Alpha1antitrypsin deficiency: The clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z

Br. J. Dis. Chest (1983)

77, 14

ALPHAIANTITRYPSIN DEFICIENCY: THE CLINICAL AND PHYSIOLOGICAL FEATURES OF PULMONARY EMPHYSEMA IN SUBJECTS HOMOZYGOUS FOR Pi TYPE Z A survey by the British Thoracic Association* M. J. TOBIN, Medical

P. J. L. COOK

AND D. C. S. HUTCHISON

Chest Unit, King’s College Hospital and Medical School and Research Council Human Biochemical Genetics Unit, University College, London

Summary Hereditary deficiency of alphalantitrypsin, the main serum inhibitor of proteolytic enzymes is associated with pulmonary emphysema of early onset. A multicentre survey of this disorder was started in 1976 and details of 166 subjects homozygous for the Z phenotype form the main body of this report. There were 126 index cases who were identified through chest clinics and 40 non-index cases who were identified through family studies. The index cases and many of the non-index cases had severe radiological and physiological abnormalities. A history of cigarette smoking had a significant effect upon the prognosis, but sex and occupational exposure to dust or fumes did not. There was a wide variance in lung function even among those who had never smoked. Introduction The association of hereditary alphalantitrypsin (AT) deficiency and pulmonary emphysema is well recognized (Laurel1 & Eriksson 1963; Eriksson 1965). AT is one of the principal serum inhibitors of proteolytic enzymes and one of its functions is believed to be the protection of the lung against a powerful elastase released from neutrophil leucocytes. In severe AT deficiency, this enzyme can degrade the pulmonary elastic tissue bringing about the familiar pathological features of emphysema. The current state of our knowledge has been reviewed elsewhere (Hutchison 1973, 1981). AT is now known to exist in a number of molecular variants (the ‘Pi’ types) and individuals homozygous for type Z, who have between 10 and 20% of the *This study was coordinated by Dr D. C. S. Hut&son on behalf of a subcommittee of the Research Committee of the British Thoracic Association. Members of the subcommittee were: Professor J. G. Scadding (Chairman), Mr G. Berry, Dr.P. J. L. Cook, Professor C. M. Fletcher (resigned 1979), Dr E. A. Hills (resigned 1980), Dr D. C. S. Hut&son, Dr S. J. Pearce, Dr G. M. Sterling and Professor M. Turner-Warwick (resigned 1975).

Alpha,antitrypsin

Deficiency

15

normal serum AT, are believed to have a strong risk of developing emphysema. The precise extent of this risk remains unknown since type Z homozygotes have usually been identified only after attendance at a chest clinic with established lung disease. A better estimate of the risk might therefore be obtained if we could study a group of type Z individuals who have not been selected in this way. The rarity of the condition in the UK (0.03% of the newborn population or 1 in 3300; Cook 1975) means that the most practical method of achieving this is to identify type Z individuals among brothers and sisters (the ‘sibs’) of patients already known to be of this phenotype; approximately one in four sibs wouldbe expected to have the deficiency which can be regarded as recessively inherited. The British Thoracic Association has therefore undertaken a multicentre survey in order to accumulate data on as large a number of AT deficient subjects as possible and to obtain through family studies information about individuals who have not been selected by attendance at a chest clinic. The eventual objective of this study is to obtain evidence on the influence of smoking and other factors upon the rate of decline in lung function in AT deficient patients. Sufficient time has not yet elapsed for this to be possible and our purpose in this paper is to present data obtained at the patients’ entry into the survey. The report is limited to patients homozygous for type Z; preliminary reports have already been published (Hutchison 1979, 1980). Further details of the radiological findings (Gishen et al. 1982) and of the clinical features associated with the SZ phenotype (Hutchison et al. 1983) are reported elsewhere.

Patients

and Methods

Blood samples from patients suspected of having alpharantitrypsin deficiency were submitted by chest physicians to one of two specialized laboratories for assessment of the alpharantitrypsin phenotype (Pi type) by starchgel electrophoresis (Fagerhol & Braend 1965; Cook 1975) or isoelectric focusing (Frants & Eriksson 1976). The laboratories were the Medical Research Council Human Biochemical Genetics Unit and the Supra-Regional Protein Reference Laboratory, Sheffield. The convention adopted by Fagerhol et al. (1975) for nomenclature of Pi phenotypes will be used for all cases; the term Pi Z refers to subjects who are apparently homozygous for type Z but where the ‘Null’ gene (by which no alpharantitrypsin is produced whatsoever) has not been excluded. This applies to the majority of cases in this survey. Further information (see below) was sought in patients who were found to be homozygous for type Z or S, heterozygous for type SZ or who possessed other uncommon deficient phenotypes. Patients who were identified through attendance at a chest clinic were classified as ‘index cases’. Blood samples were also requested from full brothers and sisters (the ‘sibs’) of the index cases; blood samples from other relatives were not specifically requested but were assessed as above if received. Subjects of the above phenotypes who were identified through family studies were classified as the ‘non-index’ cases. Completion of a standardized questionnaire was requested in all cases with aview to obtaining the following information: grade of dyspnoea (Fletcher et al. 1976) and age of onset of dyspnoea and grade of chronic bronchitis (Medical Research Council 1965) ; history of asthma, liver disease or peptic ulcer; and occupational exposure to dust or fumes. The following data on tobacco smoking were requested: age of starting; age of stopping in ex-smokers; number of manufactured cigarettes smoked per day (each cigarette considered to contain 1 g of tobacco) or the weekly tobacco consumption in ounces for those smoking hand-rolled cigarettes or a pipe. An index of the total lifetime tobacco consumption in kg was calculated from the current 2

16

M. J. Tobin, P. J. L. Cook and D. C. S. Hutchison

daily consumption and duration of smoking. Any subject (whether current or ex-smoker) who had smoked at least one cigarette per day for one year or more was classified as a ‘smoker’; the remainder were classified as ‘non-smokers’. Lung function tests were measured for each subject in the laboratory of choice; the equipment used differed from place to place. The best of three measurements of forced expiratory volume in 1 set (FEVi) and vital capacity (VC) were recorded before inhalation of bronchodilator (pre-bd) and in the majority of subjects repeated after the bronchodilator (post-bd). The carbon monoxide transfer factor (tC0) and transfer coefficient (kC0) were measured by the single breath method (Ogilvie et al. 1957). Predictedvalues were obtained from tables prepared by Cotes (1979). Standard posteroanterior chest radiographs were taken in full inspiration and were assessed by two experienced radiologists independently without knowledge of the clinical or physiological features. Each lung field was divided into three zones of equal height which were examined for the presence of vascular attenuation and bullae; a diagnosis of emphysema was made if either abnormality was present in one or more zones (Laws & Heard 1962). In cases of doubt, emphysema was reported as absent. Selection of subjects The subjects included 1. 2. 3. 4. 5.

in this report

were selected according

identified as Pi type Z before 1 May 1980. known to be alive on 1 January 1976. over 20 years of age. classifiable as ‘smoker’ or ‘non-smoker’ as defined FEVr available as % of predicted.

to the following

criteria:

above.

Statistical methods The data were processed on the University of London Computer Centre’s CDC 7600 using the SPSS statistical package (Nie et al. 19 75). Probability values for differences between the various groups of patients were established by unpaired t-test or by chi’ test with Yates’ correction. Multiple regression analysis was carried out to assess the independent influences upon the lung function indices of age, sex, smoking, smoking-sex interaction and occupational exposure to dust or fumes. For this part of the analysis, the index and non-index cases were pooled; this gives a valid test of association in the total population of type Z subjects on the assumption that the separate probabilities of persons with or without lung function impairment being referred to a chest clinic (and thus becoming index cases) are independent of sex, smoking and occupational hazard. We also accept that the sampling fractions of index and non-index cases from the whole population to the study sample are different.

Results One hundred and sixty-six homozygotes of type Z (126 index cases and 40 nonindex cases) fulfilled the five selection criteria; 23 (14%) died during the study period at a mean age of 53 years (SD 10). Of these 23 deaths, 19 were reported to have died as a direct consequence of emphysema, the cause of death being unknown in the remaining four. Twenty deaths occurred among the index smokers and the remaining three among the female index non-smokers who had survived to a greater age than the other groups of index cases. There were no deaths among the 40 non-index cases. During the course of the survey, an additional 38 type Z subjects were detected who fulfilled the first three criteria only (29 index cases and nine non-index cases). Of these subjects 15 (39%) died at a mean age of 58 years (SD 10); 14 were index

Alpha,antitrypsin

Deficiency

17

cases, nine died as a result of emphysema (mean age at death 61 years, SD 12), one of subarachnoid haemorrhage, one of pulmonary embolism, one of status asthmaticus and two of unknown cause. One non-index case died of emphysema at the age of 52 years. These 38 subjects will not be further considered in this report. Clinical features

(Table I)

Age. The mean age of the 166 subjects on entry into the survey was 50 years (range 21-78). The 34 non-smokers (mean age 56 years) were significantly (P < 0.01) older th an the 132 smokers (mean age 48 years). There was no significant difference in age between index and non-index cases nor between males and females. Male to female (M: F) ra t io. There were more males than females among the index cases (M : F = 1.9 : 1); th is was reversed in the non-index cases, (M : F = 0.7 : 1) the ratios being significantly different by chi2 test (P < 0.025). The M : F ratio among ‘smokers’ was 1.9 : 1, significantly greater (P < 0.01) than among ‘non-smokers’ (M : F = 0.62 : 1). Grade of dyspnoea (Fig. 1). The grade of dyspnoea could not be assessed in six of the 166 subjects because of other disabling conditions. Of the remaining 160, 137 (86%) had dyspnoea of grade 2, 3 or 4 severity; dyspnoea was commoner in males than in females (PC 0.025) an d commoner in smokers than in non-smokers (P< O.Ol), but th ere was a greater ratio of smokers to non-smokers among men (86 : 13) than among women (46 : 21). After allowing for sex the smoking effect remained significant (PC 0.05), but after allowing for smoking the sex effect was no longer significant (0.5 < P< 0.1). Age of onset of grade 2 dyspnoea. The age of onset could not be assessed in three of the 137 subjects with grade 2 dyspnoea. The mean age of onset in the remaining 134 was 41 years (Table I), and it was 7 years later in onset in nonsmokers than in smokers (PC 0.05). The main differences were in the index cases; in males, grade 2 dyspnoea appeared 7 years later in non-smokers than in smokers (P > 0.05); in females the corresponding figure was 10 years (P < 0.05). Tobacco smoking

(Table I)

Of the 166 subjects 132 (80%) were ‘smokers’ (i.e. current or ex-smokers) and 34 (20%) were ‘non-Smokers’ (i.e. had never smoked). The proportion of smokers among the index cases (867) o was significantly greater (P < 0.01) than among the non-index cases (60%). The average duration of smoking for all subjects was 24 years; the duration was similar in aII four smoking groups but the total tobacco consumption of the male index smokers was significantly greater than that of any other group (PC 0.02). A mong smokers no significant correlation was found between the estimated lifetime tobacco consumption and the lung function indices.

cases

cases

CASES

41

47 46

40 40

39 49

39 46

Mean

10

5 27

11 13

11 g-

8 ll-

SD

168

112 -

100 -

139

200

Mean

~

22 -

90

three patients;

24

23

111 137

21

77

-

25 -

Mean

(ye+

9

9

Tobacco

10

10

14

-

SD

of P4

consumption,

51

15 9

73 67

36 18

69 43

Occupation Dust &/or fumes

in subjects of Pi type Z

Duratiolz smoking

155 -

SD

(kg)

and mortality

Lifetime Tobacco

occupation

Age onset grade 2 dyspnoea,

134

11

7 3

30 8

69 6

7 4

~ n

8 16

13 4

11 10

8 18

SD

smoking,

Grade 2 dyspnoea Age of onset (years)

grade, six patients;

50

49 56

13 10

166

46 51

43 60

33 11

11 6

49 53

75 7

Not assessed: Dyspnoea

ALL

Males Smoked Never smoked Females Smoked Never smoked

Non-index

Males Smoked Never smoked Females Smoked Never smoked

Index

Age h-4 ~ n Mean

Table I. Age, dyspnoea,

53

~ -

-

43 60

55

Mean

two patients.

23

0 0

0 o-

5 3

15 o-

n

Deaths Age (ye=)

10

-

7 6

10 -

SD

Alphalantitrypsin Occupational

exposure

19

Deficiency

to inhaled dust or fumes (Table I)

Fifty-one per cent of the Z subjects reported exposure to either dust or fumes or both at their place of work. This was significantly (PC 0.001) more frequent

GRADE OF DYSPNOEA: TYPE Z FEMALES

MALES

Smoked

Never Smoked

Smoked

Never Smoked

INDEX CASES

dLl 1234

No. of cases

72

NON-INDEX

CASES

7

122

10 0[

Ll!cs4-

E?K

No. of cases

10

123L

5

13

1234

10 TOTAL

38 -160

Fig. 1. Grade of dyspnoea in 160 subjects of Pi type Z. The number of cases (vertical axis) for each of the four grades of dyspnoea is indicated for each group. The grade was not assessed in six subjects

(P < 0.01) among males (68%) th an among females (25%) and more frequent among smokers (56%) than among non-smokers (29%). The variance in lung function indices due to this factor was not significant on multiple regression analysis (see Table III).

cases

CASES

* bd: bronchodilator.

ALL

Males Smoked Never smoked Females Smoked Never smoked

Non-index

Males Smoked Never smoked Females Smoked Never smoked

Index cases

56 63

68 82

42

13 10

164

28

37 25

30 34

141

9 8

8 6

27 8

15 34

32 11

34 56

69 6

17 30

SD n

74 30 7 42

Mean

11 6

n

45

65 87

59 74

35 56

35 52

Mean

26 164

13 10

30 26

32 11

74 7

11 6

n

29 32

14 32

16 33

SD

Pre-bd

Post-bd

Pre-bd *

75

87 90

85 91

67 73

72 79

Mean

136

27

8 6

24 7

68 6

9 8

n

Post-bd

84

94 95

89 102

75 78

83 91

Mean

24

22 13

68 90

133

52

13 60 7 79

9 5

22 41 5 96

22 21

26 27

65 43 7 52

Mean

26 24

SD

n

tco

in subjects of Pi type Z

22 20

28 31

28 26

26 30

SD

tests (% of predicted) vc

Lung function

FE V1

Table II.

29

29 9

36 26

17 53

21 38

SD

89

7 3

7 4

16 3

44 5

n

KC0

56

60 84

71 72

45 102

51 52

Mean

32

22 12

30 4

21 45

33 46

SD

NJ 0

A1phalantitrypsin Chronic

Deficiency

21

bronchitis

Chronic bronchitis was present in 53% of the 166 subjects; 15% had grade 1 chronic bronchitis and 38% had grade 2. It was significantly more common (PC 0.01) among smokers (59%) than among non-smokers (29%). The mean age of onset of chronic bronchitis was similar to that of dyspnoea.

Other disorders The physician’s opinion whether the subject had bronchial asthma was available in 129 cases: 14 (11%) were stated to have asthma (nine index cases, five nonindex cases), eight were regarded as ‘atopic’ and six as ‘non-atopic’. Eight were males and six were females. A present or past history of liver disease was obtained in nine subjects and eight had a history of peptic ulceration.

Table

Lung

III

Multiple patients

function

regression analysis of Pi Type Z

index

n

of effects of various

Factor

factors on lung function Variance accounted

FEVi

pre-bd

164

FEVi

post-bd

141

VC tco kC0 Factors

164 133 89

Smoking Sex Smoking Age NIL Smoking Smoking

13.1% 3.9% 20.5% 2.8% 16.2% 6.1%

indices

in

P for

< 0.001 0.006 < 0.001 0.026 < 0.001 0.02

smoking, age, occupational exposure to dust or fumes, sex and sex-smoking Results given in table only for factors in which variance > 2% and P < 0.05.

studied:

interaction.

Lung function

(Tables II and III)

The mean values for the various groups of patient results of a multiple regression analysis in Table III.

are given in Table II and the

FEI’r . FEVl (pre-bd) as % of predicted (% P) was measured in 164 subjects in whom the mean value was 42%. FEVr (post-bd) % P was measured in 141, the mean value being 45%. The mean FEV, (pre-bd) % P was significantly below the predicted normal value in all eight groups of subjects, as was the mean FEVr (post-bd) % P in all groups except the male and female non-index non-smokers. FEVr (pre-bd) % P was lower in index cases than in non-index cases (PC 0.001). It was also lower in smokers than in non-smokers (PC 0.001) and lower in males than in females (PC 0.001); both the smoking effect and the sex effect remained significant on multiple regression analysis (Table III).

22

M. J. Tobin, P. J. L. Cook and D. C. S. Hutchison

Vital capacity. VC (pre-bd) % P was measured in 164 subjects, the mean value being 75%. VC (post-bd) % P was measured in 136, the mean value being 84%. VC (pre-bd) % P and VC (post-bd) % P were significantly reduced in all index case groups except for the male non-smokers; they were not significantly reduced in any of the four non-index groups. On multiple regression analysis, none of the factors selected contributed to the variance. Carbon monoxide transfer factor (tC0). tC0 % P was measured in 133 subjects; the mean value was 52% P which was significantly below normal (P< 0.001). tC0 % P was lower in index cases than in non-index cases (PC 0.001). It was also lower in smokers than in non-smokers (PC 0.001) and lower in males than in females, though the difference was not significant at the 5% level. The smoking effect remained significant on multiple regresssion analysis (Table III). Transfer coefficient (kC0). kc0 value being 56%. The relationships those described above for tC0 % P.

% P was measured in 89 subjects, the mean between the various groups were similar to

Chest radiographs There was evidence of emphysema in 139 (87%) of the 160 type Z subjects for whom PA chest radiographs were available. Emphysema was found more frequently in index cases (91%) than in non-index cases (73%) (PC 0.01) and more frequently in smokers (90%) than in non-smokers (65%) (P < 0.05). There was lower zone disease in 98% of the 139 subjects with emphysema. Generalized emphysema (i.e. upper, middle and lower zone disease) was seen in 23% of subjects with emphysema. Thirteen per cent had involvement of the lower and upper zones without disease of the middle zones. The lower zones were spared in only three subjects with radiological emphysema. In no subject were the middle zones affected in isolation.

Discussion The 126 index cases reported in this study are a very seriously affected group of patients; their mean age on onset of exertional dyspnoea was 40 years and by the age of 50 82% had deteriorated as far as grade 3 or 4 dyspnoea. Twenty-three died during the observation period many of them prematurely and 19 of them almost certainly as a direct consequence of advanced emphysema. Their clinical and physiological features are very similar to those in the original description of the disease by Eriksson (1965) in the cases of Hutchison et al. (1971), and those reviewed by Kueppers and Black (1974). Indeed apart from the generally earlier onset of symptoms the clinical and physiological features are very similar to those observed in non-deficient cases of emphysema (Hutchison et al. 1972; Hughes et al. 1982). The majority had severe expiratory airflow limitation which can be attributed to airway collapse resulting from the reduction in pulmonary elastic

Alp halan titrypsin

Deficiency

23

recoil and reduction in CO transfer was another obvious feature, indicating the loss of surface area for alveolar gas exchange. The effect on VC was less severe and VC was improved by administration of bronchodilator aerosol as can be observed in a majority of emphysematous patients with normal serum AT (Bellamy & Hutchison 198 1). No less than 112 (9 1%) of the index cases had some radiological evidence of emphysema and 97% of these 112 cases had involvement of the lower zones in one or both lungs. In fact, abnormalities of lung function were found in the majority of those without radiographic changes. In only three subjects were the lower zones spared, in sharp contrast to the frequent involvement of the upper zones in emphysematous patients with normal serum AT (Hutchison et al. 1972) and the lower zone localization of radiological lesions is very characteristic of AT deficiency (Eriksson 1965; Kueppers & Black 1974). Eriksson (1965) suggested that the lung destruction could result from the release of lysosomal elastase from polymorphonuclear leucocytes and the predominance of the disease in the lower zones may be due to the greater blood flow per unit volume observed in the lower zones in the upright posture (Anthonisen & Milic-Emili 1966). In pathological studies, AT deficiency has been associated with the panlobular form of emphysema (Eriksson 1965; Thurlbeck et al. 1970). Nearly all of the 40 non-index cases were full sibs of the index cases. Group for group they were of similar age to the index cases but, in contrast, had significantly less disability, only 34% having grade 3 or 4 dyspnoea. Lung function was likewise much less severely impaired in the non-index cases and, among those who had never smoked, the tC0 and post-bronchodilator FEVr were not on average significantly abnormal. Radiological abnormalities were quite common, however, 73% of the non-index cases having some evidence of emphysema, though the average number of ‘affected zones’ per subject was much less than in the index cases (Gishen et al. 1982). It has been previously observed that a history of cigarette smoking has a considerable influence on the prognosis in AT deficiency (Eriksson 1965; Kueppers & Black 1974; Black & Kueppers 1978). In this study. a high proportion of the subjects (80%) were or had been cigarette smokers and we observed that those who had smoked had greater prevalences of dyspnoea, impaired lung function and radiological evidence of emphysema. Dyspnoea occurred at an earlier age in smokers though this effect was limited to the index cases. Persistent sputum production, sufficient to earn the description ‘chronic bronchitis’ occurred in 59% of the smokers and as many as 29% of the non-smokers; an even higher frequency among non-smoking AT deficient subjects was found by Eriksson (1965) and by Black and Kueppers (1978). Th e multiple regression analysis (Table III) indicates that apart from the phenotype, a history of smoking was the major factor associated with lung function abnormality, sex and age having small additional effects. We found, on the other hand, that there was no significant correlation between the calculated lifetime tobacco consumption and the severity of lung function impairment, though it is recognized that long-term smoking histories are prone to considerable error.

24

M. J. Tobin, P. J- L. Cook and D. C. S. Hutchison

The ratio of males to females among the index cases in this study was 1.9 : 1, significantly greater than the 1 : 1 ratio which would be expected in a condition determined by a single autosomal locus. Among smokers, who formed the large majority of the cases, the male to female ratio was also 1.9 : 1 and Kueppers and Black (1974) observed a similar ratio of 2.5 : 1. Examination of smoking statistics for the UK (Lee 1976) shows that the male to female ratio of overall tobacco consumption was approximately 2 : 1 among current and ex-smokers in 1975, so that there is no evidence that men and women of type Z have different tendencies towards emphysema. This is confirmed by the multiple regression analysis in which we observed no significant interaction between smoking and sex in the effect upon lung function. Among the non-smokers in this survey a comparison of males and females suggested that females had deteriorated rather less rapidly than males in that they had reached a greater age with less impairment of lung function. The differences in lung function did not reach statistical significance at the 5% level but this section of the analysis is hampered by the relatively small number of subjects who had never smoked. One of the important points to emerge from this study was the large variance which we observed in all lung function indices in all groups, so that one could find severe disability in either sex, even among those who had never smoked. Certain occupational dusts and fumes contain substances in particulate and vapour phases which could theoretically contribute to the development of emphysema, though the concentration of such material in the airways could rarely approach that of cigarette smoke. In the patients reported here, any such occupational exposure was commoner among males than females and commoner among smokers than among those who had never smoked, though our data have not been analysed to indicate the precise sources of these pollutants; multiple regression analysis did not however suggest that such exposure contributed to the lung function deterioration (Table III). An association between AT deficiency and chronic liver disease has been recognized (Berg & Eriksson, 1972) and characteristic inclusion bodies of AT can be observed within the liver parenchymal cells of subjects with the Z variant (Lieberman et al. 1972). The defect in the molecular structure of the Z variant apparently interferes with the intracellular transport mechanism and storage of the abnormal protein within the hepatocytes predisposes to subsequent liver disease. In this survey, a history of liver disease was reported in only nine subjects (5%) and none was stated to have died from cirrhosis, though autopsy data was sparse. Indeed, Larsson (1978) found that liver disease was the main cause of death in 12 out of 91 deceased patients of Pi type Z, though these cases may have been drawn from specialities other than respiratory medicine. The British Thoracic Association survey naturally has a strong bias towards selection for emphysema and cases dying of cirrhosis without obvious lung disease are not likely to have come to our notice. The prevalence of cirrhosis in type Z subjects may indeed be much higher than is clinically apparent. Peptic ulceration was observed by Eriksson (1965) in 30% of his 37 subjects

Alphalantitrypsin

Deficiency

25

with AT deficiency but in contrast only eight of the subjects (5%) in our study had a history of peptic ulceration; there is no obvious explanation for this difference. Eleven per cent of the subjects were believed to have bronchial asthma but no other lung disorders of significance were reported. Treatment for this form of emphysema is limited. Counselling Pi Z subjects to avoid cigarette smoking or occupations with any form of atmospheric pollution is a common-sense measure and for those already suffering from emphysema administration of a bronchodilator may improve lung function as shown in our results (Table II). Replacement of the missing plasma fraction would require frequent intravenous administration as the half-life of AT in the body is only some 4 days (Kueppers & Fallat 1969). Synthetic elastase inhibitors have been developed which are highly effective in vitro, though their suitability for human administration is still in question. Gadek et al. (1980) administered danazol, a derivative of testosterone but without its masculinizing properties, to six Pi Z patients and showed that serum AT could be increased by an average of 37% by augmenting its discharge from the liver, though the patients were still left with a severely deficient serum concentration. Lung transplantation would be the only radical treatment for severe emphysema, and liver transplantation can correct the primary metabolic disorder and raise serum AT concentration to normal (Hood et al. 1980), but neither of these procedures is likely to be commonly practised in the foreseeable future. The natural history of AT deficiency indicates that in many cases it is a very serious disorder. Nearly 20% of our index cases died during the observation period at an average age of 53 years, the majority of deaths occurring among those who had at some time been cigarette smokers. Larsson (1978) determined the cumulative probability of survival in 248 Pi Z subjects and showed it to be very significantly reduced as compared with the normal Swedish population and that smokers were more severely affected than non-smokers. It is important to note that our index cases and the bulk of the cases of Larsson were a highly selected group in that they were incorporated into these surveys largely because of the development of clinical symptoms. There was only one death among our non-index cases though there was physiological and radiological evidence of emphysema in many of them; likewise Larsson (1978) f ound that only about one-third of the cases identified through family studies had normal lung function. Females who have never smoked appear to have a more favourable prognosis though even in this group a certain number develop emphysema at an early age. As we have already pointed out, the very wide variations in the outcome indicate that there must be other prognostic factors which have not yet been identified. The uncertainties in any estimate of prognosis are given additional emphasis by other considerations. The prevalence of type Z homozygotes among the newborn population has been estimated at 0.03% (Cook 1975) but at least 92% of these infants avoid or survive liver disease (Psacharopoulos et al. 1981) and few die of emphysema under the age of 40. On the evidence of this survey the majority of Pi Z subjects with respiratory symptoms would present to a chest physician between the ages of 45 and 54 years and in this age band the adult population of

M. J. Tobin, P. J. L. Cook and D. C. S. Hutchison

26

the UK is roughly six million. Assuming that the adult prevalence differs little from the newborn figure, we would therefore expect the number of type Z homozygotes in this age band to be about 2000, of whom we have detected a mere 90. Many of the AT deficient subjects in this survey have been followed up for some years and it will therefore be possible to determine the rate of change in the lung function indices in various groups of patients. A serial study will be important if a serious estimate of prognostic factors is to be made and quite essential to the evaluation of any therapeutic measures that may become available in the future. Acknowledgements We are grateful to the chest physicians (over 150 in number) who submitted patients to this survey, completed questionnaires, arranged lung function tests and chest radiographs; to the many general practitioners who obtained blood samples at our request, to Mr P. A. Carlile of the MRC Human Biochemical Genetics Unit and Professor Milford Ward of the Supra-Regional Protein Reference Unit, Sheffield for assessment of Pi phenotypes, to Mr D. Cooper of King’s College Hospital Computer Unit for help with data processing, to Dr P. Gishen and Dr A. J. S. Saunders for assessment of the radiographs and to biochemical and physiological measurement technicians, secretarial staff and radiographers for their cooperation. Mrs Claire Robertson and Mrs Yvonne Phillips provided invaluable secretarial help. This research project was initiated and received the major part of its support through a generous grant from the Morriston-Davies Trust; additional funds were kindly contributed by Roche Products Ltd. References Anthonisen,

N. R. & Mibc-Emili,

J. appl.

Physiol.

21,

J. (1966)

Distribution

of pulmonary

perfusion

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