Corticosteroid Therapy for Management of Hemolysis, Elevated Liver Enzymes, and Low Platelet Count (HELLP) Syndrome: A Meta-Analysis.

BACKGROUND Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is a severe condition of pregnancy that is associated with significant morbidity and mortality. Corticoteroid (CORT) therapy is common in the management of HELLP syndrome. This study evaluates the efficacy of CORT therapy to patients with HELLP Syndrome. MATERIAL AND METHODS A literature search was carried out in multiple electronic databases. Meta-analyses of means difference and odds ratio were carried under the random-effects model. RESULTS Fifteen studies (675 CORT treated and 787 control HELLP patients) were included. CORT treatment significantly improved platelet count (mean difference between CORT treated and controls in changes from baseline, MD: 38.08 [15.71, 60.45]×109; p=0.0009), lactic dehydrogenase (LDH) levels (MD: -440 [-760, -120] IU/L; p=0.007), and alanine aminotransferase (ALT) levels (MD: -143.34 [-278.69, -7.99] IU/L; p=0.04) but the decrease in aspartate aminotransferase (AST) levels was not statistically significant (MD: -48.50 [-114.32, 17.32] IU/L; p=0.15). Corticosteroid treatment was also associated with significantly less blood transfusion rate (odds ratio, OR: 0.42 [0.24, 0.76]; p=0.004) and hospital/ICU stay (MD: -1.79 [-3.54, -0.05] days; p=0.04). Maternal mortality (OR: 1.27 [0.45, 3.60]; p=0.65), birth weight (MD: 0.09 [-0.11, 0.28]; p=0.38) and the prevalence of morbid conditions (OR: 0.79 [0.58, 1.08]; p=0.14) did not differ significantly between both groups. CONCLUSIONS Corticosteroid administration to HELLP patients improves platelet count, and the serum levels of LDH and ALT, and reduces hospital/ICU stay and blood transfusion rate, but is not significantly associated with better maternal mortality and overall morbidity.

Increased plasma levels of CK-18 as potential cell death biomarker in patients with HELLP syndrome.

HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome represents a life-threatening pregnancy disorder with high fetal and maternal mortality, but its underlying molecular mechanisms remain unknown. Although apoptosis has been implicated in HELLP syndrome, its pathogenic role remains largely unclear. In the present study, we investigated whether the detection of apoptosis by novel plasma biomarkers is of diagnostic value in HELLP patients. For this purpose, we analyzed two biomarkers that specifically detect apoptosis or overall cell death of epithelial cells, such as hepatocytes or placental trophoblasts, through the release of caspase-cleaved or total (caspase-cleaved and uncleaved) cytokeratin-18 (CK-18) in plasma of HELLP patients compared with pregnant as well as non-pregnant healthy women. In addition, caspase activation and cell death were determined in placental tissues of HELLP patients and individuals with normal pregnancy. In contrast to pregnant or non-pregnant healthy controls, we observed significantly increased levels of both caspase-cleaved and total CK-18 in plasma of HELLP patients. Following delivery, CK-18 levels rapidly decreased in HELLP patients. Caspase activation and cell death were also elevated in placental tissues from HELLP patients compared with healthy pregnant women. These data demonstrate not only that apoptosis is increased in HELLP syndrome, but also that caspase-cleaved or total CK-18 are promising plasma biomarkers to identify patients with HELLP syndrome. Thus, further studies are warranted to evaluate the utility of these biomarkers for monitoring disease activity in HELLP syndrome.

Placental apoptosis in preeclampsia, intrauterine growth retardation, and HELLP syndrome: an immunohistochemical study with caspase-3 and bcl-2.

OBJECTIVE: To examine the placental expression of caspase-3 and bcl-2 in pregnancies complicated by preeclampsia, IUGR, and HELLP syndrome. MATERIALS AND METHODS: A prospective case-control study was conducted on 50 pregnant women between December 2006 and August 2007 at Dr. Zekai Tahir Burak Women Health Research and Education Hospital, Ankara, Turkey. Placental tissue samples were obtained from 15 pregnancies complicated by preeclampsia, 15 pregnancies with normotensive IUGR, five pregnancies with HELLP syndrome, and 15 gestational age-matched normotensive pregnancies without intrauterine infection as a control group. The placental expression of caspase-3 and bcl-2 has been investigated by immunohistochemical staining. RESULTS: Caspase-3 immunostaining score was significantly higher in each group when compared with the control group (p = 0.002). However there was no statistically signifant difference with bcl-2 immunostaining in each group when compared with the control group. CONCLUSIONS: Apoptotic marker caspase-3 is significantly increased in the villous trophoblasts of patients with preeclampsia, HELLP syndrome, and IUGR indicating increased placental apoptosis.

[Correlation between severe preeclampsia and abnormal expression of long-chain fatty acid oxidative enzyme].

OBJECTIVE: To explore the correlation between severe preeclampsia and abnormal expression of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). METHODS: Serum-free trophoblast cells cultured in vitro were divided into 4 groups under the stimulations of normal pregnancy serum (NP group), early onset severe preeclampsia serum (E-PE group), late onset severe preeclampsia serum (L-PE group) and HELLP (hemolysis, elevated liver enzymes & low platelets) syndrome serum (HELLP group) respectively. The expressions of mRNA and protein of LCHAD in trophoblast cells were detected by real-time polymerase chain reaction (PCR) and Western blot. RESULT: (1) Expression of LCHAD mRNA: the relative expressions of mRNA of LCHAD in NP, E-PE, L-PE and HELLP groups were 1.00 ± 0.00, 3.08 ± 0.22, 1.62 ± 0.23 and 3.36 ± 0.18 respectively. The relative expressions of LCHAD mRNA were significantly reduced in the E-PE, L-PE and HELLP groups versus the NP group (P < 0.05). Compared with the L-PE group, the gene expressions of LCHAD significantly decreased in the E-PE and HELLP groups (P < 0.05) while no significant difference was found between the E-PE and HELLP groups (P > 0.05). (2) Expression of LCHAD protein: the relative expressions of LCHAD protein were 4.94 ± 0.02, 2.93 ± 0.13, 4.14 ± 0.06 and 2.80 ± 0.09 in the NP, E-PE, L-PE and HELLP groups respectively. The protein expressions of LCHAD were remarkably reduced in the E-PE, L-PE and HELLP groups versus the NP group (P < 0.05). The expressions of LCHAD protein remarkably decreased in the E-PE and HELLP groups versus the L-PE group (P < 0.05) while no significant difference was found between the E-PE and HELLP groups (P > 0.05). CONCLUSION: Long chain fatty acid oxidation is involved in the pathogenesis and development of preeclampsia. The expressions of LCHAD gene and protein are remarkably affected by early onset severe preeclampsia and HELLP syndrome. The interacting mechanism and influence between fatty acid oxidation and the development of preeclampsia are worth further exploring.

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome with pituitary apoplexy.

After hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome was diagnosed in a 35-year-old woman at 39 weeks' gestation, magnetic resonance imaging and hormone examination revealed pituitary apoplexy with panhypopituitarism and diabetes insipidus. Evaluation of pituitary function should be considered in patients with HELLP syndrome.

The role of p38alpha mitogen-activated protein kinase gene in the HELLP syndrome.

Mitogen-activated protein kinase (MAPK) p38alpha was shown to be implicated in the organogenesis of the placenta, and such placental alteration is crucial for the development of hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. We aimed to analyze for the first time human placental expression of MAPK p38alpha in pregnancies complicated by HELLP. The placental expression of MAPK p38alpha was investigated by semiquantitative polymerase chain reaction using cDNA extracted from placental tissue of 15 pregnancies with HELLP syndrome and 15 gestational age-matched controls. Seven patients with HELLP also had intrauterine fetal growth restriction (IUGR). In placenta from pregnancy complicated by HELLP, the expression of MAPK p38alpha is significantly decreased compared to the group with normal pregnancy (p < 0.001), while no difference was found between the HELLP and HELLP with IUGR subpopulations. Our study shows for the first time that MAPK p38alpha is expressed in the human placenta. Pregnancies with placental dysfunction and hypertensive complications are characterized by a significantly decreased expression of MAPK p38alpha. Our observations suggest that p38 MAPK signaling may be essential in placental angiogenesis and functioning.

Placental expression of proteases and their inhibitors in patients with HELLP syndrome.

In preeclampsia and hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome, impaired trophoblast invasion and excessive fibrin deposition in the placental intervillous space is associated with fetal compromise. However, little information is available whether modulation of placental protease expression--potentially causing impaired trophoblast invasion--is associated with the HELLP syndrome. Total RNA and protein were extracted from placental tissue from 11 females with HELLP syndrome and 8 controls matched for gestational age. mRNA expression of matrix metalloprotease (MMP) -2 and -9, tissue inhibitors of metalloprotease (TIMP) -1, -2, and -3, and urokinase-type plasminogen activator receptor (uPAR) was determined by Northern blotting. Protein expression of MMP-2 and -9, and TIMP-1 and -2 was detected by Western blotting and that of uPA, uPAR, and plasminogen activator inhibitor (PAI) -1 by ELISA. In patients with HELLP syndrome, mRNA expression of MMP-2 and TIMP-2 was decreased, whereas TIMP-1 and -3 levels were unchanged. MMP-9 and uPAR mRNA was undetectable in both groups. Protein expression of all investigated proteolytic factors remained unchanged. Our findings at the mRNA level suggest a decrease in matrix remodeling in placentae from patients with HELLP syndrome compared with control pregnancies, although this is not supported at the protein level.

Increased plasma von Willebrand factor antigen levels but normal von Willebrand factor cleaving protease (ADAMTS13) activity in preeclampsia.

The activity of ADAMTS13, the von Willebrand factor (VWF) cleaving protease is low in several conditions, including HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome. As HELLP syndrome develops in most cases on the basis of preeclampsia, our aim was to determine whether plasma ADAMTS13 activity is decreased in preeclampsia. Sixty-seven preeclamptic patients, 70 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Plasma ADAMTS13 activity was determined with the FRETS-VWF73 assay, while VWF antigen (VWF:Ag) levels with an enzyme-linked immunosorbent assay. The multimeric pattern of VWF was analyzed by SDS-agarose gel electrophoresis. There was no significant difference in plasma ADAMTS13 activity between the preeclamptic and the healthy pregnant and non-pregnant groups (median [25-75 percentile]: 98.8 [76.5-112.8] %, 96.3 [85.6-116.2] % and 91.6 [78.5-104.4] %, respectively; p > 0.05). However, plasma VWF:Ag levels were significantly higher in preeclamptic patients than in healthy pregnant and non-pregnant women (187.1 [145.6-243.1] % versus 129.3 [105.1-182.8] % and 70.0 [60.2-87.3] %, respectively; p < 0.001). The multimeric pattern of VWF was normal in each group. Primiparas had lower plasma ADAMTS13 activity than multi-paras (92.6 [75.8-110.6] % versus 104.2 [92.1-120.8] %; p = 0.011). No other relationship was found between clinical characteristics, laboratory parameters and plasma ADAMTS13 activity in either study group. In conclusion, plasma ADAMTS13 activity is normal in preeclampsia despite the increased VWF:Ag levels. However, further studies are needed to determine whether a decrease in plasma ADAMTS13 activity could predispose preeclamptic patients to develop HELLP syndrome.

Reduced pseudocholinesterase activity in patients with HELLP syndrome.

The authors previously reported a case of decreased pseudocholinesterase activity in a patient with HELLP syndrome. It was assumed that the reduced pseudocholinesterase activity in HELLP syndrome is associated with impaired liver function. The present study assesses the prevalence of low pseudocholinesterase in patients with HELLP syndrome. Serum pseudocholinesterase activity was determined with spectrophotometer in 15 patients with HELLP syndrome. Two control groups matched for gestational age were recruited: 15 healthy women with uncomplicated pregnancy and 15 women with severe preeclampsia without HELLP. The prevalence of reduced pseudocholinesterase activity lower than normal limit was 60.0% (9/15) in patients with HELLP syndrome, 33.3% (5/15) in patients with severe preeclampsia, and 6.6% (1/15) in women with normal pregnancy, respectively (P =.009). The pseudocholinesterase activity was found to correlate with serum alanine aminotransferase levels (r = 0.417, P = .006) and with serum aspartate aminotransferase levels (r = 0.462, P = .002). Considering the increased prevalence of reduced pseudocholinesterase activity in patients with HELLP syndrome, the authors suggest that whenever general anesthesia is applied in these patients, the anesthesiologist should be aware that the patient may show slow metabolic degradation of choline-ester drugs.

[Screening for G1528C mutation in mitochondrial trifunctional protein gene in pregnant women with severe preeclampsia and new born infant].

OBJECTIVE: Severe preeclampsia, and hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP) are serious complications of pregnancy, and evidence suggests a genetic basis for these conditions. A G1528C mutation in the alpha-subunit of the mitochondrial trifunctional protein (MTP) gene has been identified in association with these conditions. The aim of this study is to explore the carrier rate of the G1528C mutation in the MTP gene in pregnant women with severe preeclampsia, HELLP syndrome and in their newborns, as well as in a normal pregnant population, so as to determine its association with maternal liver disease among women in Beijing. METHODS: A multicenter, prospective, case control study was carried out. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to screen the G1528C mutations in the MTP gene. One hundred and forty cord blood samples from cases with severe preeclampsia (n = 130) and HELLP syndrome (n = 10) were collected. Ninety maternal peripheral blood samples among them (84 from severe preeclampsia and 6 from HELLP syndrome) were also collected for screening the common disease-causing mutation in Caucasians. Five hundred and sixty cord blood samples and 90 maternal peripheral blood samples obtained from normal pregnant women served as controls. RESULTS: The G1528C mutations in the MTP gene were not found in samples from women with severe preeclampsia and their newborns, from women with HELLP syndrome and their new borns, as well as in samples from the normal pregnant women and their new borns. CONCLUSIONS: The common disease-causing mutation of G1528C in MTP gene in Caucasians is probably not a common mutation in Chinese Han people in Beijing. Further study is needed to expand the sample size among HELLP syndrome and maternal liver diseases in Chinese population.

Placental expression of nitric oxide synthase during HELLP syndrome: the correlation with maternal-fetal Doppler velocimetry.

BACKGROUND: To correlate Doppler waveform of the uterine and umbilical vessels to placental nitric oxide synthase (NOS) expression in pregnant women with HELLP (hemolysis, elevated liver enzymes, low platelets count) syndrome. METHODS: mRNA expression of inducible NOS (iNOS) and endothelial NOS (eNOS) was assessed, after cesarean section, in placental samples from 10 women affected by HELLP syndrome and 10 controls. Pulsatility indices on Doppler waveform analysis from uterine and umbilical arteries were measured. RESULTS: iNOS expression was significantly lower in placenta from women with HELLP syndrome than controls. When comparing the results with Doppler flow measurements, we found a negative correlation between umbilical pulsatility index and eNOS expression (r = -0.91) and a positive correlation with iNOS expression (r = 0.86). CONCLUSIONS: The reduced iNOS expression in women with HELLP syndrome may indicate the extreme placental dysfunction that is unable to compensate for the endothelial derangement and related hypertension in spite of trying to improve fetoplacental perfusion and the delivery of nutrients to the fetus.

Maternal heterozygosity for a mitochondrial trifunctional protein mutation as a cause for liver disease in pregnancy.

Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are serious complications of pregnancy associated with significant maternal and perinatal morbidity and mortality. In previous reports, we have documented an association between AFLP and fetal deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) [N. Engl. J. Med. 340 (1999) 1723-1731; JAMA 288 (2002) 2163-2166]. LCHAD activity resides in the alpha-subunit of the mitochondrial trifunctional protein (MTP), a complex protein that catalyzes beta-oxidation of long chain fatty acids. In all reported cases, the fetus carried a common alpha-subunit MTP mutation (G1528C, E474Q) on one or both alleles. However, the association between fetal LCHAD deficiency and the maternal HELLP syndrome has been limited. Here, we report a case history of a 27-year-old black female who underwent Cesarean section for placenta previa and fetal distress at 36 weeks gestation. The newborn was a healthy male child. Post-delivery, the mother developed severe HELLP syndrome with complications resulting in death of the patient. We used single strand conformation variance and nucleotide sequence analyses to screen DNA isolated from the mother and the newborn for mutations in the MTP alpha-subunit. The mother was heterozygous for a novel mutation (C1072A, Q322K) in exon 11 of the LCHAD domain of the MTP, while the fetal genotype was completely normal. We hypothesize that, in some cases, maternal heterozygosity for an MTP mutation maybe sufficient to cause the development of maternal liver disease without carrying an affected fetus. Combination of the metabolic stress of pregnancy and other environmental stresses may overwhelm the heterozygous mother's capacity for effective metabolism of long chain fatty acids, leading to an accumulation of potentially toxic fatty acid metabolites in the maternal circulation with subsequent damage to the maternal liver.

[Activity loss of Von Willebrand factor cleaving protein (ADAMTS-13) is diagnostic for primary and pregnancy-related thrombotic thrombocytopenic purpura]. / Afwezige activiteit van Von Willebrand-factorsplitsend eiwit (ADAMTS-13) diagnostisch voor primaire en zwangerschapsgerelateerde trombotische trombocytopenische purpura.

OBJECTIVE: To determine whether the measurement of the Von Willebrand factor cleaving protease ADAMTS-13, such as is carried out at the University Medical Centre of Utrecht, The Netherlands, contributes towards the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura (TTP). DESIGN: Descriptive. METHOD: In a group of 98 patients from 21 hospitals, with a Coombs-negative haemolytic anaemia and thrombocytopenia, the ADAMTS-13 activity was measured. Treatment was given irrespective of ADAMTS-13 activity. RESULTS: ADAMTS-13 activity was absent in 27 of 29 patients diagnosed with primary TTP and in all 5 pregnancy-TTP patients. In patients suffering from TTP after bone marrow transplantation (post-BMT) and in all other patients included in this study, ADAMTS-13 activity was normal. Of the 32 patients with absent ADAMTS-13 activity, 28 underwent plasmapheresis. This treatment proved effective as all 28 patients responded well. 17 patients with normal ADAMTS-13 activity also underwent plasmapheresis; 5 (30%) responded well to treatment. In 2 cases a final diagnosis of primary TTP was made, in a further 2, haemolytic uraemic syndrome and in 1 case sepsis was diagnosed. CONCLUSION: In this study, the absence of ADAMTS-13 activity predicted primary TTP and TTP of pregnancy with a sensitivity of 93% and a specificity of 100%. Absence of ADAMTS-13 activity is a strong indication for plasma exchange.

Pseudocholinesterase deficiency associated with HELLP syndrome.

We report a case of decreased plasma pseudocholinesterase activity in a patient with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. The pseudocholinesterase activity returned to normal with concomitant recovery of HELLP syndrome. This possible association is significant when general anesthesia is provided to patients with HELLP syndrome.

Matrix-metalloproteinase activity in first trimester placental bed biopsies in further complicated and uncomplicated pregnancies.

UNLABELLED: Trophoblast invasion is partly regulated by matrix-metalloproteinases (MMPs). Aberrations in MMP-activity in early pregnancy are thought to play a role in the pathophysiology of pregnancy associated conditions like pre-eclampsia and intra-uterine growth restriction (IUGR). A direct relation however, has not been published. We tested the hypothesis that MMP activity in the decidua is compromised in the first trimester of pregnancies, which are complicated by hypertensive disorders or IUGR in later pregnancy. During chorionic villus biopsy, decidua is microscopically separated from the villi and stored. A selection of pregnancies complicated by pre-eclampsia or HELLP-syndrome or IUGR was made, with two matched controls each. Zymography was performed to identify the presence of MMPs, and subsequently immunohistochemistry for MMP-2 and -9 and cytokeratin 7 to examine differences between cases and controls. Next, a specific immuno-capture assay was used to determine the activity of MMP-1, -2, -3, -8, -9, and 13, total as well as active. Although presence of MMP-2 and MMP-9 was found, which corresponded with the immunohistochemistry, no significant differences could be demonstrated between activity of total MMP-2 and total MMP-9 in complicated and uncomplicated pregnancies. Activity of MMP-1, -3, -8 and -13 could not be detected. IN CONCLUSION: our study confirms the presence of MMP-2 and -9 in first trimester placental bed biopsies, but does not support the current concept of deranged MMP-activity in early pregnancy in further complicated pregnancies.

Abdominal pain and preeclampsia: sonographic findings in the maternal liver.

OBJECTIVE: To describe sonographic findings in livers of pregnant women with severe preeclampsia and abdominal pain. METHODS: Over a 12-month period, we performed serial sonographic examinations on 32 pregnant women with severe preeclampsia and acute right upper quadrant and epigastric pain. On each sonogram we observed the liver size and texture, "periportal halo" sign, gallbladder wall, Glisson capsule thickness, painful compression of the liver and gallbladder, and ascites. The pancreas, spleen, kidneys, and uterus were also studied. Sonography was repeated after delivery. RESULTS: Initial sonograms showed liver abnormalities in 28 patients. Abnormalities consisted of liver hypertrophy (n = 24), hyperechoic thickening of the periportal area (periportal halo sign; n = 23), striated thickening of the gallbladder wall (n = 27), hyperechoic thickening of the Glisson capsule (n = 11), liver areas of increased echogenicity (n = 11), subcapsular hematoma (n = 1), and subcapsular calcification (n = 1). Probe compression of the liver enhanced abdominal pain (n = 13), whereas the gallbladder was painless in all cases. No gallbladder stones were detected. Ascites (n = 16) and pleural effusion (n = 11) were also present. In no case did we detect abnormalities of the pancreas, kidneys, or spleen. All patients eventually had hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome according to the American College of Obstetricians and Gynecologists classification. In 7 cases, HELLP syndrome developed postpartum. Three patients also had eclampsia. Follow-up sonograms highlighted quick regression of abnormalities after delivery. CONCLUSIONS: The livers of women with severe preeclampsia who had HELLP syndrome showed sonographic abnormalities before biological abnormalities. Serial sonographic examinations could therefore contribute to the obstetric care of these women. Preeclampsia and HELLP syndrome should be routinely checked for in all pregnant women with acute abdominal pain.

Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review.

Since the first report of long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency a little more than a decade ago, its phenotypic and genotypic heterogeneity in individuals homozygous for the enzyme defect has become more and more evident. Even more interesting is its association with pregnancy-specific disorders, including preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), hyperemesis gravidarum, acute fatty liver of pregnancy, and maternal floor infarct of the placenta. In this review we discuss the biochemical and molecular basis, clinical features, diagnosis, and management of long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency.