BRITISH MEDICAL JOURNAL
LONDON, SATURDAY 12 APRIL 1975
Bronchial Secretions About 100 ml of fluid is produced each day in the respiratory by the mucous and serous cells of the bronchial submucosa and the goblet cells of the surface epithelium. This secretion is not coughed up; presumably it is swallowed. Sputum, or coughed-up bronchial secretion, is evidence of hypersecretion within the bronchial tree. The small amount of bronchial mucus normally produced is composed of about 95 % water, about 1% each of carbohydrate, protein, lipid, and inorganic material, and small amounts of secretory IgA, bronchial lactoferrin, bronchial lysozyme, and serum proteins.' This bronchial secretion has some antimicrobial properties and has an important role in maintaining the sterility and proper function of the distal or gas-exchanging parts of the lung through maintaining an efficient mucociliary clearance mechanism. Apparently bronchial cilia do not move in the mucus and propel it forward, but there is a low viscosity fluid surrounding the cilia, and it is in this bath that the cilia beat and on which the mucous blanket floats.2 Drugs and systemic and local dehydration may result in malfunction of the mucociliary clearance mechanism, leading to retention of secretion in the peripheral lung units, when infection is potentially an everpresent hazard. Sputum may be mucoid owing to hypersecretion or purulent or mucopurulent owing to pus, usually secondary to bacterial infection, especially with Streptococcus pneumoniae and Haemophilus influenzae. Mucoid sputum contains glycoproteins, and to a large extent the amount of acid glycoprotein determines its physical properties.3 The molecule of acid glycoprotein consists of a polypeptide core with branching oligosaccharide side chains, which include fructose and a sialic acid radicle, probably in terminal positions on the side chains. The mutual repulsion of the negatively charged acid radicles leads to stiffening of the coil structure of acid glycoprotein, thereby increasing its viscosity.4 Purulent or mucopurulent sputum contains in addition to acid glycoproteins parallel bundles of fibres of desoxyribonucleoprotein derived from the nuclei of degenerated pus cells.5 Mucoid sputum from patients with asthma contains more sialic acid and fructose and is more viscous than sputum from patients with chronic bronchitis, bronchiectasis, or cystic fibrosis.6 The viscosity of the sputum appears to have an effect on ventilatory function: in one group of chronic bronchitics the forced expiratory volume in 1 second was shown to fall as the sputum viscosity rose.7 Some investigators have found purulent sputum more viscous than mucoid,8 9 while others have found it to be less viscid.'0 tract
BansH MEDICAL JOURNAL 1975. All reproduction
rights reserved.
Clearly the flow or rheological properties of sputum are of importance, and these have been defined using the FerrantiShirley cone and plate viscometer and the Weissenberg rheogoniometer, which tests at very low rates of shear.8 10 Bronchitic sputum is a non-Newtonian fluid-that is to say, its viscosity varies with the applied shear rate. It shows a timedependant loss of consistency under shear or thixotrophy; and the effect of this characteristic is that the beating cilia lower the viscosity of the mucus surrounding them, thereby allowing the mucous blanket of higher viscosity to move upwards towards the trachea. Bronchitic sputum has an initial yield value (the minimal force required to cause flow) and a terminal yield value, which reflects the realignment of the molecules after shearing has finished. If sputum is retested after being sheared at comparatively high rates in a Ferranti-Shirley viscometer it assumes more Newtonian properties, presumably owing to irretrievable breakdown of the molecular structure, though an initial yield value is preserved.'0 Sputum also has important elastic properties, the elastic recoil on deformation being greater for mucoid than purulent sputum," which may explain the clinical observation that mucoid sputum is often more difficult to expectorate than is purulent. A simple clinical assessment of pourability or fluidity has been found to have some predictive value for viscosity of mucoid sputum but not of purulent sputum, which seems to pour well regardless of viscosity.12 For many years mixtures have been taken by mouth to thin sputum and increase its volume, but when over 30 years ago the traditional expectorants were shown by controlled trial to be ineffective13 14 their popularity waned. Purulent sputum can be rendered less viscid by aerosol administration of a specific enzyme, desoxyribonuclease,5 but it is expensive and irritant and has little place in routine practice: purulent sputum can usually be controlled
with antibiotics. The main problem has been to find a satisfactory method of aiding the expectoration of mucoid sputum. Aerosol detergents are no more effective than a simple water mist,15 which when inhaled for an hour or so can lead to a definite reduction in sputum viscosity and so can aid expectoration.'6 A solution contining a mixture of ascorbic acid in the presence of molecular oxygen from sodium percarbonate (a reaction catalysed by cupric or ferric ions) may when given by aerosol lead to a decrease in sputum viscosity in chronic bronchitis,'7 but this effect has now been shown to be due to the low pH of this mixture. There is a linear relationship between pH and reduction in sputum viscosity-the lower the NO. 5962 PAGE 51
BRITISH MEDICAL JOURNAL
52
pH of the solution the greater the fall in viscosity.18 Sulphur containing amino-acids have been used by aerosol19 and by mouth20 to reduce the viscosity of mucoid sputum. They are thought to act by disrupting disulphide bonds, which are important in maintaining the gel structure of mucus. In a single-blind study in which S-carboxymethylcysteine was given to bronchitics expectoration was eased, sputum volume was increased, and there was an improvement in ventilatory tests.21 Bromhexine is a synthetic derivative from a plant Abhatoda vasica, and when given to chronic bronchitics by mouth it leads to an increase in sputum volume and a reduction in sputum viscosity,22 but it is possible to show an improvement in ventilatory capacity or the clinical condition only in mildly disabled outpatient bronchitics.2' This disappointing result is true of expectorants in general, even when the substances used are shown to be pharmacologically active. Yeager, H., American Journal of Medicine, 1971, 50, 493. Denton, R., et al., American Review of Respiratory Disease, 1968, 98, 380. 3 Gibbons, R. A., and Glover, F. A., Biochemical_Journal, 1959, 73, 217. 4 Gottschalk, A., Glycoproteins, Their Composition, Structure and Function. London, Elsevier, 1966. 5 Armstrong, J. B., and White, J. C., Lancet, 1950, 11, 739. 6 Charman, J., and Reid, L., Biorheology, 1972, 9, 185. 7 Lopez-Vidriero, M. T., et al., Thorax, 1973, 28, 401. 8 Charman, J., et al., British_Journal of Diseases of the Chest, 1974, 68, 215. 9 Adler, K., et al., American Review of Respiratory Disease, 1972, 106, 86. 10 Palmer, K. N. V., et al., British J7ournal of Diseases of the Chest, 1970, 64, 185. 1 Dulfano, M. J., Adler, K., and Philippoff, W., American Review of Disease, 1971, 104, 88. Respiratory 12 Keal, E., and Reid, L., Poumon et le Coeur, 1970, 26, 51. 13 Alstead, S., Lancet, 1939, 2, 932. 14 Alstead, S., Lancet, 1941, 1, 308. 15 Palmer, K. N. V., Lancet, 1957, 1, 611. 16 Palmer, K. N. V., Lancet, 1960, 1, 91. 17 Palmer, K. N. V., Lancet, 1961, 2, 802. 18 Palmer, M. N. V., Bulletin de Physio-pathologie Respiratoire, 1973,9, 433. 19 Hirsch, S. R., and Kory, R. C., Journal of Allergy, 1967, 39, 265. 20 Palmer, K. N. V., Geake, M. R., and Brass, W., British Medical Journal, 1962, 1, 280. 21 Aylward, M., Current Medical Research and Opinion, 1974, 2, 387. 22 Hamilton, W. F. D., Palmer, K. N. V., and Gent, M., British Medical journal, 1970, 3, 260. 23 Gent, M., Knowlson, P. A., and Prime, F. J., Lancet, 1969, 2, 1094. 1 2
Hormone Patterns in Anorexia Nervosa Recent neurophysiological and hormonal research is supporting the concept' that primary anorexia nervosa reflects a psychological avoidance-response to the maturational demands of adolescence. Two separate groups have now reported2 3 studies of patients with primary anorexia nervosa showing immaturity of the 24 hour pattern of output of luteinizing hormone (L.H.), with very low hormone levels during wakefulness together with substantially higher levels in the plasma during sleep. This pattern is characteristic of prepubertal and pubertal children and in these patients it proved to be reversible through restoration of weight. Other workers4-9 have previously shown that urinary gonadotrophin levels and plasma L.H. levels are very low during the day in the advanced stages of anorexia nervosa. Both Marshall and Russell Fraser7 and Beumont et al.8 found that if clomiphene citrate (which normally stimulates L.H. secretion) is administered at this late stage it fails to cause an increase in L.H. blood levels; but once the patient has gained a considerable amount of weight then the drug again becomes effective. Crisp et al.9 showed that the patient's weight before the onset of her illness was crucial in determining whether or not there was a spontaneous
12 APRIL 1975
rise in L.H. levels when her weight came back to normal in conjunction with eating a normal diet. Those patients who had been grossly obese before their anorexia did not show an increase of L.H. output under these treatment conditions while those of near normal premorbid weight did so. More recently, it has been found10 1 that the hormonal responses to L.H./F.S.H./R.H. (luteinizing hormone, folliclestimulating hormone, releasing hormone) are particularly dependent on body weight. When patients treated with a normal diet (but not ambulant) were studied it became clear that there is a weight threshold of close to 45 kg. Below this weight gonadotrophic responses to the releasing hormone were restricted, with F.S.H. levels sometimes exceeding those of L.H.-another prepubertal-like phenomenon. Above 45 kg the responses were characteristic of those usually observed in the normal healthy adult. Other workers,'2 13 however, studying anorectic patients but using twice the amount of releasing hormone (100 ,tg instead of 50 jig) as a stimulus found that pituitary responsivity was adequate. Apparently the pituitary is capable of releasing L.H. and F.S.H. at low weights but it requires a greater stimulus. This differential response to releasing hormone distinguishes anorectics with low weights from other women with secondary "functional" amenorrhoea, in whom the response to 50 jig of the releasing hormone is normal.14 It has been suggested15 that in normal young women the development of a positive feedback between oestrogen and L.H., paving the way for ovulation, is a feature which occurs late in the course of puberty. Certainly Crisp et al.9 found little evidence of any ovarian steroid activity in the period immediately after restoration of weight in anorectic patients in whom output of L.H. and F.S.H. had been rekindled; not until a year or more later was menstrual bleeding resumed. In normal pubertal and adolescent girls the weight at which the menarche occurs has been identified as 47-5±0-8 kg. Frisch and McArthur16 have now suggested that fatness may prove to be an even more critical determinant of the menarche and ovulation than body weight. Older adolescent girls who had had an episode of secondary amenorrhoea seemed to need to have a higher weight and a greater amount of fat before menstrual bleeding resumed. This is in line with findings in anorexia nervosa.'7 Patients who had previously been obese and had been growing rapidly-and who on average had achieved an early menarche, probably at an above average weight-lost their menstrual bleeding at a weight of 52±6 kg at a mean age of 18 years; after treatment they regained it when they had again achieved a similar weight. Frisch'8 has proposed that the mechanism is a critical change in metabolic rate; and again in anorexia nervosa such a change in basal metabolic activity in both terms of measured B.M.R. and body temperature19-2' has been claimed to operate as a threshold as weight is returned to fully adult proportions. Subgroups of patients with both primary and secondary anorexia nervosa can be recognized on the basis of their eating habits and associated metabolic patterns. These findings suggest that as such patients are helped to achieve a normal weight and a normal dietary intake, concurrent investigation should lead to clearer understanding of the "pubertal" evolution of gonadotrophic activity, including its dependence on what may turn out to be a number of weight/nutritional thresholds and related feedback mechanisms. 1
Crisp, A. H., Hospital Medicine 1966/1967, 1, 713. Boyar, R. M., et al., New England 3ournal of Medicine, 1974, 291, 861. 3 Kalucy, R. S., et al., Paper read at 1st International Congress of Obesity, London, 1974. 4 Bell, E. T., et al., Acta Endocrinologica, 1966, 51, 140. 2
LONDON, SATURDAY 12 APRIL 1975
Bronchial Secretions About 100 ml of fluid is produced each day in the respiratory by the mucous and serous cells of the bronchial submucosa and the goblet cells of the surface epithelium. This secretion is not coughed up; presumably it is swallowed. Sputum, or coughed-up bronchial secretion, is evidence of hypersecretion within the bronchial tree. The small amount of bronchial mucus normally produced is composed of about 95 % water, about 1% each of carbohydrate, protein, lipid, and inorganic material, and small amounts of secretory IgA, bronchial lactoferrin, bronchial lysozyme, and serum proteins.' This bronchial secretion has some antimicrobial properties and has an important role in maintaining the sterility and proper function of the distal or gas-exchanging parts of the lung through maintaining an efficient mucociliary clearance mechanism. Apparently bronchial cilia do not move in the mucus and propel it forward, but there is a low viscosity fluid surrounding the cilia, and it is in this bath that the cilia beat and on which the mucous blanket floats.2 Drugs and systemic and local dehydration may result in malfunction of the mucociliary clearance mechanism, leading to retention of secretion in the peripheral lung units, when infection is potentially an everpresent hazard. Sputum may be mucoid owing to hypersecretion or purulent or mucopurulent owing to pus, usually secondary to bacterial infection, especially with Streptococcus pneumoniae and Haemophilus influenzae. Mucoid sputum contains glycoproteins, and to a large extent the amount of acid glycoprotein determines its physical properties.3 The molecule of acid glycoprotein consists of a polypeptide core with branching oligosaccharide side chains, which include fructose and a sialic acid radicle, probably in terminal positions on the side chains. The mutual repulsion of the negatively charged acid radicles leads to stiffening of the coil structure of acid glycoprotein, thereby increasing its viscosity.4 Purulent or mucopurulent sputum contains in addition to acid glycoproteins parallel bundles of fibres of desoxyribonucleoprotein derived from the nuclei of degenerated pus cells.5 Mucoid sputum from patients with asthma contains more sialic acid and fructose and is more viscous than sputum from patients with chronic bronchitis, bronchiectasis, or cystic fibrosis.6 The viscosity of the sputum appears to have an effect on ventilatory function: in one group of chronic bronchitics the forced expiratory volume in 1 second was shown to fall as the sputum viscosity rose.7 Some investigators have found purulent sputum more viscous than mucoid,8 9 while others have found it to be less viscid.'0 tract
BansH MEDICAL JOURNAL 1975. All reproduction
rights reserved.
Clearly the flow or rheological properties of sputum are of importance, and these have been defined using the FerrantiShirley cone and plate viscometer and the Weissenberg rheogoniometer, which tests at very low rates of shear.8 10 Bronchitic sputum is a non-Newtonian fluid-that is to say, its viscosity varies with the applied shear rate. It shows a timedependant loss of consistency under shear or thixotrophy; and the effect of this characteristic is that the beating cilia lower the viscosity of the mucus surrounding them, thereby allowing the mucous blanket of higher viscosity to move upwards towards the trachea. Bronchitic sputum has an initial yield value (the minimal force required to cause flow) and a terminal yield value, which reflects the realignment of the molecules after shearing has finished. If sputum is retested after being sheared at comparatively high rates in a Ferranti-Shirley viscometer it assumes more Newtonian properties, presumably owing to irretrievable breakdown of the molecular structure, though an initial yield value is preserved.'0 Sputum also has important elastic properties, the elastic recoil on deformation being greater for mucoid than purulent sputum," which may explain the clinical observation that mucoid sputum is often more difficult to expectorate than is purulent. A simple clinical assessment of pourability or fluidity has been found to have some predictive value for viscosity of mucoid sputum but not of purulent sputum, which seems to pour well regardless of viscosity.12 For many years mixtures have been taken by mouth to thin sputum and increase its volume, but when over 30 years ago the traditional expectorants were shown by controlled trial to be ineffective13 14 their popularity waned. Purulent sputum can be rendered less viscid by aerosol administration of a specific enzyme, desoxyribonuclease,5 but it is expensive and irritant and has little place in routine practice: purulent sputum can usually be controlled
with antibiotics. The main problem has been to find a satisfactory method of aiding the expectoration of mucoid sputum. Aerosol detergents are no more effective than a simple water mist,15 which when inhaled for an hour or so can lead to a definite reduction in sputum viscosity and so can aid expectoration.'6 A solution contining a mixture of ascorbic acid in the presence of molecular oxygen from sodium percarbonate (a reaction catalysed by cupric or ferric ions) may when given by aerosol lead to a decrease in sputum viscosity in chronic bronchitis,'7 but this effect has now been shown to be due to the low pH of this mixture. There is a linear relationship between pH and reduction in sputum viscosity-the lower the NO. 5962 PAGE 51
BRITISH MEDICAL JOURNAL
52
pH of the solution the greater the fall in viscosity.18 Sulphur containing amino-acids have been used by aerosol19 and by mouth20 to reduce the viscosity of mucoid sputum. They are thought to act by disrupting disulphide bonds, which are important in maintaining the gel structure of mucus. In a single-blind study in which S-carboxymethylcysteine was given to bronchitics expectoration was eased, sputum volume was increased, and there was an improvement in ventilatory tests.21 Bromhexine is a synthetic derivative from a plant Abhatoda vasica, and when given to chronic bronchitics by mouth it leads to an increase in sputum volume and a reduction in sputum viscosity,22 but it is possible to show an improvement in ventilatory capacity or the clinical condition only in mildly disabled outpatient bronchitics.2' This disappointing result is true of expectorants in general, even when the substances used are shown to be pharmacologically active. Yeager, H., American Journal of Medicine, 1971, 50, 493. Denton, R., et al., American Review of Respiratory Disease, 1968, 98, 380. 3 Gibbons, R. A., and Glover, F. A., Biochemical_Journal, 1959, 73, 217. 4 Gottschalk, A., Glycoproteins, Their Composition, Structure and Function. London, Elsevier, 1966. 5 Armstrong, J. B., and White, J. C., Lancet, 1950, 11, 739. 6 Charman, J., and Reid, L., Biorheology, 1972, 9, 185. 7 Lopez-Vidriero, M. T., et al., Thorax, 1973, 28, 401. 8 Charman, J., et al., British_Journal of Diseases of the Chest, 1974, 68, 215. 9 Adler, K., et al., American Review of Respiratory Disease, 1972, 106, 86. 10 Palmer, K. N. V., et al., British J7ournal of Diseases of the Chest, 1970, 64, 185. 1 Dulfano, M. J., Adler, K., and Philippoff, W., American Review of Disease, 1971, 104, 88. Respiratory 12 Keal, E., and Reid, L., Poumon et le Coeur, 1970, 26, 51. 13 Alstead, S., Lancet, 1939, 2, 932. 14 Alstead, S., Lancet, 1941, 1, 308. 15 Palmer, K. N. V., Lancet, 1957, 1, 611. 16 Palmer, K. N. V., Lancet, 1960, 1, 91. 17 Palmer, K. N. V., Lancet, 1961, 2, 802. 18 Palmer, M. N. V., Bulletin de Physio-pathologie Respiratoire, 1973,9, 433. 19 Hirsch, S. R., and Kory, R. C., Journal of Allergy, 1967, 39, 265. 20 Palmer, K. N. V., Geake, M. R., and Brass, W., British Medical Journal, 1962, 1, 280. 21 Aylward, M., Current Medical Research and Opinion, 1974, 2, 387. 22 Hamilton, W. F. D., Palmer, K. N. V., and Gent, M., British Medical journal, 1970, 3, 260. 23 Gent, M., Knowlson, P. A., and Prime, F. J., Lancet, 1969, 2, 1094. 1 2
Hormone Patterns in Anorexia Nervosa Recent neurophysiological and hormonal research is supporting the concept' that primary anorexia nervosa reflects a psychological avoidance-response to the maturational demands of adolescence. Two separate groups have now reported2 3 studies of patients with primary anorexia nervosa showing immaturity of the 24 hour pattern of output of luteinizing hormone (L.H.), with very low hormone levels during wakefulness together with substantially higher levels in the plasma during sleep. This pattern is characteristic of prepubertal and pubertal children and in these patients it proved to be reversible through restoration of weight. Other workers4-9 have previously shown that urinary gonadotrophin levels and plasma L.H. levels are very low during the day in the advanced stages of anorexia nervosa. Both Marshall and Russell Fraser7 and Beumont et al.8 found that if clomiphene citrate (which normally stimulates L.H. secretion) is administered at this late stage it fails to cause an increase in L.H. blood levels; but once the patient has gained a considerable amount of weight then the drug again becomes effective. Crisp et al.9 showed that the patient's weight before the onset of her illness was crucial in determining whether or not there was a spontaneous
12 APRIL 1975
rise in L.H. levels when her weight came back to normal in conjunction with eating a normal diet. Those patients who had been grossly obese before their anorexia did not show an increase of L.H. output under these treatment conditions while those of near normal premorbid weight did so. More recently, it has been found10 1 that the hormonal responses to L.H./F.S.H./R.H. (luteinizing hormone, folliclestimulating hormone, releasing hormone) are particularly dependent on body weight. When patients treated with a normal diet (but not ambulant) were studied it became clear that there is a weight threshold of close to 45 kg. Below this weight gonadotrophic responses to the releasing hormone were restricted, with F.S.H. levels sometimes exceeding those of L.H.-another prepubertal-like phenomenon. Above 45 kg the responses were characteristic of those usually observed in the normal healthy adult. Other workers,'2 13 however, studying anorectic patients but using twice the amount of releasing hormone (100 ,tg instead of 50 jig) as a stimulus found that pituitary responsivity was adequate. Apparently the pituitary is capable of releasing L.H. and F.S.H. at low weights but it requires a greater stimulus. This differential response to releasing hormone distinguishes anorectics with low weights from other women with secondary "functional" amenorrhoea, in whom the response to 50 jig of the releasing hormone is normal.14 It has been suggested15 that in normal young women the development of a positive feedback between oestrogen and L.H., paving the way for ovulation, is a feature which occurs late in the course of puberty. Certainly Crisp et al.9 found little evidence of any ovarian steroid activity in the period immediately after restoration of weight in anorectic patients in whom output of L.H. and F.S.H. had been rekindled; not until a year or more later was menstrual bleeding resumed. In normal pubertal and adolescent girls the weight at which the menarche occurs has been identified as 47-5±0-8 kg. Frisch and McArthur16 have now suggested that fatness may prove to be an even more critical determinant of the menarche and ovulation than body weight. Older adolescent girls who had had an episode of secondary amenorrhoea seemed to need to have a higher weight and a greater amount of fat before menstrual bleeding resumed. This is in line with findings in anorexia nervosa.'7 Patients who had previously been obese and had been growing rapidly-and who on average had achieved an early menarche, probably at an above average weight-lost their menstrual bleeding at a weight of 52±6 kg at a mean age of 18 years; after treatment they regained it when they had again achieved a similar weight. Frisch'8 has proposed that the mechanism is a critical change in metabolic rate; and again in anorexia nervosa such a change in basal metabolic activity in both terms of measured B.M.R. and body temperature19-2' has been claimed to operate as a threshold as weight is returned to fully adult proportions. Subgroups of patients with both primary and secondary anorexia nervosa can be recognized on the basis of their eating habits and associated metabolic patterns. These findings suggest that as such patients are helped to achieve a normal weight and a normal dietary intake, concurrent investigation should lead to clearer understanding of the "pubertal" evolution of gonadotrophic activity, including its dependence on what may turn out to be a number of weight/nutritional thresholds and related feedback mechanisms. 1
Crisp, A. H., Hospital Medicine 1966/1967, 1, 713. Boyar, R. M., et al., New England 3ournal of Medicine, 1974, 291, 861. 3 Kalucy, R. S., et al., Paper read at 1st International Congress of Obesity, London, 1974. 4 Bell, E. T., et al., Acta Endocrinologica, 1966, 51, 140. 2
