Abstract
Simple SummaryHELLP syndrome ((H) for hemolysis, (EL) for elevated liver transaminases, and (LP) for low platelets) occurs in up to 20% of women with severe preeclampsia. Disrupted placental development is causal to both preeclampsia and HELLP syndrome, yet why HELLP syndrome develops in some women remains unclear. Targeted treatments for this devastating disease are currently unavailable, and the development of preclinical models is imperative. Therefore, we sought to determine whether the blood pressure high subline 5 (BPH/5) mouse, a spontaneous model of preeclampsia, could also serve as a model of HELLP syndrome. Although anemia, thrombocytopenia, and plasma markers of liver dysfunction were not found in the BPH/5 mouse during pregnancy, precluding it as a model of PE associated with HELLP syndrome, a progressive fatty liver phenotype was identified. The BPH/5 mouse may be useful as a model of hepatic steatosis in superimposed preeclampsia.Preeclampsia (PE) is a multisystemic disease of pregnancy affecting 2–8% of women worldwide. PE-induced liver disease is a rare but important complication of pregnancy. The pathogenesis of liver dysfunction in PE is poorly understood, but is correlated with dysregulated angiogenic, inflammatory, and hypoxic events in the early phase of placental development. Because BPH/5 mice develop the maternal and fetal hallmarks of PE during pregnancy, we hypothesized that they may also share the clinicopathologic findings of the human PE-associated hemolysis elevated liver transaminases low platelets (HELLP) syndrome. Using this model, we determined that microangiopathic hemolysis, thrombocytopenia, and elevated liver enzymes do not occur in mid to late gestation. Pregnant BPH/5 mice do not develop histologic evidence of hepatic inflammation, but they do have increased microsteatosis scores at preconception and in mid to late gestation that progress to macrosteatosis in a subset of mice in late gestation. The transcriptional upregulation of TNF-α, CXCL-10, and TLR-2 occurs in mid gestation prior to the onset of macrosteatosis. The BPH/5 female mouse is not a model of HELLP syndrome, but may be a model of fatty liver disease associated with pregnancy.
Highlights
Preeclampsia (PE) affects up to 8% of all pregnant women [1]
There were no significant differences in lactate dehydrogenase (LDH), ALT, blood urea nitrogen (BUN), or total bilirubin between groups (Figure 1)
The plasma albumin levels in blood pressure high subline 5 (BPH/5) mice at mid (2.95 g/dL) and late (2.86 g/dL) gestation were significantly decreased from NP BPH/5 mice (3.38 g/dL; p < 0.01, p < 0.001, respectively)
Summary
Hemolysis, elevated liver transaminases, and low platelets (HELLP) syndrome occurs in 0.2–0.6% of all pregnancies and in up to 20% of women with severe PE [2,3]. The pathogenesis of liver dysfunction in PE and HELLP syndrome are poorly understood. Dysregulated angiogenesis in early pregnancy leading to endothelial injury and maternal–fetal metabolic irregularities contribute to the pathogenesis of both syndromes [4,5,6,7,8]. In HELLP syndrome, secondary hepatic microangiopathy results in a proinflammatory cascade promoting sinusoidal occlusion and hepatocellular necrosis [9,10]. The diagnosis of HELLP relies predominantly on clinical signs and liver function tests as biopsies of the liver are risky in late gestation
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