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1. Congenital dyserythropoietic anemia type II and ineffective erythropoiesis: challenges in diagnosis and management

Author

Imo J. Akpan, Kelsie Bogyo, Rebecca J. Leeman-Neill, Julia Wattacheril, and Richard O. Francis

Subjects
congenital dyserythropoietic anemia, ineffective erythropoiesis, iron overload, hemolysis, splenomegaly, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Congenital dyserythropoietic anemia (CDA) is characterized by anemia—mild to severe, hemolysis, ineffective erythropoiesis, and in some cases, iron overload. There are three major types of CDA (I, II, and III), and the other types are rarer. The rarity of this disease, as well as signs and symptoms that overlap with other hematological diseases, can make the diagnosis difficult and delayed over several years. Evaluation includes basic laboratory testing, magnetic resonance imaging of organs for assessment of iron overload, bone marrow assessment, and genetic testing. Laboratory tests to evaluate for ineffective erythropoiesis include indirect bilirubin level, which can be normal or increased, reticulocyte production index < 2 signifying hyperproliferation of erythrocytes, and complete iron panel (serum iron, ferritin, and iron saturation), which may suggest iron overload. Genetic testing is crucial for CDA diagnosis and includes next-generation sequencing. A multidisciplinary team of providers including a hematologist, hepatologist, hematopathologist, and genetic counselor are important and sometimes necessary for the evaluation, diagnosis, and management of these patients. Management depends on the clinical phenotype, and some severe cases may require blood transfusion, iron chelation therapy, splenectomy, and in extreme cases, hematopoietic stem cell transplant may be necessary. This mini-review illustrates the challenges involved in the diagnosis and management of the most common CDA, which is type II. It will highlight clinical signs and symptoms in patients that should prompt providers to test for CDA. It will also increase awareness of this disease, discuss possible barriers to testing, and provide guidance on how to manage the disease.

Published
2024
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2. The diagnostic yield of exome sequencing in liver diseases from a curated gene panel

Author

Xiao-Fei Kong, Kelsie Bogyo, Sheena Kapoor, Patrick R. Shea, Emily E. Groopman, Amanda Thomas-Wilson, Enrico Cocchi, Hila Milo Rasouly, Beishi Zheng, Siming Sun, Junying Zhang, Mercedes Martinez, Jennifer M. Vittorio, Lorna M. Dove, Maddalena Marasa, Timothy C. Wang, Elizabeth C. Verna, Howard J. Worman, Ali G. Gharavi, David B. Goldstein, and Julia Wattacheril

Subjects
Medicine, Science
Abstract

Abstract Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10–4 for dominant disorders and MAF ≤ 10–3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X 2 test OR 5.00, 95% CI 3.06–8.18, p value = 4.5e−12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.

Published
2023
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3. Hepatocellular Carcinoma in Hispanic Patients: Trends and Outcomes in a Large United States Cohort

Author

Sydney Pomenti, Cassandra Gandle, Hamzah Abu Sbeih, Meaghan Phipps, Alexandra Livanos, Averill Guo, Jonathan Yeh, Heather Burney, Hao Liu, Lara Dakhoul, Carla Kettler, Samer Gawrieh, Andrew deLemos, Andrew Scanga, Naga Chalasani, Ethan Miller, and Julia Wattacheril

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Hepatocellular carcinoma (HCC) has a strong racial and ethnic association, with Hispanic patients having a higher incidence and mortality. However, there are limited data regarding clinical features and outcomes. This study includes Hispanic and non‐Hispanic White patients with HCC diagnosed between January 2000 and June 2014 from five United States academic medical centers. The chi‐square test for categorical variables and analysis of variance for continuous variables were used for statistical analysis, with two‐tailed P

Published
2020
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4. Lipoprotein Profiles in Class III Obese Caucasian and African American Women with Nonalcoholic Fatty Liver Disease.

Author

Anna E Garcia, Nader Kasim, Robyn A Tamboli, Raul S Gonzalez, Joseph Antoun, Emily A Eckert, Pamela A Marks-Shulman, Julia Dunn, Julia Wattacheril, Taylor Wallen, Naji N Abumrad, and Charles Robb Flynn

Subjects
Medicine, Science
Abstract

Triglyceride content in the liver is regulated by the uptake, production and elimination of lipoproteins, and derangements in these processes contribute to nonalcoholic fatty liver disease (NAFLD). Previous studies show a direct relationship between intrahepatic fat and production of apolipoprotein B100 (apoB100) containing particles, VLDL and LDL, but little consensus exists regarding changes in lipoprotein production in the development of simple steatosis (SS) versus nonalcoholic steatohepatitis (NASH). Further, ethnic variations in lipoproteins among SS and NASH are unknown as is how such variations might contribute to the differential prevalence of disease among Caucasians versus African Americans. In this study, we assessed plasma lipoprotein profiles by nuclear magnetic resonance (NMR) spectroscopy in 70 non-diabetic class III obese females recruited from the surgical weight loss clinic. Of these, 51 females were stratified by biopsy-staged NAFLD severity (histologically normal, SS, or NASH). NASH females displayed increased circulating triglycerides and increased VLDL particle number and size relative to those with histologically normal livers, while total and large LDL concentration decreased in SS versus NASH and correlated with increased insulin resistance (via HOMA2-IR). When Caucasian women were examined alone (n = 41), VLDL and triglycerides increased between normal and SS, while total LDL and apoB100 decreased between SS and NASH along with increased insulin resistance. Compared to Caucasians with SS, African American women with SS displayed reduced triglycerides, VLDL, and small LDL and a more favorable small to large HDL ratio despite having increased BMI and HOMA2-IR. These findings suggest that ApoB100 and lipoprotein subclass particle number and size can delineate steatosis from NASH in obese Caucasian females, but should be interpreted with caution in other ethnicities as African Americans with SS display relatively improved lipoprotein profiles. This may reflect variation in the relationship between dyslipidemia and NAFLD progression across gender and ethnicity.

Published
2015
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5. Differential intrahepatic phospholipid zonation in simple steatosis and nonalcoholic steatohepatitis.

Author

Julia Wattacheril, Erin H Seeley, Peggi Angel, Heidi Chen, Benjamin P Bowen, Christian Lanciault, Richard M Caprioli, Naji Abumrad, and Charles Robb Flynn

Subjects
Medicine, Science
Abstract

Nonalcoholic fatty liver disease (NAFLD) occurs frequently in a setting of obesity, dyslipidemia and insulin resistance, but the etiology of the disease, particularly the events favoring progression to nonalcoholic steatohepatitis (NASH) as opposed to simple steatosis (SS), are not fully understood. Based on known zonation patterns in protein, glucose and lipid metabolism, coupled with evidence that phosphatidylcholine may play a role in NASH pathogenesis, we hypothesized that phospholipid zonation exists in liver and that specific phospholipid abundance and distribution may be associated with histologic disease. A survey of normal hepatic protein expression profiles in the Human Protein Atlas revealed pronounced zonation of enzymes involved in lipid utilization and storage, particularly those facilitating phosphatidylcholine (PC) metabolism. Immunohistochemistry of obese normal, SS and NASH liver specimens with anti-phosphatidylethanomine N-methyltransferase (PEMT) antibodies showed a progressive decrease in the zonal distribution of this PC biosynthetic enzyme. Phospholipid quantitation by liquid chromatography mass spectrometry (LC-MS) in hepatic extracts of Class III obese patients with increasing NAFLD severity revealed that most PC species with 32, 34 and 36 carbons as well as total PC abundance was decreased with SS and NASH. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) imaging revealed strong zonal distributions for 32, 34 and 36 carbon PCs in controls (minimal histologic findings) and SS that was lost in NASH specimens. Specific lipid species such as PC 34:1 and PC 36:2 best illustrated this phenomenon. These findings suggest that phospholipid zonation may be associated with the presence of an intrahepatic proinflammatory phenotype and thus have broad implications in the etiopathogenesis of NASH.

Published
2013
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6. A multi-society Delphi consensus statement on new fatty liver disease nomenclature

Author

Mary E, R, Jeffrey V, L, Vlad, R, Sven M, F, Arun J, S, Fasiha, K, Diana, R, Manal F, A, Quentin M, A, Juan Pablo, A, Marco, A, Ramon, B, Ulrich, B, Jerome, B, Elisabetta, B, Christopher, B, Graciela E, C, Abhijit, C, Helena, C, Donna, C, Kenneth, C, Mohamed, E, Samuel, K, Wayne, E, Jiangao, F, Samer, G, Cynthia D, G, Stephen A, H, Seung Up, K, Bart, K, Marko, K, Kris, K, Florence, L, Rohit, L, Robert, M, Timothy R, M, Elisabeth, P, Michael, R, Manuel, R, Marcelo, S, Shivaram Prasad, S, Silvia C, S, C Wendy, S, Dina, T, Luca, V, Miriam B, V, Vincent, W, Stavra, X, Yusuf, Y, Zobair, Y, Ansley, H, Marcela, V, Newsome, NVeeral Ajmeral, P, Alazawi, W, Alkhatry, M, Alkhouri, N, Allen, A, Allison, M, Alswat, K, R Alvares-da-Silva, M, Alves-Bezerra, M, J Armstrong, M, Arufe, D, Aschner, P, Baffy, G, Bansal, M, Bedossa, P, Belfort, R, Berg, T, Berzigotti, A, Betel, M, Bianco, C, Brass, C, L Brosgart, C, Matthews Brunt, E, Buti, M, Caldwell, S, Carr, R, Casanovas, T, Castera, L, Caussy, C, Cerda, E, Chalasani, N, Kheong Chan, W, Charatcharoenwitthaya, P, Charlton, M, Cheung, A, Chiodi, D, Chung, R, Cohen, D, Corey, K, P Cotrim, H, Crespo, J, Dassanayake, A, Davidson, N, De Knegt, R, De Ledinghen, V, Demir, M, Diaz, S, Mae Diehl, A, Dimmig, B, Dirchwolf, M, Duseja, A, Dvorak, K, Ekstedt, M, El Wakil, R, Lucía Ferraz, M, Friedman, S, Fuchs, M, Gastaldelli, A, Geerts, A, Geier, A, Girala, M, Goh, G, Goossens, N, Graupera, I, Hagström, H, Henry, Z, Hunyady, B, Hutchison, A, Isaacs, S, Jornayvaz, F, Kemp, C, Kile, D, Kim, W, Kleiner, D, Kohli, R, Kugelmas, M, Lavine, J, Lazo, M, Leite, N, Lozano, A, Luukkonen, P, Macedo, P, Mansour, D, Mantzoros, C, Marchesini, G, Marciano, S, Martinez, K, Vladimirova Mateva, L, M Mato, J, Mccary, A, Miele, L, Mikolasevic, I, Miller, V, Moreno, R, Moylan, C, Nakajima, A, Charles Nault, J, Norris, S, Noureddin, M, P Oliveira, C, Ong, A, Padilla, M, Pais, R, Panduro, A, K Panigrahi, M, Papatheodoridis, G, Pelusi, S, Pérez, M, Perez Escobar, J, Perseghin, G, Pessoa, M, Petta, S, Pinzani, M, Platon Lupsor, M, Rabiee, A, Romeo, S, Rotman, Y, Rowe, I, Salupere, R, Satapathy, S, M Schattenberg, J, Schaufert, W, Schnabl, B, Seim, L, Serfaty, L, Shapiro, D, K Singal, A, Skladany, L, Stefan, N, Stine, J, Sundaram, S, Svegliati-Baroni, G, Szabo, G, Tacke, F, Tanwandee, T, Targher, G, Terrault, N, Tetri, B, Thiele, M, Tisthammer, B, Torre Delgadillo, A, Trauner, M, Tsochatzis, E, Van Kleef, L, Van Mil, S, Vanwagner, L, Antonio Velarde Ruiz Velasco, J, Vesterhus, M, Vilar-Gomez, E, Watt, K, Wattacheril, J, Wilkins, F, Willemse, J, Zekry, A, Zelber-Sagi, S, Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela E, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wai-Sun Wong, Vincent, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Philip NVeeral Ajmeral, William Alazawi, Maryam Alkhatry, Naim Alkhouri, Alina Allen, Michael Allison, Khalid Alswat, Mario R Alvares-da-Silva, Michele Alves-Bezerra, Matthew J Armstrong, Diego Arufe, Pablo Aschner, Gyorgy Baffy, Meena Bansal, Pierre Bedossa, Renata Belfort, Thomas Berg, Annalisa Berzigotti, Michael Betel, Cristiana Bianco, Clifford Brass, Carol L Brosgart, Elizabeth Matthews Brunt, Maria Buti, Steve Caldwell, Rotonya Carr, Teresa Casanovas, Laurent Castera, Cyrielle Caussy, Eira Cerda, Naga Chalasani, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Michael Charlton, Amanda Cheung, Daniela Chiodi, Ray Chung, David Cohen, Kathleen Corey, Helma P Cotrim, Javier Crespo, Anuradha Dassanayake, Nicholas Davidson, Robert De Knegt, Victor De Ledinghen, Münevver Demir, Sebastian Diaz, Anna Mae Diehl, Bruce Dimmig, Melisa Dirchwolf, Ajay Duseja, Karel Dvorak, Mattias Ekstedt, Reda El Wakil, María Lucía Ferraz, Scott Friedman, Michael Fuchs, Amalia Gastaldelli, Anja Geerts, Andreas Geier, Marcos Girala, George Goh, Nicolas Goossens, Isabel Graupera, Hannes Hagström, Zachary Henry, Bela Hunyady, Alan Hutchison, Scott Isaacs, François Jornayvaz, Cynthia Kemp, Denise Kile, Won Kim, David Kleiner, Rohit Kohli, Marcelo Kugelmas, Joel Lavine, Mariana Lazo, Nathalie Leite, Adelina Lozano, Panu Luukkonen, Paula Macedo, Dina Mansour, Christos Mantzoros, Giulio Marchesini, Sebastián Marciano, Kim Martinez, Lyudmila Vladimirova Mateva, Jose M Mato, Alexis McCary, Luca Miele, Ivana Mikolasevic, Veronica Miller, Rosalba Moreno, Cynthia Moylan, Atsushi Nakajima, Jean Charles Nault, Suzanne Norris, Mazen Noureddin, C P Oliveira, Arlin Ong, Martín Padilla, Raluca Pais, Arturo Panduro, Manas K Panigrahi, George Papatheodoridis, Serena Pelusi, Marlene Pérez, Juanita Perez Escobar, Gianluca Perseghin, Mario Pessoa, Salvatore Petta, Massimo Pinzani, Monica Platon Lupsor, Atoosa Rabiee, Stefano Romeo, Yaron Rotman, Ian Rowe, Riina Salupere, Sanjaya Satapathy, Jörn M Schattenberg, Wendy Schaufert, Bernd Schnabl, Lynn Seim, Lawrence Serfaty, David Shapiro, Ashwani K Singal, Lubomir Skladany, Norbert Stefan, Jonathan Stine, Shikha Sundaram, Gianluca Svegliati-Baroni, Gyonzgi Szabo, Frank Tacke, Tawesak Tanwandee, Giovanni Targher, Norah Terrault, Brent Tetri, Maja Thiele, Baron Tisthammer, Aldo Torre Delgadillo, Michael Trauner, Emmanuel Tsochatzis, Laurens Van Kleef, Saskia Van Mil, Lisa VanWagner, Jose Antonio Velarde Ruiz Velasco, Mette Vesterhus, Eduardo Vilar-Gomez, Kymberly Watt, Julia Wattacheril, Fonda Wilkins, José Willemse, Amany Zekry, Shira Zelber-Sagi, Mary E, R, Jeffrey V, L, Vlad, R, Sven M, F, Arun J, S, Fasiha, K, Diana, R, Manal F, A, Quentin M, A, Juan Pablo, A, Marco, A, Ramon, B, Ulrich, B, Jerome, B, Elisabetta, B, Christopher, B, Graciela E, C, Abhijit, C, Helena, C, Donna, C, Kenneth, C, Mohamed, E, Samuel, K, Wayne, E, Jiangao, F, Samer, G, Cynthia D, G, Stephen A, H, Seung Up, K, Bart, K, Marko, K, Kris, K, Florence, L, Rohit, L, Robert, M, Timothy R, M, Elisabeth, P, Michael, R, Manuel, R, Marcelo, S, Shivaram Prasad, S, Silvia C, S, C Wendy, S, Dina, T, Luca, V, Miriam B, V, Vincent, W, Stavra, X, Yusuf, Y, Zobair, Y, Ansley, H, Marcela, V, Newsome, NVeeral Ajmeral, P, Alazawi, W, Alkhatry, M, Alkhouri, N, Allen, A, Allison, M, Alswat, K, R Alvares-da-Silva, M, Alves-Bezerra, M, J Armstrong, M, Arufe, D, Aschner, P, Baffy, G, Bansal, M, Bedossa, P, Belfort, R, Berg, T, Berzigotti, A, Betel, M, Bianco, C, Brass, C, L Brosgart, C, Matthews Brunt, E, Buti, M, Caldwell, S, Carr, R, Casanovas, T, Castera, L, Caussy, C, Cerda, E, Chalasani, N, Kheong Chan, W, Charatcharoenwitthaya, P, Charlton, M, Cheung, A, Chiodi, D, Chung, R, Cohen, D, Corey, K, P Cotrim, H, Crespo, J, Dassanayake, A, Davidson, N, De Knegt, R, De Ledinghen, V, Demir, M, Diaz, S, Mae Diehl, A, Dimmig, B, Dirchwolf, M, Duseja, A, Dvorak, K, Ekstedt, M, El Wakil, R, Lucía Ferraz, M, Friedman, S, Fuchs, M, Gastaldelli, A, Geerts, A, Geier, A, Girala, M, Goh, G, Goossens, N, Graupera, I, Hagström, H, Henry, Z, Hunyady, B, Hutchison, A, Isaacs, S, Jornayvaz, F, Kemp, C, Kile, D, Kim, W, Kleiner, D, Kohli, R, Kugelmas, M, Lavine, J, Lazo, M, Leite, N, Lozano, A, Luukkonen, P, Macedo, P, Mansour, D, Mantzoros, C, Marchesini, G, Marciano, S, Martinez, K, Vladimirova Mateva, L, M Mato, J, Mccary, A, Miele, L, Mikolasevic, I, Miller, V, Moreno, R, Moylan, C, Nakajima, A, Charles Nault, J, Norris, S, Noureddin, M, P Oliveira, C, Ong, A, Padilla, M, Pais, R, Panduro, A, K Panigrahi, M, Papatheodoridis, G, Pelusi, S, Pérez, M, Perez Escobar, J, Perseghin, G, Pessoa, M, Petta, S, Pinzani, M, Platon Lupsor, M, Rabiee, A, Romeo, S, Rotman, Y, Rowe, I, Salupere, R, Satapathy, S, M Schattenberg, J, Schaufert, W, Schnabl, B, Seim, L, Serfaty, L, Shapiro, D, K Singal, A, Skladany, L, Stefan, N, Stine, J, Sundaram, S, Svegliati-Baroni, G, Szabo, G, Tacke, F, Tanwandee, T, Targher, G, Terrault, N, Tetri, B, Thiele, M, Tisthammer, B, Torre Delgadillo, A, Trauner, M, Tsochatzis, E, Van Kleef, L, Van Mil, S, Vanwagner, L, Antonio Velarde Ruiz Velasco, J, Vesterhus, M, Vilar-Gomez, E, Watt, K, Wattacheril, J, Wilkins, F, Willemse, J, Zekry, A, Zelber-Sagi, S, Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela E, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wai-Sun Wong, Vincent, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Philip NVeeral Ajmeral, William Alazawi, Maryam Alkhatry, Naim Alkhouri, Alina Allen, Michael Allison, Khalid Alswat, Mario R Alvares-da-Silva, Michele Alves-Bezerra, Matthew J Armstrong, Diego Arufe, Pablo Aschner, Gyorgy Baffy, Meena Bansal, Pierre Bedossa, Renata Belfort, Thomas Berg, Annalisa Berzigotti, Michael Betel, Cristiana Bianco, Clifford Brass, Carol L Brosgart, Elizabeth Matthews Brunt, Maria Buti, Steve Caldwell, Rotonya Carr, Teresa Casanovas, Laurent Castera, Cyrielle Caussy, Eira Cerda, Naga Chalasani, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Michael Charlton, Amanda Cheung, Daniela Chiodi, Ray Chung, David Cohen, Kathleen Corey, Helma P Cotrim, Javier Crespo, Anuradha Dassanayake, Nicholas Davidson, Robert De Knegt, Victor De Ledinghen, Münevver Demir, Sebastian Diaz, Anna Mae Diehl, Bruce Dimmig, Melisa Dirchwolf, Ajay Duseja, Karel Dvorak, Mattias Ekstedt, Reda El Wakil, María Lucía Ferraz, Scott Friedman, Michael Fuchs, Amalia Gastaldelli, Anja Geerts, Andreas Geier, Marcos Girala, George Goh, Nicolas Goossens, Isabel Graupera, Hannes Hagström, Zachary Henry, Bela Hunyady, Alan Hutchison, Scott Isaacs, François Jornayvaz, Cynthia Kemp, Denise Kile, Won Kim, David Kleiner, Rohit Kohli, Marcelo Kugelmas, Joel Lavine, Mariana Lazo, Nathalie Leite, Adelina Lozano, Panu Luukkonen, Paula Macedo, Dina Mansour, Christos Mantzoros, Giulio Marchesini, Sebastián Marciano, Kim Martinez, Lyudmila Vladimirova Mateva, Jose M Mato, Alexis McCary, Luca Miele, Ivana Mikolasevic, Veronica Miller, Rosalba Moreno, Cynthia Moylan, Atsushi Nakajima, Jean Charles Nault, Suzanne Norris, Mazen Noureddin, C P Oliveira, Arlin Ong, Martín Padilla, Raluca Pais, Arturo Panduro, Manas K Panigrahi, George Papatheodoridis, Serena Pelusi, Marlene Pérez, Juanita Perez Escobar, Gianluca Perseghin, Mario Pessoa, Salvatore Petta, Massimo Pinzani, Monica Platon Lupsor, Atoosa Rabiee, Stefano Romeo, Yaron Rotman, Ian Rowe, Riina Salupere, Sanjaya Satapathy, Jörn M Schattenberg, Wendy Schaufert, Bernd Schnabl, Lynn Seim, Lawrence Serfaty, David Shapiro, Ashwani K Singal, Lubomir Skladany, Norbert Stefan, Jonathan Stine, Shikha Sundaram, Gianluca Svegliati-Baroni, Gyonzgi Szabo, Frank Tacke, Tawesak Tanwandee, Giovanni Targher, Norah Terrault, Brent Tetri, Maja Thiele, Baron Tisthammer, Aldo Torre Delgadillo, Michael Trauner, Emmanuel Tsochatzis, Laurens Van Kleef, Saskia Van Mil, Lisa VanWagner, Jose Antonio Velarde Ruiz Velasco, Mette Vesterhus, Eduardo Vilar-Gomez, Kymberly Watt, Julia Wattacheril, Fonda Wilkins, José Willemse, Amany Zekry, and Shira Zelber-Sagi

Abstract

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmati

Published
2023

7. A multi-society Delphi consensus statement on new fatty liver disease nomenclature

Author

Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela E, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wong, Vincent Wai-Sun, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Newsome, Philip NVeeral Ajmeral, William Alazawi, Maryam Alkhatry, Naim Alkhouri, Alina Allen, Michael Allison, Khalid Alswat, Mario R Alvares-da-Silva, Michele Alves-Bezerra, Matthew J Armstrong, Diego Arufe, Pablo Aschner, Gyorgy Baffy, Meena Bansal, Pierre Bedossa, Renata Belfort, Thomas Berg, Annalisa Berzigotti, Michael Betel, Cristiana Bianco, Clifford Brass, Carol L Brosgart, Elizabeth Matthews Brunt, Maria Buti, Steve Caldwell, Rotonya Carr, Teresa Casanovas, Laurent Castera, Cyrielle Caussy, Eira Cerda, Naga Chalasani, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Michael Charlton, Amanda Cheung, Daniela Chiodi, Ray Chung, David Cohen, Kathleen Corey, Helma P Cotrim, Javier Crespo, Anuradha Dassanayake, Nicholas Davidson, Robert De Knegt, Victor De Ledinghen, Münevver Demir, Sebastian Diaz, Anna Mae Diehl, Bruce Dimmig, Melisa Dirchwolf, Ajay Duseja, Karel Dvorak, Mattias Ekstedt, Reda El Wakil, María Lucía Ferraz, Scott Friedman, Michael Fuchs, Amalia Gastaldelli, Anja Geerts, Andreas Geier, Marcos Girala, George Goh, Nicolas Goossens, Isabel Graupera, Hannes Hagström, Zachary Henry, Bela Hunyady, Alan Hutchison, Scott Isaacs, François Jornayvaz, Cynthia Kemp, Denise Kile, Won Kim, David Kleiner, Rohit Kohli, Marcelo Kugelmas, Joel Lavine, Mariana Lazo, Nathalie Leite, Adelina Lozano, Panu Luukkonen, Paula Macedo, Dina Mansour, Christos Mantzoros, Giulio Marchesini, Sebastián Marciano, Kim Martinez, Lyudmila Vladimirova Mateva, Jose M Mato, Alexis McCary, Luca Miele, Ivana Mikolasevic, Veronica Miller, Rosalba Moreno, Cynthia Moylan, Atsushi Nakajima, Jean Charles Nault, Suzanne Norris, Mazen Noureddin, C P Oliveira, Arlin Ong, Martín Padilla, Raluca Pais, Arturo Panduro, Manas K Panigrahi, George Papatheodoridis, Serena Pelusi, Marlene Pérez, Juanita Perez Escobar, Gianluca Perseghin, Mario Pessoa, Salvatore Petta, Massimo Pinzani, Monica Platon Lupsor, Atoosa Rabiee, Stefano Romeo, Yaron Rotman, Ian Rowe, Riina Salupere, Sanjaya Satapathy, Jörn M Schattenberg, Wendy Schaufert, Bernd Schnabl, Lynn Seim, Lawrence Serfaty, David Shapiro, Ashwani K Singal, Lubomir Skladany, Norbert Stefan, Jonathan Stine, Shikha Sundaram, Gianluca Svegliati-Baroni, Gyonzgi Szabo, Frank Tacke, Tawesak Tanwandee, Giovanni Targher, Norah Terrault, Brent Tetri, Maja Thiele, Baron Tisthammer, Aldo Torre Delgadillo, Michael Trauner, Emmanuel Tsochatzis, Laurens Van Kleef, Saskia Van Mil, Lisa VanWagner, Jose Antonio Velarde Ruiz Velasco, Mette Vesterhus, Eduardo Vilar-Gomez, Kymberly Watt, Julia Wattacheril, Fonda Wilkins, José Willemse, Amany Zekry, Shira Zelber-Sagi, Mary E, R, Jeffrey V, L, Vlad, R, Sven M, F, Arun J, S, Fasiha, K, Diana, R, Manal F, A, Quentin M, A, Juan Pablo, A, Marco, A, Ramon, B, Ulrich, B, Jerome, B, Elisabetta, B, Christopher, B, Graciela E, C, Abhijit, C, Helena, C, Donna, C, Kenneth, C, Mohamed, E, Samuel, K, Wayne, E, Jiangao, F, Samer, G, Cynthia D, G, Stephen A, H, Seung Up, K, Bart, K, Marko, K, Kris, K, Florence, L, Rohit, L, Robert, M, Timothy R, M, Elisabeth, P, Michael, R, Manuel, R, Marcelo, S, Shivaram Prasad, S, Silvia C, S, C Wendy, S, Dina, T, Luca, V, Miriam B, V, Vincent, W, Stavra, X, Yusuf, Y, Zobair, Y, Ansley, H, Marcela, V, Newsome, NVeeral Ajmeral, P, Alazawi, W, Alkhatry, M, Alkhouri, N, Allen, A, Allison, M, Alswat, K, R Alvares-da-Silva, M, Alves-Bezerra, M, J Armstrong, M, Arufe, D, Aschner, P, Baffy, G, Bansal, M, Bedossa, P, Belfort, R, Berg, T, Berzigotti, A, Betel, M, Bianco, C, Brass, C, L Brosgart, C, Matthews Brunt, E, Buti, M, Caldwell, S, Carr, R, Casanovas, T, Castera, L, Caussy, C, Cerda, E, Chalasani, N, Kheong Chan, W, Charatcharoenwitthaya, P, Charlton, M, Cheung, A, Chiodi, D, Chung, R, Cohen, D, Corey, K, P Cotrim, H, Crespo, J, Dassanayake, A, Davidson, N, De Knegt, R, De Ledinghen, V, Demir, M, Diaz, S, Mae Diehl, A, Dimmig, B, Dirchwolf, M, Duseja, A, Dvorak, K, Ekstedt, M, El Wakil, R, Lucía Ferraz, M, Friedman, S, Fuchs, M, Gastaldelli, A, Geerts, A, Geier, A, Girala, M, Goh, G, Goossens, N, Graupera, I, Hagström, H, Henry, Z, Hunyady, B, Hutchison, A, Isaacs, S, Jornayvaz, F, Kemp, C, Kile, D, Kim, W, Kleiner, D, Kohli, R, Kugelmas, M, Lavine, J, Lazo, M, Leite, N, Lozano, A, Luukkonen, P, Macedo, P, Mansour, D, Mantzoros, C, Marchesini, G, Marciano, S, Martinez, K, Vladimirova Mateva, L, M Mato, J, Mccary, A, Miele, L, Mikolasevic, I, Miller, V, Moreno, R, Moylan, C, Nakajima, A, Charles Nault, J, Norris, S, Noureddin, M, P Oliveira, C, Ong, A, Padilla, M, Pais, R, Panduro, A, K Panigrahi, M, Papatheodoridis, G, Pelusi, S, Pérez, M, Perez Escobar, J, Perseghin, G, Pessoa, M, Petta, S, Pinzani, M, Platon Lupsor, M, Rabiee, A, Romeo, S, Rotman, Y, Rowe, I, Salupere, R, Satapathy, S, M Schattenberg, J, Schaufert, W, Schnabl, B, Seim, L, Serfaty, L, Shapiro, D, K Singal, A, Skladany, L, Stefan, N, Stine, J, Sundaram, S, Svegliati-Baroni, G, Szabo, G, Tacke, F, Tanwandee, T, Targher, G, Terrault, N, Tetri, B, Thiele, M, Tisthammer, B, Torre Delgadillo, A, Trauner, M, Tsochatzis, E, Van Kleef, L, Van Mil, S, Vanwagner, L, Antonio Velarde Ruiz Velasco, J, Vesterhus, M, Vilar-Gomez, E, Watt, K, Wattacheril, J, Wilkins, F, Willemse, J, Zekry, A, Zelber-Sagi, S, and Vincent Wai-Sun, W

Subjects
steatotic liver disease, MASLD, alcohol, steatohepatiti, MetALD, NASH, nonalcoholic, Delphi, Fatty liver disease, NAFLD, cardiometabolic, nomenclature, mafld, type 2 diabetes, MED/13 - ENDOCRINOLOGIA
Abstract

Unlabelled: The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Methods: A modified Delphi process was led by three large pan-national liver associations. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Results: A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms 'non-alcoholic' and 'fatty' were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350g/week and 210 to 420g/week for females and males respectively). Conclusions: The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification.

Published
2023

8. Challenges associated with diagnostic exome sequencing in liver diseases

Author

Xiao-Fei Kong, Kelsie Bogyo, Sheena Kapoor, Emily E. Groopman, Amanda Thomas-Wilson, Enrico Cocchi, Hila Milo Rasouly, Beishi Zheng, Siming Sun, Junying Zhang, Mercedes Martinez, Jennifer M Vittorio, Lorna M. Dove, Maddalena Marasa, Timothy C. Wang, Elizabeth C. Verna, Howard J. Worman, Ali G. Gharavi, David B. Goldstein, and Julia Wattacheril

Abstract

Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We analyzed ES data in 758 patients with liver diseases., We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7,856 self-declared healthy controls (HC), and 2,187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and stringent filtering based on population minor allele frequency, we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2test OR: 5.00, 95% CI:3.06-8.18,, p-value=4.5 e-12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Clinically confirmed sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.

Published
2022

9. Bariatric Surgery in the Peritransplant Period

Author

Julia Wattacheril, Averill Guo, Sanket S Mehta, and Sydney Pomenti

Subjects
medicine.medical_specialty, Hepatology, business.industry, General surgery, MEDLINE, Reviews, Medicine, business, Period (music)
Published
2021

10. Nonalcoholic Fatty Liver Disease: Evidence-Based Management and Early Recognition of Nonalcoholic Steatohepatitis

Author

Julia Wattacheril and Nicole Kelly

Subjects
Advanced and Specialized Nursing, medicine.medical_specialty, Cirrhosis, business.industry, medicine.medical_treatment, Inflammation, 030204 cardiovascular system & hematology, Liver transplantation, medicine.disease, Obesity, Gastroenterology, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Fibrosis, Internal medicine, Nonalcoholic fatty liver disease, medicine, 030212 general & internal medicine, Metabolic syndrome, medicine.symptom, business
Abstract

Nonalcoholic fatty liver disease is the most prevalent liver disease in the world. Metabolic syndrome and obesity are associated risk factors. The inflammatory subtype, nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis, is predicted to become the primary indication for liver transplantation within the next decade. Although there are no approved medications for NASH, there are ongoing multicenter trials aimed at targeting aspects of fat accumulation, inflammation, and fibrosis throughout the disease process. Nurse practitioners should focus on identifying patients at risk for NASH, while using guidelines for the management of nonalcoholic fatty liver disease and the comorbidities contributing to disease progression.

Published
2019

11. Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study

Author

Julia Wattacheril, Carla Kettler, Ethan Miller, Lara Dakhoul, Hamzah Abu-Sbeih, Heather Burney, Andrew Scanga, Samer Gawrieh, Andrew deLemos, Naga Chalasani, and Hao Liu

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Milan criteria, medicine.disease_cause, Gastroenterology, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Aged, Hepatitis B virus, Hepatology, business.industry, Liver Neoplasms, Fatty liver, Hepatitis C, Middle Aged, Hepatitis B, medicine.disease, United States, digestive system diseases, Hepatocellular carcinoma, Female, 030211 gastroenterology & hepatology, business
Abstract

BACKGROUND Limited data exist on the burden and features of non-cirrhotic hepatocellular carcinoma (HCC) in the United States. AIM To evaluate characteristics, aetiologies, trends and outcomes of non-cirrhotic HCC from 2000 to 2014 at five large US centres METHODS: Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non-cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P

Published
2019

12. Rapid Identification and Phenotyping of Nonalcoholic Fatty Liver Disease Patients Using an Algorithmic Approach in Diverse, Urban Healthcare Systems

Author

Anurag Verma, Brittney Destin, Gunaretnam Rajagopal, Julia Wattacheril, Ava Farrell, Abraham Krikhely, Leigh Anne Tang, Muredach P. Reilly, Rotonya M. Carr, Andrew Scanga, Marc Bessler, Nicholas P. Tatonetti, Anuli Anyanwu-Ofili, Marylyn D. Ritchie, Anna O. Basile, Marina Serper, and Joshua C. Denny

Subjects
education.field_of_study, medicine.medical_specialty, business.industry, Population, Psychological intervention, Context (language use), medicine.disease, Chronic liver disease, Liver disease, Nonalcoholic fatty liver disease, medicine, Observational study, Diagnosis code, education, business, Intensive care medicine
Abstract

ObjectivesNonalcoholic Fatty Liver Disease (NAFLD) is the most common global cause of chronic liver disease. Therapeutic interventions are rapidly advancing for its inflammatory phenotype, nonalcoholic steatohepatitis (NASH) at all stages of disease. Diagnosis codes alone fail to accurately recognize and stratify at-risk patients. Our work aims to rapidly identify NAFLD patients within large electronic health record (EHR) databases for automated stratification and targeted intervention based on clinically relevant phenotypes.MethodsWe present a rule-based phenotyping algorithm for the rapid identification of NAFLD patients developed using EHRs from 6.4 million patients at Columbia University Irving Medical Center (CUIMC) and validated at two independent healthcare centers. The algorithm uses the Observational Medical Outcomes Partnership (OMOP) Common Data Model and queries multiple structured and unstructured data elements, including diagnosis codes, laboratory measurements, radiology and pathology modalities.ResultsOur approach identified 16,006 CUIMC NAFLD patients, 10,753 (67%) of whom were previously unidentifiable by NAFLD diagnosis codes. Fibrosis scoring on patients without histology identified 943 subjects with scores indicative of advanced fibrosis (FIB-4, APRI, NAFLD–FS). The algorithm was validated at two independent healthcare systems, University of Pennsylvania Health System (UPHS) and Vanderbilt Medical Center (VUMC), where 20,779 and 19,575 NAFLD patients were identified, respectively. Clinical chart review identified a high positive predictive value (PPV) across all healthcare systems: 91% at CUIMC, 75% at UPHS, and 85% at VUMC, and a sensitivity of 79.6%.ConclusionsOur rule-based algorithm provides an accurate, automated approach for rapidly identifying, stratifying, and sub-phenotyping NAFLD patients within a large EHR system.Study HighlightsWHAT IS KNOWNNAFLD is the leading form of chronic liver disease with a rising prevalence in the population.NAFLD is often under-recognized in at-risk individuals, including within healthcare settings.Current means of identification and stratification are complex and dependent on provider recognition of clinical risk factors.WHAT IS NEW HEREAn accurate, validated rule-based algorithm for the high-throughput and rapid EHR identification of NAFLD patients.Rapid discovery of a NAFLD cohort from diverse EHR systems comprising approximately 12.1 million patients.Our algorithm has high performance (mean PPV=85%, sensitivity=79.6%) in NAFLD patient discovery.The majority of algorithmically derived NAFLD patients were previously unidentified within healthcare systems.Computational stratification of individuals with advanced fibrosis can be achieved rapidly.

Published
2021

14. Gender Matters: Characteristics of Hepatocellular Carcinoma in Women From a Large, Multicenter Study in the United States

Author

Julia Wattacheril, Ethan Miller, Meaghan Phipps, Averill Guo, Alexandra E. Livanos, Jonathan Yeh, Sydney Pomenti, Samer Gawrieh, Hao Liu, Naga Chalasani, Heather Burney, Carla Kettler, Andrew Scanga, Lara Dakhoul, and Andrew deLemos

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Alcoholic liver disease, Cirrhosis, Carcinoma, Hepatocellular, Milan criteria, Gastroenterology, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Sex Factors, Non-alcoholic Fatty Liver Disease, Internal medicine, Nonalcoholic fatty liver disease, Carcinoma, Medicine, Humans, Liver Diseases, Alcoholic, Aged, Hepatology, business.industry, Liver Neoplasms, Middle Aged, medicine.disease, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cohort, 030211 gastroenterology & hepatology, Female, business
Abstract

INTRODUCTION Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).

Published
2020

15. Distinctive Features and Outcomes of Hepatocellular Carcinoma in Patients With Alcohol-Related Liver Disease: A US Multicenter Study

Author

Julia Wattacheril, Milin Patel, Andrew deLemos, Lara Dakhoul, Carla Kettler, Andrew Scanga, Hao Liu, Heather Burney, Samer Gawrieh, Ethan Miller, Patrick Roche, and Naga Chalasani

Subjects
Male, endocrine system, congenital, hereditary, and neonatal diseases and abnormalities, Alcoholic liver disease, medicine.medical_specialty, Carcinoma, Hepatocellular, endocrine system diseases, medicine.medical_treatment, Liver transplantation, Milan criteria, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, In patient, Liver Diseases, Alcoholic, Aged, Retrospective Studies, business.industry, Liver Neoplasms, nutritional and metabolic diseases, Middle Aged, medicine.disease, Survival Analysis, digestive system diseases, United States, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cohort, Etiology, Disease Progression, 030211 gastroenterology & hepatology, Female, Viral hepatitis, business
Abstract

Introduction: The burden of hepatocellular carcinoma (HCC) occurring in patients with alcoholic liver disease (ALD) is increasing at an alarming rate. The aims of this study were to compare the patient and tumor characteristics of HCC occurring in ALD-alone relative to and in addition to other chronic liver diseases. Methods: Patients diagnosed with HCC between 2000 and 2014 were identified at 5 US clinical centers. The patients were categorized as ALD-alone, ALD plus viral hepatitis, or a non-ALD etiology. Clinical and tumor characteristics among the 3 groups were compared, and survival probability was estimated by the Kaplan-Meier method. The frequency of noncirrhotic HCC was compared across the 3 groups. Results: A total of 5,327 patients with HCC were analyzed. Six hundred seventy (12.6%) developed HCC due to underlying ALD. Ninety-one percent of ALD-related HCC arose in men, in contrast to non-ALD etiologies where men accounted for 70% of HCCs cases (P < 0.001). Patients with ALD-alone-related HCC were older at diagnosis and had tumors less likely to be detected as part of routine surveillance. The ALD-alone cohort was least likely to be within the Milan criteria and to undergo liver transplantation. Overall survival in the ALD-alone HCC cohort was lower than the other 2 groups (1.07 vs 1.31 vs 1.41 years, P < 0.001). HCC in the noncirrhotic ALD cohorts occurred in only 3.5% of the patients compared with 15.7% in patients with non-ALD etiologies (P < 0.001). DISCUSSION: HCC occurring in patients with ALD occurred mostly in older men and almost exclusively in a cirrhotic background. They present with advanced tumors, and their survival is lower than HCCs occurring in non-ALD.

Published
2020

16. Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease

Author

Julia Wattacheril

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, Fatty liver, Gastroenterology, nutritional and metabolic diseases, Type 2 diabetes, medicine.disease, digestive system diseases, 03 medical and health sciences, Liver disease, 030104 developmental biology, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, Diabetes mellitus, Nonalcoholic fatty liver disease, medicine, 030211 gastroenterology & hepatology, Metabolic syndrome, business, Disease burden, Kidney disease
Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a global public health burden. NAFLD, while strongly associated with the metabolic syndrome, can occur independently from existing metabolic diseases. In addition to liver-related disease burden and mortality, significant extrahepatic disease outcomes coexist with NAFLD, including cardiovascular diseases, chronic kidney disease, and type 2 diabetes. Management of these comorbidities contributes to the overall public health burden of NAFLD. These extrahepatic manifestations require healthcare interventions that are vigilant in monitoring for progression of liver disease while simultaneously managing overall morbidity and mortality from other organ systems.

Published
2020

17. rs641738C>T near MBOAT7 is positively associated with liver fat, ALT, and histological severity of NAFLD: a meta-analysis

Author

Jesus M. Banales, Jerome I. Rotter, Connor A. Emdin, Leon A. Adams, Sreekumar G. Pillai, Stephan Buch, Yu Ri Im, Thomas Berg, Claudia Langenberg, Kendra A. Young, Felix Stickel, Elizabeth K. Speliotes, Julia Kozlitina, Sonia Caprio, Madison Fairey, Kevin Teo, Hanieh Yaghootkar, Abhijit Chowdhury, Eu-Pnafld Investigators, Yii-Der Ida Chen, Harriet Hunter, Faiza Qayyum, Pavel Strnad, Matthias C. Reichert, Elmar Aigner, Marcin Krawczyk, Dana de Gracia Hahn, Lin Li, Matthew Hickman, Nicholette D. Palmer, Panu K. Luukkonen, Jiawen Dong, Christian Datz, Ali Canbay, Kent D. Taylor, Joel E. Lavine, Philip E. Melton, Nicola Santoro, Richard M. Watanabe, Xiuqing Guo, Giuseppina Rosaria Umano, Lynne E. Wagenknecht, Amedine Duret, Pallav Bhatnagar, Trevor A. Mori, Johanna K. DiStefano, Anne Tybjærg-Hansen, Stefano Romeo, Julia Wattacheril, Jake P. Mann, Luca Valenti, Ankita Chatterjee, Stefan Stender, Jochen Hampe, Rajarshi Banerjee, Glenn S. Gerhard, Frank Lammert, Rohit Loomba, Christian A. Hudert, Kushala W M Abeysekera, L Heintz, Constantinos A. Parisinos, Hong Kai Lim, Christopher D. Still, Matt Kelly, Mrudula Utukuri, Priyadarshi Basu, Nicholas J. Wareham, Hannele Yki-Järvinen, and Clemens Schafmayer

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, Insulin, medicine.medical_treatment, Fatty liver, Genome-wide association study, medicine.disease, Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Internal medicine, Genetic model, medicine, Steatosis, Risk factor, business, 030304 developmental biology
Abstract

Background & AimsA common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis.MethodsWe performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models.ResultsData from 1,047,265 participants (8,303 with liver biopsies) across 42 studies was included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05]) and diagnosis of NAFLD (OR 1.22 [95% CI 1.08 - 1.39]) in Caucasian adults. The variant was also positively associated with presence of severe steatosis, NASH, and advanced fibrosis (OR: 1.32 [95% CI: 1.06 - 1.63]) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (Pz=0.002) and lower serum triglycerides (Pz=1.5×10−4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.ConclusionOur study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Published
2019

18. Nonalcoholic Steatohepatitis (NASH) and Hepatic Fibrosis: Emerging Therapies

Author

Danny Issa, Arun J. Sanyal, and Julia Wattacheril

Subjects
Liver Cirrhosis, 0301 basic medicine, Pathology, medicine.medical_specialty, Disease, Toxicology, Bioinformatics, 03 medical and health sciences, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, Diabetes mellitus, Nonalcoholic fatty liver disease, medicine, Clinical endpoint, Animals, Humans, Pharmacology, business.industry, Fatty liver, medicine.disease, 030104 developmental biology, Clinical Trials, Phase III as Topic, Liver, 030211 gastroenterology & hepatology, Hepatic fibrosis, business, Dyslipidemia
Abstract

Nonalcoholic fatty liver disease remains a major cause of liver-related morbidity and mortality worldwide. It is a complex disease associated with obesity, diabetes, and dyslipidemia but is increasingly recognized in normal-weight individuals. Its progressive inflammatory phenotype, nonalcoholic steatohepatitis (NASH), currently has no effective treatment apart from lifestyle interventions. Multiple pathogenic pathways are involved in disease progression, and targets for intervention have been identified. These targets mediate glucose, lipid, and bile acid metabolism; inflammation; apoptosis; and fibrosis. Novel therapeutic agents are being developed in each of these pathways, and several have shown promise in early phase testing. Given the complexity of the disease, intervention trials are large and long and require histologic confirmation as a primary endpoint for disease improvement or regression. We highlight active Phase 2 and 3 therapeutic trials for NASH as this field rapidly expands in development.

Published
2018

19. Response to Braillon

Author

Julia Wattacheril and Meaghan Phipps

Subjects
medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Gastroenterology, medicine, Carcinoma, MEDLINE, medicine.disease, business
Published
2021

20. Treatment options for nonalcoholic steatohepatitis - a safety evaluation

Author

Julia Wattacheril, Arun J. Sanyal, and Danny Issa

Subjects
0301 basic medicine, medicine.medical_specialty, Pharmacology, Gut flora, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Non-alcoholic Fatty Liver Disease, Fibrosis, Weight loss, law, Weight Loss, Nonalcoholic fatty liver disease, medicine, Animals, Humans, Pharmacology (medical), Molecular Targeted Therapy, Intensive care medicine, biology, business.industry, Fatty liver, Drugs, Investigational, General Medicine, medicine.disease, biology.organism_classification, Clinical trial, 030104 developmental biology, Tolerability, Drug Design, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract

There is an urgent as yet unmet need to develop highly effective and safe therapeutics for nonalcoholic fatty liver disease (NAFLD). The remarkable progress in understanding NAFLD pathogenesis allowed the identification of injury pathways which may be recruited as therapy targets. Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis. Expert opinion: Current therapies continue to remain suboptimal. Weight loss is effective but hard to achieve. Traditional and endoscopic bariatric procedures are promising although more randomized trials are needed and the long-term safety remains to be established. Clinical trials have demonstrated the efficacy of several drugs for the treatment of NASH. Of these, there remains some uncertainty about the long-term safety of vitamin E. Pioglitazone is associated with osteopenia, fluid retention and weight gain. Obeticholic acid causes pruritus in a substantial proportion of subjects and elafibranor has been associated with transient rises in creatinine. Several exciting therapies are under development and results of clinical and post-marketing trials will help elucidate their safety.

Published
2017

21. Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle

Author

Matthew D. Spann, Kristie L. Rose, Christian Lanciault, Naji N. Abumrad, Salisha Hill, Julia Wattacheril, Kay Washington, Charles R. Flynn, Ronald H. Clements, Clark R. Murray, Brandon Williams, and Wayne J. English

Subjects
0301 basic medicine, medicine.medical_specialty, Hepatology, medicine.diagnostic_test, Fatty liver, Phosphoproteomics, Lipid metabolism, Biology, Carbohydrate metabolism, medicine.disease, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Infectious Diseases, Endocrinology, chemistry, Liver biopsy, Phosphoserine, Internal medicine, medicine, Phosphorylation, 030211 gastroenterology & hepatology, Signal transduction
Abstract

Background Molecular signaling events associated with the necroinflammatory changes in nonalcoholic steatohepatitis (NASH) are not well understood. Aims To understand the molecular basis of NASH, we evaluated reversible phosphorylation events in hepatic tissue derived from Class III obese subjects by phosphoproteomic means with the aim of highlighting key regulatory pathways that distinguish NASH from non-alcoholic fatty liver disease (also known as simple steatosis; SS). Materials & Methods Class III obese subjects undergoing bariatric surgery underwent liver biopsy (eight normal patients, eight with simple steatosis, and eight NASH patients). Our strategy was unbiased, comparing global differences in liver protein reversible phosphorylation events across the 24 subjects. Results Of the 3078 phosphorylation sites assigned (2465 phosphoserine, 445 phosphothreonine, 165 phosphotyrosine), 53 were altered by a factor of 2 among cohorts, and of those, 12 were significantly increased or decreased by ANOVA (P < 0.05). Discussion Statistical analyses of canonical signaling pathways identified carbohydrate metabolism and RNA post-transcriptional modification among the most over-represented networks. Conclusion Collectively, these results raise the possibility of abnormalities in carbohydrate metabolism as an important trigger for the development of NASH, in parallel with already established abnormalities in lipid metabolism.

Published
2017

22. Risk factors for hepatocellular carcinoma in cirrhosis due to nonalcoholic fatty liver disease: A multicenter, case-control study

Author

Samer Gawrieh, Krista Bossi, Megan Comerford, Naga Chalasani, Jorge Sanchez, Julia Wattacheril, Samina Munir, Andrew Scanga, Kathleen E. Corey, Christopher J. Danford, Andrew deLemos, Hui Zheng, and Jennifer W. Haglund

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Hepatocellular carcinoma, Case-control study, Case Control Study, medicine.disease, Gastroenterology, digestive system diseases, Cirrhosis, Gender, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Nonalcoholic fatty liver disease, medicine, Ethnicity, 030211 gastroenterology & hepatology, business
Abstract

AIM To identify risk factors associated with hepatocellular carcinoma (HCC), describe tumor characteristics and treatments pursed for a cohort of individuals with nonalcoholic steatohepatitis (NASH) cirrhosis. METHODS We conducted a retrospective case-control study of a well-characterized cohort of patients among five liver transplant centers with NASH cirrhosis with (cases) and without HCC (controls). RESULTS Ninety-four cases and 150 controls were included. Cases were significantly more likely to be male than controls (67% vs 45%, P < 0.001) and of older age (61.9 years vs 58 years, P = 0.002). In addition, cases were more likely to have had complications of end stage liver disease (83% vs 71%, P = 0.032). On multivariate analysis, the strongest association with the presence of HCC were male gender (OR 4.3, 95%CI: 1.83-10.3, P = 0.001) and age (OR = 1.082, 95%CI: 1.03-1.13, P = 0.001). Hispanic ethnicity was associated with a decreased prevalence of HCC (OR = 0.3, 95%CI: 0.09-0.994, P = 0.048). HCC was predominantly in the form of a single lesion with regional lymph node(s) and distant metastasis in only 2.6% and 6.3%, respectively. Fifty-nine point three percent of individuals with HCC underwent locoregional therapy and 61.5% underwent liver transplantation for HCC. CONCLUSION Male gender, increased age and non-Hispanic ethnicity are associated with HCC in NASH cirrhosis. NASH cirrhosis associated HCC in this cohort was characterized by early stage disease at diagnosis and treatment with locoregional therapy and transplant.

Published
2017

23. Impact of Obeticholic Acid on the Lipoprotein Profile in Patients with Nonalcoholic Steatohepatitis

Author

Margery A. Connelly, Srinivasan Dasarathy, Rohit Loomba, Raj Vuppalanchi, Naga Chalasani, Brent A. Neuschwander-Tetri, Cynthia D. Guy, Mohammad S. Siddiqui, Arun J. Sanyal, James Tonascia, Mark L. Van Natta, and Julia Wattacheril

Subjects
0301 basic medicine, Adult, Male, Very low-density lipoprotein, medicine.medical_specialty, Biopsy, Receptors, Cytoplasmic and Nuclear, Lipoproteins, VLDL, Chenodeoxycholic Acid, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Non-alcoholic Fatty Liver Disease, Internal medicine, Medicine, Humans, Hepatology, Cholesterol, business.industry, Obeticholic acid, Middle Aged, medicine.disease, eye diseases, Lipoproteins, LDL, 030104 developmental biology, Endocrinology, Treatment Outcome, chemistry, Liver, Low-density lipoprotein, 030211 gastroenterology & hepatology, Farnesoid X receptor, lipids (amino acids, peptides, and proteins), Drug Therapy, Combination, Female, Steatohepatitis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Lipoproteins, HDL, Lipoprotein
Abstract

Obeticholic acid (OCA), a farnesoid X receptor agonist, increases total and low-density lipoprotein cholesterol (LDL-C) in patients with non-alcoholic steatohepatitis. In the present study, we aimed to evaluate the impact of OCA therapy on lipoprotein sub-particles.This study included 196 patients (99 OCA group and 97 placebo group) who were enrolled in the FLINT trial and had samples available for lipid analysis and liver biopsies at enrollment and end-of-treatment (EOT) at 72 weeks. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particles were evaluated at baseline, 12 and 72 weeks after randomization, and 24 weeks following EOT.Baseline lipoprotein profiles were similar among OCA and placebo groups. OCA did not affect total VLDL particle concentrations, but OCA vs. placebo treatment was associated with decreased large VLDL particle concentration at 12 weeks (baseline-adjusted mean: 6.8 vs. 8.9 nmol/L; p = 0.002), mirrored by an increase in less atherogenic, small VLDL particle concentration (33.9 vs. 28.0 nmol/L; p = 0.02). After 12 weeks, total LDL particle concentration was higher in the OCA group than the placebo group (1,667 vs. 1,329 nmol/L; p 0.0001), characterized by corresponding increases in both less atherogenic, large-buoyant LDL (475 vs. 308 nmol/L; p ≤0.001) and more atherogenic small-dense LDL particles (1,015 vs. 872 nmol/L; p = 0.002). The changes in LDL particle concentrations were similar between treatment groups (OCA and placebo) 24 weeks following EOT due to improvement in the OCA cohort. Compared to placebo, a reduction in total HDL particle concentration, particularly large and medium HDL particles, was noted in the OCA-treated patients, but this resolved after drug discontinuation.OCA therapy is associated with increases in small VLDL particles, large and small LDL particles, and a reduction in HDL particles at 12 weeks. These lipoprotein concentrations reverted to baseline values 24 weeks after drug discontinuation.Non-alcoholic steatohepatitis is a chronic liver disease that is associated with an increased risk of developing cirrhosis and cardiovascular disease. Recently, obeticholic acid (OCA), a farnesoid X receptor agonist, improved liver disease but led to an increase in cholesterol. However, the impact of OCA on cholesterol is not well understood. In the present study, we show that OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.

Published
2019

24. Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals

Author

Julia Wattacheril and Meaghan Phipps

Subjects
0301 basic medicine, Nonalcoholic steatohepatitis, Hepatology, business.industry, Fatty liver, Gastroenterology, nutritional and metabolic diseases, Disease, medicine.disease, Chronic liver disease, Bioinformatics, digestive system diseases, 03 medical and health sciences, Liver disease, 030104 developmental biology, 0302 clinical medicine, Insulin resistance, Non obese, Liver, Medicine, 030211 gastroenterology & hepatology, Disease management (health), business
Abstract

Individuals with non-alcoholic fatty liver disease (NAFLD) who lack classical risk factors also have the ability to develop nonalcoholic steatohepatitis (NASH) and progression to more advanced liver disease. The pathophysiology and risk factors for the development of NAFLD in non-obese persons are not fully understood but seem to be closely related to insulin resistance, atherogenic dyslipidaemia and alterations in body composition, with some patients harbouring predisposing genetic polymorphisms. In normal-weight individuals, also called ‘lean’, there is limited potential for effective lifestyle change in disease management. Additionally, biological mechanisms underlying the development of NASH in non-obese individuals may reveal novel targets for intervention. In this review, the authors discuss the clinical, histological and genetic features and risk factors for non-obese NAFLD and highlight gaps in knowledge and areas for future research.

Published
2019

26. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension

Author

Naga Chalasani, Manal F. Abdelmalek, Guadalupe Garcia-Tsao, Raj Vuppalanchi, Naim Alkhouri, Mary Rinella, Mazen Noureddin, Maxmillan Pyko, Mitchell Shiffman, Arun Sanyal, Adam Allgood, Harold Shlevin, Rex Horton, Eliezer Zomer, William Irish, Zachary Goodman, Stephen A. Harrison, Peter G. Traber, Manal Abdelmalek, Luis Balart, Brian Borg, Michael Charlton, Hari Conjeevaram, Michael Fuchs, Reem Ghalib, Pierre Gholam, Dina Halegoua-De Marzio, Stephen Harrison, Christopher Jue, Nyingi Kemmer, Kris Kowdley, Michelle Lai, Eric Lawitz, Rohit Loomba, Angelo Paredes, Don Rockey, Miguel Rodriguez, Raymond Rubin, Michael Ryan, Andrew Scanga, Thomas Sepe, Brent Tetri, Paul Thuluvath, Dawn Torres, John Vierling, Julia Wattacheril, Amanda Weiland, and Donald Zogg

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Portal venous pressure, Biopsy, Galectin 3, Galectins, Placebo, Gastroenterology, Severity of Illness Index, Drug Administration Schedule, Placebos, Esophageal varices, Double-Blind Method, Non-alcoholic Fatty Liver Disease, Internal medicine, Nonalcoholic fatty liver disease, Hypertension, Portal, Medicine, Humans, Infusions, Intravenous, Aged, Intention-to-treat analysis, Hepatology, business.industry, Blood Proteins, Middle Aged, medicine.disease, Portal Pressure, Treatment Outcome, Liver, Portal hypertension, Pectins, Female, business, Varices
Abstract

Background & Aims Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. Methods Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. Results We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (–0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (–0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. Conclusions In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices. ClinicalTrials.gov number: NCT02462967

Published
2019

27. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Author

Zobair M Younossi, Vlad Ratziu, Rohit Loomba, Mary Rinella, Quentin M Anstee, Zachary Goodman, Pierre Bedossa, Andreas Geier, Susanne Beckebaum, Philip N Newsome, David Sheridan, Muhammad Y Sheikh, James Trotter, Whitfield Knapple, Eric Lawitz, Manal F Abdelmalek, Kris V Kowdley, Aldo J Montano-Loza, Jerome Boursier, Philippe Mathurin, Elisabetta Bugianesi, Giuseppe Mazzella, Antonio Olveira, Helena Cortez-Pinto, Isabel Graupera, David Orr, Lise Lotte Gluud, Jean-Francois Dufour, David Shapiro, Jason Campagna, Luna Zaru, Leigh MacConell, Reshma Shringarpure, Stephen Harrison, Arun J Sanyal, Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Cindy Cai, Amy Calderon, José Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrión, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Charlote Costentin, Kathleen Corey, Lynsey Corless, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Mamie Dong, Jean-François Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Marek Hartleb, Tarek Hassanein, Dieter Häussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Hyder Hussaini, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Shoba Joshi, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Scott Kuwada, Damien Labarriere, Michelle Lai, Wim Laleman, Pietro Lampertico, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Velimir Anthony Christopher Luketic, Yoav Lurie, Guilherme Macedo, Joana Magalhaes, Mihály Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Linda Martinez, Marlyn Mayo, Mark McCullen, William McLaughlin, Uta Merle, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Amilcar Morales Cardona, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Müller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Hans Orlent, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Sonali Paul, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Joseph Pisegna, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Justin Reynolds, Andres Riera, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Sandor Romero, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jörn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Albert Tran, Michael Trauner, Christian Trautwein, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Julia Wattacheril, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin, Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z., Bedossa P., Geier A., Beckebaum S., Newsome P.N., Sheridan D., Sheikh M.Y., Trotter J., Knapple W., Lawitz E., Abdelmalek M.F., Kowdley K.V., Montano-Loza A.J., Boursier J., Mathurin P., Bugianesi E., Mazzella G., Olveira A., Cortez-Pinto H., Graupera I., Orr D., Gluud L.L., Dufour J.-F., Shapiro D., Campagna J., Zaru L., MacConell L., Shringarpure R., Harrison S., Sanyal A.J., Abdelmalek M., Abrams G., Aguilar H., Ahmed A., Aigner E., Aithal G., Ala A., Alazawi W., Albillos A., Allison M., Al-Shamma S., Andrade R., Andreone P., Angelico M., Ankoma-Sey V., Anstee Q., Anty R., Araya V., Arenas Ruiz J.I., Arkkila P., Arora M., Asselah T., Au J., Ayonrinde O., Bailey R.J., Balakrishnan M., Bambha K., Bansal M., Barritt S., Bate J., Beato J., Behari J., Bellot P., Ben Ari Z., Bennett M., Berenguer M., Beretta-Piccoli B.T., Berg T., Bonacini M., Bonet L., Borg B., Bourliere M., Bowman W., Bradley D., Brankovic M., Braun M., Bronowicki J.-P., Bruno S., Cai C., Calleja Panero J.L., Carey E., Carmiel M., Carrion J.A., Cave M., Chagas C., Chami T., Chang A., Coates A., Cobbold J., Corey K., Corless L., Crespo J., Cruz Pereira O., de Ledinghen V., deLemos A., Diago M., Dugalic P., Dunn W., Elkhashab M., Epstein M., Escudero-Garcia M.D., Etzion O., Evans L., Falcone R., Fernandez C., Ferreira J., Fink S., Finnegan K., Firpi-Morell R., Floreani A., Fontanges T., Ford R., Forrest E., Fowell A., Fracanzani A.L., Francque S., Freilich B., Frias J., Fuchs M., Fuentes J., Galambos M., Gallegos J., Geerts A., George J., Ghali M., Ghalib R., Gholam P., Gines P., Gitlin N., Goeser T., Goff J., Gordon S., Gordon F., Goria O., Greer S., Grigorian A., Gronbaek H., Guillaume M., Gunaratnam N., Halegoua-De Marzio D., Hameed B., Hametner S., Hamilton J., Hartleb M., Hassanein T., Haussinger D., Hellstern P., Herring R., Heurich E., Hezode C., Hinrichsen H., Holland Fischer P., Horsmans Y., Huang J., Jakiche A., Jeffers L., Jones B., Jorge R., Jorquera F., Kahraman A., Kaita K., Karyotakis N., Kayali Z., Kechagias S., Kepczyk T., Khalili M., Khallafi H., Kluwe J., Kohli A., Korenblat K., Kowdley K., Krag A., Krause R., Kremer A., Krok K., Krstic M., Kugelmas M., Kumar S., Labarriere D., Lai M., Lampertico P., Lee A., Leroy V., Lidofsky S., Lim T.H., Lim J., Lipkis D., Little E., Lonardo A., Long M., Lurie Y., Macedo G., Makara M., Maliakkal B., Manns M., Manousou P., Mantry P., Marchesini G., Marinho C., Marotta P., Marschall H.-U., Mayo M., McCullen M., McLaughlin W., Merriman R., Modi A., Molina E., Montano-Loza A., Monteverde C., Moreea S., Moreno C., Morisco F., Mubarak A., Muellhaupt B., Mukherjee S., Muller T., Nagorni A., Naik J., Neff G., Nevah M., Newsome P., Nguyen-Khac E., Noureddin M., Oben J., Orlent H., Orr J., Ortiz-Lasanta G., Ozenne V., Pandya P., Paredes A., Park J., Patel J., Patel K., Uta M., Patton H., Peck-Radosavljevic M., Petta S., Pianko S., Piekarska A., Pimstone N., Pockros P., Pol S., Porayko M., Poulos J., Pound D., Pouzar J., Presa Ramos J., Pyrsopoulos N., Rafiq N., Muller K., Ramji A., Ravinuthala R., Reddy C., Reddy K G G., Reddy K R K.R., Regenstein F., Reindollar R., Riera A., Rivera Acosta J., Robaeys G., Roberts S., Rodriguez-Perez F., Romero-Gomez M., Rubin R., Rumi M., Rushbrook S., Rust C., Ryan M., Safadi R., Said A., Salminen K., Samuel D., Santoro J., Sanyal A., Sarkar S., Schaeffer C., Schattenberg J., Schiefke I., Schiff E., Schmidt W., Schneider J., Schouten J., Schultz M., Sebastiani G., Semela D., Sepe T., Sheikh A., Sheikh M., Sherman K., Shibolet O., Shiffman M., Siddique A., Sieberhagen C., Sigal S., Sikorska K., Simon K., Sinclair M., Skoien R., Solis J., Sood S., Souder B., Spivey J., Stal P., Stinton L., Strasser S., Svorcan P., Szabo G., Talal A., Tam E., Tetri B., Thuluvath P., Tobias H., Tomasiewicz K., Torres D., Trauner M., Trautwein C., Tsochatzis E., Unitt E., Vargas V., Varkonyi I., Veitsman E., Vespasiani Gentilucci U., Victor D., Vierling J., Vincent C., Vincze A., von der Ohe M., Von Roenn N., Vuppalanchi R., Waters M., Watt K., Weltman M., Wieland A., Wiener G., Williams A A., Williams J J., Wilson J., Yataco M., Yoshida E., Younes Z., Yuan L., Zivony A., Zogg D., Zoller H., Zoulim F., Zuckerman E., Zuin M., Repositório da Universidade de Lisboa, Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. -F., Shapiro, D., Campagna, J., Zaru, L., Macconell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., Al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. -P., Bruno, S., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrion, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Crespo, J., Cruz Pereira, O., de Ledinghen, V., Delemos, A., Diago, M., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-De Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Hartleb, M., Hassanein, T., Haussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. -U., Mayo, M., Mccullen, M., Mclaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Muller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Orlent, H., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., Von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., Zuin, M., Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andrea, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, Jame, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francoi, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert Jame, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thoma, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Mariu, Bronowicki, Jean-Pierre, Bruno, Savino, Cai, Cindy, Calleja Panero, José Lui, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Corey, Kathleen, Corless, Lynsey, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moise, Dufour, Jean-Françoi, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparado, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Goeser, Tobia, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, Jame, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yve, Huang, Jonathan, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nichola, Kayali, Zeid, Kechagias, Stergio, Kepczyk, Thoma, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johanne, Kohli, Anita, Korenblat, Kevin, Kowdley, Kri, Krag, Aleksander, Krause, Richard, Kremer, Andrea, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Labarriere, Damien, Lai, Michelle, Lampertico, Pietro, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Lurie, Yoav, Macedo, Guilherme, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Mayo, Marlyn, McCullen, Mark, McLaughlin, William, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlo, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobia, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moise, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Orlent, Han, Orr, Jame, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, Jame, Patel, Joykumar, Patel, Keyur, Uta, Merle, Patton, Heather, Peck-Radosavljevic, Marku, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pockros, Paul, Pol, Stanisla, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolao, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Riera, Andre, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thoma, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, Jame, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Trauner, Michael, Trautwein, Christian, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, Zuin, Massimo, and REGENERATE Study Investigators

Subjects
Male, Biopsy, Clinical Trial, Phase III, Administration, Oral, 030204 cardiovascular system & hematology, Chronic liver disease, Settore MED/04, Biomarkers/analysis, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Liver Function Tests, Non-alcoholic Fatty Liver Disease, Clinical endpoint, Medicine, 030212 general & internal medicine, 610 Medicine & health, Chenodeoxycholic Acid/administration & dosage, education.field_of_study, Liver Function Test, Research Support, Non-U.S. Gov't, Fatty liver, Obeticholic acid, NASH, OBETICHOLIC ACID, General Medicine, Middle Aged, Multicenter Study, Randomized Controlled Trial, Administration, Female, Biomarkers, Chenodeoxycholic Acid, Double-Blind Method, Humans, Human, Oral, medicine.medical_specialty, Population, Placebo, 03 medical and health sciences, Research Support, N.I.H., Extramural, Internal medicine, Journal Article, education, Intention-to-treat analysis, business.industry, Biomarker, Interim analysis, medicine.disease, Non-alcoholic Fatty Liver Disease/drug therapy, chemistry, Human medicine, business
Abstract

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Published
2019
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28. Lean NAFLD: an Underrecognized Outlier

Author

Julia Wattacheril and Arun J. Sanyal

Subjects
0301 basic medicine, medicine.medical_specialty, Population, Overweight, Bioinformatics, digestive system, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Virology, Internal medicine, Nonalcoholic fatty liver disease, Epidemiology, medicine, education, education.field_of_study, Hepatology, business.industry, nutritional and metabolic diseases, medicine.disease, digestive system diseases, Natural history, 030104 developmental biology, 030211 gastroenterology & hepatology, medicine.symptom, business, Risk assessment, Clinical risk factor
Abstract

Nonalcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese or overweight individuals. However, lean individuals with NAFLD are not rare but represent one significant end of the phenotypic spectrum of NAFLD. Although initial observations between obese and lean NAFLD reveal some metabolic parallels, these associations vary widely given differences in study populations and metabolic parameters assessed. The role of body composition in risk assessment is significant and incompletely assessed during most clinical encounters. Recent multinational investigation reveals an increased mortality in lean individuals with NASH. Many aspects of lean NAFLD need further exploration including epidemiology, clinical risk assessment, histologic changes unique to lean NAFLD, genetic and pathophysiologic mechanisms predisposing at risk individuals, natural history and treatment strategies in this underrecognized population.

Published
2016

30. Exome sequencing of an adolescent with nonalcoholic fatty liver disease identifies a clinically actionable case of Wilson disease

Author

Joy Ito, Joel E. Lavine, Laura A. Wilson, Cynthia Behling, Saeed Mohammad, Patrick R. Shea, Mark Fishbein, Julia Wattacheril, Katherine P. Yates, Nicholas Stong, Vimla Aggarwal, and David Goldstein

Subjects
0301 basic medicine, Research Report, Male, Adolescent, Disease, Bioinformatics, New diagnosis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Hepatolenticular Degeneration, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Exome Sequencing, Medicine, Humans, Exome, Longitudinal Studies, Diagnostic Errors, Exome sequencing, 24 h urine, Chelating Agents, business.industry, Penicillamine, General Medicine, Lifestyle counseling, increased urinary copper concentration, medicine.disease, Advanced fibrosis, 030104 developmental biology, Liver, Copper-Transporting ATPases, business, 030217 neurology & neurosurgery, Copper
Abstract

Diagnostic whole-exome sequencing has proven highly successful in a range of rare diseases, particularly early-onset genetic conditions. In more common conditions, however, exome sequencing for diagnostic purposes remains the exception. Here we describe a patient initially diagnosed with a common, complex liver disease, nonalcoholic fatty liver disease (NAFLD), who was determined to have Wilson disease (WD) upon research-related exome sequencing. The patient presented as a 14.5-yr-old adolescent with chronically elevated aminotransferases, normal ceruloplasmin, and histologic examination consistent with NAFLD with advanced fibrosis. He was enrolled in a large longitudinal study of patients with NAFLD and was found to have WD by exome sequencing performed 4 yr later. This new diagnosis, confirmed clinically by 24 h urine copper quantification, led to a change in the therapy from lifestyle counseling to directed treatment with d-penicillamine, a copper chelating agent. In this case, the likelihood of making the correct diagnosis and thereby choosing the appropriate treatment was increased by exome sequencing and careful interpretation. This example illustrates the utility of exome sequencing diagnostically in more common conditions not currently considered as targets for genome-wide evaluation and adds to a growing body of evidence that patients diagnosed with more common conditions often in fact have rarer genetically determined syndromes that have escaped clinical detection.

Published
2018

31. Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys

Author

Joel E. Lavine, Julia Wattacheril, James Tonascia, Jerome I. Rotter, Rohit Loomba, Naga Chalasani, Mark O. Goodarzi, Soonil Kwon, Elizabeth M. Brunt, Jean P. Molleston, Kent D. Taylor, Katherine P. Yates, Xiuqing Guo, Yii-Der Ida Chen, and Jeffrey B. Schwimmer

Subjects
0301 basic medicine, Male, Pathology, Databases, Factual, Hispanic, Genome-wide association study, Gastroenterology, Oral and gastrointestinal, Hepatitis, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, 2.1 Biological and endogenous factors, Aetiology, Child, Liver Disease, Fatty liver, Single Nucleotide, Hispanic or Latino, Liver, Child, Preschool, Cohort, Hispanic Americans, medicine.medical_specialty, Genotype, Adolescent, pediatrics, Chronic Liver Disease and Cirrhosis, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Databases, Rare Diseases, Clinical Research, Internal medicine, medicine, Genetics, SNP, Humans, Polymorphism, Preschool, Factual, Genetic association, fatty liver, business.industry, Prevention, fibrosis, Human Genome, genome wide, Human Movement and Sports Sciences, medicine.disease, 030104 developmental biology, Good Health and Well Being, Pediatrics, Perinatology and Child Health, business, Digestive Diseases, Body mass index, Genome-Wide Association Study
Abstract

Objective To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys. Study design There were 234 eligible Hispanic boys age 2-17 years with clinical, laboratory, and histologic data enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network included in the analysis of 624 297 single nucleotide polymorphisms (SNPs). After the elimination of 4 outliers and 22 boys with cryptic relatedness, association analyses were performed on 208 DNA samples with corresponding liver histology. Logistic regression analyses were carried out for qualitative traits and linear regression analyses were applied for quantitative traits. Results The median age and body mass index z-score were 12.0 years (IQR, 11.0-14.0) and 2.4 (IQR, 2.1-2.6), respectively. The nonalcoholic fatty liver disease activity score (scores 1-4 vs 5-8) was associated with SNP rs11166927 on chromosome 8 in the TRAPPC9 region (P = 8.7-07). Fibrosis stage was associated with SNP rs6128907 on chromosome 20, near actin related protein 5 homolog (p = 9.9-07). In comparing our results in Hispanic boys with those of previously reported SNPs in adult nonalcoholic steatohepatitis, 2 of 26 susceptibility loci were associated with nonalcoholic fatty liver disease activity score and 2 were associated with fibrosis stage. Conclusions In this discovery genome-wide association study, we found significant novel gene effects on histologic traits associated with nonalcoholic fatty liver disease activity score and fibrosis that are distinct from those previously recognized by adult nonalcoholic fatty liver disease genome-wide association studies.

Published
2017

32. Portal hypertensive bleeding

Author

Julia Wattacheril and Joseph Awad

Subjects
medicine.medical_specialty, business.industry, Medicine, Acute management, business, Intensive care medicine
Published
2017

33. Contributors

Author

Ghassan K. Abou-Alfa, Jad Abou Khalil, Pietro Addeo, N. Volkan Adsay, Anil Kumar Agarwal, Farzad Alemi, Peter J. Allen, Ahmed Al-Mukhtar, Thomas A. Aloia, Jesper B. Andersen, Christopher D. Anderson, Vittoria Arslan-Carlon, Horacio J. Asbun, Béatrice Aussilhou, Joseph Awad, Daniel Azoulay, Philippe Bachellier, Talia B. Baker, Zubin M. Bamboat, Jeffrey Stewart Barkun, Claudio Bassi, Olca Basturk, Rachel E. Beard, Pierre Bedossa, Jacques Belghiti, Omar Bellorin-Marin, Marc G.H. Besselink, Anton J. Bilchik, Leslie H. Blumgart, Franz Edward Boas, Lynn A. Brody, Karen T. Brown, Jordi Bruix, David A. Bruno, Elizabeth M. Brunt, Justin M. Burns, Giovanni Butturini, Juan Carlos Caicedo, Mark P. Callery, Abdul Saied Calvino, Danielle H. Carpenter, C. Ross Carter, François Cauchy, Chung Yip Chan, See Ching Chan, William C. Chapman, Daniel Cherqui, Clifford S. Cho, Jin Wook Chung, Jesse Clanton, Bryan Marshall Clary, Sean Patrick Cleary, Kelly M. Collins, John Barry Conneely, Louise C. Connell, Carlos U. Corvera, Guido Costa, Anne M. Covey, Jeffrey S. Crippin, Kristopher P. Croome, Hany Dabbous, Michael I. D'Angelica, Michael D. Darcy, Jeremy L. Davis, Jeroen de Jonge, Ronald P. DeMatteo, Danielle K. DePeralta, Niraj M. Desai, Eduardo de Santibañes, Martin de Santibañes, Euan J. Dickson, Christopher John DiMaio, Richard Kinh Gian Do, Safi Dokmak, Marcello Donati, M.B. Majella Doyle, Vikas Dudeja, Mark Dunphy, Truman M. Earl, Tomoki Ebata, Imane El Dika, Yousef El-Gohary, Itaru Endo, C. Kristian Enestvedt, N. Joseph Espat, Cecilia G. Ethun, Sheung Tat Fan, Paul T. Fanta, Olivier Farges, Cristina R. Ferrone, Ryan C. Fields, Mary Fischer, Sarah B. Fisher, Devin C. Flaherty, Yuman Fong, Scott L. Friedman, Ahmed Gabr, John R. Galloway, David A. Geller, Hans Gerdes, Scott R. Gerst, George K. Gittes, Jaime Glorioso, Jill S. Gluskin, Brian K.P. Goh, Stevan A. Gonzalez, Karyn A. Goodman, Gregory J. Gores, Eduardo H. Gotuzzo, Dirk J. Gouma, Paul D. Greig, James F. Griffin, Christopher M. Halloran, Neil A. Halpern, Chet W. Hammill, Paul D. Hansen, James J. Harding, Ewen M. Harrison, Werner Hartwig, Kiyoshi Hasegawa, Jaclyn F. Hechtman, Julie K. Heimbach, William S. Helton, Alan W. Hemming, J. Michael Henderson, Asher Hirshberg, James R. Howe, Christopher B. Hughes, Christine Iacobuzio-Donahue, William R. Jarnagin, Roger L. Jenkins, Zeljka Jutric, Christoph Kahlert, Joseph Ralph Kallini, Ivan Kangrga, Paul J. Karanicolas, Seth S. Katz, Steven C. Katz, Kaitlyn J. Kelly, Nancy E. Kemeny, Eugene P. Kennedy, Korosh Khalili, Adeel S. Khan, Saboor Khan, Heung Bae Kim, T. Peter Kingham, Allan D. Kirk, David S. Klimstra, Michael Kluger, Stuart J. Knechtle, Jonathan B. Koea, Norihiro Kokudo, Dionysios Koliogiannis, David A. Kooby, Kevin Korenblat, Simone Krebs, Michael J. LaQuaglia, Michael P. LaQuaglia, Nicholas F. LaRusso, Alexis Laurent, Konstantinos N. Lazaridis, Julie N. Leal, Eliza J. Lee, Major Kenneth Lee, Ser Yee Lee, Riccardo Lencioni, Alexandre Liccioni, Michael E. Lidsky, Chung-Wei Lin, David C. Linehan, Roberto Carlos Lopez-Solis, Jeffrey A. Lowell, David C. Madoff, Jason Maggi, Shishir K. Maithel, Ali W. Majeed, Peter Malfertheiner, Giuseppe Malleo, Shennen A. Mao, Giovanni Marchegiani, Luis A. Marcos, James F. Markmann, J. Wallis Marsh, Robert C.G. Martin, Ryusei Matsuyama, Matthias S. Matter, Francisco Juan Mattera, Jessica E. Maxwell, Oscar M. Mazza, Ian D. McGilvray, Colin J. McKay, Doireann M. McWeeney, Jose Melendez, Robin B. Mendelsohn, George Miller, Klaus E. Mönkemüller, Ryutaro Mori, Vitor Moutinho, Masato Nagino, David M. Nagorney, Satish Nagula, Attila Nakeeb, Geir I. Nedredal, John P. Neoptolemos, James Neuberger, Scott L. Nyberg, Rachel O'Connor, John G. O'Grady, Frances E. Oldfield, Karl J. Oldhafer, Kim M. Olthoff, Susan L. Orloff, Alessandro Paniccia, Valérie Paradis, Rowan W. Parks, Gérard Pascal, Stephen M. Pastores, Timothy M. Pawlik, Venu G. Pillarisetty, James Francis Pingpank, C. Wright Pinson, Henry Anthony Pitt, James J. Pomposelli, Fabio Procopio, Michael J. Pucci, Motaz Qadan, Kheman Rajkomar, Srinevas K. Reddy, Maria E. Reig, Joseph Arturo Reza, John Paul Roberts, Piera Marie Cote Robson, Flavio G. Rocha, Garrett Richard Roll, Sean M. Ronnekleiv-Kelly, Alexander S. Rosemurgy, Charles B. Rosen, Pierre F. Saldinger, Riad Salem, Suhail Bakr Salem, Roberto Salvia, Charbel Sandroussi, Dominic E. Sanford, Olivier Scatton, Mark Andrew Schattner, William Palmer Schecter, Hans Francis Schoellhammer, Richard D. Schulick, Lawrence H. Schwartz, Kevin N. Shah, Ross W. Shepherd, Hiroshi Shimada, Masafumi Shimoda, Junichi Shindoh, Hosein Shokouh-Amiri, Jason K. Sicklick, Robert H. Siegelbaum, Gagandeep Singh, Rory L. Smoot, Stephen B. Solomon, Olivier Soubrane, Nicholas Spinelli, John A. Stauffer, Lygia Stewart, Matthew S. Strand, James H. Tabibian, Guido Torzilli, James F. Trotter, Simon Turcotte, Yumirle P. Turmelle, Demetrios J. Tzimas, Thomas Van Gulik, Andrea Vannucci, Jean-Nicolas Vauthey, Diana Vetter, Valérie Vilgrain, Alejandra Maria Villamil, Louis P. Voigt, Charles M. Vollmer, Jack R. Wands, Julia Wattacheril, Sharon Marie Weber, Matthew J. Weiss, Jürgen Weitz, Jens Werner, Megan Winner, John Wong, Dennis Yang, Hooman Yarmohammadi, Charles J. Yeo, Theresa Pluth Yeo, Chang Jin Yoon, Adam Yopp, D. Owen Young, Kai Zhao, Gazi B. Zibari, and George Zogopoulos

Published
2017

34. Investigating the relationship between rare genetic variants and advanced fibrosis in pediatric nonalcoholic fatty liver disease

Author

J. Lefkowitch, Julia Wattacheril, Joel E. Lavine, Cynthia Behling, Sarah E. Kleinstein, Mani Subramanian, S. Xanthakos, R. Myers, Patrick R. Shea, and David Goldstein

Subjects
medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Nonalcoholic fatty liver disease, medicine, Genetic variants, business, medicine.disease, Gastroenterology, Advanced fibrosis
Published
2018

35. 683 – Distinct Characteristics of Hepatocellular Carcinoma in Women: Results from a Large, Multicenter Study in the United States

Author

Andrew Scanga, Sydney Pomenti, Averill Guo, Samer Gawrieh, Carla Kettler, Hao Liu, Naga Chalasani, Andrew deLemos, Alexandra E. Livanos, Jonathan Yeh, Heather Burney, Meaghan Phipps, Julia Wattacheril, Lara Dakhoul, and Ethan Miller

Subjects
Oncology, medicine.medical_specialty, Hepatology, Multicenter study, business.industry, Internal medicine, Hepatocellular carcinoma, Gastroenterology, medicine, business, medicine.disease
Published
2019

36. A micro-RNA expression-signature for human NAFLD progression

Author

Yanhua Xiong, Shilin Zhao, Julia Wattacheril, Charles R. Flynn, Quanghu Sheng, and Yan Guo

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Cirrhosis, Carcinoma, Hepatocellular, Disease, Bioinformatics, Severity of Illness Index, Article, 03 medical and health sciences, RNA, Transfer, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, microRNA, Medicine, Humans, RNA, Small Nucleolar, Obesity, Small nucleolar RNA, medicine.diagnostic_test, business.industry, Gene Expression Profiling, Fatty liver, Liver Neoplasms, Gastroenterology, Middle Aged, medicine.disease, digestive system diseases, MicroRNAs, 030104 developmental biology, RNA, Ribosomal, Hepatocellular carcinoma, Liver biopsy, Female, business, Biomarkers
Abstract

The spectrum of nonalcoholic fatty liver disease (NAFLD) describes disease conditions deteriorating from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis (CIR) to hepatocellular carcinoma (HCC). From a molecular and biochemical perspective, our understanding of the etiology of this disease is limited by the broad spectrum of disease presentations, the lack of a thorough understanding of the factors contributing to disease susceptibility, and ethical concerns related to repeat sampling of the liver. To better understand the factors associated with disease progression, we investigated by next-generation RNA sequencing the altered expression of microRNAs (miRNAs) in liver biopsies of class III obese subjects (body mass index ≥40 kg/m2) biopsied at the time of elective bariatric surgery. Clinical characteristics and unbiased RNA expression profiles for 233 miRs, 313 transfer RNAs (tRNAs), and 392 miscellaneous small RNAs (snoRNAs, snRNAs, rRNAs) were compared among 36 liver biopsy specimens stratified by disease severity. The abundances of 3 miRNAs that were found to be differentially regulated (miR-301a-3p and miR-34a-5p increased and miR-375 decreased) with disease progression were validated by RT-PCR. No tRNAs or miscellaneous RNAs were found to be associated with disease severity. Similar patterns of increased miR-301a and decreased miR-375 expression were observed in 134 hepatocellular carcinoma (HCC) samples deposited in The Cancer Genome Atlas (TCGA). Our analytical results suggest that NAFLD severity is associated with a specific pattern of altered hepatic microRNA expression that may drive the hallmark of this disorder: altered lipid and carbohydrate metabolism. The three identified miRNAs can potentially be used as biomarkers to access the severity of NAFLD. The persistence of this miRNA expression pattern in an external validation cohort of HCC samples suggests that specific microRNA expression patterns may permit and/or sustain NAFLD development to HCC.

Published
2016

37. Nonalcoholic fatty liver disease (NAFLD): Is it really a serious condition?

Author

Naga Chalasani and Julia Wattacheril

Subjects
medicine.medical_specialty, education.field_of_study, Hepatology, Extramural, business.industry, Fatty liver, Population, MEDLINE, Cause specific mortality, Disease, medicine.disease, Gastroenterology, Article, Internal medicine, Nonalcoholic fatty liver disease, medicine, education, business, All cause mortality
Abstract

OBJECTIVE To evaluate the association between non-alcoholic fatty liver disease and all cause and cause specific mortality in a representative sample of the US general population.

Published
2012

38. Regulation of adiponectin production by insulin: interactions with tumor necrosis factor-α and interleukin-6

Author

Tahar Hajri, Pamela A. Marks-Shulman, Julia Wattacheril, Naji N. Abumrad, and Huan Tao

Subjects
Adult, Male, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adipokine, Adipose tissue, Cell Separation, Body Mass Index, Mice, chemistry.chemical_compound, Organ Culture Techniques, Insulin resistance, 3T3-L1 Cells, Physiology (medical), Adipocyte, Internal medicine, Adipocytes, medicine, Animals, Humans, Hypoglycemic Agents, Insulin, Obesity, Pancreatic hormone, Adiponectin, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, business.industry, nutritional and metabolic diseases, Cell Differentiation, Articles, Middle Aged, Glucose clamp technique, medicine.disease, Culture Media, Endocrinology, Adipose Tissue, chemistry, Glucose Clamp Technique, Cytokines, Female, Insulin Resistance, Receptors, Adiponectin, business
Abstract

Obesity is often associated with insulin resistance, low-grade systemic inflammation, and reduced plasma adiponectin. Inflammation is also increased in adipose tissue, but it is not clear whether the reductions of adiponectin levels are related to dysregulation of insulin activity and/or increased proinflammatory mediators. In this study, we investigated the interactions of insulin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in the regulation of adiponectin production using in vivo and in vitro approaches. Plasma adiponectin and parameters of insulin resistance and inflammation were assessed in a cohort of lean and obese insulin-resistant subjects. In addition, the effect of insulin was examined in vivo using the hyperinsulinemic-euglycemic clamp, and in adipose tissue (AT) cultures. Compared with lean subjects, the levels of total adiponectin, and especially the high-molecular-weight (HMW) isomer, were abnormally low in obese insulin-resistant subjects. The hyperinsulinemic clamp data confirmed the insulin-resistant state in the obese patients and showed that insulin infusion significantly increased the plasma adiponectin in lean but not obese subjects ( P < 0.01). Similarly, insulin increased total adiponectin release from AT explants of lean and not obese subjects. Moreover, expression and secretion of TNF-α and IL-6 increased significantly in AT of obese subjects and were negatively associated with expression and secretion of adiponectin. In 3T3-L1 and human adipocyte cultures, insulin strongly enhanced adiponectin expression (2-fold) and secretion (3-fold). TNF-α, and not IL-6, strongly opposed the stimulatory effects of insulin. Intriguingly, the inhibitory effect of TNF-α was especially directed toward the HMW isomer of adiponectin. In conclusion, these studies show that insulin upregulates adiponectin expression and release, and that TNF-α opposes the stimulatory effects of insulin. A combination of insulin resistance and increased TNF-α production could explain the decline of adiponectin levels and alterations of isomer composition in plasma of obese insulin-resistant subjects.

Published
2011

39. Increasing trend for Hepatocellular Carcinoma (HCC) linked to Nonalcoholic Fatty Liver Disease (NAFLD) in the United States

Author

E. Mao, E. Miller, A. Scanga, Andrew deLemos, H.A. Sbeih, N. Chalasani, P. Roche, Lara Dakhoul, Julia Wattacheril, Samer Gawrieh, and E.V. Gomez

Subjects
medicine.medical_specialty, Hepatology, business.industry, medicine.disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Internal medicine, Nonalcoholic fatty liver disease, medicine, 030211 gastroenterology & hepatology, business
Published
2018

40. Endocrine and metabolic response to gastric bypass

Author

Naji N. Abumrad, Jabbar Saliba, and Julia Wattacheril

Subjects
medicine.medical_specialty, Peptide Hormones, Gastric Bypass, Medicine (miscellaneous), Gastric Inhibitory Polypeptide, Incretins, Gastroenterology, Article, Gastric inhibitory polypeptide, Glucagon-Like Peptide 1, Weight loss, Internal medicine, Diabetes mellitus, Weight Loss, medicine, Humans, Endocrine system, Caloric Restriction, Glycemic, Nutrition and Dietetics, business.industry, digestive, oral, and skin physiology, medicine.disease, Glucagon-like peptide-1, Ghrelin, Obesity, Morbid, Endocrinology, Diabetes Mellitus, Type 2, medicine.symptom, Energy Intake, business, Hormone
Abstract

Purpose of review Diabetes resolves in 80% of individuals undergoing successful Roux-en-Y gastric bypass. Absolute caloric restriction alone resulting from gastric anatomic changes indeed leads to weight loss; however, immediate effects in glycemic control often precede substantial weight loss typically associated with insulin sensitivity. One putative explanation relates to hormonal effects accompanying Roux-en-Y gastric bypass. We reviewed the existing and recent literature to investigate the hormonal changes accompanying Roux-en-Y gastric bypass. Recent findings Changes in levels of five candidate enteric hormones have been recently associated with early postoperative glycemic control following Roux-en-Y gastric bypass; the strongest effects are seen with variations in glucagon-like peptide-1, glucose-dependent insulinotropic peptide and ghrelin. Summary The unique hybridization of static anatomic restriction and dynamic absorptive bypass lends a duality to the beneficial effects of Roux-en-Y gastric bypass. This duality likely explains the short-term and long-term resolution of diabetes in patients undergoing Roux-en-Y gastric bypass.

Published
2009

41. Lipoprotein Profiles in Class III Obese Caucasian and African American Women with Nonalcoholic Fatty Liver Disease

Author

Pamela A. Marks-Shulman, Naji N. Abumrad, Joseph Antoun, Raul S. Gonzalez, Charles R. Flynn, Emily A. Eckert, Nader R. Kasim, Robyn A. Tamboli, Anna E. Garcia, Julia Wattacheril, Julia P. Dunn, and Taylor Wallen

Subjects
Very low-density lipoprotein, Magnetic Resonance Spectroscopy, Apolipoprotein B, Epidemiology, lcsh:Medicine, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Prevalence, Pathology, Medicine, Prospective Studies, lcsh:Science, 0303 health sciences, Multidisciplinary, biology, Anthropometry, Fatty liver, Middle Aged, Apolipoprotein B-100, Disease Progression, 030211 gastroenterology & hepatology, Female, lipids (amino acids, peptides, and proteins), Research Article, Adult, medicine.medical_specialty, Histology, Lipoproteins, digestive system, White People, 03 medical and health sciences, Young Adult, Insulin resistance, Ethnic groups--Diseases, Internal medicine, Humans, Obesity, Triglycerides, 030304 developmental biology, business.industry, lcsh:R, nutritional and metabolic diseases, medicine.disease, digestive system diseases, Black or African American, Endocrinology, Liver--Diseases, Case-Control Studies, biology.protein, lcsh:Q, Steatosis, Insulin Resistance, business, Dyslipidemia, Biomarkers, Lipoprotein
Abstract

Triglyceride content in the liver is regulated by the uptake, production and elimination of lipoproteins, and derangements in these processes contribute to nonalcoholic fatty liver disease (NAFLD). Previous studies show a direct relationship between intrahepatic fat and production of apolipoprotein B100 (apoB100) containing particles, VLDL and LDL, but little consensus exists regarding changes in lipoprotein production in the development of simple steatosis (SS) versus nonalcoholic steatohepatitis (NASH). Further, ethnic variations in lipoproteins among SS and NASH are unknown as is how such variations might contribute to the differential prevalence of disease among Caucasians versus African Americans. In this study, we assessed plasma lipoprotein profiles by nuclear magnetic resonance (NMR) spectroscopy in 70 non-diabetic class III obese females recruited from the surgical weight loss clinic. Of these, 51 females were stratified by biopsy-staged NAFLD severity (histologically normal, SS, or NASH). NASH females displayed increased circulating triglycerides and increased VLDL particle number and size relative to those with histologically normal livers, while total and large LDL concentration decreased in SS versus NASH and correlated with increased insulin resistance (via HOMA2-IR). When Caucasian women were examined alone (n = 41), VLDL and triglycerides increased between normal and SS, while total LDL and apoB100 decreased between SS and NASH along with increased insulin resistance. Compared to Caucasians with SS, African American women with SS displayed reduced triglycerides, VLDL, and small LDL and a more favorable small to large HDL ratio despite having increased BMI and HOMA2-IR. These findings suggest that ApoB100 and lipoprotein subclass particle number and size can delineate steatosis from NASH in obese Caucasian females, but should be interpreted with caution in other ethnicities as African Americans with SS display relatively improved lipoprotein profiles. This may reflect variation in the relationship between dyslipidemia and NAFLD progression across gender and ethnicity.

Published
2015
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44. Hepatic TLR4 signaling in obese NAFLD

Author

Naji N. Abumrad, Giovanni Suarez, Keith T. Wilson, Richard M. Peek, Charles R. Flynn, Joseph Antoun, Thomas G. Verriere, Torfay Sharifnia, and Julia Wattacheril

Subjects
Adult, Lipopolysaccharides, Male, medicine.medical_specialty, Physiology, Liver and Biliary Tract Physiology/Pathophysiology, Palmitic Acid, Blood lipids, Biology, Cell Line, Insulin resistance, Non-alcoholic Fatty Liver Disease, Physiology (medical), Internal medicine, Nonalcoholic fatty liver disease, medicine, Humans, Obesity, RNA, Messenger, Cells, Cultured, Hepatology, Fatty liver, Gastroenterology, NF-kappa B, Middle Aged, medicine.disease, Toll-Like Receptor 4, Endocrinology, Liver, Lipogenesis, Myeloid Differentiation Factor 88, Hepatocytes, Female, Interferon Regulatory Factor-3, Metabolic syndrome, Body mass index, Signal Transduction
Abstract

Nonalcoholic fatty liver disease occurs frequently in the setting of metabolic syndrome, but the factors leading to nonalcoholic steatohepatitis (NASH) are not fully understood. This study investigated Toll-like receptor 4 (TLR4) signaling in human liver with the goal of delineating whether activation of this pathway segregates those with nonalcoholic fatty liver from those with NASH. Experiments were performed using liver biopsy tissue obtained from class III obese subjects undergoing bariatric surgery, and extended to an immortalized human hepatocyte HepaRG cell line and primary human hepatocytes. The bacterial endotoxin lipopolysaccharide (LPS) and total free fatty acid levels were significantly increased in plasma of NASH patients. TLR4 mRNA levels were significantly increased in subjects with NASH compared with NAFL as was interferon regulatory factor ( IRF) 3 in the myeloid differentiation factor 88-independent signaling pathway. In HepaRG cells, nuclear factor-κB (NF-κB) nuclear translocation and functional activity increased following treatment with the fatty acid, palmitate, and following exposure to LPS compared with hepatocytes stimulated with a lipogenic treatment that induced de novo lipogenesis. Palmitate and LPS induction of NF-κB activity was partially attenuated by chemical- or small-interfering RNA-mediated inhibition of TLR4. Expression of TLR4 and its downstream mediators was upregulated with palmitate and LPS. Similar results were observed using primary human hepatocytes from a lean donor. Interestingly, NF-κB activity assays showed obese donor hepatocytes were resistant to chemical TLR4 inhibition. In conclusion, TLR4 expression is upregulated in a large cohort of NASH patients, compared with those with NAFL, and this occurs within the setting of increased LPS and fatty acids.

Published
2014

45. Differential intrahepatic phospholipid zonation in simple steatosis and nonalcoholic steatohepatitis

Author

Benjamin P. Bowen, Julia Wattacheril, Naji N. Abumrad, Erin H. Seeley, Charles R. Flynn, Peggi M. Angel, Heidi Chen, Richard M. Caprioli, and Christian Lanciault

Subjects
Male, lcsh:Medicine, Nonalcoholic Steatohepatitis, Biochemistry, Analytical Chemistry, Pathogenesis, chemistry.chemical_compound, Molecular Cell Biology, Nonalcoholic fatty liver disease, Pathology, Signaling in Cellular Processes, lcsh:Science, Chromatography, High Pressure Liquid, Phospholipids, Chromatography, 0303 health sciences, Multidisciplinary, Liver Diseases, 030302 biochemistry & molecular biology, Fatty liver, Lipids, Signaling Cascades, Chemistry, Liver, Lipid Signaling, Medicine, Female, Research Article, Signal Transduction, Adult, Spectrometry, Mass, Electrospray Ionization, medicine.medical_specialty, Histology, Phospholipid, Gastroenterology and Hepatology, Proinflammatory cytokine, 03 medical and health sciences, Insulin resistance, Internal medicine, Gastrointestinal Surgery, medicine, Humans, Biology, 030304 developmental biology, lcsh:R, Lipid metabolism, medicine.disease, Fatty Liver, Endocrinology, chemistry, Phospholipid Signaling Cascade, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Surgery, lcsh:Q, Steatosis
Abstract

Nonalcoholic fatty liver disease (NAFLD) occurs frequently in a setting of obesity, dyslipidemia and insulin resistance, but the etiology of the disease, particularly the events favoring progression to nonalcoholic steatohepatitis (NASH) as opposed to simple steatosis (SS), are not fully understood. Based on known zonation patterns in protein, glucose and lipid metabolism, coupled with evidence that phosphatidylcholine may play a role in NASH pathogenesis, we hypothesized that phospholipid zonation exists in liver and that specific phospholipid abundance and distribution may be associated with histologic disease. A survey of normal hepatic protein expression profiles in the Human Protein Atlas revealed pronounced zonation of enzymes involved in lipid utilization and storage, particularly those facilitating phosphatidylcholine (PC) metabolism. Immunohistochemistry of obese normal, SS and NASH liver specimens with anti-phosphatidylethanomine N-methyltransferase (PEMT) antibodies showed a progressive decrease in the zonal distribution of this PC biosynthetic enzyme. Phospholipid quantitation by liquid chromatography mass spectrometry (LC-MS) in hepatic extracts of Class III obese patients with increasing NAFLD severity revealed that most PC species with 32, 34 and 36 carbons as well as total PC abundance was decreased with SS and NASH. Matrix assisted laser desorption ionization - imaging mass spectrometry (MALDI-IMS) imaging revealed strong zonal distributions for 32, 34 and 36 carbon PCs in controls (minimal histologic findings) and SS that was lost in NASH specimens. Specific lipid species such as PC 34∶1 and PC 36∶2 best illustrated this phenomenon. These findings suggest that phospholipid zonation may be associated with the presence of an intrahepatic proinflammatory phenotype and thus have broad implications in the etiopathogenesis of NASH.

Published
2013

47. Contributors

Author

Ghassan K. Abou-Alfa, N. Volkan Adsay, Timothy Akhurst, Farzad Alemi, David Allegra, Peter J. Allen, Christopher D. Anderson, Taku Aoki, Ramakrishnan Arulraj, Rebecca Ann C. Auer, Béatrice Aussilhou, Joseph Awad, Chad G. Ball, Zubin M. Bamboat, Claudio Bassi, Christoph D. Becker, Pierre Bedossa, Jacques Belghiti, Paul Belletrutti, Anton J. Bilchik, Leslie H. Blumgart, Philippus C. Bornman, Cherif Boutros, Jonathan R. Brody, Lynn A. Brody, Antoine Brouquet, Karen T. Brown, William R. Brugge, Jordi Bruix, David A. Bruno, Elizabeth M. Brunt, Markus W. Büchler, Justin M. Burns, Giovanni Butturini, Mark P. Callery, David L. Carr-Locke, Charles Cha, See Ching Chan, William C. Chapman, Daniel Cherqui, Clifford S. Cho, Jin Wook Chung, Bryan Clary, Andrei Cocieru, Carlos M. Contreras, Kendra D. Conzen, Carlos U. Corvera, Anne M. Covey, Jeffrey S. Crippin, Hany Dabbous, Michael I. D’Angelica, Michael Darcy, Mark Davenport, Jeroen De Jonge, Ronald P. DeMatteo, Achilles A. Demetriou, Niraj M. Desai, Eduardo De Santibañes, Terry S. Desser, Kiran K. Dhanireddy, Safi Dokmak, M.B. Majella Doyle, Truman M. Earl, Tomoki Ebata, Yousef El-Gohary, Andrew S. Epstein, N. Joseph Espat, Sheung Tat Fan, Olivier Farges, Carlos Fernandez-Del Castillo, Cristina R. Ferrone, Mary Fischer, James E. Fisher, Yuman Fong, Alejandro Forner, Scott L. Friedman, Stefan Fritz, John R. Galloway, Hans Gerdes, George Getrajdman, Paula Ghaneh, Giorgia Ghittoni, George Gittes, Karyn A. Goodman, Gregory J. Gores, Eduardo Gotuzzo, Dirk J. Gouma, Paul D. Greig, Christopher M. Halloran, Neil A. Halpern, Lucy E. Hann, Ewen M. Harrison, Werner Hartwig, Julie K. Heimbach, William S. Helton, Alan W. Hemming, J. Michael Henderson, Amelia J. Hessheimer, Asher Hirshberg, Alice Ho, Michael G. House, Chung-Bao Hsieh, Kuo-Feng Hsu, David A. Iannitti, Hiroshi Imamura, Clem W. Imrie, William R. Jarnagin, Roger L. Jenkins, Stefan Kahl, Ivan Kangrga, Kaitlyn Kelly, Nancy E. Kemeny, Eugene P. Kennedy, Robert K. Kerlan Jr, Adeel S. Khan, Saboor Khan, T. Peter Kingham, Allan D. Kirk, Yuichi Kitagawa, David S. Klimstra, Michael D. Kluger, Stuart J. Knechtle, Peter J. Kneuertz, Jonathan Koea, Alan J. Koffron, Norihiro Kokudo, David A. Kooby, Kevin Korenblat, Robert M. Krasny, Jake Krige, Robert C. Kurtz, Matthew P. Landman, Michael P. La Quaglia, Nicholas F. LaRusso, Kwan N. Lau, Konstantinos N. Lazaridis, Markus M. Lerch, Joseph B. Lillegard, Keith D. Lillemoe, David C. Linehan, Susan Logan, Benjamin Loveday, Jeffrey A. Lowell, David C. Madoff, Shishir K. Maithel, Ali W. Majeed, Masatoshi Makuuchi, Peter Malfertheiner, Mark Mamlouk, Giovanni Marchegiani, Luis A. Marcos, James F. Markmann, J. Wallis Marsh, Maureen Martin, Robert C.G. Martin II, Dipen M. Maru, Francisco Juan Mattera, Julia V. Mayerle, Oscar M. Mazza, Ian D. McGilvray, Colin J. McKay, Jose A. Melendez, James J. Mezhir, George Miller, Klaus Mönkemüller, Tricia A. Moo-Young, Satish N. Nadig, Masato Nagino, Alexander Nagle, David M. Nagorney, Atilla Nakeeb, Hector E. Nazario, Geir Nedredal, John P. Neoptolemos, James Neuberger, Douglas L. Nguyen, Yuji Nimura, Scott L. Nyberg, John G. O’Grady, Risteard O’laoide, Kim Marie Olthoff, Mark S. Orloff, Marshall J. Orloff, Susan L. Orloff, Rish K. Pai, Katia Papalezova, Valérie Paradis, Rowan W. Parks, Steven D. Passik, Stephen M. Pastores, Patrick Pessaux, Maxim S. Petrov, Venu G. Pillarisetty, James Pingpank Jr, C. Wright Pinson, Sofija Pitka, Henry A. Pitt, James J. Pomposelli, Wande B. Pratt, Richard A. Prinz, Srinivas R. Puli, Florencia G. Que, Valentina Ravetta, Maria E. Reig, Ahsun Riaz, Barrie S. Rich, David W. Rittenhouse, John Roberts, Piera Robson, Flavio G. Rocha, Seaborn A. Roddenbery V, Carlos Rodriguez de Lopes, Garrett R. Roll, Alex S. Rosemurgy II, Charles B. Rosen, Sandro Rossi, Pierre F. Saldinger, Riad Salem, Leonard B. Saltz, Norberto J. Sanchez, Charbel Sandroussi, Tsuyoshi Sano, O. Scatton, Mark Schattner, William P. Schecter, Suzanne C. Schiffman, C. Max Schmidt, Helmut Schoellnast, Lawrence H. Schwartz, Ross W. Shepherd, Masafumi Shimoda, Hosein Shokouh-Amiri, Nasir H. Siddiqi, Stephen B. Solomon, Nathaniel J. Soper, Thomas E. Starzl, Michael Steer, Lygia Stewart, Oliver Strobel, Jerrold Teitcher, Angélica Terashima, Sylvain Terraz, William E.G. Thomas, Guido Torzilli, James F. Trotter, Yumirle P. Turmelle, Christine Van Cott, Andrea Vannucci, Eric vanSonnenberg, Jean-Nicolas Vauthey, Diana Vetter, Valerie Vilgrain, Alejandra Villamil, Louis Voigt, Charles M. Vollmer Jr, Jack R. Wands, Julia Wattacheril, Sharon Weber, Matthew Weiss, Jürgen Weitz, Jens Werner, Antony M. Wheatley, John A. Windsor, Corinne Winston, Jordan Winter, Agnieszka K. Witkiewicz, John Wong, Charles J. Yeo, Theresa P. Yeo, Chang Jin Yoon, Adam Yopp, Gazi Zibari, and Randall Zuckerman

Published
2012

48. Esophageal varices

Author

Julia Wattacheril and Joseph Awad

Subjects
medicine.medical_specialty, Esophageal varices, business.industry, Internal medicine, General surgery, medicine, Portal hypertension, Acute management, medicine.disease, business, Gastroenterology
Published
2012

50. 1007 Determinants and Effect of Lag Time Before Colorectal Cancer Diagnosis

Author

Jennifer R. Kramer, Peter Richardson, Julia Wattacheril, Benjamin D. Havemann, Linda K. Green, and Hashem B. El-Serag

Subjects
Oncology, medicine.medical_specialty, Lag time, Hepatology, Colorectal cancer, business.industry, Internal medicine, Gastroenterology, medicine, medicine.disease, business
Published
2008

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