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Bronchiectasis in patients with alpha 1-antitrypsin deficiency. A rare occurrence?

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Myung S Shin at Yale University
Myung S Shin
Kang-Jey Ho
Kang-Jey Ho
Kang-Jey Ho
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Abstract

The chest radiographs and computed tomographic (CT) scans of seven patients with homozygous proteinase inhibitor phenotype Z (PiZZ) alpha 1-antitrypsin deficiency were reviewed. All patients except one showed severe emphysema with or without bullous change. Bronchiectasis was detected in three patients by CT but only in two patients by chest radiography. A young patient developed bronchiectasis before symptomatic emphysema. We stress that patients with PiZZ are susceptible to bronchiectasis, and the widespread use of CT should reveal its true incidence which might not be as low as generally believed.
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1993;104;1384-1386Chest
M S Shin and K J Ho
deficiency. A rare occurrence?
Bronchiectasis in patients with alpha 1-antitrypsin
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1384 Bronchiectasis ki Patients with Alpha-1-Antftrypsin Deficiency (Shin, Ho)
Bronchiectasis in Patients With
a1-Antitrypsin Deficiency*
A Rare Occurrence?
Myung S. Shin, M.D., EC.C.P; and Kang-Jey Ho, M.D., Ph.D.
The chest radiographs and computed tomographic (CT)
scans of seven patients with homozygous proteinase inhibi-
tor phenotype Z (PIZZ) a,-antitrypsin deficiency were
reviewed. All patients except one showed severe emphy-
sema with or without bullous change. Bronchiectasis was
detected in three patients by CT but only in two patients
by chest radiography. A young patient developed bronchi-
ectasis before symptomatic emphysema. We stress that
patients with Pill are susceptible to bronchiectasis, and
the widespread use of CT should reveal its true incidence
which might not be as low as generaUy believed.
(Chest 1993; 104:1384-86)
IPillproteinase inhibitor phenotype Z
I generally believed that patients with a1-antitryp-
sin deficiency suffer from pulmonary emphysema
but rarely from bronchiectasis.’ Indeed, most individ-
uals who are homozygous proteinase inhibitor pheno-
type Z (PiZZ) develop severe panlobular emphysema,
predominately at the lung bases, in the third and
fourth decades oflife.”2 The cardinal clinical symptom
is progressive dyspnea with minimal cough. Some
individuals, particularly those who smoke, also de-
velop chronic bronchitis. AIpha1-antitrypsin defi-
ciency, however, is considered to be a rare cause of
ta’ During the past 5years, we have
encountered seven patients with PiZZ phenotype. All
of them complained of progressive dyspnea. Four of
them also suffered from chronic cough with sputum
#{149}Fmmthe Departments of Radiology (Dr. Shin) and Pathology (Dr.
Ho), University ofAlabama School of Medicine, Birmingham.
Manuscript received January 12, 1993; revision accepted March
23.
Reprint roquests: Dt Shin, Department of Radiology, University
Hospital, Birmingham, Alabama 35233
production. Bronchiectasis was detected in three
patients. We would like, therefore, to stress that
patients with PiZZ are also subject to development of
bronchiectasis. Its incidence is not as low as commonly
thought due to the use of improved roentgenographic
technology such as CI for its detection and better
health care for prolongation of life. Since six of the
seven patients were on the waiting list for lung
transplantation, the detection and localization of bron-
chiectasis are important for pretransplant evaluation,
especially in making the decision as to which lung to
replace.
Patients
METHODS
The clinical symptoms and chest radiographic findings of seven
patients with a,-antitrypsin deficiency were summarized in Table
1. The patients were examined at the University of Alabama
Hospital, Birmingham, during the last 5 years. The patients, four
women and three men, were all adults ranging in age from 21 to 56
years. The initial diagnosis of a1-antitrypsin deficiency was made
by measurement of its concentration in serum by either electro-
Table 1-Clinical and Chest Radiographk Findings in Seven lbtients with a,-Antitrypsin Deficiency (PiZZ)
Subject Age/Sex Symptoms
Radiographic Findings
(Chest Radiography and CT)
1 38/M Progressive dyspnea since age 28
Minimal cough
Diffuse emphysema, more severe in lower lobes
2 40fF Progressive dyspnea since age 20
Minimal cough
Severe emphysema, particularly in both lower lobes
347/M Onset ofdyspnea at age 30
Improved after quitting smoking
Recurrence of dyspnea at age 40
Occasional coughs with white-yellow sputum
Mild emphysema, pleural adhesions, and old rib
fracture
4 55/M Progressive dyspnea for many years
Repeated bronchitis with yellow sputum
Hyperinflation with bullous changes, area of fibrosis
(healed pneumonia)
552/F Progressive dyspnea since young age
Chronic cough productive ofcopious purulent sputum
Marked hyperinfiation with bullous changes, more in
lung base, saccular bronchiectasis, lower lobes
621fF Adenoviral pneumonia at age 1’/2
Haeinophilis influenzae pneumonia at age 12,
progressive dypsnea, recent years
Severe emphysema with bullous changes, more marked
in the left, bilateral bronchiectasis, right side by CT
only
7 56fF Progressive dyspnea for many years
Chronic cough with yellow sputum
Repeated pneumonia
Hyperinflation, more severe in lower lobes,
bronchiectasis, lower lobes, by CT only
© 1993 American College of Chest Physicians
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FIGURE 1.Thoracic CT of case 5 revealing bilateral cystic bronchi-
ectasis. FIGURE 3. Thoracic CT ofcase 6 showing mild cylindrical bronchi-
ectasis in the left lower lung which is not detected on chest
radiograph.
Both conventional radiography and CT showed
CHEST I104 I5INOVEMBER, 1993 1385
phoresis or nephelometry. The serum a,-antitrypsin levels of these
seven patients were less than 10 to 15 percent of the normal and
often near zero. The establishment of diagnosis was followed by
phenotyping by isoelectric focusing’ which indicated PiZZ pheno-
type in all patients. Progressive dyspnea was the predominant
symptom in all patients. Three patients (cases 1, 2, and 6) had
minimal cough, while the remaining four patients suffered also from
chronic bronchitis as defined by cough with expectoration for at
least 3 months of the year for more than two consecutive years.
These four patients with chronic bronchitis all had a history of
tobacco smoking. Case 6 contracted adenoviral pneumonia at age
1#{189}years, Haemophilus influenzae pneumonia at age 12, and
developed progressive dyspnea only in recent years. Cystic fibrosis
was ruled out in this young patient by negative sweat test. None of
the seven subjects had evidence of immunoglobulin deficiency.
Each patient had a number of conventional chest radiographic
studies. The CT scans were performed with a scanner (GE 9800,
Philips TX6O, or Picker 1200) at continuous 10-mm thickness with
a5-s scan time. Additional high-resolution scans were obtained
with 1.5-mm collimation and high-spatial-frequency reconstruction
algorithm at selected levels (aortic arch, carina, and diaphragm) in
three patients.
RESULTS
FIGURE 2. Thoracic CT of case 6 at a level below carina showing
cystic bronchiectasis in the right lung.
hyperinflation of the lung in all seven patients. Such
emphysematous changes were severe, especially in
the lower lobes, in all patients except case 3 who
showed only mild emphysema. Bullous change was
also noted in cases 5and 6. In addition, chest
radiography in case 5 showed bilateral cystic or
saccular bronchiectasis which was confirmed by CT
(Fig 1). In case 6, the chest radiograph also showed
cystic bronchiectasis in the left lung which was also
confirmed by CT (Fig 2). The milder cylindrical
bronchiectasis in the right middle and lower lobes was
demonstrated on CT (Fig 3) but not on the conven-
tional radiograph. In case 7, bronchiectasis was also
demonstrated only on CT but not on chest radiographs.
DISCUSSION
Alpha1-antitrypsin is a 52-kilodalton glycoprotein
with 12 percent carbohydrate, synthesized and se-
creted by the hepatocytes, has a high plasma concen-
tration, very broad range of antiprotease (or antielas-
tase) activity, and is an acute phase reactant.5 The a-
antitrypsin gene has been mapped to the distal portion
of the long arm of chromosome 14.6 The two a-
antitrypsin genes are codominantly expressed and
together define the a1-antitrypsin level in serum.
Most common a1-antitrypsin alleles are classified as
M-type. There are more than 75 known pleomorphic
alleles of which at least 20 can cause a clinically
relevant deficiency state.”6’7 The most common and
serious “deficiency” mutation is Z as the result of point
mutation by replacement of Glu-342 in exon V by
Lys.8 Such substitution of homozygous PiZZ patients
leads to aggregation of a1-antitrypsin in the rough
endoplasmic reticulum and impairment ofits secretion
into the circulation.
Not every person with a homozygous PiZZ state
develops symptomatic pulmonary emphysema. A re-
view by Morse9 indicated that about 70 to 80 percent
© 1993 American College of Chest Physicians
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1386 Bronchiectasis in Patients with Alpha-1-Antitrypsin Deficiency (Shin, Ho)
of subjects with PiZZ would develop symptomatic
emphysema. However, with the wide availability of
detection technique, a strong suspicion now exists that
the number of patients with asymptomatic a1-anti-
trypsin deficiency is greater than those who develop
symptomatic emphysema. Neutrophils are the major
source of elastase in the lung which damages intersti-
tial elastic fibers leading to emphysematous changes.
Any cause such as infection which recruits neutrophils
to the lung will upset the elastase-antielastase balance,
particularly in patients with a1-antitrypsin defi-
10 All our patients were susceptible to the
development of emphysema at an early age because
of a1-antitrypsin deficiency. Cigarette smoking is an-
other risk factor since the cigarette smoke is rich in
oxidants which can inactivate a1antitrypsin.l0H Four
ofour seven patients (Nos. 3, 4, 5, and 7) had histories
of tobacco smoking.
In addition to symptomatic emphysema, the four
patients who smoked also suffered from chronic bron-
chitis. Typically, they had bouts ofcough with copious
purulent sputum. Such chronic inflammation (infec-
tion) and bronchial obstruction are most frequent
conditions associated with bronchiectasis. Chronic
inflammation weakens the bronchial wall, and obstruc-
tion leads to the bronchial dilation. This is due to the
resorption of the entrapped air from the airway distal
to the obstruction, resulting in atelectasis. With ate-
lectasis, the elastic forces within the lobe disappear
and airways “relax” and dilate. Therefore, subjects
with PiZZ may have normal lung, pulmonary emphy-
sema alone (cases 1 and 2), emphysema with chronic
bronchitis (cases 3 and 4), and emphysema, chronic
bronchitis, and bronchiectasis (cases 5 and 7). It is,
therefore, speculated that the severity of lung disease
in patients with a1-antitrypsin deficiency progresses
from pulmonary emphysema to chronic bronchitis to
bronchiectases. However, this may not always be true.
The 21-year-old female patient (case 6) developed
cystic and cylindrical bronchiectasis early in her life
as the consequence of repeated pulmonary infection
which was followed by emphysematous changes. Three
similar cases have been previously reported.’2 It is
conceivable that patients with PiZZ are more suscep-
tible to bronchiectasis especially when exposed to
repeated pulmonary infection, even before the devel-
opment of emphysema. Adenovirus pneumonia at an
early age seems to be particularly important since
adenovirus has previously been described as a known
etiologic agent in severe tas’3
Bronchiectasis was not seen on chest radiographs
in case 7nor in the right lung in case 6. Computed
tomography is much more sensitive in detection of
bronchiectasis, and it also demonstrates the severity
and exact location of bronchiectasis. We predict that
the wide use of CT should detect more cases of
bronchiectasis in patients with PiZZ.
Most of our patients were admitted for evaluation
of possible lung transplantation. The detailed exami-
nation of pulmonary structure, including the ens-
tence, severity, and location of bronchiectasis, is very
important. The information can be used for setting
criteria for transplantation and also for determining
which lung to replace in the case of unilateral lung
transplantation.
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1993;104; 1384-1386Chest
M S Shin and K J Ho
occurrence?
Bronchiectasis in patients with alpha 1-antitrypsin deficiency. A rare
July 14, 2011This information is current as of
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Article
  • Aug 1981
Twenty-seven children aged 0.6 to 7.0 (mean 2.1) years were admitted to the hospital in 1967 and 1968 with type 7 adenoviral pneumonia. All ran a prolonged course. Type 7 adenovirus was isolated from 14 children, and in the other 13, the rise in the titer of complement-fixing antibodies to adenovirus was fourfold or greater. The outcome of the disease in these 27 children was reassessed in 1979, 9.6 to 12.1 (mean 10.7) years after the adenovirus type 7 pneumonia. Twenty-two were examined clinically and roentgenographically and all had lung function tests. Twelve had abnormal chest roentgenograms, and of these, six had bronchiectasis. Six of the ten children with normal chest x-ray films and ten of the 12 with abnormal chest roentgenograms had abnormal pulmonary function tests. Of the six patients with bronchiectasis, four showed no discernible cause of bronchiectasis other than the antecedent type 7 adenoviral infection. The other two patients had bronchial asthma, which can be a risk factor for bronchiectasis.
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An Overview of the Pulmonary Features of a1-Antitrypsin Deficiency
Article
  • Jul 1982
  • ARCH INTERN MED
• Extensive research, stimulated by the recognition of an association between α1-antitrypsin (α1-AT) deficiency and emphysema, has greatly advanced our understanding of emphysema in general. In this article, we review the literature concerning the basic defect, inheritance, pathogenesis of lung disease, clinical, physiologic, and roentgenographic findings in patients with severe (Pi Z) and intermediate (Pi SZ) deficiency of α1-AT. Data obtained in relatives with α1-AT deficiency, who have not been seen by a physician, should more truly reflect the risk of having lung disease. These studies confirm the increased risk of developing lung disease in cigarette smokers. The implications of the finding that subjects with Pi SZ are probably not at an increased risk of lung disease is discussed with regards to replacement therapy. The natural history of unselected subjects with α1-AT deficiency remains unknown. (Arch Intern Med 1982;142:1342-1348)
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Alpha1-antitrypsin deficiency (second of two parts)
Article
  • Dec 1978
This article has no abstract; the first 100 words appear below. Relation of the Defect to Pulmonary Disease It is clear that severely deficient subjects of phenotype PiZ and probably PiSZ are much more susceptible to the development of emphysema or chronic bronchitis (or both) than the general population, the large majority of whom are of phenotype PiM.⁵⁷,⁵⁸ The continuing question has been whether those with lesser degrees of deficiency, mainly PiMZ or PiMS, are at any greater risk for the development of such obstructive lung diseases than those of phenotype PiM. Initially, the problem was attacked by measurement of alpha1-antitrypsin levels in groups of patients with pulmonary diseases, but the . . . Supported in part by a grant (HL 14136) from the National Heart, Lung, and Blood Institute Specialized Center of Research, Tucson, AZ. Source Information From the Veterans Administration Hospital, Muskogee, of, and the Department of Medicine, University of Oklahoma, Tulsa College of Medicine (address reprint requests to Dr. Morse at the Veterans Administration Hospital, Muskogee, of 74401).
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Alpha-antitrypsin deficiency. (First of two parts)
Article
  • Dec 1978
Alpha, antitrypsin received its name from its identification as an alpha1 globulin and from the original method used for measuring its activity. Since alpha1 antitrypsin is actually capable of interfering with the action of a variety of proteolytic enzymes, alpha1 protease inhibitor may become the preferred label. Enzymes shown to be affected include trypsin, chymotrypsin, pancreatic elastase, skin collagenase, renin, urokinase. Hageman-factor cofactor and the neutral proteases of polymorphonuclear leukocytes. These enzymes include an elastase, a collagenase, and a nonspecific protease capable of digesting vascular basement membranes. Alpha1 antitrypsin can also inhibit the acid protease present in alveolar macrophages. Inhibition of kallikrein is negligible. The principal serum inhibitors of plasmin and thrombin are probably distinct from alpha1 antitrypsin. The serine proteases that are inhibited by alpha1 antitrypsin and whose mechanism of action has been thoroughly studied appear to cleave peptides by attaching the active catalytic site of the enzyme to one of two particular locations in the amino acid chain of the peptide. They probably combine with the alpha1-antitrypsin molecule in the same fashion. Since chemical modification of the lysine residues of the molecule renders it incapable of inhibiting trypsin and chymotrypsin, whereas other modifications affecting other amino acids leave its function intact, the lysyl bond is believed to be the reactive inhibitor site, at least for these two proteases. With an excess of elastase the alpha1-antitrysin molecule itself may be cleaved and inactivated; however, the peptide fragment remaining with the elastase molecule appears to inactivate it as well. Alpha1 antitrypsin can be found in a number of body fluids such as tears, lymph, saliva, colostrum, mother's milk, duodenal fluid, gallbladder bile, synovial fluid, cervical mucus, semen and amniotic fluid. It is also found on platelets and in megakaryocytes. In the serum exogenous alpha1 antitrypsin has a half-life of only about a week, most of the loss being by catabolization in the liver. Although the alpha1 antitrypsin isolated from deficient patients can be distinguished electrophoretically from that of normal persons, immunologically and functionally (i.e., as an inhibitor of trypsin or elastase in vitro) it is identical. This glycoprotein, with a molecular weight of about 54,000, consists of a single polypeptide chain with four carbohydrate side chains of two different types. That from severely deficient persons has less N-acetyl-glucosamine, mannose, galactose and sialic acid (N-acetyl-neuraminic acid) than that from normal persons.
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The molecular genetics of ?1 antitrypsin deficiency
Article
  • Apr 1991
The human serum protein alpha 1-antitrypsin is the major source of antiprotease activity found in the blood. The protein is synthesised primarily by liver cells but, to a lesser extent, by at least one other cell type. Expression of the gene has provided a paradigm for studies on transcriptional regulation in liver and of tissue-specific promoter activity. The pleiomorphic nature of the gene has given rise to a variety of alpha 1-antitrypsin variants some of which are clinically important. These abnormal variants may be poorly synthesised, rapidly degraded or inefficiently secreted; studies on the molecular mechanisms which underly these events are providing interesting insights into the general processes of protein transport and intracellular protein degradation.
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Oxidants, antioxidants and the pathogenesis of emphysema
Article
  • Feb 1985
  • Eur J Respir Dis Suppl
Emphysema is a chronic pulmonary disorder characterized by a permanent enlargement of the air spaces distal to the terminal bronchioles consequent to destruction of the alveolar walls, including the epithelial and endothelial cells and the connective tissue matrix. There is increasing evidence that an imbalance of oxidants and antioxidants in the lower respiratory tract contributes to this process. Oxidants such as O2-., H2O2, OH, OCl- are generated in the lower respiratory tract as a result of normal biochemical processes, activation of inflammatory cells and inhaled toxic gases. Under normal circumstances, the parenchymal cells are protected by intracellular antioxidants and membrane radical scavengers. In addition, the fluid lining the epithelial surface contains a catalase-like antioxidant that protects the epithelial cells from oxidants. If the oxidant burden overcomes these defenses, the parenchymal cells may be injured, the connective tissue matrix may be partially degraded, the antiprotease screen that protects the lower respiratory tract from attack by neutrophil elastase may be rendered impotent. The alveolar wall then becomes highly vulnerable to elastolytic attack, with a complete destruction of the interstitial connective tissue matrix. In this regard, it is reasonable to hypothesize that reestablishment of the oxidant-antioxidant balance in favor of the antioxidants would be useful as a therapeutic strategy to suppress the emphysematous process.
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Alpha-1-antitrypsin deficiency presenting as bronchiectasis
Article
  • Aug 1985
  • Br J Dis Chest
We describe three patients with the clinical and radiographic features of progressive bronchiectasis, and without evidence of emphysema, associated with deficiency of alpha-1-antitrypsin. The association of hereditary alpha-1-antitrypsin deficiency and pulmonary emphysema is well recognized (Eriksson 1965). About half of these subjects also have chronic bronchitis as defined by persistent sputum production (Tobin et al. 1983). Bronchographically proven bronchiectasis without apparent emphysema has been reported in only one subject with alpha-1-antitrypsin deficiency (Longstretch et al. 1975).
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The role of α1-antitrypsin deficiency in the pathogenesis of immune disorders
Article
  • Jul 1985
The association between alpha 1-antitrypsin (alpha 1-AT) deficiency and a number of immune mediated diseases including rheumatoid arthritis, anterior uveitis, systemic lupus erythematosus, and asthma suggests that alpha 1-AT may be important not only as an anti-inflammatory protein but also as an immune regulator. That the relationship between decreased amounts of this inhibitor and these diseases is causal is suggested by both some of its physical properties and evidence indicating it is able to modulate immune function. alpha 1-Antitrypsin has a high plasma concentration, very broad range of inhibitory activity and is an acute phase reactant. Among other things, it is able to modulate lymphocyte proliferation and cytotoxicity, and monocyte and neutrophil function. Additionally, some of these changes are demonstrable in vivo in patients with severe alpha 1-antitrypsin deficiency. This paper reviews the important physicochemical characteristics of this protein, the association of its presence in decreased amounts with immune disorders, and finally the important mechanism that may underlie this disease association.
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Chronic lung damage caused by adenovirus type 7: A ten-year follow-up study
Article
  • Sep 1981
Twenty-seven children aged 0.6 to 7.0 (mean 2.1) years were admitted to the hospital in 1967 and 1968 with type 7 adenoviral pneumonia. All ran a prolonged course. Type 7 adenovirus was isolated from 14 children, and in the other 13, the rise in the titer of complement-fixing antibodies to adenovirus was fourfold or greater. The outcome of the disease in these 27 children was reassessed in 1979, 9.6 to 12.1 (mean 10.7) years after the adenovirus type 7 pneumonia. Twenty-two were examined clinically and roentgenographically and all had lung function tests. Twelve had abnormal chest roentgenograms, and of these, six had bronchiectasis. Six of the ten children with normal chest x-ray films and ten of the 12 with abnormal chest roentgenograms had abnormal pulmonary function tests. Of the six patients with bronchiectasis, four showed no discernible cause of bronchiectasis other than the antecedent type 7 adenoviral infection. The other two patients had bronchial asthma, which can be a risk factor for bronchiectasis.
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