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LUNG DISEASE AND THE OESOPHAGUS
145 the lamina propria and the frequency of IgA deficiency in the serum was recently proposed by Beale et a1.,33 who demonstrated that, although their IgA serum levels may be normal, the responses of coeliac patients to oral polio vaccine are often qualitatively deficient in IgA antibody. A report on p. 121, adding 2 more cases of isolated IgA deficiency with gluten-sensitive malabsorption to those already recorded, underlines the relevance of IgA abnormalities to the immunological problem of coeliac disease. An accompanying paper (p. 124) describes a family which provides a striking link between genetic aspects of IgA deficiency and its relationship with atopy5 and with autoimmune conditions.6In this family, the occurrence of 5 members from two generations with total IgA deficiency was explicable, as has been previously suggested, by inheritance of an autosomal dominant trait; and among the 5 affected members adult coeliac disease, pernicious
anxmia,
recurrent
sino-pulmonary infection, asthma,
all represented. Other evidence of autoimmunity in coeliac disease is also coming forward in the shape of IgG anti-reticulin autoantibodies7 and antibodies supposedly directed at basement membrane,which are of particular interest not only from the viewpoint of possible pathogenesis, but also because an increased incidence of IgA deficiency is reported in some of the connective-tissue diseases.99 Whatever the link may be between immunological deficiency and autoimmune disease, it looks as if further work on the immunology of coeliac disease might well help to define it. and
eczema were
ASSESSMENT OF EQUIPMENT
A
10
electrical
safety
in hospitals a guide for consumers-a Which? -for suggested the assessment of monitoring equipment would be widely welcomed. That remark sprang from the lack of unanimity about the best method of ensuring the safety of a patient with an external pacemaker in situ. Such patients, it seems, may be thrown into ventricular fibrillation by leakage currents from monitoring apparatus in simultaneous use. Since then our attention has been drawn to the work of the Emergency Care Research Institute in Philadelphia,l1 an organisation which is carrying out just the sort of work we mentioned. 10 The Emergency Care Institute does not concern itself simply with the performance of monitoring equipment, though it is significant that the first article in the first issue of its publication, Health Devices, is concerned with the fallacy of the supposed safety of isolated electrical power supplies for monitoring equipment. The same issue, however, also contains a discussion of various types of resuscitation equipment and of tracheal suction machines. COMMENTARY
on
that
Kaufman, H. S., Hobbs, J. R. ibid. 1970, ii, 1061. Ammann, A. J., Hong, R. Clin. exp. Immun. 1970, 7, 833. Seah, P. P., Fry, L., Hoffbrand, A. V., Holborow, E. J. Lancet, 1971, i, 834. 8. Ammann, A. J., Hong, R. ibid. p. 1264. 9. Cassidy, J. F., Burt, A., Petty, R., Sullivan, D. New Engl. J. Med. 1969, 280, 275. 10. Lancet, 1971, i, 845. 11. 913 Walnut Street, Philadelphia, Pa. 19107. 5. 6. 7.
Some progress has been made on the electrical side in Britain. The Hospital Equipment Bulletin, issued by the Department of Health and Social Security comments on a number of pieces of equipment which may be bought for use in the National Health Service, but, at present, the circulation of this document is largely confined to hospital supplies officers. There is still a case for an independent assessment body, at a time when increasingly elaborate contrivances are being marketed, such as automated analysers and other expensive equipment for pathological departments, much anxsthetic and X-ray apparatus, and many devices for intensive-care units. The purchaser is not the user, but someone with a primary interest in reducing expenditure. It can be argued, therefore, that the interest of the user-the physician, surgeon, pathologist, radiologist, or anxsthetist-and of the patient for whose benefit the apparatus is purchased, may not be best served until an independent body has been established for the assessment of such apparatus.
LUNG DISEASE AND THE OESOPHAGUS
THE anatomical arrangements in man for conveying food from the exterior to the digestive portions of his alimentary canal are convenient, and even offer certain msthetic pleasures. The common embryological origins of foregut and respiratory system and their consequent proximity, however, carry some disadvantages, and the several ingenious mechanisms for diverting food and fluid from the airways may fail. They are particularly prone to do so when previously ingested substances return up the oesophagus during anaesthesia, unconsciousness, or even natural sleep, and the catastrophic consequences of inhaling vomit The insidious are well recognised and justly feared. effects of inhalations pulmonary repeated may more easily escape attention. If the patient tends to choke (as, for example, in neurological disorders of the swallowing mechanism), the cause of their pneumonia will soon be discovered, and associated dysphagia in oesophageal strictures or carcinomas will call for remedial action on their own account. The pulmonary complications of less obvious oesophageal lesions have not been studied intensively, though Plummer and Vinson1 recognised them. Hurst2 described patients with achalasia whose oesophageal symptoms were overshadowed by respiratory ones, and others 3,4 have reviewed the respiratory problems in series of patients with cesophageal diseases. They have mostly emphasised achalasia,
stenotic lesions, and diverticula
as
causes, while the
disorder-gastro-cesophageal reflux-has been discussed least in this context. It is well recognised that regurgitation of gastric contents occurs easily and frequently when the lower cesophageal sphincter mechanism is deficient (whether there is a hiatus hernia or not), and associated bronchitis or pneumonia have been accepted as possible consequences of aspirating regurgitated acid-peptic juice. commonest
1. 2. 3. 4.
Plummer, H. S., Vinson, P. P. Med. Clins. N. Am. 1921, 5, 355. Hurst, A. Guy’s Hosp. Rep. 1943, 92, 68. Belcher, J. R. Thorax, 1949, 4, 44. Belsey, R. Br. J. Dis. Chest, 1960, 54, 342.
146 Pearson and Wilson5 report the coexistence of diffuse pulmonary fibrosis and hiatus hernia in 6 patients, and they tentatively suggest a causal link. They also surveyed 143 consecutive patients with hiatus hernia and reflux symptoms, and found pulmonary fibrosis in 4%. The step to accepting reflux as the cause of the lung damage is a large one, and, since hiatus hernia is so common, it will be difficult to take. No specific features, either pathological or radiological, permit such changes to be unequivocally attributed to aspiration, and no study so far has shown arrest of progress (or even improvement) of the fibrosis But these observations when reflux is prevented. should give physicians pause when dealing with patients who have chronic respiratory troubles; at least a barium meal is justified if there is associated dysphagia or heartburn, or even if the anatomical distribution of the lung changes suggests aspiration as a cause. Unfortunately, radiological examination is an inadequate tool for assessing functional gastrooesophageal impairment, and if the reflux/lung disease association comes to be accepted, perhaps oesophageal manometers and pH recorders will take their place alongside spirometers and peak-flow meters in the
respiratory laboratory.
CARCINOMA AND THE NEPHROTIC SYNDROME
THE study of experimentally induced renal disease has established that the deposition of immune complexes in the kidney may damage the glomeruli, and this mechanism is thought to be important in the pathogenesis of human glomerulonephritis.7 In patients with systemic lupus erythematosus the antigen/ antibody complex has been shown to be D.N.A and antibody to D.N.A.,8 and in the malarial nephrotic syndrome antigens derived from the parasite have been demonstrated in the glomeruli.9 In most patients with glomerulonephritis, however, little is known about the antigen responsible, and it is in this context that reports of an association between malignant disease and glomerulonephritis are of considerable interest. Most such patients have a membranous glomerulonephritis-a condition in which immunoglobulin and complement are deposited on the basement membrane in a distribution characteristic of immune complexes. 10On p. 134 this week Professor Lewis and his colleagues describe how it was possible to elute antibody from the kidney of a patient who died of membranous nephritis associated with a bronchial carcinoma. The eluted antibody reacted specifically with an extract of the tumour, suggesting that the immune complexes in the kidney consisted of tumour antigen and antibody. It is perhaps surprising that the association between malignancy and this type of renal disease is so rare. A number of factors have been identified which may influence the formation of nephrotoxic immune complexes. The most important of these
be the nature and duration of the and the type of immune response. In virus-induced immune-complex disease in mice, genetic factors which probably act by influencing the antibody responses have been shown to be important The rarity of glomerulonephritis complicating carcinoma may be an indication of the importance of the host response to antigenic stimulation in the pathogenesis of human glomerulonephritis.
factors
CHOLECYSTOGRAPHY AND RENAL FAILURE
ABOUT 50 case-reports have appeared of acute renal failure after oral cholecystography 12: much less often, intravenous cholecystography has been implicated in renal failure. 13 One oral agent (sodium buniodyl) was withdrawn from the market after several such incidents.14 Sporadic cases continue to be reported." The mechanism is unknown. The most usual is direct tubular suggestion toxicity. 16 Another possiis that filtration glomerular decrease, 17 somebility times as a result of hypotension. 1111 A third hypothesis is obstructive renal failure caused by crystal deposition within the renal tubules. 12 Crystals have certainly been observed, but their nature is uncertain. At first sight, the dye itself might be to blame, but this is unlikely because of the solubility of the substances concerned.19 Another suggestion 20,21 is that these cholecystographic agents, being organic acids, act, like probenecid, as competitive inhibitors of urate transport by the renal tubule. At least two such substances (iopanoic acid and sodium ipodate) do indeed cause uricosuria of the same order as that produced by probenecid .20 Can the occasional case of nephrotoxicity be attributed, therefore, to urate deposits in the kidney? On the whole, it seems unlikely. Renal failure is not a common feature of probenecid therapy, despite the fact that the drug may be given for years to hyperuricxmic patients, and may indeed lead to calculus formation .22 Mudge 20 points out, however, that the circumstances in which these two groups of uricosuric drugs are given may differ. Gallbladder dyes are given in a single dose the evening before the examination. Liver insufficiency may cause high blood levels for a long time, and patients may be dehydrated by gastrointestinal disturbance or voluntary fluid restriction. Probably, therefore, the peak uricosuric effect coincides with a concentrated and acid urine. Below pH 5-6, most urate in the urine is 11. 12. 13. 14. 15. 16.
17. 5. 6. 7. 8. 9. 10.
Pearson, J. E. G., Wilson, R. S. E, Thorax, 1971, 26, 300. Lancet, 1968, ii, 267. Dixon, F. J. J. exp. Med. 1961, 113, 899. Koffler, D., Schurr, P. H., Kunkel, H. G. ibid. 1967, 126, 607. Ward, P. A., Kibukamusoke, J. W. Lancet, 1969, i, 283. Bariety, J., Druet, P., Labrue, G., Samarco, P., Millies, P. Path. Biol., Paris, 1970, 18, 5.
seems to
antigenic stimulus
18. 19. 20. 21. 22.
Oldstone, M. B. A., Dixon, F. J. J. exp. Med. 1970, 130, 1. Setter, J. G., Maher, J. F., Schreiner, G. E. J. Am. med. Ass. 1963, 184, 102. Craft, I. L., Swales, J. D. Br. med. J. 1967, ii, 736. Seaman, W. B., Cosgriff, S., Wells, J. Am. J. Roentg. 1963, 90, 859. Canales, C. O., Smith, G. H., Robinson, J. C., Remmers, A. R., Searles, H. E. New Engl. J. Med. 1969, 281, 89. Fink, H. E., Jr., Roenigk, W. J., Wilson, G. P. Am. J. med. Sci. 1964, 247, 201. Wennberg, J. E., Okun, R., Hinman, E. J., Northcutt, R. C., Griep, R. J., Walker, W. G. J. Am. med. Ass. 1963, 186, 461. Kohler, R., Holsti, L. R. Acta radiol. 1962, 57, 103. McChesney, E. W., Banks, W. F., Jr. Proc. Soc. exp. Biol. Med. 1965, 119, 1027. Mudge, G. H. New Engl. J. Med. 1971, 284, 929. Kelley, W. N. ibid. p. 975. Gutman, A. B., Yü, T-F. Am. J. Med. 1968, 45, 756.
anxmia,
recurrent
sino-pulmonary infection, asthma,
all represented. Other evidence of autoimmunity in coeliac disease is also coming forward in the shape of IgG anti-reticulin autoantibodies7 and antibodies supposedly directed at basement membrane,which are of particular interest not only from the viewpoint of possible pathogenesis, but also because an increased incidence of IgA deficiency is reported in some of the connective-tissue diseases.99 Whatever the link may be between immunological deficiency and autoimmune disease, it looks as if further work on the immunology of coeliac disease might well help to define it. and
eczema were
ASSESSMENT OF EQUIPMENT
A
10
electrical
safety
in hospitals a guide for consumers-a Which? -for suggested the assessment of monitoring equipment would be widely welcomed. That remark sprang from the lack of unanimity about the best method of ensuring the safety of a patient with an external pacemaker in situ. Such patients, it seems, may be thrown into ventricular fibrillation by leakage currents from monitoring apparatus in simultaneous use. Since then our attention has been drawn to the work of the Emergency Care Research Institute in Philadelphia,l1 an organisation which is carrying out just the sort of work we mentioned. 10 The Emergency Care Institute does not concern itself simply with the performance of monitoring equipment, though it is significant that the first article in the first issue of its publication, Health Devices, is concerned with the fallacy of the supposed safety of isolated electrical power supplies for monitoring equipment. The same issue, however, also contains a discussion of various types of resuscitation equipment and of tracheal suction machines. COMMENTARY
on
that
Kaufman, H. S., Hobbs, J. R. ibid. 1970, ii, 1061. Ammann, A. J., Hong, R. Clin. exp. Immun. 1970, 7, 833. Seah, P. P., Fry, L., Hoffbrand, A. V., Holborow, E. J. Lancet, 1971, i, 834. 8. Ammann, A. J., Hong, R. ibid. p. 1264. 9. Cassidy, J. F., Burt, A., Petty, R., Sullivan, D. New Engl. J. Med. 1969, 280, 275. 10. Lancet, 1971, i, 845. 11. 913 Walnut Street, Philadelphia, Pa. 19107. 5. 6. 7.
Some progress has been made on the electrical side in Britain. The Hospital Equipment Bulletin, issued by the Department of Health and Social Security comments on a number of pieces of equipment which may be bought for use in the National Health Service, but, at present, the circulation of this document is largely confined to hospital supplies officers. There is still a case for an independent assessment body, at a time when increasingly elaborate contrivances are being marketed, such as automated analysers and other expensive equipment for pathological departments, much anxsthetic and X-ray apparatus, and many devices for intensive-care units. The purchaser is not the user, but someone with a primary interest in reducing expenditure. It can be argued, therefore, that the interest of the user-the physician, surgeon, pathologist, radiologist, or anxsthetist-and of the patient for whose benefit the apparatus is purchased, may not be best served until an independent body has been established for the assessment of such apparatus.
LUNG DISEASE AND THE OESOPHAGUS
THE anatomical arrangements in man for conveying food from the exterior to the digestive portions of his alimentary canal are convenient, and even offer certain msthetic pleasures. The common embryological origins of foregut and respiratory system and their consequent proximity, however, carry some disadvantages, and the several ingenious mechanisms for diverting food and fluid from the airways may fail. They are particularly prone to do so when previously ingested substances return up the oesophagus during anaesthesia, unconsciousness, or even natural sleep, and the catastrophic consequences of inhaling vomit The insidious are well recognised and justly feared. effects of inhalations pulmonary repeated may more easily escape attention. If the patient tends to choke (as, for example, in neurological disorders of the swallowing mechanism), the cause of their pneumonia will soon be discovered, and associated dysphagia in oesophageal strictures or carcinomas will call for remedial action on their own account. The pulmonary complications of less obvious oesophageal lesions have not been studied intensively, though Plummer and Vinson1 recognised them. Hurst2 described patients with achalasia whose oesophageal symptoms were overshadowed by respiratory ones, and others 3,4 have reviewed the respiratory problems in series of patients with cesophageal diseases. They have mostly emphasised achalasia,
stenotic lesions, and diverticula
as
causes, while the
disorder-gastro-cesophageal reflux-has been discussed least in this context. It is well recognised that regurgitation of gastric contents occurs easily and frequently when the lower cesophageal sphincter mechanism is deficient (whether there is a hiatus hernia or not), and associated bronchitis or pneumonia have been accepted as possible consequences of aspirating regurgitated acid-peptic juice. commonest
1. 2. 3. 4.
Plummer, H. S., Vinson, P. P. Med. Clins. N. Am. 1921, 5, 355. Hurst, A. Guy’s Hosp. Rep. 1943, 92, 68. Belcher, J. R. Thorax, 1949, 4, 44. Belsey, R. Br. J. Dis. Chest, 1960, 54, 342.
146 Pearson and Wilson5 report the coexistence of diffuse pulmonary fibrosis and hiatus hernia in 6 patients, and they tentatively suggest a causal link. They also surveyed 143 consecutive patients with hiatus hernia and reflux symptoms, and found pulmonary fibrosis in 4%. The step to accepting reflux as the cause of the lung damage is a large one, and, since hiatus hernia is so common, it will be difficult to take. No specific features, either pathological or radiological, permit such changes to be unequivocally attributed to aspiration, and no study so far has shown arrest of progress (or even improvement) of the fibrosis But these observations when reflux is prevented. should give physicians pause when dealing with patients who have chronic respiratory troubles; at least a barium meal is justified if there is associated dysphagia or heartburn, or even if the anatomical distribution of the lung changes suggests aspiration as a cause. Unfortunately, radiological examination is an inadequate tool for assessing functional gastrooesophageal impairment, and if the reflux/lung disease association comes to be accepted, perhaps oesophageal manometers and pH recorders will take their place alongside spirometers and peak-flow meters in the
respiratory laboratory.
CARCINOMA AND THE NEPHROTIC SYNDROME
THE study of experimentally induced renal disease has established that the deposition of immune complexes in the kidney may damage the glomeruli, and this mechanism is thought to be important in the pathogenesis of human glomerulonephritis.7 In patients with systemic lupus erythematosus the antigen/ antibody complex has been shown to be D.N.A and antibody to D.N.A.,8 and in the malarial nephrotic syndrome antigens derived from the parasite have been demonstrated in the glomeruli.9 In most patients with glomerulonephritis, however, little is known about the antigen responsible, and it is in this context that reports of an association between malignant disease and glomerulonephritis are of considerable interest. Most such patients have a membranous glomerulonephritis-a condition in which immunoglobulin and complement are deposited on the basement membrane in a distribution characteristic of immune complexes. 10On p. 134 this week Professor Lewis and his colleagues describe how it was possible to elute antibody from the kidney of a patient who died of membranous nephritis associated with a bronchial carcinoma. The eluted antibody reacted specifically with an extract of the tumour, suggesting that the immune complexes in the kidney consisted of tumour antigen and antibody. It is perhaps surprising that the association between malignancy and this type of renal disease is so rare. A number of factors have been identified which may influence the formation of nephrotoxic immune complexes. The most important of these
be the nature and duration of the and the type of immune response. In virus-induced immune-complex disease in mice, genetic factors which probably act by influencing the antibody responses have been shown to be important The rarity of glomerulonephritis complicating carcinoma may be an indication of the importance of the host response to antigenic stimulation in the pathogenesis of human glomerulonephritis.
factors
CHOLECYSTOGRAPHY AND RENAL FAILURE
ABOUT 50 case-reports have appeared of acute renal failure after oral cholecystography 12: much less often, intravenous cholecystography has been implicated in renal failure. 13 One oral agent (sodium buniodyl) was withdrawn from the market after several such incidents.14 Sporadic cases continue to be reported." The mechanism is unknown. The most usual is direct tubular suggestion toxicity. 16 Another possiis that filtration glomerular decrease, 17 somebility times as a result of hypotension. 1111 A third hypothesis is obstructive renal failure caused by crystal deposition within the renal tubules. 12 Crystals have certainly been observed, but their nature is uncertain. At first sight, the dye itself might be to blame, but this is unlikely because of the solubility of the substances concerned.19 Another suggestion 20,21 is that these cholecystographic agents, being organic acids, act, like probenecid, as competitive inhibitors of urate transport by the renal tubule. At least two such substances (iopanoic acid and sodium ipodate) do indeed cause uricosuria of the same order as that produced by probenecid .20 Can the occasional case of nephrotoxicity be attributed, therefore, to urate deposits in the kidney? On the whole, it seems unlikely. Renal failure is not a common feature of probenecid therapy, despite the fact that the drug may be given for years to hyperuricxmic patients, and may indeed lead to calculus formation .22 Mudge 20 points out, however, that the circumstances in which these two groups of uricosuric drugs are given may differ. Gallbladder dyes are given in a single dose the evening before the examination. Liver insufficiency may cause high blood levels for a long time, and patients may be dehydrated by gastrointestinal disturbance or voluntary fluid restriction. Probably, therefore, the peak uricosuric effect coincides with a concentrated and acid urine. Below pH 5-6, most urate in the urine is 11. 12. 13. 14. 15. 16.
17. 5. 6. 7. 8. 9. 10.
Pearson, J. E. G., Wilson, R. S. E, Thorax, 1971, 26, 300. Lancet, 1968, ii, 267. Dixon, F. J. J. exp. Med. 1961, 113, 899. Koffler, D., Schurr, P. H., Kunkel, H. G. ibid. 1967, 126, 607. Ward, P. A., Kibukamusoke, J. W. Lancet, 1969, i, 283. Bariety, J., Druet, P., Labrue, G., Samarco, P., Millies, P. Path. Biol., Paris, 1970, 18, 5.
seems to
antigenic stimulus
18. 19. 20. 21. 22.
Oldstone, M. B. A., Dixon, F. J. J. exp. Med. 1970, 130, 1. Setter, J. G., Maher, J. F., Schreiner, G. E. J. Am. med. Ass. 1963, 184, 102. Craft, I. L., Swales, J. D. Br. med. J. 1967, ii, 736. Seaman, W. B., Cosgriff, S., Wells, J. Am. J. Roentg. 1963, 90, 859. Canales, C. O., Smith, G. H., Robinson, J. C., Remmers, A. R., Searles, H. E. New Engl. J. Med. 1969, 281, 89. Fink, H. E., Jr., Roenigk, W. J., Wilson, G. P. Am. J. med. Sci. 1964, 247, 201. Wennberg, J. E., Okun, R., Hinman, E. J., Northcutt, R. C., Griep, R. J., Walker, W. G. J. Am. med. Ass. 1963, 186, 461. Kohler, R., Holsti, L. R. Acta radiol. 1962, 57, 103. McChesney, E. W., Banks, W. F., Jr. Proc. Soc. exp. Biol. Med. 1965, 119, 1027. Mudge, G. H. New Engl. J. Med. 1971, 284, 929. Kelley, W. N. ibid. p. 975. Gutman, A. B., Yü, T-F. Am. J. Med. 1968, 45, 756.