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Fibrosis-4 index efficiently predicts chronic hepatitis and liver cirrhosis development based on a large-scale data of general population in Japan


Study subjects

After excluding subjects lacking essential data (Fig. 1), a consecutive 416,066 person-years of follow-up (90,709 generally healthy participants) from 1990 to 2019 were analyzed (mean age, 49.7 ± 9.5 years; range 20–93 years). The average number of follow-ups was 5.5 ± 4.8 and the average duration of follow-ups was 4.8 ± 6.1 years. The study consisted of 66,365 subjects (42,449 men and 23,916 women) between 1990–2000, 149,861 subjects (91,335 men and 58,526 women) between 2001–2010, and 199,840 subjects (116,679 men and 83,161 women) between 2011–2019. The data on fatty liver, FIB-4 index, BMI, and alcohol intake of each age group are shown in Table 1 (total 416,066 subjects), Supplementary Table S1 (250,463 men), and Supplementary Table S2 (165,603 women).

Figure 1
figure 1

Flowchart of participant recruitment in the present study.

Table 1 Detailed data on the prevalence of fatty liver, fibrosis-4 (FIB-4) index, body mass index (BMI), and alcohol intake for all the study subjects who were categorized into five age groups and three periods (1990–2000, 2001–2010, and 2011–2019).

Thirty-year trends of fatty liver, FIB-4 index, and body mass index in Japan

As shown in Table 1, compared with that in the 1990s (approximately 22%), the prevalence of fatty liver greatly increased in the 2000s (more than 35%); however, there was no remarkable change between 2001–2010 (39.2%) and 2011–2019 (35.5%). On the other hand, the rate of high FIB-4 index (≥ 2.67) did not markedly change during the 30 years (0.9% in 1990–2000, 0.6% in 2001–2010, and 1.1% in 2011–2019). Further, although BMI did not change notably (mean BMI: 23.1 in 1990–2000, 23.0 in 2001–2010, and 23.1 in 2011–2019), the prevalence of obesity (BMI ≥ 30) continuously increased from 1990 to 2019 (1.9% in 1990–2000, 2.7% in 2001–2010, and 3.8% in 2011–2019).

Although similar trends were observed for both men (Supplementary Table S1) and women (Supplementary Table S2), there was a considerable difference in their prevalence between sexes. The rates of fatty liver, high FIB-4 index (≥ 2.67), and obesity in men were higher than those in women in all three periods (1990–2000, 2001–2010, and 2011–2019) and all age groups (< 40, 40–49, 50–59, 60–69, and > 70 years). In all male and female subjects during the 30 years, the rates of fatty liver were 42.9% and 22.2%, rates of high FIB-4 index (≥ 2.67) were 1.1% and 0.6%, rates of obesity were 3.5% and 2.6%, and rates of heavy drinking were 18.4% and 5.4%, respectively.

The presence of fatty liver is significantly associated with a higher BMI but not with alcohol intake or FIB-4 index

Next, we evaluated the prevalence of fatty liver in all three periods by comparing the frequency distribution of BMI, alcohol intake, and the FIB-4 index (Fig. 2). As shown in Fig. 2a, an association between fatty liver and BMI was observed in all groups. However, the association of fatty liver with alcohol intake or the FIB-4 index could not be detected (Fig. 2b,c). Our results indicated that the presence of fatty liver significantly reflected BMI and obesity but not alcohol intake or FIB-4 index.

Figure 2
figure 2

The prevalence of fatty liver in 1990–2000, 2001–2010, and 2011–2019 regarding body mass index (BMI) (a), alcohol intake (b), and fibrosis-4 (FIB-4) index (c).

FIB-4 index is a more useful indicator of chronic hepatitis development in comparison with fatty liver

To evaluate the predictive ability of FIB-4 index and fatty liver for chronic hepatitis or liver cirrhosis, we excluded 161,696 person-years of follow-up (48,407 participants) before April 2008 which did not have detailed information of comorbidities. We further excluded 209 person-years of follow-up (63 participants) which diagnosed with chronic hepatitis or liver cirrhosis at baseline. We further excluded 2,161 person-years of follow-up (441 participants) which diagnosed with liver, collagen, and hematological diseases.

Of the 252,000 subjects (61,857 participants), 114 developed chronic hepatitis. Two models of cox regression analyses were performed to identify the contributing factor focusing on fatty liver (Fig. 3a) or FIB-4 index (Fig. 3b) for development of chronic hepatitis. Furthermore, using the time-to-event data, the adjusted survival curves for Cox proportional hazards regression were plotted to evaluate the usefulness of fatty liver (Fig. 3c) or FIB-4 index (Fig. 3d) for predicting the risk of chronic hepatitis.

Figure 3
figure 3

Cox regression analyses to evaluate the usefulness of fatty liver and FIB-4 index for prediction of chronic hepatitis development. (a) Cox regression analysis to evaluate chronic hepatitis development focusing on the presence of fatty liver. (b) Cox regression analysis to evaluate chronic hepatitis development focusing on the value of FIB-4 index. (c) Adjusted survival curves to evaluate the incidence of chronic hepatitis based on the Cox proportional hazards regression categorized by the presence of fatty liver. (d) Adjusted survival curves to evaluate the incidence of chronic hepatitis based on the Cox proportional hazards regression categorized by the value of FIB-4 index. All analyses were performed on the study participants after excluding those with chronic hepatitis, liver cirrhosis, and other diseases relating to liver, collagen, and hematological diseases at the time of entry. A p-value < 0.05 was considered statistically significant. HR hazard ratio; C.I. confidence interval.

Unexpectedly, the risk of developing chronic hepatitis was higher in subjects without fatty liver than in those with fatty liver (Fig. 3a,c; Hazard ratio [HR] = 0.09; 95% confidence interval [CI], 0.03–0.22, p < 0.001). On the other hand, the risk of developing chronic hepatitis was much higher in subjects with a high FIB-4 index (≥ 2.67) than in those without it; (Fig. 3b,d; HR = 78.6; 95% CI, 29.0–213.1, p < 0.001). Assuming the situation with insufficient information of current or previous medical history, we performed the same analyses using all the 416,066 participants. Then, similar survival curves were plotted for chronic hepatitis development regarding fatty liver (Supplementary Fig. S1a; HR = 16.0, p < 0.001) and FIB-4 index (Supplementary Fig. S1b; HR = 58.6, p < 0.001).

As for other contributing factors, our data indicated that those who drink alcohol have the lower risk of developing chronic hepatitis (Fig. 3a,b; HR = 0.47 and HR = 0.51, p = 0.024 and p = 0.033).

FIB-4 index is a more useful indicator of liver cirrhosis development in comparison with fatty liver

Of the 252,000 subjects, 23 developed liver cirrhosis. Two models of cox regression analyses were performed to identify the contributing factor focusing on fatty liver (Fig. 3a) or FIB-4 index (Fig. 3b) for development of liver cirrhosis. Furthermore, using the time-to-event data, the adjusted survival curves for Cox proportional hazards regression were plotted to evaluate the usefulness of fatty liver (Fig. 4c) and the FIB-4 index (Fig. 4d) for predicting the risk of liver cirrhosis.

Figure 4
figure 4

Cox regression analyses to evaluate the usefulness of fatty liver and FIB-4 index for prediction of liver cirrhosis development. (a) Cox regression analysis to evaluate liver cirrhosis development focusing on the presence of fatty liver. (b) Cox regression analysis to evaluate liver cirrhosis development focusing on the value of FIB-4 index. (c) Adjusted survival curves to evaluate the incidence of liver cirrhosis based on the Cox proportional hazards regression categorized by the presence of fatty liver. (d) Adjusted survival curves to evaluate the incidence of liver cirrhosis based on the Cox proportional hazards regression categorized by the value of FIB-4 index. All analyses were performed on the study participants after excluding those with liver cirrhosis, liver cirrhosis, and relating to liver, collagen, and hematological diseases at the time of entry. A p-value < 0.05 was considered statistically significant. HR hazard ratio; C.I. confidence interval.

Similar to chronic hepatitis (Fig. 3), the risk of developing liver cirrhosis was higher in subjects without fatty liver than in those with fatty liver (Fig. 4a,c, HR = 0.04; 95% CI, 0.01–0.26, p = 0.001). The risk of developing liver cirrhosis was much higher in subjects with a high FIB-4 index (≥ 2.67) than in those without it (Fig. 4b,d; HR = 5950.7; 95% CI, 761.7–46,491.4, p < 0.001). Figure 4 showed that categorization based on the value of the FIB-4 index was more useful than categorization based on the presence of a fatty liver to predict development of liver cirrhosis. Assuming the situation with insufficient information of current or previous medical history, we performed the same analyses using all the 416,066 participants. Then, similar survival curves were plotted for chronic hepatitis development regarding fatty liver (Supplementary Fig. S2a; HR = 32.1, p < 0.001) and FIB-4 index (Supplementary Fig. S2b; HR = 532.4, p < 0.001).

As for other contributing factors, our data indicated that those who drink alcohol have the lower risk of developing liver cirrhosis (Fig. 3a,b; HR = 0.04 and HR = 0.03, p < 0.001 and p < 0.001).



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