Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency

INTRODUCTION — Alpha-1 antitrypsin (AAT) deficiency is a clinically under-recognized inherited disorder affecting the lungs, liver, and rarely, skin. In the lungs, AAT deficiency causes chronic obstructive pulmonary disease (ie, emphysema and bronchiectasis).

The pulmonary manifestations, diagnosis, and natural history of this disorder will be reviewed here [1-4]. Extrapulmonary disease and therapy are discussed separately. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency" and "Treatment of emphysema from alpha-1 antitrypsin deficiency".)

BACKGROUND — AAT is a protease inhibitor (Pi) of the proteolytic enzyme elastase and also of the proteases trypsin, chymotrypsin, and thrombin [5]. It is part of a larger family of structurally unique serine protease inhibitors, referred to as serpins, which have also been implicated in the pathogenesis of neurodegenerative diseases, angioedema, and coagulation abnormalities, collectively called "serpinopathies" [1,6].

Emphysema in AAT deficiency (AATD) is thought to result from an imbalance between neutrophil elastase in the lung, which destroys elastin, and the elastase inhibitor AAT, which is synthesized in hepatocytes and protects against proteolytic degradation of elastin [4]. This mechanism is called a "toxic loss of function." Specifically, cigarette smoking and infection increase the elastase burden in the lung, thus increasing lung degradation [1]. In addition, the polymers of "Z" antitrypsin are chemotactic for neutrophils, which may contribute to local inflammation and tissue destruction in the lung [7].

The pathogenesis of the liver disease is quite different and is called a "toxic gain of function." The liver disease results from the accumulation within the hepatocyte of unsecreted variant AAT protein. Only those genotypes associated with pathologic polymerization of AAT within the endoplasmic reticulum of hepatocytes (eg, PI*ZZ type AATD) produce disease [8-10]. Most patients with liver disease due to AATD are homozygous for the Z allele (ie, PI*ZZ); liver disease does not occur in null homozygotes who have severe deficiency of AAT, but no intra-hepatocytic accumulation. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)

AAT genetics — AATD is inherited by autosomal co-dominant transmission, meaning that affected individuals have inherited an abnormal AAT gene from each parent. The gene that encodes AAT is called SERPINA1 (OMIM +107400) and is located on the long arm of chromosome 14 [11]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Autosomal recessive'.)

At least 150 alleles of AAT (SERPINA1) have been identified, and each has a letter code based upon electrophoretic mobility of the protein produced. The normal allele is referred to as "M." As AAT is a protease inhibitor (a member of the serpin family of proteins), the designation "PI" denotes "protease inhibitor" and the letters denote the alleles that are present. Thus, "PI*MM" refers to homozygosity for the normal gene, while PI*ZZ denotes homozygosity for the Z allele, the most common mutation in the SERPINA1 gene that leads to AAT deficiency [11]. The "Z" point mutation Glu342Lys (or substitution of a lysine for a glutamic acid at position 342 on the AAT molecule) is in the hinge region of the AAT molecule, which causes an increased tendency to polymerization and aggregation.

Some individuals have compound heterozygosity, meaning that they carry two different mutations of the same gene. For example, patients with AATD may have an "S" mutation (which is characterized by a single amino acid substitution of a valine for a glutamic acid at position 264) in the PI gene on one chromosome 14 and a "Z" mutation on the other chromosome 14; this pattern is indicated by PI*SZ (table 1). While PI*SS is not associated with an increased risk for emphysema, PI*SZ heterozygotes are at increased risk if they smoke [12-16]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Autosomal recessive'.)

AAT phenotypes — AAT phenotyping is based on the electrophoretic mobility of the proteins produced by the various abnormal AAT alleles. Genotyping is performed by identifying specific alleles in DNA, eg, by polymerase chain reaction tests or by gene sequencing. Variants of AAT can be categorized into four basic groups [17]:

●Normal – Normal alleles are associated with normal levels of AAT and normal function. The family of normal alleles is referred to as M and the normal genotype is MM.

●Deficient – Deficient alleles are associated with plasma AAT levels less than 35 percent of the average normal level. The most common deficient allele associated with emphysema is the Z allele.

●Null – Null alleles lead to no detectable AAT protein in the plasma. Individuals with the null genotype are the least common and are at risk for the most severe form of associated lung disease but not liver disease.

●Dysfunctional – Dysfunctional alleles produce a normal quantity of AAT protein but the protein does not function properly (eg, PI*F).

Individuals with genotypes associated with serum AAT levels below a "protective threshold" value, widely considered to be 11 micromol/L (approximately 57 mg/dL), are considered to be at increased risk for emphysema (table 1) [18-20].

Heterozygous variants — Data are conflicting regarding the risk of emphysema among PI*MZ heterozygotes.

Studies of nonsmoking PI*MZ heterozygotes show discordant results with the best designed studies suggesting increased risk for emphysema only in PI*MZ smokers [21-27]:

•In supportive studies, a comparison between individuals in the Lung Health Study with either rapid or slow decline in forced expiratory volume in one second (FEV₁) showed that the MZ genotype was associated with rapid decline (odds ratio 2.8, p = 0.03) [21]. Also, a longitudinal study showed a slightly greater annual decrease in FEV₁ in individuals with the MZ genotype compared with those who have the MM genotype (25 versus 21 mL/year, p = 0.048) [22]. The odds ratio for developing airflow obstruction was 1.3 in the MZ heterozygotes compared with normal MM homozygotes. The increase in chronic obstructive pulmonary disease (COPD) risk among PI*MZ heterozygotes may be limited to those with a symptomatic PI*ZZ first-degree relative [23].

•In an analysis of data from case-control and multicenter family studies, individuals with PI*MZ, compared to those with PI*MM, had a slightly lower ratios for FEV₁/forced vital capacity (FVC) or FEV₁/vital capacity, but no difference in FEV₁ [24].

•A population study of PI*MZ heterozygotes from the Tucson Epidemiologic Study of Airways Obstructive Diseases failed to show any increased risk of developing airflow obstruction in these MZ individuals [25]. Also, a meta-analysis highlights the inconsistency of results from available studies [26], with studies using categorical outcomes generally showing an increased risk and those using continuous measures (eg, FEV₁) not showing an excess risk in PI*MZ heterozygotes. Relatively few of the available studies adjusted for smoking status and those that did tended to show a smaller risk (odds ratio 1.61, 95% CI 0.92-2.81).

Studies among ever-smoking PI*MZ individuals suggest an increased risk of COPD:

•In the multiethnic COPDGene study of 8271 current and former smokers with ≥10 years of smoking, PI*MZ subjects had significantly lower FEV₁ percent predicted (68 ± 28 versus 75 ± 27; P = 0.0005) and FEV₁/FVC ratio (0.59 ± 0.18 versus 0.63 ± 0.17; P = 0.0008), and also more radiographic emphysema, than Z-allele noncarriers [28].

Of note, the PI*MZ genotype was identified in 0.8 percent of non-Hispanic African American (NHAA) participants [28]. Furthermore, FEV₁ percent predicted and FEV₁/FVC ratio values were lower among PI*MZ NHAA individuals, than those with PI*MM.

•A study of 196 non-index relatives of PI*MZ individuals showed that compared with PI*MM relatives, PI*MZ relatives demonstrated lower FEV₁/FVC ratios and post-bronchodilator FEV₁ percent predicted than PI*MM relatives and, in a categorical analysis, a higher prevalence of COPD was observed in PI*MZ individuals (OR 5.10, 95% CI, 1.81–14.33) [27]. When stratified by smoking status, these differences were observed only in ever-smoking PI*MZ individuals.

EPIDEMIOLOGY — Although alpha-1 antitrypsin deficiency (AATD) is generally considered to be rare, estimates that 80,000 to 100,000 individuals in the United States have severe deficiency of AAT suggest that the disease is under-recognized [29,30]. The prevalence of AAT varies considerably from one country to another [15,31,32]; however, it is estimated that more than 3 million people worldwide have allele combinations associated with severe deficiency of AAT [33,34].

●Prevalence – Two lines of evidence support prevalence estimates indicating that AATD is approximately as common as cystic fibrosis:

•One study evaluated a sample of 965 patients with chronic obstructive pulmonary disease (COPD); severe deficiency of AAT was found in 2 to 3 percent [35]. Extrapolating to the United States population of 2.1 million individuals with emphysema (based on the National Health Interview Survey [36]), 40,000 to 60,000 Americans would be expected to have emphysema caused by AATD.

•Direct population screening studies indicate that the prevalence of individuals with the PI*Z phenotype and resultant severe deficiency of AAT ranges from one in 1575 to one in 5097 individuals [37-40]. Based upon the United States population of approximately 320 million, 80,000 to 100,000 severely AAT deficient individuals would be expected. This estimate includes both symptomatic and asymptomatic patients.

●Unrecognized deficiency – Several studies indicate that AATD is far less familiar to many clinicians than its prevalence would suggest. Investigators in one report, for example, estimated that there were 700 PI*ZZ individuals in St. Louis, based upon sampling of 20,000 blood specimens submitted to the St. Louis blood bank; only 28 of these individuals (4 percent) had been identified [39]. Unrecognized individuals with severe deficiency of AAT probably comprise two separate groups: those with no clinical manifestations despite severe deficiency; and those with disease in whom the underlying AAT deficiency has not been recognized. The relative proportion of these two groups remains unknown.

Many studies have identified under-recognition of AATD in symptomatic patients [29,30,41,42]. A 5- to 8-year delay between the first symptom and recognition of AAT deficiency has been found in studies performed over more than 20 years (to 2019), indicating that under-recognition persists despite extensive educational efforts and the publication of evidence-based guidelines for diagnosis and management of AATD [2,29,30,42].

RISK FACTORS FOR LUNG DISEASE — Individuals with phenotypes associated with AAT levels below the protective threshold of 11 micromol/L (approximately 57 mg/dL using nephelometry and 80 mg/dL by older radial immunodiffusion methods) are considered to have severe deficiency of AAT and are at risk for emphysema [2,17,43]. As noted above, a number of AAT mutations are associated with severe deficiency (table 2) [18-20].

Severe deficiency of AAT poses a strong risk factor for early-onset emphysema, but not every severely deficient individual is destined to develop emphysema. Risk factors for emphysema include cigarette smoking, dusty occupational exposure, a parental history of COPD, and a personal history of asthma, chronic bronchitis, or pneumonia [44,45].

●Cigarette smoking increases the risk of developing fixed airflow obstruction and can markedly accelerate the onset of dyspnea by as much as 19 years. In three studies, for example, the age at onset of dyspnea was 48 to 54 years in nonsmokers versus 32 to 40 years in smokers [46-48]. In individuals with the PI*SZ phenotype, cigarette smoking is a particularly important risk factor for the development of COPD, which rarely occurs in nonsmokers with this phenotype [15,16,49,50].

●Occupational and other exposures – The precise role of occupational exposures in accelerating the loss of lung function in AATD is also incompletely understood. One study found a link between self-reported exposure to mineral dust and reduced lung function in PI*ZZ patients [51], while a second trial suggested that agricultural work and the use of domiciliary kerosene are also independently associated with a more rapid loss of lung function [52]. Among New York City Fire Department rescue workers who were exposed to respirable particulates and combustion by-products following the World Trade Center collapse, those with even mild or moderate deficiency of AAT (eg, PI*MZ, PI*SZ, and PI*MS) had a more rapid decline in FEV₁ over the next four years than those with normal AAT levels [53].

●Asthma – There is an uncertain relationship between severe deficiency of AAT and asthma [54]. Studies have not shown an increased prevalence of AATD among asthmatics. However, in a large cohort study of over 1000 patients with severe deficiency of AAT, 21 percent of patients met diagnostic criteria for asthma [55]. The presence of asthma was not independently associated with an accelerated decline in pulmonary function [55].

CLINICAL MANIFESTATIONS — The main clinical manifestations of AAT deficiency relate to three separate organs: the lung, the liver, and, much less often, the skin. Sporadic reports indicate other clinical conditions also may accompany AATD. The extrapulmonary manifestations of AATD are discussed separately. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

Clinical presentation of lung disease — The clinical presentation of emphysema due to AAT deficiency has many features in common with usual COPD. Dyspnea is the most common symptom, and many patients report cough, phlegm production, and wheezing, either chronically or with upper respiratory tract infections [48,56-58]. Bronchodilator responsiveness (defined as a postbronchodilator forced expiratory volume in one second [FEV₁] rise of 200 mL and 12 percent when studied or, more recently, by a change of >10 percent relative to the predicted FEV₁ or forced vital capacity [FVC] [59]) is common with or without chronic sputum production.

Two features of emphysema associated with severe deficiency of AAT that may be distinctive are onset at a younger age and a basilar-predominant pattern of emphysema (table 3), although substantial variability is noted among individuals [2]:

●The onset of airflow limitation typically occurs at a younger age in AAT-deficient individuals than in non-AAT-deficient individuals, who usually present in the sixth and seventh decades of life. In the National Heart, Lung, and Blood Institute-sponsored Registry for Patients with Severe Deficiency of Alpha-1 Antitrypsin, for example, the mean (± SD) FEV₁ in 1129 participants was 43 ± 30 percent of predicted and their mean age was 46 ± 11 years [57]. Similarly, an earlier series of 246 PI*ZZ adults found that chronic obstructive pulmonary disease was present in 74.8 percent of the participants, whose median age was approximately 52 years [46].

●Emphysema associated with AATD often shows a characteristic chest radiographic pattern, in which bullous changes are more prominent at the lung bases than at the apices (image 1) [60,61]. The prevalence of this pattern of "basilar hyperlucency" varies among series; approximately one-third of patients with severe deficiency of AAT have an upper lobe predominant pattern of emphysema that is more characteristic of "usual," non-AAT deficient COPD [58,62,63]. The largest reported series of 165 PI*Z homozygotes examined with plain chest radiographs found that 140 (85 percent) had some radiographic features of emphysema. Virtually all of these patients had emphysematous changes that included the lung bases, and 24 percent had emphysematous changes that were limited to the lung bases. More recent imaging studies have used computed tomography [63,64]. In one study of PI*ZZ individuals, emphysematous abnormalities were most prominent at the bases in 64 percent of patients and at the apices in 36 percent [63]. In another case series examining CT scan findings, emphysematous changes were less prominent overall and more likely to be upper lung zone predominant in PI*SZ individuals than PI*ZZ homozygotes, despite comparable physiologic impairment [12].

Spontaneous secondary pneumothorax may be the presenting manifestation of AAT deficiency or a complication of known disease [65-69].

Bronchiectasis has also been associated with severe deficiency of AAT. In one study, for example, bronchiectasis was present in 11.3 percent of 246 PI*Z homozygotes [46]. The estimated prevalence in other reports has varied widely from 2 to 43 percent [50,70]. The relationship between AATD and bronchiectasis remains incompletely understood, and the mechanism by which AATD could produce the latter is debated. Bronchiectasis seems to occur most commonly in lobes with higher emphysema scores, suggesting that altered airway architecture may contribute [70]. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Clinical presentation of extrapulmonary disease — Patients with at-risk alleles (eg, Z, S[iiyama], M[malton]) may develop adult-onset chronic hepatitis, cirrhosis, or hepatocellular carcinoma, the former often occurring without antecedent childhood liver disease [1]. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)

Other extrapulmonary manifestations of AATD include panniculitis (hot, painful, red nodules or plaques characteristically on the thigh or buttocks) and possibly vasculitis, inflammatory bowel disease, intracranial and intra-abdominal aneurysms, fibromuscular dysplasia, and glomerulonephritis, which are discussed separately. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

EVALUATION AND DIAGNOSIS — All adults with persistent airflow obstruction on spirometry should be tested for AATD, especially those from geographic areas with a high prevalence of AATD [71,72]. Additional features that should lead clinicians to test for AATD include (table 3) [2]:

●Emphysema in a young individual (eg, age ≤45 years)

●Emphysema in a nonsmoker or minimal smoker

●Emphysema characterized by predominant basilar changes on the chest radiograph

●A family history of emphysema and/or liver disease

●Adult-onset asthma (when airflow obstruction fails to normalize after bronchodilators)

●Clinical findings or history of panniculitis

●Clinical findings or history of unexplained chronic liver disease

However, the absence of these features should not deter testing of patients with persistent airflow limitation, all of whom should be tested for AATD.

Diagnosis — The diagnosis of severe deficiency of AAT is confirmed by demonstrating a serum level below 11 micromol/L (approximately 57 mg/dL by nephelometry) in combination with a severe deficient phenotype, generally determined by isoelectric focusing, or genotype, assessed by testing for the most common deficient alleles (ie, S, Z, I, F) (algorithm 1). The one uncommon genotype that can produce normal serum AAT levels but pose emphysema risk is PI*FF, in which the F allele is quantitatively normal but functionally impaired in binding neutrophil elastase [20]. On the other hand, if one is evaluating for the presence of particular mutations, genotyping is necessary to identify heterozygotes and mutations that have incomplete expressivity [73].

Laboratory testing — Traditionally, laboratory testing for the diagnosis of AATD used initial assessment of the serum level; if the level was low, the electrophoretic mobility of the AAT protein was assessed to determine the specific AAT variant or phenotype (algorithm 1). With the advent of molecular techniques for genotyping and the use of dried blood spots, various potential algorithms may be followed for diagnosis [74]. The preferred approach is to obtain simultaneous testing of the serum AAT level by nephelometry and targeted genotyping for the most common variants [72]. Initial genotyping would also be acceptable.

●Serum levels – Serum levels of AAT can be assessed by nephelometry or, less often, latex-enhanced immunoturbidimetric assay; radial immunodiffusion and rocket immunoelectrophoresis are no longer used [2]. These tests quantify the amount of AAT protein in serum but have a low sensitivity for detecting heterozygotes (carriers) of AAT deficiency genes. A reasonable threshold for differentiating normal Pi*MM from other genotypes with one or more deficient alleles is 20 micromol/L (100 mg/dL) [2,19,75,76].

Population studies suggest a minimum serum threshold of 11 micromol/L (approximately 57 mg/dL), below which there is insufficient AAT to protect the lung, leading to an increased risk of developing emphysema. Most patients below this threshold level are homozygous for the Z allele (designated PI*ZZ) (table 2) [18].

In general, heterozygotes (eg, PI*MZ) have AAT levels intermediate between normal and severely deficient, although complex heterozygotes (eg, PI*SZ) can have AAT levels that are severely deficient [77]. At times of inflammation, serum levels can overestimate the AAT level, as AAT is an acute phase reactant. An acute phase reaction is unlikely to mask AATD in those with the PI*ZZ genotype but can elevate AAT levels into the normal range in PI*MZ and PI*SZ heterozygotes.

The different tests have slightly different normal ranges and the optimal cut-off point for detecting AATD varies somewhat with the test. For immune turbidimetry (nephelometry), a reasonable cut-point is between 100 and 113 mg/dL (18.4 to 21 micromol/L) [78]. In an American study using nephelometry, the cut-off with the greatest area under the receiver operating curve (ROC) was 120 mg/dL (22 micromol/L) [19]. Given these variations in test results, it is essential to know the range of normal values for the test used in a given patient.

Given the variability in reference ranges, patients with a serum AAT level below 20 micromol/L (100 mg/dL) should be evaluated further with targeted genotyping or isoelectric focusing. Some mildly deficient genotypes (eg, PI*MZ) can have levels in the normal range, especially if sampled during acute inflammation. Our practice is to test for serum level and targeted genotype in all patients.

●Targeted genotyping – Genotyping of the protease inhibitor (PI) locus is generally performed on a blood sample (dried blood spot or whole blood) using polymerase chain reaction (PCR) technology or restriction fragment length polymorphisms (RFLP) [73,79]. These tests can detect the normal M allele and the most common known pathogenic variants (eg, F, I, S, Z); the specific panel of variants tested differs among laboratories. Alleles that are not tested for by the laboratory cannot be detected. Clinicians should be aware of which alleles are interrogated by the laboratory when interpreting laboratory test results. Not finding an abnormal allele that is not tested for does not exclude the presence of that allele. In particular, if a laboratory does not specifically test for the F allele, a reported result of PI*MZ could actually represent a PI*FZ individual. In this instance, the serum level may be at most mildly reduced (as the F allele is characterized by a normal serum level despite a dysfunctional F AAT protein) and the diagnosis of severe AAT deficiency in a PI*FZ individual could be missed.

●Isoelectric focusing – Isoelectric focusing is the gold standard blood test for identifying AAT variant proteins, which migrate differently under isoelectric focusing. With the availability of targeted genotyping and gene sequencing, isoelectric focusing is performed less often, but is still sometimes useful for rare variants (eg, F, I, P) [2].

The initial designation of abnormal AAT proteins was based on the speed of migration of the protein variants: M migrates in the middle; S has slow migration and stays closer to the cathode; F migrates fast to the anode; the Z phenotype migrates most slowly and is called "Z" because it is last. Interpretation of isoelectric focusing tests is complicated by the appearance of multiple minor bands for each of the various alleles, absence of protein in patients with null alleles, and M-like alleles (eg, M[Malton]).

●Gene sequencing – Sequencing of exonic DNA is used when available primers for PCR and RFLP testing fail to determine the genetic variant, which is more likely to occur with rare variants or null alleles. Gene sequencing is prudent when the serum level and the reported genotype seem discordant or when the patient's clinical features cannot be explained by the reported genotype.

It is important to review the genetic origins of samples when evaluating patients who have received a liver or hematopoietic cell transplant (HCT), particularly when there is discordance between tests [3]. As an example, a liver transplant can lead to a normal serum AAT in a PI*ZZ individual, but that individual can still pass the Z allele to their progeny. In contrast, a PI*ZZ patient who has undergone HCT from a PI*MM donor can have a PI*MM genotype reported on a peripheral blood sample but have a low serum AAT level consistent with their actual PI*ZZ genotype because the liver still produces Z-type AAT protein.

Pulmonary function testing — Pulmonary function testing is used to assess the presence and severity of lung disease. In these patients, we typically obtain spirometry before and after bronchodilator, lung volumes, and a diffusing capacity for carbon monoxide [72]. If the diffusing capacity for carbon monoxide (DLCO) is below normal or if the patient reports exertional dyspnea, a six-minute walk test is often obtained. (See "Overview of pulmonary function testing in adults".)

Patients with airflow limitation and a forced expiratory volume in one second (FEV₁) <80 percent of predicted post-bronchodilator are candidates for augmentation therapy. (See "Treatment of emphysema from alpha-1 antitrypsin deficiency", section on 'Patient selection'.)

Imaging — Chest imaging is used to determine the pattern and extent of emphysema and also exclude other causes of dyspnea. As noted above, the "classic" pattern of emphysema in AATD is basilar predominant emphysematous bullae (image 1), although a range of patterns from basilar predominant to apical predominant emphysema may be seen. The author obtains a plain chest radiograph as part of the initial assessment; some clinicians perform chest computed tomography (CT) scans for initial assessment [72]. (See 'Clinical presentation of lung disease' above.)

MONITORING ASYMPTOMATIC PATIENTS — The optimal frequency of monitoring for onset or progression of lung or liver disease in patients with known severe deficiency of AAT has not been formally studied.

For patients with no respiratory symptoms and a normal baseline spirometry (ie, forced expiratory volume in one second [FEV₁] ≥80 percent of predicted), spirometry is typically repeated when symptoms change or at 6- to 12-month intervals [2,72]. An unexplained decrease in the postbronchodilator FEV₁ to less than 80 percent predicted is an indication to initiate augmentation therapy. (See "Treatment of emphysema from alpha-1 antitrypsin deficiency", section on 'Intravenous augmentation therapy'.)

Similarly, guidelines have not been established regarding monitoring for liver disease in patients homozygous for PI*Z, PI*S[iiyama] or PI*M[malton]. Our practice is to assess serum aminotransferases (eg, alanine aminotransferase, aspartate aminotransferase), alkaline phosphatase, and bilirubin annually [2,80], as well as a FibroScan, usually with hepatology consultation. If a chest CT is performed to assess for emphysema, liver and spleen morphology should be examined. Some clinicians also obtain a complete blood count (CBC), looking for thrombocytopenia, and an abdominal ultrasound, looking for cirrhosis or hepatocellular carcinoma in cirrhotics, every 6 to 12 months. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)

NATURAL HISTORY — Current understanding of the natural history of AAT deficiency is patchy, with some aspects being reasonably clear and others still murky [2]. It is well-documented that the rate of decline in lung function is strongly dependent on cigarette smoking.

First four decades of life — In the first four decades of life, liver dysfunction is the major threat to the health of affected individuals, and pulmonary dysfunction is less of a concern [81,82]. In the largest study, 90 PI*ZZ and 40 PI*SZ subjects (approximately 20 percent had smoked at some time) had normal lung function on spirometry at age 30 [83], but some evidence of emphysema on chest computed tomography at age 32 among ever-smokers [84]. Later follow-up of this cohort at a median age of 39 showed that the few PI*ZZ smokers had a higher prevalence of COPD (67 percent) than the never or former smokers (5 to 8 percent) [85] At age 42, more PI*ZZ never smokers had lower forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) than age- and gender-matched PI*MM individuals [86]. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)

Later decades — Beyond the first four decades of life, the natural history of individuals with severe deficiency of AAT is less clear, and survival estimates for subjects with severe deficiency of AAT vary among series, presumably due to differences in study populations. Relatively normal survival appears possible for nonsmoking asymptomatic individuals, although long-term follow-up in a population-based study is needed for confirmation [87,88]. The favorable prognosis for nonsmokers is consistent with expectations that many individuals with severe deficiency are asymptomatic and therefore escape medical attention. In comparison, approximately 40 percent of adults with PI*ZZ have histologically significant liver injury and cirrhosis at the time of death. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)

The rate of decline in lung function is strongly affected by cigarette smoking. Available estimates of the yearly decline in FEV₁ among smokers range from as low as 42 to as high as 317 mL per year, compared with 44 to 110 mL per year in nonsmokers or ex-smokers [48,62,89-93]. The Registry of Patients with Severe Deficiency of Alpha-1 Antitrypsin, an NHLBI-sponsored multicenter study of 1129 patients, found an annual FEV₁ decline of 54 mL per year based upon high quality sequential pulmonary function measurements [57,94]. The rate of decline was higher (84 mL per year) among participants with FEV₁ between 50 and 79 percent predicted who were not receiving augmentation therapy. Similar findings were reported by the UK Antitrypsin Deficiency Assessment and Programme for Treatment (ADAPT) [95].

Overall, approximately 90 percent of subjects with severe deficiency of AAT who smoke will develop radiographic emphysema, compared with 65 percent of nonsmokers [47]. Mortality rates among AAT-deficient individuals have been reported using case series, but not population-based studies [46,62,94,96]:

●A 37 percent mortality rate was observed in an 11-year follow-up study of 246 PI*Z homozygotes [46]. Most deaths were ascribed to respiratory failure (59 percent), with a minority of patients (13 percent) succumbing to complications of liver disease.

●A second follow-up study (up to 7.2 years) noted a consistent 3 percent annual mortality rate among the 1129 enrollees in the NHLBI-sponsored registry [96]. Overall survival over the duration of this study was 82 percent. Most deaths were caused by respiratory failure or liver disease (72 and 10 percent, respectively). Mortality was closely associated with pulmonary function, and was greatest for patients with an FEV₁ <15 percent predicted (36 versus 3 percent for patients with FEV₁ ≥50 percent predicted).

Studies from the Danish Registry show that, in addition to FEV₁, smoking status and method of ascertainment (ie, how the subject comes to the attention of the registry) affect survival [97-99].

●Survival among smokers and among patients with symptoms was lower than among their nonsmoking asymptomatic counterparts [97,99]. Furthermore, asymptomatic nonsmokers, who were usually identified as relatives of symptomatic AAT-deficient individuals, had a survival rate equal to that of the normal age-matched Danish population.

●The FEV₁ was a major determinant of survival in AAT-deficient individuals, with the mortality rising exponentially as FEV₁ falls below 35 percent of the predicted value (figure 1). As an example, the two-year mortality rate among individuals with FEV₁ values of 15 percent predicted was almost 50 percent [98].

Parameters other than FEV₁ have been used to predict mortality in patients with AAT deficiency [100-104]. As an example, decreased lung density as assessed by chest computed tomographic (CT) scan was associated with increased mortality in a group of 256 AAT-deficient individuals followed for five years at a single center [101].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)

SUMMARY AND RECOMMENDATIONS

●Genetics – AAT (encoded by the SERPINA1 gene, MIM +107400) is a member of the serpin family of protease inhibitors. It protects the lower airways from damage caused by proteolytic enzymes, such as elastase. (See 'AAT phenotypes' above.)

The normal AAT allele is the M allele. Over 150 allelic variants have been described, of which the most common severely deficient variant is the Z allele. (See 'AAT phenotypes' above.)

●Epidemiology – Severe deficiency of AAT is known to affect approximately 100,000 Americans. However, AAT deficiency (AATD) is severely under-recognized, commonly with long intervals between the first symptom and diagnosis. (See 'Epidemiology' above.)

●Clinical manifestations – Clinical manifestations of severe deficiency of AAT typically involve the lung (eg, early onset emphysema), liver (eg, cirrhosis), and, rarely, the skin (eg, panniculitis). The severity of lung disease depends on the degree of AATD and exposures to tobacco smoke and other fumes or dusts. For patients with emphysema due to AATD, dyspnea is the most common symptom, and many patients report cough, phlegm production, and wheezing, either chronically or with upper respiratory tract infections. (See 'Clinical manifestations' above and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

Patients with at-risk alleles (eg, Z, S[iiyama], M[malton]) may develop adult-onset chronic hepatitis, cirrhosis, or hepatocellular carcinoma, the former often occurring without antecedent childhood liver disease. Other extrapulmonary manifestations of AATD include panniculitis and, possibly, vasculitis, inflammatory bowel disease, intracranial and intra-abdominal aneurysms, fibromuscular dysplasia, and glomerulonephritis. (See 'Clinical presentation of extrapulmonary disease' above and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

●Imaging – Emphysema associated with AATD often shows a characteristic radiographic pattern, in which bullous changes are more prominent at the lung bases than at the apices (image 1). However, emphysematous changes may be apical or diffusely distributed in approximately one-third of patients. (See 'Clinical presentation of lung disease' above.)

●Who needs AAT testing – All adults with persistent airflow obstruction on post-bronchodilator spirometry should be tested for AATD. Features that should especially prompt testing for AAT deficiency include emphysema in a young individual (eg, age ≤45 years), emphysema in a nonsmoker or minimal smoker, emphysema characterized by predominant basilar changes on the chest radiograph, a family history of emphysema and/or liver disease, current or prior panniculitis, and current or prior unexplained chronic liver disease (table 3). (See 'Evaluation and diagnosis' above.)

●Diagnosis – The diagnosis of severe deficiency of AAT is established by demonstrating a serum level <11 micromol/L (approximately 57 mg/dL) in combination with confirmation of a severe deficient genotype (by targeted genotyping for common variants) or phenotype (by isoelectric focusing [IEF]) (algorithm 1). (See 'Evaluation and diagnosis' above.)

•Testing strategies depend on local preferences; simultaneous testing of AAT serum level and targeted genotyping is preferred, but sequential testing is an acceptable alternative.

•Given the variability in assays, patients with an AAT serum level <20 micromol/L (<100 mg/dL) should be evaluated further by targeted genotyping (preferred) or isoelectric focusing.

•Full gene sequencing is reserved for patients with high clinical suspicion and negative targeted genotyping or IEF.

•For patients who have a low AAT level, but no I, S, or Z variants on genotyping or phenotyping, DNA sequencing may be needed to assess for null or other rare deficient alleles. (See 'Laboratory testing' above.)

●Pulmonary function tests – For patients with AATD, pulmonary function tests (eg, spirometry pre- and postbronchodilator, lung volumes, diffusing capacity for carbon monoxide) are used to assess the severity of lung disease and monitor disease progression. The typical PFT feature associated with AATD due to homozygous Z alleles (PI*ZZ) is airflow limitation that worsens over time. The rate of deterioration depends on exposures to tobacco smoke and other fumes and dusts. Partial reversibility of airflow limitation following bronchodilator inhalation is common. (See 'Pulmonary function testing' above.)

●Liver dysfunction – During the first four decades of life, liver dysfunction is the major threat to the health of affected individuals and may present as chronic elevation of liver enzymes or cirrhosis. Liver disease may also develop in adulthood. (See 'Natural history' above and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Risk and natural history'.)

●Natural history – Beyond the four decades of life, patients with severe deficiency of AAT have an accelerated rate of lung function decline, especially with cigarette smoking and some occupational exposures. Estimates of the yearly decline in FEV₁ among smokers range from as low as 42 to as high as 317 mL per year, compared with 44 to 110 mL per year in nonsmokers or ex-smokers. (See 'Natural history' above.)