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(1) Deficiency of alpha AT is one of the most common hereditary diseases affecting Caucasians in Europe. The alpha 1AT protein is extremely pleomorphic, and around 90 variants due to mutations have been recognized. The prime functions of alpha 1AT is to inhibit neutrophil elastase, and a proportion of individuals who are deficient in alpha 1AT develop emphysema. The most common deficiency variant (Z) is also associated with liver disease. The main site of alpha 1AT synthesis is in the liver. Not all deficient individuals are affected by lung or liver disease, however, so that other factors (genetic and environmental) are clearly important. (2) Investigation of alpha 1AT status is essential in any child or adult presenting with chronic liver disease. The genetic cause cannot be identified clinically or by any other laboratory investigation. The diagnosis carries important prognostic consequences and is important for other family members. Patients with emphysema should have their Pi type determined, especially if they are under the age of 50, have never smoked or there is a suggestive family history. Asymptomatic individuals who are homozygous type Z should be referred to a chest physician for a clinical and radiological assessment together with lung function tests. (3) Several laboratory tests are available to detect alpha 1AT deficiency, and the choice of test(s) will depend on circumstances. Quantitation of the serum protein is simple and cheap. Because alpha 1AT is an acute phase protein, however, quantitation used in isolation may give false negative results which are clearly unacceptable, particularly in association with paediatric liver disease. Phenotyping by isoelectric focusing requires some experience in distinguishing SZ and ZZ phenotypes, and phenotyping should ideally be used in conjunction with quantitation because heterozygous null phenotypes may appear identical to homozygous normal phenotypes. (4) Prenatal diagnosis is usually performed by DNA analysis of CVS samples obtained at 11-13 weeks. Because of the risk that CVS samples might be contaminated by maternal tissue, assays which are less likely to detect minor contaminants are preferable. At present, use of DNA tests is confined to prenatal diagnosis, but the availability of simple tests and the possibility of unequivocal identification of S and Z alleles means that these tests are likely to find greater use in the near future.

Desmosine is an amino acid specific to elastin. Animal studies suggest that urinary desmosine (UD) represents endogenous elastin degradation. Therefore, UD has previously been used to investigate endogenous elastolysis, but was not elevated in subjects with chronic obstructive airways disease (COAD), although accelerated pulmonary elastolysis is thought to contribute to COAD. We have investigated whether this reflects large day-to-day and between-subject variation in UD and whether, in man, dietary desmosine contributes significantly to that in urine. Mean 24-hour UD output (over 5 consecutive days) from 10 asymptomatic subjects (5 males) was higher in males than females (77.4 +/- 9.6 and 40.2 +/- 5.0 nmol/24 hours, respectively; mean +/- SD, P less than .001), but not significantly different when expressed in terms of creatinine (micrograms desmosine/100 mg creatinine: males, 2.5 +/- 0.4; females, 3.1 +/- 0.8; mean +/- SD). The lowest between-subject variation was observed when the mean of 5 days' 24-hour UD values was analyzed on the basis of gender (coefficient of variation [CV], 12.5%); when gender was not considered, the least between-subject variation was found for the mean of 5 days' desmosine/creatinine analysis (CV, 24.5%). Approximately 1% of dietary desmosine (ingested as [3H]elastin and [3H] desmosine) was excreted in the urine within 24 hours, contributing approximately 15% of UD while on a normal diet. Although ingestion of a low elastin diet (less than 1/10 desmosine/24 hours than a normal diet) resulted in lower within-subject variation in 24-hour UD excretion (mean CV decreased from 31.5% to 20.2%), the between-subject CV and UD levels did not alter.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha 1-protease inhibitor can exist as over seventy different biochemical variants (the Pi system) which are inherited as autosomal codominant alleles. The majority of these variants are of no clinical significance. Epidemiologically, the most abundant are Pi types M, S and Z. Homozygotes of type Z have only 10 to 20% of the normal serum concentration of the inhibitor and have an increased risk of developing pulmonary emphysema. Cigarette smoking is the most important risk factor. A minority of Pi Z homozygotes (10 to 20%) develop a form of neonatal hepatitis and a proportion of these suffer from cirrhosis in adult life. Heterozygotes of Pi type SZ have about one third of the normal serum alpha 1-protease inhibitor concentration but this phenotype does not in itself appear to be a significant emphysema risk factor. Heterozygotes of Pi type MZ are thought to have a moderately increased risk of developing emphysema but only if they smoke; there is also evidence for an increased risk of cirrhosis among subjects of type MZ. No excessive risk appears to be attached to the MS phenotype. Cumulative survival curves have suggested that type Z homozygotes have a poor prognosis but such estimates are based on clinic or hospital patients who already have respiratory symptoms. Calculations based on population frequencies however, suggest that about 90% of the total number of type Z subjects are not accounted for in such surveys. Their whereabouts remains unclear at present; some will undoubtedly have died of liver or lung disease but it is possible that the majority escape and live undetected among the general population.

The effects of inhaling 400 micrograms of salbutamol were compared with identical placebo inhaler in a double blind cross-over study of 20 patients with radiological evidence of pulmonary emphysema. There was a small but significant rise in the forced expiratory volume in one second (FEV1), but there was a much greater increase in vital capacity (VC), which was accompanied by a reduction in residual volume. Symptomatic improvement after salbutamol was reported by 14 of the patients and VC increased significantly in this group; there was no significant increase in VC in patients who did not prefer the active inhaler. There was no consistent change in the FEV1/VC ratio after salbutamol administration and this ratio is misleading as an indicator of bronchodilator responsiveness in patients with emphysema. Salbutamol is thus a valuable addition to treatment in patients with pulmonary emphysema and the response to treatment is best judged by measuring the improvement in VC.

In a multicentred survey of alpha 1-antitrypsin deficiency, radiological details have been obtained in 165 subjects homozygous for Pi type Z and in 23 subjects heterozygous for type SZ. Eight-five per cent of all type Z subjects had radiological evidence of pulmonary emphysema which was commoner in smokers than in those who had never smoked and which predominantly affected the lower zones of the lungs; 66% of the type Z subjects identified through family studies also had emphysema. Emphysema in subjects of Pi type SZ was limited to those who had smoked; this phenotype may not carry a specific risk of emphysema.

Alpha-1-protease inhibitor (A1PI) exists in over 30 biochemical variants (the Pi system), inherited as autosomal codominant alleles. Homozygotes of Pi type Z have only 10 to 20 percent of the normal serum A1PI concentration and have a high risk of developing pulmonary emphysema. A1PI is an inactivator of polymorph lysosomal elastase, the unopposed action of which may damage the lung. Cigarette smoking is an important additional risk factor. Neonatal hepatitis occurs in 10 to 20 percent of Pi type Z persons, and cirrhosis develops in a number of them in later childhood or in adult life. In heterozygotes of Pi type MZ, pulmonary or hepatic disease may also develop, though they are at lesser risk than type Z homozygotes. Specific A1PI replacement therapy derived from human plasma is now available and has been administered to Pi type Z patients by weekly intravenous infusion without adverse effects. A controlled clinical trial would be desirable, though this would be attended by organizational and economic problems.

Neutrophils contain the enzyme myeloperoxidase, which oxidizes Cl- ions into the powerful oxidant hypochlorous acid (HOCl). HOCl inactivates alpha 1-antiprotease, permitting uncontrolled protease activities. Most anti-inflammatory drugs tested are capable of reacting with HOCl, but the reactions seem insufficiently rapid under physiological conditions to protect alpha 1-antiprotease against inactivation by HOCl. However, rapid scavenging of HOCl might contribute to the anti-inflammatory effects of penicillamine, gold sodium thiomalate, phenylbutazone and primaquine.

Thiourea and dimethylthiourea are powerful scavengers of hydroxyl radicals (.OH), and dimethylthiourea has been used to test the involvement of .OH in several animal models of human disease. It is shown that both thiourea and dimethylthiourea are scavengers of HOCl, a powerful oxidant produced by neutrophil myeloperoxidase. Hence the ability of dimethylthiourea to protect against neutrophil-mediated tissue damage cannot be used as evidence for a role of .OH in causing such damage. Dimethyl sulphoxide also reacts with HOCl, but at a rate that is probably too low to be biologically significant at dimethyl sulphoxide concentrations up to 10 mM. Neither mannitol nor desferrioxamine, at the concentrations normally used in radical-generating systems, appears to react with HOCl.

Twelve male patients with radiological evidence of pulmonary emphysema performed progressive exercise tests on a cycle ergometer. Ipratropium bromide (Ip) 40 micrograms, Fenoterol (Fen) 400 micrograms, their combination (Ip/Fen) and Placebo were administered from metered-dose inhalers in a double-blind crossover study to compare the effects on ventilation (VE), heart rate (fc) and oxygen uptake (VO2) at rest and at maximal and sub-maximal workloads. There were no significant differences in resting VE (p greater than 0.05) between the 4 treatment regimes. During submaximal exercise, VE at a given workload was greater after Fen containing treatment regimes than after Ip alone or placebo. There was no significant difference in the maximal workload achieved after the active treatments compared with placebo. With respect to fc and VO2, there were no differences between treatments at rest or on submaximal or maximal exercise. Fenoterol produces a mild stimulation of VE during exercise as observed with other beta-agonists, but compared with the changes in resting vital capacity, functional residual capacity and residual volume, the bronchodilator induced changes in exercise variables were relatively small.

Of 99 patients with chest pain undergoing coronary arteriography, 31 had normal coronary arteries, 15 slight disease, and 53 significant coronary obstruction. 28 (61%) of the 46 with haemodynamically insignificant disease and 12 (23%) of the 53 with significant obstruction had psychiatric morbidity, assessed by standard interview. 37 patients had several respiratory symptoms and signs not attributable to organic disease, designated unexplained breathing disorder (UBD). UBD was found in 65% of the patients without and 13% of those with significant coronary disease; it was associated with psychiatric morbidity in the former but not in the latter group. Spirographic measurements of tidal volume and frequency were not helpful in detecting UBD but an end-tidal pCO2 below 30 mm Hg was highly suggestive. In the absence of significant coronary disease the associations of chest pain with psychiatric morbidity and UBD are striking. However, coronary disease and UBD are not mutually exclusive, and diagnostic difficulties can occur when they coexist.

Extensive research, stimulated by the recognition of an association between alpha 1-antitrypsin (alpha 1-AT) deficiency and emphysema, has greatly advanced our understanding of emphysema in general. In this article, we review the literature concerning the basic defect, inheritance, pathogenesis of lung disease, clinical, physiologic, and roentgenographic findings in patients with severe (Pi SZ) deficiency of alpha 1-AT. Data obtained in relatives with alpha 1-AT deficiency, who have not been seen by a physician, should more truly reflect the risk of having lung disease. These studies confirm the increased risk of developing lung disease in cigarette smokers. The implications of the finding that subjects with Pi SZ are probably not at an increased risk of lung disease is discussed with regards to replacement therapy. The natural history of unselected subjects with alpha 1-AT deficiency remains unknown.

Hereditary deficiency of alpha 1 antitrypsin, 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.

Fifty-six male patients with pulmonary emphysema were followed for a minimum period of three years (range 3-13), to observe the effects of smoking and smoking withdrawal. The subjects were divided into smokers (Group S) and ex-smokers (Group EX-S). Forced expiratory volume in one second (FEV1) and vital capacity (VC) declined at a significantly (p less than 0.001) faster rate in those who continued to smoke than in ex-smokers. No significant difference between the two groups was observed for kCO (permeability coefficient) and PaO2 (arterial oxygen tension). There was a significant (p less than 0.001) difference between the two groups in the annual change in body weight. We conclude that all patients with emphysema, even those with advanced disease, should be encouraged to stop smoking.

The elastase-inhibitory capacity of purified human alpha 1-antiproteinase is inactivated by low concentrations of the myeloperoxidase-derived oxidant hypochlorous acid, but much higher concentrations are required to inhibit the elastase-inhibitory capacity of serum samples. The protective effect of serum appears to be largely due to albumin. High concentrations of H2O2 also inactivate the elastase-inhibitory capacity of alpha 1-antiproteinase, by a mechanism not involving formation of hydroxyl radicals. Serum offers protection against H2O2 inactivation of alpha 1-antiproteinase. The relevance of these results to the tissue damage produced by activated phagocytes is discussed.

In a multicentre survey of alpha 1 antitrypsin deficiency 25 heterozygotes of type SZ were identified. Fourteen index cases were identified through chest clinics and 11 non-index cases through family studies. Emphysema was largely confined to index males who had smoked and there was little evidence of the disease among the non-index cases. It appears that the SZ phenotype may carry little or no extra risk of emphysema.

A number of proteolytic enzymes (proteases) and their inhibitors (anti-proteases) have been demonstrated in the bronchial secretions. The most important of these proteases is probably the potent elastase derived from polymorphonuclear leukocytes (PMN) which are recruited into the bronchial tree during inflammation. This enzyme can degrade elastin, collagen and proteoglycan and can damage the bronchial epithelium; it is inhibited by antileukoprotease and by alpha protease inhibitor (API). Pulmonary macrophages also secrete an elastase, but Pseudomonas aeruginosa is the only microorganism known to produce elastase. Antileukoprotease is probably the most important of the antiproteases to be found in bronchial secretions. Other antiproteases such as low molecular weight inhibitors, API and alpha 2 macroglobulin have been demonstrated in bronchial secretions but they are present in low concentration. A balance between proteolytic enzymes and their inhibitors is thought to be of great importance in the prevention of proteolytic damage to local tissues, not only in emphysema but also in chronic bronchitis, bronchiectasis and cystic fibrosis. Oxidants derived from PMN or from tobacco smoke can inactivate protease inhibitors and in both the bronchial tree and the lung parenchyma, a balance between oxidants and anti-oxidants must presumably also be maintained to prevent local tissue damage.

Of 72 patients with radiological evidence of pulmonary emphysema, emphysema occurred either alone or in association with bronchitis in 61, and 8 of these (13%) were found to have alpha(1)-antitrypsin deficiency. The main features of this condition are: exertional dyspnoea of relatively early onset (generally between 30 and 45 years of age), severely impaired FEV(1) and T(L)CO, and radiological emphysema predominantly affecting the lower zones of the lungs. It is probable that any patient with all the above abnormalities has alpha(1)-antitrypsin deficiency. There is evidence to suggest that cigarette smoking may hasten the onset of this type of emphysema.