Homozygous Z (PiZZ) alpha-1 antitrypsin deficiency (AATD), which is characterized by intrahepatic α1-antitrypsin (AAT) polymerization, is a risk factor for the development of liver disease among children, according to findings from a retrospective cohort study conducted in Sweden and published in the International Journal of Molecular Sciences.

Recognizing that the majority of children with PiZZ AATD are disease free and that this mutation alone is not sufficient to cause hepatic disease, the researchers sought to explore Z-ATT polymers and the expression of fibrosis-related genes in liver tissue from children with PiZZ deficiency in whom different clinical courses have been reported.

Individuals with the PiZZ genotype have severe deficiency (approximately 90%) in circulating AAT protein because of aberrant folding of the Z-AAT causing intracellular and extracellular polymerization. Clinical manifestations of PiZZ AATD include hepatic and pulmonary diseases, and, less often, dermatologic disorders. Because the liver is the main producer of AAT protein (between 80% and 90% of human AAT), hepatocytes can accumulate a large number of Z-AAT aggregates.

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Liver biopsies obtained between 1979 and 2010 in the Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden, underwent histologic reassessment, immunohistochemistry, and NanoString-based transcriptome profiling with the use of a panel of 760 fibrosis plus 8 bile acid–related genes.

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Formalin-fixed and paraffin-embedded (FFPE) liver biopsy samples were collected from children with PiZZ AATD with similar sex and age distribution, but varying clinical presentations. Study participants were divided into 3 groups, based on clinical outcomes: (1) children with neonatal cholestasis who recovered and remained healthy (n=5); (2) children who developed cholestasis and hepatic failure and underwent liver transplantation (n=4); and (3) children with no neonatal cholestasis who remained healthy (n=5).

Hepatocytes that contained Z-AAT polymers were plentiful in all groups; however, the group which developed cholestasis and hepatic failure, and underwent liver transplantation exhibited a higher expression of genes associated with liver fibrosis/cirrhosis, along with a lower expression of genes associated with lipid, aldehyde/ketone, and bile acid metabolism.

“Z-AAT accumulation per se cannot explain the clinical outcomes of PiZZ children; however, changes in the expression of specific genes and pathways involved in lipid, fatty acid, and steroid metabolism appear to reflect the degree of liver injury,” the authors concluded.


Kamp JC, Kappe NN, Moro CF, et al. Fibrosis-related gene profiling in liver biopsies of PiZZ α1-antitrypsin children with different clinical courses. Int J Mol Sci. 2023;24(3):2485. doi:10.3390/ijms24032485