Goldman, H.I.

Kanarek, D.J.

Milne, F.J.

Zwi, S

English

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144 S.A. MEDICAL JOURNAL 6 February 1971ALPHA,·ANTITRYPSIN DEFICIENCY*D. J. KANAREK, M.B., B.CH. (RAND), D.C.H. (R.c.P. & S.), F.C.P. (SA), S. ZWI, B.Sc., M.B., B.CH. (RAND), M.R.C.P.(LaND.), F. J. MJLI'.'E, M.B., CH.B. (CAPE ToWN) AND H. I. GOLDMAN, B.Sc. HONS. (RAND). Respiratory Unil,Department of Medicine, University of the Witwatersrand alld Johannesburg Hospital, Johannesbur:,;The association between homozygous alpha,-antitrypsindeficiency and chronic obstructive pulmonary disease wasfirst described by Laurell and Eriksson in 1963' and sincethen numerous reports have confirmed and extended theirobservations. The concept envisages a relatively uninhi-bited proteolytic enzymatic proce.s which is able to pro-duce type A (emphysematous), type B (chronic bronchitic)or a mixed form of lung disease, depending on the siteof maximum effect.' The first 2 South African cases withhomozygous a!pha,-antitrypsin deficiency associated withsevere obstructive airways disease are described in thispaper together with studies of some members of theirrespective families.The procedure used for measuring alpha,-antitrypsindeficiency was that of Eriksson' The normal range forthis laboratory is 1·0 - '·7 mg trypsin inhibited per mlof serum. Levels between 0·3 mg and 1·0 mg were re-garded as denoting heterozygosity while a figure less than0·3 mg conferred homozygous status.CASE REPORTSCase 1The patient's first symptoms occurred in 1956, at theage of 27, when he noticed the presence of exertionaldyspnoea. There was no cough or sputum production atthis stage. During the next 6 years the dyspnoea worsenedand, in addition, physical signs of hyperinflation andairway obstruction occurred. There was decreased cardiacand liver dullness, poor diaphragmatic movement, de-creased breath sounds and- expiratory rhonchi. In 1962 hefirst developed a cough which became productive onlyin 1966, by which time he was able to walk no morethan 50 yards. At this stage he had the physical featuresof the type A (emphysemataus or 'pink puffer') form ofobstructive disease with severe obstruction, hyperinflationand hyperventilation at rest: In addition, there was alsoclinical pulmonary hypertension. Thereafter, he developedprogressive respiratory failure with cor pulmonale anddied in 1969. In the last year of his life he exhibitedmarked paranoia.His cigarette consumption was 20/ day for 20 years. Asa child he had suffered from pneumonia, measles, whoop-ing cough and mumps. There was a strong family historyon his maternal side of lung disease, including pneumonia,asthma, chronic bronchitis and emphysema. Unfortunatelynone of these patients or their clinical records wereavailable to us.Initial chest X-rays in 1960 were normal. By 1967,however, there was marked flattening of the diaphragmswith very littie excursion, hypertranslucent lung fields,marked prominence of the pulmonary artery segment withattenuation of the peripheral vessels but no heart-chamberenlargement (Fig. I). Later, during the Jast 18 monthsof his life, some right-sided enlargement of the heart*Date received: 16 Jilt\' ]0-ndeveloped. Electrocardiographic examination in 1960(Fig. 2) showed a mean QRS frontal plane axis of aboutFig. 1. Chest X-ray of case 1 taken in 1967.!iFig. 2. Electrocardiograms of case I laken in 1960 and1969.90° and clockwise rotation. By 1969, there was verymarked right atrial and right ventricular enlargement.Full blood count, urea and electrolyte investigationswere normal. His protein electrophoretic pattern showedthe following results: albumin 4·33 g/lOO ml, alpha,-globulin 0·01 g/lOO ml, alpha,-globulin 0·53 g/lOO ml,beta-globulin 0·99 g/IOO ml and gamma-globulin 0·84g/ lOO ml. Investigation of the tryptic inhibitory capacityof the serum showed 0·28 mg trypsin inhibited per mlof serum, and therefore a homozygous state.Lung function studies were performed on 5 occasions6 Februarie 1971 S.-A. MEDIESE TYDSKRIF 145between 1960 and 1969 (Table I). Vital capacity dimi-nished on successive testing while there was increasinghyperinflation as represented by the rise in residualvolume. There was progressive airway obstruction andarterial oxygen desaturation, the latter becoming moremarked on exercise. Despite the hypoxaemia, the Iowarterial carbon dioxide tension demonstrates the alveolarhyperventilation characteristic of the 'pink puffer'. Heeventually developed respiratory acidosis and died.Specific studies of the tryptic inhibitory capacity ofthe patient's 3 daughters showed that all were heterozy-gotes. The figures measured in mg trypsin inhibited perml serum were J.L. 0'98; L.L. 0'81; and T.L. 0·89. Therewas no clinical evidence of pulmonary disease in any ofthem. The patient's wife had normal antitryptic activity.Case 2The patient first developed a cough productive of whitesputum in 1934 at 11 years of age. This cough persistedwith sputum production being at first intermittent andlater persistent, with occasional episodes of superimposedinfection. By the age of 30 he had noticed the onset ofexertional dyspnoea which was gradually progressive. Hesmoked heavily from the age of 16 for 20 years. Abrother and a sister both had asthma. He was first seenat Johannesburg Hospital in 1962 suffering from pneu-monia. On examination he was obese, slightly cyanosed,plethoric and showed evidence of cor pulmonale andright heart failure. In the chest diffuse rhonchi, poorbreath sounds and hyperinflation were present. The hae-moglobin was 18·7 g/lOO rnl with a packed cell volumeof 60%. Chest X-rays showed hypertranslucent lung fieldsand flat, poorly moving diaphragms. The pulmonaryartery segment and central pulmonary vessels were promi-nent but the heart was not enlarged. An electrocardio-gram showed right atrial and right ventricular hypertro-phy. Therapy with antibiotics, anti-failure drugs andbronchodilators was instituted and maintained, but theobstructive airways disease and cor pulmonale graduallyprogressed and he died in 1970. The clinical impressionremained predominantly that of the type B or 'bluebloater' form of obstructive airways disease.A marked feature on his final admission was thepresence of diffuse bruising. Full coagulation and fibrino-lytic studies were performed but no abnormality wasdetected. Serum protein electrophoresis was performedin 1969 and showed a total protein of 6·4 g/l00 ml withan alpha,-globulin of 0'10 g/lOO ml. Serum antitrypticactivity was measured and showed 0'347 mg trypsin inhi-bited/ml serum.The patient's 5 children, who are well, and his wifealso had their serum antitryptic activity measured. Thefigures measured in mg trypsin per ml serum were: MrD. B., age 23 years, 0·76; Miss S. B., age 19 years, 0'72.Mr F. B., age 15 years, 0'64; Miss M. B., age 13 years,0'88; and Miss L. B., age 10 years, 0·62. The patient'swife had normal antitryptic activity of 1·24 mg but thechildren are all heterozygotes. Despite the fact that thepatient's measured level was slightly above the acceptedfigure for our laboratory it is highly probable that hewas a homozygote.Lung function tests performed in 1965 showed verysevere obstructive airways disease with carbon dioxideretention, the latter feature being commonly present inthe type B form of disease. Further tests performed in1969 showed further carbon dioxide retention togetherwith a greatly increased residual volume and markedarterial oxygen desaturation at rest (Table I).DISCUSSIONThe 2 homozygous patients described above have severalcommon features such as an early onset of symptoms,death in early middle-age, strong family histories of pul-monary disease and asymptomatic heterozygous children.Equally important is the marked divergence in clinicalpresentation inasmuch as case 1 presented predominantlywith type A (emphysematous) disease while case 2 tendedtowards the clinical features of type B (bronchitic) in-volvement. If the theory of alpha I-antitrypsin deficiencyis to be accepted it should explain both the common andapparently divergent features of these 2 patients.Normally about 90% of serum antitryptic activity cir-culates as an alpha,-globulin and is called alpha,-anti-TABLE I. LUNG FUNcnON STUDIESCa.se I Case 21960 1962 1966 1967 1969 1965 1969Vital capacity litres measured .. 6'30 6·20 4-83 3·20 1'32 2'18 3·09% of predicted value I11 108 85 58 24 43 62Functional residual capacity litres measured 6·43 6-43 6·66 7-11 6·47% of predicted value .. . . . . . . . . 151 151 158 169 156Residual volume litres measured .. 3'n2 3·58 4·65 6·74 5·54% of predicted value 170 165 206 291 242Total lung capacity litres measured 992 9·78 H8 8·06 863% of predicted value .. . . . . 126 123 121 102 118MYYF htre/min me'lsured 98 96 44 35 8 22 24% of predicted value .. 57 55 27 21 6 If> 18FEV, litres 207 2·23 1·08 0·8 0·37 0·50 0·65Rest ventilation litres/min 12·0 16·4 17·8 16·0 7·9 10-4Arterial 0, saturation %-rest 90 91 82 80 88,5* 71·5Arterial 0, saturation %-ex. 82 77 61 59Blood pH 7-395 7-43 7-315 7·38 7-43Blood peo, mmHg 30·5 290 49·0 48·5 89·0*Patient was breathing O~ continuously and tolerated only 2 minutes without it, when this measurement was made.Technique':) and predicted va~ues used have been pubiished previOl:sly.4-710146 S.A. MEDICAL JOURNAL 6 February 1971trypsin. In some patients with chronic obstructive pulmo-nary disease, a decrease in alpha I-antitryptic activity hasbeen found, the defect probably being carried via anautosomal-recessive gene. Thus homozygous patientshaving about 10% of normal activity, and heterozygotes,having about 50% of the normal value, have been de-scribed.·Alpha,-antitrypsin or very similar globulins inhibitseveral other proteolytic enzymes besides trypsin, suchas chymotrypsin, plasmin, thrombin9 and elastase,'· as wellas the digestive enzymes released from leucocytes." Thetheory claims that deficiency of antitryptic activity per-mits digestion of protein. Thus continual slow release ofpoorly inhibited proteolytic enzymes from alveolar macro-phages, leucocytes and other phagocytic cells may resultin digestion of alveolar septa producing panacinar em-physema or type A disease. In those cases where thereis chronic bronchial irritation by agents such as cigarettesmoke, recurrent infections, or air pollution, the leuco-cytic enzymes would be concentrated in the airways andthe lack of proteolytic inhibition could result in predomi-nant chronic bronchitis and centrilobular emphysema(type B disease).' Obviously a combination of the 2 typesof disease could occur.It is possible that part of the bronchitic element incase 2 could be ascribed to the patient's cigarette smoking,but coughing had begun at the age of 11 years, 5 yearsbefore he had started smoking. In Eriksson's series' abouthalf of his homozygous-deficient patients had evidenceof chronic bronchitis and chronic cough before the onsetof dyspnoea.There appears to be a definite association between thehomozygous state and obstructive airways disease, especi-ally panacinar emphysema, the incidence varying fromI to 100 0",,13 or more"·lG depending on the group ofpatients studied. Whether heterozygotes have an increasedliability to disease is still disputed. Some authors havenot found this association,"'lS while others" have claimedthat heterozygous subjects do have an increased liabilityto pulmonary involvement. Lieberman," in fact, foundthat 15·2% of 66 patients hospitalized with pulmonaryemphysema had heterozygous alpha,-antitrypsin deficiency.The over-all incidence of the deficiency was 25'8 % inthis group. Of patients under the age of 50 years, 47·8%had deficient levels. If such observations are confirmed,the role of alpha,-antitrypsin activity will assume a posi-tion of great importance in this increasingly commondisease. It must be emphasized, however, that not allpeople with the deficiency-even homozygotes-will de-velop disease, and other factors must therefore be operableas well.The best and simplest screening test for alpha ,-anti-trypsin deficiency is protein electrophoresis, preferablyperformed by the cellulose acetate method.'• An alpha,-globulin level of less than 0·20 g/lOO ml should befollowed by a more specific test for antitrypsin deficiency.The most commonly used method is the enzymaticmeasurement of the trypsin-inhibitory capacity of theserum as performed in our cases described above. Alter-native techniques such as immunodiffusion'" or antigen-antibody-crossed electrophoresis" have also been de-scribed. It should be noted that, especially in a heterozy-gote, infection," pregnancy'" or contraceptive pills' mayraise the levels of alphaI-antitrypsin into the normal range.Since antitryptic activity also functions against otherproteolytic enzymes, it was thought that increased fibrino-lytic activity might be present, especially in the secondpatient, who bruised very easily. However, full testingfailed to disclose any defect. Possibly, since there is alarge degree of functional reserve in antifibrinolytic acti-vity, an additional situation involving increased fibrino-lysis might bring out such a tendency.SUMMARYThe first 2 cases of homozygous alpha,-antitrypsin deficiencyin South Africa are described, together with evidence demon-stratina the heterozygous status of their children. Their clinicalcourse~ and special investigations are described illustratingthat these cases may present with either predominantly em-physematous or bronchitic features. The condition is reviewedand the methods and importance of diagnosis are pointed out.We wish to thank the staff of the Pneumoconiosis ResearchUnit for the estimations of trypsin inhibitory capacity, andDr M. Salmon, Medical Superintendent of JohannesburgHospital, for permission to publish.REFERENCES!. Laurel!. C. B. and Eriksson, S. (1963): Scand. J. Clin. Lab. Inves!.,15, 132.2. Falk, G. A. and Briscoe, W. A. (1970): Ann. Intern. Med.. 72, 427.3. Eriksson. S. (1965): Acta med. scand., 177, supp!. 432, !.4. Goldman, H. I. and Becklake. M. R. (1959): Amer. Rev. Tuberc.,79, 457,5. Zwi, S., Goldman, H. 1., Kamener, R. and Ob"l, I. W. P. (1965):S. Afr. Med. J., 39, 922.6. Kotler, M. N., Zwi, S. and Goldman. H. 1. (1967): Ibid.. 41. 625.7. Goldman. H. I., Zwi, S., Levin, '. W .. Rubenstein, A. H .. Stables,D. P., Van As, A. W. W. and Elliott, G. A. (1967): Ibid.. 41, 97.8. Eriksson, S. (1964): Acta med. scand., 175, 197.9. Rimon, A., Shamash, B. and Shapiro, B. (1966): J. BioI. Chem., 241,5102.10. Turino, G. M., SenioI', R. M .. Garg. B. D., Keller, S., Levi, M. M.and Mandl, 1. (1969): Science, 165, 709.11. Kueppers, F. and Beam, A. G. (1966): Proc. Soc. Exp. Bio!. (N.Y.),121, 1207.12. Briscoe, W. A., Kueppers, F., Davis, A. L. and Beam. A. G. (1966):Amer. Rev. Resp. Dis:, 95, 529.13. Kueppers, F., FaUat, R. and Larson, R. K. (1969): Science. 165. 899.14. Lieberman, J. (1969): New Engl. J. Med., 281, 279.15. Tarkoff, M. P., Kueppers, F. and Miller, W. F. (1968): Amer. J.Med., 45, 220.16. Hepper, N. G., Black. 1.. F., Gleich, G. J. and Kueppers, F. (1969),Proc. Mayo Clin.. 44. 697.17. Eriksson, S. (1970): Lancet, I, 89!.18. Welch, M. H., Reinecke, M. E., Hammarstein, J. F. and Guenter,C. A. (1969): Ann. Intern. Med., 71, 533.19. Lieberman, J., Miuman. C. and Schneider, L. (1969): J. Amer. Med.As.soc., 210, 2055.20. Talamo, R. C., Alien, J. D., Kahan, M. G. and Austen. K. F.(1968): New Engl. J. Med., 278, 345.21. Laurell, C. B. (1965): Analyt. Biochem., 10. 358.22. Schultze, H. E., Heide, K. and Haupt, H. (1962): KJin. Wschr., 40,427.

Alpha1-antitrypsin deficiency

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Alpha1-antitrypsin deficiency

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