bromochloroacetic-acid and Liver-Failure

Graft dysfunction mimicking autoimmune hepatitis rarely develops after liver transplantation for nonautoimmune disease. The mechanism(s) and causes of de novo autoimmune hepatitis are unknown. We examined autoantibodies serially in a patient with de novo autoimmune hepatitis and in patients without de novo autoimmune hepatitis after liver transplantation. Anticytokeratin 8/18 antibodies were detected in the first patient's sera after the onset of de novo autoimmune hepatitis, whereas other patients without de novo autoimmune hepatitis were seronegative throughout the follow-up period even with acute cellular rejection or other cause of liver dysfunction. In conclusion, the changes in cytokeratin 8/18 in hepatocytes might be one of the sources of pathogenesis of de novo autoimmune hepatitis after liver transplantation.

Topics: Adolescent; Adult; Autoantibodies; Child; Child, Preschool; Female; Follow-Up Studies; Hepatitis, Autoimmune; Hepatocytes; Humans; Keratins; Liver Failure; Liver Transplantation; Living Donors; Male; Postoperative Complications

Keratins 8 and 18 protect the liver from stress. Keratin 8 and 18 variants in 17 of 467 liver disease explants and 2 of 349 blood bank controls were previously reported in 5 analyzed exonic regions. We asked whether mutations were present in the remaining 10 exons of keratins 8 and 18.. Exonic regions were polymerase chain reaction-amplified from genomic DNA, isolated from the above-mentioned 2 cohorts, and analyzed for the presence of mutations. Mutant keratins were also studied biochemically.. We identified 10 novel keratin 8 and 18 heterozygous variants in 44 of 467 explants and 11 of 349 controls: keratin 18 deletion (delta64-71), a keratin 8 frameshift that truncates the last 14 amino acids; 8 missense keratin 8 and 18 alterations; and several new polymorphisms. The most common variant, keratin 8 R340H, at the highly conserved R340 was found in 30 of 467 explants and 10 of 349 controls (P = .02) and was confirmed in the diseased livers by generation of an R340H-specific antibody. Germline transmission and variant protein expression were verified. The mutations involved a variety of liver diseases, and some variants had an ethnic background preponderance. Mutations that introduced disulfide bonds (keratin 8 G61C or R453C) decreased keratin solubility, particularly after oxidative stress, whereas others decreased keratin 8 phosphorylation (keratin 8 G433S).. The overall frequency of keratin 8 and 18 variants was 12.4% in 467 liver disease explants and 3.7% in 349 blood bank controls (P < .0001). Variants can alter keratin solubility or phosphorylation and may render individuals susceptible to end-stage liver disease, depending on their genetic background and exposure to other insults, such as alcohol or viral infection.

Topics: Female; Genetic Carrier Screening; Genetic Predisposition to Disease; Genetic Variation; Humans; Keratin-18; Keratin-8; Keratins; Liver Failure; Male; Mutation; Polymorphism, Single Nucleotide; Sequence Deletion

Topics: Amino Acid Substitution; Biomarkers; fas Receptor; Hepatitis, Chronic; Humans; Keratin-8; Keratins; Liver Failure; Liver Transplantation; Mutation, Missense