244
in both conditions of antibody and cells sensitised to myelin.2I 22 The major defect in the proposition is failure to explain how a viral infection may cause an autoimmune response against occurrence
of peripheral nerve, probably against its basic proteins.22-24 A simple crossof only reacting antigen can probably be excluded by the multiplicity of causal agents, and patients seem not to belong to a specific HLA group, as in other autoimmune diseases associated with a presumed abnormal response to infection.2’ It is fortunate that the observed impairment of nerve conduction can be explained on physical grounds,l6 without invocation of any of the mysterious serum factors that have dogged other neurological diseases. The speculation about mechanism is matched by doubt about treatment. Supportive measures are essential, as in the care of any potentially paralysed patient, and there is a special cry for good nursing by the patient whose nerve endings are aflame with abnormal and distressing impulses.27 28 What about immunosuppressive treatment? Unfortunately, the therapeutic uncertainty of classical neurology has not yet been cleared from this area.3 Corticosteroids have been advocated by many, often in very big doses, but with little objective evidence of real benefit. 8 29 Cytotoxic drugs have also, been employed in a poorly controlled fashion.3O As there is a selective blood-nerve barrier,jl could an effective concentration of these substances ever be achieved within a nerve, where damage might be done by cells before they are replaced from the systemic sources that are exposed to conventional cytotoxic treatment? Indeed, as existence of the blood-nerve barrier implies a discrete intraneural compartment, could its particular features influence the causation and distribution of lesions in G.B.s., and should intraneural fluid be studied like c.s.F., as a mirror of tissue: change and drug concentration? It is now possible to diagnose G.B.s. clinically and electrophysiologically with reasonable accuracy. Perhaps the next laboratory advances will be better characterisation of the antigens of peripheral nerve and of the nature of the immunological reactions against them. Meanwhile, clinicians could be looking critically at the pharmacology and efficacy of chemothe
myelin
therapy. Explanations of why infection can cause an immunological reaction against a myelin protein may be further away, but an advance here might illuminate that deeper enigma of neurology, multiple sclerosis.
one
21. Arnason, B. G. W. in Immunological Disorders of the Nervous System (edited by L. Rowland); p. 156. Baltimore, 1971. 22. Arnason, B. G. W., Winkler, G. F., Hadler, N. M. Lab. Invest. 1969, 21, 1. 23. Sheremata, W., Colby, S., Lasky, G., Cosgrove, J. B. R. Neurology, 1975,
25, 833. 24. Brostoff, S. W. in Myelin (edited by P. Morell); p. 436 New York, 1977. 25. Adams, D., Gibson, J. D., Thomas, P. K., Batchelor, J R., Hughes, R. A. C., Kennedy, L., Festenstein, H., Sachs, L. Lancet, 1977, ii, 504. 26. Rogart, R. B., Ritchie, J. M. in Myelin (edited by P. Morell); p. 353. New
Hepatotrophic
Factors
IN 1965 MARCHIORO and his colleaguesl performed operations on dogs so that splanchnic venous blood drained into one side of the liver and inferior-vena-caval blood into the other. Liver supplied by caval blood atrophied while liver supplied by splanchnic blood enlarged. They concluded that splanchnic venous blood exerted a specific "hepatotrophic" effect and believed initially that this.was due to the presence of nutrients absorbed from the intestine. Subsequently they suggested that the hepatotrophic factors were of pancreatic origin and might be insulin and glucagon. When BUCHER and her colleagues2 suggested that insulin and glucagon also stimulated regeneration after partial hepatectomy there was an even greater interest in the hepatotrophic concept. If it is true that factors in portal blood prevent hepatic atrophy and stimulate compensatory hyperplasia then their clinical relevance is obvious. They may influence the results of portacaval anastomosis or hepatic transplantation, and may determine the regenerative response to hepatectomy or to the gross cellular damage caused by various forms of acute liver injury. In May last year, a symposium on Hepatotrophic Factors was held at the Ciba Foundation and the proceedings have now been published.3 Some of the papers were on the structure and function of isolated hepatocytes, the morphological kinetics of hepatocellular regeneration, and signals for insulin and glucagon secretion; but most of them dealt with the two key topics-the atrophy which occurs in liver after diversion of portal blood, and the striking proliferation of remaining liver cells after partial hepa-,
tectomy. T. E. STARZL presented convincing evidence that insulin prevents hepatic atrophy. Atrophy is largely prevented if insulin is infused into liver tissue deprived of pancreatic venous blood. Furthermore the atrophy relative to other parts of the liver is greatly reduced if, before the diversion operation, the animal is rendered insulin deficient by pancreatectomy. But STARZL also presented evidence that non-pancreatic factors may be important for growth and cell division; in diabetic dogs liver receiving blood from the intestine synthesised more
York, 1977. 27. Rice, D. Br. med. J. 1977, ii, 1330. 28. Henschel, E. O. Anesthesiology, 1977, 17, 228. 29. Swick, H. M., McQuillen, M. P. Neurology, 26, 205. 30. Rosen, A. D., Vastola, E. F.J. neurol. Sci. 1976, 30, 179. 31. Olsson, Y. in Peripheral Neuropathy (edited by P. J. Dyck, P. K. Thomas, and E. H. Lambert); p. 190. Philadelphia, 1975.
L., Porter, K. A., Brown, B. I., Fans, T. D., Herrmann, T. J., Sudweeks, A., Starzl, T. E. Surg. Forum, 1965, 16, 280. 2. Bucher, N. L. R., Swaffield, M. N. Proc. natn. Acad. Sci. U.S.A. 1975, 72, 1. Marchioro, T.
1157.
3.
Factors (Ciba Fndn Symp. 55). Amsterdam: Elsevier 1978. Pp. 405. D. fl. 83 (about £19).
Hepatotrophic
245
than liver tissue receiving only "pancreatic" blood. That insulin plays a part in controlling hepatic cell size seems incontrovertible. Its role as a stimulus to hepatocellular regeneration is less certain. N. BUCHER and her colleagues claimed that combined administration of insulin and glucagon promoted compensatory hyperplasia after partial hepatectomy in eviscerated rats; but in the same animal U. JUNGE and W. CREUTZFELDT found no effect of insulin and glucagon on hepatic D.N.A. synthesis after partial hepatectomy. Even if insulin and glucagon play a supportive role they are highly unlikely to initiate hepatic regeneration. Firstly, they seem to have no effect on hepatocellular proliferation in animals with intact livers. Secondly, portal-vein insulin concentrations fall after partial hepatectomy even though hepatic regeneration has been stimulated. Finally, changes in systemic plasma insulin and glucagon after partial hepatectomy could surely not account for the stimulation of hepatic D.N.A. synthesis observed in normal recipients in cross-circulation experiments. BUCHER claimed that epidermal growth factor (E.G.F.), a polypeptide similar in size to insulin, can initiate D.N.A. synthesis in the liver of normal rats and that this effect is potentiated by administration of glucagon and insulin. Unfortunately the factors controlling E.G.F. release are unknown, nor do we know whether plasma levels rise after partial hepatectomy. Hyperplasia of the liver occurs in acromegaly and in rats with transplanted pituitary tumours which secrete prolactin as well as growth hormone. But, despite these isolated observations, the factors controlling the size of the liver remain D.N.A.
venous
a
mystery. At present it is difficult
to exploit the hepatotrofor the of patients. BUCHER benefit phic concept and her colleagues found that insulin and glucagon increased survival in mice infected with lethal doses of murine hepatitis virus, and on this basis it has been suggested that patients with severe viral hepatitis should be treated with insulin and glucagon. But there are as yet no clinical studies to support this suggestion, and in rats JUNGE and CREUTZFELDT were unable to demonstrate protection against the lethal effects of hepatic necrosis caused by carbon tetrachloride. It seems sensible to give large amounts of glucose to patients with acute hepatocellular necrosis, orally rather than intravenously. This will stimulate insulin secretion, though glucagon concentrations will probably fall. There are reports of benefit from such treatment, but the evidence is anecdotal. The transplant surgeon now appreciates the requirements of the donor liver for portal blood. But the surgeon performing a portacaval shunt is not yet able to harness portal factors in order to prevent or to lessen the liver damage which may follow surgery; nor can he tell whether the diversion of portal factors
is responsible for the apparent benefits of shunt surgery in some patients with homozygous type II hypercholesterolaemia and in patients with several types of glycogen-storage disease. There has been confusion and controversy in the search for hepatotrophic factors, and for several reasons. Those who have studied the effects of portal diversion have used different animals and different experimental techniques from those who have studied regeneration after hepatic resection. Both groups have relied excessively on indirect evidence. Finally, the mechanisms controlling cell size and division are clearly complex but there has been
tendency to promote simple explanations even though each of them conflicts with experimental data. But the Ciba volume shows clearly that the hepatotrophic sphere is an exciting and challenging one. There is good reason to believe that the portal blood may soon give up more of its secrets. a
Aspirin and Stroke Prevention TRANSIENT cerebral ischaemic attacks
(T.I.A.S), patient, are not important in themselves since, by definition, they cease spontaneously within 24 hours. Their importance lies in the fact that they often give warning of an impending stroke. About a third of the patients will have a stroke, the period of greatest risk being the first
though alarming
to a
months after the first T.I.A.’ For this reason anticoagulant therapy has been widely used, with2 apparent reduction in the incidence of strokes. Endarterectomy is likewise beneficial in patients with suitable lesions.34 Most T.l.A.s, and indeed many strokes, are believed to be due to emboli arising from the heart or from atheromatous lesions in the great vessels supplying the brain..5-7 The formation of emboli is a complex process but aggregation of platelets and deposition of fibrin are important first steps. One approach has therefore been to try drugs which inhibit platelet aggregation. In 1977 a multicentre, double-blind, randomised trial of 600 mg aspirin twice a day involving 178 patients with T.I.A.S over 37 months, was reported from the United States.Continued T.I.A.S, cerebral or retinal infarction, and death were taken as end-
two
points,
none
showing statistically significant they were combined in
benefit. However, when
1. Whisnant, J. P., Matsumoto, N., Elveback, L. R. Mayo Clin. Proc. 1973, 48, 194. 2. Marshall, J. The Management of Cerebrovascular Disease. Oxford, 1976. 3. Bauer, R. B., Meyer, J. S., Fields, W. S. J. Am. med. Ass. 1969, 208, 509. 4. Wylie, E. J., Ehrenfield, W. T. Extracranial Occlusive Cerebrovascular Disease. Philadelphia 1970. 5. Torvik, A., Jorgensen, L.J. neurol. Sci. 1966, 3, 410. 6. Jorgensen, L., Torvik, A. ibid. p. 490. 7. Jorgensen, L., Torvik, A. ibid. 1969, 9, 285. 8. Fields, W. S., Lemak, N. A., Frankowski, R. F., Hardy, R. J. Stroke, 1977,
8, 301.
in both conditions of antibody and cells sensitised to myelin.2I 22 The major defect in the proposition is failure to explain how a viral infection may cause an autoimmune response against occurrence
of peripheral nerve, probably against its basic proteins.22-24 A simple crossof only reacting antigen can probably be excluded by the multiplicity of causal agents, and patients seem not to belong to a specific HLA group, as in other autoimmune diseases associated with a presumed abnormal response to infection.2’ It is fortunate that the observed impairment of nerve conduction can be explained on physical grounds,l6 without invocation of any of the mysterious serum factors that have dogged other neurological diseases. The speculation about mechanism is matched by doubt about treatment. Supportive measures are essential, as in the care of any potentially paralysed patient, and there is a special cry for good nursing by the patient whose nerve endings are aflame with abnormal and distressing impulses.27 28 What about immunosuppressive treatment? Unfortunately, the therapeutic uncertainty of classical neurology has not yet been cleared from this area.3 Corticosteroids have been advocated by many, often in very big doses, but with little objective evidence of real benefit. 8 29 Cytotoxic drugs have also, been employed in a poorly controlled fashion.3O As there is a selective blood-nerve barrier,jl could an effective concentration of these substances ever be achieved within a nerve, where damage might be done by cells before they are replaced from the systemic sources that are exposed to conventional cytotoxic treatment? Indeed, as existence of the blood-nerve barrier implies a discrete intraneural compartment, could its particular features influence the causation and distribution of lesions in G.B.s., and should intraneural fluid be studied like c.s.F., as a mirror of tissue: change and drug concentration? It is now possible to diagnose G.B.s. clinically and electrophysiologically with reasonable accuracy. Perhaps the next laboratory advances will be better characterisation of the antigens of peripheral nerve and of the nature of the immunological reactions against them. Meanwhile, clinicians could be looking critically at the pharmacology and efficacy of chemothe
myelin
therapy. Explanations of why infection can cause an immunological reaction against a myelin protein may be further away, but an advance here might illuminate that deeper enigma of neurology, multiple sclerosis.
one
21. Arnason, B. G. W. in Immunological Disorders of the Nervous System (edited by L. Rowland); p. 156. Baltimore, 1971. 22. Arnason, B. G. W., Winkler, G. F., Hadler, N. M. Lab. Invest. 1969, 21, 1. 23. Sheremata, W., Colby, S., Lasky, G., Cosgrove, J. B. R. Neurology, 1975,
25, 833. 24. Brostoff, S. W. in Myelin (edited by P. Morell); p. 436 New York, 1977. 25. Adams, D., Gibson, J. D., Thomas, P. K., Batchelor, J R., Hughes, R. A. C., Kennedy, L., Festenstein, H., Sachs, L. Lancet, 1977, ii, 504. 26. Rogart, R. B., Ritchie, J. M. in Myelin (edited by P. Morell); p. 353. New
Hepatotrophic
Factors
IN 1965 MARCHIORO and his colleaguesl performed operations on dogs so that splanchnic venous blood drained into one side of the liver and inferior-vena-caval blood into the other. Liver supplied by caval blood atrophied while liver supplied by splanchnic blood enlarged. They concluded that splanchnic venous blood exerted a specific "hepatotrophic" effect and believed initially that this.was due to the presence of nutrients absorbed from the intestine. Subsequently they suggested that the hepatotrophic factors were of pancreatic origin and might be insulin and glucagon. When BUCHER and her colleagues2 suggested that insulin and glucagon also stimulated regeneration after partial hepatectomy there was an even greater interest in the hepatotrophic concept. If it is true that factors in portal blood prevent hepatic atrophy and stimulate compensatory hyperplasia then their clinical relevance is obvious. They may influence the results of portacaval anastomosis or hepatic transplantation, and may determine the regenerative response to hepatectomy or to the gross cellular damage caused by various forms of acute liver injury. In May last year, a symposium on Hepatotrophic Factors was held at the Ciba Foundation and the proceedings have now been published.3 Some of the papers were on the structure and function of isolated hepatocytes, the morphological kinetics of hepatocellular regeneration, and signals for insulin and glucagon secretion; but most of them dealt with the two key topics-the atrophy which occurs in liver after diversion of portal blood, and the striking proliferation of remaining liver cells after partial hepa-,
tectomy. T. E. STARZL presented convincing evidence that insulin prevents hepatic atrophy. Atrophy is largely prevented if insulin is infused into liver tissue deprived of pancreatic venous blood. Furthermore the atrophy relative to other parts of the liver is greatly reduced if, before the diversion operation, the animal is rendered insulin deficient by pancreatectomy. But STARZL also presented evidence that non-pancreatic factors may be important for growth and cell division; in diabetic dogs liver receiving blood from the intestine synthesised more
York, 1977. 27. Rice, D. Br. med. J. 1977, ii, 1330. 28. Henschel, E. O. Anesthesiology, 1977, 17, 228. 29. Swick, H. M., McQuillen, M. P. Neurology, 26, 205. 30. Rosen, A. D., Vastola, E. F.J. neurol. Sci. 1976, 30, 179. 31. Olsson, Y. in Peripheral Neuropathy (edited by P. J. Dyck, P. K. Thomas, and E. H. Lambert); p. 190. Philadelphia, 1975.
L., Porter, K. A., Brown, B. I., Fans, T. D., Herrmann, T. J., Sudweeks, A., Starzl, T. E. Surg. Forum, 1965, 16, 280. 2. Bucher, N. L. R., Swaffield, M. N. Proc. natn. Acad. Sci. U.S.A. 1975, 72, 1. Marchioro, T.
1157.
3.
Factors (Ciba Fndn Symp. 55). Amsterdam: Elsevier 1978. Pp. 405. D. fl. 83 (about £19).
Hepatotrophic
245
than liver tissue receiving only "pancreatic" blood. That insulin plays a part in controlling hepatic cell size seems incontrovertible. Its role as a stimulus to hepatocellular regeneration is less certain. N. BUCHER and her colleagues claimed that combined administration of insulin and glucagon promoted compensatory hyperplasia after partial hepatectomy in eviscerated rats; but in the same animal U. JUNGE and W. CREUTZFELDT found no effect of insulin and glucagon on hepatic D.N.A. synthesis after partial hepatectomy. Even if insulin and glucagon play a supportive role they are highly unlikely to initiate hepatic regeneration. Firstly, they seem to have no effect on hepatocellular proliferation in animals with intact livers. Secondly, portal-vein insulin concentrations fall after partial hepatectomy even though hepatic regeneration has been stimulated. Finally, changes in systemic plasma insulin and glucagon after partial hepatectomy could surely not account for the stimulation of hepatic D.N.A. synthesis observed in normal recipients in cross-circulation experiments. BUCHER claimed that epidermal growth factor (E.G.F.), a polypeptide similar in size to insulin, can initiate D.N.A. synthesis in the liver of normal rats and that this effect is potentiated by administration of glucagon and insulin. Unfortunately the factors controlling E.G.F. release are unknown, nor do we know whether plasma levels rise after partial hepatectomy. Hyperplasia of the liver occurs in acromegaly and in rats with transplanted pituitary tumours which secrete prolactin as well as growth hormone. But, despite these isolated observations, the factors controlling the size of the liver remain D.N.A.
venous
a
mystery. At present it is difficult
to exploit the hepatotrofor the of patients. BUCHER benefit phic concept and her colleagues found that insulin and glucagon increased survival in mice infected with lethal doses of murine hepatitis virus, and on this basis it has been suggested that patients with severe viral hepatitis should be treated with insulin and glucagon. But there are as yet no clinical studies to support this suggestion, and in rats JUNGE and CREUTZFELDT were unable to demonstrate protection against the lethal effects of hepatic necrosis caused by carbon tetrachloride. It seems sensible to give large amounts of glucose to patients with acute hepatocellular necrosis, orally rather than intravenously. This will stimulate insulin secretion, though glucagon concentrations will probably fall. There are reports of benefit from such treatment, but the evidence is anecdotal. The transplant surgeon now appreciates the requirements of the donor liver for portal blood. But the surgeon performing a portacaval shunt is not yet able to harness portal factors in order to prevent or to lessen the liver damage which may follow surgery; nor can he tell whether the diversion of portal factors
is responsible for the apparent benefits of shunt surgery in some patients with homozygous type II hypercholesterolaemia and in patients with several types of glycogen-storage disease. There has been confusion and controversy in the search for hepatotrophic factors, and for several reasons. Those who have studied the effects of portal diversion have used different animals and different experimental techniques from those who have studied regeneration after hepatic resection. Both groups have relied excessively on indirect evidence. Finally, the mechanisms controlling cell size and division are clearly complex but there has been
tendency to promote simple explanations even though each of them conflicts with experimental data. But the Ciba volume shows clearly that the hepatotrophic sphere is an exciting and challenging one. There is good reason to believe that the portal blood may soon give up more of its secrets. a
Aspirin and Stroke Prevention TRANSIENT cerebral ischaemic attacks
(T.I.A.S), patient, are not important in themselves since, by definition, they cease spontaneously within 24 hours. Their importance lies in the fact that they often give warning of an impending stroke. About a third of the patients will have a stroke, the period of greatest risk being the first
though alarming
to a
months after the first T.I.A.’ For this reason anticoagulant therapy has been widely used, with2 apparent reduction in the incidence of strokes. Endarterectomy is likewise beneficial in patients with suitable lesions.34 Most T.l.A.s, and indeed many strokes, are believed to be due to emboli arising from the heart or from atheromatous lesions in the great vessels supplying the brain..5-7 The formation of emboli is a complex process but aggregation of platelets and deposition of fibrin are important first steps. One approach has therefore been to try drugs which inhibit platelet aggregation. In 1977 a multicentre, double-blind, randomised trial of 600 mg aspirin twice a day involving 178 patients with T.I.A.S over 37 months, was reported from the United States.Continued T.I.A.S, cerebral or retinal infarction, and death were taken as end-
two
points,
none
showing statistically significant they were combined in
benefit. However, when
1. Whisnant, J. P., Matsumoto, N., Elveback, L. R. Mayo Clin. Proc. 1973, 48, 194. 2. Marshall, J. The Management of Cerebrovascular Disease. Oxford, 1976. 3. Bauer, R. B., Meyer, J. S., Fields, W. S. J. Am. med. Ass. 1969, 208, 509. 4. Wylie, E. J., Ehrenfield, W. T. Extracranial Occlusive Cerebrovascular Disease. Philadelphia 1970. 5. Torvik, A., Jorgensen, L.J. neurol. Sci. 1966, 3, 410. 6. Jorgensen, L., Torvik, A. ibid. p. 490. 7. Jorgensen, L., Torvik, A. ibid. 1969, 9, 285. 8. Fields, W. S., Lemak, N. A., Frankowski, R. F., Hardy, R. J. Stroke, 1977,
8, 301.
