Our approach to diagnosis of alpha-1 antitrypsin (AAT) deficiency

COPD: chronic obstructive pulmonary disease; ANCA: antineutrophil cytoplasmic antibody; PCR: polymerase chain reaction; IEF: isoelectric focusing (assesses protein migration).
* It is preferable to obtain simultaneous measurement of AAT level and targeted genotyping. Targeted genotyping uses PCR to identify specific common pathogenic AAT variants (eg, F, I, S, and Z) and the normal M allele, although panels vary among laboratories. Sequential testing of genotype first followed by serum level is an alternative. Refer to UpToDate content on the diagnosis of AAT deficiency.
¶ Interpretation of a specific abnormal result should be based upon the reference range reported by the laboratory. A reasonable threshold for differentiating normal Pi*MM (normal genotype) from other genotypes with one or more deficient alleles is 20 micromol/L (100 mg/dL).
Δ IEF is an alternative, but gene sequencing is typically preferred.
◊ Depending on the specific variant, heterozygotes may have a serum AAT level that is reduced or within the normal range. As AAT is an acute phase reactant, a mildly low AAT level can increase into the normal range during acute illness. However, a severely low AAt level would not increase into the normal range.
§ Targeted genotyping, in combination with a low serum AAT level, is acceptable for diagnosis of AAT deficiency. There is no need to confirm genotype result with alternative test, such as IEF, if result is clear and consistent with AAT level.
¥ AAT levels can be low in the absence of AAT deficiency (eg, variation in the assay or improper storage of specimen). If unexplained, obtain specialty consultation, as appropriate.