Alpha 1-antitrypsin deficiency

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What is Alpha 1-antitrypsin deficiency?

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.

Who gets Alpha 1-antitrypsin deficiency?

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.

Predisposing Factors

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

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.

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