Gastroenterology

Gastroenterology

Volume 126, Issue 3, March 2004, Pages 849-858
Gastroenterology

Basic-liver, pancreas, and biliary tract
Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome

https://doi.org/10.1053/j.gastro.2003.11.054Get rights and content

Abstract

Background & Aims: The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a life-threatening complication during pregnancy. The associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. CD95 (APO-1, Fas)-mediated apoptosis of liver cells is one of the major pathogenic mechanisms during liver disease. The interaction of CD95 with its ligand, CD95L(FasL), induces apoptosis and thus the source of the death-inducing ligand is critical for understanding the pathomechanism of liver damage involving the CD95-system. Methods: Sera from HELLP patients were analyzed and used in cell culture experiments to study CD95-mediated apoptosis. We established a mouse model for placenta-induced liver damage and used a new therapeutical agent, LY498919, to block CD95 apoptosis. Results: We describe apoptosis in the liver of HELLP patients and cytotoxic activity for primary human hepatocytes in HELLP serum. Blocking of CD95 signaling reduced the cytotoxic activity of HELLP serum. In addition, cytotoxic activity increased as HELLP syndrome developed. Furthermore, CD95L was found to be produced in the placenta and extracts of placenta were cytotoxic for human hepatocytes. Injection of mouse placenta extract in mice induces liver damage that could be prevented by blocking CD95L. Conclusions: Taken together, these data suggest that CD95L derived from the placenta acts systemically and is a primary cause of liver damage in HELLP syndrome. Our results also show that blocking of CD95L can reduce liver cell apoptosis, indicating that such a strategy may have therapeutic advantages.

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.

References (27)

  • P.R. Galle et al.

    Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage

    J Exp Med

    (1995)
  • S. Strand et al.

    Hepatic failure and liver cell damage in acute Wilson’s disease involve CD95 (APO-1/Fas) mediated apoptosis

    Nature Med

    (1998)
  • S. Strand et al.

    Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand expressing tumor cells—a mechanism of immune evasion?

    Nat Med

    (1996)
  • Cited by (55)

    • The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature

      2020, Pregnancy Hypertension
      Citation 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 Hypertension
      Citation 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].

    • Mechanisms of liver involvement in systemic disease

      2013, Best Practice and Research: Clinical Gastroenterology
    • Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): A review

      2013, European Journal of Obstetrics and Gynecology and Reproductive Biology
      Citation 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].

    View all citing articles on Scopus

    Supported by grants from the Deutsche Forschungsgemeinschaft (SFB 432) and the Lilly Centre for Women’s Health.

    1

    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.

    View full text