Browsing by Subject "Hepatic"

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    Micro-RNA regulation of hepatic drug metabolism : age-related changes in micro-RNA expression and genetic variants in micro-RNA target sites
    (2017-08-31) Burgess, Kimberly Sherrelle; Skaar, Todd C.; Arrizabalaga, Gustavo; Cummins, Theodore; Desta, Zeruesenay; Nass, Richard; Zhang, Jian-Tian
    Developmental changes in the liver significantly impact drug disposition. Due to the emergence of microRNAs as important regulators of drug disposition, we hypothesize that age-dependent change in microRNA expression and genetic variants in microRNA target sites contribute to variability in drug disposition. In human liver tissues, expression of 533 microRNAs and over 14,000 genes were measured. In all, 114 microRNAs were upregulated and 72 downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among these microRNAs, 99 microRNA-mRNA interactions were predicted or have previously been validated to target drug disposition genes and over 1,000 significant negative correlations were observed between miRNA-mRNA pairs. We validated these interactions using various cell culture models. Genetic variants in the promoter and coding regions of drug disposition genes have also been shown to alter enzyme expression and/or activity. However, these variants do not account for all variability in enzyme activity. Emerging evidence has shown that variants in the 3’UTR may explain variable drug response by altering microRNA regulation. Five 3’UTR variants were associated with significantly altered CYP2B6 activity in healthy human volunteers. The rs70950385 (AG>CA) variant was associated with decreased CYP2B6 activity among normal metabolizers. In vitro luciferase assays confirmed that the CA allele altered miR 1275 targeting of CYP2B6 mRNA. Due to the large number of 3’UTR variants predicted to alter microRNA regulation, a high-throughput method, PASSPORT-seq, was developed to test over 100 3’UTR variants simultaneously in different cell lines. Thirty-eight variants resulted in FDR-significant altered expression between wild-type and variant sequences. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, support a role for these age dependent microRNAs in regulating drug disposition, and provide strong evidence that 3’UTR variants are also an important source of variability in drug disposition.
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    New-onset and relapsed liver diseases following COVID-19 vaccination: a systematic review
    (BMC, 2022-10-13) Alhumaid, Saad; Al Mutair, Abbas; Rabaan, Ali A.; ALShakhs, Fatemah M.; Choudhary, Om Prakash; Yong, Shin Jie; Nainu, Firzan; Khan, Amjad; Muhammad, Javed; Alhelal, Fadil; Al Khamees, Mohammed Hussain; Alsouaib, Hussain Ahmed; Al Majhad, Ahmed Salman; Al-Tarfi, Hassan Redha; ALyasin, Ali Hussain; Alatiyyah, Yaqoub Yousef; Alsultan, Ali Ahmed; Alessa, Mohammed Essa; Alessa, Mustafa Essa; Alissa, Mohammed Ahmed; Alsayegh, Emad Hassan; Alshakhs, Hassan N.; Al Samaeel, Haidar Abdullah; AlShayeb, Rugayah Ahmed; Alnami, Dalal Ahmed; Alhassan, Hussain Ali; Alabdullah, Abdulaziz Abdullah; Alhmed, Ayat Hussain; AlDera, Faisal Hussain; Hajissa, Khalid; Al-Tawfiq, Jaffar A.; Al-Omari, Awad; Medicine, School of Medicine
    Background: Liver diseases post-COVID-19 vaccination is extremely rare but can occur. A growing body of evidence has indicated that portal vein thrombosis, autoimmune hepatitis, raised liver enzymes and liver injuries, etc., may be potential consequence of COVID-19 vaccines. Objectives: To describe the results of a systematic review for new-onset and relapsed liver disease following COVID-19 vaccination. Methods: For this systematic review, we searched Proquest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses PRISMA guideline for studies on the incidence of new onset or relapsed liver diseases post-COVID-19 vaccination, published from December 1, 2020 to July 31, 2022, with English language restriction. Results: Two hundred seventy-five cases from one hundred and eighteen articles were included in the qualitative synthesis of this systematic review. Autoimmune hepatitis (138 cases) was the most frequent pathology observed post-COVID-19 vaccination, followed by portal vein thrombosis (52 cases), raised liver enzymes (26 cases) and liver injury (21 cases). Other cases include splanchnic vein thrombosis, acute cellular rejection of the liver, jaundice, hepatomegaly, acute hepatic failure and hepatic porphyria. Mortality was reported in any of the included cases for acute hepatic failure (n = 4, 50%), portal vein thrombosis (n = 25, 48.1%), splanchnic vein thrombosis (n = 6, 42.8%), jaundice (n = 1, 12.5%), raised liver enzymes (n = 2, 7.7%), and autoimmune hepatitis (n = 3, 2.2%). Most patients were easily treated without any serious complications, recovered and did not require long-term hepatic therapy. Conclusion: Reported evidence of liver diseases post-COIVD-19 vaccination should not discourage vaccination against this worldwide pandemic. The number of reported cases is relatively very small in relation to the hundreds of millions of vaccinations that have occurred and the protective benefits offered by COVID-19 vaccination far outweigh the risks.