What is alpha-1-antitrypsin and AAT deficiency?

Alpha-1-antitrypsin (AAT) is a protein which inhibits the activity of enzymes (proteases) that degrade proteins. Hence it is referred to as a protease inhibitor. Its concentration in blood is higher than that of all other protease inhibitors. AAT protects tissue structures from damage by degrading enzymes. It is produced in the liver from where it is released into the blood. A deficiency of AAT can result in tissue damage by proteases. Especially in the lung AAT deficiency can result in a destruction of the lung air sacks (alveoli) and thus to the development of a pulmonary emphysema. Emphysema is an irreversible over-inflation of the air spaces which results in a break down of the walls of the affected alveoli. AAT deficiency not only results in an over-inflation of the lung but also promotes its degeneration. According to the Alpha One organisation about 100,000 Europeans suffer from alpha-1-antitrypsin deficiency.

Figure: Diagram of pulmonary emphysema and a microsection through the affected  lung.

How common is AAT deficiency?

One in 2000 Europeans have a deficiency in AAT. Although this number may appear to be small, AAT deficiency is nevertheless one of the most frequent potentially lethal hereditary diseases in Europe.
Nevertheless this disease is widely underdiagnosed in Europe (WHO Report, Geneva 1996) and on average there is a gap of 5-8 years between the first clinical symptoms and the diagnosis. 12 % of all known AAT-deficient patients had to consult 6-10 doctors on average until a correct diagnosis was made. In the USA and Scandinavia extensive screening examinations have been carried out for many years in order to identify and treat AAT-deficient patients at an early stage. Thus 120 out of  200,000 Swedish neonates had a homozygotic (PiZZ) AAT deficiency and thus a high risk for liver disease. 70 % of these had disorders of liver function and 14 % had developed a severe cirrhosis of the liver at the age of  8.
2.1 million people in the USA suffer from pulmonary emphysema, 60,000 of which are caused by AAT deficiency. Hence pulmonary emphysema caused by AAT defiency has the same prevalence as cystic fibrosis. 

How does AAT deficiency occur?

The cause of the AAT deficiency is a genetic defect on chromosome 14 which results in an impairment of the transport of the protein from the liver, where it is produced, into the blood. The resulting AAT accumulation in the liver cells leads to inflammation and liver damage particularly in the affected children. In addition the lack of functional AAT means that the protective function of the enzyme is limited or absent which leads to lung damage. The reason for this is that elastase, which is a protein-degrading enzyme kept under control by AAT, is free to destroy the walls of the alveoli. 

Figure: The scanning electron microscopic image shows holes in the wall of an alveolus in the lung. The spherical objects are macrophages i.e. cells which are involved in immune and inflammatory reactions. Figure by coutesy of  PD Dr. med. D. Theegarten , Institute of Pathology and Neuropathology, University Hospital, Essen http://homepage.ruhr-uni-bochum.de/ Dirk.Theegarten /

Thus chronic ostructive pulmonary diseases (COPD) and pulmonary emphysema are the most common defects caused by an AAT deficiency. They usually occur in adulthood and especially in persons in which the lung is additionally stressed by smoking. 25 % of children with a complete alpha-1-antitrypsin deficiency develop cirrhosis of the liver, ca. 75 % of the affected adults develop a lung disease. Investigations on twins indicate that external factors may also play a role in the development of lung damage.

Each gene in the cell is present in two copies: one on the maternal chromosome and the other on the paternal chromosome. But in genetics they are not referred to as copies but as alleles. For the AAT gene a distinction is made between the normal allele ("PiM") without risk of AAT deficiency and risk alleles ("PiZ", "PiS"). The risk alleles are associated with considerably reduced AAT plasma concentrations. PiZ is by far the most frequent and diagnostically important deficient allele which is of clinical relevance; ca. 95 % of all patients with a severe AAT deficiency have this mutation. The PiS allele which is also common appears to be only relevant in combination with PiT since individuals which only carry a homozygotic (= both alleles are affected) PiS mutation do not usually fall ill. Heterozygotic (= one of the two alleles are affected) carriers of the PiMZ and PiSZ phenotypes are usually asymptomatic or only have mild symptoms unless they are smokers. Most smokers with the heterozygous phenotype develop chronic obstructive pulmonary diseases which are not like those of homozygotic non-smokers. 

How can AAT deficiency be diagnosed?

The liver enzymes are elevated in most of the homozygotic (PiZZ) carriers of the disorder particularly in early childhood. A life-threatening liver disease occurs in every 10th child with PiZZ. This is often indicated by a prolongation of neonatal jaundice. However, there are often no acute symptoms immediately after birth, but in the following years a gradual inflammatory process occurs in the liver which is indicated by the following symptoms:

75 % of adults with a severe AAT deficiency develop a pulmonary emphysema between the age of 30 and 40, ca. 15 % develop a liver cirrhosis. However, both diseases rarely occur together.

Diagnostics

When an AAT deficiency is suspected, the content of the protein in blood is determined and the liver enzymes are also examined. Greatly reduced concentrations or the absence of alpha-1-antitrypsin indicate a homozygotic defect ("PiZZ"). Heterozygotic carriers of the disorder ("PiMZ", "PiSZ") usually have concentrations in the lower normal range. However, slightly elevated concentrations of alpha-1-antitrypsin may be measured when infections are present or when the patient is being treated with oestrogens or steroids. Hence the determination of the AAT level in blood is unsuitable for identifying heterozygotic carriers of the disorder. In this case it can only be reliably diagnosed by genetically typing the AAT allele.
An early diagnosis is extremely important for optimal and timely patient management. Since smoking is one of the most important risk factors, an early diagnosis helps through the initiation of patient education.

According to a WHO study, homozygotic carriers of the PiTT phenotype (males) who smoke only have an 18 % chance of surviving to the age of 55, whereas this was 65 % for non-smokers. This drastic reduction in life expectancy (by ca. 10-15 years) by the factor smoking alone shows the importance of an early identification of risk patients. Hence the WHO recommends testing of all patients with COPD or asthma for AAT deficiency and neonatal screening.

Figure: Non-smokers have a clear advantage especially when a PiZZ mutation has been diagnosed.

The GenoType® AAT test from Hain Lifescience GmbH is used to detect  the presence of the two most important mutations responsible for an AAT deficiency. These cause an amino acid substitution of glutamic acid by lysine in codon 342 (Piz) and a substitution of glutamic acid by valine in codon 264 (PiS) in the human AAT gene. This test allows a reliable differentiation and identification of homozygotic and heterozygotic carriers.

When is the GenoType® AAT-test indicated?

The test should be used in the case of: 

• patients with elevated liver enzymes
  
  
• patients with hepatitis or adults with liver cirrhosis of unclear origin
  
  
• patients with cystic fibrosis, clarification in the case of chronic obstructive pulmonary diseases, pulmonary emphysema or asthma
  
  
• patients that are known to have an AAT deficiency
  
  
• individuals who have a family history of such disorders
  
  
• clarification in the case of hepatitis and disorders of liver function of unclear origin in infants and small children, prolonged neonatal jaundice

Unfortunately genetic defects cannot be simply repaired. However, there are general methods for treating patients with liver diseases that are for example used for chronic liver diseases: 

• Administration of vitamin preparations especially those containing the fat soluble vitamins A, D, E and K because the absorption of these vitamins from the intestine is impaired in the case of liver and bile duct diseases. Deficiencies of these vitamins can result in disturbances of vision, disorders of blood coagulation and osteolysis.
  
  
• ursodeoxycholic acid to improve the flow of bile

The following methods are used to treat pulmonary emphysema:

• long-term treatment with oxygen
  
  
• learning special breathing exercises and breathing techniques
  
  
• AAT substitution treatments using synthetic or recombinant AAT (the effectiveness of this treatment is disputed and contra-indicated for liver damage).
  
  
• In the case of lung diseases in an advanced stage, only surgical procedures are effective such as lung reduction (by removing overinflated regions) or lung transplantation. 

In addition recommendations for prophylactic measures for AAT-deficient patients have been drawn up: 

• Patients with lung diseases should not smoke or should quit smoking and friends, family members or partners should not smoke in the presence of the affected individual.
  
  
• Avoid work in very dusty environments, in poorly ventilated rooms or where the oxygen supply is reduced. Avoid physical exertion..
  
  
• Vaccination against influenza and pneumonia pathogens which can put an additional burden on the lung.
  
  
• Avoid infections in general since any infection can have an effect on the production of alpha-1-antitrypsin. An elevated production can result in an additional burden in children and adults with liver disease. 

You can obtain further information from the web site of the German Emphysema Self Help Group
Deutschen Emphysem Gruppe e.V