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Buchanan RM, Reinson T, Bilson J, Woodland H, Nwoguh C, Cooper K, Harris S, Malone K, Byrne CD. Screening to identify people with type 2 diabetes at risk of liver cancer in primary care: a randomised controlled trial protocol. BMJ Open 2025; 15:e088043. [PMID: 40050060 PMCID: PMC11887308 DOI: 10.1136/bmjopen-2024-088043] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 02/07/2025] [Indexed: 03/09/2025] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is expected to become the third most common cause of cancer death worldwide by 2030. The increase in HCC is in large part due to the rising prevalence of risk factors such as type 2 diabetes mellitus (T2DM). Up to 1 in 20 people living with T2DM have liver cirrhosis, and they have a 1% to 2% incidence of HCC per year. Patients with cirrhosis enter surveillance for HCC to identify early-stage, curable tumours. A diagnosis of T2DM does not mandate testing to identify patients with cirrhosis, with testing restricted to those with additional risks. There has never been a trial and nested cost-effectiveness evaluation comparing screening all patients with T2DM for cirrhosis against usual care. METHODS AND ANALYSIS The study will use a multi-centre, unblinded individual randomised controlled trial design. The aim will be to determine the effectiveness and cost-effectiveness of screening all adults with T2DM to identify those at high risk of HCC. The recruitment strategy has been supported by patient and public involvement (PPI). Participants will be identified via an automated search of primary care records and invited to participate via text. 320 participants will be randomised for screening. The screening will include measurement of bio-markers for liver fibrosis (ELF and Fib-4) and vibration-controlled transient elastography. Another 320 participants will be randomised to standard care. Demographic and medical history data will be collected at baseline from all participants. Outcome data will be collected remotely from healthcare records. The primary outcome is the proportion of participants in each arm who are referred to HCC surveillance following testing for liver disease within 12 months of randomisation. The results will be used to calculate the incremental cost-effectiveness ratio of screening via a Markov model. ETHICS AND DISSEMINATION The results of this study will be presented directly to National Health Service England. Additional dissemination via conference proceedings and publication will be supported by our PPI team. Ethical approval was granted by the West of Scotland Research Ethics Service on 2 August 2023, REC reference 23/WS/0102. TRIAL REGISTRATION NUMBER ISRCTN17017677.
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Affiliation(s)
- Ryan M Buchanan
- University of Southampton Faculty of Medicine, Southampton, UK
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Tina Reinson
- Clinical and Experimental Sciences Division, University of Southampton Faculty of Medicine, Southampton, UK
| | - Josh Bilson
- University of Southampton Faculty of Medicine, Southampton, UK
| | - Hazel Woodland
- Salisbury District Hospital NHS Foundation Trust, Salisbury, UK
| | - Chinonso Nwoguh
- University of Southampton Faculty of Medicine, Southampton, UK
| | - Keith Cooper
- Southampton Health Technology Assessment Centre, University of Southampton, Southampton, UK
| | - Scott Harris
- University of Southampton Faculty of Medicine, Southampton, UK
| | | | - Christopher D Byrne
- University of Southampton Faculty of Medicine, Southampton, UK
- NIHR Southampton Biomedical Research Centre, Southampton, UK
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Wang Y, Wang P. Development and validation of a new diagnostic prediction model for NAFLD based on machine learning algorithms in NHANES 2017-2020.3. Hormones (Athens) 2025:10.1007/s42000-025-00634-6. [PMID: 39939537 DOI: 10.1007/s42000-025-00634-6] [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: 10/13/2024] [Accepted: 02/03/2025] [Indexed: 02/14/2025]
Abstract
AIMS Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease that can trigger the metabolic syndrome. Early prevention and treatment of NAFLD is still a huge challenge for patients and clinicians. The aim of this study was to develop and validate machine learning (ML)-based predictive models. The model with optimal performance would be developed as a set of simple arithmetic tools for predicting the risk of NAFLD individually. METHODS Statistical analyses were performed in 2428 individuals extracted from the National Health and Nutrition Examination Survey (NHANES, cycle 2017-2020.3) database. Feature variables were selected by the least absolute shrinkage and selection operator (LASSO) regression. Seven ML algorithms, including logistic regression (LR), decision tree (DT), random forest (RF), extreme gradient boosting (XGB), K-nearest neighbor (KNN), light gradient boosting machine (LightGBM), and multilayer perceptron (MLP), were used to construct models based on the feature variables and evaluate their performance. The model with the best performance was transformed into a diagnostic predictive nomogram (DPN). The DPN was developed into an online calculator and an Excel algorithm tool. Receiver operating characteristic (ROC) curve, decision curve analysis (DCA), and subgroup analyses were used to compare and assess the predictive abilities of the DPN and six existing NAFLD predictive models, including the ZJU index, the hepatic steatosis index (HSI), the triglyceride-glucose index (TyG), the Framingham steatosis index (FSI), the fatty liver index (FLI), and the visceral adiposity index (VAI). RESULTS Among the 2428 participants, the prevalence of NAFLD was 47.45%. LASSO regression identified eight variables from 39 variables, including body mass index (BMI), waist circumference (WC), alanine aminotransferase (ALT), triglyceride (TG), diabetes, hypertension, uric acid (UA), and race. Among the models constructed by the seven algorithms mentioned above, the LR-based model performed the best, demonstrating outstanding performance in terms of area under the curve (AUC, 0.823), accuracy (0.754), precision (0.768), specificity (0.804), and positive predictive value (0.768). It was then transformed into the DPN, which was successfully developed as an online calculator and an Excel algorithm tool. The diagnostic accuracy (AUC 0.856, 95% confidence interval (CI) 0.839-0.874, and AUC 0.823, 95% CI 0.793-0.854, respectively) and net clinical benefit of DPN in the training and validation sets were superior to those of the ZJU, HSI, TyG, FSI, FLI, and VAI. The results were maintained in subgroup analyses. CONCLUSIONS The LR model based on ML was developed, exhibiting good performance. DPN can be used as an individualized tool for rapid detection of NAFLD.
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Affiliation(s)
- Yazhi Wang
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Peng Wang
- The Department of Pharmacy, The 987th Hospital of Joint Logistics Support Force of People's Liberation Army, Baoji, Shaanxi, 721004, China.
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Wu G, Wu S, Xiong T, Yao Y, Qiu Y, Meng L, Chen C, Yang X, Liang X, Qin Y. Identification of biomarkers for the diagnosis of type 2 diabetes mellitus with metabolic associated fatty liver disease by bioinformatics analysis and experimental validation. Front Endocrinol (Lausanne) 2025; 16:1512503. [PMID: 39936105 PMCID: PMC11810736 DOI: 10.3389/fendo.2025.1512503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/08/2025] [Indexed: 02/13/2025] Open
Abstract
Background Type 2 diabetes (T2DM) combined with fatty liver is a subtype of metabolic fatty liver disease (MAFLD), and the relationship between T2DM and MAFLD is close and mutually influential. However, the connection and mechanisms between the two are still unclear. Therefore, we aimed to identify potential biomarkers for diagnosing both conditions. Methods We performed differential expression analysis and weighted gene correlation network analysis (WGCNA) on publicly available data on the two diseases in the Gene Expression Omnibus database to find genes related to both conditions. We utilised protein-protein interactions (PPIs), Gene Ontology, and the Kyoto Encyclopedia of Genes and Genomes to identify T2DM-associated MAFLD genes and potential mechanisms. Candidate biomarkers were screened using machine learning algorithms combined with 12 cytoHubba algorithms, and a diagnostic model for T2DM-related MAFLD was constructed and evaluated.The CIBERSORT method was used to investigate immune cell infiltration in MAFLD and the immunological significance of central genes. Finally, we collected whole blood from patients with T2DM-related MAFLD, MAFLD patients and healthy individuals, and used high-fat, high-glucose combined with high-fat cell models to verify the expression of hub genes. Results Differential expression analysis and WGCNA identified 354 genes in the MAFLD dataset. The differential expression analysis of the T2DM-peripheral blood mononuclear cells/liver dataset screened 91 T2DM-associated secreted proteins. PPI analysis revealed two important modules of T2DM-related pathogenic genes in MAFLD, which contained 49 nodes, suggesting their involvement in cell interaction, inflammation, and other processes. TNFSF10, SERPINB2, and TNFRSF1A were the only coexisting genes shared between MAFLD key genes and T2DM-related secreted proteins, enabling the construction of highly accurate diagnostic models for both disorders. Additionally, high-fat, high-glucose combined with high-fat cell models were successfully produced. The expression patterns of TNFRSF1A and SERPINB2 were verified in patient blood and our cellular model. Immune dysregulation was observed in MAFLD, with TNFRSF1A and SERPINB2 strongly linked to immune regulation. Conclusion The sensitivity and accuracy in diagnosing and predicting T2DM-associated MAFLD can be greatly improved using SERPINB2 and TNFRSF1A. These genes may significantly influence the development of T2DM-associated MAFLD, offering new diagnostic options for patients with T2DM combined with MAFLD.
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Affiliation(s)
- Guiling Wu
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Sihui Wu
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Tian Xiong
- Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
- Department of Geriatric Endocrinology and Metabolism, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, Nanning, Guangxi, China
| | - You Yao
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Yu Qiu
- Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
- Department of Geriatric Endocrinology and Metabolism, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, Nanning, Guangxi, China
| | - Liheng Meng
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Cuihong Chen
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xi Yang
- Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
- Department of Geriatric Endocrinology and Metabolism, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, Nanning, Guangxi, China
| | - Xinghuan Liang
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Barré T, Parlati L, Bourlière M, Ramier C, Marcellin F, Protopopescu C, Di Beo V, Moins C, Dorival C, Nicol J, Zucman-Rossi J, Mathurin P, Larrey D, Boursier J, Carrat F, Carrieri P. Socioeconomic Deprivation Weighs Heavily on Liver Fibrosis and Mortality After Hepatitis C Cure (ANRS CO22 Hepather). J Viral Hepat 2024; 31:830-846. [PMID: 39252600 DOI: 10.1111/jvh.14006] [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: 03/19/2024] [Revised: 07/12/2024] [Accepted: 08/23/2024] [Indexed: 09/11/2024]
Abstract
Although Hepatitis C virus (HCV) infection can be cured with direct-acting antivirals (DAA), some cured patients face a serious risk of advanced liver damage and early mortality. In order to avoid these two negative health outcomes, it is important to identify and assess related risk factors. Little is currently known about socioeconomic and behavioural factors in this context. Using data from the ANRS CO22 Hepather cohort, we tested for associations between socioeconomic and behavioural factors and (i) advanced liver fibrosis (defined as an FIB-4 > 3.25) assessed longitudinally using a mixed-effects logistic regression model (both the whole population and stratified on advanced liver fibrosis status at the time of HCV cure) and (ii) all-cause mortality (Cox proportional hazards model), during post-HCV cure follow-up. Among 5833 participants cured of HCV, living in poverty was associated with postcure advanced liver fibrosis in participants without this diagnosis at the time of HCV cure (population attributable fraction-PAF-of 8.6%) and with mortality in the whole study population (PAF of 10.6%). The detrimental effects of unhealthy alcohol use and heavy tobacco smoking, as well as the beneficial effect of living with a stable partner were also highlighted. We highlighted the major role of poverty and behavioural factors in advanced liver fibrosis and all-cause mortality in patients cured of HCV. Encouraging linkage to social support services and healthy behaviours after successful DAA treatment could limit morbidity and increase survival in this population. Clinical Trial Registration: ClinicalTrials.gov: NCT01953458.
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Affiliation(s)
- Tangui Barré
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
| | - Lucia Parlati
- Département d'Hépatologie/Addictologie, Hôpital Cochin, Université de Paris Cité, INSERM U1016, AP-HP, Paris, France
| | - Marc Bourlière
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
- Département D'hépatologie et Gastroentérologie, Hôpital Saint Joseph, Marseille, France
| | - Clémence Ramier
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
| | - Fabienne Marcellin
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
| | - Camelia Protopopescu
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
| | - Vincent Di Beo
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
| | - Cécile Moins
- Department of Clinical Research, ANRS Emerging Infectious Diseases, Paris, France
| | - Celine Dorival
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne Université, Paris, France
| | - Jérôme Nicol
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne Université, Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
- Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, Université Lille 2 and Inserm U795, Lille, France
| | - Dominique Larrey
- Liver Unit-IRB-INSERM 1183, Hôpital Saint Eloi, Montpellier, France
| | - Jérôme Boursier
- Hepato-Gastroenterology Department, Angers University Hospital, Angers, France
- HIFIH Laboratory, UPRES 3859, SFR 4208, Angers University, Angers, France
| | - Fabrice Carrat
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Hôpital Saint-Antoine, Unité de Santé Publique, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Patrizia Carrieri
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
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Mallet M, Silaghi CA, Sultanik P, Conti F, Rudler M, Ratziu V, Thabut D, Pais R. Current challenges and future perspectives in treating patients with NAFLD-related cirrhosis. Hepatology 2024; 80:1270-1290. [PMID: 37183906 DOI: 10.1097/hep.0000000000000456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/20/2023] [Indexed: 05/16/2023]
Abstract
Despite the slow, progressive nature of NAFLD, the number of patients with NAFLD-related cirrhosis has significantly increased. Although the management of patients with cirrhosis is constantly evolving, improving the prognosis of patients with NAFLD-related cirrhosis is a challenge because it is situated at the crossroads between the liver, the metabolic, and the cardiovascular diseases. Therefore, the therapeutic interventions should not only target the liver but also the associated cardiometabolic conditions and should be adapted accordingly. The objective of the current review is to critically discuss the particularities in the management of patients with NAFLD-related cirrhosis. We relied on the recommendations of scientific societies and discussed them in the specific context of NAFLD cirrhosis and the surrounding cardiometabolic milieu. Herein, we covered the following aspects: (1) the weight loss strategies through lifestyle interventions to avoid sarcopenia and improve portal hypertension; (2) the optimal control of metabolic comorbidities in particular type 2 diabetes aimed not only to improve cardiovascular morbidity/mortality but also to lower the incidence of cirrhosis-related complications (we discussed various aspects related to the safety of oral antidiabetic drugs in cirrhosis); (3) the challenges in performing bariatric surgery in patients with cirrhosis related to the portal hypertension and the risk of cirrhosis decompensation; (4) the particularities in the diagnosis and management of the portal hypertension and the difficulties in managing patients awaiting for liver transplantation; and (5) the difficulties in developing drugs and conducting clinical trials in patients with NAFLD-related cirrhosis. Moreover, we discussed the emerging options to overcome these obstacles.
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Affiliation(s)
- Maxime Mallet
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service d'hepato-gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
| | - Cristina Alina Silaghi
- Department of Endocrinology, "Iuliu Hatieganu" University of Medicine and Pharmacy Cluj-Napoca, Roumanie
| | - Philippe Sultanik
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service d'hepato-gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
- Brain Liver Pitié-Salpêtrière Study Group (BLIPS), Paris, France
| | - Filomena Conti
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service d'hepato-gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
- Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
| | - Marika Rudler
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service d'hepato-gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
- Brain Liver Pitié-Salpêtrière Study Group (BLIPS), Paris, France
- Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service d'hepato-gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- INSERM UMRS 1138 CRC, Paris, France
| | - Dominique Thabut
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service d'hepato-gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
- Brain Liver Pitié-Salpêtrière Study Group (BLIPS), Paris, France
- Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
| | - Raluca Pais
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service d'hepato-gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
- Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
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Cernea S, Onișor D, Roiban AL, Benedek T, Rat N. Metabolic dysfunction-associated steatotic liver disease-associated fibrosis and cardiac dysfunction in patients with type 2 diabetes. World J Cardiol 2024; 16:580-594. [PMID: 39492975 PMCID: PMC11525805 DOI: 10.4330/wjc.v16.i10.580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/28/2024] [Accepted: 09/19/2024] [Indexed: 10/17/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD), particularly in the presence of liver fibrosis, increases the risk of cardiovascular morbidity and mortality, but the nature of the cardio-hepatic interaction in the context type 2 diabetes mellitus (T2DM) is not fully understood. AIM To evaluate the changes in cardiac morphology and function in patients with T2DM and MASLD-associated liver fibrosis. METHODS T2DM patients with MASLD underwent a medical evaluation that included an assessment of lifestyle, anthropometric measurements, vital signs, an extensive laboratory panel, and a standard echocardiography. Liver fibrosis was evaluated using two scores [Fibrosis-4 (FIB4) and Non-alcoholic fatty liver disease-Fibrosis Score (NFS)], and subjects were classified as having advanced fibrosis, no fibrosis, or an indeterminate risk. The correlations between structural and functional cardiac parameters and markers of liver fibrosis were evaluated through bivariate and multiple regression analyses. Statistical significance was set at P < 0.05. RESULTS Data from 267 T2DM-MASLD subjects with complete assessment was analyzed. Patients with scores indicating advanced fibrosis exhibited higher interventricular septum and left ventricular (LV) posterior wall thickness, atrial diameters, LV end-systolic volume, LV mass index (LVMi), and epicardial adipose tissue thickness (EATT). Their mean ejection fraction (EF) was significantly lower (49.19% ± 5.62% vs 50.87% ± 5.14% vs 52.00% ± 3.25%; P = 0.003), and a smaller proportion had an EF ≥ 50% (49.40% vs 68.90% vs 84.21%; P = 0.0017). Their total and mid LV wall motion score indexes were higher (P < 0.05). Additionally, they had markers of diastolic dysfunction, with a higher E/e' ratio [9.64 ± 4.10 vs 8.44 (2.43-26.33) vs 7.35 ± 2.62; P = 0.026], and over 70% had lateral e' values < 10 cm/second, though without significant differences between groups. In multiple regression analyses, FIB4 correlated with left atrium diameter (LAD; β = 0.044; P < 0.05), and NFS with both LAD (β = 0.039; P < 0.05) and right atrium diameter (β = 0.041; P < 0.01), Moreover, LVMi correlated positively with age and EATT (β = 1.997; P = 0.0008), and negatively with serum sex-hormone binding protein (SHBP) concentrations (β = -0.280; P = 0.004). SHBP also correlated negatively with LAD (β = -0.036; P < 0.05). CONCLUSION T2DM patients with markers of MASLD-related liver fibrosis exhibit lower EF and present indicators of diastolic dysfunction and cardiac hypertrophy. Additionally, LVMi and LAD correlated negatively with serum SHBP concentrations.
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Affiliation(s)
- Simona Cernea
- Department M3/Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureş 540142, Romania
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş 540136, Romania.
| | - Danusia Onișor
- Department ME2/Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureş, Târgu Mureş 540142, Romania
- Gastroenterology Clinic, Mureș County Clinical Hospital, Târgu Mureş 540103, Romania
| | - Andrada Larisa Roiban
- Diabetes Compartment, Mediaș Municipal Hospital, Mediaș 551030, Romania
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş 540142, Romania
| | - Theodora Benedek
- Department M3/Internal Medicine VI, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş 540142, Romania
- Department of Cardiology, Emergency County Clinical Hospital, Târgu Mureş 540136, Romania
| | - Nora Rat
- Department M3/Internal Medicine VI, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş 540142, Romania
- Department of Cardiology, Emergency County Clinical Hospital, Târgu Mureş 540136, Romania
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Zelber-Sagi S, Carrieri P, Pericàs JM, Ivancovsky-Wajcman D, Younossi ZM, Lazarus JV. Food inequity and insecurity and MASLD: burden, challenges, and interventions. Nat Rev Gastroenterol Hepatol 2024; 21:668-686. [PMID: 39075288 DOI: 10.1038/s41575-024-00959-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/20/2024] [Indexed: 07/31/2024]
Abstract
Liver disease prevalence, severity, outcomes and hepatic risk factors (for example, unhealthy diet) are heavily affected by socioeconomic status and food insecurity. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease globally and is likely to co-occur with other liver diseases associated with food insecurity. Though weight reduction and adopting a healthy diet can reverse the course of MASLD, gaps between recommendations and practice transcend individual responsibility and preference. Broader sociocultural determinants of food choices (social nutrition) include food insecurity, community and social norms and the local environment, including commercial pressures that target people experiencing poverty, ethnic minorities and children. Food insecurity is a barrier to a healthy diet, as a low-quality diet is often less expensive than a healthy one. Consequently, food insecurity is an 'upstream' risk factor for MASLD, advanced fibrosis and greater all-cause mortality among patients with liver disease. Intervening on food insecurity at four major levels (environment, policy, community and health care) can reduce the burden of liver disease, thereby reducing social and health inequities. In this Review, we report on the current research in the field, the need for implementing proven interventions, and the role liver specialists can have.
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Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel.
- The Global NASH Council, Washington, DC, USA.
| | - Patrizia Carrieri
- Aix Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France
| | - Juan M Pericàs
- Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research, Universitat Autònoma de Barcelona, CIBERehd, Barcelona, Spain
- Johns Hopkins University-Pompeu Fabra University Public Policy Center, Barcelona, Spain
| | - Dana Ivancovsky-Wajcman
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Zobair M Younossi
- The Global NASH Council, Washington, DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
| | - Jeffrey V Lazarus
- The Global NASH Council, Washington, DC, USA
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain
- CUNY Graduate School of Public Health and Health Policy (CUNY SPH), New York, NY, USA
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8
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Ma N, Tan J, Chen Y, Yang L, Li M, He Y. MicroRNAs in metabolic dysfunction-associated diseases: Pathogenesis and therapeutic opportunities. FASEB J 2024; 38:e70038. [PMID: 39250169 DOI: 10.1096/fj.202401464r] [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: 06/27/2024] [Revised: 08/13/2024] [Accepted: 08/27/2024] [Indexed: 09/10/2024]
Abstract
Metabolic dysfunction-associated diseases often refer to various diseases caused by metabolic problems such as glucose and lipid metabolism disorders. With the improvement of living standards, the increasing prevalence of metabolic diseases has become a severe public health problem, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), diabetes and obesity. These diseases are both independent and interdependent, with complex and diverse molecular mechanisms. Therefore, it is urgent to explore the molecular mechanisms and find effective therapeutic targets of these diseases. MicroRNAs (miRNAs) have emerged as key regulators of metabolic homoeostasis due to their multitargets and network regulatory properties within the past few decades. In this review, we discussed the latest progress in the roles of miRNA-mediated regulatory networks in the development and progression of MASLD, ALD, diabetes and obesity.
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Affiliation(s)
- Ningning Ma
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jiaxin Tan
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yingfen Chen
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Liu Yang
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Man Li
- Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong He
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
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9
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Tan MY, Zhai XL. Primary hypobetalipoproteinemia as a risk factor for liver complications. J Hepatol 2024; 81:e124. [PMID: 38548068 DOI: 10.1016/j.jhep.2024.02.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 02/29/2024] [Indexed: 05/28/2024]
Affiliation(s)
- Mo-Yao Tan
- Chengdu Integrated TCM and Western Medicine Hospital, Chengdu, Sichuan, China
| | - Xiang-Long Zhai
- Chengdu Integrated TCM and Western Medicine Hospital, Chengdu, Sichuan, China.
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10
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Forte G, Donghia R, Lepore Signorile M, Tatoli R, Bonfiglio C, Losito F, De Marco K, Manghisi A, Guglielmi FA, Disciglio V, Fasano C, Sanese P, Cariola F, Buonadonna AL, Grossi V, Giannelli G, Simone C. Exploring the Relationship of rs2802292 with Diabetes and NAFLD in a Southern Italian Cohort-Nutrihep Study. Int J Mol Sci 2024; 25:9512. [PMID: 39273459 PMCID: PMC11394752 DOI: 10.3390/ijms25179512] [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: 07/22/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Background: The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. Methods: rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. Results: Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., p = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., p = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (β = 0.10, -0.003 to 0.12 95% C.I., p = 0.04) on diabetes, but only in TT genotypes. Conclusions: The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD.
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Affiliation(s)
- Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Rossella Donghia
- Data Science Unit, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (R.D.); (R.T.); (C.B.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Rossella Tatoli
- Data Science Unit, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (R.D.); (R.T.); (C.B.)
| | - Caterina Bonfiglio
- Data Science Unit, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (R.D.); (R.T.); (C.B.)
| | - Francesco Losito
- Gastroenterology Unit, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Andrea Manghisi
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Filomena Anna Guglielmi
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Filomena Cariola
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Antonia Lucia Buonadonna
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology, IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (G.F.); (M.L.S.); (K.D.M.); (A.M.); (F.A.G.); (V.D.); (C.F.); (P.S.); (F.C.); (A.L.B.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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11
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Ge Q, Liu Z. Familial clustering of MASLD: Rethinking strategies for population screening. J Hepatol 2024; 80:e289-e290. [PMID: 38309441 DOI: 10.1016/j.jhep.2024.01.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 01/15/2024] [Indexed: 02/05/2024]
Affiliation(s)
- Qiaoyue Ge
- Department of Maternal and Child Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, Chengdu, China; Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Zhenmi Liu
- Department of Maternal and Child Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, Chengdu, China; Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, Chengdu, China.
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12
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Hua R, Lam CS, Wu YK, Deng W, Chu N, Yang A, Chow E, Cheung YT. The use of potentially interacting supplement-drug pairs in adults with type 2 diabetes: A large population-based cohort study in the UK Biobank. Diabetes Res Clin Pract 2024; 211:111658. [PMID: 38583779 DOI: 10.1016/j.diabres.2024.111658] [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: 03/11/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/09/2024]
Abstract
AIMS To examine the patterns of use of potentially interacting supplement-drug pairs in adults with type 2 diabetes (T2D) in real-world settings, and to explore the impact of potentially interacting supplement-drug pairs on downstream outcomes. METHODS Potentially interacting supplement-drug pairs were identified from four tertiary databases. We categorized the potential pharmacodynamic interactions into different clinical types according to their related outcomes and explored their associations with incident outcomes using Cox models. RESULTS 26,394 participants with T2D in the UK Biobank were included. Half (48.5 %) were supplement users, of whom 85.0 % were taking potentially interacting supplement-drug pairs. The potential pharmacodynamic interactions were related to various clinical outcomes, including reducing the effects of glucose-lowering drugs (50.7 %), hypotension (49.8 %), bleeding (50.4 %) and hepatotoxicity (34.8 %). Exploratory analyses found that the use of potentially interacting supplement-drug pairs was associated with incident hepatic diseases (hazard ratio = 1.26, 95 % confidence interval 1.10-1.44, P < 0.001). CONCLUSIONS Real-world data suggests that most adults with T2D who concurrently used supplements and drugs were on potentially interacting supplement-drug combinations, with the potential of causing adverse outcomes such as incident hepatic diseases. Clinicians should communicate with patients and assess the potential risk of supplement-drug interactions in clinical settings.
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Affiliation(s)
- Rong Hua
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chun Sing Lam
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yu Kang Wu
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Weishang Deng
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Natural Chu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Aimin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China; Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yin Ting Cheung
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
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13
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Yuan Z, Qiao H, Wang Z, Wang H, Han M, Zhang W, Zhou Y, Hassan HM, Zhao W, Qin T. Taohe Chengqi decoction alleviated metabolic-associated fatty liver disease by boosting branched chain amino acids catabolism in the skeletal muscles of type 2 diabetes mellitus. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155315. [PMID: 38387274 DOI: 10.1016/j.phymed.2023.155315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 12/03/2023] [Accepted: 12/25/2023] [Indexed: 02/24/2024]
Abstract
OBJECTIVE Metabolic-associated fatty liver disease (MAFLD) is the most prevalent liver disease, whereas type 2 diabetes mellitus (T2DM) is considered an independent risk factor for MAFLD incidence. Taohe Chengqi decoction (THCQ) is clinically prescribed for T2DM treatment; however, the hepatoprotective effect of THCQ against MAFLD is still unknown. This study intended to elucidate the therapeutic effect of THCQ on T2DM-associated MAFLD and to investigate the underlying mechanisms. METHODS THCQ lyophilized powder was prepared and analyzed by UHPLC-MS/MS. A stable T2DM mouse model was established by high-fat diet (HFD) feeding combined with streptozotocin (STZ) injection. The T2DM mice were administered THCQ (2.5 g/kg or 5 g/kg) to explore the pharmacological effects of THCQ on T2DM-associated MAFLD. Liver tissue transcriptome was analyzed and the participatory roles of PPARα/γ pathways were verified both in vivo and in vitro. Serum metabolome analysis was used to explore the metabolome changes and skeletal muscle branched chain amino acid (BCAA) catabolic enzymes were further detected. Moreover, an AAV carrying BCKDHA shRNA was intramuscularly injected to verify the impact of THCQ on skeletal muscle BCAA catabolism and the potential therapeutic outcome on hepatic steatosis. RESULTS THCQ improved hepatic steatosis in MAFLD. RNA-sequencing analysis showed dysregulation in the hepatic PPARγ-related fatty acid synthesis, while PPARα-dependent fatty acid oxidation was elevated following THCQ treatment. Interestingly, in vitro analyses of these findings showed that THCQ had minor effects on fatty acid oxidation and/or synthesis. The metabolomic study revealed that THCQ accelerated BCAA catabolism in the skeletal muscles, in which knockdown of the BCAA catabolic enzyme BCKDHA diminished the THCQ therapeutic effect on hepatic steatosis. CONCLUSION This study highlighted the potential therapeutic effect of THCQ on hepatic steatosis in MALFD. THCQ upregulated fatty acid oxidation and reduced its synthesis via restoration of PPARα/γ pathways in HFD/STZ-induced T2DM mice, which is mediated through augmenting BCKDH activity and accelerating BCAA catabolism in the skeletal muscles. Overall, this study provided in-depth clues for "skeletal muscles-liver communication" in the therapeutic effect of THCQ against hepatic steatosis. These findings suggested THCQ might be a potential candidate against T2DM-associated MAFLD.
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Affiliation(s)
- Ziqiao Yuan
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, China
| | - Hui Qiao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ziwei Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Haoran Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Mingru Han
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yang Zhou
- Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, China
| | - Hozeifa Mohamed Hassan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China.
| | - Wen Zhao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Tingting Qin
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
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14
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Zhao Y, Li D, Shi H, Liu W, Qiao J, Wang S, Geng Y, Liu R, Han F, Li J, Li W, Wu F. Associations between type 2 diabetes mellitus and chronic liver diseases: evidence from a Mendelian randomization study in Europeans and East Asians. Front Endocrinol (Lausanne) 2024; 15:1338465. [PMID: 38495785 PMCID: PMC10941029 DOI: 10.3389/fendo.2024.1338465] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Objective Multiple observational studies have demonstrated an association between type 2 diabetes mellitus (T2DM) and chronic liver diseases (CLDs). However, the causality of T2DM on CLDs remained unknown in various ethnic groups. Methods We obtained instrumental variables for T2DM and conducted a two-sample mendelian randomization (MR) study to examine the causal effect on nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), viral hepatitis, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection risk in Europeans and East Asians. The primary analysis utilized the inverse variance weighting (IVW) technique to evaluate the causal relationship between T2DM and CLDs. In addition, we conducted a series of rigorous analyses to bolster the reliability of our MR results. Results In Europeans, we found that genetic liability to T2DM has been linked with increased risk of NAFLD (IVW : OR =1.3654, 95% confidence interval [CI], 1.2250-1.5219, p=1.85e-8), viral hepatitis (IVW : OR =1.1173, 95%CI, 1.0271-1.2154, p=0.0098), and a suggestive positive association between T2DM and HCC (IVW : OR=1.2671, 95%CI, 1.0471-1.5333, p=0.0150), HBV (IVW : OR=1.1908, 95% CI, 1.0368-1.3677, p=0.0134). No causal association between T2DM and HCV was discovered. Among East Asians, however, there was a significant inverse association between T2DM and the proxies of NAFLD (ALT: IVW OR=0.9752, 95%CI 0.9597-0.9909, p=0.0021; AST: IVW OR=0.9673, 95%CI, 0.9528-0.9821, p=1.67e-5), and HCV (IVW: OR=0.9289, 95%CI, 0.8852-0.9747, p=0.0027). Notably, no causal association was found between T2DM and HCC, viral hepatitis, or HBV. Conclusion Our MR analysis revealed varying causal associations between T2DM and CLDs in East Asians and Europeans. Further research is required to investigate the potential mechanisms in various ethnic groups, which could yield new insights into early screening and prevention strategies for CLDs in T2DM patients.
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Affiliation(s)
- Yue Zhao
- Department of Surgery, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Di Li
- Department of Internal Medicine, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Hanyu Shi
- Department of Internal Medicine, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Wei Liu
- Department of General Surgery, Shandong Corps Hospital of Chinese People’s Armed Police Force, Jinan, China
| | - Jiaojiao Qiao
- Department of Nursing, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Shanfu Wang
- Department of Surgery, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Yiwei Geng
- School of Statistic and Data Science, Jiangxi University of Finance and Economics, Nanchang, Jiangxi, China
| | - Ruiying Liu
- Department of Nursing, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Feng Han
- Department of Surgery, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Jia Li
- Department of Health and Epidemic Prevention, Hospital of the First Mobile Corps of the Chinese People’s Armed Police Force, Dingzhou, Hebei, China
| | - Wei Li
- Department of General Surgery, The 980Hospital of the Chinese People's Liberation Army (PLA) Joint Logistics Support Force (Primary Bethune International Peace Hospital of Chinese People's Liberation Army (PLA), Shijiazhuang, Hebei, China
| | - Fengyun Wu
- Department of General Surgery, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, China
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15
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Cernea S. NAFLD Fibrosis Progression and Type 2 Diabetes: The Hepatic-Metabolic Interplay. Life (Basel) 2024; 14:272. [PMID: 38398781 PMCID: PMC10890557 DOI: 10.3390/life14020272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/13/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
The bidirectional relationship between type 2 diabetes and (non-alcoholic fatty liver disease) NAFLD is indicated by the higher prevalence and worse disease course of one condition in the presence of the other, but also by apparent beneficial effects observed in one, when the other is improved. This is partly explained by their belonging to a multisystemic disease that includes components of the metabolic syndrome and shared pathogenetic mechanisms. Throughout the progression of NAFLD to more advanced stages, complex systemic and local metabolic derangements are involved. During fibrogenesis, a significant metabolic reprogramming occurs in the hepatic stellate cells, hepatocytes, and immune cells, engaging carbohydrate and lipid pathways to support the high-energy-requiring processes. The natural history of NAFLD evolves in a variable and dynamic manner, probably due to the interaction of a variable number of modifiable (diet, physical exercise, microbiota composition, etc.) and non-modifiable (genetics, age, ethnicity, etc.) risk factors that may intervene concomitantly, or subsequently/intermittently in time. This may influence the risk (and rate) of fibrosis progression/regression. The recognition and control of the factors that determine a rapid progression of fibrosis (or its regression) are critical, as the fibrosis stages are associated with the risk of liver-related and all-cause mortality.
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Affiliation(s)
- Simona Cernea
- Department M3, Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540142 Târgu Mureş, Romania; or
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, 540136 Târgu Mureş, Romania
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16
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Zhang Y, Pu J, Xie R. From liver to heart: Enhancing the understanding of cardiovascular outcomes in the UK biobank. J Hepatol 2024; 80:e23-e24. [PMID: 37813241 DOI: 10.1016/j.jhep.2023.09.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 09/01/2023] [Indexed: 10/11/2023]
Affiliation(s)
- Ya Zhang
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China Hengyang 421002, China; Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China
| | - Jian Pu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China.
| | - Ruijie Xie
- The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China Hengyang 421002, China; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
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17
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Chang M, Shao Z, Wei W, Shen P, Shen G. Sex-specific prevalence and risk factors of metabolic-associated fatty liver disease among 75,570 individuals in eastern China. Front Endocrinol (Lausanne) 2023; 14:1241169. [PMID: 37822594 PMCID: PMC10563804 DOI: 10.3389/fendo.2023.1241169] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/08/2023] [Indexed: 10/13/2023] Open
Abstract
Background Metabolic-associated fatty liver disease (MAFLD) is a newly proposed definition and there is limited data on MAFLD prevalence. We aimed to investigate the prevalence of MAFLD in an eastern Chinese population. Methods This cross-sectional study included participants from an eastern Chinese population who underwent regular health checkups. Based on current diagnostic criteria, MAFLD was diagnosed in individuals with both hepatic steatosis and metabolic disorders. The overall and stratified prevalence derived based on sex, age, body mass index (BMI), and various metabolic disorders were estimated. Multivariate logistic regression analysis was used to determine the risk factors for MAFLD. Results Among the 75,570 participants, the overall prevalence of MAFLD was 37.32%, with higher rates in men (45.66%) than in women (23.91%). MAFLD prevalence was highest in men aged 40-49 years (52.21%) and women aged 70-79 years (44.77%). In all the BMI subgroups, the prevalence was higher in men than in women. In both sexes, the prevalence of MAFLD increased as BMI levels increased. Furthermore, MAFLD was associated with metabolic disorders, especially in the female participants with severe obesity (odds ratio 58.318; 95% confidence interval: 46.978-72.397). Conclusion MAFLD is prevalent in the general adult population in eastern China. Sex-specific differences in MAFLD prevalence were identified based on age, BMI, and metabolic disorders. MAFLD is associated with metabolic disorders, particularly obesity.
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Affiliation(s)
| | | | | | - Peipu Shen
- Department of Health Management Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Guifang Shen
- Department of Health Management Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
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18
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Pais R, Cariou B, Noureddin M, Francque S, Schattenberg JM, Abdelmalek MF, Lalazar G, Varma S, Dietrich J, Miller V, Sanyal A, Ratziu V. A proposal from the liver forum for the management of comorbidities in non-alcoholic steatohepatitis therapeutic trials. J Hepatol 2023; 79:829-841. [PMID: 37001695 DOI: 10.1016/j.jhep.2023.03.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 02/08/2023] [Accepted: 03/13/2023] [Indexed: 06/19/2023]
Abstract
The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.
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Affiliation(s)
- Raluca Pais
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000 Nantes, France
| | | | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Belgium
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Duke University, Durham, NC, USA
| | - Gadi Lalazar
- Liver Unit, Digestive Disease Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Sharat Varma
- Novo Nordisk A/S, Vandtårnsvej 108-110, 2860 Søborg Denmark
| | - Julie Dietrich
- GENFIT, Parc Eurasanté 885, Avenue Eugène Avinée, 59120, Loos, France
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C., USA
| | - Arun Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; INSERM UMRS 1138 CRC, Paris, France.
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Reinson T, Buchanan RM, Byrne CD. Identification of individuals at risk of hepatocellular carcinoma: screening for clinically significant liver fibrosis in patients with T2DM. Expert Rev Endocrinol Metab 2023; 18:355-359. [PMID: 37587863 DOI: 10.1080/17446651.2023.2248242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/17/2023] [Accepted: 08/10/2023] [Indexed: 08/18/2023]
Affiliation(s)
- Tina Reinson
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health and Care Research, Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Ryan M Buchanan
- National Institute for Health and Care Research, Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
- Primary Care and Population Science, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health and Care Research, Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
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20
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Vell MS, Loomba R, Krishnan A, Wangensteen KJ, Trebicka J, Creasy KT, Trautwein C, Scorletti E, Seeling KS, Hehl L, Rendel MD, Zandvakili I, Li T, Chen J, Vujkovic M, Alqahtani S, Rader DJ, Schneider KM, Schneider CV. Association of Statin Use With Risk of Liver Disease, Hepatocellular Carcinoma, and Liver-Related Mortality. JAMA Netw Open 2023; 6:e2320222. [PMID: 37358849 PMCID: PMC10293910 DOI: 10.1001/jamanetworkopen.2023.20222] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/11/2023] [Indexed: 06/27/2023] Open
Abstract
IMPORTANCE Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed. OBJECTIVE To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020. Individuals were matched using propensity score matching according to the following criteria: age, sex, body mass index, ethnicity, diabetes with or without insulin or biguanide use, hypertension, ischemic heart disease, dyslipidemia, aspirin use, and number of medications taken (UKB only). Data analysis was performed from April 2021 to April 2023. EXPOSURE Regular statin use. MAIN OUTCOMES AND MEASURES Primary outcomes were liver disease and HCC development as well as liver-associated death. RESULTS A total of 1 785 491 individuals were evaluated after matching (aged 55 to 61 years on average, up to 56% men, and up to 49% women). A total of 581 cases of liver-associated death, 472 cases of incident HCC, and 98 497 new liver diseases were registered during the follow-up period. Individuals were aged 55-61 years on average, with a slightly higher proportion of men (up to 56%). In UKB individuals (n = 205 057) without previously diagnosed liver disease, statin users (n = 56 109) had a 15% lower hazard ratio (HR) for the association of developing a new liver disease (HR, 0.85; 95% CI, 0.78-0.92; P < .001). In addition, statin users demonstrated a 28% lower HR for the association with liver-related death (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and a 42% lower HR for the development of HCC (HR, 0.58; 95% CI, 0.35-0.96; P = .04). In TriNetX individuals (n = 1 568 794), the HR for the association of HCC was reduced even further for statin users (HR, 0.26; 95% CI, 0.22-0.31; P = .003). The hepatoprotective association of statins was time and dose dependent, with a significant association in PMBB individuals (n = 11 640) for incident liver diseases after 1 year of statin use (HR, 0.76; 95% CI, 0.59-0.98; P = .03). Taking statins was particularly beneficial in men, individuals with diabetes, and individuals with a high Fibrosis-4 index at baseline. Carriers of the heterozygous minor allele of PNPLA3 rs738409 benefited from statin use and had a 69% lower HR for the association with HCC (UKB HR, 0.31; 95% CI, 0.11-0.85; P = .02). CONCLUSIONS AND RELEVANCE This cohort study indicates substantial preventive associations of statins against liver disease, with an association with duration and dose of intake.
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Affiliation(s)
- Mara Sophie Vell
- Gastroenterology, Metabolic Diseases, and Intensive Care, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Rohit Loomba
- Division of Gastroenterology, University of California, San Diego, La Jolla
| | - Arunkumar Krishnan
- Section of Gastroenterology and Hepatology, West Virginia University School of Medicine, Morgantown
| | - Kirk J. Wangensteen
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Jonel Trebicka
- Medical Clinic B, Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology, University Hospital Münster, Münster, Germany
| | - Kate Townsend Creasy
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia
| | - Christian Trautwein
- Gastroenterology, Metabolic Diseases, and Intensive Care, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Eleonora Scorletti
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Katharina Sophie Seeling
- Gastroenterology, Metabolic Diseases, and Intensive Care, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Leonida Hehl
- Gastroenterology, Metabolic Diseases, and Intensive Care, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Miriam Daphne Rendel
- Gastroenterology, Metabolic Diseases, and Intensive Care, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Inuk Zandvakili
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Tang Li
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Jinbo Chen
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Marijana Vujkovic
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Saleh Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Liver Transplant Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Daniel James Rader
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Kai Markus Schneider
- Gastroenterology, Metabolic Diseases, and Intensive Care, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Carolin Victoria Schneider
- Gastroenterology, Metabolic Diseases, and Intensive Care, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
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Li D, Tian L, Nan P, Zhang J, Zheng Y, Jia X, Gong Y, Wu Z. CerS6 triggered by high glucose activating the TLR4/IKKβ pathway regulates ferroptosis of LO2 cells through mitochondrial oxidative stress. Mol Cell Endocrinol 2023; 572:111969. [PMID: 37230220 DOI: 10.1016/j.mce.2023.111969] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/20/2023] [Accepted: 05/21/2023] [Indexed: 05/27/2023]
Abstract
Lipid metabolism disorders and mitochondrial dysfunction contribute to the progression of diabetes and chronic liver disease (CLD). Ferroptosis, as a form of cell death centered on reactive oxygen species (ROS) accumulation and lipid peroxidation, is closely related to mitochondrial dysfunction. However, whether there exists mechanistic links between these processes remains unknown. Here, to explore the molecular mechanism of diabetes complicated with CLD, we showed that high glucose could restrain the activity of antioxidant enzymes, promote mitochondrial ROS (mtROS) production, and induce a state of oxidative stress in the mitochondria of human normal liver (LO2) cells. We demonstrated that high glucose induced ferroptosis and promoted the development of CLD, which was reversed by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). In addition, the mitochondria-targeting antioxidant Mito-TEMPO was used to intervene LO2 cells in high-glucose culture, and ferroptosis was found to be inhibited, whereas markers of liver injury and fibrosis improved. Furthermore, high glucose could promote ceramide synthetase 6 (CerS6) synthesis through the TLR4/IKKβ pathway. The knockout of CerS6 in LO2 cells showed that mitochondrial oxidative stress was attenuated, ferroptosis was inhibited, and markers of liver injury and fibrosis were ameliorated. In contrast, the overexpression of CerS6 in LO2 cells showed the opposite changes and these changes were inhibited by Mito-TEMPO. In short, we positioned the study of lipid metabolism to a specific enzyme CerS6, with a high degree of specificity. Our findings revealed the mechanism by which the mitochondria act as a bridge linking CerS6 and ferroptosis, confirming that under high glucose conditions, CerS6 promotes ferroptosis through mitochondrial oxidative stress, eventually leading to CLD.
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Affiliation(s)
- Dan Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Ling Tian
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Ping Nan
- Department of Obster & Gynecol, Shengli Oilfield Central Hospital, 31 Jinan Road, Dongying, 257000, Shandong, China
| | - Jun Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yin Zheng
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Xinxin Jia
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yihui Gong
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Zhongming Wu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University, Jinan, Shandong, 250021, China.
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22
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Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD. Int J Mol Sci 2023; 24:ijms24032142. [PMID: 36768465 PMCID: PMC9916810 DOI: 10.3390/ijms24032142] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
O-linked b-N-acetyl-glucosaminylation (O-GlcNAcylation) is one of the most common post-translational modifications of proteins, and is established by modifying the serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc signaling is considered a critical nutrient sensor, and affects numerous proteins involved in cellular metabolic processes. O-GlcNAcylation modulates protein functions in different patterns, including protein stabilization, enzymatic activity, transcriptional activity, and protein interactions. Disrupted O-GlcNAcylation is associated with an abnormal metabolic state, and may result in metabolic disorders. As the liver is the center of nutrient metabolism, this review provides a brief description of the features of the O-GlcNAc signaling pathway, and summarizes the regulatory functions and underlying molecular mechanisms of O-GlcNAcylation in liver metabolism. Finally, this review highlights the role of O-GlcNAcylation in liver-associated diseases, such as diabetes and nonalcoholic fatty liver disease (NAFLD). We hope this review not only benefits the understanding of O-GlcNAc biology, but also provides new insights for treatments against liver-associated metabolic disorders.
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23
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Yin J, Freedman ND, Liu Y, Dawsey SM, Yang H, Taylor PR, Yin L, Liu B, Cui J, Fan J, Chen W, Qiao Y, Abnet CC. Associations between serum glucose, insulin, insulin resistance and the risk of incident primary liver cancer or chronic liver disease mortality: a nested case-control study. Br J Cancer 2023; 128:275-284. [PMID: 36496451 PMCID: PMC9902537 DOI: 10.1038/s41416-022-02042-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/31/2022] [Accepted: 10/19/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND To evaluate the associations between pre-diagnostic levels of serum insulin, glucose and insulin resistance (HOMA-IR) and future risk of incident primary liver cancer (PLC) or chronic liver disease (CLD)-related mortality. METHODS We used a nested case-control design to evaluate subjects over 22 years of follow-up. Glucose, insulin, and three markers of hepatitis B virus (HBV) and hepatitis C virus were measured in fasting baseline serum from 119 incident PLCs, 157 CLD-death cases and 512 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression to estimate the associations between insulin, glucose, HOMA-IR and the risk of PLC or CLD death. RESULTS Compared with the lowest quartile of insulin, multivariable adjusted models showed that subjects in the highest quartile had elevated odds of developing PLC (ORQ4/Q1 = 2.42, 95% CI = 1.26-4.75, Ptrend = 0.007), particularly in HBV-positive subjects (Pinteraction = 0.040), and of CLD death (ORQ4/Q1 = 1.80, 95% CI = 1.02-3.21, Ptrend = 0.018). For glucose, in the HBV-positive group, subjects in the fourth quartile had an increased risk of PLC (ORQ4/Q1 = 2.18, 95% CI = 1.07-4.60, Ptrend = 0.009), and of CLD mortality (ORQ4/Q1 = 1.75, 95% CI = 0.95-3.28, Ptrend = 0.019). Subjects with the highest HOMA-IR values had a threefold risk of developing PLC (ORQ4/Q1 = 2.94, 95% CI = 1.54-5.87, Ptrend = 0.001), and a twofold risk of CLD death (ORQ4/Q1 = 2.20, 95% CI = 1.25-3.94, Ptrend = 0.005). CONCLUSIONS We found that serum insulin and HOMA-IR could potentially be risk factors for PLC or CLD death.
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Affiliation(s)
- Jian Yin
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Neal D Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA
| | - Yiwei Liu
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Sanford M Dawsey
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA
| | - Huan Yang
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Philip R Taylor
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA
| | - Liangyu Yin
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China
- Department of Clinical Nutrition, Daping Hospital, Third Military Medical University (Army Medical University), 400042, Chongqing, China
| | - Bin Liu
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Jianfeng Cui
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
| | - Jinhu Fan
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Wen Chen
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
| | - Youlin Qiao
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
| | - Christian C Abnet
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA
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The Determinants of Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus. Biomedicines 2022; 10:biomedicines10071487. [PMID: 35884792 PMCID: PMC9312509 DOI: 10.3390/biomedicines10071487] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/19/2022] [Accepted: 06/21/2022] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a key pathophysiology process in chronic liver disease. It is still unclear whether the impact of liver fibrosis is not fully realized in type 2 diabetes mellitus (T2D) patients with nonalcoholic fatty liver disease (NAFLD), and the factors affecting nonalcoholic steatohepatitis (NASH) or liver stiffness also remain unclear. The aim of this study was to evaluate the determinants of liver fibrosis and in T2D patients with NAFLD. Liver fibrosis and steatosis were measured using transient elastography (FibroScan). Of 226 T2D patients with NAFLD, 50 with liver fibrosis had higher body mass index, serum uric acid, triglyceride and glycated hemoglobin levels and lower high density lipoprotein levels than 176 without liver fibrosis. Multivariate analysis revealed that aging, obesity, sulfonylurea usage and high levels of AST increased the risk of liver fibrosis in T2D patients with NAFLD. Our findings provide useful information to clinical physicians for earlier detection of liver fibrosis in T2D patients with NAFLD and to prevent liver fibrosis through controlling these risk factors.
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Abstract
Initially a condition that received limited recognition and whose clinical impact was controversial, non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease. Although there are no approved therapies, major breakthroughs, which will be reviewed here, have paved the way for future therapeutic successes. The unmet medical need in NASH is no longer disputed, and progress in the understanding of its pathogenesis has resulted in the identification of many pharmacological targets. Key surrogate outcomes for therapeutic trials are now accepted by regulatory agencies, thus creating a path for drug registration. A set of non-invasive measurements enabled early-stage trials to be conducted expeditiously, thus providing early indications on the biological and possibly clinical actions of therapeutic candidates. This generated efficacy results for a number of highly promising compounds that are now in late-stage development. Intense research aimed at further improving the assessment of histological endpoints and in developing non-invasive predictive biomarkers is underway. This will help improve the design and feasibility of successful trials, ultimately providing patients with therapeutic options that can change the course of the disease.
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Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Eat Weight Disord 2022; 27:1603-1619. [PMID: 34914079 PMCID: PMC9123074 DOI: 10.1007/s40519-021-01287-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the past years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato, the Società Italiana di Diabetologia and the Società Italiana dell'Obesità reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure and Istituto Superiore di Sanità. Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources.Level of evidence Level of evidence of recommendations for each PICO question were reported according to available evidence.
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ABSTRACTS (BY NUMBER). Tissue Eng Part A 2022. [DOI: 10.1089/ten.tea.2022.29025.abstracts] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Dig Liver Dis 2022; 54:170-182. [PMID: 34924319 DOI: 10.1016/j.dld.2021.04.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 03/22/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.
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Hydes TJ, Cuthbertson DJ, Graef S, Berhane S, Teng M, Skowronska A, Singh P, Dhanaraj S, Tahrani A, Johnson PJ. The Impact of Diabetes and Glucose-Lowering Therapies on Hepatocellular Carcinoma Incidence and Overall Survival. Clin Ther 2022; 44:257-268. [DOI: 10.1016/j.clinthera.2021.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/08/2021] [Accepted: 12/31/2021] [Indexed: 12/15/2022]
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Marchesini G, Bugianesi E, Burra P, Marra F, Miele L, Alisi A, Vajro P, Masarone M, Petta S, Persico M, Svegliati-Baroni G, Valenti L, Federici M, Purrello F, Sasso FC, Targher G, Busetto L, Petroni ML, Santini F, Cammà C, Colli A. Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Nutr Metab Cardiovasc Dis 2022; 32:1-16. [PMID: 34924246 DOI: 10.1016/j.numecd.2021.04.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.
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Chhabra S, Singh SP, Singh A, Mehta V, Kaur A, Bansal N, Sood A. Diabetes Mellitus Increases the Risk of Significant Hepatic Fibrosis in Patients With Non-alcoholic Fatty Liver Disease. J Clin Exp Hepatol 2022; 12:409-416. [PMID: 35535092 PMCID: PMC9077176 DOI: 10.1016/j.jceh.2021.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/04/2021] [Indexed: 12/12/2022] Open
Abstract
Background Diabetes mellitus is associated with an increased risk of development of non-alcoholic fatty liver disease (NAFLD). However, the risk posed by diabetes mellitus in progression of liver disease is uncertain. This study compared the severity of hepatic fibrosis in patients with NAFLD with and without diabetes mellitus. Methods Consecutive adult patients with NAFLD undergoing transient elastography [FibroScan Touch 502 (Echosens, Paris, France)] at a tertiary care center in north India were analyzed for severity of hepatic fibrosis. The aspartate aminotransferase (AST) to platelet ratio index (APRI), fibrosis index based on 4 factors (FIB-4), and NAFLD Fibrosis Score (NFS) were calculated. The degree of hepatic fibrosis as determined by FibroScan and non-invasive serum fibrosis models in patients with and without diabetes mellitus were compared. Results A total of two hundred patients [118 (59%) males, mean age 50.30 ± 11.13 years] were enrolled. Significant hepatic fibrosis was present in 86 (43%) patients [mean age 50.66 ± 10.96 years, 56 (65.11%) males]. The mean FibroScan, APRI, FIB-4, and NFS scores were 9.86 ± 2.97, 0.75 ± 0.47, 2.41 ± 1.41 and -0.24 ± 1.43 in patients with diabetes compared to 5.31 ± 1.09, 0.49 ± 0.27, 1.55 ± 0.85, and -2.12 ± 1.88 in patients without diabetes, respectively (P=<0.0001). There was a fair correlation between FibroScan and non-invasive serum fibrosis models (P=<0.0001). Conclusion Presence of diabetes increases the risk of significant hepatic fibrosis in patients with NAFLD. FIB-4 correlates fairly with FibroScan in patients with diabetes and can be used as a screening tool to detect significant hepatic fibrosis.
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Key Words
- ALT, Alanine aminotransferase
- APRI, Aspartate aminotransferase to platelet ratio index
- AST, Aspartate aminotransferase
- DM, Diabetes Mellitus
- FIB-4, Fibrosis index based on 4 factors
- HDL, High-density lipoprotein
- HbA1C, Glycosylated hemoglobin
- IFG, Impaired fasting glucose
- LDL, Low-density lipoprotein
- NAFLD, Non-alcoholic fatty liver disease
- NASH, Non-alcoholic steatohepatitis
- NFS, NAFLD Fibrosis Score
- TE, Transient Elastography
- diabetes mellitus
- fibrosis
- liver cirrhosis
- non-alcoholic fatty liver disease
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Affiliation(s)
- Sandeep Chhabra
- Department of Internal Medicine, Dayanand Medical College and Hospital, Ludhiana, India
| | - Sukhraj P. Singh
- Department of Internal Medicine, Dayanand Medical College and Hospital, Ludhiana, India
| | - Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Varun Mehta
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India,Address for correspondence. Varun Mehta, Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India.
| | - Amninder Kaur
- Department of Internal Medicine, Dayanand Medical College and Hospital, Ludhiana, India
| | - Namita Bansal
- Department of Research and Development, Dayanand Medical College and Hospital, Ludhiana, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
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A personalized treatment program in persons with type 2 diabetes is associated with a reduction in liver steatosis. Eur J Gastroenterol Hepatol 2021; 33:1420-1426. [PMID: 32796353 DOI: 10.1097/meg.0000000000001882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS It is unclear if improving glycemic control in persons with type 2 diabetes (T2D) also has liver-related effects. We aimed to evaluate if a personalized treatment program associates with improvement of liver-related parameters in persons with advanced T2D in a real-life setting. METHODS Persons with advanced T2D underwent a 4-day personalized treatment program, with the aim of improving glycemic control by dietary advice, instructions on how to achieve optimal glucose control and individualized dosage of medications. Transient elastography was used to estimate liver steatosis and fibrosis. Persons with liver diseases other than non-alcoholic fatty liver disease (NAFLD) were excluded. After 3 months, study participants were offered re-examination. RESULTS Ninety-one persons were included. Of these, 75 persons (82%) had controlled attenuation parameter (CAP) measurements of acceptable quality at baseline. Of these, 57 (76%) had NAFLD (defined as >268 dB/m). Twenty-two persons (24%) had elevated liver stiffness (>7.9 kPa), and eight (9%) had liver stiffness above 13.9 kPa, indicating advanced fibrosis. Over a median follow-up of 101 days, mean CAP in persons with NAFLD was reduced by 18.33 dB/m (P = 0.035). In persons with elevated liver stiffness, mean stiffness was reduced by 2.6 kPa (P = 0.047). In linear regression, one-unit improvement in fasting glucose (mg/dl) was associated with a decrease in hepatic steatosis with 0.48 dB/m (adjusted R2 = 0.35, P < 0.01). CONCLUSION The prevalence of NAFLD with advanced fibrosis is high in persons with advanced T2D. Improving glycemic control through a personalized treatment program is associated with a reduction in liver steatosis and stiffness in this cohort.
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The Interplay between Insulin Resistance, Inflammation, Oxidative Stress, Base Excision Repair and Metabolic Syndrome in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms222011128. [PMID: 34681787 PMCID: PMC8537238 DOI: 10.3390/ijms222011128] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most common chronic liver disorders, affecting mainly people in Western countries, is nonalcoholic fatty liver disease (NAFLD). Unfortunately, its pathophysiological mechanism is not fully understood, and no dedicated treatment is available. Simple steatosis can lead to nonalcoholic steatohepatitis and even to fibrosis, cancer, and cirrhosis of the liver. NAFLD very often occurs in parallel with type 2 diabetes mellitus and in obese people. Furthermore, it is much more likely to develop in patients with metabolic syndrome (MS), whose criteria include abdominal obesity, elevated blood triacylglycerol level, reduced high-density lipoprotein cholesterol level, increased blood pressure, and high fasting glucose. An important phenomenon in MS is also insulin resistance (IR), which is very common in NAFLD. Liver IR and NAFLD development are linked through an interaction between the accumulation of free fatty acids, hepatic inflammation, and increased oxidative stress. The liver is particularly exposed to elevated levels of reactive oxygen species due to a large number of mitochondria in hepatocytes. In these organelles, the main DNA repair pathway is base excision repair (BER). The present article will illustrate how impairment of BER may be related to the development of NAFLD.
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Asbaghi O, Naeini F, Ashtary-Larky D, Kaviani M, Rezaei Kelishadi M, Eslampour E, Moradi S, Mirzadeh E, Clark CCT, Naeini AA. Effects of chromium supplementation on blood pressure, body mass index, liver function enzymes and malondialdehyde in patients with type 2 diabetes: A systematic review and dose-response meta-analysis of randomized controlled trials. Complement Ther Med 2021; 60:102755. [PMID: 34237387 DOI: 10.1016/j.ctim.2021.102755] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 05/10/2021] [Accepted: 06/21/2021] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Several studies reported beneficial effects of chromium supplementation for management of type 2 diabetes mellitus (T2DM). The present study aimed to provide a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the effects of chromium supplementation on blood pressure, body mass index (BMI), liver function enzymes and malondialdehyde (MDA) in patients with T2DM. METHODS PubMed, Scopus, and Embase were searched up to 15 November 2020 with no language and time restriction. RCTs that reported the effects of chromium supplementation on blood pressure, BMI, liver function enzymes and MDA in patients with T2DM were included. A random-effects model was used to compute weighted mean differences (WMDs) with 95 % confidence intervals (CIs). Between-study heterogeneity was assessed by Cochran's Q test and quantified by I2 statistic. RESULTS Of 3586 publications, 15 RCTs were included for the meta-analysis. Pooled effect sizes indicated that chromium significantly reduced diastolic blood pressure (DBP) (WMD): -2.36 mmHg, 95 % CI: -4.14, -0.60; P = 0.008), and MDA (WMD: -0.55 umol/l, 95 % CI: -0.96, -0.14; P = 0.008). However, chromium supplementation did not significantly affect BMI, systolic blood pressure (SBP), alanine aminotransferase (ALT), aspartate aminotransferase (AST). Meta-regression analysis did not show significant linear relationship between dose of chromium and change in BMI (p = 0.412), SBP (p = 0. 319), DBP (p = 0.102), ALT (p = 0.923), AST (p = 0.986) and MDA (p = 0.055). CONCLUSION The present systematic review and meta-analysis shows that supplementation with chromium at dose of 200-1000 μg/day may reduce DBP and MDA in T2DM patients.
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Affiliation(s)
- Omid Asbaghi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Fatemeh Naeini
- Department of Clinical Nutrition, School of Nutritional Science, Tehran University of Medical Science, Tehran, Iran.
| | - Damoon Ashtary-Larky
- Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Mojtaba Kaviani
- Faculty of Pure & Applied Science, School of Nutrition and Dietetics, Acadia University, Wolfville, NS, Canada.
| | - Mahnaz Rezaei Kelishadi
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Elham Eslampour
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran.
| | - Sajjad Moradi
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Elahe Mirzadeh
- Department of Physical Education and Sports Science, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Cain C T Clark
- Centre for Intelligent Healthcare, Coventry University, Coventry, CV1 5FB, UK.
| | - Amirmansour Alavi Naeini
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
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Hussain A, Patel PJ, Rhodes F, Srivastava A, Patch D, Rosenberg W. Decompensated cirrhosis is the commonest presentation for NAFLD patients undergoing liver transplant assessment. Clin Med (Lond) 2021; 20:313-318. [PMID: 32414722 DOI: 10.7861/clinmed.2019-0250] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) accounts for 10-15% of orthotopic liver transplants (OLTs) in the UK. Index presentations with cirrhotic decompensation represent missed opportunities for preventive treatment leaving OLT or palliation as the only options.We retrospectively reviewed patient records for all NAFLD patients undergoing assessment for OLT between January 2003 and December 2017.Data were available for 81 patients with NAFLD as the primary diagnosis. Fifty-two patients had decompensated cirrhosis at first presentation; 91.7% presented to secondary care compared to 52.7% referred from primary care (p=0.001). Cirrhosis was not suspected at the time of referral to hospital in 24.7% of patients subsequently assessed for OLT. Most patients undergoing assessment for OLT for NAFLD had decompensated cirrhosis at their first diagnosis of chronic liver disease. These data highlight the plight of patients with NAFLD cirrhosis in whom chronic liver disease is diagnosed late.
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Affiliation(s)
- Ahmed Hussain
- UCL Institute for Liver and Digestive Health, London, UK
| | - Preya J Patel
- UCL Institute for Liver and Digestive Health, London, UK
| | - Freya Rhodes
- UCL Institute for Liver and Digestive Health, London, UK
| | | | - David Patch
- UCL Institute for Liver and Digestive Health, London, UK
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Wang W, Zhong X, Guo J. Role of 2‑series prostaglandins in the pathogenesis of type 2 diabetes mellitus and non‑alcoholic fatty liver disease (Review). Int J Mol Med 2021; 47:114. [PMID: 33907839 PMCID: PMC8083810 DOI: 10.3892/ijmm.2021.4947] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/24/2021] [Indexed: 02/06/2023] Open
Abstract
Nowadays, metabolic syndromes are emerging as global epidemics, whose incidence are increasing annually. However, the efficacy of therapy does not increase proportionately with the increased morbidity. Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are two common metabolic syndromes that are closely associated. The pathogenic mechanisms of T2DM and NAFLD have been studied, and it was revealed that insulin resistance, hyperglycemia, hepatic lipid accumulation and inflammation markedly contribute to the development of these two diseases. The 2-series prostaglandins (PGs), a subgroup of eicosanoids, including PGD2, PGE2, PGF2α and PGI2, are converted from arachidonic acid catalyzed by the rate-limiting enzymes cyclooxygenases (COXs). Considering their wide distribution in almost every tissue, 2-series PG pathways exert complex and interlinked effects in mediating pancreatic β-cell function and proliferation, insulin sensitivity, fat accumulation and lipolysis, as well as inflammatory processes. Previous studies have revealed that metabolic disturbances, such as hyperglycemia and hyperlipidemia, can be improved by treatment with COX inhibitors. At present, an accumulating number of studies have focused on the roles of 2-series PGs and their metabolites in the pathogenesis of metabolic syndromes, particularly T2DM and NAFLD. In the present review, the role of 2-series PGs in the highly intertwined pathogenic mechanisms of T2DM and NAFLD was discussed, and important therapeutic strategies based on targeting 2-series PG pathways in T2DM and NAFLD treatment were provided.
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Affiliation(s)
- Weixuan Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China
| | - Xin Zhong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China
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Abstract
The epidemiology and the current burden of chronic liver disease are changing globally, with non-alcoholic fatty liver disease (NAFLD) becoming the most frequent cause of liver disease in close relationship with the global epidemics of obesity, type 2 diabetes and metabolic syndrome. The clinical phenotypes of NAFLD are very heterogeneous in relationship with multiple pathways involved in the disease progression. In the absence of a specific treatment for non-alcoholic steatohepatitis (NASH), it is important to understand the natural history of the disease, to identify and to optimize the control of factors that are involved in disease progression. In this paper we propose a critical analysis of factors that are involved in the progression of the liver damage and the occurrence of extra-hepatic complications (cardiovascular diseases, extra hepatic cancer) in patients with NAFLD. We also briefly discuss the impact of the heterogeneity of the clinical phenotype of NAFLD on the clinical practice globally and at the individual level.
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Affiliation(s)
- Raluca Pais
- Institut de Cardiométabolisme et Nutrition, Hôpital Pitié Salpetrière, Assistance Publique Hôpitaux de Paris, 75013 Paris, France;
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Sharma R. Descriptive epidemiology of incidence and mortality of primary liver cancer in 185 countries: evidence from GLOBOCAN 2018. Jpn J Clin Oncol 2021; 50:1370-1379. [PMID: 32719873 DOI: 10.1093/jjco/hyaa130] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 07/03/2020] [Indexed: 12/24/2022] Open
Abstract
PURPOSE This study aims to examine the burden of primary liver cancer in 185 countries in 2018. METHODS The estimates of incidence, mortality and prevalence of primary liver cancer were procured from GLOBOCAN 2018. The development status of a country was measured using the human development index-a composite indicator of income per capita, education and life expectancy. RESULTS Globally, primary liver cancer resulted in an estimated 781 631 deaths at age-standardized mortality rate of 8.5/100 000, and 841 080 cases were estimated to be diagnosed in 2018. Males accounted for 596 574 cases and 548 375 deaths, which is more than twice the burden of primary liver cancer in females (cases: 244 506; deaths: 233 456). The global age-standardized incidence rate was 9.3/100 000 in 2018, varying from Morocco (1.1/100 000) to Mongolia (93.7/100 000). There were remarkable variations in terms of age-standardized mortality rate, too, which ranged from 1/100 000 in Nepal to 75.4/100 000 in Mongolia. East Asia was the top region contributing 55.6% of global cases and 54.7% of global deaths. CONCLUSIONS Since majority of the primary liver cancer burden pertains to hepatocellular carcinoma and screening approaches are yet to be fully proven, the policy focus must be on prevention approaches through the hepatitis-B vaccine, early detection of hepatitis-C infection, reduced alcohol consumption, obesity control, reduced aflatoxin exposure and containment of other modifiable risk factors.
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Affiliation(s)
- Rajesh Sharma
- University School of Management and Entrepreneurship, Delhi Technological University, Delhi, India
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Dewidar B, Kahl S, Pafili K, Roden M. Metabolic liver disease in diabetes - From mechanisms to clinical trials. Metabolism 2020; 111S:154299. [PMID: 32569680 PMCID: PMC7305712 DOI: 10.1016/j.metabol.2020.154299] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/04/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma. NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Both multisystem diseases share several common mechanisms. Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle. On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression. Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance. Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM. This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression. Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials. Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM.
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Affiliation(s)
- Bedair Dewidar
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Sabine Kahl
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Kalliopi Pafili
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany
| | - Michael Roden
- Institute of Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
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Ahn SB, Powell EE, Russell A, Hartel G, Irvine KM, Moser C, Valery PC. Type 2 Diabetes: A Risk Factor for Hospital Readmissions and Mortality in Australian Patients With Cirrhosis. Hepatol Commun 2020; 4:1279-1292. [PMID: 32923832 PMCID: PMC7471423 DOI: 10.1002/hep4.1536] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/05/2020] [Accepted: 04/15/2020] [Indexed: 12/23/2022] Open
Abstract
Although there is evidence that type 2 diabetes mellitus (T2D) impacts adversely on liver-related mortality, its influence on hospital readmissions and development of complications in patients with cirrhosis, particularly in alcohol-related cirrhosis (the most common etiological factor among Australian hospital admissions for cirrhosis) has not been well studied. This study aimed to investigate the association between T2D and liver cirrhosis in a population-based cohort of patients admitted for cirrhosis in the state of Queensland, Australia. A retrospective cohort analysis was conducted using data from the Queensland Hospital Admitted Patient Data Collection, which contains information on all hospital episodes of care for patients with liver cirrhosis, and the Death Registry during 2008-2017. We used demographic, clinical data, and socioeconomic characteristics. A total of 8,631 patients were analyzed. A higher proportion of patients with T2D had cryptogenic cirrhosis (42.4% vs. 27.3%, respectively; P < 0.001) or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (13.8% vs. 3.4%, respectively; P < 0.001) and an admission for hepatocellular carcinoma (18.0% vs. 12.2%, respectively; P < 0.001) compared to patients without T2D. Patients with liver cirrhosis with T2D compared to those without T2D had a significantly increased median length of hospital stay (6 [range, 1-11] vs. 5 [range, 1-11] days, respectively; P < 0.001), double the rate of noncirrhosis-related admissions (incidence rate ratios [IRR], 2.03; 95% confidence interval [CI], 1.98-2.07), a 1.35-fold increased rate of cirrhosis-related admissions (IRR, 1.35; 95% CI, 1.30-1.41), and significantly lower survival (P < 0.001). Conclusion: Among hospitalized patients with cirrhosis, the cohort with T2D is at higher risk and may benefit from attention to comorbidities and additional support to reduce readmissions.
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Affiliation(s)
- Sang Bong Ahn
- QIMR Berghofer Medical Research InstituteHerstonAustralia
- Department of Internal MedicineEulji University School of MedicineSeoulKorea
| | - Elizabeth E. Powell
- Centre for Liver Disease ResearchTranslational Research InstituteFaculty of MedicineUniversity of QueenslandBrisbaneAustralia
- Department of Gastroenterology and HepatologyPrincess Alexandra HospitalBrisbaneAustralia
| | - Anthony Russell
- Department of Diabetes and EndocrinologyUniversity of QueenslandBrisbaneAustralia
| | - Gunter Hartel
- QIMR Berghofer Medical Research InstituteHerstonAustralia
| | - Katharine M. Irvine
- Centre for Liver Disease ResearchTranslational Research InstituteFaculty of MedicineUniversity of QueenslandBrisbaneAustralia
- Mater ResearchUniversity of QueenslandBrisbaneAustralia
| | - Chris Moser
- Statistical Services BranchQueensland HealthBrisbaneAustralia
| | - Patricia C. Valery
- QIMR Berghofer Medical Research InstituteHerstonAustralia
- Centre for Liver Disease ResearchTranslational Research InstituteFaculty of MedicineUniversity of QueenslandBrisbaneAustralia
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Lonardo A, Suzuki A. Sexual Dimorphism of NAFLD in Adults. Focus on Clinical Aspects and Implications for Practice and Translational Research. J Clin Med 2020; 9:1278. [PMID: 32354182 PMCID: PMC7288212 DOI: 10.3390/jcm9051278] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) embraces the clinico-pathological consequences of hepatic lipotoxicity and is a major public health problem globally. Sexual dimorphism is a definite feature of most human diseases but, under this aspect, NAFLD lags behind other medical fields. Here, we aim at summarizing and critically discussing the most prominent sex differences and gaps in NAFLD in humans, with emphasis on those aspects which are relevant for clinical practice and translational research. Sexual dimorphism of NAFLD is covered with references to the following areas: disease prevalence and risk factors, pathophysiology, comorbidities, natural course and complications. Finally, we also discuss selected gender differences and whether sex-specific lifestyle changes should be adopted to contrast NAFLD in men and women.
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Affiliation(s)
- Amedeo Lonardo
- Operating Unit Metabolic Syndrome, Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Baggiovara MO, Italy
| | - Ayako Suzuki
- Division of Gastroenterology, Durham VA Medical Center and Duke University Medical Center, Durham, NC 27705, USA;
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Targher G. Is it time for non-alcoholic fatty liver disease screening in patients with type 2 diabetes mellitus? Hepatobiliary Surg Nutr 2020; 9:239-241. [PMID: 32355690 PMCID: PMC7188532 DOI: 10.21037/hbsn.2019.10.21] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 10/16/2019] [Indexed: 08/15/2023]
Affiliation(s)
- Giovanni Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
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Björkström K, Franzén S, Eliasson B, Miftaraj M, Gudbjörnsdottir S, Trolle-Lagerros Y, Svensson AM, Hagström H. Risk Factors for Severe Liver Disease in Patients With Type 2 Diabetes. Clin Gastroenterol Hepatol 2019; 17:2769-2775.e4. [PMID: 31009793 DOI: 10.1016/j.cgh.2019.04.038] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 03/21/2019] [Accepted: 04/13/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Type 2 diabetes is a risk factor for development of cirrhosis and hepatocellular carcinoma. However, risk factors that identify persons with the highest risk for these outcomes are missing from unselected, population-based cohorts. METHODS The National Diabetes Register contains data on about 90% of persons in Sweden with type 2 diabetes. In this cohort study, persons with type 2 diabetes listed in the National Diabetes Register were compared with 5 individuals from the general population (controls), matched for age, sex, and county. In total, 406 770 persons with type 2 diabetes and 2 033 850 controls were included and followed for 21 596 934 person-years. We used population-based registers to determine the incidence of severe liver disease, defined as a diagnosis of hepatocellular carcinoma, cirrhosis, decompensation, liver failure and/or death due to liver disease during follow up. Cox regression was performed to estimate the risk of severe liver disease and to examine risk factors in persons with type 2 diabetes. RESULTS Risk for severe liver disease was increased in patients with type 2 diabetes compared to controls (hazard ratio, 2.28; 95% CI, 2.21-2.36). Risk factors associated with severe liver disease in persons with type 2 diabetes were higher age, male sex, hypertension, higher body mass index, lower glomerular filtration rate, microalbuminuria, and smoking. Statins were associated with a decreased risk of severe liver disease. CONCLUSIONS Persons with type 2 diabetes have an increased risk for severe liver disease. Knowledge of risk factors can be helpful in identifying persons with type 2 diabetes who have a high risk for severe liver disease.
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Affiliation(s)
- Karl Björkström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Stefan Franzén
- Swedish National Diabetes Register, Centre of Registers in Region, Sweden
| | - Björn Eliasson
- Swedish National Diabetes Register, Centre of Registers in Region, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Mervete Miftaraj
- Swedish National Diabetes Register, Centre of Registers in Region, Sweden
| | - Soffia Gudbjörnsdottir
- Swedish National Diabetes Register, Centre of Registers in Region, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Ylva Trolle-Lagerros
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ann-Marie Svensson
- Swedish National Diabetes Register, Centre of Registers in Region, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Hannes Hagström
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska University Hospital, Stockholm, Sweden; Unit of Hepatology, Department of Upper Gastrointestinal Diseases, Karolinska University Hospital, Stockholm, Sweden.
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Mantovani A, Turino T, Lando MG, Gjini K, Byrne CD, Zusi C, Ravaioli F, Colecchia A, Maffeis C, Salvagno G, Lippi G, Bonora E, Targher G. Screening for non-alcoholic fatty liver disease using liver stiffness measurement and its association with chronic kidney disease and cardiovascular complications in patients with type 2 diabetes. DIABETES & METABOLISM 2019; 46:296-303. [PMID: 31786361 DOI: 10.1016/j.diabet.2019.11.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 11/09/2019] [Indexed: 12/14/2022]
Abstract
AIM Despite the high prevalence and serious clinical implications of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), NAFLD is usually overlooked during routine diabetes care. This study explored the proportion of NAFLD cases and increased liver fibrosis (LF), and the association between LF and either chronic kidney disease (CKD) or cardiovascular complications in T2DM patients. METHODS The study included 137 patients with non-insulin-treated T2DM and no known liver disease consecutively attending our diabetes outpatients' service who underwent liver ultrasonography and liver stiffness measurement (LSM) using vibration-controlled transient elastography (FibroScan®). RESULTS The proportion of patients with hepatic steatosis on ultrasonography was 73.7%, and the proportion with significant LF was 17.5% with an LSM cut-off ≥7kPa or 10.2% with an LSM cut-off ≥8.7kPa. The presence of CKD (estimated GFR <60mL/min/1.73m2 and/or abnormal albuminuria) increased significantly across LSM tertiles (from around 15% in tertile 1 to 45% in tertile 3). Cardiovascular complications (previous ischaemic heart disease, ischaemic stroke, permanent atrial fibrillation) also tended to increase across LSM tertiles (from around 15% to 30%). After adjusting for established risk factors and potential confounders, LSM tertile 3 remained significantly associated with an approximately threefold higher risk of prevalent CKD (adjusted OR: 3.28, 95% CI: 1.22-8.90; P=0.019), but not for cardiovascular complications. CONCLUSION These results suggest that NAFLD and significant LF (as assessed by FibroScan®) are very commonly seen in T2DM outpatients with no known liver disease attending a secondary-care diabetes service, and that increased LF is associated with a greater proportion of chronic vascular complications, especially CKD.
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Affiliation(s)
- A Mantovani
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - T Turino
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - M G Lando
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - K Gjini
- Gastroenterology Unit, Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - C D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK; Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - C Zusi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy; Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgical Sciences, Dentistry, Paediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - F Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), University Hospital St Orsola-Malpighi, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - A Colecchia
- Gastroenterology Unit, Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - C Maffeis
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgical Sciences, Dentistry, Paediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - G Salvagno
- Section of Clinical Biochemistry, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - G Lippi
- Section of Clinical Biochemistry, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - E Bonora
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - G Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy.
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Peter JS, Shalini M, Giridharan R, Basha KS, Lavinya UB, Evan Prince S. Administration of coenzyme Q10 to a diabetic rat model: changes in biochemical, antioxidant, and histopathological indicators. Int J Diabetes Dev Ctries 2019. [DOI: 10.1007/s13410-019-00752-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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46
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Qiu Y, Zheng J, Yang J, Li F, Zhou X, Song X. The predictive role of toll-like receptor-4 genetic polymorphisms in susceptibility to and prognosis of prostatic hyperplasia. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2019; 22:86-92. [PMID: 30944713 PMCID: PMC6437452 DOI: 10.22038/ijbms.2018.33173.7922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Objective(s): This study was aimed to evaluate whether single nucleotide polymorphisms (SNPs) of TLR4 and common living habits of prostate hyperplasia (BPH) patients would affect the subjects’ risk and prognosis. Materials and Methods: We totally recruited 501 BPH patients and 964 healthy controls. The patients’ international prostate symptom score (IPSS) and quality of life assessment (QoL) were designated as the prognostic indexes for BPH patients. Altogether 7 SNPs within TLR4 were selected, and the interactions among SNPs and living habits were explained with multi-factor dimensionality reduction (MDR) modeling. Results: The mutant alleles of rs10983755 (G>A) and rs1927907 (G>A) tended to put on risk of BPH, yet the wide alleles of rs4986791 (C>T) and rs115336889 (G>C) were associated with incremental susceptibility to BPH (P<0.05). The rs10983755 (GA) and rs1927907 (GA) were suggested as the marker of non-aggressive BPH, whereas rs4986791 (TT) could symbolize aggressive BPH (P<0.05). The homozygotes of rs4986791 (TT) and rs115336889 (CC) could improve the IPSS change, and rs115336889 (CC) was also correlated with more obviously ameliorated Qol change (P<0.05). Finally, MDR modeling suggested that rs4986791 (TT) and rs115336889 (GG) shaped the genotyping combination featured by the lowest risk of BPH when smoking or drinking history was also evaluated. Conclusion: The SNPs situated within TLR4 were potent candidates for predicting risk and prognosis of BPH patients, and their interactions within environmental parameters also helped to develop effective strategies for preventing and treating BPH.
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Affiliation(s)
- Yunhua Qiu
- Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Jinzhou Zheng
- Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Jianfeng Yang
- Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Feng Li
- Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Xiqiu Zhou
- Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Xiaoyun Song
- Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
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Williams R, Alexander G, Aspinall R, Batterham R, Bhala N, Bosanquet N, Severi K, Burton A, Burton R, Cramp ME, Day N, Dhawan A, Dillon J, Drummond C, Dyson J, Ferguson J, Foster GR, Gilmore I, Greenberg J, Henn C, Hudson M, Jarvis H, Kelly D, Mann J, McDougall N, McKee M, Moriarty K, Morling J, Newsome P, O'Grady J, Rolfe L, Rice P, Rutter H, Sheron N, Thorburn D, Verne J, Vohra J, Wass J, Yeoman A. Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK. Lancet 2018; 392:2398-2412. [PMID: 30473364 DOI: 10.1016/s0140-6736(18)32561-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/04/2018] [Accepted: 10/10/2018] [Indexed: 02/06/2023]
Abstract
This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease.
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Affiliation(s)
| | | | | | - Rachel Batterham
- National Institute of Health Research, UCLH Biomedical Research Centre, London, UK
| | - Neeraj Bhala
- Queen Elizabeth Hospital Birmingham and University of Birmingham, Edgbaston, Birmingham, UK
| | - Nick Bosanquet
- Department of Bioengineering, Imperial College London, London, UK
| | | | - Anya Burton
- Hepatocellular Carcinoma UK and National Cancer Registration and Analysis Service, Public Health England, Bristol, UK
| | | | - Matthew E Cramp
- Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | | | | | - John Dillon
- Medical Research Institute, University of Dundee, Dundee, UK
| | - Colin Drummond
- Institute of Psychiatry, Psychology & Neuroscience, King's College London and South London and Maudsley NHS Foundation Trust, London, UK
| | | | - James Ferguson
- National Institute for Health Research Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Graham R Foster
- Barts Liver Centre, Queen Mary University of London, London, UK
| | | | | | | | | | - Helen Jarvis
- Institute of Health and Society, Newcastle University, Newcastle, UK; The Royal College of General Practitioners, London, UK
| | - Deirdre Kelly
- Birmingham Women's and Children's Hospital, Birmingham, UK
| | - Jake Mann
- Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | | | - Martin McKee
- Department of Health Services Research and Policy, London School of Hygiene & Tropical Medicine, London, UK
| | | | - Joanne Morling
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - Philip Newsome
- National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | | | | | - Peter Rice
- Scottish Health Action on Alcohol Problems (SHAAP), Bath, UK
| | | | - Nick Sheron
- National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton, Southampton, UK
| | | | | | - Jyotsna Vohra
- Cancer Policy Research Centre, Cancer Research UK, London
| | - John Wass
- Department of Endocrinology, Churchill Hospital, Oxford, UK
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48
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Hamed AE, Elsahar M, Elwan NM, El-Nakeep S, Naguib M, Soliman HH, Ahmed Aboubakr A, AbdelMaqsod A, Sedrak H, Assaad SN, Elwakil R, Esmat G, Salh S, Mostafa T, Mogawer S, Sadek SE, Saber MM, Ezelarab H, Mahmoud AA, Sultan S, El Kassas M, Kamal E, ElSayed NM, Moussa S. Managing diabetes and liver disease association. Arab J Gastroenterol 2018; 19:166-179. [PMID: 30420265 DOI: 10.1016/j.ajg.2018.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/26/2018] [Indexed: 02/05/2023]
Abstract
There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening. Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival. Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention. The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients. In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted. This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.
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Affiliation(s)
- Abd Elkhalek Hamed
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt.
| | - Medhat Elsahar
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Police Medical Academy, Egypt
| | | | | | | | | | - Ashraf Ahmed Aboubakr
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | | | - Reda Elwakil
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Ain Shams University, Egypt
| | - Gamal Esmat
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Kasr Al Aini, Egypt
| | - Samira Salh
- Department of Pharmacy, Cairo University, Egypt
| | | | | | - Sameh Emil Sadek
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | - Maha M Saber
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Hanan Ezelarab
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Asem Ashraf Mahmoud
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | - Ehab Kamal
- Medical Department, National Research Centre, Egypt
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Ohkuma T, Peters SAE, Woodward M. Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events. Diabetologia 2018; 61:2140-2154. [PMID: 30027404 PMCID: PMC6133170 DOI: 10.1007/s00125-018-4664-5] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 05/02/2018] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Diabetes has been shown to be a risk factor for some cancers. Whether diabetes confers the same excess risk of cancer, overall and by site, in women and men is unknown. METHODS A systematic search was performed in PubMed for cohort studies published up to December 2016. Selected studies reported sex-specific relative risk (RR) estimates for the association between diabetes and cancer adjusted at least for age in both sexes. Random-effects meta-analyses with inverse-variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratios of RRs (RRRs) for all-site and site-specific cancers. RESULTS Data on all-site cancer events (incident or fatal only) were available from 121 cohorts (19,239,302 individuals; 1,082,592 events). The pooled adjusted RR for all-site cancer associated with diabetes was 1.27 (95% CI 1.21, 1.32) in women and 1.19 (1.13, 1.25) in men. Women with diabetes had ~6% greater risk compared with men with diabetes (the pooled RRR was 1.06, 95% CI 1.03, 1.09). Corresponding pooled RRRs were 1.10 (1.07, 1.13) for all-site cancer incidence and 1.03 (0.99, 1.06) for all-site cancer mortality. Diabetes also conferred a significantly greater RR in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower RR for liver cancer. CONCLUSIONS/INTERPRETATION Diabetes is a risk factor for all-site cancer for both women and men, but the excess risk of cancer associated with diabetes is slightly greater for women than men. The direction and magnitude of sex differences varies by location of the cancer.
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Affiliation(s)
- Toshiaki Ohkuma
- The George Institute for Global Health, University of New South Wales, Level 10, King George V Building, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, 2050, Australia.
| | - Sanne A E Peters
- The George Institute for Global Health, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, OX1 3QX, UK
| | - Mark Woodward
- The George Institute for Global Health, University of New South Wales, Level 10, King George V Building, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, 2050, Australia.
- The George Institute for Global Health, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, OX1 3QX, UK.
- Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
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50
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Jamwal R, de la Monte SM, Ogasawara K, Adusumalli S, Barlock BB, Akhlaghi F. Nonalcoholic Fatty Liver Disease and Diabetes Are Associated with Decreased CYP3A4 Protein Expression and Activity in Human Liver. Mol Pharm 2018; 15:2621-2632. [PMID: 29792708 DOI: 10.1021/acs.molpharmaceut.8b00159] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease in the Western population. We investigated the association of nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus on CYP3A4 activity in human liver tissue from brain dead donors ( n = 74). Histopathologically graded livers were grouped into normal ( n = 24), nonalcoholic fatty liver (NAFL, n = 26), and nonalcoholic steatohepatitis (NASH, n = 24) categories. The rate of conversion of midazolam to its 1-hydroxy metabolite was used to assess in vitro CYP3A4 activity in human liver microsomes (HLM). A proteomics approach was utilized to quantify the protein expression of CYP3A4 and related enzymes. Moreover, a physiologically based pharmacokinetic (PBPK) model was developed to allow prediction of midazolam concentration in NAFL and NASH livers. CYP3A4 activity in NAFL and NASH was 1.9- and 3.1-fold ( p < 0.05) lower than normal donors, respectively. Intrinsic clearance (CLint) was 2.7- ( p < 0.05) and 4.1-fold ( p < 0.01) lower in donors with NAFL and NASH, respectively. CYP3A4 protein expression was significantly lower in NAFL and NASH donors ( p < 0.05) and accounted for significant midazolam hydroxylation variability in a multiple linear regression analysis (β = 0.869, r2 = 0.762, P < 0.01). Diabetes was also associated with decreased CYP3A4 activity and protein expression. Both midazolam CLint and CYP3A4 protein abundance decreased significantly with increase in hepatic fat accumulation. Age and gender did not exhibit any significant association with the observed alterations. Predicted midazolam exposure was 1.7- and 2.3-fold higher for NAFL and NASH, respectively, which may result in a longer period of sedation in these disease-states. Data suggests that NAFLD and diabetes are associated with the decreased hepatic CYP3A4 activity. Thus, further evaluation of clinical consequences of these findings on the efficacy and safety of CYP3A4 substrates is warranted.
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Affiliation(s)
- Rohitash Jamwal
- Biomedical and Pharmaceutical Sciences, College of Pharmacy , University of Rhode Island , Kingston , Rhode Island 02881 , United States
| | - Suzanne M de la Monte
- Departments of Medicine, Pathology, Neurology, and Neurosurgery , Rhode Island Hospital and the Warren Alpert Medical School of Brown University , Providence , Rhode Island 02903 , United States
| | - Ken Ogasawara
- Biomedical and Pharmaceutical Sciences, College of Pharmacy , University of Rhode Island , Kingston , Rhode Island 02881 , United States
| | - Sravani Adusumalli
- Biomedical and Pharmaceutical Sciences, College of Pharmacy , University of Rhode Island , Kingston , Rhode Island 02881 , United States
| | - Benjamin B Barlock
- Biomedical and Pharmaceutical Sciences, College of Pharmacy , University of Rhode Island , Kingston , Rhode Island 02881 , United States
| | - Fatemeh Akhlaghi
- Biomedical and Pharmaceutical Sciences, College of Pharmacy , University of Rhode Island , Kingston , Rhode Island 02881 , United States
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