Sample "Pathophysiologic Hypothesis"

Diagram (click to enlarge)

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The diagnosis in this case is preeclampsia presenting at the beginning of the third trimester of pregnancy with the typical maternal syndrome of hypertension and proteinuria with associated edema. The diagnosis was ultimately confirmed by finding endotheliosis on renal biopsy. The renal biopsy was done because a complicating factor in this case was a history of SLE with a previous episode of Lupus nephritis. A recurrence of Lupus nephritis could cause the same presentation but would require significantly different management.

The pathogenesis of the maternal syndrome of preeclampsia (see supplemental readings list below) involves release of a placental-derived toxic substance into the maternal circulation. Removal of the placenta reverses preeclampsia. One current hypothesis (see box insert in diagram with *) is that this substance is sFlt-1, a soluble form of receptor that binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF). These growth factors normally promote vasculogenesis and maintain endothelial cell health. An excess of soluble circulating receptor inhibits interaction of the growth factors with the cell membrane-bound surface receptors on endothelial cells. This leads to the loss of the trophic influence of PlGF and VEGF and consequent endothelial cell dysfunction. In normal animals, blocking the VEGF interaction with endothelial cells reproduces the maternal syndrome (hypertension and proteinuria) and infusion of sFlt-1 causes glomerular endotheliosis.

The maternal syndrome of preeclampsia seems to be the result of systemic endothelial dysfunction. The endothelium transforms from the normal pro-vasodilatory and anti-thrombotic phenotype to a pro-vasoconstrictive and pro-thrombotic “endothelial injury” phenotype. The endothelium also loses its normal permeability characteristics. Specific changes that have been observed are a decreased production of prostacyclin (PGI2) and nitric oxide (NO) along with increased production of endothelin. These lead to an increased systemic vascular resistance (SVR) which in turn causes hypertension and decreased renal blood flow (RBF). Ultimately, the decreased renal blood flow contributes to the high serum uric acid level and to a decrease in glomerular filtration rate (GFR). The glomerular endothelium normally interacts with the podocytes (via paracrine crosstalk which includes significant secretion of VEGF from the podocytes) to maintain the filtration barrier. Endothelial cell damage disrupts this crosstalk and results in an abnormal filtration surface, which is manifest as failure of the size barrier and consequent proteinuria.

The edema seen in this patient could be the result of at least 3 factors: 1) the low plasma oncotic pressure (πcap) due to urinary protein loss and consequent hypoalbuminemia, 2) sodium retention due to a decreased GFR and 3) capillary leak in the peripheral tissues due to increased endothelial permeability.

This patient also ultimately developed the HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets). This syndrome reflects the pro-thrombotic aspects of endothelial dysfunction. Microthrombi form because of excess endothelial production of tissue factor and decreased endothelial production of inhibitors of blood clotting. Platelets are consumed in the formation of the microthrombi and circulating red blood cells, which become trapped in the clots, are mechanically lysed (microangiopathic hemolytic anemia).

The cause of the excess release of sFlt-1 appears to be placental ischemia although the reason for this response is unclear. One hypothesis is that preeclampsia reflects the “maternal-fetal conflict.” The survival of the fetus selects for a mechanism that improves placental perfusion by causing maternal hypertension, even at the risk of maternal death. 

Placental ischemia results either from placentation failure (which may be immune mediated) or from underlying vascular insufficiency. The immune mechanisms affecting placentation are not completely understood but tolerance to paternal antigens normally results in a favorable interaction of maternal NK cells with trophoblast cells allowing the trophoblast cells to penetrate deeply into the endometrium to form large vascular conduits from the maternal spiral arteries to the placenta. In most cases, preeclampsia occurs with first pregnancy when presumably there has not been establishment of tolerance. This case was unusual since it was the patient’s second pregnancy and one would expect that immune tolerance would have developed (unless the father was different, which is not addressed in the report). In any event, there are several reasons to suspect underlying vascular insufficiency in this patient. One is that her personal history includes an arterial thromboembolism while on birth control pills and her family history includes a brother who had a myocardial infarction at age 45. These events suggest an underlying genetic thrombophilia. The patient is also described as obese and there is now increasing evidence that the metabolic syndrome and its associated vasculopathy is a risk factor for preeclampsia.  Finally, there is the patient’s history of Lupus, which is associated with various types of acute and chronic vascular lesions. Whatever the mechanism of placental ischemia, poor perfusion in utero also often leads to growth retardation of the fetus, which occurred in this case.