title: Pi*Z heterozygous alpha-1 antitrypsin states accelerate parenchymal but not biliary cirrhosis.
abstract: OBJECTIVE
  The degree to which heterozygous forms of alpha-1 antitrypsin (A1AT), principally MZ, causes liver disease is uncertain. If heterozygosity is a relevant cofactor, over-representation in patients with end-stage liver disease would be predicted. We therefore assessed the prevalence and disease-related distribution of A1AT heterozygosity in the largest cohort to date for this purpose.
  
  
  METHODS
  We retrospectively analysed 1036 patients assessed for liver transplantation at our unit between 2003 and 2010. A1AT heterozygotes were identified on the basis of isoelectric focusing and/or histology, showing A1AT globule deposition consistent with an abnormal phenotype.
  
  
  RESULTS
  Z-allele frequency was the highest in patients with nonalcoholic steatohepatitis (NASH) cirrhosis (20.3%), followed by patients with 'other parenchymal' diseases (11.9%), alcohol-related liver disease (9.9%), autoimmune disease (8.6%), hepatitis C (6.1%), hepatitis B (3.0%) and biliary disease (1.9%). Compared with the heterozygote frequency in the general European population of 9.0%, the heterozygote frequency was significantly higher among patients with NASH cirrhosis (P≤0.0001) and lower in the biliary subgroup (P=0.004). The prevalence of MZ heterozygosity was significantly increased in cirrhosis because of both alcohol (9.9%) and NASH (17.3%) compared with the general European population (2.8%; P<0.0001).
  
  
  CONCLUSIONS
  Accumulation of misfolded A1AT aggregates appears to accelerate progression, in which the hepatocyte is the key injured cell. Heterozygous A1AT states worsen prognosis, particularly in NASH and alcohol-related cirrhosis, and should be identified at presentation. In cases in which genetic screening is not readily available, a low threshold for isoelectric focusing and routine specific histochemical staining of liver biopsy specimens are warranted to identify these patients.
authors: Departments of aHepatology bBiochemistry cPathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors: Tessa M
authors: TM
authors: Cacciottolo
authors: William T H
authors: WT
authors: Gelson
authors: Gerald
authors: G
authors: Maguire
authors: Susan E
authors: SE
authors: Davies
authors: William J H
authors: WJ
authors: Griffiths
mesh_terms: D001706:Biopsy; D018450:Disease Progression; D004739:England / Q000453:epidemiology; D005234:Fatty Liver / Q000175:diagnosis / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D008105:Liver Cirrhosis, Biliary / Q000175:diagnosis / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease; D010641:Phenotype; D011237:Predictive Value of Tests; D015995:Prevalence; D017510:Protein Folding; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin