FNI Outperforms FIB-4 in Predicting 20-Year MASLD Mortality in T2D

An age-independent liver fibrosis marker outperformed 2 widely used noninvasive scores in predicting long-term all-cause mortality in patients with type 2 diabetes (T2D) and metabolic dysfunction–associated steatotic liver disease (MASLD), suggesting that current risk stratification tools may leave a critical gap in identifying who is most at risk of dying, according to a 20-year retrospective cohort study published in Liver International.¹

Due to the systemic nature of the disease, patients with MASLD, and especially those who also have T2D, face an increased risk of cardiovascular disease, chronic kidney disease, and extrahepatic tumors. In addition, once MASLD progresses to fibrosis, patients with T2D face impaired glycemic control and are more likely to develop macrovascular complications.

“As such, liver fibrosis in the setting of MASLD should no longer be viewed as a collateral finding but rather as an integral component of systemic metabolic deterioration,” the authors explained.

What the 20-Year Data Revealed

The researchers followed 174 adults with T2D who enrolled after attending the outpatient metabolic clinic of Sapienza University of Rome between 2000 and 2001. At baseline, the mean age was approximately 68 years, and nearly 78% of participants had ultrasound-confirmed hepatic steatosis, which is consistent with prior estimates that between 70% and 80% of patients with T2D present with MASLD.²

Fibrosis risk was assessed using the Fibrotic NASH Index (FNI), an age-independent marker based on 3 standard laboratory values: aspartate aminotransferase (AST), hemoglobin A_1c (HbA_1c), and high-density lipoprotein cholesterol (HDL-C). The FNI was compared with 2 established noninvasive tools: the Fibrosis-4 index (FIB-4) and the AST to Platelet Ratio Index (APRI).

Over the 20-year follow-up period, all-cause mortality reached 39.7%. Deaths were significantly more concentrated among those with moderate-to-high FNI-defined fibrosis risk; mortality climbed from 12.3% in the low-risk group to 47.7% in the high-risk group.¹ In multivariable logistic regression models adjusted for age, sex, body mass index (BMI), lipids, renal function, hepatic steatosis, diabetes duration, and cardiovascular disease history, the FNI remained independently associated with 20-year mortality (OR, 11.75; 95% CI: 2.11-65.50; P = .005). Neither FIB-4 nor APRI retained statistical significance in fully adjusted models, with ORs that did not reach significance (FIB-4: OR, 1.50, P = .45; APRI: OR, 1.49, P = .63).

Why FIB-4 May Fall Short in Patients With Diabetes

The findings add clinical weight to a growing body of evidence that conventional fibrosis tools are less reliable in patients with T2D. FIB-4 incorporates age as a variable, which can systematically overestimate or underestimate fibrosis risk in older adults and in patients with the metabolic alterations common in diabetes. A study published in the Canadian Liver Journal found that FIB-4's diagnostic accuracy was meaningfully reduced in patients with diabetes compared with those without, underscoring the need for tailored approaches in this population.³

The authors of the current noted that FNI was specifically developed to screen for severe liver disease in individuals with metabolic risk factors and that prior work has demonstrated its superiority over FIB-4, APRI, and the NAFLD Fibrosis Score in predicting fibrosis resolution following bariatric surgery.¹

The Broader Stakes for MASH Risk Stratification

Metabolic dysfunction–associated steatohepatitis (MASH), which is the more severe, inflammatory form of MASLD, is a major driver of hepatic fibrosis, cirrhosis, and liver-related mortality, and its prevalence is tightly linked to diabetes and obesity. Advanced MASH in the US currently affects an estimated 4.3 million people, a number projected to approach 5 million by 2040 without meaningful intervention.⁴

The challenge of identifying at-risk patients before disease progresses remains central to the field. As Naim Alkhouri, MD, noted in an interview with The American Journal of Managed Care^® earlier this year, screening for MASLD and risk stratification in high-risk populations, including people with T2D, should become a standard quality metric that primary care physicians and endocrinologists document at every visit, but that infrastructure does not yet exist widely.⁵

“In patients with type 2 diabetes, for example, the epidemiologic data showed that up to 60% can have steatotic liver disease. But then when you look at ICD-10 [International Classification of Disease, Tenth Revision] codes, having the diagnosis in their chart, we talk about 5% to 10%. We have a big gap that we need to work on,” Alkhouri said.

Another review of MASLD and MASH care gaps similarly emphasized that fibrosis remains a critical, undercaptured prognostic marker and that noninvasive testing strategies—including blood-based composite scores—represent the most feasible pathway to broader population screening.⁶

What This Means for Risk Stratification and Care Delivery

The study points to both a clinical and operational imperative. If an age-independent, blood-based index using 3 routine lab values can identify patients with T2D who face a nearly 12-fold higher 20-year mortality risk, the case for incorporating such tools into systematic diabetes care protocols becomes difficult to dismiss. The researchers argued that early identification of liver fibrosis using tools like the FNI could enhance risk stratification and enable more personalized management in metabolically complex populations.¹

The authors acknowledged meaningful limitations: the single-center design, the relatively small cohort of 174 patients, wide confidence intervals around the FNI's OR, the absence of cause-specific mortality data, and the lack of serial FNI measurements over the follow-up period. They called for larger, multicenter studies to confirm and sharpen the risk estimates.

“…in T2D patients with high cardiovascular burden, FNI-estimated hepatic fibrosis emerged as a major determinant of long-term mortality,” the authors concluded. “These findings support the early identification of liver fibrosis, using non-invasive tools such as FNI, as a valuable clinical strategy to enhance risk stratification and guide personalised care in dysmetabolic populations.”

References

1. Barchetta I, Cimini FA, Dule S, et al. Fibrotic NASH Index (FNI) is associated with long-term mortality in individuals with type 2 diabetes and MASLD. Liver International. 2026;46:e70676. doi:10.1111/liv.70676
2. Teng ML, Ng CH, Huang DQ, et al. Global incidence and prevalence of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2022;29(Suppl):S32-S42. doi:10.3350/cmh.2022.0365
3. Rath K. Evaluation of albumin platelet product for fibrosis detection in MASLD. AJMC®. December 11, 2025. Accessed May 22, 2026. https://www.ajmc.com/view/evaluation-of-albumin-platelet-product-for-fibrosis-detection-in-masld
4. Klein HE. Global MASH burden projected to double costs, raise mortality without intervention. AJMC. September 12, 2025. Accessed May 22, 2026. https://www.ajmc.com/view/global-mash-burden-projected-to-double-costs-raise-mortality-without-intervention
5. Munz K, Alkhouri N. Early identification of MASLD/MASH saves lives: Naim Alkhouri, MD. AJMC. May 6, 2025. Accessed May 22, 2026. https://www.ajmc.com/view/early-identification-of-masld-mash-saves-lives-naim-alkhouri-md
6. Jeremias S. Advances in MASLD and MASH care highlight progress and persistent gaps. AJMC. February 10, 2026. Accessed May 22, 2026. https://www.ajmc.com/view/advances-in-masld-and-mash-care-highlight-progress-and-persistent-gaps