Baseline characteristics

A total of 405 patients with MASLD underwent serial MREs. Table 1 summarizes the characteristics of the included patients. The mean age was 58.5 ± 2.5 years, and 219 (54.1%) patients were female. The mean initial LSM was 3.13 ± 0.94 kPa. The number of patients in each group was as follows: Group 0, 155 (38.3%); Group 1, 58 (14.3%); Group 2, 83 (20.5%), Group 3, 62 (5.3%); and Group 4, 47 (11.6%). The mean interval between consecutive MREs was 23.5 ± 0.8 months, and the mean interval from the initial MRE to the end of follow-up was 72.6 ± 25.8 months.

Table 1 Patient characteristics (N = 405)Changes in LSM

During the interval between serial MRE measurements, MASLD regressed in 79 patients (19.5%), remained unchanged in 274 patients (67.7%), and progressed in 52 patients (12.8%) (Fig. 1a). As demonstrated in Fig. 1b, progressors with high ΔLSM values were observed regardless of the initial LSM value.

Fig. 1

a Distribution of LSM changes. In serial MRE measurements in patients with MASLD, LSM regressed in 79 (19.5%) patients, remained unchanged in 274 (67.7%) patients, and progressed in 52 (12.8%) patients. The mean interval between the two MRE measurements was 23.51 ± 0.47 months. b Scatterplot exhibiting the distribution of patients divided into three groups: progression, stable, and regression. MRE, magnetic resonance elastography; LSM, liver stiffness measurements by magnetic resonance elastography; ΔLSM, difference between two LSMs

Clinical outcomes

Among the 405 patients, 11 (2.71%) died during the follow-up period. Furthermore, 17 (4.20%) patients developed a total of 18 liver-related events. HCC (n = 8) was the most common liver-related event, followed by ruptured gastroesophageal varices (n = 6). Extrahepatic malignancies occurred in 22 patients (5.43%), with colorectal cancer (n = 7) being the most common malignancy. Supplementary Table 1 presents details regarding extrahepatic malignancies. Cardiovascular diseases occurred in only six patients (1.48%). Among the 386 patients without clinical cirrhosis at the time of the initial MRE, 11 (2.8%) developed cirrhosis during the study period.

Initial LSM as a predictor of clinical outcomes

Table 2 and Fig. 2 show the cumulative probabilities obtained from the Kaplan–Meier analysis of liver-related events, decompensated cirrhosis, HCC, overall mortality, extrahepatic malignancies, and cardiovascular disease, stratified by group based on the initial LSM. Within an observation period of 72.6 ± 25.8 months, there were significant among-group differences in the cumulative incidence of liver-related events (p < 0.001), decompensated cirrhosis (p < 0.001), HCC (p < 0.001), overall mortality (p < 0.001), and extrahepatic malignancies (p = 0.049) according to the log-rank test; however, there was no significant among-group difference in the incidence of cardiovascular disease (p = 0.203). Additionally, there was a significant among-group difference in the cumulative incidence of overall clinical events (p < 0.001) (Table 2 and Supplementary Fig. 1a).

Table 2 Cumulative probability of outcomes according to the initial LSM groups corresponding to the fibrosis stages (N = 405)Fig. 2

Cumulative incidence of clinical events based on the initial LSM. Patients were divided into five groups (Groups 0–4) corresponding to each fibrosis stage (fibrosis stages 0–4) according to the initial LSM. a Liver-related events; b decompensated cirrhosis; c hepatocellular carcinoma; d all-cause mortality; e extrahepatic malignancies; f cardiovascular disease. LSM: liver stiffness measurement by magnetic resonance elastography

As demonstrated in Supplementary Table 2, the HRs of liver-related events for Groups 3 and 4 vs. Group 0 were 10.48 (95% confidence interval [CI]: 1.55–70.68; p = 0.006) and 37.01 (95% CI 8.67–157.9; p < 0.001), respectively. Additionally, the respective HRs of Groups 3 and 4 vs. Group 0 were as follows: 4.81 (95% CI 0.42–54.28; p = 0.203) and 24.84 (95% CI 4.51–137.0; p < 0.001) for decompensated cirrhosis; 34.53 (95% CI 1.59–750.3; p = 0.024) and 60.29 (95% CI 6.15–591.1; p < 0.001) for HCC; 33.02 (95% CI 3.78–288.9; p = 0.003) and 45.33 (95% CI 6.17–333.0; p < 0.001) for overall death; 1.24 (95% CI 0.34–4.51; p = 0.744) and 3.66 (95% CI 1.10–12.19; p = 0.035) for extrahepatic malignancies; and 35.42 (95% CI 1.62–774.1; p = 0.024) and 64.88 (95% CI 2.52–1668; p = 0.012) for cardiovascular disease.

ΔLSM as a predictor of clinical outcomes

The cumulative incidence of clinical events among progressors and non-progressors (stable/regressors) is demonstrated in Supplementary Table 3. The cumulative incidence of liver-related events, including decompensated cirrhosis and HCC, estimated by Kaplan–Meier curves was significantly higher in progressors than in non-progressors (11.5% [6/52 patients] vs. 2.3% [8/353 patients], p = 0.001, log-rank test) (Fig. 3a). Based on classification according to events, the cumulative incidence of decompensated cirrhosis and HCC was significantly higher in progressors than in non-progressors (decompensated cirrhosis (7.7% [4/52 patients] vs. 1.4% [5/353 patients], p = 0.009); HCC (5.8% [3/52 patients] vs. 0.8% [3/353 patients], p = 0.008) (Fig. 3b, c). Contrastingly, the cumulative probabilities of all-cause mortality (p = 0.820), extrahepatic malignancies (p = 0.180), and cardiovascular events (p = 0.317) did not significantly differ between progressors and non-progressors (Fig. 3d–f and Supplementary Table 3).

Fig. 3

Cumulative incidence of clinical events in progressors vs. non-progressors (stable/regression) based on ΔLSM. a Liver-related events; b decompensated cirrhosis; c hepatocellular carcinoma; d all-cause mortality; e extrahepatic malignancies; f cardiovascular disease. ΔLSM: difference between two liver stiffness measurements by magnetic resonance elastography

Furthermore, as shown in Table 3, compared with non-progressors, progressors had a significantly higher risk of liver-related events (HR: 12.79, 95% CI 2.74–59.64; p = 0.012), decompensated cirrhosis (HR: 12.08, 95% CI 1.85–78.73; p = 0.009), HCC (HR: 25.02, 95% CI 2.35–267; p = 0.08), and overall clinical events (HR: 3.72, 95% CI 1.41–9.84; p < 0.01) (Supplementary Fig. 1b and Table 3). Alternatively, the HRs for progressors vs. non-progressors were as follows: 1.21 (95% CI 0.24–6.15; p = 0.820) for all-cause mortality, 2.66 (95% CI 0.64–11.17; p = 0.180) for extrahepatic malignancies, and 5.40 (95% CI 0.20–247; p = 0.317) for cardiovascular diseases (Table 3).

Table 3 Relative risk of clinical outcomes in progressors compared with non-progressors based on serial magnetic resonance elastography

Since LSM changes in patients with cirrhosis may be small, we evaluated the correlation between ΔLSM and clinical events in a subgroup of patients without pathologic or clinical cirrhosis at the time of the second MRE (n = 386). Even in this subgroup, progressors were at a significant risk of liver-related events (HR: 10.91, 95% CI 1.29–92.18; p = 0.028) and HCC (HR: 24.60, 95% CI 1.36–443.7; p = 0.030) compared with non-progressors; moreover, they showed a non-significant trend toward a higher risk of decompensated cirrhosis (HR: 15.09, 95% CI 0.98–232.5; p = 0.052). Contrastingly, there was no significant difference in the risk of all-cause mortality (HR: 1.85, 95% CI 0.64–5.37; p = 0.258), extrahepatic malignancies (HR: 1.71, 95% CI 0.39–7.52; p = 0.480), or cardiovascular disease (HR: 1.57, 95% CI 0.13–19.10; p = 0.127) between progressors and non-progressors (Supplementary Fig. 2).

ΔLSM predicts the progression to cirrhosis in patients without cirrhosis

Among patients without pathologic or clinical cirrhosis at the time of the second MRE (n = 386), 50 (13.0%) progressed over serial MRE measurements, whereas 336 (87.0%) had stable or regressed LSM. Within a follow-up period of 43.9 ± 39.4 months after the second MRE, progressors had a significantly higher incidence of cirrhosis than non-progressors (7/50 patients [14.0%] vs. 2/336 patients [1.2%]) (Supplementary Fig. 3). Compared with non-progressors, progressors had a significantly higher risk of developing cirrhosis (HR: 60.15, 95% CI 11.0–329; p < 0.001) (Supplementary Fig. 3, Table 3).

ΔLSM as a predictor of clinical outcomes in patients with a low initial LSM

In a subgroup of patients with an initial LSM of < 3.62 kPa (n = 296), which corresponds to fibrosis stage 0–2, indicating a low risk of clinical events, we evaluated the rate of clinical events in progressors and non-progressors. In this subgroup, the cumulative incidence of liver-related events was significantly higher in progressors than in non-progressors (4.9% [2/41] vs. 0.4% [1/255], p = 0.009) (Fig. 4a and Supplementary Table 4). Additionally, the cumulative incidence of all clinical events was significantly higher in progressors than in non-progressors (14.6% [6/41] vs. 1.6% [4/255], p = 0.012) (Fig. 4b and Supplementary Tables 4 and 5). The HRs for progressors vs. non-progressors for liver-related events and all events were 77.45 (95% CI 2.99–2006; p = 0.009) and 10.32 (95% CI 1.656–64.37; p = 0.012), respectively (Supplementary Table 5).

Fig. 4

Cumulative incidence of clinical events in progressors versus non-progressors (stable/regressive) based on ΔLSM in patients with MASLD with a low initial LSM corresponding to fibrosis stage ≤ 2 (N = 296). a Liver-related events; b Overall clinical events. LSM: liver stiffness measurement by magnetic resonance elastography; ΔLSM: difference between two liver stiffness measurements by magnetic resonance elastography