Sex Difference in the Tolerance of Hepatic Ischemia-reperfusion Injury and Hepatic Estrogen Receptor Expression According to Age and Macrosteatosis in Healthy Living Liver Donors

Abstract

Original Clinical Science-Liver Background. Hepatic estrogen signaling, which is important in liver injury/recovery, is determined by the level of systemic estrogen and hepatic estrogen receptor. We aimed to evaluate whether females' advantage in the tolerance of hepatic ischemia-reperfusion injury decreases according to the age of 40 y (systemic estrogen decrease) and macrosteatosis (hepatic estrogen receptor decrease). Methods. We included 358 living liver donors (128 female and 230 male individuals). The tolerance of hepatic ischemia-reperfusion injury was determined by the slope of the linear regression line modeling the relationship between the duration of intraoperative hepatic ischemia and the peak postoperative transaminase level. Estrogen receptor content was measured in the biopsied liver samples using immunohistochemistry. Results. In the whole cohort, the regression slope for aspartate transaminase was comparable between female and male individuals (P = 0.940). Within the subgroup of donors aged ≤40 y, the regression slope was significantly smaller in female individuals (P = 0.031), whereas it was comparable within donors aged >40 y (P = 0.867). Within the subgroup of nonmacrosteatotic donors aged ≤40 y, the regression slope was significantly smaller in female individuals in univariable (P = 0.002) and multivariable analysis (P = 0.006), whereas the sex difference was not found within macrosteatotic donors aged ≤40 y (P = 0.685). Estrogen receptor content was significantly greater in female individuals within nonmacrosteatotic donors aged ≤40 y (P = 0.021), whereas it was not different in others of age >40 y or with macrosteatosis (P = 0.450). Conclusions. The tolerance of hepatic ischemia-reperfusion injury was greater in female individuals than in male individuals only when they were <40 y and without macrosteatosis. The results were in agreement with the hepatic estrogen receptor immunohistochemistry study.

Impact of donor sex on hepatocellular carcinoma recurrence in liver transplantation after brain death

“…Interestingly, there seems to be a difference in IRI susceptibility between male and female liver grafts, although the mechanisms of the difference are not fully understood 12 . Based on previous studies, there is suggestive evidence that female livers are more tolerant than male livers to IRI, provided that estrogen is released in response to stress conditions 23,24 . However, this scenario does not apply to sex‐ or age‐mismatched liver transplants where male recipients receive female livers or elderly females receive young female livers.…”

“…12 Based on previous studies, there is suggestive evidence that female livers are more tolerant than male livers to IRI, provided that estrogen is released in response to stress conditions. 23,24 However, this scenario does not apply to sex-or age-mismatched liver transplants where male recipients receive female livers or elderly females receive young female livers. These conditions put liver grafts in a relatively lower estrogen environment.…”

Outcomes and Risk Factors for Liver Transplantation Using graft-to-Recipient Weight Ratio Less than 0.8 Graft from Living Donors: Multicentric Cohort Study

“…Estrogen receptors in female livers also improve tolerance of ischemia-reperfusion injury, which may contribute to better graft survival with female donors than male donors. 24 Together, these factors appear to increase the risk of small grafts from male donors in LDLT, an issue requiring further investigation.…”

“…Moreover, alcohol consumption is usually more frequent in male donors than in female donors, as noted in our study population results (Table S5, Supplemental Digital Content 1, http://links.lww.com/SLA/E861). Estrogen receptors in female livers also improve tolerance of ischemia-reperfusion injury, which may contribute to better graft survival with female donors than male donors 24 . Together, these factors appear to increase the risk of small grafts from male donors in LDLT, an issue requiring further investigation.…”

Abrogation of greater graft failure risk of female-to-male liver transplantation with donors older than 40 years or graft macrosteatosis greater than 5%

“…Although the exact mechanisms underlying the sex difference is not fully understood, hepatic estrogen signaling mismatch is considered to play an important role 12 – 15 . The liver is one of the target organs of estrogen, and hepatic estrogen signaling plays an important role in mitigating injury and enhancing recovery of the liver 10 , 12 , 16 – 18 . Hepatic estrogen signaling increases in relation to the increase in systemic estrogen secretion or hepatic estrogen receptor content 19 .…”