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1. Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice

Author

Stavra A. Xanthakos, Joel E. Lavine, Katherine P. Yates, Jeffrey B. Schwimmer, Jean P. Molleston, Philip Rosenthal, Karen F. Murray, Miriam B. Vos, Ajay K. Jain, Ann O. Scheimann, Tamir Miloh, Mark Fishbein, Cynthia A. Behling, Elizabeth M. Brunt, Arun J. Sanyal, James Tonascia, Stephanie Abrams, Donna Garner, Paula Hertel, Ryan Himes, Alicia Lawson, Nicole Triggs, Kristin Bramlage, April Carr, Kim Cecil, Meghan McNeill, Marialena Mouzaki, Andrew Trout, Stavra Xanthakos, Kimberlee Bernstein, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Daniel Podberesky, Alex Towbin, Ali Mencin, Elena Reynoso, Adina Alazraki, Rebecca Cleeton, Maria Cordero, Albert Hernandez, Saul Karpen, Jessica Cruz Munos, Nicholas Raviele, Miriam Vos, Molly Bozic, Laura Carr, Oscar W. Cummings, Kathryn Harlow, Ann Klipsch, Emily Ragozzino, Girish Rao, Kimberly Kafka, Ann Scheimann, Mark H. Fishbein, Joy Ito, Saeed Mohammad, Peter F. Whitington, Sarah Barlow, Danielle Carpenter, Theresa Cattoor, Jose Derdoy, Janet Freebersyser, Ajay Jain, Debra King, Jinping Lai, Joan Siegner, Susan Stewart, Susan Torretta, Kristina Wriston, Jorge Angeles, Jennifer Arin, Cynthia Behling, Craig Bross, Carissa Carrier, Jennifer Collins, Diana De La Pena, Janis Durelle, Mary Catherine Huckaby, Michael S. Middleton, Kimberly Newton, Claude Sirlin, Patricia Ugalde-Nicalo, Jesse Courtier, Ryan Gill, Camille Langlois, Emily Rothbaum Perito, Patrika Tsai, Niviann Blondet, Kara Cooper, Karen Murray, Randolph Otto, Matthew Yeh, Melissa Young, Kathryn Fowler, David E. Kleiner, Edward C. Doo, Sherry Hall, Jay H. Hoofnagle, Patricia R. Robuck, Averell H. Sherker, Rebecca Torrance, Patricia Belt, Jeanne M. Clark, John Dodge, Michele Donithan, Milana Isaacson, Mariana Lazo, Jill Meinert, Laura Miriel, Emily P. Sharkey, Jacqueline Smith, Michael Smith, Alice Sternberg, Mark L. Van Natta, Annette Wagoner, Laura A. Wilson, and Goro Yamada

Subjects
Blood Glucose, Male, 0301 basic medicine, Pediatric Obesity, Time Factors, Cirrhosis, Biopsy, Type 2 diabetes, Chronic liver disease, Severity of Illness Index, Gastroenterology, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Risk Factors, Nonalcoholic fatty liver disease, Medicine, Glucose homeostasis, Prospective Studies, Child, Randomized Controlled Trials as Topic, Fatty liver, Age Factors, Alanine Transaminase, Treatment Outcome, Disease Progression, Female, 030211 gastroenterology & hepatology, medicine.medical_specialty, Adolescent, Risk Assessment, digestive system, Article, 03 medical and health sciences, Internal medicine, Humans, Aspartate Aminotransferases, Healthy Lifestyle, Hepatology, business.industry, nutritional and metabolic diseases, Odds ratio, medicine.disease, digestive system diseases, 030104 developmental biology, Diabetes Mellitus, Type 2, business, Risk Reduction Behavior, Body mass index, Biomarkers
Abstract

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth. METHODS: We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8–17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis. RESULTS: At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH or in fibrosis occurred in 36% of the children, and both occurred in 11% of the children. Any improvement in NASH or fibrosis occurred in 52%, and both occurred in 20% of children. Type 2 diabetes developed in 5% of the cohort. Any progression to NASH and/or fibrosis was associated with adolescent age, higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein-cholesterol at baseline, increasing level of alanine aminotransferase, and hemoglobin A1C (P < .05). Progression to NASH and/or fibrosis were also associated with increasing level of gamma-glutamyl transferase and development of type 2 diabetes (P < .01). Increasing level of gamma-glutamyl transferase also associated with reduced odds of any improvement (P = .003). CONCLUSIONS: One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.

Published
2020

2. Low and High Birth Weights are Risk Factors for Nonalcoholic Fatty Liver Disease in Children

Author

Kimberly P. Newton, Haruna S. Feldman, Christina D. Chambers, Laura Wilson, Cynthia Behling, Jeanne M. Clark, Jean P. Molleston, Naga Chalasani, Arun J. Sanyal, Mark H. Fishbein, Joel E. Lavine, Jeffrey B. Schwimmer, Stephanie H. Abrams, Sarah Barlow, Ryan Himes, Rajesh Krisnamurthy, Leanel Maldonado, Rory Mahabir, April Carr, Kimberlee Bernstein, Kristin Bramlage, Kim Cecil, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Daniel Podberesky, Alex Towbin, Stavra Xanthakos, Daniela Allende, Srinivasan Dasarathy, Arthur J. McCullough, Mangesh Pagadala, Rish Pai, Cha'Ron Winston, Gerald Behr, Jay H. Lefkowitch, Ali Mencin, Elena Reynoso, Manal F. Abdelmalek, Mustafa Bashir, Stephanie Buie, Anna Mae Diehl, Cynthia Guy, Christopher Kigongo, David Malik, Yi-Ping Pan, Dawn Piercy, Mariko Kopping, Tyler Thrasher, Adina Alazraki, Rebecca Cleeton, Maria Cordero, Albert Hernandez, Saul Karpen, Jessica Cruz Munos, Nicholas Raviele, Miriam Vos, Molly Bozic, Oscar W. Cummings, Samer Gawrieh, Ann Klipsch, Emily Ragozzino, Linda Ragozzino, Kumar Sandrasegaran, Girish Subbarao, Raj Vuppalanchi, Laura Walker, Kimberly Kafka, Ann Scheimann, Joy Ito, Saeed Mohammad, Cynthia Rigsby, Lisa Sharda, Peter F. Whitington, Theresa Cattoor, Jose Derdoy, Janet Freebersyser, Ajay Jain, Debra King, Jinping Lai, Pat Osmack, Joan Siegner, Susan Stewart, Brent A. Neuschwander-Tetri, Susan Torretta, Kristina Wriston, Fereshteh Assadian, Vanessa Barone, Maria Cardona Gonzalez, Jodie Davila, Oren Fix, Kelly Anne Hennessey, Kris V. Kowdley, Kacie Lopez, Erik Ness, Michelle Poitevin, Nicholas Procaccini, Brook Quist, Alana Saddic, Cara Wiseman, Matthew Yeh, Susan S. Baker, Diana Lopez-Graham, Sonja Williams, Lixin Zhu, Jonathan Africa, Brandon Ang, Hannah Awai, Archana Bhatt, Craig Bross, Jennifer Collins, Janis Durelle, Kathryn Harlow, Rohit Loomba, Michael Middleton, Kimberly Newton, Melissa Paiz, Claude Sirlin, Patricia Ugalde-Nicalo, Mariana Dominguez Villarreal, Bradley Aouizerat, Nathan M. Bass, Danielle Brandman, Jesse Courtier, Linda D. Ferrell, Natasha Feier, Ryan Gill, Bilal Hameed, Camille Langlois, Jacqueline Maher, Emily Rothbaum Perito, Claudia Ramos, Philip Rosenthal, Norah Terrault, Patrika Tsai, Ashley Ungermann, Pradeep Atla, Brandon Croft, Rebekah Garcia, Sonia Garcia, Muhammad Sheikh, Mandeep Singh, Kara Cooper, Simon Horslen, Evelyn Hsu, Karen Murray, Randolph Otto, Melissa Young, Sherry Boyett, Laura Carucci, Melissa J. Contos, Sherri Kirwin, Kenneth Kraft, Velimir A.C. Luketic, Puneet Puri, Jolene Schlosser, Mohammad S. Siddiqui, Elizabeth M. Brunt, Kathryn Fowler, David E. Kleiner, Sherry Brown, Edward C. Doo, Jay H. Hoofnagle, Patricia R. Robuck, Averell Sherker, Rebecca Torrance, Patricia Belt, Michele Donithan, Erin Hallinan, Milana Isaacson, Kevin P. May, Laura Miriel, Alice Sternberg, James Tonascia, Mark Van Natta, and Katherine Yates

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Databases, Factual, Cross-sectional study, Biopsy, Birth weight, Population, 030209 endocrinology & metabolism, Article, Infant, Postmature, Fetal Development, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Risk Factors, Internal medicine, Nonalcoholic fatty liver disease, Epidemiology, medicine, Birth Weight, Humans, education, Child, education.field_of_study, Obstetrics, business.industry, Infant, Low Birth Weight, medicine.disease, Obesity, United States, Low birth weight, Cross-Sectional Studies, 030104 developmental biology, Endocrinology, Liver, Pediatrics, Perinatology and Child Health, Female, medicine.symptom, business, Body mass index
Abstract

To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD.A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category.Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62).Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.

Published
2017

3. Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin

Author

Kathryn J. Fowler, Nicholas Raviele, Linda D. Ferrell, Maximillian Lee, Debra King, Melissa Paiz, Puneet Puri, Michael Fuchs, Michael S. Middleton, Tarek Hassanein, Edward Doo, Danielle Brandman, Katie Gelinas, Kim M. Cecil, Ryan M. Gill, Katie Amsden, Sherry Boyett, Archana Bhatt, Melissa Young, Mangesh R. Pagadala, Carol Sargeant, Jean P. Molleston, Mark Fishbein, Averell H. Sherker, Deana Rich, Muhammad Y. Sheikh, Kumar Sandrasegaran, Jaividhya Dasarathy, Sarah E. Barlow, Cheryl Shaw, Laura R. Carucci, Randolph K. Otto, Kimberly Pfeifer, James Tonascia, Ann O. Scheimann, Kimberlee Bernstein, Karen F. Murray, Laura A. Wilson, Amy Jones, Carol Hawkins, Evelyn K. Hsu, Laura Miriel, Miriam B. Vos, Joan Siegner, Gerald Behr, Brandon Ang, Stavra A. Xanthakos, Adina Alazraki, Elizabeth M. Brunt, Michael Torbenson, Cynthia Behling, Alexander Ko, Daniel J. Podberesky, Milana Isaacson, Peter F. Whitington, Elizabeth Kirwan, Girish Subbarao, Emily R. Perito, Saeed Mohammad, Ryan Himes, Pat Osmack, Jolene Schlosser, Patrika Tsai, Kenneth A. Kraft, Patricia Ugalde-Nicalo, Ronen Arnon, Melissa J. Contos, Bimalijit Sandhu, Mariel Boyd, Cynthia D. Guy, ünalp-Arida Aynur ünalp-Arida, Elena Reynoso, Pradeep R. Atla, Ajay Jain, Oscar W. Cummings, Shetal N. Shah, Shannon Cooney, Rajesh Krisnamurthy, Srinivasan Dasarathy, Sonia Garcia, Matthew M. Yeh, Rohit Loomba, Rohit Kohli, Ruth Sargent, Patricia Belt, Patricia R. Robuck, Ivana A. Vaughn, Mandeep Singh, Marwan Ghabril, Mohhamad S. Siddiqui, Kimberly Noble, Kara Cooper, Kimberly P. Newton, Kevin P. May, Brent A. Neuschwander-Tetri, Joel E. Lavine, Rish K. Pai, Chia Wang, Stephanie H. Abrams, Velimir A. Luketic, Kris V. Kowdley, Christopher J. N. Kigongo, Arthur J. McCullough, David E. Kleiner, Jay H. Hoofnagle, Katherine P. Yates, Sandra Arroyo, Jeanne M. Clark, Erin Corless, Melanie B. White, Dawn Piercy, Yi Ping Pan, Iliana Doycheva, Camille Langlois, Philip J. Rosenthal, Ann Quinn, James E. Nelson, Ali A. Mencin, Cynthia K. Rigsby, Stephanie Buie, Nadia Ovchinsky, Tracey Pierce, Jose Derdoy, Kathleen Lake, Cynthia Fleming, Mark L. Van Natta, Asma Siddique, Arun J. Sanyal, Janis Durelle, Phirum Nguyen, Anna Mae Diehl, Crystal Slaughter, Mazen Noureddin, Leanel Maldonado, Rebekah Garcia, Nathan M. Bass, Linda Ragozzino, Jody Mooney, Smitha Marri, Claudia Ortiz Zein, Beverly Morris, Bilal Hameed, Claude B. Sirlin, Alice L. Sternberg, Jeffrey B. Schwimmer, Melissa Wagner, David L. Coy, Michele Donithan, Naga Chalasani, Heather Patton, Susan Stewart, Dana Romo, Stephanie DeVore, Manal F. Abdelmalek, Shannon Fleck, Gilman D. Grave, Saul J. Karpen, Aliya Qayyum, Ann Klipsch, Bradley E. Aouizerat, Simon Horslen, Mustafa R. Bashir, Norah A. Terrault, Lacey Siekas, Elizabeth Byam, Sarah Ackermann, Jennifer Collins, Patricia Brandt, Ben Wolford, Raj Vuppalanchi, Rebecca Cleeton, and Cathy Hurtado

Subjects
Adult, Male, Serum, medicine.medical_specialty, Interleukin-1beta, Ferroportin, Article, Body Mass Index, Young Adult, Sex Factors, Hepcidins, Non-alcoholic Fatty Liver Disease, Risk Factors, Hepcidin, Internal medicine, Diabetes mellitus, Nonalcoholic fatty liver disease, medicine, Humans, Obesity, Aged, Aged, 80 and over, Hepatology, biology, Interleukin-6, Transferrin saturation, business.industry, Racial Groups, Gastroenterology, Iron Deficiencies, Iron deficiency, Middle Aged, medicine.disease, Endocrinology, biology.protein, Female, Metabolic syndrome, business, Body mass index, Alaska
Abstract

Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines interleukin (IL) 6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin, and IL6 and IL1β, and other risk factors in patients with nonalcoholic fatty liver disease (NAFLD) with iron deficiency.We collected data on 675 adult subjects (18 years old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, and serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency.One-third of patients (231 of 675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61 ± 45 vs 81 ± 51 ng/mL; P.0001). Iron deficiency was significantly associated with female gender, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, black or American Indian/Alaska Native race (P ≤ .018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal, P ≤ .0001; and 0.45 vs 0.32 for iron normal, P ≤ .005).Iron deficiency is prevalent in patients with NAFLD and associated with female gender, increased body mass index, and nonwhite race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiologic response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

Published
2014

4. Diagnostic Accuracy of Noninvasive Fibrosis Models to Detect Change in Fibrosis Stage

Author

Mohammad Shadab Siddiqui, Goro Yamada, Raj Vuppalanchi, Mark Van Natta, Rohit Loomba, Cynthia Guy, Danielle Brandman, James Tonascia, Naga Chalasani, Brent Neuschwander-Tetri, Arun J. Sanyal, Daniela Allende, Srinivasan Dasarathy, Arthur J. McCullough, Revathi Penumatsa, Jaividhya Dasarathy, Joel E. Lavine, Manal F. Abdelmalek, Mustafa Bashir, Stephanie Buie, Anna Mae Diehl, Christopher Kigongo, Mariko Kopping, David Malik, Dawn Piercy, Oscar W. Cummings, Samer Gawrieh, Linda Ragozzino, Kumar Sandrasegaran, Elizabeth M. Brunt, Theresa Cattoor, Danielle Carpenter, Janet Freebersyser, Debra King, Jinping Lai, Brent A. Neuschwander-Tetri, Joan Siegner, Susan Stewart, Susan Torretta, Kristina Wriston, Maria Cardona Gonzalez, Jodie Davila, Manan Jhaveri, Kris V. Kowdley, Nizar Mukhtar, Erik Ness, Michelle Poitevin, Brook Quist, Sherilynn Soo, Brandon Ang, Cynthia Behling, Archana Bhatt, Michael S. Middleton, Claude Sirlin, Maheen F. Akhter, Nathan M. Bass, Ryan Gill, Bilal Hameed, Jacqueline Maher, Norah Terrault, Ashley Ungermann, Matthew Yeh, Sherry Boyett, Melissa J. Contos, Sherri Kirwin, Velimir A.C. Luketic, Puneet Puri, Jolene Schlosser, Mohammad S. Siddiqui, Leslie Yost-Schomer, Kathryn Fowler, David E. Kleiner, Edward C. Doo, Sherry Hall, Jay H. Hoofnagle, Jessica J. Lee, Patricia R. Robuck, Averell H. Sherker, Rebecca Torrance, Patricia Belt, Jeanne M. Clark, John Dodge, Michele Donithan, Erin Hallinan, Milana Isaacson, Mariana Lazo, Jill Meinert, Laura Miriel, Jacqueline Smith, Michael Smith, Alice Sternberg, Mark L. Van Natta, Annette Wagoner, Laura A. Wilson, and Katherine Yates

Subjects
Adult, Liver Cirrhosis, Male, Longitudinal study, medicine.medical_specialty, Biopsy, Sensitivity and Specificity, Severity of Illness Index, Gastroenterology, Article, Non-alcoholic Fatty Liver Disease, Predictive Value of Tests, Median follow-up, Fibrosis, Internal medicine, Nonalcoholic fatty liver disease, medicine, Humans, Aspartate Aminotransferases, Stage (cooking), Retrospective Studies, Hepatology, medicine.diagnostic_test, Platelet Count, business.industry, Alanine Transaminase, Middle Aged, medicine.disease, Clinical research, Liver, Disease Progression, Female, Hepatic fibrosis, business
Abstract

BACKGROUND & AIMS: Noninvasive methods are needed to determine disease stage in patients with nonalcoholic fatty liver disease (NAFLD). We evaluated the diagnostic performance of several widely available fibrosis models for the assessment of hepatic fibrosis in patients with NAFLD. METHODS: We performed a retrospective analysis of data from individuals enrolled in the NIDDK NASH Clinical Research Network, from 2004 through 2018. Using biopsy as the reference standard, we determined the diagnostic performance of the aspartate aminotransferase (AST):platelet ratio (APRI), FIB-4, ratio of AST:alanine aminotransferase (ALT) and the NAFLD fibrosis score (NFS) in a cross-sectional study of 1904 subjects. The ability of these models to detect changes in fibrosis stage was assessed in a longitudinal data set of 292 subjects with 2 biopsies and accompanying laboratory data. Outcomes were detection of fibrosis of any stage (stages 0 to 4), detection of moderate fibrosis (stages 0–1 vs 2–4), and detection of advanced fibrosis (stages 0–2 vs 3–4). Diagnostic performance was evaluated using the C-statistic, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) analyses. RESULTS: In the cross-sectional study, FIB-4 and NFS outperformed other non-invasive models for detecting advanced fibrosis; the C-statistics were 0.80 for FIB-4 and 0.78 for NFS. In the longitudinal study, 216 patients had non-advanced fibrosis at baseline and 35 patients progressed to advanced fibrosis after median follow up of 2.6 years. After we adjusted for fibrosis stage and model score at initial biopsy, change in APRI, FIB-4, and NFS were significantly associated with change in fibrosis. A unit change in APRI, FIB-4, or NFS was associated with changes in fibrosis stage of 0.33 (95% CI, 0.20-0.45; P

Published
2019

5. In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis

Author

Jonathan A. Africa, Cynthia A. Behling, Elizabeth M. Brunt, Nan Zhang, Yunjun Luo, Alan Wells, Jiayi Hou, Patricia H. Belt, Rohit Kohil, Joel E. Lavine, Jean P. Molleston, Kimberly P. Newton, Peter F. Whitington, Jeffrey B. Schwimmer, Stephanie H. Abrams, Sarah Barlow, Ryan Himes, Rajesh Krisnamurthy, Leanel Maldonado, Rory Mahabir, April Carr, Kimberlee Bernstein, Kristin Bramlage, Kim Cecil, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Daniel Podberesky, Alex Towbin, Stavra Xanthakos, Gerald Behr, Jay H. Lefkowitch, Ali Mencin, Elena Reynoso, Adina Alazraki, Rebecca Cleeton, Maria Cordero, Albert Hernandez, Saul Karpen, Jessica Cruz Munos, Nicholas Raviele, Miriam Vos, Molly Bozic, Oscar W. Cummings, Ann Klipsch, Emily Ragozzino, Kumar Sandrasegaran, Girish Subbarao, Laura Walker, Kimberly Kafka, Ann Scheimann, Joy Ito, Mark H. Fishbein, Saeed Mohammad, Cynthia Rigsby, Lisa Sharda, Theresa Cattoor, Jose Derdoy, Janet Freebersyser, Ajay Jain, Debra King, Jinping Lai, Pat Osmack, Joan Siegner, Susan Stewart, Susan Torretta, Kristina Wriston, Susan S. Baker, Diana Lopez–Graham, Sonja Williams, Lixin Zhu, Jonathan Africa, Hannah Awai, Cynthia Behling, Craig Bross, Jennifer Collins, Janis Durelle, Kathryn Harlow, Michael Middleton, Kimberly Newton, Melissa Paiz, Claude Sirlin, Patricia Ugalde-Nicalo, Mariana Dominguez Villarreal, Bradley Aouizerat, Jesse Courtier, Linda D. Ferrell, Natasha Feier, Ryan Gill, Camille Langlois, Emily Rothbaum Perito, Philip Rosenthal, Patrika Tsai, Kara Cooper, Simon Horslen, Evelyn Hsu, Karen Murray, Randolph Otto, Matthew Yeh, Melissa Young, and Kathryn Fowler

Subjects
0301 basic medicine, Liver Cirrhosis, Male, medicine.medical_specialty, Adolescent, Biopsy, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, Nonalcoholic fatty liver disease, medicine, Humans, Child, Hepatology, business.industry, Histocytochemistry, nutritional and metabolic diseases, Baseline data, medicine.disease, Fibrosis, Response to treatment, Obesity, Hepatitis C, digestive system diseases, Advanced fibrosis, Fatty Liver, 030104 developmental biology, Cross-Sectional Studies, Liver, Disease Progression, 030211 gastroenterology & hepatology, Female, Steatosis, Steatohepatitis, business, Body mass index
Abstract

BACKGROUND & AIMS: Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. METHODS: We performed a cross-sectional study of baseline data from 813 children (age less than 18 years; mean age, 12.8±2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the NASH Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. RESULTS: Zone 1 steatosis was present in 18% of children with NAFLD (n=146) and zone 3 steatosis was present in 32% (n=244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P

Published
2016

6. Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

Author

Kathryn E. Harlow, Jonathan A. Africa, Alan Wells, Patricia H. Belt, Cynthia A. Behling, Ajay K. Jain, Jean P. Molleston, Kimberly P. Newton, Philip Rosenthal, Miriam B. Vos, Stavra A. Xanthakos, Joel E. Lavine, Jeffrey B. Schwimmer, Stephanie H. Abrams, Sarah Barlow, Ryan Himes, Rajesh Krisnamurthy, Leanel Maldonado, Rory Mahabir, April Carr, Kimberlee Bernstein, Kristin Bramlage, Kim Cecil, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Daniel Podberesky, Alex Towbin, Gerald Behr, Jay H. Lefkowitch, Ali Mencin, Elena Reynoso, Adina Alazraki, Rebecca Cleeton, Maria Cordero, Albert Hernandez, Saul Karpen, Jessica Cruz Munos, Nicholas Raviele, Molly Bozic, Oscar W. Cummings, Ann Klipsch, Emily Ragozzino, Kumar Sandrasegaran, Girish Subbarao, Laura Walker, Kimberly Kafka, Ann Scheimann, Joy Ito, Mark H. Fishbein, Saeed Mohammad, Cynthia Rigsby, Lisa Sharda, Peter F. Whitington, Theresa Cattoor, Jose Derdoy, Janet Freebersyser, Debra King, Jinping Lai, Pat Osmack, Joan Siegner, Susan Stewart, Susan Torretta, Kristina Wriston, Susan S. Baker, Diana Lopez-Graham, Sonja Williams, Lixin Zhu, Hannah Awai, Craig Bross, Jennifer Collins, Janis Durelle, Michael Middleton, Melissa Paiz, Claude Sirlin, Patricia Ugalde-Nicalo, Mariana Dominguez Villarreal, Bradley Aouizerat, Jesse Courtier, Linda D. Ferrell, Natasha Feier, Ryan Gill, Camille Langlois, Emily Rothbaum Perito, Patrika Tsai, Kara Cooper, Simon Horslen, Evelyn Hsu, Karen Murray, Randolph Otto, Matthew Yeh, Melissa Young, Elizabeth M. Brunt, Kathryn Fowler, David E. Kleiner, Sherry Brown, Edward C. Doo, Jay H. Hoofnagle, Patricia R. Robuck, Averell Sherker, Rebecca Torrance, Jeanne M. Clark, Michele Donithan, Erin Hallinan, Milana Isaacson, Kevin P. May, Laura Miriel, Alice Sternberg, James Tonascia, Mark Van Natta, Laura Wilson, and Katherine Yates

Subjects
Male, medicine.medical_specialty, Statin, medicine.drug_class, Hypercholesterolemia, Article, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, 030225 pediatrics, Internal medicine, Intervention (counseling), Diabetes mellitus, Nonalcoholic fatty liver disease, Humans, Medicine, Longitudinal Studies, Child, Life Style, Triglycerides, Hypertriglyceridemia, business.industry, Cholesterol, LDL, medicine.disease, Diet, Clinical research, Pediatrics, Perinatology and Child Health, Female, 030211 gastroenterology & hepatology, business, Dietary modifications, Dyslipidemia
Abstract

OBJECTIVE:To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN:This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS:There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS:More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.

Published
2018

7. Estimation of fish and ω-3 fatty acid intake in pediatric nonalcoholic fatty liver disease

Author

Kathryn J. Fowler, Sandra Arroyo, Rajesh Krisnamurthy, Patricia Belt, Leanel Maldonado, Corilee A. Watters, Michael S. Middleton, Jennifer Collins, Elizabeth M. Brunt, Claude B. Sirlin, Debra King, Cynthia K. Rigsby, Ajay Jain, Adina Alazraki, Nicholas Raviele, Laura A. Wilson, Katherine P. Yates, Evelyn K. Hsu, Ryan Himes, Kathleen Lake, Nadia Ovchinsky, Elena Reynoso, Katie Amsden, Simon Horslen, Laura Miriel, Miriam B. Vos, Saul J. Karpen, Girish Subbarao, Ann O. Scheimann, Stavra A. Xanthakos, Joan Siegner, Cynthia Behling, Stephanie H. Abrams, Michael Torbenson, Philip J. Rosenthal, Emily R. Perito, Ann Quinn, Daniel J. Podberesky, Milana Isaacson, Patricia Ugalde-Nicalo, Elizabeth Kirwan, Saeed Mohammad, Mark L. Van Natta, Mariel Boyd, James Tonascia, Ivana A. Vaughn, Jeanne M. Clark, Kevin P. May, Patrika Tsai, Matthew M. Yeh, Janis Durelle, Bradley E. Aouizerat, Joel E. Lavine, Karen F. Murray, Rohit Kohli, Dana Romo, Kara Cooper, Stephanie DeVore, Alice L. Sternberg, Gerald Behr, Jeffrey B. Schwimmer, Shannon Fleck, Linda D. Ferrell, Melissa Paiz, Mark Fishbein, Elizabeth Byam, Kimberlee Bernstein, Peter F. Whitington, Crystal Slaughter, Oscar W. Cummings, Michele Donithan, Kimberly Pfeifer, Randolph K. Otto, Ronen Arnon, Susan Stewart, Erin Corless, Deana Rich, Sarah E. Barlow, Ali A. Mencin, Kimberly P. Newton, Rachel Novotny, Kim M. Cecil, David E. St-Jules, Jose Derdoy, Pat Osmack, Kumar Sandrasegaran, Lynne R. Wilkens, Cynthia Fleming, Camille Langlois, Ryan M. Gill, Melissa Young, Rebecca Cleeton, Beverly Morris, Ann Klipsch, Aynur Unalp-Arida, and Jean P. Molleston

Subjects
Male, medicine.medical_specialty, Pathology, Adolescent, Cross-sectional study, Adolescent Nutritional Physiological Phenomena, Child Behavior, Health Promotion, Gastroenterology, Severity of Illness Index, Article, Nutrition Policy, Non-alcoholic Fatty Liver Disease, Internal medicine, Severity of illness, Nonalcoholic fatty liver disease, Fatty Acids, Omega-3, medicine, Animals, Humans, Child, chemistry.chemical_classification, business.industry, Fatty liver, Fishes, Fatty acid, Anthropometry, medicine.disease, United States, Diet, Fatty Liver, Clinical research, Cross-Sectional Studies, chemistry, Liver, Seafood, Adolescent Behavior, Pediatrics, Perinatology and Child Health, Patient Compliance, Female, Disease Susceptibility, Steatohepatitis, business, Child Nutritional Physiological Phenomena
Abstract

Aims: Fish and v-3 fatty acids are reported to be beneficial in pediatric nonalcoholic fatty liver disease (NAFLD), but no studies have assessed their relation to histological severity. The objectives of this study were to evaluate the dietary intake of fish and v-3 fatty acids in children with biopsy-proven NAFLD, and examine their association with serological and histological indicators of disease. Methods: This was a cross-sectional analysis of 223 children (6–18 years) who participated in the Treatment of Nonalcoholic Fatty Liver Disease in Children trial or the NAFLD Database study conducted by the Nonalcoholic Steatohepatitis Clinical Research Network. The distribution of fish and v-3 fatty acid intake was determined from responses to the Block Brief 2000 Food Frequency Questionnaire, and analyzed for associations with serum alanine aminotransferase, histological features of fatty liver disease, and diagnosis of steatohepatitis after adjusting for demographic, anthropometric, and dietary variables. Results: The minority of subjects consumed the recommended 8 ounces of fish per week (22/223 [10%]) and 200 mg of long-chain v-3 fatty acids per day (12/223 [5%]). Lack of fish and long-chain v-3 fatty acid intake was associated with greater portal (P ¼ 0.03 and P ¼ 0.10, respectively) and lobular inflammation (P ¼ 0.09 and P ¼ 0.004, respectively) after controlling for potential confounders. Conclusions: Fish and v-3 fatty acid intake was insufficient in children with NAFLD, which may increase susceptibility to hepatic inflammation. Patients with pediatric NAFLD should be encouraged to consume the recommended amount of fish per week.

Published
2013

8. Portal Chronic Inflammation in Nonalcoholic Fatty Liver Disease: An Histologic Marker of Advanced NAFLD Clinicopathologic Correlations from the NASH Clinical Research Network

Author

Matthew M. Yeh, Patricia Belt, Linda D. Ferrell, Monique Rosenthal, Wana Kim, Manual Celedon, Kevin Edwards, Yao Chang Liu, Naga Chalasani, Jay E. Everhart, Rosemary Hollick, Nathan M. Bass, Linda Ragozzino, Jody Mooney, Aynur Unalp-Arida, Milana Isaacson, Melissa Smith, Denise Espinosa, Katherine P. Yates, Alison Lyndecker, Kavita Nair, James E. Nelson, Arun J. Sanyal, Aynur Unalp, Joan Siegner, Susana Mendoza, Diane Bringman, Kiran Bambha, Dawn Piercy, Margaret Stager, Melissa J. Contos, Claude B. Sirlin, Grace Gyurkey, Alice L. Sternberg, Ann O. Scheimann, Cynthia Behling, Jeffrey B. Schwimmer, Parvathi Mohan, Cynthia E. Behling, Ryan Colvin, Ann Klipsch, Sarah E. Barlow, Oscar W. Cummings, Ruth Sargent, Lydia Lee, Laura A. Wilson, Amy Jones, Marcia R. Gottfried, Anna Mae Diehl, Laura Miriel, Brent A. Neuschwander-Tetri, Michael Torbenson, David E. Kleiner, Manal F. Abdelmalek, Barbara Calabrese, Mika Green, Michel Donithan, Martin F. Graham, Kris V. Kowdley, Raj Vuppalanchi, Leanel Fairly, Elizabeth M. Brunt, Melissa J. Coffey, Arthur J. McCullough, Joyce Hoffmann, Paul G. Killenberg, Allison Tobin, Jose Derdoy, Melissa Young, Mark L. Van Natta, Janis Durelle, Susan Stewart, Prajakta Bhimalli, Cheryl Saunders, Judy Thompson, Michael Fuchs, Sherry Boyett, Daphne Bryan, Melanie B. White, Karen F. Murray, Srinivasan Dasarathy, Gilman D. Grave, Sarah Roberts, Tarek Hassanein, Edward Doo, Velimir A. Luketic, Jeanne M. Clark, Debra King, Fred Brancati, Alice Stead, Terry T.-K. Huang, Mark Pabst, James Tonascia, Tanya Stein, Laura Wilson, Brent A. Tetri, Bimalijit Sandhu, Danuta Filipowski, Kimberly Selph, Tessa Steel, Chia Wang, Yi Ping Pan, Raphael B. Merriman, Carol Hawkins, Debra Peglow, Nicholette Rogers, Joel E. Lavine, Stephanie H. Abrams, Philip J. Rosenthal, Leonard B. Seeff, Jay H. Hoofnagle, Diana Arceo, Girish Subbarao, Patricia R. Robuck, Carol Sargeant, Cynthia D. Guy, Lisa Clark, Jean P. Molleston, D Kleiner, and Samantha Kwan

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Biopsy, Gastroenterology, digestive system, Article, Sex Factors, Insulin resistance, Internal medicine, Diabetes mellitus, Nonalcoholic fatty liver disease, medicine, Humans, Child, Inflammation, Hepatology, biology, business.industry, Liver Diseases, Fatty liver, Age Factors, nutritional and metabolic diseases, Alanine Transaminase, Middle Aged, medicine.disease, digestive system diseases, Fatty Liver, Phenotype, Liver, Alanine transaminase, Chronic Disease, Disease Progression, biology.protein, Female, Steatohepatitis, Steatosis, business
Abstract

Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally-graded biopsies and temporally-related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with “more than mild” in adults were older age (P < 0.0001), female gender (P = 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P = 0.001), higher homeostasis model assessment of insulin resistance score (HOMA-IR) (P < 0.0001), and medications used for NAFLD (P = 0.0004), diabetes (P < 0.0001), and hypertension (P < 0.0001). “More than mild” in the pediatric biopsies correlated with younger age (P = 0.01), but not with body mass index, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with “more than mild” were steatosis amount (P = 0.01) and location (P < 0.0001), ballooning (P < 0.0001), and advanced fibrosis (P < 0.0001). In the pediatric biopsies, “more than mild” was associated with steatosis location (P = 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). Conclusion: Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease. (HEPATOLOGY 2009.)

Published
2009

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