Adult coeliac disease

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1 Postgrad. med. J. (August 1968) 44, PATENTS with idiopathic steatorrhoea present in many different ways. The dominant feature of the clinical presentation in 100 patients is shown in Table 1. TABLE Presentation in 100 patients Abdominal symptoms Diarrhoea 33 Pain 11 Sore mouth 3 Vomiting 3 Total 50 Symptoms and signs of deficiency Symptoms of anaemia 17 Anaemia found 13 Osteomalacia 6 Macro and Howell Jolly bodies 3 Tetany 2 Oedema 2 Purpura 1 Total 44 Coeliac follow up From childhood 5 Relation 1 Total 6 Only half the patients presented primarily with abdominal symptoms. Diarrhoea dominated the picture in thirty-three and pain was the main complaint in eleven. Most of the rest presented with the symptoms and signs of deficiency, chiefly of iron and folic acid, but also of calcium and the fat-soluble vitamins D and K, and albumin, a bad prognostic sign. When macrocytes and Howell Jolly bodies are found together in the peripheral blood, the most likely diagnosis in this country is idiopathic steatorrhoea unless the patient has had a gastrectomy during which the spleen has had to be removed. The significant symptoms in this group of patients are shown in Table 2. Nineteen had entirely normal stools. Although two of these patients had a perforation of the small intestine, this is a rare complication of idiopathic steatorrhoea. Neither of these patients had evidence of malignant disease. The skin lesions were mainly seborrhoeic dermatitis and psoriasis. Adult coeliac disease J. S. STEWART West Middlesex Hospital, sleworth To establish the diagnosis an intestinal biopsy is needed, but before proceeding to this it is wiser to examine the gross anatomy of the small intestine with a barium follow-through in view of the risk of perforation in a particularly dilated loop or a diverticulum. The barium followthrough examination may be normal in these patients, but characteristically shows dilatation of the small bowel and thickening of the mucosal folds (Laws et al., 1963). TABLE 2 ncidence of symptoms in 100 patients Diarrhoea Normal stools Steatorrhoeic, normal frequency Marked weight loss Sore mouth Abdominal pain Vomiting Abdominal fullness Perforation Breathlessness Lassitude only Blurred vision Oedema Bone pain Tetany Paraesthesiae Dwarfed Purpura Skin lesions Once the intestinal biopsy is obtained it is useful first to examine it under the dissecting microscope (Holmes, Hourihane & Booth, 1961). Macroscopic and histological appearances found in control subjects are illustrated in Figs. 1-4 and the distribution of the dominant proximal mucosal appearances in fifty control subjects without symptoms or signs of gastro-intestinal disease is seen in Fig. 5. The absence of joining leafy villi and the virtual absence of broad leafy villi as dominant appearances are probably due to the limitation of this control group to patients living in a temperate climate without such symptoms as functional diarrhoea. The macroscopic and histological appearances of the proximal intestinal biopsies in patients

2 =...S. FG. la. Finger-like villi. x 40. FG. 2a. Narrow leafy villi. x 40. Adult coeliac disease 633 At.. FG. lb. Finger-like villi (section). H & E, x 80. * V *~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......~~ FG. 2b. Narrow leafy villi (section). H & E, x 80.

634 J. S. Stewart 01R11 FG. 3a. Broad leafy villi.

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3 634 J. S. Stewart 01R11 FG. 3a. Broad leafy villi. x 40. ḡ: 4 4,~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~... Fig. 3b. Broad leafy villi (section). H & E, x 80..~~~~~~ * 4 Postgrad Med J: first published as /pgmj on 1 August Downloaded from FG. 4a. Joining leafy villi. x 40. A.*z 4 FG. 4b. Joining leafy villi (section). H & E, x 80. on 3 September 2018 by guest.

30 28 20- Adult coeliac disease 635 2 1 Fingers Narrow Brood Joining leoves leaves leaves FG. 5.

.... * Postgrad Med J: first published as 10.1136/pgmj.44.514.632 on 1 August 1968.

4 Adult coeliac disease Fingers Narrow Brood Joining leoves leaves leaves FG. 5. Distribution of dominant proximal mucosal appearances in fifty control subjects...., * Postgrad Med J: first published as /pgmj on 1 August Downloaded from Fig. 6a. Flat mucosa. x 40. FG. 6b. Flat mucosa (section). H & E, x 80. on 3 September 2018 by guest.

.. l.:... :z...... :~~~~~~~~~~~~~~~~~~~~~~ FG. 7a.

l W1 ~~~~ Postgrad Med J: first published as 10.1136/pgmj.44.514.

5 636 J. S. Stewart,g,......':".';....'.''..:.^ *: ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. b... l.:... :z :~~~~~~~~~~~~~~~~~~~~~~ FG. 7a. Flat mucosa with mosaic. x 40...:..i.- * =U :... t,..5.2.~~~~~~~~n-s.; FG. 7b. Flat mucosa with mosaic (section). H & E, x Ff.i. l W1 ~~~~ Postgrad Med J: first published as /pgmj on 1 August Downloaded from FG. 8a. Convoluted mucosa with mosaic. x 40. FG. 8b. Convoluted mucosa with mosaic (section) H&E, x 80. on 3 September 2018 by guest.

~~~~~~~~~~~~~~~~~~~~~~~~~~~..::... k. z.:..i... R..,k. B..:.R..... FG. 9a. Convoluted mucosa. x 40. with idiopathic steatorrhoea are illustrated in Figs. 6-9.

cell infiltration. The distribution of the macroscopic appearances in sixty patients with idiopathic steatorrhoea is seen in Fig. 10.

6 ~~~~~~~~~~~~~~~~~~~~~~~~~~~..::... k. z.:..i... R..,k. B..:.R..... FG. 9a. Convoluted mucosa. x 40. with idiopathic steatorrhoea are illustrated in Figs The histological features common to all these biopsies are increased mucosal thickness, absence of villi or reduced villous height, decreased epithelial surface cell-height and increased inflammatory cell infiltration. The distribution of the macroscopic appearances in sixty patients with idiopathic steatorrhoea is seen in Fig z 5 3 Convoluted Convoluted Flat Flot mosaic mosoic Proximol mucosal appearance FG. 10. Distribution of proximal mucosal appearances in sixty patients with idiopathic steatorrhoea. This same sequence of changes from flat, through flat-with-mosaic pattern and convolutedwith-mosaic pattern to the dominantly convoluted appearance, illustrated in these different patients, can also be found in the same patient Adult coeliac disease "~~~~~~~~~~~~~~~~~~~~~... FG. 9b. Convoluted mucosa (section). H & E, x 80, at different levels down the small intestine. Further down the ileum leafy villi and then fingerlike villi may be found (Fig. 11). This decreasing severity of the mucosal lesion is compatible with its production by a dietary factor. Using measurements of villous height and epithelial surface cell height, we did not find an entirely normal ileum in any of these patients although finger-like villi were seen in the distal ileum of several. There was always a reduction in the height of the villi or surface cells. These surface cells are the structural units primarily responsible for absorption. Their height can be measured from the basement membrane to the brush border on the luminal surface. Abnormal surface cells from a patient with idiopathic steatorrhoea show many signs of gross damage and the simplest way to quantitate this is to measure the reduced cell-height. This reduction can take place with remarkable rapidity. A patient whose jejunal mucosa had returned to normal on treatment with a gluten-free diet for 22 months was given a gluten load following a jejunal biopsy. A further jejunal biopsy from the same level 36 hr after the gluten load showed a considerable reduction in cell height. With Dr Ernst Riecken and Professor A. G. E. Pearse at the Hammersmith Hospital we investigated the mechanism of production of this mucosal lesion histochemically (Riecken et al., 1966). Acid phosphatase is a highly destructive

638 J. S. Stewart FG. 1 a. Finger-like villi from lower ileum of patient whose proximal mucosa was flat. x 40.

The stain is intense and the localization is discrete. The pre-treatment appearance in idiopathic steatorrhoea (Fig.

Acid phosphatase. The activity is confined to lysosomal bodies beneath the brush border of the absorptive epithelium and to macrophages. of the lamina propria. x 130. FG. 1 b.

Jejunum in untreated idiopathic steatorrhoea. Acid phosphatase. Flat mucosa and severe reduction in height of surface cells associated with almost complete loss of activity and lysosomes. x 130.

7 638 J. S. Stewart FG. 1 a. Finger-like villi from lower ileum of patient whose proximal mucosa was flat. x 40. enzyme normally contained within the lysosomes, situated below the terminal web of the surface cells. The normal histochemical appearance, stained for acid phosphatase, is shown in Fig. 12. The stain is intense and the localization is discrete. The pre-treatment appearance in idiopathic steatorrhoea (Fig. 13) shows a marked decrease in the intensity of staining and a loss of the 0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~... FG. 12. Normal jejunum. Acid phosphatase. The activity is confined to lysosomal bodies beneath the brush border of the absorptive epithelium and to macrophages. of the lamina propria. x 130. FG. 1 b. Histological section of biopsy shown in Fig. lla. x 80. ~~~~~~~~~~~...!';...:.:.B ;''.oi.j;.: la 1 l ie i i X5u.^;ORf... 9E....'5u.;.:..i!~~~qp FG. 13. Jejunum in untreated idiopathic steatorrhoea. Acid phosphatase. Flat mucosa and severe reduction in height of surface cells associated with almost complete loss of activity and lysosomes. x 130. discrete localization, giving rise to a remarkable diffusion of the staining. With the return of these appearances towards normality on gluten withdrawal the intensity of staining for acid phosphatase becomes normal, but even after 27 months of gluten-free diet the distribution is not yet confined to the area of the lysosomes. There is also considerable intensity of staining in the region of the Golgi apparatus lower down

the cell (Fig. 14). This indicates a high level of enzyme activity. Aft ~ 4 FG. 14. Jejunum of a patient with idiopathic steatorrhoea 27 months after treatment with gluten-free diet. Acid phosphatase.

8 the cell (Fig. 14). This indicates a high level of enzyme activity. Aft ~ 4 FG. 14. Jejunum of a patient with idiopathic steatorrhoea 27 months after treatment with gluten-free diet. Acid phosphatase. Marked activity in the Golgi zone indicates enhanced enzyme production. x 130. t seems, therefore, that the mucosal lesion is at least partly due to the direct effect of gluten on the surface-cells because of the short time needed to demonstrate the lesion following a gluten load. On the other hand, the surfacecells may still show histochemical abnormalities after 27 months of strict gluten withdrawal. So much for the structural changes. How do these relate to the impairment of absorptive function in these patients? No correlation was found between the severity of the proximal mucosal lesion and the degree of impaired absorption of any of the substances absorbed proximally such as xylose, folic acid and pyridoxine. The finding supports the observation of MacDonald et al. (1964) who demonstrated that the clinical severity of the condition was not related to the severity of the mucosal lesion at any one point, but rather to its extent down the small intestine. n the ileum, however, a correlation was found between the surface cell height and the absorption of vitamin B12, the dose being given with intrinsic factor (Fig. 15). This association was statistically significant (r=0-65; P<005). None of the other tests of absorptive function showed any relationship with ileal cell height except for fat absorption, which showed a trend towards a significant correlation. The fairly close correlation between ileal surface cell-height and vitamin B12 absorption and the less clear relationship between fat absorption and ileal surface cell-height suggested that the F.V.. Adult coeliac disease _ e. Z-~ 0 04 ~~~~S _ mo0 2 > 0i * lleal surface cell height (pl) FG. 15. Vitamin B1, absorption and ileal surface cell height. P < 0 05, r severity of vitamin B12 malabsorption might show some relationship with the severity of the steatorrhoea. f this were so, it might be concluded that the degree of steatorrhoea in these patients is determined more by ileal than by jejunal function. f it is the degree of damage to the ileum which determines the severity of the steatorrhoea, then there should be some correlation between the steatorrhoea and the malabsorption of vitamin B12. This suggestion was confirmed by plotting the two sets of results obtained from the fifty patients in whom both these tests had been performed (Fig. 16). ntrinsic factor was given with each oral dose of vitamin B12. The log scale was used for the daily faecal fat excretion. The degree of correlation, calculated independently of * *. 30 _ 0 320~0 ->20 0~ * 0 *o- 1 ~~0 * l 0!, / %/ 15% 200/ 25% Vitamin B12 absorption FG. 16. Vitamin B1, absorption (0,,ug, 0, %) and daily faecal fat. P < 0-001, r

9 640 J. S. Stewart the graph by regression analysis, is statistically highly significant (r=0-67; P<0 001). t seems likely, therefore, that the degree of steatorrhoea in these patients may be determined more by the relatively normal ileum than by the absorptive function of the abnormal jejunum. Acknowledgments Most of the 100 patients whose clinical presentations are analysed were under the care of Professor C. C. Booth at Hammersmith Hospital or Dr N. F. Coghill at West Middlesex Hospital. A joint paper is in preparation, giving the detailed results, in collaboration also with Professor D. L. Mollin and Dr P. D. Roberts and am most grateful to all these colleagues for allowing me to include these preliminary observations in this publication. All sixty patients whose detailed investigations are reported here were under the care of Professor C. C. Booth (see Stewart et al., 1967). References HOLMES, R., HOURHANE, D.O'B. & BOOTH, C.C. (1961) Dissecting-micoscope appearances ofjejunal biopsy specimens from patients with idiopathic steatorrhoea. Lancet, i, 83. LAWS, J.W., SHAWDON, H., BOOTH, C.C. & STEWART, J.S. (1963) Correlation of radiological and histological findings in idiopathic steatorrhoea. Brit. med. J. i, MACDONALD, W.C., BRANDBORG, L.L., FLCK, A.L. TRER, J.S. & RUBN, C.E. (1964) Studies of celiac sprue. V. The response of the whole length of the small bowel to a glutenfree diet. Gastoenterology, 47, 573. RECKEN, E.O., STEWART, J.S., BOOTH, C.C. & PEARSE, A.G.E. (1966) A histochemical study on the role of lysosomal enzymes in idiopathic steatorrhoea before and during a gluten-free diet. Gut, 7, 317. STEWART, J.S., POLLOCK, D.J., HOFFBRAND, A.V., MOLLN, D.L. & BOOTH, C.C. (1967) A study of proximal and distal intestinal structure and absorptive function in idiopathic steatorrhoea. Quart. J. Med. 36, 425. Postgrad Med J: first published as /pgmj on 1 August Downloaded from on 3 September 2018 by guest.

coeliac syndrome per day. Investigations showed a megaloblastic anaemia showed a flat mucosa. ileum were resected and he made an uninterrupted

coeliac syndrome per day. Investigations showed a megaloblastic anaemia showed a flat mucosa. ileum were resected and he made an uninterrupted Gut, 1965, 6, 466 Post-mortem examination of a small intestine in the coeliac syndrome B. CREAMER AND P. LEPPARD From the Gastro-Intestinal Laboratory, St Thomas's Hospital, London EDITORIAL SYNOPSIS This