Serena Pelusi1, Annalisa Cespiati2, Raffaela Rametta3, Grazia Pennisi4, Ville Mannisto5, Chiara Rosso6, Guido Baselli1, Paola Dongiovanni3, Anna Ludovica Fracanzani2, Sara Badiali7, Marco Maggioni8, Antonio Craxi4, Silvia Fargion2, Daniele Prati9, Valerio Nobili10, Elisabetta Bugianesi6, Stefano Romeo11, Jussi Pihlajamaki5, Salvatore Petta4, Luca Valenti12. 1. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 2. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 3. General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 4. Section of Gastroenterology, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy. 5. Department of Medicine, University of Eastern Finland and Kuopio, University Hospital, Kuopio, Finland. 6. Division of Gastroenterology, Department of Medical Sciences, University of Torino, Turin, Italy. 7. Surgery Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 8. Pathology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 9. Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 10. Department of Gastroenterology, Ospedale Bambin Gesù, Roma, Italy. 11. Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Cardiology Department, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy. 12. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: luca.valenti@unimi.it.
Abstract
BACKGROUND & AIMS: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis. METHODS: We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy. RESULTS: In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3 I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3 I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016). CONCLUSIONS: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3 I148M variant identified those at risk of significant fibrosis.
BACKGROUND & AIMS: In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis. METHODS: We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also collected data on demographic features, metabolic comorbidities, and genetic factors, and performed logistic regression analyses. Findings were validated using data from 118 consecutive patients with NAFLD who underwent sequential liver biopsies at tertiary referral centers in Italy. RESULTS: In the cross-sectional cohort, 132 of 389 patients (33.9%) with significant fibrosis had no NASH and 39 patients (10.0%) had no inflammation. The dissociation between NASH and fibrosis was significantly greater in patients with severe obesity (P < .005). Steatosis, ballooning, and lobular inflammation each were associated independently with significant fibrosis (P < .001); age, adiposity, fasting hyperglycemia, and the PNPLA3I148M variant also were associated with fibrosis. In patients without, but not in those with NASH, significant fibrosis was associated with steatosis grade and the PNPLA3I148M variant. In patients without NASH, age, fasting hyperglycemia, ballooning, and inflammation were associated with fibrosis. In the validation cohort, 16 of 47 patients (34.0%) with clinically significant fibrosis did not have NASH at baseline. In patients with fibrosis without baseline NASH, worsening of fibrosis (based on later biopsies) was associated with fasting hyperglycemia and more severe steatosis (P = .016). CONCLUSIONS: In an analysis of biopsy specimens collected from patients with NAFLD at a single time point, one third of patients with significant fibrosis did not have NASH. We validated this finding in a separate cohort. In patients without NASH, fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and the PNPLA3I148M variant identified those at risk of significant fibrosis.
Authors: Jongsin Park; Heon-Ju Kwon; Won Sohn; Ju-Yeon Cho; Soo Jin Park; Yoosoo Chang; Seungho Ryu; Byung Ik Kim; Yong Kyun Cho Journal: PLoS One Date: 2022-06-02 Impact factor: 3.752
Authors: Mandana Khalili; Wendy C King; David E Kleiner; Mamta K Jain; Raymond T Chung; Mark Sulkowski; Mauricio Lisker-Melman; David K Wong; Marc Ghany; Arun Sanyal; Richard K Sterling Journal: Clin Infect Dis Date: 2021-11-02 Impact factor: 20.999
Authors: Wan-Qiang Huang; Man-Ling Liu; Si-Ceng Lin; Xiao-Zhou Zhang; Yan Zhang; Xiao-Qing He; Jun-Lin Liu; Gong Feng; Zi-Jun Chen; Zi-Kai Guo; Jie Gao; Cheng-Zi Yao; Na He; Qin-Qin Yan; Man Mi Journal: SN Compr Clin Med Date: 2020-08-24
Authors: Olubunmi O Olubamwo; Jyrki K Virtanen; Jussi Pihlajamaki; Pekka Mantyselka; Tomi-Pekka Tuomainen Journal: BMJ Open Date: 2019-09-05 Impact factor: 2.692