Pre-eclampsia – a disease of oxidative stress resulting from the catabolism of DNA (primarily fetal) to uric acid by xanthine oxidase in the maternal liver: A hypothesis

Pre-eclamptic toxaemia or toxaemia has become outdated terminology for the disease of pregnancy called pre-eclampsia (PE) but, according to this hypothesis, these may be more relevant. This hypothesis is that PE is a toxaemia or poisoning of the blood that results in multi-organ dysfunction and injury, putting at risk the lives of both the infant and the mother. Yet these dysfunctions and injuries are reversible with the cessation of the pregnancy and the disease can be reduced with vitamins (antioxidants) and aspirin. This hypothesis is that the PE cascade starts with excessive shedding/embolisation of trophoblast from the placenta into the maternal venous circulation. This trophoblast embolisation (‘deportation’) is secondary either to an excessively large amount of trophoblast tissue (‘hyperplacentosis’) or to vascular trophoblast injury from a faulty uteroplacental circulation. The deported nuclear rich trophoblast is largely filtered out of the circulation in the lungs, and breaks down releasing fetal DNA. Accordingly, the level of fetal DNA in the maternal circulation rises. This DNA is then broken down in the maternal liver with the hepatocytes being presented with excessive amounts of purines for catabolism. In the hepatocytes of patients who subsequently develop PE, there is activation of xanthine oxidase (XO), the more toxic isoenzyme of xanthine oxidoreductase (XOR), with the generation of superoxide anion (O2−) as a by-product. Excessive superoxide production overwhelms the normal antioxidant ability of the tissues to produce oxidative stress. In the hepatocytes, the excessive superoxide causes the peroxidation of polyunsaturated lipids to form microvesicular fat deposition. Excessive superoxide also causes hepatocellular damage with leakage of enzymes, lipids, DNA and superoxide into the circulation. In the circulation, oxidative injury of the blood corpuscles occurs releasing more DNA and accelerating purine catabolism and oxidative stress. The toxins, superoxide and the other reactive oxygen species (ROS), then travel in the arterial blood to the peripheral circulation where the microvasculature, the arterioles, capillaries, endothelial cells and venules, is injured. The damaged microvasculature leaks intravascular fluid into the extravascular compartment causing an intravascular dehydration and tissue oedema. In the kidneys, protein leaks through the damaged glomerular capillaries causing proteinuria. ROS causes arteriolar vasospasm and impairs vasorelaxation, mechanisms of hypertension. Micro-haemorrhages can occur and in the brain these, in combination with hypertension and oedema, can result in seizures or eclampsia.