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(Chest. 2000;118:867-871.)
© 2000 American College of Chest Physicians

Normal Diffusing Capacity in Patients With PiZ {alpha}1-Antitrypsin Deficiency, Severe Airflow Obstruction, and Significant Radiographic Emphysema*

Jeffrey S. Wilson, MD and Jeffrey R. Galvin, MD, FCCP

* From the Departments of Internal Medicine and Radiology, University of Iowa, Iowa City, IA.

Correspondence to: Jeff Wilson, MD, University of Iowa, Department of Internal Medicine, C33 GH, 200 Hawkins Dr, Iowa City, IA 52242-1081; e-mail: jeff-wilson{at}uiowa.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
{alpha}1-Antitrypsin deficiency is usually suspected clinically in young adults with irreversible airflow obstruction that is out of proportion to their smoking history. Many patients with {alpha}1-antitrypsin deficiency receive an initial diagnosis of asthma or chronic bronchitis. Measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) has been recommended as a way to help distinguish emphysema from asthma and chronic bronchitis. In this article, we describe four patients with severe {alpha}1-antitrypsin deficiency, each of whom had a repeatedly normal DLCO despite having a significant component of fixed airway obstruction and prominent panacinar emphysema on high-resolution CT scan (HRCT). Each patient also demonstrated significant bronchodilator responsiveness, and two patients received an initial diagnosis of asthma. Potential explanations for these findings are discussed. We report these findings to illustrate the limitations of DLCO in this setting. {alpha}1-Antitrypsin deficiency should be considered in patients with fixed airway obstruction that is out of proportion to their age and smoking history, regardless of their diffusing capacity and response to bronchodilators.

Key Words: {alpha}1-antitrypsin deficiency • chronic obstructive lung disease • CT • diffusing capacity • emphysema


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Severe {alpha}1-antitrypsin ({alpha}1-AT) deficiency may result in the development of premature emphysema. It is usually suspected clinically in young adults with irreversible airflow obstruction that is out of proportion to their smoking history.1 2 3 Early diagnosis is important to prevent disease progression, through implementation of smoking cessation.4 5 The data supporting the efficacy of {alpha}1-AT augmentation therapy6 7 make early identification of this disease even more important.

Wheezing is common in people with {alpha}1-AT deficiency. Because emphysema is uncommon in young adults, {alpha}1-AT deficiency may initially be diagnosed as asthma or chronic bronchitis.8 9 10 Measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) is recommended as a way to help distinguish emphysema from asthma and chronic bronchitis.11 12 DLCO appears to be the best single physiologic measurement of emphysema severity, but it is relatively insensitive in the presence of mild emphysema.13 14 15 The grading of emphysema by high-resolution CT (HRCT) has shown good correlation with pathology scoring, but may also underestimate early emphysema.16 17 18 19

We recently evaluated four patients with severe {alpha}1-AT deficiency (PiZ), who all had a component of fixed airway obstruction (three severe) and normal DLCO. HRCT showed each patient had significant panacinar emphysema. Two of these patients had initially received a diagnosis of asthma, based on significant improvement in airflow obstruction following bronchodilator therapy. We report these findings to emphasize that {alpha}1-AT deficiency can present like asthma and that overreliance on DLCO to exclude emphysema can delay the diagnosis of {alpha}1-AT deficiency.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All four patients were seen at the University of Iowa and were part of approximately 40 patients with PiZ {alpha}1-AT followed in the Pulmonary Clinic. Each patient was clinically stable when they were evaluated. None had evidence of congestive heart failure, hyperthyroidism, or pulmonary hemorrhage. Serum {alpha}1-AT levels and Pi phenotyping (isoelectric focusing) were performed on at least two occasions. Pulmonary function tests were performed on Medical Graphics systems 1070 and 1085 (Medical Graphics; St. Paul, MN) according to American Thoracic Society standards. DLCO was determined by the single-breath technique, analyzed by gas chromatography, using predicted values from Miller et al.20 Each patient had two or more separate measurements of DLCO. In addition, DLCO was remeasured in two patients using the SensorMedics System 6200 (SensorMedics; Yorba Linda, CA) and predicted values from Crapo and Morris.21 Arterial blood gases were run on an ABL 520 radiometer (Radiometer International; Ehsan, Malaysia). HRCT chest scans were performed onan Imitron C-150 scanner (Imitron; South San Francisco, CA) during breath holding after deep inspiration; 1.5- or 3.0-mm collimation scans were performed every 2 cm from the lung apices to the bases. Lung windows are + 2,000, level-500.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
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We saw all patients between November 1991 and August 1994 (Table 1 ). They ranged in age from 33 to 44 years. Two were women, two were men, and all were white. Each patient was over his or her ideal body weight. At their initial visit, two patients were ex-smokers. One was smoking 1 to 2 cigarettes per day, and the other patient smoked 10 to 20 cigarettes per day. All four patients presented with dyspnea and wheezing; none had clinical evidence of liver disease. Each patient was phenotype PiZ, with serum {alpha}1-AT levels ranging from 24 to 38 mg/dL. One patient was receiving {alpha}1-AT augmentation therapy, and the other three patients were subsequently started.


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  		Table 1. Clinical Characteristics*

 
Pulmonary function tests revealed severe airflow obstruction in three patients and mild airflow obstruction in the other patient (Table 2 ). All patients demonstrated significant (American Thoracic Society criteria) improvement in airflow following bronchodilator treatment on one or more clinical visits. DLCO (measured on at least three separate occasions) was normal in each patient (Table 3 ).


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  		Table 2. Spirometry and Blood Gas Results

 

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  		Table 3. Serial DLCO, mL/min/mm Hg*

 
HRCT scans revealed panacinar emphysema in each patient (Fig 1 ,2 ). This appeared as hyperlucency, most prominent in the lung bases. Routine chest radiographs in three of the four patients were interpreted as having no clear evidence of obstructive lung disease (Fig 3 ). There was no evidence of bronchiectasis. We did not quantify the degree of panacinar emphysema. Qualitatively, it was judged to be moderate to severe.



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  		Figure 1. Patient 1, upper lung zone (top) and lower lung zone (bottom).

 


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  		Figure 2. Patient 3, upper lung zone (top) and lower lung zone (bottom).

 


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  		Figure 3. Patient 4, posteroanterior chest radiograph (top) and lateral chest radiograph (bottom).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The early identification of patients with {alpha}1-AT deficiency appears valuable in reducing the morbidity and mortality associated with this disease, through avoidance of smoking.4 5 Data supporting the efficacy of {alpha}1-AT augmentation therapy makes diagnosis even more important. It has been estimated that < 10% of {alpha}1-AT-deficient patients have been identified.22 There are several reasons for this. Many patients may have received a diagnosis of asthma and never had {alpha}1-AT levels measured. Wheezing and increased bronchial reactivity are common in patients with {alpha}1-AT deficiency. As reported by Silverman et al,8 59% of PiZ patients with an FEV1 < 65% had a history of wheezing, and 25% had received a diagnosis of asthma. Brantly et al9 reported that 20% of 120 PiZ patients had reactive airways disease, defined as wheezing and/or a significant FEV1 response to bronchodilators. Whether this represents the presence of two separate diseases, a relation to smoking, or a predisposition of {alpha}1-AT-deficient patients to develop asthma is unknown. In addition, chronic severe asthmatics can develop a component of fixed airway obstruction also, making it difficult to separate asthma from emphysema.23

DLCO has been recommended as a way to help distinguish asthma from emphysema. DLCO has the highest correlation with pathology grading of emphysema of any routinely performed lung function test.13 It is relatively insensitive, however, to mild emphysema. The relationship between DLCO and pathology grade of emphysema has been demonstrated in unselected populations of patients with chronic obstructive lung disease and may not hold true for patients with emphysema secondary to {alpha}1-AT deficiency.

In 1989, Lieberman and Littner10 reported a PiZ patient similar to ours, with asthmatic symptoms, a component of fixed airway obstruction, and a normal DLCO. A chest CT scan revealed blebs, and the static lung compliance was elevated, suggesting early emphysema. Guest and Hansell24 reported the results of HRCT in 17 patents with severe {alpha}1-antitrypsin deficiency. In this series is one patient with severe airflow obstruction, normal DLCO, and an estimated 70% of the lung involved with emphysema on HRCT. These reports, and the four patients reported here, demonstrate that significant emphysema may exist in the presence of a normal DLCO. There are several potential explanations for this. Asthma and obesity have both been reported to cause an elevated DLCO.25 26 Two of our patients had a history of wheezing, and all four had significant improvement in airflow following treatment with bronchodilators. In addition, all four patients were overweight, two severely. These two factors may have offset the negative effect of emphysema on DLCO. None of our patients had any of the other conditions known to elevate DLCO. Determination of DLCO was believed to be accurate, based on a series of internal normal controls, the reproducibility of serial measurements in our patients, and similar results on two separate systems.

Another possible explanation for these findings is the lower-lobe predominance of the panacinar emphysema associated with {alpha}1-AT deficiency. The diffusing capacity may be relatively insensitive to the loss of surface area for gas exchange, as long as ventilation and perfusion in the lung remain well matched. This matching may persist in panacinar emphysema in selected patients.

In summary, some patients with {alpha}1-AT deficiency present with a normal DLCO despite severe fixed airway obstruction and radiographic emphysema on HRCT scanning. We feel that {alpha}1-AT deficiency should be considered in patients with fixed airway obstruction that is out of proportion to their age and smoking history, regardless of their diffusing capacity and response to bronchodilators. Additionally, the World Health Organization now recommends that all patients with COPD, and adults and adolescents with asthma, be tested once for {alpha}1-AT deficiency.27


   Footnotes
 
Abbreviations: {alpha}1-AT = {alpha}1-antitrypsin; DLCO = diffusing capacity of the lung for carbon monoxide; HRCT = high-resolution CT

Received for publication June 26, 1997. Accepted for publication March 13, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Idell, S, Cohen, AB (1983) {alpha}1-antitrypsin deficiency. Clin Chest Med 4,359-375[ISI][Medline]
  2. Janus, ED, Phillips, NT, Carrell, RW (1985) Smoking, lung function, and {alpha}1-antitrypsin deficiency. Lancet 1,152-154[ISI][Medline]
  3. Larson, C (1978) Natural history and life expectancy in severe {alpha}1-antitrypsin deficiency, PiZ. Acta Med Scand 204,345-351[ISI][Medline]
  4. Wall, M, Moe, E, Eisenberg, J, et al (1990) Long-term follow-up of a cohort of children with {alpha}l-antitrypsin deficiency. J Pediatr 116,248-251[CrossRef][ISI][Medline]
  5. Seersholm, N, Kok-Jensen, A (1995) Survival in relation to lung function and smoking cessation in patients with severe hereditary {alpha}1-antitrypsin deficiency. Am J Respir Crit Care Med 151,369-373[Abstract]
  6. . The {alpha}1-Antitrypsin Deficiency Registry Study Group (1998) Survival and FEV1 decline in individuals with severe deficiency of {alpha}1-antitrypsin. Am J Respir Crit Care Med 158,49-59[Abstract/Free Full Text]
  7. Seersholm, N, Wencker, M, Banik, K, et al (1997) Does {alpha}1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary {alpha}1-antitrypsin deficiency? Eur Respir J 10,2260-2263[Abstract]
  8. Silverman, EK, Pierce, JA, Province, MA, et al (1989) Variability of pulmonary function in {alpha}1-antitrypsin deficiency: clinical correlates. Ann Intern Med 111,982-991
  9. Brantly, ML, Paul, LD, Miller, BH, et al (1988) Clinical features and history of the destructive lung disease associated with {alpha}1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 138,327-336[ISI][Medline]
  10. Lieberman, J, Littner, M (1989) Emphysema vs. asthma with anti-trypsin deficiency. Chest 96,1217-1218[Free Full Text]
  11. Petty, TL (1990) Definitions in chronic obstructive pulmonary disease. Clin Chest Med 11,363-373
  12. Hoppin, F, Jr (1991) Pulmonary function tests for diagnosis and evaluation of COPD. Cherniack, NS eds. Chronic obstructive pulmonary disease ,363-373 WB Saunders Philadelphia, PA.
  13. Morrison, NJ, Abboud, RT, Ramadan, F, et al (1989) Comparison of single breath carbon monoxide diffusing capacity and pressure-volume curves in detecting emphysema. Am Rev Respir Dis 139,1179-1187[ISI][Medline]
  14. West, WW, Nagai, A, Hodgkin, JE, et al (1987) The National Institutes of Health intermittent positive pressure breathing trial-pathology studies: the diagnosis of emphysema. Am Rev Respir Dis 135,123-129[ISI][Medline]
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  17. Miller, RR, Muller, NL, Vedal, S, et al (1989) Limitations of computed tomography in the assessment of emphysema. Am Rev Respir Dis 139,980-983[ISI][Medline]
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