Disease risks and management implications of selected SERPINA1 genotypes

Disease risks and management implications of selected SERPINA1 genotypes

Genotype	AAT level^¶	Lung disease	Liver disease
Unaffected (no variant or mild deficiency variants only)
PI*MM	20-53 micromol/L 100-220 mg/dL	Not at increased risk of lung disease	Not at increased risk of liver disease
PI*SS	15-33 micromol/L 100-200 mg/dL	Not considered at increased risk of lung disease	Not considered at increased risk for liver disease
Heterozygous for SERPINA1 disease variants
PIMZ -or- PISZ	17-33 micromol/L 90-210 mg/dL -or- 8-16 micromol/L 75-120 mg/dL	Emphysema risk is thought to be confined to smokers (longitudinal data are lacking) Never-smokers with normal lung function generally do not require serial monitoring of lung function Not considered candidates for augmentation therapy	Higher than average risk for liver disease Liver disease often exacerbated by concomitant steatohepatitis
Homozygous or compound heterozygous for SERPINA1 disease variants
PI*ZZ	2.5-7 micromol/L 20-45 mg/dL	Emphysema risk: Increased in never-smokers Markedly increased in smokers Likely increased following exposure to occupational dusts, marijuana, vaping Follow pulmonary function tests every 6 to 12 months Candidates for augmentation therapy if emphysema is established Lung transplantation may be an option	Lifetime prevalence of cirrhosis in PI*ZZ homozygotes up to 40% Cirrhosis risk may appear higher in never-smokers, as they may escape mortality risk of emphysema Follow liver biochemical tests every 6 to 12 months; consider elastography and ultrasound yearly Liver transplantation may be an option
Null	0 micromol/L 0 mg/dL	High risk of developing emphysema	Not increased (there is no abnormal protein to polymerize or accumulate in hepatocytes)
PI*FF^Δ	20-53 micromol/L 100-220 mg/dL	Increased risk of emphysema, although data are lacking to estimate the magnitude of the risk	Not increased (abnormal protein does not polymerize intrahepatically)

Homozygosity for Z, the most common AAT disease variant (PI*ZZ), accounts for >95% of all clinical disease. Lung disease and liver disease may be exacerbated by other conditions such as smoking or steatohepatitis, respectively. In addition to emphysema and liver disease, PI*ZZ individuals are also predisposed to panniculitis and ANCA-positive vasculitis. Heterozygosity for Z (PI*MZ) has a prevalence of approximately 3% in the United States.

AAT: alpha-1 antitrypsin; PI: protease inhibitor (another name for AAT); ANCA: antineutrophil cytoplasmic antibody; ELISA: enzyme-linked immunosorbent assay; AATD: alpha-1 antitrypsin deficiency.

¶ Molarity is generally determined by ELISA; concentration in mg/dL can be determined by nephelometry. The protective threshold for AAT is considered to be 11 micromol/L (57 mg/dL) or above.

Δ The F allele (Arg223Cys) is very rare. It produces normal AAT protein levels, but the protein is dysfunctional with markedly impaired antineutrophil elastase activity. PI*FF individuals are at risk for emphysema; however, assaying their serum AAT level may be insufficient to diagnose AATD.

Graphic 129289 Version 3.0

خرید پکیج

Disease risks and management implications of selected SERPINA1 genotypes