Clinical Features

ICP is characterized by the triad of pruritus, abnormal liver function test results (especially fasting serum bile acid levels greater than 10 µmol/L), and spontaneous resolution of signs and symptoms after delivery or pregnancy termination. ICP occurs most commonly in the third trimester, although it can manifest any time during pregnancy.

Pruritus, which is the typical presenting symptom, tends to be more severe at night and most often affects the palms of hands, the soles of feet, and the trunk. Jaundice occurs in 10% to 25% of cases, making ICP the second leading cause of jaundice in pregnancy (after viral hepatitis). When jaundice occurs, it typically follows the onset of pruritus by 2 to 4 weeks. Other symptoms, such as dark urine, light stools or steatorrhea, nausea, vomiting, and abdominal discomfort, may occur but are less specific. Symptoms of ICP typically persist for the duration of pregnancy, but in most cases, they resolve within 1 to 3 weeks after delivery or pregnancy termination.

Clinical laboratory findings in ICP ( Box 53.1 ) include a mildly elevated serum bilirubin level (mostly direct), mildly elevated levels of serum aminotransferases, and most importantly, markedly elevated levels of fasting serum bile acids. The concentration of cholic acid that is free or conjugated to taurine or glycine progressively rises from 20 to 40 weeks’ gestation in women with ICP. The ratio of cholic acid to chenodeoxycholic acid is significantly higher in women with ICP (>1.5 : 1) than in women with a normal pregnancy. Elevated GGT levels may occur in as many as one half of cases, providing a clue to the cause of the condition. Dyslipidemia with elevated levels of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B-100 has also been observed.

Except for a mildly elevated risk (<8%) of gallstone disease, the maternal outcome in ICP is generally favorable. However, recent cohort studies have found an association of ICP with other liver disorders such as chronic hepatitis C and cirrhosis. In addition, women with severe ICP may be at increased risk of preterm delivery relative to a healthy pregnancy comparison group (25% versus 6.5%, with adjusted odds ratio of 5.39). The fetal complications of ICP are more serious and consist of prematurity (19% to 60%), fetal distress (22% to 33%), meconium staining (9% to 24%), and perinatal death (1% to 2%).

Observations have provided evidence for a direct link between maternal fasting bile acid levels and maternal-fetal complications of ICP. In a prospective cohort study of almost 45,000 pregnancies with 693 cases of ICP, no increase in fetal risk was detected when maternal serum bile acid levels were less than 40 µmol/L. These observations suggest expectant management of mild ICP (serum bile acids < 40 µmol/L). There are no specific guidelines for the management of more severe ICP, although some studies have shown the effectiveness of ursodeoxycholic acid in treating the pruritus and normalizing liver function test levels. In randomized, clinical trials, ursodeoxycholic acid was more effective than cholestyramine or dexamethasone in providing symptomatic relief for patients with ICP, although the dexamethasone trial was for only 1 week versus 3 weeks for the ursodeoxycholic acid trial. The benefit of S -adenosyl- l -methionine in treating pruritus, reduction of total bile acid levels, and normalization of liver function test results has been mixed in trials.

Pathologic Features

Because a diagnosis of ICP is typically made according to clinical criteria, liver histopathology in ICP has not been extensively reported. Findings are thought to be subtle and consist primarily of hepatocellular bile and canalicular bile plugs, occurring predominantly in a pericentral distribution with minimal or no hepatocellular necrosis and minimal portal inflammation ( Fig. 53.1 ). The histologic differential diagnosis of intrahepatic cholestasis is broad and includes other common entities such as drug-induced hepatocellular injury and early extrahepatic biliary obstruction. Nevertheless, the combination of intrahepatic cholestasis with clinical features (i.e., pruritus and elevated levels of serum bile acids) virtually limits the diagnosis to ICP.

Liver biopsy specimen from a 19-year-old woman with benign, recurrent, intrahepatic cholestasis who had jaundice early in the second trimester. High-power view of hepatic parenchyma in the vicinity of a central vein ( asterisk ) shows moderate cholestasis with prominent canalicular bile plugs ( arrows ) . A minimal mononuclear infiltrate is identified in the portal tracts, and occasional acidophilic bodies can be seen (not shown).

One study showed an association of ICP with abnormalities of the placenta, including syncytial knots, focally thickened amniotic basement membranes, small chorionic villi for gestational age with dense fibrotic stroma, and crowding and congestion of the villi. These abnormalities may increase the incidence of fetal demise.

Pathogenesis

The pathogenesis of ICP is not fully characterized. Several lines of evidence point to altered metabolism of steroid hormones and bile acids, and various mechanistic roles for disruption of bile acid transport into and out of the hepatocyte by estriol, progesterone, and their intrahepatocellular conjugates have been proposed. Familial clustering and increased incidence in the first-degree relatives of patients with ICP and linkage to human leukocyte antigens (HLAs) indicate one or more genetic factors. Recently it has been suggested that immune dysregulation resulting in disturbed placental bile acid and serum lipids transportation plays a key role.

Environmental factors such as dietary selenium and seasonal variations in incidence suggest one or more exogenous factors in the pathogenesis of ICP. Demonstration of increased intestinal permeability in patients with ICP during and after pregnancy provides evidence that the hepatic pathogenesis of ICP may be under the control or influence of extrahepatic or exogenous factors. Collectively, these somewhat disjointed observations and hypotheses about the pathogenesis of ICP and its associated risk factors suggest that ICP may represent the end result of a heterogeneous group of pregnancy-associated hepatic insults rather than a unique pathophysiologic entity.

The most specific data come from genetic studies of a subset of patients with ICP in whom the disease is associated with elevated serum GGT activity. Two pedigrees were initially reported, with ICP in the mothers of children who were born with the autosomal recessive form of progressive familial intrahepatic cholestasis (PFIC) and elevated serum GGT activity, a disease commonly referred to as type 3 PFIC. The affected children had homozygous mutations in the hepatocellular phospholipid transporter ABCB4 gene (formerly referred to as multidrug resistance 3, or MDR3 ), whereas ICP developed during pregnancy in mothers who were heterozygous for ABCB4 . ABCB4 is a class III multidrug-resistance P-glycoprotein that mediates translocation (i.e., flipping) of phosphatidylcholine (lecithin) across the bile canalicular membrane of hepatocytes.

To better characterize the pathogenic role of ABCB4 in the development of ICP, Dixon and associates investigated eight women with ICP and increased serum GGT activity who had no personal or family history of PFIC. DNA sequence analysis revealed a heterozygous missense mutation in ABCB4 , resulting in the expression of a nonfunctional protein at the cell surface in one of eight patients. Several subsequent reports on the association between ABCB4 and ICP provide further evidence for a defect in this canalicular transporter protein in the pathogenesis of ICP. As many as 16% of all patients with ICP are thought to have the disease as a consequence of mutations in the ABCB4 gene, and many different mutations of the gene have been found.

In addition to the compelling data regarding the role of ABCB4 in the pathogenesis of a subset of ICP cases, other cases have been associated with benign, recurrent intrahepatic cholestasis (BRIC) (see Fig. 53.1 ) and with mutations in the same gene. BRIC, which is genetically associated with a mutation in the same region of chromosome 18 as type 1 PFIC, is an intrahepatic cholestatic disease in which the affected patients have normal serum GGT activity. This sharp biochemical contrast with ABCB4-associated cases of ICP points to alternative mechanistic pathways for another subset of women with ICP.

The ABCB11 gene, which is associated with PFIC type 2, may also contribute to ICP. Mutations in the bile salt export pump, which is the product of the ABCB11 gene, have been identified in ICP. Variations in the farnesoid X receptor, a key transcription factor driving the expression of ABCB11 , were significantly associated with ICP and markedly reduced the capacity to activate the ABCB11 promoter in vitro.

It is not surprising that different defects in transport across the hepatocyte canalicular membrane can lead to similar clinical phenotypes, which are collectively recognized as ICP. Fundamentally, ICP can result from any disruption in the steady state between the uptake of bile salts into the hepatocytes and transport of bile salts across the canalicular membrane into bile. Estrogens, progesterone, and their conjugates disrupt the steady state by interfering with bile acid transporters at the basolateral membrane and inhibiting efficient bile acid transport across the canalicular membrane. In compromised hosts, such as heterozygous mothers with ABCB4 mutations, the added insult from pregnancy-associated hormones is sufficient to tilt the balance toward a cholestatic disease. As evidenced by the discovery of an association between specific variants of the multidrug-resistance–associated gene (ABCC2) and ICP, future research will undoubtedly reveal other molecular pathways and canalicular transporters that can result in ICP through similar or related pathways.

Clinical Features

The initial clinical presentation of AFLP is somewhat vague and includes headache, abdominal pain, nausea, vomiting, and a variety of other nonspecific symptoms. Approximately 80% of women have these prodromal symptoms. At least 70% of all patients have right upper quadrant or epigastric pain accompanied by nausea and vomiting. Prodromal symptoms are typically followed by jaundice as the disease progresses. Progressive and severe hepatic failure accompanied by coagulopathy and encephalopathy occurs rapidly after the onset of jaundice, and it is reported in more than 50% of cases within 1 to 2 weeks of the onset of jaundice. If untreated, patients may rapidly deteriorate, with gastrointestinal bleeding, seizures, coma, and renal failure with acute tubular necrosis.

AFLP may be associated with preeclampsia in 20% to 40% of patients. In these circumstances, the presenting signs and symptoms include those of pregnancy-induced hypertensive disorders (discussed later). A rare association between AFLP and ICP has been reported in which the patient had pruritus at presentation, which is more common for ICP than AFLP.

Because early diagnosis and prompt treatment of AFLP are essential to maternal and fetal well-being, liver function test parameters must be measured immediately in any pregnant woman past 22 to 24 weeks’ gestation who has any of the aforementioned symptoms or signs. The liver function test results for AFLP typically suggest mild to moderate hepatocellular damage with mild cholestasis ( Box 53.2 ). Serum aminotransferase levels usually are elevated in AFLP, although rarely to the extent observed in acute viral hepatitis. The bilirubin level is normal early in the course, but it rises if the pregnancy is not immediately terminated. Alkaline phosphatase levels are also elevated, but distinguishing hepatic from placental isoenzymes may not be practical or fruitful. The peripheral blood analysis may show leukocytosis and thrombocytopenia, and disseminated intravascular coagulation is relatively common. Blood urea nitrogen and serum creatinine levels may be elevated, but uric acid levels are disproportionately high, making them diagnostically valuable. Blood glucose levels are typically low, and clinically significant hypoglycemia may occur.

Historically, liver biopsy has been the gold standard for the diagnosis of AFLP, but coagulopathy often prevents its application in the acute clinical setting. Fatty infiltration of the liver can be easily assessed by noninvasive imaging methods such as ultrasonography or magnetic resonance imaging (MRI). The Swansea criteria, which use the clinical symptoms and laboratory findings of women with liver disease in pregnancy, constitute a reliable indicator of AFLP, with or without a liver biopsy ( Box 53.3 ). In one study, application of the Swansea criteria resulted in 100% sensitivity, 57% specificity, an 85% positive predictive value, and a 100% negative predictive value for diffuse or perivenular microvesicular steatosis on liver biopsy.

Regardless of the cause or type of presentation, the mainstay of therapy for AFLP is immediate delivery and supportive care. Liver transplantation and artificial liver support have been tried as alternative therapies, but their clinical role remains experimental. Despite all clinical efforts, AFLP continues to be a serious complication of pregnancy with maternal or fetal death occurring in 1% to 20% of all cases.

Pathologic Features

AFLP is commonly diagnosed without a liver biopsy based on clinical presentation and laboratory data. Nevertheless, microvesicular steatosis of hepatocytes is considered the diagnostic hallmark of AFLP. Classically, steatosis involves the pericentral zone and spares the periportal hepatocytes, although periportal involvement may be seen. In most cases, the fat droplets are large enough and their location well enough preserved to produce readily recognizable vacuolar change on routine sections with hematoxylin and eosin (H&E) staining ( Fig. 53.2, A ). Occasionally, individual fat droplets may be too small to be resolved by routine light microscopy or too poorly preserved to result in a classic vacuolar pattern on H&E-stained sections (see Fig. 53.2, B and C ). In these circumstances, hepatocytes may look essentially normal, be somewhat dilated, or exhibit diffuse cytoplasmic ballooning not readily distinguishable from ballooning degeneration or other forms of acute hepatocellular damage. A portion of the liver biopsy specimen obtained for clinical suspicion of AFLP must be processed as a frozen section for oil red O or Sudan black staining for fat or be submitted for electron microscopy.

A, Microvesicular steatosis can be identified by numerous, optically clear vacuoles on routine hematoxylin and eosin (H&E) staining, as shown in this liver biopsy specimen from a 32-year-old woman at 34 weeks’ gestation who had mildly increased levels of aminotransferases and a “giant fatty liver” seen on ultrasonography. B, Microvesicular steatosis in metabolic fatty liver disease may not always be apparent on routine H&E staining, as demonstrated in this biopsy specimen from a patient with liver failure and suspected long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency . C, Toluidine blue–stained plastic sections of an adjacent piece of the biopsy specimen shown in B demonstrates numerous hepatocellular fat droplets.

Although fatty change is considered the diagnostic histologic hallmark of AFLP, a host of other microscopic abnormalities were reported in a detailed study of 35 cases by Rolfes and Ishak. Hypertrophied Kupffer cells containing lipid or lipofuscin were prominent in areas of fatty change in most cases. Evidence of intrahepatic cholestasis, including bile canalicular plugs and acute cholangiolitis, was seen in two thirds of cases. Significant mononuclear lobular inflammation (comparable with acute viral hepatitis) and inflammation of the central veins were identified in 25% of cases, and 75% showed evidence of extramedullary hematopoiesis with prominent megakaryocytes and cells of erythroid lineage. Most notable by its absence in this large series of cases was sinusoidal fibrin deposition. Despite frequent clinical signs and symptoms of pregnancy-induced hypertensive disorders in patients with AFLP, the absence of fibrin deposition was considered evidence of a lack of histologic overlap between these two entities.

Although fatty infiltration of the liver is an extremely sensitive diagnostic marker for AFLP, it is nonspecific. The histopathologic differential diagnosis of AFLP is therefore broad and includes essentially all toxic, metabolic, and drug-induced conditions that may lead to microvesicular steatosis of hepatocytes. Definitive diagnosis of AFLP can therefore be made only in conjunction with the appropriate clinical signs and symptoms.

Pathogenesis

Significant progress has been made in understanding the pathogenesis of AFLP. A strong association between fetal fatty acid oxidation (FAO) disorders and maternal AFLP has been established, suggesting that AFLP is a disorder of mitochondrial fatty acid β-oxidation (see Fig. 53.2, B and C ).

Mitochondrial β-oxidation of fatty acids is a critical step in intermediary metabolism in the liver. FAO is a source of energy for the liver under physiologic stress and results in production of various metabolic intermediates that can be used as a source of energy by other vital organs such as the brain. One of the key enzymes in mitochondrial fatty acid β-oxidation is long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHAD), which catalyzes the third step in β-oxidation of long-chain fatty acids on the inner mitochondrial membrane. LCHAD activity occurs on the C-terminal portion of the α subunit of the microsomal triglyceride transfer protein (MTTP, also known as trifunctional protein [TFP]). MTTP also contains the active sites of long-chain 2,3-enoyl-CoA hydratase and long-chain 3-ketoacyl-CoA thiolase, catalyzing the second and fourth steps in fatty acid β-oxidation, respectively.

A recessively inherited defect in LCHAD in the infant is responsible for most of the occurrences of AFLP in the mother. Most abnormalities result from a 1528G→C mutation in exon 15 of the α subunit of MTTP , which results in the exchange of glutamic acid for glutamine at amino acid 474. Although MTTP deficiencies have emerged as important causes of metabolic disease in children, only one mutation in the α subunit of MTTP resulting in abnormal LCHAD activity has been associated with maternal liver disease in pregnancy.

In addition to MTTP mutations with LCHAD deficiency, other components of mitochondrial FAO have been associated with maternal disease in pregnancy. Fetal short-chain acyl-CoA dehydrogenase deficiency and fetal carnitine palmitoyltransferase deficiency were each reported in association with maternal AFLP several years ago ( Fig. 53.3 ). Santos and colleagues provided the first description of a normal fetus with a maternal FAO defect in medium-chain acyl-CoA dehydrogenase resulting in AFLP in the late third trimester. In a case-control study comparing fetal oxidation defects with the occurrence of maternal liver disease during pregnancy, two cases of medium chain acyl-CoA dehydrogenase deficiency were associated with AFLP. Remarkably, the maternal liver disease occurring with FAO in the children also included preeclampsia and HELLP syndrome ( h emolysis, e levated l iver enzymes, and l ow p latelets). The risk of liver disease developing in a mother in pregnancy if the child had LCHAD or short- and medium-chain defects was, respectively, 50 times or 12 times more likely than in control patients. Collectively, these results firmly establish a mechanistic association between FAO and AFLP.

A, Newborn infant had massive hepatomegaly that was seen as a homogenously enlarged liver on computed tomography. B, The liver occupies more than one half of the abdominal cavity and displaces the intestines to the left. Wedge biopsy of the liver shown at low magnification shows diffuse microvesicular and macrovesicular steatosis that is most prominent in the periportal zone. Subsequent biochemical studies confirmed a carnitine palmitoyltransferase 1 deficiency. The mother, who met the Swansea criteria for the diagnosis of acute fatty liver of pregnancy, was managed expectantly, and no biopsy was performed.

The precise mechanisms through which LCHAD or other FAO deficiencies result in fatty liver or hepatic failure are unknown. It has been postulated that the increasing metabolic demands of the third trimester in a compromised host result in excessive metabolic stress that cannot be handled by the heterozygous mother’s deficient metabolism.

The placenta may be an important factor in the pathophysiology. The genetic makeup of the placenta is identical to that of the fetus. Natarajan and colleagues found that the placentas at birth in mothers with AFLP showed oxidative stress in the mitochondria and peroxisomes and had compromised mitochondrial function compared with controls. The patient’s serum also showed elevation of oxidative and nitrosative stress markers with decreased antioxidant levels. The placentas and sera showed increased levels of arachidonic acid, which caused mitochondrial damage in the Chang liver cell line and increased lipid accumulation as identified by Nile red staining. This potential mechanism has many similarities to various forms of ICP in which normally masked deficiencies in bile canalicular transporters or their associated proteins are manifested only during the altered physiologic state of pregnancy.

Clinical Features

Preeclampsia usually manifests after 20 weeks’ gestation and is most common near term. Severe cases are characterized by blood pressure of 160/110 mm Hg or higher and proteinuria of greater than 5 g/day, with or without multiorgan involvement such as oliguria of less than 400 mL/day, thrombocytopenia, and severe central nervous system symptoms, such as mental status changes, blurred vision, or headache. The liver is a nonspecific target organ, and liver function test results may include increased levels of aminotransferases, which may be accompanied by a mild increase in serum bilirubin, alkaline phosphatase, and uric acid levels ( Box 53.5 ). Serum heat shock protein 70 levels show significant correlation with elevation of AST (not ALT), lactate dehydrogenase, and C-reactive protein levels. Clinical and laboratory findings often include moderate thrombocytopenia and disseminated intravascular coagulation with evidence of microangiopathic hemolysis.

Untreated preeclampsia can progress to hypertensive crisis with life-threatening renal failure. Progression to eclampsia is heralded by seizures, and coma eventually ensues. Maternal and fetal morbidity and mortality correlate with the severity of disease, the time of onset of the condition during the pregnancy (before 34 or after 36 weeks’ gestation), multiple gestations, preexisting maternal disease, and clinical management. The overall maternal mortality rate in developed countries is as high as 1.8%, with more than 80% of cases caused by complications of the central nervous system and the remainder resulting from catastrophic hepatic complications such as hepatic rupture and fulminant failure. The highest risk of death is among older women, women without prenatal care, and women with preeclampsia before 28 weeks’ gestation. Patients with severe preeclampsia or eclampsia have similar risks of developing intravascular coagulation (8%), HELLP syndrome (10% to 15%), and liver hematoma (1%).

Fetal complications are also common and include increased risk of abruptio placentae, prematurity, and intrauterine fetal growth retardation. Reduced risk of preeclampsia has been achieved with low-dose aspirin treatment at 16 weeks or earlier but not at a later gestational age. Trials of diet, vitamin C, vitamin E, vitamin D, heparin, diuretics, and antihypertensive medications to prevent preeclampsia have been disappointing. Delivery is the treatment of choice for mild preeclampsia that develops after 34 weeks’ gestation, for severe preeclampsia after 34 weeks’ gestation (controversial before 34 weeks), and for eclampsia.

Management of mild preeclampsia remote from term is often expectant management. However, early identification of high-risk mothers is key because aspirin can be used before 16 weeks’ gestation. The long-term sequelae of preeclampsia affect both mother and infant. Women with pregnancy complicated by preeclampsia have a subsequent increased risk of preeclampsia in future pregnancies, as well as hypertension, type 2 diabetes mellitus, and stroke. Offspring of women with preeclampsia also have increased blood pressure and double the risk of stroke in later life. Male children born to mothers with preeclampsia may have alterations in neonatal microvascular adaptation after birth. Being born preterm or with intrauterine growth retardation because of preeclampsia or other causes is associated with an increased risk for gestational diabetes and preeclampsia in adulthood.

Pathologic Features

Hepatic involvement in preeclampsia and eclampsia is primarily characterized by patchy parenchymal and subcapsular hemorrhage. Microscopically, the periportal zone is preferentially affected and may reveal a combination of fibrin deposition, hemorrhage, and hepatocellular necrosis ( Fig. 53.4 ). Thrombi and evidence of endothelial damage may be seen in the branches of the hepatic arteries and less commonly in the portal veins. In practice, the diagnosis of preeclampsia or eclampsia is always made clinically, and the classic pathologic changes are seen only in rare instances of maternal death due to severe disease.

A, Classic histopathology of eclampsia is characterized by patchy areas of hemorrhage, fibrin deposition, and hepatocellular necrosis in the vicinity of the portal tracts ( asterisks ). The pericentral areas ( arrowheads ) are virtually free of disease, and no significant inflammatory infiltrate is seen. B, The liver biopsy specimen also shows fibrin in the vicinity of a portal tract ( arrowhead points to the bile duct), with obliteration of sinusoids and damaged periportal hepatocytes ( arrows ) . This biopsy specimen, which came from a 30-year-old pregnant woman with abnormal liver function test results, can be distinguished from a pregnancy-induced hypertensive disorder only on the basis of clinical data (i.e., first-trimester pregnancy and a hypercoagulable state with antiphospholipid antibodies).

Liver biopsies may be done (but rarely are) for patients with mild or clinically indeterminate liver disease. In these circumstances, the histologic finding may be nonspecific and limited to mild and focal portal or periportal abnormalities. Because of the focal nature of the hepatic involvement, the absence of specific findings on a liver biopsy should not be used to exclude a diagnosis of preeclampsia. These findings are not specific to hypertensive disorders, and an almost identical morphology may be seen in other conditions of altered hemostasis, such as a hypercoagulable state (see Fig. 53.4, B ).

Pathogenesis

The placenta plays a key role in the pathogenesis of preeclampsia or eclampsia. Occurrence of the disease in molar pregnancies in which there is no fetal development suggests a required and sufficient role for the placenta in the pathogenesis of preeclampsia, and rapid disappearance of the disease after delivery provides evidence for a placenta-derived factor in the maintenance of maternal symptoms. The clinical manifestations of preeclampsia indicate systemic endothelial dysfunction in the mother.

The pathogenesis of preeclampsia is thought to constitute a two-stage model in which there is an abnormal placentation in early pregnancy followed by events that directly lead to endothelial activation in the third trimester. In the first stage, there is inadequate spiral artery remodeling in the placenta. This condition may result in placental hypoxia or an abnormal flow in the spiral arteries. Because of this hemodynamic abnormality, the placenta is physiologically stressed, resulting in a systemic inflammatory response. Several genetic predispositions have been suggested to underlie these processes, but a unifying genetic profile has not emerged. It has been argued that one or more placenta-derived circulating factors may be directly responsible for development of preeclampsia. Serologic markers of endothelial activation can be seen in women with preeclampsia; the appearance of serologic markers precedes clinically evident disease; and their disappearance accompanies resolution of the disease.

Scientific progress has significantly advanced understanding of the role of placenta-derived factors in the pathophysiology of preeclampsia. High levels of placenta-derived, soluble FMS-related tyrosine kinase 1 (sFLT1), also known as soluble vascular endothelial growth factor receptor 1 (VEGFR1), herald the onset of clinical symptoms in women with preeclampsia, and circulating levels of sFLT1 correlate with the severity of preeclampsia and proximity to the onset of hypertension or proteinuria. sFLT1 acts as an antagonist for VEGF and placental growth factor (PGF). The resulting decreased levels of VEGF and PGF produce endothelial dysfunction. These conclusions are supported by the fact that overexpression of sFLT1 in pregnant rats results in preeclampsia and that antiangiogenic therapy with VEGF in patients with cancer has been associated with preeclampsia-like complications of hypertension and proteinuria. The physiological effects of endothelial dysfunction are further magnified by activation of the renin-angiotensin system (RAS) and increased serum levels of angiotensin type II receptor autoantibodies (AT1-AA), resulting in hypertension and proteinuria.

The central role of soluble vascular regulatory factors in the pathogenesis of preeclampsia is further advanced by the discovery of the role of endoglin. Endoglin (ENG or CD105) is a cell surface receptor for transforming growth factor-β1 and -β3, and it is highly expressed on the vascular endothelium and placental syncytiotrophoblast. In addition to its central role in the pathogenesis of hereditary hemorrhagic telangiectasia, endoglin affects systemic endothelial function through interaction with endothelial nitric oxide synthase and regulation of endothelium-derived nitric oxide. Nitric oxide is a potent vasorelaxant that plays a key role in the regulation of systemic blood pressure, vascular permeability, and angiogenesis. Placental endoglin is upregulated in preeclampsia, resulting in the release of soluble endoglin (sENG) into the maternal circulation of symptomatic individuals in a dose-dependent fashion. Elevation of circulating sENG levels begins 2 to 3 months before preeclampsia is clinically apparent. sENG interferes with transforming growth factor-β signaling and endothelial nitric oxide synthase activation in maternal endothelial cells.

Collectively, these findings support the hypothesis that placenta-derived circulating factors that alter maternal endothelial function play a central role in disease development in maternal preeclampsia. Future research will undoubtedly result in translation of these fundamental discoveries into targeted therapies and monitoring strategies for preeclampsia and eclampsia.