The alcohol dehydrogenase isoenzyme (ADH I) as a marker of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is an important pregnancy liver disorder. The alterations of different enzymes activity in the hepatocytes in the course of liver diseases are reflected in an increase in the activity of the corresponding enzymes in the blood. In present study we assayed the activity of alcohol dehydrogenase (ADH) and its isoenzyme in the serum of patients with ICP. Serum were collected from 100 pregnancies with ICP in the second or third trimester of pregnancy. Serum samples were also taken from 100 healthy pregnant women. The activity of ADH I was measured by spectrofluorometric method, ADH total was measured by photometric method. There was significant increase in the activity of ADH I (2.79 mU/l vs. 1.72 mU/l) and total ADH activity (1103 mU/l vs. 682 mU/l) in the sera of women with ICP compared to the healthy pregnant women. Importantly, the sensitivity and specificity of ADH I for diagnosis of ICP were 85% and 91%, respectively. Area under the Receiver Operating Curve for ADH I in ICP was 0.81. The activity of ADH I in the sera of women with ICP is statistically significantly increased, which may have a diagnostic significance for ICP patients.

Functional and pathological role of 15-Lipoxygenase and its metabolites in pregnancy and pregnancy-associated complications.

Maternal lipid metabolism status during pregnancy may have pivotal effects on a healthy pregnancy, the progression of labor, and childbirth. Based on evidence, changes in maternal lipid profile and metabolism is related to various alterations in fetal metabolic status, fat mass, birth weight and can result in serious maternal and fetal complications. 15-lipoxygenase accounts as a key enzyme in metabolizing polyunsaturated fatty acids that generate various inflammatory lipid metabolites. The possible involvement of 15- lipoxygenase and its metabolites in the inflammatory process, cell proliferation and death, and immune response has been postulated. The indicative role of the 15- lipoxygenase enzymatic pathway in the implantation process, stages of pregnancy, embryogenesis, organogenesis, progression of labor, pregnancy period, and pregnancy-associated complications is remarkable. Accordingly, this study will review the research conducted on the role of 15- lipoxygenase in different reproductive tissues, and its pathological role in pregnancy-related diseases to provide more insight regarding the emerging role of 15-lipoxygenase in normal pregnancy.

ACE2: a key modulator of the renin-angiotensin system and pregnancy.

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound protein containing 805 amino acids. ACE2 shows approximately 42% sequence similarity to somatic ACE but has different biochemical activities. The key role of ACE2 is to catalyze the vasoconstrictor peptide angiotensin (ANG) II to Ang-(1-7), thus regulating the two major counterbalancing pathways of the renin-angiotensin system (RAS). In this way, ACE2 plays a protective role in end-organ damage by protecting tissues from the proinflammatory actions of ANG II. The circulating RAS is activated in normal pregnancy and is essential for maintaining fluid and electrolyte homeostasis and blood pressure. Renin-angiotensin systems are also found in the conceptus. In this review, we summarize the current knowledge on the regulation and function of circulating and uteroplacental ACE2 in uncomplicated and complicated pregnancies, including those affected by preeclampsia and fetal growth restriction. Since ACE2 is the receptor for SARS-CoV-2, and COVID-19 in pregnancy is associated with more severe disease and increased risk of abnormal pregnancy outcomes, we also discuss the role of ACE2 in mediating some of these adverse consequences. We propose that dysregulation of ACE2 plays a critical role in the development of preeclampsia, fetal growth restriction, and COVID-19-associated pregnancy pathologies and suggest that human recombinant soluble ACE2 could be a novel therapeutic to treat and/or prevent these pregnancy complications.

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications.

The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.

Association between pregravid liver enzyme levels and gestational diabetes in twin pregnancies: a secondary analysis of national cohort study.

Multiple pregnancies are prone to gestational diabetes mellitus (GDM). This study investigated the association between pregravid liver enzyme levels and the development of GDM in a twin pregnancy. Women who had the National Health Screening Examination and delivered their twin babies within one year were enrolled. Pregravid liver enzyme levels were divided into high and low level. Risks for developing GDM by high levels of liver enzymes were analyzed, in subgroups by pregravid obesity or metabolic syndrome. Among the 4348 twin pregnancies, 369 women (8.5%) developed GDM not requiring insulin treatment (GDM - IT), and 119 women (2.7%) developed GDM requiring insulin treatment(GDM + IT). High levels of pregravid GGT and ALT were related to risks of GDM + IT not only in women with obesity or metabolic syndrome (odds ratio[OR] 6.348, 95% confidence interval [CI] 2.579-15.624 and OR 6.879, 95% CI 2.232-21.204, respectively), but also in women without obesity (OR 3.05, 95% CI 1.565-5.946) or without metabolic syndrome (OR 3.338, 95% CI 1.86-5.992), compared to in women with low levels of those. However, there were no significant associations in the pregravid ALT and GGT levels and risks for development of GDM - IT, unrelated to pregravid obesity or metabolic syndrome. Therefore, this study suggests that women with high levels of pregravid GGT and ALT need to recognize their increased risk of GDM + IT, regardless of pregravid obesity or MetS, when they get pregnant twin.

Differences in gene expression of enzymes involved in branched-chain amino acid metabolism of abdominal subcutaneous adipose tissue between pregnant women with and without PCOS.

OBJECTIVE: Polycystic ovary syndrome (PCOS) appears to be a common endocrine disorder of women in reproductive age. Adipose tissue (AT) is known as an active tissue in the metabolism of branched-chain amino acids (BCAA; Valine, Leucine, and Isoleucine) that they have associated with blood BCAA levels is a prognostic factor for insulin-resistant. Although the crucial roles of AT in women suffering from PCOS was reported, little information exists on the BCAA metabolism in AT of PCOS women. The aim was to assess and compare the expression of BCAAs metabolism pathway genes in abdominal subcutaneous AT of pregnant women with PCOS and non-PCOS pregnant women. MATERIALS AND METHODS: AT samples from 13 PCOS were compared with samples collected from 6 non-PCOS women, all of whom underwent caesarean. Quantitative real-time PCR technique was used for gene expression of branched chain aminotransferase 2 mitochondrial (BCAT2), branched chain ketoacid dehydrogenase E1-alpha (BCKDHA), branched chain ketoacid dehydrogenase E1-Beta (BCKDHB), dihydrolipoamide branched chain transacylase E2 (DBT), dihydrolipoamide dehydrogenase E3 (DLD), branched chain ketoacid dehydrogenase kinase (BCKDK), Data were analyzed using t-test or U-test. RESULTS: No significant differences were found in age and body mass index (BMI) between non-PCOS and PCOS women. The mRNA level of BCAT2 and DLD in PCOS group was not significantly different from non-PCOS group whereas mRNA level of BCKDHB and DBT was significantly increased in PCOS group (P < 0.0001). In contrast, mRNA level of BCKDHA (P = 0.0001) and BCKDK (P < 0.0001) was significantly decreased in PCOS group. CONCLUSION: The alterations in gene expressions involved BCAA metabolism in age-matched and BMI- matched non-PCOS and PCOS pregnant women at delivery day was shown which warrants further studies regards functional activity. More attention should be given to AT of PCOS mothers that was previously ignored.

Angiopoietin 2 stimulates trophoblast invasion via a mechanism associated with JNK signaling.

Extravillous trophoblast cell (EVT) invasion is tightly controlled, and its dysregulation can lead to altered spiral artery remodeling and contribute to a number of different pregnancy complications. Angiopoietin-2 (Ang-2) is expressed by trophoblast cells and various cells in the decidua, and trophoblast cells express its receptor, Tie2. Ang-2 has been shown to play roles in tumor progression and metastasis but it is not known if it also regulates EVT invasion. Here, we show that both the HTR-8/SVneo cell line and primary isolates of human EVT expressed various integrins and the Tie2 receptor, and Ang-2 stimulated their migration and/or invasion. Ang-2 increased expression of matrix metalloproteinase (MMP)2 and MMP9, altered the cytoskeleton of HTR-8/SVneo cells and also induced phosphorylation of Tie2, JNK and c-Jun. Inhibition of p-JNK (using SP600125) blocked the Ang-2 induced invasion of HTR-8/SVneo cells. In addition, inhibition of Tie2 (pexmetinib) and integrin signaling (RGDS and ATN-161) also blocked Ang-2-induced invasion. In conclusion, we demonstrate that Ang-2 can stimulate EVT invasion via a mechanism associated with activation of both the Tie2 receptor and integrins, which appear to work through different pathways; Tie2 through the JNK/c-JUN pathway and integrins through an as yet unidentified pathway(s). We therefore propose that any alterations in Ang-2 expression in the decidua would lead to an imbalance in pro- and anti-invasive factors, disrupting regulation of EVT invasion and spiral artery remodeling and thereby contribute to the etiology of several complications of pregnancy.

The Alterations in Alcohol Dehydrogenase Activity in the Sera of Women With Intrahepatic Cholestasis of Pregnancy.

BACKGROUND/AIM: The liver of pregnant women undergoes physiological and pathological changes and the changes in liver enzyme activity and release reflect changes in serum enzymatic activity. We aimed to assess the activity of alcohol dehydrogenase (ADH) isoenzymes, and aldehyde dehydrogenase (ALDH) in the sera of women with intrahepatic cholestasis of pregnancy (ICP), the most common pregnancy-related liver disease. PATIENTS AND METHODS: Serum samples were taken from 40 women with ICP in the second or third trimester of pregnancy. Serum samples were also obtained from 40 healthy pregnant women at the same time of pregnancy and 40 healthy non-pregnant women. Class I and II of ADH and ALDH activity was measured by a spectrofluorometric method. Class III, IV ADH and total ADH activity was measured by photometric methods. RESULTS: The total ADH activity was significantly higher in women with ICP than in healthy pregnant and non-pregnant women (about 42%). The median total activity of ADH was 1067 mU/l in women with ICP, 628 mU/l in healthy pregnant and 605 mU/l in non-pregnant women. A statistically significant increase in class I ADH isoenzymes was found in the sera of pregnant women with ICP. The median activity of this class in the ICP group increased about 62% and 80% in comparison to the healthy pregnant women and non-pregnant women, respectively. CONCLUSION: The activity of class I ADH isoenzymes in the sera of women with ICP is statistically significantly increased and may have a diagnostic significance.

[The activity of enzymes of amino acid metabolism of the placenta in different terms of the physiological and complicated pregnancy.]

The activity of amino acid metabolism enzymes and the content of free amino acids in the placenta during physiological pregnancy and placental insufficiency (PI) were studied using spectrophotometric methods and ion-exchange chromatography. It was found that in PI placental activity of the studied enzymes: alanine-, cysteine-e, tyrosine-, glutamino- transferase, glutathione synthetase, glutamate dehydrogenase decreases at different periods of gestation. The opposite variations occur for aspartataminotranferase and glutaminase. Similar changes are detected for amino acids synthesized or used in the course of appropriate reactions: aspartic acid, glutamic acid, glutamine, alanine, cysteine, tyrosine, arginine. The correlation between enzyme activity and amino acid content was revealed. Different periods of pregnancy are characterized by varying degrees of change, especially expressed in the second trimester, characterized by the most intense growth and development of the fetus, and its increased needs for trophic material. The revealed changes obviously play a pathogenetic role in the formation and further development of PI.

Analysis of Vascular Hydrogen Sulfide Biosynthesis.

With potent vasodilatory and pro-angiogenic properties, hydrogen sulfide (H2S) is now accepted as the third gasotransmitter after nitric oxide (NO) and carbon monoxide. Endogenous H2S is mainly synthesized by cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE). Akin to previous studies showing hormonal regulation of NO biosynthesis, we first reported that uterine and systemic artery H2S biosynthesis is regulated by exogenous estrogens in an ovariectomized sheep model of estrogen replacement therapy, specifically stimulating CBS, but not CSE, expression, in uterine (UA) and mesenteric (MA), but not carotid (CA), arteries in ovariectomized nonpregnant sheep. We have found significantly elevated H2S biosynthesis due to CBS upregulation under estrogen-dominant physiological states, the proliferative phase of menstrual cycle and pregnancy in primary human UAs. Our studies have pioneered the role of H2S biology in uterine hemodynamics regulation although there is still much that needs to be learned before a thorough elucidation of a role that H2S plays in normal physiology of uterine hemodynamics and its dysregulation under pregnancy complications can be determined. In this chapter we describe a series of methods that we have optimized for analyzing vascular H2S biosynthesis, including (1) real-time quantitative PCR (qPCR) for assessing tissue and cellular levels of CBS and CSE mRNAs, (2) immunoblotting for assessing CBS and CSE proteins, (3) semiquantitative immunofluorescence microscopy to specifically localize CBS and CSE proteins on vascular wall and to quantify their cellular expression levels, and (4) methylene blue assay for assessing H2S production in the presence of selective CBS and CSE inhibitors.

Celastrol Attenuates Intrahepatic Cholestasis of Pregnancy by Inhibiting Matrix Metalloproteinases-2 and 9.

INTRODUCTION AND AIM: Matrix metalloproteinase (MMP)-2 and MMP-9 are reported to participate in several pregnancy-related diseases, including intrahepatic cholestasis of pregnancy (ICP), which is a severe liver disorder in pregnant women. Meanwhile, ample evidences have demonstrated that celastrol inhibits the activity and expression of MMPs. The present study aims to examine the effect of celastrol to alleviate symptoms of ICP in rat model. MATERIAL AND METHODS: By inducing ICP with 17 - ethinylestradiol in pregnant female rats, we assessed the impact of celastrol administration on symptoms of ICP, such as the rate of bile flow, the level of total bile acids (TBA), and the activities of MMP-2 and -9. Furthermore, the correlations between the levels of MMPs with the examined ICP symptoms were investigated. RESULTS: In rats with ICP, both MMP-2 and -9 exhibited significantly elevated activities, which were inhibited by the administration of celastrol. Furthermore, ICP symptoms such as bile flow rate and total TBA were restored by celastrol. Lastly, there were strong correlations between levels of the two MMPs and TBA. CONCLUSION: Our findings described for the first time the effects of celastrol to attenuate ICP symptoms through an inhibition of both MMP-2 and -9, providing evidence for a potential role of celastrol as a new drug for the treatment of ICP.

Beyond the lungs: Alpha-1 antitrypsin's potential role in human gestation.

Alpha-1 antitrypsin (AAT) is an acute-phase protein with strong inhibitory activity towards proteolytic enzymes, mainly elastase but also trypsin, chymotrypsin and thrombin. The biological role of the protein and the effects of its deficiency have been subjects of scientific research for years, yet in many areas our knowledge remains incomplete. Alpha-1 antitrypsin deficiency (AATD), a defect in AAT synthesis and functionality, is one of the most frequently inherited genetic disorders among Caucasian populations. Its severe form is characterized by very low serum levels of AAT, and it most often affects the lungs (causing early-onset emphysema or chronic obstructive lung disease (COPD)) and/or liver (leading to jaundice and liver cirrhosis in children and adults). However, little is known about other possible clinical consequences of AAT deficiency. We discuss AAT's potential role in mechanisms regulating human fertility and gestation, with a particular emphasis on the clinical context and on indications for AATD diagnostic testing.

Gestational stress induced differential expression of HDAC2 in male rat offspring hippocampus during development.

Accumulating evidence from preclinical and clinical studies indicates prenatal exposure to stress or excess glucocorticoids can affect offspring brain. HDAC2 is an important target of glucocorticoid. Here we detected HDAC2 expression in male offspring hippocampus from gestational restraint stressed rat during development and the relationship between HDAC2 expression and behaviors and neurogenesis in male offspring. Pregnant rats received restrained stress during the last week of pregnancy. Expressions of HDAC2 in offspring hippocampus were detected on postnatal 0 day (P0) and 60 days (P60). Neurogenesis was evaluated by Doublecortin (DCX) staining on P60. Anxiety-like behavior and cognition were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. We found that HDAC2 expression in the hippocampus of male prenatally stressed offspring (MPSO) was similar to the male control offspring on P0, but significantly lower on P60. Corresponding to the decreased expression of HDAC2 in MPSO hippocampus at P60, neurogenesis in the dentate gyrus of MPSO was significantly lower than the control male offspring. And MPSO also showed greater anxiety and poorer learning and memories abilities than control male offspring. These showed that HDAC2 could partly explain the effects of gestational stress on male offspring behaviors.

Stillbirth in Western Australia, 2005-2013: the influence of maternal migration and ethnic origin.

OBJECTIVE: To investigate prevalence rates and the risk of ante- and intrapartum stillbirth in Western Australia with respect to maternal country of birth and ethnic origin. DESIGN, SETTING AND PARTICIPANTS: Whole population retrospective cohort analysis of de-identified, linked routinely collected birth, perinatal and mortality data for all births to non-Indigenous women in WA during 2005-2013. MAIN OUTCOME MEASURES: Crude and adjusted odds ratios (aORs) with 95% confidence intervals were estimated by logistic regression and adjusted for confounding factors, for all stillbirths, antepartum stillbirths and intrapartum stillbirths, stratified by migrant status and ethnic background (white, Asian, Indian, African, Maori, other). RESULTS: Women born overseas were more likely to have a stillbirth than Australian-born women (aOR, 1.26; 95% CI, 1.09-1.37). There was no significant difference for any type of stillbirth between Australian-born women of white and non-white backgrounds, but non-white migrant women were more likely than white migrants to have a stillbirth (OR, 1.42; 95% CI, 1.19-1.70). Compared with Australian-born women, migrants of Indian (aOR, 1.71; 95% CI, 1.17-2.47), African (aOR, 2.12; 95% CI, 1.46-3.08), and "other" ethnic origins (aOR, 1.43; 95% CI, 1.06-1.93) were more likely to have antepartum stillbirths; women of African (aOR, 5.08; 95% CI, 3.14-8.22) and "other" (aOR, 1.86; 95% CI, 1.15-3.00) background were more likely to have an intrapartum stillbirth. CONCLUSIONS: Immigrants of African or Indian background appear to be at greater risk of ante- and intrapartum stillbirth in WA. Specific strategies are needed reduce the prevalence of stillbirth in these communities.

Placental lipoprotein lipase activity is positively associated with newborn adiposity.

INTRODUCTION: Recent data suggest that in addition to glucose, fetal growth is related to maternal triglycerides (TG). To reach the fetus, TG must be hydrolyzed to free fatty acids (FFA) and transported across the placenta, but regulation is uncertain. Placental lipoprotein lipase (pLPL) hydrolyzes TG, both dietary chylomicron TG (CM-TG) and very-low density lipoprotein TG (VLDL-TG), to FFA. This may promote fetal fat accretion by increasing the available FFA pool for placental uptake. We tested the novel hypothesis that pLPL activity, but not maternal adipose tissue LPL activity, is associated with newborn adiposity and higher maternal TG. METHODS: Twenty mothers (n = 13 normal-weight; n = 7 obese) were prospectively recruited. Maternal glucose, insulin, TG (total, CM-TG, VLDL-TG), and FFA were measured at 14-16, 26-28, and 36-37 weeks, and adipose tissue LPL was measured at 26-28 weeks. At term delivery, placental villous biopsies were immediately analyzed for pLPL enzymatic activity. Newborn percent body fat (newborn %fat) was assessed by skinfolds. RESULTS: Placental LPL activity was positively correlated with birthweight (r = 0.48;P = 0.03) and newborn %fat (r = 0.59;P = 0.006), further strengthened by correcting for gestational age at delivery (r = 0.75;P = 0.0001), but adipose tissue LPL was not. Maternal TG and BMI were not correlated with pLPL activity. Additionally, pLPL gene expression, while modestly correlated with enzymatic activity (r = 0.53;P < 0.05), was not correlated with newborn adiposity. DISCUSSION: This is the first study to show a positive correlation between pLPL activity and newborn %fat. Placental lipase regulation and the role of pLPL in pregnancies characterized by nutrient excess and fetal overgrowth warrant further investigation.

UGT polymorphisms and lamotrigine clearance during pregnancy.

OBJECTIVE: To evaluate the impact of maternal UGT1A4 and UGT2B7 genetic polymorphisms and sex of foetus on gestation-induced changes in lamotrigine (LTG) clearance during pregnancy and post-partum (PP). METHODS: Single nucleotide polymorphisms UGT1A4 142T > G, L48V (*3), UGT1A4 70C > A, P24T (*2) and UGT2B7 802C > T, H268Y (*2) were determined in 40 women (47 pregnancies) with epilepsy treated with LTG. Retrospectively collected data included LTG dosage and LTG plasma levels before pregnancy (T0), and LTG dosage and LTG plasma level changes in the first (T1), second (T2) and third trimester (T3), and post-partum (PP) as well as the sex of the foetus. RESULTS: Reductions in the LTG concentration-to-dose ratio (C/D ratio) during pregnancy were seen in all genotype panels and varied between -53% and -74% in T3. Genetic polymorphism of UGT1A4 T142G (*3) and UGT2B7 C802T (*2) had the most pronounced influence on LTG clearance. Women with UGT1A4 142TG had a lower decrease in the C/D ratio in T3 than those with wild type: -53% (95%CI: -68% to -39%) versus -65% (95%CI: -69% to -60%) (p = 0.04). In homozygous carriers of UGT2B7 802TT the LTG C/D ratio was reduced significantly already in T1 (p = 0.015) as well as in T3 compared to the heterozygous carriers (802CT) (p = 0.04). Multiple regression analysis demonstrated that women who carried a female foetus had a significantly higher reductions in the LTG C/D ratio from T0 to the end of pregnancy than those with a male foetus (p = 0.003). In the univariate analysis the reductions in LTG C/D ratio were -64% in T2 (95%CI: -69% to -59%) and -67% in T3 (95%CI: -71% to -63%) in women who expected a female child compared to whose with a male child -58% in T2 (p = 0.002, 95%CI: -67% to -48%) and -57% in T3 (p < 0.001, 95%CI: -65% to -48%). CONCLUSION: Genetic polymorphism in UGT1A4 and UGT2B7 may play a modest role in LTG clearance changes during pregnancy. In addition, our study indicates that the sex of the foetus influenced significantly the change in LTG clearance.

Epigallocatechin-3-gallate ameliorates intrahepatic cholestasis of pregnancy by inhibiting matrix metalloproteinase-2 and matrix metalloproteinase-9.

Matrix metalloproteinase (MMP)-2 and matrix metalloproteinase-9 are involved in many illnesses affecting pregnant women, including intrahepatic cholestasis of pregnancy (ICP), a serious liver abnormality during pregnancy. Epigallocatechin-3-gallate (EGCG) has been widely reported to inhibit activities of MMP-2 and MMP-9. We aimed to investigate the role of EGCG in ameliorating ICP symptoms in a rat model. Using 17α-ethinylestradiol to induce ICP in pregnant rats, we investigated the efficacy of EGCG administration on ICP symptoms, including bile flow rate, total bile acids (TBA) and MMP-2 and MMP-9 activities. Correlation study was conducted among levels of the two MMPs with other ICP symptoms. In ICP rats, activities of both MMP-2 and MMP-9 were significantly elevated. EGCG administration could inhibit the upregulation of MMP-2 and MMP-9 post-transcriptionally. Furthermore, EGCG ameliorated ICP symptoms, as evidenced by restored bile flow rate and TBA, showing efficient treatment outcomes. At last, levels of TBA and the two MMPs were found to be strongly correlated. Our study demonstrates that, for the first time, the efficacy of EGCG in ameliorating ICP symptoms by inhibiting both MMP-2 and MMP-9, which supports its potential as a novel drug in ameliorating ICP.

Identification of Matrix Metalloproteinase-2 and 9 as Biomarker of Intrahepatic Cholestasis of Pregnancy

ABSTRACT Intrahepatic cholestasis of pregnancy (ICP) is a severe liver disease uniquely occurring during pregnancy. In this study we aimed to identify novel biomarker for the diagnosis of ICP in Chinese population. 50 healthy pregnant women, 50 mild ICP patients and 48 severe ICP patients were enrolled for this study. Liver function tests, including serum total bilirubin, direct bilirubin, alanine transaminase, aspartate aminotransferase and cholyglycine, were performed in all participants. After an overnight fast serum levels of total bile acids (TBA), matrix metalloproteinase (MMP)-2 and MMP-9 were measured, and their correlation with liver function tests were analyzed. The observed increase in serum TBA in ICP patients was not statistically significant which made it unreliable for diagnosis of ICP in Chinese population. On the other hand, both MMP-2 and MMP-9 serum levels exhibited a progressive and significant elevation in mild and severe ICP patients compared with healthy pregnant women, which also positively correlated with liver function tests. Serum levels of both MMP-2 and MMP-9 could be reliably used as laboratory abnormalities for accurate diagnosis and sensitive grading of ICP in Chinese population.

Identification of Matrix Metalloproteinase-2 and 9 as Biomarker of Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a severe liver disease uniquely occurring during pregnancy. In this study we aimed to identify novel biomarker for the diagnosis of ICP in Chinese population. 50 healthy pregnant women, 50 mild ICP patients and 48 severe ICP patients were enrolled for this study. Liver function tests, including serum total bilirubin, direct bilirubin, alanine transaminase, aspartate aminotransferase and cholyglycine, were performed in all participants. After an overnight fast serum levels of total bile acids (TBA), matrix metalloproteinase (MMP)-2 and MMP-9 were measured, and their correlation with liver function tests were analyzed. The observed increase in serum TBA in ICP patients was not statistically significant which made it unreliable for diagnosis of ICP in Chinese population. On the other hand, both MMP-2 and MMP-9 serum levels exhibited a progressive and significant elevation in mild and severe ICP patients compared with healthy pregnant women, which also positively correlated with liver function tests. Serum levels of both MMP-2 and MMP-9 could be reliably used as laboratory abnormalities for accurate diagnosis and sensitive grading of ICP in Chinese population.

Maternal liver elasticity determined by acoustic radiation force impulse elastosonography in intrahepatic cholestasis of pregnancy.

PURPOSE: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by maternal pruritus and impaired liver function. The objective of the study was to evaluate maternal liver elasticity by acoustic radiation force impulse (ARFI) elastosonography in ICP and to compare it with that in healthy pregnant women. METHODS: This descriptive, case-control study consisted of 33 women with healthy pregnancies and 22 women with ICP in the third trimester of gestation. Maternal liver elasticity measurements were performed by ARFI elastosonography. The maternal characteristics and perinatal outcomes of the participants were also collected. RESULTS: All maternal liver ARFI elastosonography scores were elevated in women with ICP compared to healthy controls (p = 0.015, p = 0.011, and p = 0.004, respectively). There was a significant positive correlation between maternal liver enzymes and ARFI elastosonography scores (r = 0.404, p = 0.002 and r = 0.389, p = 0.003, respectively). The optimal cut-off point of maternal liver ARFI-mean elastography score to identify the risk of ICP was >1.23 m/s, and the sensitivity and specificity were 68.2 and 69.7%, respectively [area under curve (AUC) 0.731, 95% confidence interval (CI) 0.594-0.869). CONCLUSION: The current study found that maternal liver stiffness measured by ARFI elastosonography was increased in pregnancies complicated with ICP.