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The purpose
of this review of alpha1-antitrypsin (AAT) deficiency is
twofold. First, it will present some of the features of
this condition; and second, it will provide a current, annotated
list of references for those who wish to read more than
this space will permit. In part, the motivation for this
review is that current medical and even subspecialty textbooks
are not current, and often not accurate, in their descriptions
of the deficiency. The American Thoracic Society and the
European Respiratory Society have published a joint statement
regarding evidence-based standards for the diagnosis and
management of AAT deficiency in 2003 (1). While useful for
reference, this comprehensive document is too lengthy for
casual reading.
Many individuals
with AAT deficiency remain clinically healthy, or have minimal
disease. Thus, people who have recently discovered that
they have AAT deficiency should neither be unduly alarmed
nor inappropriately unconcerned about their diagnoses.
AAT deficiency
is the most prevalent potentially lethal hereditary disease
of Caucasians. Individuals with AAT deficiency have an increased
risk of early onset, severe pulmonary emphysema (2) and
for liver disease (3).
Discovery
of AAT deficiency by Laurell and Eriksson in 1963 (4) provided
a foundation for current thinking about the pathogenesis
of pulmonary emphysema.
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Although AAT
deficiency has become one of the best understood genetic disorders
at a molecular and protein level, many questions about the clinical
disease remain unanswered. Current American and International
research projects should provide answers to some of these questions
in the future.
Biochemistry of AAT
Serum
was shown to inhibit trypsin nearly a century ago. A specific
trypsin-inhibitory protein was isolated from the alpha1-globulin
region of human serum in 1962, and was named alpha1-antitrypsin.
Following the recognition that this protein also inhibits a number
of other proteinases, it has also been named alpha1-proteinase
inhibitor. When used in a clinical context, the original terms
"alpha1-antitrypsin" and "alpha1-antitrypsin
deficiency" are used most often, to respect the investigators
who discovered the protein and its deficiency. Details about the
biochemistry of AAT have been reviewed (5).
AAT is synthesized by hepatocytes, and to a lesser extent by monocytes
and other cells. Most of the circulating AAT is synthesized by
the liver.
Function: It is now thought that
inhibition of human leukocyte elastase is the major function of
AAT. Leukocyte elastase is a serine proteinase found within granules
of neutrophils and monocytes. This enzyme has a number of biologically
important activities; for example, it is probably very important
in killing bacteria (6), in digesting injured tissue during wound
healing, and in allowing neutrophils and monocytes to exit from
the vasculature and penetrate tissues to reach sites of inflammation.
However, if its activity is uncontrolled, it can injure a variety
of structural components of normal tissues, and uncontrolled leukocyte
elastase may be pro-inflammatory (7;8). Deficiency of AAT removes
a major control mechanism for leukocyte elastase, and this deficiency
can allow leukocyte elastase to injure the delicate gas-exchanging
region of the lung, eventually leading to pulmonary emphysema.
Uncontrolled leukocyte elastase also has the potential for inactivating
tissue inhibitors of metalloproteinases (9;10), and thus promoting
uncontrolled, injurious activity of metalloproteinases.
AAT
Deficiency
The
synthesis of AAT is controlled by a pair of genes at the proteinase
inhibitor (Pi) locus. The genes are inherited as co-dominant alleles
(products of both genes can be found in the circulation). Many
abnormal variants have been very well characterized; they result
from point mutations in the gene, and most commonly have one or
two amino acid substitutions when compared to the normal protein.
Some of these changes result in little (or rarely, no) AAT in
the circulation (11;12).
Heterozygotes
and individuals with the S variant (see below) usually
do not have "normal" circulating levels of AAT.
However, in this discussion the term "AAT deficiency"
will be reserved for individuals with severely diminished AAT
levels (<11 µM).
Variant
types of AAT: More than 75 different genetic variants of AAT
are now recognized (11;12), but many of these are quite rare.
AAT in the serum can be characterized by phenotyping, which is
accomplished by isoelectric focusing of serum. DNA for AAT (most
often in white blood cells) can also by typed by genotyping, which
is accomplished by allele-specific amplification. The identity
of rare alleles can only be learned with certainty by nucleotide
sequencing. The most common variants of AAT will be discussed
below. The remainder are beyond the scope of this review, but
most are described in the excellent review by Brantly (11).
Nomenclature
for phenotypes and genotypes:
The names of phenotypes and genotypes begin with the name of the
locus (Pi), followed by the letter names that have been given
to the AAT alleles. The alleles have been named with letters of
the alphabet, corresponding in order to their migration in a test
system. By convention (13), genotypes are printed in italics,
with the alleles in superscript. For example, the most common
type of heterozygote ("carrier") for AAT deficiency
(see below) is phenotype Pi MZ and genotype PiMZ.
Genetic
transmission: Individuals with AAT deficiency have two deficient
alleles for the protein. Thus, the deficiency is inherited as
an autosomal recessive condition. Brothers and sisters of deficient
individuals have a 25% chance of also having the condition. Children
of deficient individuals can usually be expected to be heterozygotes
("carriers") for the deficiency. These children have
only a small risk of being AAT deficient, and this risk is present
only if the partner of the deficient individual is a carrier.
Phenotyping or genotyping is necessary to reliably detect carriers,
since AAT levels of normals and carriers overlap significantly.
The
normal M alleles: The normal M alleles represent by far the
largest group of AAT alleles. They result in normal amounts, and
normal functionality, of AAT in the blood. The M1, M2, and M3
alleles differ only subtly from one another, and the differences
are not clinically important. Usually, no distinction is made
among the M alleles in clinical laboratory testing. In normals,
only the M variant is seen on phenotyping. By convention, the
phenotype of these individuals is Pi M (not Pi MM), because a
small fraction of individuals with apparently normal phenotype
results will have a null (non-expressing) AAT deficiency allele
that is not detected when plasma proteins are phenotyped. Genotyping
detects specific abnormal nucleotide sequences, so it cannot
be used to identify the normal M alleles. Normal plasma levels
of AAT, in combination with Pi M phenotype, provide some assurance
that two normal M alleles are present, but only family studies
or exon sequencing can identify PiMM genotype
with certainty.
The
Z variant: By far the most prevalent type of clinically important
AAT deficiency is classified as phenotype Pi Z. In these
individuals, isoelectric focusing reveals only an abnormally migrating
Z type AAT. These individuals may be either Pi ZZ homozygotes
or Pi Znull heterozygotes, since no AAT attributable to the null
genes can be found in the circulation. Genotyping is necessary
to distinguish between these two possibilities, although family
studies of the pattern of inheritance of low AAT levels may also
be helpful.
The
Z variant has two amino acid substitutions when compared to the
most prevalent normal type of AAT. It is subtly abnormal as an
inhibitor of leukocyte elastase (14). However, the most striking
abnormality in affected individuals is that circulating levels
of the protein are only 10-15% of normal. When livers of these
individuals are examined, the hepatocytes contain an abnormal
accumulation of AAT (15). The Pi Z type of AAT is secreted abnormally
slowly by both hepatocytes and monocytes. This abnormality is
thought to cause the deficiency. One of the amino acid substitutions
(Glu342->Lys342) results in misfolding of
the AAT, leading to intracellular accumulation and intracellular
degradation of the abnormal protein (16). The structural alteration
in the Z variant appears to allow "loop-sheet polymerization"
of the molecule, during which the reactive center loops of one
molecule become inserted into an opening in the A sheet of another
molecule(17-20). Chains of these AAT polymers become tangled within
the endoplasmic reticulum of hepatocytes, and most (~85%) are
degraded before they reach the circulation.
The
S variant: The S variant has a single amino acid substitution
(Glu264->Val264) when compared with the
most prevalent normal type of AAT. The S mutation is not
associated with intracellular accumulation of the protein, and
the S protein inhibits elastase nearly normally. The amounts of
the S protein that reach the circulation are slightly lower than
normal, because of intracellular degradation of the AAT before
it is secreted (21). The S allele is slightly more prevalent than
the Z allele among U.S. Caucasians, and it is much more prevalent
in the Iberian peninsula and neighboring countries. Individuals
with the Pi S phenotype do not appear to be at increased risk
for lung or liver disease.
Common
heterozygotes: Pi MS individuals have one normal allele and
one S allele. They have nearly normal, and occasionally normal,
levels of AAT. They do not appear to be at increased risk for
lung or liver disease.
Pi
MZ individuals have one normal allele and one allele for the Z
variant. They usually have decreased levels of AAT in their circulation;
however, since they are capable of mounting an acute phase response,
their levels can fall within the normal range (particularly if
they are ill or are taking oral contraceptives). The livers of
Pi MZ heterozygotes show mild intracellular accumulation of the
protein. There have been a number of attempts to demonstrate an
excess risk of lung disease among Pi MZ individuals. Pi MZ individuals
appear to be more prevalent in lung disease populations than in
the general population (22). A longitudinal study of the Danish
general population showed that Pi MZ individuals demonstrated
a slightly greater annual decrease in lung function, greater prevalence
of airway obstruction, and greater hospitalization and mortality
from COPD when compared with Pi M individuals (23). A meta-analysis
of published studies of Pi MZ risk showed increased odds of COPD
in Pi MZ individuals in case-control studies but not in cross-sectional
studies (24). Taken together, the available data are consistent
with a very small excess risk of airways disease among all Pi
MZ individuals and/or a greater (but probably still small) excess
risk in a subset of these heterozygotes. A slight excess risk
of liver disease among Pi MZ heterozygotes seems to be demonstrated
by the excess prevalence of Pi MZ individuals with end-stage liver
disease (25). Again, it may be true that only a subset of heterozygotes
are at excess risk. When discussing these issues with patients,
it seems to be advisable to offer a great deal of reassurance
to Pi MZ heterozygotes regarding their own risk of developing
lung or liver disease, but to counsel them about the risk of genetic
transmission of the deficient allele.
Pi
SZ individuals have one allele for the S variant and one for the
Z variant (the classical deficiency variant). These "complicated
heterozygotes" have AAT levels that range from approximately
1/3 to ½ of normal. Pi SZ heterozygotes are slightly more
common than Pi Z (AAT deficient) individuals in American populations.
The livers of Pi SZ heterozygotes show mild accumulation of AAT.
Studies of the risk of lung disease in Pi SZ heterozygotes have
reached variable conclusions (26;27), this issue is discussed
in Hutchison's review (28). Some of these Pi SZ individuals have
AAT levels that are slightly less than the 11 :M plasma concentration
that is arbitrarily used to define AAT deficiency; however, the
available data appears to show no excess risk of lung disease
in these individuals when compared with that of the remainder
of the Pi SZ population (27). The unfortunate lack of more extensive
data regarding the risk to Pi SZ heterozygotes is related to the
relatively small number of known individuals. The risk of liver
disease in this group should be related to the Z allele, and thus
should be the same as that in the Pi MZ population discussed above.
In summary, based upon the limited information available, Pi SZ
individuals appear to have the same or somewhat greater risk of
lung disease as to the Pi MZ heterozygotes discussed above. It
again seems advisable to offer these individuals considerable
reassurance regarding their own risk, but to counsel them regarding
the risk of transmission of the Z allele.
Lung
and Liver Disease in AAT Deficiency
Pulmonary
emphysema.
As noted above, AAT normally provides an important defense against
attack on the normal structural components of the lung parenchyma
by leukocyte elastase. Thus, deficiency of this inhibitor increases
the risk that leukocyte elastase will injure alveolar walls when
it is released from inflammatory cells in the lower respiratory
tract. Over many years, the cumulative effect of this injury is
alveolar septal destruction and airspace enlargement, which presents
clinically as pulmonary emphysema. As lung disease develops, additional
mechanisms may accelerate or contribute to lung function impairment.
Pulmonary
emphysema was described as a complication of AAT deficiency by
Eriksson in 1964 (2). In the classic description of AAT deficiency
(28;29), patients have: 1) insidious onset of progressive shortness
of breath between ages 25 and 40, 2) increasing dyspnea and increasing
evidence of airflow obstruction as the disease progresses; 3)
chest radiographic abnormalities including hyperinflation and
symmetrical loss of parenchymal vascularity; and 4) chest radiographic
abnormalities most marked in the lung bases, and commonly associated
with bullae. About half of the patients have chronic or episodic
productive cough.
Interestingly,
however, only a very small fraction (probably about 5%, in the
United States) of all individuals with AAT deficiency have been
diagnosed, and there is reason to believe that many of those
who have escaped diagnosis have either: 1) no lung disease; or
2) mild or atypical disease. This most interesting "hidden"
population of individuals with AAT deficiency is further discussed
below.
When
lung disease becomes established, lung function impairment tends
to be progressive in severity. In British and American studies,
the range of decline in FEV1 tends to be between 51 and 100 ml/year
(with a large variability) in the absence of intervention (28;29).
This rate is in the range of 1.5 to 3 times the normal rate of
lung function decline.
Liver
disease. Ten to 20% of infants with AAT deficiency have neonatal
hepatitis with cholestatic jaundice; others may have abnormal
liver enzymes, hepatomegaly, or both (30). A very small proportion
(1-2%) of children with AAT deficiency develop end-stage liver
disease in childhood. Despite these small numbers, AAT deficiency
is the most common genetic cause of neonatal liver disease, and
the most frequent diagnosis necessitating liver transplantation
(31). In the remainder of affected children, liver abnormalities
tend to diminish or disappear (32;33), although mild hepatomegaly
or mild elevations in liver enzymes may persist in a few.
Adults with AAT deficiency have a significant risk of cirrhosis
and hepatoma in middle to late life (3). The exact risk for individual
patients is difficult to determine, however, and this risk probably
should be given little emphasis when counseling patients who currently
have no clinically detectable liver abnormalities.
The liver disease appears to be related to chronic stress on hepatocytes
resulting from the burdens of accumulated intracellular AAT and
the increased requirement for intracellular protein degradation
(11;16).
Variability
In Severity of Clinical Disease
The extent of lung and liver disease in AAT deficiency varies
strikingly. An interesting paradox is that adults with severe
lung disease often do not have liver disease, and vice versa.
While some patients with AAT deficiency develop end-stage lung
disease in the third to fifth decades of life, many others escape
clinically-important lung disease into mid to late life (34-36).
Many individuals ascertained through non-standard means escape
significant lung disease.
Cigarette smoking clearly has an adverse effect on the course
of lung disease. This has been shown to be true early in life
for a Swedish cohort of individuals who were identified at birth
and studied at an average age of 22.5 (37), and it has been repeatedly
shown in adult populations, such as a Swedish cohort (38). Asthma,
repeated pulmonary infections, and as-yet unidentified additional
familial factors also appear to be associated with a more severe
course of lung disease (34).
The
prognosis for newly-identified individuals with little or no lung
disease is not known. However, many may escape significant
lung disease, especially if they do not smoke. It is prudent to
follow such individuals with periodic lung function testing, at
least until continued research clarifies their prognosis. Ongoing
research may provide further information about the natural history
of lung disease in these individuals.
Liver
disease: The severity of clinically-apparent liver disease
is highly variable. A minority of infants and children are affected,
as noted above (33;39). Only 1-2% of children have a severe course,
with death from cirrhosis (or requirement for liver transplantation)
in childhood. Only some adults with AAT deficiency eventually
develop cirrhosis and/or hepatocellular carcinoma (3;40). The
risk for adult liver disease increases with age. The reason for
the variability in severity of liver disease is the subject of
ongoing research (41;42).
Treatment
of AAT Deficiency
A
major goal in the management of patients with AAT deficiency is
the prevention of lung disease, or reduction in the rate of progression
of any lung function impairment that is already present. It is
important to realize that few inflammatory cells are found within
the normal lung parenchyma. Therefore, the potential for lung
injury in AAT deficiency may be small in the absence of other
pro-inflammatory stimuli (smoking, asthma, respiratory infections,
etc.). A mainstay of management is to reduce the number of inflammatory
cells in the lung. A specific treatment, "augmentation"
therapy, is also available to increase circulating levels of AAT.
Smoking
cessation: This should be the first priority in management
of AAT deficiency. Lifelong nonsmokers can be told that if they
continue to refrain from smoking they will have a good chance
of avoiding serious lung disease. Once they have been informed
about their diagnosis and about the very serious consequences
of continuing to smoke, most current smokers are successful in
quitting.
Aggressive
treatment of asthma: Asthma is now recognized as an inflammatory
disease of the airways. Inflammatory cells (particularly neutrophils)
accumulate in and around the airways, and increase the burden
of leukocyte elastase in the lower respiratory tract. There is
evidence that asthma can lead to permanent lung injury in patients
with AAT deficiency. Thus, aggressive treatment of asthma, with
an emphasis on controller medications, may reduce the long-term
impact of AAT deficiency on lung function.
It is prudent to treat even mild asthma in patients with AAT deficiency
with inhaled corticosteroids. In patients with AAT deficiency,
systemic corticosteroids may be especially appropriate, to suppress
the increase in airway inflammation (as well as to relieve symptoms).
Early
and aggressive treatment of respiratory infections: AAT deficient
patients with severe lung disease often have a history of repeated
respiratory infections (34). Even minor respiratory infections
probably warrant antibiotic coverage for common respiratory pathogens.
General
supportive care: When lung disease is severe, patients may
require supplemental oxygen and home health care. Motorized carts
may help in allowing patients to retain mobility. Pulmonary rehabilitation
programs and support groups have been very helpful for many patients.
Augmentation
therapy: Concentrated preparations of human
 1-proteinase
inhibitor are available for intravenous administration to AAT-deficient
patients. These preparations, when infused weekly at a dose of
60 mg/kg body weight, increase circulating levels of AAT to concentrations
(>11 µM) that are thought to lessen the risk of continued
lung injury. Each of the available products is purified from large
lots of pooled human plasma.
Prolastin®,
manufactured by Talecris Biotherapeutics, was the first product
for augmentation therapy to become available, having received
FDA approval in late 1988. Aralast®, manufactured by Baxter
Healthcare, was the second product to receive FDA approval. The
most recent product to receive FDA approval is Zemaira®, manufactured
by ZLB Behring.
In
Pi Z individuals, once-weekly intravenous infusion of each of
these products, at a dose of 60 mg/kg body weight, maintains circulating
levels of AAT that are thought to be adequate for protection of
the lung parenchyma (43-48). Infusions increase levels of AAT
in broncho-alveolar lavage fluid, and the AAT recovered from the
broncho-alveolar lavage is functionally active. These intravenous
infusions appear to substantially correct the biochemical deficiency
in Pi Z individuals.
FDA
approvals of Aralast® and Zemaira® were based upon clinical
studies designed to show that they were substantially equivalent
("non-inferiority" study design) to Prolastin® in
safety and in their ability to increase AAT concentrations and
AAT activity in plasma and broncho-alveolar lavage fluid. Since
Prolastin® was the first product to be marketed, early attempts
to demonstrate clinical efficacy for augmentation therapy employed
it as the augmenation product. There have been several attempts
to show that it alters the clinical course of AAT deficiency.
Data from a large North American registry of patients with AAT
deficiency showed that augmentation with Prolastin® was associated
with a statistically significant diminution in the rate of decline
of lung function among individuals with moderately impaired lung
function, and with a lower mortality(49). While encouraging, this
study suffered from the flaw that treatment was not randomized.
Thus, true treatment effects could have been confounded by other
variables in the study population, such as socioeconomic status
or access to medical care. A European study, also not randomized,
compared German with Danish patients (the latter not augmented)
and showed a similar effect of augmentation therapy on slowing
the rate of decline of lung function (50). A Danish-Dutch randomized,
controlled trial showed a strong trend toward a lowering of the
rate of decline of lung function in the augmented group, but the
difference did not quite reach statistical significance at the
0.05 level in the modest number of subjects studied (51). Ongoing
and planned randomized, controlled clinical trials, using improved
end-points, may eventually provide the scientifically sound evidence
for a clinical benefit of augmentation that has been sought for
many years.
In
summary, intravenous augmentation is a logical approach to specific
treatment of AAT deficiency, and clinical studies have shown promise
for the treatment. Definitive proof of its efficacy has not been
demonstrated to date, largely because of the logistical difficulties
and expense associated with a large, long-term randomized, double-blind
clinical trial in patients who are spread over a wide geographic
area.
Some
risks of reactions infusion to any biological product should be
expected, and these products are not exceptions. However, there
appear to be no mechanism-specific reactions to the products,
and they are all well tolerated. The three products are manufactured
using differing methods, and thus they differ in the amounts and
types of impurities and in the amount of inactivation of the AAT
that has occurred during the manufacturing process. All three
products are dosed based upon their content of active AAT, which
minimizes the clinical importance of differences in the relative
activity of the AAT that they contain. All three manufacturers
use diligence to detect and eliminate donors with infectious diseases
from the plasma pools, and all three manufacturers take pains
to eliminate and/or inactivate viral and other pathogens. There
has been no documented transmission of infection with these products.
All
three products have been approved for once-weekly intravenous
infusion of 60 mg of active product per kilogram of body weight.
A once-monthly infusion of larger amounts has also been shown
to be safe, but to be associated with AAT levels less than the
goal levels in the fourth week (52). A more prolonged monthly
infusion regimen might be more convenient than a more brief weekly
regimen, and may offer some cost savings for disposable IV supplies.
This convenience must be balanced against the suboptimal circulating
AAT levels in the week prior to the succeeding dose. Other dosing
schedules have been used in clinical practice; however, weekly
administration is the only schedule that has been approved by
the FDA. Full prescribing information can be found in the package
inserts for the products.
The
three products differ in their mechanisms for distribution to
patients, and some patients and their health care practitioners
may prefer one distribution model over another.
The augmentation products can be administered in a physician's
office or in a facility where intravenous infusions are routinely
given for other indications. However, home administration is the
option chosen by the majority of patients.
Augmentation is usually not recommended for individuals with normal
lung function. It should be reserved for those with phenotypes
Pi Z, Pi Znull, Pi null null, or other phenotypes with equally
severe deficiency. It should not be given to individuals who do
not have AAT deficiency or to individuals with mildly deficient
phenotypes. Further guidelines can be found in a statement by
The American Thoracic Society regarding the approach to individuals
with AAT deficiency (53), and in the ATS/ERS Standards (1).
Augmentation
by inhalation: Several manufacturers of biologicals have shown
interest in providing augmentation of AAT directly into the lung
by the inhaled route. There is some logic to support this route,
and such an approach could allow sparing of these expensive products.
Early, small clinical studies have appeared to show that this
route is safe, and that augmentation by this route may reduce
airway inflammation. Current studies are determining the optimal
device for delivery of protein into the deep lung, which may be
a particular challenge in individuals with airways disease. Normally,
the airway epithelial barrier to protein movement is quite tight,
so delivery into the interstitial space of the lung may be challenging
by this route. The future of augmentation by inhalation awaits
the completion of randomized, controlled clinical trials.
Lung
transplantation: Lung transplantation is increasingly becoming
a viable option for patients with advanced disease. Lung volume
reduction surgery may be beneficial for highly selected individuals.
Liver
transplantation: Successful liver transplantation can obviously
be lifesaving. This may be an option for carefully-selected individuals
with end-stage liver disease.
Future
prospects: AAT delivered by inhalation, genetically engineered
AAT, and other inhibitors of leukocyte elastase are in early stages
of clinical trials. Even under the most optimistic timetable,
these alternatives will not be available for a number of years.
Some animal experiments have begun to demonstrate the feasibility
of gene therapy and gene repair, and preliminary human studies
of gene therapy have begun. Obviously, the latter therapies must
be shown to be absolutely safe before they could be recommended
for this condition.
References
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