Non-invasive liver fibrosis markers are increased in obese individuals with non-alcoholic fatty liver disease and the metabolic syndrome

Abstract

The need for early non-invasive diagnostic tools for chronic liver fibrosis is growing, particularly in individuals with obesity, non-alcoholic fatty liver disease (NAFLD), and the metabolic syndrome (MetS) since prevalence of these conditions is increasing. This case-control study compared non-invasive liver fibrosis markers in obesity with NAFLD and MetS (NAFLD-MetS, n = 33), in obese (n = 28) and lean (n = 27) control groups. We used MRI (T1 relaxation times (T1) and liver stiffness), circulating biomarkers (CK18, PIIINP, and TIMP1), and algorithms (FIB-4 index, Forns score, FNI, and MACK3 score) to assess their potential in predicting liver fibrosis risk. We found that T1 (892 ± 81 ms vs. 818 ± 64 ms, p < 0.001), FNI (15 ± 12% vs. 9 ± 7%, p = 0.018), CK18 (166 ± 110 U/L vs. 113 ± 41 U/L, p = 0.019), and MACK3 (0.18 ± 0.15 vs. 0.05 ± 0.04, p < 0.001) were higher in the NAFLD-MetS group compared with the obese control group. Moreover, correlations were found between CK18 and FNI (r = 0.69, p < 0.001), CK18 and T1 (r = 0.41, p < 0.001), FNI and T1 (r = 0.33, p = 0.006), MACK3 and FNI (r = 0.79, p < 0.001), and MACK3 and T1 (r = 0.50, p < 0.001). We show that liver fibrosis markers are increased in obese individuals with NAFLD and MetS without clinical signs of liver fibrosis. More studies are needed to validate the use of these non-invasive biomarkers for early identification of liver fibrosis risk.

Keywords: Liver fibrosis risk; Non-alcoholic fatty liver disease; Non-invasive biomarkers; Obesity; Obesity phenotype; The metabolic syndrome.

Fig. 1

Flow chart (consort diagram) showing the study population as (1) Lean control group, (2) Obese control group, and (3) Obese NAFLD-MetS group. The flow chart further shows the number of participants that were screened and found eligible as participants to be included in final data analysis as well as information on participants that were excluded.

Fig. 2

Dot plots showing T1 relaxation times and liver stiffness (measured by MRE). (a) T1 relaxation times in Lean control group (n = 26), Obese control group (n = 28), and Obese NAFLD-MetS group (n = 33). (b) Liver stiffness in Lean control group (n = 27), Obese control group (n = 28), and Obese NAFLD-MetS group (n = 32). Error bars: Mean ± SD. Significance levels: *(p value < 0.05), **(p value < 0.01), ***(p value < 0.001). MRE magnetic resonance elastography.

Fig. 3

Scatter plot showing associations of T1 relaxation times and liver stiffness with liver steatosis in the three study groups combined (a,b) and in the Obese NAFLD-MetS group (c,d). (a) Associations between T1 relaxation times (n = 87) and liver steatosis (n = 88), (b) associations between liver stiffness (n = 87) and liver steatosis (n = 88), (c) associations between T1 relaxation times (n = 33) and liver steatosis (n = 33), and (d) associations between liver stiffness (n = 32) and liver steatosis (n = 33). MRE magnetic resonance elastography.

Fig. 4

Dot plots showing levels of the circulating biomarkers CK18, TIMP1, and PIIINP in Lean control group (n = 27), Obese control group (n = 28), and Obese NAFLD-MetS group (n = 33). (a) CK18 levels in U/L. (b) TIMP1 levels in ng/mL, and (c) PIIINP levels in µg/L. Error bars: Mean ± SD. Significance levels: *(p value < 0.05), **(p value < 0.01), ***(p value < 0.001). CK18 cytokeratin-18, PIIINP procollagen-III peptide, TIMP1 tissue inhibitor of metalloproteinases 1.

Fig. 5

Dot plots showing levels of the combination biomarkers FIB-4 index, Forns score, FNI, and MACK3 score in Lean control group (n = 27), Obese control group (n = 28), and Obese NAFLD-MetS group (n = 33). (a) the FIB-4 index, (b) the Forns score, (c) FNI scores in %, and (d) MACK3 scores. Error bars: Mean ± SD. Significance levels: *(p value < 0.05), **(p value < 0.01), ***(p value < 0.001). FIB4-index fibrosis-4 index, FNI fibrosis non-alcoholic steatohepatitis index.

Fig. 6

Scatter plots showing associations between CK18, FNI, T1 relaxation times, and MACK3 score: (a) CK18 (n = 88) and T1 relaxation times (n = 87), (b) CK18 (n = 88) and FNI (n = 88), (c) FNI (n = 88) and T1 relaxation times (n = 87), (d) MACK3 score (n = 88) and T1 relaxation times (n = 87), and (e) MACK3 score (n = 88) and FNI (n = 88). CK18 cytokeratin-18, FNI fibrosis non-alcoholic steatohepatitis index.