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Iordan L, Gaita L, Timar R, Avram V, Sturza A, Timar B. The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review. Int J Mol Sci 2024; 25:7057. [PMID: 39000165 PMCID: PMC11241663 DOI: 10.3390/ijms25137057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.
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Affiliation(s)
- Liana Iordan
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Laura Gaita
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Romulus Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Vlad Avram
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Adrian Sturza
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Bogdan Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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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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Boncan DAT, Yu Y, Zhang M, Lian J, Vardhanabhuti V. Machine learning prediction of hepatic steatosis using body composition parameters: A UK Biobank Study. NPJ AGING 2024; 10:4. [PMID: 38195699 PMCID: PMC10776620 DOI: 10.1038/s41514-023-00127-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 10/16/2023] [Indexed: 01/11/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease worldwide, yet detection has remained largely based on surrogate serum biomarkers, elastography or biopsy. In this study, we used a total of 2959 participants from the UK biobank cohort and established the association of dual-energy X-ray absorptiometry (DXA)-derived body composition parameters and leveraged machine learning models to predict NAFLD. Hepatic steatosis reference was based on MRI-PDFF which has been extensively validated previously. We found several significant associations with traditional measurements such as abdominal obesity, as defined by waist-to-hip ratio (OR = 2.50 (male), 3.35 (female)), android-gynoid ratio (OR = 3.35 (male), 6.39 (female)) and waist circumference (OR = 1.79 (male), 3.80 (female)) with hepatic steatosis. Similarly, A Body Shape Index (Quantile 4 OR = 1.89 (male), 5.81 (female)), and for fat mass index, both overweight (OR = 6.93 (male), 2.83 (female)) and obese (OR = 14.12 (male), 5.32 (female)) categories were likewise significantly associated with hepatic steatosis. DXA parameters were shown to be highly associated such as visceral adipose tissue mass (OR = 8.37 (male), 19.03 (female)), trunk fat mass (OR = 8.64 (male), 25.69 (female)) and android fat mass (OR = 7.93 (male), 21.77 (female)) with NAFLD. We trained machine learning classifiers with logistic regression and two histogram-based gradient boosting ensembles for the prediction of hepatic steatosis using traditional body composition indices and DXA parameters which achieved reasonable performance (AUC = 0.83-0.87). Based on SHapley Additive exPlanations (SHAP) analysis, DXA parameters that had the largest contribution to the classifiers were the features predicted with significant association with NAFLD. Overall, this study underscores the potential utility of DXA as a practical and potentially opportunistic method for the screening of hepatic steatosis.
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Affiliation(s)
- Delbert Almerick T Boncan
- Snowhill Science Ltd, Units 801-803, Level 8, Core C, Hong Kong SAR, China
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Yan Yu
- Snowhill Science Ltd, Units 801-803, Level 8, Core C, Hong Kong SAR, China
| | - Miaoru Zhang
- Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jie Lian
- Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Varut Vardhanabhuti
- Snowhill Science Ltd, Units 801-803, Level 8, Core C, Hong Kong SAR, China.
- Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, 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: 14] [Impact Index Per Article: 14.0] [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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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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Mohan V, Uma Sankari G, Amutha A, Anjana RM, Jeba Rani S, Unnikrishnan R, Venkatesan U, Shanthi Rani CS. Clinical and biochemical profile of childhood-adolescent-onset type 1 diabetes and adult-onset type 1 diabetes among Asian Indians. Acta Diabetol 2023; 60:579-586. [PMID: 36700996 DOI: 10.1007/s00592-023-02034-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023]
Abstract
AIM To compare the clinical and biochemical profile and prevalence of complications among childhood/adolescent-onset (CAO; onset of diabetes< 20 years of age) and adult-onset (AO; onset of diabetes- ≥ 20 years of age) type 1 diabetes (T1D), seen at a tertiary care diabetes center in south India. METHOD Data of 5578 individuals with T1D, diagnosed based on a history of diabetic ketoacidosis or ketonuria, fasting C-peptide < 0.3 pmol/mL and stimulated C-peptide values < 0.6 pmol/mL, and requirement of insulin right from the time of diagnosis, presenting to our center between 1991 and 2021, were retrieved from our electronic medical records. Retinopathy was assessed by retinal photography, chronic kidney disease (CKD) by urinary albumin excretion ≥ 30 µg/mg of creatinine and/or eGFR < 60 mL/min, and neuropathy by vibration perception threshold >= 20v on biothesiometry. RESULTS Overall, 3559 (63.8%) of individuals with T1D, belonged to CAO group and 2019 (36.2%) to AO category. AO had higher prevalence of all microvascular complications compared to CAO at every diabetes duration interval, even after adjusting for A1c. Among the AO group, prevalence of retinopathy, CKD, and neuropathy was higher in the GAD negative group. Among CAO there were no differences between the GAD negative and GAD positive groups with respect to prevalence of complications of diabetes. CONCLUSION AO with T1D had higher prevalence of microvascular complications compared to CAO. Among AO, GAD negative individuals had higher percentage of retinopathy and CKD compared to GAD positive group.
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Affiliation(s)
- Viswanathan Mohan
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India.
| | - Ganesan Uma Sankari
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India
| | - Anandakumar Amutha
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India
| | - Ranjit Mohan Anjana
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India
| | - Saravanan Jeba Rani
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India
| | - Ranjit Unnikrishnan
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India
| | - Ulagamathesan Venkatesan
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India
| | - Coimbatore Subramanian Shanthi Rani
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research On Diabetes) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India
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Bellini MI, Urciuoli I, Del Gaudio G, Polti G, Iannetti G, Gangitano E, Lori E, Lubrano C, Cantisani V, Sorrenti S, D’Andrea V. Nonalcoholic fatty liver disease and diabetes. World J Diabetes 2022; 13:668-682. [PMID: 36188142 PMCID: PMC9521438 DOI: 10.4239/wjd.v13.i9.668] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/03/2022] [Accepted: 08/06/2022] [Indexed: 02/05/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world and represents a clinical-histopathologic entity where the steatosis component may vary in degree and may or may not have fibrotic progression. The key concept of NAFLD pathogenesis is excessive triglyceride hepatic accumulation because of an imbalance between free fatty acid influx and efflux. Strong epidemiological, biochemical, and therapeutic evidence supports the premise that the primary pathophysiological derangement in most patients with NAFLD is insulin resistance; thus the association between diabetes and NAFLD is widely recognized in the literature. Since NAFLD is the hepatic manifestation of a metabolic disease, it is also associated with a higher cardio-vascular risk. Conventional B-mode ultrasound is widely adopted as a first-line imaging modality for hepatic steatosis, although magnetic resonance imaging represents the gold standard noninvasive modality for quantifying the amount of fat in these patients. Treatment of NAFLD patients depends on the disease severity, ranging from a more benign condition of nonalcoholic fatty liver to nonalcoholic steatohepatitis. Abstinence from alcohol, a Mediterranean diet, and modification of risk factors are recommended for patients suffering from NAFLD to avoid major cardiovascular events, as per all diabetic patients. In addition, weight loss induced by bariatric surgery seems to also be effective in improving liver features, together with the benefits for diabetes control or resolution, dyslipidemia, and hypertension. Finally, liver transplantation represents the ultimate treatment for severe nonalcoholic fatty liver disease and is growing rapidly as a main indication in Western countries. This review offers a comprehensive multidisciplinary approach to NAFLD, highlighting its connection with diabetes.
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Affiliation(s)
- Maria Irene Bellini
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Irene Urciuoli
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Giovanni Del Gaudio
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Giorgia Polti
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Giovanni Iannetti
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Elena Gangitano
- Department of Experimental Medicine, Section of Medical Physiopathology, Food Science and Endocrinology, Sapienza University of Rome, Rome 00161, Italy
| | - Eleonora Lori
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Carla Lubrano
- Department of Experimental Medicine, Section of Medical Physiopathology, Food Science and Endocrinology, Sapienza University of Rome, Rome 00161, Italy
| | - Vito Cantisani
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Salvatore Sorrenti
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Vito D’Andrea
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
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Sharma N, Sircar A, Anders HJ, Gaikwad AB. Crosstalk between kidney and liver in non-alcoholic fatty liver disease: mechanisms and therapeutic approaches. Arch Physiol Biochem 2022; 128:1024-1038. [PMID: 32223569 DOI: 10.1080/13813455.2020.1745851] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver and kidney are vital organs that maintain homeostasis and injury to either of them triggers pathogenic pathways affecting the other. For example, non-alcoholic fatty liver disease (NAFLD) promotes the progression of chronic kidney disease (CKD), vice versa acute kidney injury (AKI) endorses the induction and progression of liver dysfunction. Progress in clinical and basic research suggest a role of excessive fructose intake, insulin resistance, inflammatory cytokines production, activation of the renin-angiotensin system, redox imbalance, and their impact on epigenetic regulation of gene expression in this context. Recent developments in experimental and clinical research have identified several biochemical and molecular pathways for AKI-liver interaction, including altered liver enzymes profile, metabolic acidosis, oxidative stress, activation of inflammatory and regulated cell death pathways. This review focuses on the current preclinical and clinical findings on kidney-liver crosstalk in NAFLD-CKD and AKI-liver dysfunction settings and highlights potential molecular mechanisms and therapeutic targets.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Anannya Sircar
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
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Seo DH, Suh YJ, Cho Y, Ahn SH, Seo S, Hong S, Lee YH, Choi YJ, Lee E, Kim SH. Advanced Liver Fibrosis Is Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Diabetes Metab J 2022; 46:630-639. [PMID: 35081304 PMCID: PMC9353562 DOI: 10.4093/dmj.2021.0130] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/24/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and CKD is uncertain, particularly in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with T2DM. METHODS In this longitudinal cohort study of patients with T2DM, 3,188 patients with preserved renal function were followed up for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography, without any other causes of chronic liver disease. Advanced liver fibrosis of NAFLD was defined as a fibrosis-4 index ≥2.67. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. RESULTS At baseline, 1,729 (54.2%) patients had NAFLD, of whom 94 (5.4%) had advanced liver fibrosis. During the follow-up of 8.3±3.6 years, 472 (14.8%) patients developed incident CKD: 220 (15.1%) in the non-NAFLD group, 231 (14.1%) in the NAFLD without advanced fibrosis group and 28 (31.1%) in the NAFLD with advanced fibrosis group. There was no increased risk of incident CKD in the NAFLD group compared to the non-NAFLD group (P=0.435). However, among patients with NAFLD, advanced liver fibrosis was associated with an increased risk of CKD (adjusted hazard ratio, 1.75; 95% confidence interval, 1.15 to 2.66; P=0.009). CONCLUSION Advanced liver fibrosis in patients with NAFLD is independently associated with an increased risk of incident CKD in patients with T2DM.
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Affiliation(s)
- Da Hea Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Young Ju Suh
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, Korea
| | - Yongin Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Seong Hee Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Seongha Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Seongbin Hong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Yong-ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | - Eunjig Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - So Hun Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
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10
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Tao Z, Li Y, Cheng B, Zhou T, Gao Y. Influence of Nonalcoholic Fatty Liver Disease on the Occurrence and Severity of Chronic Kidney Disease. J Clin Transl Hepatol 2022; 10:164-173. [PMID: 35233386 PMCID: PMC8845149 DOI: 10.14218/jcth.2021.00171] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/10/2021] [Accepted: 08/25/2021] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is reported to affect 20-30% of adults and is accompanied by various metabolic comorbidities, where the economic and clinical burden of NAFLD is attributed to the progression of liver disease as well as the presence of extrahepatic diseases. Chronic kidney disease (CKD), which has a high incidence rate, high morbidity and mortality rates, and high medical costs, has been linked to NAFLD. CKD is associated with some metabolism-related risk factors that overlap with metabolic comorbidities of NAFLD. Therefore, to investigate the potential factors that influence CKD occurrence, the association between NAFLD and CKD should be clarified. Some studies have confirmed that NAFLD influences the occurrence and severity of CKD, whereas some studies have indicated that there is no correlation. In this review, the results of a few studies have been discussed, the potential risk factors for CKD in NAFLD are explored, and the respective biological mechanisms are elaborated to help clinicians identify CKD in patients much earlier than it is diagnosed now and thus help in reducing the incidence of liver and kidney transplants.
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Affiliation(s)
| | | | | | | | - Yanjing Gao
- Correspondence to: Yanjing Gao, Department of Gastroenterology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China. ORCID: https://orcid.org/0000-0001-8153-3754. Tel: +86-18560086087, E-mail:
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11
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Cao Y, Deng Y, Wang J, Zhao H, Zhang J, Xie W. The association between NAFLD and risk of chronic kidney disease: a cross-sectional study. Ther Adv Chronic Dis 2021; 12:20406223211048649. [PMID: 34777740 PMCID: PMC8586173 DOI: 10.1177/20406223211048649] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/07/2021] [Indexed: 02/06/2023] Open
Abstract
Objective: The aim of this study was to evaluate the association between nonalcoholic fatty liver disease (NAFLD) and NAFLD with different comorbidities and risk of chronic kidney disease (CKD) and abnormal albuminuria. Materials and Methods: A total of 3872 Chinese individuals excluding those with hepatitis B or C infection and absence of alcohol abuse were included in the study. NAFLD was diagnosed by abdominal ultrasonography. The liver fibrosis was assessed by NAFLD fibrosis score (NFS) and fibrosis-4 index (FIB-4). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 and/or abnormal albuminuria (urinary albumin-to-creatinine ratio ⩾ 3 mg/mmol). The logistic regression analysis was performed to examine the association between NAFLD and NAFLD with different comorbidities and risk of CKD. Results: The prevalence of CKD and abnormal albuminuria was higher in individuals with NAFLD than in those without NAFLD (15.8% vs 11.9%, p < 0.001; 14.8% vs 11.0%, p < 0.001). Logistic regression analysis demonstrated that NAFLD was risk factor of CKD. Notably, after adjustment for sex, age, and DM, NAFLD was associated with 1.31-fold higher risk of prevalent CKD ⩾ 1 (p < 0.05). NAFLD individuals with elder age, DM, obesity, hypertension, MetS, and advanced liver fibrosis had higher risks of both prevalent CKD and abnormal albuminuria than those without comorbidities. Conclusions: NAFLD and NAFLD with traditional comorbidities are strongly associated with risk of prevalence of CKD and abnormal albuminuria. Patients with NAFLD especially those with coexisting comorbidities were recommended to carefully access the development of CKD.
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Affiliation(s)
- Ying Cao
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - You Deng
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jingjing Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hong Zhao
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jingyu Zhang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China
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12
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Mertens J, De Block C, Spinhoven M, Driessen A, Francque SM, Kwanten WJ. Hepatopathy Associated With Type 1 Diabetes: Distinguishing Non-alcoholic Fatty Liver Disease From Glycogenic Hepatopathy. Front Pharmacol 2021; 12:768576. [PMID: 34759828 PMCID: PMC8573337 DOI: 10.3389/fphar.2021.768576] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
Autoimmune destruction of pancreatic β-cells results in the permanent loss of insulin production in type 1 diabetes (T1D). The daily necessity to inject exogenous insulin to treat hyperglycemia leads to a relative portal vein insulin deficiency and potentiates hypoglycemia which can induce weight gain, while daily fluctuations of blood sugar levels affect the hepatic glycogen storage and overall metabolic control. These, among others, fundamental characteristics of T1D are associated with the development of two distinct, but in part clinically similar hepatopathies, namely non-alcoholic fatty liver disease (NAFLD) and glycogen hepatopathy (GlyH). Recent studies suggest that NAFLD may be increasingly common in T1D because more people with T1D present with overweight and/or obesity, linked to the metabolic syndrome. GlyH is a rare but underdiagnosed complication hallmarked by extremely brittle metabolic control in, often young, individuals with T1D. Both hepatopathies share clinical similarities, troubling both diagnosis and differentiation. Since NAFLD is increasingly associated with cardiovascular and chronic kidney disease, whereas GlyH is considered self-limiting, awareness and differentiation between both condition is important in clinical care. The exact pathogenesis of both hepatopathies remains obscure, hence licensed pharmaceutical therapy is lacking and general awareness amongst physicians is low. This article aims to review the factors potentially contributing to fatty liver disease or glycogen storage disruption in T1D. It ends with a proposal for clinicians to approach patients with T1D and potential hepatopathy.
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Affiliation(s)
- Jonathan Mertens
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Christophe De Block
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Maarten Spinhoven
- Department of Radiology, Antwerp University Hospital, Edegem, Belgium
| | - Ann Driessen
- Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.,CORE, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Wilhelmus J Kwanten
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
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13
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Heda R, Yazawa M, Shi M, Bhaskaran M, Aloor FZ, Thuluvath PJ, Satapathy SK. Non-alcoholic fatty liver and chronic kidney disease: Retrospect, introspect, and prospect. World J Gastroenterol 2021; 27:1864-1882. [PMID: 34007127 PMCID: PMC8108029 DOI: 10.3748/wjg.v27.i17.1864] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/07/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
With the growing prevalence of obesity and diabetes in the United States and across the world, a rise in the overall incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is expected. The risk factors for NAFLD are also associated with the development of chronic kidney disease (CKD). We review the epidemiology, risk factors, genetics, implications of gut dysbiosis, and specific pathogenic mechanisms linking NAFLD to CKD. Mechanisms such as ectopic lipid accumulation, cellular signaling abnormalities, and the interplay between fructose consumption and uric acid accumulation have led to the emergence of potential therapeutic implications for this patient population. Transplant evaluation in the setting of both NAFLD and CKD is also reviewed. Potential strategies for surveillance and management include the monitoring of comorbidities, the use of non-invasive fibrosis scoring systems, and the measurement of laboratory markers. Lastly, we discuss the management of patients with NAFLD and CKD, from preventative measures to experimental interventions.
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Affiliation(s)
- Rajiv Heda
- Department of Internal Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Masahiko Yazawa
- Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Michelle Shi
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
| | - Madhu Bhaskaran
- Department of Nephrology, Northwell Health/Zucker School of Medicine at Hosftra, Manhasset, NY 11030, United States
| | - Fuad Zain Aloor
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Paul J Thuluvath
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD 21202, United States
| | - Sanjaya K Satapathy
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
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14
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Barros BSV, Monteiro FC, Terra C, Gomes MB. Prevalence of non-alcoholic fatty liver disease and its associated factors in individuals with type 1 diabetes: a cross-sectional study in a tertiary care center in Brazil. Diabetol Metab Syndr 2021; 13:33. [PMID: 33741024 PMCID: PMC7977593 DOI: 10.1186/s13098-021-00649-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 03/03/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Data on non-alcoholic fatty liver disease (NAFLD) in individuals with type 1 diabetes (T1D) is controversial and so far, there are no published data on the Brazilian population. We investigated the prevalence of steatosis and hepatic fibrosis in a population with T1D from a tertiary care center in Brazil and its associated factors. METHODS Ninety-five participants with T1D, aged 39 ± 13 years, with disease duration of 21 ± 9 years, being 55 (57.9%) females, from a university hospital in Rio de Janeiro, were screened for NAFLD with hepatic ultrasound (US) and transient elastography (TE). RESULTS Prevalence of steatosis was, respectively, 12.6% and 16.8% when US and TE were used for diagnosis of NAFLD. Fibrosis was present in 8.4% of participants. A total of 31.6% of participants had at least one of the hepatic exams altered, which was associated with higher body mass index, waist circumference, hip circumference and waist-to-hip ratio,, presence of metabolic syndrome and higher triglycerides levels, even within the normal range. After multivariate analysis, presence of steatosis was only associated with metabolic syndrome and its component, triglycerides. CONCLUSION In our study, prevalence of NAFLD in ultrasound approximates the one found with TE. Fibrosis was not frequent. Screening should be reserved for participants with T1D and metabolic syndrome, as this was the main factor associated with NAFLD. Triglycerides levels were the only component of metabolic syndrome associated with steatosis. Further studies are necessary to determine the best screening strategy for NAFLD in individuals with T1D. Also, predisposing factors for development in fibrosis in T1D should be further explored in prospective studies.
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Affiliation(s)
- Bianca Senger Vasconcelos Barros
- Department of Internal Medicine, Diabetes Unit, Pedro Ernesto Hospital, State University of Rio de Janeiro (UERJ), 20.551-030, Boulevard 28 de Setembro, 77 - 3º andar - Vila Isabel, Rio de Janeiro, RJ, CEP 20551-030, Brazil.
| | - Fernanda Cruz Monteiro
- Department of Radiology, Pedro Ernesto Hospital, State University of Rio de Janeiro (UERJ), 20.551-030, Rio de Janeiro, RJ, Brazil
| | - Carlos Terra
- Department of Gastroenterology, Pedro Ernesto Hospital, State University of Rio de Janeiro (UERJ), 20.551-030, Rio de Janeiro, RJ, Brazil
- Department of Gastroenterology, Federal Hospital of Lagoa, Rio de Janeiro, RJ, 22470-050, Brazil
| | - Marilia Brito Gomes
- Department of Internal Medicine, Diabetes Unit, Pedro Ernesto Hospital, State University of Rio de Janeiro (UERJ), 20.551-030, Boulevard 28 de Setembro, 77 - 3º andar - Vila Isabel, Rio de Janeiro, RJ, CEP 20551-030, Brazil
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15
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Gomes MB, Pizarro MH, Muniz LH, Barros BSV, Melo LGN, Santos DC, Negrato CA. Prevalence of chronic kidney disease in an admixed population of patients with type 1 diabetes. A multicenter study in Brazil. Diabetes Res Clin Pract 2020; 170:108490. [PMID: 33010359 DOI: 10.1016/j.diabres.2020.108490] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 09/18/2020] [Accepted: 09/28/2020] [Indexed: 12/11/2022]
Abstract
AIMS To evaluate diagnosis, prevalence and associated factors of CKD in Brazilian patients with type 1 diabetes. METHODS This cross-sectional, multicenter study was conducted in 14 public clinics in 10 Brazilian cities. From 1760 patients, 1736 were included (98.6%): 977 females (56.3%), 932 (54%) Caucasians, aged 29.9 ± 11.9 years, age at diagnosis 14.7 ± 8.9 years, diabetes duration 15.5 ± 9.3 years and 12.2 ± 3.8 years of school attendance. CKD was determined by using estimated glomerular filtration rate and by the presence of albuminuria in two out of three morning urine samples. RESULTS The prevalence of CKD was 33.7%. Overall, 28.1% of the patients could not be classified due to insufficient number of urine samples for albuminuria determination. Multivariable analysis showed that female gender, diabetes duration, high levels of HbA1c and uric acid, use of renin-angiotensin system inhibitors, retinopathy, high systolic blood pressure, and economic status (medium, low and very low) were associated with CKD. CONCLUSIONS Although a high prevalence of CKD, associated comorbidities and retinopathy was observed in our study, a large number of patients are still undiagnosed, making CKD a challenge in routine clinical practice in admixed populations with T1D in a developing country like Brazil.
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Affiliation(s)
- Marília Brito Gomes
- Department of Internal Medicine, Diabetes Unit, State University of Rio de Janeiro, Brazil
| | - Marcela Haas Pizarro
- Department of Internal Medicine, Diabetes Unit, State University of Rio de Janeiro, Brazil
| | - Luiza Harcar Muniz
- Department of Internal Medicine, Diabetes Unit, State University of Rio de Janeiro, Brazil
| | | | - Laura Gomes Nunes Melo
- Department of Ophthalmology, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil
| | - Deborah Conte Santos
- Department of Internal Medicine, Diabetes Unit, State University of Rio de Janeiro, Brazil
| | - Carlos Antonio Negrato
- Medical Doctor Program, University of São Paulo- School of Dentistry, Bauru, São Paulo, Brazil.
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16
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Wang Y, Yu Y, Wan H, Chen Y, Xia F, Zhang W, Zhang K, Gu X, Zhang Y, Lin Z, Yu Y, Wang N, Lu Y. Lower eGFR is associated with increased probability of liver fibrosis in Chinese diabetic patients. Diabetes Metab Res Rev 2020; 36:e3294. [PMID: 32017389 DOI: 10.1002/dmrr.3294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 12/15/2019] [Accepted: 01/22/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Kidney dysfunction is linked to nonalcoholic fatty liver disease (NAFLD) progression including fibrosis, steatosis, or inflammation. We aimed to explore whether lower levels of estimated glomerular filtration rate (eGFR) was associated with increased probability of liver fibrosis. METHODS Two thousand six hundred eighty-nine subjects enrolled from Shanghai, China, were included in this study. NAFLD fibrosis score (NFS) was used to risk stratify NAFLD patients for fibrosis. eGFR was used to assess kidney function. The association of eGFR level with elevated NFS, and thus high risk of fibrosis, was analysed by linear regression and multinomial logistic regression. The predictive power of eGFR was evaluated via receiver operating characteristic (ROC) curve. RESULTS A negative association was found between eGFR and NFS (B = -0.21, 95% CI, -0.37 to -0.04, P = .016). As eGFR quartiles decreased, the prevalence of probable fibrosis increased after adjusting for age, sex, current smoking, waist circumference, duration of diabetes, HbA1c , hypertension, dyslipidaemia, and homeostasis model assessment index of insulin resistance (HOMA-IR) (Q4: reference; Q3: 1.49, 95% CI, 0.82-2.71; Q2: 1.88, 95% CI, 0.97-3.67; Q1: 2.70, 95% CI, 1.36-5.37, Pfor trend = .002, 1SD increment: 0.73, 95% CI, 0.58-0.92). The eGFR level can be an effective indicator in differentiating patients with probable presence of fibrosis from those without (AUROC: 0.71, cut-off point: 92.78 mL/min/1.73 m2 , P < .001). CONCLUSIONS Lower levels of eGFR were associated with higher NFS and thus greater risk of presence of fibrosis in patients with NAFLD and T2DM. Individuals with NAFLD and diabetes should carefully monitor eGFR and receive regular urinalysis, especially when advanced fibrosis is suspected.
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Affiliation(s)
- Yuying Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yuetian Yu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Heng Wan
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yi Chen
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Fangzhen Xia
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Wen Zhang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Kun Zhang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Xinjie Gu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yihao Zhang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Zhiqi Lin
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yuefeng Yu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Ningjian Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yingli Lu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
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17
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Therapeutic implications of shared mechanisms in non-alcoholic fatty liver disease and chronic kidney disease. J Nephrol 2020; 34:649-659. [PMID: 32440840 DOI: 10.1007/s40620-020-00751-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023]
Abstract
The most common cause of liver disease worldwide is now non-alcoholic fatty liver disease (NAFLD). NAFLD refers to a spectrum of disease ranging from steatosis to non-alcoholic steatohepatitis, causing cirrhosis, and ultimately hepatocellular carcinoma. However, the impact of NAFLD is not limited to the liver. NAFLD has extra-hepatic consequences, most notably, cardiovascular and renal disease. NAFLD and chronic kidney disease share pathogenic mechanisms including insulin resistance, lipotoxicity, inflammation and oxidative stress. Not surprisingly, there has been a recent surge in efforts to manage NAFLD in an integrated way that not only protects the liver but also delays comorbidities such as chronic kidney disease. This concept of simultaneously addressing the main disease target and comorbidities is key to improve outcomes, as recently demonstrated by clinical trials of SGLT2 inhibitors and GLP1 receptor agonists in diabetes. HIF activators, already marketed in China, also have the potential to protect both liver and kidney, as suggested by preclinical data. This review concisely discusses efforts at identifying common pathogenic pathways between NAFLD and chronic kidney disease with an emphasis on potential paradigm shifts in diagnostic workup and therapeutic management.
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18
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Mantovani A, Zusi C, Dalbeni A, Grani G, Buzzetti E. Risk of Kidney Dysfunction IN Nafld. Curr Pharm Des 2020; 26:1045-1061. [DOI: 10.2174/1381612825666191026113119] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/21/2019] [Indexed: 02/06/2023]
Abstract
Background:
The timely identification of traditional and non-traditional precursors and risk factors for
chronic kidney disease (CKD) (a common systemic disease defined as a decreased kidney function documented
by reduced glomerular filtration rate, or markers of kidney damage, or both) is relevant in clinical practice, as
CKD increases the risk of end-stage renal disease and other serious comorbidities. A possible relationship between
non-alcoholic fatty liver disease (NAFLD) (which is to date the most common chronic disease worldwide)
and CKD has recently gained significant attention of researchers.
Methods :
A systematic literature search using appropriate keywords was made in order to identify relevant articles
that have investigated the association between NAFLD and CKD.
Results:
Several observational studies and meta-analyses have reported the existence of an independent association
between NAFLD and risk of CKD in patients with and without diabetes. However, whilst the association
between NAFLD and risk of prevalent CKD is strong across various patient populations, whether NAFLD is
independently associated with the development and progression of CKD is still debatable. Moreover, emerging
evidence now suggests a potential association between patatin-like phospholipase domain-containing protein-3
(PNPLA3) rs738409 genotype (the most important genetic variant associated to NAFLD) and decreasing kidney
function, independent of NAFLD.
Conclusions :
Convincing evidence now indicates that CKD is increased among patients with NAFLD. For this
reason, patients with NAFLD should be regularly monitored for renal function and, on the other hand , NAFLD
should be considered in all patients with CKD, especially if they are obese or have type 2 diabetes.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Chiara Zusi
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Andrea Dalbeni
- Section of General Medicine, Hypertension and Liver Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Giorgio Grani
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Elena Buzzetti
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
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19
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Kiapidou S, Liava C, Kalogirou M, Akriviadis E, Sinakos E. Chronic kidney disease in patients with non-alcoholic fatty liver disease: What the Hepatologist should know? Ann Hepatol 2020; 19:134-144. [PMID: 31606352 DOI: 10.1016/j.aohep.2019.07.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 06/19/2019] [Accepted: 07/08/2019] [Indexed: 02/04/2023]
Abstract
The association of non-alcoholic fatty liver disease (NAFLD) with several other diseases has gained increased interest during the recent years. Among them, the association with chronic kidney disease (CKD) has emerged as an important one regarding both its prevalence and significance. The early recognition of this association is important for the prognosis of patients with NAFLD and CKD. Apart from early diagnosis, the accurate assessment of renal function is also crucial in the clinical practice of hepatologists. Several methods have been used in the literature for the evaluation of kidney function in patients with NAFLD up to now. In this respect, calculators (or formulas) for the estimation of Glomerular Filtration Rate (eGFR) and Albumin to Creatinine Ratio (ACR) are simple, practical and easily available methods for this purpose. The aim of this review is to report on the epidemiology and pathophysiology of the relationship between NAFLD and CKD and to describe the different methods of kidney function assessment in patients with NAFLD. The collection of all relevant data regarding this association will provide hepatologists with pertinent knowledge on this topic and allow them to use the most accurate methods for the assessment of kidney function in these patients in their clinical practice.
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Affiliation(s)
- Stefania Kiapidou
- 4th Department of Internal Medicine, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Konstantinoupoleos, Thessaloniki, Greece
| | - Christina Liava
- 4th Department of Internal Medicine, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Konstantinoupoleos, Thessaloniki, Greece
| | - Maria Kalogirou
- 4th Department of Internal Medicine, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Konstantinoupoleos, Thessaloniki, Greece
| | - Evangelos Akriviadis
- 4th Department of Internal Medicine, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Konstantinoupoleos, Thessaloniki, Greece
| | - Emmanouil Sinakos
- 4th Department of Internal Medicine, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Konstantinoupoleos, Thessaloniki, Greece.
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Khneizer G, Rizvi S, Gawrieh S. Non-alcoholic Fatty Liver Disease and Diabetes Mellitus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1307:417-440. [PMID: 32424494 DOI: 10.1007/5584_2020_532] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading liver disease globally. NAFLD patients can have a progressive phenotype, non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis, liver failure and cancer. There is a close bi-directional relationship between NAFLD and type 2 diabetes mellitus (T2DM); NAFLD increases the risk for T2DM and its complications whereas T2DM increases the severity of NAFLD and its complications. The large global impact of NAFLD and T2DM on healthcare systems requires a paradigm shift from specialty care to early identification and risk stratification of NAFLD in primary care and diabetes clinics. Approach to diagnosis, risk stratification and management of NAFLD is discussed. In addition to optimizing the control of coexisting cardiometabolic comorbidities, early referral of NAFLD patients at high risk of having NASH or significant fibrosis to hepatology specialist care may improve management and allow access for clinical trials. Lifestyle modifications, vitamin E, pioglitazone and metformin are currently available options that may benefit patients with T2DM and NAFLD. The burst of clinical trials investigating newer therapeutic agents for NAFLD and NASH offer hope for new, effective and safe therapies in the near future.
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Affiliation(s)
- Gebran Khneizer
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Syed Rizvi
- A&M College of Medicine, Round Rock, Austin, TX, USA
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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21
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Cipponeri E, Vitturi N, Mariano V, Boscari F, Galasso S, Crepaldi C, Fadini GP, Vigili de Kreutzenberg S, Marescotti MC, Iori E, Cavallin F, Sartori L, Baritussio A, Avogaro A, Bruttomesso D. Vitamin D status and non-alcoholic fatty liver disease in patients with type 1 diabetes. J Endocrinol Invest 2019; 42:1099-1107. [PMID: 30847862 DOI: 10.1007/s40618-019-01031-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/27/2019] [Indexed: 12/22/2022]
Abstract
PURPOSE In patients with type 1 diabetes (T1D), the prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 10 to 53% and contrasting evidence suggests that vitamin D deficiency may favor liver fat accumulation. Here, we investigated the association between vitamin D status and NAFLD in adults with T1D. METHODS 220 consecutive adult T1D patients on multiple daily injections or continuous subcutaneous insulin infusion and not taking calcium or vitamin D supplements were included. Patient characteristics, 25(OH)D serum levels, and metabolic parameters were analyzed. Vitamin D status was defined as sufficiency ( ≥ 75 nmol/L; 30 ng/ml), insufficiency (50-75 nmol/L; 20-30 ng/ml), or deficiency ( < 50 nmol/L; 20 ng/ml). NAFLD was diagnosed at ultrasound examination and graded 0-3. RESULTS NAFLD was present in 57 patients (29.5%): 51 grade 1, 5 grade 2, and 1 grade 3. Median 25(OH)D levels were 53 nmol/L (IQR 38-70) in patients with NAFLD and 50 nmol/L (34-69) in patients without (p = 0.46). At multivariable analysis, NAFLD was not associated with 25(OH)D levels (p = 0.42) or vitamin D deficiency (p = 0.55), while BMI (OR 1.16, 95% CI 1.07-1.27) and serum triglycerides (OR 1.02, 95% CI 1.01-1.03) were independently associated with NAFLD. CONCLUSIONS Vitamin D status appears to have no link with low-grade NAFLD in patients with type 1 diabetes.
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Affiliation(s)
- E Cipponeri
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - N Vitturi
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - V Mariano
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - F Boscari
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - S Galasso
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - C Crepaldi
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - G P Fadini
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - S Vigili de Kreutzenberg
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - M C Marescotti
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - E Iori
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | | | - L Sartori
- Department of Medicine, Clinica Medica 1, University of Padova, Padova, Italy
| | - A Baritussio
- Department of Medicine, Clinica Medica 1, University of Padova, Padova, Italy
| | - A Avogaro
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - D Bruttomesso
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy.
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Wilechansky RM, Pedley A, Massaro JM, Hoffmann U, Benjamin EJ, Long MT. Relations of liver fat with prevalent and incident chronic kidney disease in the Framingham Heart Study: A secondary analysis. Liver Int 2019; 39:1535-1544. [PMID: 31033142 PMCID: PMC6675651 DOI: 10.1111/liv.14125] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/13/2019] [Accepted: 04/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Prior studies demonstrated an association between non-alcoholic fatty liver disease and chronic kidney disease (CKD), though data are conflicting. We examined the association between liver fat and prevalent and incident CKD in the Framingham Heart Study (FHS). METHODS We included FHS participants who underwent computed tomography (CT) from 2002 to 2005 (n = 1315). After excluding heavy alcohol use (n = 211) and missing covariates (n = 117), the final sample included 987 participants. For the incident CKD analysis, we excluded 73 participants with prevalent CKD. Liver fat was measured by the average liver attenuation on CT. Estimated glomerular filtration rate (eGFR) was obtained using the CKD Epidemiology Collaboration Creatinine-Cystatin C equation, and CKD was defined as eGFR < 60 ml/min/1.73 m2 . Microalbuminuria was defined by sex-specific urinary albumin-creatinine ratio cut-offs. Multivariable-adjusted regression models were performed to determine the association between liver fat and CKD. RESULTS The prevalence of hepatic steatosis and CKD were 19% and 14% respectively (55.9% women, mean age 60 ± 9 years). After adjusting for covariates, we observed no significant associations between liver fat and CKD, microalbuminuria or eGFR in cross-sectional analyses. We observed positive associations between liver fat, incident microalbuminuria and reduced eGFR in age- and sex-adjusted models; these relationships were not significant in multivariable-adjusted models. CONCLUSIONS In this community-based cohort study, we did not observe significant associations between liver fat and prevalent or incident CKD with a median follow-up time of 12.5 years. The association between NAFLD and CKD may be accounted for by shared risk factors; confirmatory studies are needed.
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Affiliation(s)
| | - Alison Pedley
- National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, MA
| | - Joseph M. Massaro
- Department of Mathematics and Statistics, Boston University, Boston, MA
| | - Udo Hoffmann
- Radiology Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Emelia J. Benjamin
- National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, MA,Evans Department of Medicine, Whitaker Cardiovascular Institute and Cardiology Section, Boston University School of Medicine, Boston, MA,Department of Epidemiology, Boston University School of Public Health, Boston, MA
| | - Michelle T. Long
- National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, MA,Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA
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Boyle M, Anstee QM. Nonalcoholic Fatty Liver Disease. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 4E 2019:523-546. [DOI: 10.1002/9781119211419.ch35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Vendhan R, Amutha A, Anjana RM, Unnikrishnan R, Mohan V. Clinical profile of nonalcoholic Fatty liver disease among young patients with type 1 diabetes mellitus seen at a diabetes speciality center in India. Endocr Pract 2019; 20:1249-57. [PMID: 25100370 DOI: 10.4158/ep14044.or] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To estimate the prevalence and clinical profile of nonalcoholic fatty liver disease (NAFLD) among young type 1 diabetes mellitus (T1DM) patients at a tertiary care diabetes center in India. METHODS Electronic medical records of T1DM patients (age at first diagnosis of T1DM ≤25 years) registered between January 1992 and May 2013 who had undergone ultrasonography and denied history of any alcohol intake (n = 736) were reviewed. NAFLD was diagnosed if there was any degree of fatty liver. Retinopathy was initially assessed by direct and indirect ophthalmoscopy and later by retinal photography. Nephropathy was diagnosed if urine protein excretion was >500 mg/day, and neuropathy was diagnosed if a patient's vibration perception threshold on biothesiometry was ≥20 V. RESULTS A total of 204/736 (27.7%) T1DM patients had NAFLD. Compared to T1DM subjects without NAFLD those with NAFLD had higher body mass index (BMI) (18.9 ± 4.2 vs. 20.2 ± 4.7 kg/m2, P<.001), waist circumference (67.9 ± 13.2 vs. 71.9 ± 13.3 cm, P<.05), systolic blood pressure (110 ± 15 vs. 116 ± 18 mm Hg, P<.001) and diastolic blood pressure (72 ± 9 vs. 74 ± 10 mm Hg, P<.05), while fasting blood glucose (201 ± 101 vs. 183 ± 101 mg/dL, P<.05) and alkaline phosphatase (419 [12.5] vs. 315 [15.8], P<.001) levels were lower in patients with T1DM with NAFLD. Multiple logistic regression analysis showed a significant association between NAFLD and retinopathy (odds ratio [OR]: 2.01, 95% confidence interval [CI]: 1.13-3.43; P = .017, after adjusting for sex, duration of diabetes, overweight/obesity, hypertension, fasting plasma glucose, nephropathy, and nephropathy (OR: 1.89, 95% CI: 1.02-3.50; P = .042), after adjusting for sex and fasting plasma glucose. CONCLUSIONS This study suggests that NAFLD is also seen among T1DM patients and that it has an independent and significant association with retinopathy and nephropathy.
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Affiliation(s)
- Ramanujam Vendhan
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Gopalapuram, Chennai, India
| | - Anandakumar Amutha
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Gopalapuram, Chennai, India
| | - Ranjit Mohan Anjana
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Gopalapuram, Chennai, India
| | - Ranjit Unnikrishnan
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Gopalapuram, Chennai, India
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Gopalapuram, Chennai, India
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Abstract
BACKGROUND/OBJECTIVES The relationship between nonalcoholic fatty liver disease (NAFLD) and albuminuria has been shown in many epidemiologic studies, although the results were inconsistent. This meta-analysis was conducted to summarize all available data and to estimate the risk of albuminuria among patients with NAFLD. METHODS Comprehensive literature review was conducted utilizing Medline and Embase database through January 2018 to identify studies that compared the risk of albuminuria among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS Nineteen studies (17 cross-sectional studies and two cohort studies) with 24 804 participants fulfilled the eligibility criteria and were included in this meta-analysis. The risk of albuminuria among patients with NAFLD was significantly higher than those without NAFLD with the pooled odds ratio (OR) of 1.67 [95% confidence interval (CI): 1.32-2.11]. Subgroup analysis demonstrated the significantly increased risk of albuminuria among patients with NAFLD without diabetes with pooled OR of 2.25 (95% CI: 1.65-3.06). However, we found no significant association between albuminuria and NAFLD among diabetic patients [pooled OR 1.28 (95% CI: 0.94-1.75)]. CONCLUSION A significantly increased risk of albuminuria among patients with NAFLD was observed in this meta-analysis. Physicians should pay more attention to the early detection and subsequent treatment of individuals with microalbuminuria especially in patients with NAFLD.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is an important cause of chronic hepatic disease and liver transplant in Western societies. The increasing prevalence is related to dietary changes and sedentarism and follows the increasing frequency of obesity and type 2 diabetes mellitus. Growing evidence of association of NAFLD with cardiovascular diseases (CVD), independent of cardiovascular risk factors, has prompted the clarification of whether the liver is mainly a key-effector or a target-organ of the metabolic disarrangements in the metabolic syndrome. The therapeutic strategies able to alter liver disease progression and, through this, reduce the cardiovascular risk have also been tested in the last 2 decades. This review focus on the possible interactions between hepatic disease, metabolic syndrome, and CVD, and on their implications for clinical practice.
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Affiliation(s)
- Elisabete Martins
- Department of Medicine, Faculty of Medicine.,Instituto de Investigação e Inovação em Saúde (i3s), University of Porto.,Department of Cardiology
| | - Ana Oliveira
- Department of Nuclear Medicine, São João Hospital Center, Porto, Portugal
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Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol 2018; 14:99-114. [PMID: 29286050 DOI: 10.1038/nrendo.2017.173] [Citation(s) in RCA: 293] [Impact Index Per Article: 41.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus are common diseases that often coexist and might act synergistically to increase the risk of hepatic and extra-hepatic clinical outcomes. NAFLD affects up to 70-80% of patients with type 2 diabetes mellitus and up to 30-40% of adults with type 1 diabetes mellitus. The coexistence of NAFLD and diabetes mellitus increases the risk of developing not only the more severe forms of NAFLD but also chronic vascular complications of diabetes mellitus. Indeed, substantial evidence links NAFLD with an increased risk of developing cardiovascular disease and other cardiac and arrhythmic complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus. NAFLD is also associated with an increased risk of developing microvascular diabetic complications, especially chronic kidney disease. This Review focuses on the strong association between NAFLD and the risk of chronic vascular complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus, thereby promoting an increased awareness of the extra-hepatic implications of this increasingly prevalent and burdensome liver disease. We also discuss the putative underlying mechanisms by which NAFLD contributes to vascular diseases, as well as the emerging role of changes in the gut microbiota (dysbiosis) in the pathogenesis of NAFLD and associated vascular diseases.
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Affiliation(s)
- Giovanni Targher
- Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani 1, 37126 Verona, Italy
| | - Amedeo Lonardo
- Azienda Ospedaliera Universitaria di Modena, Ospedale Civile Sant'Agostino Estense, Via Giardini 1355, 41126 Baggiovara, Modena, Italy
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, Institute of Developmental Sciences (IDS), MP887, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
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Saande CJ, Jones SK, Rowling MJ, Schalinske KL. Whole Egg Consumption Exerts a Nephroprotective Effect in an Acute Rodent Model of Type 1 Diabetes. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:866-870. [PMID: 29345464 DOI: 10.1021/acs.jafc.7b04774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Nephropathy is a well-characterized complication of type 1 diabetes (T1D), resulting in proteinuria and urinary loss of micronutrients. We previously found that a whole egg-based diet maintained vitamin D balance in type 2 diabetic rats despite excessive urinary losses due to nephropathy. The goal of this study was to investigate the impact of whole egg consumption in T1D rats. Sprague-Dawley rats were randomly assigned to T1D or nondiabetic control groups and fed a casein or whole egg-based diet for 32 days. On day 26, two-thirds of the rats received a streptozotocin injection to induce T1D. Whole egg consumption attenuated polyuria, proteinuria, and renal hypertrophy in T1D rats. These data suggest that dietary intervention with whole egg may offer renal protection in T1D.
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Affiliation(s)
- Cassondra J Saande
- Interdepartmental Graduate Program in Nutritional Sciences and Department of Food Science and Human Nutrition, Iowa State University , Ames, Iowa 50011, United States
| | - Samantha K Jones
- Interdepartmental Graduate Program in Nutritional Sciences and Department of Food Science and Human Nutrition, Iowa State University , Ames, Iowa 50011, United States
| | - Matthew J Rowling
- Interdepartmental Graduate Program in Nutritional Sciences and Department of Food Science and Human Nutrition, Iowa State University , Ames, Iowa 50011, United States
| | - Kevin L Schalinske
- Interdepartmental Graduate Program in Nutritional Sciences and Department of Food Science and Human Nutrition, Iowa State University , Ames, Iowa 50011, United States
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The utility of noninvasive scores in assessing the prevalence of nonalcoholic fatty liver disease and advanced fibrosis in type 1 diabetic patients. Hepatol Int 2018; 12:37-43. [PMID: 29318450 DOI: 10.1007/s12072-017-9840-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 12/25/2017] [Indexed: 12/18/2022]
Abstract
GOALS The aim of our study is to assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and advanced hepatic fibrosis in patients with type 1 diabetes (T1D) using simple noninvasive scores. BACKGROUND There is paucity of data on the prevalence of NAFLD in T1D. Moreover, T1D could be a risk factor for advanced disease in NAFLD patients. STUDY Using ICD-9 codes, all patients with the diagnosis of T1D were reviewed and a retrospective chart analysis was carried out on 23,314 patients between the ages of 18 and 80. To predict the prevalence of NAFLD, we calculated the hepatic steatosis index (HSI). To estimate the prevalence of advanced fibrosis, NAFLD fibrosis score (NFS), FIB-4 index, AST to platelet ratio index (APRI), and AST/ALT ratio were calculated. RESULTS Of the 4899 patients included in the analysis, 86.9% were Caucasian and 67% were above normal weight limit. NAFLD based on HSI > 36 was present in 71.3% of patients. Advanced fibrosis was present in 20.3% based on NFS > 0.676, 6.7% based on FIB-4 > 2.67, 2.1% based on APRI > 1.5, and 22.1% based on AST/ALT > 1.4%, indicating a high risk of developing cirrhosis and end-stage liver disease. CONCLUSION In this large cohort of patients with T1DM, we detected a high prevalence of hepatic steatosis and advanced fibrosis using noninvasive scores. These scores are easy and inexpensive tools to screen for NAFLD and advanced fibrosis, although the significant variability of the percentage of advanced fibrosis using these scores indicates the need for further validation in diabetic populations. CLINICAL TRIAL REGISTRATION NUMBER CCF-16-018.
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Serra-Planas E, Aguilera E, Castro L, Rodríguez R, Salinas I, Lucas A, Joaquín C, Puig R, Mauricio D, Puig-Domingo M. Low prevalence of non-alcoholic fatty liver disease in patients with type 1 diabetes is associated with decreased subclinical cardiovascular disease. J Diabetes 2017; 9:1065-1072. [PMID: 28220621 DOI: 10.1111/1753-0407.12539] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 01/10/2017] [Accepted: 02/16/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has been proposed as an independent cardiovascular risk factor. The present study evaluated the prevalence of NAFLD in a cohort of type 1 diabetic (T1D) patients and its potential relationship with subclinical cardiovascular disease (CVD). METHODS One hundred T1D patients (mean [±SD] age 39.4 ± 7.8 years, disease duration 21.7 ± 8.6 years) were included in the present cross-sectional study. All subjects underwent abdominal ultrasonography for detection of NAFLD, carotid ultrasonography to measure the carotid intima-media thickness (CIMT) and atheroma plaques, and cardiac tomography for evaluation of the coronary artery calcium score (CACS). RESULTS Of the study cohort, 12% had NAFLD and 23% had a CACS >0. The T1D subjects with NAFLD had a greater CIMT than those without NAFLD (0.65 ± 0.17 vs 0.55 ± 0.14 mm; P = 0.029), but there were no significant differences between the two groups with regard to CACS, glycemic control, or the presence of carotid plaques. Patients with high liver enzyme concentrations (>20 U/L) had a higher CIMT (0.60 ± 0.16 vs 0.54 ± 0.13; P = 0.04) and there was a higher proportion of altered CACS (17 [73.9%] vs 6 [26.1%]; P = 0.001) and detection of carotid plaques (10 [76.9%] vs 3 [23.1%]; P = 0.014) in this group. CONCLUSIONS A low prevalence of NAFLD was found in the T1D cohort that was associated globally with a low proportion of abnormal CVD imaging markers, although these imaging parameters were worse in subjects in whom NAFLD was detected.
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Affiliation(s)
- Enric Serra-Planas
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Eva Aguilera
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Department of Endocrinology and Nutrition, CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Spain
| | - Laura Castro
- Service of Radiology, Institute of Research and Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Raúl Rodríguez
- Service of Radiology, Institute of Research and Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Isabel Salinas
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Anna Lucas
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Department of Endocrinology and Nutrition, CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Spain
| | - Clara Joaquín
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Rocio Puig
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Dídac Mauricio
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Department of Endocrinology and Nutrition, CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Spain
| | - Manel Puig-Domingo
- Department of Endocrinology and Nutrition, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
- Department of Endocrinology and Nutrition, CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Spain
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Mantovani A, Rigolon R, Mingolla L, Pichiri I, Cavalieri V, Salvotelli L, Stoico V, Zoppini G, Bonora E, Targher G. Nonalcoholic fatty liver disease is associated with an increased prevalence of distal symmetric polyneuropathy in adult patients with type 1 diabetes. J Diabetes Complications 2017; 31:1021-1026. [PMID: 28254449 DOI: 10.1016/j.jdiacomp.2017.01.024] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 12/27/2016] [Accepted: 01/31/2017] [Indexed: 02/06/2023]
Abstract
AIMS Presently, data on the association between nonalcoholic fatty liver disease (NAFLD) and distal symmetric polyneuropathy in people with diabetes are scarce and conflicting. The aim of this retrospective, cross-sectional study was to examine whether NAFLD was associated with an increased prevalence of distal symmetric polyneuropathy in type 1 diabetic adults. METHODS We studied all white type 1 diabetic outpatients (n = 286, 42.3% male, mean age 43 ± 14 years, median diabetes duration 17 [10-30] years), who participated in a foot screening program at our adult diabetes clinic after excluding those who had excessive alcohol consumption and other known causes of chronic liver disease. NAFLD was diagnosed by ultrasonography. Distal symmetric polyneuropathy was detected using the Michigan Neuropathy Screening Instrument method and the biothesiometer Vibrotest. RESULTS Overall, the prevalence rates of NAFLD and distal symmetric polyneuropathy were 52.4% and 35.3%, respectively. Patients with NAFLD had a substantially increased prevalence of distal symmetric polyneuropathy compared to their counterparts without NAFLD (51.0% vs. 17.1%, p < 0.001). In univariate analysis, NAFLD was associated with an approximately 5-fold increased risk of prevalent distal symmetric polyneuropathy (odds ratio [OR] 5.32, 95% confidence interval [CI] 3.1-9.3, p < 0.001). This association remained significant even after adjustment for age, sex, diabetes duration, hemoglobin A1c, diabetic retinopathy, smoking, metabolic syndrome, chronic kidney disease and carotid artery stenoses ≥ 40% (adjusted-OR 2.23, 95% CI 1.1-4.8, p < 0.05). CONCLUSIONS Our results show that NAFLD, diagnosed by ultrasonography, is strongly associated with an increased risk of distal symmetric polyneuropathy in type 1 diabetic adults, independently of several cardio-metabolic risk factors.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy.
| | - Riccardo Rigolon
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Lucia Mingolla
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Isabella Pichiri
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Valentina Cavalieri
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Laura Salvotelli
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Vincenzo Stoico
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Giacomo Zoppini
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Enzo Bonora
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
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Zeng J, Sun C, Sun WL, Chen GY, Pan Q, Yan SY, Xu ZJ, Chen YW, Fan JG. Association between non-invasively diagnosed hepatic steatosis and chronic kidney disease in Chinese adults on their health check-up. J Dig Dis 2017; 18:229-236. [PMID: 28296249 DOI: 10.1111/1751-2980.12465] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 02/21/2017] [Accepted: 03/06/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To explore the association between chronic kidney disease (CKD), graded by the estimated glomerular filtration rate (eGFR), and non-alcoholic fatty liver disease (NAFLD) using controlled attenuation parameter (CAP) and fatty liver index (FLI) values in Chinese adults undergoing routine health examinations. METHODS A total of 731 adult participants without diabetes mellitus or significant alcohol consumption who underwent routine health examinations were included. Their eGFR, CAP, FLI and abdominal ultrasonography results were assessed. RESULTS The prevalence of ultrasound-diagnosed NAFLD and CKD (eGFR <60 mL/min per 1.73 m2 ) was 36.1% and 6.6%, respectively. CKD was more common in NAFLD patients than in those without (10.6% vs 4.3%, P < 0.001). The CAP and FLI values were significantly higher in the NAFLD group than in those without, but the change in the eGFR was negligible between the two groups. eGFR was negatively correlated with CAP (r = -0.189, P = 0.003) and FLI values (r = -0.130, P = 0.045). Moreover, eGFR was significantly lower in participants with CAP >292 dBm or FLI ≥60 than in those with CAP <238 dBm or FLI <30, respectively (both P < 0.05). The CAP value (odds ratio [OR] 1.099, 95% confidence interval [CI] 1.091-1.108, P = 0.021) was an independent risk factor for CKD. CONCLUSIONS A diagnosis of hepatic steatosis is related to an increased risk of CKD among non-alcoholic and non-diabetic Chinese adults regardless of whether the diagnosis was acquired via ultrasound, CAP or FLI. Increased hepatic lipid content may contribute to CKD development.
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Affiliation(s)
- Jing Zeng
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chao Sun
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wan Lu Sun
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guang Yu Chen
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qin Pan
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shi Yan Yan
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zheng Jie Xu
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuan Wen Chen
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jian Gao Fan
- Department of Gastroenterology, Center for Fatty Liver, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Elkabbany ZA, Elbarbary NS, Ismail EA, Mohamed NA, Ragab D, Abdel Alem S, Ezzat YM, Maurice SS, Hashem NU. Transient elastography as a noninvasive assessment tool for hepatopathies of different etiology in pediatric type 1 diabetes mellitus. J Diabetes Complications 2017; 31:186-194. [PMID: 27742550 DOI: 10.1016/j.jdiacomp.2016.09.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 09/17/2016] [Accepted: 09/21/2016] [Indexed: 02/08/2023]
Abstract
AIM To identify the prevalence and effect of hepatopathies of different etiologies among pediatric patients with type 1 diabetes mellitus (T1DM) using transient elastography (TE) and its relation to glycemic control. METHODS One hundred T1DM patients were studied focusing on liver functions, fasting lipid profile, hemoglobin A1c (HbA1c), hepatitis C virus (HCV), serum immunoglobulins, autoimmune antibodies; anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and anti-liver kidney microsomal antibody (anti-LKM). Abdominal ultrasound was performed and TE was done for patients with HCV, positive autoimmune antibody and/or abnormal ultrasound findings. RESULTS Thirty-one patients were found to have one or more hepatic abnormalities; clinical hepatomegaly in 8%, elevated alanine aminotransferase (ALT) in 10%, HCV in 6%, autoimmune hepatitis (AIH) in 11% (10 were positive for ASMA and 2 were positive for ANA while anti-LKM antibodies were negative) and abnormal hepatic ultrasound in 20% (12 non-alcoholic fatty liver disease, 5 AIH, 2 HCV, 1 Mauriac syndrome). Mean liver stiffness in those 31 patients was 7.0±2.1kPa (range, 3.1-11.8kPa); 24 were Metavir F0-F1, 7 were F2-F3 while none was F4. Type 1 diabetic patients with abnormal hepatic ultrasound had higher fasting blood glucose, HbA1c and total cholesterol than those with normal findings. Liver stiffness was significantly higher in patients with abnormal liver ultrasound compared with normal sonography. Liver stiffness was positively correlated to HbA1c and ALT. CONCLUSIONS Hepatic abnormalities are prevalent in T1DM and related to poor metabolic control. TE provides a non-invasive method for detection of hepatopathy-induced fibrosis.
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Affiliation(s)
- Zeinab A Elkabbany
- Department of Pediatrics, Faculty of medicine, Ain shams University, Cairo, Egypt
| | - Nancy S Elbarbary
- Department of Pediatrics, Faculty of medicine, Ain shams University, Cairo, Egypt.
| | - Eman A Ismail
- Department of Clinical Pathology, Faculty of medicine, Ain shams University, Cairo, Egypt
| | - Nesrine A Mohamed
- Department of Clinical Pathology, Faculty of medicine, Ain shams University, Cairo, Egypt
| | - Dina Ragab
- Department of Clinical Pathology, Faculty of medicine, Ain shams University, Cairo, Egypt
| | - Shereen Abdel Alem
- Department of Endemic medicine and Hepatology, Faculty of medicine, Cairo University, Cairo, Egypt
| | - Yasmine M Ezzat
- Department of Pediatrics, Faculty of medicine, Ain shams University, Cairo, Egypt
| | - Sarah S Maurice
- Department of Pediatrics, Faculty of medicine, Ain shams University, Cairo, Egypt
| | - Noha U Hashem
- Department of Pediatrics, Faculty of medicine, Ain shams University, Cairo, Egypt
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Silvares RR, Pereira ENGDS, Flores EEI, Estato V, Reis PA, Silva IJD, Machado MP, Neto HCDCF, Tibiriça E, Daliry A. Combined therapy with metformin and insulin attenuates systemic and hepatic alterations in a model of high-fat diet-/streptozotocin-induced diabetes. Int J Exp Pathol 2016; 97:266-77. [PMID: 27381700 DOI: 10.1111/iep.12184] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 03/16/2016] [Indexed: 12/22/2022] Open
Abstract
In this study we have explored the pathogenesis of the hepatic alterations which occur in diabetes and the modulation of these complications by the combination of metformin adjunct treatment and insulin monotherapy. For this purpose, diabetic rats were treated with insulin (DM + Ins) or metformin plus insulin (DM + Met + Ins). Biochemical and cardiometabolic parameters were analysed by spectrophotometry. Intravital microscopy was used to study the hepatic microcirculation. In the liver tissue, real-time PCR was used to analyse oxidative stress enzymes, inflammatory markers and receptors for advanced glycation end products (AGE) (RAGE) gene expression. Lipid peroxidation was assessed by thiobarbituric acid reactive species (TBARs) analyses. AGE deposition and RAGE protein expression were studied by fluorescence spectrophotometry and Western blot respectively. Body weight, %HbA1c , urea, total proteins and oxidative stress parameters were found to be similarly improved by insulin or Met + Ins treatments. On the other hand, Met + Ins treatment showed a more pronounced effect on fasting blood glucose level than insulin monotherapy. Fructosamine, uric acid, creatinine, albumin and amylase levels and daily insulin dose requirements were found to be only improved by the combined Met + Ins treatment. Liver, renal and pancreatic dysfunction markers were found to be more positively affected by metformin adjunct therapy when compared to insulin treatment. Liver microcirculation damage was found to be completely protected by Met + Ins treatment, while insulin monotherapy showed no effect. Our results suggest that oxidative stress, microcirculatory damage and glycated proteins could be involved in the aetiology of liver disease due to diabetes. Additionally, metformin adjunct treatment improved systemic and liver injury in induced diabetes and showed a more pronounced effect than insulin monotherapy.
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Affiliation(s)
- Raquel Rangel Silvares
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | | | - Edgar Eduardo Ilaquita Flores
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Vanessa Estato
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Patrícia Alves Reis
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Igor José da Silva
- Laboratório de Patologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Marcelo Pelajo Machado
- Laboratório de Patologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | | | - Eduardo Tibiriça
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
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Nonalcoholic Fatty Liver Disease is Associated with Increased Carotid Intima-Media Thickness in Type 1 Diabetic Patients. Sci Rep 2016; 6:26805. [PMID: 27226159 PMCID: PMC4880892 DOI: 10.1038/srep26805] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 05/09/2016] [Indexed: 01/04/2023] Open
Abstract
A growing body of evidence suggests that NAFLD is associated with an increased risk of incident CVD events both in patients without diabetes and in those with type 2 diabetes (T2DM). However, no published data are available regarding the association between NAFLD and C-IMT in T1DM. A total of 722 patients (371 men) with T1DM were included in this cross-sectional study. The main outcome measures were detection of NAFLD, C-IMT and classical risk factors. The mean age of the subjects was 46.2 years, and 51.1% were male. The prevalence of NAFLD was 15.9%. NAFLD patients had a markedly greater C-IMT (0.81 ± 0.25 vs. 0.69 ± 0.18 mm; p < 0.001) and frequency of carotid plaque (28.9% vs. 16.9%; p < 0.05) than those without fatty liver. Moreover, the differences in C-IMT remained after adjusting for potential confounders. A stepwise linear regression analysis revealed that age (standardized β, 0.326; p < 0.001), NAFLD (standardized β, 0.151, p < 0.001), and hsCRP (standardized β, 0.115, p = 0.008) were independently associated with C-IMT in all subjects. Our data show NAFLD is associated with elevated C-IMT in T1DM independent of conventional cardiovascular disease risk factors.
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Marcuccilli M, Chonchol M. NAFLD and Chronic Kidney Disease. Int J Mol Sci 2016; 17:562. [PMID: 27089331 PMCID: PMC4849018 DOI: 10.3390/ijms17040562] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 03/25/2016] [Accepted: 03/28/2016] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries and it is now considered a risk factor for cardiovascular disease. Evidence linking NAFLD to the development and progression of chronic kidney disease (CKD) is emerging as a popular area of scientific interest. The rise in simultaneous liver-kidney transplantation as well as the significant cost associated with the presence of chronic kidney disease in the NAFLD population make this entity a worthwhile target for screening and therapeutic intervention. While several cross-sectional and case control studies have been published to substantiate these theories, very little data exists on the underlying cause of NAFLD and CKD. In this review, we will discuss the most recent publications on the diagnosis of NAFLD as well new evidence regarding the pathophysiology of NAFLD and CKD as an inflammatory disorder. These mechanisms include the role of obesity, the renin-angiotensin system, and dysregulation of fructose metabolism and lipogenesis in the development of both disorders. Further investigation of these pathways may lead to novel therapies that aim to target the NAFLD and CKD. However, more prospective studies that include information on both renal and liver histology will be necessary in order to understand the relationship between these diseases.
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Affiliation(s)
- Morgan Marcuccilli
- Division of Renal Diseases and Hypertension, University of Colorado Hospital, Aurora, CO 80045, USA.
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado Denver, 13199 East Montview Boulevard, Suite 495, Aurora, CO 80045, USA.
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Munukutla S, Pan G, Deshpande M, Thandavarayan RA, Krishnamurthy P, Palaniyandi SS. Alcohol Toxicity in Diabetes and Its Complications: A Double Trouble? Alcohol Clin Exp Res 2016; 40:686-97. [PMID: 27013182 DOI: 10.1111/acer.13008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 01/11/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND Eight percent of the U.S. population has been diagnosed with diabetes mellitus (DM), while another large percentage has gone undiagnosed. As the epidemiology of this disease constitutes a larger percentage of the American population, another factor presents a dangerous dilemma that can exacerbate the hazardous effects imposed by DM. Excessive alcohol consumption concerns the health of more than 50% of all adults. When this heavy-alcohol-drinking population overlaps with DM and its complications, the effects can be dangerous. In this review, we term it as "double trouble." METHODS We provide evidence of alcohol-induced exacerbation of organ damage in diabetic conditions. In certain cases, we have explained how diabetes and alcohol induce similar pathological effects. RESULTS Known exacerbated complications include those related to heart diseases, liver damage, kidney dysfunction, as well as retinal and neurological impairment. Often, pathophysiological damage concludes with end-stage disorders and even mortality. The metabolic, cell signaling, and pathophysiological changes associated with "double trouble" would lead to the identification of novel therapeutic targets. CONCLUSIONS This review summarizes the epidemiology, diagnosis, pathophysiology, metabolic, and cell signaling alterations and finally brushes upon issues and strategies to manage the "double trouble."
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Affiliation(s)
- Srikar Munukutla
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan
| | - Guodong Pan
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan
| | - Mandar Deshpande
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan
| | - Rajarajan A Thandavarayan
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas
| | - Prasanna Krishnamurthy
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas
| | - Suresh S Palaniyandi
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan.,Department of Physiology, Wayne State University, Detroit, Michigan
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Petit JM, Pedro L, Guiu B, Duvillard L, Bouillet B, Jooste V, Habchi M, Crevisy E, Fourmont C, Buffier P, Hillon P, Cercueil JP, Verges B. Type 1 diabetes is not associated with an increased prevalence of hepatic steatosis. Diabet Med 2015; 32:1648-51. [PMID: 25981893 DOI: 10.1111/dme.12805] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2015] [Indexed: 02/06/2023]
Abstract
AIM Non-alcoholic fatty liver disease (NAFLD) is commonly associated with Type 2 diabetes. Recently, it has been suggested that NAFLD is also frequently associated with Type 1 diabetes and diabetic complications. In this study, we set out to determine whether Type 1 diabetes was associated with liver fat content measured using magnetic resonance imaging. METHODS One hundred and twenty-eight patients with Type 1 diabetes, 264 patients with Type 2 diabetes and 67 participants without diabetes were included in this study. Hepatic steatosis was defined as a liver fat content > 5.5%. RESULTS People with Type 1 diabetes and controls were similar for age and BMI. Liver fat content was significantly higher in patients with Type 2 diabetes than in patients with Type 1 diabetes and controls. In the control group, nine people (13.4%) had steatosis compared with six (4.7%) patients with Type 1 diabetes (P = 0.04). Among patients with Type 2 diabetes group, 166 (62.8%) had steatosis. In multivariate analysis that included patients with Type 1 diabetes and participants without diabetes, steatosis was associated only with BMI, whereas age, sex, statin therapy and Type 1 diabetes were not. In patients with Type 1 diabetes, there was no correlation between liver fat content and estimated glomerular filtration rate or carotid intima media thickness. CONCLUSIONS Our data showed that Type 1 diabetes was not associated with an increased prevalence of steatosis. Moreover, our study provided no specific arguments concerning a link between liver fat content and diabetic complications in patients with Type 1 diabetes.
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Affiliation(s)
- J-M Petit
- Centre de Recherche INSERM Unité 866
- Services de diabétologie et endocrinologie
| | - L Pedro
- Services de diabétologie et endocrinologie
| | - B Guiu
- Centre de Recherche INSERM Unité 866
- Services de radiologie, Université de Bourgogne, Dijon, France
| | | | - B Bouillet
- Centre de Recherche INSERM Unité 866
- Services de diabétologie et endocrinologie
| | - V Jooste
- Centre de Recherche INSERM Unité 866
| | - M Habchi
- Services de diabétologie et endocrinologie
| | - E Crevisy
- Services de diabétologie et endocrinologie
| | - C Fourmont
- Services de diabétologie et endocrinologie
| | - P Buffier
- Services de diabétologie et endocrinologie
| | - P Hillon
- Centre de Recherche INSERM Unité 866
| | - J-P Cercueil
- Centre de Recherche INSERM Unité 866
- Services de radiologie, Université de Bourgogne, Dijon, France
| | - B Verges
- Centre de Recherche INSERM Unité 866
- Services de diabétologie et endocrinologie
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Regnell SE, Peterson P, Trinh L, Broberg P, Leander P, Lernmark Å, Månsson S, Elding Larsson H. Magnetic resonance imaging reveals altered distribution of hepatic fat in children with type 1 diabetes compared to controls. Metabolism 2015; 64:872-8. [PMID: 25982699 DOI: 10.1016/j.metabol.2015.04.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 04/06/2015] [Accepted: 04/07/2015] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Children with type 1 diabetes have been identified as a risk group for non-alcoholic fatty liver disease (NAFLD). The aim was to compare total hepatic fat fraction and fat distribution across Couinaud segments in children with type 1 diabetes and controls and the relation of hepatic fat to plasma and anthropometric parameters. METHODS Hepatic fat fraction and fat distribution across Couinaud segments were measured with magnetic resonance imaging (MRI) in 22 children with type 1 diabetes and 32 controls. Blood tests and anthropometric data were collected. RESULTS No children had NAFLD. Children with type 1 diabetes had a slightly lower hepatic fat fraction (median 1.3%) than controls (median 1.8%), and their fat had a different segmental distribution. The fat fraction of segment V was the most representative of the liver as a whole. An incidental finding was that diabetes patients treated with multiple daily injections of insulin (MDI) had a fat distribution more similar to controls than patients with continuous subcutaneous insulin infusion (CSII). CONCLUSIONS In children with type 1 diabetes, NAFLD may be less common than recent studies have suggested. Children with type 1 diabetes may have a lower fat fraction and a different fat distribution in the liver than controls. Diabetes treatment with MDI or CSII may affect liver fat, but this needs to be confirmed in a larger sample of patients. The heterogeneity of hepatic fat infiltration may affect results when liver biopsy is used for diagnosing fatty liver.
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Affiliation(s)
- Simon E Regnell
- Paediatric Endocrinology, Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University/Clinical Research Centre and Skåne University Hospital, Malmö, Sweden.
| | - Pernilla Peterson
- Medical Radiation Physics, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Lena Trinh
- Medical Radiation Physics, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Per Broberg
- Department of Oncology and Pathology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
| | - Peter Leander
- Department of Radiology, Department of Clinical Sciences, Lund University and Skåne University Hospital, Malmö, Sweden
| | - Åke Lernmark
- Paediatric Endocrinology, Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University/Clinical Research Centre and Skåne University Hospital, Malmö, Sweden
| | - Sven Månsson
- Medical Radiation Physics, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Helena Elding Larsson
- Paediatric Endocrinology, Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University/Clinical Research Centre and Skåne University Hospital, Malmö, Sweden
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Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015; 62:S47-64. [PMID: 25920090 DOI: 10.1016/j.jhep.2014.12.012] [Citation(s) in RCA: 2105] [Impact Index Per Article: 210.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/06/2014] [Accepted: 12/09/2014] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that is predicted to become also the most frequent indication for liver transplantation by 2030. Over the last decade, it has been shown that the clinical burden of NAFLD is not only confined to liver-related morbidity and mortality, but there is now growing evidence that NAFLD is a multisystem disease, affecting extra-hepatic organs and regulatory pathways. For example, NAFLD increases risk of type 2 diabetes mellitus (T2DM), cardiovascular (CVD) and cardiac diseases, and chronic kidney disease (CKD). Although the primary liver pathology in NAFLD affects hepatic structure and function to cause morbidity and mortality from cirrhosis, liver failure and hepatocellular carcinoma, the majority of deaths among NAFLD patients are attributable to CVD. This narrative review focuses on the rapidly expanding body of clinical evidence that supports the concept of NAFLD as a multisystem disease. The review discusses the factors involved in the progression of liver disease in NAFLD and the factors linking NAFLD with other extra-hepatic chronic diseases, such as T2DM, CVD, cardiac diseases and CKD. The review will not discuss NAFLD treatments as these are discussed elsewhere in this issue of the Journal. For this review, PubMed was searched for articles using the keywords "non-alcoholic fatty liver disease" or "fatty liver" combined with "diabetes", "cardiovascular (or cardiac) disease", "cardiovascular mortality" or "chronic kidney disease" between 1990 and 2014. Articles published in languages other than English were excluded.
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Affiliation(s)
- Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK; Southampton National Institute for Health Research, Biomedical Research Centre, University Hospital Southampton, UK.
| | - Giovanni Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Bang KB, Cho YK. Comorbidities and Metabolic Derangement of NAFLD. J Lifestyle Med 2015; 5:7-13. [PMID: 26528424 PMCID: PMC4608226 DOI: 10.15280/jlm.2015.5.1.7] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 02/23/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease worldwide and is becoming a major public health problem. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. Growing evidence supports that NAFLD is associated with systemic diseases such as cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes, obesity, and metabolic syndrome. The majority of deaths in patients with NAFLD come from cardiovascular disease. These findings are strongly attributed to nonalcoholic steatohepatitis (NASH) rather than simple steatosis. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic disease. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. Further investigation is needed for future therapeutic strategies for NAFLD. This review focuses on the relationship between NAFLD and various comorbid diseases and metabolic derangement.
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Affiliation(s)
- Ki Bae Bang
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Shah RV, Allison MA, Lima JAC, Abbasi SA, Mongraw-Chaffin M, Jerosch-Herold M, Ding J, Budoff MJ, Murthy VL. Liver steatosis and the risk of albuminuria: the multi-ethnic study of atherosclerosis. J Nephrol 2015; 28:577-84. [PMID: 25712234 DOI: 10.1007/s40620-015-0177-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 01/30/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To measure association between hepatic fat and albuminuria (an early marker of renal injury) in individuals without diabetes or hypertension. METHODS 2,281 individuals in the Multi-Ethnic Study of Atherosclerosis without diabetes or hypertension, renal disease, or excess alcohol consumption underwent computed tomography (CT) for assessment of liver attenuation (marker of hepatic lipid content) and urinalysis (for albuminuria) at initial study visit, with assessment of incident and prevalent albuminuria by logistic regression in follow-up. RESULTS After adjustment for age, gender, race, smoking, blood pressure, insulin resistance, and body mass index, individuals with less liver fat (higher liver CT attenuation) had a lower probability of having albuminuria at Exam 1 (OR per 10 unit increase in attenuation 0.77, 95 % CI 0.61-0.97, P = 0.02). At median 9.3 years follow-up, albuminuria was identified in 129 individuals were (5.8 %). In fully adjusted models (with age, smoking, body mass index, blood pressure, diabetes and hypertension as time-dependent covariates), lower liver attenuation (greater liver fat) was associated with higher risk of incident albuminuria (OR 0.79, 95 % CI 0.66-0.94, P = 0.008). CONCLUSIONS Hepatic attenuation is associated with prevalent and incident albuminuria, an early, potent risk factor for renal risk in a population not clearly at risk for future renal failure.
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Affiliation(s)
- Ravi V Shah
- Department of Cardiology and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Suite 454-East, Boston, MA, 02215, USA.
| | - Matthew A Allison
- Department of Family and Preventative Medicine, University of California-San Diego, San Diego, CA, USA
| | - Joao A C Lima
- Cardiology Division, Johns Hopkins Medical Institute, Baltimore, MD, USA
| | - Siddique A Abbasi
- Department of Cardiology and Medicine, Brown University, Providence, RI, USA
| | - Morgana Mongraw-Chaffin
- Department of Family and Preventative Medicine, University of California-San Diego, San Diego, CA, USA
| | | | - Jingzhong Ding
- Department of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Matthew J Budoff
- Department of Cardiology and Medicine, University of California-Los Angeles, Los Angeles, CA, USA
| | - Venkatesh L Murthy
- Cardiovascular Medicine Division, Department of Medicine, Nuclear Medicine and Cardiothoracic Imaging Divisions, Department of Radiology, University of Michigan, 1338 Cardiovascular Center, Ann Arbor, MI, USA.
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Pallayova M, Taheri S. Non-alcoholic fatty liver disease in obese adults: clinical aspects and current management strategies. Clin Obes 2014; 4:243-53. [PMID: 25825857 DOI: 10.1111/cob.12068] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 05/15/2014] [Accepted: 05/28/2014] [Indexed: 12/18/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder whose prevalence is strongly linked to the current epidemic of obesity in many western countries. The prevalence of NAFLD is two to four times higher in populations with pre-existing metabolic comorbidities than in the general population. The diagnosis of primary NAFLD involves establishing the presence of hepatic steatosis or steatohepatitis by imaging or histology, along with establishing the non-alcoholic nature of the disease process and excluding competing aetiologies for hepatic steatosis. Among the indirect serum biomarkers, the NAFLD fibrosis score can help to identify patients with NAFLD and with higher likelihood of having fibrosis or cirrhosis. A liver biopsy should be considered in NAFLD patients at increased risk for steatohepatitis/advanced fibrosis and in cases where a liver biopsy is necessary to exclude co-existing chronic liver diseases and other aetiologies for hepatic steatosis. The treatment and management recommendations for obesity-associated NAFLD are aimed towards weight reduction. The currently available interventions employed to promote weight loss and improve the metabolic responses in NAFLD include lifestyle modification, pharmacotherapy and bariatric surgery.
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Affiliation(s)
- M Pallayova
- Faculty of Medicine, PJ Safarik University, Kosice, Slovak Republic
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Li Y, Zhu S, Li B, Shao X, Liu X, Liu A, Wu B, Zhang Y, Wang H, Wang X, Deng K, Liu Q, Huang M, Liu H, Holthöfer H, Zou H. Association between non-alcoholic fatty liver disease and chronic kidney disease in population with prediabetes or diabetes. Int Urol Nephrol 2014; 46:1785-91. [DOI: 10.1007/s11255-014-0796-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 07/21/2014] [Indexed: 02/06/2023]
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Targher G, Chonchol MB, Byrne CD. CKD and nonalcoholic fatty liver disease. Am J Kidney Dis 2014; 64:638-52. [PMID: 25085644 DOI: 10.1053/j.ajkd.2014.05.019] [Citation(s) in RCA: 160] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 05/30/2014] [Indexed: 02/06/2023]
Abstract
The possible link between nonalcoholic fatty liver disease and chronic kidney disease (CKD) recently has attracted considerable scientific interest. Accumulating clinical evidence indicates that the presence and severity of nonalcoholic fatty liver disease is associated significantly with CKD (defined as decreased estimated glomerular filtration rate and/or proteinuria) and that nonalcoholic fatty liver disease predicts the development and progression of CKD, independently of traditional cardiorenal risk factors. Experimental evidence also suggests that nonalcoholic fatty liver disease itself may exacerbate systemic and hepatic insulin resistance, cause atherogenic dyslipidemia, and release a variety of proinflammatory, procoagulant, pro-oxidant, and profibrogenic mediators that play important roles in the development and progression of CKD. However, despite the growing evidence linking nonalcoholic fatty liver disease with CKD, it has not been definitively established whether a causal association exists. The clinical implication for these findings is that patients with nonalcoholic fatty liver disease may benefit from more intensive surveillance or early treatment interventions to decrease the risk of CKD. In this review, we discuss the evidence linking nonalcoholic fatty liver disease with CKD and the putative mechanisms by which nonalcoholic fatty liver disease contributes to kidney damage. We also briefly discuss current treatment options for this increasingly prevalent disease that is likely to have an important future impact on the global burden of disease.
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Affiliation(s)
- Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
| | - Michel B Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Southampton National Institute for Health Research Biomedical Research Centre, Southampton, United Kingdom
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Musso G, Gambino R, Tabibian JH, Ekstedt M, Kechagias S, Hamaguchi M, Hultcrantz R, Hagström H, Yoon SK, Charatcharoenwitthaya P, George J, Barrera F, Hafliðadóttir S, Björnsson ES, Armstrong MJ, Hopkins LJ, Gao X, Francque S, Verrijken A, Yilmaz Y, Lindor KD, Charlton M, Haring R, Lerch MM, Rettig R, Völzke H, Ryu S, Li G, Wong LL, Machado M, Cortez-Pinto H, Yasui K, Cassader M. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014; 11:e1001680. [PMID: 25050550 PMCID: PMC4106719 DOI: 10.1371/journal.pmed.1001680] [Citation(s) in RCA: 516] [Impact Index Per Article: 46.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 06/12/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD. METHODS AND FINDINGS English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies. CONCLUSION The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.
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Affiliation(s)
| | - Roberto Gambino
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - James H. Tabibian
- Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota, United States of America
| | - Mattias Ekstedt
- Division of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden
| | - Stergios Kechagias
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Masahide Hamaguchi
- Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Rolf Hultcrantz
- Departments of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Hagström
- Departments of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Seung Kew Yoon
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kangnam St. Mary Hospital, Catholic University Medical College, Seoul, Korea
| | | | - Jacob George
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, New South Wales, Australia
| | - Francisco Barrera
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, New South Wales, Australia
| | - Svanhildur Hafliðadóttir
- Dept of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbrau, Reykjavik, Iceland
| | - Einar Stefan Björnsson
- Dept of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbrau, Reykjavik, Iceland
| | - Matthew J. Armstrong
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Laurence J. Hopkins
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - An Verrijken
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Yusuf Yilmaz
- Department of Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey
| | - Keith D. Lindor
- Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota, United States of America
| | - Michael Charlton
- Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota, United States of America
| | - Robin Haring
- Institute of Clinical Chemistry and Laboratory Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Rainer Rettig
- Institute of Physiology, Ernst-Moritz-Arndt-University Medicine Greifswald, Karlsburg, Germany
| | - Henry Völzke
- Institute for Community Medicine, Ernst-Moritz-Arndt University Medicine Greifswald, Greifswald, Germany
| | - Seungho Ryu
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea
| | - Guolin Li
- College of Life Sciences, Hunan Normal University, Changsha, China
| | - Linda L. Wong
- John A. Burns School of Medicine at University of Hawaii, Transplant Institute, Hawaii Medical Center, Honolulu, Hawaii, United States of America
| | - Mariana Machado
- Department of Gastroenterology, University Hospital of Santa Maria, Institute of Molecular Medicine, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Department of Gastroenterology, University Hospital of Santa Maria, Institute of Molecular Medicine, Lisbon, Portugal
| | - Kohichiroh Yasui
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Japan
| | - Maurizio Cassader
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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Targher G, Mantovani A, Pichiri I, Mingolla L, Cavalieri V, Mantovani W, Pancheri S, Trombetta M, Zoppini G, Chonchol M, Byrne CD, Bonora E. Nonalcoholic fatty liver disease is independently associated with an increased incidence of chronic kidney disease in patients with type 1 diabetes. Diabetes Care 2014; 37:1729-36. [PMID: 24696459 DOI: 10.2337/dc13-2704] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE There is no information about the role of nonalcoholic fatty liver disease (NAFLD) in predicting the development of chronic kidney disease (CKD) in type 1 diabetes. RESEARCH DESIGN AND METHODS We studied 261 type 1 diabetic adults with preserved kidney function and with no macroalbuminuria at baseline, who were followed for a mean period of 5.2 years for the occurrence of incident CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 and/or macroalbuminuria). NAFLD was diagnosed by ultrasonography. RESULTS At baseline, patients had a mean eGFR of 92 ± 23 mL/min/1.73 m2; 234 (89.7%) of them had normoalbuminuria and 27 (10.3%) microalbuminuria. NAFLD was present in 131 (50.2%) patients. During follow-up, 61 subjects developed incident CKD. NAFLD was associated with an increased risk of incident CKD (hazard ratio [HR] 2.85 [95% CI 1.59-5.10]; P < 0.001). Adjustments for age, sex, duration of diabetes, hypertension, A1C, and baseline eGFR did not appreciably attenuate this association (adjusted HR 2.03 [1.10-3.77], P < 0.01). Results remained unchanged after excluding those who had microalbuminuria at baseline (adjusted HR 1.85 [1.03-3.27]; P < 0.05). Addition of NAFLD to traditional risk factors for CKD significantly improved the discriminatory capability of the regression models for predicting CKD (e.g., with NAFLD c statistic 0.79 [95% CI 0.73-0.86] vs. 0.76 [0.71-0.84] without NAFLD, P = 0.002). CONCLUSIONS This is the first study to demonstrate that NAFLD is strongly associated with an increased incidence of CKD. Measurement of NAFLD improves risk prediction for CKD, independently of traditional cardio-renal risk factors, in patients with type 1 diabetes.
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Affiliation(s)
- Giovanni Targher
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Isabella Pichiri
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Lucia Mingolla
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Valentina Cavalieri
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - William Mantovani
- Department of Public Health and Community Medicine, University of Verona, Verona, ItalyDepartment of Prevention, Public Health Trust, Trento, Italy
| | - Serena Pancheri
- Department of Public Health and Community Medicine, University of Verona, Verona, ItalyDepartment of Prevention, Public Health Trust, Trento, Italy
| | - Maddalena Trombetta
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Giacomo Zoppini
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, U.K
| | - Enzo Bonora
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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The Wide and Complex Field of NAFLD Biomarker Research: Trends. ISRN HEPATOLOGY 2014; 2014:846923. [PMID: 27335843 PMCID: PMC4890912 DOI: 10.1155/2014/846923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 02/19/2014] [Indexed: 12/18/2022]
Abstract
Background. Nonalcoholic fatty liver disease is now acknowledged as a complex public health issue linked to sedentary lifestyle, obesity, and related disorders like type 2 diabetes and metabolic syndrome. Aims. We aimed to retrieve its trends out of the huge amount of published data. Therefore, we conducted an extensive literature search to identify possible biomarker and/or biomarker combinations by retrospectively assessing and evaluating common and novel biomarkers to predict progression and prognosis of obesity related liver diseases. Methodology. We analyzed finally 62 articles accounting for 157 cohorts and 45,288 subjects. Results. Despite the various approaches, most cohorts were considerably small and rarely comparable. Also, we found that the same standard parameters were measured rather than novel biomarkers. Diagnostics approaches appeared incomparable. Conclusions. Further collaborative investigations on harmonizing ways of data acquisition and identifying such biomarkers for clinical use are necessary to yield sufficient significant results of potential biomarkers.
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Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014; 59:1174-97. [PMID: 24002776 DOI: 10.1002/hep.26717] [Citation(s) in RCA: 433] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 08/26/2013] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease, and is strongly associated with the metabolic syndrome. In the last decade, it has become apparent that the clinical burden of NAFLD is not restricted to liver-related morbidity or mortality, and the majority of deaths in NAFLD patients are related to cardiovascular disease (CVD) and cancer. These findings have fuelled concerns that NAFLD may be a new, and added risk factor for extrahepatic diseases such as CVD, chronic kidney disease (CKD), colorectal cancer, endocrinopathies (including type 2 diabetes mellitus [T2DM] and thyroid dysfunction), and osteoporosis. In this review we critically appraise key studies on NAFLD-associated extrahepatic disease. There was marked heterogeneity between studies in study design (cross-sectional versus prospective; sample size; presence/absence of well-defined controls), population (ethnic diversity; community-based versus hospital-based cohorts), and method of NAFLD diagnosis (liver enzymes versus imaging versus biopsy). Taking this into account, the cumulative evidence to date suggests that individuals with NAFLD (specifically, nonalcoholic steatohepatitis) harbor an increased and independent risk of developing CVD, T2DM, CKD, and colorectal neoplasms. We propose future studies are necessary to better understand these risks, and suggest an example of a screening strategy.
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Affiliation(s)
- Matthew J Armstrong
- NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
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50
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Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, Takasu T, Imamura M, Li Q, Tomiyama H, Kobayashi Y, Noda A, Sasamata M, Shibasaki M. Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol 2014; 66:975-87. [PMID: 24533859 DOI: 10.1111/jphp.12223] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 01/01/2013] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption and has been highlighted as a therapeutic target for the treatment of diabetes. Here, we investigated the therapeutic effects of SGLT2 selective inhibitor ipragliflozin in type 1 diabetic rats. METHODS Type 1 diabetic rats were prepared by intravenous administration of streptozotocin (STZ). Ipragliflozin was acutely or chronically administered, and therapeutic effects were investigated. KEY FINDINGS Single administration of ipragliflozin significantly increased urinary glucose excretion, and its effect lasted over 12 h. In addition, ipragliflozin improved glucose tolerance and sustainably reduced hyperglycaemia. Repeated administration of ipragliflozin to diabetic rats for 4 weeks significantly improved not only hyperglycaemia, but also hyperlipidaemia and hepatic steatosis with concomitant increases in urinary glucose excretion. In addition, ipragliflozin ameliorates renal glomerular hyperfiltration and albuminuria. Further, ipragliflozin reduced liver levels of oxidative stress biomarkers and plasma levels of inflammatory markers, and improved liver injury as assessed by plasma levels of aminotransferases. CONCLUSION These results suggest that SGLT2 selective inhibitor ipragliflozin exerts a beneficial effect on glycaemic control and ameliorates diabetes-associated metabolic abnormalities and complications in STZ-induced diabetic rats, and would be a potential agent for the treatment of type 1 diabetes.
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Affiliation(s)
- Atsuo Tahara
- Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan
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