- Email: [email protected]
Methionine and Hepatic Cirrhosis
617
LEADING ARTICLES
am nothing but by temperament if you want to transadventurer Conquistador-an late the word-with the curiosity, the boldness and the tenacity that belongs to that type of being." His excursions into fields of human endeavour remote from clinical medicine derived from his overmastering desire to understand human nature. Medicine gave him, in psychotherapy, the springboard ; from it he plunged into literature, sculpture, history, and anthropology, seeking always to find the ulterior meaning of men’s conduct and the motives of creative action. In these audacious forays cautious deduction, which his teacher BRÜCKE had once commended in him, was a quality hard to find : he took risks and made mistakes, as any amateur must. But these counted for little, when set against the stir he caused, the incitement to fresh inquiry, the lively light cast into dull-seeming corners and neglected depths. Our ideas about education, religion, crime, and many other human concerns have been shaken about by the impact of this restless, penetrating, subtle mind. Techniques of which FREUD had no inkling or for which he would have no sympathy are now being deployed to test the validity of his theories and suggestions, not only in dynamic psychology and psychiatry, but in the social sciences at large. It is appropriate that FREUD’s centenary should be commemorated with especial regard in this country ; for it was here that FREUD came as a young man (on a journey that he said had a decisive influence on his whole life), here that he thought of settling, and here that he found refuge when driven from Vienna by the Nazi occupation. He probably owed some ideas to 19th-century English thinkersJOHN STUART MILL and HUGHLINGS JACKSON notably -and he found in an English disciple his faithful and gifted biographer. Though his work transcended frontiers, and was accepted in some other countries, particularly the United States, more readily and eagerly, nowhere more than here can there be respect for the courage and intellectual integrity which led FREUD along strange paths, on a noble and endless
and not
a
thinker..1
a
THE LANCET LONDON ::
b-11 T URDI L Y, 2-IAY 5,
1956
Freud SELDOM has one man been so incontestably the a new field of thought as FREUD was of we accept it as a profound psycho-analysis. Whether new science or doubt it as a far-fetched speculative system, we must wonder at the massive and daring product of one fertile original mind, working with intense concentration through more than forty years. Now, a century after FREUD’s birth, there is still dispute about the value of his achievement, but hardly about the force of its impact on contemporary thought. It can be said of him (as it was of another notable disturber of pleasant illusions concerned, in part, with the sexual impulse) that he dug into the mine of truth, bringing up ore mixed with dross, to such purpose that he did not leave opinion where he found it : his theory provided a ground on which to fix the levers that may move the world." creator of
Psycho-analysis is, of course, not only a theory a therapy. It took its origin in efforts to cure hysteria, and almost all its medical expositors and investigators have been dependent on the practice of psychotherapy as a source of evidence and experience, and generally as a means of livelihood. This has influenced the development of the subject, and its critical study. Whether the effect has, on the whole, been for the good of psycho-analysis as a branch of but also
medicine is hard to say. No-one has succeeded in amassing statistical evidence that it is more effective in the treatment of neurotic or other mental illness than other methods, though in the opinion of many people statistics has not the final say in this matter. FREUD himself saw some of the inherent obstacles to statistical evaluation-small numbers of patients, heterogeneity in form and severity of illness, mutability of technique, premature termination of treatment-and he asserted that in any case the therapeutic aspect of psycho-analysis was not the most
important.
It is one of the many paradoxes in FREUD’s career that he was deeply indebted to his medical training yet rejected it in retrospect : I have never really been a doctor in the proper sense. I became a doctor through being compelled to deviate from my original purpose; and the triumph of my life lies in my having, after a long and roundabout journey, found my way back to my earliest path." It is impossible to tell what he would have done if his training had
been in philosophy was then. What
or
in
psychology,
as
psychology
clear is that his earliest in neural researches, structure, the action of cocaine, and the aphasia, paralyses of children, confirmed him in habits of minute observation, organisation of diverse material, deduction, and lucid expression which served him well in the bolder studies that occupied his mature years. In this matter he was unjust to his own achievement, and his self-estimate erred on the romantic side : "I am not really a man of science, not an observer, not an experimenter seems
pregnant
quest.
Methionine and Hepatic Cirrhosis THE mental disturbances that may be associated with hepatic cirrhosis include clouding of consciousness, confusion, apathy, personality changes, abnormalities in behaviour, and, finally, delirium and coma.l Signs may appear in the motor system, such as spasticity, increased limb reflexes, involuntary movements, and a peculiar flapping tremor2 consisting of a series of rapid flexion-extension movemepts at the wrist and metacarpophalangeal joints, best demonstrated with the arms outstretched and fingers separated. It is important to appreciate the diffuse nature of the cerebral disturbances and their connection with liver disease, since, as SHERLOCK and her colleagues have pointed out,3 the patient may all too easily be admitted to a mental hospital before the true diagnosis is reached. These complications arise in patients with hepatic cirrhosis who have large collateral channels between the portal and systemic venous systems, and they Walshe, J. M. Quart. J. Med. 1951, 20, 421. Sherlock, S., Summerskill, W. H. J., White, L. P., Phear, E. A. Lancet, 1954, ii, 453. 3. See Ibid, 1955, i, 1023.
1. 2.
618
may develop after a surgical portacaval anastomosis if hepatic function is impaired ; but shunting of portal blood into the systemic circulation in the presence of a healthy liver does not produce the syndrome. Neurological and mental changes may also appear as the result of the severe liver damage which occasionally follows virus hepatitis. Clearly hepatic function must be depressed before this condition can arise, and its onset is precipitated by the development of communications between the portal and systemic veins. Moreover, the neurological disorders can be induced by raising the intake of nitrogenous substances, such as dietary protein, ammonium salts, and urea. Methionine, which has in the past been used in the treatment of liver disease, may have a similar effect, 4-7
and SHERLOCK and her associates have investigated the mechanism of this action.8 Methionine given by mouth produced neurological deterioration in 7 out of 9 patients who had previously had episodes of impending hepatic coma. It was without effect in other patients with hepatic cirrhosis who had never had neurological complications. The rise in the bloodmethionine level was the same in the two groups. Intravenous methionine had no effect in 3 patients who had previously relapsed after oral administration and in 1 it produced only a delayed exacerbation. No significant change in blood ammonium, pH, or bilirubin level accompanied the neurological deterioration produced by methionine. When chlortetracycline (aureomycin) was given at the same time as methionine, no toxic disturbances developed in patients who had previously reacted, despite the fact that higher blood-methionine levels were reached when the antibiotic and amino-acid were given together. These observations suggested that the toxicity was not due directly to methionine but to some substance derived from methionine by the action of intestinal bacteria sensitive to chlortetracycline. Bacteriological studies showed that the faecal flora of patients with liver disease and neurological disturbances was no different, from that of healthy people and of patients with uncomplicated cirrhosis. Methionine by itself did not alter the bacterial composition of the faeces. Chlortetracycline produced similar changes in all three groups-namely, a rise in proteus with elimination of bacteroides and an inconstant fall in Escherichia The streptococcal types changed and lactobacilli increased. The breakdown product of methionine responsible for the neurological changes has not so far been identified. Clearly, however, methionine is potentially toxic if given by mouth to patients with hepatic cirrhosis. In the past methionine has been recommended on rather slender grounds as a treatment of liver disease, but there is no definite evidence that it does any good, and its use should certainly be abandoned. Chlortetracycline has already been given with apparent success in the treatment of hepatic The neurological disturbances that may coma.9 appear spontaneously in cirrhosis of the liver vary
in severity, and the effect of treatment is difficult to assess accurately ; but SHERLOCK et al.’s clinical impression is that chlortetracycline therapy is of benefit in spontaneous hepatic coma. Other measures must of course be used-in particular, curtailment of the intake of protein and other nitrogenous substances during the acute phase of the disturbance.
greatly
Hypoglycæmia in Diabetics in a diabetic cannot be of its usual causes-failure to eat, over-exertion, or too much insulin-other possibilities must be considered. The blood-glucose comes from the alimentary tract or from the liver by glycogenomay cause lysis or gluconeogenesis. Poor absorption 1 in and and myxoedema sprue,2 hypoglycaemia is in of some deficient glycogenolysis hepatic types failure, even without other obvious signs of liver disease.3 The liver may fail because it contains too little glycogen or because it is unable to mobilise stored glycogen as in von Gierke’s disease, and possibly in the type of brittle diabetes with hepatomegaly 4recently described by EvANS and his colleagues. Gluconeogenesis is largely dependent on the adequate function of the adrenal cortex and thus indirectly of the anterior pituitary. The association of diabetes with Addisondisease and Simmonds’s disease is admittedly uncommon5 6 ; but early recognition of adrenal insufficiency in a diabetic is particularly important, for these patients become extremely7 sensitive to insulin, in the same way as the Long cat or the Houssay dog,8 and hypoglycsemia may well be fatal before the true state of affairs is appreciated.9 Such a diabetic, previously needing much insulin, may be able to do without any at all, although an intravenous glucose-tolerance test will still show a After infarction of the anterior diabetic curve. for pituitary example, there is characteristically a severe headache followed in a day or two by hypoglycaemic reactions to the usual doses of insulin." If the patient survives, and insulin treatment is either drastically curtailed or stopped, signs of hypofunction of the gonads and thyroid gradually appear, but they respond well to replacement treatment. Diabetic WHENEVER
attributed to
hypoglycaemia
one
(Kimmelstiel-Wilson coli. intercapillary glomerulosclerosis sometimes be associated with decreas-
4. Watson, C. J. Ann. intern. Med. 1949, 31, 405. 5. Kinsell, L. W., Harper, H. A., Giese, G. K., Morgan S., MeCallic, D. P., Hess, J. R. J. clin. Invest. 1949, 28, 1439. 6. Singh, I. D., Barclay. J. A., Cooke, W. T. Lancet, 1954, i, 1004. 7. Phear, E. A., Sherlock, S., Summerskill, W. H. J. Ibid, 1955, i, 836. 8. Phear, E. A., Ruebner, B., Sherlock, S., Summerskill, W. H. J. Clin. Sci. 1956, 15, 93. 9. Farquabar, J. D., Stokes, J., Whitlock, C. M., Bluemle, L. W., Gambescia, J. M. Amer. J. med. Sci. 1950, 220, 166.
syndrome) may ing insulin needs,ll but no satisfactory explanation has been suggested. 11UNYAN et al.12 concluded that the renal lesions were not related to any change in’ insulin needs. The importance of hypoglycsemic episodes in prognosis lies in the susceptibility of the brain to what may be irreversible damage.13 The risk is greatest after long-continued severe hypoglycaemia and in 1. Wilder, R. M., Foster, R. F., Pemberton, J. J. Endocrin. 1934, 18, 455. 2. Landmann, II. R. Amer. J. digest. Dis. 1952, 19, 110. 3. Mellinkoff, S. M., Tumulty, P. A. New Engl. J. Med. 1952, 745. 247, 4. Evans, R. W., Littler, T. R., Pemberton, H. S. J. clin. Path. 1955, 8, 110. 5. McCullagh, E. P., Allivisatos, J. G. Diabetes, 1954, 3, 349. 6. Balfour, W. M., Sprague, R. G. Amer. J. Med. 1949, 7, 596. 7. Long, C. N. H. Harvey Lect. 1936-37, 32, 194. 8. Houssay, B. A. New Engl. J. Med. 1936, 214, 971. 9. Canghey, J. E., Garrod, O. Brit. med. J. 1954, ii, 554. 10. Harvey, J. C., Klerk, J. Amer. J. Med. 1955, 19, 327. 11. Zubrod, C. G., Eversole, S. L., Dana, G. W. New Engl. J. Med. 1951, 245, 518. 12. Hunyan, J. W. jun., Hurwitz, D., Robbins, S. L. Ibid, 1955, 252, 388. 13. Jones, G. M. Amer. J. med. Sci. 1947, 213, 206.
LEADING ARTICLES
am nothing but by temperament if you want to transadventurer Conquistador-an late the word-with the curiosity, the boldness and the tenacity that belongs to that type of being." His excursions into fields of human endeavour remote from clinical medicine derived from his overmastering desire to understand human nature. Medicine gave him, in psychotherapy, the springboard ; from it he plunged into literature, sculpture, history, and anthropology, seeking always to find the ulterior meaning of men’s conduct and the motives of creative action. In these audacious forays cautious deduction, which his teacher BRÜCKE had once commended in him, was a quality hard to find : he took risks and made mistakes, as any amateur must. But these counted for little, when set against the stir he caused, the incitement to fresh inquiry, the lively light cast into dull-seeming corners and neglected depths. Our ideas about education, religion, crime, and many other human concerns have been shaken about by the impact of this restless, penetrating, subtle mind. Techniques of which FREUD had no inkling or for which he would have no sympathy are now being deployed to test the validity of his theories and suggestions, not only in dynamic psychology and psychiatry, but in the social sciences at large. It is appropriate that FREUD’s centenary should be commemorated with especial regard in this country ; for it was here that FREUD came as a young man (on a journey that he said had a decisive influence on his whole life), here that he thought of settling, and here that he found refuge when driven from Vienna by the Nazi occupation. He probably owed some ideas to 19th-century English thinkersJOHN STUART MILL and HUGHLINGS JACKSON notably -and he found in an English disciple his faithful and gifted biographer. Though his work transcended frontiers, and was accepted in some other countries, particularly the United States, more readily and eagerly, nowhere more than here can there be respect for the courage and intellectual integrity which led FREUD along strange paths, on a noble and endless
and not
a
thinker..1
a
THE LANCET LONDON ::
b-11 T URDI L Y, 2-IAY 5,
1956
Freud SELDOM has one man been so incontestably the a new field of thought as FREUD was of we accept it as a profound psycho-analysis. Whether new science or doubt it as a far-fetched speculative system, we must wonder at the massive and daring product of one fertile original mind, working with intense concentration through more than forty years. Now, a century after FREUD’s birth, there is still dispute about the value of his achievement, but hardly about the force of its impact on contemporary thought. It can be said of him (as it was of another notable disturber of pleasant illusions concerned, in part, with the sexual impulse) that he dug into the mine of truth, bringing up ore mixed with dross, to such purpose that he did not leave opinion where he found it : his theory provided a ground on which to fix the levers that may move the world." creator of
Psycho-analysis is, of course, not only a theory a therapy. It took its origin in efforts to cure hysteria, and almost all its medical expositors and investigators have been dependent on the practice of psychotherapy as a source of evidence and experience, and generally as a means of livelihood. This has influenced the development of the subject, and its critical study. Whether the effect has, on the whole, been for the good of psycho-analysis as a branch of but also
medicine is hard to say. No-one has succeeded in amassing statistical evidence that it is more effective in the treatment of neurotic or other mental illness than other methods, though in the opinion of many people statistics has not the final say in this matter. FREUD himself saw some of the inherent obstacles to statistical evaluation-small numbers of patients, heterogeneity in form and severity of illness, mutability of technique, premature termination of treatment-and he asserted that in any case the therapeutic aspect of psycho-analysis was not the most
important.
It is one of the many paradoxes in FREUD’s career that he was deeply indebted to his medical training yet rejected it in retrospect : I have never really been a doctor in the proper sense. I became a doctor through being compelled to deviate from my original purpose; and the triumph of my life lies in my having, after a long and roundabout journey, found my way back to my earliest path." It is impossible to tell what he would have done if his training had
been in philosophy was then. What
or
in
psychology,
as
psychology
clear is that his earliest in neural researches, structure, the action of cocaine, and the aphasia, paralyses of children, confirmed him in habits of minute observation, organisation of diverse material, deduction, and lucid expression which served him well in the bolder studies that occupied his mature years. In this matter he was unjust to his own achievement, and his self-estimate erred on the romantic side : "I am not really a man of science, not an observer, not an experimenter seems
pregnant
quest.
Methionine and Hepatic Cirrhosis THE mental disturbances that may be associated with hepatic cirrhosis include clouding of consciousness, confusion, apathy, personality changes, abnormalities in behaviour, and, finally, delirium and coma.l Signs may appear in the motor system, such as spasticity, increased limb reflexes, involuntary movements, and a peculiar flapping tremor2 consisting of a series of rapid flexion-extension movemepts at the wrist and metacarpophalangeal joints, best demonstrated with the arms outstretched and fingers separated. It is important to appreciate the diffuse nature of the cerebral disturbances and their connection with liver disease, since, as SHERLOCK and her colleagues have pointed out,3 the patient may all too easily be admitted to a mental hospital before the true diagnosis is reached. These complications arise in patients with hepatic cirrhosis who have large collateral channels between the portal and systemic venous systems, and they Walshe, J. M. Quart. J. Med. 1951, 20, 421. Sherlock, S., Summerskill, W. H. J., White, L. P., Phear, E. A. Lancet, 1954, ii, 453. 3. See Ibid, 1955, i, 1023.
1. 2.
618
may develop after a surgical portacaval anastomosis if hepatic function is impaired ; but shunting of portal blood into the systemic circulation in the presence of a healthy liver does not produce the syndrome. Neurological and mental changes may also appear as the result of the severe liver damage which occasionally follows virus hepatitis. Clearly hepatic function must be depressed before this condition can arise, and its onset is precipitated by the development of communications between the portal and systemic veins. Moreover, the neurological disorders can be induced by raising the intake of nitrogenous substances, such as dietary protein, ammonium salts, and urea. Methionine, which has in the past been used in the treatment of liver disease, may have a similar effect, 4-7
and SHERLOCK and her associates have investigated the mechanism of this action.8 Methionine given by mouth produced neurological deterioration in 7 out of 9 patients who had previously had episodes of impending hepatic coma. It was without effect in other patients with hepatic cirrhosis who had never had neurological complications. The rise in the bloodmethionine level was the same in the two groups. Intravenous methionine had no effect in 3 patients who had previously relapsed after oral administration and in 1 it produced only a delayed exacerbation. No significant change in blood ammonium, pH, or bilirubin level accompanied the neurological deterioration produced by methionine. When chlortetracycline (aureomycin) was given at the same time as methionine, no toxic disturbances developed in patients who had previously reacted, despite the fact that higher blood-methionine levels were reached when the antibiotic and amino-acid were given together. These observations suggested that the toxicity was not due directly to methionine but to some substance derived from methionine by the action of intestinal bacteria sensitive to chlortetracycline. Bacteriological studies showed that the faecal flora of patients with liver disease and neurological disturbances was no different, from that of healthy people and of patients with uncomplicated cirrhosis. Methionine by itself did not alter the bacterial composition of the faeces. Chlortetracycline produced similar changes in all three groups-namely, a rise in proteus with elimination of bacteroides and an inconstant fall in Escherichia The streptococcal types changed and lactobacilli increased. The breakdown product of methionine responsible for the neurological changes has not so far been identified. Clearly, however, methionine is potentially toxic if given by mouth to patients with hepatic cirrhosis. In the past methionine has been recommended on rather slender grounds as a treatment of liver disease, but there is no definite evidence that it does any good, and its use should certainly be abandoned. Chlortetracycline has already been given with apparent success in the treatment of hepatic The neurological disturbances that may coma.9 appear spontaneously in cirrhosis of the liver vary
in severity, and the effect of treatment is difficult to assess accurately ; but SHERLOCK et al.’s clinical impression is that chlortetracycline therapy is of benefit in spontaneous hepatic coma. Other measures must of course be used-in particular, curtailment of the intake of protein and other nitrogenous substances during the acute phase of the disturbance.
greatly
Hypoglycæmia in Diabetics in a diabetic cannot be of its usual causes-failure to eat, over-exertion, or too much insulin-other possibilities must be considered. The blood-glucose comes from the alimentary tract or from the liver by glycogenomay cause lysis or gluconeogenesis. Poor absorption 1 in and and myxoedema sprue,2 hypoglycaemia is in of some deficient glycogenolysis hepatic types failure, even without other obvious signs of liver disease.3 The liver may fail because it contains too little glycogen or because it is unable to mobilise stored glycogen as in von Gierke’s disease, and possibly in the type of brittle diabetes with hepatomegaly 4recently described by EvANS and his colleagues. Gluconeogenesis is largely dependent on the adequate function of the adrenal cortex and thus indirectly of the anterior pituitary. The association of diabetes with Addisondisease and Simmonds’s disease is admittedly uncommon5 6 ; but early recognition of adrenal insufficiency in a diabetic is particularly important, for these patients become extremely7 sensitive to insulin, in the same way as the Long cat or the Houssay dog,8 and hypoglycsemia may well be fatal before the true state of affairs is appreciated.9 Such a diabetic, previously needing much insulin, may be able to do without any at all, although an intravenous glucose-tolerance test will still show a After infarction of the anterior diabetic curve. for pituitary example, there is characteristically a severe headache followed in a day or two by hypoglycaemic reactions to the usual doses of insulin." If the patient survives, and insulin treatment is either drastically curtailed or stopped, signs of hypofunction of the gonads and thyroid gradually appear, but they respond well to replacement treatment. Diabetic WHENEVER
attributed to
hypoglycaemia
one
(Kimmelstiel-Wilson coli. intercapillary glomerulosclerosis sometimes be associated with decreas-
4. Watson, C. J. Ann. intern. Med. 1949, 31, 405. 5. Kinsell, L. W., Harper, H. A., Giese, G. K., Morgan S., MeCallic, D. P., Hess, J. R. J. clin. Invest. 1949, 28, 1439. 6. Singh, I. D., Barclay. J. A., Cooke, W. T. Lancet, 1954, i, 1004. 7. Phear, E. A., Sherlock, S., Summerskill, W. H. J. Ibid, 1955, i, 836. 8. Phear, E. A., Ruebner, B., Sherlock, S., Summerskill, W. H. J. Clin. Sci. 1956, 15, 93. 9. Farquabar, J. D., Stokes, J., Whitlock, C. M., Bluemle, L. W., Gambescia, J. M. Amer. J. med. Sci. 1950, 220, 166.
syndrome) may ing insulin needs,ll but no satisfactory explanation has been suggested. 11UNYAN et al.12 concluded that the renal lesions were not related to any change in’ insulin needs. The importance of hypoglycsemic episodes in prognosis lies in the susceptibility of the brain to what may be irreversible damage.13 The risk is greatest after long-continued severe hypoglycaemia and in 1. Wilder, R. M., Foster, R. F., Pemberton, J. J. Endocrin. 1934, 18, 455. 2. Landmann, II. R. Amer. J. digest. Dis. 1952, 19, 110. 3. Mellinkoff, S. M., Tumulty, P. A. New Engl. J. Med. 1952, 745. 247, 4. Evans, R. W., Littler, T. R., Pemberton, H. S. J. clin. Path. 1955, 8, 110. 5. McCullagh, E. P., Allivisatos, J. G. Diabetes, 1954, 3, 349. 6. Balfour, W. M., Sprague, R. G. Amer. J. Med. 1949, 7, 596. 7. Long, C. N. H. Harvey Lect. 1936-37, 32, 194. 8. Houssay, B. A. New Engl. J. Med. 1936, 214, 971. 9. Canghey, J. E., Garrod, O. Brit. med. J. 1954, ii, 554. 10. Harvey, J. C., Klerk, J. Amer. J. Med. 1955, 19, 327. 11. Zubrod, C. G., Eversole, S. L., Dana, G. W. New Engl. J. Med. 1951, 245, 518. 12. Hunyan, J. W. jun., Hurwitz, D., Robbins, S. L. Ibid, 1955, 252, 388. 13. Jones, G. M. Amer. J. med. Sci. 1947, 213, 206.