THE CAUSATION OF THE LOW BLOOD-SUGAR CURVE IN COELIAC DISEASE 1

Transcription

1 : THE CAUSATION OF THE LOW BLOOD-SUGAR CURVE IN COELIAC DISEASE 1 BY THEODORE CRAWFORD (From the Department of Paediatrics, University of Glasgow, and the Bioohemical Laboratory, Royal Hospital for Sick Children, Glasgow) Introduction CONVINCING evidence has been brought forward by Thaysen (1929 b, 12, 15) that tropical and non-tropical sprue in adults and coeliac disease in children are essentially identical conditions, and he has grouped the three together as subdivisions of ' idiopathic steatorrhoea', a syndrome which has also been referred to as ' Gee-Thaysen disease'. In 1926 Thaysen first drew attention to the abnormally small rise in the blood-sugar content following the ingestion of glucose in cases of non-tropical sprue. In subsequent papers (Thaysen, 1929 a, 12, 15; Thaysen and Norgaard, 1929) he extended this observation and defined the low blood-sugar curve as one showing a rise of 40 mg. per 100 c.c. or less during two hours following the ingestion of 60 gm. of glucose in adults. He showed such a curve to occur as an inconstant phenomenon in 5 per cent, of normal subjects, while in nontropical sprue it occurred fairly constantly in 50 per cent, of the cases. Thaysen's findings in non-tropical sprue have been confirmed by many later observers (Hoist, 1927 ; Engel, 11 ; Bennett, Hunter, and Vaughan, 12 ; Thorfinn, 13 ; Anderson and Lyall, 13 ; Moore, O'Farrell, Geraghty, Hayden, and Moriarty, 16 ; Mogensen, 17; Nussbrecher and Morton, 17). A similar low blood-sugar curve in children suffering from coeliac disease was demonstrated independently by Fanconi (1928), Svensgaard (1929), and MacLean and Sullivan (1929), and their findings have been frequently confirmed (Thaysen, 1929 b; MacRae and Morris, 11 ; Badenoch and Morris, 16). The low curve appears to be a more constant feature of coeliac disease than of sprue. The present paper is concerned with the cause of the low blood-sugar curve in coeliac disease. Accepting Thaysen's contention that sprue and coeliac disease are essentially the same condition, deductions from biochemical changes found in one should be applicable to the other. The origin of the low blood-sugar curve in these conditions has been the subject of considerable experiment and discussion. The possible causes of such a curve are : 1. Lowered renal threshold to glucose. 1 Received April 25, 19.

2 252 QUARTERLY JOURNAL OF MEDICINE 2. Diminished or delayed absorption of sugar from the bowel. 3. Increased rate of utilization or storage of glucose in the tissues following absorption. MacLean and Sullivan (1929) investigated the possibility of a lowered renal threshold to glucose and showed that glycosuria was not a feature of the patients showing the low blood-sugar curve; its occurrence in one of their ] 4 cases must be regarded as a coincidence. Their observations have been abundantly verified by subsequent observers (Svensgaard, 11; MacRae and Morris, 11 ; Badenoch and Morris, 16). The low curve must, therefore, be caused either by faulty absorption or by an abnormality of the intermediary carbohydrate metabolism. In view of the generally accepted fact that there is defective fat absorption in idiopathic steatorrhoea, a similar abnormality of carbohydrate absorption seems the likely explanation of the low blood-sugar curve, and this view has been supported by the observations of MacRae and Morris (11), Badenoch and Morris (16), Fairley (16), Ross (16), and Nussbrecher and Morton (17). The opposing view, however, that an abnormality of the intermediary carbohydrate metabolism is present, was put forward by Thaysen (1929 a, 12, 15) and has received support from Mogensen (17). As abnormalities in the blood-sugar curve after oral administration of glucose may be caused either by defective absorption from the bowel or by disturbance of intermediary metabolism, the most direct evidence of the latter should be afforded by a study of the response to intravenously injected glucose; for, by this procedure, variations caused by alterations in the rate of absorption of glucose from the bowel are excluded. Rapid removal of injected glucose from the blood indicates increased rate of storage, utilization, or excretion; conversely, slow disappearance of the excess sugar from the blood gives evidence of defective storage power, or of a diminished rate of utilization or excretion. Thaysen (1929 o) and Mogensen (17) found a rapidly falling blood-sugar curve following intravenous injection of glucose, indicating increased glucose tolerance, whereas Fairley (16) and Ross (16) found high, slowly falling curves indicative of impaired glucose tolerance. Previous work on this question having yielded such discordant results, the present investigation was undertaken in an attempt to arrive at some definite decision. The Intravenous Curve in Normal Subjects Owing to the wide variations in the response to the intravenous injection of glucose found in normal subjects by different workers, variations probably due to difference in technique, the investigations on coeliac disease were preceded by a detailed examination of the response of healthy children and adults to the intravenous injection of glucose. This work has already been published (Crawford, 18) and the relevant features are briefly summarized here:

3 THE LOW BLOOD-SUGAR CURVE LN COELIAC DISEASE 253 A test dose of 0-5 gm. of glucose per kg. body-weight, as a 20 per cent, solution in normal saline, is injected intravenously following an eight-hour fast. Capillary blood is removed for sugar estimation prior to the injection, two minutes after its completion, and at fifteen-minute intervals until ninety minutes after the injection. Tolerance is gauged by noting the time after the injection at which the blood contains a sugar concentration of 100 mg. TABLE I Intravenous Glucose Tolerance Tests in Normal Subjects. Age group. 0 to 2 years 2 to 4 4 to 10 Over 10.. Time of fall of blood-sugar to 100 mg. per 100 c.c. 30 to 45 minutes 45 to to 60 to per 100 c.c. or lessthe upper limit of normal fasting blood-sugar values with the technique employed. The time at which this occurs was shown to be constant for the individual under standard conditions and to vary within definite limits among normal subjects. It was shown that, with normal intermediary mechanism the blood-sugar reached a level of 100 mg. per 100 c.c. at thirty, forty-five, sixty, or seventy-five minutes after the injection according to the age of the subject (Table I). The amount of sugar excreted in the urine after the injection varied from 3 to 9 per cent, of the injected glucose. Ross (18) has recently criticized the value of this series of normal curves on the grounds that the subjects were ' convalescents'. The great majority, however, were many weeks recovered from ailments unassociated with disturbance of carbohydrate metabolism; the remainder were healthy, active subjects. As the curves from the ' healthy' and the ' convalescent' subjects were similar in all respects, it seems probable that the series as a whole may be regarded as normal. The Intravenous Curve in Coeliac Disease Twelve well-established cases of coeliao disease have been investigated. All but one (Case 10) showed a rise of less than 40 mg. per 100 c.c. in the blood-sugar level following the ingestion of 2 gm. glucose per kg. of bodyweight. The remaining case showed the alternative ' low-level' curve described by Thaysen (1929 a, 12), the blood-sugar rising from the low fasting level of 56 mg. per 100 c.c. to a maximum height of 106 mg. per 100 c.c. at one hour. The results of the oral glucose tolerance tests are given in Table II. Using the technique described above, intravenous glucose tolerance tests were carried out during an active period of the disease in all 12 cases; in five cases the test was repeated during a quiescent phase. The results of these tests are detailed in Table III. In every instance, during both active and quiescent phases, the time of fall' of the blood-sugar to normal fasting levels was within the normal limits defined in Table I.

4 254 QUARTERLY JOURNAL OF MEDICINE Sugar excretion in the urine was also within normal limits in each of the seven cases in which it was estimated. In Table IV the cases are subdivided into age groups and compared with the averagefindingsfrom normal subjects ase TABLE II Blood-sugar Curves after Oral Glucose (2 gm. per kg. of body-ioeigm) in 12 Cases of Coeliac Disease. Fasting Blood-sugar in mg. per 100 c.c. 30 rain min Maximum rise of blood-sugar mg. per 100 c.c g> o 1 2 3/ /12 1 6/ TABLE III Intravenous Glucose Tolerance Tests in 12 Ca^es of Coeliac Disease..9.9 IS / Pn a IM Blood-augar in mg. per 100 c.c..a a 1O II a o CO a / / / / a a a o CD a 5 V 11 w.2 M. %> I! Quiescent Quiescent Quiescent Quiescent Quiescent of the same age, the average age of coeliac patients and normal subjects in each age group being the same. It will be seen that the times at whioh normal fasting levels are regained are the same in patients and controls, and the slight differences found between the average curves from the coeliao

5 THE LOW BLOOD-SUGAR CURVE IN COELIAC DISEASE 256 patients and the corresponding figures from normal subjects cannot be regarded as significant; the tendency to lower levels in the coeliao curves no doubt reflects the low fasting blood-sugar values found in many of these cases. Fig. 1 shows composite curves constructed from the results of tests carried out during active and quiescent phases of the disease in Cases 1 to 5. Here again there is no significant difference. Time of Specimen. Fasting TABLE IV Mean Figures from Intravenous Glucose Tolerance Tests in Coeliac Disease and Normal Children, Divided in Age Groups. 5 Coeliacs. 100 c.c to 2 years. 2 to 4 years. 4 to 9 years. 6 Normals. 100 c.c Coeliacs. 100 c.c Normals. 100 o.c Coeliacs. 100 c.c Normals. 100 c.c FIG IB Time in minutes - Quiescent Phase 1 Phase Mean intravenous curves during active and quiescent phases in five cases of coeliac disease Discussion From these results it does not appear that there is any abnormality in the intermediary metabolism of carbohydrate in coeliac disease. In view of this, and as all the evidence points to there being no abnormality in the renal threshold, the remaining hypothesis, namely, defective absorption from the bowel, seems to be the most likely explanation of the low blood-sugar curve. Ross (16) has reached a similar conclusion based upon very different experimental findings. Using a different technique from that employed in

6 256 QUARTERLY JOURNAL OF MEDICINE the present investigation he found a high, slowly falling curve after the intravenous injection of glucose in cases of coeliac disease. He argued that this impairment of carbohydrate tolerance was the result of carbohydrate starvation, a condition shown by Himsworth (13, 15) to produce an impairment of tolerance as gauged by the oral test. Thus, in spite of the presence of carbohydrate in the diet, the patients showed a curve characteristic Minutes after injection On ordinary diet After 2 weeks on low carbohydrate diet *»»««_-_ yi j n n n v fi FIG. 2. Intravenous glucose tolerance tests in a healthy child aged 8 years, on ordinary diet and on a low carbohydrate diet for three weeks of carbohydrate starvation, and from this Ross concluded that carbohydrate was not being absorbed. It seems probable, however, that carbohydrate deprivation in coeliac disease is rarely severe, for ketonuria is seldom seen ; none of the cases in the present series gave a positive Rothera's test at the time when the low oral blood-sugar curve was obtained. It is known that if carbohydrate deprivation is persisted in over a prolonged period the ketonuria diminishes, but it does not disappear completely unless the deprivation is of quite a mild degree. In our experience even severe carbohydrate starvation does not interfere with the tolerance to injected glucose. This is illustrated by the experiment recorded in Fig. 2 which shows curves obtained from a healthy child kept for three weeks on a diet severely restricted in carbohydrate. Though gross ketonuria persisted throughout this period, no impairment of glucose tolerance, as gauged by the intravenous test, occurred. Closely comparable results have been obtained from four other subjects. Thaysen (1929 a, 12) demonstrated in patients with idiopathic steatorrhoea that the respiratory quotient, following ingestion of carbohydrate, rose to levels which indicated that considerable quantities of sugar were being metabolized, and he also showed that these patients yielded a higher respiratory quotient when given a high carbohydrate diet than when on

7 THE LOW BLOOD-SUGAR CURVE IN COELIAC DISEASE 257 ordinary diet. Thaysen regarded these results as indicating that there was no interference with carbohydrate absorption, but, as MaoRae and Morris (11) have pointed out, these results merely show that there was not an absolute failure of carbohydrate absorption; they do not exclude the possibility of delayed or inefficient absorption. Indeed the striking point which Thaysen's experiments show is that there is no failure on the part of the Minutes after injection gm, glucose per kg. actual body weight. 0-5 gm. glucose per kg. body weight of a healthy child or 9 years FIG. 3. Effect of increased dosage of glucose on intravenous glucose tolerance test in a oase of coeliac disease, aged 9 years and weighing 16-2 kg. tissues in coeliac disease to oxidize carbohydrate. This, taken in conjunction with the fact that ketosis is not a feature of coeliac disease, and with the experimental findings recorded in Fig. 2, suggests that it is improbable that there is sufficient deprivation of carbohydrate in coeliac disease to cause intolerance to intravenous glucose. There can be little doubt that the discrepancies between the results obtained by Ross and those arrived at in the present investigation depend on differences in the technique employed in carrying out the intravenous glucose tolerance tests. The essential difference lies in the dosage of glucose. In the present series a dose of 0-5 gm. of glucose per kg. of body-weight has been used, whereas Ross employed a standard dose of 10 gm. of glucose both for normal and coeliac cases, irrespective of body-weight. He does not report the weights of his coeliac patients, but as these children are usually from 30 to 50 per cent, below the weight of healthy children of the same age, it is evident that his patients received, relative to body-weight, a much larger dose of glucose

8 258 QUARTERLY JOURNAL OF MEDICINE than did his normal subjects. The results of the administration of such increased dosage of glucose to a child with coeliac disease are shown in Fig. 3. In this case, when a dose appropriate to a normal child of the same age was given, the time of fall to a normal fasting blood-sugar level was increased. This curve closely resembles many of those given by Ross (16). It seems evident that the ' impaired tolerance' which Ross reports in his coeliac patients is in fact the result of a relatively greater dosage of glucose as compared with normal subjects. The same explanation is applicable to similar findings reported by Fairley (16) in cases of tropical sprue. Thaysen (1929 a, 12), in contrast to Ross, observed an increased tolerance to intravenous glucose in three out of six cases of idiopathic steatorrhoea which he investigated, using the technique devised by Jorgensen and Plum (Jorgensen and Plum, 1922; Jorgensen, 1926). The remaining cases gave normal results. The reason for the difference between Thaysen's results and those of the present investigation is not evident; it is noteworthy, however, that Thaysen examined no normal series of his own, but compared his results with the normal series reported by Jorgensen. While differences of technique prevent direct comparison with the normal curves in this study, Jorgensen's normal curves appear to he within narrower limits than experience here has indicated. The Response to Insulin in Coeliac Disease The reaction of the blood-sugar level to insulin injections has been used as a test of the normality of the carbohydrate metabolism of patients with coeliac disease. Badenoch and Morris (16), using a subcutaneous injection of 4 units, obtained a fall in the blood-sugar level greater than they found in normal subjects of the same age, and they suggest that in coeliac disease there is a deficiency of some contra-insular hormone. On the other hand, Ross (16), using an intravenous injection of 4 units of crystalline insulin, found a smaller depression of the blood-sugar level in coeliac than in normal children. A similar curve to that found in coeliac disease was obtained from normal children when the test was performed after a period on a low carbohydrate diet. Ross interpreted his findings as indicating again that the patient with coeliac disease was, in respect of carbohydrate, in the same condition as a normal subject starved of carbohydrate. Carbohydrate, while present in the diet, was not being absorbed. The effect of intravenously injected crystalline insulin on the blood-sugar level has been studied in six of the cases of coeliac disease in the present series, and has been compared with the results from six normal children. A dosage of one-third of a unit of insulin per kg. of body-weight was employed, and the bloodsugar was estimated before the injection and at ten-minute intervals thereafter for one hour. The results of these insulin sensitivity tests are detailed in Table V. They show that the time and extent of the maximum response to insulin

9 THE LOW BLOOD-SUGAR CURVE IN COELIAC DISEASE 259 vary considerably amongst the normal subjects, and that a similar variability occurs amongst the coeliac cases. From the figures it seems clear that there is no significant difference between the two groups in their response to insulin. The normality of the insulin sensitivity tests in the present series of cases of coeliao disease provides further corroborative evidence that in coeliac disease there is no disturbance of the intermediate carbohydrate metabolism. TABLE V Insulin Sensitivity Tests in Normal Subjects and in Cases of Coeliac Disease. (1/3 unit insulin per kg. body-weight intravenously.) Blood-sugar mg. per 100 c.c. Time. Normal subjects. Cases of coeliac disease Mean Mean. Fasting minutes Summary 1. The intravenous glucose tolerance test has been carried out on 12 cases of coeliac disease, 11 of whom showed a typical low oral blood-sugar curve. No significant difference was found between the curves from the coeliac patients and curves from normal subjects; and in five of the patients no difference was observed between curves obtained during active and latent phases of the disease. 2. Insulin sensitivity tests on six of the patients gave results closely similar to those obtained from six normal subjects. 3. From these results it is concluded that there is no abnormality of intermediate carbohydrate metabolism in patients with coeliac disease ; and, by exclusion, it seems certain that the low blood-sugar curve of coeliac disease must be due to delayed or defective absorption of carbohydrate from the bowel. This conclusion is presumably applicable to other forms of idiopathic steatorrhoea as well as to coeliac disease. I have pleasure in expressing my indebtedness to Professor G. B. Fleming for his valuable criticism and advice, and to the clinical and biochemical staffs at the Hospital for the assistance which they have given. Part of the expenses of this work were defrayed by a grant from the Medical Research Council.

10 260 QUARTERLY JOURNAL OF MEDICINE REFERENCES Anderson, A. G., and Lyall, A., Quart. Journ. Med., Oxford, 13, N.S. ii Badenoch, E., and Morris, N., ibid., Oxford, 16, N.S. v Bennett, I., Hunter, D., and Vaughan, J. M., ibid., Oxford, 12, N.S. i Crawford, T., Arch. Dis. Childh., Lond., 18, xiii. 69. Engel, A., Ada Med. Scand., Stockholm, 11, lxxv Fairley, N. H., Trans. Roy. Soc. Trop. Med. Hyg., Lond., 16-7, xxx. 9. Fanconi, G., Abhandl. a. d. Kinderh., Berl., 1928, xxi. 1. Hoist, J. E., Ada Med. Scand., Stockholm, 1927, lxvi.. Himsworth, H. P., Clinical Science, Lond., 13-4, i. 1. Himsworth, H. P., ibid., Lond., 15-6, ii. 67. JOrgensen, S., Ada Med. Scand., Stockholm, , lxv J6rgensen, S., and Plum, T., ibid., Stockhobn, 1923, lviii Macrae, 0., and Morris, N., Arch. Dis. Childh., Lond., 11, vi.. MacLean, A. B., and Sullivan, R. C, Amer. Journ. Dis. Child., Chicago, 1929, xxxviii. 16. Mogensen, E., Quart. Journ. Med., Oxford, 17, N. 8. vi Moore, H., O'Farrell, W. R., Geraghty, J. A., Hayden, J. M., and Moriarty, M. A., ibid., Oxford, 16, N. S. v. 4. Nussbrecher, A. M., and Morton, F., Brit. Med. Journ., Lond., 17, i Ross, C. W., Trans. Boy. Soc. Trop. Med. Hyg., Lond., 16-7, xxx. 33. Ross, C. W., Arch. Dis. Childh., Lond., 18, xiii Svensgaard, E., Ada Paedriatica, Stockholm, 1929, ix. 22. Svensgaard, E., ibid., Stockholm, 11, xii. Suppl. 4. Thaysen, T. E. H., Ada Med. Scand., Stockholm, 1926, briv Thaysen, T. E. H., Arch. Int. Med., Chicago, 1929 a, xliv. 4. Thaysen, T. E. H., Lancet, Lond., , i. 10. Thaysen, T. E. H., Non-tropical Sprue: A Study in Idiopathic Steatorrhoea, Lond., 12. Thaysen, T. E. H., Quart. Journ. Med., Oxford, 15, N. S. iv Thaysen, T. E. H., and Norgaard, A., Arch. Int. Med., Chicago, 1929, xliv. 17. Thorfinn, E., Ada Med. Scand., Stockholm, 13, lxxx. 389.