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Pedersen K, Poojari A, Colberg SF, Mechernsee SM, Iversen JF, Barrès R, Lykkesfeldt J, Tveden-Nyborg P. A Guinea Pig Model of Pediatric Metabolic Dysfunction-Associated Steatohepatitis: Poor Vitamin C Status May Advance Disease. Nutrients 2025; 17:291. [PMID: 39861421 PMCID: PMC11767659 DOI: 10.3390/nu17020291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/10/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Children and teenagers display a distinct metabolic dysfunction-associated steatohepatitis (MASH) phenotype, yet studies of childhood MASH are scarce and validated animal models lacking, limiting the development of treatments. Poor vitamin C (VitC) status may affect MASH progression and often co-occurs with high-fat diets and related metabolic imbalances. As a regulator of DNA methylation, poor VitC status may further contribute to MASH by regulating gene expression This study investigated guinea pigs-a species that, like humans, depends on vitC in the diet-as a model of pediatric MASH, examining the effects of poor VitC status on MASH hallmarks and global DNA methylation levels. Methods: Sixty-two juvenile guinea pigs were exposed to a high-fat diet for 16 weeks. Results: Juvenile guinea pigs exhibited hepatic histopathology representative of pediatric MASH, confirmed by portal inflammation and fibrosis. Consistent with pediatric MASH, juvenile guinea pigs displayed increased lobular and portal inflammation (p < 0.05 and p < 0.0001, respectively) but less steatosis (p < 0.001) compared to adults. Compared to the controls, the guinea pigs deprived in VitC showed lower body weight (p < 0.01), higher expression of hepatic inflammatory genes (p < 0.05), and a lower global hydroxymethylcytosine to methylcytosine ratio in the high-fat groups (p < 0.05). Conclusions: Our study validates guinea pigs as a model of pediatric MASH and suggests that VitC contributes to an altered gene expression signature through the regulation of DNA hydroxymethylation. We postulate that nutritional co-deficiencies in MASH, such as low VitC, may accelerate disease progression and deserve further attention.
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Affiliation(s)
- Kamilla Pedersen
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark; (K.P.); (S.F.C.); (S.M.M.); (J.L.)
| | - Ankita Poojari
- Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA;
| | - Simone Frederikke Colberg
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark; (K.P.); (S.F.C.); (S.M.M.); (J.L.)
| | - Stine Marguerite Mechernsee
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark; (K.P.); (S.F.C.); (S.M.M.); (J.L.)
| | - Jo Frøkjær Iversen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; (J.F.I.); (R.B.)
| | - Romain Barrès
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; (J.F.I.); (R.B.)
- Institut de Pharmacologie Moléculaire et Cellulaire, CNRS and Université de Nice Côte d’Azur, 06560 Valbonne, France
| | - Jens Lykkesfeldt
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark; (K.P.); (S.F.C.); (S.M.M.); (J.L.)
| | - Pernille Tveden-Nyborg
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark; (K.P.); (S.F.C.); (S.M.M.); (J.L.)
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Ling L, Li R, Xu M, Zhou J, Hu M, Zhang X, Zhang XJ. Species differences of fatty liver diseases: comparisons between human and feline. Am J Physiol Endocrinol Metab 2025; 328:E46-E61. [PMID: 39636211 DOI: 10.1152/ajpendo.00014.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most widespread chronic liver disease that poses significant threats to public health due to changes in dietary habits and lifestyle patterns. The transition from simple steatosis to nonalcoholic steatohepatitis (NASH) markedly increases the risk of developing cirrhosis, hepatocellular carcinoma, and liver failure in patients. However, there is only one Food and Drug Administration-approved therapeutic drug in the world, and the clinical demand is huge. There is significant clinical heterogeneity among patients with NAFLD, and it is challenging to fully understand human NAFLD using only a single animal model. Interestingly, felines, like humans, are particularly prone to spontaneous fatty liver disease. This review summarized and compared the etiology, clinical features, pathological characteristics, and molecular pathogenesis between human fatty liver and feline hepatic lipidosis (FHL). We analyzed the key similarities and differences between those two species, aiming to provide theoretical foundations for developing effective strategies for the treatment of NAFLD in clinics.
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Affiliation(s)
- Like Ling
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Ruilin Li
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Mengqiong Xu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Junjie Zhou
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Manli Hu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xin Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xiao-Jing Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
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Săsăran MO, Muntean C, Lupu A, Lupu VV. Neutrophils: tissue and circulating signatures of pediatric non-alcoholic fatty liver disease. Front Cell Dev Biol 2024; 11:1336033. [PMID: 38239291 PMCID: PMC10794720 DOI: 10.3389/fcell.2023.1336033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 12/18/2023] [Indexed: 01/22/2024] Open
Abstract
The recent rise in non-alcoholic fatty liver disease (NAFLD) among children and adolescents led to a thorough investigation of the peculiarities of the cellular infiltrate which characterize the disease at young ages. This review aims to highlight the key involvement of neutrophils in the pathogenesis of pediatric NAFLD and the potential biomarker role of neutrophil-to-lymphocyte ratio (NLR) in the same pediatric disorder. Neutrophils, which are first responders to inflammation, constitute an abundant component of an infiltrate which is particularly disposed within the portal area of children with NAFLD. The involvement of neutrophils in triggering liver fibrosis has been related amongst others to reactive oxygen species (ROS) production, to the stimulation of hepatic stellate cells, and to their synthesis of neutrophil elastase. As immune imbalance characterizes NAFLD, potentially emerging non-invasive biomarkers such as NLR have been proposed for the detection and prognosis of NAFLD. In adults, several studies asserted the role of NLR in the prediction of advancing liver fibrosis and mortality in subjects with NAFLD. In children, data is scarce with contradicting findings, as some studies failed to identify significant shifting in NLR values in children with NAFLD when compared with obese controls without liver impairment. However, NLR seems to significantly increase in children with obesity and different degrees of NAFLD when compared to healthy counterparts and their changes seem to be reversible with weight loss. Still, paucity of pediatric studies calls for future research addressing the role of NLR in predicting NAFLD development and progression in children with obesity.
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Affiliation(s)
- Maria Oana Săsăran
- Department of Pediatrics 3, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Targu Mures, Romania
| | - Carmen Muntean
- Department of Pediatrics 1, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Targu Mures, Romania
| | - Ancuța Lupu
- Department of Pediatrics, University of Medicine and Pharmacy Gr. T. Popa Iași, Iași, Romania
| | - Vasile Valeriu Lupu
- Department of Pediatrics, University of Medicine and Pharmacy Gr. T. Popa Iași, Iași, Romania
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Rupasinghe K, Hind J, Hegarty R. Updates in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) in Children. J Pediatr Gastroenterol Nutr 2023; 77:583-591. [PMID: 37592398 DOI: 10.1097/mpg.0000000000003919] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
Abstract
The obesity epidemic is one of the major health concerns of the 21st century. Nonalcoholic fatty liver disease (NAFLD) is linked with the increased adiposity associated with obesity. NAFLD has become the most frequent cause of chronic liver disease in adults and children worldwide. Metabolic dysfunction-associated fatty liver disease (MAFLD) also known in children as pediatric fatty liver disease (PeFLD) type 2 has begun to supersede NAFLD as the preferred nomenclature in the pediatric population. Evidence suggests the etiology of MAFLD is multifactorial, related to the complex interplay of hormonal, nutritional, genetic, and environmental factors. Current limitations in accurate diagnostic biomarkers have rendered it a diagnosis of exclusion and it is important to exclude alternative or coexisting causes of PeFLD. Lifestyle changes and modifications remains the primary treatment modality in MAFLD in children. Weight loss of 7%-10% is described as reversing MAFLD in most patients. The Mediterranean diet also shows promise in reversing MAFLD. Pharmacological intervention is debatable in children, and though pediatric trials have not shown promise, other agents undergoing adult clinical trials show promise. This review outlines the latest evidence in pediatric MAFLD and its management.
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Affiliation(s)
- Kushila Rupasinghe
- From the Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
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Green S, Mouzaki M, Abu Ata N, Trout AT. Prevalence of incidental sonographic findings of hepatic steatosis in children under 4 years of age. Pediatr Radiol 2023; 53:2221-2228. [PMID: 37563321 DOI: 10.1007/s00247-023-05729-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 08/12/2023]
Abstract
BACKGROUND The age of onset of nonalcoholic fatty liver disease (NAFLD) and its prevalence in young children is incompletely understood. OBJECTIVE We sought to evaluate the prevalence of ultrasound findings of hepatic steatosis in a cohort of children less than 4 years of age. MATERIALS AND METHODS This is an institutional review board-approved retrospective review of ultrasounds performed on children less than 4 years of age from January 2022 to August 2022 at a single quaternary care center. Two independent blinded reviewers evaluated for qualitative and semi-quantitative findings of hepatic steatosis. Per prior literature, hepatorenal index (HRI)>1.75 was used as a threshold suggestive of hepatic steatosis. Chi-square, Mann-Whitney U test, and logistic regression analyses were performed for univariable and multivariable statistical analyses. Kappa statistics were used to assess agreement between reviewers. RESULTS Eighty-five males and 102 females, median age of 1.1 years (interquartile range 2.1 years), were included. Qualitative findings of hepatic steatosis were seen in 26/187 (14%; 95% CI 10-20%). An HRI>1.75 was present in 15/187 (8%; 95% CI: 5-13%) of examinations, including 11 females and 4 males, and 7/123 (6%) participants <2 years old. Among participants with overweight or obesity, 8/43 (19%) had HRI>1.75 vs. 7/144 (5%) participants without overweight or obesity (P=0.004). Each percentile increase in anthropometrics percentile (weight-to-length or BMI, depending on age) was associated with 22 increased odds of HRI>1.75 (P=0.02). CONCLUSION Prevalence of sonographic findings of hepatic steatosis in an unselected sample of preschool-age children is 8-14%, and are more common in participants with overweight/obesity.
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Affiliation(s)
- Shannon Green
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
| | - Marialena Mouzaki
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Nadeen Abu Ata
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Andrew T Trout
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Goyal NP, Mencin A, Newton KP, Durelle J, Carrier C, Ugalde-Nicalo P, Noel B, Mouton J, Vargas D, Magrez D, Tadde B, Birman P, Best BM, Addy C, Schwimmer JB. An Open Label, Randomized, Multicenter Study of Elafibranor in Children With Nonalcoholic Steatohepatitis. J Pediatr Gastroenterol Nutr 2023; 77:160-165. [PMID: 37084342 PMCID: PMC10523882 DOI: 10.1097/mpg.0000000000003796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/23/2023]
Abstract
OBJECTIVES Nonalcoholic fatty liver disease is the most common chronic liver disease in children. Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). The aims were to (1) describe pharmacokinetics (PK), safety, and tolerability of oral elafibranor at 2 doses (80 and 120 mg) in children 8-17 years and (2) assess changes in aminotransferases. METHODS Children with NASH were randomized to open-label elafibranor 80 mg or 120 mg daily for 12 weeks. The intent-to-treat analysis included all participants who received at least 1 dose. Standard descriptive statistics and PK analyses were performed. RESULTS Ten males [mean 15.1 years, standard deviation (SD) 2.2] with NASH were randomized to 80 mg (n = 5) or 120 mg (n = 5). Baseline mean alanine aminotransferase (ALT) was 82 U/L (SD 13) and 87 U/L (SD 20) for 80 mg and 120 mg groups, respectively. Elafibranor was rapidly absorbed and well tolerated. Elafibranor plasma exposure increased between the 80 mg and 120 mg dose with a 1.9- and 1.3-fold increase in median Cmax and AUC 0-24 , respectively. End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of -37.4% (SD 23.8%) at 12 weeks. CONCLUSIONS Once daily dosing of elafibranor was well tolerated in children with NASH. There was a 37.4% relative reduction from mean baseline ALT in the 120 mg group. Decreasing ALT may be associated with improvement in liver histology, thus could be considered a surrogate for histology in early phase trials. These results may support further exploration of elafibranor in children with NASH.
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Affiliation(s)
- Nidhi P. Goyal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, UC San Diego, School of Medicine, La Jolla, California
- Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, California
| | - Ali Mencin
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Columbia University, New York, New York
| | - Kimberly P. Newton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, UC San Diego, School of Medicine, La Jolla, California
- Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, California
| | - Janis Durelle
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, UC San Diego, School of Medicine, La Jolla, California
| | - Carissa Carrier
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, UC San Diego, School of Medicine, La Jolla, California
| | - Patricia Ugalde-Nicalo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, UC San Diego, School of Medicine, La Jolla, California
| | | | | | | | | | | | | | - Brookie M. Best
- Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego La Jolla
- Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, California
| | | | - Jeffrey B. Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, UC San Diego, School of Medicine, La Jolla, California
- Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, California
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8
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Abdallah HR, Youness ER, Bedeir MM, Abouelnaga MW, Ezzat WM, Elhosary Y, El-Hariri HM, Hussein MAEA, Ahmed HR, Eladawy R. Clinical and diagnostic characteristics of non-alcoholic fatty liver disease among Egyptian children and adolescents with type1 diabetes. Diabetol Metab Syndr 2023; 15:52. [PMID: 36941617 PMCID: PMC10029237 DOI: 10.1186/s13098-023-01029-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 03/12/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Type 1 diabetes mellitus (T1DM) patients are at an increased risk for non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the clinical criteria associated with the diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD) among T1DM Egyptian children and adolescents. METHODS 74 T1DM patients aged 8-18 year were enrolled in this cross sectional study. Assessments of Clinical status, anthropometric measures, lipid profile, glycated haemoglobin (HbA1c) and liver enzymes were done. Abdominal Ultrasound evaluation of hepatic steatosis was done. Accordingly, patients were divided into two groups (NAFLD and normal liver group) and compared together. Assessment of liver fibrosis using acoustic radiation force impulse elastography (ARFI) was done. Statistical analysis included; independent t-test, Chi square and Fisher's Exact, Pearson and Spearman tests and Logistic regression models for factors associated with fatty liver were used when appropriate. RESULTS In this study; 74 patients were enrolled; 37 males (50%) and 37 females with mean age 14.3 ± 3.0 year. The mean insulin dose was 1.1 ± 0.4 U/kg and mean disease duration was 6.3 ± 3.0 year. NAFLD was detected in 46 cases while 28 cases had normal liver as diagnosed by abdominal ultrasound. Cases with NAFLD had statistically significant higher BMI-Z scores, waist/hip, waist/height and sum of skin fold thicknesses compared to those with normal liver (P < 0.05). The mean value of HbA1c % was significantly higher in NAFLD group (P = 0.003). Total cholesterol, triglycerides and LDL serum levels were significantly elevated (p < 0.05), while the HDL level was significantly lower in NAFLD cases (p = 0.001). Although, serum levels of liver enzymes; ALT and AST were significantly higher among cases with NAFLD than in normal liver group (p < 0.05), their means were within normal. Using the ARFI elastography; NAFLD cases exhibited significant fibrosis (F2, 3 and 4). BMI, patient age and female gender were among risk factors for NAFLD. CONCLUSIONS NAFLD represents a serious consequence in type 1 diabetic children and adolescents that deserves attention especially with poor glycemic control. NAFLD has the potential to evolve to fibrosis. This study demonstrated a very high prevalence of NAFLD in T1D children and adolescents using US which was (62.2%) with the percent of liver fibrosis among the NAFLD cases (F2-F4) using ARFI elastography was 26%. BMI, age of patients and female gender were detected as risk factors for NAFLD.
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Affiliation(s)
- Hanaa Reyad Abdallah
- Biological Anthropology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt.
| | - Eman Refaat Youness
- Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Manar Maher Bedeir
- Child Health Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Marwa W Abouelnaga
- Child Health Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Wafaa M Ezzat
- Internal Medicine Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Yasser Elhosary
- Internal Medicine Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Hazem Mohamed El-Hariri
- Community Medicine Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | | | - Heba R Ahmed
- National Institute of Diabetes and Endocrinology, Cairo, Egypt
| | - Rasha Eladawy
- Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Simon TG, Roelstraete B, Alkhouri N, Hagström H, Sundström J, Ludvigsson JF. Cardiovascular disease risk in paediatric and young adult non-alcoholic fatty liver disease. Gut 2023; 72:573-580. [PMID: 36522149 DOI: 10.1136/gutjnl-2022-328105] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/18/2022] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Longitudinal evidence is lacking regarding the long-term risk of major adverse cardiovascular events (MACE) in children and young adults with non-alcoholic fatty liver disease (NAFLD). DESIGN This nationwide cohort study included all Swedish children and young adults ≤25 years old with histologically confirmed NAFLD and without underlying cardiovascular disease (CVD) at baseline (1966-2016; n=699). NAFLD was defined from prospectively recorded histopathology, and further categorised as simple steatosis or non-alcoholic steatohepatitis (NASH). NAFLD patients were matched to ≤5 population controls without NAFLD or CVD (n=3353). Using Cox proportional hazards modelling, we calculated multivariable-adjusted HRs (aHRs) and 95% CIs for incident MACE (ie, ischaemic heart disease, stroke, congestive heart failure or cardiovascular mortality). In secondary analyses, we also explored rates of incident cardiac arrhythmias. RESULTS Over a median follow-up of 16.6 years, incident MACE was confirmed in 33 NAFLD patients and 52 controls. NAFLD patients had significantly higher rates of MACE than controls (3.1 vs 0.9/1000 person-years (PY); difference=2.1/1000 PY; aHR=2.33, 95% CI=1.43 to 3.78), including higher rates of ischaemic heart disease (difference=1.4/1000 PY; aHR=3.07, 95% CI 1.62 to 5.83) and congestive heart failure (difference=0.5/1000 PY; aHR=3.89, 95% CI=1.20 to 12.64). Rates of incident MACE outcomes appeared to be further augmented with NASH (aHR=5.27, 95% CI=1.96 to 14.19). In secondary analyses, NAFLD patients also had significantly higher rates of cardiac arrythmias (aHR=3.16, 95% CI=1.49 to 6.68). CONCLUSION Compared with matched population controls, children and young adults with biopsy-proven NAFLD had significantly higher rates of incident MACE, including ischaemic heart disease and congestive heart failure. Research to better characterise cardiovascular risk in children and young adults with NAFLD should be prioritised.
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Affiliation(s)
- Tracey G Simon
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Naim Alkhouri
- Hepatology, Arizona Liver Health, Chandler, Arizona, USA
| | - Hannes Hagström
- Karolinska Institute, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI Diseases, Karolinska Hospital, Stockholm, Sweden
| | - Johan Sundström
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
- Department of Pediatrics, Örebro University, Örebro, Sweden
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10
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Abstract
Metabolic-associated fatty liver disease (MAFLD) has become the most common cause for chronic liver disease among children and adolescents globally. Although liver biopsy remains the gold standard for diagnosis, emerging technology, like velocity controlled transient elastography, a noninvasive method, is being utilized to evaluate degree of fibrosis in these patients. The discovery of multiple gene polymorphisms has brought new hope for possible treatment targets. However, this research is still ongoing, making lifestyle changes and weight reduction the current mainstay of treatment. This review briefly reviews the most recent data regarding the epidemiology, pathophysiology, diagnostic modalities, and treatment of pediatric MAFLD.
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11
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Theel W, Boxma-de Klerk BM, Dirksmeier-Harinck F, van Rossum EFC, Kanhai DA, Apers J, van Dalen BM, de Knegt RJ, Holleboom AG, Tushuizen ME, Grobbee DE, Wiebolt J, Castro Cabezas M. Evaluation of nonalcoholic fatty liver disease (NAFLD) in severe obesity using noninvasive tests and imaging techniques. Obes Rev 2022; 23:e13481. [PMID: 35692179 DOI: 10.1111/obr.13481] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 12/15/2022]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high-risk patients, that is those with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of NAFLD can be as high as 80% while NASH may be present in 20% of these subjects. With the worldwide increase of obesity, it is most likely that these numbers will rise. Since advanced stages of NAFLD and NASH are strongly associated with morbidity and mortality-in particular, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma-it is of great importance to identify subjects at risk. A great variety of noninvasive tests has been published to diagnose NAFLD and NASH, especially using blood- and imaging-based tests. Liver biopsy remains the gold standard for NAFLD/NASH. This review aims to summarize the different mechanisms leading to NASH and liver fibrosis, the different noninvasive liver tests to diagnose and evaluate patients with severe obesity.
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Affiliation(s)
- Willy Theel
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.,Obesity Center CGG, Rotterdam, The Netherlands
| | - Bianca M Boxma-de Klerk
- Department of Statistics and Education, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Femme Dirksmeier-Harinck
- Department of Gastroenterology and Hepatology, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Elisabeth F C van Rossum
- Obesity Center CGG, Rotterdam, The Netherlands.,Department of Internal Medicine, Division of Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Danny A Kanhai
- Department of Pediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Jan Apers
- Department of Bariatric Surgery, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Bas M van Dalen
- Department of Cardiology, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | | | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden UMC, Leiden, The Netherlands
| | - Diederick E Grobbee
- Julius Centre for Health Science and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.,Julius Clinical, Zeist, The Netherlands
| | - Janneke Wiebolt
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.,Obesity Center CGG, Rotterdam, The Netherlands
| | - Manuel Castro Cabezas
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.,Department of Internal Medicine, Division of Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Julius Clinical, Zeist, The Netherlands
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12
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Yao K, Tarabra E, Sia D, Morotti R, Fawaz R, Valentino P, Santoro N, Caprio S, Liu S, Yimlamai D. Transcriptomic profiling of a multiethnic pediatric NAFLD cohort reveals genes and pathways associated with disease. Hepatol Commun 2022; 6:1598-1610. [PMID: 35312185 PMCID: PMC9234638 DOI: 10.1002/hep4.1940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/18/2022] [Accepted: 02/19/2022] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in children. The mechanisms that drive NAFLD disease progression in this specific patient population remain poorly defined. In this study, we obtained liver biopsy samples from a multiethnic cohort of pediatric patients with NAFLD (n = 52, mean age = 13.6 years) and healthy liver controls (n = 5). We analyzed transcriptomic changes associated with NAFLD stages using high-throughput RNA sequencing. Unsupervised clustering as well as pairwise transcriptome comparison distinguished NAFLD from healthy livers. We identified perturbations in pathways including calcium and insulin/glucose signaling occurring early in NAFLD disease, before the presence of histopathologic evidence of advanced disease. Transcriptomic comparisons identified a 25-gene signature associated with the degree of liver fibrosis. We also identified expression of the insulin-like growth factor binding protein (IGFBP) gene family (1/2/3/7) as correlating with disease stages, and it has the potential to be used as a peripheral biomarker in NAFLD. Comparing our data set with publicly available adult and adolescent transcriptomic data, we identified similarities and differences in pathway enrichment and gene-expression profiles between adult and pediatric patients with NAFLD. Regulation of genes including interleukin-32, IGFBP1, IGFBP2, and IGFBP7 was consistently found in both NAFLD populations, whereas IGFBP3 was specific to pediatric NAFLD. Conclusion: This paper expands our knowledge on the molecular mechanisms underlying pediatric NAFLD. It identifies potential biomarkers and directs us toward new therapies in this population.
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Affiliation(s)
- Kangning Yao
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
| | - Elena Tarabra
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
| | - Daniela Sia
- Division of Liver DiseasesDepartment of MedicineTisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | | | - Rima Fawaz
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
| | | | - Nicola Santoro
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
- Department of Medicine and Health Sciences“V. Tiberio,” University of MoliseCampobassoItaly
| | - Sonia Caprio
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
| | - Silvia Liu
- Department of PathologySchool of MedicinePittsburgh Liver Research CenterUniversity of PittsburghUniversity of Pittsburgh Medical CenterPittsburghPennsylvaniaUSA
| | - Dean Yimlamai
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
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13
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Wang C, Pai AK, Putra J. Paediatric non-alcoholic fatty liver disease: an approach to pathological evaluation. J Clin Pathol 2022; 75:443-451. [PMID: 35414523 DOI: 10.1136/jclinpath-2022-208246] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/30/2022] [Indexed: 11/03/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly important healthcare issue along with the rising rates of obesity worldwide. It is the most common chronic liver disease in the paediatric population and the fastest growing indication for liver transplant in young adults. The pathogenesis is complex with contributions from multiple factors and genetic predisposition. While non-invasive laboratory tests and imaging modalities are being increasingly used, the liver biopsy continues to play a crucial role in the diagnosis and prognosis of NAFLD. Histologically, the assessment of paediatric fatty liver disease requires special considerations with respect to a periportal predominant pattern seen in prepubertal patients, as well as a different set of disease processes in the differential diagnosis. In this review, we provide a summary of current knowledge on the epidemiology, pathogenesis and clinical course of paediatric NAFLD as well as the clinical guidelines on diagnosis and management. We discuss the indications and limitations of liver biopsy, histological patterns seen in paediatric NAFLD, other entities to be considered in the differential diagnosis, and conclude with appropriate triaging of liver biopsies and essential elements of pathology reporting.
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Affiliation(s)
- Chiyun Wang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Anita K Pai
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Juan Putra
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA
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14
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Liu F, Wei L, Leow WQ, Liu SH, Ren YY, Wang XX, Li XH, Rao HY, Huang R, Wu N, Wee A, Zhao JM. Developing a New qFIBS Model Assessing Histological Features in Pediatric Patients With Non-alcoholic Steatohepatitis. Front Med (Lausanne) 2022; 9:925357. [PMID: 35833109 PMCID: PMC9271828 DOI: 10.3389/fmed.2022.925357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/06/2022] [Indexed: 11/19/2022] Open
Abstract
Background The evolution of pediatric non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is associated with unique histological features. Pathological evaluation of liver specimen is often hindered by observer variability and diagnostic consensus is not always attainable. We investigated whether the qFIBS technique derived from adult NASH could be applied to pediatric NASH. Materials and Methods 102 pediatric patients (<18 years old) with liver biopsy-proven NASH were included. The liver biopsies were serially sectioned for hematoxylin-eosin and Masson trichrome staining for histological scoring, and for second harmonic generation (SHG) imaging. qFIBS-automated measure of fibrosis, inflammation, hepatocyte ballooning, and steatosis was estabilshed by using the NASH CRN scoring system as the reference standard. Results qFIBS showed the best correlation with steatosis (r = 0.84, P < 0.001); with ability to distinguish different grades of steatosis (AUROCs 0.90 and 0.98, sensitivity 0.71 and 0.93, and specificity 0.90 and 0.90). qFIBS correlation with fibrosis (r = 0.72, P < 0.001) was good with high AUROC values [qFibrosis (AUC) > 0.85 (0.85–0.95)] and ability to distinguish different stages of fibrosis. qFIBS showed weak correlation with ballooning (r = 0.38, P = 0.028) and inflammation (r = 0.46, P = 0.005); however, it could distinguish different grades of ballooning (AUROCs 0.73, sensitivity 0.36, and specificity 0.92) and inflammation (AUROCs 0.77, sensitivity 0.83, and specificity 0.53). Conclusion It was demonstrated that when qFIBS derived from adult NASH was performed on pediatric NASH, it could best distinguish the various histological grades of steatosis and fibrosis.
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Affiliation(s)
- Feng Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Wei Qiang Leow
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Shu-Hong Liu
- Department of Pathology and Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ya-Yun Ren
- HistoIndex Pte Ltd., Singapore, Singapore
| | - Xiao-Xiao Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xiao-He Li
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Hui-Ying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Rui Huang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Nan Wu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Aileen Wee
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital, Singapore, Singapore
- *Correspondence: Aileen Wee
| | - Jing-Min Zhao
- Department of Pathology and Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Jing-Min Zhao
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15
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Comparison of the Lipidomic Signature of Fatty Liver in Children and Adults: A Cross-Sectional Study. J Pediatr Gastroenterol Nutr 2022; 74:734-741. [PMID: 35185113 PMCID: PMC7613028 DOI: 10.1097/mpg.0000000000003418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterised by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease. METHODS We performed untargeted liquid chromatography-mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9500 adults with metabolic phenotyping. RESULTS More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (pC) and triglycerides (TG). Similar trends in pC and TG chain length and saturation were seen in adults with hepatic steatosis; however, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants. CONCLUSION These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different.
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16
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Fatty Liver through the Ages- Non-Alcoholic Steatohepatitis (NASH). Endocr Pract 2021; 28:204-213. [PMID: 34952219 DOI: 10.1016/j.eprac.2021.12.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND The global epidemic of obesity and type 2 diabetes mellitus is the main driver of the growing global prevalence of non-alcoholic fatty liver disease (NAFLD). We aimed to review the current literature on NAFLD and NASH as it impacts children and adults. METHODS We performed a literature search on fatty liver specifically non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) among children and adults. RESULTS The prevalence of NAFLD in children ranges from 8%-12% while the prevalence in adults ranges 25%-48%. The prevalence of NASH among children with NAFLD is 23% while it ranges from 13% to 65% in the adults. There are similar risk factors for NAFLD among children and adults. However, in children, the diagnostic tests in the studies of NAFLD are limited to elevation of ALT level or a liver biopsy. In adults, additional diagnostic modalities, including non-invasive tests (NITs), have been used. From the spectrum of NAFLD, those with NASH are predominantly at risk of progressive liver disease to cirrhosis and liver-related mortality. NAFLD is associated with impairment of health-related quality of life and substantial economic burden. CONCLUSION The comprehensive burden (clinical, HRQL and economic) of NAFLD is high and increasing.
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17
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Metabolic Associated Fatty Liver Disease in Children-From Atomistic to Holistic. Biomedicines 2021; 9:biomedicines9121866. [PMID: 34944682 PMCID: PMC8698557 DOI: 10.3390/biomedicines9121866] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease has become the most common chronic liver disease in children due to the alarmingly increasing incidence of pediatric obesity. It is well-documented that MAFLD prevalence is directly related to an incremental increase in BMI. The multiple hits theory was designed for providing insights regarding the pathogenesis of steatohepatitis and fibrosis in MAFLD. Recent evidence suggested that the microbiome is a crucial contributor in the pathogenesis of MAFLD. Aside from obesity, the most common risk factors for pediatric MAFLD include male gender, low-birth weight, family history of obesity, MAFLD, insulin resistance, type 2 diabetes mellitus, obstructive sleep apnea, and polycystic ovarium syndrome. Usually, pediatric patients with MAFLD have nonspecific symptoms consisting of fatigue, malaise, or diffuse abdominal pain. A wide spectrum of biomarkers was proposed for the diagnosis of MAFLD and NASH, as well as for quantifying the degree of fibrosis, but liver biopsy remains the key diagnostic and staging tool. Nevertheless, elastography-based methods present promising results in this age group as potential non-invasive replacers for liver biopsy. Despite the lack of current guidelines regarding MAFLD treatment in children, lifestyle intervention was proven to be crucial in the management of these patients.
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18
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Cohen CC, Castillo-Leon E, Farris AB, Caltharp SA, Cleeton RL, Sinclair EM, Shevell DE, Karsdal MA, Nielsen MJF, Leeming DJ, Vos MB. PRO-C3, a Serological Marker of Fibrosis, During Childhood and Correlations With Fibrosis in Pediatric NAFLD. Hepatol Commun 2021; 5:1860-1872. [PMID: 34558828 PMCID: PMC8557318 DOI: 10.1002/hep4.1766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/07/2021] [Accepted: 05/08/2021] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease in children and may lead to cirrhosis requiring liver transplant. Thus, prompt diagnosis of advanced fibrosis is essential. Our objectives were to examine PRO-C3 (a neo-epitope pro-peptide of type III collagen formation) levels across childhood/adolescence and associations with advanced fibrosis in pediatric NAFLD. This cross-sectional study included 88 children and adolescents with biopsy-proven NAFLD (mean age: 13.9 ± 2.9 years, 71% male) and 65 healthy participants (11.8 ± 4.5 years, 38% male). PRO-C3, and the bone remodeling biomarkers C-terminal telopeptide of type I collagen (CTX-I; bone resorption) and osteocalcin (N-MID; bone formation), were measured in serum by enzyme-linked immunosorbent assay. Fibrosis was assessed by liver biopsy in participants with NAFLD, who were categorized as having advanced (Ishak score ≥ 3) or none/mild fibrosis (Ishak score ≤ 2). Overall, PRO-C3 was similar in participants with NAFLD (median [interquartile range]: 20.6 [15.8, 25.9] ng/mL) versus healthy participants (19.0 [13.8, 26.0] ng/mL), but was significantly lower in older adolescents ≥ 15 years old (16.4 [13.0, 21.2] ng/mL) compared with children ≤ 10 years old (22.9 [18.1, 28.4] ng/mL; P < 0.001) or 11-14 years old (22.4 [18.3, 31.2] ng/mL; P < 0.001). PRO-C3 was also directly correlated with levels of CTX-I and N-MID (r = 0.64 and r = 0.62, respectively; both P < 0.001). Among participants with NAFLD, PRO-C3 was higher in those with advanced fibrosis (median [IQR]: 28.5 [21.6, 37.6]) compared with none/mild fibrosis (20.3 [18.2, 22.8]; P = 0.020) in models adjusted for age, sex, and body mass index z-score. However, associations were attenuated after additionally adjusting for bone-remodeling CTX-I (P = 0.09) or N-MID (P = 0.08). Conclusion: Collectively, these findings show that PRO-C3 levels are higher in children with advanced fibrosis in NAFLD, but are also influenced by age and pubertal growth spurt, assessed by bone remodeling biomarkers, and therefore may not be a reliable biomarker for liver fibrosis in pediatric NAFLD until late adolescence.
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Affiliation(s)
- Catherine C Cohen
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA.,Department of PediatricsUniversity of Colorado Denver Anschutz Medical CampusAuroraCOUSA
| | | | - Alton B Farris
- Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaGAUSA
| | - Shelley A Caltharp
- Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaGAUSA.,Children's Healthcare of AtlantaAtlantaGAUSA
| | - Rebecca L Cleeton
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA
| | - Elizabeth M Sinclair
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA.,Children's Healthcare of AtlantaAtlantaGAUSA
| | - Diane E Shevell
- Translational MedicineBristol Myers SquibbLawrencevilleNJUSA
| | | | | | - Diana J Leeming
- Nordic BioscienceFibrosis Biology and BiomarkersHerlevDenmark
| | - Miriam B Vos
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA.,Children's Healthcare of AtlantaAtlantaGAUSA
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19
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Steinman JB, Salomao MA, Pajvani UB. Zonation in NASH - A key paradigm for understanding pathophysiology and clinical outcomes. Liver Int 2021; 41:2534-2546. [PMID: 34328687 DOI: 10.1111/liv.15025] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance - WNT/β-Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch - have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient-specific activation of these pathways may explain the variability in clinical presentation, and the zone-specific response observed in clinical trials.
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Affiliation(s)
| | - Marcela A Salomao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, NY, USA
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20
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Simon TG, Roelstraete B, Hartjes K, Shah U, Khalili H, Arnell H, Ludvigsson JF. Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality. J Hepatol 2021; 75:1034-1041. [PMID: 34224779 PMCID: PMC8530955 DOI: 10.1016/j.jhep.2021.06.034] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 05/27/2021] [Accepted: 06/20/2021] [Indexed: 01/13/2023]
Abstract
BACKGROUND & AIMS Longitudinal data are scarce regarding the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD). METHODS This nationwide, matched cohort study included all Swedish children and young adults (≤25 years) with biopsy-confirmed NAFLD (1966-2017; n = 718). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, and further categorized as simple steatosis or steatohepatitis (NASH). Patients with NAFLD were matched to ≤5 general population controls by age, sex, calendar year and county (n = 3,457). To account for shared genetic and early-life factors, we also matched patients with NAFLD to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% CIs. RESULTS Over a median of 15.8 years, 59 patients with NAFLD died (5.5/1,000 person-years [PY]) compared to 36 population controls (0.7/1,000 PY; difference = 4.8/1,000 PY; multivariable aHR 5.88; 95% CI 3.77-9.17), corresponding to 1 additional death per 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among patients with NAFLD, and 1.1% among controls (difference = 6.6%; 95% CI 4.0-9.2). Findings persisted after excluding those who died within the first 6 months (aHR 4.65; 95% CI 2.92-7.42), and after using full-sibling comparators (aHR 11.72; 95% CI 3.18-43.23). Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality compared to controls (95% CI 3.05-9.07), and this was amplified with NASH (aHR 11.51, 95% CI 4.77-27.79). Most of the excess mortality was from cancer (1.67 vs. 0.07/1,000PY; aHR 15.60; 95% CI 4.97-48.93), liver disease (0.93 vs. 0.04/1,000PY; aHR 16.46; 95% CI 2.75-98.43) and cardiometabolic disease (1.12 vs. 0.14/1,000PY; aHR 4.32, 95% CI 1.73-10.79). CONCLUSIONS Swedish children and young adults with biopsy-confirmed NAFLD have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality compared to matched general population controls. LAY SUMMARY Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study compared the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD to matched general population controls. We found that compared to controls, children and young adults with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality.
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Affiliation(s)
- Tracey G. Simon
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA,Harvard Medical School, Boston, MA, USA,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Bjorn Roelstraete
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Kayla Hartjes
- Harvard Medical School, Boston, MA, USA,Division of Pediatric Gastroenterology, Hepatology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, USA
| | - Uzma Shah
- Harvard Medical School, Boston, MA, USA,Division of Pediatric Gastroenterology, Hepatology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, USA
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA,Harvard Medical School, Boston, MA, USA,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Henrik Arnell
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden,Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Jonas F. Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden,Department of Pediatrics, Orebro University Hospital, Orebro, Sweden.,Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, UK.,Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
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21
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Kulkarni S, Naz N, Gu H, Stoll JM, Thompson MD, DeBosch BJ. A clinical model to predict fibrosis on liver biopsy in paediatric subjects with nonalcoholic fatty liver disease. Clin Obes 2021; 11:e12472. [PMID: 34106515 PMCID: PMC8928096 DOI: 10.1111/cob.12472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/09/2021] [Accepted: 05/28/2021] [Indexed: 12/19/2022]
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) in children is rapidly increasing. Liver fibrosis is a poor prognostic feature that independently predicts cirrhosis. The time that intercedes the first medical encounter and biopsy is rate-limiting to multi-modal treatment. This study aimed to identify non-invasive parameters to predict advanced NAFLD and fibrosis. We conducted a single-center, retrospective 10-year analysis of 640 paediatric patients who underwent liver biopsy. 55 patients, age 3-21 years, had biopsy-confirmed NAFLD. We assessed primary outcomes, NAFLD activity score (NAS) and fibrosis scores, against non-invasive parameters by linear regression, by using binary cutoff values, and by a multivariate logistic regression fibrosis prediction model. NAS correlated with platelets and female sex. Fibrosis scores correlated with platelet counts, gamma glutamyl transferase (GGT), and ultrasound shear wave velocity. 25-hydroxy-vitamin D and GGT differentiated mild versus moderate-to-advanced fibrosis. Our multivariate logistical regression model-based scoring system predicted F2 or higher (parameters: BMI%, vitamin D, platelets, GGT), with sensitivity and specificity of 0.83 and 0.95 (area under the ROC curve, 0.944). We identify a clinical model to identify high-risk patients for expedited biopsy. Stratifying patients to abbreviate time-to-biopsy can attenuate delays in aggressive therapy for high-risk patients.
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Affiliation(s)
- Sakil Kulkarni
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Nadia Naz
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Hongjie Gu
- Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
| | - Janis M. Stoll
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Michael D. Thompson
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Digestive Diseases Research Center (DDRCC), Washington University School of Medicine, St. Louis, MO, USA
| | - Brian J. DeBosch
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Digestive Diseases Research Center (DDRCC), Washington University School of Medicine, St. Louis, MO, USA
- Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
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22
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DiStefano JK, Shaibi GQ. The relationship between excessive dietary fructose consumption and paediatric fatty liver disease. Pediatr Obes 2021; 16:e12759. [PMID: 33305889 PMCID: PMC8195317 DOI: 10.1111/ijpo.12759] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/16/2020] [Accepted: 11/11/2020] [Indexed: 12/19/2022]
Abstract
The global prevalence of non-alcoholic fatty liver disease (NAFLD) in children and adolescents is escalating and currently represents the most common chronic liver disease in the paediatric population. NAFLD is associated with high daily caloric intake and sedentary behaviour, with excessive consumption of added sugar emerging as an important contributor to NAFLD risk in children. This is a particularly important factor for adolescents with obesity, who are the heaviest consumers of added sugar. Table sugar, or sucrose, is a disaccharide comprised of fructose and glucose, yet only fructose has been strongly linked to NAFLD pathogenesis largely due to the unique characteristics of its metabolism and detrimental effects on key metabolic pathways. To date, the relationship between excessive fructose intake and risk of NAFLD in children and adolescents remains incompletely understood, and it is not yet known whether fructose actually causes NAFLD or instead exacerbates hepatic fat accumulation and possible hepatocellular injury only within the context of cardiometabolic factors. The purpose of this review is to summarize recent studies linking fructose consumption with NAFLD in the paediatric population and integrate results from interventional studies of fructose restriction in children and adolescents on NAFLD and related metabolic markers. Given the overall positive impact of lifestyle modifications in the management of paediatric NAFLD, reduction of added sugar consumption may represent an important, early opportunity to mitigate or prevent NAFLD in high-risk children and adolescents.
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Affiliation(s)
- Johanna K. DiStefano
- Diabetes and Fibrotic Disease Research Unit, Translational Genomics Research Institute,corresponding author: 445 N 5 Street, Phoenix, AZ 85004,
| | - Gabriel Q. Shaibi
- Center for Health Promotion and Disease Prevention, Edson College of Nursing, Arizona State University
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Yodoshi T, Orkin S, Arce-Clachar AC, Bramlage K, Xanthakos SA, Valentino PL, Mouzaki M. Alternative Etiologies of Liver Disease in Children With Suspected NAFLD. Pediatrics 2021; 147:e2020009829. [PMID: 33785637 PMCID: PMC8015155 DOI: 10.1542/peds.2020-009829] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/06/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES To determine the prevalence of alternative causes of liver disease in a cohort of youth with overweight and obesity undergoing evaluation for suspected nonalcoholic fatty liver disease (NAFLD). METHODS Multicenter, retrospective cohort study of patients aged ≤18 years with overweight and obesity and evidence of elevated serum aminotransferases and/or hepatic steatosis on imaging, referred for suspected NAFLD to Cincinnati Children's Hospital Medical Center (2009-2017) or Yale New Haven Children's Hospital (2012-2017). Testing was performed to exclude the following: autoimmune hepatitis (AIH), Wilson disease, viral hepatitis (B and C), thyroid dysfunction, celiac disease, α-1 antitrypsin deficiency, and hemochromatosis. RESULTS A total of 900 children with overweight and obesity (63% boys, 26% Hispanic ethnicity) were referred, with a median age of 13 years (range: 2-18). Most had severe obesity (n = 666; 76%) with a median BMI z score of 2.45 (interquartile range [IQR]: 2.2-2.7). Median alanine aminotransferase level at presentation was 64 U/L (IQR: 42-95). A clinically indicated liver biopsy was performed in 358 children (40%) at a median of 6 months (IQR: 1-14) post initial visit; of those, 46% had confirmed nonalcoholic steatohepatitis. Positive autoantibodies were observed in 13% of the cohort, but none met criteria for AIH. Only 19 (2%) were found to have other causes of liver disease, with no cases of viral hepatitis or Wilson disease detected. CONCLUSIONS In a large, multicenter cohort, the vast majority of children with overweight and obesity with presumed or confirmed NAFLD tested negative for other causes of liver disease. In contrast to a previous pediatric report, no patient was diagnosed with AIH.
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Affiliation(s)
- Toshifumi Yodoshi
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Sarah Orkin
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ana Catalina Arce-Clachar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Kristin Bramlage
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Stavra A Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Pamela L Valentino
- Section of Gastroenterology and Hepatology, Department of Pediatrics, School of Medicine, Yale University, New Haven, Connecticut
| | - Marialena Mouzaki
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio; and
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24
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Geier A, Tiniakos D, Denk H, Trauner M. From the origin of NASH to the future of metabolic fatty liver disease. Gut 2021; 70:gutjnl-2020-323202. [PMID: 33632710 PMCID: PMC8292567 DOI: 10.1136/gutjnl-2020-323202] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/13/2021] [Accepted: 02/05/2021] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Understanding the pathological and molecular hallmarks from its first description to definitions of disease entities, classifications and molecular phenotypes is crucial for both appropriate clinical management and research in this complex disease. We provide an overview through almost two hundred years of clinical research from the beginnings as a nebulous disease entity of unknown origin in the 19th century to the most frequent and vigorously investigated liver disease today. The clinical discrimination between alcohol-related liver disease and NAFLD was uncommon until the 1950s and likely contributed to the late acceptance of NAFLD as a metabolic disease entity for long time. Although the term 'fatty liver hepatitis' first appeared in 1962, it was in 1980 that the term 'non-alcoholic steatohepatitis' (NASH) was coined and the histopathological hallmarks that are still valid today were defined. The 2005 NASH Clinical Research Network scoring was the first globally accepted grading and staging system for the full spectrum of NAFLD and is still used to semiquantify main histological features. In 2021, liver biopsy remains the only diagnostic procedure that can reliably assess the presence of NASH and early fibrosis but increasing efforts are made towards non-invasive testing and molecular classification of NAFLD subtypes.
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Affiliation(s)
- Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Bayern, Germany
| | - Dina Tiniakos
- Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece & Translational & Clinical Research Institute; Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Helmut Denk
- Institute of Pathology, Medical University of Graz, Graz, Steiermark, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Wien, Wien, Austria
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25
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Mosca A, Panera N, Crudele A, Alisi A. Noninvasive diagnostic tools for pediatric NAFLD: where are we now? Expert Rev Gastroenterol Hepatol 2020; 14:1035-1046. [PMID: 32715793 DOI: 10.1080/17474124.2020.1801413] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in the pediatric population. It is a significant liver complication of obesity that also prominently affects children. Over the past decade, several noninvasive methods have been investigated for replacing liver biopsy to identify which children with NAFLD have nonalcoholic steatohepatitis (NASH) and fibrosis. These methods that aim to differentiate the type and extent of liver damage are based on two main different methodologies: a 'biological' approach centered on the quantification of circulating biomarkers; and a 'physical' approach established by analyzing different imaging data. AREAS COVERED In this review, we illustrate the state of the art and recent discoveries on noninvasive methods for the diagnosis of NAFLD, NASH, and advanced fibrosis. EXPERT OPINION Currently, noninvasive tests cannot diagnose NASH or determine the degree of fibrosis. However, several lines of evidence have suggested that if these tests are used in a complementary way with other laboratory tests and imaging they have the potential to be used to monitor progression of disease and response to therapy in pediatric NAFLD. Future scientific research will focus on combining these methods with multiple potential predictors of genetic susceptibility.
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Affiliation(s)
- Antonella Mosca
- Hepatology Gastroenterology and Nutrition, Bambino Gesù Children's Hospital , Rome, Italy
| | - Nadia Panera
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
| | - Annalisa Crudele
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
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26
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Chen YY, Yeh MM. Non-alcoholic fatty liver disease: A review with clinical and pathological correlation. J Formos Med Assoc 2020; 120:68-77. [PMID: 32654868 DOI: 10.1016/j.jfma.2020.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/04/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in North America and Europe, with increasing prevalence in other regions of the world. Its spectrum encompass steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. It is considered as the manifestation of metabolic syndrome in liver, and its development and progression is influenced by complex interaction of environmental and genetic factors. In this review we discuss the histopathological features, differential diagnoses, and the commonly used grading and staging systems of NAFLD. NAFLD associated with other diseases, histological changes after therapeutic intervention and recurrence or occurrence of NAFLD after liver transplantation are also addressed.
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Affiliation(s)
- Yen-Ying Chen
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, United States; Department of Medicine, University of Washington School of Medicine, Seattle, United States.
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27
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Zen Y, Kondou H, Nakazawa A, Tanikawa K, Hasegawa Y, Bessho K, Imagawa K, Ishige T, Inui A, Suzuki M, Kasahara M, Yamamoto K, Yoshioka T, Kage M, Hayashi H. Proposal of a liver histology-based scoring system for bile salt export pump deficiency. Hepatol Res 2020; 50:754-762. [PMID: 32073700 DOI: 10.1111/hepr.13494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 02/08/2023]
Abstract
AIM Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition. METHODS After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined. RESULTS Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged. CONCLUSIONS The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.
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Affiliation(s)
- Yoh Zen
- Department of Diagnostic Pathology, Kobe University, Hyogo, Japan
| | - Hiroki Kondou
- Department of Pediatrics, Kindai University Nara Hospital, Nara, Japan
| | - Atsuko Nakazawa
- Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Yasuhiro Hasegawa
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Takashi Ishige
- Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Tobu Hospital, Kanagawa, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Kouji Yamamoto
- Department of Biostatistics, School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Masayoshi Kage
- Kurume University Research Center for Innovative Cancer Therapy, Fukuoka, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
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28
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Goldner D, Lavine JE. Nonalcoholic Fatty Liver Disease in Children: Unique Considerations and Challenges. Gastroenterology 2020; 158:1967-1983.e1. [PMID: 32201176 DOI: 10.1053/j.gastro.2020.01.048] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/30/2019] [Accepted: 01/05/2020] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence in concert with the global epidemic of obesity and is being diagnosed at increasingly younger ages. The unique histologic features and early presentation of disease in pediatrics suggest that children and adults may differ with regard to etiopathogenesis, with children displaying a greater vulnerability to genetic and environmental factors. Of significant relevance to pediatrics, in utero and perinatal stressors may alter the lifelong health trajectory of a child, increasing the risk of NAFLD and other cardiometabolic diseases. The development and progression of disease in childhood is likely to carry increased risk of long-term morbidity. Novel biomarkers and therapeutic agents are needed to avoid the otherwise inevitable health and societal consequences of this rapidly expanding pediatric population.
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Affiliation(s)
- Dana Goldner
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University Medical Center, New York, New York
| | - Joel E Lavine
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University Medical Center, New York, New York.
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29
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Doulberis M, Polyzos SA, Papaefthymiou A, Katsinelos P, Kiosses C, Kountouras J. Treatment of nonalcoholic fatty liver disease: from adult trials to perspectives in the management of children and adolescents. Expert Opin Pharmacother 2020; 21:247-251. [PMID: 31893958 DOI: 10.1080/14656566.2019.1702967] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Michael Doulberis
- Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland.,Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece.,First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Apostolis Papaefthymiou
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece.,Department of Gastroenterology, General Military Hospital of Athens, Athens, Greece
| | - Panagiotis Katsinelos
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Christos Kiosses
- Department Gastroenterology and Hepatology, General Hospital Thun, Thun, Switzerland
| | - Jannis Kountouras
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
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30
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Alkhouri N, Kohli R, Feldstein AE. Designing Clinical Trials in Pediatric Nonalcoholic Steatohepatitis: Tips for Patient Selection and Appropriate Endpoints. Hepatol Commun 2019; 3:1563-1570. [PMID: 31832567 PMCID: PMC6887671 DOI: 10.1002/hep4.1449] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/20/2019] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is common in children and may progress to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and even cirrhosis in childhood or early adulthood, indicating the need for pharmacologic treatment in this age group. Multiple trials are evaluating different therapeutic targets for NASH with fibrosis in adults, and the U.S. Food and Drug Administration has recently provided clear guidance to the pharmaceutical industry on developing drugs for the treatment of noncirrhotic NASH with liver fibrosis. Pediatric NAFLD has several unique aspects that distinguish it from the adult disease in terms of histology, our understanding of the natural history, and the utility of noninvasive tests. These differences have the potential to impact the design of clinical trials to test different drugs in the pediatric population. The aim of this article is to provide a review of common misconceptions regarding pediatric NAFLD and key differences from adult NAFLD. We have provided our recommendations on the design of early proof-of-concept and late phase 2 trials based on lessons learned from previous clinical trials. We believe that clinical drug development for children with NAFLD should happen in parallel with ongoing adult trials.
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Affiliation(s)
- Naim Alkhouri
- Metabolic Health Center Texas Liver Institute University of Texas Health San Antonio San Antonio TX
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology and Nutrition Children's Hospital Los Angeles Keck School of Medicine of University of Southern California Los Angeles CA
| | - Ariel E Feldstein
- Department of Pediatric Gastroenterology University of California San Diego La Jolla CA
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31
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Tzifi F, Fretzayas A, Chrousos G, Kanaka-Gantenbein C. Non-alcoholic fatty liver infiltration in children: an underdiagnosed evolving disease. Hormones (Athens) 2019; 18:255-265. [PMID: 31140156 DOI: 10.1007/s42000-019-00107-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 03/25/2019] [Indexed: 12/21/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease, one that is still underdiagnosed in pediatric populations (as well as in the general population), this due to the progressive increase in childhood obesity observed both in developed and developing countries during the last few decades. The pathophysiology of the disease has not been thoroughly clarified yet. The condition displays common pathways in adults and children; however, there are age-related differences. Unlike adults, children with NAFLD require extensive laboratory analysis, because underlying pathologies other than obesity may contribute to the evolution of the disease. Despite the presence of several serum markers and imaging techniques that contribute to NAFLD diagnosis, liver biopsy remains the gold standard diagnostic procedure. Early intervention and obesity prevention are mandatory, as NAFLD is reversible at an early stage. If left undiagnosed and untreated, NAFLD can progress to steatohepatitis (NASH) and subsequent liver failure, a potentially lethal complication. Of note, there are no treatment options when advanced liver fibrosis occurs. This review summarizes literature data on NAFLD in childhood indicating that this is an evolving disease and a significant component of the metabolic syndrome. Pediatricians should be aware of this entity, screening children at high risk and providing appropriate early management, in collaboration with pediatric subspecialists.
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Affiliation(s)
- Flora Tzifi
- First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece.
- Athens Medical Group, Marousi, Greece.
| | | | - George Chrousos
- First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Christina Kanaka-Gantenbein
- First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece
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32
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NAFLD in children: new genes, new diagnostic modalities and new drugs. Nat Rev Gastroenterol Hepatol 2019; 16:517-530. [PMID: 31278377 DOI: 10.1038/s41575-019-0169-z] [Citation(s) in RCA: 195] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/04/2019] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has rapidly become the most common form of chronic liver disease in children and adolescents. Over the past 5 years, developments have revolutionized our understanding of the genetic factors, natural history, diagnostic modalities and therapeutic targets for this disease. New polymorphisms, such as those in PNPLA3, TM6SF2, MBOAT7 and GCKR, have been identified and used to predict the development and severity of NAFLD in both adults and children, and their interaction with environmental factors has been elucidated. Studies have demonstrated the true burden of paediatric NAFLD and its progression to end-stage liver disease in adulthood. In particular, nonalcoholic steatohepatitis can progress to advanced fibrosis and cirrhosis, emphasizing the importance of early diagnosis. Non-invasive imaging tests, such as transient elastography, will probably replace liver biopsy for the diagnosis of nonalcoholic steatohepatitis and the assessment of fibrosis severity in the near future. The therapeutic landscape is also expanding rapidly with the development of drugs that can modify liver steatosis, inflammation and fibrosis, indicating that pharmacotherapy for NAFLD will become available in the future. In this Review, we summarize current knowledge and new advances related to the pathogenesis and management of paediatric NAFLD.
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A Systematic Review of NAFLD-Associated Extrahepatic Disorders in Youths. J Clin Med 2019; 8:jcm8060868. [PMID: 31213030 PMCID: PMC6617181 DOI: 10.3390/jcm8060868] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/04/2019] [Accepted: 06/13/2019] [Indexed: 02/07/2023] Open
Abstract
Background: There is growing evidence that non-alcoholic fatty liver disease (NAFLD) is a disease affecting not only the liver but also extrahepatic organs. Aim: To investigate whether in youths NAFLD is associated with extrahepatic complications such as subclinical atherosclerosis, cardiac abnormalities, hypertension, type 2 diabetes, decreased bone mineral density, renal dysfunction, obstructive sleep apnea, and polycystic ovary syndrome. Methods: We systematically reviewed PubMed; Scopus; Embase; and the Cochrane Library databases up to 28 February 2019 and assessed the quality of studies using the Newcastle-Ottawa Scale. Results: Thirty-five articles were selected for this systematic review: fifteen (4627 participants) evaluated the association of NAFLD with subclinical atherosclerosis; four (969 participants) with cardiac abnormalities; two (550 participants) with hypertension; four (1328 participants) with diabetes; six (523 participants) with low bone mineral density; two (865 participants) with renal dysfunction; one with obstructive sleep apnea; and one with polycystic ovary syndrome. Most studies found that youths with NAFLD have increased features of subclinical atherosclerosis; as well as of cardiac alterations. Limited data were available to endorse a solid estimate of the prevalence of diabetes; low mineral density and renal dysfunction in the pediatric NAFLD population. Conclusion: NAFLD-related intermediate CVD outcomes can occur and be detected early in young populations.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) was first described as a distinct clinical entity four decades ago. However, the condition has become the centre of attention within hepatology owing to its high prevalence and growing contribution to the burden of end-stage liver disease in the general population. This Perspective provides an overview on the development of knowledge related to NAFLD with a focus on landmark findings that have influenced current paradigms and key knowledge gaps that need to be filled to make progress. Specifically, a timeline of scientific discovery of both basic disease mechanisms (with a focus on human data) and the evolution of knowledge about the clinical course of the disease is provided and related to current approaches to treat and eventually prevent NAFLD.
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Affiliation(s)
- Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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35
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Draijer L, Benninga M, Koot B. Pediatric NAFLD: an overview and recent developments in diagnostics and treatment. Expert Rev Gastroenterol Hepatol 2019; 13:447-461. [PMID: 30875479 DOI: 10.1080/17474124.2019.1595589] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adults in industrialized countries. Besides liver-related morbidity, NAFLD is also associated with an increased risk of cardiovascular disease, type 2 diabetes and mortality at adult age. However, despite the high prevalence and serious complications, diagnosing and staging of disease remains complicated due to a lack of accurate screening tools and non-invasive methods to detect fibrosis. Areas covered: Recent insights in epidemiology, pathogenesis, diagnostic evaluation and treatment options in pediatric NAFLD are being reviewed, with a particular focus on new developments in diagnostic tools. Expert opinion: Due to their long life span, children with NAFLD are particularly at risk of complications in their lifetime. Therefore, an effective screening strategy for children to identify those with NAFLD at risk of complications is urgently needed. This is further underscored by new pharmacological therapies that are expected to become available in the next 5 years. Momentarily no accurate non-invasive method for diagnosing pediatric NAFLD is available. New promising biomarkers and imaging tools could hopefully provide better screening tools and could contribute to the development of a successful management plan to identify children with NAFLD.
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Affiliation(s)
- Laura Draijer
- a Department of Pediatric Gastroenterology and Nutrition , Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children's Hospital , Amsterdam , The Netherlands
| | - Marc Benninga
- a Department of Pediatric Gastroenterology and Nutrition , Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children's Hospital , Amsterdam , The Netherlands
| | - Bart Koot
- a Department of Pediatric Gastroenterology and Nutrition , Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children's Hospital , Amsterdam , The Netherlands
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36
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Adolescent Bariatric Surgery: Current Concepts and Future Directions. CURRENT SURGERY REPORTS 2019. [DOI: 10.1007/s40137-019-0232-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Establishment and Comparison of Juvenile Female Mouse Models of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Gastroenterol Res Pract 2018; 2018:8929620. [PMID: 30158971 PMCID: PMC6109512 DOI: 10.1155/2018/8929620] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 04/06/2018] [Accepted: 07/08/2018] [Indexed: 12/14/2022] Open
Abstract
Experimental research has successfully established an adult offspring animal model of nonalcoholic fatty liver disease (NAFLD), but the female offspring model of NAFLD in young age has not been well characterized yet. The aim of this study was to present a direct comparison of the maternal versus postweaning female juvenile NAFLD and nonalcoholic steatohepatitis (NASH) animal models. Four different female mouse models were established and compared using different high-fat diet feeding (HF) strategies in maternal mice and their offspring. The models were non-HF maternal mice and HF offspring with high-high fat (C/HHF), non-HF maternal mice and HF offspring with low-high fat (C/LHF), HF maternal mice and offspring both with high-high fat (HHF/HHF), and HF maternal mice and offspring both with low-high fat (LHF/LHF). A female control group (C/C) was also established. The offspring mice were raised to the age of 8 weeks and then euthanized. Blood glucose levels, lipid profiles, liver function, and triglycerides/total cholesterol contents were examined. Hepatic morphology and superoxide anion levels were evaluated. The nicotinamide-adenine dinucleotide phosphate activity and related regulatory subunits protein expression in the liver tissue were also determined. Our data demonstrated that offspring fat intake contributed to the successful establishment of NAFLD and maternal-offspring fat intake contributed to the successful establishment of NASH in juvenile female mice. Offspring high-fat exposure might be associated with the development of NAFLD and maternal high-fat exposure might be associated with the development of NASH in juvenile female offspring. Higher calories from a fat diet program (both in maternal and offspring) are more prone to inducing liver injury in offspring. In addition, the combination of the aforementioned two factors could aggravate this process. Moreover, oxidative stress was prominent in the juvenile female mouse model of NAFLD/NASH, and the mechanism might be related to the activation of liver NADPH oxidase.
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Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased substantially in the past two decades and NAFLD has now become the most common cause of chronic liver disease in children and adolescents. NAFLD is a broad clinicopathologic spectrum ranging from simple steatosis to varying degrees of necroinflammation called nonalcoholic steatohepatitis (NASH), leading to fibrosis and subsequently to cirrhosis. Despite the increasing prevalence and progressive nature of NAFLD even among children, therapy for NAFLD in both adults and children are limited. Weight loss remains the only consistently effective therapy for NAFLD. Pharmacologic options are even more limited in children than in adults with NAFLD. Vitamin E has been shown to be effective in improving histology in children with NASH. Few pharmacologic options such as metformin, probiotics, omega-3 fatty acids, and cysteamine bitartrate have been studied in children, with limited beneficial effects. However, these studies are limited by small sample size and heterogeneity of outcome assessment after treatment. Recent studies show promising results with bariatric surgery with regards to weight loss and improvement in liver histology in adolescents with NAFLD. In this review article, we discuss epidemiology, pathophysiology, and extrahepatic comorbidities of pediatric NAFLD and review existing therapeutic options for children with NAFLD. We also review novel therapeutic strategies studied in adults that could potentially be studied in children in the future.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major health concern and the prevalence continues to increase in many industrialized and developing countries around the world. NAFLD affects adults and children. NAFLD-related cirrhosis is expected to become the top indication for liver transplantation in the near future, and the incidence of NAFLD-related hepatocellular carcinoma is also increasing. Nonalcoholic steatohepatitis is the more severe form of NAFLD. The pathogenesis of NALFD/nonalcoholic steatohepatitis is complex and new concepts continue to evolve. The diagnosis and categorization of nonalcoholic steatohepatitis currently rests on hepatopathologists. Accurate morphologic interpretation is important for therapeutic, prognostic, and investigational purposes.
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Affiliation(s)
- Michael H Schild
- Department of Pathology, Duke University, DUHS, Box 3912, Durham, NC 27710, USA
| | - Cynthia D Guy
- Department of Pathology, Duke University, DUHS, Box 3912, Durham, NC 27710, USA.
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Hegarty R, Deheragoda M, Fitzpatrick E, Dhawan A. Paediatric fatty liver disease (PeFLD): All is not NAFLD - Pathophysiological insights and approach to management. J Hepatol 2018; 68:1286-1299. [PMID: 29471012 DOI: 10.1016/j.jhep.2018.02.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/11/2018] [Accepted: 02/13/2018] [Indexed: 12/14/2022]
Abstract
The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease, but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease has since become the most common chronic liver disease in adults owing to the global epidemic of obesity. However, in paediatrics, the term NAFLD seems incongruous: alcohol consumption is largely not a factor and inherited metabolic disorders can mimic or co-exist with a diagnosis of NAFLD. The term paediatric fatty liver disease may be more appropriate. In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. We offer this model as a means to provide pathophysiological insights and an approach to management of the ever more complex subject of fatty liver.
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Affiliation(s)
- Robert Hegarty
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom
| | - Maesha Deheragoda
- Liver Histopathology, Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Emer Fitzpatrick
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom.
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Kim MY. [The Progression of Liver Fibrosis in Non-alcoholic Fatty Liver Disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018. [PMID: 28637102 DOI: 10.4166/kjg.2017.69.6.341] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Understanding the pathogenesis of non-alcoholic steatohepatitis (NASH) and its fibrosis progression is still evolving. Nonetheless, current evidence suggests that mechanisms involved are very complex parallel processes with multiple metabolic factors. Lipotoxicity related with excess saturated free fatty acids, obesity, and insulin resistance acts as the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence are also contribute to the activation of inflammasome via various intra- and inter-cellular signaling mechanisms that lead to fibrosis. Current evidence suggests that periportal components, including ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the T-helper 17 cell response may mediate disease progression. This review aims to provide a brief overview of the pathogenesis of NASH and fibrosis progression from inflammation to fibrosis.
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Affiliation(s)
- Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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Jackson JA, Konomi JV, Mendoza MV, Krasinskas A, Jin R, Caltharp S, Mouzaki M, Vos MB. Performance of fibrosis prediction scores in paediatric non-alcoholic fatty liver disease. J Paediatr Child Health 2018; 54:172-176. [PMID: 28948665 DOI: 10.1111/jpc.13689] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 05/23/2017] [Accepted: 07/21/2017] [Indexed: 01/29/2023]
Abstract
AIM Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. The phenotype of NAFLD varies widely, and non-invasive predictors of disease severity are scarce and are needed to tailor clinical management. METHODS We compared liver fibrosis by histology with proposed non-invasive predictors of fibrosis, including alanine transaminase (ALT), aspartate transaminase (AST), AST/ALT ratio, AST to platelet ratio index, fibrosis-4, paediatric NAFLD fibrosis index and paediatric NAFLD fibrosis score. RESULTS The area under the curve of scores obtained while predicting fibrosis in children with NAFLD ranged from 0.51 to 0.67. CONCLUSION The tested non-invasive fibrosis scoring systems, some of which were originally designed for adult populations, did not adequately predict fibrosis in a paediatric cohort. Further development of risk prediction scores in children are needed for the management of paediatric patients and will likely need to be developed within a large paediatric data set in order to improve specificity and sensitivity.
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Affiliation(s)
- Jasmine A Jackson
- Emory University School of Medicine, Atlanta, Georgia, United States
| | - Juna V Konomi
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States
| | - Michael V Mendoza
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States
| | - Alyssa Krasinskas
- Department of Pathology, Emory University, Atlanta, Georgia, United States
| | - Ran Jin
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States
| | - Shelley Caltharp
- Department of Pathology, Emory University, Atlanta, Georgia, United States
| | - Marialena Mouzaki
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Miriam B Vos
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States
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Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67:328-357. [PMID: 28714183 DOI: 10.1002/hep.29367] [Citation(s) in RCA: 4854] [Impact Index Per Article: 693.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023]
Affiliation(s)
| | - Zobair Younossi
- Center for Liver Disease and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA
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Pampanini V, Inzaghi E, Germani D, Alterio A, Puglianiello A, Alisi A, Nobili V, Cianfarani S. Serum Fetuin-A levels in obese children with biopsy proven nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2018; 28:71-76. [PMID: 29122442 DOI: 10.1016/j.numecd.2017.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 09/19/2017] [Accepted: 09/25/2017] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIMS Fetuin-A has been proposed as a marker of liver damage in adults with obesity-related NAFLD. The aim of this study was to test serum fetuin-A concentrations in obese children with NAFLD diagnosed either by ultrasonography or by liver biopsy and to determine its applicability as predictive tool in pediatric NAFLD. METHODS AND RESULTS Metabolic parameters and fetuin-A levels were investigated in 81 obese children with NAFLD diagnosed by biopsy, 79 obese children with NAFLD defined by liver ultrasonography and 23 lean subjects. Serum fetuin-A correlated significantly with age, waist circumference, systolic blood pressure, fasting insulin and 2-h postload insulin during OGTT, HOMA-IR, ISI, CRP, and apo B levels. Obese children with NAFLD detected by ultrasonography had significantly higher fetuin-A levels compared to those with normal liver. In obese children who underwent liver biopsy, no significant differences were detected in fetuin-A levels between subject with nonalcoholic steatohepatitis and those with simple steatosis. Fetuin-A was not different between obese and lean children. CONCLUSION Fetuin-A is not related with the degree of liver damage in obese children with NAFLD and its routine measurement as marker of liver disease severity is therefore not recommended.
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Affiliation(s)
- V Pampanini
- Department of Women's and Children's Health, Pediatric Endocrinology Unit, Karolinska Institutet and University Hospital, 17176, Stockholm, Sweden.
| | - E Inzaghi
- Dipartimento Pediatrico Universitario Ospedaliero "Bambino Gesù" Children's Hospital - Tor Vergata University, 00165, Rome, Italy
| | - D Germani
- Department of Systems Medicine, Tor Vergata University, 00173, Rome, Italy
| | - A Alterio
- Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital - IRCCS, Rome, Italy
| | - A Puglianiello
- Department of Systems Medicine, Tor Vergata University, 00173, Rome, Italy
| | - A Alisi
- Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital - IRCCS, Rome, Italy
| | - V Nobili
- Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital - IRCCS, Rome, Italy
| | - S Cianfarani
- Department of Women's and Children's Health, Pediatric Endocrinology Unit, Karolinska Institutet and University Hospital, 17176, Stockholm, Sweden; Dipartimento Pediatrico Universitario Ospedaliero "Bambino Gesù" Children's Hospital - Tor Vergata University, 00165, Rome, Italy
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46
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Zhou L, Tang J, Xiong X, Dong H, Huang J, Zhou S, Zhang L, Qin H, Yan S. Psoralea corylifolia L. Attenuates Nonalcoholic Steatohepatitis in Juvenile Mouse. Front Pharmacol 2017; 8:876. [PMID: 29249967 PMCID: PMC5715270 DOI: 10.3389/fphar.2017.00876] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 11/13/2017] [Indexed: 12/17/2022] Open
Abstract
Psoralea corylifolia L. (PC) is a traditional Chinese herb used to treat yang deficiency of the spleen and kidney in pediatric disease. Recent studies have shown its liver protection and anti-oxidative effects. The aim of this study was to explore the effect and mechanism of PC on nonalcoholic steatohepatitis in juvenile mice. The juvenile mouse model of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) was established by being fed a high-fat diet in maternal-offspring manner. PC granules were prepared and the quality was assessed. The main components were identified by high performance liquid chromatography. Then, different dosages of PC were administered for 6 weeks. Homeostatic model assessment of insulin resistance, plasma liver enzymes, hepatic morphology, hepatic superoxide anion, and triglyceride/total cholesterol levels were examined. The changes of nuclear factor-κB (NF-κB) activity phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and protein kinase C-α (PKC-α)/nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase signaling pathways in hepatic tissues were also determined. Our data demonstrated that PC significantly improved liver dysfunction, liver triglyceride/total cholesterol accumulation and insulin resistance in juvenile NAFLD/NASH mice. PC also alleviated hepatic steatosis, inflammatory cell infiltration, and fibroplasia in the portal area. Additionally, PC inhibited the activation of NF-κB and the mRNA expression of inflammatory factors while enhancing PI3K/Akt signaling in hepatic tissues. PC could also reduce hepatic superoxide anion levels, and NADPH oxidase activity as well as p47phox protein expression and PKCα activation in hepatic tissues. The results suggest that PC is effective in the treatment of NASH in juvenile mice. The mechanism may be related to the attenuation of hepatic oxidative stress through the PKC-α/NADPH oxidase signaling pathway.
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Affiliation(s)
- Lishan Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianqiao Tang
- Department of Integrated Traditional Chinese and Western Medicine, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Xiong
- Department of Integrated Traditional Chinese and Western Medicine, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Huang
- Department of Pathology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shunchang Zhou
- Center of Experimental Animals, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingling Zhang
- Department of Pediatrics, Integrated Traditional Chinese and Western Medicine Hospital of Wuhan, Wuhan, China
| | - Huan Qin
- Laboratory, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suqi Yan
- Department of Integrated Traditional Chinese and Western Medicine, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Schwimmer JB, Behling C, Angeles JE, Paiz M, Durelle J, Africa J, Newton KP, Brunt EM, Lavine JE, Abrams SH, Masand P, Krishnamurthy R, Wong K, Ehman RL, Yin M, Glaser KJ, Dzyubak B, Wolfson T, Gamst AC, Hooker J, Haufe W, Schlein A, Hamilton G, Middleton MS, Sirlin CB. Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease. Hepatology 2017; 66:1474-1485. [PMID: 28493388 PMCID: PMC5650504 DOI: 10.1002/hep.29241] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/23/2017] [Accepted: 04/24/2017] [Indexed: 12/14/2022]
Abstract
UNLABELLED Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two-dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross-validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P < 0.001). Overall cross-validated accuracy for detecting any fibrosis was 72.2% for all methods (95% confidence interval [CI], 61.8%-81.1%). Overall cross-validated accuracy for assessing advanced fibrosis was 88.9% (95% CI, 80.5%-94.5%) for center 1, 90.0% (95% CI, 81.9%-95.3%) for center 2, and 86.7% (95% CI, 77.9%-92.9%) for automated analysis. CONCLUSION 2D MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will require prospective evaluation. (Hepatology 2017;66:1474-1485).
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Affiliation(s)
- Jeffrey B. Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, California,Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Cynthia Behling
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Jorge Eduardo Angeles
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Melissa Paiz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Janis Durelle
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Jonathan Africa
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Kimberly P. Newton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, California
| | - Elizabeth M. Brunt
- Department of Pathology and Immunology, Washington University, St. Louis, Missouri
| | | | - Stephanie H. Abrams
- Columbia University, New York, NY,Baylor College of Medicine, Houston, Texas,Houston Methodist Hospital, Houston, Texas
| | | | | | - Kelvin Wong
- Miller Children’s & Women’s Hospital Long Beach, California
| | | | - Meng Yin
- Mayo Clinic, Rochester, Minnesota
| | | | | | - Tanya Wolfson
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center, University of California, San Diego, California
| | - Anthony C. Gamst
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center, University of California, San Diego, California
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - William Haufe
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Alexandra Schlein
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Gavin Hamilton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Michael S. Middleton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
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48
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Xanthakos SA. Nonalcoholic steatohepatitis in children with severe obesity: A global concern. Surg Obes Relat Dis 2017; 13:1609-1611. [PMID: 28935179 DOI: 10.1016/j.soard.2017.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 06/07/2017] [Accepted: 06/15/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Stavra A Xanthakos
- Surgical Weight Loss Program for Teens, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Steatohepatitis Center, Division of Gastroenterology Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
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49
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Liyanagedera S, Williams RP, Veraldi S, Nobili V, Mann JP. The pharmacological management of NAFLD in children and adolescents. Expert Rev Clin Pharmacol 2017; 10:1225-1237. [PMID: 28803504 DOI: 10.1080/17512433.2017.1365599] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) represents a spectrum, including 'simple' steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. Increasing prevalence of NAFLD has followed the international rise in obesity and lifestyle modification is the mainstay therapy for children. To date, pharmacological trials have had varying efficacy but a large number of new agents are in early phase trials for adults. Areas covered: This review explores the effect of current and potential future paediatric NAFLD treatments in terms of histological and biochemical endpoints. The potential for the extension of adult treatments to children is discussed, as well as what limits the use of certain agents in children. Expert commentary: No drugs have yet to be licenced for NAFLD. Trial heterogeneity makes comparison of drugs between studies challenging. FXR agonists are yet to be trialled in children but may represent a safe and potentially efficacious therapy. Future treatments would likely encompass a multimodal approach that may include bariatric surgery.
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Affiliation(s)
- Savinda Liyanagedera
- a Department of Paediatrics , Cardiff University School of Medicine , Cardiff , UK
| | | | - Silvio Veraldi
- b Hepatometabolic Unit , Bambino Gesu Hospital - IRCCS , Rome , Italy.,c Liver Research Unit , Bambino Gesu Hospital, IRCCS , Rome , Italy
| | - Valerio Nobili
- b Hepatometabolic Unit , Bambino Gesu Hospital - IRCCS , Rome , Italy.,c Liver Research Unit , Bambino Gesu Hospital, IRCCS , Rome , Italy
| | - Jake P Mann
- d Metabolic Research Laboratories, Institute of Metabolic Science , University of Cambridge , Cambridge , UK.,e Department of Paediatrics , University of Cambridge , Cambridge , UK
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50
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Which Method is Superior in the Diagnosis of Nonalcoholic Fatty Liver and Steatohepatatis in Children? HEPATITIS MONTHLY 2017. [DOI: 10.5812/hepatmon.13584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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