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1
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Haley HN, Ikram FG, Ward AM. Backtracking to the Brain: A Journey From Cirrhosis to Hypothalamic Insight. Cureus 2025; 17:e84644. [PMID: 40416908 PMCID: PMC12097879 DOI: 10.7759/cureus.84644] [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] [Accepted: 05/21/2025] [Indexed: 05/27/2025] Open
Abstract
We present a 31-year-old female patient with cryptogenic cirrhosis admitted for rectal bleeding secondary to rectal prolapse. During her hospital course, she was found to have severe multi-endocrine dysfunction as evidenced by persistent hypotension, bradycardia, and intermittent hypothermia with hypothyroidism, adrenal insufficiency, and diabetes insipidus, which were confirmed by laboratory testing. Due to the patient's hypothalamic-pituitary dysfunction along with biopsy-confirmed cirrhosis of unknown etiology, magnetic resonance imaging (MRI) of the brain was ordered. The MRI demonstrated a large, heterogeneously enhancing mass centered in the hypothalamus and infiltrating the pituitary stalk. This case stands out because of its diagnostic trajectory where investigating the cause of endocrine dysfunction revealed a cerebral neoplasm that contributed to the patient's development of cirrhosis. There is an established association between hepatic pathologies and hypothalamic masses with the proposed mechanism being deficiencies of growth hormone (GH), insulin-like growth factor-1 (IGF-1), thyroid stimulating hormone (TSH), and consequently, triiodothyronine (T3). GH deficiency predisposes patients to hepatic steatosis while IGF-1 and T3 deficiencies leave the liver more vulnerable to oxidative damage. As such, cranial imaging and endocrine evaluation should be considered in young patients with cryptogenic cirrhosis.
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Affiliation(s)
- Holly N Haley
- Internal Medicine, Methodist Dallas Medical Center, Dallas, USA
| | - Farukh G Ikram
- Internal Medicine, Methodist Dallas Medical Center, Dallas, USA
| | - Anne M Ward
- The Liver Institute, Methodist Dallas Medical Center, Dallas, USA
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2
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Al-Share QY, Tahrawi AY, Khasawneh DM, Alshare AW, Alkhasawneh SA. Retrospective evaluation of medication appropriateness in older adults with hepatic cirrhosis. Sci Prog 2025; 108:368504251330037. [PMID: 40179219 PMCID: PMC11970046 DOI: 10.1177/00368504251330037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
ObjectiveTo assess medication appropriateness using the medication appropriateness index (MAI) criteria, the prevalence of potentially inappropriate medication (PIM) prescribing, and factors associated with increased PIM use in elderly ambulatory patients with cirrhosis.MethodsA cross-sectional study of 70 elderly ambulatory patients with cirrhosis (≥65 years old), from January to December 2021. Two clinical pharmacists evaluated medication appropriateness using the MAI tool. Data were analyzed using SPSS version 27.0. Descriptive statistics were used to present patient demographics, clinical characteristics, and MAI responses. Regression analysis was used to identify predictive factors for PIM prescribing. The kappa statistic was used to assess interrater agreement.ResultsAll participants had at least one medication with ≥ 1 inappropriate MAI criterion, with the most common issue being incorrect treatment duration (18%). Of 610 evaluated medications, 44.1% were classified as PIMs. The mean MAI scores per patient and per medication were 15.97 (±10.48) and 1.83 (±3.18), respectively, consistent with other studies. However, the prevalence of PIMs was higher, likely due to the specific disease population studied, as this is the first study to evaluate medication appropriateness in cirrhotic patients. Good interrater agreement was observed (kappa = 0.74), indicating good interrater reliability. Increased inappropriate prescribing was associated with the number of medications, age and severe renal impairment.ConclusionsPIMs are common in elderly patients with cirrhosis, highlighting the need for better prescribing practices to ensure medication safety. Involving clinical pharmacists with geriatrics expertise and using medication appropriateness tools can reduce PIMs and drug-related problems. Further, healthcare team training is essential to improve prescribing practices. Assessing PIMs in this population could enhance clinical outcomes, reduce adverse drug reactions, and lower healthcare costs. Incorporating comprehensive medication management into routine care for elderly cirrhotic patients is a key strategy to improve patient safety and quality of life.
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Affiliation(s)
- Qusai Y Al-Share
- Department of Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Aseel Y Tahrawi
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Ohio, USA
| | - Dyala M Khasawneh
- Department of Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Aya W Alshare
- Department of Clinical Pharmacy and Pharmacy Practice, College of Pharmacy, Yarmouk University, Irbid, Jordan
| | - Shrouq A Alkhasawneh
- Department of Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
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Mejía-Guzmán JE, Belmont-Hernández RA, Chávez-Tapia NC, Uribe M, Nuño-Lámbarri N. Metabolic-Dysfunction-Associated Steatotic Liver Disease: Molecular Mechanisms, Clinical Implications, and Emerging Therapeutic Strategies. Int J Mol Sci 2025; 26:2959. [PMID: 40243565 PMCID: PMC11988898 DOI: 10.3390/ijms26072959] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a highly prevalent metabolic disorder characterized by hepatic steatosis in conjunction with at least one cardiometabolic risk factor, such as obesity, type 2 diabetes, hypertension, or dyslipidemia. As global rates of obesity and metabolic syndrome continue to rise, MASLD is becoming a major public health concern, with projections indicating a substantial increase in prevalence over the coming decades. The disease spectrum ranges from simple steatosis to metabolic-dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma, contributing to significant morbidity and mortality worldwide. This review delves into the molecular mechanisms driving MASLD pathogenesis, including dysregulation of lipid metabolism, chronic inflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota alterations. Recent advances in research have highlighted the role of genetic and epigenetic factors in disease progression, as well as novel therapeutic targets such as peroxisome proliferator-activated receptors (PPARs), fibroblast growth factors, and thyroid hormone receptor beta agonists. Given the multifaceted nature of MASLD, a multidisciplinary approach integrating early diagnosis, molecular insights, lifestyle interventions, and personalized therapies is critical. This review underscores the urgent need for continued research into innovative treatment strategies and precision medicine approaches to halt MASLD progression and improve patient outcomes.
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Affiliation(s)
- Jeysson E. Mejía-Guzmán
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (J.E.M.-G.); (R.A.B.-H.); (N.C.C.-T.)
| | - Ramón A. Belmont-Hernández
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (J.E.M.-G.); (R.A.B.-H.); (N.C.C.-T.)
- Postgraduate Program in Experimental Biology, División de Ciencias Básicas y de la Salud (DCBS), Universidad Autonoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
| | - Norberto C. Chávez-Tapia
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (J.E.M.-G.); (R.A.B.-H.); (N.C.C.-T.)
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
| | - Natalia Nuño-Lámbarri
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (J.E.M.-G.); (R.A.B.-H.); (N.C.C.-T.)
- Surgery Department, Faculty of Medicine, The National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico
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4
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Rosina M, Scaricamazza S, Fenili G, Nesci V, Valle C, Ferri A, Paronetto MP. Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis. Trends Endocrinol Metab 2025:S1043-2760(25)00044-X. [PMID: 40090808 DOI: 10.1016/j.tem.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/13/2025] [Accepted: 02/21/2025] [Indexed: 03/18/2025]
Abstract
Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.
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Affiliation(s)
- Marco Rosina
- Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, Rome, Italy; Department of Neuroscience, Italian National Institute of Health (ISS), Rome, Italy
| | - Silvia Scaricamazza
- Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, Rome, Italy; National Research Council (CNR), Institute of Translational Pharmacology (IFT), Rome, Italy
| | - Gianmarco Fenili
- Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, Rome, Italy; Department of Movement, Human, and Health Sciences, University of Rome 'Foro Italico', Rome, Italy
| | - Valentina Nesci
- Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, Rome, Italy; Department of Systems Medicine, University of Roma 'Tor Vergata', Rome, Italy
| | - Cristiana Valle
- Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, Rome, Italy; National Research Council (CNR), Institute of Translational Pharmacology (IFT), Rome, Italy
| | - Alberto Ferri
- Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, Rome, Italy; National Research Council (CNR), Institute of Translational Pharmacology (IFT), Rome, Italy.
| | - Maria Paola Paronetto
- Laboratories of Neurochemistry and of Molecular and Cellular Neurobiology, IRCCS, Fondazione Santa Lucia, Rome, Italy; Department of Movement, Human, and Health Sciences, University of Rome 'Foro Italico', Rome, Italy.
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Liu Y, Xue H, Liu Y, Li H, Liang Q, Ma L, Zhao M, Liu J. Serum Insulin-Like Growth Factor 1 and the Prognosis of Patients With Advanced Liver Diseases: A Meta-Analysis. Clin Transl Gastroenterol 2025:01720094-990000000-00374. [PMID: 39981963 DOI: 10.14309/ctg.0000000000000829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 02/12/2025] [Indexed: 02/22/2025] Open
Abstract
INTRODUCTION Serum insulin-like growth factor 1 (IGF-1), a hepatocyte-derived cytokine, has been suggested to reflect hepatic function reserve. The aim of this systematic review and meta-analysis was to investigate the association between serum IGF-1 levels on the admission and prognosis of patients with advanced liver diseases. METHODS A thorough examination of the literature was conducted across various databases, namely PubMed, Embase, Web of Science, Wanfang, and CNKI, with the aim of identifying relevant cohort studies. The data were synthesized using the random-effects model, taking into account the potential impact of heterogeneity. RESULTS A total of 9 cohorts were included. Patients with a low serum level of IGF-1, as compared with those with a high IGF-1 at baseline, exhibited a significantly poorer transplant-free survival (risk ratio: 3.03, 95% confidence interval: 2.17 to 4.22, P < 0.001), with no significant heterogeneity observed ( P for Cochrane Q test = 0.92, I2 = 0%). A sensitivity analysis, which was conducted by excluding 1 study at a time, yielded consistent results (risk ratio: 2.94-3.24, P all < 0.05). In addition, consistent results were observed in further subgroup analyses based on various factors, including cutoffs of IGF-1, country of the study, patient diagnosis, methods for measuring serum IGF-1, follow-up duration, analytic model, and quality scores ( P for subgroup difference all > 0.05). DISCUSSION A diminished serum IGF-1 level on admission could potentially serve as an indicator for an unfavorable prognosis among patients afflicted with advanced liver disease, such as severe hepatitis and cirrhosis.
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Affiliation(s)
- Yihan Liu
- Zhoukou Central Hospital Affiliated to Xinxiang Medical University, Zhoukou, Henan, China
| | - Haojie Xue
- Zhoukou Central Hospital Affiliated to Xinxiang Medical University, Zhoukou, Henan, China
| | - Yang Liu
- Ward 1, Department of Gastroenterology, Zhoukou Central Hospital, Zhoukou, Henan, China
| | - Han Li
- Ward 1, Department of Gastroenterology, Zhoukou Central Hospital, Zhoukou, Henan, China
| | - Qian Liang
- Zhoukou Central Hospital, Zhoukou, Henan, China
| | - Longhui Ma
- Zhoukou Central Hospital, Zhoukou, Henan, China
| | - Ming Zhao
- Ward 1, Department of Gastroenterology, Zhoukou Central Hospital, Zhoukou, Henan, China
| | - Junying Liu
- Zhoukou Central Hospital, Zhoukou, Henan, China
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Zhao K, Zhang H, Ding W, Yu X, Hou Y, Liu X, Li X, Wang X. Adipokines regulate the development and progression of MASLD through organellar oxidative stress. Hepatol Commun 2025; 9:e0639. [PMID: 39878681 PMCID: PMC11781772 DOI: 10.1097/hc9.0000000000000639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/13/2024] [Indexed: 01/31/2025] Open
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which is increasingly being recognized as a leading cause of chronic liver pathology globally, is increasing. The pathophysiological underpinnings of its progression, which is currently under active investigation, involve oxidative stress. Human adipose tissue, an integral endocrine organ, secretes an array of adipokines that are modulated by dietary patterns and lifestyle choices. These adipokines intricately orchestrate regulatory pathways that impact glucose and lipid metabolism, oxidative stress, and mitochondrial function, thereby influencing the evolution of hepatic steatosis and progression to metabolic dysfunction-associated steatohepatitis (MASH). This review examines recent data, underscoring the critical interplay of oxidative stress, reactive oxygen species, and redox signaling in adipokine-mediated mechanisms. The role of various adipokines in regulating the onset and progression of MASLD/MASH through mitochondrial dysfunction and endoplasmic reticulum stress and the underlying mechanisms are discussed. Due to the emerging correlation between adipokines and the development of MASLD positions, these adipokines are potential targets for the development of innovative therapeutic interventions for MASLD management. A comprehensive understanding of the pathogenesis of MASLD/MASH is instrumental for identifying therapies for MASH.
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Affiliation(s)
- Ke Zhao
- Central laboratory, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, Shandong, China
| | - Heng Zhang
- Central laboratory, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, Shandong, China
- Central laboratory, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Wenyu Ding
- Central laboratory, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, Shandong, China
| | - Xiaoshuai Yu
- Central laboratory, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, Shandong, China
- Central laboratory, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yanli Hou
- Central laboratory, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, Shandong, China
| | - Xihong Liu
- Department of Pathology, The Fourth People’s Hospital of Jinan, Jinan, Shandong, China
| | - Xinhua Li
- Central laboratory, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, Shandong, China
| | - Xiaolei Wang
- Central laboratory, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Central laboratory, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, Shandong, China
- First school of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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Kaur P, Verma N, Wadhawan A, Garg P, Ralmilay S, Kalra N, Baloji A, Dutta P, Sharma G, Rathi S, De A, Premkumar M, Taneja S, Duseja A, Singh V. Insulin-like Growth Factor-1 Levels Reflect Muscle and Bone Health and Determine Complications and Mortality in Decompensated Cirrhosis. J Clin Exp Hepatol 2025; 15:102402. [PMID: 39296665 PMCID: PMC11405804 DOI: 10.1016/j.jceh.2024.102402] [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: 06/29/2024] [Accepted: 08/06/2024] [Indexed: 09/21/2024] Open
Abstract
Background The growth hormone-insulin-like growth factor (GH-IGF-1) axis and its impairment with sarcopenia, frailty, bone health, complications, and prognosis are not well characterized in cirrhosis. Methods We investigated the adult decompensated cirrhosis out-patients at a tertiary care institute between 2021 and 2023 for serum GH and IGF-1 levels, and associated them with sarcopenia (CT-SMI in cm2/m2), liver frailty index (LFI), osteodystrophy (DEXA), clinical decompensations (overall, ascites, encephalopathy, infection, and bleed), and survival up to 180 days. Results One-hundred-seventy-two patients, 95% males, aged 46.5 years (median). logIGF-1 levels were negatively associated with sarcopenia, osteodystrophy, LFI, CTP, and MELD-Na score (P < 0.05 each). Patients with low IGF-1 levels had a higher incidence of complications (overall, ascites and encephalopathy) than those with intermediate, and high IGF-1 levels (P < 0.05 each). Both logIGF-1 (AUC: 0.686) and MELD (AUC: 0.690) could predict 180-day mortality (P < 0.05, each). Adding logIGF-1 with MELDNa further improved discriminative accuracy of MELDNa (AUC: 0.729) P < 0.001. The increase in IGF-1 on follow-up was associated with better survival and fewer complications. Conclusion Reduced IGF-1 levels reflect sarcopenia, frailty, and osteodystrophy in cirrhosis. Low IGF-1 are associated with severity, development of decompensations, and mortality.
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Affiliation(s)
- Parminder Kaur
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Nipun Verma
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Aishani Wadhawan
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Pratibha Garg
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Samonee Ralmilay
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Naveen Kalra
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Abhiman Baloji
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Pinaki Dutta
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Gaurav Sharma
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Sahaj Rathi
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Arka De
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Madhumita Premkumar
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Sunil Taneja
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Ajay Duseja
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Virendra Singh
- Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India
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Byun J, Kim HS, Han Y, Thrift AP, Lin SM, Xiao X, Lim H, Jun G, Desantis SM, El-Serag HB, Kanwal F, Amos CI. Shared genetic architecture of non-viral cirrhosis with several pleiotropic traits: A nested case-control study in the UK Biobank. LIVER INTERNATIONAL COMMUNICATIONS 2024; 5:e70002. [PMID: 40248461 PMCID: PMC12002564 DOI: 10.1002/lci2.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 09/04/2024] [Indexed: 04/19/2025]
Abstract
Background & Aims Cirrhosis is a leading cause of liver-related mortality and a multifactorial disease. To date, the complex genetic architecture of non-viral cirrhosis has not been fully explored. Cross-trait genetic correlations can elucidate the common genetic etiology of genetically correlated phenotypes. This study aims to identify polygenic and pleiotropic traits associated with cirrhosis using the linkage disequilibrium score regression analysis. Methods We conducted genome-wide association analysis of 9,622,842 imputed SNPs on 3,368 non-viral cirrhosis cases and 258,258 controls, and cross-trait analysis between non-viral cirrhosis and various polygenic and pleiotropic traits using the UK Biobank cohort study. We further performed sensitivity analyses by removing genomic regions of alcohol intake, smoking behaviors, and obesity. We observed multiple traits showing robust genetic correlations (rg) with non-viral cirrhosis. Results We found strong genetic correlations between the genetic architectures of non-viral cirrhosis and clinical/physiologic factors, including BMI (rg=0.82), alanine aminotransferase (0.71), diabetes (0.70), number of cigarettes currently smoked daily (0.67), amount of alcohol drunk on a typical drinking day (0.60), insomnia (0.59), gout (0.57), depression (0.50), apoliprotein-A (-0.33), HDL cholesterol (-0.49). Exclusion of genomic regions associated with alcohol intake, smoking behaviors, and obesity demonstrated consistent directions and persistent associations in genetic patterns. The inheritability of cirrhosis on the observed scale showed 0.56%. Conclusions This study provides a comprehensive assessment of the shared genetic architecture of non-viral cirrhosis predisposition and numerous polygenic and pleiotropic traits, most notably BMI, alanine aminotransferase, and diabetes. These findings provide new information on underlying comorbid conditions that can increase the non-viral cirrhosis risk.
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Affiliation(s)
- Jinyoung Byun
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Hyun-Seok Kim
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Younghun Han
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Aaron P. Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Sabrina M. Lin
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular Biology, Colgate University, Hamilton, New York, USA
| | - Xiangjun Xiao
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA
| | - Hyeyeun Lim
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Goo Jun
- Department of Epidemiology, Human Genetics & Environmental Sciences and Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Stacia M. Desantis
- Department of Biostatistics and Data Science, The University of Texas Health Science Center at Houston, School of Public Health, Houston, Texas, USA
| | - Hashem B. El-Serag
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Christopher I. Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
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Ehrhardt M, Schreiber S, Duderstadt Y, Braun‐Dullaeus R, Borucki K, Brigadski T, Müller NG, Leßmann V, Müller P. Circadian rhythm of brain-derived neurotrophic factor in serum and plasma. Exp Physiol 2024; 109:1755-1767. [PMID: 39105714 PMCID: PMC11442779 DOI: 10.1113/ep091671] [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: 11/19/2023] [Accepted: 07/05/2024] [Indexed: 08/07/2024]
Abstract
The neurotrophic growth factor brain-derived neurotrophic factor (BDNF) plays a crucial role in various neurodegenerative and psychiatric diseases, such as Alzheimer's disease, schizophrenia and depression. BDNF has been proposed as a potential biomarker for diagnosis, prognosis and monitoring therapy. Understanding the factors influencing BDNF levels and whether they follow a circadian rhythm is essential for interpreting fluctuations in BDNF measurements. We aimed to investigate the circadian rhythm of BDNF by collecting multiple peripheral venous blood samples from young, healthy male participants at 12 different time points over 24 h. In addition, vital parameters, cortisol and insulin like growth factor 1 (IGF1) were measured to explore potential regulatory mechanisms, interfering variables and their correlations with BDNF concentration. The findings revealed that plasma BDNF did not exhibit any significant fluctuations over 24 h, suggesting the absence of a circadian rhythm. However, serum BDNF levels decreased during sleep. Furthermore, serum BDNF showed a positive correlation with heart rate but a negative correlation with IGF1. No significant correlation was observed between cortisol and BDNF or IGF1. Although plasma BDNF suggests steady-state conditions, the decline of serum BDNF during the nocturnal period could be attributed to physical inactivity and associated with reduced haemodynamic blood flow (heart rate reduction during sleep). The type of sample collection (peripheral venous cannula vs. blood sampling using a butterfly system) does not significantly affect the measured BDNF levels. The sample collection during the day did not significantly affect BDNF analysis, emphasizing the importance of considering activity levels rather than timing when designing standardized protocols for BDNF assessments.
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Affiliation(s)
- Maren Ehrhardt
- Division of Cardiology and AngiologyUniversity Hospital MagdeburgMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
| | - Stefanie Schreiber
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C‐I‐R‐C)MagdeburgGermany
- Division of NeurologyUniversity Hospital MagdeburgMagdeburgGermany
- Department of Neurology, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany
| | - Yves Duderstadt
- Division of Cardiology and AngiologyUniversity Hospital MagdeburgMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
- Institute of Sport ScienceOtto‐von‐Guericke UniversityMagdeburgGermany
| | | | - Katrin Borucki
- Institute of Clinical Chemistry and PathobiochemistryOtto‐von‐Guericke UniversityMagdeburgGermany
| | - Tanja Brigadski
- Institute of PhysiologyOtto‐von‐Guericke UniversityMagdeburgGermany
- Department of Informatics and Microsystems TechnologyUniversity of Applied Sciences KaiserslauternZweibrückenGermany
| | - Notger G. Müller
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
- Degenerative and Chronic Diseases, Faculty of Health Sciences BrandenburgUniversity of PotsdamPotsdamGermany
| | - Volkmar Leßmann
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C‐I‐R‐C)MagdeburgGermany
- Institute of PhysiologyOtto‐von‐Guericke UniversityMagdeburgGermany
- German Center for Mental Health (DZPG)MagdeburgGermany
- Center for Behavioural Brain Sciences (CBBS)MagdeburgGermany
| | - Patrick Müller
- Division of Cardiology and AngiologyUniversity Hospital MagdeburgMagdeburgGermany
- German Center for Neurodegenerative Diseases (DZNE)MagdeburgGermany
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C‐I‐R‐C)MagdeburgGermany
- German Center for Mental Health (DZPG)MagdeburgGermany
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10
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Saeki C, Saito M, Tsubota A. Association of chronic liver disease with bone diseases and muscle weakness. J Bone Miner Metab 2024; 42:399-412. [PMID: 38302761 DOI: 10.1007/s00774-023-01488-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/16/2023] [Indexed: 02/03/2024]
Abstract
The liver is a vital organ involved in nutrient metabolism, hormone regulation, immunity, cytokine production, and gut homeostasis. Impairment in liver function can result in malnutrition, chronic inflammation, decreased anabolic hormone levels, and dysbiosis. These conditions eventually cause an imbalance in osteoblast and osteoclast activities, resulting in bone loss. Osteoporosis is a frequent complication of chronic liver disease (CLD) that adversely affects quality of life and increases early mortality. Sarcopenia is another common complication of CLD characterized by progressive loss of skeletal muscle mass and function. Assessment criteria for sarcopenia specific to liver disease have been established, and sarcopenia has been reported to be associated with an increase in the risk of liver disease-related events and mortality in patients with CLD. Owing to their similar risk factors and underlying pathophysiological mechanisms, osteoporosis and sarcopenia often coexist (termed osteosarcopenia), progress in parallel, and further exacerbate the conditions mentioned above. Therefore, comprehensive management of these musculoskeletal disorders is imperative. This review summarizes the clinical implications and characteristics of osteoporosis, extending to sarcopenia and osteosarcopenia, in patients with CLD caused by different etiologies.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Mitsuru Saito
- Department of Orthopedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Akihito Tsubota
- Project Research Units, Research Center for Medical Science, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
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11
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Hari A, AbdulHameed MDM, Balik-Meisner MR, Mav D, Phadke DP, Scholl EH, Shah RR, Casey W, Auerbach SS, Wallqvist A, Pannala VR. Exposure to PFAS chemicals induces sex-dependent alterations in key rate-limiting steps of lipid metabolism in liver steatosis. FRONTIERS IN TOXICOLOGY 2024; 6:1390196. [PMID: 38903859 PMCID: PMC11188372 DOI: 10.3389/ftox.2024.1390196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/10/2024] [Indexed: 06/22/2024] Open
Abstract
Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (Acadm, Acox1, Cpt2, Cyp4a1-3) and downregulation of lipid transport genes (Apoa1, Apoa5, Pltp). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis (Pck1) and bile acid synthesis (Cyp7a1) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis (Scd) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.
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Affiliation(s)
- Archana Hari
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Mohamed Diwan M. AbdulHameed
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | | | - Deepak Mav
- Sciome LLC, Research Triangle Park, NC, United States
| | | | | | | | - Warren Casey
- Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Scott S. Auerbach
- Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Anders Wallqvist
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
| | - Venkat R. Pannala
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
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12
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Di Cola S, Khan S, Lapenna L, Merli M. Emerging drugs for the treatment of sarcopenia in cirrhosis of the liver. Expert Opin Emerg Drugs 2024; 29:81-91. [PMID: 38549232 DOI: 10.1080/14728214.2024.2332428] [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: 01/22/2024] [Accepted: 03/14/2024] [Indexed: 04/19/2024]
Abstract
INTRODUCTION Malnutrition and sarcopenia are common and impact the prognosis in patients with liver cirrhosis. The etiology is multifactorial and includes periods of reduced caloric intake, increased catabolism and direct molecular mechanisms that inhibit muscle synthesis. Although these conditions are widely acknowledged, and there is a growing interest in their diagnosis, robust evidence regarding the treatment and reversibility of these conditions is still lacking. AREAS COVERED We have explored the current evidence on the pharmacological treatment of sarcopenia in patients with cirrhosis. Additionally, we have searched for drugs already in use and ongoing trials for other chronic diseases. EXPERT OPINION The current guidelines recommend the use of a protein-adequate diet and moderate physical activity for treating sarcopenia in patients with cirrhosis. Currently, robust evidence is derived only from the supplementation of Branched-Chain Amino Acids, capable of increasing muscle mass and function. There are many drugs targeting various pathways that contribute to sarcopenia. However, evidence is sporadic and insufficient to suggest their use in clinical practice.Novel drugs specifically designed to enhance muscle mass and function should be developed. Finally, gender significantly influences the type of muscle alteration and therapeutic mechanisms; therefore, future studies should be designed taking gender differences into consideration.
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Affiliation(s)
- Simone Di Cola
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Saniya Khan
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Lucia Lapenna
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Manuela Merli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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13
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Pei X, Jiang W, Li L, Zeng Q, Liu CH, Wang M, Chen E, Zhou T, Tang H, Wu D. Mendelian-randomization study revealed causal relationship between nonalcoholic fatty liver disease and osteoporosis/fractures. J Gastroenterol Hepatol 2024; 39:847-857. [PMID: 38240493 DOI: 10.1111/jgh.16448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/12/2023] [Accepted: 12/03/2023] [Indexed: 05/03/2024]
Abstract
BACKGROUND Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have a higher risk of osteoporosis/fractures; however, the causal relationship remains unclear. METHODS Publicly available genome-wide association studies (GWASs) were used for Mendelian randomization (MR) analysis. GWASs of NAFLD and fractures were obtained from the FinnGen Consortium. GWASs of bone mineral density (BMD) were derived from a meta-analysis. GWASs of obesity, diabetes, liver function, and serum lipid-related metrics were used to clarify whether the accompanying NAFLD symptoms contributed to fractures. Moreover, two additional GWASs of NAFLD were applied. RESULTS A causal association was not observed between NAFLD and BMD using GWASs from the FinnGen Consortium. However, a causal relationship between NAFLD and femoral neck-BMD (FN-BMD), a suggestive relationship between fibrosis and FN-BMD, and between NAFLD and osteoporosis were identified in replication GWASs. Genetically proxied body mass index (BMI), high-density lipoprotein (HDL), and hip circumference increased the likelihood of lower limb fractures. The waist-to-hip ratio decreased, whereas glycated hemoglobin (HbA1C) and homeostasis model assessment of β-cell function (HOMA-B) increased the risk of forearm fractures. Low-density lipoprotein (LDL) reduced, whereas HbA1C increased the incidence of femoral fractures. Alkaline phosphatase (ALP) raised the risk of foot fractures. However, after a multivariate MR analysis (adjusted for BMI), all the relationships became insignificant. CONCLUSIONS NAFLD caused reduced BMD, and genetically predicted HDL, LDL, HbA1C, HOMA-B, ALP, hip circumference, and waist-to-hip ratio causally increased the risk of fractures. BMI may mediate causal relationships. Larger GWASs are required to verify this finding.
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Affiliation(s)
- Xiong Pei
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lianchi Li
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qingmin Zeng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ming Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Taoyou Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
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14
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Lu H. Inflammatory liver diseases and susceptibility to sepsis. Clin Sci (Lond) 2024; 138:435-487. [PMID: 38571396 DOI: 10.1042/cs20230522] [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: 09/03/2023] [Revised: 01/09/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024]
Abstract
Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.
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Affiliation(s)
- Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, U.S.A
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15
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Szydlowska-Gladysz J, Gorecka AE, Stepien J, Rysz I, Ben-Skowronek I. IGF-1 and IGF-2 as Molecules Linked to Causes and Consequences of Obesity from Fetal Life to Adulthood: A Systematic Review. Int J Mol Sci 2024; 25:3966. [PMID: 38612776 PMCID: PMC11012406 DOI: 10.3390/ijms25073966] [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: 02/20/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
This study examines the impact of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) on various aspects of children's health-from the realms of growth and puberty to the nuanced characteristics of metabolic syndrome, diabetes, liver pathology, carcinogenic potential, and cardiovascular disorders. A comprehensive literature review was conducted using PubMed, with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method employing specific keywords related to child health, obesity, and insulin-like growth factors. This study reveals associations between insulin-like growth factor 1 and birth weight, early growth, and adiposity. Moreover, insulin-like growth factors play a pivotal role in regulating bone development and height during childhood, with potential implications for puberty onset. This research uncovers insulin-like growth factor 1 and insulin-like growth factor 2 as potential biomarkers and therapeutic targets for metabolic dysfunction-associated liver disease and hepatocellular carcinoma, and it also highlights the association between insulin-like growth factors (IGFs) and cancer. Additionally, this research explores the impact of insulin-like growth factors on cardiovascular health, noting their role in cardiomyocyte hypertrophy. Insulin-like growth factors play vital roles in human physiology, influencing growth and development from fetal stages to adulthood. The impact of maternal obesity on children's IGF levels is complex, influencing growth and carrying potential metabolic consequences. Imbalances in IGF levels are linked to a range of health conditions (e.g., insulin resistance, glucose intolerance, metabolic syndrome, and diabetes), prompting researchers to seek novel therapies and preventive strategies, offering challenges and opportunities in healthcare.
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Affiliation(s)
- Justyna Szydlowska-Gladysz
- Department of Pediatric Endocrinology and Diabetology with Endocrine-Metabolic Laboratory, Medical University in Lublin, 20-093 Lublin, Poland
| | | | | | | | - Iwona Ben-Skowronek
- Department of Pediatric Endocrinology and Diabetology with Endocrine-Metabolic Laboratory, Medical University in Lublin, 20-093 Lublin, Poland
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16
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Nijenhuis-Noort EC, Berk KA, Neggers SJCMM, Lely AJVD. The Fascinating Interplay between Growth Hormone, Insulin-Like Growth Factor-1, and Insulin. Endocrinol Metab (Seoul) 2024; 39:83-89. [PMID: 38192102 PMCID: PMC10901670 DOI: 10.3803/enm.2024.101] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/06/2023] [Indexed: 01/10/2024] Open
Abstract
This review intends to provide the reader with a practical overview of several (patho)physiological conditions in which knowledge of the interplay between growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin is important. This might help treating physicians in making the right decisions on how to intervene and improve metabolism for the benefit of patients, and to understand why and how metabolism responds in their specific cases. We will specifically address the interplay between GH, IGF-1, and insulin in type 1 and 2 diabetes mellitus, liver cirrhosis, and acromegaly as examples in which this knowledge is truly necessary.
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Affiliation(s)
- Eline C Nijenhuis-Noort
- Division of Endocrinology, Department of Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Kirsten A Berk
- Division of Endocrinology, Department of Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Sebastian J C M M Neggers
- Division of Endocrinology, Department of Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Aart J van der Lely
- Division of Endocrinology, Department of Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
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17
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Nakamura A, Yoshimura T, Ichikawa T. Liver Disease-Related Sarcopenia: A Predictor of Poor Prognosis by Accelerating Hepatic Decompensation in Advanced Chronic Liver Disease. Cureus 2023; 15:e49078. [PMID: 38024081 PMCID: PMC10658123 DOI: 10.7759/cureus.49078] [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: 11/19/2023] [Indexed: 12/01/2023] Open
Abstract
Background Sarcopenia is considered a prognostic factor for advanced chronic liver disease (ACLD) independent of liver function, but the underlying mechanisms are unknown. Here, we investigated whether sarcopenia contributed to hepatic decompensation and worsened prognosis. Methods This was a single-center retrospective study of 708 patients with chronic liver disease who underwent magnetic resonance elastography (MRE). Magnetic resonance imaging (MRI) was used to diagnose sarcopenia and hepatic decompensation (presence of ascites). Results The incidence of sarcopenia (29% overall) and age were significantly correlated to increased liver stiffness (LS) (p < 0.01 each), but age did not differ for LS ≥ 4 kPa. Rates of thrombocytopenia and varices increased at ≥4 kPa, and ascites (n = 52) accounted for 81% of patients with ≥6 kPa LS. Age, alcoholic liver disease, C-reactive protein, sodium level, and controlling nutritional status score were extracted as factors contributing to sarcopenia (all p < 0.05). In ACLD, sarcopenia was an independent predictor of ascites (p < 0.01), and in a follow-up analysis of 163 patients without ascites at baseline, the incidence of ascites in patients with sarcopenia was significantly higher, even after adjusting for LS and liver severity (p < 0.01). The Cox proportional hazards model indicated albumin-bilirubin score and sarcopenia as independent prognostic factors (p < 0.01 each). Conclusions In ACLD, both portal hypertension and liver disease-related sarcopenia were found to occur at ≥4 kPa. Sarcopenia was accompanied by mildly decreased sodium levels and contributed to the early development of ascites and poor prognosis, independent of liver function.
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18
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Bao Z, Guo C, Chen Y, Li C, Lei T, Zhou S, Qi D, Xiang Z. Fatty acid metabolization and insulin regulation prevent liver injury from lipid accumulation in Himalayan marmots. Cell Rep 2023; 42:112718. [PMID: 37384524 DOI: 10.1016/j.celrep.2023.112718] [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: 10/22/2022] [Revised: 04/04/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
Fat storage and weight gain are dominant traits for hibernating mammals. However, excessive fat accumulation may cause liver damage. Here, we explore the lipid accumulation and metabolic processes of the Himalayan marmot (Marmota himalayana), a hibernating rodent species. We find that the unsaturated fatty acid (UFA) content in food was consistent with a large increase in the body mass of Himalayan marmots. Metagenomic analysis shows that Firmicutes Bacterium CAG:110 plays a synergistic role by synthesizing UFAs, which is demonstrated by fecal transplantation experiments, indicating that the gut microbiome promotes fat storage in Himalayan marmots for hibernation. Microscopic examination results indicate that the risk of fatty liver appears at maximum weight; however, liver function is not affected. Upregulations of UFA catabolism and insulin-like growth factor binding protein genes provide an entry point for avoiding liver injury.
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Affiliation(s)
- Ziqiang Bao
- College of Life Science and Technology, Central South University of Forestry and Technology, Changsha, Hunan 410004, China; Institute of Evolutionary Ecology and Conservation Biology, Central South University of Forestry & Technology, Changsha, Hunan 410004, China
| | - Cheng Guo
- College of Life Science and Technology, Central South University of Forestry and Technology, Changsha, Hunan 410004, China; Institute of Evolutionary Ecology and Conservation Biology, Central South University of Forestry & Technology, Changsha, Hunan 410004, China
| | - Yi Chen
- Institute of Evolutionary Ecology and Conservation Biology, Central South University of Forestry & Technology, Changsha, Hunan 410004, China; College of Forestry, Central South University of Forestry and Technology, Changsha, Hunan 410004, China
| | - Cheng Li
- College of Life Science and Technology, Central South University of Forestry and Technology, Changsha, Hunan 410004, China; Chengdu Research Base of Giant Panda Breeding, Chengdu, Sichuan Province 610081, China
| | - Tao Lei
- College of Life Science and Technology, Central South University of Forestry and Technology, Changsha, Hunan 410004, China
| | - Shuailing Zhou
- College of Life Science and Technology, Central South University of Forestry and Technology, Changsha, Hunan 410004, China
| | - Dunwu Qi
- Chengdu Research Base of Giant Panda Breeding, Chengdu, Sichuan Province 610081, China
| | - Zuofu Xiang
- Institute of Evolutionary Ecology and Conservation Biology, Central South University of Forestry & Technology, Changsha, Hunan 410004, China; College of Forestry, Central South University of Forestry and Technology, Changsha, Hunan 410004, China; Yuelushan Laboratory, Carbon Sinks Forests Variety Innovation Center, Changsha, Hunan 410004, China.
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19
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Xie ZY, Xu YX, Yao L. Angiotensin II can trigger HSC-LX2 pyroptosis through both classical and non-classical pathways. Life Sci 2022; 307:120878. [PMID: 35961596 DOI: 10.1016/j.lfs.2022.120878] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Current evidence suggests that liver fibrosis is reversible even at late stages. Pyroptosis is reportedly regulated by classical and non-classical pathways and is also involved in the activation of the human hepatic stellate cell line LX2. This study sought to identify regulatory pathways that pyroptosis of HSC during AngII-ROS-induced HSC activation and provides novel insights for anti-fibrosis therapy by targeting HSC. MATERIALS AND METHODS All experiments were conducted in HSC-LX2. The expressions of α-SMA, NLRP3, Caspases-1, -4, -5, ASC and GSDMD-N were detected in HSC-LX2 cells induced with AngII by Western blot and qRT-PCR. CCK8 was used to detect cell proliferation and activity. 2'-7'dichlorofluorescin diacetate (DCFH-DA) was used to measure ROS generation. An LDH assay kit was used to detect LDH released from damaged cells, and ELISA was used to quantify IL-18 and IL-1β levels. RESULTS After AngII stimulation, HSC-LX2 cell viability, ROS, LDH, IL-18, and IL-1β were increased compared with Control group. At the same time, the protein and mRNA levels of α-SMA, NLRP3, Caspases-1, -4, -5, ASC and GSDMD-N were increased. In addition, after NAC and NSA treatment, LDH, IL-18 and IL-1β levels and the protein and mRNA expression of α-SMA, Caspases-4 and -5, and GSDMD-N were decreased. CONCLUSION HSC-LX2 pyroptosis induced by AngII-ROS is mediated by the classical pathway involving NLRP3/Caspase-1 and the non-classical pathway involving Caspases-4 and -5. Our results provide compelling evidence that AngII could activate Caspases-4 and -5 by producing ROS.
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Affiliation(s)
- Ze-Yu Xie
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311400, China
| | - Yi-Xiao Xu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311400, China
| | - Li Yao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311400, China.
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Pugliese N, Arcari I, Aghemo A, Lania AG, Lleo A, Mazziotti G. Osteosarcopenia in autoimmune cholestatic liver diseases: Causes, management, and challenges. World J Gastroenterol 2022; 28:1430-1443. [PMID: 35582674 PMCID: PMC9048470 DOI: 10.3748/wjg.v28.i14.1430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/05/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the most common cholestatic liver diseases (CLD) in adults and are both characterized by an immune pathogenesis. While primary biliary cholangitis is a model autoimmune disease, with over 90% of patients presenting very specific autoantibodies against mitochondrial antigens, PSC is considered an immune mediated disease. Osteoporosis is the most common bone disease in CLD, resulting in frequent fractures and leading to significant morbidity. Further, sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients. The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected. Although timely diagnosis, prevention, and management of osteosarcopenia are crucial to limit the consequences, there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD. International guidelines recommend screening for bone disease at the time of diagnosis of CLD. However, the optimal monitoring strategies and treatments have not been defined yet and vary among centers. We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD, and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.
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Affiliation(s)
- Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ivan Arcari
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Andrea G Lania
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Gherardo Mazziotti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
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21
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Sherwood JS, Ullal J, Kutney K, Hughan KS. Cystic fibrosis related liver disease and endocrine considerations. J Clin Transl Endocrinol 2022; 27:100283. [PMID: 35024343 PMCID: PMC8724940 DOI: 10.1016/j.jcte.2021.100283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/23/2021] [Accepted: 11/27/2021] [Indexed: 12/12/2022] Open
Abstract
Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.
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Key Words
- APRI, aspartate aminotransferase to platelet ratio
- BMI, body mass index
- CFBD, CF bone disease
- CFLD, Cystic fibrosis-liver disease
- CFRD, CF related diabetes
- CFTR, cystic fibrosis transmembrane conductance regulator
- Cirrhosis
- Cystic fibrosis liver disease
- Cystic fibrosis-related diabetes
- FFA, free fatty acids
- Fib-4, Fibrosis-4
- GH, growth hormone
- IGF-1, insulin-like growth factor-1
- Insulin resistance
- UDCA, ursodeoxycholic acid
- ULN, upper limit of normal
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Affiliation(s)
- Jordan S. Sherwood
- Department of Pediatrics, Diabetes Research Center, Division of Pediatric Endocrinology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, United States
| | - Jagdeesh Ullal
- Department of Medicine, UPMC Center for Diabetes and Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Katherine Kutney
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, United States
| | - Kara S. Hughan
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
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22
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The Change in Metabolic Syndrome Status and the Risk of Nonviral Liver Cirrhosis. Biomedicines 2021; 9:biomedicines9121948. [PMID: 34944764 PMCID: PMC8698513 DOI: 10.3390/biomedicines9121948] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/06/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease is considered to be the hepatic component of metabolic syndrome (MetS). However, the association between changes in MetS status and the risk of liver cirrhosis (LC) has not been investigated to date. This study assessed the association between changes in MetS and subsequent nonviral LC development. Methods: Data were obtained from the Korean National Health Insurance Service. Individuals who participated in health screenings from both 2009 to 2010 and 2011 to 2012 were included. The primary outcome was LC development according to the static and dynamic MetS status. Subjects were stratified into four groups according to the change in MetS status observed from the two-year interval screening (2009–2011). Cox regression analysis was used to examine the hazard ratios of LC. Results: During a median of 7.3 years of follow-up, 24,923 incident LC cases developed among 5,975,308 individuals. After adjusting for age, sex, smoking, alcohol, regular exercise, and body mass index, the adjusted hazard ratios (95% confidence intervals) for LC development were 1.39 (1.33–1.44) for the MetS-Developed group, 1.32 (1.26–1.37) for the MetS-Recovered group, and 1.51 (1.45–1.56) for the MetS-Sustained group, relative to the MetS-Free group. Stratified analyses according to age, sex, smoking, alcohol intake, exercise, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease showed similar results. Conclusions: Both static and dynamic MetS status are independent risk factors for LC development. The risk of LC was the highest in people with sustained MetS and was lower in the MetS-Recovered group than in the MetS-Sustained group. These results suggest that improving a person’s MetS status may be helpful in preventing LC.
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23
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Wang M, Liu H, Zhang X, Zhao W, Li D, Xu C, Wu Z, Xie F, Li X. Lack of Mof reduces acute liver injury by enhancing transcriptional activation of Igf1. J Cell Physiol 2021; 236:6559-6570. [PMID: 33634483 DOI: 10.1002/jcp.30332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/25/2021] [Accepted: 02/08/2021] [Indexed: 12/30/2022]
Abstract
Acute liver injury (ALI) is a rapid pathological process that may cause severe liver disease and may even be life-threatening. During ALI, the function of males absent on the first (MOF) has not yet been elucidated. In this study, we unveiled the expression pattern of MOF during carbon tetrachloride (CCl4 )-induced ALI and role of MOF in the regulation of liver regeneration. In the process of ALI, MOF is significantly overexpressed in the liver injury area. Knockdown of Mof attenuated CCl4 -induced ALI, and promoted liver cell proliferation, hepatic stellate cell activation and aggregation to the injured area, and liver fibrosis. Simultaneously, overexpression of Mof aggravated liver dysfunction caused by ALI. By directly binding to the promoter, MOF suppressed the transcriptional activation of Igf1. Knockdown of Mof promotes the expression of Igf1 and activates the Insulin-like growth factor 1 signaling pathway in the liver. Through this pathway, Knockdown of Mof reduces CCl4 -induced ALI and promotes liver regeneration. Our results provide the first demonstration for MOF contributing to ALI. Further understanding of the role of MOF in ALI may lead to new therapeutic strategies for ALI.
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Affiliation(s)
- Meng Wang
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
- Department of Cell and Neurobiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Haoyu Liu
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
| | - Xu Zhang
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
| | - Wenbo Zhao
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Danyang Li
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
- Department of Rehabilitation, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Chengpeng Xu
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
| | - Zhen Wu
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
| | - Fei Xie
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
| | - Xiangzhi Li
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, Shandong, China
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24
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Transcription factors linked to the molecular signatures in the development of hepatocellular carcinoma on a cirrhotic background. Med Oncol 2021; 38:121. [PMID: 34468893 DOI: 10.1007/s12032-021-01567-x] [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] [Received: 05/16/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023]
Abstract
Mechanisms underlying the regulation of gene expression in cancer have been surveyed for decades to find novel prognostic factors and new targets for molecular targeted therapies in cancer. Because most cases of liver cancer are associated with liver cirrhosis, we aimed to analyze the gene expression signatures and the gene regulatory mechanism in hepatocellular carcinoma (HCC) on a cirrhotic background using high-throughput data analysis. In the present study, three valid array-based datasets containing HCC and liver cirrhosis samples were obtained to identify common differentially expressed genes (DEGs). Moreover, a comprehensive data analysis was conducted based on RNA-Seq data and using Kaplan-Meier curve analysis to find molecular signatures that reduce patients' survival rate. Furthermore, we proposed a gene regulatory network (GRN) to explore the possible regulatory mechanism of these molecular signatures by transcription factors in HCC progression from cirrhosis. Besides, we analyzed protein-protein interactions, gene ontology (GO), and pathway enrichment to elucidate the cellular and molecular function of the GRN elements in HCC. In this way, we found a list of 231 molecular signatures in HCC derived from cirrhosis. We also found the importance of TCF4, RUNX1, HINFP, KDM2B, MAF, JUN, NR5A2, NFYA, and AR as key differentially expressed transcription factors (DETFs) in the progression of HCC from cirrhosis. In conclusion, the identified molecular signatures and their transcription factors propose candidate prognostic markers and possible molecular targets in the progression of HCC.
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Liu ZJ, Yan YJ, Weng HL, Ding HG. Type 2 diabetes mellitus increases liver transplant-free mortality in patients with cirrhosis: A systematic review and meta-analysis. World J Clin Cases 2021; 9:5514-5525. [PMID: 34307604 PMCID: PMC8281398 DOI: 10.12998/wjcc.v9.i20.5514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/27/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The impact of type 2 diabetes mellitus (T2DM) on the prognosis and complications of liver cirrhosis is not fully clarified. AIM To clarify the mortality and related risk factors as well as complications in cirrhotic patients with T2DM. METHODS We searched PubMed, EMBASE, and the Cochrane Library from their inception to December 1, 2020 for cohort studies comparing liver transplant-free mortality, hepatocellular carcinoma (HCC), ascites, spontaneous bacterial peritonitis (SBP), variceal bleeding, and hepatic encephalopathy (HE) in cirrhotic patients with vs without T2DM. Odds ratios (ORs) were combined by using fixed-effects or random-effects models with RevMan software. RESULTS The database search generated a total of 17 cohort studies that met the inclusion criteria. Among these studies, eight reported the risk of mortality, and eight reported the risk of HCC. Three studies provided SBP rates, and two documented ascites rates. Four articles focused on HE rates, and three focused on variceal bleeding rates. Meta-analysis indicated that T2DM was significantly associated with an increased risk of liver transplant-free mortality [OR: 1.28, 95% confidence intervals (CI): 1.16-1.41, P < 0.0001] and HCC incidence (OR: 1.82, 95%CI: 1.32-2.51, P = 0.003). The risk of SBP was not significantly increased (OR: 1.16 95%CI: 0.86-1.57, P = 0.34). Additionally, T2DM did not significantly increase HE (OR: 1.31 95%CI: 0.97-1.77, P = 0.08), ascites (OR: 1.11 95%CI: 0.84-1.46, P = 0.46), and variceal bleeding (OR: 1.34, 95%CI: 0.99-1.82, P = 0.06). CONCLUSION The findings suggest that cirrhotic patients with T2DM have a poor prognosis and high risk of HCC. T2DM may not be associated with an increased risk of SBP, variceal bleeding, ascites, or HE in cirrhotic patients with T2DM.
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Affiliation(s)
- Zi-Jin Liu
- Department of Gastroenterology and Hepatology, Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
| | - Yi-Jie Yan
- Department of Gastroenterology and Hepatology, Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
| | - Hong-Lei Weng
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Hui-Guo Ding
- Department of Gastroenterology and Hepatology, Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
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26
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Bentz Damholt B, Dombernowsky SL, Dahl Bendtsen M, Bisgaard C, Højby Rasmussen M. Effect of Kidney or Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Somapacitan: Two Open-Label, Parallel-Group Trials. Clin Pharmacokinet 2021; 60:1015-1027. [PMID: 33754315 PMCID: PMC8332591 DOI: 10.1007/s40262-021-00990-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2021] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Somapacitan is a long-acting growth hormone (GH) derivative being developed for once-weekly dosing in patients with GH deficiency (GHD). Our objective was to evaluate the impact of kidney or hepatic impairment on somapacitan exposure in adults. METHODS In two open-label, parallel-group, single-center, 6-week trials, eligible subjects (18-75 years of age, body mass index 18.5-34.9 kg/m2, GH-naïve, without GHD) were divided into five kidney (total n = 44) or three hepatic (n = 34) function groups. Subjects with normal kidney/hepatic function were matched to those with kidney/hepatic impairment by age, sex, and body weight. Subjects received three subcutaneous somapacitan administrations (0.08 mg/kg) on days 1, 8, and 15. Blood samples were collected before each dose, at 28 time points throughout 2 weeks after the last dose, and at follow-up (3-4 weeks after the last dose). The primary endpoint was area under the somapacitan serum concentration-time curve up to 1 week after the last dose (AUC0-168 h), while secondary endpoints included AUC0-168 h of insulin-like growth factor (IGF)-I. RESULTS In the kidney impairment trial, somapacitan AUC0-168 h was higher in groups with severe kidney impairment and requiring hemodialysis versus the normal kidney function group (estimated ratio and 90% confidence interval 1.75 [1.00-3.06] and 1.63 [1.01-2.61], respectively). AUC0-168 h of IGF-I was increased in the moderate impairment group (1.35 [1.09-1.66]), severe impairment group (1.40 [1.10-1.78]), and requiring hemodialysis group (1.24 [1.01-1.52]), compared with the normal function group. In the hepatic impairment trial, somapacitan AUC0-168 h was significantly higher in the moderate impairment group compared with the normal hepatic function group (4.69 [2.92-7.52]). IGF-I AUC0-168 h was lower in both hepatic impairment groups (0.85 [0.67-1.08] for the mild impairment group and 0.75 [0.60-0.95] for the moderate impairment group) compared with the normal function group. No new safety or tolerability issues were observed. CONCLUSIONS In summary, somapacitan exposure increased with level of kidney/hepatic impairment. Clinically, this will be taken into account when treating adults with GHD with somapacitan, as doses should be individually titrated. CLINICAL TRIAL REGISTRATION NCT03186495 (kidney impairment trial, registered 12 June 2017); NCT03212131 (hepatic impairment trial, registered 30 June 2017).
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Late Health Effects of Partial Body Irradiation Injury in a Minipig Model Are Associated with Changes in Systemic and Cardiac IGF-1 Signaling. Int J Mol Sci 2021; 22:ijms22063286. [PMID: 33807089 PMCID: PMC8005067 DOI: 10.3390/ijms22063286] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 12/30/2022] Open
Abstract
Clinical, epidemiological, and experimental evidence demonstrate non-cancer, cardiovascular, and endocrine effects of ionizing radiation exposure including growth hormone deficiency, obesity, metabolic syndrome, diabetes, and hyperinsulinemia. Insulin-like growth factor-1 (IGF-1) signaling perturbations are implicated in development of cardiovascular disease and metabolic syndrome. The minipig is an emerging model for studying radiation effects given its high analogy to human anatomy and physiology. Here we use a minipig model to study late health effects of radiation by exposing male Göttingen minipigs to 1.9–2.0 Gy X-rays (lower limb tibias spared). Animals were monitored for 120 days following irradiation and blood counts, body weight, heart rate, clinical chemistry parameters, and circulating biomarkers were assessed longitudinally. Collagen deposition, histolopathology, IGF-1 signaling, and mRNA sequencing were evaluated in tissues. Our findings indicate a single exposure induced histopathological changes, attenuated circulating IGF-1, and disrupted cardiac IGF-1 signaling. Electrolytes, lipid profiles, liver and kidney markers, and heart rate and rhythm were also affected. In the heart, collagen deposition was significantly increased and transforming growth factor beta-1 (TGF-beta-1) was induced following irradiation; collagen deposition and fibrosis were also observed in the kidney of irradiated animals. Our findings show Göttingen minipigs are a suitable large animal model to study long-term effects of radiation exposure and radiation-induced inhibition of IGF-1 signaling may play a role in development of late organ injuries.
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28
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Yang YJ, Kim DJ. An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia. Int J Mol Sci 2021; 22:2604. [PMID: 33807573 PMCID: PMC7961345 DOI: 10.3390/ijms22052604] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.
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Affiliation(s)
- Young Joo Yang
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
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Stroup BM, Marom R, Li X, Hsu CW, Chang CY, Truong LD, Dawson B, Grafe I, Chen Y, Jiang MM, Lanza D, Green JR, Sun Q, Barrish JP, Ani S, Christiansen AE, Seavitt JR, Dickinson ME, Kheradmand F, Heaney JD, Lee B, Burrage LC. A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance. Hum Mol Genet 2020; 29:2171-2184. [PMID: 32504080 PMCID: PMC7399531 DOI: 10.1093/hmg/ddaa107] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 04/30/2020] [Accepted: 05/19/2020] [Indexed: 12/18/2022] Open
Abstract
Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.
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Affiliation(s)
- Bridget M Stroup
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children's Hospital, Houston, TX 77030, USA
| | - Xiaohui Li
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chih-Wei Hsu
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Cheng-Yen Chang
- Department of Medicine-Pulmonary, Baylor College of Medicine, Houston, TX 77030, USA
| | - Luan D Truong
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Brian Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ingo Grafe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Center for Healthy Aging, University Clinic, Dresden D-01307, Germany
| | - Yuqing Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ming-Ming Jiang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Denise Lanza
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jennie Rose Green
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Qin Sun
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Baylor Genetics, Houston, TX 77021, USA
| | - J P Barrish
- Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA
| | - Safa Ani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Audrey E Christiansen
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - John R Seavitt
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mary E Dickinson
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Farrah Kheradmand
- Department of Medicine-Pulmonary, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jason D Heaney
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lindsay C Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children's Hospital, Houston, TX 77030, USA
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30
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Hosnedlova B, Vernerova K, Kizek R, Bozzi R, Kadlec J, Curn V, Kouba F, Fernandez C, Machander V, Horna H. Associations between IGF1, IGFBP2 and TGFß3 Genes Polymorphisms and Growth Performance of Broiler Chicken Lines. Animals (Basel) 2020; 10:E800. [PMID: 32380764 PMCID: PMC7277336 DOI: 10.3390/ani10050800] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 01/18/2023] Open
Abstract
Marker-assisted selection based on fast and accurate molecular analysis of individual genes is considered an acceptable tool in the speed-up of the genetic improvement of production performance in chickens. The objective of this study was to detect the single nucleotide polymorphisms (SNPs) in the IGF1, IGFBP2 and TGFß3 genes, and to investigate their associations with growth performance (body weight (BW) and average daily gain (ADG) at 14, 21, 28, 35 and 42 days of age) and carcass traits in broilers. Performance (carcass) data (weight before slaughter; weights of the trunk, giblets, abdominal fat, breast muscle and thigh muscle; slaughter value and slaughter percentage), as well as blood samples for DNA extraction and SNP analysis, were obtained from 97 chickens belonging to two different lines (Hubbard F15 and Cobb E) equally divided between the two sexes. The genotypes were detected using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) methods with specific primers and restrictase for each gene. The statistical analysis discovered significant associations (p < 0.05) between the TGFβ3 SNP and the following parameters: BW at 21, 28 and 35 days, trunk weight and slaughter value. Association analysis of BWs (at 21, 28 and 35 days) and SNPs was always significant for codominant, dominant and overdominant genetic models, showing a possible path for genomic selection in these chicken lines. Slaughter value was significant for codominant, recessive and overdominant patterns, whereas other carcass traits were not influenced by SNPs. Based on the results of this study, we suggested that the TGFβ3 gene could be used as a candidate gene marker for chicken growth traits in the Hubbard F15 and Cobb E population selection programs, whereas for carcass traits further investigation is needed.
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Affiliation(s)
- Bozena Hosnedlova
- Veterinary Research Institute, Hudcova 296/70, 621 00 Brno, Czech Republic;
| | - Katerina Vernerova
- Biotechnological Centre, Faculty of Agriculture, University of South Bohemia in České Budějovice, Studentská 1668, 370 05 České Budějovice, Czech Republic; (K.V.); (V.C.)
| | - Rene Kizek
- Veterinary Research Institute, Hudcova 296/70, 621 00 Brno, Czech Republic;
- Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1946/1, 612 42 Brno, Czech Republic
- Department of Biomedical and Environmental Analyses, Faculty of Pharmacy with Division of Laboratory Medicine, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
| | - Riccardo Bozzi
- Food, Environment and Forestry, Animal Science Section, Department of Agriculture, University of Florence, Via delle Cascine, 5, 50144 Firenze, Italy;
| | - Jaromir Kadlec
- Department of Agricultural Products’ Quality, Faculty of Agriculture, University of South Bohemia in České Budějovice, Studentská 1668, 370 05 České Budějovice, Czech Republic;
| | - Vladislav Curn
- Biotechnological Centre, Faculty of Agriculture, University of South Bohemia in České Budějovice, Studentská 1668, 370 05 České Budějovice, Czech Republic; (K.V.); (V.C.)
| | - Frantisek Kouba
- State Veterinary Administration, Regional Veterinary Administration of the South Bohemian Region, Severní 9, 370 10 České Budějovice, Czech Republic;
| | - Carlos Fernandez
- School of Pharmacy and Life Sciences, Robert Gordon University, Garthdee Road, Aberdeen AB10 7QB, UK;
| | - Vlastislav Machander
- International Testing of Poultry, Ústrašice 63, 390 02 Tábor, Czech Republic; (V.M.); (H.H.)
| | - Hana Horna
- International Testing of Poultry, Ústrašice 63, 390 02 Tábor, Czech Republic; (V.M.); (H.H.)
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31
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Jeong HM, Kim DJ. Bone Diseases in Patients with Chronic Liver Disease. Int J Mol Sci 2019; 20:4270. [PMID: 31480433 PMCID: PMC6747370 DOI: 10.3390/ijms20174270] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 08/25/2019] [Accepted: 08/28/2019] [Indexed: 02/07/2023] Open
Abstract
Osteoporosis is a frequently observed complication in patients with chronic liver disease, particularly liver cirrhosis and cholestatic liver diseases. In addition, osteoporosis is critical in patients receiving a liver transplant. Nevertheless, few studies have evaluated bone diseases in patients with more frequently observed chronic liver disease, such as chronic viral hepatitis, nonalcoholic fatty liver disease and alcoholic liver disease. Osteoporosis is a disease caused by an imbalance in the activities of osteoblasts and osteoclasts. Over the last few decades, many advances have improved our knowledge of the pathogenesis of osteoporosis. Importantly, activated immune cells affect the progression of osteoporosis, and chronic inflammation may exert an additional effect on the existing pathophysiology of osteoporosis. The microbiota of the intestinal tract may also affect the progression of bone loss in patients with chronic liver disease. Recently, studies regarding the effects of chronic inflammation on dysbiosis in bone diseases have been conducted. However, mechanisms underlying osteoporosis in patients with chronic liver disease are complex and precise mechanisms remain unknown. The following special considerations in patients with chronic liver disease are reviewed: bone diseases in patients who underwent a liver transplant, the association between chronic hepatitis B virus infection treatment and bone diseases, the association between sarcopenia and bone diseases in patients with chronic liver disease, and the association between chronic liver disease and avascular necrosis of the hip. Few guidelines are currently available for the management of low bone mineral density or bone diseases in patients with chronic liver disease. Due to increased life expectancy and therapeutic advances in chronic liver disease, the importance of managing osteoporosis and other bone diseases in patients with chronic liver disease is expected to increase. Consequently, specific guidelines need to be established in the near future.
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Affiliation(s)
- Hae Min Jeong
- Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24253, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Gangwon-do 24253, Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Gangwon-do 24253, Korea.
- Department of Internal Medicine, Hallym University College of Medicine, Seoul 05355, Korea.
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32
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Yao Y, Miao X, Zhu D, Li D, Zhang Y, Song C, Liu K. Insulin-like growth factor-1 and non-alcoholic fatty liver disease: a systemic review and meta-analysis. Endocrine 2019; 65:227-237. [PMID: 31243652 DOI: 10.1007/s12020-019-01982-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 06/10/2019] [Indexed: 12/11/2022]
Abstract
AIM The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide. A number of researchers have studied the relationship between Insulin-like growth factor-1(IGF-1) and NAFLD. However, the results are controversial. This meta-analysis, aimed to systemically evaluate the correlation between IGF-1 and NAFLD. METHODS We searched for four online databases: PubMed, Web of Science, Embase and CNKI up to Feb 2018. We then applied a random-effects model to evaluate the overall effect sizes by calculating Standard mean difference (SMD) and its 95% confidence intervals (CIs). RESULTS Twelve articles were included in this meta-analysis. The pooled analysis showed that the level of IGF-1 in the control group was significantly higher than that in the NAFLD group. (SMD: 1.00, 95% CI: 0.54-1.46, P < 0.00001). However, significant heterogeneity was discovered among the included studies (P < 0.00001, I2 = 96%). Then a series of subgroup analyses were performed. Compared to the nonalcoholic steatohepatitis (NASH) group, the level of IGF-1 was significantly higher in the Non- or probable-NASH group (SMD: 1.42, 95% CI: 0.25-2.58, P = 0.02). The level of IGF-1 in patients with increased insulin resistance (SMD: 0.49; 95% CI: 0.36-0.63; P < 0.00001) and high Body Mass Index (SMD: 0.50; 95% CI: 0.22-0.79; P < 0.05) were significantly lower than healthy control. In addition, the same conclusion were found in studies carried out in Asia and Europe (Asia: SMD: 0.69, 95% CI: -0.29-1.66, P = 0.17; Europe: SMD: 0.89, 95% CI: 0.41-1.38, P < 0.05). CONCLUSION The level of IGF-1 is down-regulated in NAFLD patients compared to healthy controls, suggesting that IGF-1 might be used as a potential biomarker and therapeutic target for NAFLD.
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Affiliation(s)
- Yang Yao
- Department of Central Laboratory, the First Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi, 710077, PR China
| | - Xiangxia Miao
- Clinical Medicine (three-year program) of Postgrade 2016, Xi'an Medical University, Xi'an, Shaanxi, 710021, PR China
| | - Donglie Zhu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China
| | - Ying Zhang
- Clinical Medicine (three-year program) of Postgrade 2017, Xi'an Medical University, Xi'an, Shaanxi, 710021, PR China
| | - Chengyan Song
- Clinical Medicine (three-year program) of Postgrade 2017, Xi'an Medical University, Xi'an, Shaanxi, 710021, PR China
| | - Kaige Liu
- Department of Gastroenterology, the First Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi, 710077, PR China.
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33
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Lonardo A, Mantovani A, Lugari S, Targher G. NAFLD in Some Common Endocrine Diseases: Prevalence, Pathophysiology, and Principles of Diagnosis and Management. Int J Mol Sci 2019; 20:2841. [PMID: 31212642 PMCID: PMC6600657 DOI: 10.3390/ijms20112841] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/04/2019] [Indexed: 02/07/2023] Open
Abstract
Secondary nonalcoholic fatty liver disease (NAFLD) defines those complex pathophysiological and clinical consequences that ensue when the liver becomes an ectopic site of lipid storage owing to reasons other than its mutual association with the metabolic syndrome. Disorders affecting gonadal hormones, thyroid hormones, or growth hormones (GH) may cause secondary forms of NAFLD, which exhibit specific pathophysiologic features and, in theory, the possibility to receive an effective treatment. Here, we critically discuss epidemiological and pathophysiological features, as well as principles of diagnosis and management of some common endocrine diseases, such as polycystic ovary syndrome (PCOS), hypothyroidism, hypogonadism, and GH deficiency. Collectively, these forms of NAFLD secondary to specific endocrine derangements may be envisaged as a naturally occurring disease model of NAFLD in humans. Improved understanding of such endocrine secondary forms of NAFLD promises to disclose novel clinical associations and innovative therapeutic approaches, which may potentially be applied also to selected cases of primary NAFLD.
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Affiliation(s)
- Amedeo Lonardo
- Operating Unit Internal Medicine-Ospedale Civile di Baggiovara-AOU, 41125 Modena, Italy.
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy.
| | - Simonetta Lugari
- Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, 41125 Modena, Italy.
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy.
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34
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Michalson KT, Macintyre AN, Sempowski GD, Bourland JD, Howard TD, Hawkins GA, Dugan GO, Cline JM, Register TC. Monocyte Polarization is Altered by Total-Body Irradiation in Male Rhesus Macaques: Implications for Delayed Effects of Acute Radiation Exposure. Radiat Res 2019; 192:121-134. [PMID: 31161966 DOI: 10.1667/rr15310.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Radiation-induced fibrosis (RIF) is a common delayed effect of acute ionizing radiation exposure (DEARE) affecting diverse tissues including the heart, lungs, liver and skin, leading to reduced tissue function and increased morbidity. Monocytes, which may be classified into classical (CD14++, CD16-), intermediate (CD14++, CD16+) and non-classical (CD14+/low, CD16++) subtypes in humans and non-human primates (NHPs), and monocyte-derived macrophages may play an integral role in the pathogenesis of RIF. We tested the hypothesis that moderate to high levels of total-body exposure to radiation would alter monocyte polarization and produce phenotypes that could promote multi-organ fibrosis in a wellestablished NHP model of DEARE. Subjects were 16 young adult male rhesus macaques, ten of which were exposed to high-energy, 4 Gy X-ray total-body irradiation (TBI) and six that received sham irradiation (control). Total monocytes assessed by complete blood counts were 89% depleted in TBI animals by day 9 postirradiation (P < 0.05), but recovered by day 30 postirradiation and did not differ from control levels thereafter. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) and sorted into classical, intermediate and non-classical subsets using fluorescence-activated cell sorting (FACS) prior to and at 6 months post-TBI. At 6 months postirradiation, monocyte polarization shifted towards lower classical (92% → 86%) and higher intermediate (7% → 12%) and non-classical monocyte subsets (0.6% → 2%) (all P < 0.05) in TBI animals compared to baseline. No change in monocyte subsets was observed in control animals. Transcriptional profiles in classical and intermediate monocyte subsets were assessed using RNAseq. Classical monocyte gene expression did not change significantly over time or differ cross-sectionally between TBI and control groups. In contrast, significant numbers of differentially expressed genes (DEGs) were detected in intermediate monocyte comparisons between the TBI animals and all animals at baseline (304 DEGs), and in the TBI versus control animals at 6 months postirradiation (67 DEGs). Intermediate monocytes also differed between baseline and 6 months in control animals (147 DEGs). Pathway analysis was used to identify genes within significant canonical pathways, yielding 52 DEGs that were specific to irradiated intermediate monocytes. These DEGs and significant canonical pathways were associated with pro-fibrotic and anti-inflammatory signaling pathways that have been noted to induce M2 macrophage polarization. These findings support the hypothesis that TBI may alter monocyte programming and polarization towards a profibrotic phenotype, providing a novel target opportunity for therapies to inhibit or prevent RIF.
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Affiliation(s)
- Kristofer T Michalson
- Department of a Pathology/Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Andrew N Macintyre
- d Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina
| | - Gregory D Sempowski
- d Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina
| | - J Daniel Bourland
- b Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Timothy D Howard
- c Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Gregory A Hawkins
- c Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Gregory O Dugan
- Department of a Pathology/Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - J Mark Cline
- Department of a Pathology/Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Thomas C Register
- Department of a Pathology/Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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35
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Laube R, Wang H, Park L, Heyman JK, Vidot H, Majumdar A, Strasser SI, McCaughan GW, Liu K. Frailty in advanced liver disease. Liver Int 2018; 38:2117-2128. [PMID: 29935102 DOI: 10.1111/liv.13917] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/20/2018] [Indexed: 12/15/2022]
Abstract
Prognostication of patients with cirrhosis is complex, depending on more than just the severity of liver disease. Scores such as the model for end-stage liver disease (MELD) and Child Pugh can assist with prognostication, yet by focusing on physiological parameters they fail to completely capture the elements contributing to a patient's clinical status. Evidence is increasing to support an important role for physical functioning in patient outcomes. Frailty has been increasingly recognised in medical literature over recent years, including in hepatology where it is identified in nearly half of cirrhosis patients. It is a complex construct consisting of multisystemic physiological decline and increased vulnerability to stressors. Diagnosis is complicated by lack of a consensus definition and measurement tool for frailty in cirrhosis. Frailty heralds a poor prognosis, predicting increased morbidity and mortality both pre- and postliver transplant, independent of MELD score. It is thought to be reversible, with promising data supporting prehabilitation and lifestyle intervention programs. In the future, assessment of patients with cirrhosis is likely to incorporate a measure of frailty, however, further research is required.
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Affiliation(s)
- Robyn Laube
- Gastroenterology and Liver Services, Concord Hospital, Sydney, NSW, Australia
| | - Hogan Wang
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Laura Park
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Joanne K Heyman
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Department Nutrition & Dietetics, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Helen Vidot
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Department Nutrition & Dietetics, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Avik Majumdar
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Simone I Strasser
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.,AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Geoffrey W McCaughan
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.,AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Injury and Cancer Program, Centenary Institute, The University of Sydney, Sydney, NSW, Australia
| | - Ken Liu
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.,AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Injury and Cancer Program, Centenary Institute, The University of Sydney, Sydney, NSW, Australia
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36
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Singh MK, Das BK, Choudhary S, Gupta D, Patil UK. Diabetes and hepatocellular carcinoma: A pathophysiological link and pharmacological management. Biomed Pharmacother 2018; 106:991-1002. [PMID: 30119271 DOI: 10.1016/j.biopha.2018.06.095] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 06/15/2018] [Accepted: 06/16/2018] [Indexed: 02/07/2023] Open
Abstract
Both diabetes mellitus (DM) and cancer are multifarious, dissimilar, and long-lasting, fatal diseases with a remarkable influence on health worldwide. DM is not only related to cardiovascular diseases, neuropathy, nephropathy, and retinopathy, but also related to a number of liver diseases such as nonalcoholic fatty liver disease, steatohepatitis, and liver cirrhosis. Recently, it is hypothesized that DM has a greater risk for many forms of cancer, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer including hepatocellular carcinoma (HCC). Both DM and cancer have many common risk factors, but the association between these two is poorly stated. Several epidemiologic studies have revealed the association between pathogenic and prognostic characteristics of DM and a higher incidence of HCC, thus representing DM as an independent risk factor for HCC development. The etiological and pathophysiological relationship between DM and HCC has been presented in this review by linking hyperglycemia, hyperinsulinemia, insulin resistance, and activation of insulin-like growth factor signaling pathways and pharmacological management of HCC associated with DM.
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Affiliation(s)
- Mandeep Kumar Singh
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India
| | - Bhrigu Kumar Das
- Department of Pharmacology, K.L.E.U's College of Pharmacy, Hubballi, Karnataka, India
| | - Sandeep Choudhary
- Division of Radiation Biodosimetry, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organisation, New Delhi, India.
| | - Deepak Gupta
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India
| | - Umesh K Patil
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India
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37
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Li B, Zhang C, Zhan YT. Nonalcoholic Fatty Liver Disease Cirrhosis: A Review of Its Epidemiology, Risk Factors, Clinical Presentation, Diagnosis, Management, and Prognosis. Can J Gastroenterol Hepatol 2018; 2018:2784537. [PMID: 30065915 PMCID: PMC6051295 DOI: 10.1155/2018/2784537] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 05/31/2018] [Accepted: 06/13/2018] [Indexed: 12/11/2022] Open
Abstract
Cirrhosis is the common end stage of a number of chronic liver conditions and a significant cause of morbidity and mortality. With the growing epidemic of obesity and metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide and will become one of the leading causes of cirrhosis. Increased awareness and understanding of NAFLD cirrhosis are essential. To date, there has been no published systematic review on NAFLD cirrhosis. Thus, this article reviews recent studies on the epidemiology, risk factors, clinical presentation, diagnosis, management, and prognosis of NAFLD cirrhosis.
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Affiliation(s)
- Bei Li
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Chuan Zhang
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Yu-Tao Zhan
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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38
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Cabrera D, Cabello-Verrugio C, Solís N, San Martín D, Cofré C, Pizarro M, Arab JP, Abrigo J, Campos F, Irigoyen B, Carrasco-Avino G, Bezares K, Riquelme V, Riquelme A, Arrese M, Barrera F. Somatotropic Axis Dysfunction in Non-Alcoholic Fatty Liver Disease: Beneficial Hepatic and Systemic Effects of Hormone Supplementation. Int J Mol Sci 2018; 19:ijms19051339. [PMID: 29724029 PMCID: PMC5983806 DOI: 10.3390/ijms19051339] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/30/2018] [Accepted: 04/10/2018] [Indexed: 02/07/2023] Open
Abstract
Background: Somatotropic axis dysfunction associated with non-alcoholic fatty liver disease (NAFLD) has potential multisystemic detrimental effects. Here, we analysed the effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) supplementation on liver histology, adipokine profile and muscle function in an NAFLD model. Methods: C57BL/6 mice were fed with a high fat diet (HFD) for 12 weeks and were separated into three groups treated for 4 weeks with: (1) High fat diet (HFD) (n = 10); (2) HFD + GH 9 μg/g/d (n = 10); (3) HFD + IGF-1 0.02 µg/g/d (n = 9). A control group fed a chow diet was included (n = 6). Liver histology, liver triglycerides content, serum alanine aminotransferase (ALT) activity, adiponectin and leptin serum levels, in vivo muscle strength, tetanic force and muscle fibre cross-sectional area (CSA) were measured. Results: HFD + GH and HFD + IGF-1 groups showed significantly lower ALT activity compared to HFD (p < 0.01). Liver triglyceride content in HFD + GH was decreased compared to HFD (p < 0.01). Histologic steatosis score was increased in HFD and HFD + GH group (p < 0.01), whereas HFD + IGF-1 presented no difference compared to the chow group (p = 0.3). HFD + GH group presented lower serum leptin and adiponectin levels compared to HFD. GH and IGF-1 supplementation therapy reverted HFD-induced reduction in muscle strength and CSA (sarcopenia). Conclusions: GH and IGF-1 supplementation induced significant improvement in liver steatosis, aminotransferases and sarcopenia in a diet-induced NAFLD model.
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Affiliation(s)
- Daniel Cabrera
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | | | - Nancy Solís
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Diego San Martín
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Catalina Cofré
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Margarita Pizarro
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Juan Pablo Arab
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Johanna Abrigo
- Faculty of Biological Sciences, Universidad Andrés Bello, Santiago 8320000, Chile.
| | - Fabián Campos
- Faculty of Biological Sciences, Universidad Andrés Bello, Santiago 8320000, Chile.
| | - Betzabé Irigoyen
- Faculty of Biological Sciences, Universidad Andrés Bello, Santiago 8320000, Chile.
| | - Gonzalo Carrasco-Avino
- Departament of Pathotology, Clínica Las Condes, Santiago 8320000, Chile.
- Department of Pathology, Hospital Clínico Universidad de Chile, Santiago 8320000, Chile.
| | - Katiuska Bezares
- Department of Pathology, Hospital Clínico San Juan de Dios, Santiago 8320000, Chile.
| | - Valentina Riquelme
- Faculty of Arts, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Arnoldo Riquelme
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
- Department of Health Sciences, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Marco Arrese
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
- Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Francisco Barrera
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
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