan
| | - Miwa Nahata
- Tsumura Kampo Research Laboratories, Tsumura & Co., 3586, Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan
| | - Naoki Fujitsuka
- Tsumura Kampo Research Laboratories, Tsumura & Co., 3586, Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan
| | - Norihiro Sakai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.,Department of General Medicine, School of Medicine, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
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Structural and Functional Modulation of Gut Microbiota by Jiangzhi Granules during the Amelioration of Nonalcoholic Fatty Liver Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2234695. [PMID: 34966475 PMCID: PMC8712166 DOI: 10.1155/2021/2234695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/26/2021] [Indexed: 11/17/2022]
Abstract
Recently, accumulating evidence revealed that nonalcoholic fatty liver disease (NAFLD) is highly associated with the dysbiosis of gut microbiota. Jiang Zhi Granule (JZG), which is composed of five widely used Chinese herbs, has shown hypolipidemic effect, while whether such effect is mediated by gut microbiota is still unclear. Here, we found that both low and high doses of JZG (LJZ and HJZ) could improve hepatic steatosis and function, as well as insulin resistance in NAFLD mice. 16S rRNA gene sequencing revealed that JZG treatment could reverse the dysbiosis of intestinal flora in NAFLD mice, exhibiting a dose-dependent effect. Notably, HJZ could significantly reduce the relative abundance of Desulfovibrionaceae, while increasing the relative abundance of such as S24_7 and Lachnospiraceae. PICRUSt analysis showed that HJZ could significantly alter the functional profile of gut microbiota, including the reduction of the lipopolysaccharide biosynthesis and sulfur metabolism pathway, which is verified by the decreased levels of fecal hydrogen sulfide (H2S) and serum lipopolysaccharide binding protein (LBP). In addition, hepatic mRNA sequencing further indicated that the HJZ group can regulate the peroxisome proliferator-activated receptor (PPAR) pathway and inflammatory signaling pathway, as validated by RT-PCR and Western blot. We also found that different doses of JZG may regulate lipid metabolism through differentiated pathways, as LJZ mainly through the promotion of hepatic lipid hydrolysis, while HJZ mainly through the improvement of hepatic lipid oxidation. Taken together, JZG could modulate gut dysbiosis with dose-effect, alleviate inflammation level, and regulate hepatic lipid metabolism, which may subsequently contribute to the improvement of NAFLD. Our study revealed the underlying mechanisms in the improvement of NAFLD by a Chinese herbal compound, providing future guidance for clinical usage.
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Sumida Y, Yoneda M, Seko Y, Takahashi H, Hara N, Fujii H, Itoh Y, Yoneda M, Nakajima A, Okanoue T. Role of vitamin E in the treatment of non-alcoholic steatohepatitis. Free Radic Biol Med 2021; 177:391-403. [PMID: 34715296 DOI: 10.1016/j.freeradbiomed.2021.10.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | | | - Nagisa Hara
- Liver Center, Saga University Hospital, Saga, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Kamada Y, Takahashi H, Shimizu M, Kawaguchi T, Sumida Y, Fujii H, Seko Y, Fukunishi S, Tokushige K, Nakajima A, Okanoue T. Clinical practice advice on lifestyle modification in the management of nonalcoholic fatty liver disease in Japan: an expert review. J Gastroenterol 2021; 56:1045-1061. [PMID: 34718870 DOI: 10.1007/s00535-021-01833-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/01/2021] [Indexed: 02/04/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide, including in Japan. The Japanese Society of Gastroenterology (JSGE) and the Japanese Society of Hepatology (JSH) have established the Japanese NAFLD/NASH guidelines in 2014 and revised these guidelines in 2020. As described in these guidelines, weight reduction by diet and/or exercise therapy is important for the treatment of NAFLD patients. The I148M single nucleotide polymorphism (rs738409 C > G) of PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is widely known to be associated with the occurrence and progression of NAFLD. In the Japanese, the ratio of PNPLA3 gene polymorphisms found is approximately 20%, which is higher than that found in Westerners. In addition, the ratio of lean NAFLD patients is also higher in Japan than in Western countries. Therefore, the method for lifestyle guidance for the NAFLD patients in Japan would be different from that for the people in Western countries. The problems in the treatment of NAFLD patients include alcohol consumption and sarcopenia. Therefore, guidelines that can help clinicians treat Japanese patients with NAFLD are needed. In this expert review, we summarize evidence-based interventions for lifestyle modification (diet, exercise, alcohol, and sarcopenia) for the treatment of patients with NAFLD, especially from Japan and Asian countries.
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Affiliation(s)
- Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
| | - Hirokazu Takahashi
- Department of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, 840-8502, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Shinya Fukunishi
- Premier Departmental Research of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-8686, Japan
| | - Katsutoshi Tokushige
- Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, 1-2 Kawazonocho, Suita, Osaka, 564-0013, Japan
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Kogiso T, Sagawa T, Kodama K, Taniai M, Hashimoto E, Tokushige K. Outcomes of Japanese patients with non-alcoholic fatty liver disease according to genetic background and lifestyle-related diseases. Ann Hepatol 2021; 21:100260. [PMID: 32987175 DOI: 10.1016/j.aohep.2020.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Genetic background may be involved in the mechanisms of liver injury and the development of non-alcoholic fatty liver disease (NAFLD). However, its contributions to the long-term outcome of NAFLD have been unclear. METHODS We enrolled 314 Japanese patients with biopsy-confirmed NAFLD from 2000 to 2018 (161 men [51.3%]; median age, 53 [14-84] years; 114 with advanced fibrosis [37.5%]) in the patients without hepatocellular carcinoma at diagnosis. Genomic DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) were analyzed. Associations of mortality with patatin-like phospholipase 3 (PNPLA3) and aldehyde dehydrogenase 2 (ALDH2) were analyzed. Finally, a subgroup analysis according to lifestyle-related disease was performed. RESULTS During the median 7 years of follow-up, 20 patients (6.4%) died (13 liver-related [4.1%] and 7 non-liver-related deaths [2.2%]). Patients with ALDH2 (non-GG genotype) who had reduced alcohol metabolism tended to have a poor prognosis (p = 0.06). Patients carrying both risk SNPs of PNPLA3 (GG) and ALDH2 (non-GG) had a significantly poor prognosis (p = 0.01). In the subgroup analysis, patients with PNPLA3 (GG) who were non-diabetics (p = 0.06) or non-dyslipidemic (p = 0.03), with ALDH2 (non-GG) who were non-dyslipidemic (p = 0.01) or hypertensive (p = 0.03), also had a poor prognosis. The Cox analysis revealed that ALDH2 (non-GG) was associated with a poor prognosis (Hazard ratio: 4.568, 95% Confidence Interval: 1.294-16.131, p = 0.02) similar to the liver function tests. CONCLUSIONS Genetic background may affect NAFLD prognosis and ALDH2 SNP could predict the outcome.
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Affiliation(s)
- Tomomi Kogiso
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
| | - Takaomi Sagawa
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Kazuhisa Kodama
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Makiko Taniai
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Etsuko Hashimoto
- Seibu Railway Health Support Center, 1-11-2 Seibu Second Building 7th Floor, Kusunoki-dai, Tokorozawa-shi, Saitama, 359-0037, Japan
| | - Katsutoshi Tokushige
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Nishimiya N, Tajima K, Imajo K, Kameda A, Yoshida E, Togashi Y, Aoki K, Inoue T, Nakajima A, Utsunomiya D, Terauchi Y. Effects of Canagliflozin on Hepatic Steatosis, Visceral Fat and Skeletal Muscle among Patients with Type 2 Diabetes and Non-alcoholic Fatty Liver Disease. Intern Med 2021; 60:3391-3399. [PMID: 33994437 PMCID: PMC8627812 DOI: 10.2169/internalmedicine.7134-21] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/23/2021] [Indexed: 12/19/2022] Open
Abstract
Objective We assessed the effect of canagliflozin, an sodium-glucose co-transporter type-2 inhibitor, on hepatic steatosis using three imaging modalities: magnetic resonance imaging (MRI), computed tomography, and transient elastography. We further determined factors associated with improving hepatic steatosis by canagliflozin among patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods We conducted a six-month prospective single-arm study between August 2015 and June 2017. The primary outcome was the change in hepatic steatosis assessed using the hepatic proton density fat fraction (PDFF) on MRI before and after treatment with canagliflozin. The secondary outcomes were changes in measures of glucose metabolism, including the hepatic glucose uptake on fluorodeoxyglucose-positron emission tomography, and the inflammation and volumes of visceral and subcutaneous adipose tissue and skeletal muscle. Patients Nine patients with type 2 diabetes and NAFLD completed this study. All participants received canagliflozin at a dose of 100 mg daily. Results Canagliflozin caused a significant reduction in hepatic PDFF from baseline [median 20.6% (interquartile range 11.7%, 29.8%)] after 6 months [10.6% (5.4%, 22.6%), p=0.008]. Canagliflozin also significantly reduced the body weight, glycated hemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hs-CRP), and volumes of adipose tissue and skeletal muscle (all p<0.05). The reduction in hepatic PDFF was not correlated with changes in the body weight, HOMA-IR, hs-CRP, or volume of adipose tissue and skeletal muscle from baseline after six months. Conclusion Among patients with type 2 diabetes and NAFLD, canagliflozin improved hepatic steatosis. The effect may be independent of reducing adiposity, insulin resistance, inflammation, and skeletal muscle volume.
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Affiliation(s)
- Noriko Nishimiya
- Department of Radiology, Yokohama City University Graduate School of Medicine, Japan
| | - Kazuki Tajima
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Japan
| | - Akiko Kameda
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan
| | - Eiko Yoshida
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan
| | - Kazutaka Aoki
- Internal Medicine, Kanagawa Dental University, Japan
| | - Tomio Inoue
- Department of Radiology, Yokohama City University Graduate School of Medicine, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Japan
| | - Daisuke Utsunomiya
- Department of Radiology, Yokohama City University Graduate School of Medicine, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Japan
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Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y, Akuta N, Yoneda M, Iwasa M, Yoneda M, Otsuka M, Tamaki N, Kogiso T, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020. Hepatol Res 2021; 51:1013-1025. [PMID: 34533266 DOI: 10.1111/hepr.13688] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
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Affiliation(s)
- Katsutoshi Tokushige
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan.,Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kenichi Ikejima
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masafumi Ono
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yuichiro Eguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yoshihiro Kamada
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yoshito Itoh
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Norio Akuta
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masato Yoneda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Motoh Iwasa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masashi Yoneda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Motoyuki Otsuka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Nobuharu Tamaki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Tomomi Kogiso
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | | | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | | | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
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Hsu CS, Kao JH. Management of non-alcoholic fatty liver disease in patients with sarcopenia. Expert Opin Pharmacother 2021; 23:221-233. [PMID: 34541964 DOI: 10.1080/14656566.2021.1978978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Sarcopenia usually occurs with aging, sedentary lifestyle, unhealthy dietary habits, and chronic disorders pathophysiologically and bi-directionally linked to obesity and nonalcoholic fatty liver disease (NAFLD). Because of the global increase in aging and obesity populations, patients with concomitant sarcopenia and NAFLD are common, accompanied by various disorders relevant to obesity and sarcopenia, with across-the-board impact on socio-economic and public health life worldwide. Therefore, developing effective and practical management of these patients has become a pressing clinical issue. AREAS COVERED The authors searched literature from PubMed and Ovid MEDLINE up until Feb 2020. Emerging data on the management of sarcopenia and nonalcoholic fatty liver disease were examined and discussed. EXPERT OPINION Although NAFLD in patients with sarcopenia has become a critical problem worldwide, we still don't know much about the management of such patients. Based on theoretical speculations, we can recommend lifestyle intervention, including diet control with adequate protein intake, exercise intervention, and weight reduction as the mainstay of management at the first stage. More studies are needed in the future to identify the most suitable treatment and solve this important problem.
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Affiliation(s)
- Ching-Sheng Hsu
- Division of Gastroenterology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.,School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Taiwan, Hualien, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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Non-alcoholic fatty liver disease frequency and associated factors at admission of acute stroke. Hepatol Int 2021; 16:81-88. [PMID: 34524608 PMCID: PMC8844138 DOI: 10.1007/s12072-021-10253-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/01/2021] [Indexed: 11/09/2022]
Abstract
Background/purpose of the study If non-alcoholic fatty liver disease (NAFLD) frequency is very high in stroke patients, NAFLD may be a risk factor for stroke and identifying factors of NAFLD presence may lead to stroke prevention. This retrospective study aimed to investigate whether NAFLD frequency was very high and identify factors associated with NAFLD presence at acute stroke admission. Methods We included stroke patients aged 40 − 79 years who (1) were admitted from 2016 to 2019, within 24 h of onset; (2) underwent abdominal ultrasonography; and (3) underwent blood examination of biomarkers. We evaluated the frequency and significant factors of NAFLD presence. Results Among 1672 stroke patients, 676 patients met our inclusion criteria, and 267 patients (39.5%) had NAFLD. Compared to patients without NAFLD, patients with NAFLD were young; had high anthropometric values; high blood pressure; low aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT) ratio; high levels of liver enzymes, serum albumin, HbA1c, and serum lipids; low-density lipoprotein; high serum level of some fatty acids; and high fatty acid% of palmitic acid (PA) and dihomo-gamma-linolenic acid (DGLA). After excluding variables with multicollinearity, independent NAFLD-presence factors were high body mass index (BMI), low AST/ALT ratio, high serum albumin level, high PA%, and high DGLA level. Conclusions The frequency of NAFLD was high in our patient group. Significant NAFLD-presence factors were high BMI, low AST/ALT ratio, high serum albumin level, high PA%, and high DGLA level. A further study is warranted to determine the effects of the NAFLD-presence factors on stroke onset or prevention. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-021-10253-z.
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Endo T, Koike Y, Miyoshi H, Hisada Y, Fujita R, Suzuki R, Tanaka M, Tsujimoto T, Shimamura Y, Hasegawa Y, Kanayama M, Hashimoto T, Oha F, Noro N, Komano K, Ishii M, Ito YM, Iwasaki N, Takahata M. Close association between non-alcoholic fatty liver disease and ossification of the posterior longitudinal ligament of the spine. Sci Rep 2021; 11:17412. [PMID: 34465807 PMCID: PMC8408257 DOI: 10.1038/s41598-021-96714-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 08/13/2021] [Indexed: 11/30/2022] Open
Abstract
Ossification of the posterior longitudinal ligament (OPLL) of the spine is a disease of unknown etiology occurring frequently in individuals with metabolic disturbances. Obesity has been suggested as a potential risk factor for the severity of OPLL. We aimed to investigate whether non-alcoholic fatty liver disease (NAFLD) is associated with OPLL severity. We assessed the severity of NAFLD by a liver-to-spleen (L/S) ratio on computed tomography (CT) scans of 85 symptomatic OPLL patients at a single institution in Japan. We also assessed the severity of OPLL by CT reconstruction sagittal and axial images. The prevalence of NAFLD in middle-aged patients (age < 70 years, n = 50) was 80.3%, which was 2.5-8 times higher than that in the general Japanese population (9-30%). The ossification index of the spinal ligaments increased in proportion to the severity of fatty liver. The L/S ratio was revealed as a significant risk factor associated with the total ossification index (standardized β: -0.40, 95% confidence interval - 54.34 to - 4.22). This study suggests the potential contribution of NAFLD to the progression of OPLL. The close association between NAFLD and OPLL demonstrated in this study warrants further study to elucidate the causal nature of this relationship.
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Affiliation(s)
- Tsutomu Endo
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Yoshinao Koike
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Hideaki Miyoshi
- Division of Diabetes & Obesity, Faculty of Medicine & Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yuichiro Hisada
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Ryo Fujita
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Ryota Suzuki
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masaru Tanaka
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Takeru Tsujimoto
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Yukitoshi Shimamura
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Yuichi Hasegawa
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Masahiro Kanayama
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Tomoyuki Hashimoto
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Fumihiro Oha
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Naoki Noro
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Kiyofumi Komano
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Misaki Ishii
- Department of Orthopedics, Hakodate Central General Hospital, 33-2 Hon-cho, Hakodate, Hokkaido, 040-8585, Japan
| | - Yoichi M Ito
- Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Kita-14 Nishi-5, Kita-ku, Sapporo, Hokkaido, 060-8648, Japan
| | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masahiko Takahata
- Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
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Hatanaka T, Kakizaki S, Saito N, Nakano Y, Nakano S, Hazama Y, Yoshida S, Hachisu Y, Tanaka Y, Kashiwabara K, Yoshinaga T, Tojima H, Naganuma A, Uraoka T. Impact of Pemafibrate in Patients with Hypertriglyceridemia and Metabolic Dysfunction-associated Fatty Liver Disease Pathologically Diagnosed with Non-alcoholic Steatohepatitis: A Retrospective, Single-arm Study. Intern Med 2021; 60:2167-2174. [PMID: 33612679 PMCID: PMC8355409 DOI: 10.2169/internalmedicine.6574-20] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022] Open
Abstract
Objective The therapeutic effect of pemafibrate on metabolic dysfunction-associated fatty liver disease (MAFLD) remains unknown. This retrospective, single-arm study investigated the efficacy and safety of pemafibrate in MAFLD patients with hypertriglyceridemia. Methods A total of 10 patients who received pemafibrate (oral, 0.1 mg, twice a day) at Gunma Saiseikai Maebashi Hospital between September 2018 and September 2019 were included. All patients underwent a liver biopsy, and the disease grade and stage were pathologically assessed based on the FLIP algorithm. Results The median age was 66.0 (53.8-74.8) years old, and 5 patients (50.0%) were men. All patients were diagnosed with non-alcoholic steatohepatitis (NASH). The fasting and non-fasting triglyceride (TG) levels were 175 (149-247) mg/dL and 228 (169-335) mg/dL, respectively. The AST and ALT values at 6 months were significantly lower than at baseline [AST: 28.0 (22.0-33.8) U/L vs. 43.5 (24.0-55.0) U/L, p=0.008, ALT: 23.0 (14.8-26.5) U/L vs. 51.5 (23.0-65.3) U/L, p=0.005, respectively], especially in NASH patients with significant activity and advanced fibrosis (p=0.040 and 0.014, respectively). Fasting TG levels were significantly lower and HDL-C levels significantly higher at 6 months than at baseline (p=0.005 and 0.032, respectively). At six months, FIB-4, the aspartate aminotransferase-to-platelet ratio index, and the macrophage galactose-specific lectin-2 binding protein glycosylation isomer level were significantly improved compared with baseline (p=0.041, 0.005 and 0.005, respectively). Treatment-related adverse events were not observed. Conclusion Pemafibrate treatment may be safe and effective for MAFLD patients with hypertriglyceridemia.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Japan
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | - Naoto Saito
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Yuya Nakano
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Sachi Nakano
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Yoichi Hazama
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Sachiko Yoshida
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Yoko Hachisu
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Yoshiki Tanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Kenji Kashiwabara
- Department of Pathological Diagnosis, Gunma Saiseikai Maebashi Hospital, Japan
| | - Teruo Yoshinaga
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
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Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, Jang BK, Kim SG, Ahn SB, Kim H, Jun DW, Choi JI, Song DS, Kim W, Jeong SW, Kim MY, Koh H, Jeong S, Lee JW, Cho YK. KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021; 27:363-401. [PMID: 34154309 PMCID: PMC8273632 DOI: 10.3350/cmh.2021.0178] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, Bucheon, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul Korea
| | - Tae Hee Lee
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, Bucheon, Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Joon-Il Choi
- Department of Radiology, Seoul St.Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Do Seon Song
- Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hong Koh
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| | - Sujin Jeong
- Division of Pediatric Gastroenterology Hepatology and Nutrition, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Yong Kyun Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Akhavan Rezayat A, Ghasemi Nour M, Bondarsahebi Y, Hozhabrossadati SA, Amirkhanlou F, Akhavan Rezayat S, Kiani M, Imani B. The effects of melatonin therapy on the treatment of patients with Non-alcoholic steatohepatitis: A systematic review and Meta-analysis on clinical trial studies. Eur J Pharmacol 2021; 905:174154. [PMID: 34058202 DOI: 10.1016/j.ejphar.2021.174154] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022]
Abstract
Melatonin has shown promising effects in controlling the progress of non-alcoholic fatty liver disease (NAFLD), introducing it as a possible candidate for NAFLD treatment. In this context, the current study is aimed to evaluate melatonin's effect on the plasma levels of Gamma-glutamyl transpeptidase, cholesterol, triglyceride, and liver aminotransferases in NAFLD patients. NAFLD and melatonin, as well as their related terms, were searched in electronic databases, until May 1st, 2020. The initial search identified 1152 studies. Considering inclusion and exclusion criteria, the final seven articles were included in the study. The methodology of the articles was assessed by the Newcastle-Ottawa Scale. Alanine transaminase levels were significantly lowered with melatonin treatment but not earlier than the 4th week (P = 0.010 and 0.519, respectively). Aspartate aminotransferase levels didn't show significant alteration before 4 weeks, although exhibiting substantial decline in total (P = 0.697 and 0.008, respectively). Alkaline phosphatase changes under 4 weeks of follow-up were not significant (P = 0.3), however, it decreased significantly in total (P = 0.006). A significant decline was detected in triglyceride levels after melatonin treatment (P = 0.015). There was a significant reduction in cholesterol levels (P = 0.005). Gamma-glutamyl transpeptidase levels were also significantly different after the administration of melatonin (P < 0.001). Melatonin could reduce the progress of NAFLD. It might also decrement hepatic function parameters. Thus, it could be used for managing NAFLD and possibly as part of the treatment plan for patients with NAFLD.
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Affiliation(s)
- Arash Akhavan Rezayat
- Students Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ghasemi Nour
- Students Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yones Bondarsahebi
- Students Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Fatemeh Amirkhanlou
- Students Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mohammadali Kiani
- Pediatric Gastroenterology, Mashhad University of Medical Sciences, Mashhad, Khorasan, Iran
| | - Bahareh Imani
- Social Determinants of Health Research Center, Mashhad University of Medical Science, Mashhad, Iran.
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Seko Y, Yamaguchi K, Tochiki N, Yano K, Takahashi A, Okishio S, Kataoka S, Okuda K, Umemura A, Moriguchi M, Itoh Y. The Effect of Genetic Polymorphism in Response to Body Weight Reduction in Japanese Patients with Nonalcoholic Fatty Liver Disease. Genes (Basel) 2021; 12:628. [PMID: 33922278 PMCID: PMC8145113 DOI: 10.3390/genes12050628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/11/2021] [Accepted: 04/21/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of PNPLA3 rs738409 and HSD17B13 rs6834314 variants in response to diet therapy in Japanese patients with NAFLD. METHODS we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to PNPLA3 and HSD17B13 genotypes. RESULTS the bodyweight (BW) reduction rate was greater in patients with the PNPLA3 genotype CC than CG and GG (p = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in PNPLA3 CG/GG (r = 0.279/0.381), but not in PNPLA3 CC (p = 0.187). Change in LSM was correlated with change in BW only in patients with HSD17B13 AG/GG (r = 0.425), but not the AA genotype (p = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of HSD17B13 AG/GG (B = 3.043, p = 0.032), but not HSD17B13 AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) (p = 0.038). CONCLUSIONS in Japanese patients with NAFLD, HSD17B13 rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (Y.S.); (K.Y.); (N.T.); (K.Y.); (A.T.); (S.O.); (S.K.); (K.O.); (A.U.); (M.M.)
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Yoneda M, Honda Y, Saito S, Nakajima A. What considerations are there for the pharmacotherapeutic management of nonalcoholic steatohepatitis? Expert Opin Pharmacother 2021; 22:1217-1220. [PMID: 33880982 DOI: 10.1080/14656566.2021.1912014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
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Mizuno K, Haga H, Okumoto K, Hoshikawa K, Katsumi T, Nishina T, Saito T, Katagiri H, Ueno Y. Intrahepatic distribution of nerve fibers and alterations due to fibrosis in diseased liver. PLoS One 2021; 16:e0249556. [PMID: 33852613 PMCID: PMC8046205 DOI: 10.1371/journal.pone.0249556] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/21/2021] [Indexed: 01/23/2023] Open
Abstract
Autonomic nerve fibers in the liver are distributed along the portal tract, being involved in the regulation of blood flow, bile secretion and hepatic metabolism, thus contributing to systemic homeostasis. The present study investigated changes in hepatic nerve fibers in liver biopsy specimens from patients with normal liver, viral hepatitis and non-alcoholic steatohepatitis, in relation to clinical background. The areal ratio of nerve fibers to the total portal area was automatically calculated for each sample. The nerve fiber areal ratios (NFAR) for total nerve fibers and sympathetic nerve fibers were significantly lower in liver affected by chronic hepatitis, particularly viral hepatitis, and this was also the case for advanced liver fibrosis. However, the degree of inflammatory activity did not affect NFAR for either whole nerves or sympathetic nerves. Comparison of samples obtained before and after antiviral treatment for HCV demonstrated recovery of NFAR along with improvement of liver fibrosis.
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Affiliation(s)
- Kei Mizuno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Kazuo Okumoto
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kyoko Hoshikawa
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Taketo Nishina
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Takafumi Saito
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
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Wakabayashi SI, Joshita S, Kimura K, Motoki H, Kobayashi H, Yamashita Y, Sugiura A, Yamazaki T, Kuwahara K, Umemura T. Protocol: Prospective observational study investigating the prevalence and clinical outcome of portopulmonary hypertension in Japanese patients with chronic liver disease. PLoS One 2021; 16:e0249435. [PMID: 33793649 PMCID: PMC8016266 DOI: 10.1371/journal.pone.0249435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 03/17/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Portopulmonary hypertension (PoPH) is a subtype of the pulmonary arterial hypertension (PAH) associated with portal hypertension. There is a dissociation between the proportion of PoPH in PAH and that of PoPH in patients with liver cirrhosis, suggesting PoPH underdiagnosis and an incomplete understanding of this entity in the clinical setting. Specifically, real-world data in Japan is largely unknown as compared with in Europe and the United States. The present study aims to elucidate the prevalence and etiology of PoPH in Japanese patients with chronic liver disease. METHODS AND DESIGN In this prospective, single-center, observational investigation of PoPH patients with chronic liver disease, a targeted 2,500 Japanese adult patients regularly visiting Shinshu University Hospital in Matsumoto, Japan, for chronic liver disease will complete a standardized questionnaire on the presence of PoPH symptoms. If the respondent has signs of possible PoPH, ultrasound echocardiography (UCG) will be performed as a primary screening. In the case that UCG findings indicate pulmonary hypertension, the patient will be referred to a cardiologist for further evaluation, whereby a definitive diagnosis PoPH can be made. PoPH prevalence and etiology will be investigated at the time of diagnosis. Afterwards, patients with PoPH will be followed for five years for determination of survival rate. DISCUSSION This study will reveal the prevalence, etiology, and 5-year survival rate of PoPH in Japanese patients with chronic liver disease. TRIAL REGISTRATION This study is being performed at Shinshu University following registration as UMIN 000042287 on October 29, 2020.
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Affiliation(s)
- Shun-ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kazuhiro Kimura
- Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hirohiko Motoki
- Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Koichiro Kuwahara
- Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
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Zhu X, Wu M, Wang H, Li H, Lin J, Peng Y, Hu Y, Li C, Ding Y. Safety, tolerability, and pharmacokinetics of the novel pan-phosphodiesterase inhibitor ZSP1601 in healthy subjects: a double-blinded, placebo-controlled first-in-human single-dose and multiple-dose escalation and food effect study. Expert Opin Investig Drugs 2021; 30:579-589. [PMID: 33682556 DOI: 10.1080/13543784.2021.1900822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background: The pharmacokinetics (PK), safety, and tolerability profiles of ZSP1601, a first-in-class pan-phosphodiesterase (PDE) inhibitor, were evaluated in healthy Chinese volunteers.Research design and methods: This Phase 1a study consisted of a double-blinded, randomized, placebo-controlled single ascending dose (SAD) (25 to 350 mg), multiple ascending doses (MAD) (50 or 100 mg QD), and a two-period crossover food effect study (100 mg).Results: ZSP1601 was quickly absorbed, with maximum plasma concentrations (Cmax) reached at 1.25 to 2.50 h (median Tmax). The exposures exhibited dose-proportional increases, while the mean half-life (t1/2) ranged from 6.34-8.64 h. Steady-state was reached within seven days in the MAD study. The mean steady trough concentrations were 423 and 588 ng/mL, respectively. ZSP1601 accumulation was low, with ratios ≤ 1.5. The bioavailability of ZSP1601 was equivalent under fasted and fed states. All adverse events (AEs) were assessed as mild or moderate, with headaches as the most common. The highest single doses (275 and 350 mg) yielded more AEs, yet the rates were similar with the placebo cohorts in the MAD study.Conclusions: The safety and PK profiles of ZSP1601 support further efficacy evaluation in nonalcoholic steatohepatitis patients.Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03392779).
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Affiliation(s)
- Xiaoxue Zhu
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Min Wu
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Hong Wang
- Jilin Medical Products Administration, Changchun, China
| | - Haijun Li
- Medical Affairs, Guangdong Raynovent Biotech Co., Ltd, Shenzhen, China
| | - Junjie Lin
- Medical Affairs, Guangdong Raynovent Biotech Co., Ltd, Shenzhen, China
| | - Yun Peng
- Medical Affairs, Guangdong Zhongsheng Pharmaceutical Co., Ltd, Dongguan, China
| | - Yue Hu
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Cuiyun Li
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Yanhua Ding
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
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Arai T, Atsukawa M, Tsubota A, Mikami S, Ono H, Kawano T, Yoshida Y, Tanabe T, Okubo T, Hayama K, Nakagawa-Iwashita A, Itokawa N, Kondo C, Kaneko K, Emoto N, Nagao M, Inagaki K, Fukuda I, Sugihara H, Iwakiri K. Effect of sodium-glucose cotransporter 2 inhibitor in patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus: a propensity score-matched analysis of real-world data. Ther Adv Endocrinol Metab 2021; 12:20420188211000243. [PMID: 33815743 PMCID: PMC7989116 DOI: 10.1177/20420188211000243] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/12/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM. METHODS This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed via transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors. RESULTS The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1-6.7 kPa) (p < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight (p < 0.001), alanine aminotransferase (p = 0.02), uric acid (p < 0.001), and Fibrosis-4 (FIB-4) index (p = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group (p < 0.001). CONCLUSION SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.
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Affiliation(s)
- Taeang Arai
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Shigeru Mikami
- Division of Gastroenterology, Department of Internal Medicine, Kikkoman General Hospital, Miyazaki Noda, Japan
| | - Hiroki Ono
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Tadamichi Kawano
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Yuji Yoshida
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Tomohide Tanabe
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Korenobu Hayama
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Ai Nakagawa-Iwashita
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Keiko Kaneko
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Naoya Emoto
- Division of Endocrinology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Mototsugu Nagao
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Kyoko Inagaki
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Izumi Fukuda
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Hitoshi Sugihara
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
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Yoneda M, Honda Y, Ogawa Y, Kessoku T, Kobayashi T, Imajo K, Ozaki A, Nogami A, Taguri M, Yamanaka T, Kirikoshi H, Iwasaki T, Kurihashi T, Saito S, Nakajima A. Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial. BMJ Open Diabetes Res Care 2021; 9:e001990. [PMID: 33593749 PMCID: PMC7888333 DOI: 10.1136/bmjdrc-2020-001990] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/13/2021] [Accepted: 01/24/2021] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION The treatment of diabetes has a significant impact on the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We compared the effectiveness of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and pioglitazone for the treatment of NAFLD patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS This open-label, prospective, single-center, randomized clinical trial recruited NAFLD patients with type 2 diabetes mellitus and a hepatic fat fraction of at least 10% as assessed based on the MRI-proton density fat fraction (MRI-PDFF). Eligible patients were stratified according to hemoglobin A1c (HbA1c), alanine transaminase, and MRI-PDFF levels and randomly assigned (1:1) to receive either 20 mg tofogliflozin or 15-30 mg pioglitazone, orally, once daily for 24 weeks. The primary endpoint was an absolute change in MRI-PDFF at 24 weeks. Efficacy and safety was assessed in all treated patients. This trial was registered in the Japan Registry of Clinical Trials. RESULTS Overall, 40 eligible patients were randomly assigned to receive tofogliflozin (n=21) or pioglitazone (n=19). Changes in hepatic steatosis after 24 weeks of treatment were evaluated by MRI-PDFF, which showed a significant decrease in both groups (-7.54% (p<0.0001) and -4.12% (p=0.0042) in the pioglitazone and tofogliflozin groups, respectively). Compared with baseline, the body weight decreased by 2.83±2.86 kg (-3.6%, p=0.0443) in the tofogliflozin group and increased by 1.39±2.62 kg (1.7%, p=0.0002) in the pioglitazone group after 24 weeks. No life-threatening events or treatment-related deaths occurred. CONCLUSIONS Tofogliflozin was well tolerated, and it reduced the MRI-PDFF levels in NAFLD patients with type 2 diabetes mellitus. TRIAL REGISTRATION NUMBER jRCTs031180159.
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Affiliation(s)
- Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University, Yokohama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Hiroyuki Kirikoshi
- Clinical Laboratory Department, Yokohama City University, Yokohama, Japan
| | | | - Takeo Kurihashi
- Department of Internal Medicine, Kanagawa Dental University Yokohama Clinic, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
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Yoshio S, Kanto T. Macrophages as a source of fibrosis biomarkers for non-alcoholic fatty liver disease. Immunol Med 2021; 44:175-186. [PMID: 33444517 DOI: 10.1080/25785826.2020.1868664] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) are becoming major liver diseases worldwide. Liver fibrosis and cirrhosis are among the most significant risk factors of hepatocellular carcinoma (HCC) and associated with the long-term prognosis of NAFLD patients. To stratify the risk of HCC in NAFLD patients clinically, the discovery of non-invasive fibrosis markers is needed urgently. Liver macrophages play critical roles in the regulation of inflammation and fibrosis by interacting with hepatic stellate cells (HSCs) and other immune cells. Thus, it is rational to explore feasible biomarkers for liver fibrosis by focusing on macrophage-related factors. We examined serum factors comprehensively in multiple cohorts of NAFLD/NASH patients to determine whether they were correlated with the biopsy-proven fibrosis stage. We found that the serum levels of interleukin (IL)-34, YKL-40 and soluble Siglec-7 (sSiglec7) were closely associated with liver fibrosis and served as diagnostic biomarkers in patients with NAFLD/NASH. In the NAFLD liver, IL-34 was produced by activated fibroblasts, and YKL-40 and sSiglec-7 were secreted from macrophages. The sensitivity and specificity of these markers to detect advanced liver fibrosis varied, supporting the notion that the combination of these markers with other modalities is an option for clinical application.
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Affiliation(s)
- Sachiyo Yoshio
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
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