TY - JOUR
T1 - Increased Frequency of Heterozygous Alpha-1-Antitrypsin Deficiency in Liver Explants From Nonalcoholic Steatohepatitis Patients
AU - Cheeney, Gregory
AU - Pac, Lincoln J.
AU - Gopal, Purva
AU - Landis, Charles S.
AU - Konnick, Eric Q.
AU - Swanson, Paul E.
AU - Greene, Dina N.
AU - Lockwood, Christina M.
AU - Westerhoff, Maria
N1 - Publisher Copyright:
Copyright © 2019 by the American Association for the Study of Liver Diseases.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Cirrhotic explanted livers occasionally have unexpected periodic acid–Schiff-diastase (PASD)–positive globules within the hepatocyte cytoplasm. It is often unclear whether this finding is a nonspecific consequence of cirrhosis or is indicative of an underlying alpha-1-antitrypsin deficiency (A1ATD) contributing to the cirrhosis. In this study, explanted livers were retrospectively evaluated for histopathology (including PASD status with confirmatory alpha-1-antitrypsin [A1AT] immunohistochemistry [IHC]), and chart review provided etiology of liver failure and general clinical parameters. Real-time polymerase chain reaction was used to detect A1AT genotype (SERPINA1 S and Z alleles) by melting curve analysis on liver explant tissue from selected cases. Of 196 explanted livers, 21 (11%) had PASD+ globules, which were significantly enriched in patients with a clinical diagnosis of nonalcoholic steatohepatitis (NASH; 47%) compared with other causes (P < 0.001). IHC confirmed all PASD+ globules were A1AT+, with 20 of 21 cases demonstrating diffuse A1AT staining. In an expanded NASH cohort, 42% (14/33) of explants had PASD+ globules, 92% of which were homozygous (n = 1) or heterozygous (n = 11) for the SERPINA1 Z allele, corresponding to nearly 40% of all NASH patients. Overall, the Z allele was present in 10% of all tested liver explants, with 85% of PASD+ cases genotyping homozygous (n = 2) or heterozygous (n = 20), which is far in excess of the estimated 2% in the general population. These results indicate PASD+ A1AT globules (with confirmatory genotyping showing at least 1 Z allele) are commonly observed in NASH, suggesting a synergistic relationship toward liver fibrosis. In addition, the high frequency of SERPINA1 Z alleles in liver transplantation patients supports the utility of pretransplant genotyping.
AB - Cirrhotic explanted livers occasionally have unexpected periodic acid–Schiff-diastase (PASD)–positive globules within the hepatocyte cytoplasm. It is often unclear whether this finding is a nonspecific consequence of cirrhosis or is indicative of an underlying alpha-1-antitrypsin deficiency (A1ATD) contributing to the cirrhosis. In this study, explanted livers were retrospectively evaluated for histopathology (including PASD status with confirmatory alpha-1-antitrypsin [A1AT] immunohistochemistry [IHC]), and chart review provided etiology of liver failure and general clinical parameters. Real-time polymerase chain reaction was used to detect A1AT genotype (SERPINA1 S and Z alleles) by melting curve analysis on liver explant tissue from selected cases. Of 196 explanted livers, 21 (11%) had PASD+ globules, which were significantly enriched in patients with a clinical diagnosis of nonalcoholic steatohepatitis (NASH; 47%) compared with other causes (P < 0.001). IHC confirmed all PASD+ globules were A1AT+, with 20 of 21 cases demonstrating diffuse A1AT staining. In an expanded NASH cohort, 42% (14/33) of explants had PASD+ globules, 92% of which were homozygous (n = 1) or heterozygous (n = 11) for the SERPINA1 Z allele, corresponding to nearly 40% of all NASH patients. Overall, the Z allele was present in 10% of all tested liver explants, with 85% of PASD+ cases genotyping homozygous (n = 2) or heterozygous (n = 20), which is far in excess of the estimated 2% in the general population. These results indicate PASD+ A1AT globules (with confirmatory genotyping showing at least 1 Z allele) are commonly observed in NASH, suggesting a synergistic relationship toward liver fibrosis. In addition, the high frequency of SERPINA1 Z alleles in liver transplantation patients supports the utility of pretransplant genotyping.
UR - http://www.scopus.com/inward/record.url?scp=85075448974&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075448974&partnerID=8YFLogxK
U2 - 10.1002/lt.25652
DO - 10.1002/lt.25652
M3 - Article
C2 - 31597010
AN - SCOPUS:85075448974
SN - 1527-6465
VL - 26
SP - 17
EP - 24
JO - Liver Transplantation
JF - Liver Transplantation
IS - 1
ER -