Alpha-1 Antitrypsin Deficiency (AATD)
Metabolic, Biliary Atresia & Related Diseases
Description
Alpha1-antitrypsin deficiency (“the Viking Disease”) is an inborn genetic disorder that affects in Europe about 1 in 2500 individuals. It is a “Rare Disease”. It is also a systemic disease, which means that different organs can be affected (liver, lung, skin, vessels, immunity …) Mainly it increases susceptibility to lung disease in adults (emphysema, which is loss of lung tissue density, like “smokers lung”) and liver disease in both, children and adults. It is one of the main causes of neonatal cholestasis (newborn stay with a yellow skin several days), and can lead to chronic liver scaring (fibrosis) and later cirrhosis. Genetically PiZZ is the classic form of severe alpha1-antitrypsin deficiency, the level of antitrypsin in the blood is very low. Combinations of other genetic variants exist, they are often less damaging, but also should be taken in care and supervised.
As a Rare Disease in all 46 European countries together there are about 120 000 PIZZ individuals estimated, but less than 10 000 individuals are known today (highly under diagnosed). A lot of “Alphas” with lung problems are misdiagnosed (COPD, asthma). The parents of ZZ-Alphas are often MZ carriers: they carry the Z-gene. There are some millions of them in Europe, mainly undiagnosed.
Diagnosis
To confirm the diagnosis, your doctor can prescribe a blood test assessing the serum level of antitrypsin and the analysis of the serum phenotype. A genetic analysis is performed to complete the diagnosis. A liver biopsy is not required to establish the diagnosis, but can be performed in order to characterize the stage of the liver disease or to confirm the diagnosis in case of atypical presentation. Individuals with lung symptoms (cough, sputum, short of breath,…) should be tested by spirometry, which visualizes your respiration (inhale, exhale), and emphysema could be assessed by CT scan. Also a genetic analysis is performed to complete the diagnosis. In some countries (Germany) the testing can be quickly performed at the General Practitioners office from a blood drop.
Treatment
Alpha-1 antitrypsin deficiency is a rare genetic condition; today there is no cure, which would allow producing only normal antitrypsin in a healthy liver. For PiZZ individuals the Z-protein is often stored in the liver cell. The Z-protein in the blood is not sufficient to protect the lung.
A usual treatment is a therapy by augmentation of antitrypsin, which is collected from plasma donors. For one year of treatment of an Alpha ZZ-patient by augmentation therapy there is a need of 900 plasma donations. In case of lung affection the symptoms of chronic obstructive pulmonary disease (emphysema) should be eased by bronchodilators or oxygen. Cough, sputum, and a whistling sound of respiration are present. A limited airflow causes obstruction. There is an irritation and chronic inflammation of the airways. Smokers should stop smoking. If bronchitis or pneumonia is present, antibiotics should be prescribed.
To monitor the liver a regular non invasive testing for liver fibrosis by elastography (ie.fibroscan) or blood-based markers (APRI, Fib-4 or similar) is indicated (see also MANGEMANT).
In 2024 there are lots of new treatments designed by researchers: drugs to empty the liver of stored ZZ clusters, silencing methods to stop production of the Z-protein in the liver, products to stop activity of the enzyme which destroys the lung tissue, molecules which allow the Z-protein to fold in a way that it leaves the liver cell, and others… A lot of clinical trials are on the way to test these drugs in next years.
Management
Concerning the liver disease, the management is essentially preventive (limited alcohol consumption, avoid overweight and prevent viral hepatic infections (hepatitis A and B vaccination, prevention of hepatitis C). A treatment with ursodeoxycholic acid can be considered in children. In case of cirrhosis, the follow-up should be provided by a hepatologist in order to manage the complications of portal hypertension (monitoring and prophylactic treatment of gastroesophageal varices, treatment of ascites, screening for liver carcinoma). In case of decompensated cirrhosis, a liver transplantation may be considered.
The pulmonary disease requires a follow-up by a pneumologist. In addition to the treatment of chronic obstructive pulmonary disease/and or emphysema (bronchodilators, oxygen), it may require once a week an intravenous augmentation with alpha1-antitrypsin, so the lungs stay protected. Prevention of microbial infections, like pneumonia, by vaccination is important. Family testing: look for Alphas in your family, avoid exacerbations by not getting cold
Lifestyle advices: diminish overweight, start with regular sports, keep your body in good shape, eat fresh vegetables, avoid fast-food, keep current drugs slow (aspirin, antibiotics), avoid hard drugs, limit alcohol consumption, try sauna regularly, get enough sleep, try to see a dietician to explain your food habits, Support: contact an Alpha-1 patient support group, meet Alphas, learn how they adapt best to their situations and learn more about the disease (books, video, support group).
Further Readings
Books and Articles
- Ignacio Blanco, Blanco’s overview of Alpha-1 Antitrypsin Deficiency, Academic Press, 2017
- Strnad P, McElvaney NG, Lomas DA. Alpha1-Antitrypsin Deficiency. N Engl J Med. 2020 Apr 9;382(15):1443-1455. doi: 10.1056/NEJMra1910234. PMID: 32268028.
- Ruiz M, Lacaille F, Schrader C, Pons M, Socha P, Krag A, Sturm E, Bouchecareilh M, Strnad P. Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency. Semin Liver Dis. 2023 Aug;43(3):258-266. doi: 10.1055/a-2122-7674. Epub 2023 Jul 4. PMID: 37402396.
- Fromme M, Schneider CV, Trautwein C, Brunetti-Pierri N, Strnad P. Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder. J Hepatol. 2022 Apr;76(4):946-958. doi: 10.1016/j.jhep.2021.11.022. Epub 2021 Nov 27. PMID: 34848258.