What Is Alpha-1 Antitrypsin Deficiency?

Overview

Alpha-1 antitrypsin is a protein that inhibits the protease enzyme, which breaks down the protein into smaller polypeptides or single amino acids. Alpha-1 antitrypsin is produced in the liver and then transported to the lungs through the blood. A defect in the gene responsible for the synthesis of Alpha-1 antitrypsin protein leads to the development of Alpha-1 antitrypsin deficiency.¹

Alpha-1 antitrypsin deficiency is an inherited genetic disorder that increases your risk of developing lung disease and liver disease.² It is a common disorder but under-recognised and potentially life-threatening, which is often diagnosed late due to the late development of the symptoms. The symptoms can take years to develop, leading most individuals to seek medical attention late, in the course of their condition, when their clinical state has progressed. Clinical manifestations are more common in the lungs (chronic obstructive pulmonary disease (COPD), emphysema, bronchiectasis) and liver (cirrhosis and hepatocellular carcinoma). However, it can also affect the skin (panniculitis) and blood vessels (vasculitis).^3,4,5

Causes of alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency is caused by a mutation (a change in the DNA sequence of an organism) in a gene called SERPINA1, which leads to structural defects during the synthesis of alpha-1 antitrypsin protein in the liver.^5,6 The abnormal protein produced cannot leave the liver in the blood where it is supposed to be carried out to the lungs. This results in abnormal protein accumulation in the liver (which becomes harmful to the liver) and reduced circulating levels of the protein in the blood and lungs. 

There are different types of the mutated gene SERPINA1.⁷ The severity of the disease depends on the type of defective gene inherited from the parents.  For example, the S type (allele) results in moderately reduced production of alpha-1 antitrypsin protein, the Z allele results in deficient levels, while the null allele results in no production. The Z allele is most commonly responsible for severe deficiency.⁸

Signs and symptoms of alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin protects the lungs from inflammation caused by infection and inhaled environmental pollutants like cigarette smoke by inhibiting the neutrophil elastase enzyme, which, when unregulated, can lead to tissue damage.⁹ Neutrophil elastase has some good effects on the human body, such as inflammatory immune reactions, mucus secretion in the lungs and antibacterial and anticancer properties.¹⁰ However, when its effect is uncontrolled, these actions can be overwhelming to the lungs; for example, the inflammatory reactions become damaging to the body and the mucus is secreted in excess, which the lung struggles to clear. 

Symptoms of alpha-1 antitrypsin deficiency-related lung disease include

• Shortness of breath
• Fatigue
• Chronic cough
• Phlegm production
• Wheezing
• Recurrent respiratory infections^11,12 

Symptoms of alpha-1 antitrypsin deficiency-related liver disease include:

• Swelling of the abdomen (due to an enlarged liver, bleeding, or ascites, abnormal accumulation of fluids within the abdominal cavity)
• Poor appetite
• Swelling of the legs
• Poor growth^11,13 

Symptoms in babies, infants and children include:

• Jaundice (yellowish discolouration of the eyes or skin)
• Mildly elevated liver enzymes
• Dark urine
• Pale stools
• Poor appetite
• Itching¹¹

Clinical diagnosis in neonates, infants and children can be difficult due to the nonspecific nature of symptoms.^6,14,20,22

Management and treatment for alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency can manifest as a lung disease like COPD. Thus, it is treated using standard medications such as inhaled bronchodilators (medication to help widen the bronchi and bronchioles in the lungs), inhaled steroids, anticholinergics, and oxygen therapy. In addition, antibiotics or phosphodiesterase 5 inhibitors (an enzyme that breaks a phosphodiester bond) are administered if the respiratory infections are recurrent.^1,8

If the patient has severe emphysema and is a non-smoker or has stopped smoking, specific treatment includes:

• Augmentation therapy: This therapy involves the administration of a long-term infusion of purified, pooled human plasma alpha-1 antitrypsin into the veins once weekly^9,15 
• Lung volume reduction surgery: A treatment for patients with severe emphysema (bullae) or COPD. Studies show it is more beneficial in patients whose emphysema is not associated with genetic causes like alpha-1 antitrypsin deficiency
• Lung transplantation: It may be offered only to patients with end-stage severe lung disease¹⁵

Suppose alpha-1 antitrypsin deficiency manifests as skin diseases such as panniculitis. In that case, treatment includes:¹⁵ 

• Dapsone or doxycycline therapy
• High-dose intravenous augmentation therapy where there is no response to doxycycline therapy

If alpha-1 antitrypsin deficiency manifests as liver disease, treatment is mainly supportive as there is no specific cure for alpha-1 antitrypsin deficiency.^5,10 In children, ursodeoxycholic acid is used. 

Other supportive management to prevent further liver injury include: 

• Hepatitis A and B vaccinations 
• Healthy nutrition 
• Limiting alcohol consumption^5,6 
• Liver transplantation^15,16 

Diagnosis of alpha-1 antitrypsin deficiency

Diagnosis of alpha-1 antitrypsin deficiency is made by measuring blood levels of the alpha-1 antitrypsin protein. If the level is low, alpha-1 antitrypsin genotyping or protein phenotyping is used to confirm the diagnosis.^15,16 The alpha-1 antitrypsin serum level test is relatively affordable and is usually offered to the following groups:⁹

• All symptomatic adults with COPD or emphysema
• Adults with asthma in whom airflow obstruction is incompletely reversed after treatment
• Asymptomatic people with persistent obstruction on pulmonary function tests and identifiable risk factors (e.g., cigarette smoking, occupational exposure)
• Individuals with unexplained liver disease
• Adults with necrotising panniculitis (inflammation of the subcutaneous fatty and fibrous tissue layer)
• Siblings of people with alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin genotyping is a specific allele analysis used to check common alleles like Z and S. It may also detect other relatively common ones like the F and I alleles.¹⁶ However, the genotyping may be inconclusive as it may miss many rare alleles; thus, protein phenotyping by isoelectric focusing is performed.^13,16

Risk factors

• Cigarette smoking
• Alcohol consumption
• Ethnic group-more common in white people
• Environmental pollution^9,17

Complications

Lung disease complications due to alpha-1 antitrypsin deficiency include:

• Bronchiectasis
• Chronic bronchitis
• Emphysema

Liver disease complications include:

• Chronic hepatitis
• Cirrhosis
• Hepatocellular carcinoma
• Portal hypertension^18,16 

The most common cause of death in individuals with alpha-1 antitrypsin deficiency is respiratory failure, followed by liver cirrhosis.⁸

FAQs

How can I prevent Alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency runs in families, meaning it cannot be prevented. There are ways you can manage the condition and reduce the risk of life-threatening complications:

• Genetic counselling of patients and their families: If you’re thinking of starting a family, you should consider genetic counselling to understand the risks and explore options
• Behavioural practices: Such as smoking cessation, limiting alcohol intake, avoiding environmental (such as second-hand tobacco smoke) and occupational (such as fumes, dust, and non-medical aerosol sprays) exposures
• Immunization: (influenza vaccines, pneumococcal vaccines and hepatitis A and B vaccines) to prevent infections
• Exercise regularly, eat healthily and maintain optimal weight^8,9

How common is Alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency affects 1 in 3000 in the UK.¹³

When should I see a doctor?

You should see your doctor if:¹⁸

• You are below 45 years old and have been diagnosed with COPD
• You have never been a smoker or have only smoked for a few years but have been diagnosed with COPD
• You have a family member who has been diagnosed with COPD

Summary

Alpha-1 antitrypsin deficiency is an inherited genetic disorder caused by a defect in the SERPINA1 gene, affecting the synthesis of the protective protein. It often leads to under-recognised medical conditions, with symptoms emerging late, primarily in the lungs and liver. Diagnosis involves screening blood levels and confirming with genotyping or protein phenotyping. Treatment varies based on symptom location. Prevention measures include smoking cessation, limiting alcohol consumption, and vaccinations.