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

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Abstract

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.

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Acknowledgment

Study sponsors did not play any role in the study design, data collection or analysis, interpretation of data, in the writing of the report, or in the decision to submit the manuscript for publication.

Funding

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.

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Authors and Affiliations

  1. Division of Gastroenterology, University Health Network Toronto, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada

    Heather Mary-Kathleen Kosick & Keyur Patel

  2. Division of Gastroenterology and Hepatology, McGill University Health Center, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada

    Aline Keyrouz & Giada Sebastiani

  3. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

    Oyedele Adeyi

Authors
  1. Heather Mary-Kathleen Kosick
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Correspondence to Heather Mary-Kathleen Kosick.

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Conflict of interest

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.

Ethics and consent

This study was performed according to the protocol and guidelines of Good Clinical Practice/ICH, based upon the principles outlined in the Declaration of Helsinki and local and national guidelines governing the conduct of clinical research studies. All patient data used for the purpose of this retrospective study were de-identified and anonymized, and patient consent was not required. This study was approved by the Institutional Research Ethics Board at both the University Health Network and the McGill University Health Centre.

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Kosick, H.MK., Keyrouz, A., Adeyi, O. et al. A Stepwise Algorithmic Approach and External Validation Study for Noninvasive Prediction of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease. Dig Dis Sci 66, 4046–4057 (2021). https://doi.org/10.1007/s10620-020-06748-8

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  • DOI: https://doi.org/10.1007/s10620-020-06748-8

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