Heterozygosity for the Alpha-1-Antitrypsin
Z Allele in Cirrhosis Is Associated
With More Advanced Disease
and Heinz Zoller
Department of Medicine I, Gastroenterology, Hepatology and Endocrinology and
Department of Visceral, Transplant and
Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria; and
Division of Gastroenterology and Hepatology,
Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
Alpha-1-antitrypsin deﬁciency (A1ATD) due to homozygosity for the Z allele (ZZ) is an established risk factor for cirrhosis,
but the liver disease risk in heterozygous Z allele carriers (MZ) is controversial. The aim of the present study was to determine
the prevalence of the MZ genotype among patients with cirrhosis and the associated risk of decompensation and liver trans-
plantation/mortality. An unselected cohort of 561 patients with cirrhosis and 248 deceased liver donors were genotyped for
the A1ATD risk alleles Z and S using a validated allelic discrimination assay. Clinical and biochemical parameters were
assessed in 488 genotype MM and 52 MZ patients at baseline when cirrhosis was diagnosed and at the last contact, before
liver transplantation or death, as study endpoints. MZ prevalence was 2.8% among liver donors, 5.8%, 9.1%, 10.9%, and
19.0% in patients with cirrhosis and Model for End-Stage Liver Disease–sodium (MELD-Na) £ 10, 11-20, 21-30, and >30,
respectively. Among liver transplant recipients, MZ prevalence was 9.7%. MS prevalence was not different between donors,
patients with cirrhosis, or transplant recipients. At the end of follow-up, MELD-Na scores were higher among heterozygous
Z risk allele carriers (16 versus 19; P 5 0.03). Decompensation of cirrhosis with ascites or encephalopathy was signiﬁcantly
more frequent in patients with MZ than in MM patients. In the subgroup with transferrin (Tf) saturation >50% or Tf <180
mg/dL, MZ patients had a signiﬁcantly higher risk of liver transplantation or death than MM patients. In conclusion, the
genotype MZ is a genetic risk factor for more advanced cirrhosis and decompensation. MZ patients with cirrhosis and hypo-
transferrinemia or increased Tf saturation are at higher risk of death and liver transplantation.
Liver Transplantation 24 744–751 2018 AASLD.
Received December 5, 2017; accepted March 6, 2018.
Alpha-1-antitrypsin deﬁciency (A1ATD)–associated
liver disease is caused by the aggregation and intracel-
lular accumulation of the mutant protein in hepato-
cytes. The most relevant hepatic risk allele for A1ATD
is the serpin peptidase inhibitor A1 (SERPINA1)Z
allele. A substitution of a glutamic acid to lysine in
position 342 of the serine protease inhibitor (PI)
alpha-1-antitrypsin (A1AT) causes irreversible mis-
folding and intracellular protein polymerization.
Clinical consequences of A1AT accumulation in
hepatocytes include cholestatic hepatitis in newborns
and development of cirrhosis, which can affect
patients at all ages.
Homozygosity for the Z allele
is an established risk factor, but it is unclear why only
a minority of homozygous individuals ever develop
clinically signiﬁcant liver disease.
The risk con-
ferred by heterozygosity for the Z allele is controver-
sial, and genotype MZ is not a generally accepted
risk factor. The S allele is another common A1ATD
risk allele, which does not cause abnormal protein
folding and is not associated with an increased liver
disease risk, unless in compound heterozygosity with
the Z allele (SZ).
Abbreviations: A1AT, alpha-1-antitrypsin; A1ATD, alpha-1-anti-
trypsin deﬁciency; ALT, alanine transaminase; BMI, body mass index;
CI, conﬁdence interval; CRP, C-reactive protein; ER, endoplasmic
reticulum; INR, international normalized ratio; IQR, interquartile
range; MELD, Model for End-Stage Liver Disease; MELD-Na,
Model for End-Stage Liver Disease–sodium; NAFLD, nonalcoholic
fatty liver disease; PI, protease inhibitor; SERPINA1, serpin pepti-
dase inhibitor A1; Tf, transferrin.
Address reprint requests to Heinz Zoller, M.D., Department of
Medicine I, Gastroenterology, Hepatology and Endocrinology, Medi-
cal University of Innsbruck, Anichstrasse 35, 6020 Innsbruck,
Austria. Telephone: 14351250483206; FAX: 14351250423133;
SCHAEFER ET AL.