Sequential metabolic cascade from normal liver to multimorbidity in lean Asian adults: Multistate progression modelling.

BACKGROUND

Metabolic disorders may progress sequentially from fatty liver to hypertension and diabetes, but this cascade has not been well characterised in lean Asian populations. We aimed to quantify this progression and develop practical risk prediction tools in a large longitudinal Japanese cohort.

METHODS

We analysed 75,781 health examination records from 24,718 Japanese adults between 2009 and 2019. Continuous-time multistate modelling quantified transitions across four states: no fatty liver, hypertension, or diabetes; fatty liver alone; fatty liver with hypertension; and fatty liver with hypertension and diabetes. Individual risk prediction tools were developed and internally validated.

FINDINGS: Among 38,858 observed transitions, 2880 were prespecified forward cascade-transition events. Annual transition intensities were 0.699 for state 0 to 1, 0.809 for state 1 to 2, and 0.769 for state 2 to 3, corresponding to a summed mean progression time of 3.97 years. Normal-range body mass index accounted for 1394 cascade events (48.4%), whereas obesity accounted for 238 events (8.3%). The simplified clinical score showed moderate discrimination (C-statistic, 0.63; 95% confidence interval, 0.58-0.68) and good calibration.

INTERPRETATION AND FUNDING: Metabolic disease progressed rapidly and sequentially in this Asian cohort, frequently among adults without obesity. These findings support earlier body mass index-independent metabolic screening and prospective evaluation of shorter surveillance intervals in Asian populations.