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Le P, Payne JY, Zhang L, Deshpande A, Rothberg MB, Alkhouri N, Herman W, Hernandez AV, Schleicher M, Ye W, Dasarathy S. Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies. Clin Gastroenterol Hepatol 2023; 21:1154-1168. [PMID: 35933075 PMCID: PMC9898457 DOI: 10.1016/j.cgh.2022.07.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS We conducted a meta-analysis to summarize the rates of progression to and regression of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). METHODS We searched PubMed/Medline and 4 other databases from 1985 through 2020. We included observational studies and randomized controlled trials in any language that used liver biopsy or imaging to diagnose NAFLD in adults with a follow-up period ≥48 weeks. Rates were calculated as incident cases per 100 person-years and pooled using the random-effects Poisson distribution model. Heterogeneity was assessed using the I2 statistic. RESULTS We screened 9744 articles and included 54 studies involving 26,738 patients. Among observational studies, 20% of healthy adults developed NAFL (incidence rate, 4.8/100 person-years) while 21% of people with fatty liver had resolution of NAFL (incidence rate, 2.4/100 person-years) after a median of approximately 4.5 years. In addition, 31% of patients developed NASH after 4.7 years (incidence rate, 7.4/100 person-years), whereas in 29% of those with NASH, resolution occurred after a median of 3.5 years (incidence rate, 5.1/100 person-years). Time to progress by 1 fibrosis stage was 9.9, 10.3, 13.3, and 22.2 years for F0, F1, F2, and F3, respectively. Time to regress by 1 stage was 21.3, 12.5, 20.4, and 40.0 years for F4, F3, F2, and F1, respectively. Rates estimated from randomized controlled trials were higher than those from observational studies. CONCLUSIONS In our meta-analysis, progression to NASH was more common than regression from NASH. Rates of fibrosis progression were similar across baseline stage, but patients with advanced fibrosis were more likely to regress than those with mild fibrosis.
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Affiliation(s)
- Phuc Le
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio.
| | - Julia Yang Payne
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio; Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Lu Zhang
- Department of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Abhishek Deshpande
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio
| | - Michael B Rothberg
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio
| | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Tucson, Arizona
| | - William Herman
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
| | - Adrian V Hernandez
- Health Outcomes, Policy, and Evidence Synthesis Group, University of Connecticut School of Pharmacy, Storrs, Connecticut; Unidad de Revisiones Sistemáticas y Meta-Análisis, Universidad San Ignacio de Loyola, Lima, Peru
| | - Mary Schleicher
- The Floyd D. Loop Alumni Library, Cleveland Clinic, Cleveland, Ohio
| | - Wen Ye
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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Yin H, Shi A, Wu J. Platelet-Activating Factor Promotes the Development of Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes 2022; 15:2003-2030. [PMID: 35837578 PMCID: PMC9275506 DOI: 10.2147/dmso.s367483] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/28/2022] [Indexed: 11/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted clinicopathological syndrome characterised by excessive hepatic lipid accumulation that causes steatosis, excluding alcoholic factors. Platelet-activating factor (PAF), a biologically active lipid transmitter, induces platelet activation upon binding to the PAF receptor. Recent studies have found that PAF is associated with gamma-glutamyl transferase, which is an indicator of liver disease. Moreover, PAF can stimulate hepatic lipid synthesis and cause hypertriglyceridaemia. Furthermore, the knockdown of the PAF receptor gene in the animal models of NAFLD helped reduce the inflammatory response, improve glucose homeostasis and delay the development of NAFLD. These findings suggest that PAF is associated with NAFLD development. According to reports, patients with NAFLD or animal models have marked platelet activation abnormalities, mainly manifested as enhanced platelet adhesion and aggregation and altered blood rheology. Pharmacological interventions were accompanied by remission of abnormal platelet activation and significant improvement in liver function and lipids in the animal model of NAFLD. These confirm that platelet activation may accompany a critical importance in NAFLD development and progression. However, how PAFs are involved in the NAFLD signalling pathway needs further investigation. In this paper, we review the relevant literature in recent years and discuss the role played by PAF in NAFLD development. It is important to elucidate the pathogenesis of NAFLD and to find effective interventions for treatment.
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Affiliation(s)
- Hang Yin
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
| | - Anhua Shi
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
| | - Junzi Wu
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
- Correspondence: Junzi Wu; Anhua Shi, Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China, Tel/Fax +86 187 8855 7524; +86 138 8885 0813, Email ;
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Qu Y, Middleton MS, Loomba R, Glaser KJ, Chen J, Hooker JC, Wolfson T, Covarrubias Y, Valasek MA, Fowler KJ, Zhang YN, Sy E, Gamst AC, Wang K, Mamidipalli A, Schwimmer JB, Song B, Reeder SB, Yin M, Ehman RL, Sirlin CB. Magnetic resonance elastography biomarkers for detection of histologic alterations in nonalcoholic fatty liver disease in the absence of fibrosis. Eur Radiol 2021; 31:8408-8419. [PMID: 33899143 PMCID: PMC8530863 DOI: 10.1007/s00330-021-07988-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/25/2021] [Accepted: 04/02/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To investigate associations between histology and hepatic mechanical properties measured using multiparametric magnetic resonance elastography (MRE) in adults with known or suspected nonalcoholic fatty liver disease (NAFLD) without histologic fibrosis. METHODS This was a retrospective analysis of 88 adults who underwent 3T MR exams including hepatic MRE and MR imaging to estimate proton density fat fraction (MRI-PDFF) within 180 days of liver biopsy. Associations between MRE mechanical properties (mean shear stiffness (|G*|) by 2D and 3D MRE, and storage modulus (G'), loss modulus (G″), wave attenuation (α), and damping ratio (ζ) by 3D MRE) and histologic, demographic and anthropometric data were assessed. RESULTS In univariate analyses, patients with lobular inflammation grade ≥ 2 had higher 2D |G*| and 3D G″ than those with grade ≤ 1 (p = 0.04). |G*| (both 2D and 3D), G', and G″ increased with age (rho = 0.25 to 0.31; p ≤ 0.03). In multivariable regression analyses, the association between inflammation grade ≥ 2 remained significant for 2D |G*| (p = 0.01) but not for 3D G″ (p = 0.06); age, sex, or BMI did not affect the MRE-inflammation relationship (p > 0.20). CONCLUSIONS 2D |G*| and 3D G″ were weakly associated with moderate or severe lobular inflammation in patients with known or suspected NAFLD without fibrosis. With further validation and refinement, these properties might become useful biomarkers of inflammation. Age adjustment may help MRE interpretation, at least in patients with early-stage disease. KEY POINTS • Moderate to severe lobular inflammation was associated with hepatic elevated shear stiffness and elevated loss modulus (p =0.04) in patients with known or suspected NAFLD without liver fibrosis; this suggests that with further technical refinement these MRE-assessed mechanical properties may permit detection of inflammation before the onset of fibrosis in NAFLD. • Increasing age is associated with higher hepatic shear stiffness, and storage and loss moduli (rho = 0.25 to 0.31; p ≤ 0.03); this suggests that age adjustment may help interpret MRE results, at least in patients with early-stage NAFLD.
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Affiliation(s)
- Yali Qu
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Michael S Middleton
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA
- Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, CA, USA
| | - Kevin J Glaser
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Jun Chen
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Jonathan C Hooker
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Tanya Wolfson
- Computational and Applied Statistics Laboratory, the San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA, USA
| | - Yesenia Covarrubias
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Mark A Valasek
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Kathryn J Fowler
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Yingzhen N Zhang
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Ethan Sy
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Anthony C Gamst
- Computational and Applied Statistics Laboratory, the San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA, USA
| | - Kang Wang
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Adrija Mamidipalli
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA
| | - Jeffrey B Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California at San Diego, La Jolla, CA, USA
- Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, CA, USA
| | - Bin Song
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Scott B Reeder
- Departments of Radiology, Medical Physics, Biomedical Engineering, Medicine, and Emergency Medicine, University of Wisconsin, Madison, WI, USA
| | - Meng Yin
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | | | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA.
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Dennis BB, Sallam S, Perumpail BJ, Shah ND, Kim D, Cholankeril G, Ahmed A. Management of Cardiometabolic Complications in Patients With Nonalcoholic Fatty Liver Disease: A Review of the Literature With Recommendations. J Clin Gastroenterol 2021; 55:747-756. [PMID: 34469404 DOI: 10.1097/mcg.0000000000001555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 04/01/2021] [Indexed: 12/16/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver conditions characterized by significant lipid deposition within hepatocytes. As an overarching diagnosis, NAFLD contains a continuum of progressive liver diseases ranging from isolated liver steatosis to necroinflammatory states leading to end-stage liver disease. Nonalcoholic fatty liver and nonalcoholic steatohepatitis are distinguished by their histologic patterns, with the former exhibiting steatosis without fibrosis or inflammation. This important distinction provides clinicians a timeline within the NAFLD staging to target appropriate interventions against modifiable risk factors. NAFLD is likely formed in response to metabolic imbalances that damage the livers adaptive capacity. Metabolic conditions leading to steatosis mirror common cardiovascular risk factors, including dyslipidemia, diabetes mellitus, and obesity. Acknowledging the common risk factors for development and progression of NAFLD, it is unsurprising the first-line management focuses on the treatment of metabolic syndrome with an emphasis on weight reduction in obese populations. The purpose of this review is to provide a detailed summary of the literature as well as outline the current treatment recommendations for patients with NAFLD with a detailed focus on pharmacologic antiobesity interventions.
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Affiliation(s)
- Brittany B Dennis
- Department of Medicine, McMaster University, Hamilton ON
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
| | - Sandy Sallam
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
| | | | - Neha D Shah
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
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Dufour JF, Scherer R, Balp MM, McKenna SJ, Janssens N, Lopez P, Pedrosa M. The global epidemiology of nonalcoholic steatohepatitis (NASH) and associated risk factors–A targeted literature review. ENDOCRINE AND METABOLIC SCIENCE 2021. [DOI: 10.1016/j.endmts.2021.100089] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Basavarajappa L, Baek J, Reddy S, Song J, Tai H, Rijal G, Parker KJ, Hoyt K. Multiparametric ultrasound imaging for the assessment of normal versus steatotic livers. Sci Rep 2021; 11:2655. [PMID: 33514796 PMCID: PMC7846566 DOI: 10.1038/s41598-021-82153-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/15/2021] [Indexed: 12/13/2022] Open
Abstract
Liver disease is increasing in prevalence across the globe. We present here a multiparametric ultrasound (mpUS) imaging approach for assessing nonalcoholic fatty liver disease (NALFD). This study was performed using rats (N = 21) that were fed either a control or methionine and choline deficient (MCD) diet. A mpUS imaging approach that includes H-scan ultrasound (US), shear wave elastography, and contrast-enhanced US measurements were then performed at 0 (baseline), 2, and 6 weeks. Thereafter, animals were euthanized and livers excised for histological processing. A support vector machine (SVM) was used to find a decision plane that classifies normal and fatty liver conditions. In vivo mpUS results from control and MCD diet fed animals reveal that all mpUS measures were different at week 6 (P < 0.05). Principal component analysis (PCA) showed that the H-scan US data contributed the highest percentage to the classification among the mpUS measurements. The SVM resulted in 100% accuracy for classification of normal and high fat livers and 92% accuracy for classification of normal, low fat, and high fat livers. Histology findings found considerable steatosis in the MCD diet fed animals. This study suggests that mpUS examinations have the potential to provide a comprehensive estimation of the main components of early stage NAFLD.
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Affiliation(s)
- Lokesh Basavarajappa
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Jihye Baek
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA
| | - Shreya Reddy
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Jane Song
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Haowei Tai
- Department of Electrical and Computer Engineering, University of Texas at Dallas, Richardson, TX, USA
| | - Girdhari Rijal
- Department of Medical Laboratory Sciences, Tarleton State University, Forth Worth, TX, USA
| | - Kevin J Parker
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA
| | - Kenneth Hoyt
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA. .,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Clusterin overexpression protects against western diet-induced obesity and NAFLD. Sci Rep 2020; 10:17484. [PMID: 33060605 PMCID: PMC7562726 DOI: 10.1038/s41598-020-73927-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is a significant risk factor for various metabolic diseases and is closely related to non-alcoholic fatty liver disease (NAFLD) characterized by inflammation and oxidative stress. Clusterin is a multi-functional protein that is up-regulated in the pathogenesis of various metabolic diseases, including obesity and NAFLD. Our previous studies indicated that hepatocyte-specific overexpression of clusterin alleviates methionine choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Here we generated transgenic mice with whole-body clusterin overexpression (wCLU-tg) and investigated the role of clusterin in Western diet-induced obesity and NAFLD. We confirmed that obesity parameters and the spectrum of NAFLD of wCLU-tg mice were improved compared to wild type mice. Contrarily, clusterin deficiency deteriorated metabolic disruptions. We also found that clusterin activates target molecules for obesity and NAFLD, namely Nrf2 and AMPK, suggesting that clusterin protects against Western diet-induced obesity and NAFLD by activating Nrf2 and AMPK.
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Kechagias S, Nasr P, Blomdahl J, Ekstedt M. Established and emerging factors affecting the progression of nonalcoholic fatty liver disease. Metabolism 2020; 111S:154183. [PMID: 32061907 DOI: 10.1016/j.metabol.2020.154183] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease affecting approximately 25% of the global population. Although a majority of NAFLD patients will never experience liver-related symptoms it is estimated that 5-10% will develop cirrhosis-related complications with risk of death or need for liver transplantation. NAFLD is closely associated with cardiovascular disease and components of the metabolic syndrome. However, NAFLD is not uncommon in lean individuals and may in these subjects represent a different entity with separate pathophysiological mechanisms involved implying a higher risk for development of end-stage liver disease. There is considerable fluctuation in the histopathological course of NAFLD that may partly be attributed to lifestyle factors and dietary composition. Nutrients such as fructose, monounsaturated fatty acids, and trans-fatty acids may aggravate NAFLD. Presence of type 2 diabetes mellitus seems to be the most important clinical predictor of liver-related morbidity and mortality in NAFLD. Apart from severity of the metabolic syndrome, genetic polymorphisms and environmental factors, such as moderate alcohol consumption, may explain the variation in histopathological and clinical outcome among NAFLD patients.
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Affiliation(s)
- Stergios Kechagias
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Patrik Nasr
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Julia Blomdahl
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
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Luu C, Thapa R, Rose T, Woo K, Jeong D, Thomas K, Chen DT, Friedman M, Malafa MP, Hodul PJ. Identification of nonalcoholic fatty liver disease following pancreatectomy for noninvasive intraductal papillary mucinous neoplasm. Int J Surg 2018; 58:46-49. [PMID: 30218781 DOI: 10.1016/j.ijsu.2018.09.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 06/27/2018] [Accepted: 09/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) following pancreatectomy is a potential cause of long term morbidity in patients undergoing pancreatic resection with curative intent. Prior studies have reported an incidence of NAFLD up to 30% following pancreatectomy but the investigated cohorts were typically a mix of benign and malignant disease. Here we examined the incidence of NAFLD in a homogenous cohort of patients following pancreatectomy for benign intraductal papillary mucinous neoplasm (IPMN). METHODS A retrospective review of patients who underwent pancreatic resection for IPMN from 2000 to 2016 was performed. Post pancreatectomy CT/MRI scans were obtained as standard surveillance. We investigated changes in the liver parenchymal density on post surgical imaging to estimate the frequency with which NAFLD occurred. Radiographic criteria for NAFLD included Hounsfield units less than 40 on CT or liver:spleen ratio <0.9 on CT or MRI. Fischer's exact test, Kruskal-Wallis test, and logistic regression were performed. RESULTS Our study cohort included 109 patients who underwent pancreatectomy for nonmalignant intraductal papillary mucinous neoplasm with no evidence of NAFLD preoperatively and at least 6 months follow-up. Mean follow-up was 52 months (range 8-130/months). The incidence of postoperative NAFLD was 17/109 (15.6%). Most cases occurred within 12 months of pancreatectomy. On multivariate analysis, proximal pancreatectomy (pancreaticoduodenectomy) and development of atrophy of the pancreas remnant were significant risk factors for development of hepatic steatosis (p < 0.05). CONCLUSION Patients undergoing pancreatectomy for benign disease have a significant risk of developing NAFLD but the frequency is lower than previously reported in cohorts that included individuals with malignant disease. Highest risk was observed in individuals who underwent pancreaticoduodenectomy or developed pancreatic atrophy. Further investigations to define the mechanisms that promote steatosis and interventions to prevent subsequent morbidity from NAFLD are warranted.
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Affiliation(s)
- Carrie Luu
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Ram Thapa
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Trevor Rose
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Katherine Woo
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Daniel Jeong
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Kerry Thomas
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Dung-Tsa Chen
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Mark Friedman
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Mokenge P Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Pamela J Hodul
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA.
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Allen J, Zhang J, Quickel MD, Kennett M, Patterson AD, Hankey-Giblin PA. Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model. J Proteome Res 2018; 17:3268-3280. [PMID: 30091925 DOI: 10.1021/acs.jproteome.8b00379] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is commonly observed in the terminal stages of nonalcoholic steatohepatitis (NASH) and with no specific and effective antifibrotic therapies available, this disease is a major global health burden. The MSP/Ron receptor axis has been shown to have anti-inflammatory properties in a number of mouse models, due at least in part, to its ability to limit pro-inflammatory responses in tissue-resident macrophages and hepatocytes. In this study, we established the role of the Ron receptor in steatohepatitis-induced hepatic fibrosis using Ron ligand domain knockout mice on an apolipoprotein E knockout background (DKO). After 18 weeks of high-fat high-cholesterol feeding, loss of Ron activation resulted in exacerbated NASH-associated steatosis which is precedent to hepatocellular injury, inflammation and fibrosis. 1H nuclear magnetic resonance (NMR)-based metabolomics identified significant changes in serum metabolites that can modulate the intrahepatic lipid pool in hepatic steatosis. Serum from DKO mice had higher concentrations of lipids, VLDL/LDL and pyruvate, whereas glycine levels were reduced. Parallel to the aggravated steatohepatitis, increased accumulation of collagen, inflammatory immune cells and collagen producing-myofibroblasts were seen in the livers of DKO mice. Gene expression profiling revealed that DKO mice exhibited elevated expression of genes encoding Ron receptor ligand MSP, collagens, ECM remodeling proteins and pro-fibrogenic cytokines in the liver. Our results demonstrate the protective effects of Ron receptor activation on NASH-induced hepatic fibrosis.
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Affiliation(s)
- Joselyn Allen
- Department of Veterinary and Biomedical Sciences , The Pennsylvania State University , University Park , Pennsylvania United States
| | - Jingtao Zhang
- Department of Veterinary and Biomedical Sciences , The Pennsylvania State University , University Park , Pennsylvania United States
| | - Michael D Quickel
- Department of Veterinary and Biomedical Sciences , The Pennsylvania State University , University Park , Pennsylvania United States
| | - Mary Kennett
- Department of Veterinary and Biomedical Sciences , The Pennsylvania State University , University Park , Pennsylvania United States
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences , The Pennsylvania State University , University Park , Pennsylvania United States
| | - Pamela A Hankey-Giblin
- Department of Veterinary and Biomedical Sciences , The Pennsylvania State University , University Park , Pennsylvania United States
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Nasr P, Ignatova S, Kechagias S, Ekstedt M. Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies. Hepatol Commun 2017; 2:199-210. [PMID: 29404527 PMCID: PMC5796332 DOI: 10.1002/hep4.1134] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 11/04/2017] [Accepted: 11/14/2017] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high‐quality follow‐up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow‐up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow‐up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end‐stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty‐six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy‐proven fibrosis stage F3‐F4 and 2 patients with end‐stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end‐stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end‐stage liver disease. (Hepatology Communications 2018;2:199–210)
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Affiliation(s)
- Patrik Nasr
- Department of Gastroenterology and Hepatology, Department of Medical and Health Sciences Linköping University Linköping Sweden
| | - Simone Ignatova
- Department of Clinical Pathology and Clinical Genetics, Department of Clinical and Experimental Medicine Linköping University Linköping Sweden
| | - Stergios Kechagias
- Department of Gastroenterology and Hepatology, Department of Medical and Health Sciences Linköping University Linköping Sweden
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Medical and Health Sciences Linköping University Linköping Sweden
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12
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Abstract
Purpose of Review The purpose of this review is to summarize the latest knowledge on the natural history of non-alcoholic fatty liver disease (NAFLD). The review focuses on mortality, liver-related complications, and histological course. Recent Findings Studies during the last decade have established NAFLD as a potentially progressive liver disease. Age and diabetes are the strongest clinical predictors of progressive disease. Fibrosis stage is the most important histological variable to predict mortality and liver-related complications. So far, no study has been able to show that non-alcoholic steatohepatitis at baseline predicts mortality or future liver-related complications when adjusting for fibrosis. Summary The outlines of the natural history of NAFLD have become clearer during the last decade. There is limited data on factors that predict clinical progression. Prospective longitudinal studies are needed to help us predict worse outcome in individual patients.
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Affiliation(s)
- Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Patrik Nasr
- Department of Gastroenterology and Hepatology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Stergios Kechagias
- Department of Gastroenterology and Hepatology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
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13
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Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a disease spectrum ranging from benign hepatic steatosis to non-alcoholic steatohepatitis with inflammation (NASH) and liver cirrhosis. NAFLD is now recognised as the hepatic manifestation of the metabolic syndrome. Simple steatosis is benign, whereas NASH can progress to cirrhosis with its resultant complications. Liver biopsy remains the gold standard in the diagnosis of NAFLD/NASH. Lifestyle and dietary modifications to achieve sustained weight loss is the cornerstone of NAFLD/NASH treatment.
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Affiliation(s)
- Hui-Hui Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Jason Pik-Eu Chang
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
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14
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Dulai PS, Sirlin CB, Loomba R. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice. J Hepatol 2016; 65:1006-1016. [PMID: 27312947 PMCID: PMC5124376 DOI: 10.1016/j.jhep.2016.06.005] [Citation(s) in RCA: 260] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 05/19/2016] [Accepted: 06/06/2016] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease, and its prevalence is rising worldwide. The occurrence of non-alcoholic steatohepatitis (NASH) is associated with a substantial increase in disease related morbidity and mortality. Accordingly, there has been a surge of innovation surrounding drug development in an effort to off-set the natural progression and long-term risks of this disease. Disease assessment within clinical trials and clinical practice for NAFLD is currently done with liver biopsies. Liver biopsy-based assessments, however, remain imprecise and are not without cost or risk. This carries significant implications for the feasibility and costs of bringing therapeutic interventions to market. A need therefore arises for reliable and highly accurate surrogate end-points that can be used in phase 2 and 3 clinical trials to reduce trial size requirements and costs, while improving feasibility and ease of implementation in clinical practice. Significant advances have now been made in magnetic resonance technology, and magnetic resonance imaging (MRI) and elastrography (MRE) have been demonstrated to be highly accurate diagnostic tools for the detection of hepatic steatosis and fibrosis. In this review article, we will summarize the currently available evidence regarding the use of MRI and MRE among NAFLD patients, and the evolving role these surrogate biomarkers will play in the rapidly advancing arena of clinical trials in NASH and hepatic fibrosis. Furthermore, we will highlight how these tools can be readily applied to routine clinical practice, where the growing burden of NAFLD will need to be met with enhanced monitoring algorithms.
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Affiliation(s)
- Parambir S Dulai
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, United States
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, United States
| | - Rohit Loomba
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, United States; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, United States.
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15
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Siddiqui MS, Charlton M. Liver Transplantation for Alcoholic and Nonalcoholic Fatty Liver Disease: Pretransplant Selection and Posttransplant Management. Gastroenterology 2016; 150:1849-62. [PMID: 26971826 DOI: 10.1053/j.gastro.2016.02.077] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 02/12/2016] [Accepted: 02/16/2016] [Indexed: 02/07/2023]
Abstract
Alcoholic fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are common causes of chronic liver disease throughout the world. Although they have similar histologic features, a diagnosis of NAFLD requires the absence of significant alcohol use. ALD is seen commonly in patients with a long-standing history of excessive alcohol use, whereas NAFLD is encountered commonly in patients who have developed complications of obesity, such as insulin resistance, hypertension, and dyslipidemia. Lifestyle contributes to the development and progression of both diseases. Although alcohol abstinence can cause regression of ALD, and weight loss can cause regression of NAFLD, many patients with these diseases develop cirrhosis. ALD and NAFLD account for nearly 30% of liver transplants performed in the United States. Patients receiving liver transplants for ALD or NAFLD have similar survival times as patients receiving transplants for other liver disorders. Although ALD and NAFLD recur frequently after liver transplantation, graft loss from disease recurrence after transplantation is uncommon. Cardiovascular disease and de novo malignancy are leading causes of long-term mortality in liver transplant recipients with ALD or NAFLD.
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Affiliation(s)
- M Shadab Siddiqui
- Division of Gastroenterology & Hepatology, Virginia Commonwealth University, Richmond, Virginia
| | - Michael Charlton
- Division of Transplant Hepatology, Intermountain Medical Center, Murry, Utah
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16
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Calzadilla Bertot L, Adams LA. The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2016; 17:ijms17050774. [PMID: 27213358 PMCID: PMC4881593 DOI: 10.3390/ijms17050774] [Citation(s) in RCA: 446] [Impact Index Per Article: 49.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 05/12/2016] [Accepted: 05/12/2016] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death.
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Affiliation(s)
- Luis Calzadilla Bertot
- School of Medicine and Pharmacology, the University of Western Australia, Nedlands, WA 6009, Australia.
| | - Leon Anton Adams
- School of Medicine and Pharmacology, the University of Western Australia, Nedlands, WA 6009, Australia.
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia.
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17
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Abstract
Nonalcoholic fatty liver disease (NAFLD) remains among the most common liver diseases worldwide, with increasing prevalence in concert with the obesity and metabolic syndrome epidemic. The evidence on the natural history, albeit with some ambiguity, suggests the potential for some subsets of NAFLD to progress to cirrhosis, liver-related complications and mortality with fibrosis being the most important predictor of hard long-term endpoints such as mortality and liver complications. In this setting, NAFLD proves to be a formidable disease entity, with considerable clinical burden, for both the present and the future. Our understanding of the natural history of NAFLD is constantly evolving, with nascent data challenging current dogma. Further clarification of the natural history is required with well-designed, well-defined studies using prospectively collected data. Identifying the predictors of long-term outcomes should be used to direct development of clinical trial endpoints in NAFLD.
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Affiliation(s)
- George Boon-Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Arthur J McCullough
- Department of Gastroenterology, Cleveland Clinic Foundation, 9500 Euclid Avenue/A30, Cleveland, OH, 44195, USA.
- Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, OH, USA.
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18
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Kleiner DE, Makhlouf HR. Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children. Clin Liver Dis 2016; 20:293-312. [PMID: 27063270 PMCID: PMC4829204 DOI: 10.1016/j.cld.2015.10.011] [Citation(s) in RCA: 210] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver disease associated with obesity, diabetes, and the metabolic syndrome. Although steatosis is a key histologic feature, liver biopsies of patients with NAFLD can show a wide range of findings. Nonalcoholic steatohepatitis (NASH) is a progressive subtype of NAFLD first defined by analogy to alcoholic hepatitis. Young children may have an alternate pattern of progressive NAFLD characterized by a zone 1 distribution of steatosis, inflammation, and fibrosis. Several grading and staging systems exist, but all require adequate biopsies. Although NASH generally shows fibrosis progression over time, some patients show regression of disease.
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Affiliation(s)
- David E. Kleiner
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute
| | - Hala R. Makhlouf
- Cancer Diagnosis Program, Pathology Investigation and Resources Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute and Professor of Pathology, Ain Shams University
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19
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Abstract
Liver-related mortality is the third cause of death in patients with nonalcoholic fatty liver disease, but the long-term prognosis basically depends on the presence and severity of liver damage. Thus, life expectancy in patients with simple steatosis is not different from the general population, but liver-related mortality is significantly higher in patients with nonalcoholic steatohepatitis (NASH), particularly in those with advanced fibrosis. Progression of liver disease is observed in up to one-third of patients with NASH. The long-term hepatic prognosis mostly depends on the histologic stage at initial liver biopsy, but multiple risk factors may concur.
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20
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Goceri E, Shah ZK, Layman R, Jiang X, Gurcan MN. Quantification of liver fat: A comprehensive review. Comput Biol Med 2016; 71:174-89. [PMID: 26945465 DOI: 10.1016/j.compbiomed.2016.02.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 02/18/2016] [Accepted: 02/19/2016] [Indexed: 12/19/2022]
Abstract
Fat accumulation in the liver causes metabolic diseases such as obesity, hypertension, diabetes or dyslipidemia by affecting insulin resistance, and increasing the risk of cardiac complications and cardiovascular disease mortality. Fatty liver diseases are often reversible in their early stage; therefore, there is a recognized need to detect their presence and to assess its severity to recognize fat-related functional abnormalities in the liver. This is crucial in evaluating living liver donors prior to transplantation because fat content in the liver can change liver regeneration in the recipient and donor. There are several methods to diagnose fatty liver, measure the amount of fat, and to classify and stage liver diseases (e.g. hepatic steatosis, steatohepatitis, fibrosis and cirrhosis): biopsy (the gold-standard procedure), clinical (medical physics based) and image analysis (semi or fully automated approaches). Liver biopsy has many drawbacks: it is invasive, inappropriate for monitoring (i.e., repeated evaluation), and assessment of steatosis is somewhat subjective. Qualitative biomarkers are mostly insufficient for accurate detection since fat has to be quantified by a varying threshold to measure disease severity. Therefore, a quantitative biomarker is required for detection of steatosis, accurate measurement of severity of diseases, clinical decision-making, prognosis and longitudinal monitoring of therapy. This study presents a comprehensive review of both clinical and automated image analysis based approaches to quantify liver fat and evaluate fatty liver diseases from different medical imaging modalities.
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Affiliation(s)
- Evgin Goceri
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, USA.
| | - Zarine K Shah
- Department of Radiology, Wexner Medical Center, The Ohio State University, Columbus, USA
| | - Rick Layman
- Department of Radiology, Wexner Medical Center, The Ohio State University, Columbus, USA
| | - Xia Jiang
- Department of Radiology, Wexner Medical Center, The Ohio State University, Columbus, USA
| | - Metin N Gurcan
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, USA
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21
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Zhou Z, Liu YC, Chen XM, Li FQ, Tong XJ, Ding YP, Tang CL. Treatment of experimental non-alcoholic steatohepatitis by targeting α7 nicotinic acetylcholine receptor-mediated inflammatory responses in mice. Mol Med Rep 2015; 12:6925-31. [PMID: 26397391 DOI: 10.3892/mmr.2015.4318] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 06/26/2015] [Indexed: 11/05/2022] Open
Abstract
Non‑alcoholic fatty liver disease (NAFLD) is one of the most common types of liver disease, affecting up to 30% of the general population worldwide. Non‑alcoholic steatohepatitis (NASH) is a severe form of NAFLD without any effective therapies available. The present study showed that activation of α7‑nicotinic acetylcholine receptor (α7 nAChR) may be a novel potential strategy for NASH therapy. Treatment with the α7 nAChR agonist nicotine for three weeks obviously attenuated hepatic steatosis in a high-fat diet‑induced mouse model of NASH. Investigation of the underlying mechanism showed that nicotine reduced the secretion of the pro‑inflammatory cytokines tumor necrosis factor α and interleukin 6 in vitro and in vivo. Inflammation is an integral part of NASH and is the most prevalent form of hepatic pathology found in the general population; therefore, the effect of α7 nAChR activation against NASH may be ascribed to its anti‑inflammatory effects. In addition, the present study showed that nicotine‑stimulated α7 nAChR activation led to a significant downregulation of nuclear factor kappa B (NK‑κB) and extracellular signal-regulated kinase (ERK). It therefore appeared that activation of α7 nAChR suppressed the production of pro‑inflammatory cytokines through NK‑κB and ERK pathways. In conclusion, the present study indicated that targeting α7 nAChR may represent a novel treatment strategy for NASH.
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Affiliation(s)
- Zhou Zhou
- Department of Anesthesiology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Ying-Chao Liu
- Department of Digestive Diseases, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Xiao-Mei Chen
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Fu-Qiang Li
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Xiao-Juan Tong
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Yue-Ping Ding
- Department of Intensive Care Unit, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Cui-Lan Tang
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
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22
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Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13:643-54.e1-9; quiz e39-40. [PMID: 24768810 PMCID: PMC4208976 DOI: 10.1016/j.cgh.2014.04.014] [Citation(s) in RCA: 1202] [Impact Index Per Article: 120.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 04/02/2014] [Accepted: 04/08/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about differences in rates of fibrosis progression between patients with nonalcoholic fatty liver (NAFL) vs nonalcoholic steatohepatitis (NASH). We conducted a systematic review and meta-analysis of all studies that assessed paired liver biopsy specimens to estimate the rates of fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) including NAFL and NASH. METHODS Through a systematic search of multiple databases and author contact, up to June 2013, we identified studies of adults with NAFLD that collected paired liver biopsy specimens at least 1 year apart. From these, we calculated a pooled-weighted annual fibrosis progression rate (number of stages changed between the 2 biopsy samples) with 95% confidence intervals (CIs), and identified clinical risk factors associated with progression. RESULTS We identified 11 cohort studies including 411 patients with biopsy-proven NAFLD (150 with NAFL and 261 with NASH). At baseline, the distribution of fibrosis for stages 0, 1, 2, 3, and 4 was 35.8%, 32.5%, 16.7%, 9.3%, and 5.7%, respectively. Over 2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had an improvement in fibrosis stage. The annual fibrosis progression rate in patients with NAFL who had stage 0 fibrosis at baseline was 0.07 stages (95% CI, 0.02-0.11 stages), compared with 0.14 stages in patients with NASH (95% CI, 0.07-0.21 stages). These findings correspond to 1 stage of progression over 14.3 years for patients with NAFL (95% CI, 9.1-50.0 y) and 7.1 years for patients with NASH (95% CI, 4.8-14.3 y). CONCLUSIONS Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alina M Allen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Zhen Wang
- Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota
| | - Larry J Prokop
- Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota
| | - Mohammad H Murad
- Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California, San Diego, California.
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23
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Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, Seike M, Takei Y, Takehara T, Tokushige K, Nakajima A, Yoneda M, Saibara T, Shiota G, Sakaida I, Nakamuta M, Mizuta T, Tsubouchi H, Sugano K, Shimosegawa T. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J Gastroenterol 2015; 50:364-77. [PMID: 25708290 DOI: 10.1007/s00535-015-1050-7] [Citation(s) in RCA: 147] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 12/25/2014] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various noninvasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 to January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.
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Affiliation(s)
- Sumio Watanabe
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13 Ginza, Chuo, Tokyo, 104-0061, Japan,
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24
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Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, Seike M, Takei Y, Takehara T, Tokushige K, Nakajima A, Yoneda M, Saibara T, Shiota G, Sakaida I, Nakamuta M, Mizuta T, Tsubouchi H, Sugano K, Shimosegawa T. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatol Res 2015; 45:363-77. [PMID: 25832328 DOI: 10.1111/hepr.12511] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various non-invasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 through January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.
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25
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Hashimoto E, Tokushige K, Ludwig J. Diagnosis and classification of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: Current concepts and remaining challenges. Hepatol Res 2015; 45:20-8. [PMID: 24661406 DOI: 10.1111/hepr.12333] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 03/07/2014] [Accepted: 03/20/2014] [Indexed: 12/12/2022]
Abstract
The high prevalence of non-alcoholic fatty liver disease (NAFLD) has made the condition an important public health issue. Two clinical entities are manifestations of NAFLD, namely, non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). The former tends to be benign and non-progressive while the latter can progress to cirrhosis, which in rare cases gives rise to hepatocellular carcinoma. The diagnosis of NAFLD is based on: (i) a history of no or limited daily alcohol intake (<20 g for women and <30 g for men); (ii) presence of hepatic steatosis by imaging or by histology; and (iii) exclusion of other liver diseases. NAFL is defined histologically by the presence of bland, primarily macrovesicular, hepatocellular fatty change, while NASH features fatty change with inflammation and evidence of hepatocyte injury, such as ballooning degeneration. Presence of fibrosis is a sign of chronicity. Thus, the diagnosis of NAFL/NASH rests on clinicopathological criteria; it always requires both clinical and biopsy-based information. NAFLD could be both the result and the cause of metabolic syndrome, with a vicious cycle operating between these conditions. Remaining challenges are: (i) the lack of a clear threshold alcohol intake for defining "non-alcoholic"; (ii) a lacking consensus for the classification of fatty liver disease; and (iii) absence of a histological definition of NASH, which currently remains the gold standard for the diagnosis. Further challenges include the overlap of the criteria for NAFLD and alcoholic liver disease as many obese individuals also consume considerable volumes of alcohol.
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Affiliation(s)
- Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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Khullar V, Dolganiuc A, Firpi RJ. Pre-and-post transplant considerations in patients with nonalcoholic fatty liver disease. World J Transplant 2014; 4:81-92. [PMID: 25032097 PMCID: PMC4094954 DOI: 10.5500/wjt.v4.i2.81] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 02/17/2014] [Accepted: 03/12/2014] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the third most common indication for liver transplantation in the United States. With the growing incidence of obesity, NAFLD is expected to become the most common indication for liver transplantation over the next few decades. As the number of patients who have undergone transplantation for NAFLD increases, unique challenges have emerged in the management and long-term outcomes in patients. Risk factors such as obesity, hypertension, diabetes, and hyperlipidemia continue to play an important role in the pathogenesis of the disease and its recurrence. Patients who undergo liver transplantation for NAFLD have similar long-term survival as patients who undergo liver transplantation for other indications. Research shows that post-transplantation recurrence of NAFLD is commonplace with some patients progressing to recurrent non-alcoholic steatohepatitis and cirrhosis. While treatment of comorbidities is important, there is no consensus on the management of modifiable risk factors or the role of pharmacotherapy and immunosuppression in patients who develop recurrent or de novo NAFLD post-transplant. This review provides an outline of NAFLD as indication for liver transplantation with a focus on the epidemiology, pathophysiology and risk factors associated with this disease. It also provides a brief review on the pre-transplant considerations and post-transplant factors including patient characteristics, role of obesity and metabolic syndrome, recurrence and de novo NAFLD, outcomes post-liver transplantation, choice of medications, and options for immunosuppression.
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Bastati N, Feier D, Wibmer A, Traussnigg S, Balassy C, Tamandl D, Einspieler H, Wrba F, Trauner M, Herold C, Ba-Ssalamah A. Noninvasive differentiation of simple steatosis and steatohepatitis by using gadoxetic acid-enhanced MR imaging in patients with nonalcoholic fatty liver disease: a proof-of-concept study. Radiology 2014; 271:739-47. [PMID: 24576046 DOI: 10.1148/radiol.14131890] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE To determine whether gadoxetic acid-enhanced magnetic resonance (MR) imaging can be used to distinguish between simple steatosis and nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD), defined according to the steatosis activity and fibrosis (SAF) scoring system, which is based on the semiquantitative scoring of steatosis activity and liver fibrosis. MATERIALS AND METHODS The local institutional review committee approved this study and waived written informed consent. This was a retrospective study of gadoxetic acid-enhanced 3-T MR imaging performed in 81 patients with NAFLD (45 men [56%]; mean age, 56 years; range, 25-78 years). The MR images were analyzed by using the relative enhancement (the ratio of signal intensities of the liver parenchyma before and 20 minutes after intravenous administration of gadoxetic acid). Univariate and multiple regression analyses were applied to identify variables associated with relative enhancement measurements. The ability of relative enhancement to allow differentiation between simple steatosis and NASH was assessed by using area under the receiver operating characteristic (ROC) curve analysis. RESULTS Relative enhancement negatively correlated with the degree of lobular inflammation (r = -0.59, P < .0001), ballooning (r = -0.44, P < .0001), and fibrosis (r = -0.59, P ≤ .0001), but not with steatosis (r = -0.16, P = .15). Patients with NASH had a significantly lower relative liver enhancement (0.82 ± 0.22) than those with simple steatosis (1.39 ± 0.52) (P < .001). Relative enhancement measurements performed well in the differentiation between simple steatosis and NASH, with an area under the ROC curve of 0.85 (95% confidence interval: 0.75, 0.91) (cutoff = 1.24, sensitivity = 97%, specificity = 63%). CONCLUSION Gadoxetic acid relative enhancement was significantly lower in patients with NASH than in patients with simple steatosis, but further prospective studies are warranted.
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Affiliation(s)
- Nina Bastati
- From the Department of Radiology (N.B., D.F., A.W., C.B., D.T., H.E., C.H., A.B.S.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III (S.T., M.T.), and Department of Pathology (F.W.), Medical University Vienna, General Hospital of Vienna, Vienna, Austria
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Hashimoto E, Taniai M, Tokushige K. Characteristics and diagnosis of NAFLD/NASH. J Gastroenterol Hepatol 2013; 28 Suppl 4:64-70. [PMID: 24251707 DOI: 10.1111/jgh.12271] [Citation(s) in RCA: 179] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/23/2013] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome. NAFLD has become an important public health issue because of its high prevalence. NAFLD consists of two clinicopathological entities: simple steatosis, which generally follows a benign non-progressive clinical course, and non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. The diagnosis of NAFLD is based on the following three criteria: non-alcoholic, detection of steatosis either by imaging or by histology, and appropriate exclusion of other liver diseases. Alcoholic liver disease can occur when daily alcohol consumption exceeds 20 g in women or 30 g in men. Thus, non-alcoholic indicates lower levels of these alcohol consumptions. However, there is still no clear consensus regarding the threshold alcohol consumption for defining non-alcoholic liver disease. Then, there is the strong recommendation for a change in the nomenclature, such as use of the term metabolic fatty liver and metabolic steatohepatitis. NASH has emerged as a clinicopathological entity, and even now, a liver biopsy remains the gold standard for making a definitive diagnosis. However, liver biopsy has several drawbacks. In general practice, NAFLD is a convenient-to-use term for the diagnosis and management of these patients, and serum biomarkers that indicate the severity of fibrosis serve as clinically useful tools for the identification of NAFLD in patients with bridging fibrosis or cirrhosis. In the future, improved understanding of the pathogenesis of NASH and new technologies may contribute to the diagnostic process and provide reliable, non-invasive alternatives to liver biopsy.
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Affiliation(s)
- Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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Abstract
Non-alcoholic fatty liver disease (NAFLD), once regarded as an innocuous condition, is now considered to be the most common cause of chronic liver disease worldwide. Evidence suggests a strong association between NAFLD and other potentially life-threatening diseases. A significant proportion of these patients develops progressive liver injury leading to cirrhosis and hepatocellular carcinoma. Unrecognized NAFLD constitutes a substantial proportion of patients with cryptogenic cirrhosis. Several large community-based studies have found increased mortality in NAFLD patients compared to the expected mortality of the general population of the same age and sex. Cardiovascular disease is an important cause of morbidity and mortality in patients with NAFLD and accounts for up to 30 % of overall death. Cardiovascular mortality does not seem to differ between simple steatosis and non-alcoholic steatohepatitis. NAFLD is associated with increased risk of both hepatic and extra-hepatic malignancy. Malignancy is among the most important causes of death in NAFLD patients. NAFLD is a risk factor for liver cancer even without cirrhosis. The steatotic liver has poor ability to regenerate after volume loss, which may lead to the development of liver failure and increased mortality after extended liver resection. Also, transplantation of steatotic liver results in an increased rate of poor graft function, primary graft non-function, and poorer outcome. There is a high recurrence rate of fatty liver disease in patients transplanted for NASH.
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Affiliation(s)
- Ramesh Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), Sector D1, Vasant Kunj, New Delhi, 110070, India.
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Lomonaco R, Sunny NE, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs 2013; 73:1-14. [PMID: 23329465 DOI: 10.1007/s40265-012-0004-0] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world. It is commonly associated with insulin resistance, obesity, dyslipidaemia, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is characterized by steatosis with necroinflammation and eventual fibrosis, which can lead to end-stage liver disease and hepatocellular carcinoma. Its pathogenesis is complex, and involves a state of 'lipotoxicity' in which insulin resistance, with increased free fatty acid release from adipose tissue to the liver, play a key role in the onset of a 'lipotoxic liver disease' and its progression to NASH. The diagnosis of NASH is challenging, as most affected patients are symptom free and the role of routine screening is not clearly established. A complete medical history is important to rule out other causes of fatty liver disease (alcohol abuse, medications, other). Plasma aminotransferase levels and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for a definitive diagnosis. However, there is an active search for plasma biomarkers and imaging techniques that may non-invasively aid in the diagnosis. The treatment of NASH requires a multifaceted approach. The goal is to reverse obesity-associated lipotoxicity and insulin resistance via lifestyle intervention. Although there is no pharmacological agent approved for the treatment of NAFLD, vitamin E (in patients without T2DM) and the thiazolidinedione pioglitazone (in patients with and without T2DM) have shown the most consistent results in randomized controlled trials. This review concentrates on our current understanding of the disease, with a focus on the existing therapeutic approaches and potential future pharmacological developments for NAFLD and NASH.
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Affiliation(s)
- Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, 32610-0226, USA
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Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10:330-44. [PMID: 23507799 DOI: 10.1038/nrgastro.2013.41] [Citation(s) in RCA: 1305] [Impact Index Per Article: 108.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).
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Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK
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Chen J, Yin M, Glaser KJ, Talwalkar JA, Ehman RL. MR elastography of liver disease: State of the art. APPLIED RADIOLOGY 2013. [DOI: 10.37549/ar1982] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Almeida F, Salgueiro-Paradigorria C, Franzói-de-Moraes S, Nachbar R, Chimin P, Natali M. Aerobic physical training after weaning improves liver histological and metabolic characteristics of diet-induced obese rats. Sci Sports 2013. [DOI: 10.1016/j.scispo.2012.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Chen J, Yin M, Glaser KJ, Talwalkar JA, Ehman RL. MR Elastography of Liver Disease: State of the Art. APPLIED RADIOLOGY 2013; 42:5-12. [PMID: 26366024 PMCID: PMC4564016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
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Shigefuku R, Takahashi H, Kobayashi M, Ikeda H, Matsunaga K, Okuse C, Matsumoto N, Maeyama S, Sase S, Suzuki M, Itoh F. Pathophysiological analysis of nonalcoholic fatty liver disease by evaluation of fatty liver changes and blood flow using xenon computed tomography: can early-stage nonalcoholic steatohepatitis be distinguished from simple steatosis? J Gastroenterol 2012; 47:1238-47. [PMID: 22576023 DOI: 10.1007/s00535-012-0581-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Accepted: 03/05/2012] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Effective noninvasive tests that can distinguish early-stage nonalcoholic steatohepatitis (NASH) from simple steatosis (SS) have long been sought. Our aim was to determine the possibility of noninvasively distinguishing early-stage NASH from SS. MATERIALS AND METHODS We used Fick's principle and the Kety-Schmidt equation to determine the hepatic tissue blood flow (TBF) in 65 NASH patients who underwent xenon computed tomography (Xe-CT). We calculated the lambda value (LV), i.e., Xe gas solubility coefficient, in liver and blood. We assessed the histological severity of fatty changes and fibrosis on the basis of Brunt's classification. Liver biopsy revealed SS in 9 patients and NASH in 56 patients. NASH stages 1 and 2 were classified as early-stage NASH (Ea-NASH; 38 patients) and stages 3 and 4 as advanced-stage NASH (Ad-NASH; 18 patients). We evaluated the differences in LV and TBF among the 3 groups. RESULTS LV was significantly lower in the Ad-NASH group than in the SS and Ea-NASH groups. Portal venous TBF (PVTBF) was significantly lower in the Ea-NASH group than in the SS group, and PVTBF was lower in the Ad-NASH group than in the Ea-NASH group. Total hepatic TBF (THTBF) was significantly different between the SS and Ea-NASH groups and between the SS and Ad-NASH groups. CONCLUSIONS In conclusion, measurements of TBF and LV are useful for evaluating the pathophysiological progression of NASH. In addition, these measurements can facilitate the differential diagnosis of SS and Ea-NASH, which may not be distinguishable by other means.
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Affiliation(s)
- Ryuta Shigefuku
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
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The spontaneous course of liver enzymes and its correlation in nonalcoholic fatty liver disease. Dig Dis Sci 2012; 57:1925-31. [PMID: 22373863 DOI: 10.1007/s10620-012-2098-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Accepted: 02/10/2012] [Indexed: 12/29/2022]
Abstract
BACKGROUND The course of liver enzymes and their clinical correlations in nonalcoholic fatty liver disease (NAFLD) remains largely undescribed. AIMS The objective of this study was to determine the spontaneous course of liver enzymes, and the association between changes in liver enzymes with changes in body weight and liver histology in NAFLD. METHODS Follow-up data were prospectively collected for 2 years in 73 untreated patients with NAFLD. Liver enzymes were measured every 3 months, and liver biopsy repeated at 2 years. RESULTS A significant improvement in serum levels of aminotransferases, alkaline phosphatase, and γ-glutamyltransferase levels, and a significant decrease in albumin levels occurred with no significant change in body weight over the 2 years. During this period, alanine aminotransferase levels were persistently elevated in 68% of patients, fluctuated between normal and elevated in 22% of patients, and normalized in 10% of patients. There was no clear-cut correlation between the pattern of alanine aminotransferase levels and changes in steatosis, inflammation, hepatocyte ballooning, or fibrosis stage over time. CONCLUSIONS Liver enzyme levels and aminotransferase activity are insensitive tools to follow changes in liver histological features in NAFLD. These data should be taken into consideration in patient counseling and monitoring, and in the design of future therapeutic trials.
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Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, Kobayashi M, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Ohmoto Y, Amakawa K, Tsuji H, Kumada H. Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol 2012; 107:253-61. [PMID: 22008893 DOI: 10.1038/ajg.2011.327] [Citation(s) in RCA: 230] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD). METHODS This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan-Meier methodology and Cox's proportional hazards analysis. RESULTS In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56-26.26; P<0.001), platelet count <150 × 10(3)/μl (HR: 7.19; 95% CI: 2.26-23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30-14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09-9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3-4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02-69.52; P<0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3-4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40-3.37; P=0.780). CONCLUSIONS This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC.
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Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States. Liver Transpl 2012; 18:29-37. [PMID: 21932374 DOI: 10.1002/lt.22435] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Because of the ongoing epidemics of obesity and diabetes, nonalcoholic steatohepatitis (NASH) may become a leading indication for liver transplantation. There are concerns about the posttransplant survival of patients with NASH because of associated cardiovascular and metabolic risk factors. We aimed to determine recent trends in the proportion of patients undergoing transplantation for NASH-related cirrhosis in the United States and to estimate their posttransplant survival. We used data provided by the United Network for Organ Sharing for first-time adult cadaveric liver transplants performed in the United States between January 1, 1997 and October 31, 2010 (n = 53,738). The proportion of liver transplants performed for NASH-related cirrhosis increased dramatically from 1.2% in 1997-2003 to 7.4% in 2010 when NASH was the fourth most common indication for transplantation. The posttransplant survival of patients with NASH (n = 1810) at 1 (87.6%), 3 (82.2%), and 5 years (76.7%) was superior to the survival of patients with hepatocellular carcinoma, hepatitis C virus, alcoholic liver disease, acute hepatic necrosis, hemochromatosis, or cryptogenic liver disease and was inferior to the survival of only 4 groups of patients (those with primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, or hepatitis B virus). In conclusion, NASH-related cirrhosis is increasing rapidly as an indication for liver transplantation in the United States and is associated with excellent posttransplant survival.
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Affiliation(s)
- Anita Afzali
- Department of Medicine, Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, 1959 N.E. Pacific Street, Seattle, WA 98195, USA.
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Hashimoto E, Tokushige K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: Growing evidence of an epidemic? Hepatol Res 2012; 42:1-14. [PMID: 21917086 DOI: 10.1111/j.1872-034x.2011.00872.x] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The incidence of hepatocellular carcinoma in non-viral-related chronic liver disease has gradually increased in Japan. Obesity and diabetes mellitus type 2 have been established as a significant risk factor for hepatocellular carcinoma (HCC) by epidemiologic observations and experimental studies. The risks of these factors for HCC are likely conferred by two factors: the increased risk for development of non-alcoholic steatohepatitis (NASH) and the carcinogenic potential of themselves. Hepatocellular carcinoma in NASH is difficult to evaluate because histological diagnosis is required for diagnosis of NASH, which can lead selection bias. Furthermore, end-stage NASH is in effect "burned-out" NASH, for which the diagnosis of NASH cannot be made any more. At all events, previous studies on the etiology of Japanese HCC showed that non-alcoholic fatty liver disease accounts for 1-5% of all HCC (male predominant, median age 72 years). They have high prevalences of obesity and/or diabetes mellitus type 2 and 10-75% of the HCC arose from non-cirrhotic livers. HCC in NASH may be of multicentric origin, similar to HCC based on viral hepatitis. Regular screening for HCC is extremely important especially in cirrhotic NASH patients and recurrence should be warned. In western and Asian countries, the prevalence of non-alcoholic fatty liver disease in the general population is increasing dramatically. Therefore, there is an urgent need to elucidate pathogenesis and clinical features of HCC in NASH. In this review we summarize current concepts for HCC in NASH.
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Affiliation(s)
- Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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Abstract
Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis not due to excess alcohol consumption. The prevalence of NAFLD is up to 30% in developed countries and nearly 10% in developing nations, making NAFLD the most common liver condition in the world. The pathogenesis of NAFLD is related to insulin resistance and, thus, it is frequently found in individuals who have central obesity or diabetes. Insulin resistance and excess adiposity are associated with increased lipid influx into the liver and increased de novo hepatic lipogenesis, promoting hepatic triglyceride accumulation. Defects in lipid utilization via mitochondrial oxidation and lipid export may also contribute to hepatic lipid build-up. Adipocytokine alterations, lipotoxicity from saturated fatty acids and fructose have been all been implicated in causing hepatocyte injury in NAFLD through pathways involving oxidative and endoplasmic reticulum stress. Clinically, NAFLD is commonly asymptomatic and frequently detected incidentally by blood liver function tests or imaging performed for other reasons. Subjects with NAFLD have a higher mortality rate than the general population and are at increased risk of developing cardiovascular disease and diabetes in the future. Histologically, NAFLD occurs as a spectrum from mild hepatic steatosis only, to non-alcoholic steatohepatitis (NASH) characterized by hepatocellular injury and inflammation, to cirrhosis. A diagnosis of NASH with associated fibrosis heralds a more significant prognosis as it is more likely to progressive to cirrhosis with complications of hepatic failure and hepatocellular carcinoma. Currently, the diagnosis of NASH requires a liver biopsy, however, serum based markers of hepatocyte apoptosis such as cytokeratin-18 fragments offer promise as accurate non-invasive diagnostic tests. Treatment of NAFLD revolves around addressing concomitant metabolic risk factors and improving insulin resistance through weight loss measures and exercise. Insulin sensitizing agents such as pioglitazone and anti-oxidant agents such as vitamin E show some promise in improving liver histology in patients with NASH, however, the long-term benefit of these medications has not been demonstrated.
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Affiliation(s)
- Briohny W Smith
- School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, Australia
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Lazarin MDO, Ishii-Iwamoto EL, Yamamoto NS, Constantin RP, Garcia RF, da Costa CEM, Vitoriano ADS, de Oliveira MC, Salgueiro-Pagadigorria CL. Liver mitochondrial function and redox status in an experimental model of non-alcoholic fatty liver disease induced by monosodium l-glutamate in rats. Exp Mol Pathol 2011; 91:687-94. [DOI: 10.1016/j.yexmp.2011.07.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Revised: 07/11/2011] [Accepted: 07/11/2011] [Indexed: 12/20/2022]
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de Oliveira MC, Torrezan R, da Costa CEM, Ambiel CR, Constantin RP, Ishii-Iwamoto EL, Salgueiro-Pagadigorria CL. Changes in calcium fluxes in mitochondria, microsomes, and plasma membrane vesicles of livers from monosodium L-glutamate-obese rats. Metabolism 2011; 60:1433-41. [PMID: 21489575 DOI: 10.1016/j.metabol.2011.02.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Revised: 02/09/2011] [Accepted: 02/17/2011] [Indexed: 01/11/2023]
Abstract
The purpose of this work was to evaluate if the fat liver accumulation interferes with intracellular calcium fluxes and the liver glycogenolytic response to a calcium-mobilizing α(1)-adrenergic agonist, phenylephrine. The animal model of monosodium L-glutamate (MSG)-induced obesity was used. The adult rats develop obesity and steatosis. Calcium fluxes were evaluated through measuring the (45)Ca(2+) uptake by liver microsomes, inside-out plasma membrane, and mitochondria. In the liver, assessments were performed on the calcium-dependent glycogenolytic response to phenylephrine and the glycogen contents. The Ca(2+) uptake by microsomes and plasma membrane vesicles was reduced in livers from obese rats as a result of reduction in the Ca(2+)-ATPase activities. In addition, the plasma membrane Na(+)/K(+)-ATPase was reduced. All these matched effects could contribute to elevated resting intracellular calcium levels in the hepatocytes. Livers from obese rats, albeit smaller and with similar glycogen contents to those of control rats, released higher amounts of glucose in response to phenylephrine infusion, which corroborates these observations. Mitochondria from obese rats exhibited a higher capacity of retaining calcium, a phenomenon that could be attributed to a minor susceptibility of the mitochondrial permeability transition pore opening.
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Affiliation(s)
- Monique Cristine de Oliveira
- Laboratory of Biological Oxidations, Department of Biochemistry, University of Maringá, 87020900 Maringá, Brazil
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Abstract
The last decade has seen many studies examining the prevalence and natural history of NAFLD in the United States and it is clear that this disease is likely to be an important cause of liver-related morbidity in the future. Several pharmacologic therapies have shown some promise; currently, vitamin E and insulin-sensitizing agents such as pioglitazone can be considered in appropriate cases. Conservative measures to promote weight loss still have a role to play, but the obesity epidemic in the Western World has reached such proportions that bariatric surgery is proving to be an attractive option for patients with a BMI greater than 35 to 40 kg/m2. Well-designed prospective studies are required to ensure that all of these therapies are safe and effective in the long term. Newer agents will likely be investigated as the pathogenesis of NAFLD and fibrosis progression in NASH are further elucidated.
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Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 2011. [PMID: 21460032 DOI: 10.1148/radiol.11101942.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
PURPOSE To investigate the diagnostic accuracy (area under the receiver operating characteristic curve [AUROC]) of magnetic resonance (MR) elastography for the early detection of nonalcoholic steatohepatitis (NASH) among patients with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS An institutional review board-approved and HIPAA-compliant retrospective study was conducted in 58 NAFLD patients. Informed consent was waived by the review board. Hepatic stiffness, relative fat fraction, inflammation grade, and fibrosis stage were assessed from MR elastography, in-phase and out-of-phase gradient-echo imaging, and liver biopsy histopathologic review, respectively. Pairwise t testing, receiver operating characteristic analysis, and partial correlation analysis were performed. RESULTS The mean hepatic stiffness for patients with simple steatosis (2.51 kPa) was less (P = .028) than that for patients with inflammation but no fibrosis (3.24 kPa). The mean hepatic stiffness for patients with inflammation but no fibrosis was less (P = .030) than that for patients with hepatic fibrosis (4.16 kPa). Liver stiffness had high accuracy (AUROC = 0.93) for discriminating patients with NASH from those with simple steatosis, with a sensitivity of 94% and a specificity 73% by using a threshold of 2.74 kPa. CONCLUSION In patients with NAFLD, hepatic stiffness measurements with MR elastography can help identify individuals with steatohepatitis, even before the onset of fibrosis; NAFLD patients with inflammation but no fibrosis have greater liver stiffness than those with simple steatosis and lower mean stiffness than those with fibrosis.
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Affiliation(s)
- Jun Chen
- Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
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The Possibility of differentiation between nonalcoholic steatohepatitis and fatty liver in rabbits on Gd-EOB-DTPA-enhanced open-type MRI scans. Acad Radiol 2011; 18:525-9. [PMID: 21237679 DOI: 10.1016/j.acra.2010.11.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2010] [Revised: 11/23/2010] [Accepted: 11/29/2010] [Indexed: 12/29/2022]
Abstract
RATIONALE AND OBJECTIVES We used rabbits to investigate the possibility of differentiating between nonalcoholic steatohepatitis (NASH) and fatty liver (FL) on scans acquired by open-type‒ and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)‒enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS We divided 15 adult rabbits into three equal groups; they received standard (control group), high-fat (FL) content (FL group), or choline-deficient chow (NASH group). With the animals under general anesthesia we acquired scans on an open 0.3-Tesla MRI system. Signal intensity (SI) was measured before and after contrast administration and defined as SI-pre and SI-post, respectively. Relative SI enhancement (Sr) was calculated using the equation: Sr = (average of three SI-post- minus average of three SI values in no-signal fields)/(average of three SI-pre- minus average of three SI values in no-signal fields) × 100. Maximum Sr (Srmax), the time (in seconds) required to reach Srmax (Tmax), and the difference between Srmax and Sr at 30 minutes (Sr(30m)R) were analyzed. RESULTS Srmax was significantly higher in the NASH rabbits than the other two groups (P < .05). CONCLUSIONS In rabbits, the Srmax value made it possible to differentiate NASH from normal and fatty liver.
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Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 2011; 259:749-56. [PMID: 21460032 DOI: 10.1148/radiol.11101942] [Citation(s) in RCA: 330] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE To investigate the diagnostic accuracy (area under the receiver operating characteristic curve [AUROC]) of magnetic resonance (MR) elastography for the early detection of nonalcoholic steatohepatitis (NASH) among patients with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS An institutional review board-approved and HIPAA-compliant retrospective study was conducted in 58 NAFLD patients. Informed consent was waived by the review board. Hepatic stiffness, relative fat fraction, inflammation grade, and fibrosis stage were assessed from MR elastography, in-phase and out-of-phase gradient-echo imaging, and liver biopsy histopathologic review, respectively. Pairwise t testing, receiver operating characteristic analysis, and partial correlation analysis were performed. RESULTS The mean hepatic stiffness for patients with simple steatosis (2.51 kPa) was less (P = .028) than that for patients with inflammation but no fibrosis (3.24 kPa). The mean hepatic stiffness for patients with inflammation but no fibrosis was less (P = .030) than that for patients with hepatic fibrosis (4.16 kPa). Liver stiffness had high accuracy (AUROC = 0.93) for discriminating patients with NASH from those with simple steatosis, with a sensitivity of 94% and a specificity 73% by using a threshold of 2.74 kPa. CONCLUSION In patients with NAFLD, hepatic stiffness measurements with MR elastography can help identify individuals with steatohepatitis, even before the onset of fibrosis; NAFLD patients with inflammation but no fibrosis have greater liver stiffness than those with simple steatosis and lower mean stiffness than those with fibrosis.
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Affiliation(s)
- Jun Chen
- Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
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Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol 2011; 46 Suppl 1:63-9. [PMID: 20844903 DOI: 10.1007/s00535-010-0311-8] [Citation(s) in RCA: 197] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 08/05/2010] [Indexed: 02/07/2023]
Abstract
We provide an update review on the prevalence, gender, ethnic variations, and prognosis of nonalcoholic steatohepatitis (NASH). According to annual health checks, 9-30% of Japanese adults have nonalcoholic fatty liver disease (NAFLD) by ultrasonography (US) and prevalence of NASH is estimated to be 1-3%. These conditions are strongly associated with the presence of obesity and lifestyle-related diseases. NAFLD and NASH exhibit age and gender differences in both prevalence and severity. Among younger patients, these conditions are more common in men (2-3 times); however, after 60 years of age, the prevalence of NASH is higher in women. According to a systemic analysis of histological findings for NASH, 37.6% of patients had progressive fibrosis, 20.8% improved, and 41.6% remained stable over a mean duration of follow-up of 5.3 years. Age and presence of inflammation on initial biopsy were independent predictors of progression to advanced fibrosis. The frequencies of development of cirrhosis in NASH are 5-25% during around 7-year follow-up periods. Survival in NASH is lower than the expected survival of the matched general population due to the higher prevalence of cardiovascular and liver-related death. In patients with cirrhotic NASH, hepatocellular carcinoma (HCC) and liver failure are the main causes of morbidity and mortality (5-year cumulative HCC development rate 11.3%, 5-year survival rate 75.2%, respectively). The cumulative rate of recurrence of HCC at 5 years was 72.5%. Regular screening for complications of liver cirrhosis and HCC is extremely important for cirrhotic NASH patients.
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Affiliation(s)
- Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
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Adams LA, Feldstein AE. Nonalcoholic steatohepatitis: risk factors and diagnosis. Expert Rev Gastroenterol Hepatol 2010; 4:623-35. [PMID: 20932147 DOI: 10.1586/egh.10.56] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) represents the progressive form of nonalcoholic fatty liver disease with greater potential to lead to liver-related morbidity and mortality. Diagnosing NASH mandates more intensive clinical management and consideration for clinical trials. Currently, the diagnosis of NASH requires a liver biopsy, which is invasive, with drawbacks in sampling and interpretation error. Clinical risk factors for NASH include diabetes and the metabolic syndrome; however, these are not sufficiently predictive of the condition by themselves. Routine liver aminotransaminase levels are not reliable; however, novel plasma hepatocyte apoptosis markers, either alone or in combination with clinical risk factors, are potential noninvasive diagnostic tools for the future.
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Affiliation(s)
- Leon A Adams
- School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital Unit, Nedlands, WA 6009, Australia
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Pacifico L, Poggiogalle E, Cantisani V, Menichini G, Ricci P, Ferraro F, Chiesa C. Pediatric nonalcoholic fatty liver disease: A clinical and laboratory challenge. World J Hepatol 2010; 2:275-88. [PMID: 21161009 PMCID: PMC2998974 DOI: 10.4254/wjh.v2.i7.275] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Revised: 07/06/2010] [Accepted: 07/13/2010] [Indexed: 02/06/2023] Open
Abstract
The true prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is unknown. Challenges in determining the population prevalence of NAFLD include the type of test (and the reference intervals used to define normal and abnormal), the type of population (general population, hospital series), the demographic characteristics of the population sampled, and the nature of the study design. The natural history of pediatric NAFLD remains uncertain. The issue of when to perform a liver biopsy in children with suspected NAFLD remains controversial. Children with NAFLD but normal alanine aminotransferase are rarely investigated. However, evidence of alterations in glucose metabolism parameters should prompt a better understanding of the natural history of pediatric NAFLD not only in terms of the progression of liver disease but also regarding its potential relationship with other health outcomes such as type 2 diabetes mellitus and cardiovascular disease. This evidence could make liver biopsy mandatory in the majority of cases at risk of progressive and severe hepatic and extrahepatic disease. This conclusion, however, raises the question of the feasibility of liver biopsy assessment in an extremely large at risk population, and of the cost/effectiveness of this policy. There is a considerable, continuous interest in reliable, noninvasive alternatives that will allow the prognosis of pediatric NAFLD to be followed in large community or population-based studies.
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Affiliation(s)
- Lucia Pacifico
- Lucia Pacifico, Eleonora Poggiogalle, Flavia Ferraro, Claudio Chiesa, Departments of 1 Pediatrics, Sapienza University of Rome, Rome 00161, Italy
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Sorrentino P, Terracciano L, D'Angelo S, Ferbo U, Bracigliano A, Vecchione R. Predicting fibrosis worsening in obese patients with NASH through parenchymal fibronectin, HOMA-IR, and hypertension. Am J Gastroenterol 2010; 105:336-44. [PMID: 19861959 DOI: 10.1038/ajg.2009.587] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Few published studies have examined the results obtained from repeat liver biopsies in obese patients with nonalcoholic fatty liver disease (NAFLD). The progressive form of this disease may be largely limited to a subgroup of NAFLD patients with nonalcoholic steatohepatitis (NASH). The presence of intralobular fibronectin (Fn) and other variables was investigated in relation to subsequent fibrosis progression. METHODS In this prospective study, 271 obese patients admitted to the hospital with NAFLD and abnormal liver enzymes were scheduled to undergo a repeat liver biopsy at least 5 years after the initial biopsy. After excluding cirrhotic patients, basal biopsy specimens obtained from patients who underwent a second liver biopsy were stained with antibodies against Fn. The progression of fibrosis in the follow-up sample was correlated with the amount of Fn and other clinicopathological variables. RESULTS We obtained a second liver biopsy from 149 patients after a median time of 6.4 years. Of these, 132 showed suitable Fn staining for semi-quantitative assessments. In all, 44 out of 83 patients (53%) with basal NASH showed fibrosis progression by at least one stage in the second liver biopsy. The amount of Fn (odds ratio=14.1; P<0.001), a diagnosis of hypertension (odds ratio=4.8; P=0.028), and homeostasis model assessment parameter of insulin resistance (HOMA-IR) scores (>8, odds ratio=1.9; P=0.004) were independent predictive factors of worsening fibrosis. CONCLUSIONS A semi-quantitative assessment of the amount of parenchymal Fn present at an early stage in obese patients with NASH is valuable for predicting the progression of fibrosis. Similarly, lobular Fn deposition may be a sensitive and early indicator of active fibrogenetic processes in the liver. Hypertension and higher HOMA-IR scores are other clinical independent risk factors that predict the progression of fibrosis.
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Affiliation(s)
- Paolo Sorrentino
- Liver Unit, Department of Internal Medicine, Clinical and Experimental Hepatology, S.G. Moscati Hospital, Avellino, Italy.
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