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PIG-LIVER PERFUSION IN HEPATIC COMA
509 ESTIMATED AND ACTUAL TARGETS FOR MORE CHILDREN ACCORDING TO PROBABILITY DISTRIBUTION OF LIVEBORN SONS, FOR EACH FAMILY SIZE
sure that one will survive to adult life. If m=0-25, in many malarious areas, they are likely to aim at having at least 3 sons; but if child mortality is reduced to 0 10, this aim is achieved by having only 2 live sons. To aim at having 3 liveborn sons means, initially, aiming at having 6 children. It is striking that in Kenya, for instance, the 1962 census showed an average achieved family size of 6,8 children; a recent rural sample survey 6 of attitudes to family size in the same country showed that, despite acute awareness of the economic disability imposed by a large family, the average number of children wanted (by 774 women interviewed) was 6-03, and that this aim was largely, independent of the number of children they already had. One would expect the number of children wanted to alter with the number of sons actually born. The probabilities of having 0, 1, 2, 3,... liveborn sons for any family size n is easily calculated from the terms of the binomial expansion (1/2 +1/ 2)n and results in a modified Pascal’s triangle in which the sum of probabilities for each value of n is, of course, unity. To estimate how the family " target " alters with the number of sons born, in a community which aims at 3 liveborn sons, the simplest model is as follows:
reasonably as
Thus when 3 living sons are achieved, the average couple have pressing wish for further children. If the targets in this model are applied to the probability distribution of liveborn sons for each family size, one may directly calculate the average target for more children (shown in column ii of the accompanying table), which is seen to be in reasonably close correspondence to the distribution of numbers of further children wanted by mothers questioned in the Kenya rural survey 6 (shown in column iii). This model does not, of course, take into account the likely variation in the number of liveborn sons considered desirable, which might be greater in particular communities where there is traumatic mortality in early adult life (due to wars or other intercommunal strife), or less in maternal cohorts which experience lessening mortality amongst their children. At present there is insufficient evidence on the size of these factors, though it is evident that they might progress in advance of current attitudes among older mothers, and thus explain the less-close fit to the model expectation in larger-sized families. This is suggested in the Kenya study,in which 37% of women considered 4 or fewer children to be best, and accords with the expectation of that proportion of mothers who already have several surviving sons-i.e., the lucky families turning up in the more favoured (right-hand edge) segments of Pascal’s triangle. These are the mothers who, for obvious reasons, desire to limit their families, and for whom family-planning information and facilities need to be provided. There is, then, a big need for these facilities in rural areas, even though their provision may not make a
no
significant difference
to
overall fertility-rates.
We consider that the conclusions which can be drawn from this 6.
Heisel, D. F. Fertility Limitation among Rural Women in Kenya (mimeographed report). Institute for Development Studies, University College, Nairobi, Kenya, 1968.
simple analysis
are:
(1) family-planning programmes aiming to
reduce the present high rates of natural increase are unlikely to succeed until some alternative form of social security is organised in patrilineal rural societies; and (2) until major health measures (e.g., malaria eradication) reduce the generally high mortality-rates in childhood, there will be no desire to limit fertility in rural communities. We consider that Quenumwas correct in stating that " economic and social progress is the first condition that must be satisfied before a population policy can succeed in any country ". We believe that these conclusions are supported by the experience of family-planning campaigns, which receive limited support and have made no significant difference to fertility in any area in which malaria remains endemic. Unfortunately, too, the argument that educated children give greater security to parents in old age (and provision for education entails a limitation in family size) seldom applies to children from rural areas, who are less successful than their urban brethren on the labour market, and may indeed have to settle so far from home in order to get employment that the older ties of the extended family are more or less disrupted. Department of Preventive Medicine, M. A. GUMBI Makerere University College Medical School,
Kampala, Uganda.
S. A. HALL.
PIG-LIVER PERFUSION IN HEPATIC COMA SIR,-We have been engaged in developing a successful technique of extracorporeal pig-liver perfusion with human blood during the past 18 months. This technique has now been used for the treatment of four patients in terminal hepatic failure with considerable clinical and biochemical improvement. We report here, very briefly, our findings in one of these patients who was in coma as a result of acute fulminat-
ing hepatitis. A 47-year-old
man was admitted in coma to this hospital, under the care of Dr. H. A. Dewar and Dr. T. B. Stretton. For 5 weeks before admission he had had progressive jaundice, ascites, and oedema culminating in pre-coma and later coma during the week before admission. His liver-function tests on admission showed: serum bilirubin 20 mg. per 100 ml., alkaline phosphatase 206 i.u., and glutamic-pyruvic-transaminase in excess of 100 i.u. Prothrombin was 22% of normal, plasma-ammonia 116 jig. per 100 ml., and plasma-proteins 5-3 g. per 100 ml. Hepatic necrosis from viral hepatitis was clinically diagnosed. He was treated along conventional lines with intravenous fluids, glucose, vitamins, colonic washouts, and oral neomycin. In the next 48 hours his condition deteriorated and he became oliguric with a blood-urea of 81 mg. per 100 ml. His bilirubin rose to 24-2 mg. per 100 ml., and his plasma-ammonia to 135 g. per 100 ml. He was found to have thrombocytopenia and prolonged clotting-time. Extracorporeal pig-liver perfusion was carried out on the 4th day after admission by means of an indwelling arteriovenous shunt in the upper arm, using regional heparinisation. During 51/2 hours of perfusion the liver functioned well, excreting a total of 80 ml. of bile with a bilirubin concentration of around 300 mg. per 100 ml. At the termination of perfusion the patient began to respond to painful stimuli and 6 hours later he opened his eyes and was able to answer questions. During the next 8 hours he began to talk rationally, and by next day he sat up and was able to give his history for the first time. The biochemical improvement was equally striking: after perfusion the serum-bilirubin dropped to 12 mg. per 100 ml. and the plasma-ammonia to 24 g. per 100 ml. The prothrombin rose from 20% to 32%, and later to 45%. The serum-alkalinephosphatase dropped to 48 i.u. He remained well for another 48 hours, when he suddenly developed a large hxmatemesis with melasna, which was finally controlled with blood-transfusion and aminocaproic acid. After this episode his liver-function tests deteriorated but he remained fully conscious. On the 4th day after perfusion his condition rapidly worsened, and he became
Quenum, A. W. Afr. med. J. 1967, 16, 149. 8. Abouna, G. M. Br. J. Surg. (in the press).
7.
510
drowsy and grossly oliguric, and later comatose. Arrangements were made to carry out a second pig-liver perfusion but unfortunately, only 30 minutes before the pig liver could be brought to him, he developed another haematemesis and died. Necropsy showed a very soft and shrunken liver which on histological examination revealed extensive hepatic necrosis and other features of acute viral hepatitis. There was a myriad of minute gastric and small-bowel erosions. The mortality from hepatic coma due to acute hepatic necrosis is exceedingly high,9 10 and when accompanied by oliguria and uraemia there is very often a fatal outcome.ll Nevertheless, owing to the enormous capacity of the liver for regeneration, the hepatic damage may be regarded as potentially reversible. It follows therefore that, if some form of effective temporary and repeated hepatic support can be provided for these patients, the inevitable gloomy outcome might be prevented. With exchange blood-transfusion some salvage has been reported by Berger et all and Saunders,t3 though Jones a1.14 had no survivors among seven cases thus treated. In view of the complexities of liver functions only a normal liver can be substituted for another which has failed, and for this reason the use of a healthy extracorporeal liver, we believe, is the rational method of therapy. The effectiveness of such a liver is very well demonstrated in this case. The clinical improvement in this patient after 51/2 hours of perfusion was very striking, and in parallel with this were the dramatic hmmatological and biochemical changes. Unfortunately, the patient in coma from acute hepatic necrosis develops other very serious complications—namely, renal failure, haemorrhage, hypoglycxmia, respiratory failure, and electrolyte imbalance. Gastrointestinal haemorrhage seems to be the commonest terminal complication, as in this case. et
C.M. ABOUNA R. GARRY C. HULL J. KIRKLEY D. N. WALDER.
The Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP
COPROPORPHYRINURIA AND HUMAN HEART TRANSPLANTATION wish to draw attention to a disturbance in urinary SiR,ŇI porphyrin excretion observed in two patients after cardiac transplantation and to express the hope that other cardiactransplant teams will be encouraged to undertake serial studies of porphyrin excretion. Both patients developed pronounced coproporphyrinuria. Uroporphyrin excretion was unaffected. 8-aminolaevulinic acid (A.L.A.) and porphobilinogen (P.B.G.) excretion showed little if any deviation from normal except for a preterminal rise in urinary A.L.A. in the first patient. Both patients had a temporary mild increase in urinary coproporphyrin soon after operation; about the 10th post-operative day the coproporphyrin increased again to reach initial peak values of 500 g. and 596 g. per day respectively. In the first patient the peak excretion of 500 g. was reached on the 12th postoperative day, 5 days before his death from a fulminant Klebsiella-Pseudomonas pneumonia. In the second patient, the initial peak value was reached on the 18th postoperative day. Thereafter the urinary coproporphyrin excretion (mainly isomer III) remained well above normal and only approached 150-200 ;jtg. per day 4 days before his discharge from hospital on the 74th postoperative day. The fall in coproporphyrin output was evanescent and, despite striking physical improvement, the level rose sharply again and has remained raised since then, isomer III constituting 48-58% of the copro9. 10.
Cook, G. C., Sherlock, S. Lancet, 1965, i, 175. Chalmers, T. C. in The Liver (edited by A. E. Read); p. 287. London, 1967. 1121.
11. Hecker, R., Sherlock, S. Lancet, 1956, ii, 12. Berger, R. L., Liverage, R. M., Chalmers, T. C., Graham, J. H., McGoldrick, D. M., Stohlman, F. New Engl. J. Med. 1966, 274, 497. 13. Saunders, S. J. in The Liver (edited by A. E. Read); p. 289. London, 1967. 14. Jones, E. A., Clain, D., Clink, H. M., MacGillivray, M., Sherlock, S. Lancet, 1967, ii, 169.
increases (up to 835 (Lg. per day) have accompanied complications such as deterioration in cardiac function, development of a septicaemia with meningitis, hepatitis, and suspected pulmonary embolism and pneumonia. In view of the multiplicity of factors influencing the progress following organ transplantation, the precise aetiology of the porphyrinuria is difficult to establish. Among the factors to be considered early in the course after transplantation are the post-
porphyrin. Striking
operative
metabolic response, the effects of
cardiopulmonary
bypass, and the pericardial and myocardial reaction with or without congestive heart-failure. Later, other factors supervene : the toxicity of prolonged immunosuppressive therapy, the effects of tissue damage due to rejection, infection, or pulmonary embolism, and hepatic dysfunction due to liver congestion. Haemolytic anaemia, sometimes a cause of copro-
porphyrinuria, also needs to be excluded. Of some help in interpretation was the observation that two other patients undergoing open-heart surgery with cardiopulmonary bypass showed no disturbance in serial porphyrin excretion. Patients with myocardial infarction had only an immediate, short-lived, mild disturbance. Two patients on immunosuppressive therapy after renal transplantation also showed no abnormality of urinary porphyrin excretion even during rejection episodes. In the first of the two cardiac-transplant patients the coproporphyrinuria can reasonably be related to the severe pneumonic infection. In the second patient, however, many of the abovementioned factors need to be considered, including myocardial and pericardial involvement at a time when there was no evidence of infection, liver disease, or congestive heart-failure. Hasmolytic anaemia was seriously considered in view of a persistent reticulocytosis but there was no other supporting evidence, although later increased osmotic fragility developed. However, variations in therapy, meningitis, hepatitis, poor tissue perfusion, and suspected pulmonary embolism probably all contributed to the disturbance in porphyrin excretion. This multiplicity made correlation with other clinical, biochemical, and serological features difficult. For these reasons it is important that more patients be carefully studied, so as to evaluate the role of coproporphyrin excretion in assessing the progress of the patient after heart University of Cape Town, Department of Medicine, Observatory, Cape, South Africa.
transplantation. LENNOX EALES.
HORMONAL ACTIVITY AND END-ORGAN RESPONSE
SiR,ŇThe responsiveness of peripheral receptor-sites to hormonal action, and its role in the determination of the endocrine status of the individual, is again in the limelight as shown by a wealth of recent experimental studies and clinical observations on the subject, and recently by the paper by Dr. Merimee and his co-workers (July 27, p. 191). These workers found, in a male dwarf, abnormally raised levels of growth hormone (H.G.H.) with subresponsiveness of the peripheral tissues to exogenous H.G.H. They tentatively suggest that the underlying defect was abnormal responsiveness of the end-organs rather than abnormal secretion of the pituitary gland. The role played by the peripheral tissues in the pathogenesis of endocrine disease has concerned me for a long time, and from the early 1920s onwards I have approached the problem from various angles, though with less refined and elegant laboratory techniques than are used today. On the strength of clinical observations and simple model experiments revealing the significance of the pH, ionic environment, and other environmental factors for hormonal activity at the cell membrane,! I formulated in 1924 my peripheral theory "2 and I am happy to find that my postulate has been amply confirmed by elaborate physical and histochemical techniques. 1. Zondek, H., Reiter, T. Klin. Wschr. 1923, 2, 1344. Zondek, H., Ucko, H. "
ibid. 1924, 29, 1752; Hoppe-Seyler’s Z. physiol. Chem. 1925, 148, 8. Zondek, H., Bansi, H. Klin. Wschr. 1927, 6; Biochem. Z. 1928, 195, 376. 2. Zondek, H. Dt. med. Wschr. 1924, 50, 364.
sure that one will survive to adult life. If m=0-25, in many malarious areas, they are likely to aim at having at least 3 sons; but if child mortality is reduced to 0 10, this aim is achieved by having only 2 live sons. To aim at having 3 liveborn sons means, initially, aiming at having 6 children. It is striking that in Kenya, for instance, the 1962 census showed an average achieved family size of 6,8 children; a recent rural sample survey 6 of attitudes to family size in the same country showed that, despite acute awareness of the economic disability imposed by a large family, the average number of children wanted (by 774 women interviewed) was 6-03, and that this aim was largely, independent of the number of children they already had. One would expect the number of children wanted to alter with the number of sons actually born. The probabilities of having 0, 1, 2, 3,... liveborn sons for any family size n is easily calculated from the terms of the binomial expansion (1/2 +1/ 2)n and results in a modified Pascal’s triangle in which the sum of probabilities for each value of n is, of course, unity. To estimate how the family " target " alters with the number of sons born, in a community which aims at 3 liveborn sons, the simplest model is as follows:
reasonably as
Thus when 3 living sons are achieved, the average couple have pressing wish for further children. If the targets in this model are applied to the probability distribution of liveborn sons for each family size, one may directly calculate the average target for more children (shown in column ii of the accompanying table), which is seen to be in reasonably close correspondence to the distribution of numbers of further children wanted by mothers questioned in the Kenya rural survey 6 (shown in column iii). This model does not, of course, take into account the likely variation in the number of liveborn sons considered desirable, which might be greater in particular communities where there is traumatic mortality in early adult life (due to wars or other intercommunal strife), or less in maternal cohorts which experience lessening mortality amongst their children. At present there is insufficient evidence on the size of these factors, though it is evident that they might progress in advance of current attitudes among older mothers, and thus explain the less-close fit to the model expectation in larger-sized families. This is suggested in the Kenya study,in which 37% of women considered 4 or fewer children to be best, and accords with the expectation of that proportion of mothers who already have several surviving sons-i.e., the lucky families turning up in the more favoured (right-hand edge) segments of Pascal’s triangle. These are the mothers who, for obvious reasons, desire to limit their families, and for whom family-planning information and facilities need to be provided. There is, then, a big need for these facilities in rural areas, even though their provision may not make a
no
significant difference
to
overall fertility-rates.
We consider that the conclusions which can be drawn from this 6.
Heisel, D. F. Fertility Limitation among Rural Women in Kenya (mimeographed report). Institute for Development Studies, University College, Nairobi, Kenya, 1968.
simple analysis
are:
(1) family-planning programmes aiming to
reduce the present high rates of natural increase are unlikely to succeed until some alternative form of social security is organised in patrilineal rural societies; and (2) until major health measures (e.g., malaria eradication) reduce the generally high mortality-rates in childhood, there will be no desire to limit fertility in rural communities. We consider that Quenumwas correct in stating that " economic and social progress is the first condition that must be satisfied before a population policy can succeed in any country ". We believe that these conclusions are supported by the experience of family-planning campaigns, which receive limited support and have made no significant difference to fertility in any area in which malaria remains endemic. Unfortunately, too, the argument that educated children give greater security to parents in old age (and provision for education entails a limitation in family size) seldom applies to children from rural areas, who are less successful than their urban brethren on the labour market, and may indeed have to settle so far from home in order to get employment that the older ties of the extended family are more or less disrupted. Department of Preventive Medicine, M. A. GUMBI Makerere University College Medical School,
Kampala, Uganda.
S. A. HALL.
PIG-LIVER PERFUSION IN HEPATIC COMA SIR,-We have been engaged in developing a successful technique of extracorporeal pig-liver perfusion with human blood during the past 18 months. This technique has now been used for the treatment of four patients in terminal hepatic failure with considerable clinical and biochemical improvement. We report here, very briefly, our findings in one of these patients who was in coma as a result of acute fulminat-
ing hepatitis. A 47-year-old
man was admitted in coma to this hospital, under the care of Dr. H. A. Dewar and Dr. T. B. Stretton. For 5 weeks before admission he had had progressive jaundice, ascites, and oedema culminating in pre-coma and later coma during the week before admission. His liver-function tests on admission showed: serum bilirubin 20 mg. per 100 ml., alkaline phosphatase 206 i.u., and glutamic-pyruvic-transaminase in excess of 100 i.u. Prothrombin was 22% of normal, plasma-ammonia 116 jig. per 100 ml., and plasma-proteins 5-3 g. per 100 ml. Hepatic necrosis from viral hepatitis was clinically diagnosed. He was treated along conventional lines with intravenous fluids, glucose, vitamins, colonic washouts, and oral neomycin. In the next 48 hours his condition deteriorated and he became oliguric with a blood-urea of 81 mg. per 100 ml. His bilirubin rose to 24-2 mg. per 100 ml., and his plasma-ammonia to 135 g. per 100 ml. He was found to have thrombocytopenia and prolonged clotting-time. Extracorporeal pig-liver perfusion was carried out on the 4th day after admission by means of an indwelling arteriovenous shunt in the upper arm, using regional heparinisation. During 51/2 hours of perfusion the liver functioned well, excreting a total of 80 ml. of bile with a bilirubin concentration of around 300 mg. per 100 ml. At the termination of perfusion the patient began to respond to painful stimuli and 6 hours later he opened his eyes and was able to answer questions. During the next 8 hours he began to talk rationally, and by next day he sat up and was able to give his history for the first time. The biochemical improvement was equally striking: after perfusion the serum-bilirubin dropped to 12 mg. per 100 ml. and the plasma-ammonia to 24 g. per 100 ml. The prothrombin rose from 20% to 32%, and later to 45%. The serum-alkalinephosphatase dropped to 48 i.u. He remained well for another 48 hours, when he suddenly developed a large hxmatemesis with melasna, which was finally controlled with blood-transfusion and aminocaproic acid. After this episode his liver-function tests deteriorated but he remained fully conscious. On the 4th day after perfusion his condition rapidly worsened, and he became
Quenum, A. W. Afr. med. J. 1967, 16, 149. 8. Abouna, G. M. Br. J. Surg. (in the press).
7.
510
drowsy and grossly oliguric, and later comatose. Arrangements were made to carry out a second pig-liver perfusion but unfortunately, only 30 minutes before the pig liver could be brought to him, he developed another haematemesis and died. Necropsy showed a very soft and shrunken liver which on histological examination revealed extensive hepatic necrosis and other features of acute viral hepatitis. There was a myriad of minute gastric and small-bowel erosions. The mortality from hepatic coma due to acute hepatic necrosis is exceedingly high,9 10 and when accompanied by oliguria and uraemia there is very often a fatal outcome.ll Nevertheless, owing to the enormous capacity of the liver for regeneration, the hepatic damage may be regarded as potentially reversible. It follows therefore that, if some form of effective temporary and repeated hepatic support can be provided for these patients, the inevitable gloomy outcome might be prevented. With exchange blood-transfusion some salvage has been reported by Berger et all and Saunders,t3 though Jones a1.14 had no survivors among seven cases thus treated. In view of the complexities of liver functions only a normal liver can be substituted for another which has failed, and for this reason the use of a healthy extracorporeal liver, we believe, is the rational method of therapy. The effectiveness of such a liver is very well demonstrated in this case. The clinical improvement in this patient after 51/2 hours of perfusion was very striking, and in parallel with this were the dramatic hmmatological and biochemical changes. Unfortunately, the patient in coma from acute hepatic necrosis develops other very serious complications—namely, renal failure, haemorrhage, hypoglycxmia, respiratory failure, and electrolyte imbalance. Gastrointestinal haemorrhage seems to be the commonest terminal complication, as in this case. et
C.M. ABOUNA R. GARRY C. HULL J. KIRKLEY D. N. WALDER.
The Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP
COPROPORPHYRINURIA AND HUMAN HEART TRANSPLANTATION wish to draw attention to a disturbance in urinary SiR,ŇI porphyrin excretion observed in two patients after cardiac transplantation and to express the hope that other cardiactransplant teams will be encouraged to undertake serial studies of porphyrin excretion. Both patients developed pronounced coproporphyrinuria. Uroporphyrin excretion was unaffected. 8-aminolaevulinic acid (A.L.A.) and porphobilinogen (P.B.G.) excretion showed little if any deviation from normal except for a preterminal rise in urinary A.L.A. in the first patient. Both patients had a temporary mild increase in urinary coproporphyrin soon after operation; about the 10th post-operative day the coproporphyrin increased again to reach initial peak values of 500 g. and 596 g. per day respectively. In the first patient the peak excretion of 500 g. was reached on the 12th postoperative day, 5 days before his death from a fulminant Klebsiella-Pseudomonas pneumonia. In the second patient, the initial peak value was reached on the 18th postoperative day. Thereafter the urinary coproporphyrin excretion (mainly isomer III) remained well above normal and only approached 150-200 ;jtg. per day 4 days before his discharge from hospital on the 74th postoperative day. The fall in coproporphyrin output was evanescent and, despite striking physical improvement, the level rose sharply again and has remained raised since then, isomer III constituting 48-58% of the copro9. 10.
Cook, G. C., Sherlock, S. Lancet, 1965, i, 175. Chalmers, T. C. in The Liver (edited by A. E. Read); p. 287. London, 1967. 1121.
11. Hecker, R., Sherlock, S. Lancet, 1956, ii, 12. Berger, R. L., Liverage, R. M., Chalmers, T. C., Graham, J. H., McGoldrick, D. M., Stohlman, F. New Engl. J. Med. 1966, 274, 497. 13. Saunders, S. J. in The Liver (edited by A. E. Read); p. 289. London, 1967. 14. Jones, E. A., Clain, D., Clink, H. M., MacGillivray, M., Sherlock, S. Lancet, 1967, ii, 169.
increases (up to 835 (Lg. per day) have accompanied complications such as deterioration in cardiac function, development of a septicaemia with meningitis, hepatitis, and suspected pulmonary embolism and pneumonia. In view of the multiplicity of factors influencing the progress following organ transplantation, the precise aetiology of the porphyrinuria is difficult to establish. Among the factors to be considered early in the course after transplantation are the post-
porphyrin. Striking
operative
metabolic response, the effects of
cardiopulmonary
bypass, and the pericardial and myocardial reaction with or without congestive heart-failure. Later, other factors supervene : the toxicity of prolonged immunosuppressive therapy, the effects of tissue damage due to rejection, infection, or pulmonary embolism, and hepatic dysfunction due to liver congestion. Haemolytic anaemia, sometimes a cause of copro-
porphyrinuria, also needs to be excluded. Of some help in interpretation was the observation that two other patients undergoing open-heart surgery with cardiopulmonary bypass showed no disturbance in serial porphyrin excretion. Patients with myocardial infarction had only an immediate, short-lived, mild disturbance. Two patients on immunosuppressive therapy after renal transplantation also showed no abnormality of urinary porphyrin excretion even during rejection episodes. In the first of the two cardiac-transplant patients the coproporphyrinuria can reasonably be related to the severe pneumonic infection. In the second patient, however, many of the abovementioned factors need to be considered, including myocardial and pericardial involvement at a time when there was no evidence of infection, liver disease, or congestive heart-failure. Hasmolytic anaemia was seriously considered in view of a persistent reticulocytosis but there was no other supporting evidence, although later increased osmotic fragility developed. However, variations in therapy, meningitis, hepatitis, poor tissue perfusion, and suspected pulmonary embolism probably all contributed to the disturbance in porphyrin excretion. This multiplicity made correlation with other clinical, biochemical, and serological features difficult. For these reasons it is important that more patients be carefully studied, so as to evaluate the role of coproporphyrin excretion in assessing the progress of the patient after heart University of Cape Town, Department of Medicine, Observatory, Cape, South Africa.
transplantation. LENNOX EALES.
HORMONAL ACTIVITY AND END-ORGAN RESPONSE
SiR,ŇThe responsiveness of peripheral receptor-sites to hormonal action, and its role in the determination of the endocrine status of the individual, is again in the limelight as shown by a wealth of recent experimental studies and clinical observations on the subject, and recently by the paper by Dr. Merimee and his co-workers (July 27, p. 191). These workers found, in a male dwarf, abnormally raised levels of growth hormone (H.G.H.) with subresponsiveness of the peripheral tissues to exogenous H.G.H. They tentatively suggest that the underlying defect was abnormal responsiveness of the end-organs rather than abnormal secretion of the pituitary gland. The role played by the peripheral tissues in the pathogenesis of endocrine disease has concerned me for a long time, and from the early 1920s onwards I have approached the problem from various angles, though with less refined and elegant laboratory techniques than are used today. On the strength of clinical observations and simple model experiments revealing the significance of the pH, ionic environment, and other environmental factors for hormonal activity at the cell membrane,! I formulated in 1924 my peripheral theory "2 and I am happy to find that my postulate has been amply confirmed by elaborate physical and histochemical techniques. 1. Zondek, H., Reiter, T. Klin. Wschr. 1923, 2, 1344. Zondek, H., Ucko, H. "
ibid. 1924, 29, 1752; Hoppe-Seyler’s Z. physiol. Chem. 1925, 148, 8. Zondek, H., Bansi, H. Klin. Wschr. 1927, 6; Biochem. Z. 1928, 195, 376. 2. Zondek, H. Dt. med. Wschr. 1924, 50, 364.