Alpha-1 Antitrypsin Deficiency (AATD)


Laboratory Studies

Laboratory tests to diagnose alpha-1 antitrypsin deficiency (AATD) involve a simple blood test to measure the level of the alpha-1 antitrypsin (AAT) protein in the blood. If these serum levels are lower than normal, this indicates that one or two genes may be mutated that are responsible for producing AAT.1 

Genetic testing is required to determine the specific number and types of mutated genes via isoelectric focusing and/or targeted genotyping of predefined mutations. These traditional methods of testing have limitations. Whole-genome sequencing of the SERPINA1 gene is a possibility although this type of testing is costly. Whole-genome sequencing is usually only used if the targeted genotyping does not successfully identify the mutated gene.2 

A new method of genetic testing is next-generation sequencing (NGS). Next-generation sequencing, also labeled as massively parallel or deep sequencing, is a revolutionary DNA sequencing technology that can rapidly sequence an entire human genome in a single day. NGS platforms process millions of small fragments of DNA in parallel and these fragments are pieced together by bioinformatics analyses. It is possible also to target specific areas of the genome, such as the SERPINA1 gene, to sequence a specific area of interest.3

Imaging Studies

Chest Radiography

The effects of AATD are visualized on chest radiography as hyperinflated and hyperlucent due to the destruction of healthy lung tissue. The hyperinflated lungs are indicative of a barrel chest morphology. This process of destruction impacts certain areas of the lung more than others. Usually these affected regions are called “oligemic” because they lack the normal branching pattern of vasculature. In two-thirds of PiZZ patients, the pattern of destruction is found in the base of the lungs; whereas, in emphysema, caused by cigarette smoking, the most severe destruction is at the apex of the lungs.4,5

High-Resolution CT Scanning

Computed tomography (CT) densitometry is used to image the lungs of individuals with emphysema or chronic obstructive pulmonary disease (COPD) and AATD. The scans show widespread hypoattenuation due to the destruction of lung tissue. As the lung tissue is destroyed, the pulmonary vessels are smaller, fewer, and spread further apart as there is less lung tissue to supply with blood and less gas exchange surface areas requiring deoxygenated blood to absorb atmospheric oxygen.5 It is easiest to make the diagnosis of AATD using high-resolution CT scanning when the disease is moderate because there is a prevalent basilar zone of tissue destruction. The milder forms of AATD may be missed on this type of imaging, and the more severe forms can be harder to differentially diagnose from other diseases impacting the lungs.5 

The most common density threshold for high-resolution CT scanning of the lungs is -950 HU. A systematic review of the literature in 2018 demonstrated a significant association between all clinically relevant parameters in patients with emphysema and CT density scans.6

CT scanning of the abdomen is also helping in visualizing liver changes associated with AATD, such as hepatomegaly, cirrhosis, and tumors.5 

Spirometry

Quality spirometry, or pulmonary function tests (PFTs), should be conducted as a screening process to determine chronic airflow restriction. If this is present, then the physician must initiate the diagnostic process to differentially diagnose patients with COPD or emphysema, and AATD or patients with only COPD or emphysema, pulmonary fibrosis, asthma, or chronic bronchitis.4,7,8

PFTs assess the mechanical function of the entire breathing apparatus including the lungs, airways, chest wall, and muscles of respiration.7 Key measurements of PFTs include:

  • the forced vital capacity (FVC), or the largest amount of air forcefully exhaled after the deepest inhalation possible, and 
  • the forced expiratory volume (FEV1), or the amount of air forcefully exhaled in one second.8

Lower FEV1 measurements indicate a larger obstruction.8

Procedures

Histological Findings

In AATD, the areas affected by emphysema are primarily found at the bottom of the lobes in addition to a more even distribution throughout the lobule compared with the centrilobular emphysema caused by cigarette smoking, which affects tissue along the central bronchioles.9 

Pathological findings from liver biopsies may include the presence of periodic acid-Schiff (PAS)-positive stained globules. These periportal red hyaline globules contain collections of the alpha-1 antitrypsin (AAT) protein that the hepatocytes are not excreting properly.10 

Staging

There is no specific gradation to characterize AATD progression; however, the degree of emphysema severity can be staged using the BODE index –  Body mass index (BMI), airflow Obstruction, Dyspnea, and Exercise capacity. This 4-step examination can identify patients with a limited survival rate who might benefit from more intensive therapy. The BODE index has not been used to evaluate the AATD population at present.11

The 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging has also been studied as a possibility of staging AATD.12 The National Institutes of Health, the National Heart, Lung and Blood Institute, and the World Health Organization first initiated the GOLD system in 1997. This older version of GOLD staging only used the results of pulmonary function tests. Now, the 2017 version of GOLD staging categorizes the stage of COPD based on the current symptoms, the exacerbation risk, the presence and number of comorbidities, and the results from spirometry.13

References 

  1. Alpha-1 antitrypsin deficiency symptoms, causes, and risk factors. American Lung Association. Accessed on May 27, 2021. 
  2. Kueppers F, Sanders C. State-of-the-art testing for alpha-1 antitrypsin deficiency. Allergy Asthma Proc. 2017;38(2):108-114. doi:10.2500/aap.2017.38.4031
  3. Behjati S, Tarpey PS. What is next generation sequencing? Arch Dis Child Educ Pract Ed. 2013;98(6):236-238. doi:10.1136/archdischild-2013-304340
  4. Soriano JB. An epidemiological overview of chronic obstructive pulmonary disease: what can real life data tell us about disease management? COPD: Journal of Chronic Obstructive Pulmonary Disease. 2017; 14(1):3-7. doi:10.1080/15412555.2017.1286165 
  5. Anariba, DEI. How is alpha1-antitrypsin deficiency (AATD) characterized in chest x-rays? Medscape. Accessed on May 28, 2021. 
  6. Crossley D, Renton M, Khan M, Low EV, Turner AM. CT densitometry in emphysema: a systematic review of its clinical utility. Int J Chron Obstruct Pulmon Dis. 2018;13:547-563. Published 2018 Feb 7. doi:10.2147/COPD.S143066
  7. McCarthy, K. Pulmonary function testing. Medscape. Accessed on May 28, 2021. 
  8. Spirometry. Mayo Clinic. Accessed on May 28, 2021.
  9. Anariba, DEI. What are the histologic findings in alpha1-antitrypsin deficiency (AATD)? Medscape. Accessed on May 28, 2021.
  10. Alpha-1-antitrypsin deficiency, liver, PAS stain. WebPath. Accessed on May 28, 2021.
  11. Alpha1-antitrypsin (AAT) deficiency workup. Medscape. Accessed on May 28, 2021.
  12. Soriano JB, Lucas SJ, Jones R, et al. Trends of testing for and diagnosis of α1-antitrypsin deficiency in the uk: more testing is needed. European Respiratory Journal. 2018;52(1). doi:10.1183/13993003.00360-2018
  13. COPD stages and the gold criteria. WebMD. Accessed on May 28, 2021.

Article reviewed by Harshi Dhingra, MD, on July 1, 2021.