**3.1 COPD**

The World Health Organisation definition of chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. The more familiar terms 'chronic bronchitis' and 'emphysema' are still in common use, but are to be included within the umbrella term COPD. COPD is not simply a "smoker's cough" but an under-diagnosed, lifethreatening lung disease. A diagnosis of COPD should be considered in any patient who has symptoms of cough, sputum production, or dyspnea, and/or a history of exposure to risk factors for the disease. Diagnosis is confirmed by spirometry, however, even with the ready availability of a simple test, COPD is largely under-diagnosed (Mannino and Braman 2007). Despite being a very common disease which affects 5% of the US population and the fourth

(DLCO), but not FEV1 (Needham and Stockley 2005). Interestingly, a study investigated exacerbation frequency in AATD patients with COPD who were receiving augmentation therapy and found subjects with frequent exacerbations had the worst baseline HRQoL scores, as well as more physician visits and hospitalizations. Unfortunately, AATD patients not receiving augmentation therapy were not included for comparison (Campos, Alazemi,

A recent longitudinal study by Campos et al., (2009) undertaken in the United States, evaluated the effectiveness of a disease management and prevention program for AATD individuals, involving 905 individuals, over a 2 year period. The program comprised of written educational material for self-study and individualised treatment plans for exacerbations. This study illustrated improved patient compliance in the use of bronchodilators, oxygen therapy, and steroids during exacerbations. The management program significantly reduced medical visits and showed a considerably slower deterioration of HRQoL during an exacerbation (Campos, Alazemi, Zhang, Wanner, and Sandhaus 2009). A follow-up study would be beneficial by providing additional evidence to

Replacement therapy is a specific therapy for AATD, and the therapy comprises of intravenous administration of AAT derived from human plasma (Stoller and Aboussouan 2004). At present, this treatment is available in a number of European countries and the United States (Chapman et al. 2009). Some AATD individuals may be candidates for AAT replacement therapy; however, the efficacy of this treatment remains controversial (McCarthy and Dimitrov 2010). Uncertainty persists concerning the therapy's effectiveness and ongoing randomised clinical trials are being performed to definitively assess the efficacy of the treatment. Previous trials have been under-powered and have mostly shown only biochemical efficacy with AAT levels restored to above the putative threshold in the blood and lung. There is some evidence that augmentation therapy can slow lung function decline in patients with AAT deficiency, however, patients with moderate obstruction are most likely to benefit (Modrykamien and Stoller 2009). The therapy comprises of weekly or fortnightly intravenous infusion of an AAT preparation that augments existing levels of

The World Health Organisation definition of chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. The more familiar terms 'chronic bronchitis' and 'emphysema' are still in common use, but are to be included within the umbrella term COPD. COPD is not simply a "smoker's cough" but an under-diagnosed, lifethreatening lung disease. A diagnosis of COPD should be considered in any patient who has symptoms of cough, sputum production, or dyspnea, and/or a history of exposure to risk factors for the disease. Diagnosis is confirmed by spirometry, however, even with the ready availability of a simple test, COPD is largely under-diagnosed (Mannino and Braman 2007). Despite being a very common disease which affects 5% of the US population and the fourth

evaluate the long-term benefits of an AATD disease management program.

Zhang, Wanner, Salathe, et al. 2009).

**2.2.4.4 Replacement therapy** 

circulating AAT in the blood.

**3.1 COPD** 

**3. Alpha-1 antitrypsin deficiency (AATD) and COPD** 

leading cause of death in the United States (Eisner et al. 2010), COPD often is a silent and unrecognised disease, particularly in its early phases (Mannino et al. 2000). Globally, COPD is a growing cause of mortality and will become the third biggest killer by 2020 according to the WHO (WHO 2004).

#### **3.2 What we have learned about COPD from AATD**

In the mid-1960s there were two major discoveries that led to an exponential increase in our knowledge of COPD and the development of the proteolytic hypothesis of lung disease. These were the discovery of AATD and its association with COPD, and the induction of emphysema by intratracheal instillation of a protease (Gross et al. 1965). While numerous different elastases were subsequently shown to cause emphysema in the same model, none of the elastases known at that time had access to the human lung. This changed in 1968 when a potent elastase was discovered within human neutrophilic leukocytes, the primary acute inflammatory white blood cell in the body (Janoff and Scherer 1968). Called neutrophil elastase or NE, it was found to be exquisitely sensitive to inhibition by AAT. It was then discovered that certain products of cigarette smoke were able to destroy the anti-elastase properties of AAT (Johnson and Travis 1979). While AAT is an excellent inhibitor of NE, the Met358 amino acid at its active site is easily oxidised by cigarette smoke and oxidants released by immune cells (Carp et al. 1982; Hubbard et al. 1987). On foot of these revelations, it was proposed in the 1970s that all COPD could be due, at least in part, to a deficiency of AAT (Gadek, Fells, and Crystal 1979). In the majority of individuals who develop COPD due to smoking, the deficiency is functional and due to the inactivation of AAT by cigarette smoke and the influx of inflammatory cells. In individuals with AATD, the deficiency is genetic.

#### **3.3 The ZZ phenotype as a genetic risk factor for COPD**

While smoking-related COPD is acquired, AATD is a form of inherited COPD and is responsible for approximately 1 – 3 % of COPD cases. A US study in 1986 investigated 965 COPD patients and found 1.9% were ZZ and over 8% were MZ (Lieberman, Winter, and Sastre 1986). Another US study investigated 969 patients with diagnosed with emphysema, asthma, or chronic bronchitis and found 1 ZZ case in every 31 samples, which is a case detection rate of over 3% (Brantly M 2003). Moreover, the contribution of SERPINA1 heterozygosity to COPD, while controversial, may account for over 10% of COPD cases if one includes ZZ, SZ and MZ phenotypes (Carroll et al. 2011). The classic pulmonary presentation of lung disease in AATD is severe, early onset panacinar emphysema with a basilar predominance in adults (Gishen et al. 1982). Evaluation of the lungs in ZZ individuals often shows diffuse destruction of the alveoli, first in the lower lung zones, and eventually throughout the entire lungs (Parr et al. 2004). This contrasts with the classic pattern of emphysema observed in smoking-related COPD, which is centrilobular (centriacinar) (Kim et al. 1991). However, emphysema in ZZ individuals may also occur in a diffuse distribution or predominantly in the upper lobes (Parr et al. 2004). Bronchiectasis, with or without accompanying emphysema, is less frequent (Parr et al. 2007). The most prominent early symptom is dyspnea, particularly upon exercise (McElvaney et al. 1997).

COPD is characterized by neutrophil-dominated airway inflammation and elevated protease levels in the lung (Abboud and Vimalanathan 2008). The main physiological role of AAT is to protect fragile alveolar lung tissue from attack by proteases, in particular

Alpha-1 Antitrypsin Deficiency – A Genetic Risk Factor for COPD 195

Historically there has been a widespread acceptance that the SZ genotype confers increased susceptibility to COPD, particularly in smokers. This could explain why the susceptibility of SZ subjects to COPD has not been the subject of as many studies compared to MZ subjects. In addition, the typical SZ serum AAT level of approximately 11 µM is also deemed the putative protective threshold above which there is presumed to be no increased risk for emphysema in individuals with AATD and it is this level at which augmentation therapy levels are aimed (Wewers et al. 1987). Unfortunately, as a result there have been few studies aimed at assessing COPD risk in SZ individuals and most of these have been underpowered. The first study examined 25 cases, 14 of whom were index cases and concluded the SZ phenotype was of much less importance than the ZZ type in the development of emphysema (Hutchison, Tobin, and Cook 1983). Another study concluded that only a small percentage of SZ individuals are at increased risk of developing emphysema and that in non-smoking individuals the SZ phenotype conferred little or no added risk of developing COPD. However, it was noted that cigarette smoking correlated more strongly with airflow obstruction in SZ rather than ZZ subjects. Again this was a relatively small study of 59 individuals with no specific distinction between index and nonindex subjects (Turino et al. 1996). In 1998 a Danish group investigated a cohort of 94 SZ individuals on the Danish AATD Registry and came to the same conclusion that a small proportion of SZ individuals are at increased risk of emphysema (Seersholm and Kok-Jensen 1998). A meta-analysis in 2005 examining COPD risk in the SZ group sought to shed some light on the issue and calculated that there was a three-fold elevated risk of COPD (Dahl et al. 2005). Unfortunately, due to the limited number of subjects with accurate smoking information, it was not possible to calculate separate odds ratios for SZ smokers and non-smokers. The most recent study was an audit of SZ individuals on the UK AATD registry. SZ subjects showed less emphysema on CT scans and less abnormal spirometry test results, but equivalent health status impairment compared to matched ZZ subjects (Holme and Stockley 2009). Like the MZ genotype, attempts to explain the risk of COPD in SZ subjects have stopped at the decreased AAT levels, and other pathological mechanisms have

**3.4 The SZ phenotype as a genetic risk factor for COPD** 

**3.5 The MZ phenotype as a genetic risk factor for COPD** 

It is well established that MZ heterozygotes have moderately reduced serum levels of AAT, but whether they have an increased risk of COPD remains an area of some controversy. Over the last 40 years, over 100 studies have attempted to assess the risk of lung disease in MZ individuals with discordant and contentious results. A meta-analysis of 22 of these studies was published in 2004 (Hersh et al. 2004). Six of the 16 studies examining the categorical outcome of obstructive lung disease found significantly increased odds ratios (OR) for COPD in MZ heterozygotes compared to MM individuals. In nine other studies, the OR was increased, but not significantly. The individual study ORs ranged from 0.15 to 16.78. In summary, the study found that the OR for COPD in MZ compared to MM individuals was elevated at 2.31 (95% CI 1.60 to 3.35). Since this metaanalysis another US study has shown that MZ individuals exhibit accelerated decline in diffusing capacity of the lung for carbon monoxide (DLCO) in a large prospective population-based study of 1,075 individuals (Silva et al. 2008). More recently, a 2010 study

not been explored.

neutrophil elastase. NE is a powerful protease and can degrade most protein components of the extracellular matrix (Taggart et al. 2005), several complement proteins and immunoglobulins (Tosi, Zakem, and Berger 1990; Fick et al. 1984), antimicrobial proteins (Britigan et al. 1993; Hirche et al. 2004), and other antiproteases such as secretory leucoprotease inhibitor (SLPI) and elafin (Weldon et al. 2009; Guyot et al. 2008). NE can also induce mucin production and inflammatory gene expression in the lung (Fischer and Voynow 2002; Kohri, Ueki, and Nadel 2002; Carroll et al. 2005). In addition, there is the prospect that NE is situated at the apex of a hierarchical tree of cysteine and metalloproteases, acting as a master regulator of several classes of tissue-degrading proteases (Geraghty et al. 2007). The role of AAT in regulating NE activity *in vivo* is underscored by the fact that inhaled AAT therapy reduced MMP-2 and cathepsin B activity in lavage fluid from ZZ patients (Geraghty et al. 2008).

The traditional protease-antiprotease imbalance theory which explains COPD in ZZ individuals by a loss of function mechanism, while certainly attractive, is not the only explanation for the development of COPD. There are a host of gain of function effects caused by mutations within the SERPINA1 gene discussed in more detail elsewhere (Carroll, McElvaney, and Greene 2010; Greene and McElvaney 2010; Ekeowa, Marciniak, and Lomas 2011). Evidence is mounting to suggest other pathways contribute to tissue injury and inflammation. For example, rogue Z AAT protein can form polymers, and these polymers are present in the epithelial lining fluid of the lung. Polymers of Z AAT made by lung cells or reaching the lungs through the blood can cause the local release of chemokines and the recruitment of immune cells to the lung, contributing to the neutrophilic inflammation characteristic of COPD (Parmar et al. 2002; Mulgrew et al. 2004; Mahadeva et al. 2005). In addition, the expression of Z AAT in immune cells can lead to a more exuberant immune response. Monocytes from asymptomatic ZZ individuals with preserved lung function produced more pro-inflammatory cytokines and chemokines than MM individuals, and this inflammatory phenotype may explain some of the predisposition to COPD (Carroll et al. 2010).

Additional pathways leading to tissue injury highlighted recently include a role for AAT in apoptosis and in the regulation of chemotaxis. Wild-type AAT protein prevents lung alveolar endothelial cell apoptosis, possibly by inhibiting caspase-3 (Petrache, Fijalkowska, Medler, et al. 2006) and reducing oxidative stress (Petrache, Fijalkowska, Zhen, et al. 2006). These prosurvival benefits are lacking in ZZ individuals and could favour structural cell apoptosis and contribute to the development of emphysematous changes, particularly as the COPD lung is an environment with high levels of oxidative stress (Yao and Rahman 2011). A novel antiinflammatory role for AAT as a "brake" on immune cell chemotaxis was also described. Wildtype AAT was shown to regulate neutrophil chemotaxis by both binding the chemokine IL-8 and preventing shedding of the immune receptor FcRIIIb (Bergin et al. 2010).

The data accumulated unequivocally demonstrates that the ZZ phenotype is a major risk factor for COPD and this is thought to be mediated by at least four pathological mechanisms:


neutrophil elastase. NE is a powerful protease and can degrade most protein components of the extracellular matrix (Taggart et al. 2005), several complement proteins and immunoglobulins (Tosi, Zakem, and Berger 1990; Fick et al. 1984), antimicrobial proteins (Britigan et al. 1993; Hirche et al. 2004), and other antiproteases such as secretory leucoprotease inhibitor (SLPI) and elafin (Weldon et al. 2009; Guyot et al. 2008). NE can also induce mucin production and inflammatory gene expression in the lung (Fischer and Voynow 2002; Kohri, Ueki, and Nadel 2002; Carroll et al. 2005). In addition, there is the prospect that NE is situated at the apex of a hierarchical tree of cysteine and metalloproteases, acting as a master regulator of several classes of tissue-degrading proteases (Geraghty et al. 2007). The role of AAT in regulating NE activity *in vivo* is underscored by the fact that inhaled AAT therapy reduced MMP-2 and cathepsin B activity

The traditional protease-antiprotease imbalance theory which explains COPD in ZZ individuals by a loss of function mechanism, while certainly attractive, is not the only explanation for the development of COPD. There are a host of gain of function effects caused by mutations within the SERPINA1 gene discussed in more detail elsewhere (Carroll, McElvaney, and Greene 2010; Greene and McElvaney 2010; Ekeowa, Marciniak, and Lomas 2011). Evidence is mounting to suggest other pathways contribute to tissue injury and inflammation. For example, rogue Z AAT protein can form polymers, and these polymers are present in the epithelial lining fluid of the lung. Polymers of Z AAT made by lung cells or reaching the lungs through the blood can cause the local release of chemokines and the recruitment of immune cells to the lung, contributing to the neutrophilic inflammation characteristic of COPD (Parmar et al. 2002; Mulgrew et al. 2004; Mahadeva et al. 2005). In addition, the expression of Z AAT in immune cells can lead to a more exuberant immune response. Monocytes from asymptomatic ZZ individuals with preserved lung function produced more pro-inflammatory cytokines and chemokines than MM individuals, and this inflammatory phenotype may explain some of the predisposition to COPD (Carroll et al. 2010). Additional pathways leading to tissue injury highlighted recently include a role for AAT in apoptosis and in the regulation of chemotaxis. Wild-type AAT protein prevents lung alveolar endothelial cell apoptosis, possibly by inhibiting caspase-3 (Petrache, Fijalkowska, Medler, et al. 2006) and reducing oxidative stress (Petrache, Fijalkowska, Zhen, et al. 2006). These prosurvival benefits are lacking in ZZ individuals and could favour structural cell apoptosis and contribute to the development of emphysematous changes, particularly as the COPD lung is an environment with high levels of oxidative stress (Yao and Rahman 2011). A novel antiinflammatory role for AAT as a "brake" on immune cell chemotaxis was also described. Wildtype AAT was shown to regulate neutrophil chemotaxis by both binding the chemokine IL-8

and preventing shedding of the immune receptor FcRIIIb (Bergin et al. 2010).

mechanisms:

1. Increased protease activity in the lung,

3. Loss of anti-apoptotic properties of AAT, 4. Loss of anti-inflammatory properties of AAT.

2. Polymer formation locally,

The data accumulated unequivocally demonstrates that the ZZ phenotype is a major risk factor for COPD and this is thought to be mediated by at least four pathological

in lavage fluid from ZZ patients (Geraghty et al. 2008).

#### **3.4 The SZ phenotype as a genetic risk factor for COPD**

Historically there has been a widespread acceptance that the SZ genotype confers increased susceptibility to COPD, particularly in smokers. This could explain why the susceptibility of SZ subjects to COPD has not been the subject of as many studies compared to MZ subjects. In addition, the typical SZ serum AAT level of approximately 11 µM is also deemed the putative protective threshold above which there is presumed to be no increased risk for emphysema in individuals with AATD and it is this level at which augmentation therapy levels are aimed (Wewers et al. 1987). Unfortunately, as a result there have been few studies aimed at assessing COPD risk in SZ individuals and most of these have been underpowered. The first study examined 25 cases, 14 of whom were index cases and concluded the SZ phenotype was of much less importance than the ZZ type in the development of emphysema (Hutchison, Tobin, and Cook 1983). Another study concluded that only a small percentage of SZ individuals are at increased risk of developing emphysema and that in non-smoking individuals the SZ phenotype conferred little or no added risk of developing COPD. However, it was noted that cigarette smoking correlated more strongly with airflow obstruction in SZ rather than ZZ subjects. Again this was a relatively small study of 59 individuals with no specific distinction between index and nonindex subjects (Turino et al. 1996). In 1998 a Danish group investigated a cohort of 94 SZ individuals on the Danish AATD Registry and came to the same conclusion that a small proportion of SZ individuals are at increased risk of emphysema (Seersholm and Kok-Jensen 1998). A meta-analysis in 2005 examining COPD risk in the SZ group sought to shed some light on the issue and calculated that there was a three-fold elevated risk of COPD (Dahl et al. 2005). Unfortunately, due to the limited number of subjects with accurate smoking information, it was not possible to calculate separate odds ratios for SZ smokers and non-smokers. The most recent study was an audit of SZ individuals on the UK AATD registry. SZ subjects showed less emphysema on CT scans and less abnormal spirometry test results, but equivalent health status impairment compared to matched ZZ subjects (Holme and Stockley 2009). Like the MZ genotype, attempts to explain the risk of COPD in SZ subjects have stopped at the decreased AAT levels, and other pathological mechanisms have not been explored.

#### **3.5 The MZ phenotype as a genetic risk factor for COPD**

It is well established that MZ heterozygotes have moderately reduced serum levels of AAT, but whether they have an increased risk of COPD remains an area of some controversy. Over the last 40 years, over 100 studies have attempted to assess the risk of lung disease in MZ individuals with discordant and contentious results. A meta-analysis of 22 of these studies was published in 2004 (Hersh et al. 2004). Six of the 16 studies examining the categorical outcome of obstructive lung disease found significantly increased odds ratios (OR) for COPD in MZ heterozygotes compared to MM individuals. In nine other studies, the OR was increased, but not significantly. The individual study ORs ranged from 0.15 to 16.78. In summary, the study found that the OR for COPD in MZ compared to MM individuals was elevated at 2.31 (95% CI 1.60 to 3.35). Since this metaanalysis another US study has shown that MZ individuals exhibit accelerated decline in diffusing capacity of the lung for carbon monoxide (DLCO) in a large prospective population-based study of 1,075 individuals (Silva et al. 2008). More recently, a 2010 study

Alpha-1 Antitrypsin Deficiency – A Genetic Risk Factor for COPD 197

examination of AATD heterozygosity may lead to a new appreciation of this understudied

Guidelines issued by both the World Health Organisation and the American Thoracic Society/European Respiratory Society (ATS/ERS) recommend the establishment of targeted screening programmes for the detection of patients with AATD (Alpha 1 antitrypsin deficiency: memorandum from a WHO meeting 1997; American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. 2003). The biggest problem in the area of AATD is under-diagnosis with most cases misdiagnosed as COPD or non-responsive asthma. As a result, long delays between presentation of first symptoms and correct diagnosis are commonplace and prevent optimal management of the condition, despite education and awareness efforts (Stoller et al. 2005; Campos et al. 2005; Kohnlein, Janciauskiene, and Welte 2010). Compared to population-based studies, which are difficult and expensive to perform on a large scale, targeted detection programmes offer a much higher rate of AATD detection, are easier to perform, and are more cost-effective. However, as they target symptomatic groups the possibility of missing asymptomatic individuals remains. For this reason, comprehensive screening of family members of known AATD individuals is crucial as it offers the most realistic prospect of detecting asymptomatic relatives (Hogarth and Rachelefsky 2008). In the Irish targeted detection programme first-degree relatives of not only ZZ, but SZ and MZ

Data from several countries suggests that less than 10% of individuals with severe AATD have been recognised clinically (Aboussouan and Stoller 2009), and improving detection rates is the most urgent issue in the coming years. Several barriers to testing for AATD in

Adults with asthma with airflow obstruction that is incompletely reversible after

Asymptomatic individuals with persistent obstruction on pulmonary function tests with

Individuals with unexplained liver disease, including neonates, children, and adults,

identifiable risk factors (e.g. cigarette smoking, occupational exposure)

Table 2. ATS/ERS recommendations for diagnostic testing for AATD (type A

area and the development of new therapies.

individuals are recommended for testing.

**ATS/ERS Recommendations for Diagnostic Testing** 

Adults with symptomatic emphysema or COPD

aggressive treatment with bronchodilators

Adults with necrotising panniculitis

Siblings of individuals with AATD

particularly the elderly

recommendations).

**4.1 Who should be tested?** 

**4. Testing for alpha-1 antitrypsin deficiency (AATD)** 

demonstrated that MZ heterozygosity was associated with airflow obstruction in two large populations (Sorheim et al. 2010). In general, studies comparing COPD cases with healthy controls have found an excess of MZ individuals among COPD cases, but many studies comparing FEV1 (% predicted) in MZ and MM subjects from population-based samples have not found significant differences. There are several factors that undermine many of these conclusions. Firstly, a lack of correction for active and passive cigarette smoking exists in many studies. Secondly, the use of spirometry in defining lung disease is flawed, as subjects with normal spirometry values can have evidence of emphysema on high-resolution CT (Spaggiari et al. 2005). However, it is clear that the weight of evidence is now in favour of a risk of COPD in MZ individuals, but explanations of this risk are limited to the decreased antiprotease levels in subjects, and have not taken into account alternative mechanisms such as Z polymer generation. In the setting of disease management, an individual with smoking-related COPD who is informed of a diagnosis of MZ AATD may be further motivated towards smoking cessation (Carpenter et al. 2007).

#### **3.6 Other AATD phenotypes as genetic risk factors for COPD**

Early studies that examined the relatively common MS phenotype found no increase in COPD risk but an increase in bronchial hyperreactivity among MS individuals (Townley et al. 1990) but this was not replicated in a larger study (Miravitlles et al. 2002). In a recent meta-analysis of case-control and cross-sectional studies examining COPD risk in MS individuals a small but significantly increased risk was found (Dahl et al. 2005). However, after correction for smoking the MS phenotype was not associated with elevated risk for COPD. Moreover, studies that measured pulmonary function did not find a difference between MS and MM individuals. Another study did attempt to address the risk of COPD in SS individuals but found no increased risk of obstructive lung disease and was limited by small sample size (McGee et al. 2010). The effect of the I and F mutations on the AAT molecule has been described earlier, but to date any mention of COPD risk associated with these mutations is limited to case reports describing compound heterozygotes (Kelly et al. 1989; Baur and Bencze 1987).

#### **3.7 Conclusion**

It is well established that ZZ individuals have a high risk of developing COPD. However, MZ and SZ individuals also have significantly reduced levels of AAT, and are at risk of developing COPD. Anecdotally, a significant number of MZ and SZ individuals (both smokers and non-smokers) from our AATD clinic have severe COPD at a young age. The risk of COPD in heterozygotes has traditionally been explained by the weakening of the antiprotease shield in the lung. However, we know the Z mutation confers harmful gain of function properties on the AAT protein. While the ZZ genotype is relatively well-studied, there is little information regarding MZ, SZ, and other less common genotypes and to date there have been no investigations into the functional consequences of AATD heterozygosity. This is a vital clinical and public health question, as there are predicted to be over 6.6 million MZ and 230,000 SZ individuals in the US alone (de Serres, Blanco, and Fernandez-Bustillo 2010) and the total economic costs of COPD in the US were estimated to be almost \$50 billion in 2010 (National Heart 2009). From a basic research perspective, a careful examination of AATD heterozygosity may lead to a new appreciation of this understudied area and the development of new therapies.
