- Email: [email protected]
GAMMA-GLUTAMYL TRANSPEPTIDASE IN ALCOHOLISM
1122 obtain a medical education. We wondered any of your readers may be able to advise further course of action we might take. any possible
ates
wishing
whether you on
to
or
St. Cuthbert’s Society, University of Durham, 12 South Bailey, Durham City, Co. Durham.
C. RAMSEY N. REILLY.
Fig. 2-Case 2. E.C.G. recording (lead I) during chest-pounding 32 hours after death.
*** Local education authorities
have
a
discretionary
power to assist graduates with grants towards second degrees, but, very properly, their first duty is to support
and medicine is a five-year course. If the National Health Service or medical research or teaching can benefit by being able to draw on doctors with a science background more thorough than an intercalated, usually biological, B.SC., then the Departments of Health and of Education and Science should want to provide support where local education authorities cannot. However, the Department of Health can suggest no course of action which might help our two correspondents or those with a similar ambition.-ED. L.
non-graduates;
Fig. 3-Case 2. E.C.G. recording (lead I) during chest-pounding 32 hours after death and removal of the heart.
depolarisation of the myocardium and thus can be dangerously misleading. If adequate circulation is not obtained, cardiac massage is mandatory. My observations raise the questions: how and where do these complexes arise ? Further electrophysiological and haemodynamic inquiries are
in progress.
Medical Department, Rogaland Hospital, 4000
Stavanger, Norway.
KAARE SKAALAND.
PROLAPSING POSTERIOR CUSP OF THE MITRAL VALVE SIR,-We have lately assessed three unrelated cases of this condition,1-4 diagnosed on a clinical basis. Cardiac .screening has shown abnormal atrial and atrioventricular
junctional pulsation of what seems to be a consistent and ,abnormal type, differing from the usual pulsation associated with mitral incompetence. One case progressed to true mitral incompetence and lost the earlier type of pulsation. We are wondering whether this feature has been assessed accurately, using electronic scanning equipment, because it seems a useful finding in supporting the clinical diagnosis of this condition. Southland Hospital,
Kew,
Invercargill,
New Zealand.
A. P. POOLE N. R. JEFFERSON.
MEDICAL EDUCATION FOR SCIENCE GRADUATES
SIR,-We are in our third year at Durham University reading honours chemistry and biology, respectively. We both wish to go on to study medicine but are experiencing difficulty in obtaining financial support. Approaches to our local education authorities have to date met with very little success. One of us received an immediate and absolute refusal of financial aid, while the other was informed that the situation was unpromising and that in any event a full grant would be most unlikely. It seems to be general policy of local education authorities not to give financial support for second degrees, even in medicine. Undaunted, we have approached several scientific foundations and similar bodies, but have again been disappointed. Last year5 you drew attention to a proposal, made by a group of clinical biochemists, that the Department of Health might provide financial support for science gradu-
4.
Barlow, J. B. J. chron. Dis. 1965, 18, 665. Barlow, J. B., Bosman, C. K. Am. Heart J. 1966, 71, 166. Barlow, J. B., Pocock, W. A., Marchand, P., Denny, M. ibid. 1963, 66, 443. Stannard, M., Sloman, J. G., Hare, W. S. C., Goble, A. J. Br. med. J.
5.
1967, iii, 71. Lancet, 1971, ii, 966.
1. 2. 3.
GAMMA-GLUTAMYL TRANSPEPTIDASE IN ALCOHOLISM
SIR,-Dr. Rosalki and his colleaguesdrew attention to their finding that patients receiving long-term anticonvulsant therapy had raised serum activities of the hepatic microsomal enzyme, gamma-glutamyl transpeptidase (G.G.T.P.). Dr. I dec and others2 reported iindings which showed that barbiturates and ethanol can both induce synthesis of this enzyme in rat’s liver, though, during the rather short duration of their experiments, no rise was noted in. the levels of serum-G.G.T.P. However, high 3 serum levels of this enzyme have been found in alcoholism, and such increases could be due to hepatic damage or, possibly, to enzyme induction caused by ethanol. They could also have resulted from induction of enzyme synthesis by barbiturates, habitually taken as hypnotics by many alcoholics, or by anticonvulsants given therapeutically for a short period only, to cover withdrawal of alcohol. We were impressed by Dr. Rosalki’s findings of raised serum-G.G.T.P. levels in alcoholic patients treated by one of us (M. M. G.) elsewhere,3 and have applied the method he described to the examination of patients admitted to the regional alcoholism unit at this hospital. We have found, from estimations made on serial samples collected from 12 male alcoholics, that administration of chlormethiazole and phenytoin for up to seven days only, to cover the immediate period of alcohol withdrawal, does not result in an increase in the level of serum-G.G.T.P. However, in a consecutive series of 30 male patients who had been taking alcohol until admission, 24 (80%) were found to have raised levels of serum-G.G.T.P., ranging from 70 to 1020 units, at that time. (Normal males: less than 60 international units per 1. at 37 °C.) Of the patients with raised levels, 20 (83%) gave no history of taking barbiturates or similar compounds during the previous few weeks, though many had occasionally taken some other drug, most commonly
nitrazepam, chlordiazepoxide,
or
diazepam.
However,
results obtained by us make it unlikely that these other drugs cause elevation of the serum-G.G.T.P. level. Of 143 patients admitted to general psychiatric wards at this hospital, initially for reasons other than an alcoholic complaint, only 16 were found to have raised levels of this enzyme, and 12 of these gave a history of recent continuous use of alcohol or barbiturates. The 127 with 1. 2. 3.
Rosalki, S. B., Tarlow, D., Rau, D. Lancet, 1971, ii, 376. Idéo, G., de Franchis, D., Del Ninno, E., Dioguardi, N. ibid. p. 825. Rosalki, S. B., Rau, D., Lehmann, D., Prentice, M. Ann. clin. Biochem. 1970, 7, 143.
1123 normal
G.G.T.P.
activities had been
taking
a
wide range of
drugs, including phenothiazines, tricyclic antidepressants, lithium salts, nitrazepam, chlordiazepoxide, and diazepam. Of the 20 alcoholic patients with raised G.G.T.P. activities but without any history of barbiturate ingestion, 9 gave normal results in standard tests for liver function, but the remainder showed some increases in serum alkaline
phosphatase or glutamic-oxaloacetic and/or glutamicpyruvic transaminase. Raised serum-G.G.T.P. levels fall steadily when alcohol and/or barbiturates are withdrawn, except in patients with persistently abnormal results from other liver-function tests. It appears, therefore, that there is a substantial group of alcoholics with no recognised cause for high serumG.G.T.P. levels, since we have found in them no history of recent anticonvulsant therapy or barbiturate intake nor evidence of liver damage revealed by changes in the other serum enzymes which were estimated. Work is continuing in an attempt to establish the significance of these findings and it is hoped to publish the results elsewhere in the near future. St. Bernard’s
Hospital, Southall,
Middlesex.
PREVIOUSLY UNDESCRIBED INTRAEPITHELIAL DEPOSITS IN MEMBRANOUS GLOMERULONEPHRITIS SIR,-Membranous glomerulonephritis is characterised by diffuse thickening of peripheral capillary walls of the glomeruli with slight increase of mesangial matrix and slight hypercellularity in hsEmatoxylin-and-eosin preparations.! The Jones silver stain demonstrates silver-positive
spikes projecting from the glomerular basement membrane.2 Subepithelial deposits associated with projections from the lamina densa have been described.l,3 We wish to report a lesion previously undescribed in fine structural studies of membranous glomerulonephritis. A 5-year-old White boy presented Hospital at age 3 years 8 months with
at an
Fitzsimons General 18-month history of
J. SPENCER-PEET D. WOOD M. M. GLATT.
CONGENITAL MALFORMATIONS AND REFUSED TERMINATION
SiR,-It has been suggested 1-3 that attempted abortion drugs may play some part in the etiology of certain congenital skeletal defects. We have therefore tried to discover the outcome of pregnancies in women refused a termination at this hospital. From May, 1968, to June, 1971, there were 1273 requests for termination of pregnancy, and 225 (18%) were refused by one or more of the consultant gynxcologists. Inquiries from general practitioners and local executive councils failed to trace 26 of these patients. In the remaining 199 patients the outcome was found by contacting general practitioners and examining obstetric records. The results
with
were as
Fig. 1-Typical early membranous glomerulonephritis. Mild basement-membrane thickening with numerous silverpositive projections (spikes). Jones silver stain ( x 860).
follows:
at 30 weeks, the mother having genitourinary gonococcal infection and gonococcal
One stillbirth occurred a severe
arthritis. The other stillbirth occurred after a severe antepartum haemorrhage in a pregnancy already complicated by placental insufficiency. In both cases necropsy revealed no congenital abnormalities. Of the abnormal infants, one was a trisomy-21 mongol who died at the age of two months because of congenital heart-disease, the second had an umbilical hernia which resolved without operation, and the third had a large facial cavernous haemangioma. We have therefore not observed an increased frequency of congenital malformations in the offspring of women refused a termination. This in no way excludes attempted abortion as being responsible for congenital deformities. Indeed aminopterin is known to be teratogenic when used in this way,4 and it is reasonable to be concerned about other drugs when taken in large doses in an attempt to procure an abortion. General Hospital, Bristol BS1 6SY. 1. 2. 3. 4.
T. J. DAVID D. G. J. BATTIN.
Papp, Z., Gardó, S. Lancet, 1971, i, 753. Gardner, L. I., Assemany, S. R., Neu, R. L. ibid. 1971, ii, 98. Kučera, J. ibid. Jan. 29, 1972, p. 260. Warkany, J. Congenital Malformations. Chicago, 1971.
Fig. 2-Electron micrograph illustrating epithelial deposit (D). Osmium-tetroxide fixation, uranyl-acetate and lead-citrate stains
(reduced tofrom x 9000).
microscopic haEmaturia and proteinuria. Renal biopsy at that time demonstrated diffuse increase in mesangial matrical material and slight glomerular hypercellularity. The Jones silver stain demonstrated subepithelial deposits of silver-positive material in the basement membrane of peripheral capillary walls (fig. 1). Tubules and interstitium were unremarkable. Biopsy 8 months later revealed similar changes by light microscopy. The patient is now in remission. 1. 2. 3.
Rosen, S. Hum. Path. 1971, 2, 209. Jones, D. Am.J. Path. 1957, 33, 313. Mostofi, F. K., Antonvych, T. A., Limas, E. Hum. Path. 1971, 2, 233.
ates
wishing
whether you on
to
or
St. Cuthbert’s Society, University of Durham, 12 South Bailey, Durham City, Co. Durham.
C. RAMSEY N. REILLY.
Fig. 2-Case 2. E.C.G. recording (lead I) during chest-pounding 32 hours after death.
*** Local education authorities
have
a
discretionary
power to assist graduates with grants towards second degrees, but, very properly, their first duty is to support
and medicine is a five-year course. If the National Health Service or medical research or teaching can benefit by being able to draw on doctors with a science background more thorough than an intercalated, usually biological, B.SC., then the Departments of Health and of Education and Science should want to provide support where local education authorities cannot. However, the Department of Health can suggest no course of action which might help our two correspondents or those with a similar ambition.-ED. L.
non-graduates;
Fig. 3-Case 2. E.C.G. recording (lead I) during chest-pounding 32 hours after death and removal of the heart.
depolarisation of the myocardium and thus can be dangerously misleading. If adequate circulation is not obtained, cardiac massage is mandatory. My observations raise the questions: how and where do these complexes arise ? Further electrophysiological and haemodynamic inquiries are
in progress.
Medical Department, Rogaland Hospital, 4000
Stavanger, Norway.
KAARE SKAALAND.
PROLAPSING POSTERIOR CUSP OF THE MITRAL VALVE SIR,-We have lately assessed three unrelated cases of this condition,1-4 diagnosed on a clinical basis. Cardiac .screening has shown abnormal atrial and atrioventricular
junctional pulsation of what seems to be a consistent and ,abnormal type, differing from the usual pulsation associated with mitral incompetence. One case progressed to true mitral incompetence and lost the earlier type of pulsation. We are wondering whether this feature has been assessed accurately, using electronic scanning equipment, because it seems a useful finding in supporting the clinical diagnosis of this condition. Southland Hospital,
Kew,
Invercargill,
New Zealand.
A. P. POOLE N. R. JEFFERSON.
MEDICAL EDUCATION FOR SCIENCE GRADUATES
SIR,-We are in our third year at Durham University reading honours chemistry and biology, respectively. We both wish to go on to study medicine but are experiencing difficulty in obtaining financial support. Approaches to our local education authorities have to date met with very little success. One of us received an immediate and absolute refusal of financial aid, while the other was informed that the situation was unpromising and that in any event a full grant would be most unlikely. It seems to be general policy of local education authorities not to give financial support for second degrees, even in medicine. Undaunted, we have approached several scientific foundations and similar bodies, but have again been disappointed. Last year5 you drew attention to a proposal, made by a group of clinical biochemists, that the Department of Health might provide financial support for science gradu-
4.
Barlow, J. B. J. chron. Dis. 1965, 18, 665. Barlow, J. B., Bosman, C. K. Am. Heart J. 1966, 71, 166. Barlow, J. B., Pocock, W. A., Marchand, P., Denny, M. ibid. 1963, 66, 443. Stannard, M., Sloman, J. G., Hare, W. S. C., Goble, A. J. Br. med. J.
5.
1967, iii, 71. Lancet, 1971, ii, 966.
1. 2. 3.
GAMMA-GLUTAMYL TRANSPEPTIDASE IN ALCOHOLISM
SIR,-Dr. Rosalki and his colleaguesdrew attention to their finding that patients receiving long-term anticonvulsant therapy had raised serum activities of the hepatic microsomal enzyme, gamma-glutamyl transpeptidase (G.G.T.P.). Dr. I dec and others2 reported iindings which showed that barbiturates and ethanol can both induce synthesis of this enzyme in rat’s liver, though, during the rather short duration of their experiments, no rise was noted in. the levels of serum-G.G.T.P. However, high 3 serum levels of this enzyme have been found in alcoholism, and such increases could be due to hepatic damage or, possibly, to enzyme induction caused by ethanol. They could also have resulted from induction of enzyme synthesis by barbiturates, habitually taken as hypnotics by many alcoholics, or by anticonvulsants given therapeutically for a short period only, to cover withdrawal of alcohol. We were impressed by Dr. Rosalki’s findings of raised serum-G.G.T.P. levels in alcoholic patients treated by one of us (M. M. G.) elsewhere,3 and have applied the method he described to the examination of patients admitted to the regional alcoholism unit at this hospital. We have found, from estimations made on serial samples collected from 12 male alcoholics, that administration of chlormethiazole and phenytoin for up to seven days only, to cover the immediate period of alcohol withdrawal, does not result in an increase in the level of serum-G.G.T.P. However, in a consecutive series of 30 male patients who had been taking alcohol until admission, 24 (80%) were found to have raised levels of serum-G.G.T.P., ranging from 70 to 1020 units, at that time. (Normal males: less than 60 international units per 1. at 37 °C.) Of the patients with raised levels, 20 (83%) gave no history of taking barbiturates or similar compounds during the previous few weeks, though many had occasionally taken some other drug, most commonly
nitrazepam, chlordiazepoxide,
or
diazepam.
However,
results obtained by us make it unlikely that these other drugs cause elevation of the serum-G.G.T.P. level. Of 143 patients admitted to general psychiatric wards at this hospital, initially for reasons other than an alcoholic complaint, only 16 were found to have raised levels of this enzyme, and 12 of these gave a history of recent continuous use of alcohol or barbiturates. The 127 with 1. 2. 3.
Rosalki, S. B., Tarlow, D., Rau, D. Lancet, 1971, ii, 376. Idéo, G., de Franchis, D., Del Ninno, E., Dioguardi, N. ibid. p. 825. Rosalki, S. B., Rau, D., Lehmann, D., Prentice, M. Ann. clin. Biochem. 1970, 7, 143.
1123 normal
G.G.T.P.
activities had been
taking
a
wide range of
drugs, including phenothiazines, tricyclic antidepressants, lithium salts, nitrazepam, chlordiazepoxide, and diazepam. Of the 20 alcoholic patients with raised G.G.T.P. activities but without any history of barbiturate ingestion, 9 gave normal results in standard tests for liver function, but the remainder showed some increases in serum alkaline
phosphatase or glutamic-oxaloacetic and/or glutamicpyruvic transaminase. Raised serum-G.G.T.P. levels fall steadily when alcohol and/or barbiturates are withdrawn, except in patients with persistently abnormal results from other liver-function tests. It appears, therefore, that there is a substantial group of alcoholics with no recognised cause for high serumG.G.T.P. levels, since we have found in them no history of recent anticonvulsant therapy or barbiturate intake nor evidence of liver damage revealed by changes in the other serum enzymes which were estimated. Work is continuing in an attempt to establish the significance of these findings and it is hoped to publish the results elsewhere in the near future. St. Bernard’s
Hospital, Southall,
Middlesex.
PREVIOUSLY UNDESCRIBED INTRAEPITHELIAL DEPOSITS IN MEMBRANOUS GLOMERULONEPHRITIS SIR,-Membranous glomerulonephritis is characterised by diffuse thickening of peripheral capillary walls of the glomeruli with slight increase of mesangial matrix and slight hypercellularity in hsEmatoxylin-and-eosin preparations.! The Jones silver stain demonstrates silver-positive
spikes projecting from the glomerular basement membrane.2 Subepithelial deposits associated with projections from the lamina densa have been described.l,3 We wish to report a lesion previously undescribed in fine structural studies of membranous glomerulonephritis. A 5-year-old White boy presented Hospital at age 3 years 8 months with
at an
Fitzsimons General 18-month history of
J. SPENCER-PEET D. WOOD M. M. GLATT.
CONGENITAL MALFORMATIONS AND REFUSED TERMINATION
SiR,-It has been suggested 1-3 that attempted abortion drugs may play some part in the etiology of certain congenital skeletal defects. We have therefore tried to discover the outcome of pregnancies in women refused a termination at this hospital. From May, 1968, to June, 1971, there were 1273 requests for termination of pregnancy, and 225 (18%) were refused by one or more of the consultant gynxcologists. Inquiries from general practitioners and local executive councils failed to trace 26 of these patients. In the remaining 199 patients the outcome was found by contacting general practitioners and examining obstetric records. The results
with
were as
Fig. 1-Typical early membranous glomerulonephritis. Mild basement-membrane thickening with numerous silverpositive projections (spikes). Jones silver stain ( x 860).
follows:
at 30 weeks, the mother having genitourinary gonococcal infection and gonococcal
One stillbirth occurred a severe
arthritis. The other stillbirth occurred after a severe antepartum haemorrhage in a pregnancy already complicated by placental insufficiency. In both cases necropsy revealed no congenital abnormalities. Of the abnormal infants, one was a trisomy-21 mongol who died at the age of two months because of congenital heart-disease, the second had an umbilical hernia which resolved without operation, and the third had a large facial cavernous haemangioma. We have therefore not observed an increased frequency of congenital malformations in the offspring of women refused a termination. This in no way excludes attempted abortion as being responsible for congenital deformities. Indeed aminopterin is known to be teratogenic when used in this way,4 and it is reasonable to be concerned about other drugs when taken in large doses in an attempt to procure an abortion. General Hospital, Bristol BS1 6SY. 1. 2. 3. 4.
T. J. DAVID D. G. J. BATTIN.
Papp, Z., Gardó, S. Lancet, 1971, i, 753. Gardner, L. I., Assemany, S. R., Neu, R. L. ibid. 1971, ii, 98. Kučera, J. ibid. Jan. 29, 1972, p. 260. Warkany, J. Congenital Malformations. Chicago, 1971.
Fig. 2-Electron micrograph illustrating epithelial deposit (D). Osmium-tetroxide fixation, uranyl-acetate and lead-citrate stains
(reduced tofrom x 9000).
microscopic haEmaturia and proteinuria. Renal biopsy at that time demonstrated diffuse increase in mesangial matrical material and slight glomerular hypercellularity. The Jones silver stain demonstrated subepithelial deposits of silver-positive material in the basement membrane of peripheral capillary walls (fig. 1). Tubules and interstitium were unremarkable. Biopsy 8 months later revealed similar changes by light microscopy. The patient is now in remission. 1. 2. 3.
Rosen, S. Hum. Path. 1971, 2, 209. Jones, D. Am.J. Path. 1957, 33, 313. Mostofi, F. K., Antonvych, T. A., Limas, E. Hum. Path. 1971, 2, 233.