Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) is a protease inhibitor, an enzyme produced in the liver to help protect the tissues of the body during infections.

There are many different genetic variants that affect this protein.

• M is the normal variant and produces the normal ‘PiM’ protein.
• The two most important abnormal variants are called S and Z. S produces moderately low levels of AAT whilst Z produces very little AAT.
• In ZZ homozygotes, the abnormal AAT can build up in the liver causing liver disease and low level of AAT in the blood contributes to lung damage from environmental agents e.g. smoke or pathogens. The common phenotypes are PiMM, PiMS, PiMZ, PiSS, PiSZ, and PiZZ. Null variants are rare and are only distinguishable from homozygotes by genotyping.

AATD is a recessive condition, such that both parents must be carriers for a child to be at risk of inheriting the condition. Around 1 in 10 people in the population are carriers for AATD (around 1 in 25 people carry the Z variant, around 1 in 17 carry the S variant).

There are varying degrees of severity depending upon the combination of variants:

• 90% of North Europeans are MM and have normal AAT levels.
• PiMZ or PiMS (carriers) and PiSS have lower but sufficient levels of AAT. They do not have a significant increased risk of lung or liver disease but should be advised that is sensible not to smoke and to only take alcohol in moderation.
• PiSZ individuals have a moderately increased risk of developing emphysema and a slight increased risk of liver disease.
• PiZZ individuals have a high risk of developing emphysema and liver disease. However, there is variable expressivity and only a very few individuals with the ZZ pattern experience clinically significant disease.
• PiZZ infants have a small risk of severe neonatal liver disease (about 2%) although this risk can be higher in siblings of a child with ZZ and liver disease (estimated at 20-30%).

Arranging testing for AATD in primary care

It is appropriate to offer phenotyping to siblings and this can be arranged by primary care.

The concentration of AAT can be directly measured in blood (serum sample). If it is found to be low the lab will go on to do phenotyping studies to establish whether there is a deficiency variant.

Of note:

• We do not recommend testing healthy children for AATD as it is generally an adult-onset condition. Testing can be considered in adulthood when an individual can consent to testing themselves.
• The possibility that apparently healthy parents of a ZZ or SZ child may themselves be ZZ or SZ should be borne in mind when offering phenotyping.
• If AAT phenotyping is to be attempted on an individual who has had a liver transplant, the AAT phenotype will reflect the genotype of the donor liver (since this protein is made in the liver) and genetic testing of DNA from lymphocytes will be needed to determine the genotype.

Individuals with existing emphysema or liver disease identified as having AATD should be offered a referral to a specialist for advice and management as should those with a ZZ or SZ phenotype.

Testing eligibility criteria

Please see the National Genomic Test Directory (opens in a new tab), rare and inherited disease criteria, test R191.

Test ordering

Genetic testing is indicated for patients that meet the eligibility criteria. This can be arranged by the local hospital or primary care using the referral form (GLH genetic test form link).

When to refer to clinical genetics

We DO NOT routinely accept referrals for people with a family history of this condition or individuals who are carriers as the population carrier frequency is so high.

We DO accept referrals for:

• Couples of childbearing age who are both carriers for AATD (PiMZ only) to discuss risks and implications for their children.
• Individuals who are affected with AATD (PiZ or PiSZ) who wish to discuss the genetic implications of their condition.

Advice for relatives

The most important advice in families is to avoid smoking, being in smoky areas, and other lung irritants.

Even where an individual inherits two variants, the majority of such individuals do not have any clinical problems providing they do not smoke.

It is also important to avoid excessive alcohol consumption. Excess alcohol or obesity increase the risk of chronic liver disease in ZZ individuals and heterozygous Z carriers.

Further information about AATD can be found here (opens in a new tab).

Support groups

• Alpha-1 UK Support group (opens in a new tab)