The important role of primary care providers in the detection of alpha-1 antitrypsin deficiency

ABSTRACT

Objective: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder that can cause chronic obstructive pulmonary disease (COPD) and liver cirrhosis, two clinical conditions commonly seen by primary care physicians. AATD is estimated to affect 1/4000–1/5000 people in the United States and 1–2% of all COPD cases.

Methods: PubMed was searched for relevant articles using AAT/AATD-related terms.

Results: Unfortunately, <10% of symptomatic individuals have been properly diagnosed primarily due to the underdiagnosis of COPD and the lack of awareness of AATD as a possible underlying cause. Because primary care providers are most likely to be the first to encounter symptomatic individuals, their role in the identification and early diagnosis of AATD patients is instrumental, particularly since therapy to slow lung disease progression is available. The diagnosis of AATD is laboratory-based rather than clinical. Testing for AATD should be part of the reflex testing that follows any COPD diagnosis or unexplained liver disease and can be performed by determining the AAT phenotype or genotype along with serum AAT levels. Both nonpharmacological and pharmacological approaches are recommended for treatment of lung disease, including smoking cessation, bronchodilators or supplemental oxygen as needed. Specific augmentation of AAT levels with regular purified AAT infusions has been found to slow lung function decline and emphysema progression in patients with moderate airflow obstruction and severely low serum AAT levels.

Conclusions: Improving primary care provider awareness and promoting regular reflex testing all COPD patients for AATD may significantly improve the care of COPD patients.

KEYWORDS:

• Alpha-1 antitrypsin
• alpha-1 antitrypsin deficiency
• chronic obstructive pulmonary disease
• pulmonary dysfunction

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by incompletely reversible airflow obstruction that affects approximately 15 million people in the USA [1,2]. COPD is the third-leading cause of death in the USA [2–4] and is a major cause of morbidity and healthcare costs [5,6]. These statistics, and the fact that the majority of patients consider their primary care provider as mainly responsible for their COPD care, highlight the importance of this disease for primary care providers [7].

COPD usually results from the combination of environmental triggers, particularly tobacco smoke, in the presence of susceptibility gene variants. The best-characterized gene conferring increased COPD risk is the SERPINA1 gene, which encodes the alpha-1 antitrypsin protein (AAT) [8]. Some SERPINA1 genotype variants result in deficient serum levels of AAT or a dysfunctional AAT protein. In the lung, AAT protects lung parenchymal tissue from proteolytic damage, in particular by proteases released by inflammatory cells such as neutrophil elastase [9–11]. The resulting protease/antiprotease imbalance in AAT deficiency (AATD), often leads to early-onset COPD and accelerated emphysema progression, which highlights the importance of early diagnosis in order to apply impactful preventive and therapeutic interventions [12]. Overall, it is estimated that 1–2% of all COPD patients have severe AATD [9] with up to 10% exhibiting some level of protein deficiency [9,13].

There is significant underrecognition of both COPD and AATD as a cause of COPD. COPD is underrecognized particularly during its early stages with different assessments estimating that at least 50% of symptomatic COPD patients remain undetected [12,14,15]. Although COPD affects up to 10% of patients in the general population in the USA, the clinic prevalence reported by general practitioners is less than 2% [16]. AATD as a cause of COPD is also rarely considered, with up to 95% of symptomatic individuals not being properly identified [12,14,15,17]. Primary care physicians are in a key position to improve these dire estimates as they are the healthcare providers who will likely interact with these patients first, and are therefore in a unique position to significantly impact the care of these patients [18,19].

A better understanding of AATD by primary care providers may improve patient outcomes and reduce healthcare costs. The purpose of this review is to provide an overview of AATD diagnosis and treatment and highlight the important role of primary care physicians in the identification and diagnosis of patients with AATD.

Methods

For this review, the PubMed database was queried for relevant articles published beginning in 1 January 1950, using the following terms alone or in combination: alpha-1 antitrypsin deficiency, α1-antitrypsin deficiency, alpha-1 antitrypsin genotype. These terms were then combined with chronic pulmonary obstructive disease or COPD, emphysema, FEV₁, hepatic or liver disease (including cirrhosis), vasculitis, panniculitis, and granulomatosis. Specific attention was paid to articles that referenced the treatment of COPD and alpha-1 antitrypsin deficiency in primary care. Abstracts and articles were selected for consideration based on their relevance to the pathophysiology or clinical features of AATD-associated conditions, factors affecting AATD diagnosis, and the influence of COPD diagnosis on the diagnosis of AATD.

Overview of the pathophysiology of AATD

The SERPINA1 allele is coded in the protease inhibitor locus (Pi) of chromosome 14, with the normal allele called the ‘M’ allele and a normal genotype being ‘MM’ (or PiMM). From approximately 100 genetic variants described [20], the most common mutant SERPINA1 alleles associated with disease are the ‘S’ and ‘Z’ alleles, and all together, combinations of the M, S, and Z alleles comprise the AAT genotypes of 96–98% of the world population [21]. The Z allele is the most frequent mutation associated with severe AAT deficiency, while the S allele confers only mild deficiency [22,23]. As shown in Table 1, median AAT concentrations in individuals with different genotypes vary, with individuals who are homozygous for the Z allele (PiZZ) or null mutations having the lowest serum AAT concentrations [11,24,25]. Overall, genotypes PiMZ and PiSS confer mild deficiency, PiSZ confers moderate to severe deficiency, and PiZZ and null mutations confer severe deficiency [11], which is defined as AAT serum levels below 11 µM (57–60 mg dL⁻¹) [14,24–26].

Table 1. Serum alpha₁ antitrypsin concentrations in patients with different genotypes [24,25].

	Genotype
	MM	MS	MZ	SS	SZ	ZZ
Median serum concentration (mg/dL)	147	125	90	95	62	≤29
Percent of normal (MM genotype = 100%)	100	85	61	65	42	20

Clinical features of AATD

The primary clinical manifestations of AATD are respiratory and hepatic disease (Table 2) [31]. A reduction in serum AAT levels leads to unopposed activity of neutrophil elastase and other proteases, which derives into alveolar wall damage (loss of function) [10]. Affected individuals classically develop panacinar emphysema [27,32]. Although AATD has been classically viewed as a condition in which COPD develops in the absence of tobacco smoke exposure, this notion is erroneous since smoking significantly accelerates disease progression; in fact studies show that more than 85% of symptomatic individuals have an important smoking history [32].

Table 2. Clinical manifestations associated with alpha-1 antitrypsin deficiency [13,14,27–30].

Pulmonary	Hepatic	Other manifestations
Shortness of breath	Liver disease or elevated serum transaminases	Panniculitis
Wheezing	Jaundice	Granulomatosis with polyangiitis
Chronic obstructive pulmonary disease Chronic bronchitis	Ascites or lower extremity edema
Panacinar emphysema, usually at lung bases One third may have predominantly upper lobe emphysema	Hematemesis (from enlarged veins in the esophagus or stomach secondary to portal vein hypertension)
Recurring upper respiratory tract infections
Reduced exercise tolerance
Airflow obstruction that cannot be completely reversed with aggressive medical treatment
Bronchiectasis

AATD-associated liver disease is observed in early life and in older adults. Liver damage occurs secondary to the intracellular accumulation of the Z-variant of AAT in hepatocytes (gain of toxic function) [31]. The Z mutation causes a single amino acid change in the AAT protein, which predisposes it to polymerization in the endoplasmic reticulum because of a conformational change [33,34]. Despite the compensatory cellular mechanisms activated in response to this abnormal protein accumulation [35], approximately 12% of PiZZ individuals develop hepatic dysfunction as neonates, with 2.5% developing severe liver disease that may require liver transplantation [27,36]. Later in life, approximately up to 30% of PiZZ adults develop chronic liver disease (cirrhosis) and are at increased risk for hepatocellular carcinoma [27,37]. Liver damage is probably accelerated in the presence of other hepatotoxic stimuli [38]. In addition to the liver, Z-AAT polymers can be found in the circulation and in some tissues [39]. These polymers are proinflammatory and likely reasons for other rarer AATD-associated conditions such as panniculitis [40]. Bronchiectasis [41], granulomatosis with polyangiitis (Wegener’s granulomatosis) [42] are also other manifestations associated with AATD.

Underdiagnosis of AATD

The number of cases with severe AATD registered and the number of estimated cases varies substantially among some countries. Out of the estimated prevalence of patients with abnormal AAT alleles in the US population of approximately 100,000 individuals, no more than 10,000 individuals have been diagnosed [14,32]. In Belgium, France, and Spain, the percentage of registered cases is less than 5% of expected; in Canada, Germany, Ireland, Italy, Poland, and the UK this percentage ranges from 5 to 15%; in Netherlands is 20%; and it reaches the remarkable rate of 75% in Sweden, where there is much awareness for this condition in both the Swedish population and the public health services [43]

As mentioned, the underrecognition of COPD plays an important part in these poor AATD detection estimates. Studies have shown that as many as 80% of patients [44], including up to 53% of those with severe or very severe COPD [45], are undiagnosed or misdiagnosed by primary care physicians. Important reasons for this are because patients adapt to their symptoms, dismissing and not reporting them, and a general lack of COPD awareness by providers [46]. A second major reason for the underdiagnosis of AATD is that it is rarely considered as a possible etiology when a clinician evaluates a patient with COPD [47].

Unawareness of AATD

On the whole, general practitioners usually do not include AATD testing as part of their initial COPD evaluation [48]. A 1994 survey found that more than 40% of patients with severe AATD were evaluated by at least three healthcare providers before being diagnosed, and this trend did not change significantly years later [15,49]. The average delay between symptom onset and diagnosis of AATD ranges between 5.6 and 8.3 years [15,32]. There is a general assumption by clinicians that COPD is not related to AATD if the patient is a smoker, older (≥50 years) and/or non-Caucasian. However, contrary to these assumptions, in the UK registry, >50% of index AATD-associated COPD patients were current or ex-smokers diagnosed at an average age of 49.7 years while the nonsmokers were diagnosed at 60.5 years [50]. In the USA, >85% of diagnosed symptomatic subjects had a significant smoking history [32]. Alpha-1 antitrypsin deficiency has been described in almost every race [51]. An exploratory study using genetic epidemiologic studies in peer-reviewed literature indicated that an estimated 40 million non-Caucasian individuals from Africa, the Middle East and North Africa, Central Asia, and Far East Asia and Southeast Asia are expected to have abnormal AAT alleles [13]. For these reasons, current guidelines enforce AATD testing to all patients with COPD, regardless of age, smoking history, or race [14,52].

Advantages of early diagnosis

Primary care providers are at a unique position for early detection of COPD. Approximately 80% of Canadian COPD patients receive most of their care by a primary care physician and not by pulmonary specialists [53]. Early diagnosis of AATD allows for the advent of interventions before irreversible lung damage becomes more severe.

Clinical evaluation of COPD and AATD

Detection of COPD can be improved by awareness of cardinal symptoms including coughing, sputum production, or dyspnea [54] in the presence of risk factors such as current or previous use of tobacco, smoking, or exposure to environmental pollutants [55]. This should be followed by prompt evaluation with spirometry to determine the presence of airflow obstruction (forced expiratory volume in 1 s/forced expiratory vital capacity [FEV₁/FVC] < 70%) [54]. The measurement of FEV₁ also helps to determine the severity of COPD. It has been suggested that improvements in spirometry use and interpretation could lead to improved rates of COPD and AATD diagnosis [56].

Testing for AATD should be included as part of the reflex testing that follows after COPD has been diagnosed. Guidelines by the World Health Organization and other respiratory organizations recommend testing for AATD in all patients with COPD regardless of clinical features (Table 2) [14,52,57]. However, certain clinical presentations particularly increase the suspicion of AATD, including early-onset emphysema, the presence of bronchiectasis of unknown cause or history of family members with AATD or a family history of COPD and cirrhosis [14]. Patients with AATD may present with asthma-like symptoms (e.g. coughing, especially at night; wheezing; shortness of breath; chest tightness; pain; or pressure) and adults diagnosed with asthma that is incompletely reversible following bronchodilator therapy are also candidates for AATD testing [58]. Other nonpulmonary clinical conditions that require AATD consideration are the presence of unexplained liver disease, panniculitis, and granulomatosis with polyangiitis.

Diagnosis of AATD

Diagnosis of AATD is accomplished by determining serum AAT levels, AAT genotype, and/or the AAT phenotype (Table 3) depending on the algorithm adopted by the testing laboratory. Detection of a serum AAT level of less than 11 µM (57–60 mg dL⁻¹) indicates increased risk of emphysema [14]. Common laboratory techniques to measure AAT concentrations include rocket immunoelectrophoresis, radial immunodiffusion, and nephelometry [14], all widely available and any can be easily ordered with other routine blood work panels. However, it is important to recognize that although severely deficient cases can be detected if only AAT levels are measured, due to overlap in AAT level ranges, detection of individuals with intermediate deficiencies (PiMZ, PiSZ, PiMS) can be missed [11]. In addition, it should be noted that as an acute-phase reactant, AAT concentrations may rise in the context of infections, pregnancy, vaccinations or other ongoing inflammatory processes. For these reasons, blood AAT determinations must be made when the patient clinically stable and some recommend performing concomitant C-reactive protein measurements to correctly diagnosed heterozygotes [66,67].

Table 3. AATD diagnosis and treatment [4,14,15,27,28,30,54,58–65].

Diagnosis	Treatment	Psychosocial support
Physical examination Review of the patients’ medical history and symptoms Active case finding Blood tests ○ Genetic: identifying genes associated with the condition ○ Phenotypic: identifying the type of AAT deficiency in the patient ○ AAT levels: level of AAT in the blood Imaging to diagnose AATD-related conditions ○ MRI ○ Radiography ○ CT scans Pulmonary function tests ○ Spirometry ○ Bronchodilator testing Other tests to diagnose AATD-related conditions ○ Liver function tests ○ Liver biopsy Monitoring for development of comorbid disease ○ Cardiovascular disease ○ Asthma ○ Depression ○ Type 2 diabetes	AAT augmentation therapy for: ○ AAT serum levels below 57–60 mg/dL (11 µM) ○ S- or Z-type alleles for AAT gene ○ Patients with modest airflow obstruction (FEV1 35–60% of expected) For the associated conditions such as COPD ○ Inhaled corticosteroids ○ Bronchodilators ○ Supplemental oxygen as needed ○ Antibiotics ○ Surgical intervention Immunizations ○ Influenza ○ Pneumonia Therapy for severe liver disease ○ Liver transplant as curative therapy	Environmental factors ○ Avoid smoking ○ Change smoking habit ○ Avoid occupational exposure to environmental irritants ○ AATD testing for smokers older than 40 years of age ○ Use of questionnaires to identify high risk for COPD ○ Use of questionnaires to determine AATD-associated COPD Patient counseling/education ○ Change in occupation if it is in an environment with smoke, dust or fumes ○ Smoking accelerates disease progression ○ Smoking increases annual declines in lung function ○ Cessation of smoking reduces decline in lung function ○ Use of survey to identify high risk for COPD ○ Use of survey to determine ○ AATD-associated COPD ○ Family screening and counseling

AAT: alpha-1 antitrypsin; AATD: AAT deficiency; COPD: chronic obstructive pulmonary disease; CT: computed tomography; FEV₁: forced expiratory volume in 1 s; MRI: magnetic resonance imaging.

Alpha-1 antitrypsin genotyping and/or phenotyping are usually examined simultaneously with the evaluation of AAT levels [14], and are mandatory for confirmation of patients with low AAT levels. AAT genotyping examines the genetic make-up of patients, while AAT phenotyping identifies the type of circulating AAT proteins. The genotype evaluation is performed using genomic DNA extracted from circulating mononuclear blood cells or saliva and samples can be easily drawn in the office with a finger stick using the dry spot method [68] or a buccal swab. These samples are then mailed to specialized alpha-1 testing laboratories. Phenotyping is performed using a combination of techniques including isoelectric focusing and immunodiffusion, and requires a certain level of expertise in interpretation [59]. Nevertheless, phenotyping is considered the ‘gold standard’ for confirming a diagnosis of AAT deficiency [14].

Improving AATD diagnosis

AATD detection is likely to increase with improvements in the detection of COPD and there are numerous strategies that can be used for this, such as watching a short instructional video [69], using reminders in electronic health records [70,71] or doing reflex-testing in patients with airflow obstruction in the pulmonary function laboratory [72]. A recent consensus conference suggested that a pilot project of newborn testing could be evaluated as it may be a more effective approach than targeted detection [73]. But in general, the most important is physician awareness to test patients with known risk factors such as emphysema, liver disease or affected family members.

Overview of therapeutic strategies

Both non-pharmacological (monitoring, counseling) and pharmacological approaches are recommended for the treatment of COPD patients with AATD. Management of this disease can be done in primary care in conjunction with a specialist in AATD. Physicians specializing in AATD can be found at Alpha-1 Foundation Clinical Resource Centers listed on the foundation’s website (www.alpha1.org).

Smoking-cessation counseling is a crucial aspect of AATD management and smoking habits should be discussed with all patients [74]. Providers should educate AATD patients that in patients with severe disease (PiZZ), smoking results in more rapid decline in lung function [60], and that smoking cessation reduces annual decline in FEV₁ in patients [61,62]. All patients should be encouraged to participate in pulmonary rehabilitation and be part of a disease management program to improve their overall quality of life [75]. Patients should also be advised to avoid environmental pollutants, which may even involve a change in occupation if the patient works in an environment with smoke, dust, or fumes [14].

Pharmacological treatment options

Treatment strategies (Table 3) for COPD in patients with AATD are similar to those used in patients without AATD, and include use of bronchodilators, supplemental oxygen as needed, and treatment of exacerbations using antibiotics and corticosteroids [52]. Encouraging patients to receive influenza, pneumococcal, and hepatitis A and B vaccinations is also advised, since it has been shown to decrease COPD-related mortality [63].

Alpha-1 antitrypsin augmentation therapy, the administration of purified intravenous AAT protein, is recommended for patients with moderate airflow obstruction (FEV₁ 35–60% of that expected for sex and age) and AAT serum levels below 11 µM [14]. Alpha-1 antitrypsin augmentation has been found to slow the decline of lung function and slow the progression of emphysema as measured by serial computed tomography scans [76,77]. It is therefore logical to assume that early intervention, as soon as emphysema progression is detected, will have a higher impact in modifying the natural history of the disease. Alpha-1 antitrypsin augmentation has also been described to be effective in other AATD-related conditions such as panniculitis and granulomatosis with polyangiitis [78]. Augmentation therapy is not effective or recommended for the treatment of liver disease in AATD since the pathophysiology mostly involves the intracellular accumulation of AAT polymers.

Transplant

Severe AATD is among the most frequent conditions that require lung transplantation [79] and is indicated for patients with end-stage lung disease whose pulmonary function continues to decline despite intensive therapy. For patients with the PiZZ genotype and severe emphysema, the median survival time was significantly longer for those who underwent lung transplantation (11 years) compared to those who did not (6 years, p = 0.0006) [80]. Also, severe liver disease may progress to the point to require transplantation, a situation more commonly seen in pediatric patients than adults with the PiZZ genotype [81,82].

Monitoring patients with AATD

Lung disease progression is monitored by regular lung function (spirometry and diffusing capacity of carbon monoxide) [14]. Computed tomography scanning for the assessment of lung density is also useful to determine progression of emphysema and is being currently used in clinical trials as an accepted outcome. Primary care physicians should also monitor for comorbidities since patients with COPD commonly present with cardiovascular disease, asthma, depression, and type 2 diabetes [64]. Patients with AATD should also be monitored for hepatic dysfunction, due to their estimated 30–40% lifetime risk of hepatic diseases [14]. Liver disease surveillance should include transaminase levels and hepatocellular carcinoma screening with liver ultrasound up to twice a year [83]. It is recommended that primary care physicians follow these patients along with a specialist familiar with AATD.

Conclusion

Primary care physicians are the first point of patient contact and thus play a vital role in the detection of COPD and AATD. Providers should view AATD as a diagnosis of exclusion when encountering patients with COPD and consider AATD to be a laboratory diagnosis, not a clinical one. Improving awareness of signs of COPD and testing all COPD patients for AATD may significantly improve the overall diagnosis and care of patients with COPD.

Declaration of interest

M Campos has received research grants from the Alpha-1 Foundation and CSL Behring, participated in clinical trials sponsored by Baxalta, CSL Behring, and Grifols. He has also participated in Advisory Boards for CSL Behring and Grifols. Editorial assistance was provided by Jill See, PhD, and Cole Brown, MD, of QSci Communications and was sponsored by Grifols, a manufacturer of AAT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Funding for this review was provided by Grifols.