Alpha-1-antitrypsin deficiency (AATD)

Metabolic, Biliary Atresia & Related Diseases


AATD is a common inherited genetic condition that increases the risk of lung and liver disease. The prevalence of the severe forms is approximately 1 in 2500 individuals. The disease results from a mutation leading to the production of a misfolded protein alpha1-antitrypsin (AAT) in the liver, that causes a “gain-of-function toxicity” through its polymerization and retention. The lung disease is due to the lack of AAT in the blood circulation, resulting to a “loss-of-function” phenotype. Given that AAT constitutes an important anti-protease, its lack results in increased tissue digestion thereby causing early emphysema.

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The gene encoding for alpha1-antitrypsin (SERPINA1) is localized on the long arm of chromosome 14. The wild type allele named “M” is the most widespread and leads to normal blood concentration of AAT when in homozygous state. The most severe mutation (Glu342Lys) produces the Z allele. In the homozygous state (termed as PiZZ), it is responsible for low concentration of circulating alpha1-antitrypsin and the classic severe form of AATD. Other alleles are mostly responsible for intermediate phenotypes in lung and liver diseases, or are of uncertain significance.

Clinical presentation

Liver: During childhood, one mode of presentation of the liver disease is neonatal cholestasis. This condition can regress spontaneously, but also may lead to a chronic injury and sometimes to cirrhosis. Usually, the liver expression of this disease, in both children and adults, is a chronic injury with possible evolution to cirrhosis and portal hypertension.
Lung: The lung phenotype is primarily seen in adults aged of 30 years and older which develop an early emphysema and a chronic obstructive pulmonary disease.

Risk factors

Liver: Alcohol consumption, obesity, and presence of an additional liver disorder such as non-alcoholic fatty liver disease, chronic viral hepatitis B or C and cystic fibrosis act as co-factors for the liver disease related to AATD, and should be prevented in order to decrease the risk of cirrhosis.
Lung: Smoking increases the risk of early pulmonary emphysema.
In addition, some genetic polymorphisms probably contribute to the development of severe pulmonary and liver expression forms of the disease.


Some common liver disease symptoms in newborns include neonatal cholestasis, with jaundice, white stool and high level of conjugated bilirubin. In older children, chronic injury is usually asymptomatic, and can be fortuitously diagnosed on investigations for asthenia or abdominal pain. Sometimes, the disease is detected during a cirrhosis assessment, which manifests as asthenia, splenomegaly, ascites, jaundice or low platelets count.
Lung disease expression is manifested by dyspnea and cough, initially during physical activity, and which progressively worsens. At physical examination, thoracic distension may be observed.


To establish the diagnosis, the measurement of circulating AAT level is done first. When the concentration of AAT in serum is under 1.1g/L, a genotyping and phenotyping is performed. Liver biopsy is rarely required for the diagnosis of liver disease, but may be needed to rule out co-morbidities.
To assess the lung phenotype, respiratory function tests are performed. CT-scan might be useful to quantify the extent and localization of emphysema.


Patients with liver disease should be managed by an experienced hepatologist. To date, there is no specific treatment for liver disease, but clinical studies are under way. Liver transplantation is the only available treatment and achieves good survival rates in carefully selected patients (Clark, Clin Liver Dis, 2017). Ursodeoxycholic acid can be prescribed to improve the liver enzyme levels, but its impact on long-term prognosis remains uncertain.
Patients with severe lung disease may require inhalative treatment, long-term oxygen therapy as well as augmentation therapy with intravenous application of purified alpha1-antitrypsin. Individuals with severe AATD should be under a regular control of an experienced pneumologist (Chapman et al., Lancet 2015). Lung transplantation should be considered in advanced disease.
Avoidance of risk factors (smoking, alcohol consumption, obesity) can delay the onset of liver and lung disease.


3% and 10-15% of individuals with severe AATD develop liver cirrhosis during childhood and adulthood, respectively. Hepatocellular carcinoma seems to develop primarily in subjects with advanced liver fibrosis, but further studies are needed to clarify this issue. In case of decompensated cirrhosis, a severe or worsening portal hypertension, end-stage liver disease and hepatocellular carcinoma, a liver transplantation may be required.
An emphysema can develop gradually in lungs, and lead to end stage pulmonary disease requiring lung transplantation.


If you wish to discuss an alpha1 antitrypsin deficient (AATD) patient with experts from the ERN, you can upload cases to the CPMS.
The CPMS is essential for interaction between healthcare professionals and experts on clinical decision making, and is provided by the European Union to all ERNs. CPMS supports online multidisciplinary meetings (tele-boards) to discuss patients with diagnostic or therapeutic dilemmas in need of expert consultation. CPMS offers the opportunity to upload and share clinical data of patients and pictures such as histological slides or MRI images. Importantly, this is fully in line with European data protection law. It is obligatory to inform patients about CPMS and obtain their informed consent before their data are entered into the system (see CPMS Privacy Statement published by the European Commission on 14 December 2017). The consent form is available in all EU languages in CPMS.


Source: Alpha-1 European Expert Group Recommendations
Source: Alpha-1 European Expert Group Recommendations

Clinical practice guidelines

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