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, which may be harmful, such as tobacco smoke.
However, these protease enzymes must be carefully regulated because 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, known as the SERPINA 1 gene. 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 to 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 because 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 to 40 years in smokers and 10 to 15 years later in non-smokers. Over the next 15 to 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 to 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.
Adult liver disease
The symptoms of liver disease due to alpha-1 antitrypsin deficiency in adults are similar to those in older children. But the disease may not become apparent for years.
The symptoms are the same as with any other liver cirrhosis: jaundice, abdominal swelling, bleeding into the gut and, ultimately, coma.
Alpha-1 antitrypsin deficiency is associated with an increased risk of hepato-cellular carcinoma or primary liver cancer. This cancer may be the first sign of disease.
Disease in alpha-1 antitrypsin carriers
It is unclear whether heterozygous carriers, eg those with one abnormal gene, are more prone to develop liver disease. Some liver disease currently of unknown cause may be due to alpha-1 antitrypsin deficiency.
Alternatively, reduced alpha-1 antitrypsin may worsen or increase susceptibility to liver disease due to other causes such as infection or alcohol.
How is alpha-1 antitrypsin deficiency diagnosed?
As with any uncommon condition, an important factor is for your doctor to consider the diagnosis.
Liver disease is rare in children, so alpha-1 antitrypsin deficiency will probably spring to mind. But it may be overlooked in adults, as there are many more common causes of liver disease.
Many cases are probably never diagnosed. It has been suggested that only 5 per cent of UK sufferers are ever identified. However, alpha-1 antitrypsin deficiency is relatively easy to detect by testing the blood alpha-1 antitrypsin levels.
The next step is to identify the exact alpha-1 antitrypsin variant, usually from blood tests. The exact gene defect can also be detected in this way.
Family screening
Genetic counselling for affected families is recommended, as well as tests to identify relatives at risk.
Prenatal diagnosis is possible, but may not predict the future severity of the disease.
What else could it be?
In children
- Liver disease in babies and children may be caused by infections either during the mother's pregnancy or after birth, producing hepatitis or liver inflammation. It may also be caused by drugs and inherited or familial diseases – including alpha-1 antitrypsin deficiency.
- Other genetic disorders include abnormal sugar or amino-acid metabolism and cystic fibrosis.
- Bile duct obstruction must be ruled out in infants, as patients may need corrective surgery.
- Diseases that cause clotting of the liver's blood supply should be investigated in older children.
In adults
- Emphysema and chronic lung disease in adults is usually linked to smoking or industrial lung disorders. Only 1 to 2 per cent of cases of emphysema are due to alpha-1 anti trypsin deficiency.
- Cirrhosis and liver failure is commonly caused by alcohol, chronic liver infections and autoimmune liver disease, and more rarely by haemochromatosis and Wilson's disease.
What can your doctor do?
Your GP is unlikely to be able to fully diagnose alpha-1 antitrypsin deficiency.
Liver disease in children is unusual, so referral to a hospital specialist would be necessary. Children may also require referral to a centre specialising in liver diseases in children.
In adults, lung and liver disease are often jointly managed by GPs and hospital specialists.
Good advice
It is extremely important to stop smoking. Smoking greatly increases the lung damage in alpha-1 antitrypsin deficiency.
What treatment is available?
The standard treatment for emphysema from any cause is with inhaled medicinesand antibiotics, which may be required to treat infections. The liver disease requires standard therapy for cirrhosis and liver failure as in many liver diseases.
If conventional long-term treatment does not prevent chronic progressive disease in the liver or lungs, organ transplantation may be considered.
In end-stage emphysema, single lung transplantation is an option. Volume reduction lung surgery may also benefit some patients.
Alpha-1 antitrypsin deficiency is the most common genetic disease requiring liver transplantation in children. But very few children with alpha-1 antitrypsin deficiency ever require a liver transplant.
Those who do have a good outlook with 90 per cent surviving one year and 80 per cent surviving five years. Results in adults are not so good, possibly due to associated lung complications. Specific therapy for alpha-1 antitrypsin deficiency is difficult. Regular weekly infusions of alpha-1 antitrypsin protein concentrate (prolastin) have been used, which should particularly help those with severe lung disease. However, prolonged benefit has not been established.
Alpha-1 antitrypsin replacement therapy is not currently available in the UK. There has also been research into gene therapy but trials have so far been disappointing.
How do you live with alpha-1 antitrypsin deficiency?
The outlook for patients with alpha-1 antitrypsin deficiency is good. Many people do not even know they have the condition. Progressive liver or lung disease affects only a minority but can be serious, so patients need monitoring regularly.
Liver function should be assessed by examination and blood tests, and further scans may be needed. Lung function can be measured by breathing tests, chest X-ray and CT scans.
<RETURN
<RETURN
