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Gui PP, Deng YL, Zhang M, Miao Y, Liu PH, Zeng JY, Wu Y, Li CR, Liu XY, Li YJ, Zhu JQ, Liu AX, Zhou B, Yang F, Zeng Q. Urinary biomarkers of drinking water disinfection byproducts in relation to blood-based liver function parameters among reproductive-aged Chinese women. THE SCIENCE OF THE TOTAL ENVIRONMENT 2025; 970:179016. [PMID: 40037233 DOI: 10.1016/j.scitotenv.2025.179016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025]
Abstract
BACKGROUND Toxicological studies have documented that disinfection byproducts (DBPs), the ubiquitous drinking water pollutants, induce hepatotoxicity. Yet epidemiological evidence is sparse. OBJECTIVE To assess urinary biomarkers of drinking water DBPs in relation to liver function parameters. METHODS We included 1204 reproductive-aged women from the Tongji Reproductive and Environmental (TREE) study in Wuhan, China between December 2018 and July 2021. Urinary trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) as biomarkers of drinking water DBPs were assessed. Serum liver function parameters such as albumin (ALB), total cholesterol (TC), and alkaline phosphatase (ALP) were determined. Urinary DCAA and TCAA concentrations in relation to liver function parameters were examined by multivariate linear regression or restricted cubic spline (RCS) models. RESULTS There was no evidence of urinary TCAA in relation to serum parameters of liver function. However, monotonic dose-response relationships were estimated between elevated tertiles of urinary DCAA concentrations and increased serum ALP (percent change = 4.25 %; 95 % CI: 0.34 %, 8.32 % for the upper vs. lower tertile) and TC levels (percent change = 3.84 %; 95 % CI: 0.63 %, 7.17 % for the upper vs. lower tertile). These associations remained for urinary DCAA modeled as the continuous exposure variable and were linear in the RCS models. Age, body mass index, and passive smoking status did not modify these associations. CONCLUSION DCAA but not TCAA exposure may contribute to damaged liver function in reproductive-aged women.
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Affiliation(s)
- Ping-Ping Gui
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Yan-Ling Deng
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Min Zhang
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yu Miao
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Peng-Hui Liu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jia-Yue Zeng
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang Wu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cheng-Ru Li
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiao-Ying Liu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang-Juan Li
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jin-Qin Zhu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - A-Xue Liu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bin Zhou
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
| | - Fei Yang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
| | - Qiang Zeng
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Ranjbar M, Shab-Bidar S, Mohammadi H, Djafarian K. Effect of Intermittent Fasting on Liver Function Tests: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Nutr Rev 2025; 83:e965-e979. [PMID: 38917447 DOI: 10.1093/nutrit/nuae070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2024] Open
Abstract
CONTEXT Intermittent fasting (IF) is a diet strategy with alternate intervals of calorie reduction and normal eating. Despite its beneficial effects on weight loss and cardiometabolic risk factors, the effect of IF on liver function tests (LFTs) remains unclear. OBJECTIVE This study aimed to investigate the effect of IF on LFTs through a systematic review and meta-analysis of randomized clinical trials. DATA SOURCES An electronic search was performed using predefined search terms in databases including PubMed, Scopus, and ISI Web of Science until February 2023. DATA EXTRACTION The studies were selected according to PRISMA guidelines, and the risk of bias was assessed for the randomized controlled trials. DATA ANALYSIS The results of this study are reported as weighted mean differences (WMDs) with 95% CIs. Fourteen RCTs were included in the meta-analysis, with a total sample size of 908. IF significantly reduced alanine aminotransferase (ALT) (WMD: -2.88, 95% CI: -4.72 to -1.04, P-value = .002) and aspartate aminotransferase (AST) levels (WMD: -1.67, 95% CI: -3.12 to -0.22, P-value = .024). The results of the subgroup analysis showed that the impact of IF was significant in both the nonalcoholic fatty liver disease and the healthy groups for ALT. The effects of IF on the serum gamma-glutamyl transpeptidase (GGT) level were significant (WMD: -3.19, 95% CI: -6.00 to -0.39, P-value = .026), but there were no significant changes in the alkaline phosphatase (ALP) level (WMD: 1.06, 95% CI: -0.23 to 2.34, P-value = .106). Furthermore, no substantial heterogeneity between studies was reported. CONCLUSION IF can improve ALT, AST, and GGT levels but not ALP enzyme levels and may have a benefit on liver function. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42023396211.
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Affiliation(s)
- Mahsa Ranjbar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, 14155-6117, Iran
| | - Sakineh Shab-Bidar
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, 14155-6117, Iran
- Neuroscience Institute, Sports Medicine Research Center, Tehran University of Medical Sciences, Tehran, 4395-578, Iran
| | - Hamed Mohammadi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, 14155-6117, Iran
| | - Kurosh Djafarian
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, 14155-6117, Iran
- Neuroscience Institute, Sports Medicine Research Center, Tehran University of Medical Sciences, Tehran, 4395-578, Iran
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Ebrahimzadeh A, Ebrahimzadeh A, Fooladshekan S, Mohseni S, Mohtashamian A, Babajafari S, Sohrabi Z. Therapeutic effects of curcumin supplementation on liver enzymes of nonalcoholic fatty liver disease patients: A systematic review and meta-analysis of randomized clinical trials. Food Sci Nutr 2025; 13:e4144. [PMID: 39803230 PMCID: PMC11716989 DOI: 10.1002/fsn3.4144] [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: 04/15/2023] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 01/05/2025] Open
Abstract
Curcumin, as an antioxidant agent, has been proposed as a potential treatment for nonalcoholic fatty liver disease (NAFLD). The aim of the current systematic review and meta-analysis was to summarize earlier findings regarding the effect of curcumin supplementation on liver enzymes and ALP in NAFLD patients. All studies published up to November 18, 2022, were searched through the PubMed, SCOPUS, and Web of Science databases to collect all randomized clinical trials (RCTs) on NAFLD patients in which curcumin was used as a treatment. A random-effects model was used to measure pooled effect sizes. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used to report pooled effect sizes. Subgroup analysis was utilized to investigate heterogeneity. A total of 14 studies were included in this systematic review and meta-analysis. Our pooled meta-analysis indicated a significant decrease in alanine aminotransferase (ALT) following curcumin therapy by pooling 12 effect sizes (WMD: -8.72; 95% CI: -15.16, -2.27, I 2 = 94.1%) and in aspartate aminotransferase (AST) based on 13 effect sizes (WMD: -6.35; 95% CI: -9.81, -2.88, I 2 = 94.4%). However, the pooled analysis of five trials indicated that there was no significant association between curcumin therapy and alkaline phosphatase (ALP) in NAFLD patients (WMD: -4.71; 95% CI: -13.01, 3.58, I 2 = 64.2%). Nevertheless, subgroup analyses showed significant effects of curcumin on ALP with a longer duration of supplementation. The findings of this systematic review and meta-analysis support the potential effect of curcumin on the management of NAFLD. Further randomized controlled trials should be conducted in light of our findings.
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Affiliation(s)
- Armin Ebrahimzadeh
- Nutrition Research Center, School of Nutrition and Food SciencesShiraz University of Medical SciencesShirazIran
| | - Anahita Ebrahimzadeh
- Nutrition Research Center, School of Nutrition and Food SciencesShiraz University of Medical SciencesShirazIran
| | - Sara Fooladshekan
- Dental Research CenterGolestan University of Medical SciencesGorganIran
| | - Shokouh Mohseni
- Nutrition Research Center, School of Nutrition and Food SciencesShiraz University of Medical SciencesShirazIran
| | - Abbas Mohtashamian
- Student Research Committee, Department of Nutrition, Faculty of MedicineKashan University of Medical SciencesKashanIran
| | - Siavash Babajafari
- Nutrition Research Center, School of Nutrition and Food SciencesShiraz University of Medical SciencesShirazIran
| | - Zahra Sohrabi
- Nutrition Research Center, School of Nutrition and Food SciencesShiraz University of Medical SciencesShirazIran
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Huang HYR, Vitali C, Zhang D, Hand NJ, Phillips MC, Creasy KT, Scorletti E, Park J, Regeneron Centre, Schneider KM, Rader DJ, Schneider CV. Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach. JHEP Rep 2025; 7:101243. [PMID: 39687601 PMCID: PMC11647476 DOI: 10.1016/j.jhepr.2024.101243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/28/2024] [Accepted: 10/07/2024] [Indexed: 12/18/2024] Open
Abstract
Background & Aim An unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. TM6SF2 represents a good candidate for this approach due to its known association with steatotic liver disease (SLD). Methods We screened participants with whole-exome sequences in the Penn Medicine Biobank (PMBB, n >40,000) and the UK Biobank (UKB, n >200,000) for protein-altering variants in TM6SF2 and evaluated their association with liver phenotypes and clinical outcomes. Results Missense variants in TM6SF2 (E167K, L156P, P216L) were associated with an increased risk of clinically diagnosed and imaging-proven steatosis, independent of the PNPLA3 I48M risk allele and hepatitis B/C (p <0.001). E167K homozygotes had significantly increased risk of SLD (odds ratio [OR] 5.38, p <0.001), steatohepatitis (OR 5.76, p <0.05) and hepatocellular carcinoma (OR 11.22, p <0.0001), while heterozygous carriers of L156P and P216L were also at an increased risk of steatohepatitis. In addition, carriers of E167K are at a 3-fold increased risk of at-risk MASH (OR 2.75, p <0.001). CT-derived liver fat scores were higher in E167K and L156P in an allele-dose manner (p <0.05). This corresponded with the UKB nuclear magnetic resonance-derived lipidomic analyses (n = 105,348), revealing all carriers to exhibit lower total cholesterol, triglycerides and total choline. In silico predictions suggested that these missense variants cause structural disruptions in the EXPERA domain, leading to reduced protein function. This hypothesis was supported by the association of rare loss-of-function variants in TM6SF2 with an increased risk of SLD (OR 4.9, p <0.05), primarily driven by a novel rare stop-gain variant (W35X) with the same directionality. Conclusion The functional genetic study of protein-altering variants provides insights on the association between loss of TM6SF2 function and SLD and provides the basis for future mechanistic studies. Impact and implications The genome-first approach expands insights into genetic risk factors for steatotic liver disease with TM6SF2 being a focal point due to its known association with plasma lipid traits. Our findings validated the association of two missense variants (E167K and L156P) with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common PNPLA3 I48M risk variant. Notably, we also identified a predicted deleterious missense variant (P216L) linked to steatotic risk and demonstrated that an aggregated gene burden of rare putative loss-of-function variants was associated with the risk of hepatic steatosis. Combined, this study sets the stage for future mechanistic investigations into the functional consequences of TM6SF2 variants in metabolic dysfunction-associated steatotic liver disease.
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Affiliation(s)
- Helen Ye Rim Huang
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Cecilia Vitali
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - David Zhang
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas J. Hand
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael C. Phillips
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kate Townsend Creasy
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eleonora Scorletti
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joseph Park
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- NewYork-Presbyterian, Weill Cornell Medical Center, New York, NY 10065, USA
| | | | - Kai Markus Schneider
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany
- Medical Department 1, Technische Universität, Dresden, Germany
| | - Daniel J. Rader
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Carolin Victoria Schneider
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany
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Alhajlah S. Effect of grape-derived products on the serum levels of enzymes mainly produced by the liver: A systematic review and meta-analysis of parallel randomized controlled trials. Phytother Res 2024; 38:3583-3593. [PMID: 38719548 DOI: 10.1002/ptr.8226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 01/13/2024] [Accepted: 04/20/2024] [Indexed: 07/12/2024]
Abstract
In recent years, an increase in the incidence of liver diseases has been reported all over the world. This study aims to comprehensively summarize and quantitatively analyze the existing evidence concerning the effectiveness of grape-derived products on liver enzymes through a systematic review and meta-analytic approach. PubMed, Scopus, Cochrane Library, and ISI Web of Science were comprehensively searched until January 2024. Articles that reported the effect of grape-derived products on serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels were included. Weighted mean differences (WMDs) were pooled using a random-effects model. Nine studies were included in the meta-analysis. The results revealed that grape-derived products did not significantly change the concentrations of ALT (WMD: -2.70 IU/L, 95% CI: -6.14 to 0.75, p = 0.12), and AST (WMD: -1.42 IU/L, 95% CI: -3.54 to 0.70, p = 0.18). However, a significant reduction was observed in serum ALP levels (WMD: -5.49 IU/L, 95% CI: -9.57 to -1.4, p = 0.008). The present findings suggest that grape-derived products positively influence serum ALP levels among adults. However, a more comprehensive decision necessitates additional studies.
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Affiliation(s)
- Sharif Alhajlah
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia
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Ayres ABS, Carneiro CRG, Gestic MA, Utrini MP, Chaim FDM, Callejas-Neto F, Chaim EA, Cazzo E. Identification of Predictors of Non-alcoholic Steatohepatitis and Its Severity in Individuals Undergoing Bariatric Surgery. Obes Surg 2024; 34:456-466. [PMID: 38097891 DOI: 10.1007/s11695-023-06986-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/28/2023] [Accepted: 12/06/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND As obesity reached epidemic proportions, non-alcoholic fatty liver disease (NAFLD) also had a worrisome parallel increase. The non-invasive differentiation of non-alcoholic steatohepatitis (NASH) from uncomplicated NAFLD remains an important challenge in current clinical practice. OBJECTIVE To identify predictors of the occurrence and severity of NAFLD and NASH. METHODS This is an analytical cross-sectional study which included individuals undergoing bariatric surgery. Participants were histologically classified according to the presence NASH and severity of NAFLD. Demographic, clinical, anthropometric, and biochemical aspects were analyzed and compared. RESULTS Out of 171 individuals, 87.7% were female and the mean age was 38.4±9.3 years. The average BMI was 38±3.0 kg/m2. NAFLD was histologically confirmed in 74.9%; the commonest histopathological abnormalities were macrovesicular steatosis (74.9%) and ballooning (40.4%). Simple steatosis occurred in 30.4%, 44.4% presented with NASH, and 31% had severe NAFLD. NASH associated with higher levels of ALT (0.03), ALP (0.02), and glucose (0.02). Cutoff values were, respectively, 23 U/L, 67 U/L, and 81 mg/dL. Their concomitant use provided an 83.1% specificity for NASH. Severe NAFLD associated with diabetes (p=0.02), higher BMI (p=0.01), AST (p=0.04), ALT (p<0.01), ALP (p=0.01), glucose (p=0.02), and ferritin (p<0.01). BMI over 39.3 kg/m2 and ferritin over 178 ng/mL concomitantly provided a 70.5% accuracy for severe NAFLD. CONCLUSIONS NASH and severe NAFLD associated with higher levels of ALT, ALP, and glucose. Severe NAFLD associated with higher BMI and higher ferritin levels in this group. The concomitant evaluation of these laboratory tests could help ruling out NASH and safely screening severe NAFLD.
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Affiliation(s)
- Arthur Balestra Silveira Ayres
- Dept. of Surgery-School of Medical Sciences-State University of Campinas (UNICAMP), Rua Alexander Fleming, s/no, Campinas, (SP), Brazil
| | | | - Martinho Antonio Gestic
- Dept. of Surgery-School of Medical Sciences-State University of Campinas (UNICAMP), Rua Alexander Fleming, s/no, Campinas, (SP), Brazil
| | - Murillo Pimentel Utrini
- Dept. of Surgery-School of Medical Sciences-State University of Campinas (UNICAMP), Rua Alexander Fleming, s/no, Campinas, (SP), Brazil
| | - Felipe David Mendonça Chaim
- Dept. of Surgery-School of Medical Sciences-State University of Campinas (UNICAMP), Rua Alexander Fleming, s/no, Campinas, (SP), Brazil
| | - Francisco Callejas-Neto
- Dept. of Surgery-School of Medical Sciences-State University of Campinas (UNICAMP), Rua Alexander Fleming, s/no, Campinas, (SP), Brazil
| | - Elinton Adami Chaim
- Dept. of Surgery-School of Medical Sciences-State University of Campinas (UNICAMP), Rua Alexander Fleming, s/no, Campinas, (SP), Brazil
| | - Everton Cazzo
- Dept. of Surgery-School of Medical Sciences-State University of Campinas (UNICAMP), Rua Alexander Fleming, s/no, Campinas, (SP), Brazil.
- Cidade Universitária Zeferino Vaz, Campinas, (SP), CEP 13085-000, Brazil.
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Sun K, Zhao JV, Nelson EAS, Wong VWS, Lam HSHS, Hui LL. Iron status and non-alcoholic fatty liver disease: A Mendelian randomization study. Nutrition 2024; 118:112295. [PMID: 38103266 DOI: 10.1016/j.nut.2023.112295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 10/10/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023]
Abstract
OBJECTIVES The aim of this study was to assess the association of genetically determined iron status with the risk for non-alcoholic fatty liver disease (NAFLD) using two-sample Mendelian randomization (MR) analysis. METHODS We applied single nucleotide polymorphisms (SNPs) associated at genome-wide significance with iron status proxied by serum iron, ferritin, transferrin, and transferrin saturation from the Genetics of Iron status Consortium (N = 48 793), in a genome-wide association study of 1664 NAFLD cases and 400 055 controls from the United Kingdom Biobank. A SNP associated with multiple markers of iron status was only applied to one marker with the strongest association in the main analysis. Their effects on NAFLD were calculated using inverse variance weighting after excluding SNPs associated with alkaline phosphatase and lipid metabolism. RESULTS The risk for NAFLD is negatively associated with genetically predicted serum transferrin level with a 20% reduction in NAFLD risk per SD (0.65g/L) increase in transferrin (95% confidence interval [CI], 0.66-0.97), and trending positive association with transferrin saturation (odds ratio [OR], 1.50; 95% CI, 0.96-2.35) but it was not associated with serum iron (OR, 0.90; 95% CI, 0.63-1.29) and ferritin (OR, 1.33; 95% CI, 0.54-3.30). CONCLUSIONS MR analysis provided evidence that genetically predicted higher serum transferrin, indicating lower iron status, may be protective against NAFLD, whereas higher transferrin saturation, indicating higher iron status, might increase the risk for NAFLD and its pathogenesis.
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Affiliation(s)
- Kexin Sun
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Jie V Zhao
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Edmund Anthony Severn Nelson
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China; School of Medicine, The Chinese University of Hong Kong, Shenzhen, PR China
| | - Vincent Wai Sun Wong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Hugh Simon Hung San Lam
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Lai Ling Hui
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong SAR, PR China.
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Tingle SJ, Bramley R, Goodfellow M, Thompson ER, McPherson S, White SA, Wilson CH. Donor Liver Blood Tests and Liver Transplant Outcomes: UK Registry Cohort Study. Transplantation 2023; 107:2533-2544. [PMID: 37069657 DOI: 10.1097/tp.0000000000004610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2023]
Abstract
BACKGROUND Safely increasing organ utilization is a global priority. Donor serum transaminase levels are often used to decline livers, despite minimal evidence to support such decisions. This study aimed to investigate the impact of donor "liver blood tests" on transplant outcomes. METHODS This retrospective cohort study used the National Health Service registry on adult liver transplantation (2016-2019); adjusted regressions models were used to assess the effect of donor "liver blood tests" on outcomes. RESULTS A total of 3299 adult liver transplant recipients were included (2530 following brain stem death, 769 following circulatory death). Peak alanine transaminase (ALT) ranged from 6 to 5927 U/L (median = 45). Donor cause of death significantly predicted donor ALT; 4.2-fold increase in peak ALT with hypoxic brain injury versus intracranial hemorrhage (adjusted P < 0.001). On multivariable analysis, adjusting for a wide range of factors, transaminase level (ALT or aspartate aminotransferase) failed to predict graft survival, primary nonfunction, 90-d graft loss, or mortality. This held true in all examined subgroups, that is, steatotic grafts, donation following circulatory death, hypoxic brain injury donors, and donors, in which ALT was still rising at the time of retrieval. Even grafts from donors with extremely deranged ALT (>1000 U/L) displayed excellent posttransplant outcomes. In contrast, donor peak alkaline phosphatase was a significant predictor of graft loss (adjusted hazard ratio = 1.808; 1.016-3.216; P = 0.044). CONCLUSIONS Donor transaminases do not predict posttransplant outcomes. When other factors are favorable, livers from donors with raised transaminases can be accepted and transplanted with confidence. Such knowledge should improve organ utilization decision-making and prevent future unnecessary organ discard. This provides a safe, simple, and immediate option to expand the donor pool.
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Affiliation(s)
- Samuel J Tingle
- National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Rebecca Bramley
- National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - Michael Goodfellow
- National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - Emily R Thompson
- National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Stuart McPherson
- Department of Hepatology, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - Steve A White
- National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Colin H Wilson
- National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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9
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Pagano S, Bakker SJL, Juillard C, Vossio S, Moreau D, Brandt KJ, Mach F, Dullaart RPF, Vuilleumier N. Antibody against apolipoprotein-A1, non-alcoholic fatty liver disease and cardiovascular risk: a translational study. J Transl Med 2023; 21:694. [PMID: 37798764 PMCID: PMC10552329 DOI: 10.1186/s12967-023-04569-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/23/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common liver disease increasing cardiovascular disease (CVD) morbidity and mortality. Autoantibodies against apolipoprotein A-1 (AAA-1) are a possible novel CVD risk factor promoting inflammation and disrupting cellular lipid homeostasis, two prominent pathogenic features of NAFLD. We explored the role of AAA-1 in NAFLD and their association with CVD risk. METHODS HepaRG cells and liver sections from ApoE-/- mice exposed to AAA-1 were used for lipid quantification and conditional protein expression. Randomly selected sera from 312 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND) general population cohort were used to measure AAA-1. A Fatty Liver Index (FLI) ≥ 60 and a 10-year Framingham Risk Score (FRS) ≥ 20% were used as proxy of NAFLD and high CVD risk, respectively. RESULTS In-vitro and mouse models showed that AAA-1 increased triglyceride synthesis leading to steatosis, and promoted inflammation and hepatocyte injury. In the 112 PREVEND participants with FLI ≥ 60, AAA-1 were associated with higher FRS, alkaline phosphatase levels, lower HDL cholesterol and tended to display higher FLI values. Univariate linear and logistic regression analyses (LRA) confirmed significant associations between AAA-1, FLI and FRS ≥ 20%, while in adjusted LRA, FLI was the sole independent predictor of FRS ≥ 20% (OR: 1.05, 95%CI 1.01-1.09, P = 0.003). AAA-1 was not an independent FLI predictor. CONCLUSIONS AAA-1 induce a NAFLD-compatible phenotype in vitro and in mice. Intricate associations exist between AAA-1, CVD risk and FLI in the general population. Further work is required to refine the role of AAA-1 in NAFLD and to determine if the AAA-1 association with CVD is affected by hepatic steatosis.
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Affiliation(s)
- Sabrina Pagano
- Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, Rue Michel Servet 1, 1211, Geneva, Switzerland.
- Department of Medicine Specialties, Medical Faculty, Geneva University, Geneva, Switzerland.
| | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Catherine Juillard
- Department of Medicine Specialties, Medical Faculty, Geneva University, Geneva, Switzerland
| | - Stefania Vossio
- School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Dimitri Moreau
- School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Karim J Brandt
- Department of Cardiology, University Hospitals of Geneva, Geneva, Switzerland
| | - François Mach
- Department of Cardiology, University Hospitals of Geneva, Geneva, Switzerland
| | - Robin P F Dullaart
- Department of Internal Medicine, Division of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Nicolas Vuilleumier
- Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, Rue Michel Servet 1, 1211, Geneva, Switzerland
- Department of Medicine Specialties, Medical Faculty, Geneva University, Geneva, Switzerland
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10
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Herrera-Marcos LV, Martínez-Beamonte R, Macías-Herranz M, Arnal C, Barranquero C, Puente-Lanzarote JJ, Gascón S, Herrero-Continente T, Gonzalo-Romeo G, Alastrué-Vera V, Gutiérrez-Blázquez D, Lou-Bonafonte JM, Surra JC, Rodríguez-Yoldi MJ, García-Gil A, Güemes A, Osada J. Hepatic galectin-3 is associated with lipid droplet area in non-alcoholic steatohepatitis in a new swine model. Sci Rep 2022; 12:1024. [PMID: 35046474 PMCID: PMC8770509 DOI: 10.1038/s41598-022-04971-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 12/29/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood. To characterize this disease, pigs, considered to be one of the most similar to human experimental animal models, were used. To date, all swine-based settings have been carried out using rare predisposed breeds or long-term experiments. Herein, we fully describe a new experimental swine model for initial and reversible NASH using cross-bred animals fed on a high saturated fat, fructose, cholesterol, cholate, choline and methionine-deficient diet. To gain insight into the hepatic transcriptome that undergoes steatosis and steatohepatitis, we used RNA sequencing. This process significantly up-regulated 976 and down-regulated 209 genes mainly involved in cellular processes. Gene expression changes of 22 selected transcripts were verified by RT-qPCR. Lipid droplet area was positively associated with CD68, GPNMB, LGALS3, SLC51B and SPP1, and negatively with SQLE expressions. When these genes were tested in a second experiment of NASH reversion, LGALS3, SLC51B and SPP1 significantly decreased their expression. However, only LGALS3 was associated with lipid droplet areas. Our results suggest a role for LGALS3 in the transition of NAFLD to NASH.
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Affiliation(s)
- Luis V Herrera-Marcos
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain.,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain
| | - Roberto Martínez-Beamonte
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain.,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Macías-Herranz
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain
| | - Carmen Arnal
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Patología Animal, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Barranquero
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain.,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan J Puente-Lanzarote
- Servicio de Bioquímica Clínica. Hospital, Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Sonia Gascón
- Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Tania Herrero-Continente
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain
| | - Gonzalo Gonzalo-Romeo
- Servicio General de Apoyo a la Investigación. División de Experimentación Animal, Universidad de Zaragoza, Zaragoza, Spain
| | | | | | - José M Lou-Bonafonte
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Joaquín C Surra
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Producción Animal y Ciencia de los Alimentos, Escuela Politécnica Superior de Huesca, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Huesca, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - María J Rodríguez-Yoldi
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.,Departamento de Farmacología, Fisiología, Medicina Legal y Forense, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Agustín García-Gil
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Antonio Güemes
- Departamento de Cirugía, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain
| | - Jesús Osada
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain. .,Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain. .,CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
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11
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A Model Incorporating Serum Alkaline Phosphatase for Prediction of Liver Fibrosis in Adults with Obesity and Nonalcoholic Fatty Liver Disease. J Clin Med 2021; 10:jcm10153311. [PMID: 34362095 PMCID: PMC8347722 DOI: 10.3390/jcm10153311] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/22/2021] [Accepted: 07/25/2021] [Indexed: 01/06/2023] Open
Abstract
We assessed the relationship between serum alkaline phosphatase (ALP) and liver fibrosis by histology, in addition to other noninvasive parameters, in obese patients undergoing metabolic surgery. Patients scheduled for elective bariatric surgery were prospectively recruited from a bariatric clinic. An intraoperative liver biopsy was performed, and liver histology was evaluated by a pathologist blinded to the patients' data. The endpoint was significant fibrosis defined as fibrosis stage ≥ 2. Independent predictors of fibrosis were identified by logistic regression. Two hundred ten patients were recruited. Liver histology revealed steatosis in 87.1%, steatohepatitis in 21.9%, and significant fibrosis in 10%. Independent predictors of significant fibrosis were ALP (Odds Ratio (OR) 1.03; 95% Confidence interval (CI), 1.01-1.05), alanine aminotransferase (OR 1.02; 95% CI, 1.01-1.03), HbA1c (OR 1.58; 95% CI, 1.20-2.09), and body mass index (OR 1.06; 95% CI, 1.00-1.13). A tree-based model was developed to predict significant fibrosis, with a receiver operating characteristic (ROC) area of 0.845, sensitivity of 0.857, specificity of 0.836, and accuracy of 0.931. The applicability of serum ALP as an independent biomarker of liver fibrosis should be considered in obesity surgery patients, and in the broader context of obese patients with nonalcoholic fatty liver disease.
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12
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Seen TK, Sayed M, Bilal M, Reyes JV, Bhandari P, Lourdusamy V, Al-khazraji A, Syed U, Sattar Y, Bansal R. Clinical indicators for progression of nonalcoholic steatohepatitis to cirrhosis. World J Gastroenterol 2021; 27:3238-3248. [PMID: 34163108 PMCID: PMC8218360 DOI: 10.3748/wjg.v27.i23.3238] [Citation(s) in RCA: 9] [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: 10/24/2020] [Revised: 12/06/2020] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), is a disease spectrum characterized by fat accumulation in hepatocytes presenting as hepatic steatosis to advance disease with active hepatic inflammation, known as nonalcoholic steatohepatitis. Chronic steatohepatitis will lead to progressive hepatic fibrosis causing cirrhosis and increased risk for developing hepatocellular carcinoma (HCC). Fatty liver disease prevalence has increased at alarming rates alongside obesity, diabetes and metabolic syndrome to become the second most common cause of cirrhosis after alcohol related liver disease worldwide. Given this rise in prevalence, it is becoming increasingly more important to find non-invasive methods to diagnose disease early and stage hepatic fibrosis. Providing clinicians with the tools to diagnose and treat the full spectrum of NAFLD will help prevent known complications such as cirrhosis and HCC and improve quality of life for the patients suffering from this disease. This article discusses the utility of current non-invasive liver function testing in the clinical progression of fatty liver disease along with the imaging modalities that are available. Additionally, we summarize available treatment options including targeted medical therapy through four different pathways, surgical or endoscopic intervention.
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Affiliation(s)
- Tasur Kumar Seen
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Muntazir Sayed
- Division of Internal Medicine, R.C.S.M. Government College, Mahrashta 416013, India
| | - Muhammad Bilal
- Division of Gastroenterology, Hepatology and Endoscopy, Pakistan Institute of Medical Sciences, Islamabad 45710, Pakistan
| | - Jonathan Vincent Reyes
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Priyanka Bhandari
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Vennis Lourdusamy
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Ahmed Al-khazraji
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Umer Syed
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Yasar Sattar
- Division of Internal Medicine, Icahn School of Medicine, Elmhurst Hospital and Mount Sinai Hospital, Elmhurst, NY 11375, United States
| | - Raghav Bansal
- Division of Gastroenterology, Icahn School of Medicine, Elmhurst Hospital, Elmhurst, NY 11375, United States
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13
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Association of Serum Alkaline Phosphatase with the TG/HDL Ratio and TyG Index in Korean Adults. Biomolecules 2021; 11:biom11060882. [PMID: 34198561 PMCID: PMC8231902 DOI: 10.3390/biom11060882] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 11/17/2022] Open
Abstract
Alkaline phosphatase (ALP) has long been considered a marker of hepatobiliary and bone disorders, but recent studies have shown that increased ALP activity is correlated with various cardio-metabolic diseases. Thus, we investigated the association of serum ALP level with surrogate markers of insulin resistance such as triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C ratio) and triglyceride and glucose (TyG) index in the general population. The study included 12,868 men and women aged 19 years and older. Participants were categorized into four groups based on serum ALP level (U/L) as follows: Q1: 55-190 U/L, Q2: 191-224 U/L, Q3: 225-265 U/L, and Q4: 266-923 U/L for men, Q1: 48-161 U/L, Q2: 162-198 U/L, Q3: 199-245 U/L, Q4: 246-790 U/L for women. The insulin resistance cut-off levels were defined corresponding to the 75th percentile of the TyG index and TG/HDL-C ratio in the current samples. Odds ratios (ORs) with 95% confidence intervals (CIs) of insulin resistance according to quartile of serum ALP level were calculated using weighted multivariate logistic regression analysis. Compared with Q1, the adjusted OR (95% CI) for insulin resistance of the Q4 serum ALP group was 1.517 (1.234-1.866) in men and 1.881 (1.399-2.528) in women using the TG/HDL-C ratio and 1.374 (1.093-1.728) in men and 2.047 (1.468-2.855) in women using the TyG index after adjusting for confounding variables. Serum ALP levels are independently and positively associated with surrogate markers of insulin resistance in Korean adults.
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14
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Heda R, Yazawa M, Shi M, Bhaskaran M, Aloor FZ, Thuluvath PJ, Satapathy SK. Non-alcoholic fatty liver and chronic kidney disease: Retrospect, introspect, and prospect. World J Gastroenterol 2021; 27:1864-1882. [PMID: 34007127 PMCID: PMC8108029 DOI: 10.3748/wjg.v27.i17.1864] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/07/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
With the growing prevalence of obesity and diabetes in the United States and across the world, a rise in the overall incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is expected. The risk factors for NAFLD are also associated with the development of chronic kidney disease (CKD). We review the epidemiology, risk factors, genetics, implications of gut dysbiosis, and specific pathogenic mechanisms linking NAFLD to CKD. Mechanisms such as ectopic lipid accumulation, cellular signaling abnormalities, and the interplay between fructose consumption and uric acid accumulation have led to the emergence of potential therapeutic implications for this patient population. Transplant evaluation in the setting of both NAFLD and CKD is also reviewed. Potential strategies for surveillance and management include the monitoring of comorbidities, the use of non-invasive fibrosis scoring systems, and the measurement of laboratory markers. Lastly, we discuss the management of patients with NAFLD and CKD, from preventative measures to experimental interventions.
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Affiliation(s)
- Rajiv Heda
- Department of Internal Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Masahiko Yazawa
- Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Michelle Shi
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
| | - Madhu Bhaskaran
- Department of Nephrology, Northwell Health/Zucker School of Medicine at Hosftra, Manhasset, NY 11030, United States
| | - Fuad Zain Aloor
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Paul J Thuluvath
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD 21202, United States
| | - Sanjaya K Satapathy
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
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15
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Crabtree CD, Kackley ML, Buga A, Fell B, LaFountain RA, Hyde PN, Sapper TN, Kraemer WJ, Scandling D, Simonetti OP, Volek JS. Comparison of Ketogenic Diets with and without Ketone Salts versus a Low-Fat Diet: Liver Fat Responses in Overweight Adults. Nutrients 2021; 13:966. [PMID: 33802651 PMCID: PMC8002465 DOI: 10.3390/nu13030966] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/13/2021] [Accepted: 03/15/2021] [Indexed: 12/15/2022] Open
Abstract
Ketogenic diets (KDs) often contain high levels of saturated fat, which may increase liver fat, but the lower carbohydrate intake may have the opposite effect. Using a controlled feeding design, we compared liver fat responses to a hypocaloric KD with a placebo (PL) versus an energy-matched low-fat diet (LFD) in overweight adults. We also examined the added effect of a ketone supplement (KS). Overweight adults were randomized to a 6-week KD (KD + PL) or a KD with KS (KD + KS); an LFD group was recruited separately. All diets were estimated to provide 75% of energy expenditure. Weight loss was similar between groups (p > 0.05). Liver fat assessed by magnetic resonance imaging decreased after 6 week (p = 0.004) with no group differences (p > 0.05). A subset with nonalcoholic fatty liver disease (NAFLD) (liver fat > 5%, n = 12) showed a greater reduction in liver fat, but no group differences. In KD participants with NAFLD, 92% of the variability in change in liver fat was explained by baseline liver fat (p < 0.001). A short-term hypocaloric KD high in saturated fat does not adversely impact liver health and is not impacted by exogenous ketones. Hypocaloric low-fat and KDs can both be used in the short-term to significantly reduce liver fat in individuals with NAFLD.
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Affiliation(s)
- Christopher D. Crabtree
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - Madison L. Kackley
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - Alexandru Buga
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - Brandon Fell
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - Richard A. LaFountain
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - Parker N. Hyde
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - Teryn N. Sapper
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - William J. Kraemer
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
| | - Debbie Scandling
- Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA; (D.S.); (O.P.S.)
| | - Orlando P. Simonetti
- Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA; (D.S.); (O.P.S.)
- Departments of Radiology and Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Jeff S. Volek
- Department of Human Sciences, The Ohio State University, Columbus, OH 43201, USA; (C.D.C.); (M.L.K.); (A.B.); (B.F.); (R.A.L.); (P.N.H.); (T.N.S.); (W.J.K.)
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The Role of Elastography in Non-Alcoholic Fatty Liver Disease. CURRENT HEALTH SCIENCES JOURNAL 2020; 46:255-269. [PMID: 33304627 PMCID: PMC7716767 DOI: 10.12865/chsj.46.03.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 08/10/2020] [Indexed: 11/18/2022]
Abstract
The most common liver disease in developing countries is non-alcoholic fatty liver disease (NAFLD). This involves the abnormal accumulation of lipids in the liver, the pathogenesis of the disease being related to dyslipidemia, obesity, insulin resistance and type 2 diabetes. Most often, the diagnosis of NAFLD is incidental, when performing routine blood tests or when performing a transabdominal ultrasound. The NAFLD spectrum ranges from simple forms of hepatic steatosis to the most advanced form of the disease, steatohepatitis (NASH), which in evolution can cause inflammation, fibrosis, cirrhosis of the liver and even liver cancer. For the evaluation of the prognosis and the clinical evolution, the most important parameter to define is the degree of liver fibrosis. Currently, the gold standard remains the liver biopsy, the differentiation between NAFLD and NASH being made only on the basis of histological analysis. However, liver biopsy is an invasive procedure, with numerous risks such as bleeding, lesions of the other organs and complications related to anesthesia, which significantly reduces its widespread use. Moreover, the risk of a false negative result and the increased costs of the procedure further limits its use in current practice. For this reason, non-invasive methods of evaluating the degree of liver fibrosis have gained ground in recent years. Imaging techniques such as elastography have shown promising results in evaluating and staging NAFLD. The aim of this article is to review the current status of the non-invasive tests for the assessment of NAFLD with a focus on the ultrasound-based elastography techniques.
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17
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Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M, Matono T, Kato J, Tokunaga S, Sugihara T, Hiramatsu A, Hyogo H, Tobita H, Sato S, Kawanaka M, Hara Y, Hino K, Chayama K, Murawaki Y, Isomoto H. Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease. PLoS One 2020; 15:e0219412. [PMID: 32106257 PMCID: PMC7046274 DOI: 10.1371/journal.pone.0219412] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. Methods Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. Results Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism–related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. Conclusions Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.
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Affiliation(s)
- Kinya Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Masahiko Koda
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Toshiaki Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takumi Onoyama
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Kenichi Miyoshi
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Manabu Kishina
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Tomomitsu Matono
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Shiho Tokunaga
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takaaki Sugihara
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hatsukaichi, Hiroshima, Japan
| | - Hiroshi Tobita
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Shuichi Sato
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Okayama, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Yoshikazu Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Hajime Isomoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
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Regev A, Palmer M, Avigan MI, Dimick‐Santos L, Treem WR, Marcinak JF, Seekins D, Krishna G, Anania FA, Freston JW, Lewis JH, Sanyal AJ, Chalasani N. Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2019; 49:702-713. [PMID: 30761572 PMCID: PMC6593464 DOI: 10.1111/apt.15153] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/22/2018] [Accepted: 01/02/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. AIMS This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. METHODS This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. RESULTS Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. CONCLUSIONS This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.
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Sales RC, Medeiros PC, Spreafico F, de Velasco PC, Gonçalves FKA, Martín-Hernández R, Mantilla-Escalante DC, Gil-Zamorano J, Peres WAF, de Souza SAL, Dávalos A, Tavares do Carmo MG. Olive Oil, Palm Oil, and Hybrid Palm Oil Distinctly Modulate Liver Transcriptome and Induce NAFLD in Mice Fed a High-Fat Diet. Int J Mol Sci 2018; 20:ijms20010008. [PMID: 30577497 PMCID: PMC6337378 DOI: 10.3390/ijms20010008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 12/17/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. The most severe form is nonalcoholic steatohepatitis (NASH). Among risk factors for the development of NAFLD is excessive lipid intake. Since palm (P) oil is the most consumed oil in the world, we aimed to investigate the effects of high-fat diets made with P oil, hybrid palm (HP) oil, or olive (O) oil in liver. Twenty-four male mice (C57Bl/6J) were fed a high-fat diet (41% fat) containing P, HP, or O oils for 8 weeks and compared to a control (C) group fed a chow diet. Adiposity was measured with computed tomography. Body, adipose tissue, and liver weights, as well as liver fat (Bligh–Dyer), blood lipid profile, glucose, and liver enzymes were measured. Liver histology (hematoxylin–eosin) and transcriptome (microarray-based) were performed. ANOVA tests with Newman–Keuls were used. Body weight was increased in the P group (p < 0.001) and body fat in the O group (C vs. O p ≤ 0.01, P vs. O p ≤ 0.05, HP vs. O p ≤ 0.05). All high-fat diets disturbed the blood lipid profile and glucose, with marked effects of HP on very low-density lipoprotein cholesterol (VLDL), triglycerides, and alkaline phosphatase (p ≤ 0.001). HP had the highest liver fat (42.76 ± 1.58), followed by P (33.94 ± 1.13). O had a fat amount comparable to C (16.46 ± 0.34, 14.71 ± 0.70, respectively). P and HP oils induced hepatocyte ballooning. Transcriptome alterations of the O group were related to amino acid metabolism and fatty acid (FA) metabolism, the P group to calcium ion homeostasis, and HP oil to protein localization. Both P and HP oils induced NASH in mice via disturbed hepatocyte transcription. This raises concerns about the content of these oils in several industrialized foods.
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Affiliation(s)
- Rafael C Sales
- Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil.
| | - Priscylla C Medeiros
- Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21044-020, Brazil.
| | - Flavia Spreafico
- Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil.
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, 28049 Madrid, Spain.
| | - Patrícia C de Velasco
- Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil.
| | - Fernanda K A Gonçalves
- Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil.
| | - Roberto Martín-Hernández
- GENYAL Platform on Nutrition and Health, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, 28049 Madrid, Spain.
| | - Diana C Mantilla-Escalante
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, 28049 Madrid, Spain.
| | - Judit Gil-Zamorano
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, 28049 Madrid, Spain.
| | - Wilza A F Peres
- Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil.
| | - Sergio A L de Souza
- Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21044-020, Brazil.
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, 28049 Madrid, Spain.
| | - Maria G Tavares do Carmo
- Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil.
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Liu CF, Zhou WN, Lu Z, Wang XT, Qiu ZH. The associations between liver enzymes and the risk of metabolic syndrome in the elderly. Exp Gerontol 2018; 106:132-136. [PMID: 29499373 DOI: 10.1016/j.exger.2018.02.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Revised: 10/28/2017] [Accepted: 02/25/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Studies have demonstrated that liver enzymes are associated with metabolic syndrome (MetS). However, little information is available regarding these relationships in elderly populations. Our present study aimed to explore the associations between liver enzymes and the risk of MetS in elderly populations. METHODS This cross-sectional study included 1444 elder participants (970 men and 474 women) who attended annual physical examinations. Univariate and multivariate logistic regressions were performed to estimate the associations between liver enzymes and the risk of MetS and its components according to quartiles of the concentration of each liver enzyme. RESULTS The prevalence of MetS and its components increased remarkably with increasing quartiles of alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) but not with aspartate aminotransferase (AST) in the elderly. Compared with subjects in the bottom quartile, the adjusted odds ratio for MetS in the highest ALT, GGT and ALP quartiles were 1.78 (95% CI 1.21-2.61), 2.58 (95% CI 1.77-3.78) and 1.85 (95%CI 1.27-2.70) respectively. No statistically significant increases in the odds ratio for MetS according to increased quartiles of AST were found in either the univariate or multivariate logistic regression analyses. CONCLUSIONS Elevated liver enzymes levels (mainly ALT, GGT and ALP but not AST) are positively associated with the prevalence of MetS in elderly populations.
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Affiliation(s)
- Cun-Fei Liu
- Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China; Department of Cardiology, Linyi People's Hospital, Linyi, Shandong 276000, China
| | - Wei-Ning Zhou
- Department of Pathology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Zheng Lu
- Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Xue-Ting Wang
- Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Zhao-Hui Qiu
- Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
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Panasevich MR, Meers GM, Linden MA, Booth FW, Perfield JW, Fritsche KL, Wankhade UD, Chintapalli SV, Shankar K, Ibdah JA, Rector RS. High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Am J Physiol Endocrinol Metab 2018; 314:E78-E92. [PMID: 28899857 PMCID: PMC5866386 DOI: 10.1152/ajpendo.00015.2017] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 09/07/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023]
Abstract
Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.0% fat; 17.8% high-fructose corn syrup; 2% cholesterol) or low-fat diet (CON/lean; 10.5% fat) for 16 wk ( n = 6 each) or 36 wk ( n = 4 each). WD-fed pigs developed obesity, dyslipidemia, and systemic insulin resistance compared with CON pigs. In addition, obese WD-fed pigs developed severe NASH, with hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, and fibrosis after 16 wk, with further exacerbation of histological inflammation and fibrosis after 36 wk of WD feeding. WD feeding also resulted in robust cecal microbiota changes including increased relative abundances of families and genera in Proteobacteria ( P < 0.05) (i.e., Enterobacteriaceae, Succinivibrionaceae, and Succinivibrio) and LPS-containing Desulfovibrionaceae and Desulfovibrio and a greater ( P < 0.05) predicted microbial metabolic function for LPS biosynthesis, LPS biosynthesis proteins, and peptidoglycan synthesis compared with CON-fed pigs. Overall, juvenile Ossabaw swine fed a high-fat, high-fructose, high-cholesterol diet develop obesity and severe microbiota dysbiosis with a proinflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population.
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Affiliation(s)
- M. R. Panasevich
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - G. M. Meers
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri
| | - M. A. Linden
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - F. W. Booth
- Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
| | - J. W. Perfield
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
- Department of Food Science, University of Missouri, Columbia, Missouri
| | - K. L. Fritsche
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - Umesh D. Wankhade
- Department of Pediatrics, Arkansas Children’s Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Sree V. Chintapalli
- Department of Pediatrics, Arkansas Children’s Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - K. Shankar
- Department of Pediatrics, Arkansas Children’s Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - J. A. Ibdah
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri
| | - R. S. Rector
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri
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El Nakeeb N, Saleh SA, Massoud YM, Hussein A, Hamed R. Serum ferritin as a non-invasive marker in the prediction of hepatic fibrosis among Egyptian patients with non-alcoholic fatty liver disease. JGH OPEN 2017; 1:112-119. [PMID: 30483546 PMCID: PMC6207043 DOI: 10.1002/jgh3.12019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/22/2017] [Accepted: 10/03/2017] [Indexed: 12/14/2022]
Abstract
Background and Aim Many studies have found a relationship between hepatic iron, serum ferritin, and non‐alcoholic fatty liver disease (NAFLD) or its progress. The aim of this study is to assess the value of serum ferritin as a non‐invasive marker in the prediction of hepatic fibrosis in NAFLD. Methods This study included 113 subjects who were classified into three groups. Group I included 30 healthy subjects as control with no clinical, radiological, and histological features of NAFLD. Group II included 31 NAFLD patients without hepatic fibrosis. Group III included 52 patients with hepatic fibrosis on top of NAFLD. Results Serum ferritin was determined using ferritin ELISA kit. Fibrosis 4 score was calculated. Liver biopsy was conducted for included patients. Significantly higher levels of serum ferritin were found in patients with hepatic fibrosis on top of NAFLD than controls. Receiver operating characteristic curve analysis revealed that an optimum cutoff level of 51.95 ng/mL was the best to predict fibrosis on top of NAFLD with diagnostic sensitivity and specificity of 65% and 60%, respectively, and area under the curve = 0.658. Conclusion Higher serum ferritin was found in patients with hepatic fibrosis on top of NAFLD. Serum ferritin was found to be a predictor of fibrosis on top of NAFLD with moderate sensitivity and specificity.
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Affiliation(s)
- Noha El Nakeeb
- Internal Medicine Department, Faculty of Medicine Ain Shams University Cairo Egypt
| | - Shereen A Saleh
- Internal Medicine Department, Faculty of Medicine Ain Shams University Cairo Egypt
| | - Yasmine M Massoud
- Tropical Medicine Department, Faculty of Medicine Ain Shams University Cairo Egypt
| | - Ahmed Hussein
- Diagnostic and Interventional Radiology Department, Faculty of Medicine Ain Shams University Cairo Egypt
| | - Rana Hamed
- One Day Surgery Hospital Ministry of Health and Population Cairo Egypt
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Ikewuchi CC, Ikewuchi JC, Ifeanacho MO. Restoration of plasma markers of liver and kidney functions/integrity in alloxan-induced diabetic rabbits by aqueous extract of Pleurotus tuberregium sclerotia. Biomed Pharmacother 2017; 95:1809-1814. [PMID: 28968925 DOI: 10.1016/j.biopha.2017.09.075] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 09/13/2017] [Accepted: 09/18/2017] [Indexed: 02/09/2023] Open
Abstract
The effect of aqueous extract of the sclerotia of Pleurotus tuberregium on the plasma electrolytes, and markers of liver and kidney functions/integrity of normal and alloxan-induced rabbits was investigated. Diabetes mellitus was induced by injection of alloxan (120mg/kg body weight), via the marginal ear vein. The extract was administered orally at 100, 200 and 300mg/kg (both to normal and diabetic rabbits), and metformin at 50mg/kg. Gas chromatographic-flame ionization detector analysis of the extract revealed the presence of twelve known phenolic acids, consisting mainly of caffeic acid (80.24%), chlorogenic acid (11.08%), piperic acid (6.11%), sinapinic acid (2.14%) and ferulic acid (0.34%). Compared to test control, the treatment significantly (p<0.05) lowered plasma activities of alkaline phosphatase, gamma glutamyltransferase, and alanine and aspartate transaminases. Also lowered were plasma unconjugated/conjugated bilirubin ratio and concentrations of urea, blood urea nitrogen, creatinine, sodium, and total and unconjugated bilirubin. It however, significantly (p<0.05) raised plasma potassium and calcium levels. Therefore, the modulation of plasma sodium and potassium is an indication of the diuretic potential of the extract. In addition, the extract had no deleterious effect on the liver and kidney of the treated animals, at least at the doses administered in this study.
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Affiliation(s)
- Catherine Chidinma Ikewuchi
- Department of Biochemistry, Faculty of Science, University of Port Harcourt, P.M.B. 5323, Port Harcourt, Nigeria.
| | - Jude Chigozie Ikewuchi
- Department of Biochemistry, Faculty of Science, University of Port Harcourt, P.M.B. 5323, Port Harcourt, Nigeria.
| | - Mercy Onuekwuzu Ifeanacho
- Department of Biochemistry, Faculty of Science, University of Port Harcourt, P.M.B. 5323, Port Harcourt, Nigeria.
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24
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Zhou YJ, Zou H, Zheng JN, Zou TT, Vitale A, Miele L, Van Poucke S, Liu WY, Shen S, Zhang DC, Shi KQ, Zheng MH. Serum alkaline phosphatase, a risk factor for non-alcoholic fatty liver, but only for women in their 30s and 40s: evidence from a large cohort study. Expert Rev Gastroenterol Hepatol 2017; 11:269-276. [PMID: 28095261 DOI: 10.1080/17474124.2017.1283984] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Several risk factors are able to predict non-alcoholic fatty liver (NAFL) development, but the predictive value of serum alkaline phosphatase (ALP) remains uncertain. Our aim is to investigate the association between serum ALP levels and NAFL. METHODS 21,331 NAFL-free subjects were included. Sex-specific ALP quartiles (Q1 to Q4) were defined. With Q1 used as reference, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated across each quartile. RESULTS After adjusting for confounding variables, values in Q2, Q3 and Q4 had HRs (95%CIs) of 1.16 (0.94-1.43), 1.38 (1.13-1.69), 1.51 (1.24-1.83) in females and 0.99 (0.90-1.09), 1.04 (0.95-1.14), 0.96 (0.87-1.05) in males, respectively. A subgroup analysis of age factors in females, from Q2 to Q4, adjusted HRs (95%CIs) were 1.31 (0.81-1.99), 1.86 (1.23-2.81), 2.44 (1.60-3.71) in their 30 s, 1.13 (0.83-1.54), 1.17 (0.85-1.62), 1.65 (1.22-2.25) in their 40 s, and 0.95 (0.51-1.78), 0.91 (0.52-1.62), 0.89 (0.53-1.52) in their 50 s. CONCLUSIONS Higher serum ALP levels are considered a significant predictor for NAFL development in females aged 30 to 50.
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Affiliation(s)
- Yu-Jie Zhou
- a Department of Hepatology, Liver Research Center , the First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China.,b School of the First Clinical Medical Sciences , Wenzhou Medical University , Wenzhou , China
| | - Hai Zou
- c Department of Cardiology , Zhejiang Provincial People's Hospital , Hangzhou , China
| | - Ji-Na Zheng
- a Department of Hepatology, Liver Research Center , the First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China.,b School of the First Clinical Medical Sciences , Wenzhou Medical University , Wenzhou , China
| | - Tian-Tian Zou
- a Department of Hepatology, Liver Research Center , the First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China.,d School of the Second Clinical Medical Sciences , Wenzhou Medical University , Wenzhou , China
| | - Alessandro Vitale
- e Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Luca Miele
- f Institute of Internal Medicine , Catholic University of Rome , Rome , Italy.,g Gastroenterology Area, Fondazione Policlinico Gemelli , Rome , Italy
| | - Sven Van Poucke
- h Department of Anesthesiology , Critical Care, Emergency Medicine and Pain Therapy, Ziekenhuis Oost-Limburg , Genk , Belgium
| | - Wen-Yue Liu
- i Department of Endocrinology , the First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Shengrong Shen
- j Department of Food Science & Nutrition , Zhejiang University , Hangzhou , China
| | - Dong-Chu Zhang
- k Wenzhou Medical Center, Wenzhou People's Hospital , Wenzhou , China
| | - Ke-Qing Shi
- a Department of Hepatology, Liver Research Center , the First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China.,l Institute of Hepatology , Wenzhou Medical University , Wenzhou , China
| | - Ming-Hua Zheng
- a Department of Hepatology, Liver Research Center , the First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China.,l Institute of Hepatology , Wenzhou Medical University , Wenzhou , China
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Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study. Lipids Health Dis 2016; 15:207. [PMID: 27887608 PMCID: PMC5124242 DOI: 10.1186/s12944-016-0367-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 11/09/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Recently genome-wide association studies identified that NCAN rs2228603 polymorphism was associated with non-alcoholic fatty liver disease (NAFLD) mainly in subjects of European ancestry. While no research have been conducted to demonstrate the relationship between NCAN rs2228603 and NAFLD in Chinese Han adults. The aim of this study was to investigate whether NCAN rs2228603 is associated with NAFLD in Chinese population. METHODS Gene NCAN rs2228603 was genotyped in 182 patients with NAFLD and 195 healthy controls. The expression of NCAN was tested according to polymerase chain reaction analysis (PCR) and serum lipids were performed by biology techniques. RESULTS No significant difference was found in genotype and allele frequencies of NCAN rs2228603 between the NAFLD group and the controls (P > 0.05). Subjects with the NCAN rs2228603 CT genotype showed a higher level of alkaline phosphatase (AKP) (P = 0.017) and a higher high-density lipoprotein (HDL) (P < 0.05). CONCLUSIONS Our study for the first time identified that the gene NCAN rs2228603 is not a risk factor for the incidence of NAFLD in Chinese population. Also we found the dual and opposite role of T variant in protecting liver with a higher level of HDL and conferring risk for liver damage with a higher level of AKP. TRIAL REGISTRATION Chinese Clinical Trial Register.gov Identifier: ChiCTR-ROC-15006447 .
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Amaya-Cruz DM, Rodríguez-González S, Pérez-Ramírez IF, Loarca-Piña G, Amaya-Llano S, Gallegos-Corona MA, Reynoso-Camacho R. Juice by-products as a source of dietary fibre and antioxidants and their effect on hepatic steatosis. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.04.051] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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Bulum T, Kolarić B, Duvnjak M, Duvnjak L. Alkaline phosphatase is independently associated with renal function in normoalbuminuric type 1 diabetic patients. Ren Fail 2014; 36:372-7. [PMID: 24455970 DOI: 10.3109/0886022x.2013.872569] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with an increased prevalence of chronic kidney disease in patients with type 1 diabetes. The aim of this study was to explore the relationship between markers of NAFLD, namely concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALK), γ-glutamyltransferase (GGT), bilirubin, and renal function in type 1 diabetic patients. This study included 313 normoalbuminuric type 1 diabetic patients with estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m(2), without clinical evidence of cirrhosis or other causes of chronic liver disease and before any interventions with statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers. ALT, GGT, and bilirubin levels were significantly higher in subjects in the highest quartile of serum creatinine compared to those in lowest quartile (21 vs. 20 U/L, 18 vs. 14 U/L, and 14 vs. 10 µmol/L, respectively, for all p < 0.05). ALK levels were significantly higher in subjects in the highest quartile of urinary albumin excretion rate compared to those in lowest quartile (71 vs. 69 U/L, p = 0.03), as well as in hyperfiltrating subjects compared to those with normal or mildly impaired eGFR (81 vs. 68 and 64 U/L, p < 0.001). In a multiple logistic regression model adjusted for age, sex, duration of diabetes, HbA1c, and body mass index (BMI), only ALK levels were significantly associated with disturbances in serum creatinine and eGFR in our subjects (p ≤ 0.007), with odds ratios of 0.98-1.02. NAFLD associated markers, particularly ALK, are associated with renal function in normoalbuminuric type 1 diabetic patients.
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Affiliation(s)
- Tomislav Bulum
- Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur , Zagreb , Croatia
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Abstract
Non-alcoholic fatty liver disease (NAFLD) affects one in every three subjects in the occidental world. The vast majority will not progress, but a relevant minority will develop liver cirrhosis and its complications. The classical gold standard for diagnosing and staging NAFLD and assessing fibrosis is liver biopsy (LB). However, it has important sample error issues and subjectivity in the interpretation, apart from a small but real risk of complications. The decision to perform an LB is even harder in a condition so prevalent such as NAFLD, in which the probability of finding severe liver injury is low. In an attempt to overcome LB and to subcategorize patients with NAFLD in different prognoses allowing better management decisions, several non-invasive methods have been studied in the last decade. The literature is vast and confusing. This review will summarize which methods have been tested and how they perform, which tests are adequate for clinical practice and how they can change the management of these patients.
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Affiliation(s)
- Mariana V Machado
- Departamento de Gastrenterologia, Hospital Santa Maria, CHLN, Unidade de Nutrição e Metabolismo, Faculdade de Medicina de Lisboa, IMM, Lisbon, Portugal
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Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci 2013; 1281:106-22. [PMID: 23363012 PMCID: PMC3646408 DOI: 10.1111/nyas.12016] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ∼5% is believed to improve steatosis, whereas ∼10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups.
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Affiliation(s)
- Howard C Masuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide, encompasses a spectrum of abnormal liver histology ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Population studies show that NAFLD is strongly associated with insulin resistance, obesity, type 2 diabetes mellitus, and lipid abnormalities. In the context of hepatic steatosis, factors that promote cell injury, inflammation, and fibrosis include oxidative stress, early mitochondrial dysfunction, endoplasmic reticulum stress, iron accumulation, apoptosis, adipocytokines, and stellate cell activation. The exact NASH prevalence is unknown because of the absence of simple noninvasive diagnostic tests. Although liver biopsy is the "gold standard" for the diagnosis of NASH, other tests are needed to facilitate the diagnosis and greatly reduce the requirement for invasive liver biopsy. In addition, the development of new fibrosis markers in NASH is needed to facilitate the assessment of its progression and the effectiveness of new therapies. The aim of this chapter, which is overview of biomarkers in NASH, is to establish a systematic approach to laboratory findings of the disease.
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Abstract
As the hepatic manifestation of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of asymptomatic liver enzyme elevations in Western nations. Although it is easy to diagnose NAFLD, a liver biopsy is currently required to diagnose nonalcoholic steatohepatitis (NASH). Patients with NASH are those at greatest risk of progression to cirrhosis and, thus, treatment efforts are targeted to these individuals. Although currently there are no FDA-approved treatments for NASH, a multidisciplinary approach that addresses comorbid conditions and promotes modest weight loss comprises the backbone of therapy.
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Affiliation(s)
- Angelo H Paredes
- Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
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Sharma S, Barrett F, Adamson J, Todd A, Megson IL, Zentler-Munro PL, MacRury SM. Diabetic fatty liver disease is associated with specific changes in blood-borne markers. Diabetes Metab Res Rev 2012; 28:343-8. [PMID: 22576780 DOI: 10.1002/dmrr.2269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) can lead to cirrhosis and hepatocellular carcinoma and is strongly associated with obesity and insulin resistance. The aim of this study was to assess if plasma markers associated with NAFLD are increased in people with concomitant diabetes compared with those without. METHODS A total of 68 participants were recruited from diabetes and liver clinics. Fatty liver disease was indicated by routine blood tests and ultrasonography. Forty-seven participants had type 2 diabetes; of them, 18 had no fatty liver disease as defined previously (DNoFLD) and 29 had fatty liver disease (DFLD); the remaining 21 had fatty liver disease but no diabetes (NonDFLD). Serum samples were analyzed for adiponectin (APN), alanine and aspartate aminotransferases and plasma for cholesterol, triglyceride, hyaluronic acid (HA), procollagen peptide III, alkaline phosphatase and fibrinogen. RESULTS Hyaluronic acid and procollagen peptide III were significantly higher and adiponectin significantly lower in DFLD than NonDFLD and DNoFLD, the difference being particularly marked for hyaluronic acid and APN. There was no difference in these markers between NonDFLD and DNoFLD and no association between any plasma or serum marker and ultrasound grade of steatosis. CONCLUSION We have identified markers of hepatic steatosis that appear to be specific for people with type 2 diabetes. A further longitudinal study is merited to assess the role of these markers in understanding the progression of hepatic steatosis and fibrosis in people with and without diabetes.
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Affiliation(s)
- S Sharma
- Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Inverness, UK
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Diagnosis and evaluation of nonalcoholic fatty liver disease. EXPERIMENTAL DIABETES RESEARCH 2011; 2012:145754. [PMID: 22110476 PMCID: PMC3205741 DOI: 10.1155/2012/145754] [Citation(s) in RCA: 161] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Accepted: 08/31/2011] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver function tests results, after the commonly investigated causes have been excluded, and frequently coexists with type 2 diabetes mellitus (T2DM) because the conditions have common risk factors. As both T2DM and NAFLD are related to adverse outcomes of the other, diagnosis and valuation of fatty liver is an important part of the management of diabetes. Although noninvasive methods, such as biomarkers, panel markers, and imaging, may support a diagnostic evaluation of NAFLD patients, accurate histopathological findings cannot be achieved without a liver biopsy. As it is important to know whether steatohepatitis and liver fibrosis are present for the management of NAFLD, liver biopsy remains the gold standard for NAFLD diagnosis and evaluation. Therefore, new investigations of the pathogenesis of NAFLD are necessary to develop useful biomarkers that could provide a reliable noninvasive alternative to liver biopsy.
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Krishnamurthy VR, Baird BC, Wei G, Greene T, Raphael K, Beddhu S. Associations of serum alkaline phosphatase with metabolic syndrome and mortality. Am J Med 2011; 124:566.e1-7. [PMID: 21605734 PMCID: PMC5260794 DOI: 10.1016/j.amjmed.2010.11.030] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Revised: 10/28/2010] [Accepted: 11/29/2010] [Indexed: 01/30/2023]
Abstract
BACKGROUND Recent data suggest that elevated serum alkaline phosphatase levels are associated with increased mortality, but the mechanisms for this association are unknown. As metabolic syndrome is associated with higher serum alkaline phosphatase levels, we examined the joint association of mortality with metabolic syndrome and serum alkaline phosphatase levels in the US general population. METHODS Retrospective observational study of 15,234 adult participants in the National Health and Nutrition Examination Survey III. Multivariable Cox regression analyses were used to jointly relate mortality risk to serum alkaline phosphatase and indicators of metabolic syndrome. RESULTS Prevalence of metabolic syndrome was 14% to 41% among patients in lowest and higher quartiles, respectively, for baseline serum alkaline phosphatase. The mortality hazard ratio for each doubling of serum alkaline phosphatase was 1.52 (95% confidence interval [CI], 1.35-1.72) adjusting only for demographic factors, and 1.37 (95% CI, 1.21-1.56) adjusting for both demographic and metabolic syndrome factors in the full cohort, and was 1.83 (95% CI, 1.36-2.46) adjusting for demographic factors in the subgroup without any of the component conditions of metabolic syndrome. CONCLUSIONS In the US general population, higher levels of serum alkaline phosphatase is a predictor of mortality independent of the baseline prevalence of metabolic syndrome. Further studies are warranted to unravel the mechanisms of this association.
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Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2011; 33:525-40. [PMID: 21198708 PMCID: PMC3080668 DOI: 10.1111/j.1365-2036.2010.04556.x] [Citation(s) in RCA: 222] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Revised: 09/27/2010] [Accepted: 12/06/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease in Western countries. The development of non-alcoholic steatohepatitis (NASH) and fibrosis identifies an at-risk group with increased risk of cardiovascular and liver-related deaths. The identification and management of this at-risk group remains a clinical challenge. AIM To perform a systematic review of the established and emerging strategies for the diagnosis and staging of NAFLD. METHODS Relevant research and review articles were identified by searching PubMed, MEDLINE and EMBASE. RESULTS There has been a substantial development of non-invasive risk scores, biomarker panels and radiological modalities to identify at-risk patients with NAFLD without recourse to liver biopsy on a routine basis. These modalities and algorithms have improved significantly in their diagnosis and staging of fibrosis and NASH in patients with NAFLD, and will likely impact on the number of patients undergoing liver biopsy. CONCLUSIONS Staging for NAFLD can now be performed by a combination of radiological and laboratory techniques, greatly reducing the requirement for invasive liver biopsy.
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Affiliation(s)
- J K Dowman
- Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Edgbaston, UK.
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Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: a review and update. Dig Dis Sci 2010; 55:560-78. [PMID: 20101463 DOI: 10.1007/s10620-009-1081-0] [Citation(s) in RCA: 227] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2009] [Accepted: 12/01/2009] [Indexed: 12/13/2022]
Abstract
The spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from asymptomatic steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Hepatic steatosis occurs when free fatty acids, released in the setting of insulin resistance and the metabolic syndrome, are taken up by the liver. Additional biochemical insults, including oxidative stress, upregulation of inflammatory mediators, and dysregulated apoptosis, can result in inflammation (producing NASH) and fibrosis. Noninvasive methods (e.g., abdominal ultrasonography) are safe ways to support a diagnosis of hepatic steatosis, but advanced liver histopathologic findings including NASH and fibrosis cannot be identified without pursuing liver biopsy. Recent advances in serologic and imaging methods aim to determine severity of inflammation and fibrosis noninvasively. Currently, therapeutic options for NAFLD are limited to medications that reduce risk factors, but the future holds promise for therapies that might slow the progression of this increasingly prevalent disorder.
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Affiliation(s)
- Jeffrey R Lewis
- Department of Medicine, Center for Liver Diseases, University of Chicago, Chicago, IL 60637, USA.
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Crum-Cianflone N, Collins G, Medina S, Asher D, Campin R, Bavaro M, Hale B, Hames C. Prevalence and factors associated with liver test abnormalities among human immunodeficiency virus-infected persons. Clin Gastroenterol Hepatol 2010; 8:183-91. [PMID: 19800985 PMCID: PMC3121187 DOI: 10.1016/j.cgh.2009.09.025] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Revised: 08/13/2009] [Accepted: 09/20/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Liver disease is a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. We evaluated the prevalence, etiology, and factors associated with liver dysfunction in patients during the highly active antiretroviral therapy era. METHODS We performed liver tests (baseline and after a 6-month follow-up period) in HIV-infected patients treated at a large clinic. Comprehensive laboratory and ultrasound analyses were performed. Factors associated with liver test abnormalities were assessed using multivariate logistic regression models. RESULTS Eighty of 299 HIV-positive patients (27%) had abnormal liver test results during the 6-month study period. The majority of abnormalities were grade 1. Of those with liver test abnormalities, the most common diagnosis was nonalcoholic fatty liver disease (30%), followed by excessive alcohol use (13%), chronic hepatitis B (9%), chronic active hepatitis C (5%), and other (hemochromatosis and autoimmune hepatitis, 2%); 8 participants (10%) had more than 1 diagnosis. In total, 39 HIV patients with abnormal liver test results (49%) had a defined underlying liver disease. Despite laboratory tests and ultrasound examination, 41 abnormal liver test results (51%) were unexplained. Multivariate analyses of this group found that increased total cholesterol levels (odds ratio, 1.6 per 40-mg/dL increase; P = .01) were associated with liver abnormalities. CONCLUSIONS Liver test abnormalities are common among HIV patients during the highly active antiretroviral therapy era. The most common diagnosis was nonalcoholic fatty liver disease. Despite laboratory and radiologic investigations into the cause of liver dysfunction, 51% were unexplained, but might be related to unrecognized fatty liver disease.
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Affiliation(s)
- Nancy Crum-Cianflone
- HIV Clinic, Naval Medical Center San Diego, San Diego, California 92134-1005, USA.
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Woodward JM, Priest AN, Hollingsworth KG, Lomas DJ. Clinical Application of Magnetic Resonance Spectroscopy of the Liver in Patients Receiving Long-Term Parenteral Nutrition. JPEN J Parenter Enteral Nutr 2009; 33:669-76. [DOI: 10.1177/0148607109332908] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Jeremy M. Woodward
- From the Departments of Gastroenterology, Radiology, and Medical Physics, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Andrew N. Priest
- From the Departments of Gastroenterology, Radiology, and Medical Physics, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Kieren G. Hollingsworth
- From the Departments of Gastroenterology, Radiology, and Medical Physics, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - David J. Lomas
- From the Departments of Gastroenterology, Radiology, and Medical Physics, Addenbrooke's Hospital, Cambridge, United Kingdom
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Hepatic steatosis in young lean insulin resistant women with polycystic ovary syndrome. Fertil Steril 2009; 93:1220-6. [PMID: 19171337 DOI: 10.1016/j.fertnstert.2008.12.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2008] [Revised: 12/04/2008] [Accepted: 12/05/2008] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To investigate the presence of nonalcoholic fatty liver disease (NAFLD) in young lean women with polycystic ovary syndrome (PCOS) and insulin resistance (IR). DESIGN Case control study. SETTING Women with PCOS and healthy controls in a metabolic day ward. PATIENT(S) Seventeen young lean women with PCOS and 17 matched controls were studied prospectively. INTERVENTION(S) Fasting blood and a glucose tolerance test. Ovarian and liver ultrasonography, and computed tomography (CT) of the liver (women with PCOS only). MAIN OUTCOME MEASURE(S) Anthropometric variables, biochemical and hormonal parameters, and several IR indices were determined. Hepatic lipid content was assessed with ultrasonography and CT of the liver. RESULT(S) Women with PCOS had higher androgen levels, and the IR indices, glucose and insulin area under the curve, QUICKI, MATSUDA, and HOMA, compared to controls. In addition to IR, women with PCOS had normal aminotransferase levels, and higher, although within the normal range, alkaline phosphatase levels compared with controls. Women with PCOS had no evidence of NAFLD by either ultrasonography or CT of the liver. CONCLUSION(S) Young lean women with PCOS and IR do not have evidence of NAFLD. Because of the presence of IR, follow-up is required to determine whether they are at risk of developing NAFLD.
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Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008; 134:1682-98. [PMID: 18471547 DOI: 10.1053/j.gastro.2008.02.077] [Citation(s) in RCA: 256] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2007] [Revised: 02/08/2008] [Accepted: 02/25/2008] [Indexed: 02/07/2023]
Abstract
The increasing prevalence of obesity, insulin resistance, and the metabolic syndrome has significant implications for the future of chronic liver disease. The resultant increase in the number of patients with nonalcoholic fatty liver disease (NAFLD) is expected to translate into increased numbers of patients with end-stage liver disease (cirrhosis), liver failure, and hepatocellular carcinoma. It is particularly important to identify the patients who are at greatest risk of these aforementioned complications of chronic liver disease, those nonalcoholic fatty liver disease patients with nonalcoholic steatohepatitis. Currently liver biopsy is the gold standard for diagnosis, but less invasive, highly accurate, and affordable screening tools are required. These tools may include radiologic or laboratory studies to identify patients noninvasively who may benefit from therapeutic interventions. Clinical scoring systems that may be used in general practice as initial screening tools also may prove useful. Most therapeutic modalities available or under development target the major pathways thought essential in the pathogenesis of nonalcoholic steatohepatitis and often are directed at reducing body mass index and improving insulin resistance via pharmacologic, surgical, dietary, or exercise regimens. Other potential therapeutic agents directed at cytoprotection or reduction of fibrosis are under investigation. This article focuses on diagnosis and therapy available and under development for this chronic liver disease.
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Affiliation(s)
- Dawn M Torres
- Department of Gastroenterology, Fort Sam Houston, Brooke Army Medical Center, San Antonio, Texas 78234, USA
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Sterling RK, Chiu S, Snider K, Nixon D. The prevalence and risk factors for abnormal liver enzymes in HIV-positive patients without hepatitis B or C coinfections. Dig Dis Sci 2008; 53:1375-82. [PMID: 17939038 PMCID: PMC3836444 DOI: 10.1007/s10620-007-9999-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2007] [Accepted: 08/21/2007] [Indexed: 01/15/2023]
Abstract
BACKGROUND Abnormal liver enzymes (LFTs) are frequently seen in HIV patients. Because HCV and HBV overshadow other possible variables, little is known about the prevalence and predictive factors of abnormal LFTs in the absence of viral hepatitis. AIMS To determine the prevalence and factors associated with abnormal LFTs defined as >1.25 ULN. METHODS A retrospective analysis of HIV clinic patients was performed. Variables were determined at the time of abnormal LFTs or by history and included diabetes mellitus (DM), hypertension (HTN), dyslipidemia, HCV and HBV status, metabolic syndrome (MS), and HAART use (NRTI, NNRTI, and PI). RESULTS Patients without HCV/HBV (n = 679/1,208) were younger, Caucasian, had a BMI >30 and had dyslipidemia. The prevalences of elevated LFTs in those without HCV/HBV were AST 20%, ALT 15%, and ALP 43% compared to 64%, 46%, and 63% in those with HCV (all P < 0.0001), and 98% were mild-moderate (grade 1-2). While AST was highly correlated with ALT, neither was associated with increased ALP. In those without HCV/HBV, increased AST was associated with HTN, HIV RNA, and absence of PI use; increased ALT was associated with HTN, HIV RNA, CD4 < 200, MS, and absence of PI use, while increased ALP was associated with age, BMI, CD4%, DM, and NRTI use. CONCLUSIONS Mild-moderate increased liver enzymes are common in HIV patients without HCV/HBV and absence of PI use is independently associated with elevations in both AST and ALT, while features typical of hepatic steatosis (DM and BMI) are only associated with increased ALP.
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Affiliation(s)
- Richard K Sterling
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0341, USA.
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Sevastianos VA, Hadziyannis SJ. Nonalcoholic fatty liver disease: from clinical recognition to treatment. Expert Rev Gastroenterol Hepatol 2008; 2:59-79. [PMID: 19072371 DOI: 10.1586/17474124.2.1.59] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is probably the most common spectrum of metabolic liver disease in the world, encompassing simple steatosis to steatohepatitis, advanced fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD affects a significant part of the general population worldwide. The existing correlation between obesity and NAFLD in combination with the increase in the frequency of obesity in the developed world implies that the incidence and severity of NAFLD will increase in the near future. Newer data support the idea that NAFLD constitutes the more important cause of cryptogenic cirrhosis of the liver and a ground for the development of hepatocellular carcinoma. Liver biopsy remains the most specific and sensitive method to differentiate NAFLD, providing important information on the long-term prognosis of the patients. The 'two hit' hypothesis constitutes the currently prevailing theory for the development of NAFLD and nonalcoholic steatohepatitis. The first 'hit' is purported to be the increase of free fatty acids in hepatocytes, which results in a decrease of beta-oxidation. The second step includes all mechanisms contributing to the development of necroinflammation and fibrosis. Currently, an effective treatment for patients with NAFLD does not exist. Improvement in liver histology remains the primary goal of any therapeutic approach in patients with NAFLD. Viewing NAFLD in the frame of the metabolic syndrome opens the possibility that both the onset of the disease and disease progression could be prevented by changes in lifestyle. Physical exercise and a low calorie diet in combination with the gradual loss of body weight represent the cornerstone for the management of NAFLD patients.
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Affiliation(s)
- Vassilios A Sevastianos
- Department of Medicine & Hepatology, Henry Dunant Hospital, 107 Messogion Avenue, 11526 Athens, Greece.
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