Version May 2024
INTRODUCTION — This monograph discusses the interpretation and possible interventions following genetic testing of the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT). It is not intended to replace clinical judgment in the decision to test or the care of the individual who was tested.
AAT deficiency (AATD) predisposes to obstructive lung disease and sometimes liver disease and other complications. Indications for testing and management of disease complications are discussed separately in UpToDate [1].
HOW TO READ THE REPORT — The table summarizes important considerations when reviewing the report (table 1); these include obtaining a hard copy, confirming patient identity, determining whether the result is current, and reviewing which variant(s) were tested.
Another table provides a glossary of terms (table 2).
Most but not all individuals with alpha-1 antitrypsin deficiency (AATD) will be identified with genetic tests that probe for common disease alleles using single nucleotide polymorphism (SNP) probes (see 'SERPINA1 genetics' below). For results (positive or negative) that would impact clinical care, a clinician must review the report to ascertain how the genotype was determined, which alleles were assessed, and whether additional testing is needed.
SERPINA1 GENETICS
Overview of variants — SERPINA1 encodes alpha-1 antitrypsin (AAT), a protease inhibitor that inhibits neutrophil elastase and other proteases. Excess or uncontrolled neutrophil elastase activity breaks down lung tissue.
Over 150 SERPINA1 variants have been identified. Most are point mutations that introduce a single amino acid substitution and reduce AAT level and/or function. Many laboratories test for common variants using selected single nucleotide polymorphism (SNP) probes rather than gene sequencing.
●Variant nomenclature – Variants are often named with PI (for protease inhibitor) followed by a letter that reflects the migration of the associated protein on an isoelectric focusing (IEF) gel [2].
•"M" (Middle of the gel) designates the protein from the normal allele. Variants within M (M1-M4) have no clinical significance. Rare pathogenic variants produce proteins that migrate in the M region of the gel (eg, MMalton, MHeerlen).
•Letters of the alphabet before M (A, F, I) designate variants that produce faster migrating proteins; letters after M (S, Z) designate variants that produce slower migrating proteins.
-"Z" is the most common disease allele. Z produces an AAT level approximately 10 to 20 percent of normal. Homozygosity for Z (written as PI ZZ, Pi ZZ, or PI*ZZ) causes marked AAT deficiency (AATD). Z also confers impaired AAT function, which further increases emphysema risk. In addition, the protein encoded by the Z allele forms abnormal polymers within hepatocytes, which can cause liver disease, sometimes severe. Polymers produced by alveolar macrophages may also contribute to lung disease, as polymers are chemotactic for neutrophils, thereby potentially increasing the neutrophil elastase burden in the lung. (See 'Genotype-phenotype correlations' below.)
-"S" and "I" are less common alleles that cause mild deficiency (AAT serum levels approximately 60 to 80 percent of normal).
-"F" confers normal AAT levels but impaired function in binding neutrophil elastase.
-Other alleles are summarized in the table (table 3).
●Specific variant names – A specific variant may be reported using the amino acid substitution it confers. As an example, the Z allele may be called Glu342Lys (lysine substituted for the normal glutamic acid at position 342).
The position of the base-pair substitution can also be indicated (for Z: c.1096G>A), or the reference SNP cluster identification (rs ID) tag can be used (for Z: rs28929474). These designations are less commonly used clinically but may appear in genetic test reports.
Some genetic tests are performed concomitantly with serum AAT assays, usually measured by nephelometry and reported in mg/dL; this result can be converted to micromoles by dividing mg/dL by 5.20.
If an individual is tested using SNP probes and they have a disease variant not covered by the probes, the report will indicate "no abnormal allele found." If the serum AAT level is low, further diagnostic testing is needed, often with exome or whole gene sequencing.
Genotype-phenotype correlations — Correlation (or lack thereof) between SERPINA1 genotype and clinical phenotype (serum AAT level or clinical status) can be highly informative:
●Correlation with AAT level – Serum AAT levels usually correlate with genotype.
•Normal range – The AAT normal range is approximately 100 to 220 mg/dL (20 to 53 micromol/L); the lower limit of normal is approximately 100 mg/dL (20 micromol/L) [3].
•Severe deficiency – An individual's AAT level is determined by the pair of alleles that confers their genotype (table 4). Homozygosity for an allele associated with severe deficiency, such as PI*ZZ, will generally produce a serum AAT level in the range of 15 to 20 mg/dL (3 to 7 micromol/L). True null alleles (AAT level 0 mg/dL) are very rare.
•Effect of inflammation and pregnancy – AAT is an acute phase reactant; levels can increase with inflammation, especially in PI*MM individuals (unaffected) or PI*MZ heterozygotes. In PI*ZZ individuals, the magnitude of rise in the serum AAT level during inflammation is low. Levels also increase (by up to threefold) during pregnancy. (See "Normal reference ranges for laboratory values in pregnancy".)
•Qualitative defect – The rare F allele (Arg223Cys) produces a purely qualitative defect (normal AAT levels, abnormal function). F homozygotes (PI*FF) have an increased emphysema risk.
•Need for additional genetic testing – Severe AATD for which genetic testing does not identify a deficiency allele suggests an atypical variant or missed identification of a variant; a gene panel, exome sequencing, or whole gene sequencing is almost always indicated. Specialist involvement is advised to ensure this is done correctly.
●Correlation with clinical findings – The most common disease variant (Z) predisposes to both lung and liver disease (see 'Overview of variants' above). The mechanisms of lung and liver disease differ:
•Lung disease – The risk for emphysema generally correlates with the serum AAT level. An AAT level of ≥57 mg/dL (≥11 micromol/L) is considered a protective threshold above which emphysema risk is generally not increased; below this level, risk is elevated. All PI*ZZ homozygotes have levels well below 57 mg/dL. PI*ZZ homozygotes also have a qualitative defect (dysfunctional AAT protein with reduced neutrophil elastase binding).
•Liver disease – Some variants produce protein that polymerizes abnormally in hepatocytes (table 3). Examples include Z, SIiyama, King's, and MMalton. Accumulation of polymerized AAT can cause chronic liver fibrosis starting in childhood that can progress to cirrhosis.
•Other
-Increased risk for venous thromboembolism (VTE). (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Vascular disease'.)
-Increased risk for inflammatory bowel disease. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Inflammatory bowel disease'.)
-Increased risk for cancer, especially liver cancer. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)
-Homozygosity for Z can also cause panniculitis and antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. (See "Panniculitis: Recognition and diagnosis" and "Overview of and approach to the vasculitides in adults".)
-The rare Pittsburgh variant (Met358Arg) can cause a bleeding tendency.
CLINICAL IMPLICATIONS — Alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive disorder (figure 1), although the effects on alpha-1 antitrypsin (AAT) level are autosomal codominant (each allele contributes 50 percent to the serum AAT level). AATD is most common in individuals of European ancestry and is significantly underdiagnosed (table 4).
Clinical implications of genetic test results depend on the genotype, as summarized in the algorithm (algorithm 1) and discussed below. (See 'Heterozygotes' below and 'Homozygotes/compound heterozygotes' below and 'Negative test' below.)
Positive test
Heterozygotes — Heterozygotes for a SERPINA1 severe deficiency variant (eg, PI*MZ or PI*SZ) may be unaffected carriers and generally are not at increased risk of emphysema if they do not smoke and lack other inhalation exposures (industrial dust, biomass fuel exposure). They have intermediate AAT levels. Heterozygotes with a Z allele (eg, PI*MZ, PI*SZ) who smoke have an increased risk for emphysema, and PI*MZ heterozygotes may develop liver disease, especially with another hepatic insult (eg, steatohepatitis).
If confidence is high that an individual is heterozygous, serum AAT testing typically is not needed; however, it may be obtained by some clinicians. Nonsmoking heterozygotes with an AAT level ≥57 mg/dL (≥11 micromol/L) generally do not require further testing. Heterozygotes who smoke should be strongly advised to stop smoking. They are also counseled to avoid passive smoke and to inform their first-degree relatives to allow further counseling and testing.
The table summarizes additional aspects of management (table 4).
Homozygotes/compound heterozygotes — Homozygotes or compound heterozygotes for pathogenic variants have an increased risk for disease, although some may be unaffected due to variable penetrance and variable expressivity.
Surveillance for complications and decisions regarding timing of interventions is best managed by a disease expert. The following may be indicated (table 4) [4-6]:
●Lung disease
•Prevention
-Baseline pulmonary function tests (PFTs, including spirometry [with postbronchodilator testing if prebronchodilator tests show airflow obstruction] and diffusing capacity) and chest computed tomography (CT).
-Avoid smoking and other respiratory exposures. Evidence is lacking regarding the risks of vaping, marijuana use, and industrial/occupational exposures, but avoidance appears prudent, especially for inhaled substances that may cause inflammation.
•Treatment – The following may be appropriate, with shared decision-making [4]:
-PFTs annually or twice yearly
-Intravenous enzyme replacement (augmentation therapy)
-Consider lung transplant for severe disease
●Liver disease
•Prevention
-Baseline examination for liver disease, liver ultrasound, elastography, liver biochemical tests, and complete blood count (CBC) to assess platelet count
-Vaccination against hepatitis A and B viruses
-Avoid alcohol, excess body weight, other sources of liver injury
•Treatment
-Standard cirrhosis therapy
-Consider liver transplant for severe disease by Model for End-stage Liver Disease (MELD) criteria
●Other risks – Heightened level of suspicion and low threshold for evaluating other complications including VTE, inflammatory bowel disease, and cancer (especially liver cancer)
Negative test — A negative test may be sufficient to exclude disease risk, with important exceptions:
●If genetic testing is negative but the AAT level is low, referral to a genetics expert or disease specialist is needed to explain the discordance and determine next steps.
●If testing is negative (normal AAT level and/or no variants on genetic testing) but clinical features suggest AATD (emphysema in a nonsmoker or liver disease that remains unexplained after an evaluation), specialist evaluation may be indicated to identify new or rare causative variants in SERPINA1 or other causes of the findings.
RELATIVES — The range of serum alpha-1 antitrypsin (AAT) levels in heterozygotes can be quite broad; genotyping is considered more helpful than AAT level in individuals with a known familial disease variant. This is appropriate at any age because children are at risk for liver disease, and avoidance of second-hand smoke is prudent.
●First-degree relatives (siblings, parents, and children) of all PI*ZZ individuals should be genotyped. Potential genotypes in offspring depend on the genotypes of their parents:
•Both parents are Z homozygotes (PI*ZZ) – All children will be homozygous.
•Both parents are Z heterozygotes (PI*MZ) – Children have a 25 percent chance of being homozygous, 50 percent chance of being heterozygous, and 25 percent chance of being unaffected noncarriers.
•One parent is a Z homozygote and one is a Z heterozygote (PI*ZZ and PI*MZ) – Children have a 50 percent chance of being homozygous and 50 percent chance of being heterozygous.
●First-degree relatives of individuals with other SERPINA1 genotypes (Z heterozygotes, compound heterozygotes, homozygotes for other disease alleles) may also be offered testing and counseling. The strength of recommendation for testing is summarized in a joint guideline from the American Thoracic Society (ATS) and European Respiratory Society (ERS) [5,6]. Consultation with a disease specialist or genetics expert may be helpful. (See 'Resources' below.)
RESOURCES
●Specialists – Clinical assessment can be done by an appropriate specialist (pulmonologist or hepatologist/gastroenterologist). Those who require further counseling and/or testing of relatives may benefit from individual or family consultation with a genetics professional.
•AATD specialists – Alpha-1 Foundation (alpha1.org)
•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
•Genetic counselors – National Society of Genetic Counselors (NSGC)
●UpToDate topics on AATD:
•Pulmonary – (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)
•Extrapulmonary – (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)
•Treatment – (See "Treatment of alpha-1 antitrypsin deficiency".)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
