HbA1c Highly Predicts NAFLD Disease Severity

Jeremy W. Tomlinson, MB BCh, PhD, FRCP

Credit: YouTube

Glucose control measures via glycated hemoglobin (HbA1c) may be a significant, singular predictor of non-alcoholic fatty liver disease (NAFLD) severity in patients, according to new data.¹

A recent regression analysis of patients with NAFLD uncovered data showing that HbA1c is a major contributor to the severity of the liver disease. In fact, investigators observed that in patients who received treatment that resulted in reduced HbA1c, measures of steatosis similarly improved. The findings emphasize the importance to incorporate glucose control monitoring into the comprehensive management strategy of patients with NAFLD.

A team of UK-based investigators, led by Jeremy W. Tomlinson, MB BCh, PhD, FRCP, professor of metabolic endocrinology at Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford, sought to better establish the relationship between HbA1c and NAFLD severity in patients either with or without type 2 diabetes. They noted that current non-invasive NAFLD stage scoring systems do not prioritize patients’ glucose control, despite evidence suggesting it may play a role.

Indeed, prior research presented as recently as at last year’s American College of Gastroenterology (ACG) Annual Scientific Meeting suggested that elevated HbA1c may be an independent risk factor. While the exact cause of fatty liver diseases including NAFLD is unknown, it is very often associated with overweight status, high LDL-C and triglyceride levels, and diabetes.²

Tomlinson and colleagues used data from 857 patients with liver biopsy staged NAFLD. The relationship between histological NAFLD severity and factors including patient age, HbA1c and body mass index (BMI) were defined via generalized-linear models and binomial regression analysis.¹

The team further paired biopsies from 421 patients who participated in interventional trials to observe how changed BMI and HbA1c levels, as well as active versus placebo treatment, improved patients’ steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis levels.

Among the 687 patients included in the discovery cohort, investigators observed a positive correlation between HbA1c and patients’ risk of severe steatosis, NASH and advanced fibrosis when adjusting for obesity status and age. The findings were further validated in an analysis of the second cohort of 170 patients.

A predictive model suggested that HbA1c and patient age were non-inferior to fibrosis-4 index (FIB-4) scores, a principal noninvasive biomarker for NAFLD, for predicting disease severity. Interestingly, another trial this month suggested FIB-4 may be a poorly interpreted biomarker to interpret fatty liver disease-related fibrosis.³

“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” Mazen Noureddin, MD, MHSc, medical director of the Houston Research Institute and professor of medicine at Houston Methodist Academic Institute, and colleagues wrote on those findings. “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”

When assessing the interventional trial cohort biopsies, Tomlinson and colleagues noted that reduced HbA1c was linked to improved patient steatosis and NASH after adjusting for patient weight change and treatment status. However, fibrosis change was only associated with patient weight change and treatment status, not reduced HbA1c.¹

The team concluded that HbA1c is “highly informative” in predicting NAFLD severity, and in fact contributes more to interpreting disease status than BMI does. A single percent-point difference in HbA1c was associated with the same risk to patients’ liver as 8 kg in weight.

“Assessments of HbA1c must be a fundamental part of the holistic assessment of patients with NAFLD and, alongside age, can be used to identify patients with highest risk of advanced disease,” they wrote.

References

1. ^{Colosimo S, Miller H, Koutoukidis DA, et al. Glycated haemoglobin is a major predictor of disease severity in patients with NAFLD. Diabetes Res Clin Pract. Published online August 13, 2024. doi:10.1016/j.diabres.2024.111820}
2. ^{Brooks A. Insulin Resistance Aids Detection of NAFLD in Lean Patients. HCPLive. Published October 25, 2023. https://www.hcplive.com/view/insulin-resistance-aids-detection-of-nafld-in-lean-patients}
3. ^{Brooks A. Study Describes Fibrosis Risk Misclassification with FIB-4 Compared to Transient Elastography. HCPLive. Published August 9, 2024. https://www.hcplive.com/view/study-describes-fibrosis-risk-misclassification-fib-4-transient-elastography}