Alpha1-antitrypsin Deficiency


Table 1: Reasons Why We Have Not Found the Other 90% of Patients—Barriers to Testing


I: Barriers to Considering Alpha1-antitrypsin Deficiency Testing A. Misconceptions


(i) that AATD is rare and should only suspect AATD in individuals of Scandinavian descent


(ii) that AATD is easy to detect without screening (iii) that testing for AATD is complex and expensive


(iv) that participating and performing testing would be difficult for office staff (v) that no effective treatment exists for affected individuals B. Technical barriers


(i) Technical hurdles to the introduction of AAT deficiency testing in routine hospital laboratories


(ii) Inadequate methods of detecting lung and liver diseases in AATD patients


II: Barriers to Undertaking Testing


A. Patient’s logistical and physical reservations to being tested B. Psychological issues, fears of discrimination, insurance issues (life and medical) related to genetic testing C. Physician remembering to test D. Testing fatigue


III: Barriers to Changing Physician Behavior A. Need for effective guidelines


B. Need to increase effectiveness of continuing medical education C. Barriers in knowledge and training physicians about genetic diseases


AATD = alpha1-antitrypsin deficiency. gradient IEF gel.11


Phenotyping may be performed on serum or plasma samples. Some laboratories perform IEF on dried blot spot samples using a blood drop absorbed on special paper, allowing for easier collection via finger stick and easier transport of samples. This method is suitable for screening purposes, but the identification of a deficient variant should be confirmed on serum or plasma samples.


When an evaluation is performed on the basis of a family history of AAT deficiency, such testing may not detect persons who are heterozygous for a deficiency allele, who often have levels at or near the normal range.


The measurement of AAT levels is a reasonable initial test, but it has limitations, such as in nephelometry, which overestimates AAT levels because of interference with lipids or hemoglobin. It is also important to note that AAT is an acute-phase reactant, and inflammatory conditions may augment the steady-state plasma AAT levels. Even though AAT levels may also rise substantially during illness or other types of inflammatory stress, they typically remain well below the normal range in AATD persons.12


These guidelines are more expansive than those of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). In the GOLD guidelines, AATD testing is recommended specifically for patients with early-onset COPD under the age of 45 years or with a strong family history of COPD.9


The ATS/ERS recommended that a single


quantitative test for AAT should be performed on all patients with COPD who remained symptomatic despite bronchodilator therapy, and those with unexplained liver disease. They also recommended testing asymptomatic patients with both persistent airflow obstruction on pulmonary function tests and with on-going identifiable risk factors (e.g. cigarette smoking, occupational exposure).


The quantitative tests currently available include plasma AAT levels, which are detected by rocket immunoelectrophoresis, radial immunodiffusion, and nephelometry. AAT values obtained are expressed using a non-purified standardized technique versus the pure standard technique developed by the US National Institutes of Health (NIH); the former are expressed as milligrams per deciliter (mg/dl), and the latter in micromolar units (mol/L or M). The two units are used interchangeably in many European countries. The importance of these values should be recognized in that a protective threshold level of 11mol/L corresponds to 80mg/dl if measured by radial immunodiffusion and to 50mg/dl if measured by nephelometry.10


The qualitative test is the most widely used method for identifying AAT variants. It is based on the isoelectric point by means of thin layer isoelectric focusing (IEF), commonly referred to as phenotyping, performed in reference laboratories. The IEF specificity is enhanced by coupling it with an immunoblot or by using an immobilized pH


48


Commercially available genotyping kits, which often use dried blood spots, are designed for extracting DNA from circulating mononuclear blood cells, which identify the most common abnormal AAT variants.


Barriers to Testing


We have classified barriers to testing into three categories, as illustrated in Table 1. We believe there are multiple types of obstacles. This begins with unwillingness to consider testing. When testing is considered or ordered, both physicians and patients feel barriers to ordering or undergoing the test. In order to affect change, we have been keen on education, but that also has presented its own set of obstacles. The following sections will review each of these categories of barriers to testing.


I: Barriers to Considering Alpha1-antitrypsin Deficiency Testing


Epidemiological studies suggest that approximately 100,000 Americans have severe AATD, but that fewer than 10,000 have been actually identified.13


Caucasian newborns is similar to that of cystic fibrosis.15


Deficiency is relatively common in populations of European ancestry, with an estimated prevalence of one case per 3,000–5,000 persons in the US.14


The incidence of AAT deficiency in The PI*ZZ


phenotype is several-fold more common among Swedes than Americans, however; severe AATD has been observed in all ethnic groups in which it has been sought, including populations from Africa, Asia, and the Middle East.16


US RESPIRATORY DISEASE


A source of controversy in evaluating AAT levels is the variety of measurement units used to express the results; a more consistent approach may be helpful in this matter. If the AAT protein level is below the normal range, further assessment with protein phenotyping or genotyping is recommended. Protein phenotyping is performed at specialized laboratories by evaluating the isoform patterns of AAT protein with the use of an isoelectric focusing gel. One limitation of this approach is the inability to identify PI*Null alleles, since these variants produce no circulating protein. To overcome these limitations, protein phenotyping can be performed with an alternative genotype testing.13


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