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Alpha-1 antitrypsin deficiency (A1AD; Alpha-1; AATD)

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What is alpha 1-antitrypsin deficiency (A1AD, Alpha-1)?

Alpha 1-antitrypsin deficiency is an inherited disease which affects the liver and lungs. Alpha 1-antitrypsin is an enzyme which is synthesised in the liver. It is one of a family of enzymes known as protease inhibitors (Pi). The action of protease inhibitors is to stop (inhibit) another group of enzymes called proteases. Proteases break down proteins in the cells of the body. Protease inhibitors slow this process down.

When there is a normal amount of the alpha 1-antitrypsin enzyme in the body, the actions of the protease enzyme and alpha 1-antitrypsin balance each other out. If the level of alpha 1-antitrypsin is too low, however, protease enzymes can act unopposed, and cause excess protein breakdown.

A genetic mutation can cause these low levels of alpha 1-antitrypsin, potentially lead to disease in both the lungs and liver. In the liver it causes cell damage because the enzyme fails to be released from cells. In the lung it causes disease because protease enzymes go unchecked, causing degradation of lung tissue (particularly in response to smoking). This can eventually lead to emphysema.

Statistics on alpha 1-antitrypsin deficiency (A1AD, Alpha-1)

Alpha 1-antitrypsin deficiency is thought to affect approximately 1 in every 2000 – 5000 people. 1-2% of patients with emphysema probably have inherited severe alpha 1-antitrypsin deficiency. Overall, alpha 1-antitrypsin deficiency is thought to be under-diagnosed due to lack of awareness about the disease.

Risk factors for alpha 1-antitrypsin deficiency (A1AD, Alpha-1)

Alpha 1 antitrypsin deficiency is a genetic or inherited disease. The abnormal gene which causes alpha 1-antitrypsin deficiency is located on chromosome 14, and is passed down from parents to children. Every person has two copies of the alpha 1 antitrypsin gene. Three major versions of the gene have been identified: the normal version of the gene, called “M”, and two abnormal types, “S” and “Z”. These can be inherited in any combination. A person with normal levels of alpha 1 antitrypsin would have two normal copies, “MM”.

A person with alpha 1 antitrypsin deficiency may have either the “ZZ” or “SS” pattern. People with the genotype ZZ have only 15% of normal alpha-1-antitrypsin levels and people with SS have just 60%. This low level of alpha 1-antitrypsin is what causes symptoms of the disease.

Another group of people, known as heterozygotes or “carriers”, have one normal and one abnormal copy of the gene. For example, they may have an “MS” pattern, or a “MZ” pattern. This is relatively common in our society – about one in ten people are thought to be carriers – but mostly they do not show any signs of the disease.

Apart from genetics, the major factor which can change the course of disease in alpha 1-antitrypsin deficiency is cigarette smoking. Patients who smoke, or who have smoked in the past, tend to have significantly worse lung disease than those who have never smoked.

Progression of alpha 1-antitrypsin deficiency (A1AD, Alpha-1)

Alpha 1-antitrypsin deficiency usually only affects people with two abnormal copies of the gene (ZZ-type homozygotes). In these individuals it can present in infancy or childhood with jaundice, and lead to progressive liver damage and eventual liver failure requiring liver transplantation. Alpha 1-antitrypsin deficiency may also remain silent until adulthood, when it may manifest with either lung problems or liver problems.

The major lung disease caused by alpha 1-antitrypsin deficiency is emphysema. This is found in around 75% of patients. Patients may notice progressive breathlessness or a decrease in exercise tolerance.

The liver disease associated with alpha 1-antitrypsin deficiency is commonly hepatitis, presenting with jaundice (yellowing of the skin and eyes) and abdominal pain, potentially leading to cirrhosis in 10-15% of patients. 2-3% of patients with alpha 1-antitrypsin deficiency develop hepatocellular carcinoma (cancer of the liver) as a result of ongoing liver damage.

A major determining factor in the severity of lung disease with alpha 1-antitrypsin deficiency is cigarette smoking. This is because smoking markedly accelerates the rate of lung damage. People with only one abnormal copy of the gene (heterozygotes) have a small risk of developing liver or lung disease.

How is alpha 1-antitrypsin deficiency (A1AD, Alpha-1) diagnosed?

Simple tests to assess the presence of liver or lung disease include:

Specific testing is also available to assess the level of alpha 1-antitrypsin in the blood. If the level is low, then it is probable that a genetic mutation is present. Further tests are then needed to determine the genotype (eg. MM, MZ or ZZ). In some cases, a liver biopsy may be used to assess liver damage.

Prognosis of alpha 1-antitrypsin deficiency (A1AD, Alpha-1)

People with two abnormal copies of the alpha 1-antitrypsin gene have a high risk of developing liver or lung disease at some point in their lifetime. Around 10-20% will present with hepatitis in infancy or childhood, and a large proportion of the rest will present with emphysema or liver disease in adulthood.

Attacks of hepatitis in early adulthood may resolve with apparent complete recovery, or lead progressively to cirrhosis of the liver. Cirrhosis of the liver has no treatment apart from liver transplantation, but not all patients with liver disease will progress to cirrhosis.

The prognosis of emphysema depends on how well a patient abstains from smoking.

Overall, the most common cause of death in patients with alpha 1-antitrypsin deficiency is respiratory failure, accounting for about half of all deaths. Cirrhosis of the liver is the second commonest cause of death.

How is alpha 1-antitrypsin deficiency (A1AD, Alpha-1) treated?

There is currently no cure for alpha 1-antitrypsin deficiency. Treatment is mainly supportive, aimed at reducing symptoms and attempting to slow disease progress. In patients with emphysema due to alpha 1-antitrypsin deficiency, supportive treatment is given as for other patients with chronic lung disease. This may include:

  • Stopping smoking;
  • Using inhaled bronchodilators (such as salbutamol) which relax airways in the lungs, making breathing easier;
  • Pulmonary rehabilitation, which includes education, physiotherapy and exercise training;
  • Oxygen therapy;
  • Immunisations, for example against influenza;
  • Consideration of lung transplantation in carefully selected patients.

Some patients with lung disease may be offered “augmentation therapy”. This is a new type of treatment where human alpha 1-antitrypsin enzyme is collected from blood donations and given intravenously to the patient. It is recommended for use in patients with severe lung impairment. However, this treatment is expensive, not widely available, and only suitable for some patients. There is no specific treatment for liver cirrhosis. Supportive treatment can be given, and liver transplantation can be considered for patients with cirrhosis who are showing signs of liver failure.


  1. American Thoracic Society/European Respiratory Society statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. [Full text]
  2. Braunwald E, Fauci AS, Kasper DL, et al. Harrison’s Principles of Internal Medicine (15th edition). New York: McGraw-Hill Publishing; 2001.
  3. Cotran RS, Kumar V, Collins T, Robbins SL. Robbins Pathologic Basis of Disease (6th edition). Philadelphia: WB Saunders Company; 1999.
  4. Longmore M, Wilkinson I, Torok E. Oxford Handbook of Clinical Medicine (5th edition). Oxford: Oxford University Press; 2001.
  5. Kumar P, Clark M (eds). Clinical Medicine (5th edition). Edinburgh: WB Saunders Company; 2002.
  6. Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365(9478):2225-36.
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Posted On: 13 September, 2003
Modified On: 15 May, 2018
Reviewed On: 3 March, 2007


Created by: myVMC