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Zarandi PK, Ghiasi M, Heiat M. The role and function of lncRNA in ageing-associated liver diseases. RNA Biol 2025; 22:1-8. [PMID: 39697114 PMCID: PMC11660375 DOI: 10.1080/15476286.2024.2440678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 10/09/2024] [Accepted: 12/04/2024] [Indexed: 12/20/2024] Open
Abstract
Liver diseases are a significant global health issue, characterized by elevated levels of disorder and death. The substantial impact of ageing on liver diseases and their prognosis is evident. Multiple processes are involved in the ageing process, which ultimately leads to functional deterioration of this organ. The process of liver ageing not only renders the liver more susceptible to diseases but also compromises the integrity of other organs due to the liver's critical function in metabolism regulation. A growing body of research suggests that long non-coding RNAs (lncRNAs) play a significant role in the majority of pathophysiological pathways. They regulate gene expression through a variety of interactions with microRNAs (miRNAs), messenger RNAs (mRNAs), DNA, or proteins. LncRNAs exert a major influence on the progression of age-related liver diseases through the regulation of cell proliferation, necrosis, apoptosis, senescence, and metabolic reprogramming. A concise overview of the current understanding of lncRNAs and their potential impact on the development of age-related liver diseases will be provided in this mini-review.
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Affiliation(s)
- Peyman Kheirandish Zarandi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
- Cancer Biology Signaling Pathway Interest Group (CBSPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohsen Ghiasi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
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Yu L, Zhang C, Wu B, Guo J, Fan D, Wang G, Zhang W, Lin L, Xu X, Du X, Zhang XY, Xie Y, Zhao J. Combined exposure of sleep deprivation and environmental particulate matter drives aging in multiple systems. JOURNAL OF HAZARDOUS MATERIALS 2025; 491:137914. [PMID: 40090303 DOI: 10.1016/j.jhazmat.2025.137914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 03/07/2025] [Accepted: 03/09/2025] [Indexed: 03/18/2025]
Abstract
Sleep disturbance accelerates aging, with accompanying exposure to air pollution. However, most studies ignore the combined exposure. This study aimed to investigate the combined effects of sleep deprivation and PM2.5 exposure on multi-system aging and to explore the damage mechanisms. The sleep deprivation instrument and the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) were used to construct a combined exposure model for one month. Our study used multiple behavioral, imaging, and molecular biological examinations to describe the aging characteristics in the cardiovascular system, metabolism, and central nervous system. Besides, the mechanisms in Sirt1, Wnt10β pathways were explored and correlation of damage among tissues was clarified. Based on sleep disruption, PM2.5 exposure was able to induce elevated serum T-CHO levels, impaired conditioned learning ability, abnormal brain tissue metabolic levels, and aberrant expression of multiple molecular markers related to cellular senescence, whereas PM2.5 exposure alone did not induce changes in the above indices. In addition, the Sirt1, Wnt10β pathway mediated cardiac and hepatic aging induced by combined exposure. Moreover, there was a significant correlation between heart and liver aging damage, which suggesting heart-liver axis may be involved in the aging process. Sleep deprivation and PM2.5 exposure trigger senescence in multiple tissues. In particular, on the basis of sleep deprivation, PM2.5 accelerates of the aging process in several tissues and organs. The problem of air pollution on top of sleep disturbance should be taken seriously, as it has a greater potential to accelerate aging than air pollution.
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Affiliation(s)
- Lu Yu
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China
| | - Chihang Zhang
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China
| | - Biao Wu
- Jinhua Center for Disease Control and Prevention, Jinhua, Zhejiang, China
| | - Jianshu Guo
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China
| | - Dongxia Fan
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China
| | - Ge Wang
- Eye & Ent Hospital, Fudan University, Shanghai, China
| | - Wenqing Zhang
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China
| | - Lin Lin
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China
| | - Xinlei Xu
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China
| | - Xihao Du
- Department of Epidemiology and Biostatistics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Yong Zhang
- College of Health Science and Technology & Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Imaging Technology, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Yuquan Xie
- Department of Cardiology, Renji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
| | - Jinzhuo Zhao
- Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Fudan University, Shanghai, China; IRDR International Center of Excellence on Risk Interconnectivity and Governance on Weather/Climate Extremes Impact and Public Health, Fudan University, Shanghai 200433, China.
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Wang X, Chen R, Liu J, Wang E, Luo H. Liver injury related to vascular endothelial growth factor tyrosine kinase inhibitors: a pharmacovigilance analysis of the USA FDA adverse event reporting system (FAERS) database. Expert Opin Drug Saf 2025:1-9. [PMID: 39881499 DOI: 10.1080/14740338.2025.2460449] [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: 08/06/2024] [Revised: 12/24/2024] [Accepted: 01/02/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND While vascular endothelial growth factor tyrosine kinase inhibitors (VEGFR-TKIs) are known to cause adverse events like cardiotoxicity and haematotoxicity, their impact on liver injury remains understudied. This study evaluates the association between VEGFR-TKIs and liver injury using data from the FDA Adverse Event Reporting System (FAERS) database from 2006 to 2024. RESEARCH DESIGN AND METHODS Nine VEGFR-TKIs (Axitinib, Vandetanib, Cabozantinib, Lenvatinib, Pazopanib, Ponatinib, Regorafenib, Sunitinib, Sorafenib) were analyzed. Disproportionality and Bayesian analyses identified cases of VEGFR-TKI-induced liver injury, assessing onset time, mortality, and hospitalization rates. RESULTS 8,619 cases of liver injury were identified. Pazopanib had the highest association with liver injury (reporting odds ratio 3.9). The median onset of liver injury was 21 days. Mortality was 28.5%, with Sorafenib linked to the highest mortality (48.6%). Lenvatinib had the highest hospitalization rate (56%). CONCLUSION VEGFR-TKIs are associated with liver injury. Close monitoring is required to mitigate the risks of hospitalization and early mortality during treatment.
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Affiliation(s)
- Xiang Wang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Rujie Chen
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jialin Liu
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - E Wang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hui Luo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Liu S, Li J, Wong Y, Yim HJ, Hirooka M, Enomoto H, Xie Q, Dai E, Hanafy AS, Cao Z, Zhao L, Teh KB, Kim TH, Jung YK, Koizumi Y, Hiasa Y, Nishimura T, Iijima H, Tian Q, Guo X, Jia Y, Sun J, Liu C, Qi X. Prognostic impact of age on outcomes of hepatic decompensation in patients with compensated cirrhosis (CHESS2102): an international, multicenter cohort study. MedComm (Beijing) 2024; 5:e781. [PMID: 39492833 PMCID: PMC11531654 DOI: 10.1002/mco2.781] [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: 10/18/2023] [Revised: 09/13/2024] [Accepted: 09/15/2024] [Indexed: 11/05/2024] Open
Abstract
Baveno VII criteria (B7C) and Baveno VI criteria (B6C) have been widely used to estimate the risk of hepatic decompensation. However, the impact of age on these criteria warrants further investigation. The international, multicenter cohort study included 1138 patients with compensated cirrhosis (median follow-up of 40.6 months), aiming to evaluate the value of age in predicting hepatic decompensation. We identified age as an independent predictor of hepatic decompensation, with 60 years determined as the optimal cut-off value. The occurrence of decompensation was 18.7% and 6.7% in the older (age ≥60 years) and younger (age <60 years) groups, respectively (p < 0.001). We subsequently integrated age into the existing Baveno criteria. In patients not meeting Baveno criteria (defined as not meeting B6C or B7C), the older group exhibited a significantly elevated risk of decompensation compared to the younger group (p < 0.05). However, no significant difference was observed between the older and younger groups in patients meeting Baveno criteria (p > 0.05). In conclusion, our study demonstrated that integrating age into the Baveno criteria could enhance the assessment of hepatic decompensation. Age should be considered before discharging patients with compensated cirrhosis from the surveillance of hepatic decompensation.
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Affiliation(s)
- Shanghao Liu
- Liver Disease Center of Integrated Traditional Chinese and Western MedicineDepartment of RadiologyZhongda HospitalMedical SchoolSoutheast UniversityNurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University)NanjingChina
- Basic Medicine Research and Innovation Center of Ministry of EducationZhongda Hospital, Southeast UniversityState Key Laboratory of Digital Medical EngineeringNanjingChina
| | - Jia Li
- Department of Gastroenterology and HepatologyTianjin Second People's HospitalTianjinChina
| | - Yujun Wong
- Department of Gastroenterology & HepatologyChangi General HospitalSingHealthSingaporeSingapore
- Duke‐NUS Medical SchoolSingaporeSingapore
| | - Hyung Joon Yim
- Division of Gastroenterology and HepatologyKorea University Ansan HospitalAnsanGyeonggiRepublic of Korea
| | - Masashi Hirooka
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineEhimeJapan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic DiseasesDepartment of GastroenterologyHyogo Medical UniversityNishinomiyaJapan
| | - Qing Xie
- Department of Infectious DiseaseRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Erhei Dai
- Division of Liver DiseasesThe Fifth Hospital of ShijiazhuangNorth China University of Science and TechnologyShijiazhuangChina
| | - Amr Shaaban Hanafy
- Division of GastroenterologyHepatology and EndoscopyInternal MedicineZagazig University Faculty of MedicineZagazigEgypt
| | - Zhujun Cao
- Department of Infectious DiseaseRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lili Zhao
- Department of Gastroenterology and HepatologyTianjin Second People's HospitalTianjinChina
| | - Kok Ban Teh
- Department of Gastroenterology & HepatologyChangi General HospitalSingHealthSingaporeSingapore
- Duke‐NUS Medical SchoolSingaporeSingapore
| | - Tae Hyung Kim
- Division of Gastroenterology and HepatologyKorea University Ansan HospitalAnsanGyeonggiRepublic of Korea
- Division of Gastroenterology and HepatologyHallym University Sacred Heart HospitalAnyangGyeonggiRepublic of Korea
| | - Young Kul Jung
- Division of Gastroenterology and HepatologyKorea University Ansan HospitalAnsanGyeonggiRepublic of Korea
| | - Yohei Koizumi
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineEhimeJapan
| | - Yoichi Hiasa
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineEhimeJapan
| | - Takashi Nishimura
- Department of Internal MedicineDivision of Gastroenterology and HepatologyHyogo Medical UniversityNishinomiyaJapan
- Ultrasound Imaging CenterHyogo Medical UniversityNishinomiyaJapan
| | - Hiroko Iijima
- Department of Internal MedicineDivision of Gastroenterology and HepatologyHyogo Medical UniversityNishinomiyaJapan
- Ultrasound Imaging CenterHyogo Medical UniversityNishinomiyaJapan
| | - Qingyi Tian
- Liver Disease Center of Integrated Traditional Chinese and Western MedicineDepartment of RadiologyZhongda HospitalMedical SchoolSoutheast UniversityNurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University)NanjingChina
| | - Xinru Guo
- Division of Liver DiseasesThe Fifth Hospital of ShijiazhuangNorth China University of Science and TechnologyShijiazhuangChina
| | - Yansheng Jia
- Division of Liver DiseasesThe Fifth Hospital of ShijiazhuangNorth China University of Science and TechnologyShijiazhuangChina
| | - Jinfang Sun
- Department of Epidemiology and BiostatisticsSchool of Public HealthSoutheast UniversityNanjingChina
- Key Laboratory of Environmental Medicine EngineeringMinistry of EducationSchool of Public HealthSoutheast UniversityNanjingChina
| | - Chuan Liu
- Liver Disease Center of Integrated Traditional Chinese and Western MedicineDepartment of RadiologyZhongda HospitalMedical SchoolSoutheast UniversityNurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University)NanjingChina
- Basic Medicine Research and Innovation Center of Ministry of EducationZhongda Hospital, Southeast UniversityState Key Laboratory of Digital Medical EngineeringNanjingChina
| | - Xiaolong Qi
- Liver Disease Center of Integrated Traditional Chinese and Western MedicineDepartment of RadiologyZhongda HospitalMedical SchoolSoutheast UniversityNurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University)NanjingChina
- Basic Medicine Research and Innovation Center of Ministry of EducationZhongda Hospital, Southeast UniversityState Key Laboratory of Digital Medical EngineeringNanjingChina
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Chatterjee N, Sharma R, Kale PR, Trehanpati N, Ramakrishna G. Is the liver resilient to the process of ageing? Ann Hepatol 2024; 30:101580. [PMID: 39276981 DOI: 10.1016/j.aohep.2024.101580] [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: 05/25/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/17/2024]
Abstract
The liver's unique regenerative capacity, immunotolerant feature, and polyploidy status distinguish it as a metabolic organ unlike any other in the body. Despite aging, the liver generally exhibits fewer pathological abnormalities than other organs (such as the kidney), maintaining its functions near-normal balanced manner. Subtle changes in the liver, including reduced blood flow, detoxification alterations, pseudo-capillarization, and lipofuscin deposition, may occur with chronological age. Research indicates that carefully selected liver grafts from octogenarian donors can perform well post-transplant, emphasizing instances where age doesn't necessarily compromise liver function. Notably, a recent report suggests that the liver is a youthful organ, with hepatocytes averaging an age of only 3 years. Despite the liver's impressive regenerative capabilities and cellular reserve, a lingering question persists: how does the liver maintain its youthful characteristic amidst the chronological aging of the entire organism? The various adaptive mechanism possibly include:(a) cellular hypertrophy to maintain physiological capacity even before proliferation initiates, (b) the "ploidy conveyor" as a genetic adaptation to endure aging-related stress, (c) sustained telomere length indicative of youthfulness (d) active extracellular matrix remodelling for normal cellular functioning, (e) Mitochondria-Endoplasmic Reticulum based metabolic adaptation and (c) cellular plasticity as fitness mechanisms for healthy aging. However, it is crucial to note that aged livers may have compromised regenerative capacity and chronic liver disease is often associated with declining function due to premature hepatocyte senescence. This review delves into varied cellular adaptations sustaining liver homeostasis with chronological aging and briefly explores the role of accelerated hepatocyte aging as a precursor to chronic liver disease.
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Affiliation(s)
- Nirupama Chatterjee
- Artemis Education and Research Foundation, Artemis Health Institute, Sector 51 Gurugram, India
| | - Rishabh Sharma
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana Amity Education Valley, Panchgaon, Manesar Gurugram, HR 122413, India
| | - Pratibha R Kale
- Department of Clinical Microbiology, Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India.
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Lin H, Loi PL, Ng J, Shen L, Teo W, Chung A, Raj P, Chang JP. MELD3.0 is superior to MELDNa and MELD for prediction of mortality in patients with cirrhosis: An external validation in a multi-ethnic population. JGH Open 2024; 8:e13098. [PMID: 38832135 PMCID: PMC11144281 DOI: 10.1002/jgh3.13098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/08/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024]
Abstract
Background and Aim The model for end-stage liver disease (MELD) was updated to MELDNa and recently to MELD3.0 to predict survival of cirrhotic patients. We validated the prognostic performance of MELD3.0 and compared with MELDNa and MELD amongst cirrhotic inpatients. Methods Demographical, clinical, biochemical, and survival data of cirrhotic inpatients in Singapore General Hospital (SGH) from 01 January 2018 to 31 December 2018, were studied retrospectively. Patients were followed up from first admission in 2018 until death or until 01 April 2023. Area under the receiver operating characteristic curves (AUROC) were computed for the discriminative effects of MELD3.0, MELDNa, and MELD to predict 30-, 90-, and 365-day mortalities. AUROC was compared with DeLong's test. The cutoff MELD3.0 score for patients at high risk of 30-day mortality was determined using Youden's Index. Survival curves of patients with MELD3.0 score above and below the cutoff were estimated with Kaplan-Meier method and compared with log-rank analysis. Results Totally 862 patients were included (median age 71.0 years [interquartile range, IQR: 64.0-79.0], 65.4% males, 75.8% Chinese). Proportion of patients with Child-Turcotte-Pugh classes A/B/C were 55.5%/35.5%/9.0%. Median MELD3.0/MELDNa/MELD scores were 12.2 (IQR: 8.7-18.3)/11.0 (IQR: 8.0-17.5)/10.3 (IQR: 7.8-15.0). Median time of follow-up was 51.9 months (IQR: 8.5-59.6). The proportion of 30-/90-/365-day mortalities was 5.7%/13.2%/26.9%. AUROC of MELD3.0/MELDNa/MELD in predicting 30-, 90-, and 365-day mortalities, respectively, were 0.823/0.793/0.783, 0.754/0.724/0.707, 0.682/0.654/0.644 (P < 0.05). Optimal cutoff to predict 30-day mortality was MELD3.0 > 19 (sensitivity = 67.4%, specificity = 82.4%). Patients with MELD3.0 > 19, compared with patients with MELD3.0 ≤ 19, had shorter median time to death (98.0 days [IQR: 28.8-398.0] vs 390.0 days [IQR: 134.3-927.5]), and higher proportion of 30-day mortality (68.8% vs 43.0%) (P < 0.001). Conclusion MELD3.0 performs better than MELDNa and MELD in predicting mortality in cirrhotic inpatients. MELD3.0 > 19 predicts higher 30-day mortality.
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Affiliation(s)
- Hong‐Yi Lin
- Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Pooi Ling Loi
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
| | - Jeanette Ng
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
| | - Liang Shen
- Biostatistics Unit, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Wei‐Quan Teo
- SingHealth Duke‐NUS Transplant CentreSingaporeSingapore
| | - Amber Chung
- SingHealth Duke‐NUS Transplant CentreSingaporeSingapore
| | - Prema Raj
- SingHealth Duke‐NUS Transplant CentreSingaporeSingapore
| | - Jason Pik‐Eu Chang
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
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Fudeyasu K, Ushio K, Nomura T, Kawae T, Iwaki D, Nakashima Y, Nagao A, Hiramatsu A, Murakami E, Oka S, Mikami Y. Advanced liver fibrosis is associated with decreased gait speed in older patients with chronic liver disease. Sci Rep 2024; 14:6809. [PMID: 38514842 PMCID: PMC10957869 DOI: 10.1038/s41598-024-57342-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/18/2024] [Indexed: 03/23/2024] Open
Abstract
This study investigated whether the progression of liver fibrosis affects the prevalence of sarcopenia and incidence of decreased gait speed in older patients with chronic liver disease (CLD). Patients with CLD aged ≥ 60 years were classified into low, intermediate, and high fibrosis 4 (FIB-4) index groups according to the degree of liver fibrosis. The prevalence of sarcopenia and incidence of decreased gait speed (< 1.0 m/s) were compared among the three groups. Logistic regression analysis was performed to investigate factors affecting the risk of decreased gait speed. No significant difference was observed in the prevalence of sarcopenia among the three groups, but the incidence of decreased gait speed significantly differed (p = 0.029). When analyzed individually, a significant difference in decreased gait speed incidence was observed between the high and low FIB-4 index groups (p = 0.014). In logistic regression analysis, the progression of liver fibrosis (odds ratio: 1.32, 95% confidence interval: 1.13-1.55) and lower extremity muscle strength (LEMS) (odds ratio: 0.92, 95% confidence interval: 0.88-0.97) were significantly associated with decreased gait speed. As liver fibrosis progresses in older patients with CLD, it becomes important to focus on not only skeletal muscle mass and grip strength, but also gait speed and LEMS.
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Affiliation(s)
- Kenichi Fudeyasu
- Division of Rehabilitation, Department of Clinical Practice and Support, Hiroshima University Hospital, Hiroshima, Japan
| | - Kai Ushio
- Department of Rehabilitation Medicine, Hiroshima University Hospital, Hiroshima, Japan.
| | - Takuo Nomura
- Department of Physical Therapy, Faculty of Rehabilitation, Kansai Medical University, Osaka, Japan
| | - Toshihiro Kawae
- Department of Physical Therapy, Makuhari Human Care Faculty, Tohto University, Chiba, Japan
| | - Daisuke Iwaki
- Division of Rehabilitation, Department of Clinical Practice and Support, Hiroshima University Hospital, Hiroshima, Japan
| | - Yuki Nakashima
- Division of Rehabilitation, Department of Clinical Practice and Support, Hiroshima University Hospital, Hiroshima, Japan
| | - Akiko Nagao
- Division of Nutrition Management, Hiroshima University Hospital, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology, KKR Hiroshima Memorial Hospital, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yukio Mikami
- Department of Rehabilitation Medicine, Hiroshima University Hospital, Hiroshima, Japan
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O'Shea JG, Cholli P, Heil EL, Buchacz K. Considerations for long-acting antiretroviral therapy in older persons with HIV. AIDS 2023; 37:2271-2286. [PMID: 37965737 PMCID: PMC10993170 DOI: 10.1097/qad.0000000000003704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2023]
Abstract
People with HIV (PWH) can now enjoy longer, healthier lives due to safe and highly effective antiretroviral therapy (ART), and improved care and prevention strategies. New drug formulations such as long-acting injectables (LAI) may overcome some limitations and issues with oral antiretroviral therapy and strengthen medication adherence. However, challenges and questions remain regarding their use in aging populations. Here, we review unique considerations for LAI-ART for the treatment of HIV in older PWH, including benefits, risks, pharmacological considerations, implementation challenges, knowledge gaps, and identify factors that may facilitate uptake of LA-ART in this population.
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Affiliation(s)
- Jesse G O'Shea
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Preetam Cholli
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Emily L Heil
- Department of Practice, Sciences, and Health Outcomes Research, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
| | - Kate Buchacz
- Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
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Mondal A, Debnath A, Dhandapani G, Sharma A, Lukhmana S, Yadav G. Prevalence of High and Moderate Risk of Liver Fibrosis Among Patients With Diabetes at a Noncommunicable Diseases (NCD) Clinic in a Primary Healthcare Center in Northern India. Cureus 2023; 15:e49286. [PMID: 38143613 PMCID: PMC10747424 DOI: 10.7759/cureus.49286] [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] [Accepted: 11/23/2023] [Indexed: 12/26/2023] Open
Abstract
Background Diabetes is a known entity that contributes to increased incidence and progress of liver fibrosis. Despite the integration of nonalcoholic fatty liver disease (NAFLD) into the NP-NCD program (National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases, and Stroke [NPCDCS]), screening individuals in primary healthcare settings for liver fibrosis remains uncommon. The objective of this study was to determine the prevalence of the risk of liver fibrosis in individuals with diabetes. Methodology The secondary data analysis was conducted among patients with diabetes attending the noncommunicable diseases (NCD) clinic at the Primary Health Center (PHC) Najafgarh, Delhi, from January 2023 to June 2023. We used the Fibrosis-4 (FIB-4) score to assess the risk of liver fibrosis. The data analysis was carried out using Stata 17.0 software (StataCorp, College Station, TX). Results Out of 394 individuals screened, 158 (39.5%) were male and 236 (60.5%) were female. Among the study participants, 64.9% (95% confidence interval [CI] 60.0%-69.7%) were of low risk, 30.5% (95% CI 25.9%-35.3%) were of intermediate risk, and 4.6% (95% CI 2.7%-7.1%) were of high risk of developing liver fibrosis based on FIB-4 scoring. The increased risk was associated with increased age, duration of diabetes, and dyslipidemia. Conclusions The prevalence of high risk of liver fibrosis among patients with diabetes was 4.6% (95% CI 2.7%-7.1%), whereas an intermediate risk of developing liver fibrosis was observed in 30.5%. The study advocates integrating these screening tools into primary healthcare settings, alleviating the strain on larger healthcare facilities. It also underscores the importance of early detection and management of liver fibrosis in patients with diabetes.
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Affiliation(s)
- Anubhav Mondal
- Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Aninda Debnath
- Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Ghurumourthy Dhandapani
- Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Abhishek Sharma
- Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Shveta Lukhmana
- Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Geeta Yadav
- Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
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Manganas K, Delicou S, Xydaki A, Kourakli A, Evliati L, Vlachaki E, Klironomos E, Diamantidis M, Lafiatis I, Kattamis A, Koskinas J. Predisposing factors for advanced liver fibrosis in patients with sickle cell disease. Br J Haematol 2023; 202:1192-1198. [PMID: 37438880 DOI: 10.1111/bjh.18970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/14/2023]
Abstract
Sickle cell disease (SCD) is one of the most common monogenic disorders worldwide and liver complications are common in this group of patients. Our study aims to highlight the prevalence of chronic liver complications and the main predisposing factors for advanced liver fibrosis in SCD patients. For this purpose, 219 patients from eight Thalassemia and Sickle Cell Units across Greece enrolled in our study and history of liver related disease complications was recorded, as well as a full laboratory and imaging analysis concerning their liver function. 13.6% of the patients had advanced liver fibrosis. The presence of liver fibrosis was significantly correlated with advanced age, male gender, cholelithiasis and higher LDH, γ-GT, INR, direct and indirect bilirubin levels. These patients had exhibited significantly more episodes of liver crises and acute intrahepatic cholestasis. No correlation was observed with right heart failure or previous viral hepatitis. Patients with advanced liver fibrosis were receiving a more intensive transfusion therapy for a longer period of time and had higher Liver Iron Concentration levels. Our study shows that liver complications and cirrhosis is a significant cause of morbidity in patients with SCD and it is primarily associated with intravascular hemolysis and vaso-occlusive phenomena and secondarily with iron overload.
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Affiliation(s)
| | - Sophia Delicou
- Thalassemia and Sickle Cell Unit, Hippokration General Hospital, Athens, Greece
| | - Aikaterini Xydaki
- Thalassemia and Sickle Cell Unit, Hippokration General Hospital, Athens, Greece
| | - Alexandra Kourakli
- Thalassemia & Hemoglobinopathies Unit, Hematology Division, Department of Internal Medicine, University of Patras Medical School, University Hospital, Patras, Greece
| | - Loukia Evliati
- Thalassemia and Sickle Cell Unit, General Hospital of Athens "Evaggelismos", Athens, Greece
| | - Efthymia Vlachaki
- Thalassemia and Sickle Cell Unit, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Klironomos
- Thalassemia and Sickle Cell Unit, "Venizelion" General Hospital, Heraklion, Greece
| | - Michail Diamantidis
- Thalassemia and Sickle Cell Unit, General Hospital of Larissa, Larissa, Greece
| | - Ioannis Lafiatis
- Thalassemia and Sickle Cell Unit, "Vostanio" General Hospital of Mytilene, Mytilene, Greece
| | - Antonios Kattamis
- "Agia Sophia" Children Hospital, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
| | - John Koskinas
- Department of Internal Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
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11
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Christensen NM, Ringholm S, Buch BT, Gudiksen A, Halling JF, Pilegaard H. Muscle PGC-1α modulates hepatic mitophagy regulation during aging. Exp Gerontol 2023; 172:112046. [PMID: 36521568 DOI: 10.1016/j.exger.2022.112046] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 11/10/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
Aging has been suggested to be associated with changes in oxidative capacity, autophagy, and mitophagy in the liver, but a simultaneous evaluation of these key cellular processes is lacking. Moreover, skeletal muscle transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α has been reported to mediate inter-organ signaling through myokines with regulatory effects in the liver, but the potential role of muscle PGC-1α on hepatic changes with age remains to be resolved. The aim of the present study was therefore to investigate 1) the effect of aging on mitochondrial autophagy and mitophagy capacity in mouse liver and 2) whether muscle PGC-1α is required for maintaining autophagy and mitophagy capacity in the liver during aging. The liver was obtained from young (Young) and aged (Aged) inducible muscle-specific PGC-1α knockout (iMKO) and floxed littermate control mice (Lox). Aging increased liver p62, Parkin and BCL2/adenovirus E1B 19 kDa protein-interacting protein (BNIP)3 protein with no effect of muscle specific PGC-1α knockout, while liver Microtubule-associated protein 1A/1B-light chain 3(LC3) II/I was unchanged with age, but tended to be lower in iMKO mice than in controls. Markers of liver mitochondrial oxidative capacity and oxidative stress were unchanged with age and iMKO. However, Parkin protein levels in isolated liver mitochondria were 2-fold higher in Aged iMKO mice than in Aged controls. In conclusion, aging had no effect on oxidative capacity and lipid peroxidation in the liver. However, aging was associated with increased levels of autophagy and mitophagy markers. Moreover, muscle PGC-1α appears to regulate hepatic mitochondrial translocation of Parkin in aged mice, suggesting that the metabolic capacity of skeletal muscle can modulate mitophagy regulation in the liver during aging.
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Affiliation(s)
- Natascha Masselkhi Christensen
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark
| | - Stine Ringholm
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark
| | - Bjørg Thiellesen Buch
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark
| | - Anders Gudiksen
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark
| | - Jens Frey Halling
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark
| | - Henriette Pilegaard
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark.
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12
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He Y, Su Y, Duan C, Wang S, He W, Zhang Y, An X, He M. Emerging role of aging in the progression of NAFLD to HCC. Ageing Res Rev 2023; 84:101833. [PMID: 36565959 DOI: 10.1016/j.arr.2022.101833] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/10/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
With the aging of global population, the incidence of nonalcoholic fatty liver disease (NAFLD) has surged in recent decades. NAFLD is a multifactorial disease that follows a progressive course, ranging from simple fatty liver, nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC). It is well established that aging induces pathological changes in liver and potentiates the occurrence and progression of NAFLD, HCC and other age-related liver diseases. Studies of senescent cells also indicate a pivotal engagement in the development of NAFLD via diverse mechanisms. Moreover, nicotinamide adenine dinucleotide (NAD+), silence information regulator protein family (sirtuins), and mechanistic target of rapamycin (mTOR) are three vital and broadly studied targets involved in aging process and NAFLD. Nevertheless, the crucial role of these aging-associated factors in aging-related NAFLD remains underestimated. Here, we reviewed the current research on the roles of aging, cellular senescence and three aging-related factors in the evolution of NAFLD to HCC, aiming at inspiring promising therapeutic targets for aging-related NAFLD and its progression.
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Affiliation(s)
- Yongyuan He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinghong Su
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengcheng Duan
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siyuan Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Basic Medicine, Kunming Medical University, China
| | - Yingting Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofei An
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
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13
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Ren H, Li W, Liu X, Zhao N. γδ T cells: The potential role in liver disease and implications for cancer immunotherapy. J Leukoc Biol 2022; 112:1663-1668. [PMID: 36098208 DOI: 10.1002/jlb.5mr0822-733rrr] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/31/2022] [Indexed: 01/04/2023] Open
Abstract
The γδ T cell subset was discovered over 30 years ago, yet continues to be an exciting and challenging component of the adaptive immune response. While γδ T cells represent a very small fraction of all T cells in humans, γδ T cells have a vital effect on human immunity, serving as a bridge between the innate and adaptive immune systems. The characteristics of γδ T cells include recognition of non-MHC restrictive antigens, as well as the ability to secrete an abundance of cytokines, suggesting that γδ T cells have high antitumor activity. As such, they have gained ample attention with respect to tumor immunotherapy in the last decade. The γδ T cell subset comprises up to ∼15-20% of the T-lymphocyte population in the liver, although the liver is recognized as an immune organ with primary immune functions, the role of γδ T cells in liver disease has not been established. Herein, we present a comprehensive overview of molecular mechanisms underlying immune γδ T cell activity in liver disease, including immune liver injury, viral hepatitis, cirrhosis, and hepatocellular carcinoma, and review γδ T cell-based clinical immunotherapeutic approaches.
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Affiliation(s)
- He Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - WanJing Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Na Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
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14
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Zhang Y, Ren H, Zhang C, Li H, Guo Q, Xu H, Cui L. Development and validation of four ferroptosis-related gene signatures and their correlations with immune implication in hepatocellular carcinoma. Front Immunol 2022; 13:1028054. [PMID: 36304446 PMCID: PMC9592986 DOI: 10.3389/fimmu.2022.1028054] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This tumor presents with an insidious onset, rapid progression, and frequent recurrence. Ferroptosis is a newly discovered mode of programmed cell death that may play a key role in the progression of HCC. This study aimed to investigate the prognostic value of ferroptosis-related genes (FRGs) in HCC and their impact on tumor immune function, thereby providing new insights into targeted therapy for HCC. First, 43 differentially expressed FRGs were identified using the TCGA database, and four prognostically relevant methylation-driven FRGs (G6PD, HELLS, RRM2, and STMN1) were screened via survival and methylation analyses. Gene co-expression, mutation, and clinicopathological characterization indicated that these four pivotal FRGs play essential roles in tumor progression. We also validated these four genes using transcriptomic and proteomic data as well as cohort samples from our patients. Moreover, receiver operator characteristic (ROC) curves confirmed that the signatures of the four FRGs were independent prognostic factors in HCC. Gene set enrichment analysis of the four FRGs showed statistically significant associations with pathways related to HCC proliferation. Finally, the TIMER and TISIDB databases indicated that the four FRGs were statistically significantly correlated with tumor-infiltrating immune cells and immune checkpoint expression. Taken together, this study provides information guiding a novel therapeutic strategy targeting FRGs for HCC treatment.
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Affiliation(s)
- Ying Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - He Ren
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Chunting Zhang
- Department of Nursing, Air Force Medical Center, People’s Liberation Army (PLA), Beijing, China
| | - Haihua Li
- Pediatric Nursing Station of Qitaihe Maternal and Child Health Hospital, Qitaihe, Heilongjiang Qitaihe Province, China
| | - Qingzhi Guo
- Department of Renal Sixth, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang Harbin Province, China
| | - Haitao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Lina Cui, ; Haitao Xu,
| | - Lina Cui
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Lina Cui, ; Haitao Xu,
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15
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Abu-Freha N, Estis-Deaton A, Aasla M, Etzion O, Philip A, Yardeni D, Abo Abed M, Abu Tailakh M. Liver cirrhosis in elderly patients: clinical characteristics, complications, and survival-analyses from a large retrospective study. Aging Clin Exp Res 2022; 34:2217-2223. [PMID: 35670959 DOI: 10.1007/s40520-022-02152-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/06/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Liver cirrhosis (LC) is a common disease diagnosed in all ages. With the increasing population age, LC is noticeable more in the clinics. AIM To distinguish the clinical characteristics, complications, and survival of patients with liver cirrhosis. METHODS A retrospective study enrolled patients diagnosed with liver cirrhosis at Soroka University Medical Center. Patients with cirrhosis diagnosed at an age older than 65 years (group 1) were compared with patients diagnosed at an age younger than 65 years (group 2). RESULTS We included 1046 patients; 411 (39.3%) in group 1 and 635 (60.7%) in group 2. Fatty liver and cryptogenic liver disease were found to cause cirrhosis at a significantly higher rate in the elderly (23.4% vs. 13.9%, p < 0.001, 15.3% vs. 6.3%, p < 0.001, respectively). A higher rate of non-hepatocellular carcinoma cancers and mortality (17.5% vs. 9.1%, p < 0.001, 76.6% vs. 57%, respectively) was found among cirrhotic elderly patients, but a lower rate of oesophageal varices (47.7% vs. 60.1%, p = 0.002). Twenty-year follow-up Kaplan-Meier survival analysis for mortality estimated poor survival in the elderly (log-rank p < 0.001). The adjusted Cox proportional hazards regression model showed an association of age > 65 with an all-cause mortality hazard ratio of 2.26 (95% CI 1.89-2.69). CONCLUSION Higher rates of fatty liver, cryptogenic cirrhosis, non-HCC cancers, and mortality were found among patients diagnosed with cirrhosis in the elderly.
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Affiliation(s)
- Naim Abu-Freha
- The Institute of Gastroenterology and Hepatology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Asia Estis-Deaton
- Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel
| | - Muhammad Aasla
- Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel
| | - Ohad Etzion
- The Institute of Gastroenterology and Hepatology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Aerin Philip
- Medical School for International Health, Ben Gurion University of the Negev, Beer-Sheva, Israel
| | - David Yardeni
- The Institute of Gastroenterology and Hepatology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Muhammad Abo Abed
- Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel
| | - Muhammad Abu Tailakh
- Recanati School for Community Health Professions, Department of Nursing, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel and Soroka University Medical Center, P.O.Box 653, 8410501, Beer-Sheva, Israel.
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16
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Tsukahara Y, Ferran B, Minetti ET, Chong BSH, Gower AC, Bachschmid MM, Matsui R. Administration of Glutaredoxin-1 Attenuates Liver Fibrosis Caused by Aging and Non-Alcoholic Steatohepatitis. Antioxidants (Basel) 2022; 11:867. [PMID: 35624731 PMCID: PMC9138033 DOI: 10.3390/antiox11050867] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/17/2022] [Accepted: 04/24/2022] [Indexed: 02/04/2023] Open
Abstract
Liver fibrosis is a sign of non-alcoholic fatty liver disease progression towards steatohepatitis (NASH) and cirrhosis and is accelerated by aging. Glutaredoxin-1 (Glrx) controls redox signaling by reversing protein S-glutathionylation, induced by oxidative stress, and its deletion causes fatty liver in mice. Although Glrx regulates various pathways, including metabolism and apoptosis, the impact of Glrx on liver fibrosis has not been studied. Therefore, we evaluated the role of Glrx in liver fibrosis induced by aging or by a high-fat, high-fructose diet. We found that: (1) upregulation of Glrx expression level inhibits age-induced hepatic apoptosis and liver fibrosis. In vitro studies indicate that Glrx regulates Fas-induced apoptosis in hepatocytes; (2) diet-induced NASH leads to reduced expression of Glrx and higher levels of S-glutathionylated proteins in the liver. In the NASH model, hepatocyte-specific adeno-associated virus-mediated Glrx overexpression (AAV-Hep-Glrx) suppresses fibrosis and apoptosis and improves liver function; (3) AAV-Hep-Glrx significantly inhibits transcription of Zbtb16 and negatively regulates immune pathways in the NASH liver. In conclusion, the upregulation of Glrx is a potential therapeutic for the reversal of NASH progression by attenuating inflammatory and fibrotic processes.
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Affiliation(s)
- Yuko Tsukahara
- Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (Y.T.); (B.F.); (E.T.M.); (B.S.H.C.); (M.M.B.)
| | - Beatriz Ferran
- Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (Y.T.); (B.F.); (E.T.M.); (B.S.H.C.); (M.M.B.)
| | - Erika T. Minetti
- Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (Y.T.); (B.F.); (E.T.M.); (B.S.H.C.); (M.M.B.)
| | - Brian S. H. Chong
- Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (Y.T.); (B.F.); (E.T.M.); (B.S.H.C.); (M.M.B.)
| | - Adam C. Gower
- Clinical and Translational Science Institute, Boston University School of Medicine, Boston, MA 02118, USA;
| | - Markus M. Bachschmid
- Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (Y.T.); (B.F.); (E.T.M.); (B.S.H.C.); (M.M.B.)
| | - Reiko Matsui
- Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; (Y.T.); (B.F.); (E.T.M.); (B.S.H.C.); (M.M.B.)
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17
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Kinoshita A, Hagiwara N, Osawa A, Akasu T, Matsumoto Y, Ueda K, Saeki C, Oikawa T, Koike K, Saruta M. Poor tolerability of lenvatinib in elderly patients ≥80 years old with hepatocellular carcinoma: A multicenter observational study. J Oncol Pharm Pract 2022; 29:626-636. [PMID: 35112972 DOI: 10.1177/10781552221077039] [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: 11/15/2022]
Abstract
INTRODUCTION Management of elderly patients with cancer has become a global issue. We investigated the safety and tolerability of lenvatinib in hepatocellular carcinoma (HCC) patients ≥80 years old. METHODS We retrospectively evaluated 61 HCC patients and divided them into 2 groups: an elderly group (n = 13, ≥80 years old) and a younger group (n = 48, <80 years old). We compared the adverse events (AEs), administration period, dose intensity, objective response, and progression-free survival (PFS) between the two groups. RESULTS The discontinuation of lenvatinib due to AEs was more frequent in the elderly group (8/13, 61.5%) than in the younger group (10/48, 20.8%) (P = 0.0043). Fatigue and appetite loss accounted for half of the cases discontinued due to AEs in the elderly group. The elderly group had a significantly lower 8-week-delivered dose intensity/body surface area ratio (147.2) and 8-week-relative dose intensity (50.0%) than those in the younger group (267.4, 67%) (P = 0.003, 0.029). The objective response rate was significantly lower in the elderly group (15.4%) than in the younger group (61.5%) (P = 0.021). The PFS in the elderly group tended to be shorter than that in the younger group (P = 0.058, hazard ratio [HR] 1.98). The modified albumin-bilirubin (mALBI) grade (hepatic function) (HR, 2.60; P = 0.01) and objective response (HR, 0.41; P = 0.011) were independently associated with the PFS in the multivariate analysis. CONCLUSION The management of AEs is crucial for adherence and maintaining the dose intensity of lenvatinib in elderly HCC patients.
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Affiliation(s)
- Akiyoshi Kinoshita
- Division of Gastroenterology and Hepatology, 38341the Jikei University Daisan Hospital, Komae, Tokyo, Japan
| | - Noriko Hagiwara
- Division of Gastroenterology and Hepatology, 38341the Jikei University Daisan Hospital, Komae, Tokyo, Japan
| | - Akiyuki Osawa
- Division of Gastroenterology and Hepatology, 38341the Jikei University Daisan Hospital, Komae, Tokyo, Japan
| | - Takafumi Akasu
- Division of Gastroenterology and Hepatology, 26799the Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Yoshihiro Matsumoto
- Division of Gastroenterology and Hepatology, 26799the Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Kaoru Ueda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Minato, Tokyo, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Minato, Tokyo, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Minato, Tokyo, Japan
| | - Kazuhiko Koike
- Division of Gastroenterology and Hepatology, 38341the Jikei University Daisan Hospital, Komae, Tokyo, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Minato, Tokyo, Japan
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18
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Maeso‐Díaz R, Dalton GD, Oh S, Du K, Tang L, Chen T, Dutta RK, Hartman JH, Meyer JN, Diehl A. Aging reduces liver resiliency by dysregulating Hedgehog signaling. Aging Cell 2022; 21:e13530. [PMID: 34984806 PMCID: PMC8844109 DOI: 10.1111/acel.13530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/02/2021] [Accepted: 11/28/2021] [Indexed: 11/30/2022] Open
Abstract
Older age is a major risk factor for damage to many tissues, including liver. Aging undermines resiliency and impairs liver regeneration. The mechanisms whereby aging reduces resiliency are poorly understood. Hedgehog is a signaling pathway with critical mitogenic and morphogenic functions during development. Recent studies indicate that Hedgehog regulates metabolic homeostasis in adult liver. The present study evaluates the hypothesis that Hedgehog signaling becomes dysregulated in hepatocytes during aging, resulting in decreased resiliency and therefore, impaired regeneration and enhanced vulnerability to damage. Partial hepatectomy (PH) was performed on young and old wild‐type mice and Smoothened (Smo)‐floxed mice treated with viral vectors to conditionally delete Smo and disrupt Hedgehog signaling specifically in hepatocytes. Changes in signaling were correlated with changes in regenerative responses and compared among groups. Old livers had fewer hepatocytes proliferating after PH. RNA sequencing identified Hedgehog as a top downregulated pathway in old hepatocytes before and after the regenerative challenge. Deleting Smo in young hepatocytes before PH prevented Hedgehog pathway activation after PH and inhibited regeneration. Gene Ontogeny analysis demonstrated that both old and Smo‐deleted young hepatocytes had activation of pathways involved in innate immune responses and suppression of several signaling pathways that control liver growth and metabolism. Hedgehog inhibition promoted telomere shortening and mitochondrial dysfunction in hepatocytes, consequences of aging that promote inflammation and impair tissue growth and metabolic homeostasis. Hedgehog signaling is dysregulated in old hepatocytes. This accelerates aging, resulting in decreased resiliency and therefore, impaired liver regeneration and enhanced vulnerability to damage.
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Affiliation(s)
- Raquel Maeso‐Díaz
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
| | - George D. Dalton
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
| | - Sehhoon Oh
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
| | - Kuo Du
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
| | - Linda Tang
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
| | - Tianyi Chen
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
| | - Rajesh K. Dutta
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
| | - Jessica H. Hartman
- Nicholas School of the Environment Duke University Durham North Carolina USA
| | - Joel N. Meyer
- Nicholas School of the Environment Duke University Durham North Carolina USA
| | - Anna Mae Diehl
- Division of Gastroenterology Department of Medicine Duke University Health System Durham North Carolina USA
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19
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Pal P, Palui R, Ray S. Heterogeneity of non-alcoholic fatty liver disease: Implications for clinical practice and research activity. World J Hepatol 2021; 13:1584-1610. [PMID: 34904031 PMCID: PMC8637673 DOI: 10.4254/wjh.v13.i11.1584] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/29/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity. There is also substantial inter-individual variation and variable response to a different therapy. This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history. Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease. Consequently, leading experts across the globe have recently suggested a change in nomenclature of NAFLD to metabolic-associated fatty liver disease (MAFLD) which can better reflect current knowledge of heterogeneity and does not exclude concomitant factors for fatty liver disease (e.g. alcohol, viral hepatitis, etc.). Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.
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Affiliation(s)
- Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
| | - Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Sayantan Ray
- Department of Endocrinology, Jagannath Gupta Institute of Medical Sciences and Hospital, Kolkata 700137, West Bengal, India
- Diabetes and Endocrinology, Apollo Clinic, Ballygunge, Kolkata 700019, West Bengal, India.
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20
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Kim JM, Rhu J, Ha SY, Choi GS, Kwon CHD, Kim G, Joh JW. Realization of improved outcomes following liver resection in hepatocellular carcinoma patients aged 75 years and older. Ann Surg Treat Res 2021; 101:257-265. [PMID: 34796141 PMCID: PMC8564081 DOI: 10.4174/astr.2021.101.5.257] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 09/01/2021] [Accepted: 09/24/2021] [Indexed: 01/27/2023] Open
Abstract
Purpose Little is known about liver resection (LR) in hepatocellular carcinoma (HCC) patients older than 75 years of age. This study aimed to compare the postoperative and long-term outcomes of hepatectomy in this patient population according to operation period. Methods This study included 130 elderly patients who underwent LR for solitary treatment-naïve HCC between November 1998 and March 2020. Group 1 included patients who underwent LR before 2016 (n = 68) and group 2 included those who underwent LR during or after 2016 (n = 62). Results The proportion of major LR, anatomical LR, and laparoscopic LR (LLR) in group 1 was significantly lower than those in group 2. Also, the median operation time, amount of blood loss, hospitalization length, rates of intraoperative blood transfusion, and complications in group 2 were less than those in group 1. In the subgroup analysis of group 1, high proteins induced by vitamin K absence or antagonist-II, long hospitalization, and LLR were closely associated with mortality. In the subgroup analysis of group 2, however, none of the factors increased mortality. Nevertheless, the presence of tumor grade 3 or 4 and the incidence of microvascular invasion were higher in group 1 than in group 2, and the disease-free survival and overall survival were better in group 2 than in group 1 because of minimized blood loss and quicker recovery period by increased surgical techniques and anatomical approach, and LLR. Conclusion LR in elderly HCC patients has been frequently performed recently, and the outcomes have improved significantly compared to the past.
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Affiliation(s)
- Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Choon Hyuck David Kwon
- Department of Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gaabsoo Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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21
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Subhani M, Sheth A, Ahmad B, Ryder S. How to interpret and manage abnormal liver blood test results in older people. Br J Hosp Med (Lond) 2021; 82:1-8. [PMID: 34431345 DOI: 10.12968/hmed.2021.0114] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ageing impairs liver function and reduces the liver's regenerative capacity. With the predicted increase in the older population, the burden of liver disease will proportionally rise in this age group. Elevated levels of liver enzymes in an otherwise asymptomatic older individual (≥65 years) are a common observation and positively associated with the metabolic syndrome, whereas a decline in albumin levels is linked with a rise in all-cause and liver-specific mortality. Deranged liver function tests do not always indicate liver disease, nor do normal liver function tests exclude liver disease. Therefore, clinicians need to consider individual patient risk factors during the assessment of abnormal liver function tests. This article discusses various liver function tests, their pathophysiology, and the approach to interpret and manage common abnormalities in liver function test results and liver disease in the older population.
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Affiliation(s)
- Mohsan Subhani
- Nottingham Digestive Diseases Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Abhishek Sheth
- Nottingham Digestive Diseases Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Bilal Ahmad
- Department of Gastroenterology, Wrexham Maelor Hospital, Wrexham, UK
| | - Stephen Ryder
- Nottingham Digestive Diseases Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK
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22
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Obesity and aging: Molecular mechanisms and therapeutic approaches. Ageing Res Rev 2021; 67:101268. [PMID: 33556548 DOI: 10.1016/j.arr.2021.101268] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 01/19/2021] [Accepted: 02/02/2021] [Indexed: 02/08/2023]
Abstract
The epidemic of obesity is a major challenge for health policymakers due to its far-reaching effects on population health and potentially overwhelming financial burden on healthcare systems. Obesity is associated with an increased risk of developing acute and chronic diseases, including hypertension, stroke, myocardial infarction, cardiovascular disease, diabetes, and cancer. Interestingly, the metabolic dysregulation associated with obesity is similar to that observed in normal aging, and substantial evidence suggests the potential of obesity to accelerate aging. Therefore, understanding the mechanism of fat tissue dysfunction in obesity could provide insights into the processes that contribute to the metabolic dysfunction associated with the aging process. Here, we review the molecular and cellular mechanisms underlying both obesity and aging, and how obesity and aging can predispose individuals to chronic health complications. The potential of lifestyle and pharmacological interventions to counter obesity and obesity-related pathologies, as well as aging, is also addressed.
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23
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Acun A, Oganesyan R, Uygun K, Yeh H, Yarmush ML, Uygun BE. Liver donor age affects hepatocyte function through age-dependent changes in decellularized liver matrix. Biomaterials 2021; 270:120689. [PMID: 33524812 DOI: 10.1016/j.biomaterials.2021.120689] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/19/2020] [Accepted: 01/18/2021] [Indexed: 02/08/2023]
Abstract
The only treatment available for end stage liver diseases is orthotopic liver transplantation. Although there is a big donor scarcity, many donor livers are discarded as they do not qualify for transplantation. Alternatively, decellularization of discarded livers can potentially render them transplantable upon recellularization and functional testing. The success of this approach will heavily depend on the quality of decellularized scaffolds which might show variability due to factors including age. Here we assessed the age-dependent differences in liver extracellular matrix (ECM) using rat and human livers. We show that the liver matrix has higher collagen and glycosaminoglycan content and a lower growth factor content with age. Importantly, these changes lead to deterioration in primary hepatocyte function potentially due to ECM stiffening and integrin-dependent signal transduction. Overall, we show that ECM changes with age and these changes significantly affect cell function thus donor age should be considered as an important factor for bioengineering liver substitutes.
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Affiliation(s)
- Aylin Acun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Ruben Oganesyan
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Korkut Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Heidi Yeh
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Martin L Yarmush
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Basak E Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
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24
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Moradi Kelardeh B, Rahmati-Ahmadabad S, Farzanegi P, Helalizadeh M, Azarbayjani MA. Effects of non-linear resistance training and curcumin supplementation on the liver biochemical markers levels and structure in older women with non-alcoholic fatty liver disease. J Bodyw Mov Ther 2020; 24:154-160. [PMID: 32825982 DOI: 10.1016/j.jbmt.2020.02.021] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 01/30/2020] [Accepted: 02/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND With increasing age, non-alcoholic fatty liver disease is very common among women with low levels of physical activity. Nonlinear resistance training is one of the new methods to help patients who have low levels of physical activity. Curcumin is an herbal supplement that has anti-inflammatory effects. The present study aimed to examine the effects of nonlinear resistance training and curcumin supplementation on the liver structure and biochemical markers in obese older women with non-alcoholic fatty liver disease. METHODS Forty-five obese women with non-alcoholic fatty liver disease were randomly assigned into resistance training (RT), curcumin supplement (C), resistance training with curcumin supplement (RTC), and placebo (P) groups. The RT and RTC groups received 12-weeks of nonlinear resistance training while the C and P groups had a normal sedentary lifestyle. Daily, the C and RTC groups received a curcumin capsule while the P and RT groups were given a placebo capsule. Blood sampling and ultrasonography were taken before and after the protocol. RESULTS Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels significantly decreased in the RT and RTC groups (P ≤ 0.05) but not in the C and P groups (P > 0.05). Alkaline phosphatase (ALP), total bilirubin (TB) levels, platelet counts (PLT), and liver structure did not significantly change in all groups (P > 0.05). Resistance training alone and with curcumin supplementation could significantly improve liver function while taking curcumin alone did not have any significant effect on it. CONCLUSION 12-week non-linear resistance training has beneficial effects on non-alcoholic fatty liver disease in older obese women.
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Affiliation(s)
- Baharak Moradi Kelardeh
- Phd Exercise Physiology, Sama Technical and Vocational Training College, Islamic Azad University, Esfahan (Khorasgan) Branch, Esfahan, Iran
| | | | - Parvin Farzanegi
- Department of Exercise Physiology, Sari Branch, Islamic Azad University, Sari, Iran
| | - Masoumeh Helalizadeh
- Department of Exercise Physiology, Sport Medicine Research Center, Sport Sciences Research Institute, Tehran, Iran
| | - Mohammad-Ali Azarbayjani
- Department of Exercise Physiology, Central Tehran Branch, Islamic Azad University, Tehran, Iran.
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25
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Saghir SA, Ansari RA, Dorato MA. Rethinking toxicity testing: Influence of aging on the outcome of long-term toxicity testing and possible remediation. Food Chem Toxicol 2020; 141:111327. [PMID: 32380075 DOI: 10.1016/j.fct.2020.111327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/27/2020] [Accepted: 04/06/2020] [Indexed: 10/24/2022]
Abstract
Traditionally, toxicity testing is conducted at fixed dose rates (i.e., mg/kg/day) without considering life-changing events, e.g., stress, sickness, aging- and/or pregnancy-related changes in physical, physiological and biochemical parameters. In humans, life-changing events may cause systemic dose non-proportionality requiring modulation of drug dosage; similar changes occur in animals altering systemic dose during chronic/carcinogenic testing leading to "late-occurring" effects in some studies. For example, propylene monomethyl ether, an industrial chemical, initially induced sedation in rats and mice with recovery upon induction of hepatic CYPs after ~1 week. Sedation reappeared in rats but not in mice after ~12 months of exposure due to decreased CYP activity in rats, elderly mice were able to maintain slightly higher CYP activity avoiding recurrence of sedation. The systemic dose of two pharmaceuticals (doxazosin and brimonidine tartrate) increased up to 6-fold in ≥12-month old rats with no toxicity. In a rat reproductive toxicity study, systemic dose of 2,4-D, an herbicide, rapidly increased due to increased consumption of 2,4-D-fortified diet during pregnancy, lactation and neonatal growth, requiring adjustment to maintain the targeted systemic dose. Ideally, toxicological studies should be based on systemic dose with the option of modulating external dose rates to maintain the targeted systemic dose. Systemic dose can easily be monitored in selected core study animals at desired intervals considering recent developments in sampling and analysis at a fraction of the overall cost of a study.
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Affiliation(s)
- Shakil Ahmed Saghir
- Scotts Miracle-Gro, 14111 Scottslawn Road, Marysville, OH, 43041, USA; Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan; ToxInternational, Inc., 5057 Stonecroft Ct., Hilliard, OH 43026, USA.
| | - Rais Ahmad Ansari
- Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200 S University Drive, Fort Lauderdale, FL, 33328, USA.
| | - Michael A Dorato
- Inotiv, 13 Firstfield Road, Suite 110, Gaithersburg, MD, 20878, USA.
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26
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Eslam M, Sanyal AJ, George J, Neuschwander-Tetri B, Tiribelli C, Kleiner DE, Brunt E, Bugianesi E, Yki-Järvinen H, Grønbæk H, Cortez-Pinto H, George J, Fan J, Valenti L, Abdelmalek M, Romero-Gomez M, Rinella M, Arrese M, Eslam M, Bedossa P, Newsome PN, Anstee QM, Jalan R, Bataller R, Loomba R, Sookoian S, Sarin SK, Harrison S, Kawaguchi T, Wong VWS, Ratziu V, Yilmaz Y, Younossi Z. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020; 158:1999-2014.e1. [PMID: 32044314 DOI: 10.1053/j.gastro.2019.11.312] [Citation(s) in RCA: 2095] [Impact Index Per Article: 419.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/27/2019] [Accepted: 11/05/2019] [Indexed: 12/02/2022]
Abstract
Fatty liver associated with metabolic dysfunction is common, affects a quarter of the population, and has no approved drug therapy. Although pharmacotherapies are in development, response rates appear modest. The heterogeneous pathogenesis of metabolic fatty liver diseases and inaccuracies in terminology and definitions necessitate a reappraisal of nomenclature to inform clinical trial design and drug development. A group of experts sought to integrate current understanding of patient heterogeneity captured under the acronym nonalcoholic fatty liver disease (NAFLD) and provide suggestions on terminology that more accurately reflects pathogenesis and can help in patient stratification for management. Experts reached consensus that NAFLD does not reflect current knowledge, and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term. This opens the door for efforts from the research community to update the nomenclature and subphenotype the disease to accelerate the translational path to new treatments.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
| | - Arun J Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, Virginia.
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
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27
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Abou-Hashem RM, Shaat MM, Hamza SA, Mahmoud NH, Ali SM. The Relationship between Trace Elements and Depression among Older Patients with Chronic Liver Disease. ELECTRONIC JOURNAL OF GENERAL MEDICINE 2020. [DOI: 10.29333/ejgm/7887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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28
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Jadeja RN, Jones MA, Fromal O, Powell FL, Khurana S, Singh N, Martin PM. Loss of GPR109A/HCAR2 induces aging-associated hepatic steatosis. Aging (Albany NY) 2020; 11:386-400. [PMID: 30659164 PMCID: PMC6366969 DOI: 10.18632/aging.101743] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 12/20/2018] [Indexed: 12/31/2022]
Abstract
GPR109A agonists have been used for the treatment of obesity however, the role of GPR109A in regulating aging-associated alterations in lipid metabolism is unknown. In this study we used Gpr109a-/- mice to investigate the effect of aging in the regulation of lipid accumulation. We observed that in mouse and human livers, in addition to Kupffer cells, GPR109A is expressed in hepatocytes. Over 12 months, compared to wild type (WT), Gpr109a-/- mice gained significantly more weight. Food intake and levels of serum lipids were similar among both groups. Compared to age-matched WT mice, 12-months old Gpr109a-/- mice had significantly increased liver weight, hepatic steatosis and serum markers of liver injury. The fatty liver phenotype in Gpr109a-/- mice was associated with increased hepatic expression of lipogenesis genes and decreased expression of lipolysis genes. Gpr109a-/- mice had significantly increased fat tissues, which was associated with significant increase in adipocyte diameter and surface area. Adipose tissue from Gpr109a-/- mice had increased expression of lipogenesis genes; however, expression of lipolytic genes was similar in both groups. Collectively, these results indicate that during aging, GPR109A modulates de novo lipid accumulation in liver and adipose tissue, and its dysregulation can lead to age-associated obesity and hepatic steatosis.
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Affiliation(s)
- Ravirajsinh N Jadeja
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.,James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Malita A Jones
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Ollya Fromal
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Folami L Powell
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.,James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.,Education Innovation Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Sandeep Khurana
- Division of Gastroenterology, Hepatology and Nutrition and Weight Management, Geisinger Medical Center, Danville, PA 17822, USA
| | - Nagendra Singh
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.,Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Pamela M Martin
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.,James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.,Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.,Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
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29
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Pinto C, Ninfole E, Benedetti A, Maroni L, Marzioni M. Aging-Related Molecular Pathways in Chronic Cholestatic Conditions. Front Med (Lausanne) 2020; 6:332. [PMID: 32039217 PMCID: PMC6985088 DOI: 10.3389/fmed.2019.00332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022] Open
Abstract
Aging is commonly defined as the time-dependent functional decline of organs and tissues. Average life expectancy has increased considerably over the past century and is estimated to increase even further, consequently also the interest in understanding the aging processes. Although aging is not a disease, it is the major risk factor for the development of many chronic diseases. Pathologies, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) are cholestatic liver diseases characterized by chronic inflammation, biliary damage and ultimately liver fibrosis, targeting specifically cholangiocytes. To date, the influence of aging in these biliary diseases is not fully understood. Currently, liver transplantation is the only solution because of lacking in efficiently therapies. Although liver cells have a high regenerative capacity, they undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, the cells initially activate protective compensatory processes that, if hyperstimulated, can lead to the decline of regenerative ability and the development of pathologies. Recent studies have introduced novel therapeutic tools for cholangiopathies that have showed to have promising potential as novel therapies for PSC and PBC and for the development of new drugs. The recent advancements in understanding of molecular aging have undoubtedly the potential to unveil new pathways for selective drug treatments, but further studies are needed to deepen their knowledge.
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Affiliation(s)
- Claudio Pinto
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Elisabetta Ninfole
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Antonio Benedetti
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Luca Maroni
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Marco Marzioni
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
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30
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Hung MC, Chen CF, Tsou MT, Lin HH, Hwang LC, Hsu CP. Relationship Between Gallstone Disease and Cardiometabolic Risk Factors in Elderly People with Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes 2020; 13:3579-3585. [PMID: 33116709 PMCID: PMC7553650 DOI: 10.2147/dmso.s266947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The prevalence of gallstone disease (GSD) increases with age, and the elderly have a much higher mortality risk and incidence of surgical comorbidities. The aim of this study was to explore the relationship between GSD and cardiometabolic risk factors in elderly people with non-alcoholic fatty liver disease (NAFLD). METHODS In this cross-sectional study, we analyzed the data of elderly people who underwent annual health check-ups at a Northern Taiwan health examination center. These data were collected from physical examination, blood tests, abdominal ultrasonography, and medical histories. We excluded those with hepatitis B or C infections, heavy alcohol consumption, or cholecystectomy. RESULTS The analysis included 3,037 participants with a mean age of 73.6±6.0 years. Over 70% were overweight or obese, and the overall prevalence of GSD was 17.7%. In our univariate analysis, GSD was positively correlated with age, body mass index, metabolic syndrome, diabetes mellitus (DM), hypertension (HTN), and various metabolic factors (fasting plasma glucose [FPG], triglyceride, uric acid, and high-density lipoprotein cholesterol [HDL-C] levels). After adjustment for age, gender, and body mass index, metabolic syndrome showed a positive association with GSD (odds ratio [OR] 1.31 [95% confidence interval [CI], 1.05-1.64]; P=0.020). Specific components of metabolic syndrome that increased the risk for GSD in NAFLD elderly include lower levels of HDL-C (OR 1.35 [95% CI, 1.10-1.66]; P<0.001) and elevated FPG (OR 1.36 [95% CI, 1.10-1.69]; P<0.001). CONCLUSION Our study concluded that GSD is significantly associated with metabolic syndrome in elderly people with NAFLD. Reduced HDL-C and elevated FPG both heighten the risk of developing GSD. Therefore, to lower the risk of GSD in NAFLD patients, their FPG levels and HDL-C levels must be regularly followed-up, and these patients should be educated about the symptoms of GSD if they meet the criteria for metabolic syndrome.
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Affiliation(s)
- Man-Chen Hung
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Chuen-Fei Chen
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Meng-Ting Tsou
- Department of Family Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Hsin-Hui Lin
- Department of Family Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Lee-Ching Hwang
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
- Department of Family Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Ching-Ping Hsu
- Department of Family Medicine, Mackay Memorial Hospital, Taipei, Taiwan
- Correspondence: Ching-Ping Hsu Department of Family Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Road, Zhongshan District, Taipei City104, TaiwanTel +886-2-25433535Fax +886-2-25213847 Email
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31
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Carrier P, Debette-Gratien M, Jacques J, Loustaud-Ratti V. Cirrhotic patients and older people. World J Hepatol 2019; 11:663-677. [PMID: 31598192 PMCID: PMC6783402 DOI: 10.4254/wjh.v11.i9.663] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/18/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
The global population is aging, and so the number of older cirrhotic patients is increasing. Older patients are characterised by a risk of frailty and comorbidities, and age is a risk factor for mortality in cirrhotic patients. The incidence of non-alcoholic fatty liver disease as an aetiology of cirrhosis is increasing, while that of chronic viral hepatitis is decreasing. Also, cirrhosis is frequently idiopathic. The management of portal hypertension in older cirrhotic patients is similar to that in younger patients, despite the greater risk of treatment-related adverse events of the former. The prevalence of hepatocellular carcinoma increases with age, but its treatment is unaffected. Liver transplantation is generally recommended for patients < 70 years of age. Despite the increasing prevalence of cirrhosis in older people, little data are available and few recommendations have been proposed. This review suggests that comorbidities have a considerable impact on older cirrhotic patients.
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Affiliation(s)
- Paul Carrier
- Fédération d’Hépatologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
- Faculté de Médecine et de Pharmacie de Limoges, Rue Docteur Marcland, Limoges 87042, France
| | - Marilyne Debette-Gratien
- Fédération d’Hépatologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
- Faculté de Médecine et de Pharmacie de Limoges, Rue Docteur Marcland, Limoges 87042, France
| | - Jérémie Jacques
- Service de Gastroentérologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
| | - Véronique Loustaud-Ratti
- Fédération d’Hépatologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
- Faculté de Médecine et de Pharmacie de Limoges, Rue Docteur Marcland, Limoges 87042, France.
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Yoon JH, Kim SM, Kang G, Kim HJ, Jun CH, Choi SK. A case report of glecaprevir/pibrentasvir-induced severe hyperbilirubinemia in a patient with compensated liver cirrhosis. Medicine (Baltimore) 2019; 98:e17343. [PMID: 31574875 PMCID: PMC6775421 DOI: 10.1097/md.0000000000017343] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
RATIONALE Glecaprevir/pibrentasvir, a pan-genotypic and ribavirin-free direct acting antiviral agent regimen, has shown significant efficacy and very few serious complications. However, as the drug metabolizes in the liver, it is not recommended in patients with decompensated liver cirrhosis. Herein, we report the case of a patient with compensated liver cirrhosis who developed severe jaundice after glecaprevir/pibrentasvir medication. PATIENT CONCERNS A 77-year-old man diagnosed with chronic hepatitis C-related compensated liver cirrhosis visited hospital due to severe jaundice after 12 weeks of glecaprevir/pibrentasvir medication. DIAGNOSES On the laboratory work-up, the total/direct bilirubin level was markedly elevated to 21.56/11.68 from 1.81 mg/dL; the alanine aminotransferase and aspartate aminotransferase levels were within the normal range. We checked the plasma drug concentration level of glecaprevir, and 18,500 ng/mL was detected, which was more than 15 times higher than the drug concentration level verified in normal healthy adults. INTERVENTIONS Glecaprevir/pibrentasvir was abruptly stopped and after 6 days, the drug concentration level decreased to 35 ng/mL and the serum total/direct bilirubin decreased to 7.49/4.06 mg/dL. OUTCOMES Three months after drug cessation, the serum total bilirubin level normalized to 1.21 mg/dL and HCV RNA was not detected. LESSONS We report what is likely the first known case of severe jaundice after medication with glecaprevir/pibrentasvir in a patient with compensated liver cirrhosis. Clinicians should bear potential hyperbilirubinemia in mind when treating chronic hepatitis C with this regimen and should monitor the patient closely during follow-up laboratory exams, especially in elderly cirrhotic patients.
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Affiliation(s)
| | - Sun Min Kim
- Department of Gastroenterology and Hepatology
| | | | - Hee Joon Kim
- Department of Surgery, Chonnam National University Hospital and School of Medicine, Gwangju, South Korea
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Luo D, Li J, Chen K, Yin Y, Fang Z, Pang H, Rong X, Guo J. Study on Metabolic Trajectory of Liver Aging and the Effect of Fufang Zhenzhu Tiaozhi on Aging Mice. Front Pharmacol 2019; 10:926. [PMID: 31555127 PMCID: PMC6722462 DOI: 10.3389/fphar.2019.00926] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 07/22/2019] [Indexed: 01/22/2023] Open
Abstract
The aim of this study was to investigate the metabolic trajectory of liver aging, the effect of FTZ against liver aging in aging mice, and its mechanism using ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Methods: A total of 80 C57BL/6J Narl mice were randomly divided into five groups: 3-month-old group, 9-month-old group, 14-month-old group, 20-month-old group, and FTZ treatment group (20 months old). The mice in the treatment group received a therapeutic dose of oral FTZ extract (1.0 g/kg, on raw material weight basis) once daily during the experiment. The other groups received the corresponding volume of oral normal saline solution. Liver samples of all five groups were collected after 12 weeks, and UPLC-Q-TOF/MS was used to analyze metabolic changes. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to analyze the resulting data. Additionally, cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), secretion levels of TNF-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver were determined. Results: The levels of TC, TG, AST, and ALT were increased, and liver tissue structure was damaged. The secretion levels of TNF-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver also increased with aging. FTZ administration reduced the symptoms of liver aging. The OPLS-DA score plot illustrated the effect of FTZ against liver aging, with N-acetyl-leukotriene E4, 20-hydroxy-leukotriene E4, leukotriene E4, and arachidonic acid among the key biomarkers. The pivotal pathways revealed by pathway analysis included arachidonic acid metabolism and biosynthesis of unsaturated fatty acids. The mechanism by which FTZ reduces the symptoms of liver aging in mice might be related to disorders of the abovementioned pathways. Conclusion: A metabolomic approach based on UPLC-Q-TOF/MS and multivariate statistical analysis was successfully applied to investigate the metabolic trajectory of liver aging. FTZ has a protective effect against liver aging, which may be mediated via interference with the metabolism of arachidonic acid, biosynthesis of unsaturated fatty acids, and downregulation of pro-inflammatory factors in the liver in mice in vivo.
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Affiliation(s)
- Duosheng Luo
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
| | - Jingbiao Li
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
| | - Kechun Chen
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
| | - Yifan Yin
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
| | - Zhaoyan Fang
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
| | - Huiting Pang
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
| | - Xianglu Rong
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
| | - Jiao Guo
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China
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Han X, Bao X, Lou Q, Xie X, Zhang M, Zhou S, Guo H, Jiang G, Shi Q. Nicotinamide riboside exerts protective effect against aging-induced NAFLD-like hepatic dysfunction in mice. PeerJ 2019; 7:e7568. [PMID: 31523515 PMCID: PMC6717504 DOI: 10.7717/peerj.7568] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 07/29/2019] [Indexed: 12/31/2022] Open
Abstract
Background & Aims Aging is one of the risk factors of non-alcoholic fatty liver disease (NAFLD). Yet, the mechanism underlying the aging-associated NAFLD-like syndrome is not fully understood. Nicotinamide adenine dinucleotide (NAD), a ubiquitous coenzyme, has protective effects against aging. Here, we investigated the actions of NAD precursors nicotinamide riboside (NR) on the development of aging-induced NAFLD. Methods NR supplemented food (2.5 g/kg food) was applied to aged mice for three months while normal chow to the other groups. Body weight, food intake, liver weight and fat pat mass were measured. The serum concentrations of lipid content, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and NAD were determined by biochemical assays. Pathological assessment and immunohistochemistry analysis of hepatic tissues were used to evaluate the effect of NR on NAFLD development and inflammatory infiltration. Results NR repletion significantly reduced fat pat mass in aged mice, while not altered the body weight, food intake, and liver weight. NR repletion significantly rescued the NAD reduction in aged mice. The total cholesterol and triglyceride levels could be lowered by NR repletion in aged mice. The AST level was also significantly reduced by NR repletion in aged group, while the ALT level lowered but without significance. Notably, moderate NAFLD phenotypes, including steatosis and hepatic fibrosis could be markedly corrected by NR repletion. In addition, Kupffer cells accumulated and inflammatory infiltration could also be remarkably reversed by NR repletion in aged mice. Conclusion Aging was associated with NAFLD-like phenotypes in mice, which could be reversed by oral NR repletion. Therefore, oral NR uptake might be a promising strategy to halt the progression of NAFLD.
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Affiliation(s)
- Xue Han
- Laboratory Animal Center, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province, China
| | - Xiaogang Bao
- Department of Orthopedic Surgery, Spine Center, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qi Lou
- Laboratory Animal Center, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province, China
| | - Xian Xie
- Hospital of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Meng Zhang
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Shasang Zhou
- Laboratory Animal Center, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province, China
| | - Honggang Guo
- Laboratory Animal Center, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province, China
| | - Guojun Jiang
- Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang Province, China
| | - Qiaojuan Shi
- Laboratory Animal Center, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province, China
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35
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Maeso-Díaz R, Ortega-Ribera M, Lafoz E, Lozano JJ, Baiges A, Francés R, Albillos A, Peralta C, García-Pagán JC, Bosch J, Cogger VC, Gracia-Sancho J. Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease. Aging Dis 2019; 10:684-698. [PMID: 31440376 PMCID: PMC6675529 DOI: 10.14336/ad.2019.0127] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 01/27/2019] [Indexed: 12/26/2022] Open
Abstract
Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for 15 days. Hepatic and systemic hemodynamic, liver cells phenotype and hepatic fibrosis were evaluated. Additionally, the gene expression signature of cirrhosis was evaluated in a cohort of young and aged cirrhotic patients. Aged animals developed a more severe form of aCLD. Portal hypertension and liver fibrosis were exacerbated as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell-death and poorer function, LSEC were further capillarized, HSC over-activated and macrophage infiltration was significantly increased. The gene expression signature of cirrhosis significantly differed comparing young and aged patients, indicating alterations in sinusoidal-protective pathways and confirming the pre-clinical observations. Simvastatin administration for 15-day to aged cirrhotic rats improved the hepatic sinusoidal milieu, leading to significant amelioration in portal hypertension. This study provides evidence that aCLD pathobiology is different in aged individuals. As the median age of patients with aCLD is increasing, we propose a real-life pre-clinical model to develop more reliable therapeutic strategies. Simvastatin effects in this model further demonstrate its translational potential.
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Affiliation(s)
- Raquel Maeso-Díaz
- 1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
| | - Martí Ortega-Ribera
- 1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
| | - Erica Lafoz
- 1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
| | - Juan José Lozano
- 2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Anna Baiges
- 1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain.,2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Rubén Francés
- 2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain.,3Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL -Fundación FISABIO), Alicante, Spain
| | - Agustín Albillos
- 2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain.,4 Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain
| | - Carmen Peralta
- 2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain.,5Protective Strategies Against Hepatic Ischemia-Reperfusion Group, IDIBAPS, Barcelona, Spain
| | - Juan Carlos García-Pagán
- 1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain.,2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Jaime Bosch
- 1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain.,2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain.,6Hepatology, Department of Biomedical Research, Inselspital, Bern University, Switzerland
| | - Victoria C Cogger
- 7Centre for Education and Research on Ageing & ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia
| | - Jordi Gracia-Sancho
- 1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain.,2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain.,6Hepatology, Department of Biomedical Research, Inselspital, Bern University, Switzerland
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36
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Yang J, Fernández-Galilea M, Martínez-Fernández L, González-Muniesa P, Pérez-Chávez A, Martínez JA, Moreno-Aliaga MJ. Oxidative Stress and Non-Alcoholic Fatty Liver Disease: Effects of Omega-3 Fatty Acid Supplementation. Nutrients 2019; 11:E872. [PMID: 31003450 PMCID: PMC6521137 DOI: 10.3390/nu11040872] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/12/2019] [Accepted: 04/15/2019] [Indexed: 02/06/2023] Open
Abstract
Aging is a complex phenomenon characterized by the progressive loss of tissue and organ function. The oxidative-stress theory of aging postulates that age-associated functional losses are due to the accumulation of ROS-induced damage. Liver function impairment and non-alcoholic fatty liver disease (NAFLD) are common among the elderly. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and evolve to hepatic cirrhosis or hepatic carcinoma. Oxidative stress, lipotoxicity, and inflammation play a key role in the progression of NAFLD. A growing body of evidence supports the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFA), mainly docosahaexenoic (DHA) and eicosapentaenoic acid (EPA), on metabolic diseases based on their antioxidant and anti-inflammatory properties. Here, we performed a systematic review of clinical trials analyzing the efficacy of n-3 PUFA on both systemic oxidative stress and on NAFLD/NASH features in adults. As a matter of fact, it remains controversial whether n-3 PUFA are effective to counteract oxidative stress. On the other hand, data suggest that n-3 PUFA supplementation may be effective in the early stages of NAFLD, but not in patients with more severe NAFLD or NASH. Future perspectives and relevant aspects that should be considered when planning new randomized controlled trials are also discussed.
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Affiliation(s)
- Jinchunzi Yang
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
| | - Marta Fernández-Galilea
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
| | - Leyre Martínez-Fernández
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
| | - Pedro González-Muniesa
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, 28029 Madrid, Spain.
| | - Adriana Pérez-Chávez
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
| | - J Alfredo Martínez
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, 28029 Madrid, Spain.
| | - Maria J Moreno-Aliaga
- Centre for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain.
- IDISNA, Navarra's Health Research Institute, 31008 Pamplona, Spain.
- CIBERobn Physiopathology of Obesity and Nutrition, Centre of Biomedical Research Network, ISCIII, 28029 Madrid, Spain.
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37
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Liu R, Ahluwalia V, Kang JD, Ghosh SS, Zhou H, Li Y, Zhao D, Gurley E, Li X, White MB, Fagan A, Lippman HR, Wade JB, Hylemon PB, Bajaj JS. Effect of Increasing Age on Brain Dysfunction in Cirrhosis. Hepatol Commun 2019; 3:63-73. [PMID: 30619995 PMCID: PMC6312655 DOI: 10.1002/hep4.1286] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/24/2018] [Indexed: 12/28/2022] Open
Abstract
Patients with cirrhosis are growing older, which could have an impact on brain dysfunction beyond hepatic encephalopathy. Our aim was to study the effect of concomitant aging and cirrhosis on brain inflammation and degeneration using human and animal experiments. For the human study, age-matched patients with cirrhosis and controls between 65 and 85 years underwent cognitive testing, quality of life (QOL) assessment, and brain magnetic resonance (MR) spectroscopy and resting state functional MR imaging (rs-fMRI) analysis. Data were compared between groups. For the animal study, young (10-12 weeks) and old (1.5 years) C57BL/6 mice were given either CCl4 gavage to develop cirrhosis or a vehicle control and were followed for 12 weeks. Cortical messenger RNA (mRNA) expression of inflammatory mediators (interleukin [IL]-6, IL-1β, transforming growth factor β [TGF-β], and monocyte chemoattractant protein 1), sirtuin-1, and gamma-aminobutyric acid (GABA)-ergic synaptic plasticity (neuroligin-2 [NLG2], discs large homolog 4 [DLG4], GABA receptor, subunit gamma 1/subunit B1 [GABRG1/B1]) were analyzed and compared between younger/older control and cirrhotic mice. The human study included 46 subjects (23/group). Patients with cirrhosis had worse QOL and cognition. On MR spectroscopy, patients with cirrhosis had worse changes related to ammonia and lower N-acetyl aspartate, whereas rs-fMRI analysis revealed that these patients demonstrated functional connectivity changes in the frontoparietal cortical region compared to controls. Results of the animal study showed that older mice required lower CCl4 to reach cirrhosis. Older mice, especially with cirrhosis, demonstrated higher cortical inflammatory mRNA expression of IL-6, IL-1β, and TGF-β; higher glial and microglial activation; and lower sirtuin-1 expression compared to younger mice. Older mice also had lower expression of DLG4, an excitatory synaptic organizer, and higher NLG2 and GABRG1/B1 receptor expression, indicating a predominantly inhibitory synaptic organization. Conclusion: Aging modulates brain changes in cirrhosis; this can affect QOL, cognition, and brain connectivity. Cortical inflammation, microglial activation, and altered GABA-ergic synaptic plasticity could be contributory.
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Affiliation(s)
- Runping Liu
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Vishwadeep Ahluwalia
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Jason D. Kang
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Siddhartha S. Ghosh
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
- Division of NephrologyVirginia Commonwealth UniversityRichmondVA
| | - Huiping Zhou
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Yunzhou Li
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Derrick Zhao
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Emily Gurley
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Xiaojiaoyang Li
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Melanie B. White
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - H. Robert Lippman
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
- PathologyVirginia Commonwealth UniversityRichmondVA
| | - James B. Wade
- PsychiatryVirginia Commonwealth UniversityRichmondVA
| | - Phillip B. Hylemon
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
- Hunter Holmes McGuire Veterans Administration Medical CenterVirginia Commonwealth UniversityRichmondVA
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Cascales-Campos PA, Ramírez P, González-Sánchez MR, Alconchel F, Martínez-Insfran LA, Sánchez-Bueno F, Robles R, Pons JA, Vargas Á, Sanmartín J, Royo-Villanova M, Parrilla P. Orthotopic Liver Transplantation With Elderly Donors (Over 80 Years of Age): A Prospective Evaluation. Transplant Proc 2018; 50:3594-3600. [PMID: 30577243 DOI: 10.1016/j.transproceed.2018.08.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/19/2018] [Accepted: 08/03/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Our main objective was to assess the clinical outcomes obtained in a single orthotopic liver transplant (OLT) hospital with donors ≥80 years of age compared to a control group of patients subjected to OLT during the same period of time with donors who were under 65 years of age. METHODS A prospective analysis was carried out on all the OLTs performed using liver grafts from donors in a state of brain death and with an age of ≥80 years (study group) between April 2007 and January 2015. The results of the study group (n = 36) were compared with those of a control group of patients less than 65 years of age receiving transplants with grafts. RESULTS A total of 51 potential donors ≥80 years were assessed, with a total of 36 liver transplants being carried out and their results were compared with a control group of 283 patients receiving transplants. The median follow-up time of the patients in the series was 36 months (range: 24-120 months). Graft survival at 1, 2, and 3 years was 77%, 72%, and 62%, respectively, among the patients in the study group and 79%, 73%, and 65% among the patients in the control group, and there were no statistically significant differences. Patient survival at 1, 2, and 3 years was 86%, 82%, and 75%, respectively, among the patients in the study group and 82%, 76%, and 72% among the patients in the control group, also without there being any statistically significant differences. CONCLUSIONS There is no age limit for liver transplant donors. The use of octogenarian donors makes it possible to increase the pool of donors while providing enough safety for the recipient.
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Affiliation(s)
- P A Cascales-Campos
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - P Ramírez
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - M R González-Sánchez
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - F Alconchel
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain.
| | - L A Martínez-Insfran
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - F Sánchez-Bueno
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - R Robles
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - J A Pons
- Department of Hepatology, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - Á Vargas
- Department of Hepatology, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - J Sanmartín
- Intensive Care Department, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - M Royo-Villanova
- Intensive Care Department, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
| | - P Parrilla
- Liver Transplantation Unit, Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB Arrixaca, Murcia, Spain
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de Castro TG, Manickavasagan H, Muñoz SJ. Liver Disease in the Elderly. HANDBOOK OF LIVER DISEASE 2018:351-361. [DOI: 10.1016/b978-0-323-47874-8.00026-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Kim HM, Lee YH, Han K, Lee BW, Kang ES, Kim J, Cha BS. Impact of diabetes mellitus and chronic liver disease on the incidence of dementia and all-cause mortality among patients with dementia. Medicine (Baltimore) 2017; 96:e8753. [PMID: 29381970 PMCID: PMC5708969 DOI: 10.1097/md.0000000000008753] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
This study investigated the effects of the presence of type 2 diabetes mellitus (T2D) and/or chronic liver disease (CLD) on the incidence and prognosis of dementia during a 10-year period in Korea using a nationwide population-based dataset from the Korea National Health Insurance Service.To assess the impact of T2D and CLD on the incidence of dementia, we included subjects aged ≥60 years without dementia, T2D, and CLD from 2003 to 2005. We created another cohort for evaluating the all-cause mortality in subjects with dementia between 2003 and 2005. The participants were categorized into 4 groups: control (neither CLD nor T2D), CLD-only, T2D-only, and T2D-and-CLD groups, and they were followed up until 2013.The incidence of dementia was higher in the T2D-only group than in the control and CLD-only groups (2.78 vs. 2.04 and 2.00 per 1000 person-years). After adjustment for age, gender, and comorbid conditions, both T2D and CLD increased the risk of any type of dementia; however, the impact of CLD alone was much lower [hazard ratio (HR) 1.07, 95% confidence interval (CI): 1.06-1.08] than that of T2D alone (HR 1.27, 95% CI: 1.27-1.28). The risk of dementia did not significantly change in patients with the co-occurrence of T2D and CLD compared to those with T2D alone. The all-cause mortality rate was the lowest in the control group (2.59 per 1000 person-years) and the highest in the T2D-and-CLD group (3.77 per 1000 person-years). Presence of T2D or CLD alone was associated with higher mortality (HR 1.46 and HR 1.21, respectively) compared with in the absence of both the diseases. Furthermore, the presence of both the diseases further significantly increased the mortality rate compared to the presence of each disease alone (HR 1.67, 95% CI: 1.65-1.69).In conclusion, this study found that the incidence of dementia was much higher in patients with T2D. CLD was associated with a modest increase in risk of dementia; however, there was no additive effect with T2D. In the population with dementia, however, the presence of CLD was associated with high mortality in patients with or without T2D.
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Affiliation(s)
- Hyun Min Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine
| | - Yong-ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Kyungdo Han
- Department of Biostatistics, Catholic University of Korea, Seoul, Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Jaetaek Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine
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Gene pathways associated with mitochondrial function, oxidative stress and telomere length are differentially expressed in the liver of rats fed lifelong on virgin olive, sunflower or fish oils. J Nutr Biochem 2017; 52:36-44. [PMID: 29144994 DOI: 10.1016/j.jnutbio.2017.09.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 08/08/2017] [Accepted: 09/05/2017] [Indexed: 12/20/2022]
Abstract
This study investigates the effect of lifelong intake of different fat sources rich in monounsaturated (virgin olive oil), n6 polyunsaturated (sunflower oil) or n3 polyunsaturated (fish oil) fatty acids in the aged liver. Male Wistar rats fed lifelong on diets differing in the fat source were killed at 6 and at 24 months of age. Liver histopathology, mitochondrial ultrastructure, biogenesis, oxidative stress, mitochondrial electron transport chain, relative telomere length and gene expression profiles were studied. Aging led to lipid accumulation in the liver. Virgin olive oil led to the lowest oxidation and ultrastructural alterations. Sunflower oil induced fibrosis, ultrastructural alterations and high oxidation. Fish oil intensified oxidation associated with age, lowered electron transport chain activity and enhanced the relative telomere length. Gene expression changes associated with age in animals fed virgin olive oil and fish oil were related mostly to mitochondrial function and oxidative stress pathways, followed by cell cycle and telomere length control. Sunflower oil avoided gene expression changes related to age. According to the results, virgin olive oil might be considered the dietary fat source that best preserves the liver during the aging process.
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42
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Jiao L, Gan-Schreier H, Zhu X, Wei W, Tuma-Kellner S, Liebisch G, Stremmel W, Chamulitrat W. Ageing sensitized by iPLA 2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:1520-1533. [PMID: 28888832 DOI: 10.1016/j.bbalip.2017.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 08/28/2017] [Accepted: 09/05/2017] [Indexed: 01/06/2023]
Abstract
Ageing is a major risk factor for various forms of liver and gastrointestinal (GI) disease and genetic background may contribute to the pathogenesis of these diseases. Group VIA phospholipase A2 or iPLA2β is a homeostatic PLA2 by playing a role in phospholipid metabolism and remodeling. Global iPLA2β-/- mice exhibit aged-dependent phenotypes with body weight loss and abnormalities in the bone and brain. We have previously reported the abnormalities in these mutant mice showing susceptibility for chemical-induced liver injury and colitis. We hypothesize that iPLA2β deficiency may sensitize with ageing for an induction of GI injury. Male wild-type and iPLA2β-/- mice at 4 and 20-22months of age were studied. Aged, but not young, iPLA2β-/-mice showed increased hepatic fibrosis and biliary ductular expansion as well as severe intestinal atrophy associated with increased apoptosis, pro-inflammation, disrupted tight junction, and reduced number of mucin-containing globlet cells. This damage was associated with decreased expression of intestinal endoplasmic stress XBP1 and its regulator HNF1α, FATP4, ACSL5, bile-acid transport genes as well as nuclear receptors LXRα and FXR. By LC/MS-MS profiling, iPLA2β deficiency in aged mice caused an increase of intestinal arachidonate-containing phospholipids concomitant with a decrease in ceramides. By the suppression of intestinal FXR/FGF-15 signaling, hepatic bile-acid synthesis gene expression was increased leading to an elevation of secondary and hydrophobic bile acids in liver, bile, and intestine. In conclusions, ageing sensitized by iPLA2β deficiency caused a decline of key intestinal homeostatic genes resulting in the development of GI disease in a gut-to-liver manner.
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Affiliation(s)
- Li Jiao
- Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany; Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan 650118, China
| | - Hongying Gan-Schreier
- Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany
| | - Xingya Zhu
- Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany
| | - Wang Wei
- Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany
| | - Sabine Tuma-Kellner
- Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany.
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Sharma M, Ahmed A, Wong RJ. Significantly Higher Mortality Following Liver Transplantation Among Patients Aged 70 Years and Older. Prog Transplant 2017; 27:225-231. [DOI: 10.1177/1526924817715468] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: The age of liver transplantation recipients in the United States is steadily increasing. However, the impact of age on liver transplant outcomes has demonstrated contradictory results. Research Questions: We aim to evaluate the impact of age on survival following liver transplantation among US adults. Design: Using data from the United Network for Organ Sharing registry, we retrospectively evaluated all adults undergoing liver transplantation from 2002 to 2012 stratified by age (aged 70 years and older vs aged <70 years), presence of hepatocellular carcinoma, and hepatitis C virus status. Overall survival was evaluated with Kaplan-Meier methods and multivariate Cox proportional hazards models. Results: Compared to patients aged <70 years, those aged 70 years and older had significantly lower 5-year survival following transplantation among all groups analyzed (hepatocellular carcinoma: 59.9% vs 68.6%, P < .01; nonhepatocellular carcinoma: 61.2% vs 74.2%, P < .001; hepatitis C: 60.7% vs 69.0%, P < .01; nonhepatitis C: 62.6% vs 78.5%, P < .001). On multivariate regression, patients aged 70 years and older at time of transplantation was associated with significantly higher mortality compared to those aged <70 years (hazards ratio: 1.67; 95% confidence interval: 1.48-1.87; P < .001). Conclusion: The age at the time of liver transplantation has continued to increase in the United States. However, patients aged 70 years and older had significantly higher mortality following liver transplantation. These observations are especially important given the aging cohort of patients with chronic liver disease in the United States.
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Affiliation(s)
- Mokshya Sharma
- Division of Gastroenterology and Hepatology, Alameda Health System, Highland Hospital, Oakland, CA, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Robert J. Wong
- Division of Gastroenterology and Hepatology, Alameda Health System, Highland Hospital, Oakland, CA, USA
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Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J Hepatol 2017; 66:601-609. [PMID: 27871879 PMCID: PMC5316497 DOI: 10.1016/j.jhep.2016.11.004] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 10/14/2016] [Accepted: 11/08/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. The aim of this study was to use a chronic plus binge ethanol feeding model in mice to evaluate the effects of aging on alcohol-induced liver injury. METHODS C57BL/6 mice were subjected to short-term (10days) ethanol plus one binge or long-term (8weeks) ethanol plus multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. RESULTS Middle-aged (12-14months) and old-aged (>16months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term plus one binge or long-term plus multiple binges of ethanol feeding when compared to young (8-12weeks) mice. Long-term plus multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term plus binge ethanol-induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-α and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to long-term chronic-plus-multiple binges of ethanol-induced liver fibrosis with upregulation of PDGFR-α expression. CONCLUSIONS Aging exacerbates ALD in mice through the downregulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD. LAY SUMMARY Aged mice are more susceptible to alcohol-induced liver injury and fibrosis, which is, at least in part, due to lower levels of sirtuin 1 protein in hepatocytes and hepatic stellate cells. Our findings suggest that sirtuin 1 activators may have beneficial effects for the treatment of alcoholic liver disease in aged patients.
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45
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Bysani M, Perfilyev A, de Mello VD, Rönn T, Nilsson E, Pihlajamäki J, Ling C. Epigenetic alterations in blood mirror age-associated DNA methylation and gene expression changes in human liver. Epigenomics 2016; 9:105-122. [PMID: 27911095 DOI: 10.2217/epi-2016-0087] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
AIM To study the impact of aging on DNA methylation and mRNA expression in human liver. EXPERIMENTAL PROCEDURES We analysed genome-wide DNA methylation and gene expression in human liver samples using Illumina 450K and HumanHT12 expression BeadChip arrays. RESULTS DNA methylation analysis of ∼455,000 CpG sites in human liver revealed that age was significantly associated with altered DNA methylation of 20,396 CpG sites. Comparison of liver methylation data with published methylation data in other tissues showed that vast majority of the age-associated significant CpG sites overlapped between liver and blood, whereas a smaller overlap was found between liver and pancreatic islets or adipose tissue, respectively. We identified 151 genes whose liver expression also correlated with age. CONCLUSIONS We identified age-associated DNA methylation and expression changes in human liver that are partly reflected by epigenetic alterations in blood.
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Affiliation(s)
- Madhusudhan Bysani
- Epigenetics & Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
| | - Alexander Perfilyev
- Epigenetics & Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
| | - Vanessa D de Mello
- Department of Clinical Nutrition, Institute of Public Health & Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Tina Rönn
- Epigenetics & Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
| | - Emma Nilsson
- Epigenetics & Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
| | - Jussi Pihlajamäki
- Department of Clinical Nutrition, Institute of Public Health & Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Clinical Nutrition & Obesity Center, Kuopio University Hospital, Kuopio, Finland
| | - Charlotte Ling
- Epigenetics & Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
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46
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Long live the liver: immunohistochemical and stereological study of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells of male and female rats throughout ageing. Cell Tissue Res 2016; 366:639-649. [DOI: 10.1007/s00441-016-2490-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 08/03/2016] [Indexed: 01/23/2023]
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47
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Baptiste P, Akinshipo F. A case of an elderly patient with primary biliary cirrhosis. Eur Geriatr Med 2016. [DOI: 10.1016/j.eurger.2016.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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48
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Kinoshita A, Onoda H, Ueda K, Imai N, Iwaku A, Tanaka K, Fushiya N, Koike K, Nishino H, Tajiri H. Clinical characteristics and survival outcomes of super-elderly hepatocellular carcinoma patients not indicated for surgical resection. Hepatol Res 2016; 46:E5-E14. [PMID: 25753133 DOI: 10.1111/hepr.12514] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/23/2015] [Accepted: 02/26/2015] [Indexed: 12/17/2022]
Abstract
AIM Considering the dramatic increase in average life expectancy during the 20th century throughout the world, the management of elderly patients with cancer has become a global issue. We herein investigated the clinical characteristics and outcomes of super-elderly hepatocellular carcinoma (HCC) patients over 80 years old not indicated for surgical resection. METHODS We retrospectively evaluated 206 newly diagnosed HCC patients. The patients were divided into two groups according to their age at inclusion; a super-elderly group (n = 37, ≥80 years) and a younger group (n = 169, <80 years). We compared the clinical characteristics, overall survival (OS) and disease-specific survival (DSS) rates among the two groups. Both univariate and multivariate analyses were performed to identify the factors associated with the OS and DSS. RESULTS The proportion of women was higher in the super-elderly group than in the younger group (P = 0.017). There were no significant differences in the OS (P = 0.171) or DSS (P = 0.176) between the two groups. The multivariate analysis revealed that only the Cancer Liver Italian Program score (hazard ratio [HR], 2.972; P < 0.0001; HR, 3.694; P < 0.0001) was independently associated with the OS and DSS. Age was not found to be associated with the OS or DSS according to either the univariate or multivariate analysis. CONCLUSION There were no significant differences in the OS and DSS rates among the super-elderly HCC patients and younger HCC patients not indicated for surgical resection. An advanced age itself does not restrict the therapeutic approach, even in super-elderly HCC patients not indicated for surgical resection.
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Affiliation(s)
- Akiyoshi Kinoshita
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Hiroshi Onoda
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Kaoru Ueda
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Nami Imai
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Akira Iwaku
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Ken Tanaka
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Nao Fushiya
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Kazuhiko Koike
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Hirokazu Nishino
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
| | - Hisao Tajiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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49
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Kinoshita A, Koike K, Nishino H. Clinical features and prognosis of elderly patients with hepatocellular carcinoma not indicated for surgical resection. Geriatr Gerontol Int 2016; 17:189-201. [PMID: 26847184 DOI: 10.1111/ggi.12747] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2015] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide. The average life expectancy during the 20th century has increased in many parts of the world, and therefore the opportunities to examine elderly HCC patients have significantly increased worldwide. Many elderly patients develop HCC with intermediate to advanced stages of disease at the initial diagnosis, and have more comorbidities and compromised liver regeneration compared with younger patients. These circumstances show that elderly patients with HCC are poorer candidates for surgical resection or transplantation. The aim of the present review was to focus on the clinical features and prognosis of elderly HCC patients not indicated for surgical resection including multimodal treatment. Although the chronological age of 60 or 65 years as the definition of an elderly person is accepted in most countries, many studies in our review article define elderly as those aged 75 years or older. Geriatr Gerontol Int 2017; 17: 189-201.
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Affiliation(s)
- Akiyoshi Kinoshita
- Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, Tokyo, Japan
| | - Kazuhiko Koike
- Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, Tokyo, Japan
| | - Hirokazu Nishino
- Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, Tokyo, Japan
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50
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Koehler EM, Plompen EPC, Schouten JNL, Hansen BE, Darwish Murad S, Taimr P, Leebeek FWG, Hofman A, Stricker BH, Castera L, Janssen HLA. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study. Hepatology 2016; 63:138-47. [PMID: 26171685 DOI: 10.1002/hep.27981] [Citation(s) in RCA: 230] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 06/11/2015] [Accepted: 07/08/2015] [Indexed: 12/15/2022]
Abstract
UNLABELLED Given that little is known about the prevalence of, and factors associated with, liver fibrosis in the general population, we aimed to investigate this in a large, well-characterized cohort by means of transient elastography (TE). This study was part of the Rotterdam Study, a population-based study among individuals ≥45 years. All participants underwent abdominal ultrasound and TE. Liver stiffness measurement (LSM) ≥8.0 kilopascals (kPa) was used as a cutoff suggesting clinically relevant fibrosis. Of 3,041 participants (age, 66.0 ± 7.6 years) with reliable LSM, 169 (5.6%) participants had LSM ≥8.0 kPa. Age (odds ratio [OR]: 2.40; 95% confidence interval [CI]: 1.72-3.36; P < 0.001), alanine aminotransferase (ALT; OR, 1.24; 95% CI: 1.12-1.38; P < 0.001), smoking (OR, 1.77; 95% CI: 1.16-2.70; P = 0.008), spleen size (OR, 1.23; 95% CI: 1.09-1.40; P = 0.001), hepatitis B surface antigen, or anti-hepatitis C virus positivity (OR, 5.38; 95% CI: 1.60-18.0; P = 0.006), and combined presence of diabetes mellitus (DM) and steatosis (OR, 5.20; 95% CI: 3.01-8.98; P < 0.001 for combined presence) were associated with LSM ≥8.0 kPa in multivariable analyses. The adjusted predicted probability of LSM ≥8.0 kPa increased per age decade, with probabilities ranging from 1.4% (0.9-3.6) in participants ages 50-60 years to 9.9% (6.8-14.5) in participants >80 years. Participants with both DM and steatosis had the highest probabilities of LSM ≥8.0 kPa (overall probability: 17.2% [12.5-23.4]; this probability did not increase with age [P = 0.8]). CONCLUSION In this large population-based study of older adults, LSM ≥8.0 kPa, suggestive of clinically relevant fibrosis, was present in 5.6% and was strongly associated with steatosis and DM. In the context of an aging population and an increased prevalence of DM and obesity, this study illustrates that liver fibrosis may become a more prominent public health issue in the near future.
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Affiliation(s)
- Edith M Koehler
- Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | - Elisabeth P C Plompen
- Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | - Jeoffrey N L Schouten
- Department of Gastroenterology and Hepatology, University Hospital, Ghent, Ghent, Belgium
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands.,Department of Public Health, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | - Sarwa Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | - Pavel Taimr
- Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | - Frank W G Leebeek
- Department of Hematology, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | - Albert Hofman
- Department of Epidemiology, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | - Bruno H Stricker
- Department of Epidemiology, Erasmus MC University Hospital, Rotterdam, The Netherlands
| | | | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands.,Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada
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