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.

Heterozygosity for the Alpha‐1‐Antitrypsin Z Allele in Cirrhosis Is Associated With More Advanced Disease

“…In summary, our data and the findings of Schaefer et al suggest A1AT heterozygosity is underdiagnosed despite routine serum A1AT testing. It can be an important cofactor in advanced liver disease and also raises implications for screening of family members.…”

“…The findings of Schaefer et al are supported by our retrospective review of patients undergoing liver transplantation (LT) between 2000 and 2016 at a major Australian center. Explanted livers from 823 patients were assessed to identify patients with histologic evidence of A1ATD (presence of periodic acid–Schiff–positive, diastase‐resistant hepatocyte inclusions and A1AT‐positive immunohistochemistry).…”

“…Alleles are codominantly expressed, and the clinical significance of heterozygosity remains controversial . Recently, Schaefer et al showed that alpha‐1‐antitrypsin (A1AT) MZ heterozygosity is associated with a more advanced form of chronic liver disease compared with MM wildtype.…”

“…Serum A1AT is an acute‐phase protein and can be falsely elevated . Schaefer et al reported that serum A1AT levels perform poorly in detecting A1AT risk alleles. Similarly, our study found that A1AT serum levels were not abnormally low in all patients with typical A1ATD histologic changes (28/35; 80.0%).…”

Reply

“…In our study cohort of 378 patients, the positive predictive value of serum A1AT in patients with a serum concentration of A1AT ≤137 mg/dL was 43.2%. (1) As shown in Fig. 1, a receiver operating characteristic (ROC) curve analysis of the diagnostic performance of A1AT serum concentration in an extended cohort of 4682 patients from our center with an available A1AT phenotype showed that the optimal cutoff to predict heterozygosity for the Z allele was ≤112 mg/dL ( Table 1).…”