title: Isoform-specific alanine aminotransferase measurement can distinguish             hepatic from extrahepatic injury in humans.
abstract: Serum alanine aminotransferase (ALT) is used as a clinical marker to detect hepatic damage and hepatoxicity. Two isoforms of ALT have been identified, ALT1 and ALT2, which have identical enzymatic capacities and are detected simultaneously in human serum/plasma using classical clinical chemical assays. Differences exist in the expression patterns of the ALT1 and ALT2 proteins in different organs which suggest that changes in the proportion of ALT1 and ALT2 in plasma may arise and reflect damage to different human organs. However, this has not been previously studied due to the lack of a selective methodology that can quantify both ALT1 and ALT2 isoforms in the total ALT activity normally measured in clinical samples. To the best of our knowledge, our current study reveals for the first time, that under 3 different conditions of liver damage (non-alcoholic fatty liver disease, hepatitis C and during liver surgery) the leakage of ALT1 activity into plasma greatly exceeds that of ALT2, and that the measurement of ALT1 during liver damage is equal to the measurement of total ALT activity. By contrast, during skeletal muscle injury, induced in volunteers by physical exertion, the leakage of ALT2 exceeds that of ALT1 and the proportion of circulating ALT isoforms changes accordingly. The ALT isoform changes occurring in plasma reflect previously demonstrated relative contents of ALT1 and ALT2 activities in human liver and skeletal muscle. These data suggest that assessing the percentage contribution of ALT1 and ALT2 activities to total ALT activity in plasma may distinguish hepatic from extrahepatic injury using the same standard analytical platform.
authors.affiliation: Safety Assessment, AstraZeneca, Södertälje, Sweden.
authors.forename: Ingalill
authors.initials: I
authors.lastname: Rafter
authors.forename: Truls
authors.initials: T
authors.lastname: Gråberg
authors.forename: Anna
authors.initials: A
authors.lastname: Kotronen
authors.forename: Lovisa
authors.initials: L
authors.lastname: Strömmer
authors.forename: C Mikael
authors.initials: CM
authors.lastname: Mattson
authors.forename: Ray W
authors.initials: RW
authors.lastname: Kim
authors.forename: Ewa
authors.initials: E
authors.lastname: Ehrenborg
authors.forename: Håkan B
authors.initials: HB
authors.lastname: Andersson
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
authors.forename: Björn
authors.initials: B
authors.lastname: Ekblom
authors.forename: Ian
authors.initials: I
authors.lastname: Cotgreave
authors.forename: Björn
authors.initials: B
authors.lastname: Glinghammar
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D005234:Fatty Liver / Q000097:blood* / Q000473:pathology; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D008113:Liver Neoplasms / Q000097:blood / Q000601:surgery; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D005082:Physical Exertion; D020033:Protein Isoforms / Q000097:blood; D055815:Young Adult
chemical_list: D015415:Biomarkers; D020033:Protein Isoforms; D000410:Alanine Transaminase