Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in Knockout Mice.

The presence of the homozygous 'PiZ' variant of alpha-1 antitrypsin (AAT) ('PiZZ' genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene () as the major cause of hereditary iron overload in a large cohort of PiZZ subjects without liver comorbidities. The human cohort comprised of 409 PiZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (PiZ overexpressors, knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on PiZ-induced liver injury. Compared to PiZ non-carriers, PiZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of did not alter the extent of AAT accumulation. In PiZZ individuals, presence of mutations was not associated with more severe liver fibrosis. Taken together, PiZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of mutations ( and ) constitute a major contributor to liver fibrosis development.