Homozygous Alpha1 Antitrypsin Deficiency with Unusual Associations: A Case Report Roscoe C. Young, Jr., MD, Verle E. Headings, MD, PhD Sikta Bose, PhD, and Robert L. Hackney, Jr., MD Washington, D.C.
The rare association of protease inhibitor deficiency (Pizz genotype) in a black American with chronic, obstructive pulmonary disease due to asthmatic bronchitis, rather than basal pan lobular emphysema, is presented. The late onset of symptoms, despite environmental exposures, is also unusual in this homozygote, as is his ethnic background.
In 1963, Laurell and Erikson in Sweden' associated absence of the alpha, peak in serum protein electrophoresis with chronic obstructive pulmonary disease (emphysema) in families. This glycoprotein, of molecular weight 45 to 60 thousand, inhibits activity of proteases, and has been reported as a variety of inherited allelic variants. Several of these, and notably the Z variant, are accompanied by impairment of protease inhibitor (Pi) activity. Values of serum trypsin inhibitory capacity (STIC) vary above 0.8 mg/ml of serum in the majority of persons who possess the Pi-IM genotype, 0.4-0.8 in heterozygotes for the Z var-
iant (Pji1%), and below 0.4 in the homozygous state (Pizz). Later, Sharp2 at Minnesota established the relationship between absence of the M allele and a juvenile form of liver cirrhosis; and subsequently instances of both emphysema and cirrhosis have been reported in a single patient. It has been established that the Z gene frequency is more common in Nordic ethnic groups than among persons of dark-skinned races.:'-- The present case is unusual because the patient had a ZZ phenotype and asthmatic bronchitis rather than emphysema. The patient is black.
Case Report From the Pulmonary Disease Division, Howard University Hospital and Medical Genetics Unit, College of Medicine, Howard University, Washington, D.C. Requests for reprints should be addressed to Dr. Roscoe C. Young, Jr., Pulmonary Disease Division, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, D.C. 20060.
E.P.A., #039-751, a 47-year-old retired black American US Post Office supervisor, was diagnosed as having "asthma" by his private physician three years prior to the time of this study. He had been hospitalized three
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
times for respiratory difficulty. His first two hospital admissions, between June 1 and 11, 1970, were for cough with streaking of blood, wheezing and dyspnea, even at rest. Diagnostic bronchoscopy, ECG, chest radiographs, bronchograms, and an intravenous lung scan were all normal. A pulmonary function study on June 4, 1970 showed chronic obstructive airways disease. He responded to bronchodilators and was discharged. On his second hospitalization, October 18-30, 1971, he was similarly treated. His third admission was to Freedmen's Hospital, Washington, D.C. on October 20, 1972 in status asthmaticus, having been brought to the hospital by ambulance with a three-day history of grade III dyspnea, wheezing, and cough productive of moderate amounts of watery sputum, which changed in character to purulent. Past history disclosed no exposure to noxious substances. He was an excigarette smoker, having smoked 1 1/2 packs a day for 22 years. He stopped smoking in August 1968. He indicated that his mother had asthma. Examination disclosed systemic hypertension. The patient was afebrile and had a tachycardia. Bilateral wheezes were present in both phases of respiration with diminished breath sounds in the left midlung field. Faint cyanosis of the mucous membranes was also present. Gram stains and cultures of the sputum revealed a bacterial 117
Table 1. Pulmonary Function Studies, Pre and Postbronchodilator* Measurements, units
Postbronchodilator Prebronchodilator Actual Predicted % Predicted Actual Predicted % Predicted
Symbol
FVC Forced Vital Capacity, liters FEV 0.5 0.5 Second Forced Expired Volume, liters % FEV 0.5 % FVC in 0.5 second FEV 1.0 1.0 Second Forced Expired Volume, liters % FEV 1.0 % FVC in 1 second % FEV 3.0 % FVC in 3 seconds FEF 25-75% Forced Mid-Expiratory Flow, liters/min MET Mid-Expiratory Time, seconds VC-T Forced Vital Capacity Time, seconds Mean Flow Between 75% and 85% of FVC, liters/min FEF 75-85% FEF 50% Flow at 50% of FVC, liters/min FEF 75% Flow at 75% of FVC, liters/min PF Peak Expiratory Flow, liters/min MVV Maximum Voluntary Ventilation, liters/min MV Resting Minute Volume, liters/min TV Mean Resting Tidal Volume, liters VC Vital Capacity, liters N2 Nitrogen Delta, % N2 % CV/VC Closing VolumeNital Capacity, % VC Vital Capacity, liters N2 Nitrogen Delta, % N2 % CVNC Closing VolumeNital Capacity, %
exacerbation. He responded to antibiotics, bronchodilators, hydration, and adrenocorticoids. Additional studies during this hospitalization disclosed a sliding hiatal hernia, duodenal ulcer, and nephrolithiasis of the left kidney. Repeat pulmonary function studies on November 30, 1976 confirmed airways obstruction. As part of a National Heart and Lung Institute (NHLI) cooperative study, his serum trypsin inhibitory capacity was 0.18 ml/ml which was only 13 percent of the value of the pooled heterologous control sera." His Pi configuration on crossed antigen-antibody electrophoresis was consistent with a ZZ phenotype and his alpha, peak was absent on starch-gel electrophoresis. In response to a request to study his family members he stated, "I have no control over my family" and refused to cooperate further in that regard. Currently, the patient complains only of stuffiness of the left nostril and states that he has no other respiratory symptoms. "Breathlessness and wheezing occur only when I have a cold or allergy." 118
4.08 1.13 027 1.72 042 069 042 2.77 09.6 015 050 018 240 075 10.9 0.99 3.09 02.5 026 3.08 02.1 019
.75 2.59 055 3.69 078 097 216 0.54
086 044 050 047 054 071 020 401
059
026
530 135
046 056
4.75 01.9 020 4.75 01.9 020
065 135 129 065 119 094
Results of Pulmonary Function Tests Pulmonary function studies on November 30, 1976 (Tables 1 and 2) revealed moderately severe, poorly reversible obstructive airways disease as shown by a decrease in the maximum voluntary ventilation (MVV), abnormalities in percent forced expiratory volume (%FEV),. and increase in the total lung capacity which was caused by increases in the residual volume and functional residual capacity (FRC). Hyperinflation of lung tissue was noted by an increase in the residual volume/total lung capacity (RV/TLC) ratio. Uneven distribution of inspired gas was present as noted by abnormal nitrogen delta test results on two occasions and an abnormally high sevenminute nitrogen washout of about 7.2 percent alveolar nitrogen. There appeared to be hypoxic drive to respiration because the tidal volume breathing room air decreased from 0.99 liters to 0.58 liters. A concomitant decrease in the minute ventilation was present as well. Of most importance
3.26 1.11 034 1.69 052 081 055 1.77 07.5 020 064 026 266 089
4.75 2.59 055 3.69 078 097 216 0.54
069 044 062 046 067 084 025 329
059
033
530 135
051 066
was the absence of significant emphysema as demonstrated by a normal, single-breath, carbon monoxide diffusing capacity on two occasions (104 percent of predicted) and by normal lung permeability. In addition, dynamic lung compliance at low respiratory frequencies was normal. This value was 0. 16 liters/cm of water and the specific compliance was normal as well and this value was 0.03-cmH20 -l Because of the patient's claustrophobia, we were unable to obtain any meaningful measurements of airways resistance in the body box. The mechanical abnormalities stated caused a moderate degree of hypoxemia at rest, but the acid base balance was essentially normal. The hypoxemia was most likely caused by ventilation blood flow inhomogeneity in the lung. The abnormal MEFV curve is shown in Figure 1. In conclusion, the present tests on the patient confirmed the impression of the previous tests done in 1973, that is, the patient's chronic obstructive airways disease was most likely asthmatic bronchitis and not emphysema, despite poor reversibility of airways obstruc-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
Table 2. Pulmonary Function Studies, Prebronchodilator*
Symbol
Measurements, units
Actual
Predictedc
% Predicted
At Rest
Breathing Room Air 100% 02 Resting Minute Volume, liters/min 100% 02 Mean Resting Tidal Volume, liters Lung Clearance Index, unitless Total Washout Time, minutes Largest Vital Capacity (any test), liters Expiratory Reserve Volume, liters Functional Residual Capacity, liters Residual Volume, liters (RV = FRC - ERV) Total Lung Capacity, liters (TLC = VC + RV) RV/TLC Ratio, % Carbon Monoxide Diffusing Capacity, ml/min/mmHg DLco Per Unit of Alveolar Volume, 1/min/mmHg Effective Total Lung Capacity, liters Krogh's Constant, 1/min Carbon Monoxide Time Constant, seconds Carbon Monoxide Diffusing Capacity, ml/min/mmHg DLco Per Unit of Alveolar Volume, 1/min/mmHg Effective Total Lung Capacity, liters Krogh's Constant, 1/min Carbon Monoxide Time Constant, seconds Dynamic Lung Compliancet Specific Lung Compliancet
MV TV LCI
WASH-T
VC ERV FRC RV TLC % RV/TLC
DLco DLCoNA
TLCEFF k t
DLco DLCONA
TLCEFF k t CLdyn CLspec
08.5 0.58 0.89 06.2 4.08 1.83 5.79 3.96 8.04 049 26.3 5.00 6.54
3.46
17.3 26.6 5.23 6.35 3.62 16.5 0.16 0.03
07.0
127
4.75 1.67 3.94 2.28 7.06 033 25.8
086 110 147 175 114 152
3.88 15.5 25.8
089 112 104
3.88 15.5
094 107
Po2 Sao2 Pco2 pH
Saco
69 96% 41 7.35 4.0%
102
0.03 to 0.04
*Performed on M100B SRL Medical Inc., Dayton, Ohio. tPerformed on Godart Compliance test. tPredicted Normal Values from Kory et al.7
tion. Elastic recoil of the lung was iot decreased. Deterioration in lung function over the six-year period was greater than could be accounted for by age alone.
Discussion The classical form of chronic obstructive pulmonary disease, found is association with the Pi phenotype of ZZ, has been a panlobular type of emphysema involving predominently the lower lung zones." The experimental production of emphysema in rats by tracheal instillation of papain," combined with the in-vitro demonstration of Kueppers and Beam"' that proteases released from leukocytes in the absence of protease inhibitor can digest unprotected lung tissue, suggested the pathogenesis. It is reasonable to sus-
pect that emphysema would most likely occur at the lung bases where blood flow is greatest and where leucocyte sequestration is likely to occur. Studies of lung compliance have shown loss of elastic recoil in these patients." This patient had airways obstruction without destruction of the pulmonary capillary bed (normal diffusing capacity) and normal elastic lung recoil (compliance). Although antitrypsinalpha, deficient emphysema constitutes only about one to two percent of emphysema cases, Mittman:' noted that alpha, antitrypsin deficiency is more common in Nordic ethnic groups and less common in dark-skinned races. The larger epidemiologic study, of which this case presentation is part, gave additional support to this idea.) In fact, only a few groups of workers presented data which included any protease inhibitor-deficient blacks.'5"2
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
Most population studies have been noticeably devoid of them.* Emphysema in homozygotes for Piz characteristically has its onset in the third decade of life. Whether or not the heterozygous state is associated with a greater risk of chronic obstructive pulmonary disease (COPD), has been the subject of much agitated discussion fostering contrasting points of view."', Some workers believe that protection fron noxious environmental exposures will delay onset of disease in this
group."I Although a deficiency of Pi was also postulated as a possible etiology for peptic ulcer, several studies that ad-
*Of 19 respondents to queries sent to all NHLI Contract participants, only three indicated the presence of black persons with familial emphysema in their study.
119
/t
"
12|
x8I
'\
8
.4 0
r 1
2
3 (L)
VOLUME
Figure 1. Maximal expiratory flow volume curve of the alpha' antitrypsin-deficient patient (solid line) compared with that of a healthy age and sex matched control subject (dashed lihe). \v max is on the ordinate and volume expired on the abscissa. Half, one, and three-second time marks are shown on the tail of each curve.
dressed the combination found no statistically significant difference between Pi deficient emphysema and peptic ulcer patients as compared with non-Pi deficient emphysema patients with peptic ulcer.'4 The atypical phenotype accompanying Pi7' is unusual in a black American. This is evidenced by late onset of symptoms of airways obstruction occurring near the end of the fifth decade of life; asthmatic bronchitis rather than emphysema; and additional cumulative environmental exposures of 33 packyears of cigarette smoking combined with dust from his work environment. It has not been established whether or not the Pi phenotype of ZZ is etiologically related to the observed clinical phenotype. The observed unusual association warrants more careful search for its occurrence among black Americans. 120
Acknowledgement Supported by Contract NHLI 71-2222Alphal Antitrypsin Deficiency in Chronic Pulmonary Disease and a grant from Regional Medical Programs-Early Detection of Chronic Obstructive Pulmonary Disease.
Literature Cited 1. Laurell CB, Eriksson K: Alphal globulin pattern in serum in alphai antitrypsin deficiency. Scan J Clin Lab Invest 15:132-140, 1963 2. Sharp HL, Bridges RA, Drivit W, Freier EF: Cirrhosis associated with alphal antitrypsin deficiency: A previously unrecognized inherited disorder. J Lab Clin Med 73:934-939, 1969 3. Mittman C, Lieberman J: Ethnic group variation in the incidence of alphal antitrypsin deficiency. Clin Res 18:488, 1970 4. Evans HE, Bognacki NS, Perrott LM, Glass L: Prevalence of alphal antitrypsin pi types among newborn infants of different ethnic backgrounds. J Pediatr 90:621-624, 1977 5. Henderson AL, Young RC, Jr, Headings VE, et al: Relative infrequency of protease inhibitor deficiency in blacks with pulmonary diseases. Am Rev Respir Dis 1 15:119, 1977, part 2
6. Pierce JA, Eradio B, Dew TA: Antitrypsin phenotypes in St. Louis, JAMA 231:609-612, 1975 7. Kory RC, Callahan R, Boren HG: The Veterans Administration-Army cooperative study of pulmonary function: I. Clinical spirometry in normal men. Am J Med 30:243-258, 1961 8. Guenter CA, Welch MH, Russell T, et al: The pattern of lung disease associated with alphal antitrypsin deficiency. Arch Int Med 122:254, 1968 9. Gross P, Pfitzer EA, Tolkes E, et al: Experimental emphysema: Its production with papain in normal and silicotic rats. Arch Environ Health 11:50-58, 1965 10. Kueppers F, Bearn AG: Possible experimental approach to association of hereditary alphal antitrypsin deficiency and pulmonary emphysema. Proc Soc Exp Biol Med 121:12071209, 1966 11. Stevens PM, Hnilica VS, Johnson PC, et al: Pathophysiology of hereditary emphysema. Ann Intern Med 74:672-680, 1971 12. Rawlings W, Jr, Kreiss P, Levy D, et al: Clinical epidemiologic and pulmonary function studies in alphal antitrypsin-deficient subjects of Pi Z type. Am Rev Respir Dis 114:945-953, 1976 13. Welch MH, Reineke ME, Hammarsten JF, et al: Antitrypsin deficiency in pulmonary diseases: The Significance of Intermediate Levels. Ann Intern Med 71 :533-542, 1969 14. Lieberman J: Heterozygous and homozygous alphai antitrypsin deficiency in patients with pulmonary emphysema. N Eng J Med 281 :279-284, 1969
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
The rare association of protease inhibitor deficiency (Pizz genotype) in a black American with chronic, obstructive pulmonary disease due to asthmatic bronchitis, rather than basal pan lobular emphysema, is presented. The late onset of symptoms, despite environmental exposures, is also unusual in this homozygote, as is his ethnic background.
In 1963, Laurell and Erikson in Sweden' associated absence of the alpha, peak in serum protein electrophoresis with chronic obstructive pulmonary disease (emphysema) in families. This glycoprotein, of molecular weight 45 to 60 thousand, inhibits activity of proteases, and has been reported as a variety of inherited allelic variants. Several of these, and notably the Z variant, are accompanied by impairment of protease inhibitor (Pi) activity. Values of serum trypsin inhibitory capacity (STIC) vary above 0.8 mg/ml of serum in the majority of persons who possess the Pi-IM genotype, 0.4-0.8 in heterozygotes for the Z var-
iant (Pji1%), and below 0.4 in the homozygous state (Pizz). Later, Sharp2 at Minnesota established the relationship between absence of the M allele and a juvenile form of liver cirrhosis; and subsequently instances of both emphysema and cirrhosis have been reported in a single patient. It has been established that the Z gene frequency is more common in Nordic ethnic groups than among persons of dark-skinned races.:'-- The present case is unusual because the patient had a ZZ phenotype and asthmatic bronchitis rather than emphysema. The patient is black.
Case Report From the Pulmonary Disease Division, Howard University Hospital and Medical Genetics Unit, College of Medicine, Howard University, Washington, D.C. Requests for reprints should be addressed to Dr. Roscoe C. Young, Jr., Pulmonary Disease Division, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, D.C. 20060.
E.P.A., #039-751, a 47-year-old retired black American US Post Office supervisor, was diagnosed as having "asthma" by his private physician three years prior to the time of this study. He had been hospitalized three
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
times for respiratory difficulty. His first two hospital admissions, between June 1 and 11, 1970, were for cough with streaking of blood, wheezing and dyspnea, even at rest. Diagnostic bronchoscopy, ECG, chest radiographs, bronchograms, and an intravenous lung scan were all normal. A pulmonary function study on June 4, 1970 showed chronic obstructive airways disease. He responded to bronchodilators and was discharged. On his second hospitalization, October 18-30, 1971, he was similarly treated. His third admission was to Freedmen's Hospital, Washington, D.C. on October 20, 1972 in status asthmaticus, having been brought to the hospital by ambulance with a three-day history of grade III dyspnea, wheezing, and cough productive of moderate amounts of watery sputum, which changed in character to purulent. Past history disclosed no exposure to noxious substances. He was an excigarette smoker, having smoked 1 1/2 packs a day for 22 years. He stopped smoking in August 1968. He indicated that his mother had asthma. Examination disclosed systemic hypertension. The patient was afebrile and had a tachycardia. Bilateral wheezes were present in both phases of respiration with diminished breath sounds in the left midlung field. Faint cyanosis of the mucous membranes was also present. Gram stains and cultures of the sputum revealed a bacterial 117
Table 1. Pulmonary Function Studies, Pre and Postbronchodilator* Measurements, units
Postbronchodilator Prebronchodilator Actual Predicted % Predicted Actual Predicted % Predicted
Symbol
FVC Forced Vital Capacity, liters FEV 0.5 0.5 Second Forced Expired Volume, liters % FEV 0.5 % FVC in 0.5 second FEV 1.0 1.0 Second Forced Expired Volume, liters % FEV 1.0 % FVC in 1 second % FEV 3.0 % FVC in 3 seconds FEF 25-75% Forced Mid-Expiratory Flow, liters/min MET Mid-Expiratory Time, seconds VC-T Forced Vital Capacity Time, seconds Mean Flow Between 75% and 85% of FVC, liters/min FEF 75-85% FEF 50% Flow at 50% of FVC, liters/min FEF 75% Flow at 75% of FVC, liters/min PF Peak Expiratory Flow, liters/min MVV Maximum Voluntary Ventilation, liters/min MV Resting Minute Volume, liters/min TV Mean Resting Tidal Volume, liters VC Vital Capacity, liters N2 Nitrogen Delta, % N2 % CV/VC Closing VolumeNital Capacity, % VC Vital Capacity, liters N2 Nitrogen Delta, % N2 % CVNC Closing VolumeNital Capacity, %
exacerbation. He responded to antibiotics, bronchodilators, hydration, and adrenocorticoids. Additional studies during this hospitalization disclosed a sliding hiatal hernia, duodenal ulcer, and nephrolithiasis of the left kidney. Repeat pulmonary function studies on November 30, 1976 confirmed airways obstruction. As part of a National Heart and Lung Institute (NHLI) cooperative study, his serum trypsin inhibitory capacity was 0.18 ml/ml which was only 13 percent of the value of the pooled heterologous control sera." His Pi configuration on crossed antigen-antibody electrophoresis was consistent with a ZZ phenotype and his alpha, peak was absent on starch-gel electrophoresis. In response to a request to study his family members he stated, "I have no control over my family" and refused to cooperate further in that regard. Currently, the patient complains only of stuffiness of the left nostril and states that he has no other respiratory symptoms. "Breathlessness and wheezing occur only when I have a cold or allergy." 118
4.08 1.13 027 1.72 042 069 042 2.77 09.6 015 050 018 240 075 10.9 0.99 3.09 02.5 026 3.08 02.1 019
.75 2.59 055 3.69 078 097 216 0.54
086 044 050 047 054 071 020 401
059
026
530 135
046 056
4.75 01.9 020 4.75 01.9 020
065 135 129 065 119 094
Results of Pulmonary Function Tests Pulmonary function studies on November 30, 1976 (Tables 1 and 2) revealed moderately severe, poorly reversible obstructive airways disease as shown by a decrease in the maximum voluntary ventilation (MVV), abnormalities in percent forced expiratory volume (%FEV),. and increase in the total lung capacity which was caused by increases in the residual volume and functional residual capacity (FRC). Hyperinflation of lung tissue was noted by an increase in the residual volume/total lung capacity (RV/TLC) ratio. Uneven distribution of inspired gas was present as noted by abnormal nitrogen delta test results on two occasions and an abnormally high sevenminute nitrogen washout of about 7.2 percent alveolar nitrogen. There appeared to be hypoxic drive to respiration because the tidal volume breathing room air decreased from 0.99 liters to 0.58 liters. A concomitant decrease in the minute ventilation was present as well. Of most importance
3.26 1.11 034 1.69 052 081 055 1.77 07.5 020 064 026 266 089
4.75 2.59 055 3.69 078 097 216 0.54
069 044 062 046 067 084 025 329
059
033
530 135
051 066
was the absence of significant emphysema as demonstrated by a normal, single-breath, carbon monoxide diffusing capacity on two occasions (104 percent of predicted) and by normal lung permeability. In addition, dynamic lung compliance at low respiratory frequencies was normal. This value was 0. 16 liters/cm of water and the specific compliance was normal as well and this value was 0.03-cmH20 -l Because of the patient's claustrophobia, we were unable to obtain any meaningful measurements of airways resistance in the body box. The mechanical abnormalities stated caused a moderate degree of hypoxemia at rest, but the acid base balance was essentially normal. The hypoxemia was most likely caused by ventilation blood flow inhomogeneity in the lung. The abnormal MEFV curve is shown in Figure 1. In conclusion, the present tests on the patient confirmed the impression of the previous tests done in 1973, that is, the patient's chronic obstructive airways disease was most likely asthmatic bronchitis and not emphysema, despite poor reversibility of airways obstruc-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
Table 2. Pulmonary Function Studies, Prebronchodilator*
Symbol
Measurements, units
Actual
Predictedc
% Predicted
At Rest
Breathing Room Air 100% 02 Resting Minute Volume, liters/min 100% 02 Mean Resting Tidal Volume, liters Lung Clearance Index, unitless Total Washout Time, minutes Largest Vital Capacity (any test), liters Expiratory Reserve Volume, liters Functional Residual Capacity, liters Residual Volume, liters (RV = FRC - ERV) Total Lung Capacity, liters (TLC = VC + RV) RV/TLC Ratio, % Carbon Monoxide Diffusing Capacity, ml/min/mmHg DLco Per Unit of Alveolar Volume, 1/min/mmHg Effective Total Lung Capacity, liters Krogh's Constant, 1/min Carbon Monoxide Time Constant, seconds Carbon Monoxide Diffusing Capacity, ml/min/mmHg DLco Per Unit of Alveolar Volume, 1/min/mmHg Effective Total Lung Capacity, liters Krogh's Constant, 1/min Carbon Monoxide Time Constant, seconds Dynamic Lung Compliancet Specific Lung Compliancet
MV TV LCI
WASH-T
VC ERV FRC RV TLC % RV/TLC
DLco DLCoNA
TLCEFF k t
DLco DLCONA
TLCEFF k t CLdyn CLspec
08.5 0.58 0.89 06.2 4.08 1.83 5.79 3.96 8.04 049 26.3 5.00 6.54
3.46
17.3 26.6 5.23 6.35 3.62 16.5 0.16 0.03
07.0
127
4.75 1.67 3.94 2.28 7.06 033 25.8
086 110 147 175 114 152
3.88 15.5 25.8
089 112 104
3.88 15.5
094 107
Po2 Sao2 Pco2 pH
Saco
69 96% 41 7.35 4.0%
102
0.03 to 0.04
*Performed on M100B SRL Medical Inc., Dayton, Ohio. tPerformed on Godart Compliance test. tPredicted Normal Values from Kory et al.7
tion. Elastic recoil of the lung was iot decreased. Deterioration in lung function over the six-year period was greater than could be accounted for by age alone.
Discussion The classical form of chronic obstructive pulmonary disease, found is association with the Pi phenotype of ZZ, has been a panlobular type of emphysema involving predominently the lower lung zones." The experimental production of emphysema in rats by tracheal instillation of papain," combined with the in-vitro demonstration of Kueppers and Beam"' that proteases released from leukocytes in the absence of protease inhibitor can digest unprotected lung tissue, suggested the pathogenesis. It is reasonable to sus-
pect that emphysema would most likely occur at the lung bases where blood flow is greatest and where leucocyte sequestration is likely to occur. Studies of lung compliance have shown loss of elastic recoil in these patients." This patient had airways obstruction without destruction of the pulmonary capillary bed (normal diffusing capacity) and normal elastic lung recoil (compliance). Although antitrypsinalpha, deficient emphysema constitutes only about one to two percent of emphysema cases, Mittman:' noted that alpha, antitrypsin deficiency is more common in Nordic ethnic groups and less common in dark-skinned races. The larger epidemiologic study, of which this case presentation is part, gave additional support to this idea.) In fact, only a few groups of workers presented data which included any protease inhibitor-deficient blacks.'5"2
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
Most population studies have been noticeably devoid of them.* Emphysema in homozygotes for Piz characteristically has its onset in the third decade of life. Whether or not the heterozygous state is associated with a greater risk of chronic obstructive pulmonary disease (COPD), has been the subject of much agitated discussion fostering contrasting points of view."', Some workers believe that protection fron noxious environmental exposures will delay onset of disease in this
group."I Although a deficiency of Pi was also postulated as a possible etiology for peptic ulcer, several studies that ad-
*Of 19 respondents to queries sent to all NHLI Contract participants, only three indicated the presence of black persons with familial emphysema in their study.
119
/t
"
12|
x8I
'\
8
.4 0
r 1
2
3 (L)
VOLUME
Figure 1. Maximal expiratory flow volume curve of the alpha' antitrypsin-deficient patient (solid line) compared with that of a healthy age and sex matched control subject (dashed lihe). \v max is on the ordinate and volume expired on the abscissa. Half, one, and three-second time marks are shown on the tail of each curve.
dressed the combination found no statistically significant difference between Pi deficient emphysema and peptic ulcer patients as compared with non-Pi deficient emphysema patients with peptic ulcer.'4 The atypical phenotype accompanying Pi7' is unusual in a black American. This is evidenced by late onset of symptoms of airways obstruction occurring near the end of the fifth decade of life; asthmatic bronchitis rather than emphysema; and additional cumulative environmental exposures of 33 packyears of cigarette smoking combined with dust from his work environment. It has not been established whether or not the Pi phenotype of ZZ is etiologically related to the observed clinical phenotype. The observed unusual association warrants more careful search for its occurrence among black Americans. 120
Acknowledgement Supported by Contract NHLI 71-2222Alphal Antitrypsin Deficiency in Chronic Pulmonary Disease and a grant from Regional Medical Programs-Early Detection of Chronic Obstructive Pulmonary Disease.
Literature Cited 1. Laurell CB, Eriksson K: Alphal globulin pattern in serum in alphai antitrypsin deficiency. Scan J Clin Lab Invest 15:132-140, 1963 2. Sharp HL, Bridges RA, Drivit W, Freier EF: Cirrhosis associated with alphal antitrypsin deficiency: A previously unrecognized inherited disorder. J Lab Clin Med 73:934-939, 1969 3. Mittman C, Lieberman J: Ethnic group variation in the incidence of alphal antitrypsin deficiency. Clin Res 18:488, 1970 4. Evans HE, Bognacki NS, Perrott LM, Glass L: Prevalence of alphal antitrypsin pi types among newborn infants of different ethnic backgrounds. J Pediatr 90:621-624, 1977 5. Henderson AL, Young RC, Jr, Headings VE, et al: Relative infrequency of protease inhibitor deficiency in blacks with pulmonary diseases. Am Rev Respir Dis 1 15:119, 1977, part 2
6. Pierce JA, Eradio B, Dew TA: Antitrypsin phenotypes in St. Louis, JAMA 231:609-612, 1975 7. Kory RC, Callahan R, Boren HG: The Veterans Administration-Army cooperative study of pulmonary function: I. Clinical spirometry in normal men. Am J Med 30:243-258, 1961 8. Guenter CA, Welch MH, Russell T, et al: The pattern of lung disease associated with alphal antitrypsin deficiency. Arch Int Med 122:254, 1968 9. Gross P, Pfitzer EA, Tolkes E, et al: Experimental emphysema: Its production with papain in normal and silicotic rats. Arch Environ Health 11:50-58, 1965 10. Kueppers F, Bearn AG: Possible experimental approach to association of hereditary alphal antitrypsin deficiency and pulmonary emphysema. Proc Soc Exp Biol Med 121:12071209, 1966 11. Stevens PM, Hnilica VS, Johnson PC, et al: Pathophysiology of hereditary emphysema. Ann Intern Med 74:672-680, 1971 12. Rawlings W, Jr, Kreiss P, Levy D, et al: Clinical epidemiologic and pulmonary function studies in alphal antitrypsin-deficient subjects of Pi Z type. Am Rev Respir Dis 114:945-953, 1976 13. Welch MH, Reineke ME, Hammarsten JF, et al: Antitrypsin deficiency in pulmonary diseases: The Significance of Intermediate Levels. Ann Intern Med 71 :533-542, 1969 14. Lieberman J: Heterozygous and homozygous alphai antitrypsin deficiency in patients with pulmonary emphysema. N Eng J Med 281 :279-284, 1969
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 2, 1978
