ABSTRACT
AIMS AND BACKGROUND: Hyperbilirubinemia is often observed in chronic hemolysis and results in the formation of pigment cholelithiasis that could be increased by the presence of defected enzymes involved in the bilirubin metabolism. Indeed, this is the first report that interested in the study of polymorphisms in genes encoded for enzymes involved in the bilirubin metabolism: rs 4149056 of SLCO1B1 and rs4149000 of SLCO1A2 in combination with rs8175347 and rs887829 of UGT1A1 in order to find a correlation between the polymorphisms studied and the presence of gallstones in a population of sickle cell anemia (SCA) pediatric Tunisians. MATERIAL AND METHODS: Our study involved 102 unrelated Tunisian subjects. All SCA patients are children (less than 16 years old) and were characterized by hyperbilirubinemia and 52 of them have cholelithiasis. The polymorphisms of the candidate genes were analyzed for all subjects by PCR/sequencing. Genotype and allele frequencies between cases and controls were compared using Pearson's chi-square test with a significance threshold of P < 0.05 (compare 2, version 1.02). RESULTS: The novelty of this report is that children carrying the combined genotype of the rs studied: (TA7TA7)/TT/TC/GA have a higher risk to develop gallstones (P = 0.0027, RR = 18.27 (20.0061-915.28)). CONCLUSION: Altogether our data provide the implication of UGT1A1 and SLCO1A2 in sickle cell anemia-related cholelithiasis.
Subject(s)
Anemia, Sickle Cell , Cholelithiasis , Glucuronosyltransferase/genetics , Liver-Specific Organic Anion Transporter 1/genetics , Organic Anion Transporters/genetics , Adolescent , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/genetics , Child , Cholelithiasis/etiology , Cholelithiasis/genetics , Female , Humans , Male , Risk Factors , TunisiaABSTRACT
Injury due to cold ischemia reperfusion (I/R) is a major cause of primary graft non-function following liver transplantation. We postulated that I/R-induced cellular damage during liver transplantation might affect the secretory pathway, particularly at the endoplasmic reticulum (ER). We examined the involvement of ER stress in organ preservation, and compared cold storage in University of Wisconsin (UW) solution and in Institute Georges Lopez-1 (IGL-1) solution. In one group of rats, livers were preserved in UW solution for 8 h at 4 °C, and then orthotopic liver transplantation was performed according to Kamada's cuff technique. In another group, livers were preserved in IGL-1 solution. The effect of each preservation solution on the induction of ER stress, hepatic injury, mitochondrial damage and cell death was evaluated. As expected, we found increased ER stress after liver transplantation. IGL-1 solution significantly attenuated ER damage by reducing the activation of three pathways of unfolded protein response and their effector molecules caspase-12, C/EBP homologous protein-10, X-box-binding protein 1, tumor necrosis factor-associated factor 2 and eukaryotic translation initiation factor 2. This attenuation of ER stress was associated with a reduction in hepatic injury and cell death. Our results show that IGL-1 solution may be a useful means to circumvent excessive ER stress reactions associated with liver transplantation, and may optimize graft quality.
Subject(s)
Liver Transplantation , Liver/metabolism , Organ Preservation Solutions/pharmacology , Organ Preservation/methods , Signal Transduction/drug effects , Adenosine/pharmacology , Allopurinol/pharmacology , Animals , Apoptosis/drug effects , Caspase 12/genetics , Caspase 12/metabolism , Cold Ischemia , Cold Temperature , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Endoplasmic Reticulum Stress/drug effects , Gene Expression/drug effects , Glutathione/pharmacology , Insulin/pharmacology , Liver/pathology , Male , Raffinose/pharmacology , Rats , Regulatory Factor X Transcription Factors , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Reperfusion Injury/prevention & control , Signal Transduction/genetics , TNF Receptor-Associated Factor 2/genetics , TNF Receptor-Associated Factor 2/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Unfolded Protein Response/drug effects , Unfolded Protein Response/geneticsABSTRACT
AIM: Static preservation solution is critical for liver graft outcomes, especially when steatosis is present. Institut Georges Lopez (IGL)-1 solution protects fatty livers effectively against cold ischemia reperfusion injury. Its benefits are mediated by nitric oxide and prevention of oxidative stress. The supplementation of IGL-1 with epidermal growth factor (EGF) enhances steatotic graft preservation by increasing adenosine triphosphate content, thereby mitigating oxidative stress and mitochondrial damage. METHODS: After steatotic livers were preserved for 24 hours in IGL-1 solution with or without EGF supplements, they were perfused ex vivo for 2 hours at 37°C. The benefits of EGF were assessed by evidences of hepatic damage and function--transaminases, bile production, and flow rate--as well as by other factors presumably associated with the poor tolerance of fatty livers toward cold ischemia-reperfusion injury (IRI)--energy metabolism, mitochondrial damage, oxidative stress, eNOS activity and proinflammatory interleukin (IL) beta content. RESULTS: Steatotic livers preserved in IGL-1 solutions supplemented with EGF (10 µg/L) showed lower transaminase levels, greater bile production, and ameliorated flow rates when compared to IGL-1 alone. In addition, energy metabolism deterioration, mitochondrial damage, oxidative stress, and cytokine IL-1 beta release were prevented. CONCLUSION: EGF addition to IGL-1 increased fatty liver graft preservation, thereby reducing steatotic liver damage against cold IRI.
