Alpha-1-antitrypsin deficiency (AATD) is an inherited metabolic disorder. The liver produces the protective protein alpha-1-antitrypsin, which counteracts premature tissue degradation in the lungs by enzymes. In AATD, this protein is produced in an altered form in the liver due to the genetic change and cannot be released properly.

This results in two main forms of the disease: lung disease, which manifests itself as pulmonary emphysema (enlarged alveoli), and liver disease with inflammation and increasing scarring of the liver tissue.

Causes of AATD

Alpha-1-antitrypsin deficiency is caused by a mutation in the SERPINA1 gene. The normal variant of the gene is known as the ‘M’ variant, while the most common disease-causing variants are known as ‘Z’ and ‘S’. The disease is inherited recessively, which means that for the severe form of the disease to occur, an altered gene variant must be inherited from both parents.

The most severe form of both lung and liver disease can occur if both copies of the gene correspond to the ‘Z’ variant (Pi*ZZ). If only one of the two gene copies is altered (Pi*MZ or Pi*MS), a milder form of lung or liver disease can occur, whereby additional factors such as smoking, excessive alcohol consumption or obesity often play a role.

Symptoms

The symptoms of AATD are often non-specific and progress slowly over many years, which can delay diagnosis. The lung disease can be characterised by increasing breathlessness and chronic coughing.

AATD-related liver disease occurs either in childhood or later in adulthood. In children, liver disease most frequently manifests itself in the form of jaundice caused by bile stasis as early as infancy. In rare cases, bile stasis can also progress to cirrhosis of the liver in childhood, requiring an early liver transplant. However, most children are asymptomatic, with only elevated liver and bile stasis levels in the blood.

The chronic form in adults develops over many years and there are usually no symptoms in the early stages. Complete liver scarring can lead to cirrhosis-related complications. These include water in the abdomen (ascites), jaundice (icterus) or itching.

Diagnosis

AATD is diagnosed by a low level of alpha-1-antitrypsin (AAT) in the blood. If the AAT level is low, the gene variants present can then be determined in a further step. This results, for example, in the Pi*ZZ gene constellation, which can lead to severe lung or liver disease.

Treatment

Preventive measures are currently of the utmost importance: the liver and lungs should be protected at all costs by avoiding alcohol and smoking.

In the case of lung disease, it is possible to improve the symptoms with inhalation therapies (corticosteroids and beta-sympathomimetics). In the case of increasing lung disease due to AATD (this usually affects patients with the Pi*ZZ form), enzyme replacement therapy can be carried out. In severe cases, oxygen therapy and ultimately a lung transplant may be necessary.

In patients with severe AATD (usually with the Pi*ZZ form), regular liver checks are also indicated. If there are signs of scarring of the liver, the consumption of alcohol should be avoided. To date, no drugs have been approved for the treatment of liver damage caused by AATD. A promising drug is currently in the final phase of clinical trials. In the case of complete scarring of the liver (cirrhosis), the aim is to prevent or treat cirrhosis-related complications. In advanced liver disease caused by AATD, the risk of liver tumours is increased. Therefore, regular liver tumour screenings must be carried out in cases of advanced scarring. In the case of end-stage liver disease or the occurrence of liver tumours, liver transplantation is an option.