Biochemical markers of preeclampsia

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Information about Biochemical markers of preeclampsia
Health & Medicine

Published on March 27, 2014

Author: mprasadnaidu



preeclampsia the role of Biochemical markers

M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar

 Preeclampsia (PE) is one of the most serious pregnancy complications. The worldwide prevalence of PE ranges from 3 to 8% of pregnancies, affecting a total of 8.5 million women worldwide.  PE is responsible for about 18% of maternal deaths and up to 40% of fetal mortality.  At this time, PE still lacks a safe and effective therapy, as well as a reliable, early means of diagnosis or prediction

 The disease evolves in two stages. The first stage is characterized by an altered formation of the placenta .  During placentation, a defective invasion of the extra villous trophoblast cells into the muscle layers of the spiral arteries has been shown .  This contributes to a reduced uteroplacental blood flow that can result in fetal intrauterine growth restriction (IUGR), seen in one of four women with PE.  A growing body of evidence suggests that oxidative stress further aggravates vascular function in the placenta , which in turn gives rise to insufficient blood perfusion , inflammation, apoptosis and structural damage

 The second stage, the clinical manifestations ,i.e. hypertension and proteinuria, appears from 20 weeks of gestation onwards.  As the disease progresses, angiospasms in the brain and brain edema may cause severe epileptic seizures - eclampsia .

 According to the International Society for the Study of Hypertension in Pregnancy (ISSHP), PE can be defined as de novo hypertension occurring after 20 weeks of pregnancy together with proteinuria.  Hypertension is defined as a systolic blood pressure 140 and/or a diastolic blood pressure 90 mmHg measured at two occasions with at least 4 h in between.

 Proteinuria is defined as 300 mg per day Proteinuria is questionable as a marker for PE since it lacks predictive value and does not correlate with severity of the disease.  A severe form of PE is the Hemolysis, Elevated Liver enzymes and Low Platelets syndrome (the HELLP-syndrome).  It is defined by the laboratory findings of hemolysis, elevated liver enzymes and low platelet count .

 . Altogether, the wide range of clinical manifestations makes PE more syndrome-like than a defined disease, which complicates the clinical diagnosis .  Lately, the time of onset of the clinical manifestations, early onset PE (<34weeks of gestation) and late onset PE (>34 weeks of gestation), have been used to further characterize PE, but the overall classification still lacks stringency

 Primi gravida  Family history  Placental abnormalities  Obesity  Pre existing vascular disease  thrombophilias

 Failure of trophoblast invasion  Vascular endothelial damage  Inflammatory mediators (cytokines)  Immunological intolerance between maternal and fetal tissues  Coagulation abnormalities  Increased oxygen free radicals  Genetic predisposition(polygenic disorder)  Dietary deficiency or excess

 Few biochemical markers have been proven specific and sensitive as single markers to predict and/or diagnose PE.  Algorithms also include clinical measurements such as Doppler ultrasound and clinical risk factors, to further enhance the prediction rate at a low false positive rate.  In this review the most promising individual biochemical markers are described for both prediction and diagnosis of PE.  The biochemical markers are presented in the order they are shown to appear in pregnancy, i.e. first, second or thirdtrimester

 PAPP-A  HbF/A1M all show potential as predictive biochemical markers in the first trimester  PP 13  Sflt-1 & s endoglin  PIGF  Cystatin C

 PAPP-A is a glycoprotein synthesized in the placenta and the study of it as a biochemical marker in pregnancy has been pursued for almost 30 years .  The maternal plasma concentration increases through out pregnancy.  PAPP-A has been used in combination with b- human chorionic gonadotropin (b-hCG) and nuchal translucency thickness, to screen for trisomy 21, 13 and 18 at 11 to 13 weeks of gestation

 In fetuses with normal chromosomes, decreased levels of PAPP-A in the first trimester have been associated with increased risk for PE, IUGR, fetuses small for gestational age (SGA) and preterm delivery

 PAPP-A has been evaluated as a predictive and diagnostic biochemical marker for PE, but the screening performance, when used as a single biochemical marker, is only about 10 to 20 %  Combined with Doppler ultrasound, PAPP-A is a powerful predictive biochemical marker of PE with prediction rates of 70% at false positive rates of 5%.  At term, plasma PAPP-A concentrations have been shown to increase in pregnancies complicated by PE and HELLP, but its concentration is still not predictive .

 Recent reports suggest that free, extracellular fetal hemoglobin(HbF) is involved in the pathogenesis of PE.  Furthermore the heme and radical scavenger a1- microglobulin (A1M) is involved in the physiological defence against HbF.  Their concentrations in maternal serum or plasma can be used as early predictive biochemical markers.  Increased mRNA levels of HbF in the placental tissue and free HbF protein in the placental vascular lumen were described in women with PE .

 Hemoglobin is a highly reactive molecule that is capable of damaging and disrupting cell membranes , and binds and inactivates nitric oxide (NO) with vasoconstriction as a consequence .  Its metabolites, heme and iron, damage lipids, protein and DNA through direct oxidation and/or generation of reactive oxygen species (ROS).

 Heme is also a pro-inflammatory molecule that activates neutrophils .  Several Hb- and hemedetoxification systems have been described in humans.  Recently, the plasma and tissue protein A1M was shown to bind and degrade heme , have radical-scavenger properties , and protect cells and tissues against extracellular Hb, heme and ROS .

 A1Mexpression in liver and placental cells has been shown to be upregulated by Hb, heme and ROS . A pathogenic role of Hb and protective role of A1M in PE is supported by ex vivo placenta perfusion experiments .  Studies evaluating maternal serum/plasma concentrations of HbF and A1M, as predictive and diagnostic markers for PE, have shown promising results .

 In a cohort of 96 patients subsequently developed PE the serum concentrations of HbF and A1M were significantly increased at 10 to 16 weeks’ gestation in women who subsequently developed PE.  The plasma concentrations of HbF and adult hemoglobin (HbA) were also significantly correlated to maternal blood pressure in patients with established PE . These markers still need to be validated in larger cohorts

 PP13 is a member of the galectin family and is produced by the placental trophoblast cells .  The function(s) of PP13 is stillnot clearly understood, but it is involved in normal placentation  In normal pregnancies, serum levels of PP13 slowly rise with gestational age.  Several studies have shown lowered serum levels in the first trimester in pregnancies that subsequently developed PE.  As a first trimester screening marker for PE, PP13 shows different prediction rates in different studies.

 In two different cohort studies, PP13 levels were determined at 11 to 13 weeks of gestation .  Both studies showed significantly lower first trimester levels of PP13 in women who later developed PE.  When combining serum screening with Doppler ultrasound pulsatilityindex (PI), the prediction rate increased to 71% at a false positive rate of 10% .

 Romero et al. [40] studied a cohort of 300 patients 50 of whichdeveloped PE.  At a false positive rate of 20% the detection rate was 36% for all types of PE. For early onset PE it was 100% (n ¼ 6) and for preterm PE 85% (n ¼ 44).  Preterm was defined as onset before 37 weeks.  The prediction rate for severe PE at term was 24% Based on t hese findings, PP13 was concluded to be a reasonable biochemical marker for early onset and preterm PE but a weak marker for PE at term

 Two angiogenesis-related factors are particularly well studied: soluble fms-like tyrosine kinase (sFlt-1), a soluble VEGF receptor, and soluble endoglin (s-Eng), a co-receptor for TGF-beta.  Both are elevated in maternal plasma in patients with PE compared to normal pregnancies .  Elevated levels of sFlt-1 occur before the clinical symptoms. The levels correlate with the time of onset of clinically manifest PE and partly with disease severity.  Early-onset PE exhibits higher levels of sFlt-1 .  Moreover, in animal experiments, proteinuria and hypertension, as well as a HELLP-like syndrome, were induced by infusion of high levels of sFlt and endoglin .

 As a first trimester screening marker, s-Eng shows conflicting results .  Used in combination with Doppler ultrasound (PI) and PlGF, the prediction rate for early onset PE was 77.8% at a false positive rate of 5% .

 The ratio of the PlGF/sFlt-1 is well described and they are a promising set of biochemical markers for prediction of PE .  Automated fast analysis methods have been developed for these proteins , but their role as first trimester markers is not clear .  Several studies have shown the predictive power of PlGF/sFlt-1 ratio from the second trimester.  The prediction rate is about 89% .

 In a recent multicenter study by Verlohren et al. , including 351 patients (71 with PE), the sFlt-1/PlGF ratio was measured longitudinally throughout pregnancy.  At a false positive rate of 5% the detection rate was 82% for all PE.  For early onset PE, at a false positive rate of 3%, the detection rate was 89%  Hence, the sFlt-1/PlGF ratio has no predictive value in the first trimester.  As a single biochemical marker, PlGF has been shown to predict 53.5% of early onset PE at a false positive rate of 5% and 65% at a false positive rate of 10% in late first trimester.

 Metabolic profiling is a powerful strategy to investigate the metabolites that a specific cellular event leaves behind.  Metabolic profiling can be used to reveal the patho physiological mechanisms in a disease such as PE .  Recently, in a study of 60 patients who subsequently developed PE and 60 normal pregnancies, 45 metabolites were shown to be significantly altered in the first trimester in pregnancies that later developed PE.

 For early and late onset PE, the prediction rate was between 73 and 77% at a 10% false positive rate .  The findings were validated in a cohort of 39 patients with subsequent PE matched with 40 normal pregnancies. Interestingly, 3 out of the 40 up-regulated were shown to be hemoglobin metabolites.

 Cystatin C is a protease inhibitor widely used by clinicians as a sensitive marker for renal function and for estimation of glomerular filtration rate.  The maternal plasma level of cystatin C is increased in women with PE and studies have demonstrated that the level of cystatin C is a reliable diagnostic marker for PE.

 Increased levels of cystatin C are suggested to be caused by either impaired renal function and/or by increased placental synthesis  Cystatin C has recently been suggested as a predictive first trimester marker for PE .  However, given the low screening performance of the study, cystatin C is probably not clinically useful as a single marker but could be useful in combination with other biochemicalmarkers.

 As genomics, proteomics and metabolomics are being developed and made more available, the number of potential biochemical markers will increase.  Ideally, the biochemical markers will give us new hints as to the pathogenesis behind PE.  These new techniques have revealed many of the above mentioned biochemical markers, and worth mentioning are free mRNAs and miRNAs in maternal blood.  Both types of RNAs are expressed in the placenta and can be found in the maternal circulation.  Further investigation is needed but profiling of these RNAs might show potential in predicting pregnancy outcomes

 2.9. New algorithms  The lack of a specific and sensitive biochemical marker has led to the development of mathematical models that combine several factors in order to predict PE .  Akolekar et al. combined maternal characteristics, PI and mean arterial pressure (MAP) with serum levels of PAPP-A, PlGF, PP13, inhibin-A, activin-A, sEng,pentraxin-3 and p- selectin in a large study (n ¼ 33,602) at 11 +0 to 13 + 6 weeks of gestation.

 . The prediction rates, at a false positive and 60.9% for late onset PE (intermediate onset PE was defined as PE that led to delivery between 34 and 36 weeks o f gestation).  Wortel boer et al. developed a model based on the first trimester biochemical markers, PAPP-A, beta-hCG, PlGF, desintegrin and ADAM metallo peptidase domain 12 (ADAM12). Their prediction of all PE was only 44% at a 5% false positive rate].  Another first trimester model based on maternal characteristics, PI and the biochemical markers PAPP-A, inhibin-A, PP13, ADAM12, free beta- hCG and PlGF was developed by Audibert et al.

 In a large cohort (n ¼ 893) the model showed a 100% prediction rate for early onset PE at a false positive rate of 10% .  It is worth noting that PP13 and ADAM12 levels did not improve the prediction rates.  In a very recent study by Odibo et al. [65] maternal characteristics were combined with serum PP13, PAPP-A and PI in the first trimester.  In a cohort of 450 patients, the prediction rate was 68% at a false positive rate of 5%. Interestingly, PI measurements did not increase the prediction rate in this study.

The ideal biochemical marker for PE should exhibit the following characteristics:  1)Play a central role in the pathogenesis and be specific for the condition.  2) Appear early or before the clinical manifestations. Placental factors that can be detected early in pregnancy are likely to be good biochemical markers for PE prediction.  However, placental disorders can cause IUGR without PE and vice versa, which makes the clinical evaluation of new markers particularly hard.

 3) Be easy and cheap to measure in maternal blood or urine. Few of the described factors are easy to measure; most of them require advanced laboratory system.  4) Show a high sensitivity and specificity. A small number of the described biochemical markers fulfill this requirement and strategies to use them in combination with other markers and/or, with PI measurements and other clinical parameters are being investigated.  5) Correlate with the severity of the condition. As the disease progresses, several organ systems are affected, which causes the number of factors to increase throughout pregnancy. A good candidate marker ought to appear early in pregnancy andcontinue to rise as the disease progresses.  6) Be non-detected or expressed at very low levels in norma pregnancies. Again, a placental factor is favored since the clinical symptoms disappear after removal of the placenta.

 Screening pregnant women with an effective diagnostic marker for PE IUGR could reduce unnecessary suffering and major healthcare costs .  PE is still a dominant problem in the Third World, where it is often first diagnosed when the women present with eclamptic seizures.  Basic equipment for blood pressure monitoring is often lacking, which requires clinicians to make careful clinical observations and basic examinations.  Fetal monitoring with Doppler ultrasound and ECG is rarely available. Therefore, algorithms that summarize maternal risk factors are valuable and it ismost important to develop them further.

 Furthermore, the biochemical marker must be detectable before the disease progresses into a dangerous stage, so that remote health care centres can refer their pregnant women to larger hospitals in timely manner.

 Screening for Down syndrome in the first trimester is a good example where a combination of ultrasound scanning and biochemical markers are used  Potential first trimester biochemical markers are PAPP-A , HbF and A1M .  Both HbF and A1M play a role in the pathophysiology of PE .  The biochemical markers appear as early as 10 weeks of gestation . Furthermore, they can be measured with basic ELISA techniques and show a high prediction rate at a low false positive level.  Maternal plasma concentrations of free HbF have also been shown to correlate well with severity, i.e. blood pressure, in term PE pregnancies .

 Angiogenic and anti-angiogenic factors are also very promising biochemical markers.  Although the combination sFlt-1/PlGF might not be useful in the first trimester, they are definitely well evaluated in the second trimester.  Alterations of sFlt-1 and PlGF about 6 weeks before the onset of clinical symptoms and correlate with the severity of the disease.  PlGF could be a promising biochemical marker even in the first trimester particularly if combined with HbF and A1M.

 PP13 has shown potential as a biochemical marker of early onset PE Especially if combined with Doppler ultrasound uterine artery PI.  However, as a general screening marker for all types of PE, the data is conflicting and needs further investigation.

 New factors should not be viewed solely as competing biochemical markers for prediction and diagnosis of PE. I  Instead each new factor ought to be welcomed as a new important puzzle piece that contributes to illuminating the etiology of PE.  In the end these advances will hopefully lead to better prophylactic treatments reducing maternal and fetal morbidity

 It is a marker which has advantages over serum creatinine  Cystatin-c is a 13kd non glycosylated protein  Normal blood level is 0.8 to1.2 mg/L  It is seen in high concentrations in biological fluids such as breast milk, tears,& saliva  It is the most abundant extra cellular cysteine protease inhibitors

 Creatinine is the most widely used biomarker of kidney function.  But sometimes it is inaccurate in detecting mild renal impairment.  The tubular secretion contributes app. 10% of the total creatinine excretion by the kidney & this contribution can increase as GFR decreases.

 Serum creatinine does not increase until GFR has moderately decreased.  This insensitivity to moderate decreases in GFR is called ‘creatinine blind GFR area’  So serum creatinine may not be a good parameter for determination of GFR , especially at lower levels of glomerular function.

 On the other hand, cystatin-c is produced at a constant rate & is freely filtered by kidney glomeruli.  It is completely reabsorbed ;but degraded in the tubules ; thus making it an excellent GFR marker.  The blood levels are not dependent on age, sex, muscle mass or inflammatory processes.

 It is sensitive to changes in the so called creatinine blind area of GFR (40- 70ml/min/1.73m2)  So, serum level of cystatin is a better test for kidney function(GFR) than serum creatinine levels.  Since there is no tubular secretion of cystatin-c it is extremely sensitive to minor changes in the GFR in the earliest stages of chronic kidney diseases

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