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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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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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Draijer L, Voorhoeve M, Troelstra M, Holleboom A, Beuers U, Kusters M, Nederveen A, Benninga M, Koot B. A natural history study of pediatric non-alcoholic fatty liver disease over 10 years. JHEP Rep 2023; 5:100685. [PMID: 37077274 PMCID: PMC10106916 DOI: 10.1016/j.jhepr.2023.100685] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 01/07/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Background & Aims The long-term outcome of paediatric non-alcoholic fatty liver disease (NAFLD) has not been well established. Between 2008 and 2012, an unselected cohort of 133 children with severe obesity was screened for NAFLD. The aim of this study was to determine the 10-year natural history of NAFLD in this cohort. Methods All 133 participants of the original study were approached. Proton magnetic resonance spectroscopy (1H-MRS) and the Enhanced Liver Fibrosis® (ELF) test were used to assess longitudinal changes in steatosis and fibrosis, respectively. Risk factors for disease progression were explored. Results Fifty-one of the 133 participants (38%) from the original cohort were included. The mean follow-up time was 10.3 years (range 7-13 years), 65% were female and 92% had persistent obesity. The proportion of participants with steatosis remained unchanged (47%). Nine individuals developed steatosis and in nine individuals steatosis resolved. Predefined relevant individual changes in 1H-MRS were seen in 38% of the participants. The mean ELF test did not change significantly (8.70 ± 0.58 vs. 8.51 ± 0.71, p = 0.22). However, 16% had a relevant increase in ELF test and 6% of those with NAFLD developed advanced fibrosis at follow-up. Changes in steatosis correlated with changes in established metabolic risk factors, alanine aminotransferase, and bariatric surgery. A change in the ELF test was associated with a change in triglycerides. Conclusions This 10-year follow-up study shows that one-third of the young adults who had childhood obesity develop steatosis and in one-third steatosis resolves. Six percent of those with NAFLD had developed advanced fibrosis at follow-up. These data underscore the importance of screening for NAFLD and monitoring for progression to advanced NAFLD in young people with obesity. Impact and implications Childhood obesity accompanied by fat accumulation in the liver persists into young adulthood in the vast majority, and 6% develop serious liver injury. Worsening of metabolic disturbances increases the risk of liver injury.
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Affiliation(s)
- Laura Draijer
- Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children’s Hospital, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children’s Hospital, Amsterdam, the Netherlands
- Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, the Netherlands
- Corresponding author. Address: Meibergdreef 9, 1100 DD Amsterdam, the Netherlands. Tel.: +31-205662906
| | - Maaike Voorhoeve
- Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children’s Hospital, University of Amsterdam, Amsterdam, the Netherlands
| | - Marian Troelstra
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Adriaan Holleboom
- Department of Vascular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Meeike Kusters
- Department of Pediatrics, Amsterdam University Medical Centers, Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Aart Nederveen
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Marc Benninga
- Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children’s Hospital, University of Amsterdam, Amsterdam, the Netherlands
| | - Bart Koot
- Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children’s Hospital, University of Amsterdam, Amsterdam, the Netherlands
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Johansen MJ, Vonsild Lund MA, Ängquist L, Fonvig CE, Holm LA, Chabanova E, Thomsen HS, Hansen T, Holm J. Possible prediction of obesity-related liver disease in children and adolescents using indices of body composition. Pediatr Obes 2022; 17:e12947. [PMID: 35726748 PMCID: PMC9541567 DOI: 10.1111/ijpo.12947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/05/2022] [Accepted: 05/09/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND Diagnosis of nonalcoholic fatty liver disease in children and adolescents currently requires advanced or invasive technologies. OBJECTIVES We aimed to develop a method to improve diagnosis, using body composition indices and liver biochemical markers. METHODS To diagnose non-alcoholic fatty liver disease, 767 Danish children and adolescents underwent clinical examination, blood sampling, whole-body dual-energy X-ray absorptiometry scanning and proton magnetic resonance spectroscopy for liver fat quantification. Fourteen variables were selected as a starting point to construct models, narrowed by stepwise selection. Individuals were split into a training set for model construction and a validation test set. The final models were applied to 2120 Danish children and adolescents to estimate the prevalence. RESULTS The final models included five variables in different combinations: body mass index-standard deviation score, android-to-gynoid-fat ratio, android-regional fat percent, trunk-regional fat percent and alanine transaminase. When validated, the sensitivity and specificity ranged from 38.6% to 51.7% and 87.6% to 91.9%, respectively. The estimated prevalence was 24.2%-35.3%. Models including alanine transaminase alongside body composition measurements displayed higher sensitivity. CONCLUSIONS Body composition indices and alanine transaminase can be used to estimate non-alcoholic fatty liver disease, with 38.6%-51.7% sensitivity and 87.6%-91.9%, specificity, in children and adolescents with overweight (including obesity). These estimated a 24.2%-35.3% prevalence in 2120 patients.
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Affiliation(s)
- Magnus Jung Johansen
- The Children's Obesity Clinic, Accredited European Centre for Obesity Management, Department of PediatricsCopenhagen University Hospital HolbækHolbækDenmark
| | - Morten Asp Vonsild Lund
- The Children's Obesity Clinic, Accredited European Centre for Obesity Management, Department of PediatricsCopenhagen University Hospital HolbækHolbækDenmark,Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Lars Ängquist
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Cilius Esmann Fonvig
- The Children's Obesity Clinic, Accredited European Centre for Obesity Management, Department of PediatricsCopenhagen University Hospital HolbækHolbækDenmark,The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Louise Aas Holm
- The Children's Obesity Clinic, Accredited European Centre for Obesity Management, Department of PediatricsCopenhagen University Hospital HolbækHolbækDenmark,The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | | | - Henrik S. Thomsen
- Department of RadiologyHerlev Gentofte HospitalHerlevDenmark,Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Faculty of Health SciencesUniversity of Southern DenmarkOdenseDenmark
| | - Jens‐Christian Holm
- The Children's Obesity Clinic, Accredited European Centre for Obesity Management, Department of PediatricsCopenhagen University Hospital HolbækHolbækDenmark,The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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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: 79] [Impact Index Per Article: 19.8] [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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Ayonrinde OT. Historical narrative from fatty liver in the nineteenth century to contemporary NAFLD - Reconciling the present with the past. JHEP Rep 2021; 3:100261. [PMID: 34036255 PMCID: PMC8135048 DOI: 10.1016/j.jhepr.2021.100261] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/18/2021] [Accepted: 02/23/2021] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide. This historical narrative traces the evolution from basic descriptions of fatty liver in the nineteenth century to our contemporary understanding of NAFLD in the twentieth and twenty-first centuries. A detailed historiographic review of fatty liver from 1800s onwards was performed alongside a brief review of contemporary associations. Archived published literature dating back to the 1800s describe clinicopathological features of fatty liver. In the nineteenth century, doyens of medicine associated fatty liver with alcohol, malnutrition or wasting conditions, and subsequently adiposity, unhealthy diets and sedentary lifestyle. Microscopically, fatty liver was described when 5% or more hepatocytes were distended with fat. Recommendations to reverse fatty liver included reducing consumption of fat, sugar, starchy carbohydrates and alcohol, plus increasing physical exercise. Fatty liver was associated with liver fibrosis and cirrhosis in the late 1800s, and with diabetes in the early 1900s. The diagnostic labels NAFLD and non-alcoholic steatohepatitis (NASH) were introduced in the late 1900s. Metabolic dysfunction-associated fatty liver disease (MAFLD) was recently proposed to update the nosology of fatty liver, recognising the similar metabolic pathogenesis evident in individuals with typical NAFLD and those with heterogenous "secondary" co-factors including alcohol and other aetiologies. Fatty liver has emerged from being considered a disorder of nutritional extremes or alcohol excess to contemporary recognition as a complex metabolic disorder that risks progression to cirrhosis and hepatocellular carcinoma. The increasing prevalence of NAFLD and our growing understanding of its lifestyle and metabolic determinants justify the current exercise of re-examining the evolution of this common metabolic disorder.
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Affiliation(s)
- Oyekoya T. Ayonrinde
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch, WA, Australia
- Medical School, The University of Western Australia, Perth, WA, Australia
- Faculty of Health Sciences, Curtin University, Bentley, WA, Australia
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Johansen MJ, Gade J, Stender S, Frithioff-Bøjsøe C, Lund MAV, Chabanova E, Thomsen HS, Pedersen O, Fonvig CE, Hansen T, Holm JC. The Effect of Overweight and Obesity on Liver Biochemical Markers in Children and Adolescents. J Clin Endocrinol Metab 2020; 105:5588552. [PMID: 31617910 DOI: 10.1210/clinem/dgz010] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 09/20/2019] [Indexed: 02/09/2023]
Abstract
BACKGROUND Elevated plasma concentrations of liver enzymes are routinely used as markers of liver injury in adults and children. Currently, the age- and sex-specific effects of adiposity on pediatric liver enzyme concentrations are unclear. METHODS We included participants from 2 cohorts of Danish children and adolescents: 1858 from a population-based cohort and 2155 with overweight or obesity, aged from 6 to 18 years. Age- and sex-specific percentile curves were calculated for fasting plasma concentrations of alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), bilirubin, and alkaline phosphatase (ALP) in both cohorts. Hepatic fat content was assessed by proton magnetic resonance spectroscopy in 458 participants. RESULTS Concentrations of ALT, AST, LDH, and ALP decreased with age in both girls and boys, while GGT and bilirubin were comparable across age groups in girls and increased slightly with age in boys. Children and adolescents with overweight or obesity exhibited higher concentrations of ALT in all age groups. Concentrations of ALT, and to a lesser degree GGT, increased with age in boys with overweight or obesity. Optimal ALT cut-points for diagnosing hepatic steatosis (liver fat content > 5%) was 24.5 U/L for girls (sensitivity: 55.6%, specificity: 84.0%), and 34.5 U/L for boys (sensitivity: 83.7%, specificity: 68.2%). CONCLUSIONS Pediatric normal values of liver enzymes vary with both age and sex. Overweight and obesity is associated with elevated biochemical markers of liver damage. These findings emphasize the need for prevention and treatment of overweight and obesity in children and adolescents. (J Clin Endocrinol Metab XX: 0-0, 2019).
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Affiliation(s)
- Magnus J Johansen
- The Children's Obesity Clinic, European Centre of Management (COM/EASO), Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
- Department of Radiology, Herlev Gentofte Hospital, Herlev, Denmark
| | - Julie Gade
- The Children's Obesity Clinic, European Centre of Management (COM/EASO), Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
- Department of Radiology, Herlev Gentofte Hospital, Herlev, Denmark
| | - Stefan Stender
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Christine Frithioff-Bøjsøe
- The Children's Obesity Clinic, European Centre of Management (COM/EASO), Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten A V Lund
- The Children's Obesity Clinic, European Centre of Management (COM/EASO), Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Henrik S Thomsen
- Department of Radiology, Herlev Gentofte Hospital, Herlev, Denmark
- University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark
| | - Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cilius E Fonvig
- The Children's Obesity Clinic, European Centre of Management (COM/EASO), Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
- Department of Pediatrics, Kolding Hospital a part of Lillebaelt Hospital, Kolding, Denmark
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- University of Southern Denmark, Faculty of Health Sciences, Odense, Denmark
| | - Jens-Christian Holm
- The Children's Obesity Clinic, European Centre of Management (COM/EASO), Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark
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Faienza MF, Chiarito M, Molina-Molina E, Shanmugam H, Lammert F, Krawczyk M, D'Amato G, Portincasa P. Childhood obesity, cardiovascular and liver health: a growing epidemic with age. World J Pediatr 2020; 16:438-445. [PMID: 32020441 PMCID: PMC7224053 DOI: 10.1007/s12519-020-00341-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The frequency of childhood obesity has increased over the last 3 decades, and the trend constitutes a worrisome epidemic worldwide. With the raising obesity risk, key aspects to consider are accurate body mass index classification, as well as metabolic and cardiovascular, and hepatic consequences. DATA SOURCES The authors performed a systematic literature search in PubMed and EMBASE, using selected key words (obesity, childhood, cardiovascular, liver health). In particular, they focused their search on papers evaluating the impact of obesity on cardiovascular and liver health. RESULTS We evaluated the current literature dealing with the impact of excessive body fat accumulation in childhood and across adulthood, as a predisposing factor to cardiovascular and hepatic alterations. We also evaluated the impact of physical and dietary behaviors starting from childhood on cardio-metabolic consequences. CONCLUSIONS The epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence. Two key abnormalities in this context include cardiovascular diseases, and nonalcoholic fatty liver disease. Appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents. Nevertheless, improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity, cardiovascular diseases, and diabetes risk during adulthood.
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Affiliation(s)
- Maria Felicia Faienza
- Section of Pediatrics, Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy.
| | - Mariangela Chiarito
- Section of Pediatrics, Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Emilio Molina-Molina
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Harshitha Shanmugam
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | | | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
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Kim JY, Cho J, Yang HR. Biochemical Predictors of Early Onset Non-Alcoholic Fatty Liver Disease in Young Children with Obesity. J Korean Med Sci 2018; 33:e122. [PMID: 29651819 PMCID: PMC5897157 DOI: 10.3346/jkms.2018.33.e122] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 02/26/2018] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The prevalence of metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) and their associated risk factors are not well-established in young children with obesity. The purpose of this study was to evaluate the prevalence of early onset NAFLD and identify its biochemical predictors in obese children aged less than 10 years. METHODS Anthropometric measurements, blood pressure, laboratory tests, and abdominal ultrasonography (USG) were performed in all subjects. National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria for MS diagnosis and liver enzymes and USG for NAFLD diagnosis were assessed. RESULTS A total of 356 children with obesity (233 boys, 123 girls) were included, with 172 children age ≤ 10 years and 184 adolescents. The prevalence of MS was 23.3% in young children and 35.3% in adolescents (P = 0.020); while the prevalence of NAFLD was 36.0% and 70.7%, respectively (P = 0.001). In obese children aged 10 years or less, there were significant differences in levels of serum γ-glutamyltranspeptidase (γGT) (P < 0.001), triglycerides (P = 0.042), and homeostatic model assessment of insulin resistance (P < 0.001) between the non-NAFLD and the NAFLD group. Multivariate logistic regression analysis revealed significant increase in serum γGT and uric acid levels in young children. CONCLUSION Although MS and NAFLD were more prevalent in adolescents, young children also demonstrated MS and NAFLD as obesity-related complications. Elevated serum γGT and uric acid levels may serve as biochemical predictors in detecting NAFLD in young children with obesity before investigation with abdominal USG.
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Affiliation(s)
- Ju Young Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jinmin Cho
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
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Ranucci G, Spagnuolo MI, Iorio R. Obese children with fatty liver: Between reality and disease mongering. World J Gastroenterol 2017; 23:8277-8282. [PMID: 29307987 PMCID: PMC5743498 DOI: 10.3748/wjg.v23.i47.8277] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 11/14/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
Following the current epidemic of obesity, the worldwide prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with potential serious health implications. While it is established that in adults NAFLD can progress to end-stage liver disease in many cases, the risk of progression during childhood is less well defined. Since most obese children are not adherent to lifestyle modifications and hypocaloric diets, there is a growing number of studies on pharmacological interventions with the risk of disease mongering, the practice of widening the boundaries of illness in order to expand the markets for treatment. Here, we propose a critical appraisal of the best available evidence about long-term course of pediatric NAFLD and efficacy of treatments other than hypocaloric diet and physical exercise. As a result, the number of NAFLD children with a poor outcome is small in spite of the alarming tones used in some papers; large-scale longitudinal studies with long-term follow-up of pediatric NAFLD patients are lacking; the studies on ancillary pharmacological interventions have been performed in few patients with inconclusive and conflicting results.
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Affiliation(s)
- Giusy Ranucci
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Naples 80131, Italy
| | - Maria Immacolata Spagnuolo
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Naples 80131, Italy
| | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Naples 80131, Italy
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12
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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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13
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Ayonrinde OT, Olynyk JK, Marsh JA, Beilin LJ, Mori TA, Oddy WH, Adams LA. Childhood adiposity trajectories and risk of nonalcoholic fatty liver disease in adolescents. J Gastroenterol Hepatol 2015; 30:163-71. [PMID: 24989077 DOI: 10.1111/jgh.12666] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/03/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Nonalcoholic fatty liver disease (NAFLD) and its metabolic risk factors are recognized during childhood and adolescence. Identification of adolescents at risk of NAFLD from childhood anthropometry may expose opportunities to influence the hepatic and metabolic destinies of individuals. We sought associations between NAFLD diagnosed during adolescence and earlier life trajectories of anthropometry, in a population-based cohort of predominantly Caucasian adolescents. METHODS Assessment for NAFLD, using questionnaires and liver ultrasound, was performed on 1170 adolescents, aged 17 years, from the population-based Raine cohort. We sought associations between NAFLD in adolescents and serial anthropometric measurements recorded from birth, childhood, and adolescence. RESULTS NAFLD was diagnosed in 15.2% of adolescents. Birth anthropometry, including birth weight, skinfold thickness, and ponderal index, was not associated with NAFLD. However, adiposity differences between 17-year-old adolescents with NAFLD and those without NAFLD were apparent from age 3 years. Greater adiposity trajectories for weight, body mass index, skinfold thickness, mid-arm circumference, and chest circumference from age 3 years onwards, particularly in males, were associated with the diagnosis of NAFLD and severity of hepatic steatosis at age 17 years (P < 0.05). The strength of the associations increased with age after 3 years for each adiposity measure (all P < 0.001). CONCLUSIONS Trajectories of childhood adiposity are associated with NAFLD. Adiposity attained by 3 years of age and older, but not at birth, was associated with the diagnosis and severity of hepatic steatosis in late adolescence. Exploration of clinically relevant risk factors and preventative measures for NAFLD should begin during childhood.
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Affiliation(s)
- Oyekoya T Ayonrinde
- School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia; Department of Gastroenterology, Fremantle Hospital, Perth, Australia; Faculty of Health Sciences, Curtin University, Perth, Australia
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14
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Sharma A, Freese DK, Chandan V, Zarroug AE, Swain JM, Kumar S. Hepatic cirrhosis secondary to nonalcoholic fatty liver disease in a 12-year-old girl with morbid obesity. Clin Pediatr (Phila) 2014; 53:86-8. [PMID: 23564302 DOI: 10.1177/0009922813483171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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15
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Van Name M, Santoro N. Type 2 diabetes mellitus in pediatrics: a new challenge. World J Pediatr 2013; 9:293-9. [PMID: 24235062 DOI: 10.1007/s12519-013-0438-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 10/16/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND The increased prevalence of childhood obesity in the last few years has been accompanied by the increase in prevalence of type 2 diabetes in pediatrics. In this paper, we will review the risk factors and the pathogenic determinants leading to type 2 diabetes in youth. DATA SOURCES We searched on PubMed with the key words: obesity, type 2 diabetes, children, adolescents, youth, non-alcoholic fatty liver disease, genes and selected those publications written in English that we judged to be relevant to the topic of the review. RESULTS Based on the data present in the literature, we reviewed the following three topics: 1) the role of ectopic fat deposition, in particular of fatty liver, in the pathogenesis of pediatric type 2 diabetes; 2) the progression to type 2 diabetes in pediatrics and how it differs from adults, and 3) current theraputic options. CONCLUSION Type 2 diabetes in youth is a complex disease, creating new challenges in treatment and prevention.
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Affiliation(s)
- Michelle Van Name
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
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16
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Navarro-Jarabo JM, Ubiña-Aznar E, Tapia-Ceballos L, Ortiz-Cuevas C, Pérez-Aísa MA, Rivas-Ruiz F, Andrade RJ, Perea-Milla E. Hepatic steatosis and severity-related factors in obese children. J Gastroenterol Hepatol 2013; 28:1532-8. [PMID: 23701491 DOI: 10.1111/jgh.12276] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/26/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Obesity is an important health-care problem in developed countries. It is considered a multisystemic disease, but it may also affect the liver, thus provoking non-alcoholic fatty liver disease. This disease has been less extensively studied among children than among adults. We propose to analyze the prevalence of hepatic steatosis among a pediatric population within an area in southern Europe besides the variables associated with its development and severity. METHODS Cross-sectional study carried out on a population of children aged 6-14 years inclusive, using abdominal ultrasound as a method to determine the presence and severity of hepatic steatosis; in addition, anthropometric and blood-tested parameters were examined to determine which of these were associated with steatosis. RESULTS One hundred forty-four children were analyzed, 84 male (58.3%). Steatosis was detected in 50 children (34.7%; 95% confidence interval [CI]: 26.0-42.0%). In six of these cases (12%), elevated aminotransferase levels were recorded. Factors found to be associated with steatosis were body mass index ≥ 99th percentile (odds ratio [OR] 3.58, 95% CI 1.16-15.6) and the level of alanine aminotransferase (ALT) (OR 1.08, 95% CI 1.03-1.13), while its severity was associated with ALT (OR 1.17, 95% CI 1.09-1.28). A level of ALT < 23.5 UI/dL predicted lack of severe steatosis with an area under receiver operating characteristic curve of 0.805 (95% CI 0.683-0.927). CONCLUSIONS Non-alcoholic fatty liver disease is common in the obese pediatric population in our geographical area. High levels of ALT are associated with severe steatosis, although having ALT above the normal range is not common. Also, the lack of severity of steatosis can be predicted in a subgroup of children with obesity.
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Affiliation(s)
- Jose Maria Navarro-Jarabo
- Gastroenterology Unit, Costa del Sol Sanitary Agency; Research Unit, Research Network of Health Services in Chronic Diseases-REDISSEC, Marbella
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17
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Bozic MA, Subbarao G, Molleston JP. Pediatric Nonalcoholic Fatty Liver Disease. Nutr Clin Pract 2013; 28:448-58. [DOI: 10.1177/0884533613489153] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Molly A. Bozic
- Indiana University School of Medicine, Indianapolis, Indiana
| | - Girish Subbarao
- Indiana University School of Medicine, Indianapolis, Indiana
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18
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D'Adamo E, Santoro N, Caprio S. Metabolic syndrome in pediatrics: old concepts revised, new concepts discussed. Curr Probl Pediatr Adolesc Health Care 2013; 43:114-23. [PMID: 23582593 DOI: 10.1016/j.cppeds.2013.02.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ebe D'Adamo
- Department of Pediatrics, Yale University School of Medicine, PO Box 208064, New Haven, CT, USA
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19
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Alkhouri N, Sedki E, Alisi A, Lopez R, Pinzani M, Feldstein AE, Nobili V. Combined paediatric NAFLD fibrosis index and transient elastography to predict clinically significant fibrosis in children with fatty liver disease. Liver Int 2013; 33:79-85. [PMID: 23146095 DOI: 10.1111/liv.12024] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 10/04/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease from simple steatosis to steatohepatitis, to fibrosis and cirrhosis. The paediatric NAFLD fibrosis index (PNFI) and transient elastography (TE) are potential noninvasive markers for fibrosis. To prospectively evaluate the performance of PNFI and TE in assessing clinically significant fibrosis in children with biopsy-proven NAFLD. METHODS Our cohort consisted of 67 consecutive children with biopsy-proven NAFLD. The stage of fibrosis was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network. Fibrosis ≥ 2 was considered clinically significant. PNFI was calculated using age, waist circumference and triglycerides. TE was performed using the Fibroscan apparatus. RESULTS Ten patients had fibrosis stage 2-3 and 57 patients had stage 0-1. Both PNFI and TE values were significantly higher in patients with significant fibrosis (P < 0.05). The area under the receiver operating characteristic (ROC) curve for predicting significant fibrosis of PNFI and TE were 0.747 and 1.00 respectively (P = 0.005). The combined use of PNFI and TE could predict the presence or absence of clinically significant fibrosis in 98% of children with NAFLD. CONCLUSIONS In children with NAFLD, the combination of PNFI and TE can be used to accurately assess the presence of clinically significant liver fibrosis. This will help to identify patients who should undergo liver biopsy because the confirmation of advanced fibrosis would lead to closer follow-up and screening for cirrhosis-related complications.
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Affiliation(s)
- Naim Alkhouri
- Department of Pediatric Gastroenterology, Cleveland Clinic, Cleveland, Ohio, USA.
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Ghergherehchi R, Hazhir N, Mostafa Gharehbaghi M. Lifestyle Intervention and Vitamin E Therapy in Obese Children with Nonalcoholic Fatty Liver Disease. ACTA ACUST UNITED AC 2012. [DOI: 10.17795/compreped-6249] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Faith MS, Scanlon KS, Birch LL, Francis LA, Sherry B. Parent-Child Feeding Strategies and Their Relationships to Child Eating and Weight Status. ACTA ACUST UNITED AC 2012; 12:1711-22. [PMID: 15601964 DOI: 10.1038/oby.2004.212] [Citation(s) in RCA: 589] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Parental feeding styles may promote overeating or overweight in children. A comprehensive literature review was undertaken to summarize the associations between parental feeding styles and child eating and weight status. Twenty-two studies were identified. We systematically coded study attributes and outcomes and tested for patterns of association. Nineteen studies (86%) reported at least one significant association between parental feeding style and child outcome, although study methodology and results varied considerably. Studies measuring parental feeding restriction, as opposed to general feeding control or another feeding domain, were more likely to report positive associations with child eating and weight status. Certain associations differed by gender and by outcome measurement (e.g., rate of eating as opposed to total energy intake). Parental feeding restriction, but no other feeding domain, was associated with increased child eating and weight status. Longitudinal studies are needed to test underlying causal pathways, including bidirectional causal models, and to substantiate findings in the presence of other obesity risk factors.
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Affiliation(s)
- Myles S Faith
- Weight and Eating Disorders Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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22
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Brunt EM, Neuschwander-Tetri BA, Burt AD. Fatty liver disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:293-359. [DOI: 10.1016/b978-0-7020-3398-8.00006-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Kim JK, Chon NR, Lim HC, Lee KS, Han KH, Chon CY, Park YN, Paik YH. Transitional features of histologic type of non-alcoholic fatty liver disease in Korean young men. J Gastroenterol Hepatol 2012; 27:142-8. [PMID: 21883454 DOI: 10.1111/j.1440-1746.2011.06895.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in Korea as the dietary pattern and lifestyle become more Westernized and the obese population increases. The spectrum of NAFLD ranges from asymptomatic steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. Schwimmer et al. divided NASH into three types according to the histological characteristics, such as adult type, pediatric type and overlap type. We investigated clinical and histologic features of NAFLD patients in Korean young men. METHODS A total of 64 male patients under age 30 years, diagnosed as NAFLD by a liver biopsy, were reviewed retrospectively. NASH was diagnosed by NAFLD activity score (NAS), and NASH patients were classified with Schwimmer's histological classification. RESULTS Pathological features of liver biopsy revealed NASH in most cases (59 cases, 92.2%) including 29 cases (45.3%) of borderline NASH and 30 cases (46.9%) of definite NASH. The definite NASH group showed significantly high aspartate aminotransferase/alanine aminotransferase levels compared to the borderline NASH group. There were four cases (6.8%) of pediatric type, 17 cases (28.8%) of adult type, and 38 cases (64.4%) of overlap type in the NASH group. NAS was 3.75 ± 0.05 in the pediatric type, 4.29 ± 1.16 in the adult type and 4.87 ± 1.21 in the overlap type, and the overlap type showed a higher NAS than the pediatric type. The fibrosis stage was significantly higher in the overlap type than the other types. CONCLUSION Most Korean young men with NAFLD turned out to have borderline or definite NASH. More than half of the NASH cases showed overlap type in Korean young men.
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Affiliation(s)
- Ja Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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24
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D'Adamo E, Santoro N, Caprio S. Metabolic syndrome in pediatrics: old concepts revised, new concepts discussed. Pediatr Clin North Am 2011; 58:1241-55, xi. [PMID: 21981958 DOI: 10.1016/j.pcl.2011.07.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The worldwide epidemic of childhood obesity in the last decades is responsible for the occurrence in pediatrics of disorders once mainly found in adults, such as the metabolic syndrome. A key factor in the pathogenesis of metabolic syndrome is insulin resistance, a phenomenon occurring mainly in obese subjects with a general resistance to the insulin effect only on carbohydrates metabolism. Given that the metabolic syndrome is driven by obesity, the prevalence of the latter will strongly influence the prevalence of metabolic syndrome. This article addresses the causes of metabolic syndrome and the relevance of obesity in the pediatric population.
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Affiliation(s)
- Ebe D'Adamo
- Department of Pediatrics, Yale University School of Medicine, PO Box 208064, New Haven, CT 6520, USA
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25
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Jee SJ, Kim YJ, Song SY, Paik SS. Association among Histopathology, Clinical Manifestation, and Ultrasonographic Grades in Pediatric Non-alcoholic Fatty Liver Disease. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2011. [DOI: 10.4166/kjg.2011.57.3.158] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Sue Jung Jee
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
| | - Yong Joo Kim
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
| | - Soon Young Song
- Department of Radiology, Hanyang University College of Medicine, Seoul, Korea
| | - Seung Sam Paik
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
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Pacifico L, Poggiogalle E, Cantisani V, Menichini G, Ricci P, Ferraro F, Chiesa C. Pediatric nonalcoholic fatty liver disease: A clinical and laboratory challenge. World J Hepatol 2010; 2:275-88. [PMID: 21161009 PMCID: PMC2998974 DOI: 10.4254/wjh.v2.i7.275] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Revised: 07/06/2010] [Accepted: 07/13/2010] [Indexed: 02/06/2023] Open
Abstract
The true prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is unknown. Challenges in determining the population prevalence of NAFLD include the type of test (and the reference intervals used to define normal and abnormal), the type of population (general population, hospital series), the demographic characteristics of the population sampled, and the nature of the study design. The natural history of pediatric NAFLD remains uncertain. The issue of when to perform a liver biopsy in children with suspected NAFLD remains controversial. Children with NAFLD but normal alanine aminotransferase are rarely investigated. However, evidence of alterations in glucose metabolism parameters should prompt a better understanding of the natural history of pediatric NAFLD not only in terms of the progression of liver disease but also regarding its potential relationship with other health outcomes such as type 2 diabetes mellitus and cardiovascular disease. This evidence could make liver biopsy mandatory in the majority of cases at risk of progressive and severe hepatic and extrahepatic disease. This conclusion, however, raises the question of the feasibility of liver biopsy assessment in an extremely large at risk population, and of the cost/effectiveness of this policy. There is a considerable, continuous interest in reliable, noninvasive alternatives that will allow the prognosis of pediatric NAFLD to be followed in large community or population-based studies.
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Affiliation(s)
- Lucia Pacifico
- Lucia Pacifico, Eleonora Poggiogalle, Flavia Ferraro, Claudio Chiesa, Departments of 1 Pediatrics, Sapienza University of Rome, Rome 00161, Italy
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Tsuruta G, Tanaka N, Hongo M, Komatsu M, Horiuchi A, Hamamoto K, Iguchi C, Nakayama Y, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K, Aoyama T, Tanaka E. Nonalcoholic fatty liver disease in Japanese junior high school students: its prevalence and relationship to lifestyle habits. J Gastroenterol 2010; 45:666-72. [PMID: 20084525 DOI: 10.1007/s00535-009-0198-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2009] [Accepted: 12/12/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND Despite the increase in nonalcoholic fatty liver disease (NAFLD) in Japanese adults, its prevalence in adolescents remains unclear. This prompted us to evaluate the incidence and clinical characteristics of NAFLD among junior high school students. METHODS A population-based cross-sectional study was conducted among students in a single junior high school in Nagano prefecture. Serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (gammaGT) measurements and abdominal ultrasonography were performed in 249 and 288 students in 2004 and 2007, respectively. In the latter survey, student lifestyle habits were also assessed, using questionnaires. RESULTS The prevalence of NAFLD was 4.4% and 4.5% in 2004 and 2007, respectively, which was lower than that of obesity (10.0% and 5.9%). Body mass index and ALT and gammaGT levels increased significantly with hepatic steatosis severity. Multivariate logistic regression analysis demonstrated that the presence of obesity and an ALT level of 30 U/L or more were independent predictors of NAFLD (odds ratio 16.9, P<0.001 and odds ratio 16.6, P=0.001, respectively). The ratios of students commuting to and from school by car and not doing sports outside of school were higher in NAFLD students compared with non-NAFLD ones. Such tendencies were observed independently of the presence of obesity. Additionally, one obese student with severe steatosis and liver dysfunction was diagnosed as having nonalcoholic steatohepatitis (NASH). CONCLUSIONS Approximately 4% of junior high school students had NAFLD that was primarily associated with obesity and reduced daily physical activity. Serum ALT measurement during school check-ups is recommended for the early detection of young adolescent NAFLD/NASH.
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Affiliation(s)
- Goro Tsuruta
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
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Duarte MASDM, Silva GAPD. Obesity in children and adolescents: the relation between metabolic syndrome and non-alcoholic fatty-liver disease. REVISTA BRASILEIRA DE SAÚDE MATERNO INFANTIL 2010. [DOI: 10.1590/s1519-38292010000200004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This article aims to review clinical and diagnostic aspects of non-alcoholic fatty liver disease associated with obesity and its relation to metabolic syndrome in children and adolescents. An on-line search was carried out of original articles in the Medical Literature Analysis and Retrieval System Online (MEDLINE), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and Scientific Eletronic Library Online (SciELO) databases, using the following key words: "hepatic steatosis", "nonalcoholic fatty liver diseases", "overweight", "obesity", "children", "adolescents", "ultrasound" and "metabolic syndrome" in English and Portuguese. Two hundred and seventy-five articles were initially selected, all published between 1993 and 2008. After reading this was narrowed down to 67. The literature consulted revealed no consensus regarding the need to screen for metabolic syndrome and non-alcoholic fatty liver disease, especially in obese children and adolescents and those who have excess fat in the abdominal region. An ultrasound examination of the liver is typically used for screening and, in the case of children who present alterations in aminotransferases in addition to fatty infiltration of the liver, a strict clinical follow-up and a liver biopsy are recommended if these symptoms do not disappear on treatment.
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29
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Hepatic artery resistance in children with obesity and fatty liver. Indian J Pediatr 2010; 77:407-11. [PMID: 20422324 DOI: 10.1007/s12098-010-0045-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2009] [Accepted: 01/06/2010] [Indexed: 01/17/2023]
Abstract
OBJECTIVE The present study assessed whether there is a correlation between hepatic artery resistive index (HARI) and increase of body mass index and hepatosteatosis grading in children with non-alcoholic fatty liver disease (NAFLD) reflecting hemodynamic effects of hepatosteatosis. METHODS Thirty three healthy children [body mass index(BMI): mean+/- standart deviation(SD), min-max: 20.1+/-1.14(18.5-23.7), 33 overweight [BMI:25.1+/-2.2 (18.5-23.7)] and 66 obese [BMI:31.1+/-2(25.6-40)] adolescents were enrolled into the study. To search the relation of HARI with fatty liver degree, study subjects subdivided into groups according to their degree of fatty liver at ultrasonography(US). RESULTS Increase of HARI was correlated with increase in BMI (p<0.0001, r=0.533). Increase of HARI was well correlated with increase in degree of fatty liver (p<0.0001, r=0.630). CONCLUSION The present study results suggest that there are positive correlations of HARI with BMI and hepatosteatosis grade in obese children with NAFLD. HARI may be a candidate parameter to determine early alarming hemodynamic changes in hepatic tissue of obese children with fatty liver before development of severe stages NAFLD.
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Ariz U, Mato JM, Lu SC, Martínez Chantar ML. Nonalcoholic steatohepatitis, animal models, and biomarkers: what is new? Methods Mol Biol 2010; 593:109-36. [PMID: 19957147 DOI: 10.1007/978-1-60327-194-3_6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological term that encompasses a spectrum of abnormalities ranging from simple triglyceride accumulation in the hepatocytes (hepatic steatosis) to hepatic steatosis with inflammation (steatohepatitis, also known as nonalcoholic steatohepatitis or NASH). NASH can also progress to cirrhosis and hepatocellular carcinoma (HCC). Steatohepatitis has been estimated to affect around 5% of the total population and 20% of those who are overweight. The mechanisms leading to NASH and its progression to cirrhosis and HCC remain unclear, but it is a condition typically associated with obesity, insulin resistance, diabetes, and hypertriglyceridemia. This point corroborates the need for animal models and molecular markers that allow us to understand the mechanisms underlying this disease. Nowadays, there are numerous mice models to study abnormal liver function such as steatosis, NASH, and hepatocellular carcinoma. The study of the established animal models has provided many clues in the pathogenesis of steatosis and steatohepatitis, although these remain incompletely understood and no mice model completely fulfills the clinical features observed in humans. In addition, there is a lack of accurate sensitive diagnostic tests that do not involve invasive procedures. Current laboratory tests include some biochemical analysis, but their utility for diagnosing NASH is still poor. For that reason, a great effort is being made toward the identification and validation of novel biomarkers to assess NASH using high-throughput analysis based on genomics, proteomics, and metabolomics. The most recent discoveries and their validation will be discussed.
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Affiliation(s)
- Usue Ariz
- Metabolomics, Parque Technológico de Bizkaia, Derio, Spain
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Katz K, Brar PC, Parekh N, Liu YH, Weitzman M. Suspected nonalcoholic Fatty liver disease is not associated with vitamin d status in adolescents after adjustment for obesity. J Obes 2010; 2010:496829. [PMID: 21331294 PMCID: PMC3038678 DOI: 10.1155/2010/496829] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 11/22/2010] [Accepted: 12/27/2010] [Indexed: 02/08/2023] Open
Abstract
This study investigated a potential independent association between hypovitaminosis D and suspected nonalcoholic fatty liver disease (NAFLD) in a nationally representative sample of the US adolescents. Data from 1630 subjects 12-19 years of age were examined using the National Health and Nutrition Examination Survey, 2001-2004. The vitamin D status of subjects was categorized into quartiles of serum 25-hydroxyvitamin D. Subjects with serum ALT > 30 U/L were classified as having suspected NAFLD. Data regarding age, sex, race, BMI, and poverty level were also analyzed in bivariate and multivariate analyses using SAS and SUDAAN software. Suspected NAFLD was identified in 12.1% of adolescents in the lowest quartile compared to 6.9% of adolescents in the second quartile, 8.0% in the third quartile, and 13.17% in the highest quartile of serum 25(OH)D concentrations (P = .05). In analyses utilizing vitamin D as a continuous variable, no independent association was found between Vitamin D levels and rates of elevated ALT levels. In multivariate analyses, higher risks for suspected NAFLD were observed in males and overweight adolescents; however, vitamin D status was not found to be independently associated with suspected NAFLD after adjusting for obesity.
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Affiliation(s)
- Karin Katz
- Department of Pediatrics, School of Medicine, New York University, New York, NY 10016, USA
| | - Preneet Cheema Brar
- Department of Pediatrics, School of Medicine, New York University, New York, NY 10016, USA
| | - Niyati Parekh
- Department of Nutrition, Food Studies and Public Health, New York University, New York, NY 10016, USA
| | - Ying-Hua Liu
- Department of Pediatrics, School of Medicine, New York University, New York, NY 10016, USA
| | - Michael Weitzman
- Department of Pediatrics, School of Medicine, New York University, New York, NY 10016, USA
- Department of Psychiatry, School of Medicine, New York University, New York, NY 10016, USA
- New York University, Institute of Community Health and Research, School of Medicine, New York University, New York, NY 10016, USA
- *Michael Weitzman:
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Nobili V, Alisi A, Raponi M. Pediatric non-alcoholic fatty liver disease: Preventive and therapeutic value of lifestyle intervention. World J Gastroenterol 2009; 15:6017-22. [PMID: 20027672 PMCID: PMC2797656 DOI: 10.3748/wjg.15.6017] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), and eventually cirrhosis and liver failure, is seen to be increasing amongst Western children. NAFLD rates are rising in parallel with the epidemic of childhood obesity, and in particular, fatty liver evolves more easily in NASH when poor dietary habits and sedentary lifestyle are combined. In fact, its general prevalence in the child population varies between 2.6% and 10%, but increases up to 80% in obese children. Since NASH is expected to become the most common cause of pediatric chronic liver disease in the near future, there is broad interest amongst clinical researchers to move forward, both in diagnosis and treatment. Unfortunately, to date, the expensive and invasive procedure of liver biopsy is seen as the gold standard for NASH diagnosis and few noninvasive diagnostic methods can be applied successfully. Moreover, there are still no approved pharmacological interventions for NAFLD/NASH. Therefore, current management paradigms are based upon the presence of associated risk factors and aims to improve an individual’s quality of life, thus reducing NAFLD-associated morbidity and mortality. Today, lifestyle intervention (diet and exercise) is the treatment of choice for NAFLD/NASH. Thus far, no study has evaluated the potential preventive effect of lifestyle intervention on children at risk of NAFLD/NASH. Future studies will be required in this area with the perspective of developing a national program to promote nutrition education and increase physical activity as means of preventing the disease in individuals at risk. Here, we outline the clinical course, pathogenesis and management of NAFLD in children, highlighting the preventive and therapeutic value of lifestyle intervention.
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Relation between Childhood Obesity and Adult Cardiovascular Risk. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2009; 2009:108187. [PMID: 19956748 PMCID: PMC2775687 DOI: 10.1155/2009/108187] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/11/2009] [Accepted: 08/18/2009] [Indexed: 11/18/2022]
Abstract
The incidence of overweight and obesity is rising at an alarming pace in the pediatric population, just as in the adult population. The adult comorbidities associated with this risk factor are well-recognized and are being further elucidated continually. Additionally, we are gradually developing a better understanding of the risks of overweight and obesity among children while they are still young. However, there is now a growing body of evidence showing that childhood obesity not only leads all too frequently to adult obesity, but is in itself a risk factor for cardiometabolic syndrome and resultant cardiovascular risk in adulthood. If current trends continue, the problem of pediatric overweight and obesity will become of unmanageable proportions once these individuals reach adulthood. Future research efforts toward understanding this complex problem will need to focus on those overweight and obese children who later went on to change their metabolic course and become normal-weight adults.
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Alisi A, Manco M, Vania A, Nobili V. Pediatric nonalcoholic fatty liver disease in 2009. J Pediatr 2009; 155:469-74. [PMID: 19772998 DOI: 10.1016/j.jpeds.2009.06.014] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2009] [Revised: 05/06/2009] [Accepted: 06/09/2009] [Indexed: 02/08/2023]
Affiliation(s)
- Anna Alisi
- Liver Unit, Bambino Gesù, Children's Hospital and Research Institute, Rome, Italy
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Carter-Kent C, Yerian LM, Brunt EM, Angulo P, Kohli R, Ling SC, Xanthakos SA, Whitington PF, Charatcharoenwitthaya P, Yap J, Lopez R, McCullough AJ, Feldstein AE. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 2009; 50:1113-20. [PMID: 19637190 PMCID: PMC2775705 DOI: 10.1002/hep.23133] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well-characterized, biopsy-proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin-eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7-point scale. The median age was 12 years (range, 4-18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS > or =5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003). CONCLUSION Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease.
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Affiliation(s)
- Christine Carter-Kent
- Department of Pediatric Gastroenterology and Nutrition, Cleveland Clinic, Cleveland, OH
| | - Lisa M. Yerian
- Department of Pathology, Cleveland Clinic, Cleveland, OH
| | - Elizabeth M. Brunt
- Department of Pathology and Immunology, Washington University, St. Louis, MO
| | - Paul Angulo
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Simon C. Ling
- Division of Gastroenterology and Hepatology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Stavra A. Xanthakos
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Peter F. Whitington
- Division of Gastroenterology and Hepatology, Children's Memorial Hospital, Chicago, IL
| | | | - Jason Yap
- Division of Gastroenterology and Hepatology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rocio Lopez
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
| | | | - Ariel E. Feldstein
- Department of Pediatric Gastroenterology and Nutrition, Cleveland Clinic, Cleveland, OH,Department of Cell Biology, Cleveland Clinic, Cleveland, OH
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Lavine JE, Schwimmer JB, Molleston JP, Scheimann AO, Murray KF, Abrams SH, Rosenthal P, Sanyal AJ, Robuck PR, Brunt EM, Unalp A, Tonascia J. Treatment of nonalcoholic fatty liver disease in children: TONIC trial design. Contemp Clin Trials 2009; 31:62-70. [PMID: 19761871 DOI: 10.1016/j.cct.2009.09.001] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2009] [Revised: 09/04/2009] [Accepted: 09/09/2009] [Indexed: 12/25/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) in children can lead to steatohepatitis, cirrhosis, and end-stage liver disease. The cause of NAFLD is unknown, but it is commonly associated with obesity, insulin resistance, and dyslipidemia. OBJECTIVES TONIC is conducted to test whether treatment with metformin, an insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvements in biochemical and histological features of nondiabetic children with biopsy-proven NAFLD. DESIGN TONIC is a randomized, multicenter, double-masked, placebo-controlled trial of 96 weeks of treatment with metformin or vitamin E. The primary outcome measure chosen for the trial is improvement in serum alanine aminotransferase (ALT) levels with treatment as compared to placebo. An improvement in ALT is defined as reduction in serum ALT levels to below 50% of the baseline values or into the normal range (40 U/L or less) during the last 48 weeks of treatment. Histological improvement is defined by changes in liver histology between a baseline and end-of-treatment liver biopsy in regards to (1) steatohepatitis, (2) NAFLD Activity Score, consisting of scores for steatosis, lobular inflammation, and hepatocellular injury (ballooning), and (3) fibrosis score. METHODS Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States. Participants were randomized to receive either metformin (500 mg b.i.d.), vitamin E (400 IU b.i.d.), or placebo for 96 weeks. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB). (ClinicalTrials.gov number, NCT00063635.).
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Affiliation(s)
- Joel E Lavine
- University of California San Diego, La Jolla, CA, USA
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D'Adamo E, Santoro N, Caprio S. Metabolic syndrome in pediatrics: old concepts revised, new concepts discussed. Endocrinol Metab Clin North Am 2009; 38:549-63. [PMID: 19717004 DOI: 10.1016/j.ecl.2009.06.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The worldwide epidemic of childhood obesity in the last decades is responsible for the occurrence in pediatrics of disorders once mainly found in adults, such as the metabolic syndrome. A key factor in the pathogenesis of metabolic syndrome is insulin resistance, a phenomenon occurring mainly in obese subjects with a general resistance to the insulin effect only on carbohydrates metabolism. Given that the metabolic syndrome is driven by obesity, the prevalence of the latter will strongly influence the prevalence of metabolic syndrome. This article addresses the causes of metabolic syndrome and the relevance of obesity in the pediatric population.
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Affiliation(s)
- Ebe D'Adamo
- Department of Pediatrics, Yale University School of Medicine, PO Box 208064, New Haven, CT 6520, USA
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Pardee PE, Lavine JE, Schwimmer JB. Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery. Semin Pediatr Surg 2009; 18:144-51. [PMID: 19573756 PMCID: PMC2761012 DOI: 10.1053/j.sempedsurg.2009.04.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This review focuses on the diagnosis, risk factors, prevalence, pathogenesis and treatment of pediatric nonalcoholic steatohepatitis (NASH). NASH is a progressive form of nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease in children. The factors that account for differences between children with NASH and children with milder forms of NAFLD are unclear. The diagnosis of NASH requires interpretation of liver histology because no noninvasive markers predict the presence or severity of NASH. There is no proven treatment for NASH. Several clinical trials for NAFLD are in progress; however, clinical trials focusing on NASH are needed. Heightened physician awareness of NAFLD, NASH, and associated risk factors is important to identify and treat affected children.
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Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in pediatric-age individuals, in parallel with increasing obesity, and can lead to liver inflammation, fibrosis, and even cirrhosis. NAFLD appears tightly linked with features of the metabolic syndrome (MetS). This review aims to reconsider the clinical presentation, laboratory and pathologic assessment, and treatment of NAFLD, with a focus on its relationship with the MetS. RECENT FINDINGS NAFLD occurs with a high prevalence and severity in obese, insulin-resistant adolescents, especially Hispanic males. Pediatric NAFLD may improve with lifestyle therapy and agents that improve insulin sensitivity. In youth, NAFLD appears tightly correlated with components of the MetS, especially visceral fat, which appears to predict fibrosis as well as liver fat. In addition, noninvasive techniques such as transient elastography may help provide data on fibrosis in youth with NAFLD and avoid biopsy. SUMMARY The close association between NAFLD and the MetS supports screening for other comorbidities associated with the MetS. Further research is urgently required to best identify effective therapies to prevent and treat NAFLD, but its close association with MetS argues for a focus on strategies designed to improve insulin resistance and components of the MetS.
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Affiliation(s)
- Shikha S Sundaram
- Division of Gastroenterology, Hepatology and Nutrition, University of Colorado Denver, Aurora, Colorado 80045, USA
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Trends in nonalcoholic fatty liver disease-related hospitalizations in US children, adolescents, and young adults. J Pediatr Gastroenterol Nutr 2009; 48:597-603. [PMID: 19412009 DOI: 10.1097/mpg.0b013e318192d224] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To investigate temporal trends of nonalcoholic fatty liver disease (NAFLD) and obesity among hospitalized US children, adolescents, and young adults over the past 2 decades and to examine potential sex disparities in NAFLD hospitalizations. METHODS Hospitalization discharges with NAFLD or obesity were identified among children and young adults (6-25 years, weighted n = 91,687,413) from the 1986 to 2006 National Hospital Discharge Survey data. Age- and sex-specific rates and trends in hospitalizations with NAFLD and obesity were estimated. Rates were standardized to age distribution of the 2000 US Census population. Sex disparities were examined for the most recent period 2004 to 2006 (weighted n = 12,969,532). RESULTS Between 1986 to 1988 and 2004 to 2006, hospitalizations with NAFLD diagnosis increased from 0.9 to 4.3/100,000 population (P < 0.001). During the same time, hospitalizations with a diagnosis of obesity increased from 35.5 to 114.7/100,000 population (P < 0.001). During 2004 to 2006, hospitalization rates with a diagnosis of NAFLD were higher among females than among males (5.9 vs 2.7/100,000 population, P < 0.001), as were hospitalizations with a diagnosis of obesity (140.8 vs 61.5/100,000 population, P < 0.001). Obesity and diabetes were reported in 43.3% and 31.9%, respectively, of discharges with NAFLD. CONCLUSION The prevalence of NAFLD among young hospitalized patients increased in the past 2 decades, paralleling obesity-related hospitalizations. This could be a consequence of the obesity epidemic or of increased screening for liver disease.
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Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review. J Pediatr Gastroenterol Nutr 2009; 48:587-96. [PMID: 19412008 DOI: 10.1097/mpg.0b013e31818e04d1] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Uncertainty exists regarding the treatment of patients with nonalcoholic fatty liver disease (NAFLD) who are unable to lose weight and/or change lifestyle. The present study assesses the effectiveness and safety of pharmacological and dietary supplement interventions for NAFLD. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched for randomized controlled trials (RCTs) both in adults and in children. RESULTS Fifteen (2 pediatric patients and 13 adults) RCTs met the inclusion criteria. A significant effect on normalization of alanine transaminase was found in patients treated with metformin compared with vitamin E, and in those treated with high-dose (3 g) carnitine vs diet. In contrast, there was no difference in patients treated with pioglitazone combined with vitamin E versus vitamin E alone, ursodeoxycholic acid (UDCA) combined with vitamin E or alone versus placebo, or UDCA versus combination of vitamin E and vitamin C, and in patients treated with vitamin E, probucol, N-acetylcysteine, low doses of carnitine, or Yo Jyo Shi Ko compared with placebo. Aspartate aminotransferase normalization was significantly higher in those treated with UDCA combined with vitamin E versus UDCA alone or placebo, and in those treated with metformin. Small number of subjects, high drop-out rates, and numerous interventions in 1 study limit the value of many studies. Only 7 RCTs analyzed biopsy specimens, but most of them have significant methodological limitations. Pioglitazone had reduced liver necrosis and inflammation in 1 large study. CONCLUSIONS Limited data do not allow one to draw firm conclusions on the efficacy of various treatments for NAFLD.
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Reinehr T, Schmidt C, de Sousa G, Andler W. Association between leptin and transaminases: 1-year follow-up study in 180 overweight children. Metabolism 2009; 58:497-503. [PMID: 19303970 DOI: 10.1016/j.metabol.2008.11.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Accepted: 11/18/2008] [Indexed: 01/14/2023]
Abstract
Leptin and insulin resistance are being discussed to be involved in the pathogenesis of nonalcoholic fatty liver disease, which is frequently characterized by moderately elevated transaminases. However, longitudinal studies proving an association between leptin, insulin resistance, and transaminases are scarce. We examined weight status, aspartate aminotransferase (AST), alanine aminotransferase (ALT), leptin, glucose, and insulin in 180 overweight children at baseline and 1 year later. Relationships between these parameters at baseline and their changes in the course of 1 year were determined by multiple regression analysis adjusted for age, sex, pubertal stage, and body mass index (BMI). Leptin but not homeostasis model assessment of insulin resistance index correlated significantly to transaminases in both cross-sectional and longitudinal analyses. The same findings were observed in 30 children with suspected nonalcoholic fatty liver disease by ultrasound. The 130 children who participated in a 1-year lifestyle intervention reduced their overweight (standard deviation score [SDS]-BMI, -0.37 +/- 0.11). In the course of 1 year, their changes of transaminases depended on change of weight status (SDS-BMI decrease >0.5: ALT 12 [10-15] --> 9 [8-13] U/L, AST 11 [9-12] --> 9 [8-12] U/L; SDS-BMI decrease >0 but <or=0.5: ALT 14 [11-18] --> 16 [12-26] U/L, AST 10 [8-14] --> 10 [8-24] U/L; no SDS-BMI decrease: ALT 13 [11-20] --> 20[13-33] U/L, AST 11 [9-21] --> 15 [9-24] U/L; data as median and interquartile range). The 50 children without intervention increased their SDS-BMI (+0.02 +/- 0.18) and transaminases (ALT 14 [11-18] --> 19 [15-25] U/L, AST 10 [8-15] --> 16 [10-25] U/L). These findings suggest that leptin may be involved in the pathogenesis of liver diseases. However, to test this hypothesis, careful histologic assessments in correlation to leptin levels are needed.
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Affiliation(s)
- Thomas Reinehr
- Vestische Hospital for Children and Adolescents, University of Witten-Herdecke, 45711 Datteln, Germany.
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Nadeau KJ, Ehlers LB, Zeitler PS, Love-Osborne K. Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr Diabetes 2009; 10:5-13. [PMID: 18721166 DOI: 10.1111/j.1399-5448.2008.00450.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
The presence of fatty liver per ultrasound and liver-associated enzymes were measured in a select cohort of youth with both obesity and insulin resistance, and the effect of metformin on these parameters evaluated. Fifty obese, multiethnic, insulin-resistant adolescents (mean age 15.1 yr, mean body mass index 39.8 kg/m2) were randomized to receive lifestyle recommendations plus either twice per day doses of 850 mg of metformin or placebo. Fasting and post-glucose challenge biochemistries and liver ultrasounds were compared at baseline and 6 months. The prevalence of fatty liver was 74%, elevated alanine aminotransferase (ALT) 14%, aspartate aminotransferase (AST) 14%, and gamma-glutamyl transferase (GGT) 17%. Fatty liver was mild in 23%, moderate in 31%, and severe in 46%. Fatty liver was more common in male and Hispanic subjects and elevated ALT more common in Hispanic subjects. Subjects with fatty liver appeared more insulin resistant (higher fasting insulin and triglycerides, lower high-density lipoprotein cholesterol) and had higher ALT and AST. At 6 months, mean ALT, GGT, and fasting insulin improved significantly in all subjects. Fatty liver prevalence (p < 0.04), severity (p < 0.04), and fasting insulin (p < 0.025) improved significantly with metformin compared to placebo. Non-alcoholic fatty liver disease (NAFLD) occurs with a high prevalence and severity in obese, insulin-resistant adolescents. While metformin plus lifestyle intervention appears promising, defining NAFLD therapies capable of preventing fibrosis and cirrhosis requires further study.
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Affiliation(s)
- Kristen J Nadeau
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
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Nobili V, Parkes J, Bottazzo G, Marcellini M, Cross R, Newman D, Vizzutti F, Pinzani M, Rosenberg WM. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology 2009; 136:160-7. [PMID: 18992746 DOI: 10.1053/j.gastro.2008.09.013] [Citation(s) in RCA: 192] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2008] [Revised: 09/04/2008] [Accepted: 09/11/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in children and adolescents in industrialized countries. It is important to accurately determine the stage of fibrosis in these patients. The enhanced liver fibrosis (ELF) test has been validated for staging liver fibrosis in adult patients with chronic liver diseases, including NAFLD. We investigated the performance of this test in assessing liver fibrosis in children and adolescents with NAFLD, identified by biopsy. METHODS The ELF test was performed on a panel of serum samples collected from 112 consecutive subjects that were likely to have NAFLD (64 male, mean age of 13.8+/-3.3). A previously described and validated algorithm was used to analyze the data on hyaluronic acid (HA), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels. RESULTS In pediatric patients with NAFLD, the ELF test predicted liver fibrosis stage with a high degree of sensitivity and specificity; results were superior to those reported for adults. The area under receiver operating characteristic curves/best possible ELF test cut-off values for the prediction of "any" (>or= stage 1), moderate-perisinusoidal (>or= stage 1b), moderate-portal/periportal (>or= stage 1c), significant (>or= stage 2), or advanced (>or= stage 3) fibrosis were 0.92/9.28, 0.92/9.33, 0.90/9.54, 0.98/10.18 and 0.99/10.51, respectively. CONCLUSIONS The ELF test can be used to accurately assess the level of liver fibrosis in pediatric patients with NAFLD. This information is important for identifying patients with progressive fibrosis that require further histopathological analysis or therapeutic follow-up.
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Affiliation(s)
- Valerio Nobili
- Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
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Allcock D, Gardner M, Sowers J. Relation between Childhood Obesity and Adult Cardiovascular Risk. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2009. [DOI: 10.1186/1687-9856-2009-108187] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Yoo J, Lee S, Kim K, Yoo S, Sung E, Yim J. Relationship between insulin resistance and serum alanine aminotransferase as a surrogate of NAFLD (nonalcoholic fatty liver disease) in obese Korean children. Diabetes Res Clin Pract 2008; 81:321-6. [PMID: 18571268 DOI: 10.1016/j.diabres.2008.05.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2007] [Revised: 04/18/2008] [Accepted: 05/01/2008] [Indexed: 01/05/2023]
Abstract
There has been increasing number of obese children who accompany obesity-related comorbidities. It has been known that nonalcoholic fatty liver disease (NAFLD) as one of obesity-related comorbidities is related with insulin resistance. So, we investigated the relation between insulin resistance and NAFLD, using serum alanine aminotransferase (ALT) as a surrogate of NAFLD among obese children in Korea. The study subjects were 909 obese children aged 9-12 years (boys 613, girls 296). Body mass index (BMI), waist circumference (WC), blood pressure, fasting blood glucose, fasting insulin, lipid profile were measured. ALT, liver enzyme was used as a surrogate of NAFLD and homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index of insulin resistance. The prevalence of elevated serum ALT (>or=40 mg/dl) was 33.4% in boys, and 19.6% in girls respectively. In boys, ALT was correlated with BMI, waist circumference, total cholesterol, triglyceride, HDL-cholesterol, systolic and diastolic blood pressure, HOMA-IR, fasting serum insulin. Odds ratio for HOMA-IR against the elevated ALT (>or=40 mg/dl) was 1.061 (95% confidence interval, 1.020-1.103, P=0.003). In girls, ALT was correlated with BMI, waist circumference, total cholesterol, triglyceride, glucose, systolic and diastolic blood pressure, HOMA-IR, fasting serum insulin. Odds ratio for HOMA-IR against the elevated ALT (>or=40 mg/dl) was 1.042 (95% confidence interval, 0.998-1.088, P=0.063). Among obese Korean children, insulin resistance and ALT, lipid profile, BMI, WC, blood pressure showed significant correlation. Especially, in boys, higher ALT is founded to be independently associated with insulin resistance.
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Affiliation(s)
- JangSuk Yoo
- Department of Family Medicine, Inje University, College of Medicine, Sanggyepaik Hospital, Nowon-Gu, Seoul, Republic of Korea
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Nobili V, Vizzutti F, Arena U, Abraldes JG, Marra F, Pietrobattista A, Fruhwirth R, Marcellini M, Pinzani M. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 2008; 48:442-8. [PMID: 18563842 DOI: 10.1002/hep.22376] [Citation(s) in RCA: 285] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in chronic liver disease patients. In this study, we assessed the value of TE for the prediction of fibrosis stage in a cohort of pediatric patients with nonalcoholic steatohepatitis. Furthermore, TE interobserver agreement was evaluated. TE was performed in 52 consecutive biopsy-proven nonalcoholic steatohepatitis patients (32 males, 20 females, age 13.6 +/- 2.44 years). The area under the receiver operating characteristic curves for the prediction of "any" (>or=1), significant (>or=2), or advanced fibrosis (>or=3) were 0.977, 0.992, and 1, respectively. Calculation of multilevel likelihood ratios showed that TE values <5, <7, and <9 kPa, suggest the presence of "any" fibrosis, significant fibrosis, and advanced fibrosis, respectively. TE values between 5 and 7 kPa predict a fibrosis stage of 1, but with some degree of uncertainty. TE values between 7 and 9 kPa predict fibrosis stages 1 or 2, but cannot discriminate between these two stages. TE values of at least 9 kPa are associated with the presence of advanced fibrosis. The intraclass correlation coefficient for absolute agreement was 0.961. CONCLUSION TE is an accurate and reproducible methodology to identify pediatric subjects without fibrosis or significant fibrosis, or with advanced fibrosis. In patients in which likelihood ratios are not optimal to provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated.
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Affiliation(s)
- Valerio Nobili
- Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
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Association of raised liver transaminases with physical inactivity, increased waist-hip ratio, and other metabolic morbidities in severely obese children. J Pediatr Gastroenterol Nutr 2008; 47:172-8. [PMID: 18664869 DOI: 10.1097/mpg.0b013e318162a0e5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To identify factors associated with raised alanine transaminase, aspartate transaminase, and gamma-glutaryl transferase in severely obese children PATIENTS AND METHODS In all, 201 children with early-onset obesity and greater than 140% ideal weight for height were recruited. Anthropometric and body fat measurements, fasting blood tests, and oral glucose tolerance tests were performed. RESULTS The mean and standard deviation (SD) for age was 11.1 (3.0) years, for weight for height 170.5% (22.7%), and for percentage body fat was 40.7% (5.2%). Elevated liver transaminases were present in 53 subjects (26.4%), who were therefore at risk for nonalcoholic fatty liver disease, and was associated with male sex (odds ratio [OR] 2.144, 95% confidence interval [CI] 1.033-4.448), Chinese ethnicity (OR 2.062, 95% CI 1.038-4.096), reduced physical activity (OR 2.389, 95% CI 1.163-4.909), insulin resistance (P < 0.05), elevated triglyceride levels (P = 0.029), and increased waist-hip ratio (P = 0.005). Stepwise logistic regression analysis of the main factors as covariates revealed Chinese ethnicity, waist-hip ratio, reduced physical activity, and homeostasis model assessment index were significant predictors. Alanine transaminase/aspartate transaminase were not well correlated with percentage body fat and weight for height. Subjects with type 2 diabetes mellitus and impaired glucose tolerance were more likely to have raised hepatic transaminases (OR 6.176, 95% CI 1.326-28.754). The severity of metabolic syndrome correlated with increasing aspartate transaminase, alanine transaminase, and gamma-glutaryl transferase (P < 0.01). CONCLUSIONS Insulin resistance, truncal adiposity, and physical inactivity are major determinants potentially modifiable to reduce risk of nonalcoholic fatty liver disease. Increasing physical activity levels were associated with decreasing insulin resistance and transaminases, despite lack of correlation with waist-hip ratio, which supports the direct benefit of regular physical activity in preventing nonalcoholic fatty liver disease.
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