Dynamic AFP-Defined Disease State Transitions in Hospitalized Patients with Hepatocellular Carcinoma Using the Multi-State Markov Model: A Retrospective Cohort Study

Background: Hepatocellular carcinoma (HCC) exhibits highly variable disease trajectories, posing challenges for longitudinal monitoring and prognostic assessment. Alpha-fetoprotein (AFP) is widely used in HCC management, but transitions between discrete AFP states over time have not been explicitly modeled. Methods: We conducted a retrospective cohort study of 2,750 hospitalized HCC patients between 2016 and 2024, encompassing 17,076 hospitalizations. AFP measurements were categorized into four clinical relevant states (S1–S4, from low to high). A multi-state Markov (MSM) model was constructed to estimate transition probabilities, transition rates, and sojourn times, and to assess the effects of hepatitis B virus (HBV) infection, antiviral therapy, and major clinical covariates. Longitudinal AFP transitions were visualized using Sankey diagrams. Results: Among 2,750 hospitalized HCC patients, AFP-defined disease states S1 and S4 were relatively stable, whereas intermediate states S2 and S3 exhibited frequent bidirectional transitions. Tenofovir disoproxil fumarate (TDF) therapy was associated with S2→S1 AFP decrease (HR 1.350, 95% CI 1.065– 1.710). Elevated alanine aminotransferase (ALT) showed bidirectional effects (S1→S2: HR 1.310, 95% CI 1.011– 1.696; S3→S4: HR 1.517, 95% CI 1.130– 2.035; S2→S1: HR 1.493, 95% CI 1.191– 1.872; S3→S2: HR 1.685, 95% CI 1.295– 2.193; S4→S3: HR 1.527, 95% CI 1.153– 2.021), while elevated aspartate aminotransferase (AST), and total bilirubin (TBIL) were associated with lower likelihood of AFP decrease (AST S4→S3: HR 0.664, 95% CI 0.486– 0.908; TBIL S3→S2: HR 0.687, 95% CI 0.492– 0.958; S4→S3: HR 0.674, 95% CI 0.472– 0.965). Shorter sojourn times and higher hospitalization frequencies indicated clinical instability in intermediate disease states, suggesting a potentially modifiable window for clinical intervention. Conclusion: This study characterizes dynamic AFP-defined disease state transitions in hospitalized patients with HCC. Intermediate disease states represent unstable but potentially modifiable phases strongly influenced by antiviral therapy and liver function status. These findings support the value of longitudinal AFP monitoring beyond single time-point assessment and individualized clinical management.