S5854 Alpha-1 Antitrypsin Deficiency: The PiMZ Phenotype

Introduction: Alpha-1 antitrypsin (A1A) deficiency is an autosomal recessive disease due to mutations in the SERPINA1 gene. We report a rare case of a patient with pancreaticobiliary abnormalities who was found to have decompensated cirrhosis, A1A deficiency on liver biopsy, a heterozygous phenotype PiMZ and normal serum A1A levels. Case Description/Methods: A 73-year-old woman with a history of bronchitis, and a family history of A1A deficiency in her sister, presented to the clinic to establish care for cirrhosis. She reportedly had jaundice 1 year prior and was found to have elevated liver enzymes as well as an elevated CA 19-9 of 249 U/mL. She was hospitalized for the work-up and management of hepatic encephalopathy (HE). She denied alcohol or tobacco use. No risk factors for metabolic dysfunction-associated steatotic liver disease were noted. Computed tomography abdomen with contrast revealed a nodular liver, biliary and pancreatic ductal dilation, and new ascites. Initial endoscopic retrograde cholangiopancreatography (ERCP) revealed a common bile duct (CBD) stricture requiring stent placement with a follow-up ERCP demonstrating normal bile ducts and main pancreatic duct (PD) dilation. Biopsies of the CBD revealed acute and chronic inflammation. A liver biopsy revealed features of A1A deficiency. Pancreatic duct fluid sampling revealed mucinous IPMN. She was discharged on lactulose for HE and diuretics for her ascites. Outpatient work-up was normal except for an international normalized ratio of 1.2, aspartate aminotransferase of 41 U/L and alkaline phosphatase of 159 U/L. A1A level was normal at 126 mg/dL. A1A genotype was heterozygous for the Z allele which suggested that she is a carrier of A1A deficiency. Discussion: The prevalence of the PiMZ phenotype has been reported to be 2%-7.1%.1 The risk of liver disease and hepatic decompensation may be increased with the PiMZ phenotype.2 Patients are more likely to develop cirrhosis with advanced age and the PiMZ phenotype. The PiMZ variant has been noted to be a risk factor for cirrhosis in patients with MASLD, alcohol use and cystic fibrosis.3 Additionally, PiMZ has been associated with higher serum transaminases and A1A inclusions in the liver compared to those without the PiMZ variant.4 As in our case, heterozygotes for the Z allele may have serum A1AT levels that overlap with the normal ranges. Patients with the PiMZ phenotype should be counseled regarding their risk of liver disease. Additional studies are warranted to explore outcomes with the PiMZ phenotype. References 1. Strnad P, McElvaney NG, Lomas DA. Alpha1-Antitrypsin Deficiency. N Engl J Med. 2020;382(15):1443-1455. 2. Chen VL, Burkholder DA, Moran IJ, DiBattista JV, Miller MJ, Chen Y, Du X, Oliveri A, Cushing KC, Lok AS, Speliotes EK. Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype. JHEP Rep. 2022;4(6):100483. 3. Strnad P, Buch S, Hamesch K, et al. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. Gut. 2019;68(6):1099-1107. 4. Schneider CV, Hamesch K, Gross A, et al. Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers. Gastroenterology. 2020 Aug;159(2):534-548.e11.