A Stepwise Algorithmic Approach and External Validation Study for Noninvasive Prediction of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease

Heather Mary Kathleen Kosick, Aline Keyrouz, Oyedele Adeyi, Giada Sebastiani, Keyur Patel

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background and Aims: Advanced F3–4 fibrosis predicts liver-related mortality in nonalcoholic fatty liver disease (NAFLD). Noninvasive tests, designed to rule in/out advanced fibrosis, are limited by indeterminates, necessitating biopsy. We aimed to determine whether stepwise combinations of noninvasive serum-based tests and elastography (VCTE) could predict F3–4, reduce indeterminates, and decrease liver biopsies. Methods and Results: Five hundred forty-one biopsy-proven NAFLD cases were identified between 2010 and 2018 from two Canadian centers. Characteristics of training (n = 407)/validation (n = 134) cohorts included: males 54%/59%; mean age 48.5/52.5 years; mean body mass index 32.3/33.6 kg/m2; diabetes mellitus 30%/34%; and F3–4 48%/43%. For training/validation cohorts, area under the receiver operating curve (AUROC) for FIB-4, AST-platelet ratio index (APRI), NAFLD fibrosis score (NFS), BARD score, and AST/ALT ratio ranged from 0.70 to 0.83/0.68 to 0.81, with indeterminates 25–39%/34–45%, for F3–4. In the training cohort, parallel FIB-4 + NFS had good accuracy (AUROC = 0.81) but was limited by 38% indeterminates and 16% misclassified. Sequential FIB-4 → NFS reduced indeterminates to 10%, and FIB-4 → VCTE to 0%, misclassified 20–22%, while maintaining high specificity (0.88–0.92) and accuracy (AUROC 0.75–0.78) for combined cohorts. Liver biopsy could have been avoided in 27–29% of patients using sequential algorithms. Conclusions: Sequential FIB-4 ➔ NFS/VCTE predicts F3–4 with high specificity and good accuracy, while reducing indeterminates and need for biopsy. Parallel algorithms are limited by high indeterminates. Sequential FIB-4 ➔ NFS had similar accuracy to VCTE-containing algorithms. Validation in low-prevalence cohorts may allow for potential use in community or resource-limited areas for risk stratification.

Original languageEnglish (US)
Pages (from-to)4046-4057
Number of pages12
JournalDigestive Diseases and Sciences
Issue number11
Early online dateJan 3 2021
StatePublished - Nov 2021

Bibliographical note

Funding Information:
This study was supported by a research Grant from Gilead Sciences Canada. GS is supported by a Junior 1 and 2 Salary Award from FRQS (Nos. 27127 and 267806) and research salary from the Department of Medicine of McGill University.

Funding Information:
GS has acted as speaker for Merck, Gilead, Abbvie, Novonordisk, Novartis, served as an advisory board member for Merck, Novartis, Gilead and Intercept, and has received unrestricted research funding from Merck and Theratechnologies Inc. KP has the following declarations: (1) Gilead-Advisory Board, consulting, research grants; (2) Novartis-Advisory Board; (3) Intercept-Advisory Board.

Publisher Copyright:
© 2021, Springer Science+Business Media, LLC, part of Springer Nature.


  • Liver biopsy
  • Liver fibrosis
  • Nonalcoholic fatty liver disease
  • Noninvasive

PubMed: MeSH publication types

  • Journal Article
  • Observational Study
  • Research Support, Non-U.S. Gov't


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