The Role of Liver Fat and Insulin Resistance as Determinants of Plasma Aminotransferase Elevation in Nonalcoholic Fatty Liver Disease
Maryann Maximos, DO1,2; Fernando Bril, MD2,3; Paola Portillo Sanchez, MD2,3; Romina Lomonaco, MD2,3; Beverly Orsak, RN4,5; Diane Biernacki, RN2,3; Amitabh Suman, MD2; Michelle Weber, MD2; and Kenneth Cusi, MD2,3,4,5
1
Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of
Florida, Gainesville, Florida; 2Malcom Randall VA Hospital - North Florida/South Georgia Veterans Health System, Gainesville, FL; 3Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida; 4Division of Diabetes, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas; 5Audie L. Murphy Veterans Administration Medical Center (VAMC) San Antonio, Texas.
Corresponding author: Kenneth Cusi, M.D., F.A.C.P., F.A.C.E. Professor of Medicine Chief, Endocrinology, Diabetes and Metabolism Division University of Florida 1600 SW Archer Road, room H-2. Gainesville, Florida 32610 Phone: 352-273-8662 Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27395
Hepatology
Page 2 of 29
2 Keywords: Fatty liver disease, NASH, plasma aminotransferase levels, insulin resistance, magnetic resonance and spectroscopy (1H-MRS)
Abbreviations NAFLD: Nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; ALT: plasma alanine aminotransferase; T2DM: type 2 diabetes mellitus; BMI: body mass index; HOMA-IR: homeostatic model assessment; 1H-MRS: magnetic resonance and spectroscopy; FFA: free fatty acid; OGTT: oral glucose tolerance test; HGP: hepatic glucose production; TBF: total body fat; DXA: dual energy Xray absorptiometry; Rd: whole-body insulin-stimulated glucose uptake; HIRi: hepatic insulin resistance index; ATIRi: fasting adipose tissue insulin resistance index
Financial Support Supported by the Burroughs Wellcome Fund (K.C.), the American Diabetes Association (1-08-CR-08 [K.C.]), and a VA Merit Award (1 I01 CX000167-01 [K.C.]).
Hepatology
Page 3 of 29
Hepatology
3 Abstract Plasma aminotransferases (AST/ALT) are usually increased in patients with nonalcoholic fatty liver disease (NAFLD). However, the factors behind their elevation remain unclear. The aim of this study was to assess the role of insulin resistance and liver triglyceride content in relation to histology in patients with NAFLD/NASH with normal or elevated ALT levels. To this end, we enrolled 440 patients, divided into three groups: no NAFLD (n=60), NAFLD with normal ALT (n=165), and NAFLD with elevated ALT (n=215). We measured: 1) liver fat by magnetic resonance spectroscopy (1H-MRS); 2) severity of liver disease by biopsy (n=293); and 3) insulin sensitivity in liver, muscle, and adipose tissue by a euglycemic hyperinsulinemic clamp with 3-3H-glucose. Patients with NAFLD and elevated ALT, even when well matched for BMI to those with normal ALT, had worse adipose tissue insulin resistance (p
Maryann Maximos, DO1,2; Fernando Bril, MD2,3; Paola Portillo Sanchez, MD2,3; Romina Lomonaco, MD2,3; Beverly Orsak, RN4,5; Diane Biernacki, RN2,3; Amitabh Suman, MD2; Michelle Weber, MD2; and Kenneth Cusi, MD2,3,4,5
1
Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of
Florida, Gainesville, Florida; 2Malcom Randall VA Hospital - North Florida/South Georgia Veterans Health System, Gainesville, FL; 3Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida; 4Division of Diabetes, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas; 5Audie L. Murphy Veterans Administration Medical Center (VAMC) San Antonio, Texas.
Corresponding author: Kenneth Cusi, M.D., F.A.C.P., F.A.C.E. Professor of Medicine Chief, Endocrinology, Diabetes and Metabolism Division University of Florida 1600 SW Archer Road, room H-2. Gainesville, Florida 32610 Phone: 352-273-8662 Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27395
Hepatology
Page 2 of 29
2 Keywords: Fatty liver disease, NASH, plasma aminotransferase levels, insulin resistance, magnetic resonance and spectroscopy (1H-MRS)
Abbreviations NAFLD: Nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; ALT: plasma alanine aminotransferase; T2DM: type 2 diabetes mellitus; BMI: body mass index; HOMA-IR: homeostatic model assessment; 1H-MRS: magnetic resonance and spectroscopy; FFA: free fatty acid; OGTT: oral glucose tolerance test; HGP: hepatic glucose production; TBF: total body fat; DXA: dual energy Xray absorptiometry; Rd: whole-body insulin-stimulated glucose uptake; HIRi: hepatic insulin resistance index; ATIRi: fasting adipose tissue insulin resistance index
Financial Support Supported by the Burroughs Wellcome Fund (K.C.), the American Diabetes Association (1-08-CR-08 [K.C.]), and a VA Merit Award (1 I01 CX000167-01 [K.C.]).
Hepatology
Page 3 of 29
Hepatology
3 Abstract Plasma aminotransferases (AST/ALT) are usually increased in patients with nonalcoholic fatty liver disease (NAFLD). However, the factors behind their elevation remain unclear. The aim of this study was to assess the role of insulin resistance and liver triglyceride content in relation to histology in patients with NAFLD/NASH with normal or elevated ALT levels. To this end, we enrolled 440 patients, divided into three groups: no NAFLD (n=60), NAFLD with normal ALT (n=165), and NAFLD with elevated ALT (n=215). We measured: 1) liver fat by magnetic resonance spectroscopy (1H-MRS); 2) severity of liver disease by biopsy (n=293); and 3) insulin sensitivity in liver, muscle, and adipose tissue by a euglycemic hyperinsulinemic clamp with 3-3H-glucose. Patients with NAFLD and elevated ALT, even when well matched for BMI to those with normal ALT, had worse adipose tissue insulin resistance (p
