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Original Research: COPD |

α1-Antitrypsin Phenotypes and Associated Serum Protein Concentrations in a Large Clinical PopulationAntitrypsin Phenotypes and Serum Concentrations FREE TO VIEW

Joshua A. Bornhorst, PhD; Dina N. Greene, PhD; Edward R. Ashwood, MD; David G. Grenache, PhD
Author and Funding Information

From the Department of Pathology (Dr Bornhorst), University of Arkansas for Medical Sciences, Little Rock, AR; The Permanente Medical Group Regional Laboratories (Dr Greene), Kaiser Permanente Northern California, Berkeley, CA; and the Department of Pathology (Drs Ashwood and Grenache), University of Utah School of Medicine, and ARUP Laboratories Institute of Clinical and Experimental Pathology (Drs Ashwood and Grenache), Salt Lake City, UT.

Correspondence to: Joshua Bornhorst, PhD, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205; e-mail: jabornhorst@uams.edu


Funding/Support: This work was supported by the ARUP Institute for Clinical and Experimental Pathology.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(4):1000-1008. doi:10.1378/chest.12-0564
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Background:  α1-Antitrypsin (AAT) deficiency variants reduce the concentration of serum AAT protease inhibitor and can lead to the development of pulmonary and hepatic disease. Relative frequencies of rare AAT variant phenotypes (non-M, Z, and S) and associated serum concentrations in the clinical population have not been thoroughly described.

Methods:  Protein phenotypes were determined by isoelectric focusing electrophoresis for 72,229 consecutive samples. Phenotype frequencies, median serum concentrations, and central 95% concentration intervals were determined for observed phenotypes. Concurrent AAT phenotype and concentration data were used to evaluate the efficacy of using serum AAT concentration alone to detect AAT deficiency.

Results:  Age, race, and sex had only slight effects on the median 95% serum protein concentration intervals of the 58,087 PiMM (wild type) phenotype specimens. Positive predictive values were calculated for the detection of potential deficiency phenotypes at different serum cutoff concentrations, aiding potential screening effort design. For example, the PiZZ deficiency phenotype (n = 814) could be detected at 99.5% sensitivity and 96.5% specificity using a cutoff of ≤ 85 mg/dL. However, at-risk specimens with two putative deleterious variants (Z, S, I, F, P, T, and Null variants) were detected with only 85.9% sensitivity at this cutoff (n = 1,661). Rare phenotype variants were observed in 2.5% of samples.

Conclusions:  This analysis provides novel information on serum AAT concentrations associated with different AAT phenotypes and provides insight into the severity of depression of AAT concentration in the presence of rare deficiency variants. Additionally, it allows for evaluation of efficacy of testing algorithms incorporating AAT serum concentration determination.

Figures in this Article

α1-Antitrypsin (AAT) is the major serine protease inhibitor in human serum.1,2 If circulating AAT concentration is inadequate, the protease neutrophil elastase inexorably degrades elastin in the pulmonary alveolar matrix. Patients with AAT deficiency often do not develop clinically significant symptoms, such as emphysema and COPD, until they reach 40 or 50 years of age.3,4 Smoking and other environmental factors, such as excessive dust and fumes, appear to increase the rate of pulmonary function reduction.5 In addition to pulmonary dysfunction, certain AAT variants, such as the Z deficiency variant, exhibit damaging AAT protein aggregation in hepatic cells.1 One-third of adult men with PiZZ will develop cirrhosis, and 10% of neonates will exhibit hepatitis.6

The prevalence of severe AAT deficiency is believed to be approximately one in 3,000 individuals in the United States.710 The native or “wild-type” PiMM phenotype is present in individuals with two M variant alleles. Common M variants, such as M1, M2, and M3, have been considered functionally equivalent.11 Individuals who possess two deleterious AAT alleles (such as the relatively common Z and S deficiency variants) are at significant risk for developing symptoms related to AAT deficiency due to insufficient circulating AAT protease inhibitor (Pi).3,12 A pulmonary damage threshold of less than or equal to a serum AAT concentration of approximately 60 mg/dL or 11 μM has been proposed.1,13,14 A number of less common deficiency variants have been observed in a variety of populations. Relative frequencies and associated serum concentrations of these rare AAT variants in clinical populations remain largely unexplored.12

For individuals who possess only one deficiency allele, the risk of developing any clinically significant symptoms, although believed to be either slight or negligible, has not been completely established. There is some evidence linking the PiMZ phenotype to a slightly increased risk of pulmonary disorders,15,16 but the association of PiMZ phenotype with liver disease remains controversial.6 A small retrospective case control study has raised the question of whether the presence of a single Z allele increases the risk for development of lung cancer.17

Despite the establishment of World Health Organization guidelines regarding testing criteria, AAT deficiency is underrecognized.1820 Population screening for AAT deficiency has been proposed, and pilot studies have been reported.2,10,21,22 Currently, the median time between the observation of symptoms and diagnosis can be as long as 8 years.23 Once AAT deficiency is identified, disease progression can be substantially reduced by AAT protein augmentation therapy and lifestyle modification such as smoking cessation.3,4,12,19,24

The underrecognition of AAT deficiency underscores the need for effective testing to increase detection of individuals at risk.25 Pi protein phenotype determination by isoelectric focusing electrophoresis (IEF) is a commonly used method, although a number of other techniques (including genetic testing) have also been used.2629 The effectiveness of assays or algorithms for characterization or screening for AAT deficiency is dependent on their ability to detect both common and rare clinically relevant deficiency variants.30,31

Studies suggest that individuals at risk for AAT deficiency disorders may be identified by decreased concentrations of circulating AAT.32,33 Although the use of AAT concentration determination to screen for AAT deficiency is relatively simple and inexpensive, there are potential drawbacks.21 Although substantial correlation of protein phenotype and circulating AAT concentrations has been established, confounding factors include normal intraindividual variation, positive acute phase response of AAT, and depression of AAT production in substantial liver disease or malnutrition.34,35

Understanding the effects of parameters such as variant, age, sex, and race is critical to establishing the usefulness of AAT concentration testing. To investigate the relative frequencies and associated serum concentrations corresponding to the presence of common and rare AAT variants, a large database consisting of the AAT phenotype and serum concentration of 72,229 consecutive patient samples submitted for AAT protein phenotyping was created and analyzed.

A retrospective database was generated consisting of patient age in years, sex, patient race (when available), reported AAT phenotypes, and measured AAT concentrations for patient serum samples consecutively submitted for AAT phenotyping by IEF electrophoresis and concurrent AAT serum concentration determination to ARUP Laboratories. All samples were treated in accordance with procedures approved by the institutional review board of the University of Utah (IRB 7275).

Pi protein phenotypes were classified by IEF electrophoresis. Serum samples were applied to a 5% polyacrylamide IEF gel (pH, 4-5), electrophoresed, and fixed before staining with Brilliant Blue G stain. Serum concentrations of AAT were determined using a Roche P Module (F. Hoffman-La Roche Ltd) immunoturbidimetric assay (coefficient of variation of 2.7% at 74 mg/dL and 2.4% at 165 mg/dL). The lower limit of the analytical measurement range of this assay is 30 mg/dL.

Descriptive statistics were generated using Excel (Microsoft), EP Evaluator, Release 4 (Data Innovations, LLC) and GraphPad Prism (GraphPad Software, Inc). Variants considered to be deleterious were Z, S, F, I, P, T, and Null.1,3638 The Null deficiency phenotype was defined as no protein apparent by IEF and a serum concentration of < 30 mg/dL.1

The observed protein phenotypes and associated serum concentrations are summarized in Table 1. A total of 1,664 patient samples had two apparent deficiency phenotype alleles and were classified as at-risk phenotypes. Of these, 99 samples contained a rare deficiency allele paired with an S or Z deficiency allele, and nine samples harbored two rare deficiency alleles (Pi FF, PP, II, TT). Three Null phenotype samples exhibiting no apparent AAT variant were classified at risk. Additionally, 16,893 samples exhibited one deleterious variant paired with a nondeficiency phenotype and were classified as carriers; samples with no deficiency alleles were deemed to be low risk (Fig 1).1

Table Graphic Jump Location
Table 1 —Distribution and Associated Serum Concentrations of AAT Phenotypes

Nonparametric median 95% intervals are given for phenotypes that were represented > 40 times. If a phenotype was identified in < 40 samples, the concentration range, rather than the reference interval, is provided. Median serum concentrations are provided for all phenotypic variants represented by more than two samples. Nonparametric CIs of the central 95% range limits were calculated by exact formula (EP Evaluator program, National Committee for Clinical Laboratory Standards C28-A method) for phenotypes represented > 100 times. Phenotypes with two deleterious variants are denoted as at risk for AAT deficiency-related disorders, samples with one deleterious phenotype are listed as a carrier, and samples with two nondeleterious AAT variants are considered to be low risk. All AAT phenotype concentrations for phenotypes represented > 40 times were compared with the MM phenotype by Dunnett multiple comparison test. With the exception of FM and LM, all exhibited significant differences (P < .05). AAT = α1-antitrypsin; IEF = isoelectric focusing; Pi = protease inhibitor.

Figure Jump LinkFigure 1. Distribution of the observed serum concentrations associated with the presence of deficiency variants. Percentages of each phenotype classification (ZZ, at-risk, carrier, low-risk) at different AAT serum concentrations. These classifications are grouped as follows: PiZZ (n = 814), at-risk (includes PiZZ, n = 1,661), carrier (n = 11,358), and low-risk (n = 59,201). These data were generated by determining the normalized percentage of each phenotype classification in 5 mg/dL AAT concentration histogram bins. The normalized fractions of PiZZ phenotype samples (74.69%) and at-risk phenotype samples (36.85%) that exhibited serum AAT concentrations of ≤ 30 mg/dL are not shown. AAT = α1-antitrypsin.Grahic Jump Location

The AAT reference interval in the 58,087 individuals with the PiMM or native phenotype was 102 to 254 mg/dL with a median value of 147 mg/dL (Table 2). The PiM1M1, PiM2M2, and PiM3M3 phenotype variants demonstrated nearly identical median 95% intervals and medians. Men and women were represented almost equally, with men representing 51% of the low-risk patients and 53% of the at-risk patients. The observed male PiMM AAT reference interval was slightly lower than that of women, with men having a 7 mg/dL lower median AAT concentration (P < .01).

Table Graphic Jump Location
Table 2 —Serum Concentrations of Different Subsets of the MM Phenotype Population

All central 95% ranges were determined nonparametrically. The CIs of the central 95% range limits were calculated using exact formula (EP Evaluator program, NCCLS C28-A method). Only samples with known age, race, sex, and M phenotype variant subtype parameters were included in each section of this table. A significant difference was observed by unpaired t test between the observed male and female AAT concentrations (P ≤ .01). No significant differences were observed between the M1M1, M2M2, and M3M3 phenotype-associated AAT concentrations by Bonferroni multiple comparison test (P ≤ .05). Concentrations of AAT in individuals designated as Asian differed significantly from other racial designations (P ≤ .05), but no other significant differences were observed using Bonferroni multiple comparison test. Numerous pairwise differences were observed for different age groups by Bonferroni multiple comparison test (P ≤ .05). See Table 1 legend for expansion of abbreviations.

Significant variation in AAT concentration with age was apparent (Table 2). A median AAT concentration of 140 mg/dL was observed for the ≤ 1-year-old age group, which differed significantly from the 146 mg/dL median AAT concentration observed for the 40- to 49-year-old age group (P ≤ .05). Reference intervals increased significantly after age 49 years, with individuals 80 to 89 years old exhibiting an approximate 13% increase in median AAT serum concentrations as compared with the 40- to 49-year age group (P < .01).

Although the majority of specimens in this reference laboratory population lacked racial identification, a sufficient subset of PiMM phenotype samples with racial designation were present to survey PiMM phenotype and AAT concentrations for broad racial categories (n = 6,972). No difference was observed between the white, black, and Hispanic categories. However, a significant depression of measured AAT concentrations was present in the relatively poorly represented Asian category (P < .05).

As expected, the presence of deleterious variants in patient phenotypes lowered the median observed serum concentration values (Table 1). The PiZZ phenotype resulted in a median AAT concentration of ≤ 29 mg/dL, corresponding to a > 80% reduction of circulating AAT when compared with the PiMM median concentration (147 mg/dL). The PiSZ phenotype had a median AAT serum concentration of 62 mg/dL, or 42% of the PiMM value. The PiSS phenotype resulted in a median AAT concentration of 95 mg/dL, or 65% of the PiMM median value. Heterozygous PiMS and PiMZ phenotypes resulted in median serum protein concentrations of approximately 85% and 61% of the PiMM phenotype median, respectively.

Rare phenotype variants (non-M, Z, and S) were observed in 1,866 or 2.5% of all samples in this clinical population. The I, P, and T variants, which have been previously reported as deleterious, all resulted in significantly reduced (P < .05) median serum concentrations in heterozygous individuals (PiIM, PiPM, and PiTM) as compared with the PiMM phenotype.1,3638 The deleterious F variant did not result in an observed decrease in serum AAT values.36 However, other variants traditionally not considered deleterious (G and V) yielded significant yet small reductions in AAT serum concentration for heterozygous individuals (PiGM and PiVM) when compared with the PiMM phenotype (P ≤ .05). Unexpectedly, the nondeleterious C and D variants exhibited significant increases in observed median serum concentrations in the PiCM and PiDM heterozygous states (P ≤ .05).

The median age of phenotype testing was 49 years of age. A histogram showing the relative ages of testing for all samples, at-risk samples, and PiZZ phenotype samples is shown in Figure 2. The distribution of age of testing was similar for low-risk samples, carrier samples, at-risk samples, and PiZZ phenotype samples. The exception was for children < 10 years of age, in whom a relatively higher proportion of the PiZZ and at-risk phenotypes were observed.

Figure Jump LinkFigure 2. Patient age at the time of testing for different phenotype classifications. The y axis is the percentage of samples for each classification that fall within the specific age group at the time of testing. Patient ages at testing for all samples, at-risk phenotype samples, and ZZ phenotype samples are shown. Eleven patient specimens were submitted as age > 90 years and are not shown.Grahic Jump Location

Concurrent phenotype and serum concentrations were used to determine the diagnostic sensitivity and specificity of different AAT serum concentrations in distinguishing at-risk, carrier, and low-risk patient samples (Table 3). Serum AAT concentrations can be used to detect the PiZZ phenotype effectively. However, inclusion of other phenotypic at-risk patients reduces the overall usefulness of using only AAT serum concentration in the detection of patients vulnerable for development of AAT deficiency-related symptoms (Fig 3).

Table Graphic Jump Location
Table 3 —AAT Serum Concentration Cutoffs

Percentage of common phenotypes at or below AAT serum cutoff concentrations (mg/dL). Different AAT concentration cutoffs were evaluated for at-risk and carrier classifications. The at-risk classification included all samples with two deficiency variants by IEF (including the ZZ variant). Specificity is given for the exclusion of all low-risk (no deleterious variants by IEF) and carrier samples (no deleterious variants by IEF). Positive predictive values for detecting at-risk and PiZZ phenotypes were calculated using a putative population prevalence of at risk or PiZZ of 1 in 3,000 individuals. The rate of false positive results was calculated using the specificity from the carrier and low-risk population. See Table 1 legend for expansion of abbreviations.

Figure Jump LinkFigure 3. Receiver operating characteristic (ROC) plot of the detection of AAT deficiency variants using AAT serum concentration cutoffs. The solid diamonds indicate the ROC line for the PiZZ phenotype, the solid squares indicate the at-risk phenotype, and the solid triangles indicate the set of carrier phenotypes. All phenotype sets were compared with the low-risk phenotype data set. The unity line is also shown. Areas under the curve were 0.9998 for the PiZZ phenotype, 0.9832 for the at-risk phenotype set, and 0.8114 for the low-risk phenotype set. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

The large number of native PiMM individuals in this study allowed for investigation of differences in normal populations.35 As expected, the M1, M2, and M3 variants had no significant effect on serum AAT concentrations.11 Median AAT concentrations were slightly lower in males (P ≤ .01), although the magnitude of this effect is likely not clinically significant. Interestingly, PiMM individuals broadly designated as Asian exhibited significantly (P ≤ .05) lower AAT concentrations when compared with all other racial designations. Median values of AAT concentration rose with increasing age after age 49, agreeing with reports of higher concentrations of positive acute-phase reactants in the elderly.39 The observed 10% depression of the AAT reference interval lower limit in the ≤ 1 year age cohort bears further exploration, as it may have implications for future newborn screening. It should be noted that the overall PiMM median 95% interval presented here is similar to an interval established in a smaller population using a purified AAT standard.40

The classic deficiency variants (S and Z) resulted in substantially decreased circulating AAT concentrations, and AAT deficiency-related symptoms frequently develop in individuals with PiZZ or PiSZ phenotypes (Table 1). Respectively, 98.53% of PiZZ and 45.37% of PiSZ phenotypes exhibited an AAT concentration below a putative pulmonary damage threshold of ≤ 60 mg/dL.1,13 It should be noted that the PiSS phenotype may exhibit a much lower pulmonary risk than PiSZ, as only 8.0% of the PiSS phenotypic individuals presented AAT serum concentrations below this threshold.41 Very few (0.05%) of the PiMS phenotypic individuals exhibit circulating AAT concentrations ≤ 60 mg/dL (roughly the same as PiMM), substantiating previous studies that concluded PiMS individuals appear to be at no discernible increased risk for developing pulmonary impairment.16 However, a higher fraction of PiMZ individuals (2.12%) exhibited AAT concentrations ≤ 60 mg/dL, in accordance with observations that deleterious pulmonary effects may arise in individuals with a PiMZ phenotype (albeit rarely), especially in those individuals who may be at increased risk due to environmental factors.16,42 Although the widely cited putative damage threshold of ≤ 60 mg/dL has been explored here, the data presented in Table 3 allow for evaluation of the number of individuals who exhibit AAT concentrations below alternate circulating AAT concentration damage thresholds for different phenotypes.1,13

A number of rare variants classically considered to be deleterious (P, I, and T) reduced the observed median AAT serum values (Table 1). Of the heterozygous deficiency variant carriers, PiPM exhibited the largest decrease in median AAT concentrations (median AAT concentration was 23% less than PiMM).43 Smaller decreases in median concentrations were observed for PiIM (17% reduction) and in the eleven PiTM samples (4% reduction).

Some variation was observed for putative nondeleterious heterozygous phenotypes (Table 1). Although median concentrations of the nondeleterious phenotypes PiGM and PiLM were about 90% of the PiMM phenotype, PiDM and PiCM phenotypes increased relative median concentrations to 135% and 125%, respectively. The differences in observed relative serum concentrations as compared with PiMM were significant for PiGM, PiDM, and PiCM (P < .05). This implies that the presence of a D or C heterozygous phenotype might buffer the increased risk of developing pulmonary damage when paired with a deficiency variant. Although the exact mechanism(s) of the alterations in circulating serum concentrations of these variants are unknown, other AAT variants can exhibit differences in expression, posttranslational processing, and polymerization propensity as compared with native protein.13,44,45

Variations in the antiproteolytic activity of AAT must be considered when evaluating any testing algorithm that uses serum AAT concentration determination to predict patient risk. Some variants, such as the Z variant, may have both decreased activity and decreased circulating concentrations.46 The F variant is of particular concern because the presence of the F variant results in little change in circulating AAT concentrations (PiFM median concentration is 96% of that of PiMM), but is known to result in a protein product with decreased ability to inhibit leukocyte elastase. Thus, the F variant results in a functional AAT deficiency.36 Individuals with Pi FZ, FS, or FF phenotypes (present in 4% of the at-risk specimens) will present challenges for any algorithm dependent on detection of reduced serum AAT concentrations. At present, most laboratories use AAT concentration determination, although an activity assay has been described.47

The use of serum AAT concentrations was excellent at identifying patients with the PiZZ phenotype but was less effective in identifying other at-risk phenotypes. This dataset allowed for evidence-based evaluation of different serum concentration cutoffs (Fig 3, Table 3). For example, using a cutoff of 85 mg/dL, PiZZ is detected with a sensitivity of 99.5% and a specificity of 96.5%. When all at-risk samples including PiZZ are considered, the sensitivity of the ≤ 85 mg/dL cutoff drops to 85.9%. Results for other cutoff concentrations and estimated positive predictive values for PiZZ and all at-risk phenotypes are shown in Table 3. A cutoff of ≤ 60 mg/dL performs fairly well, as it detected 98.5% of PiZZ homozygotes with 99.8% specificity. However, this cutoff only detects 65% of all designated at-risk patient samples. The positive predictive value at the ≤ 60 mg/dL cutoff is estimated to be 13.5% for PiZZ and 9.3% for at-risk phenotypes in the general population. The use of lower cutoffs, such as ≤ 50 mg/dL, increased the estimated positive predictive values substantially (to 33.1% for PiZZ and 21.4% for all at-risk phenotypes). Factors that may preclude complete sensitivity for deleterious phenotypes include: the presence of a concurrent acute-phase reaction, potential analytical variation, and the presence of an inactive AAT protein such as the F deficiency variant.34 As discussed previously, the heterogeneous cohort of at-risk phenotypes appeared to exhibit varied serum concentrations, with many of the at-risk phenotypes conferring less apparent risk than PiZZ.

In this study, a small percentage of the PiZZ phenotypes did not exhibit expected substantially depressed AAT serum concentrations (1.47% of PiZZ serum concentrations were > 60 mg/dL). This observation cannot be solely explained by analytical variation, as the coefficient of variation of the assay was determined to be about 3% (see the “Materials and Methods” section). Although it is known that acute-phase reactions do moderately raise serum AAT concentrations in the presence of the Z allele, the exact mechanism in these retrospective cases remains undetermined.48,49 An alternative hypothesis is that these patients may harbor a previously unidentified rare AAT genetic variant that has a migration pattern indistinguishable from the classic deleterious Z phenotype variant. Similar phenomena have been documented for other phenotype variants.43

The use of serum AAT concentration cutoffs that provide more complete sensitivity for at-risk individuals might be deemed more appropriate for potential screening or initial evaluations that use AAT concentration determination alone, despite reduced specificity (Table 3). The use of a higher serum concentration cutoff, such as ≤ 120 mg/dL, provides complete sensitivity for PiZZ phenotypes (100%) and 96.9% percent sensitivity for other at-risk individuals (in particular, at-risk individuals with phenotypes containing the F deficiency variant are not extensively detected).

Although severe deficiency alleles may be overrepresented in this clinical population, this dataset provides insight into the relative frequencies of different at-risk phenotypes. Approximately one-half of the at-risk samples with two deleterious protein variants consisted of the PiZZ phenotype (814 out of 1,661samples). Significantly, 6.7% (111 of 1,664) of the at-risk subjects contained a rare (non-Z, non-S) deficiency variant, suggesting that these variants account for a substantial number of patients with an AAT deficiency.

Less than 10% of the 100,000 PiZZ phenotypic individuals in the United States are believed to have been diagnosed with AAT deficiency.7 One-half (48%) of all at-risk specimens were from patients > 50 years of age, or years following the typical onset of AAT pulmonary symptoms (Fig 2).7 This study suggests that early diagnosis is sporadic and agrees with surveys that indicate the average age of diagnosis is 45.5 ± 9.5 years.23,25,50 The higher proportional detection rate of the PiZZ phenotype observed in infants might be the result of testing guidelines regarding neonatal liver abnormalities or family history.18,19

Although the prevalence of AAT deficiency in the United States is at least as prevalent as well-known genetic disorders such as phenylketonuria or cystic fibrosis, widespread testing for AAT deficiency has not been implemented.7 Multiple testing algorithms, some incorporating serum concentration testing, have been proposed.2,25,30,31 This large study provides a unique opportunity to determine the relative frequencies and resulting associated AAT serum concentrations of AAT protein phenotypes and can be used to evaluate the efficacy of AAT testing using serum concentration determination.

Author contributions: Dr Bornhorst had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Bornhorst: contributed to the study design, data collection, data analyses, and manuscript writing.

Dr Greene: contributed to the study design, data analyses, and manuscript writing.

Dr Ashwood: contributed to the study design, data collection, data analyses, and manuscript writing.

Dr Grenache: contributed to the study design, data analyses, and manuscript writing.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Bornhorst has served as a consultant to Geonostics Inc. Drs Greene, Ashwood, and Grenache have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, collection and analysis of the data, or in the preparation of the manuscript.

Other contributions: We thank the M.C. Elliot-Jelf, BS, and the Electrophoresis/Manual Endocrinology clinical laboratory section. We also thank Shannon Swenson, BS, and Martin Miller, BS, for assistance in database extraction.

AAT

α1-antitrypsin

IEF

isoelectric focusing

Pi

protease inhibitor

Crystal RG. The alpha 1-antitrypsin gene and its deficiency states. Trends Genet. 1989;5(12):411-417. [CrossRef] [PubMed]
 
Aboussouan LS, Stoller JK. Detection of alpha-1 antitrypsin deficiency: a review. Respir Med. 2009;103(3):335-341. [CrossRef] [PubMed]
 
Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365(9478):2225-2236. [CrossRef] [PubMed]
 
Needham M, Stockley RA. Alpha 1-antitrypsin deficiency. 3: clinical manifestations and natural history. Thorax. 2004;59(5):441-445. [CrossRef] [PubMed]
 
Janus ED, Phillips NT, Carrell RW. Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet. 1985;1(8421):152-154. [CrossRef] [PubMed]
 
Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol. 2008;103(8):2136-2141. [CrossRef] [PubMed]
 
de Serres FJ. Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed. Environ Health Perspect. 2003;111(16):1851-1854. [CrossRef] [PubMed]
 
de Serres FJ, Blanco I, Fernández-Bustillo E. Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet. 2003;64(5):382-397. [CrossRef] [PubMed]
 
Luisetti M, Seersholm N. Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency. Thorax. 2004;59(2):164-169. [CrossRef] [PubMed]
 
Silverman EK, Miletich JP, Pierce JA, et al. Alpha-1-antitrypsin deficiency. High prevalence in the St. Louis area determined by direct population screening. Am Rev Respir Dis. 1989;140(4):961-966. [PubMed]
 
Massi G, Cotumaccia R, Auconi P, Patriarchi P, Mirabella A, Rizzo G. Alpha 1-antitrypsin PiM subtypes and chronic obstructive pulmonary disease (COPD). Chest. 1982;82(4):513. [CrossRef] [PubMed]
 
DeMeo DL, Silverman EK. Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax. 2004;59(3):259-264. [CrossRef] [PubMed]
 
Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259. [CrossRef] [PubMed]
 
Turino GM, Barker AF, Brantly ML, et al. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1996;154(6 pt 1):1718-1725. [PubMed]
 
Dahl M, Tybjaerg-Hansen A, Lange P, Vestbo J, Nordestgaard BG. Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes: a longitudinal study of the general population. Ann Intern Med. 2002;136(4):270-279. [PubMed]
 
Dahl M, Hersh CP, Ly NP, Berkey CS, Silverman EK, Nordestgaard BG. The protease inhibitor PI*S allele and COPD: a meta-analysis. Eur Respir J. 2005;26(1):67-76. [CrossRef] [PubMed]
 
Yang P, Sun Z, Krowka MJ, et al. Alpha1-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk. Arch Intern Med. 2008;168(10):1097-1103. [CrossRef] [PubMed]
 
Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415. [PubMed]
 
Stoller JK, Sandhaus RA, Turino G, Dickson R, Rodgers K, Strange C. Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Chest. 2005;128(4):1989-1994. [CrossRef] [PubMed]
 
Jain A, McCarthy K, Xu M, Stoller JK. Impact of a clinical decision support system in an electronic health record to enhance detection of α1-antitrypsin deficiency. Chest. 2011;140(1):198-204. [CrossRef] [PubMed]
 
Sveger T, Thelin T. A future for neonatal alpha1-antitrypsin screening?. Acta Paediatr. 2000;89(3):259-261. [PubMed]
 
Bals R, Koczulla R, Kotke V, Andress J, Blackert K, Vogelmeier C. Identification of individuals with alpha-1-antitrypsin deficiency by a targeted screening program. Respir Med. 2007;101(8):1708-1714. [CrossRef] [PubMed]
 
Campos MA, Wanner A, Zhang G, Sandhaus RA. Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest. 2005;128(3):1179-1186. [CrossRef] [PubMed]
 
Stoller JK, Snider GL, Brantly ML, et al;, American Thoracic Society American Thoracic Society; European Respiratory Society European Respiratory Society. American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency [in German]. Pneumologie. 2005;59(1):36-68. [CrossRef] [PubMed]
 
Brantly M. Efficient and accurate approaches to the laboratory diagnosis of alpha1-antitrypsin deficiency: The promise of early diagnosis and intervention. Clin Chem. 2006;52(12):2180-2181. [CrossRef] [PubMed]
 
Righetti PG, Gianazza E, Bianchi-Bosisio A, Sinha P, Köttgen E. Isoelectric focusing in immobilized pH gradients: applications in clinical chemistry and forensic analysis. J Chromatogr A. 1991;569(1-2):197-228.
 
Gorrini M, Ferrarotti I, Lupi A, et al. Validation of a rapid, simple method to measure alpha1-antitrypsin in human dried blood spots. Clin Chem. 2006;52(5):899-901. [CrossRef] [PubMed]
 
Aslanidis C, Nauck M, Schmitz G. High-speed detection of the two common alpha(1)-antitrypsin deficiency alleles Pi*Z and Pi*S by real-time fluorescence PCR and melting curves. Clin Chem. 1999;45(10):1872-1875. [PubMed]
 
Chen Y, Snyder MR, Zhu Y, et al. Simultaneous phenotyping and quantification of α-1-antitrypsin by liquid chromatography-tandem mass spectrometry. Clin Chem. 2011;57(8):1161-1168. [CrossRef] [PubMed]
 
Snyder MR, Katzmann JA, Butz ML, et al. Diagnosis of alpha-1-antitrypsin deficiency: an algorithm of quantification, genotyping, and phenotyping. Clin Chem. 2006;52(12):2236-2242. [CrossRef] [PubMed]
 
Bornhorst JA, Procter M, Meadows C, Ashwood ER, Mao R. Evaluation of an integrative diagnostic algorithm for the identification of people at risk for alpha1-antitrypsin deficiency. Am J Clin Pathol. 2007;128(3):482-490. [CrossRef] [PubMed]
 
Steiner SJ, Gupta SK, Croffie JM, Fitzgerald JF. Serum levels of alpha1-antitrypsin predict phenotypic expression of the alpha1-antitrypsin gene. Dig Dis Sci. 2003;48(9):1793-1796. [CrossRef] [PubMed]
 
Corda L, Bertella E, Pini L, et al. Diagnostic flow chart for targeted detection of alpha1-antitrypsin deficiency. Respir Med. 2006;100(3):463-470. [CrossRef] [PubMed]
 
Lisowska-Myjak B. AAT as a diagnostic tool. Clin Chim Acta. 2005;352(1-2):1-13. [CrossRef] [PubMed]
 
Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O. Reference distributions for the positive acute phase proteins, alpha1-acid glycoprotein (orosomucoid), alpha1-antitrypsin, and haptoglobin: a comparison of a large cohort to the world’s literature. J Clin Lab Anal. 2000;14(6):265-270. [CrossRef] [PubMed]
 
Cook L, Burdon JG, Brenton S, Knight KR, Janus ED. Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human neutrophil elastase. Pathology. 1996;28(3):242-247. [CrossRef] [PubMed]
 
Crystal RG, Brantly ML, Hubbard RC, Curiel DT, States DJ, Holmes MD. The alpha 1-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy. Chest. 1989;95(1):196-208. [CrossRef] [PubMed]
 
Faber JP, Poller W, Weidinger S, et al. Identification and DNA sequence analysis of 15 new alpha 1-antitrypsin variants, including two PI*Q0 alleles and one deficient PI*M allele. Am J Hum Genet. 1994;55(6):1113-1121. [PubMed]
 
Milman N, Graudal N, Andersen HC. Acute phase reactants in the elderly. Clin Chim Acta. 1988;176(1):59-62. [CrossRef] [PubMed]
 
Brantly ML, Wittes JT, Vogelmeier CF, Hubbard RC, Fells GA, Crystal RG. Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha 1-antitrypsin phenotypes. Chest. 1991;100(3):703-708. [CrossRef] [PubMed]
 
McGee D, Schwarz L, McClure R, et al. Is PiSS alpha-1 antitrypsin deficiency associated with disease?. Pulm Med. 2010;2010:570679. [PubMed]
 
Eriksson S, Lindell SE, Wiberg R. Effects of smoking and intermediate alpha 1-antitrypsin deficiency (PiMZ) on lung function. Eur J Respir Dis. 1985;67(4):279-285. [PubMed]
 
Bornhorst JA, Calderon FR, Procter M, Tang W, Ashwood ER, Mao R. Genotypes and serum concentrations of human alpha-1-antitrypsin “P” protein variants in a clinical population. J Clin Pathol. 2007;60(10):1124-1128. [CrossRef] [PubMed]
 
Lomas DA, Parfrey H. Alpha1-antitrypsin deficiency. 4: molecular pathophysiology. Thorax. 2004;59(6):529-535. [CrossRef] [PubMed]
 
Sifers RN. Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc. 2010;7(6):376-380. [CrossRef] [PubMed]
 
Ogushi F, Fells GA, Hubbard RC, Straus SD, Crystal RG. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest. 1987;80(5):1366-1374. [CrossRef] [PubMed]
 
Roche D, Mesner A, Al Nakib M, Leonard F, Beaune P. Automated determination of serum alpha1-antitrypsin by antitryptic activity measurement. Clin Chem. 2009;55(3):513-518. [CrossRef] [PubMed]
 
Sandford AJ, Chagani T, Spinelli JJ, Paré PD. alpha1-antitrypsin genotypes and the acute-phase response to open heart surgery. Am J Respir Crit Care Med. 1999;159(5 pt 1):1624-1628. [PubMed]
 
Hill AT, Campbell EJ, Bayley DL, Hill SL, Stockley RA. Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). Am J Respir Crit Care Med. 1999;160(6):1968-1975. [PubMed]
 
Stoller JK, Fromer L, Brantly M, Stocks J, Strange C. Primary care diagnosis of alpha-1 antitrypsin deficiency: issues and opportunities. Cleve Clin J Med. 2007;74(12):869-874. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Distribution of the observed serum concentrations associated with the presence of deficiency variants. Percentages of each phenotype classification (ZZ, at-risk, carrier, low-risk) at different AAT serum concentrations. These classifications are grouped as follows: PiZZ (n = 814), at-risk (includes PiZZ, n = 1,661), carrier (n = 11,358), and low-risk (n = 59,201). These data were generated by determining the normalized percentage of each phenotype classification in 5 mg/dL AAT concentration histogram bins. The normalized fractions of PiZZ phenotype samples (74.69%) and at-risk phenotype samples (36.85%) that exhibited serum AAT concentrations of ≤ 30 mg/dL are not shown. AAT = α1-antitrypsin.Grahic Jump Location
Figure Jump LinkFigure 2. Patient age at the time of testing for different phenotype classifications. The y axis is the percentage of samples for each classification that fall within the specific age group at the time of testing. Patient ages at testing for all samples, at-risk phenotype samples, and ZZ phenotype samples are shown. Eleven patient specimens were submitted as age > 90 years and are not shown.Grahic Jump Location
Figure Jump LinkFigure 3. Receiver operating characteristic (ROC) plot of the detection of AAT deficiency variants using AAT serum concentration cutoffs. The solid diamonds indicate the ROC line for the PiZZ phenotype, the solid squares indicate the at-risk phenotype, and the solid triangles indicate the set of carrier phenotypes. All phenotype sets were compared with the low-risk phenotype data set. The unity line is also shown. Areas under the curve were 0.9998 for the PiZZ phenotype, 0.9832 for the at-risk phenotype set, and 0.8114 for the low-risk phenotype set. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Distribution and Associated Serum Concentrations of AAT Phenotypes

Nonparametric median 95% intervals are given for phenotypes that were represented > 40 times. If a phenotype was identified in < 40 samples, the concentration range, rather than the reference interval, is provided. Median serum concentrations are provided for all phenotypic variants represented by more than two samples. Nonparametric CIs of the central 95% range limits were calculated by exact formula (EP Evaluator program, National Committee for Clinical Laboratory Standards C28-A method) for phenotypes represented > 100 times. Phenotypes with two deleterious variants are denoted as at risk for AAT deficiency-related disorders, samples with one deleterious phenotype are listed as a carrier, and samples with two nondeleterious AAT variants are considered to be low risk. All AAT phenotype concentrations for phenotypes represented > 40 times were compared with the MM phenotype by Dunnett multiple comparison test. With the exception of FM and LM, all exhibited significant differences (P < .05). AAT = α1-antitrypsin; IEF = isoelectric focusing; Pi = protease inhibitor.

Table Graphic Jump Location
Table 2 —Serum Concentrations of Different Subsets of the MM Phenotype Population

All central 95% ranges were determined nonparametrically. The CIs of the central 95% range limits were calculated using exact formula (EP Evaluator program, NCCLS C28-A method). Only samples with known age, race, sex, and M phenotype variant subtype parameters were included in each section of this table. A significant difference was observed by unpaired t test between the observed male and female AAT concentrations (P ≤ .01). No significant differences were observed between the M1M1, M2M2, and M3M3 phenotype-associated AAT concentrations by Bonferroni multiple comparison test (P ≤ .05). Concentrations of AAT in individuals designated as Asian differed significantly from other racial designations (P ≤ .05), but no other significant differences were observed using Bonferroni multiple comparison test. Numerous pairwise differences were observed for different age groups by Bonferroni multiple comparison test (P ≤ .05). See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
Table 3 —AAT Serum Concentration Cutoffs

Percentage of common phenotypes at or below AAT serum cutoff concentrations (mg/dL). Different AAT concentration cutoffs were evaluated for at-risk and carrier classifications. The at-risk classification included all samples with two deficiency variants by IEF (including the ZZ variant). Specificity is given for the exclusion of all low-risk (no deleterious variants by IEF) and carrier samples (no deleterious variants by IEF). Positive predictive values for detecting at-risk and PiZZ phenotypes were calculated using a putative population prevalence of at risk or PiZZ of 1 in 3,000 individuals. The rate of false positive results was calculated using the specificity from the carrier and low-risk population. See Table 1 legend for expansion of abbreviations.

References

Crystal RG. The alpha 1-antitrypsin gene and its deficiency states. Trends Genet. 1989;5(12):411-417. [CrossRef] [PubMed]
 
Aboussouan LS, Stoller JK. Detection of alpha-1 antitrypsin deficiency: a review. Respir Med. 2009;103(3):335-341. [CrossRef] [PubMed]
 
Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365(9478):2225-2236. [CrossRef] [PubMed]
 
Needham M, Stockley RA. Alpha 1-antitrypsin deficiency. 3: clinical manifestations and natural history. Thorax. 2004;59(5):441-445. [CrossRef] [PubMed]
 
Janus ED, Phillips NT, Carrell RW. Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet. 1985;1(8421):152-154. [CrossRef] [PubMed]
 
Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol. 2008;103(8):2136-2141. [CrossRef] [PubMed]
 
de Serres FJ. Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed. Environ Health Perspect. 2003;111(16):1851-1854. [CrossRef] [PubMed]
 
de Serres FJ, Blanco I, Fernández-Bustillo E. Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet. 2003;64(5):382-397. [CrossRef] [PubMed]
 
Luisetti M, Seersholm N. Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency. Thorax. 2004;59(2):164-169. [CrossRef] [PubMed]
 
Silverman EK, Miletich JP, Pierce JA, et al. Alpha-1-antitrypsin deficiency. High prevalence in the St. Louis area determined by direct population screening. Am Rev Respir Dis. 1989;140(4):961-966. [PubMed]
 
Massi G, Cotumaccia R, Auconi P, Patriarchi P, Mirabella A, Rizzo G. Alpha 1-antitrypsin PiM subtypes and chronic obstructive pulmonary disease (COPD). Chest. 1982;82(4):513. [CrossRef] [PubMed]
 
DeMeo DL, Silverman EK. Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax. 2004;59(3):259-264. [CrossRef] [PubMed]
 
Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259. [CrossRef] [PubMed]
 
Turino GM, Barker AF, Brantly ML, et al. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1996;154(6 pt 1):1718-1725. [PubMed]
 
Dahl M, Tybjaerg-Hansen A, Lange P, Vestbo J, Nordestgaard BG. Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes: a longitudinal study of the general population. Ann Intern Med. 2002;136(4):270-279. [PubMed]
 
Dahl M, Hersh CP, Ly NP, Berkey CS, Silverman EK, Nordestgaard BG. The protease inhibitor PI*S allele and COPD: a meta-analysis. Eur Respir J. 2005;26(1):67-76. [CrossRef] [PubMed]
 
Yang P, Sun Z, Krowka MJ, et al. Alpha1-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk. Arch Intern Med. 2008;168(10):1097-1103. [CrossRef] [PubMed]
 
Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415. [PubMed]
 
Stoller JK, Sandhaus RA, Turino G, Dickson R, Rodgers K, Strange C. Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Chest. 2005;128(4):1989-1994. [CrossRef] [PubMed]
 
Jain A, McCarthy K, Xu M, Stoller JK. Impact of a clinical decision support system in an electronic health record to enhance detection of α1-antitrypsin deficiency. Chest. 2011;140(1):198-204. [CrossRef] [PubMed]
 
Sveger T, Thelin T. A future for neonatal alpha1-antitrypsin screening?. Acta Paediatr. 2000;89(3):259-261. [PubMed]
 
Bals R, Koczulla R, Kotke V, Andress J, Blackert K, Vogelmeier C. Identification of individuals with alpha-1-antitrypsin deficiency by a targeted screening program. Respir Med. 2007;101(8):1708-1714. [CrossRef] [PubMed]
 
Campos MA, Wanner A, Zhang G, Sandhaus RA. Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest. 2005;128(3):1179-1186. [CrossRef] [PubMed]
 
Stoller JK, Snider GL, Brantly ML, et al;, American Thoracic Society American Thoracic Society; European Respiratory Society European Respiratory Society. American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency [in German]. Pneumologie. 2005;59(1):36-68. [CrossRef] [PubMed]
 
Brantly M. Efficient and accurate approaches to the laboratory diagnosis of alpha1-antitrypsin deficiency: The promise of early diagnosis and intervention. Clin Chem. 2006;52(12):2180-2181. [CrossRef] [PubMed]
 
Righetti PG, Gianazza E, Bianchi-Bosisio A, Sinha P, Köttgen E. Isoelectric focusing in immobilized pH gradients: applications in clinical chemistry and forensic analysis. J Chromatogr A. 1991;569(1-2):197-228.
 
Gorrini M, Ferrarotti I, Lupi A, et al. Validation of a rapid, simple method to measure alpha1-antitrypsin in human dried blood spots. Clin Chem. 2006;52(5):899-901. [CrossRef] [PubMed]
 
Aslanidis C, Nauck M, Schmitz G. High-speed detection of the two common alpha(1)-antitrypsin deficiency alleles Pi*Z and Pi*S by real-time fluorescence PCR and melting curves. Clin Chem. 1999;45(10):1872-1875. [PubMed]
 
Chen Y, Snyder MR, Zhu Y, et al. Simultaneous phenotyping and quantification of α-1-antitrypsin by liquid chromatography-tandem mass spectrometry. Clin Chem. 2011;57(8):1161-1168. [CrossRef] [PubMed]
 
Snyder MR, Katzmann JA, Butz ML, et al. Diagnosis of alpha-1-antitrypsin deficiency: an algorithm of quantification, genotyping, and phenotyping. Clin Chem. 2006;52(12):2236-2242. [CrossRef] [PubMed]
 
Bornhorst JA, Procter M, Meadows C, Ashwood ER, Mao R. Evaluation of an integrative diagnostic algorithm for the identification of people at risk for alpha1-antitrypsin deficiency. Am J Clin Pathol. 2007;128(3):482-490. [CrossRef] [PubMed]
 
Steiner SJ, Gupta SK, Croffie JM, Fitzgerald JF. Serum levels of alpha1-antitrypsin predict phenotypic expression of the alpha1-antitrypsin gene. Dig Dis Sci. 2003;48(9):1793-1796. [CrossRef] [PubMed]
 
Corda L, Bertella E, Pini L, et al. Diagnostic flow chart for targeted detection of alpha1-antitrypsin deficiency. Respir Med. 2006;100(3):463-470. [CrossRef] [PubMed]
 
Lisowska-Myjak B. AAT as a diagnostic tool. Clin Chim Acta. 2005;352(1-2):1-13. [CrossRef] [PubMed]
 
Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O. Reference distributions for the positive acute phase proteins, alpha1-acid glycoprotein (orosomucoid), alpha1-antitrypsin, and haptoglobin: a comparison of a large cohort to the world’s literature. J Clin Lab Anal. 2000;14(6):265-270. [CrossRef] [PubMed]
 
Cook L, Burdon JG, Brenton S, Knight KR, Janus ED. Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human neutrophil elastase. Pathology. 1996;28(3):242-247. [CrossRef] [PubMed]
 
Crystal RG, Brantly ML, Hubbard RC, Curiel DT, States DJ, Holmes MD. The alpha 1-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy. Chest. 1989;95(1):196-208. [CrossRef] [PubMed]
 
Faber JP, Poller W, Weidinger S, et al. Identification and DNA sequence analysis of 15 new alpha 1-antitrypsin variants, including two PI*Q0 alleles and one deficient PI*M allele. Am J Hum Genet. 1994;55(6):1113-1121. [PubMed]
 
Milman N, Graudal N, Andersen HC. Acute phase reactants in the elderly. Clin Chim Acta. 1988;176(1):59-62. [CrossRef] [PubMed]
 
Brantly ML, Wittes JT, Vogelmeier CF, Hubbard RC, Fells GA, Crystal RG. Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha 1-antitrypsin phenotypes. Chest. 1991;100(3):703-708. [CrossRef] [PubMed]
 
McGee D, Schwarz L, McClure R, et al. Is PiSS alpha-1 antitrypsin deficiency associated with disease?. Pulm Med. 2010;2010:570679. [PubMed]
 
Eriksson S, Lindell SE, Wiberg R. Effects of smoking and intermediate alpha 1-antitrypsin deficiency (PiMZ) on lung function. Eur J Respir Dis. 1985;67(4):279-285. [PubMed]
 
Bornhorst JA, Calderon FR, Procter M, Tang W, Ashwood ER, Mao R. Genotypes and serum concentrations of human alpha-1-antitrypsin “P” protein variants in a clinical population. J Clin Pathol. 2007;60(10):1124-1128. [CrossRef] [PubMed]
 
Lomas DA, Parfrey H. Alpha1-antitrypsin deficiency. 4: molecular pathophysiology. Thorax. 2004;59(6):529-535. [CrossRef] [PubMed]
 
Sifers RN. Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc. 2010;7(6):376-380. [CrossRef] [PubMed]
 
Ogushi F, Fells GA, Hubbard RC, Straus SD, Crystal RG. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest. 1987;80(5):1366-1374. [CrossRef] [PubMed]
 
Roche D, Mesner A, Al Nakib M, Leonard F, Beaune P. Automated determination of serum alpha1-antitrypsin by antitryptic activity measurement. Clin Chem. 2009;55(3):513-518. [CrossRef] [PubMed]
 
Sandford AJ, Chagani T, Spinelli JJ, Paré PD. alpha1-antitrypsin genotypes and the acute-phase response to open heart surgery. Am J Respir Crit Care Med. 1999;159(5 pt 1):1624-1628. [PubMed]
 
Hill AT, Campbell EJ, Bayley DL, Hill SL, Stockley RA. Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). Am J Respir Crit Care Med. 1999;160(6):1968-1975. [PubMed]
 
Stoller JK, Fromer L, Brantly M, Stocks J, Strange C. Primary care diagnosis of alpha-1 antitrypsin deficiency: issues and opportunities. Cleve Clin J Med. 2007;74(12):869-874. [CrossRef] [PubMed]
 
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