acNASH index to diagnose nonalcoholic steatohepatitis: a prospective derivation and global validation study

Xi-Xi Wu; Kenneth I Zheng; Jérôme Boursier; Wah-Kheong Chan; Yusuf Yilmaz; Manuel Romero-Gómez; Mohamed El Kassas; Giovanni Targher; Christopher D Byrne; Zhi-Ming Huang; Ming-Hua Zheng

doi:10.1016/j.eclinm.2021.101145

acNASH index to diagnose nonalcoholic steatohepatitis: a prospective derivation and global validation study

EClinicalMedicine. 2021 Oct 1:41:101145. doi: 10.1016/j.eclinm.2021.101145. eCollection 2021 Nov.

Authors

Xi-Xi Wu¹, Kenneth I Zheng², Jérôme Boursier³, Wah-Kheong Chan⁴, Yusuf Yilmaz^{5

6}, Manuel Romero-Gómez⁷, Mohamed El Kassas⁸, Giovanni Targher⁹, Christopher D Byrne¹⁰, Zhi-Ming Huang¹, Ming-Hua Zheng^{2

11

12}

Affiliations

¹ Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
² MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ Department of Hepato-Gastroenterology, Angers University Hospital, Angers, France.
⁴ Gastroenterology and Hepatology Unit, Gastrointestinal Endoscopy Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁵ Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul, Turkey.
⁶ Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey.
⁷ Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Sevilla, Spain.
⁸ Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt.
⁹ Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy.
¹⁰ Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK.
¹¹ Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.
¹² The Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.

Abstract

Background: There is an unmet need for non-invasive biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) in non-specialized settings. We aimed to develop and validate a non-invasive test for diagnosing NASH in individuals with biopsy-proven nonalcoholic fatty liver disease (NAFLD).

Methods: We developed a non-invasive test named the acNASH index that combines serum creatinine and aspartate aminotransferase levels in a derivation cohort of 390 Chinese NAFLD patients admitted to the hepatology center of the First Affiliated Hospital of Wenzhou Medical University (China) between December 2016 and September 2019 and subsequently validated in five external cohorts of different ethnicities of patients with biopsy-confirmed NAFLD (pooled n=1,089).

Findings: The performance of the acNASH index for identifying NASH (defined as NAFLD activity score ≥5 with score of ≥1 for each steatosis, lobular inflammation and ballooning) was good in the derivation cohort with an area under receiver operating characteristics (AUROC) of 0·818 (95%CI 0·777-0·860). A cutoff of acNASH index <4·15 gave a sensitivity (Se) of 91%, a specificity (Sp) of 48% and a negative predictive value (NPV) of 83% for ruling-out NASH, conversely, a cutoff of acNASH >7·73 gave a Sp of 91%, Se of 53% and a positive predictive value (PPV) of 85% for ruling-in NASH. In the pooled validation cohort (n=1,089), the diagnostic performance of the index was also good with AUROC=0·805 (95%CI 0·780-0·830), NPV of 93% for ruling-out NASH and PPV of 73% for ruling-in NASH. Subgroup analyses showed similar performance in patients with diabetes or subjects with normal serum transaminase levels.

Interpretation: The acNASH index shows promising utility as a simple non-invasive biomarker for diagnosing NASH among adults with biopsy-proven NAFLD of different ethnicities from different countries.

Funding: The National Natural Science Foundation of China (82070588), High Level Creative Talents from Department of Public Health in Zhejiang Province (S2032102600032) and Project of New Century 551 Talent Nurturing in Wenzhou.

Keywords: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under receiver operating characteristics; BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CRN, Clinical Research Network; GAA, guanidine-acetic acid; HBV, chronic viral hepatitis B; HCV, chronic viral hepatitis C; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; NPV, negative predictive value; Nonalcoholic steatohepatitis; PERSONS, Prospective Epidemic Research Specifically Of NASH; PPV, positive predictive value; SCr, serum creatinine; Se, sensitivity; Sp, specificity; T2DM, type 2 diabetes mellitus; e-GFR, estimated glomerular filtration rate; metabolic dysfunction-associated fatty liver disease; nonalcoholic fatty liver disease; primary care; scoring system; screening.