title: Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end-stage liver disease.
abstract: OBJECTIVE
  To evaluate the association between alpha-1 antitrypsin deficiency (A1ATD) and hepatocellular carcinoma (HCC) in patients with end-stage liver disease (ESLD).
  
  
  METHODS
  Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study (N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension (ascites, variceal bleeding, thrombocytopenia, or hepatic encephalopathy). A1ATD was diagnosed using phenotype characterization (MZ or ZZ), liver biopsy detection of PAS-positive diastase-resistant (PAS+) globules, or both. Patients with other causes of liver diseases such as hepatitis C virus (HCV), alcoholic liver disease and non-alcoholic steatohepatitis (NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities, biopsy findings, or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma, or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-to-interval analysis for interval censored data.
  
  
  RESULTS
  This study included 675 patients. 7% of subjects had A1ATD (n = 47). Out of all subjects who did not have A1ATD, 46% had HCV, 17% had alcoholic liver disease, 19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1ATD, 15 had a primary diagnosis of A1ATD (PI*ZZ phenotype and PAS+ globules), 8 had a PI*MZ phenotype alone, 14 had PAS+ alone, and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4 (25(th), 75(th) percentiles: 1, 5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29% (n = 199). In the A1ATD group, the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis (P = 0.001). Patients with ESLD due to A1ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis, 1.5% in patients with NASH and 0.9% in alcohol-induced liver disease (P < 0.001).
  
  
  CONCLUSIONS
  Within this group of patients with ESLD, there was no significant association between A1ATD and increased risk of HCC.
authors.affiliation: Clara Antoury, Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, United States.
authors.forename: Clara
authors.initials: C
authors.lastname: Antoury
authors.affiliation: Clara Antoury, Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, United States.
authors.forename: Rocio
authors.initials: R
authors.lastname: Lopez
authors.affiliation: Clara Antoury, Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, United States.
authors.forename: Nizar
authors.initials: N
authors.lastname: Zein
authors.affiliation: Clara Antoury, Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, United States.
authors.forename: James K
authors.initials: JK
authors.lastname: Stoller
authors.affiliation: Clara Antoury, Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, United States.
authors.forename: Naim
authors.initials: N
authors.lastname: Alkhouri
keywords: Alpha-1 antitrypsin deficiency; End-stage liver disease; Hepatitis C virus; Hepatocellular carcinoma; Liver cirrhosis