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MILK-AND-CHEESE DIET IN PORTAL-SYSTEMIC ENCEPHALOPATHY
164
MILK-AND-CHEESE DIET IN PORTAL-SYSTEMIC ENCEPHALOPATHY M.B.
J. C. B. FENTON Cantab., D.C.P., M.C.Path.
E. J. KNIGHT
P. L. HUMPHERSON
M.B. Birm.
B.Sc. Lond., S.R.D.
CLINICAL RESEARCH ASSISTANT
CHIEF DIETITIAN
BARTHOLOMEW’S HOSPITAL, LONDON, E.C.1
dietary restriction of protein is advised for the treatment of hepatic encephalopathy the source of protein is not defined, because all protein foods are generally believed to be equally harmful. Although several years have elapsed since Bessman et al. (1958) reported that the WHEN
oral administration of whole blood was more toxic to patients with advanced liver-disease than was an equivalent quantity of casein, little further consideration seems to have been given to the possible significance of these
findings. During an investigation of a patient with chronic portalsystemic encephalopathy we noticed that when the protein of the low-protein diet was given in liquid form the patient’s mental condition deteriorated, and at the same time the plasma-ammonia level rose rapidly. We therefore made a preliminary study of the effect of different sources of dietary protein in patients subject to hepatic encephalopathy, in the hope that this might lead to an improved dietary treatment and also incidentally give more information on factors responsible for this condition. Patients and Methods Three patients, who were attending a clinic for postoperative care following portacaval anastomosis (Mr. A. H. Hunt), were chosen because of a recent history of portal-systemic encephalopathy and persistently raised plasma-ammonia levels. Many of the patients attending the clinic had abnormal plasmaammonia levels, but our choice was limited to the few whose cerebral function was impaired enough for them to accept the prolonged admission necessary for the study. Plasma-ammonia Venous plasma-ammonia levels of the method of Fenton (1962).
were
estimated
"
Case-reports
SENIOR LECTURER IN CHEMICAL PATHOLOGY
ST.
Lactobacillus acidophilus Culture A commercial preparation of this organism was used (’Enpac’, Aplin Barrett Ltd.). This is stated to contain at least 1 x 10’ viable cells of L. acidophilus per g. of powder.
by
a
modification
Case 1 A man aged 62 was admitted to St. Bartholomew’s Hospital in September, 1964, with hepatic encephalopathy. An end-toside portacaval anastomosis had been constructed 17 months previously, but since operation he had experienced severe protein intolerance. Although the dietary protein had been restricted to 40 g. per day and treatment with neomycin given, his mental status deteriorated, and on two occasions he required hospital treatment for encephalopathy. An exacerbation of his encephalopathy led to his present admission. At this time he was jaundiced, drowsy, and confused and had slurred speech There was no other significant and a flapping tremor.
abnormality. Blood analysis.-Total protein 5,6 g. per 100 ml.; albumin 3-9 g. per 100 ml.; alkaline phosphatase 27 King-Armstrong units; bilirubin 5-1 mg. per 100 ml.; potassium 3-0 mEq. per litre; prothrombin-time 6 seconds delay; aspartate aminotransferase 27 units per litre; hemoglobin 10-1 g. per 100 ml.; platelets 92,000 per c.mm.; venous plasma-ammonia 265 g. nitrogen per 100 ml. Progress (fig. 1).-The patient was treated by withdrawal of all dietary protein and by giving oral glucose liquids and potassium supplements. Neomycin, 4 g. per day, was continued. On this regimen he improved rapidly, and by the 6th day his only symptom was mild drowsiness; plasmaammonia had fallen and the potassium level returned to normal. Protein was reintroduced into the diet and increased over the next 5 days to 50 g. per day. The dietary protein was composed of the basic protein diet to which was added increments of mixed animal-derived protein. On this diet the patient remained slightly drowsy. The mixed protein component was then replaced by 30 g. protein in the form of milk and cheese. During this period of 7 days the plasma-ammonia level fell, the drowsiness disappeared, and the mental status improved. The milk and cheese proteins were then replaced by an equivalent amount of red meat. The plasma-ammonia rose again, and after 4 days the patient became increasingly drowsy and slightly confused. After 7 days of meat protein, vegetable protein was tried; but he found this unpalatable, and because of continued drowsiness and confusion he returned to a milkand-cheese diet and was discharged to attend as an outpatient, with instructions to continue this diet at home.
Composition of Diets The basic low-protein diet, providing 1767 calories, consisted of 17 g. protein derived from bread, potatoes, cereals, and 3 oz. pasteurised milk in tea. In case 2 the basic diet was increased to 38 g. protein to satisfy the patient’s appetite. In a mixed protein diet, raw or cooked cheddar cheese, whole egg, beef, lamb, pork, ham, chicken, fish, and additional pasteurised milk were added in weighed amounts to provide the total protein required. Fruit and green and root vegetables were not weighed. The patients were allowed fruit squashes, fruit, and boiled sweets. In the special protein diets, milk and cheese, meat, or eggs were given in addition to the basic diet to make up the protein content to the quantities mentioned in respect of each patient. Food values for calculation of the diets of McCance and Widdowson (1960).
were
taken from the data
DR. ACHAR AND OTHERS: REFERENCES
Barham- Carter, A. (1957) Q. Jl Med. 26, 335. Barrows, H. S., Dyck, P., Kurze, T. (1965) Neurology, Minneap. 15, 361. Brinker, R. A., King, D. L., Taveras, J. M. (1965) Am. J. Roentg. 93, 781. Bull, J. W. D., Marshall, J., Shaw, D. A. (1960) Lancet, i, 562. Dalsgaard-Nielsen, T. (1956) Acta psychiat. neurol. scand. Suppl. 108, 101.
Ford, R., Ambrose, J. (1963) Brain, 86, 189. Glynn, A. A. (1956) Br. med. J. i, 1216. Groch, S., McDevitt, E., Wright, I. S. (1961) Ann. intern. Med. 55, Jeppsson, S. (1961) Acta chirg. scand. Suppl. 272. Kessler, G. B. (1965) Bull. Los Ang. neurol. Soc. 30, 21. Lithlander, B. (1960) Acta psychiat. scand. 35, 241. McKissock, W., Richardson, A., Walsh, L. (1960) Brain, 83, 1. Marshall, J., Shaw, D. A. (1960) Lancet, i, 995. Riishede, J. (1956) Acta psychiat. neurol. scand. Supp. 108, 347. Sugar, O., Uematsu, S. (1964) Surg. Clin. N. Am. 44, 55.
358.
Fig.
I-Plasma-ammonia levels in relation
Although neomycin was given throughout, during the milk-and-cheese diet.
to
diet in
case
1.
the ammonia level feU
165 TABLE I-ORIGIN OF DIETARY PROTEIN IN CASE
2
phosphatase fLg. nitrogen
32 King-Armstrong per 100 ml.
units; plasma-ammonia 200
Variations in diet.-Throughout the trial 80 g. protein per day was allowed (table l). Progress.-There was no apparent change in the mental status at any time during the patient’s stay in hospital. The levels of plasma-ammonia are shown in fig. 2. He was discharged with instructions to continue his diet of milk and cheese. At subsequent outpatient attendances his father said he was mentally brighter and less moody and irritable. ’
During the last day.
8
days dried culture
of L.
acidophilus
was
given,
6 g. per
Follow-up.-The patient attended the outpatient department improved considerably in the first 3 months, remaining free of stupor and able to do full outdoor work as a farm-hand. His mental condition appeared to be better than at any time since his operation, and for this reason his family encouraged him to adhere to his diet. His mental state gradually deteriorated in the next 7 months. The symptoms became severe enough to require a further hospital admission, but this time he failed to respond to medical treatment. He
every 6 weeks. He
died after
a
TABLE II-ORIGIN OF DIETARY PROTEIN IN CASE
3
colonic-exclusion operation.
During the last day.
14
days dried culture
of L. acidophilus
was
given,
6 g. per
Case 3
Fig. 2-Plasma-ammonia levels in case 2. The effect of milk and cheese upon the ammonia level is similar the result in case 1.
Case2 A 16-year-old youth was admitted for dietary trial in November, 1964. When he was 6 a portacaval anastomosis had been constructed on account of recurrent bleeding from cesophageal varices. There was no further haemorrhage after operation, and growth and development were uneventful until 9 months before admission, when his parents noted that he was becoming slow in response and forgetful. The plasma-ammonia was high (310 4g. nitrogen per all ml.), and he was advised to reduce his dietary protein intake to 60 g. per day. He improved on this diet, and although the plasma-ammonia level fell it was thought that he might benefit further from a diet of milk and cheese; he was therefore admitted for investigation. Examination disclosed no abnormal physical signs apart from slight jaundice and perhaps a slow response to questioning. Blood analysis.-Urea and electrolytes within normal limits; bilirubin 4-4 mg. per 100 ml.; albumin 2-7 g., globulin 2-9 g. per 100 ml.; thymol turbidity 6-4 units; alkaline
to
A 64-year-old woman was admitted to St. Bartholomew’s Hospital in November, 1964, with hepatic encephalopathy. An end-to-side portacaval anastomosis had been constructed 10 months previously after haemorrhage from oesophageal varices. Symptoms of hepatic encephalopathy were noted at subsequent outpatient attendances, and three hospital admissions were needed for treatment of coma. Dietary protein restriction and oral neomycin failed to prevent further minor episodes of encephalopathy: one happened on the day before admission. On admission the patient was mildly confused, spoke rapidly, and made repeated grimacing facial expressions. The liver was palpable one fingerbreadth below the costal margin, but no other abnormal physical signs were noted. Blood analysis.-Electrolytes normal; total protein 5-9 g. per 100 ml.; albumin 3-4 g., globulin 2-5 g. per 100 ml.; alkaline phosphatase 20 King-Armstrong units; aspartate aminotransferase 73 units per litre; plasma-ammonia 130 fLg. nitrogen per 100 ml.; bilirubin 0-8 mg. per 100 ml.; haemoglobin 11 g. per 100 ml. ; prothrombin-time 5 seconds delay. Treatnient and dietary alterations.-Initial treatment con-
Fig. 3-Plasma-ammonia levels in
case
3.
Although the levels fluctuated, the tendency for a fall to occur during the milkand-cheese period is seen again. There is a suggestion that meat has the opposite effect.
166 sisted of oral glucose fluids and neomycin 4 g. per day. After 3 days she had improved enough to allow the reintroduction of protein into the diet, and on the 6th day neomycin was discontinued. The protein intake was increased over 9 days to 50 g. per day. The details of the diet are shown in table n. By the end of the 1st week the symptoms of encephalopathy had disappeared, and during the remainder of the dietary trial the patient’s mental status remained unchanged. The plasmaammonia levels are shown in fig. 3. The trial had to be discontinued after 7 weeks because she developed subacute intestinal obstruction. Eventually she was discharged with instructions to restrict her protein intake to 50 g. per day, avoiding red meat and taking a high proportion of milk and cheese. She did not follow this advice, and she had two further episodes of encephalopathy in 8 weeks, for which she received treatment elsewhere. The second episode was severe and appeared to leave some permanent neurological damage. At a later outpatient attendance moderately severe stupor was noted, and inquiry revealed that she was taking a 30 g. mixed protein diet. She was therefore strongly advised to accept a diet containing 40 g. dietary protein, of which 20 g. was derived from milk and cheese. At outpatient visits 4 and 8 weeks later she showed a substantial improvement, and for the next 5 months she remained free of stupor. But her symptoms have since returned, and although they are less severe than in the past an operation for colonic exclusion seems to be the only means of controlling her condition. Discussion
It has
far proved practicable to screen all the foods for their influence upon the plasmaprotein ammonia level in each patient-partly because of the prolonged hospital admissions required and partly because some diets may be distasteful, especially when the same form of protein is offered for each meal. Fortunately the three patients described here accepted the milk-and-cheese diet which is better tolerated by patients with shunt not so
common
encephalopathy. In each case the plasma-ammonia level fell during periods of milk-and-cheese diet (figs. 1-3) and was always lowest towards the end of the period. In case 1 drowsiness and confusion cleared while the dairy proteins were being taken, but on changing to meat diet the symptoms returned. The subsequent early response to this diet was most gratifying, although the beneficial effect did not last more than a few months. This patient’s symptoms eventually became resistant to all medical treatment. In cases 2 and 3 the mental symptoms were mild during the trial period and showed no obvious change when the diet was altered. In case 2, the milk-and-cheese diet was continued after discharge from hospital and at follow-up there was clearly some improvement. The third patient had had recurring episodes of encephalopathy, which necessitated six hospital admissions in 12 months. On a 30 g. mixed protein diet she still showed signs of episodic stupor, but she improved when this was increased to 40 g. (20 g. basic protein and 20 g. milk and cheese) and had no further episode for 5 months. As an explanation of the apparently beneficial effect of the milk-and-cheese diet, it, is possible either that the proteins themselves underwent less putrefactive degradation and ammonia production before being assimilated or that there was a change in the intestinal bacterial flora which resulted in a reduction in the number of ammoniaproducing organisms. The latter change could occur if the proteins or other constituents of the diet were favourable to the induction of a new balance among the bacterial
species.
Alternatively the high bacterial content of milk and cheese might provide enough fresh organisms to change the balance between the resident strains of bacteria. On the evidence of past experiments it appears that the nature of the diet is more important than its microbial content in determining the character of the intestinal flora (Torrey and Montu 1931). Nevertheless, good results in the treatment of two patients with chronic relapsing encephalopathy have been claimed by Macbeth et al. (1965), who used large volumes of a liquid culture of L. acidophilus to alter the intestinal flora and reduce the number of ammonia-producing organisms. We tried to assess the importance of the bacterial content of milk and cheese by administering a diet of cooked cheese and sterilised milk. This diet was given to two patients, but in both it unexpectedly produced such severe constipation that the investigation had to be abandoned. We also noted the effects of a dried culture of L. acidophilus added during the dietary periods of meat, egg, and mixed protein, but more work will be required to establish whether or not the intake of bacteria is more important than the type of food. If a change in fxcal flora is the reason for the benefit derived from a milk-and-cheese diet, why did not the beneficial effects last more than a few months in casesI and 3 ? A sim.ple answer might be that a progressive deterioration in liver function was part of the natural history of the disease in these patients. In case 1 a fall in serum-albumin would support this explanation. On the other hand Torrey and Montu (1931), studying the effects of a meat diet in volunteers, found that during the first few months a change in faecal flora resulted in a decrease in L. acidophilus and a relative increase in Clostridium welchii. This alteration in flora tended to revert to normal as the diet was continued.
Summary The effects of different dietary proteins have been observed in three patients who were subject to portalsystemic encephalopathy. A diet of milk-and-cheese protein was better tolerated than mixed animal protein. The reason for this difference in protein tolerance is not yet known, but it may be due to a change in the intestinal bacterial flora. We wish to thank Mr. Alan H. Hunt for his encouragement and interest in this work; the physicians of St. Bartholomew’s Hospital for allowing us access to their patients; the nursing staff for their help and kind understanding of special requirements; Miss S. J. Vale and other members of the dietetic department for their help in preparing the diets. One of us (E. J. K.) was in receipt of a grant from the St. Bartholomew’s Hospital Research Funds.
Requests for reprints should Department of Pathology, St.
be sent to Dr. J. C. B. Fenton, Bartholomew’s Hospital, London,
E.C. 1. REFERENCES
Bessman, A. N., Mirick, G. S., Hawkins, R. (1958) J. clin. Invest. 37, 990. Fenton, J. C. B. (1962) Clinica chim. Acta, 7, 163. Macbeth, W. A. A. G., Kass, E. H., McDermott, W. V. (1965) Lancet, i, 399. McCance, R. A., Widdowson, E. M. (1960) Spec. Rep. Ser. med. Res. Coun. no. 297.
Torrey, J. C., Montu, E. (1931) J. infect. Dis. 49, 141.
" ... The so-called ’practical’ outlook has been and is a great obstacle to the advance of Medicine. The plaintive cry for what is ’useful’ as against ’theoretical knowledge’ echoes down the ages. We hear it still. But when and where that cry swells into a chorus, then and there Science dies."-The late CHARLES SINGER. A Short History of Anatomy and Physiology From the Greeks to Harvey; p. 37. New York, 1957.
MILK-AND-CHEESE DIET IN PORTAL-SYSTEMIC ENCEPHALOPATHY M.B.
J. C. B. FENTON Cantab., D.C.P., M.C.Path.
E. J. KNIGHT
P. L. HUMPHERSON
M.B. Birm.
B.Sc. Lond., S.R.D.
CLINICAL RESEARCH ASSISTANT
CHIEF DIETITIAN
BARTHOLOMEW’S HOSPITAL, LONDON, E.C.1
dietary restriction of protein is advised for the treatment of hepatic encephalopathy the source of protein is not defined, because all protein foods are generally believed to be equally harmful. Although several years have elapsed since Bessman et al. (1958) reported that the WHEN
oral administration of whole blood was more toxic to patients with advanced liver-disease than was an equivalent quantity of casein, little further consideration seems to have been given to the possible significance of these
findings. During an investigation of a patient with chronic portalsystemic encephalopathy we noticed that when the protein of the low-protein diet was given in liquid form the patient’s mental condition deteriorated, and at the same time the plasma-ammonia level rose rapidly. We therefore made a preliminary study of the effect of different sources of dietary protein in patients subject to hepatic encephalopathy, in the hope that this might lead to an improved dietary treatment and also incidentally give more information on factors responsible for this condition. Patients and Methods Three patients, who were attending a clinic for postoperative care following portacaval anastomosis (Mr. A. H. Hunt), were chosen because of a recent history of portal-systemic encephalopathy and persistently raised plasma-ammonia levels. Many of the patients attending the clinic had abnormal plasmaammonia levels, but our choice was limited to the few whose cerebral function was impaired enough for them to accept the prolonged admission necessary for the study. Plasma-ammonia Venous plasma-ammonia levels of the method of Fenton (1962).
were
estimated
"
Case-reports
SENIOR LECTURER IN CHEMICAL PATHOLOGY
ST.
Lactobacillus acidophilus Culture A commercial preparation of this organism was used (’Enpac’, Aplin Barrett Ltd.). This is stated to contain at least 1 x 10’ viable cells of L. acidophilus per g. of powder.
by
a
modification
Case 1 A man aged 62 was admitted to St. Bartholomew’s Hospital in September, 1964, with hepatic encephalopathy. An end-toside portacaval anastomosis had been constructed 17 months previously, but since operation he had experienced severe protein intolerance. Although the dietary protein had been restricted to 40 g. per day and treatment with neomycin given, his mental status deteriorated, and on two occasions he required hospital treatment for encephalopathy. An exacerbation of his encephalopathy led to his present admission. At this time he was jaundiced, drowsy, and confused and had slurred speech There was no other significant and a flapping tremor.
abnormality. Blood analysis.-Total protein 5,6 g. per 100 ml.; albumin 3-9 g. per 100 ml.; alkaline phosphatase 27 King-Armstrong units; bilirubin 5-1 mg. per 100 ml.; potassium 3-0 mEq. per litre; prothrombin-time 6 seconds delay; aspartate aminotransferase 27 units per litre; hemoglobin 10-1 g. per 100 ml.; platelets 92,000 per c.mm.; venous plasma-ammonia 265 g. nitrogen per 100 ml. Progress (fig. 1).-The patient was treated by withdrawal of all dietary protein and by giving oral glucose liquids and potassium supplements. Neomycin, 4 g. per day, was continued. On this regimen he improved rapidly, and by the 6th day his only symptom was mild drowsiness; plasmaammonia had fallen and the potassium level returned to normal. Protein was reintroduced into the diet and increased over the next 5 days to 50 g. per day. The dietary protein was composed of the basic protein diet to which was added increments of mixed animal-derived protein. On this diet the patient remained slightly drowsy. The mixed protein component was then replaced by 30 g. protein in the form of milk and cheese. During this period of 7 days the plasma-ammonia level fell, the drowsiness disappeared, and the mental status improved. The milk and cheese proteins were then replaced by an equivalent amount of red meat. The plasma-ammonia rose again, and after 4 days the patient became increasingly drowsy and slightly confused. After 7 days of meat protein, vegetable protein was tried; but he found this unpalatable, and because of continued drowsiness and confusion he returned to a milkand-cheese diet and was discharged to attend as an outpatient, with instructions to continue this diet at home.
Composition of Diets The basic low-protein diet, providing 1767 calories, consisted of 17 g. protein derived from bread, potatoes, cereals, and 3 oz. pasteurised milk in tea. In case 2 the basic diet was increased to 38 g. protein to satisfy the patient’s appetite. In a mixed protein diet, raw or cooked cheddar cheese, whole egg, beef, lamb, pork, ham, chicken, fish, and additional pasteurised milk were added in weighed amounts to provide the total protein required. Fruit and green and root vegetables were not weighed. The patients were allowed fruit squashes, fruit, and boiled sweets. In the special protein diets, milk and cheese, meat, or eggs were given in addition to the basic diet to make up the protein content to the quantities mentioned in respect of each patient. Food values for calculation of the diets of McCance and Widdowson (1960).
were
taken from the data
DR. ACHAR AND OTHERS: REFERENCES
Barham- Carter, A. (1957) Q. Jl Med. 26, 335. Barrows, H. S., Dyck, P., Kurze, T. (1965) Neurology, Minneap. 15, 361. Brinker, R. A., King, D. L., Taveras, J. M. (1965) Am. J. Roentg. 93, 781. Bull, J. W. D., Marshall, J., Shaw, D. A. (1960) Lancet, i, 562. Dalsgaard-Nielsen, T. (1956) Acta psychiat. neurol. scand. Suppl. 108, 101.
Ford, R., Ambrose, J. (1963) Brain, 86, 189. Glynn, A. A. (1956) Br. med. J. i, 1216. Groch, S., McDevitt, E., Wright, I. S. (1961) Ann. intern. Med. 55, Jeppsson, S. (1961) Acta chirg. scand. Suppl. 272. Kessler, G. B. (1965) Bull. Los Ang. neurol. Soc. 30, 21. Lithlander, B. (1960) Acta psychiat. scand. 35, 241. McKissock, W., Richardson, A., Walsh, L. (1960) Brain, 83, 1. Marshall, J., Shaw, D. A. (1960) Lancet, i, 995. Riishede, J. (1956) Acta psychiat. neurol. scand. Supp. 108, 347. Sugar, O., Uematsu, S. (1964) Surg. Clin. N. Am. 44, 55.
358.
Fig.
I-Plasma-ammonia levels in relation
Although neomycin was given throughout, during the milk-and-cheese diet.
to
diet in
case
1.
the ammonia level feU
165 TABLE I-ORIGIN OF DIETARY PROTEIN IN CASE
2
phosphatase fLg. nitrogen
32 King-Armstrong per 100 ml.
units; plasma-ammonia 200
Variations in diet.-Throughout the trial 80 g. protein per day was allowed (table l). Progress.-There was no apparent change in the mental status at any time during the patient’s stay in hospital. The levels of plasma-ammonia are shown in fig. 2. He was discharged with instructions to continue his diet of milk and cheese. At subsequent outpatient attendances his father said he was mentally brighter and less moody and irritable. ’
During the last day.
8
days dried culture
of L.
acidophilus
was
given,
6 g. per
Follow-up.-The patient attended the outpatient department improved considerably in the first 3 months, remaining free of stupor and able to do full outdoor work as a farm-hand. His mental condition appeared to be better than at any time since his operation, and for this reason his family encouraged him to adhere to his diet. His mental state gradually deteriorated in the next 7 months. The symptoms became severe enough to require a further hospital admission, but this time he failed to respond to medical treatment. He
every 6 weeks. He
died after
a
TABLE II-ORIGIN OF DIETARY PROTEIN IN CASE
3
colonic-exclusion operation.
During the last day.
14
days dried culture
of L. acidophilus
was
given,
6 g. per
Case 3
Fig. 2-Plasma-ammonia levels in case 2. The effect of milk and cheese upon the ammonia level is similar the result in case 1.
Case2 A 16-year-old youth was admitted for dietary trial in November, 1964. When he was 6 a portacaval anastomosis had been constructed on account of recurrent bleeding from cesophageal varices. There was no further haemorrhage after operation, and growth and development were uneventful until 9 months before admission, when his parents noted that he was becoming slow in response and forgetful. The plasma-ammonia was high (310 4g. nitrogen per all ml.), and he was advised to reduce his dietary protein intake to 60 g. per day. He improved on this diet, and although the plasma-ammonia level fell it was thought that he might benefit further from a diet of milk and cheese; he was therefore admitted for investigation. Examination disclosed no abnormal physical signs apart from slight jaundice and perhaps a slow response to questioning. Blood analysis.-Urea and electrolytes within normal limits; bilirubin 4-4 mg. per 100 ml.; albumin 2-7 g., globulin 2-9 g. per 100 ml.; thymol turbidity 6-4 units; alkaline
to
A 64-year-old woman was admitted to St. Bartholomew’s Hospital in November, 1964, with hepatic encephalopathy. An end-to-side portacaval anastomosis had been constructed 10 months previously after haemorrhage from oesophageal varices. Symptoms of hepatic encephalopathy were noted at subsequent outpatient attendances, and three hospital admissions were needed for treatment of coma. Dietary protein restriction and oral neomycin failed to prevent further minor episodes of encephalopathy: one happened on the day before admission. On admission the patient was mildly confused, spoke rapidly, and made repeated grimacing facial expressions. The liver was palpable one fingerbreadth below the costal margin, but no other abnormal physical signs were noted. Blood analysis.-Electrolytes normal; total protein 5-9 g. per 100 ml.; albumin 3-4 g., globulin 2-5 g. per 100 ml.; alkaline phosphatase 20 King-Armstrong units; aspartate aminotransferase 73 units per litre; plasma-ammonia 130 fLg. nitrogen per 100 ml.; bilirubin 0-8 mg. per 100 ml.; haemoglobin 11 g. per 100 ml. ; prothrombin-time 5 seconds delay. Treatnient and dietary alterations.-Initial treatment con-
Fig. 3-Plasma-ammonia levels in
case
3.
Although the levels fluctuated, the tendency for a fall to occur during the milkand-cheese period is seen again. There is a suggestion that meat has the opposite effect.
166 sisted of oral glucose fluids and neomycin 4 g. per day. After 3 days she had improved enough to allow the reintroduction of protein into the diet, and on the 6th day neomycin was discontinued. The protein intake was increased over 9 days to 50 g. per day. The details of the diet are shown in table n. By the end of the 1st week the symptoms of encephalopathy had disappeared, and during the remainder of the dietary trial the patient’s mental status remained unchanged. The plasmaammonia levels are shown in fig. 3. The trial had to be discontinued after 7 weeks because she developed subacute intestinal obstruction. Eventually she was discharged with instructions to restrict her protein intake to 50 g. per day, avoiding red meat and taking a high proportion of milk and cheese. She did not follow this advice, and she had two further episodes of encephalopathy in 8 weeks, for which she received treatment elsewhere. The second episode was severe and appeared to leave some permanent neurological damage. At a later outpatient attendance moderately severe stupor was noted, and inquiry revealed that she was taking a 30 g. mixed protein diet. She was therefore strongly advised to accept a diet containing 40 g. dietary protein, of which 20 g. was derived from milk and cheese. At outpatient visits 4 and 8 weeks later she showed a substantial improvement, and for the next 5 months she remained free of stupor. But her symptoms have since returned, and although they are less severe than in the past an operation for colonic exclusion seems to be the only means of controlling her condition. Discussion
It has
far proved practicable to screen all the foods for their influence upon the plasmaprotein ammonia level in each patient-partly because of the prolonged hospital admissions required and partly because some diets may be distasteful, especially when the same form of protein is offered for each meal. Fortunately the three patients described here accepted the milk-and-cheese diet which is better tolerated by patients with shunt not so
common
encephalopathy. In each case the plasma-ammonia level fell during periods of milk-and-cheese diet (figs. 1-3) and was always lowest towards the end of the period. In case 1 drowsiness and confusion cleared while the dairy proteins were being taken, but on changing to meat diet the symptoms returned. The subsequent early response to this diet was most gratifying, although the beneficial effect did not last more than a few months. This patient’s symptoms eventually became resistant to all medical treatment. In cases 2 and 3 the mental symptoms were mild during the trial period and showed no obvious change when the diet was altered. In case 2, the milk-and-cheese diet was continued after discharge from hospital and at follow-up there was clearly some improvement. The third patient had had recurring episodes of encephalopathy, which necessitated six hospital admissions in 12 months. On a 30 g. mixed protein diet she still showed signs of episodic stupor, but she improved when this was increased to 40 g. (20 g. basic protein and 20 g. milk and cheese) and had no further episode for 5 months. As an explanation of the apparently beneficial effect of the milk-and-cheese diet, it, is possible either that the proteins themselves underwent less putrefactive degradation and ammonia production before being assimilated or that there was a change in the intestinal bacterial flora which resulted in a reduction in the number of ammoniaproducing organisms. The latter change could occur if the proteins or other constituents of the diet were favourable to the induction of a new balance among the bacterial
species.
Alternatively the high bacterial content of milk and cheese might provide enough fresh organisms to change the balance between the resident strains of bacteria. On the evidence of past experiments it appears that the nature of the diet is more important than its microbial content in determining the character of the intestinal flora (Torrey and Montu 1931). Nevertheless, good results in the treatment of two patients with chronic relapsing encephalopathy have been claimed by Macbeth et al. (1965), who used large volumes of a liquid culture of L. acidophilus to alter the intestinal flora and reduce the number of ammonia-producing organisms. We tried to assess the importance of the bacterial content of milk and cheese by administering a diet of cooked cheese and sterilised milk. This diet was given to two patients, but in both it unexpectedly produced such severe constipation that the investigation had to be abandoned. We also noted the effects of a dried culture of L. acidophilus added during the dietary periods of meat, egg, and mixed protein, but more work will be required to establish whether or not the intake of bacteria is more important than the type of food. If a change in fxcal flora is the reason for the benefit derived from a milk-and-cheese diet, why did not the beneficial effects last more than a few months in casesI and 3 ? A sim.ple answer might be that a progressive deterioration in liver function was part of the natural history of the disease in these patients. In case 1 a fall in serum-albumin would support this explanation. On the other hand Torrey and Montu (1931), studying the effects of a meat diet in volunteers, found that during the first few months a change in faecal flora resulted in a decrease in L. acidophilus and a relative increase in Clostridium welchii. This alteration in flora tended to revert to normal as the diet was continued.
Summary The effects of different dietary proteins have been observed in three patients who were subject to portalsystemic encephalopathy. A diet of milk-and-cheese protein was better tolerated than mixed animal protein. The reason for this difference in protein tolerance is not yet known, but it may be due to a change in the intestinal bacterial flora. We wish to thank Mr. Alan H. Hunt for his encouragement and interest in this work; the physicians of St. Bartholomew’s Hospital for allowing us access to their patients; the nursing staff for their help and kind understanding of special requirements; Miss S. J. Vale and other members of the dietetic department for their help in preparing the diets. One of us (E. J. K.) was in receipt of a grant from the St. Bartholomew’s Hospital Research Funds.
Requests for reprints should Department of Pathology, St.
be sent to Dr. J. C. B. Fenton, Bartholomew’s Hospital, London,
E.C. 1. REFERENCES
Bessman, A. N., Mirick, G. S., Hawkins, R. (1958) J. clin. Invest. 37, 990. Fenton, J. C. B. (1962) Clinica chim. Acta, 7, 163. Macbeth, W. A. A. G., Kass, E. H., McDermott, W. V. (1965) Lancet, i, 399. McCance, R. A., Widdowson, E. M. (1960) Spec. Rep. Ser. med. Res. Coun. no. 297.
Torrey, J. C., Montu, E. (1931) J. infect. Dis. 49, 141.
" ... The so-called ’practical’ outlook has been and is a great obstacle to the advance of Medicine. The plaintive cry for what is ’useful’ as against ’theoretical knowledge’ echoes down the ages. We hear it still. But when and where that cry swells into a chorus, then and there Science dies."-The late CHARLES SINGER. A Short History of Anatomy and Physiology From the Greeks to Harvey; p. 37. New York, 1957.