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
Abstract
:1. Introduction
2. Material and Methods
2.1. Human Cohort
2.1.1. Cohort of Pi*ZZ and Non-Carrier Subjects
2.1.2. Assessment of Iron Parameters and Exclusion of Concomitant Liver Disease
2.1.3. HFE Mutation Analysis in Pi*ZZ Subjects
2.1.4. Ethical Statement
2.2. Mouse Experiments
2.3. Statistical Analysis
3. Results
3.1. Pi*ZZ Individuals Displayed Mildly Elevated Iron Parameters
3.2. Mild Iron Overload in Double Transgenicmice Did Not Alter the Course of Pi*Z-Associated Liver Disease
3.3. Presence of HFE Mutations Did Not Associate with Increased Liver Injury in Pi*ZZ Individuals
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AAT | alpha-1 antitrypsin |
AATD | Alpha-1 antitrypsin deficiency |
ALT | alanine aminotransferase |
AST | aspartate aminotransferase |
CAP | Controlled attenuation parameter (via transient elastography (FibroScan®) |
CAT | COPD assessment test |
COPD | chronic obstructive pulmonary disease |
HFE | Hereditary Hemochromatosis Protein |
LSM | liver stiffness measurement (via transient elastography (FibroScan®) |
LTOT | long-term oxygen therapy |
SERPINA1 | serpin family A member 1 (AAT gene) |
TF | transferrin |
TSAT | transferrin saturation |
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Category | Non-Carriers (n = 254) | Pi*ZZ Carriers (n = 409) | p Value |
---|---|---|---|
Age (years) | 51.8 ± 15.4 | 56.1 ± 12.2 | <0.0001 |
Women (%) | 50.8 | 46.0 | 0.23 |
BMI (kg/m2) | 25.5 ± 4.6 | 25.0 ± 4.3 | 0.30 |
BMI ≥ 30 kg/m2 (%) | 17.8 | 15.7 | 0.48 |
Diabetes (%) | 5.1 | 3.4 | 0.28 |
Mean alcohol consumption (g/d) | 7.5 ± 10.3 | 6.0 ± 9.5 | 0.15 |
COPD assessment test (points) | 7.6 ± 6.4 | 17.3 ± 8.8 | <0.0001 |
Long-term oxygen therapy (%) | 0.4 | 21.1 | <0.0001 |
AAT augmentation therapy (%) | 0 | 60.4 | <0.0001 |
Liver stiffness (kPa) * | 4.7 ± 2.8 | 7.1 ± 7.3 | <0.0001 |
Controlled attenuation parameter (dB/m) | 245 ± 59 | 268 ± 60 | <0.0001 |
Experimental Group | WT | HFE-KO | PiZ | DTg |
---|---|---|---|---|
Body weight (g) | 22.9 ± 1.04 | 23.4 ± 1.6 | 22.3 ± 1.5 | 22.8 ± 1.7 |
Liver/Body weight (g) | 0.04 ± 0.002 a,b | 0.04 ± 0.004 c,d | 0.05 ± 0.004 a,c | 0.05 ± 0.005 b,d |
ALT (U/L) | 21 ± 6.3 | 18.6 ± 5.4 | 25.5 ± 6 | 24.6 ± 3.9 |
AST (U/L) | 42.6 ± 11.1 | 48.6 ± 6.5 | 57.7 ± 13.5 | 56.4 ± 17.3 |
ALP (U/L) | 99.6 ± 40.7 | 77.4 ± 9.1 | 84.4 ± 11.3 | 99.6 ± 46.3 |
Experimental Group | WT | HFE-KO | PiZ | DTg |
---|---|---|---|---|
Body weight (g) | 33.2 ± 2.9 a,b | 32.8 ± 3.6 c,d | 27.8 ± 1.5 a,c | 26.4 ± 2.4 b,d |
Liver/Body weight (g) | 0.04 ± 0.004 | 0.05 ± 0.01 | 0.05 ± 0.004 | 0.05 ± 0.005 |
ALT (U/L) | 49 ± 18.8 | 75.6 ± 48.6 | 56.6 ± 18.6 | 51.2 ± 20.6 |
AST (U/L) | 79.8 ± 32.3 | 106 ± 48.6 | 122.7 ± 29 | 118.1 ± 26.5 |
(U/L) | 105.8 ± 47.2 e,f | 94.2 ± 32 g,h | 204 ± 68.8 e,g | 189.4 ± 76.7 f,h |
Category | C282Y & H63D Non-Carriers (n = 246) | C282Y Hetero-zygous (n = 24) | H63D Hetero-zygous (n = 99) | H63D Homo-zygous (n = 7) | C282Y/H63D Compound Heterozygous (n = 4) |
---|---|---|---|---|---|
Age (years) | 56.5 ± 12.1 | 53.1 ± 13.8 | 56.0 ± 11.7 | 55.6 ± 15.9 | 65.7 ± 11.1 |
Women (%) | 44.3 | 50.0 | 50.5 | 42.9 | 46.3 |
BMI (kg/m2) | 24.9 ± 3.8 | 25.8 ± 5.0 | 25.2 ± 5.4 | 23.8 ± 2.3 | 23.5 ± 2.2 |
BMI ≥ 30 kg/m2 (%) | 14.3 | 20.8 | 20.2 | 0 | 0 |
Diabetes (%) | 2.8 | 0 | 6.1 | 0 | 25.0 |
Mean alcohol consumption (g/d) | 6.6 ± 9.6 | 2.6 ± 3.5 | 5.3 ± 10.3 | 2.9 ± 4.4 | 3.0 ± 5.9 |
COPD assessment test (points) | 17.3 ± 8.9 | 15.8 ± 8.5 | 18.7 ± 8.3 | 14.4 ± 13.2 | 13.2 ± 8.2 |
Long-term oxygen therapy (%) | 20.8 | 20.8 | 24.5 | 14.3 | 25.0 |
AAT augmentation therapy (%) | 61.1 | 50.0 | 64.6 | 57.1 | 50.0 |
Ferritin (ng/mL) | 205.8 ± 203.2 | 160.7 ± 154.6 | 246.9 ± 228.3 | 167.6 ± 93.9 | 238.0 ± 160.8 |
Transferrin (mg/dL) | 268.8 ± 55.3 | 259.6 ± 37.9 | 261.4 ± 3.6 | 247.7 ± 57.2 | 233.8 ± 43.1 |
TSAT (%) * | 29.2 ± 10.4 | 33.9 ± 17.1 | 30.3 ± 9.3 | 38.3 ± 8.9 | 57.8 ± 20.1 |
Liver stiffness (kPa) | 7.1 ± 6.7 | 6.0 ± 2.8 | 5.9 ± 3.1 | 5.1 ± 1.3 | 6.4 ± 3.7 |
LSM ≥ 7.1 kPa (%) | 25.6 | 22.7 | 20.4 | 14.3 | 25.0 |
LSM ≥ 10 kPa (%) | 13.0 | 9.1 | 5.1 | 0 | 25.0 |
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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. https://doi.org/10.3390/cells8111415
Guldiken N, Hamesch K, Schuller SM, Aly M, Lindhauer C, Schneider CV, 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(11):1415. https://doi.org/10.3390/cells8111415
Chicago/Turabian StyleGuldiken, Nurdan, Karim Hamesch, Shari Malan Schuller, Mahmoud Aly, Cecilia Lindhauer, Carolin V. Schneider, Malin Fromme, Christian Trautwein, and Pavel Strnad. 2019. "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 8, no. 11: 1415. https://doi.org/10.3390/cells8111415