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Velayutham V, Benitez-Aguirre PZ, Liew G, Jenkins AJ, Craig ME, Donaghue KC. Markers of Early Liver Dysfunction Associate With Reduced Heart Rate Variability in Adolescents With Type 1 Diabetes. Pediatr Diabetes 2025; 2025:1910554. [PMID: 40406225 PMCID: PMC12097865 DOI: 10.1155/pedi/1910554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 04/25/2025] [Indexed: 05/26/2025] Open
Abstract
Aim: Data on the impact of metabolic dysfunction-associated fatty liver disease (MAFLD) on diabetes complications in youth with type 1 diabetes are lacking. However, MAFLD is well known to contribute to cardiovascular disease (CVD) in people with type 2 diabetes. We aimed to investigate markers of MAFLD in youth with type 1 diabetes and their relationship with chronic complications. Methods: A prospective study of 102 adolescents (mean age 14.7 ± 1.9 years) with type 1 diabetes underwent repeated annual diabetes complications assessments, including annual measures of liver enzymes. Early cardiac autonomic nerve dysfunction (CAN) was defined as ≥1 abnormality in seven heart rate variability parameters derived from a 10-min resting electrocardiogram. Multivariate generalized estimating equations explored predictors of CAN and other microvascular complications (retinopathy and early kidney dysfunction). Results: After a median follow-up of 3.5 years (IQR 2.7-4.6), there were significant increases in the mean alanine transaminase level (ALT) and systolic blood pressure (SBP) percentiles. Upper ALT and gamma-glutamyl transferase (GGT) tertiles (T3 vs. T1-2: odds ratio [OR], 95% confidence interval [CI], 2.05 [1.20, 3.48], and 2.99 [1.61, 5.58], respectively) predicted CAN development (23%, n = 24) independent of HbA1c and diabetes duration. They were not associated with retinopathy or early kidney dysfunction. Conclusion: Higher ALT and GGT associate with early CAN in adolescents with type 1 diabetes, suggesting hepatic inflammation may compound the impact of the diabetes milieu on systemic endothelial dysfunction.
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Affiliation(s)
- Vallimayil Velayutham
- Paediatrics, University of Sydney, Sydney, New South Wales, Australia
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
| | - Paul Z. Benitez-Aguirre
- Paediatrics, University of Sydney, Sydney, New South Wales, Australia
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
| | - Gerald Liew
- Ophthalmology, The Children's Hospital Westmead, Sydney, New South Wales, Australia
- Ophthalmology, University of Sydney, Sydney, New South Wales, Australia
| | - Alicia J. Jenkins
- Diabetic and Vascular Medicine, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Maria E. Craig
- Paediatrics, University of Sydney, Sydney, New South Wales, Australia
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
- Paediatrics, University of New South Wales, Sydney, New South Wales, Australia
| | - Kim C. Donaghue
- Paediatrics, University of Sydney, Sydney, New South Wales, Australia
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
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Qi GY, Wang F, Shi YB, Feng J, Xu J. Analysis of postprandial time trends and influencing factors of blood glucose and insulin in type 2 diabetes mellitus (T2DM) with metabolic dysfunction-associated steatotic liver disease (MASLD): a retrospective study based on propensity score matching (PSM). Acta Diabetol 2025:10.1007/s00592-025-02503-5. [PMID: 40167632 DOI: 10.1007/s00592-025-02503-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/24/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) are increasingly prevalent metabolic disorders worldwide, with a complex bidirectional relationship between them. Currently, there is a lack of research on the trajectories of blood glucose and insulin concentration over time after eating in patients with MASLD and T2DM. METHODS This clinical cohort included diagnosed T2DM patients in a large hospital over the past five years, was divided into an observation group (with MASLD) and a control group (without MASLD). The postprandial time trends of blood glucose and insulin concentration were analysed within two hours after eating. A strategy of backward iterative feature elimination combined with propensity score matching (PSM) was employed to screen for potential associated factors that might influence these trends. RESULTS In total, there were 521 in the observation group and 373 in the control group. In terms of blood glucose, the postprandial time-concentration trajectories for both groups shown a significant time main effect (F = 1145.567, P < 0.001), a significant group main effect (F = 15.340, P < 0.001), and a significant time*group interaction effect (F = 2.873, P = 0.035); After matching all the factors, the time*group interaction effect of blood glucose was not significant, but the differences from group main effect still existed. In terms of insulin, the postprandial time-concentration trajectories for both groups shown a significant time main effect (F = 309.429, P < 0.001), a significant group main effect (F = 6.319, P < 0.012), and a significant time*group interaction effect (F = 20.057, P < 0.001), but the trajectories crossed; After matching 4 factors such as Smoking, Essential Hypertension (EH), Body Mass Index (BMI), Triglyceride (TG) and Ca2+, neither the group main effect nor the time*group interaction effect on insulin was significant any more. CONCLUSION The postprandial trends of blood glucose and insulin concentration over time shown significant differences between T2DM patients with and without MASLD. IL-6 might be associated with the insulin resistance, while EH and Ca2+ might be related to the islet β-cell function. Smoking and TG might participate in both of the above processes. The strategy of backward iterative with PSM had demonstrated a relatively satisfactory effect in feature screening.
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Affiliation(s)
- Ge-Yao Qi
- Department of Internal Medicine, No. 32186 Unit Hospital of People's Liberation Army of China (PLA), Baoding, 071000, Hebei, China
| | - Fei Wang
- Department of Cardiology, No. 940 Hospital of Logistics Support Force of People's Liberation Army of China (PLA), Lanzhou, 730050, Gansu, China
| | - Yuan-Bo Shi
- Department of Information, No. 940 Hospital of Logistics Support Force of People's Liberation Army of China (PLA), Lanzhou, 730050, Gansu, China
| | - Juan Feng
- Department of Cardiology, No. 940 Hospital of Logistics Support Force of People's Liberation Army of China (PLA), Lanzhou, 730050, Gansu, China
| | - Jin Xu
- Department of Endocrinology, No. 940 Hospital of Logistics Support Force of People's Liberation Army of China (PLA), No. 333, Middle Section of South Binhe Road, Qilihe District, Lanzhou, 730050, Gansu, China.
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Wada N, Iwaki M, Kobayashi T, Nakajima A, Yoneda M. Reducing complications of metabolic dysfunction-associated steatotic liver disease. Expert Rev Gastroenterol Hepatol 2025; 19:577-588. [PMID: 40366767 DOI: 10.1080/17474124.2025.2502549] [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: 02/03/2025] [Accepted: 05/02/2025] [Indexed: 05/16/2025]
Abstract
INTRODUCTION Complications from metabolic dysfunction-associated steatotic liver disease (MASLD) include liver-related and extrahepatic complications, and the all-cause mortality rate is significantly higher in patients with MASLD than in those without MASLD. AREAS COVERED We review the complications of MASLD and their management based on the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) guidelines as well as medical papers. For the papers, we focused on studies referenced in the EASL and AASLD guidelines. Additionally, a search was conducted in PubMed to gather relevant literature. EXPERT OPINION Identifying and managing MASLD early, before it progresses to cirrhosis, is crucial to reducing mortality rates, and collaboration among healthcare professionals, including dietitians, nurses, and physical therapists, is vital for comprehensive management. There is active development of new drugs for MASLD, and we hope that new treatments will be developed soon.
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Affiliation(s)
- Naohiro Wada
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Ebeid A, Mokhtar F, Martinez-Lebron V, Park S, Degann S, Payano J, Vahora Z, Gray S, Johnson L, El-Maouche D, Abutaleb A. Use of noninvasive fibrosis calculators in an urban diabetes center suggests a large burden of undetected advanced liver disease. BMC Endocr Disord 2025; 25:53. [PMID: 40011894 PMCID: PMC11866707 DOI: 10.1186/s12902-025-01881-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 02/13/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Metabolic dysfunction associated steatotic liver disease (MASLD) is prevalent in up to 60% of patients with type 2 diabetes mellitus (T2DM). T2DM accelerates the risk of hepatic fibrosis and hepatocellular carcinoma in patients with MASLD. Our goal in this study was to identify patients with suspected MASLD and hepatic fibrosis in a large T2DM clinic by using noninvasive fibrosis scoring systems. METHODS We conducted a retrospective study of patients with T2DM seen by our endocrinologists at the Medical Faculty Associates (MFA) Diabetes Center in Washington, DC, from November 1, 2021, until November 1, 2022. We included all subjects who were over 18 years old with a hemoglobin A1c (HbA1c) of 6.5 or higher. Patients with a history of significant alcohol consumption, decompensated cirrhosis, previous bariatric surgery, or prior chronic liver disease were excluded from the study. We identified patients at risk for hepatic fibrosis by using the Fibrosis-4 (FIB-4) Index, NAFLD Fibrosis Score (NFS) and AST to Platelet Ratio Index (APRI) when lab values were available. RESULTS A total of 1,411 patients were evaluated for T2DM by an endocrinology provider during the one-year period. Out of these, 336 patients met one or more of the exclusion criteria, leaving a total of 1075 patients included in the analysis. The majority were African American (n = 582, 54%), 261 were Caucasian (24.3%), and 85 were Hispanic (7.9%). Most patients were females (n = 675, 62.7%). The mean HbA1c was 8.1 ± 2.3. 643 patients (59.8%) were insulin dependent. Based on FIB-4 scores, we found that 35 (3.9%) patients had a score of > 2.67 associated with advanced fibrosis and 257 (29%) patients with scores of 1.3-2.67 had moderate fibrosis. Using the NFS calculator, there were 281 (28%) patients with values of > 0.675 consistent with F3-F4 disease. 715 (71.8%) patients with values of < 0.675 consistent with F0-F2 fibrosis. A total of 6(< 1%) patients met criteria for advanced fibrosis by APRI scoring. CONCLUSION In our urban Diabetes Center, utilizing the NFS calculator may detect many patients with advanced liver disease. Further research is needed to ensure the internal validity of the non-invasive tests in predicting liver fibrosis and to correlate these findings with transient elastography and other imaging evidence of fatty liver disease. CLINICAL TRIAL NUMBER Non-applicable.
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Affiliation(s)
- Ahmed Ebeid
- The George Washington University, Washington, DC, USA
| | - Fatma Mokhtar
- The George Washington University, Washington, DC, USA
| | | | - Susie Park
- Department of Medicine, The George Washington University Hospital, Washington, DC, USA
| | - Seta Degann
- Department of Medicine, The George Washington University Hospital, Washington, DC, USA
| | - Jeremy Payano
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Zahid Vahora
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Stephen Gray
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Lynt Johnson
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA
| | - Diala El-Maouche
- Department of Endocrinology, The George Washington University Medical Faculty Associates, Washington, DC, USA
| | - Ameer Abutaleb
- Department of Surgery, The George Washington Transplant Institute, The George Washington University Hospital, Washington, DC, USA.
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Mirijello A, Pacilli G, Siena A, Mangiacotti A, D'Errico MM, Dilalla D, Lamacchia O, Fontana A, Copetti M, Piscitelli P, Targher G, De Cosmo SA. The Fibrosis-4 index predicts all-cause mortality in a cohort of patients at high cardiovascular risk partly through glomerular filtration rate reduction. Nutr Metab Cardiovasc Dis 2025; 35:103768. [PMID: 39561690 DOI: 10.1016/j.numecd.2024.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/21/2024] [Accepted: 10/07/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND AND AIM Fibrosis-4 (FIB-4) index is a widely used test for non-invasively assessing liver fibrosis. We aimed to investigate the association between FIB-4 index and risk of all-cause mortality in patients at high cardiovascular (CV) risk and to determine whether coexisting renal dysfunction mediates this association. METHODS AND RESULTS Single-center prospective study of 994 patients with established or suspected coronary artery disease undergoing coronary angiography, followed for a median of 44 months. Mortality data were obtained through the Italian Health Card Database. At baseline, the median FIB-4 index was greater in deceased vs. alive patients (1.71 vs. 1.38, p < 0.001) and in those with reduced eGFR than in those with normal eGFR (1.65 vs. 1.37, p < 0.001). For each unit increase in the baseline log-FIB-4 index, the risk of all-cause mortality sharply increased during the follow-up (hazard ratio [HR] 2.31, 95%CI 1.31-4.08, p = 0.004). Similarly, assuming the lowest baseline FIB-4 risk category as the reference, the risk of all-cause mortality progressively increased across the indeterminate (HR 1.82, 95%CI 1.18-2.82, p = 0.007) and the highest baseline FIB-4 risk categories (HR 2.33, 95%CI 1.37-3.97; p = 0.002). A causal mediation analysis showed that about one-third of the effect of FIB-4 index on mortality risk was mediated by reduced eGFR (32.8 %, p = 0.01). CONCLUSIONS Increased FIB-4 index predicts the long-term risk of all-cause mortality in patients at high CV risk, and this risk is, at least in part, mediated by reduced eGFR. Further prospective studies are needed to confirm these findings.
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Affiliation(s)
- Antonio Mirijello
- Unit of Internal Medicine, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy.
| | - Gabriella Pacilli
- Unit of Internal Medicine, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy
| | - Antonio Siena
- Unit of Internal Medicine, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy
| | - Antonio Mangiacotti
- Unit of Internal Medicine, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy
| | - Maria Maddalena D'Errico
- Unit of Geriatrics, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Daria Dilalla
- Endocrinology Unit, Department of Medical Sciences, University of Foggia, Foggia, Italy
| | - Olga Lamacchia
- Endocrinology Unit, Department of Medical Sciences, University of Foggia, Foggia, Italy
| | - Andrea Fontana
- Unit of Biostatistics, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy
| | - Massimiliano Copetti
- Unit of Biostatistics, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy
| | - Pamela Piscitelli
- Unit of Internal Medicine, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy.
| | - Giovanni Targher
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, 37024, Negrar di Valpolicella VR, Italy; Department of Medicine, University of Verona Faculty of Medicine and Surgery, 37126 Verona, Italy
| | - Salvatore A De Cosmo
- Unit of Internal Medicine, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, Italy.
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Orfanidou M, Polyzos SA. Retinopathy in Metabolic Dysfunction-Associated Steatotic Liver Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 61:38. [PMID: 39859020 PMCID: PMC11766779 DOI: 10.3390/medicina61010038] [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: 11/28/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystemic disease, i.e., influencing various organ systems beyond the liver and, thus, contributing to comorbidities. Characterized by excessive fat accumulation in the hepatocytes, MASLD is frequently linked to metabolic syndrome components, such as obesity, insulin resistance, dyslipidemia, and hypertension. Therefore, exploring the intricate connection between MASLD and other organ systems, including the eyes, seems to be essential. In this context, retinopathy has been investigated for its potential association with MASLD, since both conditions share common pathogenetic pathways. Chronic low-grade inflammation, oxidative stress, insulin resistance, and endothelial dysfunction are only some of those mechanisms contributing to disease progression and, possibly, determining the bidirectional interplay between the liver and retinal pathology. This narrative review aims to summarize data concerning the multisystemicity of MASLD, primarily focusing on its potential association with the eyes and, particularly, retinopathy. Identifying this possible association may emphasize the need for early screening and integrated management approaches that address the liver and eyes as interconnected components within the framework of a systemic disease. Further research is necessary to delineate the precise mechanisms and develop targeted interventions to mitigate the bidirectional impact between the liver and eyes, aiming to reduce the overall burden of disease and improve patient outcomes.
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Affiliation(s)
- Myrsini Orfanidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- First Department of Ophthalmology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stergios A. Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Fan YQ, Wang H, Wang PP, Shi ZY, Wang Y, Xu J. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio as a predictive indicator of CKD risk in NAFLD patients: NHANES 2017-2020. Front Nutr 2024; 11:1501494. [PMID: 39777076 PMCID: PMC11703712 DOI: 10.3389/fnut.2024.1501494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are both closely related to dyslipidemia. However, the relationship between dyslipidemia in patients with NAFLD and CKD is not yet clear. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is an innovative and comprehensive lipid index. The purpose of this study was to investigate the correlation between NHHR and CKD risk in NAFLD patients with or without fibrosis. Methods This study used data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020 for analysis, including a total of 4,041 subjects diagnosed with NAFLD. Among the NAFLD subjects, 3,315 individuals without liver fibrosis and 726 individuals with fibrosis. Weighted multivariate linear regression, weighted logistic regression, restricted cubic spline (RCS) curves, and subgroup analysis were used to evaluate the correlation between NHHR and CKD in patients with NAFLD. Results Our findings indicate that in NAFLD subjects without liver fibrosis, the highest tertile of NHHR, as compared to the lowest tertile, was inversely related to glomerular filtration rate (eGFR) (β: -2.14, 95% CI: -3.97, -0.32, p < 0.05) and positively related to CKD (OR: 1.67, 95% CI: 1.12, 2.49, p < 0.05). No significant associations were observed between NHHR and eGFR, urinary albumin to creatinine ratio (ACR) in NAFLD subjects with liver fibrosis. The RCS revealed a linear relationship between NHHR and ACR, CKD in NAFLD subjects without liver fibrosis, while a U-shaped relationship was observed between NHHR and ACR, CKD in NAFLD subjects with liver fibrosis. Conclusion In patients with non-fibrotic NAFLD, a significantly elevated NHHR is closely associated with an increased risk of CKD and shows a linear relationship with CKD. In patients with fibrotic NAFLD, NHHR shows a U-shaped relationship with CKD. LD, Our findings underscore the practical utility of NHHR as a biomarker for early risk stratification of CKD in patients with NAFLD.
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Affiliation(s)
- Yong-Qiang Fan
- Liver Transplantation Center, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Hao Wang
- Liver Transplantation Center, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Pei-Pei Wang
- Department of Respiratory, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhi-Yong Shi
- Liver Transplantation Center, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yan Wang
- Liver Transplantation Center, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jun Xu
- Liver Transplantation Center, The First Hospital of Shanxi Medical University, Taiyuan, China
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Rahmanian M, Deravi N, Poudineh M, Poopak A, Mirmohammadali SN, Fekrvand S, Tadbir K, Ebrahimian S, Zargarzadeh N, Pirzadeh M, Abdi A, Firouzabadi FD, Mechanick JI. Prevalence of metabolic dysfunction–associated fatty liver disease among patients with diabetic kidney disease: a systematic review and meta-analysis. EGYPTIAN LIVER JOURNAL 2024; 14:87. [DOI: 10.1186/s43066-024-00393-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 11/08/2024] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background
Mechanistic relationships between metabolic dysfunction–associated fatty liver disease (MAFLD) and chronic kidney disease are well characterized. Specifically, in type 2 diabetes (T2D), insulin resistance leads to MAFLD, and hyperglycemia leads to microvascular complications such as diabetic kidney disease (DKD). This systematic review and meta-analysis aims to describe the specific association between MAFLD and DKD for the first time.
Methods
PubMed, Web of Science, Google Scholar, and Scopus databases were searched up to February 2023 to identify relevant published articles. After screening the titles, abstracts, and full texts of the retrieved articles, cross-sectional studies and cohorts reporting on MAFLD in patients with DKD were identified and then analyzed.
Results
A total of 2615 articles were identified, of which 5 had sufficient data and fulfilled the eligibility criteria for meta-analysis. A total of 2345 patients with DKD were in the included studies. The prevalence rates of radiologically diagnosed MAFLD among patients with DKD ranged from 25 to 96%. The pooled prevalence rate of radiologically diagnosed MAFLD among patients with DKD was 0.55 (95% CI = 0.21–0.89, I2 = 99.79%, P-value < 0.01).
Conclusion
MAFLD is prevalent in patients with DKD. This finding emphasizes the need for aggressive case finding and then guideline-directed medical therapy of MAFLD, especially in patients with T2D and DKD to prevent further complications. Future studies should investigate mechanisms underpinning MAFLD and DKD in patients with T2D, especially in the context of cardiometabolic risk.
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Lai M, Lai JC, Allegretti AS, Patidar KR, Cullaro G. Investigating the Association between Steatotic Liver Disease and CKD in a Nationally Representative Sample. KIDNEY360 2024; 5:1844-1852. [PMID: 39235870 PMCID: PMC11687990 DOI: 10.34067/kid.0000000569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 08/23/2024] [Indexed: 09/07/2024]
Abstract
Key Points CKD is more common among those with steatotic liver disease compared with those without liver disease in the United States. Higher degrees of liver fibrosis are associated with greater prevalence of CKD independent of other common risk factors of kidney disease. Background Steatotic liver disease (SLD) and CKD are common conditions that are strongly associated. Yet, there is a paucity of data regarding the prevalence of this overlap and the factors that may drive its occurrence. Methods Using the National Health and Nutrition Examination Survey, we examined trends among adult participants from 2005 to 2020 that defined SLD using the Fatty Liver Index. We completed correlative analyses among adult participants from 2017 to 2020 that defined SLD on the basis of FibroScan results. We used multivariable survey-weighted binomial generalized linear models to determine the factors that were associated with CKD, defined as eGFR <60 or urine albumin-creatinine ratio >30. Results Among the 76,496 participants included in trend analyses, the estimated prevalence of CKD was 15.7% (95% confidence interval [CI], 15.2% to 16.2%) and SLD was 42.3% (95% CI, 41.4% to 43.2%). As compared with those without SLD, those with SLD had a significantly higher estimated prevalence of CKD (SLD, 15.7%; 95% CI, 14.9% to 16.5%; versus no SLD, 11.2%; 95% CI, 10.7% to 11.7%). In multivariate analyses of 3667 participants who underwent FibroScan and had SLD defined using the Fatty Liver Index, adjusting for control and presence of diabetes mellitus, hypertension, and hyperlipidemia/dyslipidemia, compared with those with normal liver stiffness, those with moderate scarring (F2) had similar odds of CKD (1.53; 95% CI, 0.91 to 2.56), those with severe scarring (F3) had higher odds of CKD (2.28; 95% CI, 1.20 to 4.32), and those with cirrhosis had higher odds of CKD (2.21; 95% CI, 1.13 to 4.32). Conclusions Our findings highlight that CKD is common among patients with SLD and that higher degrees of hepatic fibrosis are associated with CKD independent of other comorbidities of the metabolic syndrome.
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Affiliation(s)
- Mason Lai
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Jennifer C. Lai
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Andrew S. Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Kavish R. Patidar
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Michael E. DeBakey Veterans Affairs Medical Center, Houtson, Texas
| | - Giuseppe Cullaro
- Department of Medicine, University of California San Francisco, San Francisco, California
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Kaylan KB, Paul S. NAFLD No More: A Review of Current Guidelines in the Diagnosis and Evaluation of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Curr Diab Rep 2024; 25:5. [PMID: 39535566 DOI: 10.1007/s11892-024-01558-y] [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] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
PURPOSE OF REVIEW Provide a concise update on metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as a practical approach to screening and initial evaluation. RECENT FINDINGS Nomenclature changes have placed a greater focus on cardiometabolic risk factors in the definition of MASLD. Screening for MASLD is by stepwise noninvasive serum and imaging tests which can identify patients at risk for advanced fibrosis and liver-related complications. MASLD has been increasing in prevalence and disease burden but is underrecognized in primary care and endocrinology clinics. Multiple society guidelines, synthesized here, provide a framework for the initial approach in the diagnosis and evaluation of MASLD. Recent advances in pharmacologic treatment underline the importance of screening for patients who are at risk for advanced fibrosis as they are most likely to benefit from new drug classes, such as the liver-directed thyroid receptor agonist resmiterom.
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Affiliation(s)
- Kerim B Kaylan
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago Medicine, Chicago, IL, USA
| | - Sonali Paul
- Section of Gastroenterology, Hepatology, and Nutrition, Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL, USA.
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11
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Nishihara S, Koseki M, Tanaka K, Omatsu T, Saga A, Sawabe H, Inui H, Okada T, Ohama T, Okuzaki D, Kamada Y, Ono M, Nishida M, Watanabe M, Sakata Y. Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice. Endocr J 2024; 71:1055-1067. [PMID: 39261088 PMCID: PMC11778388 DOI: 10.1507/endocrj.ej24-0087] [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: 02/09/2024] [Accepted: 07/04/2024] [Indexed: 09/13/2024] Open
Abstract
We previously demonstrated hepatic, cardiac, and skin inflammation in a high-fat diet-induced steatotic liver disease (SLD) model. However, the molecular mechanism in the kidneys in this model remains unclear. It has been recently reported that SGLT2 inhibitors improve chronic kidney disease (CKD). Therefore, we used this model to evaluate the effects of tofogliflozin on renal lipid metabolism and inflammation. Male 8-10-week-old C57Bl/6 mice were fed a high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or an HF/HC/HS/BA diet alone (SLD group). After eight weeks, serum lipid profiles, histology, lipid content, and mRNA/microRNA and protein expression levels in the kidney were examined. The Tofo group showed significant reductions in body (26.9 ± 0.9 vs. 24.5 ± 1.0 g; p < 0.001) and kidney weight compared to those of the SLD group. Renal cholesterol (9.1 ± 1.6 vs. 7.5 ± 0.7 mg/g; p < 0.05) and non-esterified fatty acid (NEFA) (12.0 ± 3.0 vs. 8.4 ± 1.5 μEq/g; p < 0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed the presence of fewer lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. MicroRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Notably, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and Cpt1 in the Tofo group. Tofogliflozin decreased renal cholesterol and NEFA levels and improved inflammation through the regulation of PPARα and miR-21a.
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MESH Headings
- Non-alcoholic Fatty Liver Disease/drug therapy
- Non-alcoholic Fatty Liver Disease/genetics
- Non-alcoholic Fatty Liver Disease/immunology
- Non-alcoholic Fatty Liver Disease/metabolism
- Diet, High-Fat/adverse effects
- Animals
- Mice
- Disease Models, Animal
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
- Kidney/drug effects
- Kidney/immunology
- Kidney/metabolism
- Kidney/pathology
- Lipid Metabolism/drug effects
- Lipid Metabolism/genetics
- Lipid Metabolism/immunology
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/immunology
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Microscopy, Electron, Transmission
- Lipid Droplets/metabolism
- Lipid Droplets/pathology
- Lipid Droplets/ultrastructure
- Mice, Inbred C57BL
- Male
- MicroRNAs/analysis
- MicroRNAs/metabolism
- Cholesterol/analysis
- Cholesterol/metabolism
- Fatty Acids, Nonesterified/analysis
- Fatty Acids, Nonesterified/metabolism
- PPAR alpha/metabolism
- Up-Regulation/drug effects
- Up-Regulation/genetics
- Up-Regulation/immunology
- Inflammation/drug therapy
- Inflammation/genetics
- Inflammation/immunology
- Inflammation/metabolism
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Affiliation(s)
- Sae Nishihara
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Masahiro Koseki
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Katsunao Tanaka
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Takashi Omatsu
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Ayami Saga
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hiroshi Sawabe
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hiroyasu Inui
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Takeshi Okada
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Tohru Ohama
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Masafumi Ono
- Division of Innovative Medicine for Hepatobiliary & Pancreatology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan
| | - Makoto Nishida
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
- Health Care Division, Health and Counseling Center, Osaka University, Osaka 565-0871, Japan
| | - Mikio Watanabe
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yasushi Sakata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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12
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Erman H, Boyuk B, Arslan S, Akin S, Keskin Ö. Noninvasive Liver Fibrosis Indices as Indicators of Microvascular and Macrovascular Complications in Type 2 Diabetes. Metab Syndr Relat Disord 2024; 22:619-625. [PMID: 38836748 DOI: 10.1089/met.2024.0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2024] Open
Abstract
Objective: Nonalcoholic fatty liver disease (NAFLD) is more prevalent in patients with obesity, diabetes, and metabolic syndrome, which are risk factors for nonalcoholic steatohepatitis and liver fibrosis. NAFLD is related to cardiovascular outcomes in diabetes. We aimed to investigate the relationship between diabetic complications and NAFLD fibrosis score (NFS) and Fibrosis-4 score (FIB-4). Methods: Three hundred patients with type 2 diabetes mellitus (T2DM) were retrospectively evaluated according to NAFLD diagnosis on ultrasound in outpatient clinic. Risk of advanced fibrosis was estimated using FIB-4 and NFS. Diabetic complications of the patients were noted. Results: Presence of diabetic retinopathy is related to FIB-4 (P = 0.001) and NFS (P < 0.001) scores. NFS score (P = 0.037), not FIB-4 (P = 0.517), is related to diabetic nephropathy. Among macrovascular complications, only coronary artery disease is related to NFS and FIB-4 scores (P = 0.037 and P = 0.004, respectively). Although we cannot establish any association between fasting blood glucose, glycosylated hemoglobin (HbA1c) values and noninvasive liver fibrosis scores (P > 0.05), diabetes duration, and age positively correlated with the FIB-4 score (P = 0.033, P = 0.001). In logistic regression analysis, NFS > 0.676 values are associated with increased rates of diabetic retinopathy, independent of age, sex, HbA1c, and duration diabetes (odds ratio: 1.155, P = 0.030). FIB-4 has no relation with microvascular complications according to logistic regression analysis (P > 0.05 for all). Neither FIB-4 nor NFS has an effect on the presence of macrovascular complications (P > 0.05 for all). Conclusion: Our findings suggest that increase in NFS score is associated with the presence of diabetic retinopathy, independent of confounding factors. Further studies are needed on the applicability of noninvasive fibrosis scores in monitoring the presence of diabetic microvascular and macrovascular complications.
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Affiliation(s)
- Hande Erman
- Department of Internal Medicine, Istanbul Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
| | - Banu Boyuk
- Department of Internal Medicine, Istanbul Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
| | - Seyma Arslan
- Istanbul Arnavutköy District Health Directorate, Ministry of Health, Istanbul, Turkey
| | - Seydahmet Akin
- Department of Internal Medicine, Istanbul Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
| | - Özcan Keskin
- Department of Internal Medicine, Istanbul Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
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13
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Hara T, Watanabe T, Yamagami H, Miyataka K, Yasui S, Asai T, Kaneko Y, Mitsui Y, Masuda S, Kurahashi K, Otoda T, Yuasa T, Kuroda A, Endo I, Honda S, Kondo A, Matsuhisa M, Aihara KI. Development of Liver Fibrosis Represented by the Fibrosis-4 Index Is a Specific Risk Factor for Tubular Injury in Individuals with Type 2 Diabetes. Biomedicines 2024; 12:1789. [PMID: 39200252 PMCID: PMC11352124 DOI: 10.3390/biomedicines12081789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/22/2024] [Accepted: 08/05/2024] [Indexed: 09/02/2024] Open
Abstract
Although hyperglycemia and hypertension are well-known risk factors for glomerular injury in individuals with type 2 diabetes (T2D), specific risk factors for tubular injury remain unclear. We aimed to clarify the differences between risk factors for glomerular injury and risk factors for tubular injury in individuals with T2D. We categorized 1243 subjects into four groups based on urinary biomarkers, including the albumin-to-creatinine ratio (uACR) and L-type fatty acid-binding protein-to-creatinine ratio (uL-ABPCR) as a normal (N) group (uACR < 30 mg/gCr and uL-FABPCR < 5 μg/gCr; n = 637), a glomerular specific injury (G) group (uACR ≥ 30 mg/gCr and uL-FABPCR < 5 μg/gCr; n = 248), a tubular specific injury (T) group (uACR < 30 mg/gCr and uL-FABPCR ≥ 5 μg/gCr; n = 90), and a dual injury (D) group (uACR ≥ 30 mg/gCr and uL-FABPCR ≥ 5 μg/gCr; n = 268). Logistic regression analysis referencing the N group revealed that BMI, current smoking, and hypertension were risk factors for the G group, creatinine (Cr) and Fibrosis-4 (FIB-4) index were risk factors for the T group, and BMI, hypertension, HbA1c, Cr, and duration of diabetes were risk factors for the D group. While hypertension was a distinct specific risk factor for glomerular injury, the FIB-4 index was a specific contributor to the prevalence of tubular injury. On the other hand, the logistic regression analysis revealed that the hepatic steatosis index (HSI) did not show any significant association with the G group, T group, or D group. Taken together, the development of liver fibrosis rather than liver steatosis is an inherent threat relating to tubular injury in individuals with T2D.
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Affiliation(s)
- Tomoyo Hara
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Takeshi Watanabe
- Department of Preventive Medicine, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Hiroki Yamagami
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Kohsuke Miyataka
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
- Department of Diabetology and Metabolism, Tokushima Prefectural Central Hospital, 1-10-3 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Saya Yasui
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Takahito Asai
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Yousuke Kaneko
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
- Department of Internal Medicine, Tokushima Prefectural Kaifu Hospital, 266 Sugitani, Nakamura, Mugi-cho, Kaifu-gun, Tokushima 775-0006, Japan
| | - Yukari Mitsui
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Shiho Masuda
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Kiyoe Kurahashi
- Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (H.Y.); (S.Y.); (T.A.); (Y.M.); (S.M.); (K.K.)
| | - Toshiki Otoda
- Department of Community Medicine and Medical Science, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (T.O.); (T.Y.); (K.-i.A.)
| | - Tomoyuki Yuasa
- Department of Community Medicine and Medical Science, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (T.O.); (T.Y.); (K.-i.A.)
| | - Akio Kuroda
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (A.K.); (M.M.)
| | - Itsuro Endo
- Department of Bioregulatory Sciences, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan;
| | - Soichi Honda
- Minami Municipal National Insurance Hospital, 105-1 Tai, Minami-cho, Kaifu-gun, Tokushima 779-2109, Japan
| | - Akira Kondo
- Kondo Naika Hospital, 1-6-25 Nishi Shinharma-cho, Tokushima 770-8008, Japan
| | - Munehide Matsuhisa
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (A.K.); (M.M.)
| | - Ken-ichi Aihara
- Department of Community Medicine and Medical Science, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; (T.O.); (T.Y.); (K.-i.A.)
- Department of Internal Medicine, Anan Medical Center, 6-1 Kawahara Takarada-cho, Anan 774-0045, Japan
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14
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Erdogan BT, Tam AA, Baser H, Cuhaci Seyrek FN, Polat SB, Ersoy R, Topaloglu O, Cakir B. Relationship between fibrosis-4 score and microvascular complications in patients with type 2 diabetes mellitus. Arab J Gastroenterol 2024; 25:269-274. [PMID: 38719663 DOI: 10.1016/j.ajg.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 03/31/2024] [Accepted: 04/19/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND AND STUDY AIMS Nonalcoholic fatty liver disease is the most prevalent chronic liver disease globally and is linked to augmented susceptibility to type 2 diabetes mellitus (DM), cardiovascular disease, and microvascular complications inherent to DM, such as nephropathy, neuropathy, and retinopathy. The fibrosis-4 (FIB-4) scoring system, a noninvasive tool, is useful for predicting the extent of liver fibrosis across diverse pathologies. This study aimed to assess the potential predictive role of FIB-4 scores in microvascular complications associated with diabetes. PATIENTS AND METHODS The medical records of patients with type 2 DM admitted to our endocrinology clinic between February 2019 and December 2020 were retrospectively evaluated. Parameters including demographic attributes, fasting blood glucose, glycated hemoglobin, aspartate aminotransferase, alanine aminotransferase, thrombocyte levels, and microvascular complications were recorded. The FIB-4 score was computed, and patients were categorized based on these scores (<1.3 and ≥ 1.3). RESULTS The analysis included 312 patients with a median age of 60 (50-68 years); 39.7 % were men. The median duration of diabetes was 10 years (5-20 years), and the median FIB-4 score was 0.93 (0.63-1.34). Neuropathy, nephropathy, and retinopathy were observed in 50.6 %, 31.4 %, and 34 % of the patients, respectively. Although the FIB-4 score did not differ significantly between patients with and without neuropathy or retinopathy, patients with nephropathy exhibited higher FIB-4 scores. Notably, patients with FIB-4 scores ≥ 1.3 demonstrated a significantly higher prevalence of nephropathy. Logistic regression analysis demonstrated that higher FIB-4 scores were significantly associated with an increased risk of nephropathy. CONCLUSION The FIB-4 score is a cost-effective and straightforward tool with potential applicability in predicting nephropathy in individuals with type 2 DM.
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Affiliation(s)
- Beril Turan Erdogan
- University of Health Sciences, Ankara City Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey.
| | - Abbas Ali Tam
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Husniye Baser
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Fatma Neslihan Cuhaci Seyrek
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Sefika Burcak Polat
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Reyhan Ersoy
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Oya Topaloglu
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
| | - Bekir Cakir
- Ankara Yildirim Beyazit University School of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey
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15
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Alfieri CM, Molinari P, Cinque F, Vettoretti S, Cespiati A, Bignamini D, Nardelli L, Fracanzani AL, Castellano G, Lombardi R. What Not to Overlook in the Management of Patients with Type 2 Diabetes Mellitus: The Nephrological and Hepatological Perspectives. Int J Mol Sci 2024; 25:7728. [PMID: 39062970 PMCID: PMC11276657 DOI: 10.3390/ijms25147728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/17/2024] [Accepted: 06/22/2024] [Indexed: 07/28/2024] Open
Abstract
Diabetes mellitus (DM) significantly impacts renal and hepatic function, necessitating comprehensive understanding and management strategies. Renal involvement, namely diabetic kidney disease (DKD), presents a global challenge, with increasing prevalence paralleling DM rates. Lifestyle modifications and pharmacotherapy targeting hypertension and glycemic control have pivotal roles in DKD management. Concurrently, hepatic involvement in DM, characterized by metabolic dysfunction-associated steatotic liver disease (MASLD), presents a bidirectional relationship. DM exacerbates MASLD progression, while MASLD predisposes to DM development and worsens glycemic control. Screening for MASLD in DM patients is of high importance, utilizing non-invasive methods like ultrasound and fibrosis scores. Lifestyle modifications, such as weight loss and a Mediterranean diet, mitigate MASLD progression. Promising pharmacotherapies, like SGLT2 inhibitors and GLP-1 agonists, demonstrate efficacy in both DM and MASLD management. Special populations, such as diabetic individuals undergoing hemodialysis or kidney transplant recipients, demand special care due to unique clinical features. Similarly, DM exacerbates complications in MASLD patients, elevating the risks of hepatic decompensation and hepatocellular carcinoma. Recognizing the interconnectedness of DM, renal, and hepatic diseases underscores the need for multidisciplinary approaches for optimal patient outcomes. The present review aims to present the main characteristics and crucial points not to be overlooked regarding the renal and hepatic involvement in DM patients focusing on the inter-relationships between the renal and the hepatic involvements.
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Affiliation(s)
- Carlo Maria Alfieri
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy (L.N.); (G.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Paolo Molinari
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy (L.N.); (G.C.)
- Post-Graduate School of Specialization in Nephrology, University of Milan, 20122 Milan, Italy
| | - Felice Cinque
- SC Medicina Indirizzo Metabolico, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (A.C.); (D.B.); (A.L.F.); (R.L.)
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
| | - Simone Vettoretti
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy (L.N.); (G.C.)
| | - Annalisa Cespiati
- SC Medicina Indirizzo Metabolico, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (A.C.); (D.B.); (A.L.F.); (R.L.)
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
| | - Daniela Bignamini
- SC Medicina Indirizzo Metabolico, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (A.C.); (D.B.); (A.L.F.); (R.L.)
| | - Luca Nardelli
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy (L.N.); (G.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Anna Ludovica Fracanzani
- SC Medicina Indirizzo Metabolico, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (A.C.); (D.B.); (A.L.F.); (R.L.)
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy (L.N.); (G.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Rosa Lombardi
- SC Medicina Indirizzo Metabolico, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (A.C.); (D.B.); (A.L.F.); (R.L.)
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
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16
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Gobejishvili L, Vatsalya V, Avila DV, Feygin YB, McClain CJ, Mokshagundam S, Barve S. Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes. Biomedicines 2024; 12:1227. [PMID: 38927434 PMCID: PMC11200675 DOI: 10.3390/biomedicines12061227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/15/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. METHODS Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. RESULTS Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. CONCLUSIONS These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.
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Affiliation(s)
- Leila Gobejishvili
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA; (V.V.); (C.J.M.)
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Vatsalya Vatsalya
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA; (V.V.); (C.J.M.)
| | - Diana V. Avila
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Yana B. Feygin
- Data Science Core, Norton Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Craig J. McClain
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA; (V.V.); (C.J.M.)
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
- Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA;
| | - Sriprakash Mokshagundam
- Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA;
- Division of Endocrinology, Metabolism & Diabetes, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Shirish Barve
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA; (V.V.); (C.J.M.)
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
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Gurun M, Brennan P, Handjiev S, Khatib A, Leith D, Dillon JF, Byrne CJ. Increased risk of chronic kidney disease and mortality in a cohort of people diagnosed with metabolic dysfunction associated steatotic liver disease with hepatic fibrosis. PLoS One 2024; 19:e0299507. [PMID: 38625981 PMCID: PMC11020899 DOI: 10.1371/journal.pone.0299507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 02/09/2024] [Indexed: 04/18/2024] Open
Abstract
BACKGROUND AND AIMS Metabolic dysfunction associated steatotic liver disease (MASLD) increases the risk of incident chronic kidney disease (CKD). However, the relative risk of CKD associated with increasing hepatic fibrosis, and consequent mortality risk, remains underexplored in real-world cohorts. In this study, we sought to establish whether hepatic fibrosis is associated with increased CKD risk and explore differences in mortality risk in a cohort of people living with MASLD, contingent on liver fibrosis and CKD status. METHODS This was an observational study of people who underwent routine liver function testing in Tayside, Scotland. MASLD was defined as: elevated ALT (>30 U/L) or GGT (>73 U/L); presence of diabetes, and/or hypertension, and/or obesity; weekly alcohol consumption <14 units (112g (+/-8g) alcohol); and negative screen for other aetiologies. Data was collected from digital health records. We used log-binomial models to quantify the risk of CKD among those with and without fibrosis, and Cox regression models to estimate differences in mortality risk dependent on fibrosis and CKD. RESULTS In our cohort (n = 2,046), 1,448 (70.8%) people had MASLD without fibrosis and 598 (29.2%) with fibrosis; 161 (11.1%) and 117 (19.6%) respectively also had CKD. After excluding individuals with structural, autoimmune, or malignant CKD (n = 22), liver fibrosis (n = 593; 18.9% with CKD) was associated with increased CKD risk (aRR = 1.31, 1.04-1.64, p = 0.021). Increased mortality risk was observed for those with liver fibrosis (aHR = 2.30, 1.49-3.56, p = <0.001) and was higher again among people with both fibrosis and CKD (aHR = 5.07, 3.07-8.39, p = <0.014). CONCLUSIONS Liver fibrosis was an independent risk factor for CKD in this cohort of people living with MASLD. Furthermore, those with MASLD with liver fibrosis had higher risk for mortality and this risk was further elevated among those with co-morbid CKD. Given the increased risk of CKD, and consequent mortality risk, among people living with MASLD fibrosis, renal function screening should be considered within liver health surveillance programmes and guidelines.
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Affiliation(s)
- Marc Gurun
- Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
| | - Paul Brennan
- Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
- Department of Gastroenterology, NHS Tayside, Ninewells Hospital and Medical School, Dundee, Scotland
| | - Sava Handjiev
- Department of Biochemical Medicine, NHS Tayside, Ninewells Hospital and Medical School, Dundee, Scotland
| | - Aseil Khatib
- Department of Gastroenterology, NHS Tayside, Ninewells Hospital and Medical School, Dundee, Scotland
| | - Damien Leith
- Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
| | - John F. Dillon
- Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
- Department of Gastroenterology, NHS Tayside, Ninewells Hospital and Medical School, Dundee, Scotland
| | - Christopher J. Byrne
- Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
- Directorate of Public Health, NHS Tayside, Kings Cross Hospital, Dundee, United Kingdom
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Mandal M, Ghosh S, Roy S, Mandal S, Dasgupta A. Association of Diabetic Retinopathy with Midlife Hepatic Steatosis Diagnosed by Elastography and Hepatic Steatosis Index in Type 2 Diabetes in an Indian Population. Metab Syndr Relat Disord 2024; 22:214-221. [PMID: 38417047 DOI: 10.1089/met.2023.0081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2024] Open
Abstract
Aims: People with type 2 diabetes mellitus are at increased risk of developing hepatic steatosis. We determined the prevalence of hepatic steatosis in middle-aged patients with and without diabetic retinopathy (DR) in an Indian population. We feel this information is critical, with trends of increasing chronic liver disease-related mortality at younger ages. Method: Institution-based analytical cross-sectional study with 114 middle-aged type 2 diabetes patients; 57 in each group with <15 years of duration of DM and without excessive drinking. Hepatic steatosis was determined by the hepatic steatosis index (HSI), hepatic ultrasonography (USG), and elastography. Result: The HSI in DR (37.9 ± 3.9) was more (P = 0.012) than in without diabetic retinopathy (NODR) (36.3 ± 3.3). There was no difference between two groups in liver span (P = 0.829) or in the prevalence of fatty liver (P = 0.562) as determined by conventional USG. Elastography value (kPa) was more (P = 0.001) in DR (6.51 ± 1.85) than in NODR (5.14 ± 1.60). On elastography, 50.9% in DR had a likelihood ratio (Metavir score for a stiffness value) for stage 2 Metavir score. In DR, 11.8% of those missed by USG had a likelihood ratio for ≥ stage 2 Metavir score on elastography. The presence of DR was independently correlated with kPa value (P < 0.001). Conclusion: A significantly higher prevalence of hepatic steatosis was observed in DR in this population. DR can be a useful biomarker for early hepatic screening in midlife, particularly with hepatic elastography, so that timely diagnosis of hepatic steatosis can be made.
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Affiliation(s)
- Mily Mandal
- Department of Ophthalmology, Calcutta National Medical College, Kolkata, India
| | - Sambuddha Ghosh
- Department of Ophthalmology, Calcutta National Medical College, Kolkata, India
| | - Satarupa Roy
- Department of Radiodiagnosis, Calcutta National Medical College, Kolkata, India
| | - Sayani Mandal
- Department of Radiodiagnosis, Calcutta National Medical College, Kolkata, India
| | - Anindya Dasgupta
- Department of Biochemistry, Jhargram Government Medical College, Jhargram, India
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Garofolo M, Lucchesi D, Giambalvo M, Aragona M, Bertolotto A, Campi F, Bianchi C, Francesconi P, Marchetti P, Del Prato S, Penno G. Fatty liver index is an independent risk factor for all-cause mortality and major cardiovascular events in type 1 diabetes: an 11-year observational study. Cardiovasc Diabetol 2024; 23:85. [PMID: 38419065 PMCID: PMC10902974 DOI: 10.1186/s12933-024-02171-9] [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: 12/06/2023] [Accepted: 02/16/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD), identified by the Fatty Liver Index (FLI), is associated with increased mortality and cardiovascular (CV) outcomes. Whether this also applies to type 1 diabetes (T1D) has not been yet reported. METHODS We prospectively observed 774 subjects with type 1 diabetes (males 52%, 30.3 ± 11.1 years old, diabetes duration (DD) 18.5 ± 11.6 years, HbA1c 7.8 ± 1.2%) to assess the associations between FLI (based on BMI, waist circumference, gamma-glutamyl transferase and triglycerides) and all-cause death and first CV events. RESULTS Over a median 11-year follow-up, 57 subjects died (7.4%) and 49 CV events (6.7%) occurred among 736 individuals with retrievable incidence data. At baseline, FLI was < 30 in 515 subjects (66.5%), 30-59 in 169 (21.8%), and ≥ 60 in 90 (11.6%). Mortality increased steeply with FLI: 3.9, 10.1, 22.2% (p < 0.0001). In unadjusted Cox analysis, compared to FLI < 30, risk of death increased in FLI 30-59 (HR 2.85, 95% CI 1.49-5.45, p = 0.002) and FLI ≥ 60 (6.07, 3.27-11.29, p < 0.0001). Adjusting for Steno Type 1 Risk Engine (ST1-RE; based on age, sex, DD, systolic BP, LDL cholesterol, HbA1c, albuminuria, eGFR, smoking and exercise), HR was 1.52 (0.78-2.97) for FLI 30-59 and 3.04 (1.59-5.82, p = 0.001) for FLI ≥ 60. Inclusion of prior CV events slightly modified HRs. FLI impact was confirmed upon adjustment for EURODIAB Risk Engine (EURO-RE; based on age, HbA1c, waist-to-hip ratio, albuminuria and HDL cholesterol): FLI 30-59: HR 1.24, 0.62-2.48; FLI ≥ 60: 2.54, 1.30-4.95, p = 0.007), even after inclusion of prior CVD. CV events incidence increased with FLI: 3.5, 10.5, 17.2% (p < 0.0001). In unadjusted Cox, HR was 3.24 (1.65-6.34, p = 0.001) for FLI 30-59 and 5.41 (2.70-10.83, p < 0.0001) for FLI ≥ 60. After adjustment for ST1-RE or EURO-RE, FLI ≥ 60 remained statistically associated with risk of incident CV events, with trivial modification with prior CVD inclusion. CONCLUSIONS This observational prospective study shows that FLI is associated with higher all-cause mortality and increased risk of incident CV events in type 1 diabetes.
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Affiliation(s)
- Monia Garofolo
- Section of Diabetes and Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Via A. Trivella, 1, 56126, Pisa, Italy
| | - Daniela Lucchesi
- Section of Diabetes and Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Via A. Trivella, 1, 56126, Pisa, Italy
| | - Massimo Giambalvo
- Section of Diabetes and Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Via A. Trivella, 1, 56126, Pisa, Italy
| | - Michele Aragona
- Department of Medical Specialties, University Hospital of Pisa, Pisa, Italy
| | | | - Fabrizio Campi
- Department of Medical Specialties, University Hospital of Pisa, Pisa, Italy
| | - Cristina Bianchi
- Department of Medical Specialties, University Hospital of Pisa, Pisa, Italy
| | - Paolo Francesconi
- Epidemiology Unit, Regional Health Agency (ARS) of Tuscany, Florence, Italy
| | - Piero Marchetti
- Section of Diabetes and Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Via A. Trivella, 1, 56126, Pisa, Italy
| | - Stefano Del Prato
- Section of Diabetes and Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Via A. Trivella, 1, 56126, Pisa, Italy
- Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Giuseppe Penno
- Section of Diabetes and Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Via A. Trivella, 1, 56126, Pisa, Italy.
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Li X, Zhang W, Bi Y, Chen J, Fu L, Zhang Z, Chen Q, Zhang X, Zhu Z, Zhang B. Non-alcoholic fatty liver disease is associated with brain function disruption in type 2 diabetes patients without cognitive impairment. Diabetes Obes Metab 2024; 26:650-662. [PMID: 37961040 DOI: 10.1111/dom.15354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/15/2023] [Accepted: 10/16/2023] [Indexed: 11/15/2023]
Abstract
AIMS To investigate the neural static and dynamic intrinsic activity of intra-/inter-network topology among patients with type 2 diabetes (T2D) with non-alcoholic fatty liver disease (NAFLD) and those without NAFLD (T2NAFLD group and T2noNAFLD group, respectively) and to assess the relationship with metabolism. METHODS Fifty-six patients with T2NAFLD, 78 with T2noNAFLD, and 55 healthy controls (HCs) were recruited to the study. Participants had normal cognition and underwent functional magnetic resonance imaging scans, clinical measurements, and global cognition evaluation. Independent component analysis was used to identify frequency spectrum parameters, static functional network connectivity, and temporal properties of dynamic functional network connectivity (P < 0.05, false discovery rate-corrected). Statistical analysis involved one-way analysis of covariance with post hoc, partial correlation and canonical correlation analyses. RESULTS Our findings showed that: (i) T2NAFLD patients had more disordered glucose and lipid metabolism, had more severe insulin resistance, and were more obese than T2noNAFLD patients; (ii) T2D patients exhibited disrupted brain function, as evidenced by alterations in intra-/inter-network topology, even without clinically measurable cognitive impairment; (iii) T2NAFLD patients had more significant reductions in the frequency spectrum parameters of cognitive executive and visual networks than those with T2noNAFLD; and (iv) altered brain function in T2D patients was correlated with postprandial glucose, high-density lipoprotein cholesterol, and waist-hip ratio. CONCLUSION This study may provide novel insights into neuroimaging correlates for underlying pathophysiological processes inducing brain damage in T2NAFLD. Thus, controlling blood glucose levels, lipid levels and abdominal obesity may reduce brain damage risk in such patients.
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Affiliation(s)
- Xin Li
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Wen Zhang
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China
| | - Yan Bi
- Department of Endocrinology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jiu Chen
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China
| | - Linqing Fu
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhou Zhang
- Department of Endocrinology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qian Chen
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China
| | - Xin Zhang
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China
| | - Zhengyang Zhu
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Bing Zhang
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Medical Imaging Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Institute of Medical Imaging and Artificial Intelligence, Nanjing University, Nanjing, China
- Institute of Brain Science, Nanjing University, Nanjing, China
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21
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Li Y, Zhang Q. Causal associations between liver enzymes and diabetic microvascular complications: A univariable and multivariable Mendelian randomization. PLoS One 2024; 19:e0296894. [PMID: 38232082 DOI: 10.1371/journal.pone.0296894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 12/18/2023] [Indexed: 01/19/2024] Open
Abstract
BACKGROUND Observational studies show that liver enzymes are diabetes risk factors. However, previous observational investigations on the relationship between liver enzymes and diabetic microvascular complications produced contradictory results. The purpose of this research is to examine the independent causal effects of liver enzymes on diabetic microvascular complications. METHODS Univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were utilized to disentangle the causal effects. The genome-wide association study (GWAS) summary-level statistics were collected from the UK biobank and the FinnGen consortium. Single nucleotide polymorphisms (SNPs) were selected as genetic instruments with genome-wide significance (p < 5 ×10-8). Five UVMR approaches, including inverse variance weighted (IVW), Bayesian weighted Mendelian randomization, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), weighted median, and MR-Egger, and three MVMR approaches, including the extended versions of IVW, MR-Egger, and the Q-minimization methods, were performed to evaluate the causal effects. The robustness of the MR results was further confirmed using several sensitivity analyses. RESULTS UVMR revealed that a genetically predisposed per standard deviation increase in serum alanine aminotransferase (ALT) level increased the risk of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) (IVW OR = 1.489, 95% CI = 1.206-1.772, p = 0.006). Likewise, serum aspartate aminotransferase (AST) levels showed similar results (IVW OR = 1.376, 95% CI = 1.115-1.638, p = 0.017). Furthermore, these effects were consistent after controlling for glycemia and blood pressure using MVMR analysis. Additionally, sensitivity analyses further strengthened the causality. However, no significant associations were found between alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and diabetic microvascular complications. CONCLUSIONS Robust evidence was demonstrated for an independent causal effect of serum ALT or AST concentration on the risk of DR in T2DM. Further investigations are necessary to elucidate the potential biological mechanisms and confirm their clinical significance for early prevention and intervention.
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Affiliation(s)
- Yang Li
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiu Zhang
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
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Mantovani A, Morieri ML, Aldigeri R, Palmisano L, Masulli M, Bonomo K, Baroni MG, Cossu E, Cimini FA, Cavallo G, Buzzetti R, Mignogna C, Leonetti F, Bacci S, Trevisan R, Pollis RM, Cas AD, de Kreutzenberg SV, Targher G. MASLD, hepatic steatosis and fibrosis are associated with the prevalence of chronic kidney disease and retinopathy in adults with type 1 diabetes mellitus. DIABETES & METABOLISM 2024; 50:101497. [PMID: 37992857 DOI: 10.1016/j.diabet.2023.101497] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 10/23/2023] [Accepted: 11/14/2023] [Indexed: 11/24/2023]
Abstract
AIM We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM). METHODS We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants. RESULTS Patients with MASLD and significant fibrosis (n = 93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n = 578) and those without steatosis (n = 738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95 % confidence interval 1.05-2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95 % CI 1.13-1.46) than those without steatosis. CONCLUSION This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Mario Luca Morieri
- Metabolic Diseases, Department of Medicine, University of Padua, Padua, Italy
| | | | - Luisa Palmisano
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Maria Masulli
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Katia Bonomo
- Diabetes and Metabolic Diseases Unit, San Luigi Gonzaga University Hospital, Turin, Italy
| | - Marco Giorgio Baroni
- Department of Clinical Medicine, Life, Health & Environmental Sciences, University of Aquila, L'Aquila, Italy; Neuroendocrinology and Metabolic Diseases, IRCCS Neuromed, Pozzilli, Italy
| | - Efisio Cossu
- Diabetology Unit, Policlinico Universitario of Cagliari, Cagliari, Italy
| | | | - Gisella Cavallo
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | | | - Carmen Mignogna
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Frida Leonetti
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University, Rome, Italy
| | - Simonetta Bacci
- Section of Endocrinology, Department of Medicine, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Roberto Trevisan
- Metabolic Diseases, Department of Medicine, University of Padua, Padua, Italy; Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | | | - Alessandra Dei Cas
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Division of Nutritional and Metabolic Sciences, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | | | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy; IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy.
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Yang RX, Fan JG. Metabolic comorbidities, endocrine—Diabetes, polycystic ovarian syndrome, thyroid dysfunction. METABOLIC STEATOTIC LIVER DISEASE 2024:123-136. [DOI: 10.1016/b978-0-323-99649-5.00004-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Crocombe D, Tsochatzis EA. Natural history of nonalcoholic fatty liver disease. METABOLIC STEATOTIC LIVER DISEASE 2024:61-75. [DOI: 10.1016/b978-0-323-99649-5.00014-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Bril F. Nonalcoholic fatty liver disease: What comes before and what are the consequences? CHRONIC COMPLICATIONS OF DIABETES MELLITUS 2024:185-206. [DOI: 10.1016/b978-0-323-88426-6.00017-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Binet Q, Loumaye A, Hermans MP, Lanthier N. A Cross-sectional Real-life Study of the Prevalence, Severity, and Determinants of Metabolic Dysfunction-associated Fatty Liver Disease in Type 2 Diabetes Patients. J Clin Transl Hepatol 2023; 11:1377-1386. [PMID: 37719967 PMCID: PMC10500296 DOI: 10.14218/jcth.2023.00117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/23/2023] [Accepted: 05/25/2023] [Indexed: 07/03/2023] Open
Abstract
Background and Aims Most data on liver assessment in type 2 diabetes mellitus (T2DM) patients are from retrospective cohorts with selection bias. We aimed at appraising the feasibility, results, and benefits of an outpatient systematic noninvasive screening for metabolic dysfunction-associated fatty liver disease (MAFLD) severity and determinants in T2DM patients. Methods We conducted a 50-week cross-sectional study enrolling adult T2DM outpatients from a diabetes clinic. An algorithm based on guidelines was applied using simple bioclinical scores and, if applicable, ultrasound and/or elastometry. Results Two hundred and thirteen patients were included. Mean age and body mass index were 62 years and 31 kg/m2 and 29% of patients had abnormal transaminase levels. The acceptance rate of additional liver examinations was 92%. The prevalence of MAFLD, advanced fibrosis and cirrhosis was 87%, 11%, and 4%, respectively. More than half of the cases of advanced fibrosis had not been suspected and were detected by this screening. MAFLD was associated with poor glycemic control, elevated transaminases, low HDL-C and the absence of peripheral arterial disease. Advanced fibrosis was linked to high waist circumference and excessive alcohol consumption, which should be interpreted with caution owing to the small number of patients reporting excessive consumption. Conclusions Simple bioclinical tools allowed routine triage of T2DM patients for MAFLD severity, with high adherence of high-risk patients to subsequent noninvasive exams.
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Affiliation(s)
- Quentin Binet
- Service d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Audrey Loumaye
- Service d’Endocrinologie et Nutrition, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Michel P Hermans
- Service d’Endocrinologie et Nutrition, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Nicolas Lanthier
- Service d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
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Boeriu A, Dobru D, Fofiu C. Non-Invasive Diagnostic of NAFLD in Type 2 Diabetes Mellitus and Risk Stratification: Strengths and Limitations. Life (Basel) 2023; 13:2262. [PMID: 38137863 PMCID: PMC10744403 DOI: 10.3390/life13122262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/26/2023] [Accepted: 11/25/2023] [Indexed: 12/24/2023] Open
Abstract
The progressive potential of liver damage in type 2 diabetes mellitus (T2DM) towards advanced fibrosis, end-stage liver disease, and hepatocarcinoma has led to increased concern for quantifying liver injury and individual risk assessment. The combination of blood-based markers and imaging techniques is recommended for the initial evaluation in NAFLD and for regular monitoring to evaluate disease progression. Continued development of ultrasonographic and magnetic resonance imaging methods for accurate quantification of liver steatosis and fibrosis, as well as promising tools for the detection of high-risk NASH, have been noted. In this review, we aim to summarize available evidence regarding the usefulness of non-invasive methods for the assessment of NAFLD in T2DM. We focus on the power and limitations of various methods for diagnosis, risk stratification, and patient monitoring that support their implementation in clinical setting or in research field.
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Affiliation(s)
- Alina Boeriu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Daniela Dobru
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Crina Fofiu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Internal Medicine Department, Bistrita County Clinical Hospital, 420094 Bistrita, Romania
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En Li Cho E, Ang CZ, Quek J, Fu CE, Lim LKE, Heng ZEQ, Tan DJH, Lim WH, Yong JN, Zeng R, Chee D, Nah B, Lesmana CRA, Bwa AH, Win KM, Faulkner C, Aboona MB, Lim MC, Syn N, Kulkarni AV, Suzuki H, Takahashi H, Tamaki N, Wijarnpreecha K, Huang DQ, Muthiah M, Ng CH, Loomba R. Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis. Gut 2023; 72:2138-2148. [PMID: 37491159 DOI: 10.1136/gutjnl-2023-330110] [Citation(s) in RCA: 101] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/20/2023] [Indexed: 07/27/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM. METHODS MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies. RESULTS 156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I2=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I2=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I2=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2-F4), while 14.95% (95% CI 11.03% to 19.95%, I2=99.00%) had advanced fibrosis (F3-F4). CONCLUSION This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD. PROSPERO REGISTRATION NUMBER CRD42022360251.
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Affiliation(s)
- Elina En Li Cho
- Department of Medicine, National University Hospital, Singapore
| | - Chong Zhe Ang
- Department of Medicine, National University Hospital, Singapore
| | - Jingxuan Quek
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Clarissa Elysia Fu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Lincoln Kai En Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Zane En Qi Heng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jie Ning Yong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Rebecca Zeng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Douglas Chee
- Department of Medicine, National University Hospital, Singapore
| | - Benjamin Nah
- Department of Medicine, National University Hospital, Singapore
| | | | - Aung Hlaing Bwa
- Department of Medical Research, Union of Myanmar, Naypyidaw, Myanmar
| | - Khin Maung Win
- Department of Medical Research, Union of Myanmar, Naypyidaw, Myanmar
| | - Claire Faulkner
- Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA
| | - Majd B Aboona
- Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA
| | - Mei Chin Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Diagnostic Imaging, National University Health System, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Anand V Kulkarni
- Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Hiroyuki Suzuki
- Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | | | - Nobuharu Tamaki
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, Musashino Red Cross Hospital, Musashino, Japan
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, University of Michigan, Michigan, Michigan, USA
| | - Daniel Q Huang
- Department of Medicine, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Mark Muthiah
- Department of Medicine, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Rohit Loomba
- Department of Medicine, University of California San Diego, La Jolla, California, USA
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Wu J, Duan C, Yang Y, Wang Z, Tan C, Han C, Hou X. Insights into the liver-eyes connections, from epidemiological, mechanical studies to clinical translation. J Transl Med 2023; 21:712. [PMID: 37817192 PMCID: PMC10566185 DOI: 10.1186/s12967-023-04543-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 09/19/2023] [Indexed: 10/12/2023] Open
Abstract
Maintenance of internal homeostasis is a sophisticated process, during which almost all organs get involved. Liver plays a central role in metabolism and involves in endocrine, immunity, detoxification and storage, and therefore it communicates with distant organs through such mechanisms to regulate pathophysiological processes. Dysfunctional liver is often accompanied by pathological phenotypes of distant organs, including the eyes. Many reviews have focused on crosstalk between the liver and gut, the liver and brain, the liver and heart, the liver and kidney, but with no attention paid to the liver and eyes. In this review, we summarized intimate connections between the liver and the eyes from three aspects. Epidemiologically, we suggest liver-related, potential, protective and risk factors for typical eye disease as well as eye indicators connected with liver status. For molecular mechanism aspect, we elaborate their inter-organ crosstalk from metabolism (glucose, lipid, proteins, vitamin, and mineral), detoxification (ammonia and bilirubin), and immunity (complement and inflammation regulation) aspect. In clinical application part, we emphasize the latest advances in utilizing the liver-eye axis in disease diagnosis and therapy, involving artificial intelligence-deep learning-based novel diagnostic tools for detecting liver disease and adeno-associated viral vector-based gene therapy method for curing blinding eye disease. We aim to focus on and provide novel insights into liver and eyes communications and help resolve existed clinically significant issues.
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Affiliation(s)
- Junhao Wu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Caihan Duan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Yuanfan Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Zhe Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Chen Tan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Chaoqun Han
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022 Hubei China
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Dang SW, Gao L, Li YJ, Zhang R, Xu J. Metabolic characteristics of non-obese and obese metabolic dysfunction-associated fatty liver disease in type 2 diabetes mellitus and its association with diabetic peripheral neuropathy and diabetic retinopathy. Front Med (Lausanne) 2023; 10:1216412. [PMID: 37828942 PMCID: PMC10566373 DOI: 10.3389/fmed.2023.1216412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/28/2023] [Indexed: 10/14/2023] Open
Abstract
Aim To assess the metabolic characteristics of non-obese metabolic dysfunction-associated fatty liver disease (MAFLD) compared with obese MAFLD and the relationship of MAFLD with diabetic peripheral neuropathy and diabetic retinopathy in patients with Type 2 diabetes mellitus (T2DM). Methods Data were obtained from 536 T2DM patients (355 women, 181 men; age 58.2 ± 12.0 years). We explored the difference in clinical characteristics between obese MAFLD (body mass index ≥25 kg/m2) and non-obese MAFLD (body mass index <25 kg/m2) in T2DM patients. One-way analysis of variance (ANOVA) was used to compare the means of continuous variables, and the Chi-squared test was used to compare the differences in frequencies of categorical variables. Logistic regression models were adopted to calculate odds ratios. Results The prevalence of MAFLD in hospitalized Chinese T2DM patients was calculated to be 42.7%. Both obese and non-obese MAFLD patients had higher levels of body mass index (BMI), waist circumfere nce, triglyceride, alanine aminotransferase, aspar tate aminotransferase, γ-glutamyltransferase, you nger age, higher prevalence of hyperlipidemia and shorter duration of T2DM and lower incidence of diabetic retinopathy, compared with participants with out MAFLD in the same weight group. Uric acid levels were positively correlated with the risk of MAFLD only in non-obese subjects but not in obese subjects. In non-obese patients with T2DM, a negative correlation was found between the prevalence of MAFLD and diabetic retinopathy. Conclusion Even in non-obese patients with T2DM, BMI was found to be an independent risk factor for MAFLD. These findings support a more structured, risk-factor-based approach to MAFLD management, particularly in patients with T2DM. Non-obese MAFLD has unique results in metabolic characteristics and the correlation with diabetic retinopathy and diabetic peripheral neuropathy, which should be further explored.
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Affiliation(s)
- Si-Wen Dang
- Department of Endocrinology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- International Center for Obesity and Metabolic Disease Research, Xi’an Jiaotong University, Xi’an, China
| | - Lei Gao
- Department of Endocrinology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- International Center for Obesity and Metabolic Disease Research, Xi’an Jiaotong University, Xi’an, China
| | - Yu-Jun Li
- Department of Endocrinology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- International Center for Obesity and Metabolic Disease Research, Xi’an Jiaotong University, Xi’an, China
| | - Ruo Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- International Center for Obesity and Metabolic Disease Research, Xi’an Jiaotong University, Xi’an, China
| | - Jing Xu
- Department of Endocrinology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- International Center for Obesity and Metabolic Disease Research, Xi’an Jiaotong University, Xi’an, China
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Villarroel C, Karim G, Sehmbhi M, Debroff J, Weisberg I, Dinani A. Advanced Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease Is Independently Associated With Reduced Renal Function. GASTRO HEP ADVANCES 2023; 3:122-127. [PMID: 39132183 PMCID: PMC11307954 DOI: 10.1016/j.gastha.2023.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 09/18/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims The large global population of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been shown to have an association with chronic kidney disease (CKD) due to a host of proposed mechanisms, one of which being lipoprotein dysmetabolism. Furthermore, metabolic comorbidities have been concurrently prevalent in MASLD and CKD independently. This study aimed at analyzing risk and predictive traits among an obese population for both MASLD and CKD. Methods A retrospective chart review of 546 obese patients with a diagnosis of either MASLD or metabolic dysfunction-associated steatohepatitis between January 2020 and June 2021 was performed. Markers of liver and kidney function in addition to demographic data and renoprotective medications were recorded. Both univariable and multivariable linear regression analyses were performed to understand possible associations between MASLD markers, renal function, and markers of metabolic derangements. Results Univariate analysis revealed that increased age (P < .001), elevated alanine aminotransferase (defined as alanine aminotransferase ≥ 30 IU/L, P = .01), low albumin (P = .011), and increasing fibrosis-4 (FIB-4) (P = .005) were statistically associated with a reduced renal function. A reduction in glomerular filtration was associated with an increase in FIB-4 (effect size [beta] of a one-unit increase in glomerular filtration on FIB-4 = -0.013, P < .001) in univariate linear regression. In multivariate linear regression, type 2 diabetes (T2D) was independently associated with increased liver fibrosis (effect size of T2D on FIB-4 = 0.387925, P < .02). Conclusion Our study shows that in a patient population with obesity and a diagnosis of MASLD, advanced fibrosis is independently associated with reduced renal function.
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Affiliation(s)
- Carolina Villarroel
- Department of Medicine, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gres Karim
- Division of Gastroenterology, NewYork-Presbyterian Brooklyn Methodist Hospital, New York, New York
| | - Mantej Sehmbhi
- Department of Medicine, Mount Sinai Morningside and West Hospitals, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jake Debroff
- Department of Medicine, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ilan Weisberg
- Division of Gastroenterology, NewYork-Presbyterian Brooklyn Methodist Hospital, New York, New York
| | - Amreen Dinani
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
- Division of Gastroenterology, Duke University, Durham, North Carolina
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Jacob M, Joseph M, Idiculla J. Non-alcoholic fatty liver disease and diabetic retinopathy: Is there an association? J Family Med Prim Care 2023; 12:2028-2031. [PMID: 38024900 PMCID: PMC10657063 DOI: 10.4103/jfmpc.jfmpc_2327_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/30/2023] [Accepted: 05/26/2023] [Indexed: 12/01/2023] Open
Abstract
Background Studies have not proven whether an association exists between diabetic retinopathy (DR) and non-alcoholic fatty liver disease (NAFLD). The reports from various parts of the world have not used uniform criteria, and hence, results are inconclusive. Both DR and NAFLD are common conditions encountered in primary care. Methods A total of 130 patients with type 2 diabetes from the medical wards of a tertiary care hospital were enrolled. After documentation of clinical and biochemical data, they underwent ultrasonography (USG) of the abdomen and fibroscan grading of liver. Retinopathy was assessed and classified as per the Early Treatment Diabetic Retinopathy Study. Results The mean age of the patients included in the study was 46.5+/-8.8 with 55% of the participants being male and 45% female. The mean HbA1c was 7.168+/2.4. The association between DR and hepatic fibrosis was assessed by fibroscan (p 0.003) and USG (p 0.001) and was significant on univariate analysis. Multivariate analysis did not confirm this. There was no association between increasing grades of either condition. Although fibroscan and USG significantly concorded in diagnosing NAFLD, fibroscan diagnosed more cases as compared to USG (83 vs 73). Conclusion Larger studies should be conducted to conclusively determine the association in order to investigate pathogenetic factors and treatment strategies.
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Affiliation(s)
- Mathew Jacob
- Senior Resident, Department of Medicine, St. John’s Medical College, Bangalore, India
| | - Mary Joseph
- Professor, Department of Ophthalmology, St. John’s Medical College, Bangalore, India
| | - Jyothi Idiculla
- Professor, Department of Medicine, St. John’s Medical College, Bangalore, India
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Cui Y, Qu Z, Hu W, Shi H. Relationship between Uric Acid to High Density Lipoprotein Cholesterol Ratio and Nonalcoholic Fatty Liver Disease in Nonoverweight/Obese Patients with Type 2 Diabetes. Int J Endocrinol 2023; 2023:2513175. [PMID: 37560201 PMCID: PMC10409575 DOI: 10.1155/2023/2513175] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 08/11/2023] Open
Abstract
AIMS To investigate the relationship between uric acid to high-density lipoprotein cholesterol ratio (UHR) levels and nonalcoholic fatty liver disease (NAFLD) in nonoverweight/obese patients with type 2 diabetes. METHODS A retrospective study was designed including a total of 343 inpatients with type 2 diabetes whose BMI<24 kg/m2. The population was divided into three groups as the UHR tertiles. Logistic regression analysis was performed to estimate odds ratios (ORs) of UHR for NAFLD. ROC curve analysis was used to estimate the diagnostic value of UHR for NAFLD. RESULTS The prevalence rat of NAFLD enhanced progressively from the tertile 1 to tertile 3 of UHR (30.70% vs. 56.52% vs. 73.68%). Logistic regression analysis showed that participants in the higher UHR groups, compared with those in the first tertile group, had higher occurrence risks for NAFLD. The positive association between UHR and NAFLD was independent of age, BMI, blood pressure, hepatic enzymes, and other components of metabolic disorders. ROC curve analysis showed that the area under curve (AUC), sensitivity, and specificity for UHR were 0.697, 0.761, and 0.553, respectively. CONCLUSIONS In type 2 diabetic patients without overweight or obesity, UHR is significantly associated with NAFLD and can be used as a novel and useful predictor for NAFLD onset.
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Affiliation(s)
- Yuliang Cui
- Department of Endocrinology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou 253000, China
| | - Zhenzhen Qu
- Department of Endocrinology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou 253000, China
| | - Wenmei Hu
- Department of Endocrinology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou 253000, China
| | - Haiyan Shi
- Department of Endocrinology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou 253000, China
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Terasaka Y, Takahashi H, Amano K, Fujisaki K, Kita S, Kato K, Nakayama K, Yamashita Y, Nakamura S, Anzai K. Change in Liver Fibrosis Associates with Progress of Diabetic Nephropathy in Patients with Nonalcoholic Fatty Liver Disease. Nutrients 2023; 15:3248. [PMID: 37513666 PMCID: PMC10386534 DOI: 10.3390/nu15143248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Diabetic nephropathy (DN) is a major complication of diabetes. Nonalcoholic fatty liver disease (NAFLD) is common in diabetes, and liver fibrosis is a prognostic risk factor for NAFLD. The interaction between DN and liver fibrosis in NAFLD remains unclear. In 189 patients with DN and NAFLD who received an education course about diabetic nephropathy, liver fibrosis was evaluated using the fibrosis-4 (FIB-4) index. The association between the outcome of DN and changes in liver fibrosis was examined. The FIB-4 index was maintained at the baseline level in patients with improved DN, while it was increased in other patients. The ΔFIB-4 index was positively correlated with changes in albuminuria and proteinuria (ρ = 0.22, p = 0.004). In a multivariate analysis, changes in albuminuria and proteinuria were associated with the ΔFIB-4 index (p = 0.002). Patients with a progressive FIB-4 index category from baseline to 5 years showed a lower event-free survival rate after 5 years than patients with an improved FIB-4 index category (p = 0.037). The outcome of DN is associated with changes in liver fibrosis in patients with diabetes, NAFLD and DN. Developing a preventive and therapeutic approach for these conditions is required.
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Affiliation(s)
- Yoshiko Terasaka
- Department of Internal Medicine, Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Hirokazu Takahashi
- Department of Internal Medicine, Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kazushi Amano
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Koshiro Fujisaki
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
- Fujisaki Clinic, Kagoshima 891-0141, Japan
| | - Shotaro Kita
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Kaori Kato
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
- Ryutokukai Medical Corp, Tsuruta Hospital, Miyazaki 881-0016, Japan
| | - Koujin Nakayama
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Yuko Yamashita
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Shuji Nakamura
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Keizo Anzai
- Department of Internal Medicine, Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan
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Toyama T, Shimizu M, Yamaguchi T, Kurita H, Morita T, Oshima M, Kitajima S, Hara A, Sakai N, Hashiba A, Takayama T, Tajima A, Furuichi K, Wada T, Iwata Y. A comprehensive risk factor analysis using association rules in people with diabetic kidney disease. Sci Rep 2023; 13:11690. [PMID: 37474635 PMCID: PMC10359444 DOI: 10.1038/s41598-023-38811-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 07/14/2023] [Indexed: 07/22/2023] Open
Abstract
Association rule is a transparent machine learning method expected to share information about risks for chronic kidney disease (CKD) among diabetic patients, but its findings in clinical data are limited. We used the association rule to evaluate the risk for kidney disease in General and Worker diabetic cohorts. The absence of risk factors was examined for association with stable kidney function and worsening kidney function. A confidence value was used as an index of association, and a lift of > 1 was considered significant. Analyses were applied for individuals stratified by KDIGO's (Kidney Disease: Improving Global Outcomes) CKD risk categories. A General cohort of 4935 with a mean age of 66.7 years and a Worker cohort of 2153 with a mean age of 47.8 years were included in the analysis. Good glycemic control was significantly related to stable kidney function in low-risk categories among the General cohort, and in very-high risk categories among the Worker cohort; confidences were 0.82 and 0.77, respectively. Similar results were found with poor glycemic control and worsening kidney function; confidences of HbA1c were 0.41 and 0.27, respectively. Similarly, anemia, obesity, and hypertension showed significant relationships in the low-risk General and very-high risk Worker cohorts. Stratified risk assessment using association rules revealed the importance of the presence or absence of risk factors.
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Affiliation(s)
- Tadashi Toyama
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan.
| | - Miho Shimizu
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Taihei Yamaguchi
- Life Science Business Office, Corporate Technology Planning Division, Toshiba Corporation, Tokyo, Japan
| | - Hidekazu Kurita
- Insurance Solutions Department, ICT Solutions Division, Toshiba Digital Solutions Corporation, Kawasaki, Japan
| | - Tetsurou Morita
- Insurance Solutions Department, ICT Solutions Division, Toshiba Digital Solutions Corporation, Kawasaki, Japan
| | - Megumi Oshima
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
- Department of Hygiene and Public Health, Kanazawa University, Kanazawa, Japan
| | - Norihiko Sakai
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | | | - Takuzo Takayama
- Frontier Science and Social Co-Creation Initiative, Kanazawa University, Kanazawa, Japan
| | - Atsushi Tajima
- Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kengo Furuichi
- Department of Nephrology, Kanazawa Medical University School of Medicine, Uchinada, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
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Patel P, Inayat F, Ali H, Afzal A, Taj S, Rehman AU, Hussain N, Ishtiaq R, Nawaz G, Afzal MS, Fatakhova K, Satapathy SK. Association of nonalcoholic fatty liver disease with acute cholangitis: a nationwide propensity-matched analysis from the United States. Proc AMIA Symp 2023; 36:600-607. [PMID: 37614865 PMCID: PMC10443993 DOI: 10.1080/08998280.2023.2231721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/18/2023] [Accepted: 06/24/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has previously been linked to several disease states with an impact on patient outcomes. However, clinical evidence on the association between NAFLD and acute cholangitis (AC) remains scarce. We aimed to evaluate the potential association between NAFLD and AC. METHODS We conducted a retrospective cohort study using the US National Inpatient Sample database from 2016 to 2019 to analyze primary AC hospitalizations with NAFLD compared to non-NAFLD in a 1:1 propensity-matched population. RESULTS A total of 1550 AC patients with NAFLD were matched to 1550 AC patients without NAFLD. NAFLD had a higher association with AC when compared to patients without NAFLD, with an odds ratio of 2.33 (95% CI [1.81-3.0], P < 0.001). The length of stay was higher in NAFLD than in non-NAFLD (4 vs 3 days, P < 0.001). The median inpatient charges in NAFLD were also higher than in the non-NAFLD cohort ($36,182 vs $35,244, P < 0.001). Inpatient mortality was higher in NAFLD compared to non-NAFLD (1.6% vs 0%, P < 0.001). There was an increased prevalence of portal vein thrombosis (3.2% vs 0%), acute kidney injury (24.2% vs 17.7%), sepsis (3.2% vs 1.6%), mechanical ventilation (3.2% vs 0%), and percutaneous cholecystostomy tube insertion (3.2% vs 1.6%) in NAFLD compared to non-NAFLD (P < 0.05). NAFLD also had a higher association with acute cholecystitis, with an odds ratio of 3.70 (95% CI [3.19-4.29], P < 0.001). CONCLUSIONS This study showed an association between NALFD and AC, resulting in increased length of stay, hospital charges, and inpatient mortality. Underlying NAFLD also increases acute complications of AC.
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Affiliation(s)
- Pratik Patel
- Mather Hospital and Hofstra University Zucker School of Medicine, Port Jefferson, New York, USA
| | - Faisal Inayat
- Allama Iqbal Medical College, Lahore, Punjab, Pakistan
| | - Hassam Ali
- East Carolina University Brody School of Medicine, Greenville, North Carolina, USA
| | - Arslan Afzal
- Woodhull Medical Center, Brooklyn, New York, USA
| | - Sobaan Taj
- Jersey Shore University Medical Center, Neptune, New Jersey, USA
| | | | | | - Rizwan Ishtiaq
- Saint Francis Hospital and Medical Center, Hartford, Connecticut, USA
| | - Gul Nawaz
- Allama Iqbal Medical College, Lahore, Punjab, Pakistan
| | | | - Karina Fatakhova
- Mather Hospital and Hofstra University Zucker School of Medicine, Port Jefferson, New York, USA
| | - Sanjaya K. Satapathy
- North Shore University Hospital and Hofstra University Zucker School of Medicine, Manhasset, New York, USA
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Orfanidou M, Ntenti C, Evripidou K, Mataftsi A, Goulas A, Polyzos SA. Retinal Vascular Lesions in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. J Pers Med 2023; 13:1148. [PMID: 37511760 PMCID: PMC10381395 DOI: 10.3390/jpm13071148] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/30/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Background: This systematic review and meta-analysis aimed to summarize and compare data on retinal vascular lesions between patients with nonalcoholic fatty liver disease (NAFLD) and individuals without the disease. Methods: Search was performed in PubMed, Scopus and Cochrane Library, complemented by handsearching (PROSPERO ID: CRD42022345558). Thirty-six studies comprising 24,985 individuals (12,387 NAFLD patients and 12,598 controls) were selected for the meta-analysis. Results: Apart from retinopathy, no study with a different type of retinal vascular lesion was retrieved. Overall, there was no significant difference in the presence of retinopathy in NAFLD patients compared to controls (Odds Ratio (OR) = 1.20; 95% Confidence Interval (CI): 0.91-1.59). Heterogeneity among studies was high (I2 = 93%; p < 0.00001), while Egger's test revealed no publication bias (p = 0.60). However, subgroup analysis showed positive association between retinopathy and NAFLD in type 1 diabetes mellitus (T1DM) (OR = 2.35; 95% CI: 1.53-3.60), but not in type 2 diabetes mellitus patients. Meta-regression analysis exploring potential confounders revealed no significant association. Conclusions: The presence of retinopathy was not overall different between individuals with and without NAFLD; however, T1DM patients with NAFLD had higher rates of retinopathy compared to T1DM patients without NAFLD, a finding warranting further research to show whether NAFLD may predict retinopathy in T1DM patients.
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Affiliation(s)
- Myrsini Orfanidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Charikleia Ntenti
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Kleo Evripidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Asimina Mataftsi
- Second Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Deng Z, Ren C, Tang C, Chen S, Li J, Wei J, Zhang Q, Ma B. Syringin alleviates hepatic fibrosis by enhancing autophagic flux and attenuating ER stress-TRIB3/SMAD3 in diabetic mice. Tissue Cell 2023; 83:102159. [PMID: 37467688 DOI: 10.1016/j.tice.2023.102159] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/25/2023] [Accepted: 07/11/2023] [Indexed: 07/21/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a key risk factor for the developing of metabolic liver injury and easily evolving to advanced fibrosis. Syringin (SYR), isolated from Acanthopanax senticosus, has anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, its hepatoprotective effects and mechanisms in T2DM-induced liver fibrosis remain unclear. Here, we investigated whether syringin (SYR) could serve as a therapeutic agent for liver fibrosis and its mechanism in high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetic mice. C57BL/6 mice were induced with T2DM via HFD and STZ injection and treated with different doses of SYR. Serum lipid parameters and liver function indicators were measured, and hepatic histology and fibrosis were examined. The mechanism of SYR was explored through molecular analyses Results demonstrated SYR improved oral glucose tolerance, decreased the levels of ALT, AST, and AKP, and reduced hepatic lipid deposition in diabetic mice. Moreover, SYR ameliorated epithelial-to-mesenchymal transition to reverse hepatic fibrosis via suppressing TRIB3-SMAD3 interaction to restrain nuclear localization of SMAD3. Strikingly, SYR reversed hyperglycemia-induced deficiency in autophagic flux by regulation of Raptor/mTORC1, triggering nuclear translocation of TFEB to improve autophagosome-lysosomal fusion. In brief, SYR potentially ameliorates hepatic injury and fibrosis by enhancing autophagic flux and inhibing TRIB3 activation in diabetic mice.
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Affiliation(s)
- Zhewen Deng
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China
| | - Chaoxing Ren
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China
| | - Chenglun Tang
- Nanjing Sheng Ming Yuan Health Technology Co.Ltd., Nanjing 210000, People's Republic of China
| | - Shuang Chen
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China
| | - Jiaqi Li
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China
| | - Jingxun Wei
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China.
| | - Bo Ma
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China.
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Bae J, Lee BW. Significance of Diabetic Kidney Disease Biomarkers in Predicting Metabolic-Associated Fatty Liver Disease. Biomedicines 2023; 11:1928. [PMID: 37509567 PMCID: PMC10377561 DOI: 10.3390/biomedicines11071928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/04/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) and diabetic kidney disease (DKD) share various pathophysiological factors, and epidemiological evidence suggests that these two diseases are associated. Albuminuria and the estimated glomerular filtration rate, which are conventional biomarkers of DKD, are reportedly associated with the risk or severity of MAFLD. Recently, novel DKD biomarkers reflecting renal tubular injury have been introduced to complement conventional DKD markers. In this article, we looked at previous studies that showed an association between MAFLD and DKD, and also reviewed the significance of DKD biomarkers as predictive risk factors for MAFLD.
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Affiliation(s)
- Jaehyun Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon 22711, Republic of Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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Nysather J, Kaya E, Manka P, Gudsoorkar P, Syn WK. Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease Cross Talk. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:315-335. [PMID: 37657879 DOI: 10.1053/j.akdh.2023.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/14/2022] [Accepted: 04/04/2023] [Indexed: 09/03/2023]
Abstract
Nonalcoholic fatty liver disease is a multisystem condition with effects beyond the liver. The identification of chronic kidney disease as an independent mediator of nonalcoholic fatty liver disease or associated entity with shared cardiometabolic risk factors remains controversial and continues to draw scientific interest. With increasing prevalence of nonalcoholic fatty liver disease and lack of Food and Drug Administration approved therapies, these shared cardiometabolic risk factors have drawn significant attention. In this article, we review shared pathophysiological mechanisms between nonalcoholic fatty liver disease and chronic kidney disease along with current treatment strategies that might be useful for both disease processes.
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Affiliation(s)
- Jacob Nysather
- Division of Nephrology and Kidney C.A.R.E. Program, University of Cincinnati, OH
| | - Eda Kaya
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Paul Manka
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Prakash Gudsoorkar
- Division of Nephrology and Kidney C.A.R.E. Program, University of Cincinnati, OH
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO; Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, Euskal Herriko Unibertsitatea/Universidad del País Vasco, Leioa, Spain.
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41
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Griffin C, Asrani SK, Regner KR. Update on Assessment of Estimated Glomerular Filtration Rate in Patients With Cirrhosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:307-314. [PMID: 37389536 DOI: 10.1053/j.akdh.2023.06.001] [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: 11/27/2022] [Revised: 06/01/2023] [Accepted: 06/06/2023] [Indexed: 07/01/2023]
Abstract
Kidney disease is associated with adverse outcomes in patients with cirrhosis including increased post-liver transplantation (LT) mortality. Therefore, diagnosis and staging of kidney disease are critical to timely implementation of treatment and have important implications for transplant eligibility. Serum creatinine (sCr) is a key component of the Model for End-Stage Liver Disease score in LT candidates, and sCr-based estimated glomerular filtration rate (eGFR) values play an important role in determining medical urgency for LT. However, the use of sCr to assess kidney function may be limited in the cirrhotic milieu due to decreased creatinine production, interference of bilirubin with some laboratory assays for sCr, and expansion of the volume of distribution of creatinine. Therefore, conventional eGFR equations perform poorly in patients with cirrhosis and may overestimate kidney function leading to delayed diagnosis of acute kidney injury or lower priority for LT in patients with a truly low glomerular filtration rate. In this review, we will provide an update on the use of sCr for diagnosis and staging of kidney disease in patients with cirrhosis, discuss the limitations of sCr-based eGFR equations, and discuss novel eGFR equations that have been developed in patients with cirrhosis.
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Affiliation(s)
- Connor Griffin
- Division of Hepatology, Baylor University Medical Center, Dallas, TX
| | - Sumeet K Asrani
- Division of Hepatology, Baylor University Medical Center, Dallas, TX
| | - Kevin R Regner
- Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI.
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Deravi N, Dehghani Firouzabadi F, Moosaie F, Asadigandomani H, Arab Bafrani M, Yoosefi N, Poopak A, Dehghani Firouzabadi M, Poudineh M, Rabizadeh S, Kamel I, Nakhjavani M, Esteghamati A. Non-alcoholic fatty liver disease and incidence of microvascular complications of diabetes in patients with type 2 diabetes: a prospective cohort study. Front Endocrinol (Lausanne) 2023; 14:1147458. [PMID: 37342261 PMCID: PMC10277724 DOI: 10.3389/fendo.2023.1147458] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 05/17/2023] [Indexed: 06/22/2023] Open
Abstract
Objective To investigate the association between non-alcoholic fatty liver disease (NAFLD) and liver enzymes with the incidence of microvascular complications (neuropathy, retinopathy, and nephropathy) in a cohort of Iranian patients with type 2 diabetes. Methods For a total population of 3123 patients with type 2 diabetes, a prospective study was designed for 1215 patients with NAFLD and 1908 gender and age-matched control patients without NAFLD. The two groups were followed for a median duration of 5 years for the incidence of microvascular complications. The association between having NAFLD, the level of liver enzymes, aspartate aminotransferase to platelet ratio index (APRI), Fibrosis-4 (FIB-4) value, and the incidence risk of diabetic retinopathy, neuropathy, and nephropathy were assessed through logistic regression analysis. Results NAFLD was found to be associated with incidence of diabetic neuropathy and nephropathy (Odds ratio: 1.338 (95% confidence interval: 1.091-1.640) and 1.333 (1.007-1.764), respectively). Alkaline-phosphatase enzyme was found to be associated with higher risks of diabetic neuropathy and nephropathy ((Risk estimate: 1.002 (95% CI: 1.001-1.003) and 1.002 (1.001-1.004), respectively)). Moreover, gamma-glutamyl transferase was associated with a higher risk of diabetic nephropathy (1.006 (1.002-1.009). Aspartate aminotransferase and alanine aminotransferase were inversely associated with the risk of diabetic retinopathy (0.989 (0.979-0.998) and 0.990 (0.983-0.996), respectively). Furthermore, ARPI_T (1), ARPI_T (2), and ARPI_T (3) were shown to be associated with NAFLD (1.440 (1.061-1.954), 1.589 (1.163-2.171), and 2.673 (1.925, 3.710), respectively). However, FIB-4 score was not significantly associated with risk of microvascular complications. Conclusion Despite the benign nature of NAFLD, patients with type 2 diabetes should be always assessed for NAFLD to ensure early diagnosis and entry into proper medical care. Regular screenings of microvascular complications of diabetes is also suggested for these patients.
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Affiliation(s)
- Niloofar Deravi
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Student Research committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Fatemeh Moosaie
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Asadigandomani
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Melika Arab Bafrani
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Niyoosha Yoosefi
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Poopak
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Dehghani Firouzabadi
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohadeseh Poudineh
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ibrahim Kamel
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Chen C, Zhang Y, Fan Y, Ying Z, Su Q, Li X, Qin L. The change of non-alcoholic fatty liver disease is associated with risk of incident diabetes. Front Endocrinol (Lausanne) 2023; 14:1108442. [PMID: 37214244 PMCID: PMC10194027 DOI: 10.3389/fendo.2023.1108442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 04/05/2023] [Indexed: 05/24/2023] Open
Abstract
Background & aims The effect of change in non-alcoholic fatty liver disease (NAFLD) status on incident diabetes has not been well studied. We aimed to investigate the association of NAFLD development and remission with the risk of incident diabetes during a median of 3.5-year follow-up. Methods A total of 2690 participants without diabetes were recruited in 2011-2012 and assessed for incident diabetes in 2014. Abdominal ultrasonography was used to determine the change of NAFLD. 75 g oral glucose tolerance test (OGTT) was performed to determine diabetes. NAFLD severity was assessed using Gholam's model. The odds ratios (ORs) for incident diabetes were estimated by logistic regression models. Results NAFLD was developed in 580 (33.2%) participants and NAFLD remission occurred in 150 (15.9%) participants during a median of 3.5-year follow-up. A total of 484 participants developed diabetes during follow-up, including 170 (14.6%) in consistent non-NAFLD group, 111 (19.1%) in NAFLD developed group, 19 (12.7%) in NAFLD remission group, and 184 (23.2%) in sustained NAFLD group. The development of NAFLD increased the risk of incident diabetes by 43% (OR, 1.43; 95%CI, 1.10-1.86) after adjustment for multiple confounders. Compared with sustained NAFLD group, remission of NAFLD reduced the risk of incident diabetes by 52% (OR, 0.48; 95%CI, 0.29-0.80). The effect of NAFLD alteration on incident diabetes was not changed after adjustment for body mass index or waist circumference, change of body mass index or waist circumference. In NAFLD remission group, participants with non-alcoholic steatohepatitis (NASH) at baseline were more likely to develop diabetes (OR, 3.03; 95%CI, 1.01-9.12). Conclusions NAFLD development increases the risk of incident diabetes, whereas NAFLD remission reduces the risk of incident diabetes. Moreover, presence of NASH at baseline could attenuate the protective effect of NAFLD remission on incident diabetes. Our study suggests that early intervention of NAFLD and maintenance of non-NAFLD are important for prevention of diabetes.
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Affiliation(s)
- Congling Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuecheng Zhang
- General Practice Department, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, China
| | - Yujuan Fan
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhen Ying
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qing Su
- Department of Endocrinology and Metabolism, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaoying Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Qin
- Department of Endocrinology and Metabolism, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Endocrinology, Chongming Hospital Affiliated to Shanghai University of Health & Medicine Sciences, Shanghai, China
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Copur S, Yavuz F, Kanbay M. Thyroid hormone Beta receptor agonists for treatment of kidney disease: A promising agent? Eur J Clin Invest 2023; 53:e13939. [PMID: 36537819 DOI: 10.1111/eci.13939] [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: 11/13/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND Chronic kidney disease is a common disorder affecting a significant portion of the adult population with high mortality and morbidity. Obesity and hyperlipidemia are prevalent in chronic kidney disease, and they may trigger fat accumulation in renal parenchyma and eventually fatty kidney. Chronic kidney disease and fatty kidney are also strongly associated with nonalcoholic fatty liver disease. Because they both lead to detrimental effects on organ function, they both need to be treated effectively to improve the outcome. AIM In this narrative review, we have hypothesized that thyroid hormone beta receptor agonists, a novel drug group, may potentially be beneficial in the management of chronic kidney disease due to its promising outcomes among patients with nonalcoholic fatty liver disease, a condition sharing multiple common underlying pathophysiological mechanisms. RESULTS AND CONCLUSION Thyroid hormone beta receptors are abundantly expressed in liver and kidney tissues, while both nonalcoholic fatty liver disease and chronic kidney disease share various similar pathophysiological mechanisms and triggers. Therefore, thyroid hormone beta receptor agonists may become a promising tool in the management of patients with chronic kidney disease.
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Affiliation(s)
- Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Furkan Yavuz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
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Alomari M, Rashid MU, Chadalavada P, Ragheb J, Zafar H, Suarez ZK, Khazaaleh S, Gonzalez AJ, Castro FJ. Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease: From nomenclature to clinical outcomes. World J Hepatol 2023; 15:477-496. [PMID: 37206648 PMCID: PMC10190689 DOI: 10.4254/wjh.v15.i4.477] [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: 12/27/2022] [Revised: 02/04/2023] [Accepted: 03/22/2023] [Indexed: 04/20/2023] Open
Abstract
As a result of the obesity epidemic, Nonalcoholic fatty liver disease (NAFLD) and its complications have increased among millions of people. Consequently, a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis; metabolic-associated fatty liver disease (MAFLD). This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD. This article discusses the rationale behind the nomenclature change, the main differences, and its clinical implications.
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Affiliation(s)
- Mohammad Alomari
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States.
| | - Mamoon Ur Rashid
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Pravallika Chadalavada
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Jonathan Ragheb
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Hammad Zafar
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Zoilo Karim Suarez
- Department of Internal Medicine, Florida Atlantic University Charles E Schmidt College of Medicine, Boca Raton, FL 33431, United States
| | - Shrouq Khazaaleh
- Department of Internal Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH 44126, United States
| | - Adalberto Jose Gonzalez
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Fernando J Castro
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
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Moh MC, Pek SLT, Sze KCP, Low S, Subramaniam T, Ang K, Tang WE, Lee SBM, Sum CF, Lim SC. Associations of non-invasive indices of liver steatosis and fibrosis with progressive kidney impairment in adults with type 2 diabetes. Acta Diabetol 2023; 60:827-835. [PMID: 36943479 DOI: 10.1007/s00592-023-02058-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/20/2023] [Indexed: 03/23/2023]
Abstract
AIMS Longitudinal data linking non-alcoholic fatty liver disease to kidney dysfunction in type 2 diabetes (T2D) are limited. This study evaluated the associations of non-invasive indices of liver steatosis and liver fibrosis with kidney impairment, and the mediatory role of the pro-angiogenic factor leucine-rich α-2 glycoprotein 1 (LRG1). METHODS T2D adults (n = 2057) were followed for a mean period of 6.1 ± 1.6 years. Baseline liver steatosis [(hepatic steatosis index (HSI) and Zhejiang University index (ZJU)] and liver fibrosis [aspartate transaminase/alanine transaminase ratio (AAR) and BARD] indices derived from composite scoring systems were calculated. Plasma LRG1 levels were quantified using immunoassay. The study outcomes were progressive kidney function decline defined as estimated glomerular filtration rate (eGFR) decline of ≥ 40% and albuminuria progression defined as an increase in albuminuria category. RESULTS Cross-sectionally, liver steatosis and liver fibrosis indices were associated with increased albuminuria (urinary albumin/creatinine ratio ≥ 30 µg/mg) and reduced renal function (eGFR < 60 mL/min/1.73 m2) after covariate adjustment, respectively. Approximately 32% of the participants experienced progressive kidney function decline, while 38% had albuminuria worsening over time. Longitudinal analysis revealed that baseline AAR (hazard ratio: 1.56; 95% CI 1.15-2.11) and BARD (hazard ratio: 1.16, 95% CI 1.04-1.28) predicted progressive kidney function decline, partly mediated by LRG1. In contrast, liver steatosis (HSI and ZJU) but not liver fibrosis (AAR and BARD) indices were independently associated with albuminuria progression. CONCLUSIONS Increased liver steatosis scores were associated with albuminuria deterioration. Conversely, liver fibrosis indices may be associated with progressive kidney function decline, potentially driven by increased inflammation and angiogenesis.
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Affiliation(s)
- Mei Chung Moh
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
| | | | - Kenny Ching Pan Sze
- Gastroenterology and Hepatology Unit, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Serena Low
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
- Diabetes Centre, Admiralty Medical Centre, Khoo Teck Puat Hospital, 676 Woodlands Drive 71 #03-01, Singapore, 730676, Singapore
| | - Tavintharan Subramaniam
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
- Diabetes Centre, Admiralty Medical Centre, Khoo Teck Puat Hospital, 676 Woodlands Drive 71 #03-01, Singapore, 730676, Singapore
| | - Keven Ang
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Wern Ee Tang
- National Healthcare Group Polyclinics, Singapore, Singapore
| | | | - Chee Fang Sum
- Diabetes Centre, Admiralty Medical Centre, Khoo Teck Puat Hospital, 676 Woodlands Drive 71 #03-01, Singapore, 730676, Singapore
| | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore.
- Diabetes Centre, Admiralty Medical Centre, Khoo Teck Puat Hospital, 676 Woodlands Drive 71 #03-01, Singapore, 730676, Singapore.
- Saw Swee Hock School of Public Health, National University Hospital, Singapore, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
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Association of MAFLD with end-stage kidney disease: a prospective study of 337,783 UK Biobank participants. Hepatol Int 2023; 17:595-605. [PMID: 36809487 DOI: 10.1007/s12072-023-10486-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/12/2023] [Indexed: 02/23/2023]
Abstract
INTRODUCTION Metabolic dysfunction-associated fatty liver (MAFLD) has been found to be associated with the prevalence of chronic kidney disease (CKD). However, it is unknown whether MAFLD is associated with CKD development and the incidence of end-stage kidney disease (ESKD). We aimed to clarify the association between MAFLD and incident ESKD in the prospective UK Biobank cohort. METHODS We analyzed the data of 337,783 UK Biobank participants and relative risks for the ESKD were calculated by using the Cox regression analysis. RESULTS Among 337,783 participants over a median duration of 12.8 years follow-up, a total of 618 ESKD cases were diagnosed. Participants with MAFLD were twice likely to develop ESKD (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.68-2.46, p < 0.001). The association of MAFLD with ESKD risk remained significant in both non-CKD and CKD participants. Our results also showed that there were graded associations between liver fibrosis scores and the risk of ESKD in MAFLD cases. Compared to non-MAFLD individuals, the adjusted HRs for incident ESKD in MAFLD patients with increasing levels of NAFLD fibrosis score were 1.23 (95% CI 0.96-1.58), 2.45 (1.98-3.03) and 7.67 (5.48-10.73), respectively. Furthermore, the risking alleles of PNPLA3 rs738409, TM6SF2 rs58542926, GCKR rs1260326 and MBOAT7 rs641738 amplified the MAFLD effect on ESKD risk. In conclusion, MAFLD is associated with incident ESKD. CONCLUSION MAFLD may help identify the subjects at high risk of ESKD development and MAFLD interventions should be encouraged to slow down CKD progression.
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Liu N, Wang G, Liu C, Liu J, Huang S, Zhou Y, Xiao E. Non-alcoholic fatty liver disease and complications in type 1 and type 2 diabetes: A Mendelian randomization study. Diabetes Obes Metab 2023; 25:365-376. [PMID: 36181433 DOI: 10.1111/dom.14877] [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: 06/29/2022] [Revised: 09/19/2022] [Accepted: 09/28/2022] [Indexed: 02/02/2023]
Abstract
AIM To investigate the potential causal relationship between non-alcoholic fatty liver disease (NAFLD) and complications in type 1 diabetes (T1D) and type 2 diabetes (T2D). MATERIALS AND METHODS Two-sample Mendelian randomization (MR) analysis was conducted to appraise after controlling for the confounding factors. Genetic instrument variables for NAFLD surrogated by chronically elevated serum alanine transferase were derived from a recent genome-wide association study. Diabetes-related complications, including diabetic ketoacidosis, nephropathy and retinopathy, were included as outcomes. Four complementary MR methods were used to test reliability. RESULTS Genetically instrumented NAFLD showed a suggestive causal association with ketoacidosis in T1D (odds ratio [OR]: 1.574; 95% confidence interval [CI]: 1.076, 2.302; P = .019; false discovery rate [FDR] = 0.096) and a significant causal association with early-stage kidney disease in T1D (OR: 1.249; 95% CI: 1.089, 1.432; P = 1.457 × 10-3 , FDR = 0.015). Sensitivity analysis indicated low heterogeneity, low pleiotropy and high reliability of the causal estimates. However, the MR analyses failed to show a causal association between NAFLD and T1D retinopathy, T2D ketoacidosis, nephropathy and retinopathy. CONCLUSIONS This study supports a causal effect of genetically driven chronic serum alanine aminotransferase-associated NAFLD on early-stage kidney disease in T1D and a suggestive causal effect on ketoacidosis in T1D. However, MR studies did not provide enough evidence to suggest that NAFLD independently increases the risk of retinopathy in T1D and of ketoacidosis, nephropathy and retinopathy in T2D.
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Affiliation(s)
- Ningyuan Liu
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ge Wang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Chao Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jiayi Liu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shengyuan Huang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yong Zhou
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Enhua Xiao
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
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Zou Y, Zhao L, Zhang J, Wang Y, Wu Y, Ren H, Wang T, Zhao Y, Xu H, Li L, Tong N, Liu F. Metabolic-associated fatty liver disease increases the risk of end-stage renal disease in patients with biopsy-confirmed diabetic nephropathy: a propensity-matched cohort study. Acta Diabetol 2023; 60:225-233. [PMID: 36319797 DOI: 10.1007/s00592-022-01978-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/18/2022] [Indexed: 01/21/2023]
Abstract
AIMS To investigate the relationship between metabolic-associated fatty liver disease (MAFLD) and end-stage renal disease (ESRD) in patients with biopsy-confirmed diabetic nephropathy (DN). METHODS A total of 316 participants with biopsy-confirmed DN between January 2008 and December 2019 were retrospectively assessed. Kaplan-Meier curve and Cox proportional hazard models were used to compare the risk of incident ESRD in 50 patients with MAFLD and 50 patients without MAFLD, after using propensity score matching (PSM) to address the imbalances of sex, age, baseline-estimated glomerular filtration rate, serum albumin, 24-h urine protein, hemoglobin and systolic blood pressure. RESULTS During the median follow-up period of 3 years, there were 19 ESRD outcome events (19%) in PSM cohort. Kaplan-Meier curve analysis suggested that renal survival significantly deteriorated in patients with MAFLD versus those without MAFLD (p = 0.021). Additionally, the hazard ratios (95% confidence interval) of MAFLD were 3.12 (1.09-8.95, p = 0.035), 3.36 (1.09-10.43, p = 0.036), 3.66 (1.22-10.98, p = 0.021), 4.25 (1.34-13.45, p = 0.014), 3.11 (1.08-8.96, p = 0.035) and 5.84 (1.94-18.5, p = 0.003) after adjustment for six models, including demographic, clinical and pathological characteristics as well as medication use at the time of renal biopsy, respectively. Besides, patients with higher liver fibrosis score had a greater possibility of ESRD, comparing to those with lower liver fibrosis score (p = 0.002). CONCLUSIONS MAFLD increases the risk of incident ESRD in patients with biopsy-proven DN. Further research is needed to determine whether treatment targeting MAFLD improves the prognosis of DN.
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Affiliation(s)
- Yutong Zou
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Lijun Zhao
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Junlin Zhang
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yiting Wang
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yucheng Wu
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Honghong Ren
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Tingli Wang
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yuancheng Zhao
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Huan Xu
- Division of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Lin Li
- Division of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Nanwei Tong
- Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
- Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
| | - Fang Liu
- Department of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
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Machida T, Obara T, Ishikuro M, Murakami K, Ueno F, Noda A, Onuma T, Matsuzaki F, Inoue J, Kuriyama S, Mano N. Liver steatosis and fibrosis markers' association with cardiovascular and renal damage in Japanese adults: the TMM BirThree cohort study. Ann Hepatol 2023; 28:100761. [PMID: 36179796 DOI: 10.1016/j.aohep.2022.100761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 09/05/2022] [Accepted: 09/18/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Patients with non-alcoholic fatty liver disease (NAFLD) are at risk for cardiovascular and chronic kidney diseases. Liver steatosis and fibrosis were assessed using the fatty liver index and fibrosis-4 index, respectively. This study aimed to examine the association between these two parameters in patients with atherosclerosis and chronic kidney disease. MATERIALS AND METHODS The two parameters were calculated for 11,867 adults who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Intima-media thickness and estimated glomerular filtration rate were also measured. Logistic regression models were used to estimate the odds ratios (OR). RESULTS Overall, 4257 (35.9%) and 4733 (39.9%) participants had a higher probability of liver steatosis and fibrosis, respectively. The adjusted OR of higher fatty liver index compared to lower fatty liver index for atherosclerosis and chronic kidney disease were 0.98 (95% confidence interval [CI], 0.77-1.24) and 1.79 (95% CI, 1.19-2.69), and those of higher FIB-4 compared to lower FIB-4 were 1.03 (95% CI, 0.82-1.30) and 0.79 (95% CI, 0.52-1.19) for atherosclerosis and chronic kidney disease, respectively. CONCLUSIONS A higher FLI was associated with CKD independent of other risk factors. Further research is required to identify the causal relationship between liver fat accumulation and CKD.
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Affiliation(s)
- Toshiya Machida
- Laboratory of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Taku Obara
- Department of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
| | - Mami Ishikuro
- Department of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan
| | - Keiko Murakami
- Department of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan
| | - Fumihiko Ueno
- Department of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan
| | - Aoi Noda
- Department of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tomomi Onuma
- Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan
| | - Fumiko Matsuzaki
- Department of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Shinichi Kuriyama
- Department of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan
| | - Nariyasu Mano
- Laboratory of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
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