SAFE Score Predicts Cirrhosis Risk in Steatotic Liver Disease

A cohort study using data from the national US Veterans Affairs health system found that the steatosis-associated fibrosis estimator (SAFE) score demonstrated the greatest net benefit for predicting incident cirrhosis among patients with noncirrhotic steatotic liver disease (SLD), according to findings published in JAMA Internal Medicine.

The study compared 9 clinical risk scores, including the fibrosis-4 index (FIB-4), the aspartate aminotransferase-to-platelet ratio (APRI), and SAFE, for utility in informing cirrhosis and hepatocellular carcinoma (HCC) surveillance decisions in SLD, a use the investigators said was unknown.

The cohort included adults with imaging-confirmed SLD without viral hepatitis or primary liver disease, identified from 2008 to 2020. Risk scores were calculated at first imaging showing hepatic steatosis; patients were followed until cirrhosis, HCC, death, or 6 months after their last visit, with outcomes identified via VA and Medicare diagnosis codes and the VA Cancer Registry. Cox models estimated 10-year probabilities, and decision curves calculated net benefit across risk thresholds.

The analysis included 853,131 patients (median age, 61 years; 92.7% male); 3.96% developed cirrhosis and 0.35% developed HCC within 10 years. FIB-4, APRI, and SAFE showed the greatest discrimination for cirrhosis risk, while SAFE, Tate, and FIB-4 showed the greatest for HCC risk. SAFE had the greatest net benefit for cirrhosis: at a threshold of 29.5, corresponding to a 10-year risk of 2.5%, it identified 1.9 additional individuals who developed cirrhosis per 100 at-risk individuals. For HCC, at a 0.25% risk threshold, SAFE's net benefit was smaller, at 1.6 additional true positives per 1,000 individuals; HCC risk scores showed minimal benefit for screening decisions absent cirrhosis, the authors said.

The authors concluded that SAFE may inform decisions to repeat cirrhosis screening in SLD, while HCC risk scores offered minimal utility for HCC screening decisions in noncirrhotic SLD.

Source: Mezzacappa C, Tate JP, Torgersen J, et al. Steatotic liver disease risk scores to predict cirrhosis and hepatocellular carcinoma. JAMA Intern Med. Published online September 21, 2026. doi:10.1001/jamainternmed.2026.4110