Hypercholesterolemia During Pregnancy is Caused by Increased Endogenous Cholesterol Synthesis: Let's Use it for Screening of Familial Hypercholesterolemias Too!

Abstract: Aims: To demonstrate the origin and the diagnostic significance of non-cholesterol sterols (NCSs) in healthy pregnant women with gestational hypercholesterolemia. Patients and Methods: Based on a total of 21,000 clinical biochemistry tests of healthy pregnant women with hypercholesterolemia observed during pregnancy, a group of 84 women with TC (total cholesterol) >7.0 mmol/L was recruited to analyze their NCSs using Gas Chromatography–Mass Spectrometry. The NCSs under examination comprised lathosterol (Lat) and desmosterol (Des) as markers of endogenous cholesterol synthesis, and campesterol (Cam) and sitosterol (Sit) as markers for intestinal absorption. Results: In the total of 21,000 pregnant women, the median values were: TC 6.8 mol/l, LDL-C 4.6 mmol/L, and HDL-C 2.2 mmol/L. In the testing group of 84 women, the average values were: Lat 7.8+/-1.7 μmol/L, Des 4.7+/-0.9 μmol/L, Cam 9.8+/-2.6 μmol/L, and Sit 9.6 +/-3.8 μmol/L. Lat was found to correlate with TC (r = 0.53), LDL-C (r = 0.36), and non-HDL-C (r = 0.35). No such correlations were observed for Sit (r = 0.162) or Cam (r = 0.153). Conclusion: Our findings show that the high incidence of hypercholesterolemia during pregnancy is caused by increased endogenous cholesterol synthesis via lathosterol. The enormous rise of TC levels during pregnancy can be effectively used to detect familial hypercholesterolemia in women

Hepatic Gene Expression Profiles Differentiate Steatotic and Non-steatotic Grafts in Liver Transplant Recipients

Background: Liver transplantation leads to non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in up to 40% of graft recipients. The aim of our study was to assess transcriptomic profiles of liver grafts and to contrast the hepatic gene expression between the patients after transplantation with vs. without graft steatosis.Methods: Total RNA was isolated from liver graft biopsies of 91 recipients. Clinical characteristics were compared between steatotic (n = 48) and control (n = 43) samples. Their transcriptomic profiles were assessed using Affymetrix HuGene 2.1 ST Array Strips processed in Affymetrix GeneAtlas. Data were analyzed using Partek Genomics Suite 6.6 and Ingenuity Pathway Analysis.Results: The individuals with hepatic steatosis showed higher indices of obesity including weight, waist circumference or BMI but the two groups were comparable in measures of insulin sensitivity and cholesterol concentrations. We have identified 747 transcripts (326 upregulated and 421 downregulated in steatotic samples compared to controls) significantly differentially expressed between grafts with vs. those without steatosis. Among the most downregulated genes in steatotic samples were P4HA1, IGF1, or fetuin B while the most upregulated were PLIN1 and ME1. Most influential upstream regulators included HNF1A, RXRA, and FXR. The metabolic pathways dysregulated in steatotic liver grafts comprised blood coagulation, bile acid synthesis and transport, cell redox homeostasis, lipid and cholesterol metabolism, epithelial adherence junction signaling, amino acid metabolism, AMPK and glucagon signaling, transmethylation reactions, and inflammation-related pathways. The derived mechanistic network underlying major transcriptome differences between steatotic samples and controls featured PPARA and SERPINE1 as main nodes.Conclusions: While there is a certain overlap between the results of the current study and published transcriptomic profiles of non-transplanted livers with steatosis, we have identified discrete characteristics of the non-alcoholic fatty liver disease in liver grafts potentially utilizable for the establishment of predictive signature

Evaluation of IFN-γ Enzyme-linked Immunospot Assay (ELISPOT) as a First-line Test in the Diagnosis of Non-immediate Hypersensitivity to Amoxicillin and Penicillin

The current diagnostic algorithm for beta-lactam allergy is based on skin and provocation tests, both of which carry a certain risk of inducing hypersensitivity reactions. Thus, non-invasive in vitro tests reliable enough to replace skin and provocation tests at least in a portion of patients are desirable. We aimed to verify the utility of IFN-γ ELISPOT as a first-line test in patients with suspected non-immediate hypersensitivity reaction to amoxicillin (AMX) and penicillin (PNC). The prospective observational study included 24 patients with recent, suspected non-immediate hypersensitivity reaction to AMX or PNC and 6 recently-exposed healthy subjects. In vitro tests were performed in all patients and healthy subjects: a) IFN-γ ELISPOT with PNC, AMX and amoxicillin plus clavulanic acid (AMX-CL); b) penicillin specific IgE; c) basophil activation test (BAT). Skin and provocation tests followed only in certain patients. IFN-γ ELISPOT results with PNC and AMX stimulation did not differ from the unstimulated condition. The highest IFN-γ responses to AMX-CL were close to previously published criteria in three patients; one of which had true hypersensitivity according to drug provocation tests. Five patients with confirmed hypersensitivity by skin tests showed no response to the culprit antibiotic on IFN-γ ELISPOT assay. Our results did not support the utility of IFN-γ ELISPOT in the diagnosis of mild, non-immediate hypersensitivity to amoxicillin and penicillin

Hypercholesterolemia During Pregnancy is Caused by Increased Endogenous Cholesterol Synthesis: Let’s Use it for Screening of Familial Hypercholesterolemias Too!

Aims: To demonstrate the origin and the diagnostic significance of non-cholesterol sterols (NCSs) in healthy pregnant women with gestational hypercholesterolemia. Patients and Methods: Based on a total of 21,000 clinical biochemistry tests of healthy pregnant women with hypercholesterolemia observed during pregnancy, a group of 84 women with TC (total cholesterol) >7.0 mmol/L was recruited to analyze their NCSs using Gas Chromatography–Mass Spectrometry. The NCSs under examination comprised lathosterol (Lat) and desmosterol (Des) as markers of endogenous cholesterol synthesis, and campesterol (Cam) and sitosterol (Sit) as markers for intestinal absorption. Results: In the total of 21,000 pregnant women, the median values were: TC 6.8 mol/l, LDL-C 4.6 mmol/L, and HDL-C 2.2 mmol/L. In the testing group of 84 women, the average values were: Lat 7.8+/-1.7 μmol/L, Des 4.7+/-0.9 μmol/L, Cam 9.8+/-2.6 μmol/L, and Sit 9.6 +/-3.8 μmol/L. Lat was found to correlate with TC (r = 0.53), LDL-C (r = 0.36), and non-HDL-C (r = 0.35). No such correlations were observed for Sit (r = 0.162) or Cam (r = 0.153). Conclusion: Our findings show that the high incidence of hypercholesterolemia during pregnancy is caused by increased endogenous cholesterol synthesis via lathosterol. The enormous rise of TC levels during pregnancy can be effectively used to detect familial hypercholesterolemia in women

Gestational hypercholesterolemia helps detect familial hypercholesterolemia and prevent late pregnancy complications

Introduction: In this retrospective study, we comment on the cause and diagnostic potential of the elevated serum total cholesterol and some non-cholesterol sterols in a population of healthy pregnant women from Prague, Czech Republic. Methods: Based on a total of 21,000 clinical biochemistry tests of healthy pregnant women with hypercholesterolemia observed during pregnancy, a testing group of 84 women with a total cholesterol (TC) above 7.0 mmol/l was established to analyze their non-cholesterol sterols (NCS) by Gas Chromatography–Mass Spectrometry. Lathosterol (Lat) and desmosterol (Des) were evaluated as markers of endogenous cholesterol synthesis, whereas campesterol (Cam) and sitosterol (Sit) were analysed as markers of intestinal absorption. Results: In the basic population, the frequency of gestational hypercholesterolemia with the serum TC levels > 7.0mmol/l was 1 to 136.The mean values were: TC 6.8 mmol/l, LDL-C 4.6 mmol/l, and HDL-C 2.2 mmol/l. In the selected testing group of 84, the mean values were: Lat 7.8+/-1.7 μmol/l, Des 4.7+/-0.9 μmol/l, Cam 9.8+/-2.6 μmol/l, and Sit 9.6+/-3.8 μmol/l. Lat correlated with TC (r = 0.53), LDL-C (r = 0.36), and non-HDL-C (r = 0.35). No such correlations were observed for Cam or Sit. Conclusion: Our findings prove that gestational hypercholesterolemia is caused by increased endogenous cholesterol synthesis via lathosterol. Subsequently, we demonstrate how a single cholesterol test taken in the fifth to sixth month gestation can efficiently help detect familial hypercholesterolemia, and prevent related late pregnancy circulatory complications