Repeating noninvasive fibrosis assessments every two years may substantially reduce missed cases of significant liver fibrosis among adults with type 2 diabetes, according to a prospective longitudinal study in Gastro Hep Advances validating the AGA Clinical Care Pathway for metabolic dysfunction-associated steatotic liver disease (MASLD).
Individuals with type 2 diabetes are at increased risk for MASLD and progressive liver fibrosis, making effective screening strategies a clinical priority. Current AGA and American Association for the Study of Liver Diseases guidance recommends a stepwise approach using the fibrosis-4 index (FIB-4), followed by vibration-controlled transient elastography (VCTE) in patients with indeterminate results, with reassessment every two to three years for those considered low risk.
“The AGA Clinical Care Pathway has been widely endorsed for non-invasive fibrosis risk stratification, and our cross-sectional work previously showed it performed well in patients with T2DM,” explained Veeral Ajmera, MD, study co-author and an investigator at University of California San Diego’s MASLD Research Unit. “However, the guidelines recommend reassessing low-risk patients every two to three years, and there were limited data supporting that recommendation. Given that patients with T2DM are at especially high risk for fibrosis progression, we wanted to evaluate how serial reassessment affects two key metrics: the false negative rate and the number of patients referred to specialty care.”
To achieve this aim, Dr. Ajmera and his colleagues at the MASLD Research Center evaluated 209 adults aged 50 to 79 years with type 2 diabetes who underwent baseline and two-year follow-up assessments. Magnetic resonance elastography (MRE), an imaging-based measure of liver stiffness, served as the reference standard for significant fibrosis, defined as liver stiffness of at least 3.3 kPa. In this instance, Dr. Ajmera noted, MRE was used as a research reference standard rather than as a recommended screening tool, adding: “MRE is not necessary for population-level screening; it should be reserved for specialist evaluation in the setting of clinical trials or selected patients where additional accuracy will change management.”
At the study’s baseline, nearly 70% of participants had MASLD and 19% had significant fibrosis. Applying the AGA pathway classified 52.8% of patients as low risk, 42.1% as indeterminate risk, and 5.0% as high risk. The pathway produced a false-negative rate of 7%, meaning that nine patients classified as low risk were found to have significant fibrosis on MRE. Only 17.6% of participants met criteria for referral to specialty care.
After repeat testing two years later, the false-negative rate declined to 3%. Among the patients initially categorized as low risk, 88.3% remained low risk, while others were appropriately reclassified into higher-risk categories. Additionally, most patients who were falsely classified as low risk at baseline were correctly reclassified during follow-up. Of the nine baseline false-negative cases, only two remained false negatives after repeat evaluation.
“This is a strong, real-world endorsement of the guideline-recommended two-to-three-year reassessment interval,” said Dr. Ajmera, “which meaningfully reduces misclassification without overwhelming hepatology clinics.”
The investigators also examined whether lowering the FIB-4 threshold from 1.3 to 1.0 could improve detection. Dr. Ajmera stressed that clinicians should pay close attention to patients falling within this threshold, particularly those who have elevated ALT (alanine aminotransferase) or AST (aspartate aminotransferase). “Nearly all of our missed cases at baseline fell in this range,” he added. “A lower FIB-4 cutoff of 1.0 essentially eliminated false negatives, but at the cost of a 54% increase in downstream VCTE testing. Therefore, individualized judgment, particularly when transaminases are elevated, is still recommended.”
The findings support current guideline recommendations for repeat assessment every two to three years in patients with type 2 diabetes, and suggest that longitudinal screening may help identify patients whose liver disease progresses over time.
“Serial reassessment works and the AGA Clinical Care Pathway is not meant to be applied once,” Dr. Ajmera said. “Its accuracy improves when repeated at the recommended interval, and patients initially classified as low-risk should be re-evaluated rather than considered permanently cleared.”
He added that optimal reassessment interval times and FIB-4 thresholds — particularly while emphasis on earlier detection rises and effective metabolic dysfunction-associated steatohepatitis (MASH) therapies are made more widely available — still remain “open questions”, and that future research needs to also look at the cost-effectiveness of a direct-to-VCTE approach for high-risk patients, including those with lower FIB-4 cutoffs and type 2 diabetes.
Dr. Ajmera reported consulting for Madrigal Pharmaceuticals and having been awarded research grants from Gilead Sciences. Study co-author Rohit Loomba reported consulting and research relationships with multiple pharmaceutical companies. The remaining authors reported no relevant conflicts of interest.