Alpha 1 Antitrypsin Deficiency

 

• Pathophysiology

  α1-antitripsyn (A1AT) physiology:

  • A1AT is a serine protease inhibitor which is synthesised in the liver and controls inflammatory cascades.
  • In the lung, A1AT inhibits neutrophil elastase, preventing breakdown of elastin and thus maintaining lung elasticity.

  A1AD pathophysiology:

  • Lung: basal panacinar emphysema i.e. enlarged airspaces (emphysema) from the bronchioles to the alveoli (panacinar), in the lung bases (basal). Smoking exacerbates this process.
  • Liver: abnormal A1AT accumulates in the hepatocyte endoplasmic reticulum, causing cell damage.

  Genetics:

  • A1AT gene on chromosome 14 has 3 possible alleles: M (medium), slow (S), or very slow (Z).
  • Healthy individuals have an MM genotype (aka PiMM), while symptomatic individuals are usually ZZ.
  • Those with MS and MZ genotypes are just carriers, while SS and SZ genotypes may cause a mild clinical picture.
  • Clinical disease affects 1 in 3000 white people.

• Presentation

  • Usually presents as early-onset COPD (age 30-50), especially if they are smokers.
  • Liver disease is less common. Presents as hepatitis, cirrhosis, and/or liver failure.
  • Can present in childhood with liver disease, sometimes as early as neonatal jaundice. It is one of the commonest indications for liver transplantation in children.

• Investigations

  • Serum A1AT.
  • Phenotyping – i.e. characterisation of the serum A1AT variants – if A1AT found to be low. Genotyping is only needed if the phenotype doesn't match the clinical picture.
  • Screen family members.
  • COPD and liver tests: CXR, PFTs, LFTs. Liver USS and biopsy may be needed if liver disease develops.

• Management

  COPD:

  • Manage as usual, with smoking cessation, flu and pneumococcal vaccines, and stepwise medical therapy.
  • A1AT augmentation therapy: consider pooled A1AT from human plasma for those with at least moderate COPD. However, not recommended by NICE due to lack of strong evidence for a survival benefit.

  Liver disease:

  • Prevention and monitoring for all: Hep A and B vaccine, plus LFT ± coag monitoring.
  • If liver disease develops, manage as usual: suggest avoiding alcohol, monitor α-fetoprotein, and consider transplantation in liver failure.

• Complications and prognosis

  • Poor prognosis in those with severe COPD: 10% 5 year mortality if FEV1 <50%, and 50% if FEV1 <35%.
  • Risk of hepatocellular carcinoma in those with cirrhosis.
  • May be at increased risk of granulomatosis with polyangiitis (Wegner's).