Hepatocellular ubiquitin expression in alpha1-antitrypsin deficiency.

Studies of the ubiquitin-proteasome system in alpha1-antitrypsin (AAT) deficiency have been performed using only biochemical and molecular biology techniques on human cells as well as on AAT-deficient transduced cell lines. The objective of our study was to assess the immunohistochemical and topographic features of ubiquitin in the livers of AAT-deficient children with and without active liver disease. Fourteen cases of AAT deficiency were retrieved from our archives, along with 10 control liver specimens obtained from autopsies of age-matched children with no clinical, gross anatomic, or histologic evidence of liver disease. Twelve of 14 cases of AAT deficiency were cirrhotic explanted livers from transplantations procedures. Two cases were noncirrhotic liver biopsies from asymptomatic patients. Periodic acid-Schiff (PAS) histochemistry and AAT immunostains were performed on all AAT-deficient liver specimens to verify the diagnosis. Immunohistochemistry with polyclonal ubiquitin antibodies was performed on all specimens. Ubiquitin immunoreactivity was present in all AAT livers while control livers were consistently negative or weakly reactive. In cirrhotic livers, ubiquitin immunoreactivity was strongest in the cytoplasm whereas the characteristic PAS-positive, diastase-resistant cytoplasmic granules appeared nonreactive. However, not all cirrhotic livers showed this pattern. Some were only focally positive (<5% of hepatocytes). In asymptomatic patients, ubiquitin staining was diffuse and moderate to prominent, and evenly distributed within individual hepatocytes and lobules. We therefore conclude that the ubiquitin-proteasome pathway is operative in the hepatocytes of AAT-deficient livers, as illustrated by the study of ubiquitin immunoreactivity. However, some AAT-deficient livers are only focally immunoreactive for ubiquitin. This may indicate an intrinsic defect of the ubiquitin-proteasome system in some patients.