Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort

J Hepatol. 2018 Dec;69(6):1357-1364. doi: 10.1016/j.jhep.2018.08.005. Epub 2018 Aug 21.


Background & aims: Alpha-1 antitrypsin deficiency (AATD) is an uncommonly recognized cause of liver disease in adults, with descriptions of its natural history limited to case series and patient-reported data from disease registries. Liver pathology is limited to selected patients or unavailable. Therefore, we aimed to determine the prevalence and severity of liver fibrosis in an adult AATD population who were not known to have cirrhosis, while defining risk factors for fibrosis and testing non-invasive markers of disease.

Methods: A total of 94 adults with classic genotype 'PI*ZZ' AATD were recruited from North America and prospectively enrolled in the study. Liver aminotransferases and markers of synthetic function, transient elastography, and liver biopsy were performed.

Results: The prevalence of clinically significant liver fibrosis (F ≥ 2) was 35.1%. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the F ≥ 2 group. Metabolic syndrome was associated with the presence of clinically significant fibrosis (OR 14.2; 95% CI 3.7-55; p <0.001). Additionally, the presence of accumulated abnormal AAT in hepatocytes, portal inflammation, and hepatocellular degeneration were associated with clinically significant fibrosis. The accuracy of transient elastography to detect F ≥ 2 fibrosis was fair, with an AUC of 0.70 (95% CI 0.58-0.82).

Conclusions: Over one-third of asymptomatic and lung affected adults with 'PI*ZZ' AATD have significant underlying liver fibrosis. Liver biopsies demonstrated variable amounts of accumulated Z AAT. The risk of liver fibrosis increases in the presence of metabolic syndrome, accumulation of AAT in hepatocytes, and portal inflammation on baseline biopsy. The results support the hypothesis that liver disease in this genetic condition may be related to a "toxic gain of function" from accumulation of AAT in hepatocytes.

Lay summary: Individuals diagnosed with classic alpha-1 antitrypsin deficiency (ZZ) are at risk of liver injury and scarring, because of the accumulation of abnormal alpha-1 antitrypsin in the liver. A liver biopsy in ZZ individuals can demonstrate the accumulation of alpha-1 antitrypsin within the liver and identify if any associated liver scarring is present. Indviduals with large amounts of alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Additional common medical conditions of diabetes, obesity, high cholesterol, and hypertension (known as metabolic syndrome) are associated with a greater degree of liver injury. CLINICAL TRIAL NUMBER: NCT01810458.

Keywords: Alpha-1 antitrypsin deficiency; Elasticity imaging techniques; Hepatocytes; Liver cirrhosis; Metabolic syndrome; Prevalence; Risk factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • Canada / epidemiology
  • Comorbidity
  • Cross-Sectional Studies
  • Elasticity Imaging Techniques
  • Female
  • Hepatocytes / metabolism
  • Humans
  • Liver / pathology
  • Liver Cirrhosis / epidemiology*
  • Liver Cirrhosis / etiology*
  • Lung Diseases, Obstructive / epidemiology
  • Male
  • Metabolic Syndrome / complications*
  • Middle Aged
  • Phenotype
  • Prevalence
  • Prospective Studies
  • Severity of Illness Index
  • United States / epidemiology
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / metabolism*
  • alpha 1-Antitrypsin Deficiency / complications*
  • alpha 1-Antitrypsin Deficiency / pathology*


  • alpha 1-Antitrypsin

Associated data