666
endorphins were active in peripheral assays, but did not produce significant analgesia in the brain. 19 These peptides could be merely degradation products of C-fragment; yet they were present in brain in- sufficient quantity for isolation and identification, and it is possible that they possess a neuroactivity other than the ability to produce analgesia. The ease of destruction and low receptor affinity of methionine enkephalin are properties characteristic of a short-lasting neurotransmitter, and one suggestion is that (x-endorphin and &ggr;-endorphin may be elaborated to perform a specific role in a be-
.
havioural pattern. On both scores evidence is awaited. Observations that the intact C-fragment is highly potent in inducing excessive grooming in ratsls and that* its analgesic effects are invariably accompanied by catatonia19 have led to the plausible notion that the peptides with opiate activity may be involved in the aetiology of catatonic schizophrenia. Whether or not this hypothesis will stand, the discovery of C-fragment and its related peptides has clearly opened a promising area of brain bio-
chemistry.
Bypass
hyperobesity, jejunoileal bygains popularity: in Southern California alone, almost two thousand patients have been treated in this way. But, despite its newfound respectability, the operation is not free from hazard. Postoperatively, wound infections and pulmonary embolism are frequent, and longer-term complications include renal and biliary calculi;21 renal failure;2 diarrhœa and electrolyte depletion, bypass enteritis, colonic pseudo-obstruction,20 and polyarthritis.13 Liver disease is a leading cause of death and its pathogenesis and treatment have come under intensive investigation. Greatly obese patients have fatty livers, sometimes with raised serum aminotransferases. Shortly after jejunoileal bypass these changes tend to become more striking,24-26 and the exacerbation persists for six to nine months. A few patients, perhaps 1-2%, progress to more severe liver disease with nausea, vomiting, abdominal pain, and jaundice. There may be hepatosplenomegaly and ascites, 18.
a
treatment
tests
fatty infiltration, areas of hepatic parenchymal necrosis and inflammatory change,
may include
of fibrosis in the portal tracts, sinusoids, and central-vein areas. Mallory’s hyaline is sometimes prominent. Other patients have shown progressive liver damage, leading to cirrhosis, despite repeatedly normal standard liverfunction tests.32 For detecting such cases some workers advocate sequential liver scans;8 while others favour serial liver biopsies at six-monthly intervals during the first twelve to eighteen months after operation?o What is the cause of the liver disease? No-one has offered an entirely satisfactory explanation, One notable observation was that of BONDER and PISESKY 33 who showed that laboratory animals with an 80% jejunoileal bypass died after surgery, whereas an 80% resection allowed survival and This suggested that the trouble was related to the bypass loop. The notion that bacteria or bacterial toxins may be to blame is supported by the beneficial effects in laboratory animals of antibiotics.34 broad-spectrum postoperative Another suggestion is that bile-acids may be degraded by colonic bacteria to potentially toxic forms such as lithocholic acid: the reported small rise in serum lithocholate35may be significant since this- substance is more hepatotoxic in the protein-deficient state. 36 A three-fold increase (16 µg/g of wet liver tissue) in chenodeoxycholic acid was found in hepatic tissue after bypass, and concentrations of this order produce liver injury in monkeys. Certainly the effects of absorbed colonic bile-acids need to be studied further. Alcohol is produced by bacterial fermentation of carbohydrates in the colon, but the blood-alcohol levels in bypass patients are not high enough to cause hepatic damage."’ MOXLEY et al. 38 have suggested that protein malnutrition may contribute to the liver disease: they showed that the plasma-aminoacid profile during the period of rapid weight-loss was typical of protein-calorie malnutrition; but the gross and variable
amounts
adaptation.
The Liver after Jejunoileal As pass
show a moderate rise in serum aminotransferase, low serum albumin, and prolongation of the prothrombin time. A number of such patients die in hepatic failure, usually within six months of operation,27-31 and the liver picture
and liver-function
for
Gispen, W. H., Wiegant, V. M., Bradbury, A. F., Hulme, E. C., Smyth, D. G , Snell, C. R, Nature (in the press). 19. Jacquet, Y. F., Marks, N. in Cellular Effects of Opiates (edited by H. Kosterlitz). Amsterdam (in the press). 20. Bray, G. A., Barry, R. E., Benfield, J. R., Castelnuovo-Tedesco, P. Drenick, E. J., Passaro, E. Ann. intern. Med. 1976, 85, 97. 21. Wise, L., Stein, T. Archs Surg. 1975, 110, 1043. 22. Cryer, P. E., Garber, A. J., Hoffseten, P., Lucas, B., Wise, L. Archs intern. Med. 1975, 135, 1610. 23. Wands, J R., La Mont, J. T., Mann, E., Isselbacher, K. J. New Engl J. Med. 1976, 294, 121. 24. Salmon, P., Reedy, K. L. Surgery Gynec. Obstet. 1975, 141, 75. 25. Kern, W. H., Heger, A. H., Payne, J. H, de Wind, L. T. Archs Path 1973, 96, 342. 26. Manes, J. L., Taylor, H. B., Starkloff, G. B. J. clin. Path. 1975, 26, 776.
27. Baber, J., Hayden, W. F., Thompson, B. W. Am. J. Surg. 1973, 126, 769. 28. Brown, R. G., O’Leary, J. P., Woodward, E. R. ibid. 1974, 127, 53. 29. Spin, F. P., Weismann, R. E. ibid. 1975, 130, 88. 30. Mangla, J. C., Hoy, W., Chopak, H. Am. J. dig. Dis. 1974, 19, 759 31. Peters, R. L., Gay, T., Reynolds, T. B. Am J. clin. Path. 1975, 63, 318 32. Halloran, L. G., Hutcher, N. E., Levinson, S. A., Schatzki, P F Hume, D. M. Surg. Forum, 1974, 25, 359. 33. Bonder, G. F., Pisesky, W. Archs Surg. 1967, 94, 707. 34. O’Leary, J. P., Maher, J. W., Hollenbeck, J. I., Woodward, E R Surg. Forum, 1974, 25, 356. 35. Sherr, H P., Nair, P. P, White, J. J., Lockhead, D. H. Am J clin. Nutr. 1974, 27, 1369. 36 Carey, J. B., Wilson, I D., Zaki, F. G., Hanson, R F Medicine, 1966,
37. 38.
45, 461. Mezey, E. Am J clin. Nutr. 1975, 28, 1277. Moxley, R. T., Pazefsky, T., Lockwood, D. 1974, 290, 921.
H.
et
al. New Engl. J.
Med.
667 seen after jejunoileal in to arise kwashiorkor.
hepatic changes not seem
bypass do
durof treatation of the liver disease make ment difficult. Nutritional deficiencies should certainly be corrected, and intravenous aminoacids, with or without added carbohydrate, seem to have been effective in some cases.39 40 Antibiotics directed particularly against anaerobic flora may be useful, and metronidazole is worth a trial. A proximal feeding jejunostomy, which has some experimental justification,4’ may facilitate treatment along these lines. Finally, if deterioration continues, reoperation must be considered: even advanced disease may regress after reanastomosis,27 42 but in some patients the disease continues relentlessly to a fatal The variable
severity and unpredictable assessment
end." The observation31 43 that the severe histological lesions after jejunoileal bypass are indistinguishable from those of severe alcoholic liver disease opens questions on the pathogenesis of alcoholinduced liver disease. Until very lately the clinical, epidemiological, and experimental observations all suggested that alcoholic liver disease was due to the toxic effect of alcohol alone. Particular emphasis has been placed on the work of RuBIN and LIEBER,44 who produced alcoholic hepatitis, and even cirrhosis, in baboons by prolonged feeding of alcohol despite a high-protein diet. This work does not rule out the possibility that alcohol in some way impairs utilisation of essential metabolites at cellular level, and the similarity between the hepatic lesions in the jejunoileal-bypass patients and those in the alcoholic may indicate a common path-
ogenetic pathway. Vivisection
!
THE Cruelty to Animals Act of 1876 is a hundred years old and ripe for review. The Act was passed after a Royal Commission on "experiments on living animals with a view to the advancement of science, or to the acquisition of knowledge available for the relief of human suffering or for the prolongation of human life". The Act was directed to scientific experiment, not to cruelty to animals in general, and it covered acquisition of basic knowledge as well as information which might save life or alleviate suffering in man or animals. At that time experiments on animals were done only for physiological or medical purposes, and in small numbers. Even this involved difficult ethical questions, and the British Medical Association had already, in 1871, issued guidelines of conduct for 39
40
Heimberger, S. L., Steiger, E., Ames, F.
Lo
Gerfo, Am. J. Surg. 1975, 129, C, Copeland, E. M., Leeb, D. C., Moore, D. L., Dudrick, P.
229. S. J.
J Am med Ass. 1976, 235, 1249. C. V., Heimbach, D. M., Eigenbrodt, E. H., Dowdy, A B C Surg. Forum, 1970, 21, 368. 42 Soyer, M T, Ceballos, R., Aldrete, J. S. Surgery, 1976, 79, 601. 43 Galambos,J T. Archs Path. Lab. Med. 1976, 100, 229. 41
McClelland, R. N., DeShazo,
44
Rubin, E, Lieber, C.S
New Engl.
J. Med. 1974, 290,
128.
The Commission, and subsequent Commissions, agreed that proper experiments were morally and practically necessary; that they had led to good results; but that pain should be prevented or mitigated by anaesthetics, and severe or prolonged pain should be avoided altogether. Most people, including most experimenters, dislike experiments on the living, and avoid them if possible, and some people will always object to all such experiments, just as a few will always object to the advancement of knowledge. The debate on the ethics of the procedure continues, and should continue : public opinion tends to change. Since 1876 two things have changed which merit serious consideration. The first is the object of the experiments. The number of them has increased hugely, to about five and a half million a year, and the object has changed in that most of them, three and a half million, are not done for medical research but by commercial concerns to test the safety of for example, cosmetics, foodadditives, detergents, and substitutes for tobacco. So all the original indignations which were evoked in the 1870s by the use of curare for animal experi-
experimenters.
roused
again by existing practices whereby irritating cosmetics are dripped into the eyes of animals, causing severe pain, whereby animals are killed in large numbers to determine the L.D.50 (and this as a statutory requirement), and whereby animals are made to inhale smoke in the ments
are
of will make
search for a tobacco substitute which an addict of the user without giving him cancer. Certainly, things which involve no serious operative procedures are now classified as vivisection, inflating the figures. But even a simple hypodermic injection may be excruciating; the effect depends on the substance. Practically none of the questions in this sphere have easy answers. The other thing which has changed is the Home Office Advisory Committee, which has come under strong criticism. Originally, after 1876, the Minister sought advice in difficult cases from the Association for the Advancement of Medicine by Research, which does not sound sufficiently impartial to satisfy a public feeling of uncertainty. The antivivisectionists humorously took the advantage, in 1912, of suggesting that they should be the advis-
course
a
body. Subsequent legislation provided that the duty should devolve on a special committee, nominated by the two Royal Colleges, appointed by the Minister, and presided over by a layman, a senior judge. To this have been lately added four more laymen: women members have been nominated for ory
time. On the whole, this committee has worked well, but it has been purely advisory (and let it be admitted that if the Minister wants an advisory committee, there is no reason why he should not have one); but recently there has been a strong feeling that it should be more than this, and the Littlewood Committee recommended eleven years some
endorphins were active in peripheral assays, but did not produce significant analgesia in the brain. 19 These peptides could be merely degradation products of C-fragment; yet they were present in brain in- sufficient quantity for isolation and identification, and it is possible that they possess a neuroactivity other than the ability to produce analgesia. The ease of destruction and low receptor affinity of methionine enkephalin are properties characteristic of a short-lasting neurotransmitter, and one suggestion is that (x-endorphin and &ggr;-endorphin may be elaborated to perform a specific role in a be-
.
havioural pattern. On both scores evidence is awaited. Observations that the intact C-fragment is highly potent in inducing excessive grooming in ratsls and that* its analgesic effects are invariably accompanied by catatonia19 have led to the plausible notion that the peptides with opiate activity may be involved in the aetiology of catatonic schizophrenia. Whether or not this hypothesis will stand, the discovery of C-fragment and its related peptides has clearly opened a promising area of brain bio-
chemistry.
Bypass
hyperobesity, jejunoileal bygains popularity: in Southern California alone, almost two thousand patients have been treated in this way. But, despite its newfound respectability, the operation is not free from hazard. Postoperatively, wound infections and pulmonary embolism are frequent, and longer-term complications include renal and biliary calculi;21 renal failure;2 diarrhœa and electrolyte depletion, bypass enteritis, colonic pseudo-obstruction,20 and polyarthritis.13 Liver disease is a leading cause of death and its pathogenesis and treatment have come under intensive investigation. Greatly obese patients have fatty livers, sometimes with raised serum aminotransferases. Shortly after jejunoileal bypass these changes tend to become more striking,24-26 and the exacerbation persists for six to nine months. A few patients, perhaps 1-2%, progress to more severe liver disease with nausea, vomiting, abdominal pain, and jaundice. There may be hepatosplenomegaly and ascites, 18.
a
treatment
tests
fatty infiltration, areas of hepatic parenchymal necrosis and inflammatory change,
may include
of fibrosis in the portal tracts, sinusoids, and central-vein areas. Mallory’s hyaline is sometimes prominent. Other patients have shown progressive liver damage, leading to cirrhosis, despite repeatedly normal standard liverfunction tests.32 For detecting such cases some workers advocate sequential liver scans;8 while others favour serial liver biopsies at six-monthly intervals during the first twelve to eighteen months after operation?o What is the cause of the liver disease? No-one has offered an entirely satisfactory explanation, One notable observation was that of BONDER and PISESKY 33 who showed that laboratory animals with an 80% jejunoileal bypass died after surgery, whereas an 80% resection allowed survival and This suggested that the trouble was related to the bypass loop. The notion that bacteria or bacterial toxins may be to blame is supported by the beneficial effects in laboratory animals of antibiotics.34 broad-spectrum postoperative Another suggestion is that bile-acids may be degraded by colonic bacteria to potentially toxic forms such as lithocholic acid: the reported small rise in serum lithocholate35may be significant since this- substance is more hepatotoxic in the protein-deficient state. 36 A three-fold increase (16 µg/g of wet liver tissue) in chenodeoxycholic acid was found in hepatic tissue after bypass, and concentrations of this order produce liver injury in monkeys. Certainly the effects of absorbed colonic bile-acids need to be studied further. Alcohol is produced by bacterial fermentation of carbohydrates in the colon, but the blood-alcohol levels in bypass patients are not high enough to cause hepatic damage."’ MOXLEY et al. 38 have suggested that protein malnutrition may contribute to the liver disease: they showed that the plasma-aminoacid profile during the period of rapid weight-loss was typical of protein-calorie malnutrition; but the gross and variable
amounts
adaptation.
The Liver after Jejunoileal As pass
show a moderate rise in serum aminotransferase, low serum albumin, and prolongation of the prothrombin time. A number of such patients die in hepatic failure, usually within six months of operation,27-31 and the liver picture
and liver-function
for
Gispen, W. H., Wiegant, V. M., Bradbury, A. F., Hulme, E. C., Smyth, D. G , Snell, C. R, Nature (in the press). 19. Jacquet, Y. F., Marks, N. in Cellular Effects of Opiates (edited by H. Kosterlitz). Amsterdam (in the press). 20. Bray, G. A., Barry, R. E., Benfield, J. R., Castelnuovo-Tedesco, P. Drenick, E. J., Passaro, E. Ann. intern. Med. 1976, 85, 97. 21. Wise, L., Stein, T. Archs Surg. 1975, 110, 1043. 22. Cryer, P. E., Garber, A. J., Hoffseten, P., Lucas, B., Wise, L. Archs intern. Med. 1975, 135, 1610. 23. Wands, J R., La Mont, J. T., Mann, E., Isselbacher, K. J. New Engl J. Med. 1976, 294, 121. 24. Salmon, P., Reedy, K. L. Surgery Gynec. Obstet. 1975, 141, 75. 25. Kern, W. H., Heger, A. H., Payne, J. H, de Wind, L. T. Archs Path 1973, 96, 342. 26. Manes, J. L., Taylor, H. B., Starkloff, G. B. J. clin. Path. 1975, 26, 776.
27. Baber, J., Hayden, W. F., Thompson, B. W. Am. J. Surg. 1973, 126, 769. 28. Brown, R. G., O’Leary, J. P., Woodward, E. R. ibid. 1974, 127, 53. 29. Spin, F. P., Weismann, R. E. ibid. 1975, 130, 88. 30. Mangla, J. C., Hoy, W., Chopak, H. Am. J. dig. Dis. 1974, 19, 759 31. Peters, R. L., Gay, T., Reynolds, T. B. Am J. clin. Path. 1975, 63, 318 32. Halloran, L. G., Hutcher, N. E., Levinson, S. A., Schatzki, P F Hume, D. M. Surg. Forum, 1974, 25, 359. 33. Bonder, G. F., Pisesky, W. Archs Surg. 1967, 94, 707. 34. O’Leary, J. P., Maher, J. W., Hollenbeck, J. I., Woodward, E R Surg. Forum, 1974, 25, 356. 35. Sherr, H P., Nair, P. P, White, J. J., Lockhead, D. H. Am J clin. Nutr. 1974, 27, 1369. 36 Carey, J. B., Wilson, I D., Zaki, F. G., Hanson, R F Medicine, 1966,
37. 38.
45, 461. Mezey, E. Am J clin. Nutr. 1975, 28, 1277. Moxley, R. T., Pazefsky, T., Lockwood, D. 1974, 290, 921.
H.
et
al. New Engl. J.
Med.
667 seen after jejunoileal in to arise kwashiorkor.
hepatic changes not seem
bypass do
durof treatation of the liver disease make ment difficult. Nutritional deficiencies should certainly be corrected, and intravenous aminoacids, with or without added carbohydrate, seem to have been effective in some cases.39 40 Antibiotics directed particularly against anaerobic flora may be useful, and metronidazole is worth a trial. A proximal feeding jejunostomy, which has some experimental justification,4’ may facilitate treatment along these lines. Finally, if deterioration continues, reoperation must be considered: even advanced disease may regress after reanastomosis,27 42 but in some patients the disease continues relentlessly to a fatal The variable
severity and unpredictable assessment
end." The observation31 43 that the severe histological lesions after jejunoileal bypass are indistinguishable from those of severe alcoholic liver disease opens questions on the pathogenesis of alcoholinduced liver disease. Until very lately the clinical, epidemiological, and experimental observations all suggested that alcoholic liver disease was due to the toxic effect of alcohol alone. Particular emphasis has been placed on the work of RuBIN and LIEBER,44 who produced alcoholic hepatitis, and even cirrhosis, in baboons by prolonged feeding of alcohol despite a high-protein diet. This work does not rule out the possibility that alcohol in some way impairs utilisation of essential metabolites at cellular level, and the similarity between the hepatic lesions in the jejunoileal-bypass patients and those in the alcoholic may indicate a common path-
ogenetic pathway. Vivisection
!
THE Cruelty to Animals Act of 1876 is a hundred years old and ripe for review. The Act was passed after a Royal Commission on "experiments on living animals with a view to the advancement of science, or to the acquisition of knowledge available for the relief of human suffering or for the prolongation of human life". The Act was directed to scientific experiment, not to cruelty to animals in general, and it covered acquisition of basic knowledge as well as information which might save life or alleviate suffering in man or animals. At that time experiments on animals were done only for physiological or medical purposes, and in small numbers. Even this involved difficult ethical questions, and the British Medical Association had already, in 1871, issued guidelines of conduct for 39
40
Heimberger, S. L., Steiger, E., Ames, F.
Lo
Gerfo, Am. J. Surg. 1975, 129, C, Copeland, E. M., Leeb, D. C., Moore, D. L., Dudrick, P.
229. S. J.
J Am med Ass. 1976, 235, 1249. C. V., Heimbach, D. M., Eigenbrodt, E. H., Dowdy, A B C Surg. Forum, 1970, 21, 368. 42 Soyer, M T, Ceballos, R., Aldrete, J. S. Surgery, 1976, 79, 601. 43 Galambos,J T. Archs Path. Lab. Med. 1976, 100, 229. 41
McClelland, R. N., DeShazo,
44
Rubin, E, Lieber, C.S
New Engl.
J. Med. 1974, 290,
128.
The Commission, and subsequent Commissions, agreed that proper experiments were morally and practically necessary; that they had led to good results; but that pain should be prevented or mitigated by anaesthetics, and severe or prolonged pain should be avoided altogether. Most people, including most experimenters, dislike experiments on the living, and avoid them if possible, and some people will always object to all such experiments, just as a few will always object to the advancement of knowledge. The debate on the ethics of the procedure continues, and should continue : public opinion tends to change. Since 1876 two things have changed which merit serious consideration. The first is the object of the experiments. The number of them has increased hugely, to about five and a half million a year, and the object has changed in that most of them, three and a half million, are not done for medical research but by commercial concerns to test the safety of for example, cosmetics, foodadditives, detergents, and substitutes for tobacco. So all the original indignations which were evoked in the 1870s by the use of curare for animal experi-
experimenters.
roused
again by existing practices whereby irritating cosmetics are dripped into the eyes of animals, causing severe pain, whereby animals are killed in large numbers to determine the L.D.50 (and this as a statutory requirement), and whereby animals are made to inhale smoke in the ments
are
of will make
search for a tobacco substitute which an addict of the user without giving him cancer. Certainly, things which involve no serious operative procedures are now classified as vivisection, inflating the figures. But even a simple hypodermic injection may be excruciating; the effect depends on the substance. Practically none of the questions in this sphere have easy answers. The other thing which has changed is the Home Office Advisory Committee, which has come under strong criticism. Originally, after 1876, the Minister sought advice in difficult cases from the Association for the Advancement of Medicine by Research, which does not sound sufficiently impartial to satisfy a public feeling of uncertainty. The antivivisectionists humorously took the advantage, in 1912, of suggesting that they should be the advis-
course
a
body. Subsequent legislation provided that the duty should devolve on a special committee, nominated by the two Royal Colleges, appointed by the Minister, and presided over by a layman, a senior judge. To this have been lately added four more laymen: women members have been nominated for ory
time. On the whole, this committee has worked well, but it has been purely advisory (and let it be admitted that if the Minister wants an advisory committee, there is no reason why he should not have one); but recently there has been a strong feeling that it should be more than this, and the Littlewood Committee recommended eleven years some
