Alpha-1 antitrypsin deficiency

Written by Dr David Maxton, gastroenterologist

What is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency is a disease caused by reduced or abnormal production in the body of the enzyme inhibitor alpha-1 antitrypsin. Body tissues and blood normally contain powerful enzymes - known as proteases - that can attack foreign substances within the body that may be harmful, such as tobacco smoke.

However, these protease enzymes must be carefully regulated as they could attack and damage normal tissues rather than the intended target resulting in local tissue damage.

Blood and tissues have a protease inhibitor that binds the enzyme to prevent unrestricted and potentially harmful protease activity. The commonest protease inhibitor in the blood is alpha-1 antitrypsin and its role is to protect the tissues from protease attack.

Alpha-1 antitrypsin is one of a family of proteins with similar functions known as the serine proteinase inhibitor (or serpin) superfamily. These proteins play an important role in controlling inflammation, coagulation and repair mechanisms in the body. Most alpha-1 antitrypsin in the body is produced by the liver. The liver is also damaged by alpha-1 antitrypsin deficiency, as are the lungs.

Who is at risk?

Alpha-1 antitrypsin deficiency is thought to be one of the commonest genetic deficiencies in Caucasian (or white) populations. Both sexes are at risk.

Alpha-1 antitrypsin deficiency has been found across Europe but the prevalence and type of the disease varies. The severe type of alpha-1 antitrypsin deficiency is commonest on the North Western European seaboard including the British Isles. Alpha-1 antitrypsin deficiency occurs in up to 1 in 1600 people in Scandinavia but is less common elsewhere.

Why or how do you get alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency is an inherited condition caused by a defective gene on chromosome 14. Genes are the sequences of DNA carried in chromosomes in the nucleus of cells.

Over 70 different variants of alpha-1 antitrypsin have been identified. In laboratory tests normal alpha-1 antitrypsin is labelled M.

Everyone inherits two copies of chromosome 14 and a normal person is designated PiMM. Pi stands for protease inhibitor. The two most important abnormal variants are called S and Z. Both result from mutations of the alpha-1 antitrypsin gene.

Individuals may have two of these abnormal genes labelled PiSS or PiZZ, or one of each PiSZ. This is called being homozygous. Or they may have one abnormal and one normal gene, eg PiMS or PiMZ . This heterozygous state makes you a carrier of the disease.

Alpha-1 antitrypsin genes are co-dominant, so each gene of the pair makes 50 per cent of the alpha-1 antitrypsin produced. But an abnormal PiZ gene only makes about 10 per cent of the alpha-1 antitrypsin produced by a normal PiM gene. PiZZ people have only 15-20 per cent of normal blood alpha-1 antitrypsin levels, which is linked to severe disease. People with one PiZ gene and one PiM gene, PiMZ, have alpha-1 antitrypsin levels around 60 per cent of normal (50 per cent from M and 10 per cent from Z). This is usually enough to prevent disease.

People with both PiS genes (PiSS) are less severely affected, with alpha-1 antitrypsin levels 60-70 per cent of normal. This can cause lung complications but not usually liver disease.

The mechanism by which alpha-1 antitrypsin deficiency causes damage to the lungs and liver is probably different.

How does alpha-1 antitrypsin deficiency progress?

The course of the disease largely depends on which abnormal genes a person has as this influences the amount and type of alpha-1 antitrypsin produced. But even people with apparently similar genes experience widely different effects.

Alpha-1 antitrypsin deficiency predominantly affects the lungs and the liver:

In the lungs, alpha-1 antitrypsin deficiency produces emphysema, a chronic progressive lung disease. The disease often becomes noticeable between the ages of 30-40 years in smokers and 10-15 years later in non-smokers. Over the next 15 -20 years the lung disease may gradually lead to respiratory failure and death. The progress of liver disease is even less predictable. Alpha-1 antitrypsin deficiency can produce jaundice and liver problems in babies within days of their birth. Some babies may develop a rapidly progressive disease, although symptoms often improve. A few children with alpha-1 antitrypsin deficiency develop significant liver disease before the age of 20. Liver problems due to alpha-1 antitrypsin deficiency may only become apparent in adult life. But few people, even those with the severe PiZZ variant, develop cirrhosis or liver scarring.

The progress of liver disease is even less predictable. Alpha-1 antitrypsin deficiency can produce jaundice and liver problems in babies within days of their birth. Some babies may develop a rapidly progressive disease, although symptoms often improve. A few children with alpha-1 antitrypsin deficiency develop significant liver disease before the age of 20. Liver problems due to alpha-1 antitrypsin deficiency may only become apparent in adult life. But few people, even those with the severe PiZZ variant, develop cirrhosis or liver scarring.

What are the symptoms of alpha-1 antitrypsin deficiency?

Respiratory (lung) disease The lack of alpha-1 antitrypsin leads to progressive lung damage by protease enzymes, especially when combined with other factors such as smoking.

Alpha-1 antitrypsin deficiency causes emphysema, a chronic progressive lung disease caused by destruction of lung tissue and permanent abnormal enlargement of airspaces. The abnormal airspaces tend to be at the base of the lungs. Affected people, especially smokers, complain of shortness of breath and a cough. This shortness of breath initially occurs only on exertion but can lead to difficulty breathing at rest. This usually occurs over 15-20 years, but can lead to respiratory failure and premature death.

Hepatic (liver) disease

In PiZZ people (at risk of severe liver disease), defective alpha-1 antitrypsin molecules tend to clump together in the liver cells producing toxic effects.

Childhood liver disease

Alpha-1 antitrypsin deficiency is the most common genetic or inherited cause of liver disease in infants and children. The first signs are often jaundice, pale stools, excessive bleeding or an enlarged liver - all non-specific signs of liver disease. This is described as 'neonatal hepatitis syndrome' and usually begins between four days and six weeks after birth. A few babies rapidly develop liver failure and cirrhosis.

Most infants will improve, with jaundice fading and liver blood tests returning towards normal, so urgent treatment is not required. In later childhood, patients with alpha-1 antitrypsin deficiency may develop signs of chronic liver disease and liver failure.

Some may have had jaundice or other liver problems after birth. The symptoms are the same as any other liver disease: abdominal pain, jaundice, itching, swelling of the ankles or abdomen and enlargement of the liver or spleen.

In severe cases bleeding from the gut, or drowsiness and coma, can cause complications.

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