- Email: [email protected]
IRON AND VITAMIN C
768
Although in any given case time would be saved by early rather than later abortion, if the gynaecologist sets up an outpatient abortion service he will not thereby reduce his waiting or operating list, and in the end he will find that he tions.
is performing more abortions within the National Health Service in his area. The setting up of outpatient abortion services would increase the overall clinical burden undertaken by the gynaecology team, and, however logical and efficient this service might be, under the present staffing situation few peripheral hospitals will be able to establish it. In the private sector, establishing outpatient abortions services would mean more money to provide more facilities and more staff; within the National Health Service it simply means more work. Kingston Hospital, Surrey.
PETER DIGGORY.
IMPORTANCE OF ASPIRATES IN THE RESPIRATORY-DISTRESS SYNDROME
SiR,łThe xtiology of the respiratory-distress syndrome
(R.D.s.) has not been definitely determined. Although the lack-of-surfactant and the hypoperfusion-syndrome theories are at present in vogue, they do not explain the whole pathological picture. I have proposedthat hyalinemembrane disease (H.M.D.), hyaline-membrane-like disease without membranes, lobar opacification, some cases of intra-alveolar pulmonary haemorrhage, and some cases of atelectasis in the newborn may all have a common xtiology -the aspiration of fresh unclotted maternal blood in amniotic fluid at the time of delivery. The unclotted blood clots in the alveoli, alveolar ducts, and bronchioles, causing an " adhesive atelectasis ". The hyaline membranes are probably " resolution products " of this atelectasis, formed in the presence of the excess oxygen used in therapy. The various conditions may be due to the aspiration of different amounts of varying concentrations of blood/amniotic-fluid mixture. Previously the aspiration of amniotic contents had been considered as a possible cause of H.M.D., but this theory was discarded when it was shown that amniotic fluid did not contain enough fibrin to account for that found in the membrane.2However, if the work of these investigators is studied carefully, it will be seen that they examined " pure " amniotic fluid and not the " bloody " amniotic fluid I found in the aspirates of the nose and mouth of 43% of infants delivered by caesarean section. The incidence of R.D.S. in the infants with bloody aspirates was much higher than in those with clear aspirates. Thus it may be seen that the aspirates found in the nose and mouth of infants at birth is much more important than previously recognised. The meconium-aspiration syndrome is a well-recognised entity. Why is the aspiration of maternal blood not considered dangerous ? The Apgar ratings taken at 1 minute, 2 minutes, and 5 minutes are not as important as the Apgar " at the moment of birth ", when considered in terms of respiratory distress. Many infants are active and take one or two breaths shortly after birth, and then become completely limp, making no further attempt to breathe for several minutes. Therefore the Apgar at 1 minute is not indicative of the Apgar at birth. I have reviewed the charts of infants with respiratory distress and their mothers in an attempt to determine the character of the aspirate from the nose and mouth at birth. Only an occasional chart noted meconium in the amniotic fluid or meconium coming from the nose and mouth. 1. 2.
Pender, C. B. Am. J. Obstet. Gynec. 1970, 106, 711. Gitlin, D., Craig, J. M. Pediatrics, Springfield, 1956, 17, 64.
However, in not a single case was there any record of blood in the amniotic fluid or in the aspirate of the nose and mouth. These findings are probably universal. Itis therefore essential that if any correlation between R.D.S. and blood aspiration is to be found in the future, a record of aspirates from the noses and mouths of all infants should be made at the time of delivery. Hôtel Dieu and Cornwall General Hospitals Nurseries, Cornwall, Ontario, Canada.
CHARLES B. PENDER.
IRON AND VITAMIN C
SIR,- The purpose of your editorial p.
475)
on iron (Aug. 28, apparently to draw attention to the absence explanation for the iron-lack anaemia which occurs was
of any in women
near
the menopause.
This anaemia arises
despite falling menstrual loss, responds well to oral iron, and does not relapse. In the editorial you give a full account of the characteristics of iron absorption, its relation to hxmopoiesis, its metabolism, and its excretion, but you do not refer to factors apart from the ferritin mechanism which can influence the utilisation of iron by the tissues, its storage, and capacity to form haemoglobin. One of the more important of these factors is the tissue status of ascorbic acid, its metabolic turnover-rate in the bloody and the degree of saturation of the labile-ascorbicacid pool.2 You point out that iron in the body has a very rapid turnover-rate. The rate of iron turnover undergoes a regular 24-hour cycle,3 which is precisely correlated with that of leucocyte and plasma ascorbic acid. This rhythm is similar in both sexes, even though females have the higher plasma levels of ascorbic acid. The process for uptake and storage of ascorbic acid in the white cells is also similar in both sexes, although the higher leucocyte ascorbic-acid concentrations in females are characteristic of the sex. They do not result from increased storage capacity of the vitamin in females.6 A difference in ascorbic-acid metabolism between males and females was demonstrated in guineapigs6 as well as human beings. Female guineapigs have the capacity to synthesise ascorbic acid, as demonstrated by the presence of gulonalactone oxidase in the liver of a female guineapig maintained on an ascorbic-acid-free diet for 54 days, and the survival of another female guineapig on the diet for 150 days. Male guineapigs do not survive for longer than 30 days. In your editorial you comment that iron absorption is diminished after gastrectomy. Leucocyte ascorbic-acid concentrations also diminish after gastrectomy and in other types of gastrointestinal disease.’ During the menstrual cycle you point out that there is a monthly rhythm in iron loss. There is also a regular monthly cycle in excretion of ascorbic acid in the urine.88 It has been demonstrated that there is a significant relationship between ascorbic-acid metabolism and hmmoglobin formation in adolescent boys and girls. However, administration of supplementary vitamin C to the girls changed this relationship from a stable into an unstable state, whereas it did not alter it in boys.9 These results suggest that there is a dynamic relationship between iron and ascorbic acid in haemoglobin formation, and that a relative shortase of either of these factors will interfere Loh, H. S., Wilson, C. W. M. Br. med. J. 1971, iii, 47. Wilson, C. W. M. Vitamin Documentation. Hoffman-La Roche, Basle (in the press). 3. Hamilton, L. D., Gubler, C. J., Cartwright, G. E., Wintrobe, M. M. Proc. Soc. exp. Biol. Med. 1950, 75, 65. 4. Loh, H. S., Wilson, C. W. M. Br. J. Pharmac. 1970, 40, 566P. 5. Loh, H. S., Wilson, C. W. M. Int. J. Vit. Nutr. Res. 1971, 41, 253. 6. Odumosu, A., Wilson, C. W. M. Br. J. Pharmac. 1971, 42, 637P. 7. Cohen, M. M., Duncan, A. M. Br. med. J. 1967, iv, 516. 8. Loh, H. J., Wilson, C. W. M. Lancet, 1971, i, 110. 9. Loh, H. J., Wilson, C. W. M. Int. J. Vit. Nutr. Res. (in the press). 1. 2.
769 .KCOCYIB ASCORBIC-ACID CONCENTRATIONS
IN MALE AND FEMALE
GERIATRIC PATIENTS DURING DAILY ADMINISTRATION OF ACTIVE IRON OVER A 14-WEEK PERIOD
105 mg.
after the menopause. A careful search is clearly necessary to exclude a source of blood-loss before this
or soon
explanation can be accepted. Even higher losses were found in patients with post-gastrectomy states and untreated adult coeliac disease who were iron-deficient. The importance of free-iron loss from the gut has not been appreciated. the excellence of the work done by Green et al.," measurement of faecal-free-iron loss is unsatisfactory unless a double-isotope technique is used to measure any simultaneous blood-loss. We have measured free and haem iron losses using "’Cr and 69Fe, and have substantiated the findings by chemical analysis. In normal subjects mean daily losses were 0-43 mg. as endogenous iron and 0.32 mg. as haemoglobin iron. This endogenous free iron is probably not all lost as intracellular iron but is also derived from bile and other secretions.
previously Despite
at week 0 in !J.gJ10* cells; values at week 1-14 liValues of initial values.
are
percentages
with optimal hxmoglobin formation. Cox 1has suggested the vitamin C acts by mobilising tissue iron stores. that The observation that low leucocyte ascorbic-acid concentrations are associated with raised haemoglobin levels supports this suggestion.1O Daily administration of iron alone to old men results in auniform fall in leucocyte ascorbic-acid concentrations a 14-week period. In old women a similar dose of iron, after causing a rise in leucocyte ascorbic-acid con-
i during
fall in the ascorbic-acid with centrations, is associated of the initial concentration the 6th a
62% during week (table). By the 14th week the value has increased again to 133% of the initial value, in the absence of any to
values
alteration in dietary intake of vitamin C.
These results the increased demand for that ascorbic acid indicate the of iron to administration elderly women produced by in a metabolic readjustment of their ascorbic-acid metabolism similar to that produced in female guineapigs deprived of exogenous vitamin C for a period of 5 weeks. The female guineapigs which survive continue to produce sufficient ascorbic acid for their tissue requirements. As you point out in your editorial, women given oral iron do not relapse. In consequence of this medication, they have developed their sex-linked ability to respond to the tissue demand for ascorbic acid. They are thus able to compensate for the biochemical defect which deranges their iron cycle. It has been demonstrated that the desirable ratio of ascorbic acid to iron for optimum haemopoiesis is 5 to 1.’" Department of Pharmacology, University of Dublin, H. S. LOH Trinity College,
results
I
I. r ,
C. W. M. WILSON.
Dublin 2, Eire.
West Middlesex Hospital, Isleworth, Middlesex.
D. R. SUTTON I. MCL. BAIRD J. S. STEWART N. F. COGHILL.
SIR,—We are disappointed at the lack of balance in your editorial. In particular, estimates of iron requirements involve so much guesswork that they are barely worth the paper they are written on, let alone considerable space in
your journal. We are intrigued by the " variety "
of anxmia which is described. This is said to occur in women near the menopause, who " in spite of failing or absent menstrual loss, have an iron-deficiency anxmia which responds well to oral iron and does not relapse ". Before too much effort is expended in the exploration of this phenomenon, one should consider the possibility that this condition is no different from the anaemia which occurs throughout adult female life, but the likelihood of its detection is increased simply by the increase in symptoms around the menopause which leads to more frequent medical consultation. It is perhaps unfortunate that no consideration was given to how much " iron-lack anaemia " really matters. It is all too easy to quote a textbook 1a which states that iron-lack anaemia plays an important role in contributing to the valetudinarian condition and substandard work performance of millions, but it would be interesting to see some valid supporting data. We have so far failed to
find
any.19
M.R.C. Epidemiology Unit (South Wales), 4 Richmond Road, Cardiff CF2 3AS.
A. L. COCHRANE P. C. ELWOOD.
IRON ’
SNj—Your editorial on iron (Aug. 28, p. 475) is of great interest. Although you say the cause of iron-lack anaemia ! has been identified for most situations, you do not mention the important role of endogenous non-haam iron IOSS.14.15 have reported 14 that free-iron loss is significantly We increased in the majority of patients with atrophic gastritis, ,
‘
which is
a common
condition after 50 years of age and is
I
known to be associated with a high cell turnover. 16 A mean
I
daily fæcal loss
of 0-78 mg. of free iron was found in this group, and this together with impaired absorption may account for the ansemia which occurs in many patients at 10. Loh, H. S., Wilson, C. W. M. ibid. 1971, 41, 259. 11. Cox, E. V. in Vitamins and Hormones (edited by R. S. Harris, I. G. Waal, and J. A. Loraine); vol. XXVI, p. 635. London, 1968. 12. Lee, P. C., Ledwich, J. R., Smith, D. C. Can. med. Ass. J. 1967, 13. 14. 15. 16.
97, 181. Loh, H. S., Wilson, C. W. M. Nutr. Rep. Int. (in the press). Sutton, D. R., Baird, I. McL., Stewart, J. S., Coghill, N. F. Lancet, 1970, ii, 387. Singh, A. K. Br.J. Hæmat. 1970, 18, 597. Croft, D. N., Pollock, D. J., Coghill, N. F. Gut, 1966 7, 333.
RENAL CHANGES IN HEPATIC FAILURE SIR,—In his letter of July 31 (p. 260), Dr. Wilkinson refers to our discussion 20 of certain renal changes in hepatic failure. Our hypothesis suggested that the accumulation of relatively inactive aromatic amine compounds (" false neurotransmitters ") at nerve endings of the peripheral sympathetic nervous system, and perhaps in the brain, might account for many of the neurological and circulatory disturbances which occur in severe hepatic failure. Dr. Wilkinson suggests that the improvements of renal function following the administration of metaraminol are " due merely to the rise in central arterial blood-pressure ". We would agree that such a mechanism may explain partially 17. Green, R., Charlton, R., Seftel, H., Bothwell, T., Mayet, F., Adams, B., Finch, C. A., Layrisse, M. Am. J. Med. 1968, 45, 336. 18. Harris, J. W., Kellermeyer, R. W. The Red Cell. Cambridge, Mass., 1970. 19. Elwood, P. C. Proc. R. Soc. Med. 1970, 63, 1230. 20. Fischer, J. E., Baldessarini, R. J. Lancet, July 10, 1971, p. 75.
Although in any given case time would be saved by early rather than later abortion, if the gynaecologist sets up an outpatient abortion service he will not thereby reduce his waiting or operating list, and in the end he will find that he tions.
is performing more abortions within the National Health Service in his area. The setting up of outpatient abortion services would increase the overall clinical burden undertaken by the gynaecology team, and, however logical and efficient this service might be, under the present staffing situation few peripheral hospitals will be able to establish it. In the private sector, establishing outpatient abortions services would mean more money to provide more facilities and more staff; within the National Health Service it simply means more work. Kingston Hospital, Surrey.
PETER DIGGORY.
IMPORTANCE OF ASPIRATES IN THE RESPIRATORY-DISTRESS SYNDROME
SiR,łThe xtiology of the respiratory-distress syndrome
(R.D.s.) has not been definitely determined. Although the lack-of-surfactant and the hypoperfusion-syndrome theories are at present in vogue, they do not explain the whole pathological picture. I have proposedthat hyalinemembrane disease (H.M.D.), hyaline-membrane-like disease without membranes, lobar opacification, some cases of intra-alveolar pulmonary haemorrhage, and some cases of atelectasis in the newborn may all have a common xtiology -the aspiration of fresh unclotted maternal blood in amniotic fluid at the time of delivery. The unclotted blood clots in the alveoli, alveolar ducts, and bronchioles, causing an " adhesive atelectasis ". The hyaline membranes are probably " resolution products " of this atelectasis, formed in the presence of the excess oxygen used in therapy. The various conditions may be due to the aspiration of different amounts of varying concentrations of blood/amniotic-fluid mixture. Previously the aspiration of amniotic contents had been considered as a possible cause of H.M.D., but this theory was discarded when it was shown that amniotic fluid did not contain enough fibrin to account for that found in the membrane.2However, if the work of these investigators is studied carefully, it will be seen that they examined " pure " amniotic fluid and not the " bloody " amniotic fluid I found in the aspirates of the nose and mouth of 43% of infants delivered by caesarean section. The incidence of R.D.S. in the infants with bloody aspirates was much higher than in those with clear aspirates. Thus it may be seen that the aspirates found in the nose and mouth of infants at birth is much more important than previously recognised. The meconium-aspiration syndrome is a well-recognised entity. Why is the aspiration of maternal blood not considered dangerous ? The Apgar ratings taken at 1 minute, 2 minutes, and 5 minutes are not as important as the Apgar " at the moment of birth ", when considered in terms of respiratory distress. Many infants are active and take one or two breaths shortly after birth, and then become completely limp, making no further attempt to breathe for several minutes. Therefore the Apgar at 1 minute is not indicative of the Apgar at birth. I have reviewed the charts of infants with respiratory distress and their mothers in an attempt to determine the character of the aspirate from the nose and mouth at birth. Only an occasional chart noted meconium in the amniotic fluid or meconium coming from the nose and mouth. 1. 2.
Pender, C. B. Am. J. Obstet. Gynec. 1970, 106, 711. Gitlin, D., Craig, J. M. Pediatrics, Springfield, 1956, 17, 64.
However, in not a single case was there any record of blood in the amniotic fluid or in the aspirate of the nose and mouth. These findings are probably universal. Itis therefore essential that if any correlation between R.D.S. and blood aspiration is to be found in the future, a record of aspirates from the noses and mouths of all infants should be made at the time of delivery. Hôtel Dieu and Cornwall General Hospitals Nurseries, Cornwall, Ontario, Canada.
CHARLES B. PENDER.
IRON AND VITAMIN C
SIR,- The purpose of your editorial p.
475)
on iron (Aug. 28, apparently to draw attention to the absence explanation for the iron-lack anaemia which occurs was
of any in women
near
the menopause.
This anaemia arises
despite falling menstrual loss, responds well to oral iron, and does not relapse. In the editorial you give a full account of the characteristics of iron absorption, its relation to hxmopoiesis, its metabolism, and its excretion, but you do not refer to factors apart from the ferritin mechanism which can influence the utilisation of iron by the tissues, its storage, and capacity to form haemoglobin. One of the more important of these factors is the tissue status of ascorbic acid, its metabolic turnover-rate in the bloody and the degree of saturation of the labile-ascorbicacid pool.2 You point out that iron in the body has a very rapid turnover-rate. The rate of iron turnover undergoes a regular 24-hour cycle,3 which is precisely correlated with that of leucocyte and plasma ascorbic acid. This rhythm is similar in both sexes, even though females have the higher plasma levels of ascorbic acid. The process for uptake and storage of ascorbic acid in the white cells is also similar in both sexes, although the higher leucocyte ascorbic-acid concentrations in females are characteristic of the sex. They do not result from increased storage capacity of the vitamin in females.6 A difference in ascorbic-acid metabolism between males and females was demonstrated in guineapigs6 as well as human beings. Female guineapigs have the capacity to synthesise ascorbic acid, as demonstrated by the presence of gulonalactone oxidase in the liver of a female guineapig maintained on an ascorbic-acid-free diet for 54 days, and the survival of another female guineapig on the diet for 150 days. Male guineapigs do not survive for longer than 30 days. In your editorial you comment that iron absorption is diminished after gastrectomy. Leucocyte ascorbic-acid concentrations also diminish after gastrectomy and in other types of gastrointestinal disease.’ During the menstrual cycle you point out that there is a monthly rhythm in iron loss. There is also a regular monthly cycle in excretion of ascorbic acid in the urine.88 It has been demonstrated that there is a significant relationship between ascorbic-acid metabolism and hmmoglobin formation in adolescent boys and girls. However, administration of supplementary vitamin C to the girls changed this relationship from a stable into an unstable state, whereas it did not alter it in boys.9 These results suggest that there is a dynamic relationship between iron and ascorbic acid in haemoglobin formation, and that a relative shortase of either of these factors will interfere Loh, H. S., Wilson, C. W. M. Br. med. J. 1971, iii, 47. Wilson, C. W. M. Vitamin Documentation. Hoffman-La Roche, Basle (in the press). 3. Hamilton, L. D., Gubler, C. J., Cartwright, G. E., Wintrobe, M. M. Proc. Soc. exp. Biol. Med. 1950, 75, 65. 4. Loh, H. S., Wilson, C. W. M. Br. J. Pharmac. 1970, 40, 566P. 5. Loh, H. S., Wilson, C. W. M. Int. J. Vit. Nutr. Res. 1971, 41, 253. 6. Odumosu, A., Wilson, C. W. M. Br. J. Pharmac. 1971, 42, 637P. 7. Cohen, M. M., Duncan, A. M. Br. med. J. 1967, iv, 516. 8. Loh, H. J., Wilson, C. W. M. Lancet, 1971, i, 110. 9. Loh, H. J., Wilson, C. W. M. Int. J. Vit. Nutr. Res. (in the press). 1. 2.
769 .KCOCYIB ASCORBIC-ACID CONCENTRATIONS
IN MALE AND FEMALE
GERIATRIC PATIENTS DURING DAILY ADMINISTRATION OF ACTIVE IRON OVER A 14-WEEK PERIOD
105 mg.
after the menopause. A careful search is clearly necessary to exclude a source of blood-loss before this
or soon
explanation can be accepted. Even higher losses were found in patients with post-gastrectomy states and untreated adult coeliac disease who were iron-deficient. The importance of free-iron loss from the gut has not been appreciated. the excellence of the work done by Green et al.," measurement of faecal-free-iron loss is unsatisfactory unless a double-isotope technique is used to measure any simultaneous blood-loss. We have measured free and haem iron losses using "’Cr and 69Fe, and have substantiated the findings by chemical analysis. In normal subjects mean daily losses were 0-43 mg. as endogenous iron and 0.32 mg. as haemoglobin iron. This endogenous free iron is probably not all lost as intracellular iron but is also derived from bile and other secretions.
previously Despite
at week 0 in !J.gJ10* cells; values at week 1-14 liValues of initial values.
are
percentages
with optimal hxmoglobin formation. Cox 1has suggested the vitamin C acts by mobilising tissue iron stores. that The observation that low leucocyte ascorbic-acid concentrations are associated with raised haemoglobin levels supports this suggestion.1O Daily administration of iron alone to old men results in auniform fall in leucocyte ascorbic-acid concentrations a 14-week period. In old women a similar dose of iron, after causing a rise in leucocyte ascorbic-acid con-
i during
fall in the ascorbic-acid with centrations, is associated of the initial concentration the 6th a
62% during week (table). By the 14th week the value has increased again to 133% of the initial value, in the absence of any to
values
alteration in dietary intake of vitamin C.
These results the increased demand for that ascorbic acid indicate the of iron to administration elderly women produced by in a metabolic readjustment of their ascorbic-acid metabolism similar to that produced in female guineapigs deprived of exogenous vitamin C for a period of 5 weeks. The female guineapigs which survive continue to produce sufficient ascorbic acid for their tissue requirements. As you point out in your editorial, women given oral iron do not relapse. In consequence of this medication, they have developed their sex-linked ability to respond to the tissue demand for ascorbic acid. They are thus able to compensate for the biochemical defect which deranges their iron cycle. It has been demonstrated that the desirable ratio of ascorbic acid to iron for optimum haemopoiesis is 5 to 1.’" Department of Pharmacology, University of Dublin, H. S. LOH Trinity College,
results
I
I. r ,
C. W. M. WILSON.
Dublin 2, Eire.
West Middlesex Hospital, Isleworth, Middlesex.
D. R. SUTTON I. MCL. BAIRD J. S. STEWART N. F. COGHILL.
SIR,—We are disappointed at the lack of balance in your editorial. In particular, estimates of iron requirements involve so much guesswork that they are barely worth the paper they are written on, let alone considerable space in
your journal. We are intrigued by the " variety "
of anxmia which is described. This is said to occur in women near the menopause, who " in spite of failing or absent menstrual loss, have an iron-deficiency anxmia which responds well to oral iron and does not relapse ". Before too much effort is expended in the exploration of this phenomenon, one should consider the possibility that this condition is no different from the anaemia which occurs throughout adult female life, but the likelihood of its detection is increased simply by the increase in symptoms around the menopause which leads to more frequent medical consultation. It is perhaps unfortunate that no consideration was given to how much " iron-lack anaemia " really matters. It is all too easy to quote a textbook 1a which states that iron-lack anaemia plays an important role in contributing to the valetudinarian condition and substandard work performance of millions, but it would be interesting to see some valid supporting data. We have so far failed to
find
any.19
M.R.C. Epidemiology Unit (South Wales), 4 Richmond Road, Cardiff CF2 3AS.
A. L. COCHRANE P. C. ELWOOD.
IRON ’
SNj—Your editorial on iron (Aug. 28, p. 475) is of great interest. Although you say the cause of iron-lack anaemia ! has been identified for most situations, you do not mention the important role of endogenous non-haam iron IOSS.14.15 have reported 14 that free-iron loss is significantly We increased in the majority of patients with atrophic gastritis, ,
‘
which is
a common
condition after 50 years of age and is
I
known to be associated with a high cell turnover. 16 A mean
I
daily fæcal loss
of 0-78 mg. of free iron was found in this group, and this together with impaired absorption may account for the ansemia which occurs in many patients at 10. Loh, H. S., Wilson, C. W. M. ibid. 1971, 41, 259. 11. Cox, E. V. in Vitamins and Hormones (edited by R. S. Harris, I. G. Waal, and J. A. Loraine); vol. XXVI, p. 635. London, 1968. 12. Lee, P. C., Ledwich, J. R., Smith, D. C. Can. med. Ass. J. 1967, 13. 14. 15. 16.
97, 181. Loh, H. S., Wilson, C. W. M. Nutr. Rep. Int. (in the press). Sutton, D. R., Baird, I. McL., Stewart, J. S., Coghill, N. F. Lancet, 1970, ii, 387. Singh, A. K. Br.J. Hæmat. 1970, 18, 597. Croft, D. N., Pollock, D. J., Coghill, N. F. Gut, 1966 7, 333.
RENAL CHANGES IN HEPATIC FAILURE SIR,—In his letter of July 31 (p. 260), Dr. Wilkinson refers to our discussion 20 of certain renal changes in hepatic failure. Our hypothesis suggested that the accumulation of relatively inactive aromatic amine compounds (" false neurotransmitters ") at nerve endings of the peripheral sympathetic nervous system, and perhaps in the brain, might account for many of the neurological and circulatory disturbances which occur in severe hepatic failure. Dr. Wilkinson suggests that the improvements of renal function following the administration of metaraminol are " due merely to the rise in central arterial blood-pressure ". We would agree that such a mechanism may explain partially 17. Green, R., Charlton, R., Seftel, H., Bothwell, T., Mayet, F., Adams, B., Finch, C. A., Layrisse, M. Am. J. Med. 1968, 45, 336. 18. Harris, J. W., Kellermeyer, R. W. The Red Cell. Cambridge, Mass., 1970. 19. Elwood, P. C. Proc. R. Soc. Med. 1970, 63, 1230. 20. Fischer, J. E., Baldessarini, R. J. Lancet, July 10, 1971, p. 75.