FH of Alpha-1-Antitrypsin Deficiency

This guidance applies to those with a family history of Alpha-1-antitrypsin (A1AT) deficiency or the partner of a known carrier, where current or future offspring might be affected. It does not make testing recommendations for other indications.

Alpha-1-antitrypsin is a serine protease inhibitor protein synthesised in the liver which primarily functions in the lungs. It is also increased in the acute phase response to infection.

Alpha-1 Antitrypsin Deficiency is a genetic condition associated with a decreased level of A1AT leading to an imbalance of proteinases and anti-proteinases which causes lung and/or liver damage.

Other causes of low alpha-1-antitrypsin include:

• Liver pathology
• Protein enteropathy
• Malnutrition
• Protein losing states.

Genetics

A1AT is encoded by the SERPINA1 gene. The most common version of the gene is the M allele. If an individual has two copies of the M allele (MM) then they produce normal serum levels of A1AT (1.1 to 2.1 g/L).

There are multiple variants of the SERPINA1 gene, with the majority not causing A1AT deficiency. However, a small number produce deficiency alleles, which can lead to Alpha-1 Antitrypsin Deficiency. The most common deficiency alleles are S and Z.

Inheritance of two deficiency alleles is rare, and it is far more common for patients to inherit a deficiency allele along with an M allele, i.e.: MS or MZ. People identified as MS or MZ are known as carriers of A1AT deficiency and 1 in 10 people in the Northern European population are estimated to be a carrier.

Clinical Implications:

• Carriers have a small reduction in serum level of A1AT to around 80%.

• Inheritance of two copies of the S allele (i.e. SS) causes serum level of A1AT to be reduced to around 60%.

• Inheritance of one copy of the S and one copy of the Z alleles (SZ) causes A1AT levels to be reduced to around 40%.

• Inheritance of two copies of the Z allele (ZZ) causes A1AT levels to be reduced to 10-15% of normal.

ZZ is associated with Alpha-1-Antitrypsin Deficiency and these individuals have a significantly increased risk of both lung and liver damage, even in never-smokers.

Individuals who are either MS, MZ, SS or SZ may be at increased risk of developing lung damage, particularly if they are a current or previous smoker. This is because low levels of A1AT cause lung damage due to reduced inhibition of serine proteases, which are released at sites of inflammation.  Without inhibition from A1AT, serine proteases cause local tissue damage.

Individuals who are MZ or SZ are also at increased risk of liver disease. The damage associated with the Z allele is due to accumulation of misfolded protein in the liver.  Such individuals should be advised to moderate alcohol consumption, avoid obesity and be encouraged to participate in aerobic exercise.  If additional risk factors for liver disease are present (e.g. alcohol excess, obesity, diabetes), consider checking LFTs and FIB4.  Given the SS phenotype is rarer, it is uncertain if liver disease is a complication.^2,3 Please note that in those affected, liver function can deteriorate over time.

In very rare cases a person may inherit a copy of SERPINA1 which cannot produce any A1AT. This is called the null allele. This is associated with lung damage and there is some evidence patients with null mutations have a worse prognosis.¹

It is key to note that penetrance in A1AT deficiency is extremely variable and unpredictable – people can present at any age, with a variety of clinical presentations. The biggest factor contributing towards the development of symptomatic A1AT deficiency is thought to be smoking, so smoking cessation advice and support can be helpful to prevent the development of chronic obstructive pulmonary disease.

Testing (pre referral)

Phenotyping cannot be ordered on ICE so the test should be requested as follows:

• 1x brown tube
• Use standard (not ICE) labels
• Use a paper biochemistry form, and handwrite the request for “A1AT quantification AND phenotyping”
• It can be transported in the green collection bag with other standard biochemistry samples
• The test has a turnaround time of 10 working days.

Biochemistry reporting and implications for referral to Clinical Genetics

The service only reports homozygous patients as having a single copy of the allele (e.g. Pi M, Pi Z), but can report heterozygous patients as having both variants (e.g. Pi SZ, Pi MZ). Therefore, the possibility of a patient having a copy of the null allele cannot be fully excluded on this test alone.  In recognition of this, the A1AT serum concentration is also examined, while interpreting the phenotype result, and an adequate level of A1AT for the phenotype detected effectively excludes the presence of a null phenotype. If there is a discrepancy between A1AT concentration and the phenotype, this may warrant further investigation and would be advised on the test report.

Phenotype	Lab Result	A1AT Activity	Genetics Referral
MM	Pi M	Normal Activity	Not required
MS	Pi MS	Carrier only Approx. 80% A1AT activity	Partner to be offered carrier testing if couple has children or are planning family. First degree relatives could be at risk of AATD and should be offered testing in adulthood.   Couples who have both been identified as carriers and wish to discuss recurrence risk for current and/or future children should be referred to Clinical Genetics.
MZ	Pi MZ	Carrier only Approx. 80% A1AT activity
SS	Pi S	Mildly affected Approx. 60% A1AT activity
SZ	Pi SZ	Mildly affected Approx. 40% A1AT activity
ZZ	Pi Z	A1AT DEFICIENT Approx. 10-15% A1AT activity

Please see Primary Care Management for those rare cases where the results indicate the patient has Alpha-1 Antitrypsin Deficiency and for information on what advice should be given to carrier patients, over and above considering if they should be referred to Clinical Genetics.

Rare Discordant Results

Very occasionally the result can be discordant, where the A1AT quantitative levels are higher or lower than would be expected for the phenotype. These can happen for multiple reasons such as sample degradation, the patient being unwell with an inflammatory response at the time of testing or having concurrent liver disease.

In such cases:

• Please repeat the test
• If A1AT activity is still reduced, consider if onward referral is required
• Contact the biochemistry lab if further advice is required.

C.M & S.H 11-05-23