Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort
Author(s): ,
Mark Brantly
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
Joanna Nolte
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
Tracie Kurtz
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
Jonathan Shuster
Department of Health Outcomes and Policy, University of Florida, United States
Amy Collinsworth
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, United States
Chen Liu
Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, United States
George Marek
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
Virginia C. Clark
Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, United States
Corresponding author. Address: 1600 SW Archer Rd, Box 100277, Rm M440, Gainesville, FL 32610, United States. Tel.: 352-273-9491; fax: 352-392-7393.
EASL LiverTree™. Clark V. 12/01/18; 256776
Virginia Clark
Virginia Clark
Journal Abstract
Graphical abstract

Graphical abstract

Frequency of unsuspected liver fibrosis in alpha-1 antitrypsin deficiency is high. Alpha-1 antitrypsin within the liver is variable and may explain clinical phenotype. Metabolic syndrome is a risk factor for liver fibrosis.

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.


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.


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).


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.

Liver cirrhosis, Hepatocytes, Alpha-1 antitrypsin deficiency, Prevalence, Risk factors, Metabolic syndrome, Elasticity imaging techniques
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