Diagnosis and Treatment

Alpha-1 Antitrypsin Deficiency (AATD) is one of the most common serious hereditary disorders. AATD has been identified in virtually all populations but is most common in individuals of Northern European (Scandinavian and British) and Iberian (Spanish and Portuguese) descent. Among patients with Chronic Obstructive Pulmonary Disease (COPD), 1 to 2% are predicted to have AAT Deficiency. It can also cause life threatening liver damage in adults and children and liver cancer in adults. Panniculitis and vasculitis caused by AATD are observed occasionally. Despite its prevalence, patients and healthcare providers have been poorly informed about the disorder. For this, and other reasons, the overwhelming majority of individuals with AAT Deficiency have not been detected.

What is Alpha-1 Antitrypsin Deficiency?

Alpha-1 Antitrypsin (AAT) Deficiency is a genetic disorder characterised by the production in the liver of an abnormal AAT protein. The liver cells cannot secrete this abnormal AAT protein, which accumulates within the cells and results in a marked reduction of circulating AAT levels. Although the mechanisms are not completely known, it is believed that the retained abnormal AAT protein over time leads to liver injury in some affected persons. In the lungs low-levels of AAT allow for the destructive effects of neutrophil elastase to go unchecked. This results in damage to the delicate gas exchange region of the lungs (alveoli), eventually leading to emphysema in people as young as 30 years of age. Thus, people with AAT Deficiency are at high risk of developing life-threatening liver and lung disease.

Molecular Biology

The gene encoding AAT is located on the long arm of chromosome 14 within the q31-32.3 region and it named SERPINA1 or Protease inhibitor (Pi). There are many hereditary variants of the Pi gene. The most frequently occurring family of ‘normal’ alleles is described as PiM. The most common alleles leading to AATD are PiZ and PiS. A series of null alleles (designated PiQ0 or Pinull) is associated with the most severe deficiency, producing no active AAT or less than 1% of the normal amount in the plasma.

There are more than 100 different allelic variants of AAT but most of these are very rare.

Genetics

The two most important genetic aspects of Alpha-1 Antitrypsin Deficiency are the understanding that there are many alleles for the protein and that the clinical manifestations (lung and liver disease) result from specific combinations of alleles.

Because two forms of AAT can be detected (one paternal and one maternal) the hereditary mode is recessive (also called co-dominant). In a given individual the phenotypes (protein types) describe both forms: PiMM, PiMZ, PiZZ, PiSZ, etc.

Phenotype     What Does It Mean?
Pi ZZ (Homozygote)  Patient has Alpha-1 Antitrypsin Deficiency
Pi MZ (Heterozygote)  Patient is a CARRIER of Alpha-1 Antitrypsin Deficiency and can pass these genes on to their children
Pi MM Patient does NOT have Alpha-1 Antitrypsin Deficiency

Clinical Manifestations

Clinical manifestations are always present in patients with complete absence of serum alpha-1 antitrypsin (null variants). The majority of patients with ZZ or SZ genotypes, and some with the SS genotype, have pulmonary or hepatic symptoms. Heterozygous individuals, with both a normal and a variant allele (MZ or MS), rarely develop clinical symptoms.

Emphysema

Pulmonary emphysema is described as an irreversible distension of the lungs as a result of the destruction of pulmonary tissue. AATD patients tend to present with the following profile:

  • Pulmonary emphysema in young adults (before the age of 45)
  • Pulmonary emphysema without typical risk factors, such as tobacco smoking or occupational exposure to dust or airborne particles
  • Pulmonary emphysema predominantly of the lower lobes
  • Chronic hepatitis without other explanation
  • Family members with pulmonary disease or ancestors with pulmonary emphysema in young adulthood, bronchiectasis, or liver cirrhosis

In the case of interstitial pulmonary diseases such as sarcoidosis and idiopathic fibrosis, pulmonary emphysema may occur in serious forms at a later stage of the disease. Even without the assistance of a pulmonary function test, pulmonary emphysema can be clinically determined and distinguished from chronic bronchitis.

Emphysema Bronchitis
Medical history of smoking  Medical history of smoking
Little evidence of coughing  Constant coughing and expectoration
Barrel-shaped thorax  not applicable
Reduced respiratory breadth  not applicable
Weakened respiratory sounds  Dry rhonchi
Hyper-sonorous percussion sound  not applicable
Dyspnoea on exertion  Dyspnoea with exacerbation

Around 1 to 2% of all emphysema patients have a congenitally serious Alpha-1 Antitrypsin Deficiency (AATD). In view of the fact that not all people suffering from emphysema have been diagnosed as such, the number of people with AATD cannot be specified with any precision.

If figures from the neonate screening in Sweden are taken as basis, 1 out of every 1,700–5,000 Caucasians is affected by AATD. Assuming 728 million Europeans, this is 145,000-425,000. Worldwide only some 5,000 people have so far been diagnosed and registered.

Identification of Patients

The recommendation of the World Health Organization (WHO) is that all adult patients with the following problems should be tested for AATD:

  • COPD
  • Asthma
  • Family history of AAT Deficiency
  • Chronic liver disease

Other conditions not specifically recommended by WHO, but possibly indicating increased risk for AAT Deficiency include:

  • Bronchiectasis
  • Panniculitis
  • Unexplained vasculitis, particularly of Wegener’s granulomatosis type
  • Hepatocellular carcinoma
  • Any evidence of unexplained liver disease

If these conditions are seen in non-smokers of any age, or if COPD occurs at an early age (30 to 55) in smokers, the likelihood that AAT Deficiency is a causative factor is increased.

Lung Function Tests

Pulmonary function testing is an important means of diagnosing COPD and for monitoring its progression. Spirometry is frequently used for recording long-term deterioration of patients through changes in forced expiratory volume in 1 second (FEV1). The annual loss in healthy people is approximately 30ml, this rises to 100ml in severely AAT deficient patients. FEV1 measurements require a lot of cooperation from the patient and a number of attempts may be needed to gather reliable data.

As emphysema progresses the vital capacity (VC) may slowly increase. Whole body plethysmography is required for more precise determination of this. Other tests that may be found to be necessary are for increased airway resistance (Raw) and elevated residual volume (RV).

Measurement of carbon monoxide diffusion capacity (DLCO) is another technique of lung function testing. This shows the global gas exchange potential between the alveolar pace and the pulmonary capillaries. AATD patients have a DLCO of 50 ± 22% of normal values.

Biochemical Tests

If AATD is being considered in a differential diagnosis a quantitative serum analysis should be conducted. This measurement is inexpensive. It is recommended that C-reactive protein (CRP) is assessed at the same time because AAT that may be elevated during inflammation and so appear deceptively normal in patients with medium grade deficiency. Simultaneous measurement of CRP will help identify this possibility. The normal serum concentration in adults is 1.5 to 2.5 g/L. Sometimes the concentration is expressed in micromoles per litre – these figures are roughly 20 times the value when expressed in grams per litre. Homozygotic PiZZ patients typically have a serum level of AAT less than 0.3 g/L. The minimum protective level is generally accepted to be 0.8 g/L

Phenotyping is a more complex analysis, which measures the electrophoretic mobility of the AAT molecules. The conventional names of the alleles are based on this test: F (fast: anodic), M (medium: moderate mobility), S (slow anodic mobility), Z (cathodic).

The more common M, S and Z alleles may be detected by genotyping using a polymerase chain reaction (PCR) to amplify the point mutations which are then detected by various means. This process is becoming more popular and can be cheaper than IEF. If a rare allele is suspected and a suitable PCR probe is not available then genetic sequencing may be performed. This is a more expensive option and only needed when the clinical picture is confused.

Radiology

Pulmonary emphysema is the typical manifestation of advanced disease. Chest radiographs show that the apical section is not affected in 62% of cases. When emphysematous changes predominate in the basal regions of the lungs, the central and peripheral sections are also affected. Bullous changes are not unusual in alpha-1 antitrypsin deficiency. Thickening of the bronchial walls and peripheral dilation are rare pulmonary changes.

Computed tomography (CT) allows more detailed visibility than conventional chest radiography. The base of the lungs tends to be more affected by the destruction of the lobular alveoli than in other forms of emphysema. Additionally, pronounced vascular loss can be detected in the peripheral lungs. In chronic bronchitis associated with AATD bronchial wall thickening is more pronounced than in chronic bronchitis caused by smoking.

Ongoing Care

After confirming AAT Deficiency the following baseline data should be collected for monitoring the progression of the condition:

  • Posteroanterior (PA) and Lateral Chest X-Ray or a high resolution CT
  • Lung function tests (Lung volumes, DLCO, Arterial blood gases, etc.)
  • Liver biochemical tests (AST, ALT, Bilirubin, Albumin, etc.)
  • Liver ultrasound examination

Treatment

The forms of treatment listed on this page for the confirmed AAT deficient patient are:

Behavioural & Lifestyle Change
Drug Therapy for Lung Problems
Surgical Options.
Specialised Therapy for AAT Deficiency

Behavioural & Lifestyle Change

Alpha-1 Awareness publishes Living with Alpha-1 a lifestyle guide for people diagnosed as having the genetic condition Alpha-1 Antitrypsin Deficiency.  An online version is also available.

Individuals with AAT Deficiency should NEVER smoke. Evidence shows that smoking tobacco products significantly increases the risk and severity of emphysema in AAT deficient individuals and may decrease their life span by ten years or more. Exercise and nutritional plans also contribute to maintaining a healthy body, which places less stress on the lungs. These three issues are explored in further detail below:

Smoking Cessation

This is the first priority in managing patients with AAT Deficiency. Lifelong non-smokers will have a good chance of avoiding serious lung disease, even with AAT Deficiency. Current smokers should stop smoking upon diagnosis; this is because the most severe lung function impairment is seen in current or former smokers. Smoking attracts white blood cells to the lungs in large numbers and speeds the development of lung disease. The lungs in AATD patients do not have the normal defences against the white blood cells and neutrophil elastase.

Avoiding Environmental Pollution

Although formal studies are lacking, it is probably advisable for Alphas (persons with AAT Deficiency) to avoid occupational and environmental pollutants that can be inhaled (including pollen, dust, areas with high levels of air pollution, and second-hand tobacco smoke). These substances can cause further irritation of the lungs and worsen the current condition of the patients with disease. Avoid both indoor and outdoor air pollution such as particulates smaller than 10 μm (found in highly industrialised urban regions) and exposure to aerosol sprays. Alphas may encounter pollutants and infections at both home and at work, thus there are two sets of recommendations.

In the Workplace

Patients should avoid exposure to inorganic or organic dust (brick, hay, etc.) or irritating gasses (i.e. chlorine, isocyanates, etc.). Patients should seek the healthiest possible work environment, and demand clean indoor air, with proper ventilation and filtration systems and avoid second-hand tobacco smoke whenever possible. They should wear protective clothing (gloves, etc.) when handling any type of chemical compounds since these may be absorbed through the skin and could further damage an already compromised liver. Read labels carefully and be aware of potential dangers from these agents.

In the Home

Patients should be advised to avoid the following in the home: chlorine and ammonia (found in some household cleaning products), pesticides, fireplace smoke, aerosols, powders, etc.

Since bacterial and viral infections are harmful to the lungs, patients should also be advised to try to avoid contact with sick or infectious people. Thorough handwashing with an antibacterial soap is the single most effective way to avoid both contracting and spreading infectious diseases.

Development of an Exercise Programme

Although formal studies are lacking, routine exercise can improve mental outlook, stamina and physical well being. Exercise is essential to all Alphas.

Supervised aerobic and strength exercises should begin as soon as possible after diagnosis.

Walking, strolling, swimming, and/or cycling can facilitate exercise, which may be beneficial in improving lung function and endurance.

It is important for all Alphas to have personally tailored exercise programmes carefully monitored by an exercise specialist. Patients should start exercising slowly and increase levels of exercise over time as their tolerance for exercise increases.

A Pulmonary Rehabilitation programme is highly recommended for Alphas. This can help an individual with pulmonary disease through exercise, breathing retraining, education, smoking cessation, and nutrition counselling. The programme must be tailored to the patient’s specific needs.

Alcohol Consumption

Alcoholic beverages can damage the liver even in normal people. Many authorities recommend low, infrequent or no alcohol consumption for PiZZ patients. Patients with any indications of AAT-related liver damage should avoid alcohol completely.

Development of a Nutrition Programme

Although there is a lack of formal research regarding the effects of specific dietary recommendations, proper eating habits may help to preserve lung and liver function. It is important for all patients to maintain an ideal body weight, whether he/she has lung/liver disease or not. Since scientific research indicates that people with lung disorders need to consume more calories than healthy people, this affects the manner in which the patient should approach nutrition. Supportive nutritional needs in those patients exhibiting liver complications due to AATD are highly case-specific. Since sodium and protein intake may become a concern in patients with liver failure, good dietary advice is recommended. In the AATD patient who exhibits signs of liver complications, fat absorption may be altered; therefore some physicians recommend supplementing the diet with vitamins A, D, E, and K. The dietary requirements of an infant experiencing feeding difficulties are best referred to a specialist in this field. Recommend to the patient that he/she should establish or maintain good eating habits. If the patient has lung and/or liver problems it may help to work closely with a dietician, who will be able to set up an appropriate, individualised nutritional plan.

Reducing Stress

Persons with AAT Deficiency (Alphas) report benefits with stress reduction techniques. There are many relaxation techniques that help in reducing stress. Here are a few:

  • Breathing exercises
  • Hypnotherapy
  • Mediation
  • Muscle relaxation
  • Positive thinking
  • Improving sleep patterns
  • Biofeedback
  • Yoga

A patient may have concerns about informing his or her family about Alpha-1 Antitrypsin Deficiency. If talking to family members about the genetic aspects of AATD is a real or potential source of stress then the patient could be encouraged to seek genetic counselling.

Drug Therapy for Lung Problems

This is among the most important type of medical therapy for the newly diagnosed individual with AAT Deficiency.

Vaccinations

It is important for Alpha patients to have a yearly influenza vaccine and a pneumococcal bacteria vaccine every five to six years. Since his/her lungs are vulnerable to pollutants and infections, the use of these prophylactic vaccinations is of the utmost importance.

Effective vaccines are available for hepatitis A and B. These are especially important in patients with established liver disease.

Recommendations:

  • Annual influenza vaccine
  • Pneumococcal polysaccharide vaccine (PPSV)  – administration or confirmation every 5 to 6 years
  • Hepatitis A vaccine
  • Hepatitis B vaccine

Aggressive Treatment of Lung Infections

Prompt and aggressive treatment of infections is recommended due to the increased neutrophil elastase burden during infection. It is important that Alphas seek immediate professional medical advice at the first indications of a lung infection. Here is a list of common symptoms they should be aware of:

  • Fever
  • Chills with fever
  • Increased shortness of breath
  • Changes in colour of phlegm
  • Increased coughing  – may not be productive

Because the lungs attract more leukocytes when an infection is present, and the leukocytes release neutrophil elastase, it is important to control lung inflammation. Steroids may be prescribed to reduce the severity of exacerbations. Antibiotics may be given to reduce the effects of the causative or opportunistic bacteria. Suitable patients may be given a supply of steroids and/or antibiotics to be kept at home in line with NICE Guidance on COPD.

Another piece of preventive advice for the patient is:

  • Avoid people who are sick – infected individuals
  • Avoid children under five years of age  – often infectious or exposed to infections

Aggressive Evaluation of Liver Complications

It is important for parents, caregivers or social care workers to be aware and advised of any indication of complications related to liver disease. Here is a list of common symptoms that may require therapy:

  • Increased abdominal swelling – ascites
  • Coughing up or vomiting bright red blood
  • Blood in stools or blackish/purplish stools
  • Little or no urine
  • Dark urine
  • Fever
  • Lack of energy, easily fatigued
  • Confusion, unusual crying, disorientation, lethargy
  • No appetite/refusal to eat or drink
  • Itching or increased itching
  • Peripheral oedema
  • Change in, or the appearance of, jaundice.

It is very important to inform the individual to read carefully the labels on over-the-counter medications and to be certain to inform the healthcare provider if alternative medicines or vitamin supplements are being taken.

Bronchodilators

Bronchodilators may be useful in relieving the symptoms of AAT Deficiency. Depending on the specific medical history and present condition of the patient, bronchodilators may be advisable. Short acting β2 sympathomimetics (Salbutamol, Terbutalin,etc) are the medications of choice to treat obstruction of the small bronchi caused by the smooth muscles. A combination of β2 sympathomimetics and anticholinergics is currently recommended as first-line treatment for symptomatic patients with obstructive disease of the airways. In long-term treatment, the long-acting anticholinergic tiotropium is assumed to be superior to the short-acting ipratropium.

Corticosteroids

Inhaled corticosteroids can be useful as a preventative treatment for AAT Deficiency and oral corticosteroids may be helpful during exacerbations. In the latter, Prednisolone is found to lead to faster improvement in FEV1 than placebo. However, the positive effect wears off after 14 days. Typically the oral dose given during exacerbations is reduced over fourteen days to minimise signs of adrenal insufficiency. Preventative inhaled doses however, form part of a normal long-term treatment regimen.

Supplemental Oxygen

For people who need supplemental oxygen, it has been shown to be lifesaving. Oxygen can be important for individuals with low blood oxygen levels, during active infections and/or with progressive destruction of the lung tissue. Supplemental oxygen may be needed during exercise and/or sleep. Supplemental oxygen is also recommended during exercise. For some Alphas, it is especially important when travelling by air, because cabin air pressure is reduced at altitude.

Surgical Options

Lung Volume Reduction (LVR)

Lung Volume Reduction is especially promising in the case of target zones in the apical lungs. There is some concern about the outcome in the case of basal pulmonary emphysema which is typical for AATD patients. Studies have shown that AATD patients return to baseline figures after 6 to 12 months. Further deterioration is found after 2 years.

However, with carefully selected patients, LVR and other thoracic surgical interventions such as bullectomy may be found to be beneficial.

Organ Transplantation of Lung or Liver

Lung/liver transplantation is becoming a viable option for some patients. As experience with new surgical techniques (particularly single lung transplantation) increase, lung transplantation may become more attractive to AAT deficient patients with end-stage lung disease.

Living donor transplant is also a possibility where a suitable healthy adult is prepared to donate a part of his or her liver. This is an increasingly popular option for liver transplantation in children.

Large volume paracentesis (LVP) may become necessary in end-stage liver disease when diuretic therapy is inadequate in the treatment of ascites. Portal vein decompression utilising surgical shunts is an effective means of relieving intractable cirrhotic ascites and in the treatment of portal hypertension when there is evidence of esophageal varices. The portal caval shunt surgical procedure may be used if more conservative measures utilised in controlling bleeding, such as sclerotherapy or band ligation, are ineffective. The TIPS (transjugular intrahepatic portosystemic shunt) procedure has also been effective in controlling bleeding from esophageal or gastric varices in addition to controlling cirrhotic ascites.

Surgical treatment options are highly individualised to each patient. As with all surgery, outcomes depend on a number of issues specific to each person. There are no guarantees for the extent to which there will be improvement of medical condition.

Specialised Therapy for AAT Deficiency

Replacement therapy involves giving an intravenous infusion of human alpha-1 antitrypsin. This has been performed in the United States, Canada and some European countries since 1987.

Current NHS/NICE guidelines do not yet recommend replacement therapy for patients with any severity of AATD emphysema.

Replacement therapy has been found to be a very effective treatment for panniculitis and it has been given as a treatment within the United Kingdom on a Named Patient Basis.