Distinct Alpha-Fetoprotein Trajectories Preceding Hepatocellular Carcinoma Diagnosis: A Latent Class Mixed-Model
Apichat Kaewdech1, Chanavee Toh2, Pimsiri Sripongpun1
1Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand.
Background And Aims:
Hepatocellular carcinoma (HCC) is frequently diagnosed at an advanced stage, and serum alpha-fetoprotein (AFP), the most widely used biomarker for HCC surveillance, exhibits substantial interpatient variability. However, longitudinal AFP patterns preceding HCC diagnosis and their clinical correlates remain incompletely characterized. We aimed to characterize pre-diagnostic AFP trajectories and identify clinical features associated with rising versus non-rising AFP patterns.
Methods:
We analyzed 529 patients with newly diagnosed HCC at Songklanagarind Hospital, each with at least three serum AFP measurements obtained within five years before diagnosis. Log-transformed AFP values were modeled using latent class mixed models with natural cubic splines and linear fixed and random effects. The optimal model was selected based on Bayesian Information Criterion (BIC), entropy, and clinical interpretability. Multinomial logistic regression and Cox proportional hazards models were used to evaluate associations between AFP trajectory class, baseline characteristics, and overall survival.
Results:
A two-class natural spline model (df = 3) provided the optimal fit (BIC = 9003). The non-rising trajectory (n = 440; 83.2%) showed stable AFP levels throughout follow-up, whereas the rising trajectory (n = 89; 16.8%) demonstrated exponential increase beginning 18-24 months before diagnosis. Compared to the non-rising group, patients in the rising group were significantly more likely to present with tumors >2 cm (78% vs. 62%; p = 0.009). The rising trajectory was associated with shorter overall survival in univariable analysis (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.02-1.73; p = 0.033), but not after adjustment for clinical and tumor characteristics, including Barcelona Clinic Liver Cancer stage (adjusted HR 1.01, 95% CI 0.77-1.33; p = 0.920).
Conclusions:
Two distinct AFP trajectories precede HCC diagnosis. Most patients did not demonstrate a substantial rise in AFP, underscoring the need for complementary surveillance biomarkers. Prospective validation in independent cohorts is required before AFP trajectory-based approaches can be incorporated into HCC surveillance practice. These findings are exploratory and hypothesis-generating rather than a validated clinical prediction tool.