M A T E R N A L - F E T A L M E D I C I N E
Is there an association between liver type fatty acid binding
protein and severity of preeclampsia?
Ozlem Uzunlar•Yaprak Engin-Ustun•
Sebnem Ozyer•Nuri Danısman•Tuba Candar• Senem M. Keskin•Leyla Mollamahmutoglu
Received: 5 June 2014 / Accepted: 4 November 2014 / Published online: 16 November 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract
Objective The aim of this study was to estimate the level of liver fatty acid binding protein (LFABP) in women with preeclampsia.
Method A case–control study was conducted in 90 pregnant women who were divided into the following three groups: normal pregnancy (n = 30), mild–moderate pre-eclampsia (n = 30), and severe prepre-eclampsia (n = 30). Maternal blood samples were obtained during an antenatal clinic visit in normal pregnant women, and at the time of diagnosis in women with preeclampsia. Serum LFABP levels were measured by the quantitative sandwich enzyme immunoassay technique.
Results Serum LFABP level was significantly higher in severe and mild–moderate preeclampsia groups than nor-mal pregnancy group (1,709.90 ± 94.82, 1,614.93 ± 118.22, and 1,532.36 ± 140.98 pg/ml, respectively; p\ 0.001). In multivariate analysis, the severity of pre-eclampsia was correlated with LFABP level [unadjusted odds ratio (95 % confidence interval), 1.008 (1.003–1.012), p\ 0.001 and LDH 1.063 (1.029–1.099), p \ 0.001].
Conclusion Maternal serum LFABP level appears to be correlated with the severity of the preeclampsia and can be used to confirm the diagnosis.
Keywords Severe preeclampsia Mild preeclampsia Diagnosis of preeclampsia Serum lactate dehydrogenase Serum protein Serum albumin Liver fatty acid binding protein
Introduction
Preeclampsia is a multisystem disorder unique to human pregnancy, still affecting 2–8 % of all pregnancies [1,2]. It is characterized by new onset of hypertension and pro-teinuria after the 20th week of gestation [1–3]. In its most severe form, preeclampsia is followed by eclampsia; therefore, early diagnosis of preeclampsia is important to prevent maternal death. Delivery of the fetus is the only cure, but it is highly associated with neonatal mortality (15 % of preterm births in developed countries) and mor-bidity from iatrogenic prematurity (25 % of all cases of fetal intra uterine growth restriction) [1–4].
The pathophysiology of preeclampsia is not yet fully elucidated and may include abnormal physiologic trans-formation of the spiral arteries, intravascular inflammation, endothelial cell dysfunction, excessive thrombin genera-tion, oxidative stress and/or antiangiogenic state [2,4,5]. The role of oxidative stress in the pathophysiology of preeclampsia has increasingly been postulated. The increased metabolic activity in relatively hypoxic placenta and the reduced clarification capacity of antioxidants cau-ses accumulation of reactive oxygen species, which are transferred to maternal circulation and cause oxidative stress during pregnancy [4,6].
O. Uzunlar (&) Y. Engin-Ustun S. Ozyer N. Danısman S. M. Keskin
Obstetrics and Gynecology Department, Zekai Tahir Burak Women Health Training and Research Hospital, Ankara, Turkey e-mail: ozlemuzunlars@hotmail.com
T. Candar
Department of Medical Biochemistry, Medical School of the Ufuk University, Ankara, Turkey
L. Mollamahmutoglu
Obstetrics and Gynecology Department, Etlik Zubeyde Hanim Dogumevi Women Health Training and Research Hospital, Ankara, Turkey
Preeclampsia has many features similar to the metabolic syndrome, one of which is the aberrant lipid metabolism [1,
7–9]. Since lipid peroxidation plays a role in the devel-opment of cardiovascular disease, mothers suffered from preeclampsia are known to have increased risks of car-diovascular disease in their later life [1,8,9]. In addition, circulating free fatty acids (FFAs), known as the key reg-ulators of glucose metabolism, have been shown to increase in preeclamptic patients during and before the clinical onset of the disease [1, 7, 9]. Since FFAs can become toxic within the cell at high levels, women who develop preeclampsia are at an increased risk for type 2 diabetes in their later life [1, 7, 9]. Endothelial cell dys-function, possibly due to alterations in circulating lipid profiles, is characteristic of preeclampsia; therefore, it was proposed that elevated FFA might be a predisposing factor for preeclampsia [1,9].
Fatty acid binding proteins (FABPs) are the most abundant and structurally related small (14–15 kDa) cyto-solic lipid binding proteins responsible from targeting and/ or sequestering of potentially toxic long chain fatty acids (LCFAs) [10,11]. Liver-FABP (LFABP), the first descri-bed FABP, has been shown to facilitate uptake and metabolism of LCFAs in vitro and in cultured cells; therefore, the abnormal function or loss of LFABP is expected to reduce hepatic LCFA uptake/oxidation and thereby increase LCFAs for oxidation [10].
To date, only sFLT-1/PlGF ratio was shown to be helpful for clinical validity of preeclampsia prior to its development [12]. However, there is still a need for a reliable marker to accurately predict the severity and out-come of women diagnosed with preeclampsia. Therefore, the aim of this study was to estimate the levels of LFABP in preeclampsia, and to determine its role in defining the severity of the disease to investigate its potential to be used as a marker to predict the severity of preeclampsia after admission.
Materials and methods Study design
A case–control study was conducted in 90 pregnant women admitted to the Obstetrics Department of the Zekai Tahir Burak Women Health Training and Research Hospital. The following groups were included: (1) normal pregnancy (n = 30); (2) mild–moderate preeclampsia (n = 30); and (3) severe preeclampsia (n = 30). Women with multiple pregnancies and fetuses with chromosomal and/or con-genital anomalies, as well as women with chronic hyper-tension, autoimmune diseases, clinical urgency with
maternal hemodynamic instability or fetal death at admis-sion were excluded. The study protocol was approved by the local ethics committee of the hospital and complies with the guidelines of the Helsinki Declaration. Informed consent was obtained from all study participants.
Clinical definitions
Women with a normal pregnancy, for each preeclampsia case, the following normal pregnancy matched with ges-tational age were selected as a control. ‘‘Control subjects had no medical, obstetrical, or surgical complications at the time of the study, and subsequently delivered a normal term infant (C37 weeks of gestation) without neonatal complications‘‘ [13]. Preeclampsia was defined as hyper-tension (systolic blood pressure [140 mmHg or diastolic blood pressure [90 mmHg on at least 2 occasions, 4 h to 1 week apart) and proteinuria (higher than 100 mg/dl in spot analysis twice, or higher than 300 mg in 24 h col-lecting urine) [14]. The severity of preeclampsia was defined with the presence of at least one of the following parameters: mean arterial blood pressure (MAP) higher than 126 mmHg, proteinuria (5 g/24 h), oliguria (500 ml/ 24 h), cerebral or visual symptoms, pulmonary edema or cyanosis, epigastric or right upper quadrant pain, elevated liver function tests (twofold greater than the normal ran-ges), thrombocytopenia (\100,000/mm3), or fetal growth retardation [14].
Maternal age, gestational age, smoking status, body mass index (BMI), and parity were recorded. Their height (m) and weight (kg) measurements were used to calculate the BMI (kg/m2). MAP was calculated using the following formula MAP = (2 9 diastolic blood pressure ? systolic blood pressure)/3.
Sample collection and immunoassay
Maternal blood samples were obtained from normal preg-nant women during an antenatal clinic visit and from women with preeclampsia at the time of diagnosis. Blood samples taken by venipuncture were collected into tubes, centrifuged at 1,0009g for 15 min at 4°C, and stored at -80°C until assayed. The analysis of the assay of the serum LFABP was performed by the T.C. who was blinded to the clinical data. Serum LFABP levels were measured by the quantitative sandwich enzyme immunoassay technique (Human Liver Type Fatty Acid Binding Protein (LFABP) ELISA Kit, Cusabio, Wuhan, China). Detection range was 31.2–2,000 pg/ml. The minimum detectable dose of human LFABP is typically less than 7.8 pg/ml. The inter-assay and intra-assay precisions were CV% \ 10 % and CV% \ 8 %, respectively. The sensitivity was 7.8 pg/ml.
Statistical analysis
All statistical analyses were performed using SPSS Sta-tistics for Windows 21.0 (IBM Corp, Armonk, NY). Chi-square test was performed for categorical variables. Levene test was used to evaluate the homogeneity of variances assumption. One-way ANOVA and post hoc Tukey HSD test were used when the homogeneity assumption was satisfied, and Welch-ANOVA and post hoc Tamhane’s T2 test were used when the homogeneity assumption was not satisfied. Correlation between two numerical variables was analyzed by Pearson correlation coefficient (r value). Polytomous regression analysis was performed to deter-mine the factors that can be used in estimation of the severity of preeclampsia. A p value less than 0.001 was considered statistically significant. The power analysis was performed by G-power 3.1.9 in advance of the study. The group sample sizes of 9 and 9 achieve 80 % power to detect a difference of 10.3 between two group means with a significance level (alpha) of 0.05 using a sided two-sample t test.
Results
Demographic and clinical characteristics
Ninety pregnant women included in this case–control study were divided into three groups according to the severity of preeclampsia; with severe preeclampsia (n = 30), mild–
moderate preeclampsia (n = 30), and no preeclampsia (control group, n = 30). Demographic and clinical char-acteristics of groups were summarized in Tables1 and2, respectively. No statistically significant difference was detected between groups in terms of age, nulliparity, smoking status and body mass index (BMI) (Table1), or median gestational age at blood drawn (Table2).
The comparison of differences in clinical characteristics with the severity of preeclampsia indicated a statistically significant correlation between LFABP level and the out-come (p \ 0.001, Table2). Accordingly, LFABP level was significantly higher in severe preeclampsia (1,709.90 ± 94.82 pg/ml) and lower both in pregnant women with mild–moderate (1,614.93 ± 118.22 pg/ml) and with no (1,532.26 ± 140.98 pg/ml) preeclampsia. As expected, medians of maximal systolic blood pressure (SBP; 157.90 ± 16.42 mmHg for severe, 140.87 ± 17.76 mmHg for mild–moderate and 109.00 ± 8.85 mmHg for no pre-eclampsia), diastolic blood pressure (DBP; 103.73 ± 13.97, 91.73 ± 11.00, and 71.67 ± 6.48 mmHg, respec-tively) and mean arterial pressure (MAP; 132.71 ± 16.42, 117.40 ± 12.26, and 90.33 ± 6.56, respectively) signifi-cantly increased with the severity of preeclampsia (p \ 0.001 for all, Table1). There was no difference in impaired glucose levels after a 50-g, 1-h glucose challenge test (GCT) performed at 24–28 weeks of gestation between severe or mild–moderate preeclampsia cases and control (23.3, 26.7 and 10.0 %, respectively, p = 0.233, Table2). Mean birth weight was significantly lower in women with severe (2,058.28 ± 874.28 g) and mild–moderate
Table 1 Baseline characteristics of the study group
Characteristic Severe preeclampsia (n = 30) Mild–moderate preeclampsia (n = 30) No preeclampsia (n = 30) p value Age (years)c 29.6 ± 6.7 27.1 ± 6.4 27.0 ± 5.5 0.206 20–35 (reference) 22 (73.3 %) 22 (73.3 %) 28 (93.3 %) 0.082 \20 or [35 8 (26.7 %) 8 (26.7 %) 2 (6.7 %) Nulliparous 17 (56.7 %) 19 (63.3 %) 14 (46.7 %) 0.425 BMI (kg/m2)c 27.73 ± 2.98 28.31 ± 3.16 27.07 ± 3.13 0.307 Normalb 5 (16.7 %) 3 (10.3 %) 7 (23.3 %) 0.763 Overweight 20 (66.7 %) 20 (69.0 %) 19 (63.3 %) Obese 5 (16.7 %) 6 (20.7 %) 4 (13.3 %) Smokingb 6 (20.0 %) 3 (10.0 %) 4 (13.3 %) 0.654 SBP (mmHg)d 157.90 ± 16.42 140.87 ± 17.76 109.00 ± 8.85 \0.001a DBP (mmHg)d 103.73 ± 13.97 91.73 ± 11.00 71.67 ± 6.48 \0.001a MAP (mmHg)d 132.71 ± 16.42 117.40 ± 12.26 90.33 ± 6.56 \0.001a Birth weight (g)c 2,058.28 ± 874.28 2,445.36 ± 852.74 3,488.16 ± 795.88 \0.001a
LFABP Liver type fatty acid binding protein, BMI Body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, MAP mean arterial pressure, GCT glucose challenge test, BUN blood urea nitrogen, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase
A p value \ 0.001 (a) was considered statistically significant. Values are expressed as number (percentage) or median (interquartile range). Comparisons among groups were performed with Chi-square test for categorical variables (b) and with one-way ANOVA and post hoc Tukey HSD test (c) or Welch-ANOVA and post hoc Tamhane’s T2 test (d) for continuous variables
(2,445.36 ± 852.74 g) preeclampsia compared to patients with no preeclampsia (3,488.16 ± 795.88 g) (p \ 0.001, Table1). The proportion of the infants with birthweight less than the tenth percentile for each group was calculated. It was 33.3, 26.6, 6.6 % for severe preeclampsia group, mild–moderate preeclampsia group and control group, respectively. As summarized in Table2, no statistically significant difference was found between groups in terms of serum blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Serum lactate dehydrogenase (LDH) level, on the other hand, was significantly higher in severe and mild–moderate preeclampsia groups than normal preg-nancy group (611.77 ± 267.38, 501.50 ± 267.18, and 282.73 ± 52.18 U/l, respectively; p \ 0.001, Table2). Serum protein and serum albumin levels were significantly lower in severe preeclampsia (5.39 ± 0.94 and 2.89 ± 0.47 g/dl) compared to both mild–moderate (5.96 ± 0.86 and 3.28 ± 0.54 g/dl) and control groups (6.29 ± 0.32 and 3.28 ± 0.26 g/dl) (p \ 0.001 for all, Table2).
When all data were analyzed by univariate correlation, the level of LFABP positively correlated with SBP, DBP and MAP (r = 0.388, 0.404 and 0.408, respectively; p = 0.000 for all, Table3). However, no statistically sig-nificant correlation was found with LFABP level and SBP, DBP and MAP in pregnant women with severe, mild– moderate and no preeclampsia when analyzed as separate groups (Table3). A negative, but not statistically signifi-cant, correlation was found between LFABP level and age
in women with severe and mild–moderate preeclampsia (r = -0.209, p = 0.268 and r = -0.135, p = 0.477, respectively, Table3). No significant correlation was found between LFABP level and BMI in or between groups (Table3).
The factors that are promising candidates to predict the severity of preeclampsia were analyzed by logistic regression test (Table4). Accordingly, in multivariate analysis, the severity of preeclampsia was correlated with LFABP level [unadjusted odds ratio (95 % confidence interval), 1.008 (1.003–1.012), p \ 0.001], LDH [1.063 (1.029–1.099), p \ 0.001] (Table4). In multivariate ana-lysis with adjusted odds ratio, on the other hand, only BMI [adjusted odds ratio (95 % confidence interval), 1.506 (1.029–2.204), p = 0.035] and LDH [1.071 (1.028–1.116), p \ 0.001] contributed to the prediction model (Table 4).
Discussion
In the present study, we found that LFABP level: (1) was higher in women diagnosed with severe preeclampsia compared to mild–moderate and no preeclampsia groups; (2) was positively correlated with SBP, DBP and MAP; (3) was not correlated with age; and (4) was associated with the severity and outcome of preeclampsia.
FFAs are energy sources of many cell types. Being insoluble in water, they are transported and circulated
Table 2 Clinical characteristics of the study group
Characteristic Severe preeclampsia (n = 30) Mild–moderate preeclampsia (n = 30) No preeclampsia (n = 30) p value LFABP level (pg/ml)b 1,709.90 ± 94.82 1,614.93 ± 118.22 1,532.36 ± 14,098 \0.001a Gestational age at blood sampling
(weeks.day)c
33.1 ± 3.9 34.9 ± 3.4 33.3 ± 3.5 0.871; 0.072; 0.13 Impaired GCT (n)b 7 (23.3 %) 8 (26.7 %) 3 (10.0 %) 0.233
Serum creatinin (lmol/ml)b 0.76 ± 0.65 0.68 ± 0.62 0.61 ± 0.15 0.39
Serum BUN (mg/dl)c 25.82 ± 7.84 23.11 ± 7.67 25.28 ± 5.29 0.296 Serum AST(U/l)c 24.07 ± 9.83 22.97 ± 9.42 21.73 ± 7.41 0.606 Serum ALT(U/l)c 16.87 ± 8.79 17.77 ± 10.33 14.53 ± 6.11 0.327 Serum LDH (U/l)d 611.77 ± 267.38 501.50 ± 267.18 282.73 ± 52.18 \0.001a Serum protein (g/l)d 5.39 ± 0.94 5.96 ± 0.86 6.29 ± 0.32 \0.001a Serum albumin (g/dl)d 2.89 ± 0.47 3.28 ± 0.54 3.28 ± 0.26 0.001a LFABP Liver type fatty acid binding protein, GCT glucose challenge test, BUN blood urea nitrogen, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase
1 p value between severe and moderate preeclampsia groups 2 p value between severe and no preeclampsia groups 3 p value between mild–moderate and no preeclampsia groups
A p value \ 0.001 (a) was considered statistically significant. Values are expressed as number (percentage) or median (interquartile range). Comparisons among groups were performed with Chi-square test for categorical variables (b) and with one-way ANOVA and post hoc Tukey HSD test (c) or Welch-ANOVA and post hoc Tamhane’s T2 test (d) for continuous variables
while bound to plasma protein albumin [1,15]. Cytoplas-mic FABPs, a family of structurally related intracellular proteins of molecular mass of 14–15 kDa, are involved in cellular uptake, transport, metabolism, oxidation and stor-age of fatty acids [10,11,16,17].
LFABP, expressed both in liver and intestinal mucosa, is involved in LCFA uptake and metabolism [10,11, 18]. It has unique properties among other members of FABPs; it binds two fatty acids rather than the commonly observed stoichiometry of one; it can also bind other ligands such as heme, bilirubin, lysophospholipids, bile salts and acyl-CoA esters, although in lower affinity; and it uses diffusion-mediated mechanism for fatty acid transport while other members of the family depends on protein-membrane collisional process of transport [10,11,18–20]. LFABP has cysteine and methionine groups which suggest its possible role as an antioxidant to minimize toxic effects of poorly soluble LCFAs [10]. Indeed, in vitro experiments in hepatic oxidative stress indicated LFABP can act as an endogenous cytoprotectant [16]. Recent results indicated that ablation of LFABP causes alteration of both fatty acids and monoacylglycerol metabolism [21] and serum LFABP was described as a new diagnostic marker to detect liver injury [22].
Preeclampsia is a multisystem disorder involving hyperinsulinemia, hyperlipidemia, cardiovascular risk fac-tors and changes in glucose utilization [7]. Since FFAs are easily oxidized, over accumulation of FFAs are known to induce oxidative stress, which leads to cellular damage
[15]. Increase in the by-products of lipid peroxidation and serum FFAs was proven during the clinical onset of pre-eclampsia [7,23]. FFAs were also shown to be a predis-posing factor for preeclampsia in non-obese pregnant women [1]. Among the intracellular FABPs, adipocyte fatty acid binding protein (AFABP, also known as FABP-4) was shown to increase in women with preeclampsia compared to no preeclampsia [8,24]. The higher increase of FABP-4 level in severe preeclampsia compared to mild preeclampsia, indicated its relationship with the severity of the disease and suggested a possible role of FABPs in development of preeclampsia [8,24].
The usual signs of preeclampsia, such as proteinuria, hypertension and endothelial dysfunction, are still used in limited diagnosis of preeclampsia [25]. A simple and reliable screening test is still required to detect the severity and outcome of the disease to prevent maternal and fetal death. Recent results showing the increase in FABP-4 level in preeclamptic women suggested possibility of using FABPs in the diagnosis of preeclampsia. Therefore, we have analyzed LFABP, a unique member of FABP family, concentration in women with preeclampsia and no pre-eclampsia and investigated the possibility of using LFABP levels to estimate the severity of the disease.
It is important to note that to our knowledge, there are no data available in literature regarding the alterations of LFABP in preeclampsia. Therefore, we determined LFABP level in serum of women with severe preeclampsia and mild–moderate preeclampsia at the time of diagnosis, and
Table 3 Univariate correlation of serum LFABP level with clinical parameters
BMI Body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, MAP mean arterial pressure
All patients Severe preeclampsia
Mild/moderate preeclampsia
No preeclampsia
r value p value r value p value r value p value r value p value SBP (mmHg) 0.388 0.000 -0.042 0.827 -0.048 0.802 -0.09 0.648 DBP (mmHg) 0.404 0.000 -0.259 0.167 0.163 0.388 0.191 0.331 MAP (mmHg) 0.408 0.000 -0.253 0.233 0.113 0.591 0.089 0.651 Age (years) 0.040 0.709 -0.209 0.268 -0.135 0.477 0.139 0.48 BMI (kg/m2) 0.041 0.709 -0.121 0.524 0.252 0.187 -0.16 0.416
Table 4 Multivariate logistic regression of clinical parameters for the preeclampsia
LFABP Liver type fatty acid binding protein, BMI body mass index, AST aspartate
transaminase, ALT alanine transaminase, LDH lactate dehydrogenase
Unadjusted odds ratio (95 % confidence interval)
p value Adjusted odds ratio (95 % confidence interval) p value LFABP (pg/ml) 1.008 (1.003–1.012) 0.001 Age (years) 1.036 (0.963–1.113) 0.345 BMI (kg/ m2) 1.106 (0.956–1.280) 0.174 1.506 (1.029–2.204) 0.035 Nulliparity 0.583 (0.241–1.412) 0.232 AST (U/l) 1.024 (0.972–1.080) 0.374 ALT (U/l) 1.044 (0.984–1.108) 0.153 LDH (U/l) 1.063 (1.029–1.099) \0.001 1.071 (1.028–1.116) 0.001
in an antenatal clinic visit in normal pregnant women with a similar gestational age. LFABP level was significantly higher in severe preeclampsia compared to mild–moderate and no preeclampsia. A statistically significant univariate correlation was found between LFABP level and SBP, DBP and MAP; however, no correlation was detected with age. Logistic regression test indicated positive correlation of the severity of preeclampsia with LFABP level. The sensitivity of quantitative sandwich enzyme immunoassay technique used to determine LFABP level in serum sam-ples is 7.8 pg/ml which enables a reliable prediction of the severity of the disease at the time of diagnosis.
To our knowledge, this is the first study to evaluate LFABP level in women with uncomplicated pregnancies and those with preeclampsia. The case–control nature of this study does not allow establishment of a temporal relationship between changes in LFABP level and the development of preeclampsia. The results are limited by a small sample size and prospective data with larger numbers and an analysis of the specificity of increase in LFABP level only to preeclampsia is needed to be used as a prognostic marker.
Conclusions
We conclude that LFABP level can be used to confirm the diagnosis of preeclampsia. In addition, the results indicated the potential of LFABP to be used to predict the severity and outcome of preeclampsia at the time of diagnosis. The findings of this study also indicate a possible role of increase in LFABP levels in the development of pre-eclampsia. Further studies with larger study groups are needed to determine whether LFABP level during preg-nancy can predict the subsequent development of preeclampsia.
Conflict of interest The authors have no conflict of interest.
References
1. El Beltagy NS, El Deen Sadek SS, Zidan MA et al (2011) Can serum free fatty acids assessment predict severe preeclampsia? Alex J Med 47:277–281
2. Can M, Sancar E, Harma M, Guven B, Mungan G, Acikgoz S (2011) Inflammatory markers in preeclamptic patients. Clin Chem Lab Med 49:1469–1472
3. Chelbi ST, Veitia RA, Vaiman D (2013) Why preeclampsia still exists? Med Hypotheses 81:259–263
4. Yalcin S, Ulas T, Eren MA et al (2013) Relationship between oxidative stress parameters and cystatin C levels in patients with severe preeclampsia. Medicina (Kaunas) 49:118–123
5. Engin-Ustu¨n Y, Ustu¨n Y, Karabulut AB, Ozkaplan E, Meydanli MM, Kafkasli A (2007) Serum amyloid A levels are increased in pre-eclampsia. Gynecol Obstet Invest 64(2):117–120
6. Toy H, Camuzcuoglu H, Arioz DT et al (2009) Serum prolidase activity and oxidative stress markers in pregnancies with intra-uterine growth restricted infants. J Obstet Gynaecol Res 35:1047–1053
7. Villa PM, Laivuori H, Kajantie E et al (2009) Free fatty acid profiles in preeclampsia. Prostaglandins Leukot Essent Fatty Acids 81:17–21
8. Scifres CM, Catov JM, Simhan H (2012) Maternal serum fatty acid binding protein 4 (FABP4) and the development of pre-eclampsia. J Clin Endocrinol Metab 97:E349–E356
9. Chaemsaithong P, Chaiworapongsa T, Romero R et al (2014) Maternal plasma soluble TRAIL is decreased in preeclampsia. J Matern Fetal Neonatal Med 27:217–227
10. Atshaves BP, Martin GG, Hostetler HA et al (2010) Liver fatty acid binding protein and obesity. J Nutr Biochem 21:1015–1032 11. De Gero´nimo E, Hagan RM, Wilton DC et al (2010) Natural ligand binding and transfer from liver fatty acid binding protein (LFABP) to membranes. Biochim Biophys Acta 1801:1082–1089 12. Lehnen H, Mosblech N, Reineke T et al (2013) Prenatal clinical assessment of sFlt-1 (Soluble fms-like tyrosine kinase-1)/PlGF (Placental growth factor) ratio as a diagnostic tool for pre-eclampsia, pregnancy-induced hypertension, and proteinuria. Geburtshilfe Frauenheilkd 73:440–445
13. Alexander GR, Himes JH, Kaufman RB et al (1996) A United States national reference for fetal growth. Obstet Gynecol 87:163–168
14. ACOG Committee on Obstetric Practice (2002) ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Int J Gynaecol Obstet 77:67–75 (Number 33, January 2002. American College of Obstetricians and Gynecologists) 15. Sasaki H, Kamijo-Ikemori A, Sugaya T et al (2009) Urinary fatty
acids and liver-type fatty acid binding protein in diabetic nephropathy. Nephron Clin Pract 112:c148–c156
16. Ozenirler S, Erkan G, Gulbahar O et al (2011) Serum levels of advanced oxidation protein products, malonyldialdehyde, and total radical trapping antioxidant parameter in patients with chronic hepatitis C. Turk J Gastroenterol 22:47–53
17. Basak S, Das MK, Duttaroy AK (2013) Fatty acid-induced angiogenesis in first trimester placental trophoblast cells: possible roles of cellular fatty acid-binding proteins. Life Sci 93:755–762 18. Foucaud L, Grillasca J, Niot I et al (1999) Output of liver fatty acid-binding protein (L-FABP) in bile. Biochim Biophys Acta 1436:593–599
19. Thompson J, Ory J, Reese-Wagoner A et al (1999) The liver fatty acid binding protein–comparison of cavity properties of intra-cellular lipid-binding proteins. Mol Cell Biochem 192:9–16 20. Thompson J, Reese-Wagoner A, Banaszak L (1999) Liver fatty
acid binding protein: species variation and the accommodation of different ligands. Biochim Biophys Acta 23:117–130
21. Lagakos WS, Guan X, Ho SY et al (2013) Liver fatty acid-binding protein binds monoacylglycerol in vitro and in mouse liver cytosol. J Biol Chem 288:19805–19815
22. Akbal E, Koklu S, Cakal B, Gunes F, Basar O, Tuna Y, Senes M (2013) Liver fatty acid-binding protein is a diagnostic marker to detect liver injury due to chronic hepatitis C infection. Arch Med Res 44:34–38
23. Robinson NJ, Minchell LJ, Myers JE et al (2009) A potential role for free fatty acids in the pathogenesis of preeclampsia. J Hy-pertens 27:1293–1302
24. Shangguan X, Liu F, Wang H et al (2009) Alterations in serum adipocyte fatty acid binding protein and retinol binding protein-4 in normal pregnancy and preeclampsia. Clin Chim Acta 407:58–61
25. Zar T, Kohn OF, Kaplan AA (2011) Fractional excretion of urea in pre-eclampsia: a clinical observation. Iran J Kidney Dis 5:398–403
