Testosterone and Estradiol as Novel Prognostic Indicators for HBV-Related Acute-on-Chronic Liver Failure

Shuning Sun, Baoyan Xu, Wenting Tan, Xiaomei Xiang, Yi Zhou, Yunjie Dan, Yanzhi Guo, Zhaoxia Tan, Guohong Deng, Shuning Sun, Baoyan Xu, Wenting Tan, Xiaomei Xiang, Yi Zhou, Yunjie Dan, Yanzhi Guo, Zhaoxia Tan, Guohong Deng

Abstract

Background: HBV-related acute-on-chronic liver failure (HBV-ACLF) has a high short-term mortality and urgently needs an early warning system with simplicity and high accuracy. Previous studies show that sex hormones play potential roles in the progression of HBV-related liver diseases. Aims: To explore the effect of testosterone and estradiol on the occurrence and prognosis of HBV-ACLF. Methods: A prospective cohort of 300 chronic hepatitis B (CHB) patients was enrolled among which 108 were diagnosed with HBV-ACLF at admission and 20 developed to HBV-ACLF during hospitalization. We compared the level of serum testosterone and estradiol of patients with varied ACLF background, disease severity and cirrhosis conditions and analyzed the predictive ability of short-term prognosis. A novel prognostic model involving testosterone was developed and further validated in the HBV-ACLF group. Results: The baseline estradiol level of HBV-ACLF group was significantly higher while testosterone was lower than that of non-ACLF group. The estradiol level increased while the testosterone level decreased as the number of organ failures increased. Testosterone had high accuracy in predicting the short-term mortality in HBV-ACLF (AUROC = 0.726) and estradiol did better in predicting the occurrence of ACLF during hospitalization (AUROC = 0.695). The novel prognostic model involving testosterone (TATIM model) was proved to have considerable prediction efficiency in HBV-ACLF cohort with or without cirrhosis. Conclusion: Testosterone could be utilized as short-term prognostic indicator for HBV-related ACLF and estradiol can help to predict its occurrence. TATIM model is a novel prognostic model for HBV-related ACLF with simplicity and good performance irrespectively of liver cirrhosis. Clinical Trial Registration Number: This study was based on a sub-cohort from the prospective multicenter cohort (NCT02457637).

Keywords: ACLF (acute-on-chronic liver failure); estradiol; hepatitis B; mortality; prognosis; testosterone (androgen).

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Sun, Xu, Tan, Xiang, Zhou, Dan, Guo, Tan and Deng.

Figures

Figure 1
Figure 1
Orthogonal partial least squares discriminant analysis to identify optimal short-term prognostic parameters for hepatitis-B-related acute-on-chronic liver failure. OPLS-DA was conducted in the ACLF group (n = 108). Three dimensional scatter plot (A) distinguished non-survivors from survivors. Loading scatter plot (B) was used to compare the impact of each parameters on survival. Values in prediction were ranked in VIP plot (C). VIPpred > 1.0 was considered to have significant contributions to the outcome.
Figure 2
Figure 2
Comparison of sexual hormone levels. Comparison of sexual hormone levels were conducted in CHB cohort (n = 300) and HBV-ACLF group (n = 108). (A,B) Showed the baseline estradiol and testosterone levels in hepatitis B related acute-on-chronic liver failure (HBV-ACLF, n = 108) and non-ACLF group (n = 192). (C,D) Revealed the changes of estradiol and testosterone according to the number of organ failures. (E,F) Suggested that there was no significant difference of estradiol and testosterone levels among ACLF subtypes. (G) Showed the linear correlation between estradiol levels and traditional prognostic scores. (H) Showed the linear correlation between testosterone levels and traditional prognostic scores. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.
Figure 3
Figure 3
Sexual hormone's impact on prognosis and occurrence of hepatitis B related acute-on-chronic liver failure (HBV-ACLF). ROC and K-M survival analysis were conducted in the ACLF group (n = 108, A–F) and non-ACLF group (n = 192, G,H). (A,D) Showed the area under receiver operating characteristic cure (AUROC) of estradiol and testosterone for 28 day survival. (B,C) Demonstrated the differences of 28 day and 90 day cumulative survival rates according to the estradiol levels (cut-off value = 126.6 pg/ml). (E,F) Demonstrated the differences of 28 day and 90 day cumulative survival rates according to the testosterone levels (cut-off value = 1.16 ng/ml). (G) Showed the area under receiver operating characteristic cure (AUROC) of estradiol for predicting ACLF's occurrence within 28 days. (H) Demonstrated the differences of 28 day cumulative ACLF occurrence rate according to the estradiol levels (cut-off value = 69.79 pg/ml).
Figure 4
Figure 4
TATIM model's correlation with disease severity. Correlation analysis was conducted in the ACLF group (n = 108). (A) Showed the TATIM scores in hepatitis B related acute-on-chronic liver failure (HBV-ACLF, n = 108) and non-ACLF group (n = 192). (B) Revealed the changes of TATIM scores according to the number of organ failures. (C–H) Showed the linear correlation between TATIM scores and previous prognostic scores. **p < 0.01, ***p < 0.001, and ****p < 0.0001.
Figure 5
Figure 5
Evaluation of TATIM model in predicting the short-term prognosis of ACLF. Comparison of predictive efficiency of varied prognostic models was conducted in the ACLF group (n = 108). (A) Compared the area under receiver operating characteristic cure (AUROC) of TATIM model and other prognostic scores for 28 day survival. The AUROC of TATIM was 0.828 (p < 0.001), which was higher than MELD, iMELD, SOFA, CLIF-SOFA and comparable with CLIF-C ACLF. (B,C) Demonstrated the differences of 28 day and 90 day cumulative survival rates according to the TATIM score (cut-off value = −1.855).
Figure 6
Figure 6
Validation of TATIM model in ACLF-subtypes. ROC analysis was conducted in three ACLF-subtypes (Total n = 108, Type-A n = 51, Type-B n = 15 and Type-C n = 42). (A–C) Compared the area under receiver operating characteristic cure (AUROC) of TATIM model and other prognostic scores for predicting 28day survival in ACLF-subtype A, B and C, respectively. (AUROC of type-A, type-B and type-C were 0.829, 1.000 and 0.773, respectively; all P < 0.001).

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