Publications by authors named "K Sosnowsky"

6 Publications

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2019 06 1;68(6):1099-1107. Epub 2018 Aug 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
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June 2019

Oxidatively modified LDL particles in the human placenta in early and late onset intrauterine growth restriction.

Placenta 2013 Dec;34(12):1142-9

Introduction: Reduced serum LDL concentrations have been observed in pregnancies complicated by intrauterine growth restriction (IUGR) as compared to healthy pregnant women. Since increased oxidative stress has been suggested to play a major role in IUGR we now hypothesized that the lower LDL concentrations are accompanied by an accumulation of oxidized LDLs in the placenta.

Methods: Fifteen placentas of near term and preterm born IUGR, and a gestational age matched control group (CTRL n = 15) were analyzed. Placental minimal modified LDL and fully oxidized LDL particles were measured by ELISA, and by immunohistochemistry, and were related to maternal and fetal serum lipid profiles.

Results: We found fully oxidized LDL but not minimal modified LDL being increased in the preterm subgroup of IUGR (n = 10) as compared to preterm CTRL (n = 10; p < 0.05). An increased staining intensity of trophoblasts in preterm IUGR subjects as compared to preterm CTRL has been confirmed by immunohistochemistry (p < 0.05). No difference could be found between the term groups (n = 5 each). Correlation analysis revealed an inverse relationship of maternal LDL (ρ = −0.49, p = 0.03) and fetal HDL cholesterol (ρ = −0.46, p = 0.04) with placental fully oxidized LDL particle concentration within preterms.

Discussion: IUGR is a heterogeneous entity. Different pathomechanisms seem to underlie the disease in preterm and term subjects with oxidation of LDL within the placenta possibly taking place in preterm IUGRs.

Conclusions: We conclude that the reduced maternal LDL cholesterol concentration in IUGR pregnancies is attributed to increased accumulation of oxidized LDL particles within the placenta at least in early onset IUGR
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December 2013

PP033. Oxidized LDL particles in the placenta of intrauterine growth restriction (IUGR) subgroups.

Pregnancy Hypertens 2013 Apr 6;3(2):78-9. Epub 2013 Jun 6.

Introduction: Maternal serum LDL concentrations are lower in IUGR pregnancies as compared to controls (CTRL). We now hypothesized that an increased oxidative stress results in the formation of oxidized LDL (oxLDL) particles which than accumulates within the placenta. This is particularly hypothesized for the severe early onset subgroup of IUGR with preeclampsia (PE).

Methods: OxLDL (minimal modified and fully oxidized LDL) levels in placental biopsies from term IUGR (>37 weeks, t-IUGR, n=5), preterm IUGR (<34 weeks, p-IUGR, n=5), and preterm IUGR with PE (PE-IUGR, n=5) were compared to a CTRL group consisted of gestational age matched preterm (p-CTRL, n=10) and term (t-CTRL, n=5) placentas by ELISA and immunohistochemistry (IHC).

Results: Fully oxidized LDL but not minimally oxidized LDL concentrations were higher in p-IUGR and tend to be increased in PE-IUGR when compared to p-CTRL (p=0.040 and p=0.075). There was virtually no difference of fully oxidized LDL levels between p-CTRL, t-CTRL, and t-IUGR. We confirmed a higher oxLDL accumulation in trophoblasts of p-IUGR and PE-IUGR as compared to both CTRL groups by IHC though this was not statistically significant.

Conclusion: Conformational changes of LDL during the process of oxidation might lead to an accumulation of oxLDL particles in placental tissue of IUGR. The pathogenesis of early onset IUGR might differ from those of late onset IUGR.
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April 2013

[Determination of maternal and foetal serum lipid profile and placental oxidised low density lipoprotein accumulation in preeclampsia and normotensive pregnancies].

Z Geburtshilfe Neonatol 2012 Oct 29;216(5):220-5. Epub 2012 Oct 29.

Frauenklinik für Gynäkologie und Geburtsmedizin des Universitätsklinikums der RWTH Aachen.

Background: Oxidised low density lipoproteins (oxLDL) are key players in the development of atherosclerotic cardiovascular diseases. Since there are similarities between the pathogenesis of preeclampsia and atherosclerosis we hypothesised an increased accumulation of oxLDL at the materno-foetal and foeto-foetal interface within the placental tissue of preeclamptic women compared to women with normotensive pregnancies (controls). Moreover, we analysed maternal and foetal serum lipid parameters.

Patients And Methods: oxLDL was determined by immunohistochemistry in placental paraffin sections of 14 women suffering from preeclampsia (30th-39th week of gestation) and compared to 28 preterm and term deliveries (25th-40th week of gestation). 10 high power fields were chosen randomly by the newCAST software and oxLDL expression was analysed via standardised methods by 2 independent and blinded investigators. Maternal and foetal triglycerides, total cholesterol, LDL cholesterol and HDL cholesterol were measured. Statistical examination was carried out by the Mann-Whitney test.

Results: oxLDL was found in villous trophoblast and placental endothelium. No significant differences were observed in expression intensity between preeclampsia and controls. Maternal and foetal triglyceride levels were significantly increased in preeclampsia compared to controls (pre-eclampsia mothers: 293 [SD 87.4] mg/dL, controls: 214 [SD 89.4] mg/dL, p=0.0097; preeclampsia foetuses: 26 [SD 16.6] mg/dL, controls: 18 [SD 10.4] mg/dL, p=0.0463). No significant differences in other lipid concentrations were found.

Conclusions: We could not confirm our initial hypothesis of an increased oxLDL accumulation in placental tissue of preeclampsia. However, preeclampsia is a condition of dyslipidaemia affecting both maternal and foetal serum with implications for development and programming of cardiovascular diseases in later life.
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October 2012

PP014. Estimating fully and minimal oxidized low density lipoprotein accumulation in placental tissue in intrauterine growth restriction and healthy controls.

Pregnancy Hypertens 2012 Jul 13;2(3):248. Epub 2012 Jun 13.

Institute of Cell Biology, Histology, and Embryology, Medical Faculty, Graz, Austria.

Introduction: We recently demonstrated that maternal serum LDL- and fetal serum HDL-cholesterol concentration is significantly reduced in intrauterine growth restriction (IUGR) [1].

Objectives: We now hypothesized that increased oxidative stress in IUGR placenta leads to an accumulation of oxidized LDL (oxLDL) particles which then become trapped within the placenta subsequently leading to reduced availability of cholesterol for mother and fetus.

Methods: Fully oxidized LDL (oxLDL) was determined via immunohistochemistry in placental paraffin sections of 18 women suffering from IUGR and 18 gestational age matched controls. Ten 'High Power Fields' were chosen randomly by the newCAST software and oxLDL expression was estimated via standardized methods by two independent and blinded observers. Minimal oxidatively modified LDL (MM-LDL) and non-modified Apolipoprotein B (ApoB) concentration was measured in full placental tissue lysates by ELISA. Values were correlated with maternal and fetal total cholesterol, LDL-, and HDL-cholesterol concentrations. Statistical examinations were carried out by Student's t-test and calculation of Pearson's correlation coefficient.

Results: oxLDL was found predominantly to be in villous trophoblast and placental endothelium. OxLDL intensity tended to be increased in IUGR (Table 1). We found MM-LDL concentrations in whole placental tissue lysates to be highly correlated to placental ApoB concentration (r=0.93). Both parameters were non-significantly decreased in placenta of IUGR compared to controls (Table 1). Maternal serum LDL-C, and fetal serum LDL-C, TC, and HDL-C concentrations were significantly decreased in IUGR compared to controls (Table 2). OxLDL staining intensity was mildly negatively correlated to maternal LDL-C (r=-0.315) and much less to fetal HDL-C concentrations (r=-0.212). Placental ApoB and MM-LDL concentration were moderately positively correlated with fetal HDL-C concentrations (r=0.492 and r=0.447).

Conclusion: Conformational changes of the ApoB lipoprotein during the process of oxidation might lead to an accumulation of oxLDL particles in placental tissue of IUGR and reduced fetal cholesterol bioavailability as evidenced by a decrease in fetal serum cholesterol levels. However, our analysis lacks in sufficient power and further studies are underway focussing on that subject.
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July 2012