Alpha-1 Antitrypsin Deficiency (AATD)


Early manifestations of alpha-1 antitrypsin deficiency (AATD) include liver disease, which can occur in infancy and childhood. Lung pathologies occur later in life.1 

Pi*MM

This genotype contains two normal M alleles. This indicates that an individual does not have AATD; therefore, this individual has a normal serum AAT level with no increased risk of liver or lung pathologies. 

Pi*ZZ

Individuals with the Pi*ZZ genotype produce around 10% to 20% of the normal serum alpha-1 antitrypsin levels. They are at the highest risk for developing liver and lung disease, and account for 95% of individuals exhibiting clinical manifestations of AATD, which are sometimes severe.2 

Lung function in adolescents with the Pi*ZZ genotype appears normal compared to age-matched control groups with normal alpha-1 antitrypsin levels. Lung function in a recent study was measured by spirometry. Forced vital capacity (FVC), forced expiratory volume within 1 second (FEV1), residual volume (RV), and total lung capacity (TLC) were not statistically different between the two groups.1

Another study suggested that spirometry utilizing forced expiratory maneuvers may not always be effective in detecting the early onset of emphysema as these tests do not reach some of the peripheral airways in question. They suggest the use of the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) may be more effective in detecting lung disease in all stages (even the early stages) and in all genotypes (not just Pi*ZZ) in those with AATD. This promotes more expedient treatment of lung disease at a much younger age and may positively impact prognosis.3 

A study conducted in Sweden in 2008 compared the cause of mortality and prognosis of non-smoking Pi*ZZ individuals with the general population. In 568 individuals with Pi*ZZ genotype, 93 (16%) died between 1991 and 2007. Moreover, 45% of these individuals with Pi*ZZ AATD died due to emphysema, 28% died from liver cirrhosis, and in 38% of those who died from cirrhosis, malignant transformation was present. However, when the researchers compared the Pi*ZZ individuals with the general population of Sweden, there was no increased mortality risk.4 But this study did not consider the Pi*ZZ individuals who were smokers. 

In contrast to the Swedish study, using the National Institute of Health registry in the US, researchers studied the mortality rate of 1129 individuals with the Pi*ZZ genotype. They calculated that those with the Pi*ZZ genotype had a 16% likelihood of surviving to 60 years of age as opposed to an 85% likelihood for the general US population. The most common cause of mortality was emphysema at 72%, followed by chronic liver disease at 10%. The mortality rate for these individuals was 3% per year and completely attributable to lung and liver disease.5 

Pi*SS

This genotype does not appear to be associated with an increased risk for clinical disease and, therefore, has a better prognosis than other genotypes.2 They are considered to have an intermediate AAT deficiency with a potentially mild health risk. 

Pi*SZ

Ordinarily, individuals with this genotype are not at increased risk for liver or lung disease; however, they do have serum AAT concentrations below the protective level. One study measured these levels in Pi*SZ genotypes and compared them with Pi*MM, Pi*MS, Pi*SS, and Pi*MZ genotype serum concentrations. The serum concentration ranges of AAT (in g/L) were 1.050-1.640 for PI*MM, 0.880-1.369 for PI*MS, 0.730-1.060 for PI*SS, 0.660-0.997 for PI*MZ and 0.490-0.660 for PI*SZ.6 Pi*SZ individuals had notably less AAT in their blood than the other genotypes, meaning they have less protection from neutrophil elastase in the lungs. If they have a history of smoking, Pi*SZ individuals do have an increased risk of developing emphysema or chronic bronchitis.2,7 They present to health care providers earlier than the Pi*MM genotype due to baseline differences, but otherwise, the risk of emphysema was not statistically different between Pi*SZ and Pi*MM.  However, compared with the Pi*ZZ genotype, Pi*SZ individuals are less susceptible to cigarette smoke.7 

Another German study noted that the typical differences between Pi*ZZ and Pi*SZ genotypes regarding quality of life, diffusion capacity, and frequency of exacerbations weakened with increased number of years smoking.8 

Pi*MZ

Individuals with this genotype are generally not considered to be at risk for lung disease, unless they are smokers or have exposure to environmental factors that might heighten their risk of developing chronic obstructive pulmonary disease (COPD).9,10 Like the Pi*SS genotype, Pi*MZ individuals are considered to have an intermediate AAT deficiency with a slightly enhanced health risk. 

Pi*MS

Like those with the AATD Pi*MM genotype, individuals with the Pi*MS genotype do not present with clinical manifestations of AATD and there is no discernable enhanced health risk.6

Pi*FF

While rare, this AATD genotype denotes a functional impairment of the AAT protein in binding to neutrophil elastase even though serum concentration levels are functionally normal. These Pi-FF individuals, as well as Pi*FZ individuals, are at increased risk of developing emphysema.11

Pi*Null-null 

Those individuals with the Pi*Null-null genotype (also known as the Pi*QO genotype) completely lack synthesis of AAT. Due to this complete lack of production of the protein responsible for liver inflammation in other AATD genotypes, these individuals are not at a higher risk of developing liver disease. However, these individuals are at the highest risk of developing severe lung disease since there are no AAT proteins present to protect the lungs from neutrophil elastase.2

Factors Impacting Prognosis

Better prognosis correlates with early detection and rapid, accurate diagnosis. The mean diagnostic delay interval is 8.3 + 6.9 years.12 Individuals with AATD found earlier due to proper screening have a prognosis of survival that is close to that of healthy individuals. Those who are identified due to symptom onset are more likely to have a worse prognosis.

Specific factors that influence poor prognosis include:

  • History of smoking
  • Male sex
  • Significant bronchodilator response (>12% and > 200 mL)
  • Severe airflow obstruction 
    • Individuals with spirometry FEV1 > 50% have a 5-year mortality rate of 4%
    • Individuals with spirometry FEV1 of 35-49% have a 5-year mortality rate of 12%
    • Individuals with spirometry FEV1 < 35% have a 5-year mortality rate of 50%1

Other factors that also influence prognosis and rate of decline in lung function include:

  • Age at onset of symptoms
  • Baseline respiratory symptoms
  • Repeated severe exacerbations of COPD13

The mortality rate is high in symptomatic patients, so the need for early detection and accurate diagnosis is critical to improving patient outcomes.

References

  1. Anariba, DEI. Alpha1- antitrypsin (AAT) deficiency: prognosis. Medscape. Accessed June 4, 2021.
  2. Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 antitrypsin deficiency.  Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed June 4, 2021.
  3. Fuchs SI, Schwerk N, Pittschieler K, et al. Lung clearance index for monitoring early lung disease in alpha-1-antitrypsin deficiency. Respir Med. 2016; 116:93-99. doi:10.1016/j.rmed.2016.04.015
  4. Tanash HA, Nilsson PM, Nilsson J-A, Piitulainen E. Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ). Thorax. 2008; 63(12):1091-1095. doi:10.1136/thx.2008.095497 
  5. Stoller JK, Tomashefski J, Crystal RG, et al. Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the national heart, lung, and blood institute registry. Medscape. Accessed June 4, 2021.
  6. Ferrarotti I, Thun GA, Zorzetto M, et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax. 2012; 67(8):669-674. doi:10.1136/thoraxjnl-2011-201321
  7. Green CE, Vayalapra S, Hampson JA, Mukherjee D, Stockley RA, Turner AM. PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype and prognosis relative to PiZZ AATD and PiMM COPD. Thorax. 2015; 70(10):939-945. doi:10.1136/thoraxjnl-2015-206906
  8. Fähndrich S, Bernhard N, Lepper PM, Vogelmeier C, Bals R. Differences of disease phenotypes in individuals with alpha-1-antitrypsin deficiency with genotypes PiZZ and PiSZ – Analysis from the German registry. European Respiratory Journal. 2016; 48(suppl 60). doi:10.1183/13993003.congress-2016.PA4172
  9. Al Ashry HS, Strange C. COPD in individuals with the PiMZ alpha-1 antitrypsin genotype.  Eur Respir Rev. 2017; 26(146). doi:10.1183/16000617.0068-2017
  10. Molloy K, Hersh CP, Morris VB, et al. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am J Respir Crit Care Med. 2014; 189(4):419-427. doi:10.1164/rccm.201311-1984OC
  11. Sinden NJ, Koura F, Stockley RA. The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote. BMC Pulm Med. 2014; 14:132. doi:10.1186/1471-2466-14-132
  12. Stoller JK. Detecting alpha-1 antitrypsin deficiency. Annals ATS. 2016; 13(Supplement_4):S317-S325. doi:10.1513/AnnalsATS.201506-349KV
  13. Hiller A-M, Piitulainen E, Jehpsson L, Tanash H. Decline in FEV1 and hospitalized exacerbations in individuals with severe alpha-1 antitrypsin deficiency. COPD. 2019; 14:1075-1083. doi:10.2147/COPD.S195847

Article reviewed by Kyle Habet, MD, on July 1, 2021.

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