Alpha-1 antitrypsin deficiency



Alpha-1 antitrypsin deficiency is a rare autosomal recessive disorder that causes liver and pulmonary disease.

Alpha-1 antitrypsin (AAT) is an abundant enzyme found within the body. It is produced in the liver and acts as a protease inhibitor. It is important in the inhibition of neutrophil elastase. Neutrophil elastase acts by damaging bacteria, but unchecked, it can lead to lung damage.

Alpha-1 antitrypsin deficiency (AATD) refers to a lack of circulating AAT due to mutations that prevent it from being released from hepatocytes. This has knock-on effects in the liver and lungs.

  • Liver: build up in hepatocytes. This can cause chronic damage leading to cirrhosis.
  • Lungs: absent inhibition of neutrophil elastase. This causes lung damage leading to chronic obstructive airway disease (COPD).

Around 1-2% of patients with COPD have underlying AATD. It should be suspected in patients with COPD who are young, non-smokers or have a positive family history.


Worldwide, there are > 3 million people affected by AATD.

AATD is an under-recognised condition with >100 million carriers of an abnormal AAT gene. The abnormal gene is most commonly identified amongst white Northern Europeans and has an equal sex prevalence.

There is a bimodal distribution in clinical presentation. In neonates, AATD may cause hepatitis and in children it can cause decompensated cirrhosis. In adults, it is most commonly seen in the fifth decade of life with features of liver and/or lung disease.


AATD is an autosomal recessive disorder.


AATD is considered an autosomal recessive disorder with co-dominant expression. This means that the protein products of both genes (i.e. alleles) are expressed. However, the clinical phenotype (i.e. signs and symptoms) is only seen with inheritance of two abnormal genes. 


AATD is caused by a mutation in the SERPINA1 gene found on chromosome 14. There are >100 genetic mutations (known as single nucleotide polymorphisms) that can affect the gene leading to reduced or absent production of AAT. Each mutation refers to an allele, which is subsequently linked to a letter code such as 'M', 'S' or 'Z'. The letter refers to the behaviour of the protein product of the gene during protein electrophoresis. 

The major alleles are M, S and Z. 

  • M allele: normal. Found in >95% of general population
  • S allele: found in 2-3% of the population
  • Z allele: most severe. Found in 1% of the population


Patients inherit one gene maternally and one gene paternally. The genotype is classified according to the letter system (as discussed). The genotype is denoted Pi (protease inhibitor) followed by the two alleles present. Examples:

  • PiMM: Homozygous for the normal alleles.
  • PiZZ: Homozygous for the abnormal Z allele. 
  • PiSZ: Compound heterozygous. Two abnormal recessive alleles. Variable phenotype
  • PiMZ: Heterozygous. Only one abnormal gene, unlikely to have the clinical phenotype. 

We can estimate the likelihood of developing liver and lung disease based on the genotype. There is a 80-100% chance of developing COPD with PiZZ, but only a 20-50% increase chance with PiSZ.


Abnormal gain or loss of function of the alpha-1-antitrypsin protein determines the clinical presentation.

Gain of function

Under normal conditions, AAT is produced in hepatocytes and then secreted. However, in AATD the abnormal AAT protein can polymerise and accumulate within hepatocytes leading to cellular destruction, chronic scarring and fibrosis. 

Liver disease will only occur with mutations that promote accumulation and polymerisation (e.g. Z allele). Mutations that lead to a complete deficiency of AAT will not cause liver disease because no protein is created and therefore there is no accumulation. 

AATD may be the primary cause of liver disease or a co-factor (e.g. chronic alcohol consumption and AATD). 

Loss of function

Under normal conditions, AAT secreted by hepatocytes is important for the inhibition of neutrophil elastase within the lungs. If AAT is absent, or significantly reduced, patients are at risk of elastase-mediated lung damage. 

Elastase can break down elastin, which is important for the integrity of alveoli leading too emphysema (permanent enlargement of airspaces distal to bronchioles). This reduces oxygen transfer leading to chronic hypoxia and breathlessness. Emphysema is one of the hallmarks of COPD.

Factors such as infection (e.g. pneumonia) and cigarette smoking contribute to the development of chronic lung damage because they increase the burden of elastase within the lung. 

Most abnormal alleles increase the risk of lung disease because they lead to reduced or absent AAT production.

Clinical features

AATD is characterised by development of COPD and chronic liver disease.

The clinical features of AATD depends on the underlying genotype. Patients may have features of both COPD and chronic liver disease.

Pulmonary clinical features

  • Dyspnoea
  • Cough
  • Wheeze
  • Ankle swelling (right-sided heart failure from chronic lung disease)

Hepatic clinical features

  • Jaundice
  • Bruising
  • Spider naevi
  • Palmar erythema
  • Hepatomegaly
  • Ascites
  • Leuconychia
  • Confusion
  • Asterixis: flapping tremor (suggests encephalopathy)
  • Cachexia

When to suspect

All patients with evidence of chronic liver disease or COPD should be tested for AATD.

AATD is an under-recognised condition. Many organisations, including the World Health organisation (WHO), advise testing all patients with COPD for AATD. In addition, AATD forms part of a routine chronic liver disease screen.

Indications for AATD testing:

  • COPD: particularly early onset (≤ 45 years) and non-smokers
  • Chronic liver disease
  • Family history of COPD and/or liver disease
  • Adult onset asthma with poor response to bronchodilators

Diagnosis & investigations

Serum alpha-1-antitrypsin levels form the first line investigation for AATD.

Serum AAT levels

The usual initial test to screen for AATD is serum AAT levels. This test enables qualification of the amount of AAT. 

Normal AAT levels are 0.90-1.90 g/L. Patients with PiZZ usually have AAT levels <0.3 g/L. The minimum amount of AAT required to protect against elastase-mediated lung damage is ~0.8 g/L. 

Serum AAT levels are useful at detecting patients likely to have an underlying severe deficiency (i.e. PiZZ). These patients can then undergo genetic testing. Serum AAT levels are less useful at detecting heterozygous carriers. In addition, AAT is an acute phase protein so levels may be falsely normal during acute inflammation. 


Patients with evidence of low AAT levels can have gene testing to look for the most common mutations (i.e. Z and S). Rarer alleles may not be detected by routine genetic testing because they focus solely on detection of classic mutations.

Patients with discordant results can be offered genetic sequencing that analyses the whole genetic region. Sequencing enables identification of rare mutations.

Other investigations

A variety of investigations can be utilised to assess for the degree of liver or lung disease in patients with confirmed AATD.

  • Pulmonary function tests: looking for airflow obstruction typical of COPD.
  • Pulmonary Imaging: chest x-ray and CT chest. Emphysema in AATD is typically located in the lower zones (i.e. basal regions) with panacinar involvement.
  • Liver imaging: liver ultrasound is a simple non-invasive test that can be used to look for chronic liver disease and portal hypertension. 


The management of AATD is supportive and treatment follows the usual guidelines for the management of COPD and chronic liver disease.

General management

All patients should be advised to stop smoking and given smoking cessation advice. Smoking increases the risk of severe lung disease. Patients should also be informed about the danger of concurrent alcohol consumption and advised to have low, infrequent or no alcohol consumption. Complete abstinence is needed if there are signs of chronic liver disease. 

Other treatment options include nutritional support, pulmonary rehabilitation and seasonal vaccinations (e.g. Seasonal influenza and pneumococcal). All patients require prompt treatment of respiratory infections.

COPD management

Patients should be treated according to standard guidelines for the management of COPD, which includes inhaled therapy (e.g. beta agonists, muscarinic antagonists and steroids). Patients with exacerbations of COPD may require antibiotics and short courses of corticosteroids (e.g. prednisolone 30 mg for 5 days). For more information, see our notes on COPD.

Cirrhosis management

Patients with established cirrhosis need regular surveillance for hepatocellular carcinoma with 6-monthly liver ultrasound and alpha-fetoprotein (AFP) monitoring. For further information on the management of patients with cirrhosis see our notes on chronic liver disease

Specialist treatment

Patients with severe lung or liver disease may be considered for transplantation. This is highly specialist and requires referral for assessment at a tertiary centre. Other treatment options include long-term oxygen therapy (LTOT) and lung volume reduction surgery. 

Disease modifying treatment

Trials are ongoing into the use of intravenous human alpha-1-antitrypsin therapy (e.g. Zemaira) to treat AATD. However, in the UK this is currently not recommended by NICE (see clinical guideline NG115: Chronic obstructive pulmonary disease in over 16s: diagnosis and management). 

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