title: Depletion of mitochondrial DNA in the liver of an infant with neonatal giant cell hepatitis.
abstract: A boy presented with lactic acidosis, hepatomegaly, hypoglycemia, generalised icterus, and muscle hypotonia in the first weeks of life. At the age of 2 months, neonatal giant cell hepatitis was diagnosed by light microscopy. Electron microscopy of the liver revealed an accumulation of abnormal mitochondria and steatosis. Skeletal muscle was normal on both light and electron microscopy. At the age of 5 months, the patient died of liver failure. Biochemical studies of the respiratory chain enzymes in muscle showed that cytochrome-c oxidase (complex IV) and succinate-cytochrome-c oxidoreductase (complex II + III) activities were (just) below the control range. When related to citrate synthase activity, however, complex IV and complex II + III activities were normal. Complex I activity was within the control range. The content of mitochondrial DNA (mtDNA) was severely reduced in the liver (17% to 18% of control values). Ultracytochemistry and immunocytochemistry of cytochrome-c oxidase demonstrated a mosaic pattern of normal and defective liver cells. In defective cells, a reduced amount of the mtDNA-encoded subunits II-III and the nuclear DNA-encoded subunits Vab was found. Cells of the biliary system were spared. Immunohistochemistry of mtDNA replication factors revealed normal expression of DNA polymerase gamma. The mitochondrial single-stranded binding protein (mtSSB) was absent in some abnormal hepatocytes, whereas the mitochondrial transcription factor A (mtTFA) was deficient in all abnormal hepatocytes. In conclusion, depletion of mtDNA may present as giant cell hepatitis. mtTFA and to a lesser degree mtSSB are reduced in mtDNA depletion of the liver and may, therefore, be of pathogenetic importance. The primary defect, however, is still unknown.
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-Universität München, München, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Müller-Höcker
authors.forename: Aria
authors.initials: A
authors.lastname: Muntau
authors.forename: S
authors.initials: S
authors.lastname: Schäfer
authors.forename: Michaela
authors.initials: M
authors.lastname: Jaksch
authors.forename: Franz
authors.initials: F
authors.lastname: Staudt
authors.forename: Dieter
authors.initials: D
authors.lastname: Pongratz
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
mesh_terms: D002950:Citrate (si)-Synthase / Q000032:analysis; D004272:DNA, Mitochondrial / Q000032:analysis*; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000032:analysis; D003576:Electron Transport Complex IV / Q000032:analysis; D017809:Fatal Outcome; D015726:Giant Cells / Q000473:pathology*; D006505:Hepatitis / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008099:Liver / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000473:pathology; D009097:Multienzyme Complexes / Q000032:analysis; D018482:Muscle, Skeletal / Q000201:enzymology; D010088:Oxidoreductases / Q000032:analysis; D013385:Succinate Dehydrogenase / Q000032:analysis
chemical_list: D004272:DNA, Mitochondrial; D009097:Multienzyme Complexes; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D014450:Electron Transport Complex III