- Email: [email protected]
PROTEIN-LOSING ENTEROPATHY
892
When related to human atherosclerosis, these observations support our tentative hypothesis that enzyme defects in the ageing anoxic media restrict the outward migration of cholesterol from the intima into the media, leading to its accumulation in the inner part of the arterial wall. This work was in part supported by U.S. Public Health Service grant no. H6483 of the National Heart Institute.
C. W. M. ADAMS M.A.,
M.D.
Cantab.
Lecturer
O. B. BAYLISS
PATIENTS
Albumin turnover was studied on 15 occasions in 13 patients, of whom 11 had steatorrhoea. The patients were studied on a metabolic ward; they were weighed daily, and twenty-fourhour urine and stool collections were made throughout. The dietary intake of protein was not standardised but all were taking more than 70 g. of protein per day, except patients 4 and 8 who had anorexia. The calorie content of the diet was sufficient to produce a maximum protein-sparing effect, and an assessment of total body fat, by measurement of skinfold thickness, indicated some reserve of fat in all cases. The total body fat was, however, very low in patients 2, 6(a), 7, 8, and 11.
A.I.M.L.T.
Technician
Department of Pathology, Guy’s Hospital Medical School, London, S.E.1
METHODS
M. Z. IBRAHIM M.B. Cairo Postgraduate Student
PROTEIN-LOSING ENTEROPATHY THE VALUE OF URINARY NITROGEN ESTIMATIONS IN DIAGNOSIS
IT is now well established that loss of plasma albumin into the gut may be an important cause of hypoalbuminsemia in some cases of the steatorrhoea syndrome, and the various methods of demonstrating this loss have recently been reviewed.1-3 Crane and Neuberger4 have studied extensively the absorption of 15N-labelled proteins and the elimination of the isotope in stools and urine, but little has been published about the value of urinary totalnitrogen estimations in the diagnosis of gastrointestinal
protein loss. If hypoalbuminsemia in the steatorrhoea syndrome is predominantly due to inadequate absorption of the raw materials necessary for albumin synthesis, one might expect nitrogen excretion in the urine to be low, even on a high-protein diet. If, however, hypoalbuminaemia is due to gastrointestinal loss of protein, the urinary nitrogen could well be normal, since the limiting factor would be the ability of the liver to compensate by increasing albumin synthesis. Davies et al. have demonstrated a close correlation between albumin metabolism and urinary total-nitrogen excretion in burns, trauma, and cirrhosis. My object here is to show that this correlation also occurs in steatorrhoea and that useful information may be obtained from estimating the urinary nitrogen excretion in this syndrome. 1. Lancet, 1961, ii, 299. 2. Jeejeebhoy, K. N. ibid. 1962, i, 343. 3. Waldmann, T. A., Steinfeld, J. L., Dutcher, T. F., Davidson, J. Gordon, R. Gastroenterology, 1961, 41, 197. 4. Crane, C. W., Neuberger, A. Brit. med. J. 1960, ii, 815, 888. 5. Davies, J. W. L., Ricketts, C. R., Bull, J. P. Lancet, 1959, i, 346.
D.,
Human serum-albumin (Lister Institute) was labelled to a specific activity of not more than 5 fLC per mg. of protein, and with (on average) less than one atom of iodide per protein molecule. A modification of the method of McFarlane 6 was used. 20-50 fLC of 13’I-labelled human albumin was injected intravenously and radioactivity in samples of plasma, twentyfour-hour urine, and stools measured, using a well-type scintillation counter. The results were calculated as described by Pearson et al.,’ and expressed in terms of plasma-albumin pool (serum-albumin concentration x plasma volume), urine/ plasma (u/p) ratio of radioactivity (averaged over several days, omitting the day of injection), and albumin turnover in mg. per kg. body-weight per day. The u/p ratio was taken to indicate the fractional turnover-rate. Some of the patients were also given 131I-labelled polyvinyl pyrrolidone (P.v.p.) using the method described by Gordon.Thyroid uptake was blocked by giving potassium iodide 75 mg. daily. Plasma-albumin concentrations for the albumin turnover studies were estimated from paper electrophoresis,9 but the albumin concentrations represented in fig. 2 were estimated by the sulphate-sulphite precipitation method.10 Nitrogen excretion in the urine was estimated by the micro-Kjeldahl method. RESULTS
The results of the albumin
turnover
studies and the
corresponding urinary nitrogen excretions are given in the table. Fig. 1 shows a significant correlation between albumin turnover-rate and total-nitrogen excretion in the urine (p < 0-001). There were certain striking differences between the findings in pancreatic steatorrhoea and intestinal lymphangiectasia. In the two cases of pancreatic steatorrhoea with hypoalbuminaemia (patients 3 and 5), the plasmaalbumin pool, fractional turnover-rate, albumin turnover6. 7. 8. 9. 10.
McFarlane, A. S. Nature, Lond. 1958, 182, 53. Pearson, J. D., Veall, N., Vetter, H. Strahlentherapie, 1958, 38, 290. Gordon, R. Lancet, 1959, i, 325. Hardwicke, J. Biochem. J. 1954, 57, 166. Reinhold, J. G., in Standard Methods in Clinical Chemistry (edited by M. Reiner); vol. 1, p. 88. New York, 1953.
THE INVESTIGATION
893 For these conclusions to be valid, conditions associated with impaired albumin synthesis (e.g., cirrhosis of the liver) and with an increase in metabolic rate must be excluded.
and nitrourinary gen excretion were all low, and the loss rate
I am deeply indebted to Prof. A. C. Frazer for allowing me to study these patients, and for facilities. Also to Prof. J. R. Squire and Dr. A. C. Crooke for permission to study patients 9 and 8 respectively. I am very grateful to Dr. J. W. L. Davies (M.R.C. Bums Unit) for labelling the albumin and to Mrs. J. Cope for measuring the radioactivity of the specimens from the earlier studies. The 13’I-P.V.P. was kindly supplied by Dr. R. Gordon, Bethesda. Part of this work was done during the tenure of a Medical Research Council fellowship in clinical research. Metabolic Unit, J. HENRY JONES Little Bromwich Hospital, M.B. Wales, M.R.C.P. Birmingham, 9
of 131I-p.v.p. into the gut was not
ab-
normal. In intestinal
lymphangiectasia (patients 1 and 2), the
plasma-albumin pool was 9Min low. but UUL 5’’’JUVYV,
Fig. I-The relation between albumin catabolism and urinary nitrogen excretion. -
the fractional turnover-rate, albumin turnover-rate, and ’"1-P.v.P. loss were all high, and the urinary nitrogen excretion normal or high. Thus malabsorption seems to have been the main factor in both these cases of pan- creatic steatorrhoea, whereas gastrointestinal loss with inadequate compensation was responsible for the low serum-albumin in intestinal lymphangiectasia. As shown in fig., 2, a high protein intake in patient 1 merely resulted in an increase in urinary nitrogen excretion, the serum-albumin remaining low. In contrast, patient 3 responded dramatically to treatment with pmcreatin B.P. and, as a result of improved absorption, both the serumalbumin and urinary nitrogen excretion became normal, whereas pre-
viously both had been low
despite
a
pro-
tein intake of 120 g. per day. (The vertical line in the
figure
repre-
total nitrogen excretion of 12.5 g..per day Fig. 2-Changes in serum-albumin concentration and urinary nitrogen excretion following in a 70 kg. man.) treatment. P.S.=pancreatic steatorrhoea. The results in !.L.= intestinal lymphangiectasia. patient 6 were also of some interest, because treatment with a glutenfree diet resulted in a rise in the serum-albumin without any increase in urinary nitrogen excretion, suggesting that the rise in serum-albumin was mainly due to a reduction in the amount of albumin leaking into the gut. The fall in albumin turnover-rate to a normal level with treatment (6b) supports this hypothesis. sents
a
urinary
SUMMARY AND -CONCLUSIONS
Evidence is presented which suggests that measurement of total-nitrogen excretion in the urine might be a useful screening test for protein loss into the intestine, when facilities for radioactive studies are not easily available. If, on a protein intake of 100 g. or more per day the urinary nitrogen excretion remains normal and the serum-albumin fails to reach normal levels, this is good presumptive evidence of gastrointestinal loss with
inadequate compensation.
Medical Societies OPHTHALMOLOGICAL SOCIETY OF THE UNITED KINGDOM
Society’s 82nd annual congress was held in London April 12-14, under the presidency of Mr. FRANK LAw. Therapy in Orthoptics Prof. K. CupPERS (Giessen) pointed out that visual acuity is THE
on
unrelated to the type of fixation in squint disorders. Dr. ALAN STANWORTH reviewed the factors having a favourable prognostic significance with regard to orthoptic treatment with additional surgery if necessary. Early surgery gave poor results with regard to attainment of single binocular vision, but he felt that the advantages tended to outweigh the disadvantages. He suggested that, in the routine examination of children up to the age of 3, special consideration should be given to the grade of binocular vision and type of fixation. Miss SHEILA MAYOU discussed the orthoptic aspects of a series of patients with heterophoria, and stressed the importance of occlusion in some of these patients irrespective of age, where monocular symptoms were present and the visual acuities in the two eyes were slightly different, even though no true amblyopia existed. She referred to the value of developing general well-regulated extraocular muscle tone and cooperation.
Amblyopia Dr. ALFREDO ARRUGA (Barcelona) read a paper indicating the value of occlusion of the amblyopic eye, with eccentric fixation, before pleoptic treatment aimed at the restoration of more normal fixation and improved central vision.
The Electro-oculogram Dr. G. B. ARDEN spoke about the clinical value of the electrooculogram (E.O.G.). This is an objective method of assessing ocular function, related to the state of metabolism, particularly of pigment epithelium. The most important provoking agent is change in retinal illumination. The test is particularly sensitive in lesions, both arterial and venous, of the choroidoretinal vascular system and can be used to assess progress. Increased Intraocular Pressure Dr. S. M. DRANCE described the results of experiments in the production of scotomata in glaucomatous eyes by artificially raising the intraocular pressure, using a suction dynamometer. The appearance of the scotoma was not related to the level of the diastolic pressure in the central retinal artery. His results suggested that it might be possible to identify eyes which were particularly sensitive to raised pressure before any other change in function was demonstrable.
Eye Banks Sir BENJAMIN RYCROFT made a plea for the establishment of a few national eye banks up and down the country as part of a national effort in combating corneal disease.
When related to human atherosclerosis, these observations support our tentative hypothesis that enzyme defects in the ageing anoxic media restrict the outward migration of cholesterol from the intima into the media, leading to its accumulation in the inner part of the arterial wall. This work was in part supported by U.S. Public Health Service grant no. H6483 of the National Heart Institute.
C. W. M. ADAMS M.A.,
M.D.
Cantab.
Lecturer
O. B. BAYLISS
PATIENTS
Albumin turnover was studied on 15 occasions in 13 patients, of whom 11 had steatorrhoea. The patients were studied on a metabolic ward; they were weighed daily, and twenty-fourhour urine and stool collections were made throughout. The dietary intake of protein was not standardised but all were taking more than 70 g. of protein per day, except patients 4 and 8 who had anorexia. The calorie content of the diet was sufficient to produce a maximum protein-sparing effect, and an assessment of total body fat, by measurement of skinfold thickness, indicated some reserve of fat in all cases. The total body fat was, however, very low in patients 2, 6(a), 7, 8, and 11.
A.I.M.L.T.
Technician
Department of Pathology, Guy’s Hospital Medical School, London, S.E.1
METHODS
M. Z. IBRAHIM M.B. Cairo Postgraduate Student
PROTEIN-LOSING ENTEROPATHY THE VALUE OF URINARY NITROGEN ESTIMATIONS IN DIAGNOSIS
IT is now well established that loss of plasma albumin into the gut may be an important cause of hypoalbuminsemia in some cases of the steatorrhoea syndrome, and the various methods of demonstrating this loss have recently been reviewed.1-3 Crane and Neuberger4 have studied extensively the absorption of 15N-labelled proteins and the elimination of the isotope in stools and urine, but little has been published about the value of urinary totalnitrogen estimations in the diagnosis of gastrointestinal
protein loss. If hypoalbuminsemia in the steatorrhoea syndrome is predominantly due to inadequate absorption of the raw materials necessary for albumin synthesis, one might expect nitrogen excretion in the urine to be low, even on a high-protein diet. If, however, hypoalbuminaemia is due to gastrointestinal loss of protein, the urinary nitrogen could well be normal, since the limiting factor would be the ability of the liver to compensate by increasing albumin synthesis. Davies et al. have demonstrated a close correlation between albumin metabolism and urinary total-nitrogen excretion in burns, trauma, and cirrhosis. My object here is to show that this correlation also occurs in steatorrhoea and that useful information may be obtained from estimating the urinary nitrogen excretion in this syndrome. 1. Lancet, 1961, ii, 299. 2. Jeejeebhoy, K. N. ibid. 1962, i, 343. 3. Waldmann, T. A., Steinfeld, J. L., Dutcher, T. F., Davidson, J. Gordon, R. Gastroenterology, 1961, 41, 197. 4. Crane, C. W., Neuberger, A. Brit. med. J. 1960, ii, 815, 888. 5. Davies, J. W. L., Ricketts, C. R., Bull, J. P. Lancet, 1959, i, 346.
D.,
Human serum-albumin (Lister Institute) was labelled to a specific activity of not more than 5 fLC per mg. of protein, and with (on average) less than one atom of iodide per protein molecule. A modification of the method of McFarlane 6 was used. 20-50 fLC of 13’I-labelled human albumin was injected intravenously and radioactivity in samples of plasma, twentyfour-hour urine, and stools measured, using a well-type scintillation counter. The results were calculated as described by Pearson et al.,’ and expressed in terms of plasma-albumin pool (serum-albumin concentration x plasma volume), urine/ plasma (u/p) ratio of radioactivity (averaged over several days, omitting the day of injection), and albumin turnover in mg. per kg. body-weight per day. The u/p ratio was taken to indicate the fractional turnover-rate. Some of the patients were also given 131I-labelled polyvinyl pyrrolidone (P.v.p.) using the method described by Gordon.Thyroid uptake was blocked by giving potassium iodide 75 mg. daily. Plasma-albumin concentrations for the albumin turnover studies were estimated from paper electrophoresis,9 but the albumin concentrations represented in fig. 2 were estimated by the sulphate-sulphite precipitation method.10 Nitrogen excretion in the urine was estimated by the micro-Kjeldahl method. RESULTS
The results of the albumin
turnover
studies and the
corresponding urinary nitrogen excretions are given in the table. Fig. 1 shows a significant correlation between albumin turnover-rate and total-nitrogen excretion in the urine (p < 0-001). There were certain striking differences between the findings in pancreatic steatorrhoea and intestinal lymphangiectasia. In the two cases of pancreatic steatorrhoea with hypoalbuminaemia (patients 3 and 5), the plasmaalbumin pool, fractional turnover-rate, albumin turnover6. 7. 8. 9. 10.
McFarlane, A. S. Nature, Lond. 1958, 182, 53. Pearson, J. D., Veall, N., Vetter, H. Strahlentherapie, 1958, 38, 290. Gordon, R. Lancet, 1959, i, 325. Hardwicke, J. Biochem. J. 1954, 57, 166. Reinhold, J. G., in Standard Methods in Clinical Chemistry (edited by M. Reiner); vol. 1, p. 88. New York, 1953.
THE INVESTIGATION
893 For these conclusions to be valid, conditions associated with impaired albumin synthesis (e.g., cirrhosis of the liver) and with an increase in metabolic rate must be excluded.
and nitrourinary gen excretion were all low, and the loss rate
I am deeply indebted to Prof. A. C. Frazer for allowing me to study these patients, and for facilities. Also to Prof. J. R. Squire and Dr. A. C. Crooke for permission to study patients 9 and 8 respectively. I am very grateful to Dr. J. W. L. Davies (M.R.C. Bums Unit) for labelling the albumin and to Mrs. J. Cope for measuring the radioactivity of the specimens from the earlier studies. The 13’I-P.V.P. was kindly supplied by Dr. R. Gordon, Bethesda. Part of this work was done during the tenure of a Medical Research Council fellowship in clinical research. Metabolic Unit, J. HENRY JONES Little Bromwich Hospital, M.B. Wales, M.R.C.P. Birmingham, 9
of 131I-p.v.p. into the gut was not
ab-
normal. In intestinal
lymphangiectasia (patients 1 and 2), the
plasma-albumin pool was 9Min low. but UUL 5’’’JUVYV,
Fig. I-The relation between albumin catabolism and urinary nitrogen excretion. -
the fractional turnover-rate, albumin turnover-rate, and ’"1-P.v.P. loss were all high, and the urinary nitrogen excretion normal or high. Thus malabsorption seems to have been the main factor in both these cases of pan- creatic steatorrhoea, whereas gastrointestinal loss with inadequate compensation was responsible for the low serum-albumin in intestinal lymphangiectasia. As shown in fig., 2, a high protein intake in patient 1 merely resulted in an increase in urinary nitrogen excretion, the serum-albumin remaining low. In contrast, patient 3 responded dramatically to treatment with pmcreatin B.P. and, as a result of improved absorption, both the serumalbumin and urinary nitrogen excretion became normal, whereas pre-
viously both had been low
despite
a
pro-
tein intake of 120 g. per day. (The vertical line in the
figure
repre-
total nitrogen excretion of 12.5 g..per day Fig. 2-Changes in serum-albumin concentration and urinary nitrogen excretion following in a 70 kg. man.) treatment. P.S.=pancreatic steatorrhoea. The results in !.L.= intestinal lymphangiectasia. patient 6 were also of some interest, because treatment with a glutenfree diet resulted in a rise in the serum-albumin without any increase in urinary nitrogen excretion, suggesting that the rise in serum-albumin was mainly due to a reduction in the amount of albumin leaking into the gut. The fall in albumin turnover-rate to a normal level with treatment (6b) supports this hypothesis. sents
a
urinary
SUMMARY AND -CONCLUSIONS
Evidence is presented which suggests that measurement of total-nitrogen excretion in the urine might be a useful screening test for protein loss into the intestine, when facilities for radioactive studies are not easily available. If, on a protein intake of 100 g. or more per day the urinary nitrogen excretion remains normal and the serum-albumin fails to reach normal levels, this is good presumptive evidence of gastrointestinal loss with
inadequate compensation.
Medical Societies OPHTHALMOLOGICAL SOCIETY OF THE UNITED KINGDOM
Society’s 82nd annual congress was held in London April 12-14, under the presidency of Mr. FRANK LAw. Therapy in Orthoptics Prof. K. CupPERS (Giessen) pointed out that visual acuity is THE
on
unrelated to the type of fixation in squint disorders. Dr. ALAN STANWORTH reviewed the factors having a favourable prognostic significance with regard to orthoptic treatment with additional surgery if necessary. Early surgery gave poor results with regard to attainment of single binocular vision, but he felt that the advantages tended to outweigh the disadvantages. He suggested that, in the routine examination of children up to the age of 3, special consideration should be given to the grade of binocular vision and type of fixation. Miss SHEILA MAYOU discussed the orthoptic aspects of a series of patients with heterophoria, and stressed the importance of occlusion in some of these patients irrespective of age, where monocular symptoms were present and the visual acuities in the two eyes were slightly different, even though no true amblyopia existed. She referred to the value of developing general well-regulated extraocular muscle tone and cooperation.
Amblyopia Dr. ALFREDO ARRUGA (Barcelona) read a paper indicating the value of occlusion of the amblyopic eye, with eccentric fixation, before pleoptic treatment aimed at the restoration of more normal fixation and improved central vision.
The Electro-oculogram Dr. G. B. ARDEN spoke about the clinical value of the electrooculogram (E.O.G.). This is an objective method of assessing ocular function, related to the state of metabolism, particularly of pigment epithelium. The most important provoking agent is change in retinal illumination. The test is particularly sensitive in lesions, both arterial and venous, of the choroidoretinal vascular system and can be used to assess progress. Increased Intraocular Pressure Dr. S. M. DRANCE described the results of experiments in the production of scotomata in glaucomatous eyes by artificially raising the intraocular pressure, using a suction dynamometer. The appearance of the scotoma was not related to the level of the diastolic pressure in the central retinal artery. His results suggested that it might be possible to identify eyes which were particularly sensitive to raised pressure before any other change in function was demonstrable.
Eye Banks Sir BENJAMIN RYCROFT made a plea for the establishment of a few national eye banks up and down the country as part of a national effort in combating corneal disease.