scholarly journals A patient with epilepsy suffering from repeatedly hyperbilirubinemia caused by Gilbert Syndrome: a case report and literatures review

2019 ◽  
Author(s):  
Yao-yao Zhang ◽  
Yong-li Jiang ◽  
Chang-geng Song ◽  
Zhi-han Zhao ◽  
Fang Yuan ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Liver Biopsy ◽  
Indirect Bilirubin ◽  
Gilbert Syndrome ◽  
Hepatic Diseases ◽  
Whole Exome ◽  
Elevated Bilirubin ◽  
Generalized Epilepsy ◽  
Toxic Drugs ◽  
Dose Dependent

Abstract Background: Certain antiepileptic drugs (AEDs) such as valproic acid (VPA) and lamotrigine (LTG) would bring some abnormalities on liver function, ranging from mild malfunction of liver tests to serious hepatotoxicity. The former manifests temporary and reversible elevation of bilirubin and liver enzyme, which is usually dose-dependent and the abnormality can return to normal shortly after the drug was withdrawn. Levetiracetam (LEV), as a newly broad-spectrum AED with relatively fewer side-effects and fewer drug interactions, is increasingly used as adjunctive therapy to treat generalized epilepsy. Gilbert syndrome（GS）is characterized by mild, chronic, intermittent unconjugated hyperbilirubinemia without other hepatic diseases. Fasting, stress, along with some liver toxic drugs would make it clinically apparent. However, when GS co-exists with epilepsy, how to differentiate which one is responsible for the abnormality of bilirubin poses a challenge to us. We herein describes a patient with epilepsy complicated by mildly and intermittently elevated bilirubin, and after various examinations especially for whole-exome sequencing（WES）and liver biopsy, we made a definite diagnosis of GS. Case presentation: A 25-year-old male with epilepsy suffering from intermittently and mildly elevated bilirubin, and relevant imaging information led us consider the diagnosis of idiopathic generalized epilepsy (IGE). After administration of AEDs, the indirect bilirubin remained still slightly elevated even while taking LEV. Then he was referred to the department of gastroenterology in our hospital, the results of diagnostic tests, clinical manifestation, imaging studies, WES and liver biopsy all made contributions to our diagnosis of GS rather than the hepatic injury induced by AEDs. Conclusions: This report presents us with a case of an epilepsy patient complicated by repeatedly elevated bilirubin and finally was diagnosed with GS. By referring to literatures and genetic testing, though, no shared genetic and pathophysiological basis between epilepsy and GS was found, and enzymes responsible for the metabolism of AEDs took no part in the pathogenesis of GS. Our experiences will help clinicians to better differentiate the etiology of repeatedly elevated bilirubin of epilepsy patients during the process of treatment. Key words: Epilepsy, Gilbert syndrome, Valproic acid, Lamotrigine, Levetiracetam, hyperbilirubinemia.

scholarly journals An Epileptic Patient with Recurrent Hyperbilirubinemia Caused by Gilbert Syndrome

2020 ◽  
Vol 14 (1) ◽  
pp. 39-47
Author(s):  
Yaoyao Zhang ◽  
Yongli Jiang ◽  
Fang Yuan ◽  
Changgeng Song ◽  
Zhihan Zhao ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Liver Function ◽  
Liver Biopsy ◽  
Diagnostic Tests ◽  
Epileptic Patient ◽  
Liver Function Tests ◽  
Imaging Studies ◽  
Indirect Bilirubin ◽  
Gilbert Syndrome ◽  
Whole Exome

Gilbert syndrome (GS) is characterized by intermittent indirect bilirubin elevation. Several antiepileptic drugs (AEDs) impair the liver function to different degrees, such as valproic acid, lamotrigine, phenobarbital, phenytoin, and carbamazepine. Herein, we present the case of a 26-year-old epileptic patient with frequently recurring mild hyperbilirubinemia during taking AEDs. After repeated adjustment of the doses and types of AEDs, the bilirubin level still remained elevated. He was then referred to the Gastroenterology Department. The results of diagnostic tests, clinical manifestation, imaging studies, liver biopsy and whole-exome sequencing all made contributions to our conclusion that GS played an important role in the elevation of bilirubin. Ultimately, his seizure was controlled by levetiracetam (500 mg per day) and he was advised to periodically undergo the liver function tests.

scholarly journals Clinical case of combined genetic pathology in a patient

2020 ◽  
Vol 92 (12) ◽  
pp. 180-184
Author(s):  
E. A. Losik ◽  
I. I. Yakushina ◽  
M. R. Skhirtladze ◽  
N. P. Balahonova ◽  
V. V. Kerchev ◽  
...  
Keyword(s):  
Clinical Case ◽  
Blood Lipid ◽  
Protective Role ◽  
Alcoholic Beverages ◽  
Atherosclerosis Progression ◽  
Indirect Bilirubin ◽  
Gilbert Syndrome ◽  
Elevated Bilirubin ◽  
Genetic Combination ◽  
Wrist Flexors

Family hypercholesterolemia (HSX) is a form of genetically deterministic increase in blood lipid levels associated with a high risk of cardiovascular disease, usually at a young age. HSX is a common genetic disease found in the general population in most countries in 1:500 people. Clinically xantomas are found in achilles tendor and wrist flexors, lipoid arc of the cornea, concentration of total cholesterol and low-density lipoproteins is 4.911.6 mmol/l. Gilberts syndrome is a hereditary benign hyperbilirubinium, associated with a decrease in the functional activity of the liver enzyme uridinfosfat-glucuronosil transferase. Clinically, this syndrome appers in intermittent jaundice, which is provoked by physical activity, consumption of alcoholic beverages, insulation and an increase in the level of indirect bilirubin within 20100 micromol/ml. The article presents a rare clinical case of genetic combination of HSC SSC and Gilbert syndrome a young patient has and discusses the elevated bilirubin levels protective role in the atherosclerosis progression in Gilbert syndrome.

Biallelic Mutations in Ubiquitin-Specific Peptidase 53 (USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature

2021 ◽  
pp. 109352662110511
Author(s):  
Mukul Vij ◽  
Srinivas Sankaranarayanan
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Liver Biopsy ◽  
Intrahepatic Cholestasis ◽  
Cholestatic Liver Disease ◽  
Review Of Literature ◽  
Biallelic Mutation ◽  
Whole Exome ◽  
Sequencing Studies ◽  
Biallelic Mutations

Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 ( USP53). We identified novel biallelic mutations in the USP53 gene in a 7-month-old infant with pruritus and progressive intrahepatic cholestasis. His liver biopsy showed portal and perivenular fibrosis with bland bilirubinostasis. His parents were asymptomatic heterozygous for the same mutation. He is currently on vitamin supplements and cholestyramine and his family has also been counseled for liver transplantation. Our report confirms that patients with biallelic mutation in USP53 develop cholestatic liver disease.

Dose-dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high-dose valproic acid in rats

2010 ◽  
Vol 30 (8) ◽  
pp. 775-778 ◽  
Author(s):  
Byung Hwa Jung ◽  
Bo Jun Kim ◽  
Min Sun Lee ◽  
Joo Hyun Lee ◽  
Ju-Hee Oh ◽  
...  
Keyword(s):  
Valproic Acid ◽  
High Dose ◽  
Toxic Metabolites ◽  
Dose Dependent

scholarly journals Valproic acid-associated pancytopenia: A dose-dependent adverse effect

2019 ◽  
Vol 18 (3) ◽  
pp. 150-153
Author(s):  
Jamir Pitton Rissardo ◽  
◽  
Ana Letícia Fornari Caprara ◽  
Juliana Oliveira Freitas Silveira ◽  
◽  
...  
Keyword(s):  
Adverse Effect ◽  
Valproic Acid ◽  
Dose Dependent

Association of SLC32A1 Missense Variants With Genetic Epilepsy With Febrile Seizures Plus

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011855
Author(s):  
Sarah E. Heron ◽  
Brigid M. Regan ◽  
Rebekah V. Harris ◽  
Alison E. Gardner ◽  
Matthew J. Coleman ◽  
...  
Keyword(s):  
Febrile Seizures ◽  
Sequencing Data ◽  
Causative Gene ◽  
Gaba Transport ◽  
Missense Variants ◽  
Genetic Epilepsy ◽  
Neuronal Inhibition ◽  
Whole Exome ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

ObjectiveTo identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients.MethodsWe performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing (ES) data from 1,165 epilepsy patients from the Epi4K dataset and 1,329 Australian epilepsy patients from the Epi25 dataset was interrogated. Targeted resequencing was performed on 278 patients with FS or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing.ResultsEight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid co-transporter VGAT. Two variants co-segregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE).ConclusionMissense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter GABA transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with SLC32A1 variants.

Valproic Acid Inihibts Histone Deacetylases and Proliferation and Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5165-5165
Author(s):  
Martin Kaiser ◽  
Ulrike Heider ◽  
Ivana Zavrski ◽  
Jan Sterz ◽  
Kurt Possinger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Valproic Acid ◽  
Cell Lines ◽  
Myeloma Cell ◽  
G1 Phase ◽  
Dependent Manner ◽  
Myeloma Cells ◽  
Cycle Arrest ◽  
Dose Dependent

Abstract Multiple myeloma remains an incurable disease in the majority of the patients and novel treatment strategies are urgently needed. A new class of drugs, the histone deacetylase (HDAC) inhibitors take influence in epigenetic modifications and have antiproliferative effects in some malignancies. Valproic acid (VPA) is an anticonvulsant drug and was recently shown to inhibit HDACs and suppress tumor growth. The drug is currently being evaluated in clinical studies in acute myeloid leukemia. Its effects on myeloma cells are unknown. The aim of this study was to evaluate the effects of VPA on proliferation, apoptosis and HDAC inhibition in multiple myeloma cell lines as well as in sorted human bone marrow multiple myeloma cells. Myeloma cell lines, OPM-2, NCI-H929, LP-1, and freshly isolated multiple myeloma cells from bone marrow aspirates were exposed to different concentrations of VPA for 4 to 72 hours. Cell proliferation, cell cycle distribution and apoptosis were assayed in reaction to the treatment. Proliferation decreased noticeably and apoptosis was induced in a dose-dependent manner in multiple myeloma cell lines as well as in freshly sorted primary myeloma cells. After 48 hours of incubation with VPA at 1 mM, approximately 46%, 52% and 25% of OPM-2, NCI-H929 and LP-1 cell lines had undergone specific apoptosis, respectively. Freshly sorted primary bone marrow myeloma cells from patients showed also specific apoptosis. In cell cycle analysis by flow cytometry, the population of cells in the G0/G1 phase increased, whereas cells in the S phase decreased in a time and dose dependent manner. Incubation of the cell line OPM-2, for example, with 1 mM VPA for 48 hours decreased the proportion of cells in the S phase from 39 % to 6 % of the total cell count and increased cells in the G0/G1 phase from 49 % to 85 %. Acetylation of histones and expression of cyclin D1 and the cell cycle regulators p21 and p27 were studied by western blot. Histone acetylation and p21 concentrations increased after VPA treatment whereas levels of p27 remained constant. A decrease in cyclin D1 concentrations was observed. Subapoptotic doses of VPA significantly decreased the production of VEGF in OPM-2 cell line. These data show that treatment with valproic acid effectively inhibits histone deacetylase activity, leading to the accumulation of acetylated histones in multiple myeloma cells. Parallel upregulation of cell cycle inhibitors like p21WAF1 was observed, together with a reduction of cyclin D1 levels. Myeloma cell proliferation was inhibited in a time and dose dependent manner and cell cycle arrest in the G0/G1 phase was induced by VPA treatment. VPA potently induced apoptosis in all human myeloma cell lines as well as in sorted primary multiple myeloma cells in a dose and time dependent manner. These results show for the first time that VPA acts as an HDAC inhibitor in multiple myeloma cells, induces G1 cell cycle arrest, potently inhibits tumor growth and markedly induces apoptosis. In addition to its direct antitumor effect, valproic acid may exert an antiangiogenic effect by reducing VEGF production in myeloma cells. These data provide the framework for clinical studies with valproic acid in multiple myeloma.

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