What does low alpha-1 (alpha 1 antitrypsin) protein level mean?

Low Alpha-1 Antitrypsin Protein: Clinical Significance and Management

Low alpha-1 antitrypsin (AAT) protein levels indicate alpha-1 antitrypsin deficiency, a hereditary condition that significantly increases risk for developing pulmonary emphysema and liver disease, requiring targeted testing in at-risk populations and consideration of augmentation therapy for those with clinically evident emphysema. 1

Understanding Alpha-1 Antitrypsin Deficiency

• Alpha-1 antitrypsin is a 52-kD single-chain glycoprotein that functions primarily as a protease inhibitor, with its major biological role being inhibition of neutrophil elastase (NE), an enzyme that degrades elastin and other components of lung tissue 1
• Normal serum AAT levels range from 120-200 mg/dl (or greater than 22 μM) 1, 2
• Low levels of AAT (below 50 mg/dl or less than 11 μM) result from inheriting two protease inhibitor deficiency alleles from the AAT gene located on chromosome 14q31-32.3 1
• The most common deficiency allele is PIZ, with homozygous form (PIZZ) resulting in serum concentrations typically below 50 mg/dl (less than 11 μM) 1

Clinical Manifestations of AAT Deficiency

Pulmonary Manifestations

• Pulmonary emphysema of the panacinar type is the most prevalent clinical consequence of AAT deficiency and is the major cause of disability and death 1
• Symptomatic obstructive lung disease typically presents between ages 32 and 41 in individuals with a history of smoking 1
• Common respiratory symptoms include:
  • Dyspnea on exertion (84% of patients) 1
  • Wheezing during respiratory tract infections (76%) 1
  • Chronic cough with or without sputum production 1
  • Symptoms resembling asthma, with 35% of patients self-reporting asthma history 1

Liver Manifestations

• Liver disease is the second most frequent clinical complication 1
• May present in infancy as cholestasis, which usually resolves by adolescence 1
• Cirrhosis and hepatocellular carcinoma affect approximately 30-40% of patients over age 50 and are significant causes of death in non-smoking individuals with PI*ZZ phenotype 1

Other Manifestations

• Bronchiectasis without evident etiology 1
• Necrotizing panniculitis (rare) 1
• Anti-proteinase-3 vasculitis 1

Diagnostic Approach

• Testing for AAT deficiency should be considered in:

  • Individuals with early-onset emphysema (regardless of smoking history) 1
  • All subjects with COPD 1
  • Adults with bronchiectasis without evident etiology 1
  • Patients with asthma whose spirometry fails to normalize with therapy 1
  • Liver disease of unknown cause 1
  • Family members of known AAT-deficient patients 1

• Diagnostic testing involves:

  • Measuring serum or plasma AAT levels (primary screening test) 1
  • In moderate clinical suspicion cases, an AAT level ≥ 23 mmol/L (≥ 1.2 g/L) rules out severe AAT deficiency 1
  • For AAT levels < 23 mmol/L (< 1.2 g/L) or in high suspicion cases, DNA sequencing of the SERPINA1 gene is recommended 1

Clinical Implications and Management

• Early diagnosis is crucial as late diagnosis has been associated with reduced functional status, quality of life, and worse overall survival 1
• The average delay in diagnosis is approximately 5.3 years after first clinical manifestations 1, 3
• Management approaches include:
  • Smoking cessation and avoidance of environmental irritants 1
  • Maintaining up-to-date vaccination status 1
  • Exercise, healthy diet, and pulmonary hygiene 1
  • Standard COPD management for respiratory symptoms 4
  • Augmentation therapy with purified human AAT for patients with clinically evident emphysema 2

Augmentation Therapy

• Augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe AAT deficiency who have clinically evident emphysema 2
• The goal is to raise serum AAT levels above the protective threshold of 11 μM 2
• However, the clinical efficacy in affecting the progression of emphysema has not been conclusively demonstrated in adequately powered randomized controlled trials 2
• The therapy aims to protect the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors 2

Prognosis and Long-term Monitoring

• Without treatment, AAT deficiency can lead to premature disability and death, with 72% of deaths due to emphysema 1
• Medical disability occurs at a mean age of 46 years in many patients 1
• Long-term surveillance for early detection of lung and liver diseases is recommended 1
• Family screening should be encouraged to identify relatives who may be affected 1

Common Pitfalls in Diagnosis and Management

• AAT deficiency is significantly underdiagnosed and underrecognized by clinicians 3
• Clinical picture alone is not adequately sensitive to alert clinicians to the presence of the disease 1
• Some genetic variants of AAT deficiency are associated with normal circulating levels of AAT but represent actual deficiency because the circulating AAT is nonfunctional 1
• The maintenance of blood serum levels of AAT above 11 μM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection, but this has not been definitively proven 2