Presentation: Patient with abnormal liver screen (suspected alpha-1 antitrypsin deficiency)

A 38-year-old man reports a history of recurrent chest infections over the past two years. They have recently increased in frequency and persistence. He is a non-smoker. A chest X-ray reveals early emphysematous changes. On reviewing his medical records, you find that he has had liver test anomalies in the past, which are still under investigation. He reports that his younger sister, aged 34, has also started to get chest infections.

• AATD is caused by pathogenic variants in the SERPINA1 gene.
• The MM genotype is not associated with AATD or disease. S and Z genotypes result in reduction of A1AT.
• The risk of developing symptoms of AATD depends on genotype:
  • ZZ carries the greatest risk;
  • ZS carries moderate risk;
  • MZ carries lower risk; and
  • MS and SS genotypes do not usually lower A1AT levels enough to cause disease.
• Around 10% of the European population have the S and Z variants.
• Flags for an underlying genetic diagnosis include:
  • early onset emphysema (below 40 years old) or liver disease;
  • emphysema in the absence of any risk factors (such as smoking or occupational dust exposure); and
  • strong family history of emphysema or liver disease.

• Organise appropriate investigations, such as a chest X-ray and/or liver function tests.
• Request serum A1AT levels – if this is low, the laboratory will proceed with biochemical phenotyping.
• Offer individuals with AATD a referral to a specialist centre (respiratory, gastroenterology or liver services, depending on clinical symptoms) to discuss how to manage their condition.
• Biochemical phenotyping is usually sufficient to establish a diagnosis with genomic testing.
• As per the National Genomic Test Directory, consider genomic testing for diagnostic confirmation only if serum A1AT levels are below normal range, and:
  • there is prolonged neonatal jaundice with an inconclusive A1AT phenotyping result, or
  • variant analysis will inform reproductive choices, or
  • the patient is an adult with cirrhosis or emphysema and a genetic diagnosis would influence management following an inconclusive A1AT phenotyping result.
• Cascade testing of relatives is rarely indicated.
• Provide lifestyle advice – the most important message for patients and family members is to refrain from smoking.
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Medline Plus: Alpha-1 antitrypsin deficiency
• NHS England: National Genomic Test Directory
• North Bristol NHS Trust: Alpha-1 antitrypsin fact sheet for primary care (PDF, three pages)

For patients

• Alpha-1 Antitrypsin Deficiency Support
• Asthma + Lung UK: Alpha-1-antitrypsin deficiency