Factors to Consider in Development of Drugs for Pediatric Nonalcoholic Fatty Liver Disease
2019; Elsevier BV; Volume: 157; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2019.08.048
ISSN1528-0012
AutoresMiriam B. Vos, Lara Dimick‐Santos, Ruby Mehta, Stephanie O. Omokaro, Johannes Taminiau, Elmer Schabel, David E. Kleiner, Peter Szitányi, Piotr Socha, Jeffrey B. Schwimmer, Stephanie Noviello, Debra G. Silberg, Richard Torstenson, Veronica Miller, Joel E. Lavine, Nathalie Adda, William Baldyga, Rajarshi Banerjee, Cynthia Behling, Sherif Boulos, Gary Burgess, Dania Calboli, Edgar D. Charles, Rose Christian, Claude Cohen‐Bacrie, Doina Cosma-Roman, Claus-Peter Danzer, I. Delaet, Mark H. DeLegge, Lara Dimick‐Santos, Nicholas DiProspero, Kathleen Donohue, Laurent Fischer, Emer Fitzpatrick, Michael Fried, David Hagerty, Paula M. Hale, Keri Hildick, Dean W. Hum, Khurram Jamil, Lijuan Jiang, Saul J. Karpen, Matt Kelly, David E. Kleiner, Rohit Kohli, Kattayoun Kordy, Nancy Krieger, Joel E. Lavine, Lois K. Lee, Éric Lefebvre, Patricia López, Erica Lyons, Laura Malahias, S. Megnien, Ruby Mehta, Peter Mesenbrink, Veronica Miller, Pansy Minnick, Christine Murray, Tien Nghiem, Nikki Nicholson, Stephanie Noviello, Stephanie O. Omokaro, Wenjie Pang, Lisa Percival, Dan Peres, Margaret Powell, D.A. De Luis Román, Mark Root, Claire Sampson, Arun J. Sanyal, Elmer Schabel, Kathleen B. Schwarz, Jeffrey B. Schwimmer, Star Seyedkazemi, David E. Shapiro, Reshma Shringarpure, Debra G. Silberg, Edward R. Smith, Piotr Socha, Robert R. Squires, Peter Szitányi, Johannes Taminiau, Richard Torstenson, William R. Treem, Pamela Vig, Miriam B. Vos, Mason Yamashita, Michael B. Zemel,
Tópico(s)Diet, Metabolism, and Disease
ResumoNonalcoholic fatty liver disease (NAFLD) has quickly become the most common chronic liver disease in children in many countries around the world.1Berardis S. Sokal E. Pediatric non-alcoholic fatty liver disease: an increasing public health issue.Eur J Pediatr. 2014; 173: 131-139Crossref PubMed Scopus (93) Google Scholar, 2Anderson E.L. Howe L.D. Jones H.E. et al.The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis.PLoS One. 2015; 10e0140908Crossref PubMed Scopus (460) Google Scholar, 3Wah-Kheong C. Khean-Lee G. Epidemiology of a fast emerging disease in the Asia-Pacific region: non-alcoholic fatty liver disease.Hepatol Int. 2013; 7: 65-71Crossref PubMed Scopus (33) Google Scholar, 4Blachier M. Leleu H. Peck-Radosavljevic M. et al.The burden of liver disease in Europe: a review of available epidemiological data.J Hepatol. 2013; 58: 593-608Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar, 5Bedogni G. Miglioli L. Masutti F. et al.Incidence and natural course of fatty liver in the general population: the Dionysos study.Hepatology. 2007; 46: 1387-1391Crossref PubMed Scopus (183) Google Scholar Estimates in Europe range from 1.3% to 22.5% of children being affected.2Anderson E.L. Howe L.D. Jones H.E. et al.The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis.PLoS One. 2015; 10e0140908Crossref PubMed Scopus (460) Google Scholar,6Navarro-Jarabo J.M. Ubina-Aznar E. Tapia-Ceballos L. et al.Hepatic steatosis and severity-related factors in obese children.J Gastroenterol Hepatol. 2013; 28: 1532-1538Crossref PubMed Scopus (13) Google Scholar, 7Wei C. Ford A. Hunt L. et al.Abnormal liver function in children with metabolic syndrome from a UK-based obesity clinic.Arch Dis Child. 2011; 96: 1003-1007Crossref PubMed Scopus (21) Google Scholar, 8Wiegand S. Keller K.M. Robl M. et al.Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16,390 overweight or obese children and adolescents.Int J Obes (Lond). 2010; 34: 1468-1474Crossref PubMed Scopus (96) Google Scholar, 9Armstrong M.J. Houlihan D.D. Bentham L. et al.Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort.J Hepatol. 2012; 56: 234-240Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar In the United States, 9.6% of all children and 38.0% of obese adolescents are estimated to have NAFLD.10Schwimmer J.B. Deutsch R. Kahen T. et al.Prevalence of fatty liver in children and adolescents.Pediatrics. 2006; 118: 1388-1393Crossref PubMed Scopus (1099) Google Scholar,11Welsh J.A. Karpen S. Vos M.B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010.J Pediatr. 2013; 162: 496-500Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar In China, 45% of obese adolescents are estimated to have NAFLD.12Zhou X. Hou D.Q. Duan J.L. et al.[Prevalence of nonalcoholic fatty liver disease and metabolic abnormalities in 387 obese children and adolescents in Beijing, China].Zhonghua Liu Xing Bing Xue Za Zhi. 2013; 34: 446-450PubMed Google Scholar Certain populations have notable predisposition; for example, in the United States, the highest prevalence is found in Mexican Americans.11Welsh J.A. Karpen S. Vos M.B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010.J Pediatr. 2013; 162: 496-500Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar,13Lazo M. Hernaez R. Eberhardt M.S. et al.Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994.Am J Epidemiol. 2013; 178: 38-45Crossref PubMed Scopus (595) Google Scholar Children have the full range of disease severity from mild steatosis alone to steatohepatitis with fibrosis to end-stage cirrhosis. In both the United States and Europe, fibrosis was observed in approximately 70% of biopsied pediatric NAFLD cases.14Mann J.P. De Vito R. Mosca A. et al.Portal inflammation is independently associated with fibrosis and metabolic syndrome in pediatric nonalcoholic fatty liver disease.Hepatology. 2016; 63: 745-753Crossref PubMed Scopus (48) Google Scholar,15Patton H.M. Lavine J.E. Van Natta M.L. et al.Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis.Gastroenterology. 2008; 135: 1961-1971.e1962Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar Early stage fibrosis (stages 0–1) was observed frequently and advanced fibrosis (stages 2–4) was found in 16%–31% of children with NAFLD who underwent liver biopsy.14Mann J.P. De Vito R. Mosca A. et al.Portal inflammation is independently associated with fibrosis and metabolic syndrome in pediatric nonalcoholic fatty liver disease.Hepatology. 2016; 63: 745-753Crossref PubMed Scopus (48) Google Scholar,15Patton H.M. Lavine J.E. Van Natta M.L. et al.Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis.Gastroenterology. 2008; 135: 1961-1971.e1962Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar This overview is a product of The Liver Forums' Pediatric Working Group (Appendix A), a pediatric focused group within a multistakeholder collaboration of academic, industry, patient, and regulatory experts. Part of the Forum for Collaborative Research, the mission of the Liver Forum is to accelerate drug development for NAFLD by increasing the quality, efficiency, and output of clinical trials. At the time of this writing, there were no approved pharmaceutical treatments for either adult or pediatric NAFLD, resulting in an unmet need for medical treatments. NAFLD is rapidly increasing as an indication for liver transplant, particularly for people <40 years of age.16Alkhouri N. Hanouneh I.A. Zein N.N. et al.Liver transplantation for nonalcoholic steatohepatitis in young patients.Transpl Int. 2016; 29: 418-424Crossref PubMed Scopus (47) Google Scholar Without effective treatments, children with nonalcoholic steatohepatitis (NASH) are at risk of developing cirrhosis16Alkhouri N. Hanouneh I.A. Zein N.N. et al.Liver transplantation for nonalcoholic steatohepatitis in young patients.Transpl Int. 2016; 29: 418-424Crossref PubMed Scopus (47) Google Scholar and liver-related mortality in early adulthood. The overall prevalence of NASH is even higher in patients with associated comorbidities such as type 2 diabetes.17Newton K.P. Hou J. Crimmins N.A. et al.Prevalence of prediabetes and type 2 diabetes in children with nonalcoholic fatty liver disease.JAMA Pediatr. 2016; 170e161971Crossref PubMed Scopus (149) Google Scholar The ethical basis for the US Food and Drug Administration (FDA) required initial pediatric study plan (iPSP)18Pediatric and maternal health product development.www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htmDate accessed: January 28, 2019Google Scholar and the European Medicines Agency (EMA) equivalent pediatric investigation plan (PIP) is that the inclusion of children in research promotes their safety and well-being. When there are approved medications in adults for a disease that occurs in children but no clinical trials to support pediatric dose considerations, efficacy, or safety, physicians often prescribe the medications based on data collected in adults. Such off-label use may ultimately prove harmful in children owing to delays in clinical trial development of appropriate treatments, as well as inappropriate dosing and unknown safety profile of unapproved treatments.19Caldwell P.H. Murphy S.B. Butow P.N. et al.Clinical trials in children.Lancet. 2004; 364: 803-811Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar In the United States, congress has enacted the Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA) that are intended to promote the development of safe and efficacious drugs in children. PREA requires all applications submitted to FDA under section 505 of the Act (21 U.S.C. 355) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment unless the applicant has obtained a waiver or deferral in an iPSP agreed-upon by FDA's Pediatric Review Committee. PREA applies to drugs or biological products developed for diseases that occur in both adults and children. Products intended for pediatric-specific indications are subject to the PREA requirement only if they are initially developed for a subset of the relevant pediatric population. PREA does not apply to drugs that have been granted orphan designation for a particular indication. Under the FDA Safety and Innovation Act, signed into law on July 9, 2012, PREA includes a provision that requires manufacturers of drugs subject to PREA to submit an iPSP early in the drug development process. The intent of the iPSP is to identify needed pediatric studies early in drug development and begin planning for these studies. Sponsors must submit their iPSP before submission of the required pediatric assessments and no later than 60 calendar days after the date of the end-of-phase II meeting.20Guidance for IndustryPediatric study plans: content of and process for submitting initial pediatric study plans and amended pediatric study plans.www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm360507.pdfDate accessed: January 28, 2019Google Scholar The BPCA was enacted on January 4, 2002. The BPCA21Best Pharmaceuticals for Children Act and Pediatric Research Equity Act.www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm509707.htmDate accessed: January 28, 2019Google Scholar reauthorized and amended the pediatric exclusivity incentive program by granting an additional 6 months of marketing exclusivity and creating funding mechanisms for pediatric studies that had not been conducted voluntarily under previously approved new drug applications. In Europe, there are also regulatory requirements for promoting safe and efficacious drug development in children. In 2006, the European Commission passed the Pediatric Regulation No 1901/2006 that was later amended to 1902/2006 and required pediatric studies for drug development.22Kishore R. Tabor E. EU regulations for clinical studies in pediatric patients.Regulatory Focus. 2010; 15: 39-44Google Scholar The European Pediatric Regulation requires that pharmaceutical companies submit a PIP for all new products and any line extensions for existing products. Typically, the PIP provides the design and the timelines for the studies.22Kishore R. Tabor E. EU regulations for clinical studies in pediatric patients.Regulatory Focus. 2010; 15: 39-44Google Scholar The PIP is submitted to the Pediatric Committee, an expert committee of the EMA that reviews PIPs, waivers, and deferrals of pediatric studies. Once the PIP is agreed upon by the Pediatric Committee, it is binding and issued by the EMA. The PIPs are intended to cover all children from birth to 18 years of age; however, a waiver from the requirement for certain age groups can be granted when the product is likely to be ineffective or if the disease does not occur in pediatric patients in an age group.22Kishore R. Tabor E. EU regulations for clinical studies in pediatric patients.Regulatory Focus. 2010; 15: 39-44Google Scholar Similar to iPSPs, PIPs are intended to identify the need for pediatric studies early in the development process and increase availability of safe and effective medications for children. Although the scope and procedures for the regulations in the United States and Europe differ, the agencies collaborate to be able to share results from pediatric development and limit repetition of studies in children. Most ethical guidelines for research posit that children are a vulnerable population, with a higher benefit–risk burden than adults. Although pediatric plans for NAFLD therapeutics are required, there are also additional safeguards required for children by both the FDA and EMA. For children, studies with greater than minimal risk may be approved when there is the prospect of direct benefit to the individual subjects (Department of Health and Human Services, FDA, 21 CFR Sec 50.52). If there is greater than minimal risk but no prospect of direct benefit to the subjects, a study may be ethical for children only if the risk represents only a minor increase over minimal risk, or the risk is from an intervention or procedure that is commensurate with those inherent to their disease/situation, or the intervention or procedure is likely to yield generalizable knowledge about the disease that is vital for the understanding or amelioration of the disease. These regulations are in place to protect children while balancing the need for studies to advance effective therapeutics for children's diseases. Risk factor identification in disease progression (especially fibrosis progression) is important because NAFLD (in both adults and children) has a wide phenotypic range at presentation and variable progression. Long-term nationally representative data in US adults having severe hepatic steatosis as well as elevated alanine aminotransferase (ALT), aspartate aminotransferase or gamma-glutamyl transferase were associated with increased liver disease mortality.23Unalp-Arida A. Ruhl C.E. Non-invasive fatty liver markers predict liver disease mortality in the United States population.Hepatology. 2016; 63: 1170-1183Crossref PubMed Scopus (62) Google Scholar In adults, type 2 diabetes and cardiovascular disease are also frequent adverse clinical outcomes associated with NAFLD24Targher G. Nonalcholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens.Diabet Med. 2007; 24: 1-6Crossref PubMed Scopus (201) Google Scholar and there are few data suggesting that increased incidence of type 2 diabetes is the most rapid adverse clinical outcome17Newton K.P. Hou J. Crimmins N.A. et al.Prevalence of prediabetes and type 2 diabetes in children with nonalcoholic fatty liver disease.JAMA Pediatr. 2016; 170e161971Crossref PubMed Scopus (149) Google Scholar,25Cioffi C.E. Welsh J.A. Cleeton R.L. et al.Natural history of NAFLD diagnosed in childhood: a single-center study.Children (Basel, Switzerland). 2017; 4PubMed Google Scholar in children. One of the most challenging knowledge gaps is the lack of longer term natural history information, which complicates benefit–risk determinations in the development of therapeutics for pediatric NAFLD. Available shorter term data from the Treatment of NAFLD in Children (TONIC)26Lavine J.E. Schwimmer J.B. Van Natta M.L. et al.Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.JAMA. 2011; 305: 1659-1668Crossref PubMed Scopus (789) Google Scholar trial showed that approximately 60% of children maintained or progressed in hepatic fibrosis stage over 24 months in all treatment groups, including placebo. In a small clinical cohort, 39% of children (7/18) had progression of fibrosis after an average of 28 months.27A-Kader H. Henderson J. Vanhoesen K. et al.Nonalcoholic fatty liver disease in children: a single center experience.Clin Gastroenterol Hepatol. 2008; 6: 799-802Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar There are 2 longer term studies. Sixty-six children with NAFLD (mean age, 13.9 ± 3.9 years) were followed for ≤20 years. Five underwent repeat liver biopsies showing progression of fibrosis in 4 of the children. Two children died and 2 underwent liver transplantation.28Feldstein A.E. Charatcharoenwitthaya P. Treeprasertsuk S. et al.The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.Gut. 2009; 58: 1538-1544Crossref PubMed Scopus (528) Google Scholar In another retrospective study of 44 patients diagnosed with NAFLD as children, development of type 2 diabetes was the most frequent adverse clinical outcome, occurring in 30%.25Cioffi C.E. Welsh J.A. Cleeton R.L. et al.Natural history of NAFLD diagnosed in childhood: a single-center study.Children (Basel, Switzerland). 2017; 4PubMed Google Scholar Further long-term longitudinal cohort studies are needed to assess 5-year, 10-year, and longer outcomes in pediatric patients with NAFLD and NASH and to identify risk factors for progression to associated comorbidities such as type 2 diabetes, cardiovascular disease, cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Similar to adults, NAFLD in children has a wide range of histologic phenotypes. In 2005, Schwimmer et al published the first description of a particular subset of pediatric histology in NAFLD and described it as a periportal pediatric pattern rarely found in adults.29Schwimmer J.B. Behling C. Newbury R. et al.Histopathology of pediatric nonalcoholic fatty liver disease.Hepatology. 2005; 42: 641-649Crossref PubMed Scopus (598) Google Scholar In adults, the pattern of injury is typically centered in zone 3, with the combination of steatosis, parenchymal inflammation, ballooning and perisinusoidal fibrosis. A zone 1 pattern (often called the pediatric pattern) is more prevalent in children <12 years of age, whereas teenagers are more likely to have patterns similar to adults.30Africa J.A. Behling C.A. Brunt E.M. et al.In children with nonalcoholic fatty liver disease, zone 1 steatosis is associated with advanced fibrosis.Clin Gastroenterol Hepatol. 2018; 16: 438-446 e431Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Because of the absence of classical ballooning hepatocytes in the pediatric pattern, pediatric biopsies often do not fulfill the classical criteria for adult NASH and are characterized as borderline NASH zone 1. Although the natural history of the pediatric pattern is not yet understood, it does not appear to be less severe. In the literature, there is some overlapping use of the terminology regarding phenotypes and histopathologic descriptions; these definitions are listed in Table 1.Table 1Histologic Phenotypes of NAFLDPhenotypesDefinitionsNAFLDInclusive term referring to the full spectrum of diseaseIndicates fatty infiltration of the liver in the absence of significant alcohol, genetic diseases or medications that cause steatosisFatty infiltration is typically defined as fat ≥5% of the liverNAFLSteatosis without specific changes to suggest steatohepatitisNASHHepatic steatosis with inflammation, with or without fibrosis, further subdivided as:Zone 3 centered injury pattern or confluent pattern with hepatocyte ballooning injury. Also called type 1.Zone 1 (portal) centered injury pattern with periportal to panacinar steatosis, portal inflammation, with or without hepatocyte ballooning injury. Also called type 2.Pediatric NASH – umbrella category that includes zone 3 NASH, zone 1 NASH and borderline NASH found in a child (age ≤17 years)NAFLD with fibrosisNAFL or NASH with periportal, portal or sinusoidal fibrosisNAFLD with cirrhosisNAFL or NASH with bridging fibrosis with architectural distortion and nodule formationCryptogenic CirrhosisBridging fibrosis with architectural distortion and nodule formation in the setting of obesity and the absence of any other identified liver diseaseNAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. Open table in a new tab NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. The clinical phenotypes of NAFLD in children remain not well-defined. This area requires additional research, including an exploration of whether future clinical adverse outcomes can be predicted by pediatric histologic phenotypes. Studies in pediatric NAFLD have ranged from small pilot studies to large, randomized and controlled clinical trials.26Lavine J.E. Schwimmer J.B. Van Natta M.L. et al.Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.JAMA. 2011; 305: 1659-1668Crossref PubMed Scopus (789) Google Scholar,31Lavine J. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study.J Pediatr. 2000; 136: 734-738Abstract Full Text PDF PubMed Scopus (521) Google Scholar, 32Schwimmer J.B. Middleton M.S. Deutsch R. Lavine J.E. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis.Aliment Pharmacol Ther. 2005; 21: 871-879Crossref PubMed Scopus (216) Google Scholar, 33Jin R. Welsh J.A. Le N.A. et al.Dietary fructose reduction improves markers of cardiovascular disease risk in Hispanic-American adolescents with NAFLD.Nutrients. 2014; 6: 3187-3201Crossref PubMed Scopus (86) Google Scholar, 34Nobili V. Manco M. Devito R. et al.Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2006; 24: 1553-1561Crossref PubMed Scopus (134) Google Scholar Although the outcomes and endpoints used in these studies varied, many of the early phase trials focused on rapidly changing and easily measured biomarkers such as serum ALT. To facilitate assessment of histologic disease severity, a NAFLD Activity Score (NAS) was developed by the NASH Clinical Research Network and is now commonly used for evaluating the treatment response through assessment of histological change over time in NAFLD clinical trials,35Kleiner D.E. Brunt E.M. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research.Semin Liver Dis. 2012; 32: 3-13Crossref PubMed Scopus (278) Google Scholar,36Kleiner D.E. Brunt E.M. Van Natta M. et al.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321Crossref PubMed Scopus (7113) Google Scholar including pediatric studies.26Lavine J.E. Schwimmer J.B. Van Natta M.L. et al.Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.JAMA. 2011; 305: 1659-1668Crossref PubMed Scopus (789) Google Scholar,37Lavine J. Schwimmer J. Clinical Research Network launches TONIC trial for treatment of nonalcoholic fatty liver disease in children.J Pediatr Gastroenterol Nutr. 2006; 42: 129-130Crossref PubMed Scopus (24) Google Scholar In NAS, 3 components are scored (steatosis 0–3, lobular inflammation 0–3, and hepatocyte ballooning 0–2) for a possible total score of 8. In children, hepatocyte ballooning is less common, particularly in younger children and early teenagers. In younger children, the portal pattern of inflammation predominates and lobular inflammation scores are lower compared with adult studies. For example, in the FLINT cohort study.38Neuschwander-Tetri B.A. Loomba R. Sanyal A.J. et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Abstract Full Text Full Text PDF PubMed Scopus (1515) Google Scholar the mean for lobular inflammation in adults is 1.8, compared with 1.6 in the pediatric TONIC26Lavine J.E. Schwimmer J.B. Van Natta M.L. et al.Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.JAMA. 2011; 305: 1659-1668Crossref PubMed Scopus (789) Google Scholar,38Neuschwander-Tetri B.A. Loomba R. Sanyal A.J. et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Abstract Full Text Full Text PDF PubMed Scopus (1515) Google Scholar trial, although the eligibility criteria were different. Further, in these trials, hepatocyte ballooning in adults was 1.3 ± 0.7 and in the pediatric cohort 0.6 ± 0.8. A frequently used primary outcome for early phase clinical trials in NAFLD is a reduction of NAS score of ≥2 with no worsening of fibrosis.39Sanyal A.J. Brunt E.M. Kleiner D.E. et al.Endpoints and clinical trial design for nonalcoholic steatohepatitis.Hepatology. 2011; 54: 344-353Crossref PubMed Scopus (514) Google Scholar,40Loomba R. Wesley R. Pucino F. et al.Placebo in nonalcoholic steatohepatitis: insight into natural history and implications for future clinical trials.Clin Gastroenterol Hepatol. 2008; 6: 1243-1248Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar In the adult FLINT trial, the mean NAS of the participants, who were required to have NASH for inclusion, was 5.1 at baseline, compared with 4.6 in children in TONIC. In Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children (CyNCh), the mean NAS was 4.7.41Schwimmer J.B. Lavine J.E. Wilson L.A. et al.In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores.Gastroenterology. 2016; 151: 1141-1154 e1149Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar For CyNCh, having a NAS of ≥4 was an inclusion criterion and the primary outcome was a decrease in NAS of ≥2 with no worsening of fibrosis.41Schwimmer J.B. Lavine J.E. Wilson L.A. et al.In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores.Gastroenterology. 2016; 151: 1141-1154 e1149Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar The somewhat lower baseline severity and lower frequency of ballooning in children could make a NAS change of ≥2 difficult to achieve in pediatric trials. For example, if a child's histology has no ballooning (which is a common occurrence), a 2-point improvement in NAS can only be achieved through a decrease in either steatosis or lobular inflammation or by a 1-point change in both. Given that not all drugs have mechanisms of action that impact steatosis (reduction of liver fat is thought to be less likely to predict clinical outcomes42Singh S. Allen A.M. Wang Z. et al.Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.Clin Gastroenterol Hepatol. 2015; 13 (e641-649; quiz e639-640): 643-654Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar), the 2-point improvement in NAS would need to be achieved in the lobular inflammation category. This change is unlikely in children who have a portal predominant inflammation pattern and minimal lobular inflammation. Hence, further research is needed to determine the utility of NAS in pediatric trials and to test the relationship of "change in NAS" to long-term clinical outcomes. In TONIC, although the primary endpoint of a change in ALT was not met, an improvement of NAS by ≥2 points without worsening of fibrosis was achieved in the vitamin E treatment arm compared with placebo (P = .02).26Lavine J.E. Schwimmer J.B. Van Natta M.L. et al.Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.JAMA. 2011; 305: 1659-1668Crossref PubMed Scopus (789) Google Scholar At this time, neither the United States nor the EU accepts change in NAS alone as an endpoint for trials to support a marketing/registration application for NASH. There are many different endpoints recommended for early phase proof-of-concept and dose-ranging trials that should be primarily based on the drug mechanism of action and target population. The diagnosis of NAFLD is a clinical determination based on exclusion of other chronic liver diseases and confirming the presence of steatosis. At a minimum, the diagnosis of NAFLD requires ruling out chronic alcohol use, medications known to cause steatosis, other chronic conditions causing fat deposition (uncontrolled diabetes, autoimmune hepatitis, starvation, celiac disease), metabolic diseases (cystic fibrosis, mitochondrial diseases, lysosomal disorders, Wilson's disease, alpha-1 antitrypsin deficiency), hepatitis C, and documenting the presence of steatosis in the liver.43Vos M.B. Abrams S.H. Barlow S.E. et al.NASPGHAN clinical practice guideline for the diagnosis and treatment of nonalcoholic fatty liver disease in children: recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN).J Pediatr Gastroenterol Nutr. 2017; 64: 319-334Crossref PubMed Scopus (438) Google Scholar The diagnosis of NASH requires ruling out these diseases and a histopathologic confirmation of steatohepatitis. Noninvasive modalities may be used to assess NAFLD, but most imaging modalities, such as ultrasound examination or magnetic resonance elastography, although cleared by the FDA, are not approved for the diagnosis or staging of specific disease indications. A combination of noninvasive imaging methods along with biochemical and clinical assessments are often used in clinical practice as well as early phase clinical trials to establish a probable or likely diagnosis of NAFLD/NASH. However, at this time, noninvasive imaging methods to assess inflammation remain in the early phases of development. Histopathology remains the current reference standard for NAFLD and is used as a surrogate endpoint for clinical trials in NASH along with clinical benefit endpoints (ie, improvements in mortality, transplant, and decompensation rates). Liver biopsy is generally con
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