Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: The Edinburgh Type 2 Diabetes Study

Sheila M. Grecian*, Stela McLachlan, Jonathan A. Fallowfield, Peter C. Hayes, Indra Neil Guha, Joanne R. Morling, Stephen Glancy, Rachel M. Williamson, Rebecca M. Reynolds, Brian M. Frier, Nicola N. Zammitt, Jackie F. Price, Mark W.J. Strachan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Type 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk-stratification tools are suboptimal and perform worse in people with diabetes. Aims: To determine whether the addition of complementary biomarker(s) to current NAFLD risk-stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC. Methods: The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D (n = 1066, age 60–75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow-up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression. Results: Of existing risk-stratification scores tested, the Fibrosis-4 (FIB-4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut-point ≥ 50 (Formula presented.) g/L) to FIB-4 (cut-point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as “high risk” for incident disease by ∼50%. Conclusions: The addition of hyaluronic acid to FIB-4 reduced the proportion of people inappropriately identified as “high risk” for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.

Original languageEnglish
Pages (from-to)497-508
Number of pages12
JournalObesity Science and Practice
Issue number5
Publication statusPublished - Oct 2021
Externally publishedYes

Bibliographical note

Funding Information:
Jonathan A. Fallowfield has served as a consultant or advisory board member for Novartis, Ferring Pharmaceuticals, Macrophage Pharma, Aquilla BioMedical, Galecto Biotech, Caldan Therapeutics, Cypralis, NorthSea Therapeutics, Rallybio, Tectonic, and has received research funding from Novartis and Intercept Pharmaceuticals, outside the submitted work. Peter C. Hayes has served as speaker or on advisory boards for the following AbbVie, BMS, Eisai Ltd, Falk, Ferring, Gilead, Gore, Janssen, Lundbeck, MSD, Norgine, Novartis, ONO Pharmaceuticals, Pfizer and Roche. Joanne R. Morling reports salary support from Diabetes UK for the ET2DS. Rachel M. Williamson reported salary funding by a research grant from Pfizer for 2 years. Brian M. Frier has participated in a Speakers' Bureau for: Lilly, Novo Nordisk, MSD, Sanofi, Roche, and Abbott and has served on advisory boards for Lilly, and Zucara. Mark W.J. Strachan has received consultancy fees from Servier and Novo Nordisk and speaking fees from Napp, Sanofi, Astra Zenica, Merck and Eli Lilly. No other potential conflicts of interest relevant to this article were reported.

Funding Information:
The Edinburgh Type 2 Diabetes Study was funded by a grant from the U.K. Medical Research Council (Project Grant G0500877) and the Chief Scientist Office of Scotland (Programme Support Grant CZQ/1/38), and the Liver Substudy was supported by a grant from Pfizer (unrestricted investigator led grant). The study sponsor was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

Publisher Copyright:
© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.


  • hyaluronic acid
  • risk prediction
  • type 2 diabetes


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