Contents

Alpha 1 Antitrypsin Deficiency

Alpha 1 Antitrypsin Deficiency (sometimes called alpha 1 or A1AD) is a genetic disease where patients cannot produce the enzyme inhibitor alpha 1 antitrypsin (A1A). This protein is normally produced in the liver. Sometimes there may be some A1A produced but not enough.

Many body tissues and blood contain powerful enzymes collectively known as proteases. Proteases are released from white blood cells in response to attack from foreign elements, chemicals and agents which may be harmful. An example of a common protease found in the lungs is the enzyme neutrophil elastase. This attacks foreign particles, bacteria and old lung cells. However, neutrophil elastase also has the potential to attack and destroy normal, healthy cells and tissues. Therefore, its activity needs to be regulated and controlled in order to avoid the targeting of local healthy cells. A1A is the enzyme inhibitor which would usually control the action of neutrophil elastase. But if there is a deficiency of A1A, enzymes such as neutrophil elastase cannot be controlled, leading to destruction of lung tissue. This leads to an emphysema like condition of the lungs causing difficulty in breathing. Alpha 1 can also cause problems in the liver leading to cirrhosis. Liver damage can occur in both children and adults. The only solution in cases of severe liver disease such as cirrhosis is liver transplantation.

Who Is At Risk of Having Alpha 1?

Alpha 1 is one of the commonest genetic disorders. It is particularly common amongst white Europeans. In the UK, it is probably the second commonest genetic disorder after cystic fibrosis. Alpha 1 is a recessive genetic disorder – this means that those who have the disease have inherited 2 copies of the gene. If only one copy is inherited, the individual is a carrier and may have mild A1A deficiency which is not medically significant. Approximately 1 in 25 of the British population is thought to carry an abnormal gene for alpha 1 leading to approximately 1 in 2700 babies with the full disease.

The abnormal gene has been located on chromosome 14. Normal genes for A1A production are called “M” genes. Abnormal genes are known as “S” or “Z” and a totally non-functioning gene is known as “Null”. How much A1A an individual produces depends on the many combinations of these types of genes and various environmental factors.

Symptoms of Alpha 1

How this disease affects an individual depends on many things. The exact number and type of abnormal genes involved clearly has the greatest influence on outcome and symptoms. But sometimes, patients with apparently similar genetic defects have widely differing symptoms and degrees of illness. The course of the condition therefore depends on how much A1A is actually produced by an individual. The two organs primarily affected by alpha 1 are the lungs and the liver. These organs are now discussed separately as often, only one or the other organ is primarily affected. However, there may be evidence of both lung and liver disease to some extent in some patients.

Alpha 1 Lung Disease

Patients who predominantly develop lung disease as a result of A1A deficiency usually have increasing problems with breathing. Initially, this may only be displayed during or after exercising. But as the destruction of healthy lungs continues, patients become more and more breathless until even gentle exercise becomes difficult. Ultimately, patients are short of breath even at rest.

This occurs as foreign particles such as infections and pollutants enter the lungs. The normal response of activation of neutrophil elastase is triggered enabling the lungs to repel these dangers. However, as the patient cannot produce enough A1A to counteract the neutrophil elastase, the action of neutrophil elastase goes unchecked. The result is that this enzyme continues to attack, leading to the destruction of normal healthy lung tissue. This usually occurs at the cells lining the smallest lung air pockets first. These are called alveoli and are essential for normal lung function. The destruction of alveoli leads to a condition called emphysema. As alveoli are destroyed, these small air pockets become larger. The larger they become, the more inefficient they become in bring oxygen to the blood and taking away carbon dioxide from the blood (this is called gas exchange). In addition, air becomes increasingly trapped within the lungs with the result of hyper-inflating the lungs, further reducing their efficiency.

The key factor in how quickly alpha 1 patients develop emphysema is smoking cigarettes (or any other form of tobacco). Smoking rapidly accelerates lung destruction and the progress of emphysema. Alpha 1 patients must therefore stop smoking immediately. Emphysema usually becomes noticeable at around 30-40 years of age in smokers. But the condition may be delayed by 10-15 years in non-smokers. Over the following 10-20 years, emphysema progressively gets worse leading to respiratory failure and death.

Unfortunately, these patients are also susceptible to other lung conditions such as chronic bronchitis and asthma. This may lead to a chronic cough with or without phlegm. Regular chest infections such as pneumonia may also become problematic and require frequent intervention and treatment.

Treatment of Alpha 1 Lung Disease

There is currently no cure for alpha 1 antitrypsin deficiency. But certain treatments to slow down lung disease and treat the symptoms of lung disease need to be considered. Most of these are drug treatments although some surgical options may also be considered. The most important treatment options are;

1. Stop Smoking

This is paramount and must be strongly encouraged for all alpha 1 patients as even those with predominantly liver disease may develop some degree of lung disease. Smoking and the development of emphysema is discussed above.

2. Vaccinations

As increasing lung destruction can lead to a high risk of respiratory infections, which then become increasingly difficult to treat, it is important to protect vulnerable patients from those that can be prevented. Therefore, a yearly flu vaccine and a 5 yearly pneumococcal vaccine are recommended. In addition, as lung disease sufferers may also suffer some degree of liver disease, vaccination against hepatitis A and B is also advised.

3. Treatment of Infection

Patients should be aware of all possible symptoms and signs of chest infections and pneumonia. Prompt assessment and treatment is vital. Symptoms to consider seriously include;

  • fever
  • increased shortness of breath (dyspnoea)
  • increased cough with or without phlegm (sputum)
  • changes in the colour of phlegm produced
  • coughing up blood.

Antibiotics may be required if the infection is believed to be bacterial rather than viral in origin. Sometimes, making this distinction is not possible or may take too long. In these instances, antibiotics are usually started immediately anyway.

4. Bronchodilators

These medicines are usually given to patients in the form of inhalers or in the form of liquid to be used with a nebuliser. Often, an asthma like condition develops where the upper airways of the lungs constrict (bronchospasm) and reduce airflow into and out of the lungs. Drugs that relax the airway muscles counteract this constriction and enable the airways to expand. 2 types of bronchodilators may be used;

  • beta-agonists – such as salbutamol or terbutaline. These are quick acting agents and work within 5-10 minutes of inhalation. Their effect may last around 4-6 hours.
  • anti-cholinergics – such as ipratropium. These are longer acting than beta-agonists.

Both types of bronchodilators are used when patients begin to have increasing symptoms of bronchospasm such as shortness of breath, cough or wheezing. Often, these symptoms are worst at night.

5. Corticosteroids

These drugs can be given in inhaler, nebuliser or tablet form. Often, patients are given an inhaled form to use on a regular basis to prevent flare ups (exacerbations) of bronchospasm. If these are too frequent or too severe, then regular steroid tablets may be considered. Sometimes, a short course of steroid tablets is issued to help relieve the symptoms of an exacerbation.

6. Supplemental or Domiciliary Oxygen Therapy

Oxygen may be required at home in those with severe lung disease. Patients may require oxygen during or after periods of increased activity or may require oxygen even at rest. Sometimes, it is used during sleep.

7. Augmentation Therapy

This is a relatively new form of treatment and its benefits are largely unproven. It may not be available in some countries. It consists of intravenous infusions of alpha 1 antitrypsin on a weekly basis. The A1A is obtained from human plasma. Currently, this is used for lung disease alpha 1 patients only and mainly only those with emphysema. It tends to be reserved for those with particularly low levels of A1A.

Side effects are unusual but can include headaches, muscle & joint pains, especially lower back pain and oddly, a worsening of the shortness of breath in some patients.

8. Lung Volume Reduction Surgery (LVRS)

Lung Volume Reduction Surgery (LVRS) is when portions of damaged lungs are removed, thereby shrinking the total volume of the lungs. But the effect of this tends to be improvement of the efficiency of the remaining normal and healthier areas of lung tissue. This makes breathing easier and more efficient. The benefits of LVRS are not clear cut and some patients may notice no benefit. Surgeons will therefore carefully select patients for this procedure.

9. Lung Transplantation

For those patients with end stage lung disease and where other therapies have failed, the only option may be lung transplantation. This is becoming a more realistic option as surgeons gain more experience with transplantation surgery.

Alpha 1 Liver Disease

As with lung disease discussed above, alpha 1 patients may primarily have liver disease instead or have a combination of both liver and lung disease where the liver is affected the most.

Liver disease in alpha 1 patients can occur at any age from infancy to old age. It can be mild and transient (with temporarily deranged liver tests) to severe, permanent and life threatening. Tests for liver disease in these instances are similar to liver disease from any other cause. Therefore, initially, blood tests are taken to measure clotting, liver enzymes and several other parameters. Depending on the results of these or the patient’s symptoms, other tests such as ultrasound scans, CT or MRI scans and endoscopies may be required. Ultimately, a liver biopsy may be needed for a detailed assessment of liver tissue under microscopic examination.

The exact method causing liver damage in alpha 1 patients still remains unclear. It is also unclear why only some patients with this condition go on to develop liver disease and why others do not. Liver disease tends to be less common than lung disease. The mechanism causing liver disease is thought to relate to a problem with clearing A1A from liver cells which leads to clumping of A1A inside the cells. This causes the cells to become damaged.

Symptoms and Signs of Alpha 1 Liver Disease

The symptoms and signs of liver disease in alpha 1 patients are similar to liver diseases from other causes. These include;

  • none: liver disease may be found incidentally,
  • a feeling of being unwell,
  • fatigue,
  • nausea,
  • vomiting,
  • diarrhoea,
  • weight loss,
  • dry eyes and mouth,
  • red or pink, blotchy, mottled patches on the palms of hands (palmer erythema),
  • abnormal small blood vessels on the surface of the skin, mainly on the face, chest and arms (spider naevi),
  • abdominal pain or discomfort,
  • itching of skin,
  • enlargement of the liver (hepatomegaly),
  • jaundice: yellowing of the skin and whites of the eyes,
  • passing dark urine: associated with jaundice,
  • passing pale or clay coloured stools: associated with jaundice,
  • bruising,
  • bleeding from any site e.g. gums, nose, wounds, rectum, vagina,
  • abdominal distension from fluid collecting in the abdomen (ascites),
  • vomiting of blood (haematemesis), from oesophageal varices,
  • confusion and an altered level of consciousness (hepatic encephalopathy),
  • coma,
  • death.

Primary liver cancer (hepatocellular carcinoma): alpha 1 patients have a higher risk of developing this condition. The diagnosis of cancer may be the first time that the patient becomes aware of any liver disease.

Treatment of Alpha 1 Liver Disease

There is currently no cure for alpha 1 antitrypsin deficiency related liver disease (but see below regarding liver transplantation). But certain treatments can slow down the progression of liver disease and treat the symptoms of liver disease. The most important treatment options are;

1. Stop Smoking

This is paramount and must be strongly encouraged for all alpha 1 patients as even those with predominantly liver disease may develop some degree of lung disease. Smoking and the development of emphysema is discussed above.

2. Alcohol Intake

Avoiding alcohol is just as vital for alpha 1 liver disease patients as smoking is for lung patients. Reducing and stopping alcohol intake will help to slow the progress of liver disease to cirrhosis.

3. Healthy Diet

This is again useful for liver disease patients. In those with severe disease, weight loss, deficiencies of vitamins and minerals and muscle wasting may all become a problem. It is essential to ensure that patients have the best diet possible to counteract these problems.

4. Vaccinations

Vaccination against other liver conditions such as hepatitis A and B is usually advised. In addition, it is imperative to protect the lungs as much as possible. Increasing lung destruction can lead to a high risk of respiratory infections, which then become increasingly difficult to treat. It is important to protect vulnerable patients from those infections that can be prevented. Therefore, a yearly flu vaccine and a 5 yearly pneumococcal vaccine are recommended

5. Treatment of Infection

Although this applies mostly to lung patients, it is also important for sufferers of liver disease to avoid all other complications and concurrent illnesses. Therefore, patients should be aware of all possible symptoms and signs of chest infections and pneumonia. Prompt assessment and treatment is vital. Symptoms to consider seriously include;

  • fever
  • increased shortness of breath (dyspnoea)
  • increased cough with or without phlegm (sputum)
  • changes in the colour of phlegm produced
  • coughing up blood.

Antibiotics may be required if the infection is believed to be bacterial rather than viral in origin. Sometimes, making this distinction is not possible or may take too long. In these instances, antibiotics are usually started immediately anyway.

6. Liver Transplantation

A liver transplant may be the only option for those patients with either rapid onset fulminant hepatitis or those with chronic liver disease leading to cirrhosis and liver failure. However, those that do have this major surgery usually do well. In fact, it is one of the few curative methods available. A new donated liver is likely to have a normal ability to produce the deficient alpha 1 antitrypsin protein. This can then be used by the body to neutralise neutrophil elastase as normal, thereby eliminating the problem!

As has been discussed elsewhere in this liver guide, living donor liver transplantation is becoming increasingly the method of choice for transplants. But in the case of alpha 1 patients, this may not be preferable as a living donor is likely to be a close family relative. He or she may therefore also be at increased risk of carrying faulty genes and therefore have lower than normal A1A production. A cadaveric transplant may therefore be a better choice.

Resources on Liver Transplant Surgery

Treatment Locations for Liver Transplants

Retrieved from "http://www.globehealthtours.com/directory/Alpha_1_Antitrypsin_Deficiency"

From Surgery abroad with Globe Health Tours.