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1. Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

Author

Baumert, Brittney, Fischer, Fabian, Nielsen, Flemming, Grandjean, Philippe, Bartell, Scott, Stratakis, Nikos, Walker, Douglas, Valvi, Damaskini, Kohli, Rohit, Inge, Thomas, Ryder, Justin, Jenkins, Todd, Sisley, Stephanie, Xanthakos, Stavra, Rock, Sarah, Conti, David, McConnell, Rob, Chatzi, Lida, and La Merrill, Michele

Subjects
PFAS, biopsy samples, correlation, human exposure, liver accumulation, toxicokinetics, Animals, Humans, Adolescent, Alkanesulfonic Acids, Cohort Studies, Liver, Fluorocarbons, Bariatric Surgery, Environmental Pollutants
Abstract

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Published
2023

4. Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children

Author

Li, Yijie, Baumert, Brittney O., Stratakis, Nikos, Goodrich, Jesse A., Wu, Haotian, Liu, Shelley H., Wang, Hongxu, Beglarian, Emily, Bartell, Scott M., Eckel, Sandrah Proctor, Walker, Douglas, Valvi, Damaskini, La Merrill, Michele Andrea, Inge, Thomas H., Jenkins, Todd, Ryder, Justin R., Sisley, Stephanie, Kohli, Rohit, Xanthakos, Stavra A., Vafeiadi, Marina, Margetaki, Aikaterini, Roumeliotaki, Theano, Aung, Max, McConnell, Rob, Baccarelli, Andrea, Conti, David, and Chatzi, Lida

Published
2024
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5. Changes in plasma concentrations of per- and Polyfluoroalkyl substances after bariatric surgery in adolescents from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study

Author

Baumert, Brittney O., Eckel, Sandrah P., Goodrich, Jesse A., Li, Zhenjiang, Stratakis, Nikos, Walker, Douglas I., Zhao, Yinqi, Fischer, Fabian Christoph, Bartell, Scott, Valvi, Damaskini, Lin, Xiangping, Fuentes, Zoe Coates, Inge, Thomas, Ryder, Justin, Jenkins, Todd, Kohli, Rohit, Sisley, Stephanie, Xanthakos, Stavra, Rock, Sarah, La Merrill, Michele A., McConnell, Rob, Conti, David V., and Chatzi, Lida

Published
2024
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6. Exposure to per- and Polyfluoroalkyl Substances and Markers of Liver Injury: A Systematic Review and Meta-Analysis

Author

Costello, Elizabeth, Rock, Sarah, Stratakis, Nikos, Eckel, Sandrah P, Walker, Douglas I, Valvi, Damaskini, Cserbik, Dora, Jenkins, Todd, Xanthakos, Stavra A, Kohli, Rohit, Sisley, Stephanie, Vasiliou, Vasilis, La Merrill, Michele A, Rosen, Hugo, Conti, David V, McConnell, Rob, and Chatzi, Leda

Subjects
Digestive Diseases, Chronic Liver Disease and Cirrhosis, Liver Disease, Oral and gastrointestinal, Biomarkers, Environmental Pollutants, Fluorocarbons, Humans, Non-alcoholic Fatty Liver Disease, United States, Environmental Sciences, Medical and Health Sciences, Toxicology
Abstract

BackgroundExperimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry and consumer products and bioaccumulate in food webs and human tissues, such as the liver.ObjectiveThe objective of this study was to conduct a systematic review of the literature and meta-analysis evaluating PFAS exposure and evidence of liver injury from rodent and epidemiological studies.MethodsPubMed and Embase were searched for all studies from earliest available indexing year through 1 December 2021 using keywords corresponding to PFAS exposure and liver injury. For data synthesis, results were limited to studies in humans and rodents assessing the following indicators of liver injury: serum alanine aminotransferase (ALT), nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or steatosis. For human studies, at least three observational studies per PFAS were used to conduct a weighted z-score meta-analysis to determine the direction and significance of associations. For rodent studies, data were synthesized to qualitatively summarize the direction and significance of effect.ResultsOur search yielded 85 rodent studies and 24 epidemiological studies, primarily of people from the United States. Studies focused primarily on legacy PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid. Meta-analyses of human studies revealed that higher ALT levels were associated with exposure to PFOA (z-score= 6.20, p

Published
2022

11. Longitudinal Outcomes in Young Patients with Alpha-1-Antitrypsin Deficiency with Native Liver Reveal that Neonatal Cholestasis is a Poor Predictor of Future Portal Hypertension

Author

Teckman, Jeffrey, Rosenthal, Philip, Hawthorne, Kieran, Spino, Cathie, Bass, Lee M, Murray, Karen F, Kerkar, Nanda, Magee, John C, Karpen, Saul, Heubi, James E, Molleston, Jean P, Squires, Robert H, Kamath, Binita M, Guthery, Stephen L, Loomes, Kathleen M, Sherker, Averell H, Sokol, Ronald J, ChiLDReN, Alonso, Estella, Bass, Lee, Kelly, Susan, Riordan, Mary, Melin-Aldana, Hector, Bezerra, Jorge, Bove, Kevin, Heubi, James, Miethke, Alexander, Tiao, Greg, Denlinger, Julie, Chapman, Erin, Sokol, Ronald, Feldman, Amy, Mack, Cara, Narkewicz, Michael, Suchy, Frederick, Sundaram, Shikha, Van Hove, Johan, Garcia, Benigno, Kauma, Mikaela, Kocher, Kendra, Steinbeiss, Matthew, Lovell, Mark, Loomes, Kathleen, Piccoli, David, Rand, Elizabeth, Russo, Pierre, Spinner, Nancy, Erlichman, Jessi, Stalford, Samantha, Pakstis, Dina, King, Sakya, Squires, Robert, Sindhi, Rakesh, Venkat, Veena, Bukauskas, Kathy, McKiernan, Patrick, Haberstroh, Lori, Squires, James, Bull, Laura, Curry, Joanna, Langlois, Camille, Kim, Grace, Teckman, Jeffery, Kociela, Vikki, Nagy, Rosemary, Patel, Shraddha, Cerkoski, Jacqueline, Bozic, Molly, Subbarao, Girish, Klipsch, Ann, Sawyers, Cindy, Cummings, Oscar, Horslen, Simon, Murray, Karen, Hsu, Evelyn, Cooper, Kara, Young, Melissa, Finn, Laura, Kamath, Binita, Ng, Vicky, Quammie, Claudia, Putra, Juan, Sharma, Deepika, Parmar, Aishwarya, Guthery, Stephen, Jensen, Kyle, Rutherford, Ann, Lowichik, Amy, Book, Linda, Meyers, Rebecka, Hall, Tyler, Wang, Kasper, Michail, Sonia, Thomas, Danny, Goodhue, Catherine, Kohli, Rohit, Wang, Larry, and Soufi, Nisreen

Subjects
Paediatrics, Biomedical and Clinical Sciences, Digestive Diseases, Liver Disease, Pediatric, Hypertension, Clinical Research, Rare Diseases, Transplantation, Chronic Liver Disease and Cirrhosis, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Good Health and Well Being, Adolescent, Adult, Child, Child, Preschool, Cholestasis, Intrahepatic, Disease Progression, Female, Humans, Hypertension, Portal, Infant, Infant, Newborn, Liver Transplantation, Longitudinal Studies, Male, Young Adult, alpha 1-Antitrypsin Deficiency, ChiLDReN, cirrhosis, jaundice, liver enzymes, liver transplant, metabolic liver disease, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics
Abstract

ObjectivesTo identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere.Study designThe Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected.ResultsWe enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score.ConclusionsPortal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Published
2020

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

Author

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

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Obesity, Clinical Trials and Supportive Activities, Clinical Research, Digestive Diseases, Liver Disease, Chronic Liver Disease and Cirrhosis, Pediatric, Diabetes, Hepatitis, Oral and gastrointestinal, Adolescent, Age Factors, Alanine Transaminase, Aspartate Aminotransferases, Biomarkers, Biopsy, Blood Glucose, Child, Diabetes Mellitus, Type 2, Disease Progression, Female, Healthy Lifestyle, Humans, Male, Non-alcoholic Fatty Liver Disease, Pediatric Obesity, Prospective Studies, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Risk Reduction Behavior, Severity of Illness Index, Time Factors, Treatment Outcome, ALT, Cirrhosis, Histology, Natural History, NASH Clinical Research Network, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsNonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth.MethodsWe 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.ResultsAt 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 and/or in fibrosis was associated with adolescent age, and higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein cholesterol at baseline (

Published
2020

14. International Liver Transplantation Society Global Census: First Look at Pediatric Liver Transplantation Activity Around the World

Author

Rodriguez-Davalos, Manuel I., Lopez-Verdugo, Fidel, Kasahara, Mureo, Muiesan, Paolo, Reddy, Mettu S., Flores-Huidobro Martinez, Angel, Xia, Qiang, Hong, Johnny C., Niemann, Claus U., Seda-Neto, Joao, Miloh, Tamir A., Yi, Nam-Joon, Mazariegos, George V., Ng, Vicky L., Esquivel, Carlos O., Lerut, Jan, Rela, Mohamed, Botha, Jean, Mehta, Naimish N., Bakar Hafeez Bhatti, Abu, Zamora-Valdes, Daniel, Anand, Superina, Riccardo, de Kleine, Ruben, Matamoros, Maria A., Bedregal-Mendoza, Tayana, Steve Bynon, J., Rodriguez-Sancho, Luis C., Langnas, Alan, Dhawan, Anil, Ogura, Yasuhiro, Vianna, Rodrigo, Ilyassova, Bibigul, Tantemsapya, Niramol, Bellemare, Sarah, Ovchinsky, Nadia, Bhalerao, Suryabhan, Balci, Deniz, Dip, Marcelo, Imventarza, Oscar, Mangus, Richard S., Fawcett, Jonathan, Antonini, Teresa M., Shrimal, Anurag, Zhu, Zhi-Jun, Rivera, Jairo, Dayangac, Murat, McCall, John, Utz Melere, Melina, Stormon, Michael, Mizuta, Koichi, Gao, Wei, Hening Rahayatri, Tri, Costaguta, Alejandro, Gautier, Sergei, Kazemi, Kourosh, Martinez-Castillo, Jorge, Apinyachon, Worapot, Rastogi, Mukul, Restrepo, Juan C., Takahito, Yagi, Ravichandra, Srinivasa, Vanin, Anabel, Vieira, Sandra, Luque, Carlos, Gondolesi, Gabriel, Hashimoto, Koji, Yazigi, Nada, Lebel, Sylvie, Mavis, Alisha, Arnon, Ronen, Chavez-Vargas, Ricardo, Elisofon, Scott, Desai, Dev M., Okajima, Hideaki, Chinnakotla, Srinath, Hsu, Evelyn, Reyes, Jorge, Orgoi, Sergelen, Raut, Vikram, Hee Oh, Seak, Valentino, Pamela, Emre, Sukru, Spada, Marco, Leung, Dan, Charco, Ramon, Ericzon, Bo-Goran, Fischer, Ryan, Del Rio-Martin, Juan V., Cillo, Umberto, Soliman, Hossam, Varela-Fascinetto, Gustavo, de Villa, Vanessa, Haberal, Mehmet, Covarrubias, Joshue, Colledan, Michele, de Ville de Goyet, Jean, Desai, Chirag, Sundaram, Shikha, Fronek, Jiri, Nadig, Satish N., Mali, Vidyadhar P., Tandoi, Francesco, Kohli, Rohit, Mohan, Neelam, Goyal, Neerav, Santhosh, Drisya, Debray, Dominique, Durmaz, Ozlem, De Bruyne, Ruth, Kaliciński, Piotr, Hierro, Loreto, Venick, Robert, Perito, Emily, Mozer-Glassberg, Yael, Chen, Chao-Long, Rand, Elizabeth, Nikeghbalian, Saman, Kelly, Deirdre, Boillot, Olivier, and Book, Linda S.

Published
2023
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19. Associations of dietary sugars with liver stiffness in Latino adolescents with obesity differ on PNPLA3 and liver disease severity.

Author

Schenker, Rachel B., Machle, Christopher J., Schmidt, Kelsey A., Allayee, Hooman, Kohli, Rohit, and Goran, Michael I.

Subjects
ADOLESCENT obesity, LIVER diseases, DIETARY carbohydrates, SUGARS, LIVER
Abstract

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most common paediatric liver disease. Latinos have high MASLD risk due to 50% prevalence of GG genotype of PNPLA3. Our primary aim was to evaluate associations between dietary carbohydrates/sugars and liver stiffness in Latino adolescents with obesity. Our secondary aim was to examine effect modification by (a) PNPLA3 genotype or (b) liver disease severity. Data were obtained from 114 Latino adolescents with obesity involved in two prior studies. No associations were seen between dietary carbohydrates/sugars and liver stiffness in the group as a whole. In subjects with GG genotype of PNPLA3, total sugar, fructose, sucrose, and glucose were associated with liver stiffness. Positive relationships between carbohydrate, total sugar, and sucrose and liver stiffness were stronger in those with MASLD and fibrosis compared to those with healthy livers and MASLD without fibrosis. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

Author

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

Subjects
Paediatrics, Biomedical and Clinical Sciences, Pediatric, Chronic Liver Disease and Cirrhosis, Cardiovascular, Health Disparities, Obesity, Minority Health, Prevention, Liver Disease, Digestive Diseases, Nutrition, 2.4 Surveillance and distribution, Metabolic and endocrine, Good Health and Well Being, Child, Cholesterol, LDL, Diet, Female, Humans, Hypercholesterolemia, Hypertriglyceridemia, Life Style, Longitudinal Studies, Male, Non-alcoholic Fatty Liver Disease, Triglycerides, Nonalcoholic Steatohepatitis Clinical Research Network, NAFLD, cardiovascular, diet, dyslipidemia, pediatric, statin, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics
Abstract

ObjectiveTo 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 designThis 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.ResultsThere 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.ConclusionsMore 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

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

Author

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

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Digestive Diseases, Hepatitis, Liver Disease, Chronic Liver Disease and Cirrhosis, Clinical Research, Good Health and Well Being, Adolescent, Biopsy, Child, Cross-Sectional Studies, Fatty Liver, Female, Hepatitis C, Histocytochemistry, Humans, Liver Cirrhosis, Male, Non-alcoholic Fatty Liver Disease, NASH, Disease Progression, Obesity, Nonalcoholic Steatohepatitis Clinical Research Network, Gastroenterology & Hepatology, Clinical sciences
Abstract

Background & aimsFocal 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.MethodsWe performed a cross-sectional study of baseline data from 813 children (age

Published
2018

22. Non-invasive biomarkers of Fontan-associated liver disease

Author

Emamaullee, Juliet, Khan, Sara, Weaver, Carly, Goldbeck, Cameron, Yanni, George, Kohli, Rohit, Genyk, Yuri, Zhou, Shengmei, Shillingford, Nick, Sullivan, Patrick M., Takao, Cheryl, Detterich, Jon, Kantor, Paul F., Cleveland, John D., Herrington, Cynthia, Ram Kumar, S., Starnes, Vaughn, Badran, Sarah, and Patel, Neil D.

Published
2021
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23. Spatially resolved immune exhaustion within the alloreactive microenvironment predicts liver transplant rejection

Author

Barbetta, Arianna, primary, Rocque, Brittany, additional, Bangerth, Sarah, additional, Street, Kelly, additional, Weaver, Carly, additional, Chopra, Shefali, additional, Kim, Janet, additional, Sher, Linda, additional, Gaudilliere, Brice, additional, Akbari, Omid, additional, Kohli, Rohit, additional, and Emamaullee, Juliet, additional

Published
2024
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25. Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children

Author

Newton, Kimberly P, Feldman, Haruna S, Chambers, Christina D, Wilson, Laura, Behling, Cynthia, Clark, Jeanne M, Molleston, Jean P, Chalasani, Naga, Sanyal, Arun J, Fishbein, Mark H, Lavine, Joel E, Schwimmer, Jeffrey B, Network, Nonalcoholic Steatohepatitis Clinical Research, Abrams, Stephanie H, Barlow, Sarah, Himes, Ryan, Krisnamurthy, Rajesh, Maldonado, Leanel, Mahabir, Rory, Carr, April, Bernstein, Kimberlee, Bramlage, Kristin, Cecil, Kim, DeVore, Stephanie, Kohli, Rohit, Lake, Kathleen, Podberesky, Daniel, Towbin, Alex, Xanthakos, Stavra, Allende, Daniela, Dasarathy, Srinivasan, McCullough, Arthur J, Pagadala, Mangesh, Pai, Rish, Winston, Cha'Ron, Behr, Gerald, Lefkowitch, Jay H, Mencin, Ali, Reynoso, Elena, Abdelmalek, Manal F, Bashir, Mustafa, Buie, Stephanie, Diehl, Anna Mae, Guy, Cynthia, Kigongo, Christopher, Malik, David, Pan, Yi-Ping, Piercy, Dawn, Kopping, Mariko, Thrasher, Tyler, Alazraki, Adina, Cleeton, Rebecca, Cordero, Maria, Hernandez, Albert, Karpen, Saul, Munos, Jessica Cruz, Raviele, Nicholas, Vos, Miriam, Bozic, Molly, Cummings, Oscar W, Gawrieh, Samer, Klipsch, Ann, Ragozzino, Emily, Ragozzino, Linda, Sandrasegaran, Kumar, Subbarao, Girish, Vuppalanchi, Raj, Walker, Laura, Kafka, Kimberly, Scheimann, Ann, Ito, Joy, Mohammad, Saeed, Rigsby, Cynthia, Sharda, Lisa, Whitington, Peter F, Cattoor, Theresa, Derdoy, Jose, Freebersyser, Janet, Jain, Ajay, King, Debra, Lai, Jinping, Osmack, Pat, Siegner, Joan, Stewart, Susan, Neuschwander-Tetri, Brent A, Torretta, Susan, Wriston, Kristina, Assadian, Fereshteh, Barone, Vanessa, Gonzalez, Maria Cardona, Davila, Jodie, Fix, Oren, Hennessey, Kelly Anne, Kowdley, Kris V, and Lopez, Kacie

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Perinatal Period - Conditions Originating in Perinatal Period, Preterm, Low Birth Weight and Health of the Newborn, Prevention, Digestive Diseases, Pediatric, Liver Disease, Clinical Research, Hepatitis, Chronic Liver Disease and Cirrhosis, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Adolescent, Biopsy, Birth Weight, Child, Cross-Sectional Studies, Databases, Factual, Female, Humans, Infant, Low Birth Weight, Infant, Postmature, Liver, Male, Non-alcoholic Fatty Liver Disease, Risk Factors, United States, Nonalcoholic Steatohepatitis Clinical Research Network, birth weight, children, epidemiology, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics, Paediatrics
Abstract

ObjectivesTo 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.Study designA 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.ResultsChildren 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

Published
2017

26. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children

Author

Vos, Miriam B, Abrams, Stephanie H, Barlow, Sarah E, Caprio, Sonia, Daniels, Stephen R, Kohli, Rohit, Mouzaki, Marialena, Sathya, Pushpa, Schwimmer, Jeffrey B, Sundaram, Shikha S, and Xanthakos, Stavra A

Subjects
Paediatrics, Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Pediatric, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Health Services, Liver Disease, Hepatitis, Clinical Research, Oral and gastrointestinal, Good Health and Well Being, Bariatric Surgery, Child, Combined Modality Therapy, Diet Therapy, Exercise Therapy, Gastrointestinal Agents, Humans, Incidence, Non-alcoholic Fatty Liver Disease, Prevalence, Risk Factors, Severity of Illness Index, United States, children, nonalcoholic fatty liver disease, recommendations, treatment, Medical and Health Sciences, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs in the setting of insulin resistance and increased adiposity. It has rapidly evolved into the most common liver disease seen in the pediatric population and is a management challenge for general pediatric practitioners, subspecialists and for health systems. In this guideline, the expert committee on NAFLD (ECON) reviewed and summarized the available literature, formulating recommendations to guide screening and clinical care of children with NAFLD.

Published
2017

27. Approach to the Treatment of Children and Adolescents with Obesity

Author

Hegedus, Elizabeth, Vidmar, Alaina P., Mayer, Madeline, Kohli, Roshni, and Kohli, Rohit

Abstract

Pediatric obesity continues to be an omnipresent disease; 1 in 5 children and adolescents have obesity in the United States. The comorbidities associated with youth-onset obesity tend to have a more severe disease progression in youth compared to their adult counterparts with the same obesity-related condition. A comorbidity of focus in this study is metabolism-associated steatotic liver disease (MASLD), which has rapidly evolved into the most common liver disease seen in the pediatric population. A direct association exists between the treatment of MASLD and the treatment of pediatric obesity. The current evidence supports that obesity treatment is safe and effective.

Published
2024
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28. In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores

Author

Schwimmer, Jeffrey B, Lavine, Joel E, Wilson, Laura A, Neuschwander-Tetri, Brent A, Xanthakos, Stavra A, Kohli, Rohit, Barlow, Sarah E, Vos, Miriam B, Karpen, Saul J, Molleston, Jean P, Whitington, Peter F, Rosenthal, Philip, Jain, Ajay K, Murray, Karen F, Brunt, Elizabeth M, Kleiner, David E, Van Natta, Mark L, Clark, Jeanne M, Tonascia, James, Doo, Edward, Abrams, Stephanie H, Barlow, Sarah, Himes, Ryan, Krisnamurthy, Rajesh, Maldonado, Leanel, Mahabir, Rory, Bernstein, Kimberlee, Bramlage, Kristin, Cecil, Kim, DeVore, Stephanie, Lake, Kathleen, Podberesky, Daniel, Towbin, Alex, Xanthakos, Stavra, Behr, Gerald, Lefkowitch, Jay H, Mencin, Ali, Reynoso, Elena, Alazraki, Adina, Cleeton, Rebecca, Karpen, Saul, Munos, Jessica Cruz, Raviele, Nicholas, Vos, Miriam, Bozic, Molly, Cummings, Oscar W, Klipsch, Ann, Munson, Sarah, Sandrasegaran, Kumar, Subbarao, Girish, Kafka, Kimberly, Scheimann, Ann, Amsden, Katie, Fishbein, Mark H, Kirwan, Elizabeth, Mohammad, Saeed, Rigsby, Cynthia, Sharda, Lisa, Derdoy, Jose, Jain, Ajay, King, Debra, Osmack, Pat, Siegner, Joan, Stewart, Susan, Torretta, Susan, Wriston, Kristina, Baker, Susan S, Zhu, Lixin, Africa, Jonathon, Angeles, Jorge, Arroyo, Sandra, Awai, Hannah, Behling, Cynthia, Bross, Craig, Durelle, Janis, Middleton, Michael, Newton, Kimberly, Paiz, Melissa, Sanford, Jennifer, Sirlin, Claude, Ugalde-Nicalo, Patricia, Villarreal, Mariana Dominguez, Aouizerat, Bradley, Courtier, Jesse, Ferrell, Linda D, Fleck, Shannon, Gill, Ryan, Langlois, Camille, Perito, Emily Rothbaum, Tsai, Patrika, Cooper, Kara, Horslen, Simon, and Hsu, Evelyn

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Chronic Liver Disease and Cirrhosis, Clinical Research, Hepatitis, Liver Disease, Digestive Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Oral and gastrointestinal, Adolescent, Alanine Transaminase, Aspartate Aminotransferases, Biopsy, Body Weight, Child, Cysteamine, Cystine Depleting Agents, Delayed-Action Preparations, Double-Blind Method, Female, Humans, Intention to Treat Analysis, Liver, Liver Cirrhosis, Male, Non-alcoholic Fatty Liver Disease, Severity of Illness Index, Pediatrics, ALT, AST, Obesity, NASH CRN, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsNo treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD.MethodsWe performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis.ResultsThere was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005).ConclusionsIn a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

Published
2016

29. Longitudinal Outcomes in Young Patients with Alpha-1-Antitrypsin Deficiency with Native Liver Reveal that Neonatal Cholestasis is a Poor Predictor of Future Portal Hypertension

Author

Alonso, Estella, Bass, Lee, Kelly, Susan, Riordan, Mary, Melin-Aldana, Hector, Bezerra, Jorge, Bove, Kevin, Heubi, James, Miethke, Alexander, Tiao, Greg, Denlinger, Julie, Chapman, Erin, Sokol, Ronald, Feldman, Amy, Mack, Cara, Narkewicz, Michael, Suchy, Frederick, Sundaram, Shikha, Van Hove, Johan, Garcia, Benigno, Kauma, Mikaela, Kocher, Kendra, Steinbeiss, Matthew, Lovell, Mark, Loomes, Kathleen, Piccoli, David, Rand, Elizabeth, Russo, Pierre, Spinner, Nancy, Erlichman, Jessi, Stalford, Samantha, Pakstis, Dina, King, Sakya, Squires, Robert, Sindhi, Rakesh, Venkat, Veena, Bukauskas, Kathy, McKiernan, Patrick, Haberstroh, Lori, Squires, James, Rosenthal, Philip, Bull, Laura, Curry, Joanna, Langlois, Camille, Kim, Grace, Teckman, Jeffery, Kociela, Vikki, Nagy, Rosemary, Patel, Shraddha, Cerkoski, Jacqueline, Molleston, Jean P., Bozic, Molly, Subbarao, Girish, Klipsch, Ann, Sawyers, Cindy, Cummings, Oscar, Horslen, Simon, Murray, Karen, Hsu, Evelyn, Cooper, Kara, Young, Melissa, Finn, Laura, Kamath, Binita, Ng, Vicky, Quammie, Claudia, Putra, Juan, Sharma, Deepika, Parmar, Aishwarya, Guthery, Stephen, Jensen, Kyle, Rutherford, Ann, Lowichik, Amy, Book, Linda, Meyers, Rebecka, Hall, Tyler, Wang, Kasper, Michail, Sonia, Thomas, Danny, Goodhue, Catherine, Kohli, Rohit, Wang, Larry, Soufi, Nisreen, Thomas, Daniel, Karpen, Saul, Gupta, Nitika, Romero, Rene, Jr., Vos, Miriam B., Tory, Rita, Berauer, John-Paul, Abramowsky, Carlos, McFall, Jeanette, Shneider, Benjamin, Harpavat, Sanjiv, Hertel, Paula, Leung, Daniel, Tessier, Mary, Schady, Deborah, Cavallo, Laurel, Olvera, Diego, Banks, Christina, Tsai, Cynthia, Thompson, Richard, Doo, Edward, Hoofnagle, Jay, Sherker, Averell, Torrance, Rebecca, Hall, Sherry, Magee, John, Merion, Robert, Spino, Cathie, Ye, Wen, Teckman, Jeffrey, Hawthorne, Kieran, Bass, Lee M., Murray, Karen F., Kerkar, Nanda, Magee, John C., Heubi, James E., Squires, Robert H., Kamath, Binita M., Guthery, Stephen L., Loomes, Kathleen M., Sherker, Averell H., and Sokol, Ronald J.

Published
2020
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30. Vagal activation alters prandial bile acid composition and glycemia in patients with hypoglycemia after Roux‐en‐Y gastric bypass surgery.

Author

Honka, Henri, Bhattacharjee, Jashdeep, Zadeh, Mansour, Kohli, Rohit, Gastaldelli, Amalia, and Salehi, Marzieh

Subjects
GASTRIC bypass, BILE acids, GLUCAGON-like peptide 1, HYPOGLYCEMIA, BLOOD sugar, DEOXYCHOLIC acid
Abstract

Background: Altered prandial glycemic response after Roux‐en‐Y gastric bypass (RYGB) is exaggerated in patients with post‐RYGB hypoglycemia. Increased contribution of glucagon‐like peptide 1 (GLP‐1) to prandial insulin secretion plays a key role in developing hypoglycemia after RYGB, but the role of nonhormonal gut factors remains unknown. Here, the effect of vagal activation on prandial bile acid (BA) composition in relation to glucose, insulin and gut hormone responses was examined in a small size group of nondiabetic subjects after RYGB with intact gallbladder compared to nonoperated controls. Methods: Concentrations of blood glucose, hormones, and BAs were measured in two RYGB subjects with documented hypoglycemia (HGB), three asymptomatic RYGB‐treated subjects (AGB), and four nonoperated controls with intact gallbladders during a meal‐tolerance test with (MTT‐Sham) and without (MTT) preceding modified sham feeding (chew and spit). Key Results: Meal ingestion raised serum total BAs in RYGB‐treated subjects without any effect in nonoperated controls. Modified sham feeding similarly increased meal‐induced responses of conjugated BAs (CBAs) in all subjects (p < 0.05 compared to MTT alone), whereas unconjugated BAs (UBAs), mainly deoxycholic and chenodeoxycholic acid, were raised only in the HGB group (p < 0.001 for interaction). Prandial UBAs had an inverse correlation with glucose nadir (r = −0.75, p < 0.05) and were directly associated with ISR and GLP‐1 during MTT‐Sham. Conclusions & Inferences: In this small cohort, vagal activation by modified sham feeding increases prandial CBAs in both operated and nonoperated subjects but enhances UBAs only in patients with documented post‐RYGB hypoglycemia. Our findings highlight a potential role for nonhormonal gut factors, such as BA and gut microbiome, in glucose abnormalities after RYGB. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Paediatric steatotic liver disease has unique characteristics: A multisociety statement endorsing the new nomenclature.

Author

Baumann, Ulrich, Koot, Bart G. P., Fitzpatrick, Emer, Mann, Jake, Vajro, Pietro, Krag, Aleksander, Newsome, Philip N., Shawcross, Debbie, Francque, Sven, Böttler, Tobias, Gold, Benjamin D., Lightdale, Jenifer R., Mouzaki, Marialena, Rodriguez‐Baez, Norberto, Kohli, Rohit, Ng, Vicky L., D'Agostino, Daniel, Porta, Gilda, Spolidoro, José, and Klünder‐Klünder, Miguel

Published
2024
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32. Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity

Author

Li, Yi-Jie, primary, Baumert, Brittney O, additional, Stratakis, Nikos, additional, Goodrich, Jesse A, additional, Wu, Hao-Tian, additional, He, Jing-Xuan, additional, Zhao, Yin-Qi, additional, Aung, Max T, additional, Wang, Hong-Xu, additional, Eckel, Sandrah P, additional, Walker, Douglas I, additional, Valvi, Damaskini, additional, La Merrill, Michele A, additional, Ryder, Justin R, additional, Inge, Thomas H, additional, Jenkins, Todd, additional, Sisley, Stephanie, additional, Kohli, Rohit, additional, Xanthakos, Stavra A, additional, Baccarelli, Andrea A, additional, McConnell, Rob, additional, Conti, David V, additional, and Chatzi, Lida, additional

Published
2024
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33. Changes in Plasma Concentrations of Per- and Polyfluoroalkyl Substances after Bariatric Surgery in Adolescents from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-Labs) Study

Author

Baumert, Brittney O., primary, Eckel, Sandrah P., additional, Stratakis, Nikos, additional, Goodrich, Jesse, additional, Walker, Douglas I., additional, Zhao, Yinqi, additional, Fischer, Fabian, additional, Bartell, Scott, additional, Valvi, Damaskini, additional, Lin, Xiangping, additional, Coates Fuentes, Zoe, additional, Inge, Thomas, additional, Ryder, Justin, additional, Jenkins, Todd, additional, Kohli, Rohit, additional, Sisley, Stephanie, additional, Xanthakos, Stavra, additional, Rock, Sarah, additional, La Merrill, Michele A., additional, McConnell, Rob, additional, Conti, David V., additional, and Chatzi, Leda, additional

Published
2024
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36. Bile Acid Signaling: Mechanism for Bariatric Surgery, Cure for NASH?

Author

Kohli, Rohit, Myronovych, Andriy, Tan, Brandon K, Salazar-Gonzalez, Rosa-Maria, Miles, Lili, Zhang, Wujuan, Oehrle, Melissa, Sandoval, Darleen A, Ryan, Karen K, Seeley, Randy J, and Setchell, Kenneth DR

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Obesity, Liver Disease, Digestive Diseases, Prevention, Hepatitis, Chronic Liver Disease and Cirrhosis, Nutrition, Metabolic and endocrine, Oral and gastrointestinal, Animals, Bariatric Surgery, Bile Acids and Salts, Gastrectomy, Humans, Non-alcoholic Fatty Liver Disease, Signal Transduction, Weight Loss, Bile acid metabolism, Nonalcoholic fatty liver disease, Bariatric surgery, Clinical Sciences, Gastroenterology & Hepatology, Clinical sciences
Abstract

Bariatric surgery is the most effective and durable treatment option for obesity today. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including reversal of obesity-related liver disease--nonalcoholic steatohepatitis (NASH). NASH is an important comorbidity of obesity given that it is a precursor to the development of liver cirrhosis that may necessitate liver transplantation in the long run. Simultaneously, we and others have observed increased serum bile acids in humans and animals that undergo bariatric surgery. Specifically, our preclinical studies have included experimental procedures such as 'ileal transposition' or bile diversion and established procedures such as Roux-en-Y gastric bypass and the adjustable gastric band. Importantly, these effects are not simply the result of weight loss since our data show that the resolution of NASH and increase in serum bile acids are not seen in rodents that lose an equivalent amount of weight via food restriction. In particular, we have studied the role of altered bile acid signaling, in the potent impact of a bariatric procedure termed 'vertical sleeve gastrectomy' (VSG). In this review we focus on the mechanisms of NASH resolution and weight loss after VSG surgery. We highlight the fact that bariatric surgeries can be used as 'laboratories' to dissect the mechanisms by which these procedures work to improve obesity and fatty liver disease. We describe key bile acid signaling elements that may provide potential therapeutic targets for 'bariatric-mimetic technologies' that could produce benefits similar to bariatric surgery--but without the surgery!

Published
2015

38. The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice

Author

Myronovych, Andriy, Salazar-Gonzales, Rosa-Maria, Ryan, Karen K, Miles, Lili, Zhang, Wujuan, Jha, Pinky, Wang, Li, Setchell, Kenneth DR, Seeley, Randy J, and Kohli, Rohit

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Obesity, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Disease, Nutrition, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Animals, Diet, High-Fat, Gastrectomy, Inflammation, Lipogenesis, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Obese, Non-alcoholic Fatty Liver Disease, Receptors, Cytoplasmic and Nuclear, Weight Gain, Weight Loss, Endocrinology & Metabolism
Abstract

ObjectiveBile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested.MethodsWild type (WT), SHP liver transgenic (SHP-Tg), and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level and composition, steatosis, and BA metabolism gene expression were evaluated.ResultsObese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHP-Tg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight, but developed hepatic inflammation and had increased ALT.ConclusionsVSG produces weight loss independent of SHP status. SHP ablation creates a proinflammatory phenotype which is exacerbated after VSG despite weight loss. These inflammatory alterations are possibly related to factors extrinsic to a direct manifestation of NASH.

Published
2014

39. FXR is a molecular target for the effects of vertical sleeve gastrectomy

Author

Ryan, Karen K, Tremaroli, Valentina, Clemmensen, Christoffer, Kovatcheva-Datchary, Petia, Myronovych, Andriy, Karns, Rebekah, Wilson-Pérez, Hilary E, Sandoval, Darleen A, Kohli, Rohit, Bäckhed, Fredrik, and Seeley, Randy J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Obesity, Diabetes, Nutrition, Cancer, Metabolic and endocrine, Oral and gastrointestinal, Animals, Bariatric Surgery, Bile Acids and Salts, Body Composition, Cecum, Feeding Behavior, Gastrectomy, Gastric Mucosa, Glucose Intolerance, Glucose Tolerance Test, Male, Mice, Mice, Inbred C57BL, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Stomach, Weight Loss, General Science & Technology
Abstract

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

Published
2014

40. Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight‐loss‐independent manner

Author

Myronovych, Andriy, Kirby, Michelle, Ryan, Karen K, Zhang, Wujuan, Jha, Pinky, Setchell, Kenneth DR, Dexheimer, Phillip J, Aronow, Bruce, Seeley, Randy J, and Kohli, Rohit

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Nutrition, Liver Disease, Obesity, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Animals, Bile Acids and Salts, Caloric Restriction, Cholic Acid, Diet, High-Fat, Down-Regulation, Fatty Liver, Gastroplasty, Gene Expression Profiling, Gene Expression Regulation, Lipogenesis, Liver, Male, Mice, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease, Postprandial Period, Random Allocation, Taurochenodeoxycholic Acid, Triglycerides, Up-Regulation, Weight Loss, Endocrinology & Metabolism
Abstract

ObjectiveOur objective was to investigate the role of bile acids in hepatic steatosis reduction after vertical sleeve gastrectomy (VSG).Design and methodsHigh fat diet (HFD)-induced obese C57Bl/6 mice were randomized to VSG, Sham operation (Sham), Sham operation with pair feeding to VSG (Sham-PF), or nonsurgical controls (Naïve). All mice were on HFD until sacrifice. Mice were observed postsurgery and data for body weight, body composition, metabolic parameters, serum bile acid level and composition were collected. Further hepatic gene expression by mRNA-seq and RT-PCR analysis was assessed.ResultsVSG and Sham-PF mice lost equal weight postsurgery while VSG mice had the lowest hepatic triglyceride content at sacrifice. The VSG mice had elevated serum bile acid levels that positively correlated with maximal weight loss. Serum bile composition in the VSG group had increased cholic and tauroursodeoxycholic acid. These bile acid composition changes in VSG mice explained observed downregulation of hepatic lipogenic and bile acid synthetic genes.ConclusionVSG in obese mice results in greater hepatic steatosis reduction than seen with caloric restriction alone. VSG surgery increases serum bile acids that correlate with weight lost postsurgery and changes serum bile composition that could explain suppression of hepatic genes responsible for lipogenesis.

Published
2014

41. Finance, race, ethnicity, and spoken language impact clinical outcomes for children with acute liver failure.

Author

Ascher Bartlett, Johanna, Barhouma, Sarah, Bangerth, Sarah, Mejia, Valeria, Weaver, Carly, Kohli, Rohit, and Emamaullee, Juliet

Subjects
RACE, LIVER failure, FAMILY support, TREATMENT effectiveness, ORAL communication
Abstract

Background: Pediatric acute liver failure (PALF) is an emergency, necessitating prompt referral and management at an experienced liver transplant center. Social determinants of health (SDOH) drive healthcare disparities and can affect many aspects of disease presentation, access to care, and ultimately clinical outcomes. Potential associations between SDOH and PALF outcomes, including spontaneous recovery (SR), liver transplant (LT) or death, are unknown. This study aims to investigate how SDOH may affect PALF and therefore identify areas for intervention to mitigate unrecognized disparities. Methods: A retrospective, single‐center cohort was analyzed and then compared and validated with data from the multicenter National Institutes of Health PALF Study Group. The single‐center review included 145 patients admitted with PALF using diagnostic codes. Medical records were reviewed to extract patient demographics, family structure, inpatient social worker assessments, and clinical outcomes. Data were stratified by outcome. Results: This analysis determined that level of family support (p =.02), caretaker employment (p =.02), patient age, race, and language (p =.01) may impact clinical outcomes. Specifically, the cohort of children that died had the largest proportion of non‐English speaking patients with limited support systems and parents who worked full‐time. Conversely, patients who underwent LT more often belonged to English‐speaking families with a homemaker and extensive support systems. Conclusion: This study suggests that SDOH impact PALF outcomes and highlights patient populations facing additional challenges during an already complex healthcare emergency. These associations may indicate unconscious biases held by transplant teams when evaluating waitlist candidacy, as well as barriers to healthcare access. Strategies to better understand the broader applicability of our findings and, if confirmed, efforts to mitigate social disparities, may improve clinical outcomes in PALF. [ABSTRACT FROM AUTHOR]

Published
2024
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43. PFAS exposure and changes in the extracellular microRNA profile in a cohort of adolescents undergoing bariatric surgery

Author

Li, Yijie, primary, Baumert, Brittney O., additional, Stratakis, Nikos, additional, Goodrich, Jesse, additional, Wu, Haotian, additional, Wang, Hongxu, additional, Nielsen, Flemming, additional, Grandjean, Philippe, additional, Bartell, Scott, additional, Eckel, Sandrah P., additional, Walker, Douglas I., additional, Valvi, Damaskini, additional, Merrill, Michele A. La, additional, Inge, Thomas, additional, Jenkins, Todd, additional, Ryder, Justin, additional, Sisley, Stephanie, additional, Kohli, Rohit, additional, Xanthakos, Stavra A., additional, Aung, Max, additional, Mcconnell, Rob, additional, Baccarelli, Andrea, additional, Conti, David, additional, and Chatzi, Lida, additional

Published
2023
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44. Technical optimization of spatially resolved single-cell transcriptomic datasets to study clinical liver disease.

Author

Rocque, Brittany, primary, Guion, Kate, additional, Singh, Pranay, additional, Bangerth, Sarah, additional, Pickard, Lauren, additional, Bhattacharjee, Jashdeep, additional, Eguizabal, Sofia, additional, Weaver, Carly, additional, Chopra, Shefali, additional, Zhou, Shengmei, additional, Kohli, Rohit, additional, Sher, Linda, additional, Ekser, Burcin, additional, and Emamaullee, Juliet A., additional

Published
2023
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46. Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

Author

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

Published
2018
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47. Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study

Author

Hertel, Paula M., Harpavat, Sanjiv, Brandt, Mary L., Leung, Daniel H., Karnsakul, Wikrom, Torrance, Rebecca, Hall, Sherry, Doo, Edward, Hoofnagle, Jay H., Whitington, Peter, Bass, Lee, Miethke, Alexander G., Heubi, James E., Setchell, Kenneth, Bove, Kevin E., Tiao, Greg, Mack, Cara L., Narkewicz, Michael R., Feldman, Amy G., Sundaram, Shikha S., Suchy, Frederick J., Karrer, Frederick M., Lovell, Mark, Van Hove, Johan L., Rand, Elizabeth B., Squires, James E., Venkat, Veena L., Sindhi, Rakesh, Ranganathan, Sarangarajan, Bull, Laura, Teckman, Jeffrey, Bozic, Molly, Subbarao, Girish, Horslen, Simon, Hsu, Evelyn, Finn, Laura, Healey, Patrick, Kohli, Rohit, Thomas, Danny, Soufi, Nisreen, Michail, Sonia, Clifton, Matt, Gupta, Nitika, Romero, Rene, Vos, Miriam, Caltharp, Shelley, Kamath, Binita M., Ling, Simon C., Gold, Anna, Fecteau, Annie, Guthery, Stephen L., Jensen, Kyle, Meyers, Rebecka, Lowichik, Amy, Book, Linda, Merion, Robert M., Spino, Cathie, Jones, Karen, Ng, Vicky L., Sorensen, Lisa G., Alonso, Estella M., Fredericks, Emily M., Ye, Wen, Moore, Jeff, Karpen, Saul J., Shneider, Benjamin L., Molleston, Jean P., Bezerra, Jorge A., Murray, Karen F., Loomes, Kathleen M., Rosenthal, Philip, Squires, Robert H., Wang, Kasper, Arnon, Ronen, Schwarz, Kathleen B., Turmelle, Yumirle P., Haber, Barbara H., Sherker, Averell H., Magee, John C., and Sokol, Ronald J.

Published
2018
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48. In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis

Author

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

Published
2018
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49. Effects of Dietary Sugar Reduction on Biomarkers of Cardiometabolic Health in Latino Youth: Secondary Analyses from a Randomized Controlled Trial

Author

Schmidt, Kelsey A., primary, Mokhtari, Pari, additional, Holzhausen, Elizabeth A., additional, Alderete, Tanya L., additional, Allayee, Hooman, additional, Nayak, Krishna S., additional, Sinatra, Frank R., additional, Pickering, Trevor A., additional, Mack, Wendy, additional, Kohli, Rohit, additional, and Goran, Michael I., additional

Published
2023
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50. Spatially resolved immune exhaustion within the alloreactive microenvironment predicts liver transplant rejection.

Author

Barbetta, Arianna, primary, Rocque, Brittany, additional, Bangerth, Sarah, additional, Street, Kelly, additional, Weaver, Carly, additional, Chopra, Shefali, additional, Kim, Janet, additional, Sher, Linda, additional, Gaudilliere, Brice, additional, Akbari, Omid, additional, Kohli, Rohit, additional, and Emamaullee, Juliet, additional

Published
2023
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