Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi*Z Variant of AAT (Pi*MZ vs Pi*ZZ genotype) and Non-carriers.

ABSTRACT 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 Caucasians have the Pi*MZ genotype; we compared features of adults with and without Pi*MZ genotype among persons without pre-existing 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 (non-carriers). 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 United Kingdom biobank database, levels of serum transaminases were increased in subjects with the Pi*MZ genotype compared with non-carriers. In the Alpha-1 Liver Cohort, adults with Pi*MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi*ZZ variant, but these were higher than in non-carriers. Ten percent of subjects with the Pi*MZ genotype vs 4% of non-carriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% CI, 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.