Alpha-1-Antitrypsin Deficiency - AAT

Alpha-1-antitrypsin (AAT) is the chief protease inhibitor (PI) in human serum. Alterations in the production of this PI may result in the degradation of the connective protein elastin in lung alveoli, which increases the risk for developing lung disease. Additionally, severe AAT deficiency may cause improper folding of the AAT protein leading to deposition in hepatocytes and corresponding liver disease.

Chronic obstructive pulmonary disease (COPD) caused by AAT deficiency (AATD-COPD) is the fourth most common factor associated with lung transplantation. Pooled plasma AAT infusions can be used to treat lung disease in patients with AATD-COPD; however, this treatment does not address liver disease caused by AAT deficiency (Sandhaus, 2016).

Diagnosis

Indications for Testing

Chronic obstructive pulmonary disease (COPD) or unexplained bronchiectasis, regardless of age or ethnicity
Unexplained chronic liver disease
Necrotizing panniculitis or granulomatosis with polyangiitis
First-degree relative with 1 or 2 pathogenic alpha-1-antitrypsin (AAT) gene variants
Family history of AAT deficiency
Newborns with bleeding disorder or prolonged jaundice

Laboratory Testing

Diagnostic testing for symptomatic individuals

Testing for Symptomatic Individuals
	Protease Inhibitor (PI) Typing (Phenotyping)	Genotyping of S and Z Alleles	AAT Serum Concentration	AAT Gene Sequencing (Expanded Genotyping)
Rationale	Detect abnormal phenotypes	Identify causative S and Z DNA variants	Evaluate AAT protein concentration <90mg/dL suggests patient is at least a carrier of AAT deficiency <10-15% of normal suggests patient is affected	Identify rare pathogenic variants
Strengths	Considered gold standard; identifies all abnormally migrating proteins	Identify 95% of affected individuals Allow for prenatal diagnosis in at-risk pregnancies	Determine AAT enzyme plasma concentration for the initial evaluation of AAT deficiency	Identify variants other than S and Z alleles
Limitations	May not be able to accurately identify rare deficiency alleles Does not detect null alleles	Does not detect rare deficiency alleles including null alleles	Serum AAT concentration has low sensitivity for AAT deficiency because AAT is an acute phase reactant and may be elevated by other disease processes
Description	Isoelectric focusing	Molecular testing of SERPINA1 gene	Quantification of AAT protein in serum	Molecular sequencing of SERPINA1

Testing of asymptomatic high-risk individuals
- First-degree relatives of affected individuals
- Molecular testing of known familial variant

Imaging Studies

Computed tomography (CT) scan of chest
- Recommended in newly diagnosed patients who are symptomatic or have abnormal pulmonary function testing results (Sandhaus, 2016)

Differential Diagnosis

Adults
- Non-AAT COPD
- Cystic fibrosis
- Cirrhosis from other etiologies
Pediatric
- Viral infection
- Hemochromatosis
- Wilson disease
- Autoimmune hepatitis
- Inborn errors of metabolism

Screening

American Thoracic Society (ATS) and European Respiratory Society (ERS) Guidelines (2003)
- Neonatal screening: not recommended despite high prevalence of deficiency in population
- Screening in individuals >11 years: may be indicated in areas of high alpha-1-antitrypsin (AAT) deficiency prevalence or in areas of high smoking rates

Monitoring

Pulmonary disease (Sandhaus, 2016)
- Measure lung function with baseline spirometry and annual spirometry follow-up
- Computed tomography (CT) of chest not recommended for monitoring
Liver disease: monitor annually unless clinically indicated sooner (Sandhaus, 2016)
- Laboratory monitoring
  - Aspartate aminotransferase (AST)
  - Alanine aminotransferase (ALT)
  - Gamma-glutamyl transferase (GGT)
  - Albumin, bilirubin
  - International normalized ratio (INR)
  - Platelets
- Physical examination of abdomen
- Liver ultrasound

Background

Epidemiology

Prevalence
- AAT deficiency affects ~2-3% of the 2-3 million patients with COPD in U.S.
- Severe deficiency: 1/6,000 in White populations; less frequent in other ethnicities
Incidence of variants: 1/3,000-5,000 individuals of European ancestry
Age
- Smokers develop lung disease in 40s
- Nonsmokers develop lung disease in 50s

Risk Factors

Tobacco use
- Increases risk of developing severe lung disease; symptoms begin ≥10 years earlier than in nonsmokers
- Oxidants in tobacco smoke inactivate AAT protein, causing further AAT impairment
Occupational dust/fumes
Liver insults

Genetics

SERPINA1
- Gene located on chromosome 14q31-q32.3
- Inheritance: codominant
- >100 variants identified: most are benign
- Pathogenic variant (c.1024G>A; p.E324K), known as Z allele by phenotyping, is most common severe deficiency variant
- Pathogenic variant (c.791A>T; p.E264V), known as S allele by phenotyping, is most common moderate deficiency variant
- 95% of White individuals have the M allele by phenotyping (ie, no variants present in the AAT gene [wild type])

Genotype/Phenotype Interpretation
Allele Variants	AAT Activity	Emphysema Risk	Liver Disease Risk
MM	100%	Background	Low
MS	80%	Background	Low
MZ	58%	Background	Low
SS	60%	Background	Low
SZ		20-50%	Intermediate
ZZ	15%	80-100%	Moderately high – high
Null-Null	0%	100%	Background

Pathophysiology

AAT is a glycoprotein mainly synthesized by the liver
AAT deficiency results in uninhibited free neutrophil elastase, which leads to degradation of connective protein elastin in alveoli
Hepatic disease is secondary to accumulation of improperly folded, unsecreted AAT in hepatocytes

Clinical Presentation

Adults
- Pulmonary: dyspnea, wheezing, cough, phlegm, and early onset emphysema (panacinar)
- Hepatic: liver dysfunction, cirrhosis
  - Occurs more often in individuals with Z allele
  - Hepatitis with jaundice
  - Chronic liver disease
- Skin: panniculitis
  - Necrotic areas with spontaneous suppuration
Neonates
- Small percentage of affected newborns have hepatitis with cholestatic jaundice (prolonged jaundice with conjugated hyperbilirubinemia)
- Low AAT levels are also found in neonatal respiratory distress syndrome and severe protein-losing disorders
Rare associated diseases
- Granulomatosis with polyangiitis, necrotizing panniculitis, and aneurysms of aortic and brain arteries
Complications
- Hepatocellular carcinoma and cholangiocarcinoma