Can serum protein electrophoresis (SPEP) be used to screen for alpha 1 antitrypsin deficiency?

Serum Protein Electrophoresis for Alpha-1 Antitrypsin Deficiency Screening

Serum protein electrophoresis (SPEP) can be used as a screening tool for alpha-1 antitrypsin deficiency but should not be used as the sole diagnostic test due to its limited sensitivity, particularly for heterozygous carriers. 1

Diagnostic Value of SPEP for Alpha-1 Antitrypsin Deficiency

Sensitivity and Specificity

• SPEP can detect alpha-1 antitrypsin deficiency by identifying decreased alpha-1 globulin protein fraction
• Sensitivity varies by genotype:
  • 84% sensitivity for homozygous ZZ phenotype 2
  • Only 29% sensitivity for heterozygous MZ phenotype 2
  • 88% sensitivity for homozygous ZZ using nephelometry 3
  • 45% sensitivity for heterozygous carriers using nephelometry 3
• Specificity is high at approximately 99% 3

SPEP as a Screening Tool

SPEP can serve as an opportunistic screening method when:

• Alpha-1 globulin band is <3% on electrophoresis 1
• Alpha-1 globulin concentration is <0.21 g/dL 2

Recommended Diagnostic Approach

Current Gold Standard Testing

According to the most recent guidelines, the gold standard for diagnosis of alpha-1 antitrypsin deficiency is:

1. Measurement of serum alpha-1 antitrypsin level
2. DNA sequencing of the SERPINA1 gene 4

Two-Step Testing Algorithm

The Canadian Thoracic Society recommends a two-step approach 4:

1. Initial Screening:

   • Measure serum alpha-1 antitrypsin level
   • If ≥23 mmol/L (≥1.2 g/L): Rules out severe deficiency in moderate suspicion cases
   • If <23 mmol/L (<1.2 g/L): Proceed to genetic testing

2. Confirmatory Testing:

   • DNA sequencing of SERPINA1 gene coding regions (exons 2-5)
   • Considered the definitive diagnostic test

Important Considerations

• Alpha-1 antitrypsin is an acute phase reactant; levels fluctuate during inflammation 4
• Some genetic variants have normal circulating levels but dysfunctional protein 4
• Relying solely on protein levels can lead to misclassification 4

When to Test for Alpha-1 Antitrypsin Deficiency

Testing is strongly recommended in patients with 5:

• Early-onset emphysema (before age 40)
• Emphysema without recognized risk factors (smoking <10 pack-years)
• Unexplained liver disease
• Pan-lobular emphysema
• Family history of COPD or alpha-1 antitrypsin deficiency
• First-degree relatives of individuals with abnormal alpha-1 antitrypsin genes

Clinical Implications of Diagnosis

Early diagnosis is critical for:

• Initiating augmentation therapy when criteria are met 5
• Smoking cessation and avoidance of respiratory irritants 5
• Family screening 4
• Monitoring for liver disease 5
• Improving overall survival and transplant-free survival 4

Pitfalls to Avoid

1. Relying solely on SPEP for diagnosis

   • SPEP misses approximately 16% of ZZ phenotypes and 71% of MZ phenotypes 2

2. Using only protein concentration without genotyping

   • Some variants have normal levels but dysfunctional protein 4
   • Levels fluctuate with inflammation 4

3. Delaying diagnosis

   • Late diagnosis associated with worse functional status, quality of life, and survival 4

4. Overlooking heterozygous carriers

   • MZ individuals still at increased risk, especially with environmental exposures 5

In conclusion, while SPEP can serve as an initial screening tool for alpha-1 antitrypsin deficiency, particularly when performed as part of routine testing for other conditions, it should always be followed by confirmatory testing with serum alpha-1 antitrypsin level measurement and SERPINA1 gene sequencing to ensure accurate diagnosis and appropriate management.