1345 T.R.H.

response

at

higher dosage and/or potentiation

with, for example, levodopa, amphetamine, University Psychiatric Clinic, Basle, Wilhelm Kleinstrasse 27, CH-4025 Basle, Switzerland.

or

ludiomil.

W. PÜHRINGER A. WIRZ-JUSTICE G. HOLE.

DIETARY BRAN, GUM, AND BLOOD CHOLESTEROL: A ROLE FOR HYDROXYCITRATE ?

SIR,-Dr Jenkins and his colleagues (May 17, p. 1116) have shown that the ingestion of guar gum or of pectin, but not of bran, is effective in lowering plasma-cholesterol. I wish to suggest that this effect could be mediated by (-)-hydroxycitrate. This citrate analogue has been clearly shown to inhibit competitively extramitochondrial citrate cleavage enzyme (A.T.P.: citrate lyase E.C. 4-1-3-8) in the liver both in vitroand in vivo.2 Such competition decreases the rate of triglyceride and cholesterol synthesis from carbohydrate.3 (-)-Hydroxycitrate is found in large quantities in the Indian fruit Garsinia cambogia, which is extensively used for culinary purposes over the west coast of South India, and the widespread occurrence of hydroxycitric acid in nature has been predicted.44 If this citrate analogue is present in guar gum (obtained from the seeds of Cyanopsis tetragonaloba, another Indian fruit) and also in pectin, then a ready explanation for the hypocholesterolaemic effect of these gels is available. Bran would not be expected to contain (-)-hydroxycitrate, the postulated active pharmacological agent, and was shown by Jenkins et al. to be ineffective in this respect. Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU.

C. A. R. BOYD.

SMALL-INTESTINAL HISTOLOGY IN CŒLIAC DISEASE

SiR,—Light and electron microscopic changes of the small-intestinal mucosa have been described in adults with coeliac disease, after the demonstration of the toxicity of certain fractions of wheat gluten. The degree of mucosal damage in these patients seemed to be related to the dose of The following case-report the toxic gluten fraction. illustrates the relevance of this finding to the diagnosis of coeliac disease in childhood. The patient, a 15-month-old boy, was admitted to hospital with a history of vomiting since birth, nocturnal restlessness, and excessive rocking. He was initially fed with cow’s milk formula, cereals were introduced into the diet at 2 months of age, and by 9 months he was fully weaned on to solids. At birth he weighed 3-7 kg., at 6 months 9 kg. (75th percentile), at 9 months 10-2 kg. (50th percentile), and on admission to hospital 9-1 kg. (3rd percentile). A history of abnormal stools was not obtained and the fasces were normal both macroscopically and microscopically. On admission his abdomen was not distended but there was pronounced muscular hypotonia and wasting of the buttocks. A diagnosis of coeliac disease was considered likely and 3-day faecal fat estimation was performed. The result averaged 8-1 mmol per 24 hours (normal < 18 mmol per 24 hours) on a diet of 50 g. of fat a day. A peroral intestinal biopsy specimen was obtained from the fourth part of the duodenum under fluoroscopic control using a Crosby capsule and examined under light micro The villi appeared normal (fig. 1) and morphimetric scopy. analyses of the biopsy were also within normal range for the 1. Watson, J. A., Fang, M., Lowenstein, J. M. Archs Biochem. Biophys. 1969, 135, 209. 2. Lowenstein, J. M. J. biol. Chem. 1971, 246, 629. 3. Srere, P. A. Curr. Topics Cell. Regulation, 1972, 5, 229. 4. Lewis, Y. S., Neelakantan, S. Phytochemistry, 1965, 4, 619. 5. Dissanayake, A. S., Jerrome, D. W., Offord, R. E., Truelove, S. C., Whitehead, R. Gut, 1974, 15, 931.

Fig. 1-Appearance under light microscopy of first smallintestinal biopsy specimen. Reduced to two-thirds from x 75.

patient’s age-group. The surface to volume ratio6 was 70 (normal children =74-4),’ intraepithelial lymphocyte-count8 was 33 per mm. length of surface epithelium (mean normal count in jejunal biopsies=42). The 8-hour urinary9 hydroxyindoleacetic acid (5-H.I.A.A.) (µg.) creatinine (mg.) ratio was 14 (normal value for age < 6).9 Since diagnostic histological features of cceliac disease were absent, a challenge with pure gluten (Energen) was administered. The gluten powder was mixed with feeds and 10 g. given 3 times a day. Before this challenge his diet contained an estimated 6 g. of gluten a day. After the gluten challenge the stools became loose, offensive, and more frequent, and he lost 467 g. in a week. A change in affect

was also noted and he became more miserable. 1 week later a second peroral small-intestinal biopsy specimen was obtained under fluoroscopic control from the same part of the duodenum and was examined by light microscopy. Some of the villi were now blunt and there was increased cellular infiltration of the lamina propria (fig. 2). These changes were reflected in the

6. 7. 8. 9.

Dunnill, M. S., Whitehead, R. J. clin. Path. 1972, 25, 243. Risdon, R. A., Keiling, J. W. Gut, 1974, 15, 9. Holmes, G. K. T., Asquith, P., Stokes, P. L., Cooke, W. T. ibid. p. 278. Challacombe, D. N., Goodall, M., Gaze, H., Brown, G. A. Archs Dis. Childh. (in the press).

Fig. 2-Appearance under light microscopy of second smallintestinal biopsy specimen after gluten challenge. Reduced to two-thirds from x 75.

1346

morphimetric analyses. The surface to volume ratio had fallen to 33 and the intraepithelial lymphocyte-count had risen to 54 per mm. length of surface epithelium. The 8-hour 5-H.i.A.A. ([1.g.)( creatinine (mg.) ratio had also risen to 17. After biopsy a glutenfree diet

was begun and within 10 days there was a pronounced improvement in the child’s mood, his rocking had diminished, and his weight had increased by 1-2 kg. Since discharge from hospital he has continued to thrive on a gluten-free diet.

the vagaries of aminoacid analyser systems then in use or by decomposition during older methods of chromatography. In any event we report our results lest other workers may have difficulty in trying to repeat Edozien and Modie’s work

using

logical findings

are

equivocal.

Children’s Research Unit, Musgrove Park Branch, Taunton and Somerset Hospital, Taunton, Somerset TA1 5DA.

D. N. CHALLACOMBE P. D. DAWKINS JUDITH M. BAYLIS K. ROBERTSON.

equipment.

Vancouver 8, British Columbia, Canada.

Possibly the characteristic mucosal changes

in the upper small intestine of children with coeliac disease are patchy and not uniform. Small-intestinal biopsies from more than one site in our patient, before the gluten challenge, may have revealed histological changes compatible with a diagnosis of coeliac disease. However, the increased dose of gluten seemed to be important in exacerbating the gastrointestinal signs and histological changes in the second biopsy specimen. This case demonstrates that coeliac disease may be found in association with a histologically normal small-intestinal biopsy if tissue is sampled from only one site. In addition, it also illustrates the importance of ensuring that adequate amounts of gluten are present in the diet of patients in whom coeliac disease is suspected before the small-intestinal biopsy is performed, since the morphological response of the small-intestinal mucosa to gluten may be dose dependent. Although gluten challenge should not be undertaken lightly, particularly in severely malnourished children in whom it may precipitate diarrhoea and dehydration, its use is important in confirming the clinical diagnosis of coeliac disease when the initial histo-

modern

Biochemical Diseases Laboratory, Children’s Hospital,

D. A. APPLEGARTH S. POON.

SECOND MALIGNANCIES IN TREATED HODGKIN’S PATIENTS AND SPLENECTOMY

SIR,—Dr Canellos and his colleagues (April 26, p. 947) the National Cancer Institute reported 16 second malignancies among 452 patients with treated Hodgkin’s disease. The highest risk was noted among 31 patients

at

initially presenting with localised disease who were treated by intensive radiation (I.R.) and, after a mean disease-free interval of 22 months, by intensive chemotherapy (i.c.). This group was followed for 171 man-years, and 5 malignancies occurred (leuksemia in 1); the observed (o)-toexpected (E) ratio of second malignancies was 18-4. In another group 31 initially stage-III B patients were treated by I.C. and, after an average 7 months of remission, by I.R. This group was followed for 94 man-years, and 1 patient developed leuksemia. The o/E ratio of second malignancies was 6-3. How frequently staging laparotomy with splenectomy was done is not stated. This procedure is not recommended routinely at N.C.I. for patients with initially localised disease (as in the I.R.→I.C. group), but it is more likely to have been performed in the patients with more severe

symptoms in the

I.C.→I.R.

group.’,’

immunosuppressive effects of I.R. and i.c. and the impaired cellular immunity in Hodgkin’s disease are the most likely primary causes of these second malignancies, In view of the substantial as suggested by the authors. difference of the o/E ratio of second malignancies between the two groups, splenectomy, if performed more frequently in one group, may also be aetiologically important. The following considerations corroborate this notion: The

DETERMINATION OF FORMIMINOGLUTAMIC ACID BY ION-EXCHANGE CHROMATOGRAPHY

SIR,—In 1964 Edozien and Modie1 described a method for the determination of formiminoglutamic acid using a Beckman aminoacid analyser. We have lately tried to repeat this work and have been unable to do so. Edozien and Modie stated that formiminoglutamic acid was eluted from an automatic aminoacid analyser as a basic aminoacid with a mobility approximating (but not equal) to that of ammonia. Using a Beckman 120C aminoacid analyser, we find that this compound is eluted as a neutral/acidic aminoacid giving a broad peak between cystine and methionine. When a sample of this compound is applied to the basic column, it is eluted at approximately the void volume of the column and only a small peak in the area of ammonia can be seen. In our case this peak does indeed appear to be ammonia present either as a contaminant or as a chromatographic artefact caused by the chromatography. Our data seem to be confirmed by the findings of Niederwieser et al. in which formiminoglutamic acid was eluted as a broad peak between oc-amino n-butyric acid and leucine on a Biocal aminoacid analyser. Similarly, with a lithium buffer used by Dr T. L. Perry,3 formiminoglutamic acid was eluted as a broad peak between a-amino n-butyric acid and valine.4 In neither of these latter two systems was there any evidence for formiminoglutamic acid being eluted with the basic aminoacids. It is possible that the findings of Edozien and Modie were caused either by Edozien, J. C., Modie, J. A. Lancet, 1964, ii, 1149. Niederwieser, A., Giliberti, P., Matasovic, A., Pluznik, S., Steinmann, B. Clinica chim. Acta, 1974, 54, 293. 3. Perry, T. L., Stedman, D., Hansen, S. J. Chromatog. 1968, 38, 460. 4. Perry, T. L., Applegarth, D. A., Evans, M. E., Hansen, S., Jellum, E. Pediat. Res. (in the press).

1. 2.

i. absence of splenic irradiation after splenectomy reduces the total amount and duration of radiation therapy3 and consequently its overall immunosuppressive effect. ii. Particularly with respect to the leukaemia observed, splenec4 5 tomy inhibits or reduces the frequency of experimental and it influences the of the disease and proleukxmia, activity longs remissions in children with acute myelocytic leukæmia76 and improves hæmatological depression of lymphocytic leukaemia.’ iii. The spleen of patients with Hodgkin’s disease produces very active

immunoglobulin G that coats T cells.8 Although the clinical significance of this IgG has not been established, it could conceivably be an cnhancing antibody, reduction of which by splenectomy may account for the increased tolerance to irradiation and chemotherapy observed in splenectomised patients,3,9 and possibly improve their remission-rates. iv. Contrary to the N.C.I. experience, 80 patients on roughly the same regimen (I.R→I.C.) who were followed for 152 manyears at Stanford University did not develop second malignancies," and staging laparotomy with splenectomy may have been performed in more patients at Stanford. 1. 2. 3. 4. 5. 6. 7. 8.

9. 10.

Johnson, R. E. Ann. intern. Med. 1971, 75, 459. Johnson, R. E. ibid. 1972, 76, 331. Desser, R. K., Moran, E. M., Ultmann, J. E. Med. Clins N. Am. 1973, 57, 479. Fey, F., Graffi, A. Naturwissenschaften, 1958, 45, 471. Maloney, W. C., King, V. P. Cancer Res. 1973, 33, 573. Fleming, I., Simone, J., Jackson, R., Johnson, W., Walters, T., Mason, C. Cancer, N.Y. 1974, 33, 427. Adler, S., Stutzman, C., Sokal, J. E., Mittleman, A. ibid. 1975, 35, 521. Longmire, R. C., McMillan, R., Velenosky, R., Armstrong, S., Lang, J. E., Craddock, C. G. New Engl. J. Med. 1973, 289, 763. Salzman, J. R., Kaplan, H. S. Cancer, N.Y. 1971, 27, 471. Rosenberg, S. A. New Engl. J. Med. 1973, 288, 469.

Letter: Small-intestinal histology in coeliac disease.

1345 T.R.H. response at higher dosage and/or potentiation with, for example, levodopa, amphetamine, University Psychiatric Clinic, Basle, Wilhelm...
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