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Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels

Gawrieh, Samer MD1; Wilson, Laura A. ScM2; Cummings, Oscar W. MD3; Clark, Jeanne M. MD, MPH2; Loomba, Rohit MD, MHSc4; Hameed, Bilal MD5; Abdelmalek, Manal F. MD6; Dasarathy, Srinivasan MD7; Neuschwander-Tetri, Brent A. MD8; Kowdley, Kris MD9; Kleiner, David MD, PhD10; Doo, Edward MD11; Tonascia, James PhD2; Sanyal, Arun MD12; Chalasani, Naga MD1 and the NASH Clinical Research Network

American Journal of Gastroenterology: October 2019 - Volume 114 - Issue 10 - p 1626–1635
doi: 10.14309/ajg.0000000000000388

OBJECTIVES: Patients with nonalcoholic fatty liver disease (NAFLD) and normal aminotransferase levels may have advanced liver histology. We conducted a study to characterize the prevalence of and factors associated with advanced liver histology in patients with histologically characterized NAFLD and normal aminotransferase levels.

METHODS: We evaluated 534 adults with biopsy-proven NAFLD and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <40U/L within 3 months of their liver biopsy. Histological phenotypes of primary interest were nonalcoholic steatohepatitis (NASH) with stage 2–3 fibrosis (NASH F2-3) and cirrhosis. Using multiple logistic regression models with Akaike's Information Criteria (AIC), we identified variables associated with these histological phenotypes. We developed and internally validated their clinical prediction models.

RESULTS: The prevalence of NASH F2-F3 and cirrhosis was 19% and 7%, respectively. The best multiple regression AIC model for NASH F2-3 consisted of type 2 diabetes, white race, lower low-density lipoprotein, lower platelet count, higher AST/ALT ratio, higher serum triglycerides, and hypertension. The best AIC model for cirrhosis consisted of lower platelet count, lower AST/ALT ratio, higher body mass index, and female sex. The area under the receiver operator curves of the prediction models were 0.70 (95% confidence interval: 0.65–0.76) for detecting NASH-F2-3 and 0.85 (95% confidence interval: 0.77–0.92) for detecting cirrhosis. When models were fixed at maximum Youden's index, their positive and negative predictive values were 35% and 88% for NASH F2-F3 and 30% and 98% for cirrhosis, respectively.

DISCUSSION: Clinically significant histological phenotypes are observed in patients with NAFLD and normal aminotransferase levels. Our models can assist the clinicians in excluding advanced liver histology in NAFLD patients with normal aminotransferase levels.

1Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, USA;

2Data Coordinating Center, Johns Hopkins University, Baltimore, MD, USA;

3Department of Pathology, Indiana University, Indianapolis, IN, USA;

4Division of Gastroenterology, University of California, San Diego, California, USA;

5Division of Gastroenterology, University of California, San Francisco, California, USA;

6Division of Gastroenterology, Duke University, Durham, NC, USA;

7Department of Gastroenterology, Hepatology & Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA;

8Division of Gastroenterology and Hepatology, Saint Louis University, St Louis, MO, USA;

9Digestive Health Institute, Swedish Medical Center, Seattle, WA, USA;

10Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA;

11Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA;

12Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.

Correspondence: Naga Chalasani, MD. E-mail:

SUPPLEMENTARY MATERIAL accompanies this article at

Received March 06, 2019

Accepted July 10, 2019

Online date: September 11, 2019

© The American College of Gastroenterology 2019. All Rights Reserved.
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