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Lin Y, Cui X, Zhu N, Li Y, Wang P, Wang X, Yi Y, Li X. Association Between Retinol-Binding Protein 4 Levels and Hepatitis C Virus Infection: A Meta-Analysis. Diseases 2024; 12:291. [PMID: 39589965 PMCID: PMC11592848 DOI: 10.3390/diseases12110291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/19/2024] [Accepted: 10/16/2024] [Indexed: 11/28/2024] Open
Abstract
Background and Objectives: The relationship between circulating retinol-binding protein 4 (RBP4) levels and hepatitis C virus (HCV) infection remains unclear. This study aims to systematically assess RBP4 expression in patients with HCV and its correlation with disease severity. Materials and Methods: We searched the Embase, PubMed, and Cochrane databases for relevant studies up to 1 January 2024. This study was registered on PROSPERO (CRD42023489051). Results: Our analysis included eight studies with 2612 participants (1152 controls and 1282 patients with HCV). Overall, RBP4 levels did not significantly differ between patients with HCV and controls (SMD: -0.36; 95% CI: -0.94, 0.23; p = 0.23). However, in a subgroup of Asian subjects, patients with HCV showed significantly lower RBP4 levels (SMD: -0.40; 95% CI: -0.49, -0.31; p = 0.10). Additionally, a negative correlation between RBP4 levels and disease severity was observed across all studied populations. Conclusions: RBP4 levels may vary due to HCV genotype, ethnicity, and environmental factors. In the context of HCV infection, RBP4 levels appear to reflect the severity of disease progression. Our findings indicate that RBP4 could serve as a biomarker for HCV disease progression. Further research is needed to elucidate the complex mechanisms of RBP4 in HCV infection.
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Affiliation(s)
- Yingying Lin
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (Y.L.); (X.W.)
| | - Xinyu Cui
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (X.C.); (N.Z.); (Y.L.); (P.W.); (Y.Y.)
| | - Na Zhu
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (X.C.); (N.Z.); (Y.L.); (P.W.); (Y.Y.)
| | - Yanyan Li
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (X.C.); (N.Z.); (Y.L.); (P.W.); (Y.Y.)
| | - Peng Wang
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (X.C.); (N.Z.); (Y.L.); (P.W.); (Y.Y.)
| | - Xin Wang
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (Y.L.); (X.W.)
| | - Yunyun Yi
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (X.C.); (N.Z.); (Y.L.); (P.W.); (Y.Y.)
| | - Xin Li
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, No. 8, Jingshun East Street, Chaoyang District, Beijing 100015, China; (Y.L.); (X.W.)
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Spiezia C, Di Rosa C, Fintini D, Ferrara P, De Gara L, Khazrai YM. Nutritional Approaches in Children with Overweight or Obesity and Hepatic Steatosis. Nutrients 2023; 15:nu15112435. [PMID: 37299398 DOI: 10.3390/nu15112435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/11/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Childhood obesity is a global public health problem. Worldwide, 41 million children under 5 years and 340 million children and adolescents between 5 and 19 years are overweight. In addition, the recent COVID-19 epidemic has further amplified this social phenomenon. Obesity is a condition associated with various comorbidities, such as nonalcoholic fatty liver disease (NAFLD). The pathophysiology of NAFLD in obesity is intricate and involves the interaction and dysregulation of several mechanisms, such as insulin resistance, cytokine signaling, and alteration of the gut microbiota. NAFLD is defined as the presence of hepatic steatosis in more than 5% of hepatocytes, evaluated by histological analysis. It can evolve from hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver failure. Body weight reduction through lifestyle modification remains the first-line intervention for the management of pediatric NAFLD. Indeed, studies suggest that diets low in fat and sugar and conversely rich in dietary fibers promote the improvement of metabolic parameters. This review aims to evaluate the existing relationship between obesity and NAFLD in the pediatric population and to assess the dietary patterns and nutritional supplementations that can be recommended to prevent and manage obesity and its comorbidities.
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Affiliation(s)
- Chiara Spiezia
- Research Unit of Food Science and Human Nutrition, Department of Science and Technology for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128 Roma, Italy
| | - Claudia Di Rosa
- Research Unit of Food Science and Human Nutrition, Department of Science and Technology for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128 Roma, Italy
| | - Danilo Fintini
- Endocrinology and Diabetology Unit, Bambino Gesù Children's Hospital, IRCCS L.go S.Onofrio, 4-00165 Roma, Italy
| | - Pietro Ferrara
- Operative Research Unit of Pediatrics, Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200-00128 Roma, Italy
| | - Laura De Gara
- Research Unit of Food Science and Human Nutrition, Department of Science and Technology for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128 Roma, Italy
| | - Yeganeh Manon Khazrai
- Research Unit of Food Science and Human Nutrition, Department of Science and Technology for Sustainable Development and One Health, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128 Roma, Italy
- Operative Research Unit of Nutrition and Prevention, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200-00128 Roma, Italy
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Rasmy HS, Elmalatawy MAE, ElKarmoty KZ, Abdelwarth EY, Isaac A. Serum retinol-binding protein 4 as a predictor of fibrosis regression and response to direct-acting antiviral drugs in chronic hepatitis C virus patients. EGYPTIAN LIVER JOURNAL 2023. [DOI: 10.1186/s43066-023-00251-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023] Open
Abstract
Abstract
Background
Hepatitis C virus is the underlying cause of chronic hepatitis which frequently progresses to cirrhosis and hepatocellular carcinoma. In addition, HCV is thought to cause steatosis, dyslipidemia, insulin resistance, diabetes, obesity, and cardiovascular events. The aim of this study is to evaluate the role of serum RBP-4 in the prediction of fibrosis regression and the response of treatment among chronic HCV patients receiving direct-acting antiviral agents.
Methods
This study included 40 chronic HCV Egyptian patients, divided into two groups: Naive cases, 20 chronic HCV patients before starting first line of treatment; Relapser cases, 20 chronic HCV patients who were non-responders before starting second line treatment; and 10 healthy subjects as control. Laboratory investigations including complete blood count, full hepatic profile, fibroscan assessment, and retinol-binding protein-4 level at baseline and re-assessed 12 weeks after the end of treatment [sustained virological response SVR12]. Student T test, analysis of variance, chi-square, Tukey’s test, and Pearson correlation coefficient tests were used for statistical analysis.
Results
Baseline retinol-binding protein-4 level was significantly higher in the naïve case group than in the relapser and control groups with a P value of P value of < 0.001. All the naïve patients had 100% SVR12, only 90% of the relapser group achieved SVR12. A significant reduction in retinol-binding protein-4 and fibrosis staging and measurements by fibroscan among all studied patients were noted after receiving direct acting antivirals (P value < 0.001). Retinol-binding protein-4 levels before and after treatment were significantly lower among F4 patients in comparison to those of F1–F3 patients (P value 0.002, 0.009, respectively). The best cutoff value of retinol-binding protein-4 in the prediction of liver cirrhosis (F4) was ≤ 46 pg/ml with sensitivity of 100% and specificity of 66.67%.
Conclusion
Serum retinol-binding protein-4 was found to be higher in chronic HCV infection with a significant reduction after successful eradication. Its level is much lower in cirrhotic patients [F4]. As a result, retinol-binding protein-4 may have a promising role in assessing direct acting antivirals response, as well as a prognostic value in predicting liver cirrhosis.
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4
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Non-alcoholic fatty liver disease and liver secretome. Arch Pharm Res 2022; 45:938-963. [PMCID: PMC9703441 DOI: 10.1007/s12272-022-01419-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/15/2022] [Indexed: 11/29/2022]
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Longitudinal proteomics study of serum changes after allogeneic HSCT reveals potential markers of metabolic complications related to aGvHD. Sci Rep 2022; 12:14002. [PMID: 35977993 PMCID: PMC9385631 DOI: 10.1038/s41598-022-18221-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/08/2022] [Indexed: 01/19/2023] Open
Abstract
Even though hematopoietic stem cell transplantation (HSCT) allows successful treatment for many malignant and non-malignant disorders, its curative potential remains limited by severe side effects, including infections and other transplant-related complications such as graft-versus-host disease (GvHD). This study examined changes in serum proteome via high-performance two-dimensional gel electrophoresis (2-DE) during HSCT to search for diagnostic biomarkers for post-HSCT complications. Longitudinal proteomic analysis revealed proteins related to metabolic complications and hemolytic anemia. Retinol-binding protein 4 (RBP4), a reliable marker of insulin resistance, was identified, and is possibly associated with the onset mechanism of acute graft-versus-host disease (aGvHD) and/or skin GvHD. Although the cause of insulin resistance is not fully understood, it is thought to be associated with adipocytes inflammation induced by RBP4, iron overload and hemolytic anemia after HSCT, as observed in this study. The present study has demonstrated that insulin resistance and metabolic complications could be immediate complications after transplantation and are associated with aGvHD. The biomarkers revealed in this study are promising tools to be used for improving the early diagnosis of HSCT-associated complications, especially aGvHD, possibly even before clinical manifestations.
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Moreira-Pais A, Nogueira-Ferreira R, Reis S, Aveiro S, Barros A, Melo T, Matos B, Duarte JA, Seixas F, Domingues P, Amado F, Fardilha M, Oliveira PA, Ferreira R, Vitorino R. Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach. Int J Mol Sci 2022; 23:ijms23147560. [PMID: 35886909 PMCID: PMC9315930 DOI: 10.3390/ijms23147560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/26/2022] [Accepted: 07/06/2022] [Indexed: 01/27/2023] Open
Abstract
Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer.
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Affiliation(s)
- Alexandra Moreira-Pais
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; (A.M.-P.); (S.R.); (T.M.); (P.D.); (F.A.); (R.F.)
- Laboratory for Integrative and Translational Research in Population Health (ITR), Research Center in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto (FADEUP), 4200-450 Porto, Portugal;
- Centre for Research and Technology of Agro Environmental and Biological Sciences (CITAB), Inov4Agro, University of Trás-Os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal;
| | - Rita Nogueira-Ferreira
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; (R.N.-F.); (A.B.)
| | - Stephanie Reis
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; (A.M.-P.); (S.R.); (T.M.); (P.D.); (F.A.); (R.F.)
| | - Susana Aveiro
- GreenCoLab-Green Ocean Association, University of Algarve, 8005-139 Faro, Portugal;
| | - António Barros
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; (R.N.-F.); (A.B.)
| | - Tânia Melo
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; (A.M.-P.); (S.R.); (T.M.); (P.D.); (F.A.); (R.F.)
- CESAM-Centre for Environmental and Marine Studies, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bárbara Matos
- Institute of Biomedicine—iBiMED, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal; (B.M.); (M.F.)
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO Porto), 4200-072 Porto, Portugal
| | - José Alberto Duarte
- Laboratory for Integrative and Translational Research in Population Health (ITR), Research Center in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto (FADEUP), 4200-450 Porto, Portugal;
- TOXRUN—Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, Avenida Central de Gandra 1317, 4585-116 Gandra, Portugal
| | - Fernanda Seixas
- Animal and Veterinary Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal;
| | - Pedro Domingues
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; (A.M.-P.); (S.R.); (T.M.); (P.D.); (F.A.); (R.F.)
| | - Francisco Amado
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; (A.M.-P.); (S.R.); (T.M.); (P.D.); (F.A.); (R.F.)
| | - Margarida Fardilha
- Institute of Biomedicine—iBiMED, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal; (B.M.); (M.F.)
| | - Paula A. Oliveira
- Centre for Research and Technology of Agro Environmental and Biological Sciences (CITAB), Inov4Agro, University of Trás-Os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal;
| | - Rita Ferreira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; (A.M.-P.); (S.R.); (T.M.); (P.D.); (F.A.); (R.F.)
| | - Rui Vitorino
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; (R.N.-F.); (A.B.)
- Institute of Biomedicine—iBiMED, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal; (B.M.); (M.F.)
- Correspondence:
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming increasingly common as the global economy grows and living standards improve. Timely and effective preventions and treatments for NAFLD are urgently needed. Retinol-binding protein-4 (RBP4), the protein that transports retinol through the circulation, was found to be positively related to diabetes, obesity, cardiovascular disease, and other metabolic diseases. Observational studies on the association between serum RBP4 level and the prevalence of NAFLD found contradictory results. Some of the underlying mechanisms responsible for this association have been revealed, and the possible clinical implications of treating NAFLD by targeting RBP4 have been demonstrated. Future studies should focus on the predictive value of RBP4 on NAFLD development and its potential as a therapeutic target in NAFLD.
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Affiliation(s)
- Hangkai Huang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
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Karamfilova V, Gateva A, Alexiev A, Zheleva N, Velikova T, Ivanova-Boyanova R, Ivanova R, Cherkezov N, Kamenov Z, Mateva L. The association between retinol-binding protein 4 and prediabetes in obese patients with nonalcoholic fatty liver disease. Arch Physiol Biochem 2022; 128:217-222. [PMID: 31588816 DOI: 10.1080/13813455.2019.1673429] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 08/27/2019] [Accepted: 09/23/2019] [Indexed: 02/08/2023]
Abstract
CONTEXT Retinol-binding protein 4 (RBP4) is associated with visceral fat and insulin resistance (IR) in obesity, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), but some of these data remain controversial. OBJECTIVE This study evaluated the relationship between serum RBP4 levels and prediabetes in obese patients with NAFLD. METHODS A total of 79 obese NAFLD patients without (n = 41) and with prediabetes (n = 38) were included. Serum RBP4 was measured using ELISA method. RESULTS Higher RBP4 serum levels were observed in patients with prediabetes, metabolic syndrome (MetS), or dyslipidaemia. There was correlation between RBP4 levels and visceral adiposity index (VAI), glucose, insulin, HOMA-IR, and Quicki index. RBP4 ≥ 61 mcg/ml have about 3.5-fold higher risk of prediabetes (OR 3.544, 95% CI 1.385-9.072, p=.008), and RBP4 ≥ 55 mcg/ml increased the risk for MetS approximately 3.1 times. CONCLUSIONS RBP4 is associated with increased risk for prediabetes and MetS in obese patients with NAFLD.
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Affiliation(s)
- Vera Karamfilova
- Department of Internal Medicine, Clinic of Endocrinology, University Hospital "Alexandrovska", Medical University - Sofia, Sofia, Bulgaria
| | - Antoaneta Gateva
- Department of Internal Medicine, Clinic of Endocrinology, University Hospital "Alexandrovska", Medical University - Sofia, Sofia, Bulgaria
| | - Asen Alexiev
- Department of Internal Medicine, Clinic of Gastroenterology, University Hospital "St. Ivan Rilski", Medical University - Sofia, Sofia, Bulgaria
| | - Nadejda Zheleva
- Department of Internal Medicine, Clinic of Gastroenterology, University Hospital "St. Ivan Rilski", Medical University - Sofia, Sofia, Bulgaria
| | - Tsvetelina Velikova
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia, Bulgaria
| | - Radina Ivanova-Boyanova
- Department of Endocrinology, Laboratory of Clinical Pathology, University Hospital "St. Ivan Rilski", Medical University - Sofia, Sofia, Bulgaria
| | - Raya Ivanova
- Department of Internal Medicine, Clinic of Cardiology, University Hospital "Alexandrovska", Medical University - Sofia, Sofia, Bulgaria
| | - Nikolay Cherkezov
- Medical student, Medical Faculty, Medical University, Sofia, Bulgaria
| | - Zdravko Kamenov
- Department of Internal Medicine, Clinic of Endocrinology, University Hospital "Alexandrovska", Medical University - Sofia, Sofia, Bulgaria
| | - Ludmila Mateva
- Department of Internal Medicine, Clinic of Gastroenterology, University Hospital "St. Ivan Rilski", Medical University - Sofia, Sofia, Bulgaria
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Chang ML, Chen WT, Hu JH, Chen SC, Gu PW, Chien RN. Altering retinol binding protein 4 levels in hepatitis C: Inflammation and steatosis matter. Virulence 2021; 11:1501-1511. [PMID: 33135589 PMCID: PMC7605351 DOI: 10.1080/21505594.2020.1838742] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Both hepatitis C virus (HCV) infection and retinol-binding protein 4 (RBP4) might contribute to insulin resistance (IR), how RBP4 links to IR in HCV infection remain elusive. A joint study of a prospective cohort of 842 chronically HCV-infected (CHC) patients (with 842 controls) and a line of HCV core transgenic mice was conducted. Of 842 patients, 771 had completed anti-HCV therapy and 667 had sustained virological responses (SVRs). Compared with controls, CHC patients had lower RBP4 levels. At baseline, age (95% CI β: -0.87~-0.317), BMI (0.516~2.036), triglycerides (0.03~0.127), neutrophil-to-lymphocyte ratio (NLR) (1.561~7.327), and estimated glomerular filtration rate (eGFR) (-0.342~-0.149) levels were associated with RBP4 levels in CHC patients. At 24-week post-therapy, male sex (0.652~8.129), BMI (0.199~1.254), triglycerides (0.039~0.088), uric acid (0.599~3.067), eGFR (-0.247 ~-0.14) levels, and fibrosis-4 (-3.602~-0.039) scores were associated with RBP4 levels in SVR patients; compared with baseline, except genotype 3 HCV-infected patients, SVR patients had increased RBP4 levels, which were comparable with controls, while no HOMA-IR index alteration was noted after SVR. The HCV core transgenic mice exhibited nonobese hepatic steatosis, had higher hepatic RBP4 expression, higher serum levels of RBP4 and triglycerides, but comparable HOMA-IR levels than non-transgenic littermates. In conclusion, steatosis, sex, age, uric acid, NLR, and FIB-4 levels were associated with HCV-related RBP4 levels; BMI, triglycerides, and eGFR levels were associated with non-HCV-related RBP4 levels. Reversal of low RBP4 levels after SVR was evident in non-genotype 3 HCV-infected patients. Steatosis and inflammation linked with metabolic alteration other than IR, determined RBP4 levels in HCV-infected patients.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University , Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University , Taoyuan, Taiwan
| | - Jing-Hong Hu
- Department of Internal Medicine, Chang Gung Memorial Hospital , Yunlin, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University , Taipei, Taiwan
| | - Po-Wen Gu
- Department of Medical Laboratory, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Division of Biotechnology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University , Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University , Taoyuan, Taiwan
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10
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Kim BK, Song WJ, Seo B, Kim JY, Kim SH, Jang HC, Kim KW, Chang YS. Retinol-binding protein-4 was associated with sensitization to inhalant allergens in the elderly population. Korean J Intern Med 2021; 36:447-455. [PMID: 33045798 PMCID: PMC7969066 DOI: 10.3904/kjim.2019.348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 03/18/2020] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS Recent evidence suggests an association between allergic sensitization and metabolic markers. However, this association has rarely been examined in the elderly. Retinol-binding protein-4 (RBP-4) is a recently identified adipokine that acts on the muscle and liver affecting insulin sensitivity. We evaluated the association between metabolic parameters and allergic sensitization in the elderly. METHODS We analysed the database of the Korean Longitudinal Study on Health and Aging cohort study conducted during 2005 to 2006. Atopy was identified by inhalant allergen skin prick test. Metabolic conditions were assessed using anthropometric indices and serum biomarkers such as fasting glucose, lipid, adiponectin, and RBP-4. RESULTS Among the 854 elderly subjects, 17.2% had atopy. Plasma RBP-4 levels were significantly higher in the atopic elderly than nonatopic elderly (p = 0.003). When RBP-4 percentiles were categorized as under three groups, the prevalence of atopy and current rhinitis increased significantly with percentiles of RBP-4 levels (p = 0.019 and p = 0.007, respectively). Log RBP-4 was associated with atopy (odds ratio [OR], 4.10; p = 0.009) and current rhinitis (OR, 2.73; p = 0.014), but not with current asthma (OR, 1.17; p = 0.824). Higher RBP-4 level in atopic elderly was also observed in current rhinitis patients. Atopy, but not current rhinitis, showed significant relationships with log RBP-4 levels in multivariate analyses adjusted for other metabolic markers including body mass index. CONCLUSION RBP-4 positively associated with atopy in the general elderly population irrespective of other metabolic markers.
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Affiliation(s)
- Byung-Keun Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Woo-Jung Song
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Bomi Seo
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Ju-Young Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Korea
| | - Sae-Hoon Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Hak C. Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ki-Woong Kim
- Department of Neuropsychiatry, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon-Seok Chang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
- Correspondence to Yoon-Seok Chang, M.D. Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: +82-31-787-7023, Fax: +82-31-787-4052, E-mail:
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11
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Kucukoglu O, Sowa JP, Mazzolini GD, Syn WK, Canbay A. Hepatokines and adipokines in NASH-related hepatocellular carcinoma. J Hepatol 2021; 74:442-457. [PMID: 33161047 DOI: 10.1016/j.jhep.2020.10.030] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022]
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors - in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin - for detection or even as therapeutic targets in NAFLD-related HCC.
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Affiliation(s)
- Ozlem Kucukoglu
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Jan-Peter Sowa
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Guillermo Daniel Mazzolini
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina; Liver Unit, Hospital Universitario Austral, Universidad Austral, Argentina
| | - Wing-Kin Syn
- Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA; Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, 48940 Leioa, Vizcaya, Spain
| | - Ali Canbay
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany.
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12
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Godinez-Leiva E, Bril F. Nonalcoholic Fatty Liver Disease (NAFLD) for Primary Care Providers: Beyond the Liver. Curr Hypertens Rev 2020; 17:94-111. [DOI: 10.2174/1573402116999201209203534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/20/2020] [Accepted: 09/15/2020] [Indexed: 11/22/2022]
Abstract
Abstract::
Nonalcoholic fatty liver disease (NAFLD) has consolidated as a major public health problem, affecting ~25% of the global population. This percentage is significantly higher in the setting of obesity and/or type 2 diabetes. Presence of NAFLD is associated with severe liver complications, such as nonalcoholic steatohepatitis (NASH; i.e., presence of inflammation and necrosis), cirrhosis and hepatocellular carcinoma. However, the majority of these patients die of cardiovascular disease. For this reason, management of this condition requires a multidisciplinary team, where primary care providers are at center stage. However, important misconceptions remain among primary care providers, preventing them from appropriately approach these patients. Nonalcoholic fatty liver disease should be understood as part of a systemic disease, characterized for abnormal accumulation of fat in tissues other than the adipose tissue. This, in turn, produces dysfunction of those organs or tissues (process sometimes referred to as lipotoxicity). Therefore, due to the systemic nature of this condition, it should not surprise that NAFLD is closely related to other metabolic conditions. In this review, we will focus on the extrahepatic manifestations of NAFLD and its metabolic and cardiovascular implications. We believe these are the most important issues primary care providers should understand, in order to effectively manage these complicated patients. In addition, we have provided a simple and straightforward approach to the diagnosis and treatment of patients with NAFLD and/or NASH. We hope this review will serve as a guide for primary care providers to approach their patients with NAFLD.
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Affiliation(s)
- Eddison Godinez-Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL;, United States
| | - Fernando Bril
- Internal Medicine, Department of Medicine, University of Alabama in Birmingham, Birmingham, AL., United States
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13
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Chen S, Sbuh N, Veedu RN. Antisense Oligonucleotides as Potential Therapeutics for Type 2 Diabetes. Nucleic Acid Ther 2020; 31:39-57. [PMID: 33026966 DOI: 10.1089/nat.2020.0891] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from inefficient signaling and insufficient production of insulin. Conventional management of T2D has largely relied on small molecule-based oral hypoglycemic medicines, which do not halt the progression of the disease due to limited efficacy and induce adverse effects as well. To this end, antisense oligonucleotide has attracted immense attention in developing antidiabetic agents because of their ability to downregulate the expression of disease-causing genes at the RNA and protein level. To date, seven antisense agents have been approved by the United States Food and Drug Administration for therapies of a variety of human maladies, including genetic disorders. Herein, we provide a comprehensive review of antisense molecules developed for suppressing the causative genes believed to be responsible for insulin resistance and hyperglycemia toward preventing and treating T2D.
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Affiliation(s)
- Suxiang Chen
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia.,Perron Institute for Neurological and Translational Science, Perth, Australia
| | - Nabayet Sbuh
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia.,Perron Institute for Neurological and Translational Science, Perth, Australia
| | - Rakesh N Veedu
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia.,Perron Institute for Neurological and Translational Science, Perth, Australia
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14
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Zhang L, Cheng YL, Xue S, Xu ZG. The Role of Circulating RBP4 in the Type 2 Diabetes Patients with Kidney Diseases: A Systematic Review and Meta-Analysis. DISEASE MARKERS 2020; 2020:8830471. [PMID: 33082885 PMCID: PMC7556081 DOI: 10.1155/2020/8830471] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/20/2020] [Accepted: 08/26/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Diabetic nephropathy is a common and serious complication of diabetes mellitus (DM) and is one of the leading causes of end-stage renal disease worldwide. Although there have been many investigations on biomarkers for DN, there is no consistent conclusion about reliable biomarkers. The purpose of this study was to perform a systematic review and meta-analysis of the role of circulating retinol-binding protein 4 (RBP4) in the type 2 diabetes mellitus (T2DM) patients with kidney diseases. MATERIALS AND METHODS We searched the PubMed, MEDLINE, EMBASE, and Web of Science databases for publications. For the 12 cross-sectional studies that we included in the review, we calculated standard mean differences (SMD) with 95% confidence intervals (CI) for continuous data when the applied scales were different. Risk of bias of included trials was assessed by using the Newcastle-Ottawa Scale. RESULTS RBP4 concentrations in the micro-, macro-, or micro+macroalbuminuria groups were significantly higher than those in the normal albuminuria group of T2DM patients [P = 0.001, SMD 1.07, 95% CI (0.41, 1.73)]. The estimated glomerular filtration rate (eGFR) was negatively associated with circulating RBP4 concentrations in patients with T2DM [summary Fisher's Z = -0.48, 95% CI (-0.69, -0.26), P < 0.0001]. The albumin-to-creatinine ratio (ACR) was positively associated with circulating RBP4 concentrations in patients with T2DM [summary Fisher's Z = 0.20, 95% CI (0.08, 0.32), P = 0.001]. CONCLUSION The levels of circulating RBP4 were significantly higher both in T2DM subjects with micro/macroalbuminuria and in T2DM subjects with declined eGFR. The levels of circulating RBP4 were positively correlated with ACR but negatively correlated with eGFR. Circulating RBP4 could be a reliable biomarker for kidney diseases in T2DM.
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Affiliation(s)
- Li Zhang
- Department of Nephrology, The 1st hospital of Jilin University, Changchun 130021, China
| | - Yan-Li Cheng
- Department of Nephrology, The 1st hospital of Jilin University, Changchun 130021, China
| | - Shuai Xue
- Department of Thyroid Surgery, The 1st hospital of Jilin University, Changchun 130021, China
| | - Zhong-Gao Xu
- Department of Nephrology, The 1st hospital of Jilin University, Changchun 130021, China
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15
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Tincopa MA. Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis. Endocrinol Diabetes Metab 2020; 3:e00177. [PMID: 33102798 PMCID: PMC7576258 DOI: 10.1002/edm2.177] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/17/2020] [Accepted: 07/18/2020] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION In the setting of the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent forms of chronic liver disease worldwide. Approximately 25% of adults globally have NAFLD which includes those with NAFL, or simple steatosis, and individuals with nonalcoholic steatohepatitis (NASH) where inflammation, hepatocyte injury and potentially hepatic fibrosis are found in conjunction with steatosis. Individuals with NASH, particularly those with hepatic fibrosis, have higher rates of liver-related and overall mortality, making this distinction of significant clinical importance. One of the core challenges in current clinical practice is identifying this subset of individuals with NASH without the use of liver biopsy, the gold standard for both diagnostics and staging disease severity. Identifying noninvasive biomarkers, an accurately measured and reproducible parameter, would aide in identifying patients eligible for NASH pharmacotherapy clinical trials and to help tailor intensity of monitoring required. METHODS RESULTS AND CONCLUSIONS In this review, we highlight both the currently available and novel diagnostic and interventional circulating biomarkers under investigation for NASH, underscoring their accuracy and limitations relevant to our patient population and current clinical practice.
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Affiliation(s)
- Monica A. Tincopa
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
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16
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Małecki P, Tracz J, Łuczak M, Figlerowicz M, Mazur-Melewska K, Służewski W, Mania A. Serum proteome assessment in nonalcoholic fatty liver disease in children: a preliminary study. Expert Rev Proteomics 2020; 17:623-632. [PMID: 32921203 DOI: 10.1080/14789450.2020.1810020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Nonalcoholic fatty disease (NAFLD) affects 3-10% of the pediatric population, making it the most common chronic liver disease among children. The aim of the study is to identify potential biomarkers enabling the diagnosis of NAFLD and monitoring the course of the disease. METHODS Proteome analysis was performed in a group of 30 patients (19 boys and 11 girls) in total, of whom 16 children had previously diagnosed NAFLD based on the abdominal ultrasound after excluding other diseases of this organ. RESULTS A total of 297 proteins have been identified. Thirty-seven proteins (responsible for inflammation, stress response, and regulation of this process) differentiating both experimental groups were identified. Up-regulated proteins included afamin, retinol-binding protein-4, complement components, and hemopexin; while serum protease inhibitors, clusterin, immunoglobulin chains, and vitamin D binding protein were found in the down-regulated group. The correlation between selected proteins and indicators of noninvasive assessment of liver fibrosis (APRI, FIB-4) as well as differences between the serum proteome of patients with normal weight, overweight, and obesity were also assessed. CONCLUSION The plasma protein profile is significantly altered in nonalcoholic liver disease in children and may prove to be a valuable source of biomarkers to evaluate the extent of liver disease.
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Affiliation(s)
- Paweł Małecki
- Department of Infectious Diseases, Poznan University of Medical Sciences , Poznan, Poland
| | - Joanna Tracz
- Institute of Bioorganic Chemistry Polish Academy of Sciences , Poznań, Poland
| | - Magdalena Łuczak
- Institute of Bioorganic Chemistry Polish Academy of Sciences , Poznań, Poland
| | - Magdalena Figlerowicz
- Department of Infectious Diseases, Poznan University of Medical Sciences , Poznan, Poland
| | | | - Wojciech Służewski
- Department of Infectious Diseases, Poznan University of Medical Sciences , Poznan, Poland
| | - Anna Mania
- Department of Infectious Diseases, Poznan University of Medical Sciences , Poznan, Poland
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17
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Singh SP, Barik RK. NonInvasive Biomarkers in Nonalcoholic Fatty Liver Disease: Are We There Yet? J Clin Exp Hepatol 2020; 10:88-98. [PMID: 32025168 PMCID: PMC6995889 DOI: 10.1016/j.jceh.2019.09.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 09/15/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD encompasses a spectrum of disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. However, despite the growing recognition of this important disease burden, there are significant challenges to accurately and noninvasively diagnose the various forms of NAFLD, especially to differentiate benign steatosis from the progressive NASH. This is of utmost importance because although liver biopsy is considered the current imperfect 'gold' standard for diagnosing NASH and staging fibrosis, it is an invasive procedure with significant limitations. Although, a number of noninvasive markers have been or are currently undergoing investigation, until date, no highly sensitive and specific tests are available to differentiate NASH from simple steatosis. At the moment, further investigations are needed before prediction models or blood-based biomarkers become available and acceptable for routine clinical care. There is a great need for developing inexpensive, easily accessible, highly sensitive and specific biomarkers that permit not only the identification of patients at high risk of adverse outcomes, but also the monitoring of disease progression and response after therapeutic interventions.
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Affiliation(s)
- Shivaram P. Singh
- Address for correspondence: Shivaram Prasad Singh, Professor, Dept. of Gastroenterology, S.C.B. Medical College, Cuttack, Odisha, 753007, India.
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18
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Scudiero O, Pero R, Ranieri A, Terracciano D, Fimiani F, Cesaro A, Gentile L, Leggiero E, Laneri S, Moscarella E, Mazzaccara C, Frisso G, D'Alicandro G, Limongelli G, Pastore L, Calabrò P, Lombardo B. Childhood obesity: an overview of laboratory medicine, exercise and microbiome. Clin Chem Lab Med 2019; 58:1385-1406. [PMID: 31821163 DOI: 10.1515/cclm-2019-0789] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 11/12/2019] [Indexed: 12/17/2022]
Abstract
In the last few years, a significant increase of childhood obesity incidence unequally distributed within countries and population groups has been observed, thus representing an important public health problem associated with several health and social consequences. Obese children have more than a 50% probability of becoming obese adults, and to develop pathologies typical of obese adults, that include type 2-diabetes, dyslipidemia and hypertension. Also environmental factors, such as reduced physical activity and increased sedentary activities, may also result in increased caloric intake and/or decreased caloric expenditure. In the present review, we aimed to identify and describe a specific panel of parameters in order to evaluate and characterize the childhood obesity status useful in setting up a preventive diagnostic approach directed at improving health-related behaviors and identifying predisposing risk factors. An early identification of risk factors for childhood obesity could definitely help in setting up adequate and specific clinical treatments.
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Affiliation(s)
- Olga Scudiero
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples "Federico II", Napoli, Italy.,CEINGE-Biotecnologie Avanzate, Naples, Italy
| | - Raffaela Pero
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples "Federico II", Napoli, Italy
| | - Annaluisa Ranieri
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples "Federico II", Napoli, Italy.,CEINGE-Biotecnologie Avanzate, Naples, Italy
| | - Daniela Terracciano
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Naples "Federico II", Napoli, Italy
| | - Fabio Fimiani
- Divisione di Cardiologia, Dipartimento di Scienze Cardiotoraciche e Respiratorie, Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Arturo Cesaro
- Divisione di Cardiologia, Dipartimento di Scienze Cardiotoraciche e Respiratorie, Università della Campania "Luigi Vanvitelli", Naples, Italy
| | | | | | - Sonia Laneri
- Dipartimento di Farmacia, Università degli Studi di Naples "Federico II", Napoli, Italy
| | - Elisabetta Moscarella
- Dipartimento di Scienze Mediche Traslazionali, Università della Campania "Luigi Vanvitelli", Caserta, Italy.,Unità di Cardiologia, Ospedale "Sant'Anna e San Sebastiano", Caserta, Italy
| | - Cristina Mazzaccara
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples "Federico II", Napoli, Italy.,CEINGE-Biotecnologie Avanzate, Naples, Italy
| | - Giulia Frisso
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples "Federico II", Napoli, Italy.,CEINGE-Biotecnologie Avanzate, Naples, Italy
| | - Giovanni D'Alicandro
- Centro di Medicina dello Sport e delle Disabilità, Dipartimento di Neuroscienze e Riabilitazione, AORN, Santobono-Pausillipon, Naples, Italy
| | - Giuseppe Limongelli
- Dipartimento di Scienze Mediche Traslazionali, Università della Campania "Luigi Vanvitelli", Caserta, Italy
| | - Lucio Pastore
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples "Federico II", Napoli, Italy.,CEINGE-Biotecnologie Avanzate, Naples, Italy
| | - Paolo Calabrò
- Dipartimento di Scienze Mediche Traslazionali, Università della Campania "Luigi Vanvitelli", Caserta, Italy.,Unità di Cardiologia, Ospedale "Sant'Anna e San Sebastiano", Caserta, Italy
| | - Barbara Lombardo
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Naples "Federico II", Napoli, Italy.,CEINGE-Biotecnologie Avanzate, Naples, Italy
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19
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Hudert CA, Selinski S, Rudolph B, Bläker H, Loddenkemper C, Thielhorn R, Berndt N, Golka K, Cadenas C, Reinders J, Henning S, Bufler P, Jansen PLM, Holzhütter HG, Meierhofer D, Hengstler JG, Wiegand S. Genetic determinants of steatosis and fibrosis progression in paediatric non-alcoholic fatty liver disease. Liver Int 2019; 39:540-556. [PMID: 30444569 DOI: 10.1111/liv.14006] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 11/05/2018] [Accepted: 11/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD. METHODS We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics. RESULTS Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10-06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism.
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Affiliation(s)
- Christian A Hudert
- Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Silvia Selinski
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Birgit Rudolph
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Hendrik Bläker
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Ria Thielhorn
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany
| | - Nikolaus Berndt
- Institute for Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Klaus Golka
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Cristina Cadenas
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Jörg Reinders
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Stephan Henning
- Department of Pediatric Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Philip Bufler
- Department of Pediatric Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Peter L M Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | | | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany
| | - Jan G Hengstler
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Susanna Wiegand
- Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany
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20
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Prevention of hepatic stellate cell activation using JQ1- and atorvastatin-loaded chitosan nanoparticles as a promising approach in therapy of liver fibrosis. Eur J Pharm Biopharm 2019; 134:96-106. [DOI: 10.1016/j.ejpb.2018.11.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/09/2018] [Accepted: 11/20/2018] [Indexed: 01/14/2023]
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21
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Rudolph B, Bjorklund N, Ovchinsky N, Kogan-Liberman D, Perez A, Liszewski M, Levin TL, Ewart M, Liu Q, Xue X, Viswanathan S, Strickler HD. Methods to improve the noninvasive diagnosis and assessment of disease severity in children with suspected nonalcoholic fatty liver disease (NAFLD): Study design. Contemp Clin Trials 2018; 75:51-58. [PMID: 30401631 PMCID: PMC6249118 DOI: 10.1016/j.cct.2018.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/18/2018] [Accepted: 10/25/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and is the most common liver disease in the developed world. In children with suspected NAFLD, present guidelines suggest consideration of alternative diagnoses via extensive blood testing, though the yield of this work up is unknown. Furthermore, the gold standard diagnostic test for NAFLD remains liver biopsy, making the development of non-invasive tests critically important. OBJECTIVES Our objectives are: 1) to determine the accuracy of elastography and multiple serum biomarkers - each assessed individually and as algorithms (including those previously tested in adults) - for the diagnosis of nonalcoholic steatohepatitis (NASH) and early fibrosis in children and (2) to examine the utility of extensive testing for rare alternative diagnoses in overweight or obese children with elevated alanine aminotransferase (ALT) suspected to have NAFLD. DESIGN This is an ongoing, cross-sectional study in children 2-18 years of age with up to 2 years of prospective follow up. Eligible patients are asymptomatic, overweight or obese, and have an ALT ≥35 U/L upon enrollment. Two forms of elastography are obtained serially along with anthropometric data and routine laboratory tests. Elastography and serum biomarkers are also performed immediately prior to any clinically-indicated biopsy. METHODS Between April 2015 and April 2018, 193 children have been enrolled in this ongoing study and 71 have undergone liver biopsy. Here we carefully report the rationale, methodology, and preliminary data for this study.
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Affiliation(s)
- Bryan Rudolph
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Nicole Bjorklund
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute of Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Nadia Ovchinsky
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Debora Kogan-Liberman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Adriana Perez
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Mark Liszewski
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Terry L Levin
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Michelle Ewart
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Qiang Liu
- Division of Pediatric Radiology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Xiaonan Xue
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Shankar Viswanathan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Howard D Strickler
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
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Valerio G, Maffeis C, Saggese G, Ambruzzi MA, Balsamo A, Bellone S, Bergamini M, Bernasconi S, Bona G, Calcaterra V, Canali T, Caroli M, Chiarelli F, Corciulo N, Crinò A, Di Bonito P, Di Pietrantonio V, Di Pietro M, Di Sessa A, Diamanti A, Doria M, Fintini D, Franceschi R, Franzese A, Giussani M, Grugni G, Iafusco D, Iughetti L, Lamborghini A, Licenziati MR, Limauro R, Maltoni G, Manco M, Reggiani LM, Marcovecchio L, Marsciani A, del Giudice EM, Morandi A, Morino G, Moro B, Nobili V, Perrone L, Picca M, Pietrobelli A, Privitera F, Purromuto S, Ragusa L, Ricotti R, Santamaria F, Sartori C, Stilli S, Street ME, Tanas R, Trifiró G, Umano GR, Vania A, Verduci E, Zito E. Diagnosis, treatment and prevention of pediatric obesity: consensus position statement of the Italian Society for Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Ital J Pediatr 2018; 44:88. [PMID: 30064525 PMCID: PMC6069785 DOI: 10.1186/s13052-018-0525-6] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/07/2018] [Indexed: 01/06/2023] Open
Abstract
The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention.The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase.
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Affiliation(s)
- Giuliana Valerio
- Department of Movement Sciences and Wellbeing, University of Naples Parthenope, via Medina 40, 80133 Naples, Italy
| | - Claudio Maffeis
- Pediatric Diabetes and Metabolic Disorders Unit, University of Verona, Verona, Italy
| | - Giuseppe Saggese
- Department of Pediatrics, University Hospital of Pisa, Pisa, Italy
| | | | - Antonio Balsamo
- Department of Medical and Surgical Sciences, University Hospital S.Orsola-Malpighi, Bologna, Italy
| | - Simonetta Bellone
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | | | - Sergio Bernasconi
- Italian Society for Pediatric Endocrinology and Diabetology (SIEDP), Parma, Italy
| | - Gianni Bona
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Valeria Calcaterra
- Pediatrics Unit, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Margherita Caroli
- Italian Society for Obesity (SIO), Francavilla Fontana (Brindisi), Italy
| | | | - Nicola Corciulo
- Pediatric Unit, Hospital of Gallipoli, Gallipoli (Lecce), Italy
| | - Antonino Crinò
- Autoimmune Endocrine Diseases Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Procolo Di Bonito
- Department of Internal Medicine, “S. Maria delle Grazie”, Pozzuoli Hospital, Naples, Italy
| | | | - Mario Di Pietro
- Pediatric and Neonatal Unit, “G. Mazzini”Hospital, Teramo, Italy
| | - Anna Di Sessa
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Antonella Diamanti
- Artificial Nutrition Unit Bambino Gesù, Children’s Hospital, IRCCS, Rome, Italy
| | - Mattia Doria
- Italian Federation of Pediatricians (FIMP), Venice, Italy
| | - Danilo Fintini
- Endocrinology and Diabetology Unit Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | | | - Adriana Franzese
- Department of Translational Medical Science, Regional Center for Pediatric Diabetes, University Federico II of Naples, Naples, Italy
| | | | - Graziano Grugni
- Division of Auxology, Istituto Auxologico Italiano, IRCCS, Verbania, Italy
| | - Dario Iafusco
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Lorenzo Iughetti
- Pediatric Unit, University of Modena and Reggio Emilia, Modena, Italy
| | | | | | | | - Giulio Maltoni
- Department of Medical and Surgical Sciences, University Hospital S.Orsola-Malpighi, Bologna, Italy
| | - Melania Manco
- Research Area for Multifactorial Diseases, Children’s Hospital Bambino Gesù, Rome, Italy
| | | | | | | | - Emanuele Miraglia del Giudice
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Anita Morandi
- Pediatric Diabetes and Metabolic Disorders Unit, University Hospital of Verona, Verona, Italy
| | - Giuseppe Morino
- Nutrition Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | | | - Valerio Nobili
- Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Rome, Italy
- Hepatometabolic Unit, Bambino Gesù Children’s Hospital, IRCSS, Rome, Italy
| | - Laura Perrone
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | | | | | | | | | | | - Roberta Ricotti
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Francesca Santamaria
- Department of Translational Medical Science, Regional Center for Pediatric Diabetes, University Federico II of Naples, Naples, Italy
| | - Chiara Sartori
- Department of Obstetrics, Gynaecology and Paediatrics, Arcispedale S.Maria Nuova-IRCCS, Reggio Emilia, Italy
| | | | - Maria Elisabeth Street
- Department of Obstetrics, Gynaecology and Paediatrics, Arcispedale S.Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - Rita Tanas
- Italian Society for Pediatric Endocrinology and Diabetology (SIEDP), Ferrara, Italy
| | | | - Giuseppina Rosaria Umano
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Andrea Vania
- Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Rome, Italy
| | - Elvira Verduci
- Deparment of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy
| | - Eugenio Zito
- Department of Social Sciences, University of Naples Federico II, Naples, Italy
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Qiu Y, Wang S, Wan T, Ye M, Jiang R, Pei L, Yang L. Blood-based novel biomarkers for nonalcoholic steatohepatitis. Biomark Med 2018; 12:501-515. [PMID: 29712439 DOI: 10.2217/bmm-2017-0361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Nonalcoholic fatty liver disease has become a social health challenge of global concern. The term nonalcoholic steatohepatitis (NASH) is a more severe condition than simple steatosis and distinguishing NASH from nonalcoholic fatty liver disease is particularly important. Liver biopsy remains a gold standard in diagnosing NASH. Meanwhile, radiological techniques such as ultrasonography and MRI are also applied widely. However, the invasive and expensive examination is not suitable for screening, and there is a great need for reliable and appropriate biomarkers to screen patients for NASH. Based on the current studies of blood-based novel biomarkers, we attempt to summarize the latest findings on biomarkers for NASH, including blood biomarkers encompassing proteins, lipids and miRNAs; the correlation between extracellular vesicles and NASH; and treatment strategies for NASH.
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Affiliation(s)
- Yun Qiu
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Sufan Wang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Ting Wan
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Mingtong Ye
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Rui Jiang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Lei Pei
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Lili Yang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
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Retinol-binding protein-4 expression marks the short-term mortality of critically ill patients with underlying liver disease: Lipid, but not glucose, matters. Sci Rep 2017; 7:2881. [PMID: 28588245 PMCID: PMC5460269 DOI: 10.1038/s41598-017-03096-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/21/2017] [Indexed: 12/12/2022] Open
Abstract
The implications of retinol-binding protein-4 (RBP4) expression in critically ill patients with underlying liver diseases remain unclear. A prospective cohort study involving 200 liver intensive care unit (ICU) patients was conducted, with 274 blood donors as controls. Patient outcomes were assessed using Cox and Kaplan-Meier analyses. Of the 200 ICU patients (mean age: 56.0 yrs), 79.5% were male, 72.5% were cirrhotic, 62% were septic, 29.5% were diabetic, and 29% expired in the ICU (median admission: 7.5 days). ICU patients had lower baseline RBP4 (25.6+/−18.4 vs. 43.8+/−35.0 mg/L, p < 0.001) and total cholesterol (TC) levels than controls. The surviving ICU patients had lower baseline international normalized ratios (INRs) of prothrombin time, model for end-stage liver disease (MELD) scores and sepsis rates, but higher estimated glomerular filtration rates (eGFRs) and RBP4 levels than non-surviving patients. eGFRs, INRs and TC levels were independently associated with RBP4 levels. Only surviving patients exhibited significantly increased RBP4 levels after ICU discharge. Baseline RBP4 levels and MELD scores predicted 21-day (≤10 mg/L) and 1-year (≥25) mortality, respectively. In critically ill patients with underlying liver disease, with a link to eGFRs, INRs and TC levels, the baseline RBP4 may serve as a marker for short-term mortality.
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Ajmera V, Perito ER, Bass NM, Terrault NA, Yates KP, Gill R, Loomba R, Diehl AM, Aouizerat B. Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology 2017; 65:65-77. [PMID: 27532276 PMCID: PMC5191932 DOI: 10.1002/hep.28776] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 06/02/2016] [Accepted: 08/02/2016] [Indexed: 02/06/2023]
Abstract
UNLABELLED Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), therapeutic options and noninvasive markers of disease activity and severity remain limited. We investigated the association between plasma biomarkers and liver histology in order to identify markers of disease activity and severity in patients with biopsy-proven NAFLD. Thirty-two plasma biomarkers chosen a priori as possible discriminators of NAFLD were measured in participants enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network. Dichotomized histologic outcomes were evaluated using centrally read biopsies. Biomarkers with statistically significant associations with NAFLD histology were evaluated in multivariable models adjusted for clinical factors. Of 648 participants (74.4% white, 61.7% female, mean age 47.7 years), 58.0% had definite NASH, 55.5% had mild/no fibrosis (stage 0-1), and 44.4% had significant fibrosis (stage 2-4). Increased activated plasminogen activator inhibitor 1 had a strong association with definite NASH compared to not NASH or borderline NASH in multivariable analysis (odds ratio = 1.20, 95% confidence interval 1.08-1.34, P < 0.001). Biomarkers associated with significant fibrosis (versus mild/no fibrosis) in multivariable analysis included higher levels of interleukin-8, monocyte chemoattractant protein-1, resistin, soluble interleukin-1 receptor I, soluble interleukin-2 receptor alpha, and tumor necrosis factor alpha and lower levels of insulin-like growth factor 2. CONCLUSIONS Specific plasma biomarkers are significantly associated with disease activity and severity of fibrosis in NAFLD and are potentially valuable tools for noninvasive stratification of patients with NAFLD and identification of targets for therapeutic intervention. (Hepatology 2017;65:65-77).
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Affiliation(s)
- Veeral Ajmera
- Gastroenterology, UCSF, San Francisco, CA, United States
| | - Emily R. Perito
- Pediatric Gastroenterology, UCSF, San Francisco, CA, United States
| | - Nathan M. Bass
- Gastroenterology, UCSF, San Francisco, CA, United States
| | | | | | - Ryan Gill
- Pathology, UCSF, San Francisco, CA, United States
| | - Rohit Loomba
- Gastroenterology, UCSD, San Diego, CA, United States
| | - Anna Mae Diehl
- Gastroenterology, Duke University, Durham, NC, United States
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26
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Panera N, Della Corte C, Crudele A, Stronati L, Nobili V, Alisi A. Recent advances in understanding the role of adipocytokines during non-alcoholic fatty liver disease pathogenesis and their link with hepatokines. Expert Rev Gastroenterol Hepatol 2016; 10:393-403. [PMID: 26654761 DOI: 10.1586/17474124.2016.1110485] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently considered the main cause of chronic liver disease worldwide. Mechanisms leading to the development and progression of this disease are topics of great interest for researchers and clinicians. The current multi-hit hypothesis has thrown the crosstalk between liver and adipose tissue into sharp focus. It is well known that adipose tissue produces circulating factors, known as adipocytokines, which exert several effects on liver cells, promoting the onset of NAFLD and its progression to non-alcoholic steatohepatitis in obese subjects. In a similar way, hepatocytes may also respond to obesogenic stimuli by producing and releasing hepatokines into the circulation. Here, the authors provide an overview of recent advances in our understanding of the role of the most relevant adipocytokines and hepatokines in NAFLD pathogenesis, highlighting their possible molecular and functional interactions.
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Affiliation(s)
- Nadia Panera
- a Liver Research Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Claudia Della Corte
- b Hepato-Metabolic Disease Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Annalisa Crudele
- a Liver Research Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Laura Stronati
- c Department of Radiobiology and Human Health , ENEA , Rome , Italy
| | - Valerio Nobili
- b Hepato-Metabolic Disease Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
| | - Anna Alisi
- a Liver Research Unit , 'Bambino Gesù' Children's Hospital, IRCCS , Rome , Italy
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27
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Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism 2016; 65:1062-79. [PMID: 26725002 DOI: 10.1016/j.metabol.2015.11.006] [Citation(s) in RCA: 252] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 11/19/2015] [Accepted: 11/20/2015] [Indexed: 12/13/2022]
Abstract
Since the discovery of adipose tissue as a higly active endocrine tissue, adipokines, peptides produced by adipose tissue and exerting autocrine, paracrine and endocrine function, have gained increasing interest in various obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD). Data regarding the association between NAFLD and circulating leptin and adiponectin levels are generally well documented: leptin levels increase, whereas adiponectin levels decrease, by increasing the severity of NAFLD. Data regarding other adipokines in histologically confirmed NAFLD populations are inconclusive (e.g., resistin, visfatin, retinol-binding protein-4, chemerin) or limited (e.g., adipsin, obestatin, omentin, vaspin etc.). This review summarizes evidence on the association between adipokines and NAFLD. The first part of the review provides general consideration on the interplay between adipokines and NAFLD, and the second part provides evidence on specific adipokines possibly involved in NAFLD pathogenesis. A thorough insight into the pathophysiologic mechanisms linking adipokines with NAFLD may result in the design of studies investigating the combined adipokine use as noninvasive diagnostic markers of NAFLD and new clinical trials targeting the treatment of NAFLD.
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Affiliation(s)
- Stergios A Polyzos
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece.
| | - Jannis Kountouras
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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28
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.
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Alterio A, Alisi A, Liccardo D, Nobili V. Non-alcoholic fatty liver and metabolic syndrome in children: a vicious circle. Horm Res Paediatr 2015; 82:283-9. [PMID: 25324136 DOI: 10.1159/000365192] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 06/10/2014] [Indexed: 11/19/2022] Open
Abstract
During the last decade, paediatricians have observed a dramatic increase of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in children. Furthermore, several lines of evidence have reported that a large part of children with NAFLD presents one or more traits of MS making plausible that, in the coming years, these subjects may present a rapid course of disease towards more severe cirrhosis and cardiovascular disease. Genetic susceptibility and the pressure of intrauterine environment and lifestyle are all crucial to activate molecular machinery that leads to development of NAFLD and MS in childhood. In this scenario, central obesity and consequent adipose tissue inflammation are critical to promote both MS-associated metabolic dysfunctions and NAFLD-related hepatic damage. An excessive dietary intake may in fact cause a specific lipid partitioning and induce metabolic stressors, which in turn promote insulin resistance and the release of several circulating factors. These molecules, on the one hand, trigger steatosis and the inflammatory response that characterize liver damage in NAFLD, and on the other hand contribute to the onset of other features of MS. This review provides an overview of current genetic, pathogenetic and clinical evidence of the vicious circle created by NAFLD and MS in children.
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Affiliation(s)
- Arianna Alterio
- Hepato-Metabolic Disease Unit and Liver Research Unit, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
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Marzuillo P, Grandone A, Perrone L, Miraglia del Giudice E. Controversy in the diagnosis of pediatric non-alcoholic fatty liver disease. World J Gastroenterol 2015; 21:6444-6450. [PMID: 26074683 PMCID: PMC4458755 DOI: 10.3748/wjg.v21.i21.6444] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/26/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023] Open
Abstract
In the last years childhood obesity has reached epidemic diffusion with about 200 million school-age children worldwide being overweight or obese. Simultaneously, also the prevalence of obesity comorbidities has been increased and the non-alcoholic fatty liver disease (NAFLD) has become the most common form of liver disease in childhood. Also if there are some not-invasive diagnostic possibilities, the diagnostic gold standard is represented by hepatic biopsy giving to the clinicians the possibility to both diagnose the NAFLD and evaluate its progression to fibrosis or cirrhosis with greater certainty than other techniques. The use of liver biopsy in clinical practice causes debate among health care providers. Most patients with NAFLD have a good prognosis and, therefore, the risks of a liver biopsy seem to outweigh the clinical benefits. It represents an impractical screening procedure because it is both expensive and invasive and, moreover, sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies because histological lesions of non-alcoholic steatohepatitis are unevenly distributed throughout the liver parenchyma. The liver biopsy limitations have led the clinicians to use, also if highly imperfect, non-invasive methods to diagnose and stage NAFLD. In this editorial the main diagnostic controversies in pediatric NAFLD are examined.
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Fitzpatrick E, Dhawan A. Noninvasive biomarkers in non-alcoholic fatty liver disease: Current status and a glimpse of the future. World J Gastroenterol 2014; 20:10851-10863. [PMID: 25152587 PMCID: PMC4138464 DOI: 10.3748/wjg.v20.i31.10851] [Citation(s) in RCA: 72] [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: 11/17/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
The development of non invasive biomarkers of disease has become a major focus of interest in nonalcoholic fatty liver disease (NAFLD). The large prevalence of the disease and the invasive nature of the investigation means that screening with liver biopsy is impractical. In addition to screening, the differentiation of those with simple steatosis vs steatohepatitis and fibrosis is clinically important as the prognosis of each differs. Serum biomarkers may be a combination of simple markers derived from large data sets or direct markers of disease activity. Serum markers of inflammation, apoptosis and oxidative stress in addition to fibrosis have been extensively studied in patients with NAFLD. Other techniques such as transient elastography, magnetic resonance elastography and acoustic radiation force imaging are becoming more established as noninvasive methods of detecting fibrosis in a variety of chronic liver conditions in addition to NAFLD. Newer high throughput methods such as proteomics and glycomics allow the nonhypothesis-driven identification of novel markers and may also potentially contribute to our understanding of the pathogenesis of the condition. This review addresses some of the methodological issues which need to be considered in the search for the ideal biomarker. It is likely that a combination of serum biomarkers and techniques such as transient elastography may provide the optimal diagnostic discrimination however this remains to be proven in large studies.
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Boyraz M, Cekmez F, Karaoglu A, Cinaz P, Durak M, Bideci A. Serum adiponectin, leptin, resistin and RBP4 levels in obese and metabolic syndrome children with nonalcoholic fatty liver disease. Biomark Med 2014; 7:737-45. [PMID: 24044566 DOI: 10.2217/bmm.13.13] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
AIM To investigate the relationship of adiponectin, leptin, resistin and RBP4 levels in obese and metabolic syndrome children with nonalcoholic fatty liver disease (NAFLD). PATIENTS & METHODS Group I consisted of 63 obese children with liver steatosis, group II consisted of 12 obese children with elevated serum ALT activity from group I, and group III included 85 obese children without liver steatosis. RESULTS Leptin levels were higher in the NAFLD children than in the control group. Serum RBP4 levels in obese children with NAFLD were higher than those in obese children without NAFLD and controls. Adiponectin and resistin levels were negatively correlated and RBP4 levels positively correlated with ALT activity and ultrasonographic grading. CONCLUSION These data suggest that adiponectin, resistin and RBP4 may have a role in the pathogenesis of NAFLD in obese children. Adiponectin, leptin, resistin and RBP4 may be suitable markers for predicting metabolic syndrome and NAFLD.
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Affiliation(s)
- Mehmet Boyraz
- Department of Pediatrics, Division of Endocrinology, Şişli Etfal Education & Training Hospital, Istanbul, Turkey
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33
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Maher JJ. Retinol binding protein 4 and fatty liver: A direct link? Hepatology 2013; 58:477-9. [PMID: 23703940 PMCID: PMC3729862 DOI: 10.1002/hep.26507] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 03/25/2013] [Indexed: 12/07/2022]
Affiliation(s)
- Jacquelyn J. Maher
- Liver Center and Department of Medicine, University of California, San Francisco
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34
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Codoñer-Franch P, Mora-Herranz A, Simó-Jordá R, Pérez-Rambla C, Boix-García L, Faus-Pérez A. Retinol-binding protein 4 levels are associated with measures of liver and renal function and oxidant/antioxidant status in obese children. J Pediatr 2013; 163:593-595. [PMID: 23623516 DOI: 10.1016/j.jpeds.2013.03.060] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 02/04/2013] [Accepted: 03/20/2013] [Indexed: 10/26/2022]
Abstract
Serum retinol-binding protein 4 (RBP4) has been proposed as a metabolic risk factor in obesity. We found that RBP4 levels also were associated with liver enzymes and cystatin C. Oxidant stress is a significant feature in obese children with greater values of RBP4 that can mediate the development of comorbidities.
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Xia M, Liu Y, Guo H, Wang D, Wang Y, Ling W. Retinol binding protein 4 stimulates hepatic sterol regulatory element-binding protein 1 and increases lipogenesis through the peroxisome proliferator-activated receptor-γ coactivator 1β-dependent pathway. Hepatology 2013; 58:564-75. [PMID: 23300015 DOI: 10.1002/hep.26227] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 11/15/2012] [Indexed: 12/07/2022]
Abstract
UNLABELLED Recent studies have revealed the essential role of retinol binding protein 4 (RBP4) in insulin resistance. However, the impact of RBP4 on aberrant lipogenesis, the common hepatic manifestation in insulin resistance states, and the underlying mechanism remain elusive. The present study was designed to examine the effect of RBP4 on sterol regulatory element-binding protein (SREBP-1) and hepatic lipogenesis. Treatment with human retinol-bound RBP4 (holo-RBP4) significantly induced intracellular triglyceride (TAG) synthesis in HepG2 cells and this effect is retinol-independent. Furthermore, RBP4 treatment enhanced the levels of mature SREBP-1 and its nuclear translocation, thereby increasing the expression of lipogenic genes, including fatty acid synthase (FAS), acetyl coenzyme A carboxylase-1 (ACC-1), and diacylglycerol O-acyltransferase 2 (DGAT-2). Stimulation of HepG2 cells with RBP4 strongly up-regulated the expression of transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) at both the messenger RNA (mRNA) and protein levels. The transcriptional activation of PGC-1β is necessary and sufficient for the transcriptional activation of SREBP-1 in response to RBP4. The cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) was identified as the target transcription factor involved in the RBP4-mediated up-regulation of PGC-1β transcription as a result of phosphorylation on Ser133. Furthermore, in vivo RBP4 infusion induced SREBP-1c activation and consequently accelerated hepatic lipogenesis and plasma TAG in C57BL/6J mice, a phenomenon not observed in Ppargc1b knockout mice. CONCLUSION These findings reveal a novel mechanism by which RBP4 achieves its effects on hepatic lipid metabolism.
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Affiliation(s)
- Min Xia
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong Province, China
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O'Byrne SM, Blaner WS. Retinol and retinyl esters: biochemistry and physiology. J Lipid Res 2013; 54:1731-43. [PMID: 23625372 PMCID: PMC3679378 DOI: 10.1194/jlr.r037648] [Citation(s) in RCA: 259] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 04/24/2013] [Indexed: 12/23/2022] Open
Abstract
By definition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insufficient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include efficient mechanisms to acquire vitamin A from the diet, efficient and overlapping mechanisms for the transport of vitamin A in the circulation, a specific mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review.
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Affiliation(s)
- Sheila M. O'Byrne
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
| | - William S. Blaner
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
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Yang HR. Noninvasive diagnosis of pediatric nonalcoholic fatty liver disease. KOREAN JOURNAL OF PEDIATRICS 2013; 56:45-51. [PMID: 23482433 PMCID: PMC3589590 DOI: 10.3345/kjp.2013.56.2.45] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/16/2012] [Accepted: 10/02/2012] [Indexed: 12/21/2022]
Abstract
Because nonalcoholic steatohepatitis can progress towards cirrhosis even in children, early detection of hepatic fibrosis and accurate diagnosis of nonalcoholic fatty liver disease (NAFLD) are important. Although liver biopsy is regarded as the gold standard of diagnosis, its clinical application is somewhat limited in children due to its invasiveness. Noninvasive diagnostic methods, including imaging studies, biomarkers of inflammation, oxidative stress, hepatic apoptosis, hepatic fibrosis, and noninvasive hepatic fibrosis scores have recently been developed for diagnosing the spectrum of NAFLD, particularly the severity of hepatic fibrosis. Although data and validation are still lacking for these noninvasive modalities in the pediatric population, these methods may be applicable for pediatric NAFLD. Therefore, noninvasive imaging studies, biomarkers, and hepatic fibrosis scoring systems may be useful in the detection of hepatic steatosis and the prediction of hepatic fibrosis, even in children with NAFLD.
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Affiliation(s)
- Hye Ran Yang
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Serum retinol-binding protein 4 is independently associated with pediatric NAFLD and fasting triglyceride level. J Pediatr Gastroenterol Nutr 2013; 56:145-50. [PMID: 22983378 DOI: 10.1097/mpg.0b013e3182722aee] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is identified as a major liver disease in children. The present study aimed to identify the prevalence and predictors of pediatric NAFLD and the correlation between serum retinol-binding protein 4 (RBP4) levels and metabolic characteristics in children. METHODS A total of 748 schoolchildren, ages 6 to 12 years, were enrolled in 2009. The body weight and height were measured in the morning before intake. Laboratory tests included overnight fasting serum lipids, insulin, liver enzymes, and RBP4 levels. Hepatic steatosis was determined by ultrasound in 219 volunteers. RESULTS The rates of NAFLD were 3% in the normal-weight, 25% in the overweight, and 76% in the obese children. Twenty (22%) of obese children had abnormal alanine aminotransferase (ALT) levels. In children with NAFLD, younger age and higher body mass index (BMI), insulin/homeostasis model of assessment, and male sex rate were associated with abnormal liver function. Stepwise increments in BMI, insulin, homeostasis model of assessment, and ALT were found in children with normal livers to simple steatosis, and to steatosis with abnormal ALT. Multiple logistic regression analysis confirmed that serum RBP4 levels (P = 0.048), ALT (P = 0.048), and BMI (P < 0.001) were independently predictors of pediatric NAFLD. Moreover, multiple linear regression analysis revealed that only serum triglycerides levels were positively related to RBP4 levels (P < 0.001). CONCLUSIONS Higher RBP4 and ALT levels as well as BMI are independently associated with pediatric NAFLD in Taiwan. In addition, an increment in RBP4 levels was positively correlated to hypertriglyceridemia in children.
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Cho T, Kim YJ, Paik SS. The efficacy of pharmacological treatment in pediatric nonalcoholic Fatty liver disease. Pediatr Gastroenterol Hepatol Nutr 2012; 15:256-65. [PMID: 24010096 PMCID: PMC3746059 DOI: 10.5223/pghn.2012.15.4.256] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Revised: 09/17/2012] [Accepted: 09/24/2012] [Indexed: 01/08/2023] Open
Abstract
PURPOSE With growing number of obese children, the prevalence of nonalcoholic fatty liver disease (NAFLD) in pediatric population is increasing. Nonalcoholic steatohepatitis (NASH) is a severe form of NAFLD, and can cause morbid complications. It is important to identify patients in order to grade pathologic severities and treat those children who possibly have NASH. This study was performed to evaluate whether the pharmacological therapy is also effective as well as the body weight reduction in pediatric NAFLD. METHODS Among the 52 children presenting with obesity and hepatopathy, NAFLD was diagnosed through liver biopsy in 29 children, who were 7 to 14 years of age, from January 2006 to December 2011. The patients were advised to reduce their body weight through diverse methods. Medication with Ursodeoxycholic acid (UDCA) and vitamin E was performed in children whose liver functions did not improve or their weight reductions were not successful. The therapeutic effects were monitored and assessed via the biochemical profiles and the physical measurements. RESULTS The therapy of vitamin E and UDCA combined with body mass index (BMI) reduction showed significantly higher rate of improvement in clinical profiles, which could be seen in data of aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT ratio, alkaline phosphatase, total bilirubin and γ-glutamyl transpeptidase. Children whose BMI were successfully reduced showed favorable clinical improvements without any medication, but those without BMI reduction did not show any improvement despite medications. CONCLUSION This study showed that the first line of therapy should be the BMI reduction in NAFLD and drug therapy combined with BMI reduction could have additive therapeutic effect in children with NAFLD.
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Affiliation(s)
- Taeshik Cho
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
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The novel insulin resistance parameters RBP4 and GLP-1 in patients treated with valproic acid: just a sidestep? Epilepsy Res 2012. [PMID: 23182413 DOI: 10.1016/j.eplepsyres.2012.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Valproic acid (VPA), as one of the most widely prescribed antiepileptic drugs (AED) for many types of epilepsy in adults and children, is associated with weight gain, alteration of adipocytokine homeostasis, insulin resistance and Non-Alcoholic Fatty Liver Disease (NAFLD). Retinol-binding protein 4 (RBP4) and Glucagon-like peptide-1 (GLP-1) are considered as important new targets in modern type 2 diabetes mellitus therapy linked to insulin resistance, NAFLD and visceral obesity acting via peripheral or central mechanisms. We herein demonstrate the lack of an influence of VPA treatment on RBP4 and GLP-1 in otherwise healthy patients. In summary, the absence of any relationship with RBP4 and GLP-1 concentrations does not suggest a role of these novel insulin resistance parameters as potential regulators of glucose and fat metabolism during VPA-therapy.
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Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 2012; 54:700-13. [PMID: 22395188 DOI: 10.1097/mpg.0b013e318252a13f] [Citation(s) in RCA: 378] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world.As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis.NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment.Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.
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Serum proteomics for biomarker discovery in nonalcoholic fatty liver disease. Clin Chim Acta 2012; 413:1190-3. [PMID: 22546610 DOI: 10.1016/j.cca.2012.04.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2012] [Revised: 04/14/2012] [Accepted: 04/17/2012] [Indexed: 02/08/2023]
Abstract
Proteomic platforms have gained increasing attention in the clinical spectrum of nonalcoholic fatty liver disease (NAFLD). This approach allows for the unbiased discovery of circulating biochemical markers, i.e., it is not limited to known molecules of presumed importance. This manuscript provides an overview of proteomic serum biomarker discovery in NAFLD. Hemoglobin is currently the most widely replicated proteomic circulating biomarker of NAFLD; it was identified as a biomarker of fatty liver in two distinct proteomic studies and subsequently validated using distinct analytical methods by independent research groups in large replication cohorts. Given the increasing availability of numerous serum samples and the refinement of the technological platforms available to scrutinize the blood proteome, large collaborative studies between academia and industry are warmly encouraged to identify novel, unbiased circulating biomarkers of NAFLD.
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Yang HR, Kim HR, Kim MJ, Ko JS, Seo JK. Noninvasive Parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. World J Gastroenterol 2012; 18:1525-30. [PMID: 22509085 PMCID: PMC3319949 DOI: 10.3748/wjg.v18.i13.1525] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 01/16/2012] [Accepted: 02/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the noninvasive parameters and hepatic fibrosis scores in obese children with nonalcoholic fatty liver disease (NAFLD).
METHODS: A total of 77 children diagnosed with NAFLD via liver biopsy were included and divided into 2 subgroups according to the histopathologic staging of hepatic fibrosis: mild (stage 0-1) vs significant fibrosis (stage 2-4). Clinical and laboratory parameters were evaluated in each patient. The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST/platelet ratio index (APRI), PGA index, Forns index, FIB-4, NAFLD fibrosis score, and pediatric NAFLD fibrosis index (PNFI) were calculated.
RESULTS: No clinical or biochemical parameter exhibited a significant difference between patients with mild and significant fibrosis. Among noninvasive hepatic fibrosis scores, only APRI and FIB4 revealed a significant difference between patients with mild and significant fibrosis (APRI: 0.67 ± 0.54 vs 0.78 ± 0.38, P = 0.032 and FIB4: 0.24 ± 0.12 vs 0.31 ± 0.21, P = 0.010). The area under the receiving operating characteristic curve of FIB4 was 0.81, followed by Forns index (0.73), APRI (0.70), NAFLD fibrosis score (0.58), AST/ALT ratio (0.53), PGA score (0.45), and PNFI (0.41).
CONCLUSION: APRI and FIB4 might be useful noninvasive hepatic fibrosis scores for predicting hepatic fibrosis in children with NAFLD.
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44
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Alisi A, Nobili V. Sensitive non-invasive circulating markers in paediatric non-alcoholic fatty liver disease. Pediatr Obes 2012; 7:89-91. [PMID: 22434747 DOI: 10.1111/j.2047-6310.2012.00055.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- A. Alisi
- Hepato-metabolic Disease Unit and Liver Research Unit; Bambino Gesù Children's Hospital, IRCCS; Rome; Italy
| | - V. Nobili
- Hepato-metabolic Disease Unit and Liver Research Unit; Bambino Gesù Children's Hospital, IRCCS; Rome; Italy
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45
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Manco M. Metabolic syndrome in childhood from impaired carbohydrate metabolism to nonalcoholic fatty liver disease. J Am Coll Nutr 2012; 30:295-303. [PMID: 22081615 DOI: 10.1080/07315724.2011.10719972] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Compelling evidence supports the concept that nonalcoholic fatty liver disease (NAFLD) represents the hepatic component of metabolic syndrome (MetS). Intrahepatic fat seems to predict more strongly than does visceral adiposity an individual's cardiovascular risk and the likelihood that metabolic abnormalities are present in youth. Young individuals with fatty liver are more insulin resistant and present with a higher prevalence of metabolic abnormalities than do individuals without intrahepatic fat accumulation. They also present with a certain endothelial dysfunction and greater carotid intima-media thickness. Conversely, youth with MetS seem to have an increased risk of developing liver inflammation, a condition termed nonalcoholic steatohepatitis (NASH), and fibrosis. In the context of MetS, the liver is central in that it can drive both hepatic and systemic insulin resistance, trigger low-grade inflammation, and promote atherogenic processes. In the context of MetS, NAFLD and altered carbohydrate metabolism track from childhood to adulthood. Thus, prevention, recognition, and effective treatment of these two abnormalities may limit the burden of morbidity and mortality associated with obesity and may delay onset of cardiovascular disease in early adulthood. The present review aims at systematically presenting evidence of the critical interplay of fatty liver and altered glucose metabolism in youth. It attempts to provide pathogenetic explanations for such an association and the rationale for its treatment, with particular regard to nutritional interventions. Key teaching points: Overweight and obese youth should be screened for fatty liver disease once after puberty by liver function tests and ultrasonography. Screening for fatty liver should be accurately performed in young patients with features of metabolic syndrome. Obese patients with fatty liver are at increased risk for altered glucose metabolism, thus they should undergo an oral glucose tolerance test. A nutritional and behavioral intervention aimed at achieving a permanent change of the lifestyle in patients and their parents is recommended.
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Affiliation(s)
- Melania Manco
- Unit of Preventive and Predictive Medicine, Scientific Directorate, Bambino Gesù Hospital, IRCCS, Rome, Italy.
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Brunt EM, Neuschwander-Tetri BA, Burt AD. Fatty liver disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:293-359. [DOI: 10.1016/b978-0-7020-3398-8.00006-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Toyama T, Asano Y, Takahashi T, Aozasa N, Akamata K, Noda S, Taniguchi T, Ichimura Y, Sumida H, Tamaki Z, Masui Y, Tada Y, Sugaya M, Sato S, Kadono T. Clinical significance of serum retinol binding protein-4 levels in patients with systemic sclerosis. J Eur Acad Dermatol Venereol 2011; 27:337-44. [PMID: 22211766 DOI: 10.1111/j.1468-3083.2011.04413.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Retinol binding protein-4 (RBP-4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance. OBJECTIVE To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy. METHODS Serum RBP4 levels were determined by enzyme-linked immunosorbent assay in 62 SSc patients and 19 healthy controls. RESULTS Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m(2) . Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects [median (25-75 percentile); 25.8 μg/mL (19.6-47.0) vs. 43.1 μg/mL (31.7-53.4), P < 0.05], while there was no significant difference between limited cutaneous SSc (lcSSc) [28.0 μg/mL (25.4-43.3)] and control subjects. In both of dcSSc and lcSSc, patients with Raynaud's phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc. CONCLUSION Decreased RBP4 levels are associated with the prevalence of Raynaud's phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder.
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Affiliation(s)
- T Toyama
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Chayanupatkul M, Honsawek S, Chongsrisawat V, Vimolket L, Poovorawan Y. Serum retinol binding protein 4 and clinical outcome in postoperative biliary atresia. Hepatol Int 2011; 5:906-912. [DOI: 10.1007/s12072-011-9262-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 02/18/2011] [Indexed: 01/04/2023]
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Tan Y, Sun LQ, Kamal MA, Wang X, Seale JP, Qu X. Suppression of retinol-binding protein 4 with RNA oligonucleotide prevents high-fat diet-induced metabolic syndrome and non-alcoholic fatty liver disease in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1811:1045-53. [PMID: 21983273 DOI: 10.1016/j.bbalip.2011.09.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Revised: 09/20/2011] [Accepted: 09/23/2011] [Indexed: 12/28/2022]
Abstract
Conflicting data have been reported regarding the role of retinol-binding protein (RBP4) in insulin resistance, obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In this study, we used pharmacological methods to investigate the role of RBP4. RNA oligonucleotide against RBP4 (anti-RBP4 oligo) was transfected into 3T3-L1 adipocytes. RT-PCR analysis showed that RBP4 mRNA expression decreased by 55% (p<0.01) compared with control cells. Validated RNA oligo was used in an in vivo study with high fat diet (HFD) fed - mice. 14 weeks of HFD feeding increased RBP4 expression (associated with elevated serum levels measured with immunoblotting and ELISA) by 56% in adipose tissue (p<0.05) and 68% in the liver (p<0.01). Adipose RBP4 levels were significantly reduced after 4 weeks treatment with anti-RBP4 oligo (25mg/kg, p<0.01) and rosiglitazone (RSG, 10mg/kg, p<0.05) compared with scrambled RNA oligo (25mg/kg) treated mice. Only anti-RBP4 oligo significantly inhibited RBP4 protein (p<0.01) and mRNA expression (p<0.01) in the liver and reduced serum RBP4 levels. Anti-RBP4 oligo and RSG showed comparable effects on impaired glucose tolerance, hyperinsulinaemia and hyperglycaemia. Anti-RBP4 oligo significantly enhanced adipose-GLUT4 expression (p<0.01) but did not increase muscle-GLUT4. Both RSG and anti-RBP4 oligo significantly reduced hepatic phosphoenolpyruvate carboxykinase expression (both p<0.05). Histological analysis revealed that anti-RBP4 oligo ameliorated hepatic steatosis and reduced lipid droplets associated with normalized liver function. Histological and pharmacological results of this study indicate that RBP4 is not only an adipocytokine, but also a hepatic cytokine leading to metabolic syndrome, NAFLD and type 2 diabetes.
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Affiliation(s)
- Yi Tan
- Department of Medical & Molecular BioSciences, University of Technology Sydney, Australia
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Petta S, Tripodo C, Grimaudo S, Cabibi D, Cammà C, Di Cristina A, Di Marco V, Di Vita G, Ingrao S, Mazzola A, Marchesini G, Pipitone R, Craxì A. High liver RBP4 protein content is associated with histological features in patients with genotype 1 chronic hepatitis C and with nonalcoholic steatohepatitis. Dig Liver Dis 2011; 43:404-10. [PMID: 21324757 DOI: 10.1016/j.dld.2010.12.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2010] [Revised: 12/15/2010] [Accepted: 12/20/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM To investigate the hepatic expression of retinol-binding protein-4 (RBP4) in chronic hepatitis C (CHC) and nonalcoholic steatohepatitis (NASH) patients, and its association with biochemical and histological patterns of liver damage. MATERIALS AND METHODS Sixty-six genotype 1 CHC and 32 NASH patients were tested for hepatic RBP4 expression. Liver expression at immunostaining was scored as 0 (slight), 1 (mild), 2 (moderate), and 3 (intense). In addition, the mRNA and the quantitative protein expressions of RBP4 were tested by PCR and by western blot, respectively, in 12 NASH and 28 CHC patients. Twelve subjects undergoing elective cholecystectomy served as controls. RESULTS Ten (31%), 16 (50%) and 6 (19%) NASH patients, and 21 (32%), 31 (47%) and 14 (21%) CHC patients had scores of 1, 2 and 3, respectively. All control subjects scored 0. In both CHC and NASH liver RBP4 scores were directly related to western blot (p=0.001 and p=0.03), not to mRNA expression (p=0.77 and p=0.40). Older age (OR, 1.07; 95%CI, 1.01-1.13), RBP4 score (4.26; 1.27-14.21) and HOMA (2.26; 1.15-4.42) were independently associated with steatosis≥10% in CHC patients. In NASH lobular inflammation (OR, 3.77; 95%CI, 1.01-24.22) and RBP4 score (4.87; 1.003-23.65) were the only risk factors for fibrosis ≥2 at logistic regression analysis. CONCLUSION Hepatic storage of RBP4, unrelated to its expression, could cause liver damage both in NASH and CHC.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
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