Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

BACKGROUND & AIMS: Homozygosity for the Pi*Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi*ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi*MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi*MZ genotype; we compared features of adults with and without Pi*MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi*MZ genotype, 309 adults with the Pi*ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi*Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi*MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi*MZ had lower levels of gammaglutamyl transferase in serum and lower LSMs than adults with the Pi*ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi*MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs >= 7.1 kPa in subjects with the Pi*MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi*MZ genotype, vs 97% of subjects with the Pi*ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi*MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi*MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi*ZZ genotype, but higher than adults without the Pi*Z variant. These findings should help determine risk of subjects with the Pi*MZ genotype and aid in counseling.