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Open AccessArticle

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

1
Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany
2
Coordinating Center for Alpha-1 Antitrypsin Deficiency-Related Liver Disease of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the European Association for the Study of the Liver (EASL) Registry Group “Alpha-1 Liver”, Germany
3
Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
*
Author to whom correspondence should be addressed.
The authors contributed equally.
Cells 2019, 8(11), 1415; https://doi.org/10.3390/cells8111415 (registering DOI)
Received: 27 September 2019 / Revised: 4 November 2019 / Accepted: 6 November 2019 / Published: 9 November 2019
The presence of the homozygous ‘Pi*Z’ variant of alpha-1 antitrypsin (AAT) (‘Pi*ZZ’ 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 (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ 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 (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ 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. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development. View Full-Text
Keywords: iron metabolism; α1-antitrypsin deficiency; rare liver disease; genetic liver disease; SERPINA1; HFE; liver fibrosis iron metabolism; α1-antitrypsin deficiency; rare liver disease; genetic liver disease; SERPINA1; HFE; liver fibrosis
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Guldiken, N.; Hamesch, K.; Schuller, S.M.; Aly, M.; Lindhauer, C.; Schneider, C.V.; Fromme, M.; Trautwein, C.; Strnad, P. Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice. Cells 2019, 8, 1415.

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