++
The molecular consequences of the single nucleotide change that
comprises the PI*Z genotype have now been well delineated.
The substitution of a lysine residue in place of glutamate in the
A sheet of the alpha1-antitrypsin (AAT) molecule disrupts a key
salt bridge. This allows for insertion of the reactive loop of a
neighboring AAT molecule into this beta-sheet structure. A series
of such “loop-sheet” interactions can result in
long Z-polymers, the crystal structure of which have been solved
(eFig. 516.1).
++
The previously described alteration of the secondary structure
in the A sheet of AAT may influence Z-AAT’s function in
two respects. First, the mutation may favor the misfolded conformation
of Z-AAT, resulting in secretion impairment and degradation enhancement
of Z-AAT. Second, the formation of loop-sheet polymers may further
stabilize the misfolded conformation, inhibit secretion, and enhance
accumulation of Z-AAT within hepatocytes.12
++
In general, it is thought that impaired secretion of Z-AAT leads
to serum deficiency, which in turn is primarily responsible for
AAT-deficient lung disease, while excessive retention and accumulation
of Z-AAT within hepatocytes triggers local events in susceptible
individuals that ultimately result in hepatocellular injury, hepatitis,
and clinically evident liver disease.13
++
A significant amount of Z-AAT successfully exits the endoplasmic
reticulum and moves through the secretory pathway to the extracellular
space. However, the Z mutation also renders the protein partially functional.
Specific activity estimates are consistently below 50% (Fig. 516-1). Hundreds of other AAT mutations
have been discovered. These mutations vary with respect to how much
they affect proper trafficking of AAT, proper secretion, and the
antielastase specific activity. One particular mutation, PiS, is
often associated with a variable lung disease phenotype in the compound
heterozygous state (PI*SZ).
++
The majority of patients with alpha1-antitrypsin (AAT) lung disease
present in adulthood. The average age of diagnosis is 52 years old.
By the time of diagnosis, most patients have had pulmonary symptoms
for at least 10 years. Pulmonary symptoms often include many elements
in common with asthma (including bronchodilator responsive airway
obstruction), emphysema, and chronic bronchitis. Patients often
experience exacerbations of cough, tachypnea, and respiratory distress,
which are often triggered by intercurrent illnesses, including viral
respiratory tract infections.22 The radiographic
appearance of the chest is quite variable but typically includes
variable zones of chronic hyperinflation to a more advanced degree
in the lower lobes, along with an increase in the AP diameter of
the chest wall. As noted above, some individuals have coexisting
lung and liver disease at the time of initial diagnosis. One or
the other of these manifestations may have been underappreciated
or undiagnosed prior to the definitive diagnosis of AAT deficiency.
Other extrapulmonary manifestations may be seen in AAT-deficient
patients, including panniculitis, which is a rare but characteristic
finding.
++
The key features for diagnosing AAT deficiency include a total
plasma level less than 11 micromole (approximately 570 micrograms
per mL, or 57 mg/dL) and an isoelectric focusing (IEF)
gel phenotype indicating either the presence of an abnormal migration
pattern or the absence of the normal M band, or both. In recent
years, genotyping technology has simplified and enhanced the ability
to diagnose patients rapidly and accurately in many cases. By convention,
the phenotype as determined by IEF is designated as the Pi type,
with the letters indicating all visible bands. Thus, a Z homozygote
is PiZ, a normal homozygote is PiM, and a heterozygous individual
is PiMZ. The corresponding genotypes would be indicated as PI*ZZ,
PI*MM, and PI*MZ, respectively. The serum levels
of AAT associated with various Pi phenotypes are shown in Figure 516-1. The lung pathology in AAT deficiency
is classically described as panacinar emphysema, which is greater
in the bases of the lung than in the apices. This type of emphysema
includes loss of the entire alveolar septae and an increase in alveolar
diameter. Inflammatory changes, particularly in the airways, are
also typical.
++
Patients with alpha1-antitrypsin (AAT)-deficient lung disease
should be cared for by a pulmonary subspecialist with a multidisciplinary
team in place. Anticipatory guidance should include the avoidance
of tobacco smoke exposure, which can substantially alter the outcome
for these individuals. Other environmental elements such as wood-burning
stoves and occupational exposure to smoke or other noxious inhaled
substances should also be avoided. In addition, AAT-deficient patients
should receive the pneumococcal polysaccharide vaccine and yearly
influenza immunizations. Careful attention to nutrition is also
important in these patients, as is early detection of hypoxemia,
including nocturnal or exercise-related hypoxemia. The appropriate
use of oxygen supplementation in this context is essential (eTable 516.2).
++
++
Several plasma-derived and recombinant AAT protein-replacement
therapies are now approved by the US Food and Drug Administration
for replacement of plasma levels of AAT in deficient patients. Each
of these available products has been designed for weekly IV infusion.
Numerous studies have indicated that these products are very safe
and are effective for restoring plasma levels above the threshold
value of 11 micromole, which is generally accepted as being critical
to avoid progression of lung disease23 (Fig. 516-1). Despite that, it has been difficult
to show convincing evidence of therapeutic effect on the lung disease
symptomatology in prospective, randomized clinical trials of IV
AAT replacement. While the reasons for this are not entirely clear,
the episodic nature of pulmonary symptoms, the variability of pulmonary
function measurements within individual patients, and the very slow
rate of decline in measurements of pulmonary function have made
it difficult to design a study with sufficient statistical power
to demonstrate a difference in PFT variables. Nonetheless, retrospective
registry data have demonstrated a trend toward significant benefits
from AAT replacement, including a substantial decrease in mortality.
++
While there would be a theoretical advantage to localized AAT
replacement by aerosol delivery of the protein replacement, this
modality of therapy remains investigational. The primary, well-established
end point for IV replacement is restoration of plasma levels. This
end point is not as relevant for aerosol protein replacement, since
relatively little of the protein is absorbed. While several inflammatory
markers have been shown to be decreased in bronchoalveolar lavage
fluid samples after aerosol protein replacement, there is not a
clear indication of when sufficient replacement would be achieved.
As with IV replacement, measurement of clinical pulmonary outcomes,
such as PFTs, have not shown consistent benefits.
++
Patients with severe emphysema, including those with AAT deficiency,
may benefit from partial resection of the lung in selected circumstances.
This intervention appears to provide some benefit by reversing the
severe overexpansion of the chest wall with the corresponding mechanical disadvantage for the diaphragm and
other muscles of respiration. Other theoretical benefits have also
been hypothesized, including the stimulation of repair processes
by lung progenitor cells.
++
Patients who progress to respiratory failure due to AAT-deficient
lung disease may be candidates for bilateral lung transplantation.
It is important to note that unlike lung transplant recipients with
cystic fibrosis, these patients remain fully insufficient for AAT
and require continued IV protein replacement.
++
Novel approaches to treatment or prevention of AAT lung disease
include both small molecule pharmaceutics and gene-augmentation
strategies, none of which has yet been proven to be safe and effective.
In the former category are approaches such as the chemical chaperone
strategy mentioned above, which could be therapeutic for lung disease
if it resulted in a net increase in secretion of endogenous AAT
from hepatocytes into the circulation. This class of approaches
also includes several small molecule protease inhibitors, such as
specific inhibitors of neutrophil elastase. In the latter category,
there have been clinical trials of cationic liposome mediated AAT
gene delivery and two different serotypes of recombinant adeno-associated
virus (rAAV) vectors, the latter one of which has not yet been completed.24,25 To
date, plasma levels from these forms of gene augmentation have not
approached the therapeutic threshold of 11 micromole. However, the
favorable safety profile of these vector types, as compared with some
others, make it likely that additional trials with higher doses
and more efficient delivery systems may be undertaken. Other vector
classes, including helper-dependent adenovirus vectors and novel
rAAV serotypes, may also move forward to clinical trials, as their
efficiency of expression appears to be superior to earlier version
vectors, as judged by preclinical proof-of-concept data.