Heterozygosity for the alpha-1-antitrypsin Z allele in cirrhosis is associated with more advanced disease

Abstract

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 transplantation/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 = 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 hypotransferrinemia or increased Tf saturation are at higher risk of death and liver transplantation. Liver Transplantation 24 744-751 2018 AASLD.

Figure 1

(A) MELD‐Na and (B) MELD scores of patients with MM or MZ SERPINA1 genotype at the time of follow‐up. (C) Comparison of SERPINA1 genotype frequencies in patients grouped according to MELD‐Na score quartiles. The overall degree of association between increasing MELD‐Na score and MZ prevalence was statistically significant (P = 0.01, 1‐sided Mantel‐Haenszel test for linear‐by‐linear association).

Figure 2

Comparison of SERPINA1 genotype frequencies in patients with liver cirrhosis, liver transplant recipients, and controls (healthy liver donors).

Figure 3

A1AT plasma concentrations of patients with SERPINA1 genotype MM and MZ at the time of diagnosis of cirrhosis.

Figure 4

Correlation matrix among A1AT plasma concentration, markers of liver disease, inflammation, and iron metabolism. Tile colors code for direction and magnitude of the correlation. The first 2 decimal digits of ρ are displayed. Only significant correlations are shown.

Figure 5

Kaplan‐Meier analysis: (A) transplant‐free survival in all patients stratified by SERPINA1 genotype. Transplant‐free survival in the subgroup of patients with (B) Tf saturation ≥ 50%, (C) with Tf of ≤180 mg/dL, and (D) with MELD‐Na ≥15 at baseline.