Basic-liver, pancreas, and biliary tractPlacenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome☆
Section snippets
Tissues
The liver tissues from HELLP patients diagnosed for acute hepatic failure were obtained during liver transplantation, immediately snap frozen in liquid nitrogen, and stored at −80°C until analyzed. Histologically normal liver tissue obtained from partial hepatectomy served as controls.
Mouse liver tissues were from FVB/NHSD mice injected intravenously with 3 μg agonistic CD95 antibody (clone JoII, BD, Heidelberg, Germany). Mice were sacrificed 4 hours after injection, the livers immediately snap
Apoptosis in HELLP livers
Liver sections from HELLP patients showed the typical morphological features of fulminant hepatic failure with large areas of apoptotic TUNEL-positive cells and loss of liver parenchyma. H&E staining revealed the characteristic features of apoptotic hepatocytes with condensed nuclear morphology (Figure 1A). The histology of the HELLP livers is comparable to that of liver sections from mice showing massive apoptosis on intravenous injection of agonistic CD95 antibody (Figure 1B).
Apoptosis is
Systemic CD95 ligand induces apoptosis in the liver of HELLP patients
The results of this study show that systemic CD95L is involved in the pathogenesis of HELLP syndrome. We have documented an increased cytotoxicity in the blood from HELLP patients and presented evidence that serum CD95L is the major component that causes liver damage during HELLP syndrome. In particular, we could document engagement of the CD95 system in the liver of HELLP patients by showing: (1) HELLP livers contain an increased number of apoptotic cells and appear morphologically similar to
Clinical implications
There is general agreement that termination of the pregnancy is the primary treatment of patients with HELLP syndrome and particularly in those patients with liver complications. Near-term patients who are at or near 34 weeks gestational age and/or if fetal lung maturity is confirmed are routinely delivered. However, postpartum maternal laboratory indices may normalize within 48 hours but in certain cases have not returned to normal for as long as 30 days so careful monitoring is necessary.26
Acknowledgements
The expert technical assistance of Young-Gyu Park, Daniela Gottfried, Mirjam Weisser, and Christina Grössgen is gratefully acknowledged.
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Cited by (55)
The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature
2020, Pregnancy HypertensionCitation Excerpt :As hepatocytes express large amounts of Fas-receptors on their membrane, it is conceivable that these cells are extra prone to FasL-induced apoptosis, particularly when also exposed to ischemia [78,84]. Also, liver samples of patients requiring liver transplantation after developing hepatic failure during HELLP showed large areas of apoptotic cells similar as livers of mice injected with agonistic FasL [78]. However, whether these in-vitro data can be extrapolated, awaits confirmation in in-vivo studies.
Dysregulation of the Fas/FasL system in an experimental animal model of HELLP syndrome
2017, Pregnancy HypertensionCitation Excerpt :We found that circulating and placental levels of FasL are increased in HELLP rats compared to NP rats and hepatic FasL was significantly decreased. These results correlate with data from human studies which have reported that circulating and placental FasL expression is increased in women with HELLP syndrome [10,11]. Additionally placental derived FasL has been reported to not only be the primary source of FasL in women with HELLP syndrome but to also induce liver apoptosis and cytotoxicity in these women [10].
Non-immune Hemolysis: Diagnostic Considerations
2015, Seminars in HematologyMechanisms of liver involvement in systemic disease
2013, Best Practice and Research: Clinical GastroenterologyPathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): A review
2013, European Journal of Obstetrics and Gynecology and Reproductive BiologyCitation Excerpt :Products of the intravascular hemolysis may activate coagulation and increase the risk of DIC. The hepatocyte injury is caused by placenta-derived FasL (CD95L) which is toxic to human hepatocytes [48]. The content of FasL in villous trophoblast is higher in HELLP than in PE [49], and FasL concentration in maternal blood is elevated in HELLP [48].
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Supported by grants from the Deutsche Forschungsgemeinschaft (SFB 432) and the Lilly Centre for Women’s Health.
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Dr. Lahn is an employee of Eli Lilly & Co. who supplied access to LY498919 and a grant from the Lilly Centre for Women’s Health.