IMPORTANCE OF DISACCHARIDE INTOLERANCE IN THE TREATMENT OF CŒLIAC DISEASE

172

Summary The preparation and use of a calcium-resin (calciumZeo Karb 225 ’) as an alternative to ’Resonium A ’ (sodium-zeokarb) is described. The calcium-resin is a safe and practical alternative to resonium A. The calcium liberated in exchange for potassium does not cause hypercalcaemia or other side-effects in short-term use. Calcium-resin is suitable for the treatment of hyperkalaemia. It should not be given with purgative drugs.

there was evidence suggestive of disaccharide intolerance. One patient is reported in detail, and nine other cases are cited to draw attention to the beneficial effects of this diet.

We thank Prof. D. A. K. Black and Prof. S. W. Stanbury for their advice and Prof. M. D. Milne for information about the resin used by Evans et al. (1953). K. J. and A. G. H. hold research appointments provided by the Board of Governors of the United Manchester Hospitals out of its endowment funds. Requests for reprints should be sent to Dr. G. M. Berlyne, University Department of Medicine, Royal Infirmary, Manchester, 13.

Findings A male infant was born pregnancy and low-forceps

on

May 29, 1964, after normal

delivery at 42 weeks’ gestation. was regained by 7 days; the infant was Birthweight (3-52 kg.) fed artificially; there was slight vomiting in the second week of life with occasional vomiting thereafter; bowel actions were normal. By the age of 5 months he weighed 7-3 kg. (16 lb.)i.e., at the 50th percentile for weight. Solids, including cereals, were added to diet by 5-6 months. On the infant’s first hospital admission (Feb. 22, 1965) at the age of 9 months, there had been persistent vomiting for 3 weeks. TABLE I-URINARY SUGAR CHROMATOGRAPHY

(CASE 10)

REFERENCES

Berlyne, G. M., Janabi, K., Shaw, A. B. (1966) Lancet, i, 167. Evans, B. M., Hughes Jones, N. C., Milne, M. D., Yellowlees,

H.

(1953)

ibid. ii, 791.

Greenman, L., Peters, J. H., Mateer, F. M., Weigand, F. A., Wilkins, D., Tara, I. R., Rhodes, G., Danowski, T. S. (1951) J. clin. Invest. 30, 995. Liu, S. H., Chu, H. I. (1943) Medicine, Baltimore, 22, 103. McDonald, S. J., Clarkson, E. M., de Wardener, H. E. (1964) Clin. Sci. 26, 27. Permutit Co. Ltd. (1951) Pamphlet on Zeokarb 225. Stanbury, S. W. (1962) in Renal Disease (edited by D. A. K. Black); p. 508. Oxford.

IMPORTANCE OF DISACCHARIDE INTOLERANCE IN THE TREATMENT OF CŒLIAC DISEASE A. B. ARTHUR M.B. N.Z., M.R.C.P.E., D.C.H.

BARBARA E. CLAYTON M.D., Ph.D. Edin., M.R.C.P.

RESEARCH ASSISTANT

CHEMICAL PATHOLOGIST

D. G. COTTOM M.C., B.M. Oxon., M.R.C.P., D.C.H.

J. W. T. SEAKINS M.A. Cantab., Ph.D. Lond.

PHYSICIAN

LECTURER IN CHEMICAL PATHOLOGY

HOSPITAL FOR SICK

B.M.

CHILDREN, GREAT LONDON, W.C.1

ORMOND

STREET,

J. W. PLATT Oxon.. M.R.C.P., D.C.H.

PÆDIATRICIAN, CUMBERLAND

AREA

THE incrimination of the gluten fraction of wheat-flour the causal agent in the pathogenesis of coeliac disease (Dicke 1950) enabled treatment of the disease by exclusion of gluten from the diet to become a practical and rewarding therapeutic measure. Many patients responded well to dietary treatment; in others, difficulty was experienced in establishing the diet, and remission of symptoms was

as

*

According

t Provisional

to

Moncrieff and Wilkinson (1954). to Menzies and Seakins (1965).

figures, according

was now 6-4 kg.-i.e., 1-2 kg. weight loss in 2 months. No clear diagnosis was made, but the child_was discharged home after improvement on antibiotic treatment for a chest infection. He was readmitted on April 8 with a recurrence of vomiting and exacerbation of his chest infection. He was ill and miserable, weighing 6-3 kg. at 45 weeks, with distended abdomen, wasted muscles, and scattered respiratory rhonchi.

Weight

Investigations Haemoglobin was 86%; white-cell-count was normal. Urea and electrolytes normal; serum-protein 5-2 g. per 100 ml. with normal y-globulin on electrophoresis; sweat-sodium 22 mEq. per litre and 26 mEq. per litre (normal). Duodenal juice, tryptic activity present to a dilution of 1 :256. Urine, repeatedly negative for protein, sugar, acetone, and pus cells. 5-day fat balance showed 93-5% absorption. Normal barium swallow and barium enema; barium meal showed flocculation of barium and fluid-filled, dilated coils of small bowel, with normal transit-time. A gluten-free diet was begun, but weight gain was slight (0-45 kg. in 6 weeks) and there was no clinical improvement. On June 28 the child was transferred to the Hospital for Sick Children. The physical findings were typical

delayed (Sheldon 1959). Weijers et al. (1961) showed that diarrhoea could result from deficiencies in the sugar-splitting enzymes (disaccharidases) of the intestinal mucosa, and recent work (Plotkin and Isselbacher 1964, Shmerling et al. 1964, Nordio et al. 1965, Arthur 1966, Sheldon and Tempany 1966) has disclosed disaccharidase deficiency in biopsy specimens of intestinal mucosa from patients with coeliac disease. Lactase activity was most severely depressed; that of sucrase and isomaltase was diminished to a lesser extent; and maltase was least affected. After exclusion of lactose as well as gluten from the diet, Lifshitz et al. (1965) reported increasing lactose tolerance and slow regeneration of the intestinal mucosa in their patients. It seemed reasonable therefore to exclude lactose and sucrose (as well as gluten) from the diet of patients in the initial acute phase of coeliac disease, particularly where

Fig. 1-Case 10. Sugar-tolerance tests. of Folin and blood-sugar estimated according to the method Wu, as modified by Wilkinson (1960). Blood-glucose according to the method of Huggett and Nixon (1957) as modified by Whitfield (1965). Total

estimated

173 TABLE II-INTESTINAL DISACCHARIDASE ACTIVITIES

typical of coeliac disease. Disaccharidase activities (table n) were greatly reduced. The patient was now given a combined gluten-free, lowlactose, and low-sucrose diet as devised by the dietitian at this hospital (Dixon 1965), with striking improvement in physical well-being and a gain in weight of 1’3 kg. in 3 weeks -in pronounced

(CASE 10)

contrast to

see

the

mar-

ginal improvement

For details of method and controls, Arthur (1966). * Units =v.moles of substrate hydrolysed per minute.

associated

of a malabsorption state-a miserable child, anorexic, and antisocial, with notable pallor, distended abdomen, wasted buttocks, and some muscle hypotonia. His weight was 6-8 kg. (1-8 kg. below the 3rd percentile for his age). Stools were now pale, bulky, foul-smelling, and greasy, having appeared normal 4 weeks previously.

Investigations Hxmoglobin, 71 % with slight hypochromia; serumvitamin B12 490 µµg. per ml. (normal); serum-folic-acid 4’8 mµg. per ml. (normal =5-9-21). Urea, electrolytes, liverfunction tests, and serum-proteins normal; serum-cholesterol 122 mg. per 100 ml.; sweat-sodium 19 mEq. per litre. Stool cultures repeatedly negative for pathogens and Giardia lamblia; urine chromatography showed excess lactose, with an abnormal rise in urinary lactose and sucrose after oral loading with these sugars (table i). A lactose-tolerance test (11 g.) gave a maximum rise in total blood-sugar of 23 mg. per 100 ml. A comparable load with the constituent monosaccharides, glucose and galactose, gave a rise of 61 mg. per 100 ml., suggesting impaired lactose hydrolysis (fig. 1). A biopsy specimen of the smallintestinal mucosa (July 13) revealed subtotal villous atrophy,

with a diet

gluten-free alone (fig. 2).

In the past 18 months, nine further cases of cceliac disease with evidence of associated disaccharide intolerance have been treated with a similar diet. In these infants the outstanding symptoms had been 2-Case 10. Weight chart: effect of vomiting and Fig. illness and response to diet. weight loss, rather than overt steatorrhoea, despite the grossly abnormal fatbalance in four of the infants. It is of interest that cases 6 and 7 were referred to this hospital with a provisional diagnosis of Hirschsprung’s disease. Disaccharidase

TABLE III-TEN CASES OF CCELIAC DISEASE WITH DISACCHARIDE INTOLERANCE

P.V.A. *

=partial villous atrophy.

S.V.A.

=subtotal villous atrophy.

Folic acid: normal values =5-9-21 m[jLg. per ml. blood. t Carried out in early, milder stage of condition in case 10, in

TABLE IV-RESPONSE TO

LOW-LACTOSE, LOW-SUCROSE,

G.R.

acute

=greatly reduced.

stage in others.

GLUTEN-FREE DIET

174

activities were determined on the duodenal mucosa obtained at biopsy in 5 infants: lactase was absent in 3 and greatly reduced in 2; whereas sucrase activity was much reduced in the 4 infants in whom it was estimated. Abnormal lactosuria and/or sucrosuria was found in 8 of the 9 patients. All responded well in weight-gain and well-being to the gluten-free, low-lactose, and low-sucrose diet-although the initial response was slow in case 9, which was complicated by a concurrent urinary infection (tables III and iv). ISCUSSlon Discussion The infant (case 10) whose case-report is described here in detail exhibited the typical features of coeliac disease, which was confirmed by contrast radiography and biopsy of the small-intestinal mucosa. A period of 6 weeks on gluten-free diet produced a slight gain in weight but little relief of symptoms. Associated disaccharide intolerance was suggested by the child’s striking waxy pallor (noted in several cases of lactose intolerance) and poor response to the avoidance of gluten. This was supported by disacchariduria, poor glycaemic response after oral lactose loading, and the demonstration of greatly diminished lactase and sucrase activity in the intestinal mucosa. Children with secondary disaccharide intolerance are apparently indistinguishable clinically from the remainder with coeliac disease alone-save, perhaps, for increased severity of symptoms and notable pallor. Failure to respond to a gluten-free diet (in the absence of superadded bowel infection) is suggestive of associated disaccharide intolerance, but time spent determining this is wasteful of hospital beds and entails prolonging the period of

morbidity. Chromatographic estimation (see Appendix) of urinary sugars, while the patient is receiving a normal diet-i.e., one containing sucrose, lactose, starch (and gluten)-or of urinary and fsecal sugars after an oral load of sucrose and lactose given with a marker, is a rapid and convenient means of obtaining further evidence suggestive of disaccharide intolerance. Weser and Sleisenger (1965) concluded that in adults with coeliac disease urinary excretion of lactose was a sensitive index of intestinal function, and their patients with increased lactosuria all had severe villous atrophy of the jejunum and significant lactase deficiency. This agreed with our findings, in that nine of our ten patients had abnormal lactosuria and sucrosuria, with gross depression of lactase and sucrase activity in those patients in whom this was estimated. Suspected disaccharide intolerance may be further investigated by determining the glycaemic response and the effect on stool pH and transit time of oral loading with appropriate sugars (Weijers et al. 1961), but results of these investigations may be misleading when diarrhoea and malabsorption are present. Direct evidence of disaccharidase deficit is obtained only by quantitative enzyme assay of intestinal mucosa, obtained by peroral biopsy (Dahlqvist 1964). If these procedures are contraindicated by the clinical state of an acutely ill patient, immediate exclusion of lactose and sucrose from the diet is strongly advocated and may indeed be life-saving. If further clarification is necessary formal, investigation may be undertaken when the clinical state has improved. We recommend that all acutely ill patients with coeliac disease should be treated with a low-lactose, low-sucrose, and gluten-free diet in the initial phase of the disease. Reintroduction of sugars can only be determined by therapeutic trial-sucrose is usually tolerated within a few months, but lactose intolerance may persist for upwards

of a year. This is in keeping with the persistence of mucosal damage notwithstanding long-continued dietary Weser and treatment (Madanogopalan et al. 1965). Sleisenger (1965) found persistent villous atrophy and abnormal lactosuria in patients after 2 years of gluten-free diet, although in patients who had been treated for 3 and 5 years the small-intestine mucosa seemed histologically and functionally normal.

Summary Disaccharide intolerance has been shown to accompany deficiency of disaccharidase activity in the intestinal mucosa of patients with coeliac disease. Chromatographic estimation of urinary sugars is a rapid and convenient means of obtaining evidence suggestive of disaccharide intolerance, which may be confirmed by oral sugar-loading tests and enzyme assay of biopsy specimens of intestinal mucosa. In the initial treatment of coeliac disease, where there is evidence of disaccharide intolerance, lactose and sucrose as well as gluten should be excluded from the diet. One case, reported in detail, and nine others illustrate the beneficial effects of this diet.

Appendix Chromatography of Urinary and Paecal Sugars A sample of urine (about 5 ml.) is deionised by shaking with half its volume of’Biodeminrolit ’ (Permutit, London) in the acetate form for not less than 15 min., and then centrifuged. Samples (100 µl) of the supernatant solutions are chromatographed in duplicate on separate sheets of ’Whatman ’ 3MM paper (55cm. long) using the descending technique. On one sheet, an aldose standard of lactose (30 µg.), galactose (10 µg.), and glucose (20 µg.) is placed as a single spot, and on the other a ketose standard of sucrose (20 {J.g.) and fructose (10 µg.). The sheets are developed overnight in ethyl acetatepyridine-water (60:25:20). The papers are dried in air until free of pyridine. The aldose sugars are located with aniline phosphate, and the ketose sugars with naphthoresorcinol-trichloracetic acid. Aniline phosphate reagent: A.R. aniline (10 ml.), acetic acid (90 ml.), water (10 ml.), syrupy phosphoric acid (4 ml.) are mixed and stored in a refrigerator. One part of the stock solution is mixed with four parts of acetone immediately before dipping, and the paper is heated at 100°C for about 5 min. Naphthoresorcinol reagent: naphthoresorcinol (20 mg.) (KochLight, Colnebrook), 50% trichloracetic acid (3 ml.) and acetone (17 ml.) are mixed before dipping, and the paper is heated at 100’C for about 5 min. This procedure may be used for chromatography of stools. The freshly passed marked’stool is immediately deep frozen at - 70’C on solid CO2 (to inhibit bacterial disaccharidases, and subsequent degradation of monosaccharides). A suitable portion of the stool (e.g., 5 g.) is homogenised with acetone (5 ml.) and centrifuged. Subsequent treatment is as for urine. We are greatly indebted to Sir Wilfred Sheldon for permission to include cases 3, 4, 5, and 9 and for his continuing support and advice; to Mr. R. Ersser and Mrs. A. Warren for technical assistance; and to the hospital dietitian, Miss D. Francis, for help. We gratefully acknowledge financial support from the Joint Research Board. Requests for reprints should be addressed to D. G. C. REFERENCES

Arthur, A. B. (1966) Archs Dis. Childh. (in the press). Dahlqvist, A. (1964) in Disorders due to intestinal defective carbohydrate digestion and absorption (edited by P. Durand). Rome. Dicke, W. K. (1950) Int. Congr. Pediat.; p. 117. Dixon, D. J. W. (1965) Diets for Sick Children. Oxford. Huggett, A. St. G., Nixon, D. A. (1957) Lancet, ii, 368. Lifshitz, F., Klotz, A. P., Holman, G. H. (1965) Am. J. dig. Dis. 10, 47. Madanogopalan, N., Shiner, M., Rowe, B. (1965) Am. J. Med. 38, 42. Menzies, I. S., Seakins, J. W. T. (1965) Unpublished. Moncrieff, A. A., Wilkinson, R. H. (1954) Acta pœdiat., Stockh. suppl. 100, 495.

Nordio, S., Lamedica, G. M., Vignolo, L., Berio, A. (1965) Annls pœdiat. 204, 3. Plotkin, G. R., Isselbacher, K. J. (1964) New Engl. J. Med. 271, 1033. Sheldon, W. (1959) Pediatrics, 23, 132. — Tempany, E. (1966) Gut (in the press). Shmerling, D. H., Auricchio, S., Rubino, A., Hadorn, B., Prader, A. (1964 Helv. pœdiat. Acta, 19, 507. Tanner, J. M. (1958) in Modern Trends in Pædiatrics. London. Weijers, H. A., Van de Kamer, J. H., Dicke, W. K., Ijsseling, J. (1961 Acta pœdiat., Stockh. 50, 55. Weser, E., Sleisenger, M. H. (1965) Gastroenterology, 48, 571. Whitfield, A. E. (1965) Unpublished. Wilkinson, R. H. (1960) Chemical Micro-Methods in Clinical Medicine Springfield, Ill.