Heterozygosity for the Alpha-1-Antitrypsin Z Allele in Cirrhosis is Associated with More Advanced Disease.

Potential conflict of interest: Nothing to report. To the Editor: Alpha‐1‐antitrypsin deficiency (A1ATD) is an uncommon autosomal recessive condition that can result in cirrhosis in patients with risk alleles.1 Alleles are codominantly expressed, and the clinical significance of heterozygosity remains controversial.1 Recently, Schaefer et al.2 showed that alpha‐1‐antitrypsin (A1AT) MZ heterozygosity is associated with a more advanced form of chronic liver disease compared with MM wildtype. The findings of Schaefer et al.2 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). This method was used to differentiate true A1ATD liver disease from incidental carriage (occurs in approximately 2.4% of Australians3). Typical A1ATD changes were found in 36/823 patients (4.4%). In the majority of cases (29/36; 80.6%) alternative listing diagnoses for LT were recorded (alcohol, 50.0%; nonalcoholic fatty liver disease [NAFLD], 19.4%; hepatitis C, 16.7%; and other, 5.6%). Serum A1AT is an acute‐phase protein and can be falsely elevated.1 Schaefer et al.2 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%). Additionally, routine serum A1AT screening missed 36.1% (13/36) of A1ATD diagnoses prior to LT. The median serum A1AT level was higher in those with A1ATD diagnosed on explant histology compared with those already known to have A1ATD before LT (0.84 versus 0.40 g/L; P < 0.001). Indeed, almost half (6/13, 46.2%) of the patients who were undiagnosed before LT had an A1AT level above the lower limit of normal (0.85 g/L). We also demonstrated that patients with a post‐LT diagnosis of A1ATD had more advanced liver disease compared with those with known diagnoses before LT as indicated by higher median Model for End‐Stage Liver Disease (MELD) scores (26.0 versus 18.0; P = 0.049). Table 1 compares clinical characteristics of these 2 groups. Phenotypes were available in 58.3% (21/36) with the majority exhibiting MZ heterozygosity 12/21 (57.1%), followed by ZZ 7/21 (33.3%) and SZ 2/21 (9.5%). Almost all phenotyped cases of A1ATD identified after LT were MZ heterozygotes (5/6; 83.3%) with 1 case of SZ (1/6; 16.7%). Table 1 - Patients With A1AT Deficiency Diagnosed Prior to LT Compared With Those Diagnosed on Explant Histology Identified Before LT (n = 23) Identified on Explant Histology (n = 13) P Value Sex, male 21 (91) 9 (69) 0.16 Age at transplant, years 53.0 (48.3‐60.6) 58.2 (51.7‐63.2) 0.09 MELD score 18.0 (16.0‐30.0) 26.0 (19.5‐33.5) 0.049 BMI, kg/m2 30.8 (±6.7) 29.8 (±5.1) 0.75 Number of alterative causes for liver disease listed 0.16 0 7 (30) 0 (0) 1 13 (57) 11 (85) 2 2 (9) 1 (8) 3 1 (4) 1 (8) Other causes of liver disease listed Alcohol 10 (43) 8 (62) 0.29 Hepatitis C 3 (13) 3 (23) 0.65 NAFLD 3 (13) 4 (31) 0.23 Other 2 (9) 0 (0) 0.53 Concomitant HCC 2 (9) 1 (8) >0.99 Serum A1AT level, g/L* 0.40 (<0.3‐0.60) 0.84 (0.63‐1.08) <0.001 Patients with serum A1AT above lower limit of normal (0.85 g/L)* 0/22 (0) 6 (46) 0.001 A1AT phenotypes† 0.12 MZ 7/15 (47) 5/6 (83) ZZ 7/15 (47) 0/6 (0) SZ 1/15 (7) 1/6 (17) Not performed 8 (35) 6 (46) Data are given as median (IQR), mean ± SD, or n (%).*Available in 35/36 patients.†Available in 21/36 patients. In summary, our data and the findings of Schaefer et al.2 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.