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Clinical manifestations, diagnosis, and

natural history of alpha-1 antitrypsin
deficiency
AUTHOR:
James K Stoller, MD, MS
SECTION EDITOR:
Peter J Barnes, DM, DSc, FRCP, FRS
DEPUTY EDITOR:
Paul Dieffenbach, MD
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2023.
This topic last updated: Sep 13, 2022.
INTRODUCTIONAlpha-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
alpha-1 antitrypsin deficiency".)
BACKGROUNDAAT 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.
EPIDEMIOLOGYAlthough 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 DISEASEIndividuals 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 MANIFESTATIONSThe 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 DIAGNOSISAll 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 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 PATIENTSThe 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 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 HISTORYCurrent 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 LINKSLinks 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.)

GRAPHICS
Characteristics of alpha-1 antitrypsin variants
PI allele Protein/cellular consequences Organs affected

Normal alleles

M (various None None

subtypes)

Xchristchurch None None

Deficiency alleles associated with intracellular accumulation

Z Intracellular accumulation; defective Liver, lung

inhibition of neutrophil elastase

Mmalton Intracellular accumulation Liver, lung

Siiyama Intracellular accumulation Liver, lung

Deficiency alleles associated with intracellular degradation

Mheerlen Intracellular degradation Lung

Mprocida Intracellular degradation Lung

Mmineral springs Intracellular degradation; defective Lung

inhibition of neutrophil elastase

S Intracellular degradation Lung

Null alleles*

QOgranite falls Stop codon; no mRNA or protein Emphysema

QOludwigshafen mRNA present but abnormal; protein Liver, lung

destabilized

QOhongkong1 Frameshift with stop codon; short Early-onset emphysema

protein; intracellular accumulation

QOisola di procida Deletion; no mRNA; no protein High risk of emphysema

QObolton Stop codon; no mRNA or protein High risk emphysema

Dysfunctional alleles

Pittsburg Substitution Bleeding diathesis due to change in

protein to have antithrombin properties
 F Impaired binding to neutrophil elastase Normal serum alpha-1 antitrypsin level
but impaired anti-elastase functional
activity
PI: Protease inhibitor.
* Null alleles have less than 1% of the normal concentration of alpha-1 antitrypsin.
Data adapted from:

1. DeMeo DL, Silverman EK. Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-

antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 2004;

59:259.

2. Frazier GC1, Siewertsen MA, Hofker MH, et al. A null deficiency allele of alpha 1-antitrypsin,

QOludwigshafen, with altered tertiary structure. J Clin Invest 1990; 86:1878.

3. OMIM. https://omim.org/entry/107400 (Accessed on August 18, 2020).

Graphic 103267 Version 3.0
Characteristics of alpha-1 antitrypsin deficiency genotypes
Risk for True plasma level, Commercial standard
Genotype
emphysema micromol/L (SI units) plasma level, mg/dL

MM No increase 20 to 48 80 to 220
(normal)

MZ Possible mild increase 17 to 33 90 to 210

SS No increase 15 to 33 100 to 200

SZ* Mild increase (20 to 8 to 16 75 to 120¶

50 percent)

ZZ High risk (80 to 100 2.5 to 7 20 to 45

percent)

Null High risk (100 percent 0 0

by age 30)
Pulmonary and plasma features of the different genotypes of alpha-1 antitrypsin
(AAT) deficiency. Measurement of AAT serum levels can be done by enzyme-linked
immunosorbent assay (ELISA) or nephelometry.
* Heterozygotes with the SZ genotype rarely have evidence of clinical pulmonary
disease.
¶ Protective threshold of 11 micromol/L (ELISA) is approximately equal to 57 mg/dL
by nephelometry.
Adapted from: American Thoracic Society/European Respiratory Society statement: standards for
the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit
Care Med 2003; 168:818.
Graphic 57264 Version 9.0
 Potential clues to the diagnosis of alpha-1 antitrypsin
deficiency [1,2]

Family history AAT deficiency

Emphysema
Bronchiectasis
Liver disease
Panniculitis

Lung disease Irreversible airflow limitation on spirometry

Emphysema at a young age ≤45
Emphysema in the absence of smoking or occupational risk factor
Emphysema characterized by predominant basilar changes on chest imaging
Adult onset asthma (when airflow obstruction fails to reverse completely after
bronchodilators)
Unexplained bronchiectasis

Liver disease Neonatal hepatitis

Cirrhosis in both children and adults
Hepatocellular carcinoma
Hepatomegaly
Unexplained liver disease

Skin disease Necrotizing panniculitis (thigh, buttocks)

Other associations ANCA-associated vasculitis

Abnormal laboratory Persistent mild to moderate ↑ALT, ↑AST

tests Low alpha1-globulin or presence of two bands in alpha1 globulin region on
SPEP
AAT: alpha-1 antitrypsin; ANCA: Antineutrophil cytoplasmic antibodies; ALT: alanine
aminotransferase; AST: aspartate aminotransferase; SPEP: serum protein
electrophoresis.
References:

1. American Thoracic Society; European Respiratory Society. American Thoracic Society/European

Respiratory Society statement: standards for the diagnosis and management of individuals with

alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003; 168:818.

2. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis

and treatment of pulmonary disease in alpha-1 antitrypsin deficiency. Eur Respir J 2017;

50:pii:1700610.
Graphic 61623 Version 4.0
Panacinar emphysema in alpha-1 antitrypsin deficiency

Chest radiograph shows marked hyperexpansion with paucity of vascular structures

at the bases and redistribution of vascular flow to the lesser involved upper lobes.
These findings are typical of severe panacinar emphysema.
Courtesy of Paul Stark, MD.
Graphic 65594 Version 4.0
Our approach to diagnosis of alpha-1 antitrypsin (AAT)
deficiency

COPD: chronic obstructive pulmonary disease; ANCA: antineutrophil cytoplasmic

antibody; PCR: polymerase chain reaction; IEF: isoelectric focusing (assesses protein
migration).
* It is preferable to obtain simultaneous measurement of AAT level and targeted
genotyping. Targeted genotyping uses PCR to identify specific common pathogenic
AAT variants (eg, F, I, S, and Z) and the normal M allele, although panels vary
among laboratories. Sequential testing of genotype first followed by serum level is an
alternative. Refer to UpToDate content on the diagnosis of AAT deficiency.
¶ Interpretation of a specific abnormal result should be based upon the reference
range reported by the laboratory. A reasonable threshold for differentiating normal
Pi*MM (normal genotype) from other genotypes with one or more deficient alleles is
20 micromol/L (100 mg/dL).
Δ IEF is an alternative, but gene sequencing is typically preferred.
◊ Depending on the specific variant, heterozygotes may have a serum AAT level that
is reduced or within the normal range. As AAT is an acute phase reactant, a mildly
low AAT level can increase into the normal range during acute illness. However, a
severely low AAt level would not increase into the normal range.
§ Targeted genotyping, in combination with a low serum AAT level, is acceptable for
diagnosis of AAT deficiency. There is no need to confirm genotype result with
alternative test, such as IEF, if result is clear and consistent with AAT level.
¥ AAT levels can be low in the absence of AAT deficiency (eg, variation in the assay
or improper storage of specimen). If unexplained, obtain specialty consultation, as
appropriate.
Graphic 104220 Version 5.0
Survival in AAT according to FEV1

Two year mortality rate in patients with alpha-1 antitrypsin deficiency according to
FEV1. Mortality rises dramatically when the FEV1 falls below 35 percent predicted.
FEV1: forced vital capacity in one second.
Redrawn from Seersholm N, Dirksen A, Kok-Jensen A, Eur Respir J 1994; 7:1985.
Graphic 81503 Version 2.0

Contributor Disclosures
James K Stoller, MD, MSGrant/Research/Clinical Trial Support: Alpha-1
Foundation [Alpha-1 antitrypsin detection]. Consultant/Advisory Boards:
23andMe [Alpha-1 antitrypsin deficiency]; 4DMT [Alpha-1 antitrypsin
deficiency]; Alpha-1 Foundation [Member, Board of Directors]; Bridgebio
[Alpha-1 antitrypsin deficiency]; CSL Behring [Alpha-1 antitrypsin
detection]; Dicerna [Alpha-1 antitrypsin deficiency]; Grifols [Alpha-1
antitrypsin detection]; InhibRx [Alpha-1 antitrypsin deficiency]; Insmed
[Alpha-1 antitrypsin deficiency]; Korro [Alpha-1 antitrypsin deficiency];
Takeda [Alpha-1 antitrypsin detection]; Vertex [Alpha-1 antitrypsin
deficiency]. All of the relevant financial relationships listed have been
mitigated.Peter J Barnes, DM, DSc, FRCP, FRSGrant/Research/Clinical Trial
Support: AstraZeneca [Asthma, COPD]; Boehringer [COPD]; Novartis
[COPD]. Consultant/Advisory Boards: AstraZeneca [Asthma, COPD];
Boehringer [COPD]; Epi-Endo [Asthma, COPD]; Novartis [COPD]; Teva
[COPD]. Speaker's Bureau: AstraZeneca [Asthma]; Boehringer [COPD];
Novartis [COPD]; Teva [Asthma]. All of the relevant financial relationships
listed have been mitigated.Paul Dieffenbach, MDNo relevant financial
relationship(s) with ineligible companies to disclose.
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