Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease.


Background and aims

Whether glycemic control, as opposed to diabetes status, is associated with the severity of nonalcoholic fatty liver disease (NAFLD) is unknown. We aimed to evaluate whether degree of glycemic control in the years preceding liver biopsy predicts the histologic severity of nonalcoholic steatohepatitis (NASH).

Methods & results

Using the Duke NAFLD Clinical Database we examined patients with biopsy-proven NAFLD/NASH (n=713) and the association of liver injury with glycemic control as measured by hemoglobin A1c (HbA1c). The study cohort was predominantly female (59%), Caucasian (84%) with median (IQR) age of 50 (42, 58) years; 49% had diabetes (n=348). Generalized linear regression models adjusted for age, sex, race, diabetes, body mass index, and hyperlipidemia were used to assess the association between mean HbA1c over the year preceding liver biopsy and severity of histologic features of NAFLD/NASH. Histologic features were graded and staged according to NASH Clinical Research Network system. Group-based trajectory analysis was used to examine patients with ≥3 HbA1c (n=298) measures over 5 years preceding clinically indicated liver biopsy. Higher mean HbA1c was associated with higher grade of steatosis and ballooned hepatocytes, but not lobular inflammation. Every 1% increase in mean HbA1c was associated with 15% higher odds of increased fibrosis stage (OR 1.15, 95% CI 1.01, 1.31). As compared with good glycemic control, moderate control was significantly associated with increased severity of ballooned hepatocytes (OR 1.74, 95% CI 1.01, 3.01, p=0.048) and hepatic fibrosis (OR 4.59, 95% CI 2.33, 9.06, p<0.01).


Glycemic control predicts severity of ballooned hepatocytes and hepatic fibrosis in NAFLD/NASH, and thus optimizing glycemic control may be a means of modifying risk of NASH-related fibrosis progression.





Published Version (Please cite this version)


Publication Info

Alexopoulos, Anastasia-Stefania, Matthew J Crowley, Ying Wang, Cynthia A Moylan, Cynthia D Guy, Ricardo Henao, Dawn L Piercy, Keri A Seymour, et al. (2021). Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease. Hepatology (Baltimore, Md.). 10.1002/hep.31806 Retrieved from

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Anastasia Stefania Alexopoulos

Assistant Professor of Medicine

Matthew Janik Crowley

Associate Professor of Medicine

Diabetes, Hypertension, Health Services Research


Cynthia Ann Moylan

Associate Professor of Medicine

My research interests focus on the study of chronic liver disease and primary liver cancer, particularly from metabolic dysfunction associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease (NAFLD).  As part of the MASLD Research Team at Duke, we are investigating the role of environmental contaminants, epigenetics, and genetics on the development of advanced fibrosis and liver cancer from MASLD and other chronic liver diseases.  We are also interested in understanding risks for progressive liver disease including developmental programming and in utero exposures and have been investigating these risks through studies of the Newborn Epigenetics Study (NEST).  The long term goal of our research is to develop non-invasive biomarkers to identify those patients at increased risk for cirrhosis and end stage liver disease in order to risk stratify patients as well as to develop better preventative and therapeutic strategies.


Cynthia Dianne Guy

Professor of Pathology

My research interests include:
Fine Needle Aspiration of Liver, Gastrointestinal Tract, and Pancreatic Lesions
Biliary Duct Brushings
Nonalcoholic Fatty Liver Disease/NASH
Liver Fibrogenesis


Ricardo Henao

Associate Professor of Biostatistics & Bioinformatics

Keri Anne Seymour

Associate Professor of Surgery

Ranjan Sudan

Professor of Surgery

Dana Dale Portenier

Associate Professor of Surgery

Anna Mae Diehl

Florence McAlister Distinguished Professor of Medicine

Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD).

Research by our group has advanced understanding in two main areas: 1) immune system regulation of liver injury and regeneration and 2)the role of fetal morphogens, such as the hedgehog pathway, in regulating fibrotic responses to liver damage. Our basic research programs have been enjoyed continuous NIH support since 1989. We welcome students, post-doctoral fellows and visiting scientists who have interests in this research area to contact us about training opportunities and potential collaborations.

Since 2001 we have also been an active participant in the NIDDK-funded Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), a national consortium comprised of 8 university medical centers selected to generate a national registry for patients with NAFLD and to conduct multicenter treatment trials for this disorder. We are actively recruiting patients for this program, as well as a number of other industry-supported NAFLD studies.

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