WANDERINGS IN THE SMALL INTESTINE C. F. McCarthy
Department of Medicine at~d Gastroenterology, University College and Regional Hospital, Galway. T HE small intestine is a fascinating = o r g a n through which to wander. It combines digestive, absorptive, metabolic and endocrine functions. Areas that are morphologically similar are functfonally quite different for example, bile acids and vitamin B,= are selectively absorbed in the terminal few feet of the ileum, but not from the structurally similar mid-ileum. To review the funcbons of the small intestine [s not the purpose of this article, but some concentra6on on aspects of work on the small intestine of particular interest to the group working on disorders of this organ in University Colrege, Galway is attempted. The clinical effects of cys5nuria are due to the formation of renal calculi because of a defective renal tubular reabsorption of cystine. Ornithine, lysine and arginine are also poorly re-absorbed in the renal tubules. Milne et al. (1961) first demonstrated that malabsorption of some of these amino acids was present in cystinurir patients. In 1964 it was possible to demonstrate that the active transport system of these amine acids in the small intestine of two cystinuric patients was absent (McCarthy et al., 1984). Multiple intestinal biopsies from these patients were incubated with dilute solutions of amino acids and at the end of a period of incubation the level of the amino acids in the intestinal tissue water was no higher than that in the incubation fluid. No histological abnormality was present ~n the cystinuric mucosa Intestinal tissue from non-cystinuric patients concentrated the amino acids six to eight times. Major structural differences do not exist between the proximal and distal parts of the small intestine, but
minor differences are apparent and in some instances correlate with functional dissimilarities. The villi of the proximal small intestine of the golden hamster are long and slender compared to the shorter villi of the distal intestine, and the proximal intestine is more effective to the esterification of fat. Comparison of fatty acid esterification by villi of different shape in the hamster, rat, guinea pig and pigeon also show this correlation of function and structure (McCarthy and Tyor, 1964). Coeliac disease is a common disorder of the small intestine. Described by Gee in 1585, it was not until more than 60 years later that Paulley (1954) demonstrated that the malabsorption in the disease is due to gross damage to the mucosa. This description was some years after Dicke's (1950) major breakthrough on the role of gluten in the disease. For the practical management of patients, this disorder may be described as a condition in which the small intestinar rnucosa is significantly abnormal and in which improvement occurs when gluten is excluded from the diet. Difficulties occur when this definition is applied to indNidual patients. A patient with an initial response to a gluten free diet and a return towards normal of the intestinal mucosal morphology will certainly be considered as having classical coeliac disease. When such patient is given gluten with resultant deterioration in mucosal morphology, and who then fails to improve again when g~uten is removed from the diet is difficult to classify. Initially classification as a coe[iac is certainly correct but what of later on ? What
221
222
IRISHJOURNALOF MEDICALSCIENCE
of the patient with abnormal mucosawho improves clinically, but whose jejunal histology does not ? Changes in the intestinal mueosa in eoeliac disease are most marked in the upper small intestine (McCarthy et al., 1964) and presumably improvement occurs in the less damaged ileum before, or at least, more completely than in the proximal intestine. Therefore, apparent failure to improve, as judged by a feiunal biopsy, does not exclude histological improvement ir~ the ileum. Patients are occasionally seen in whom coeliac disease bas been diagnosed years previously without a jejunal biopsy and who have improved on a gluten free diet A jeiunal biopsy after this period of time on a gluten free diet iS norma~ but then d{fficuRy exists as to the cerlainty of diagnosis Challenge with glulen is carried out but when should the next intestinal biopsy be done - - how long does it take for deterioration to occur? In many challenge experiments eight to 48 hours is suggested but yet in the studies by McNichog et aL (1974) many months elapsed before rnueoeal change was noted. Is coetiac disease a single disease or a group of entities which have yet to be separated from each other? Where do lhe patients with reduced intestinal ceh lular turnover, described by Barry and Read (1974) fit in ? All of these questions are of particular relevance in Ireland where the disease is common. Our studJes in Galway indicate that the incidence of the disorder is between one in 300 and one in 500 of the population (MyJotte et al., 1973). The studies of O'Reilty et el. (1974) suggest that the disease is equally common in the rest of the country. The reason for this high incidence or prevalence of the disorder is not clear. It appears that the genetic make-up which predisposes to coeliac disease may be more common in Ireland than elsewhere, Histocompatibility antigen B.8 occurs in 80 per cent of patients with coeliac disease and in most studies of the non-eoeliac population the inr
once is 18-30 per cent (Stokes et el., 1972). Studies in the Galway area indicate a much higher level in the population, probably greater than 40 per cent (Stevens et al., 1977). It is probable that studies of the B-lymphocyte marker described by Mann et el. (1976) in a very high percentage of eoeliac patients will throw further light on the genetic background of the disorder. The genetic factors in coeliac disease are such that when a diagnosis of cooliac disease is made the first degree relatives should be studied. Unfortunately, the only test which excJudes coeliac disease is a duodenal or jejunal biopsy and whether this needs to 6e done in all families depends on the individual circumstances. In our family studies {Mylette et al., 1974), 12 per cent of first degree re[alives who had intesinal biopsies done also had the disorder. We find that only 4 or 5 per cent of coeliacs do not have either HLA1, 8 er 12 (Stevens et al., 1977). The delermination, therefore, of these tissue antigens is useful as a preliminary screening test but can not allow confident exclusion of the disease. It may be that the B-lymphocyte coeliac marker will be of greater help. Even if it is not possible to actively exclude coeliac disease in the f~rst degree relatives, interview and examination and simple investigations such as haemoglobin estimation and serum iron will enable 50 per cent at least of coeliacs to be detected. Studies on the intake of gluten in Ireland have not been available but it is unlikely that the gluten intake is unduly high. That patients with coeliac disease may show a varied response to increasing amounts of gluten is suggested by the studies of WeinsteJn et ~1. (1974) who found that the normal mucosa in some patients with dermatitis herpetitformis became abnormal when large amounts of gluten were fed. Since Bicke's indication that gluten is harmful to coegac patients, subsequent investigations have indJceted that pepsin, tryp-
WANDERING8 iN THE SMALLINTESTINE sin and pancreatic enzymes do not destroy the toxicity of gluten to ooeliac patients although degradation of gluten to its constituent amino acids removes toxicity. Fractionation of gliadin peptides has produced various factions that are toxic to coeliac patients (Hekkens et aL, 1970; Townley et al., 1973). Phelan et at. (1974 and 1977) have suggested a differenl approach to the toxic constituent of gliadin. This approach is based on the fact that the toxicity of gliadin is greatly reduced or abolished by the reaction with carbohydrase enzyme from Aspergillus niger. From this experiment it is suggested that the molecules responsible for the toxicity, probably a carbohydrate, are widely distributed throughout the gliadin molecule. Glutenin has been considered to be non-toxic to coeliae patients. Glutenin contains the same carbohydrate as giladin and recently it was shown that glutenin is toxlc to coeliac patients (Stevens et al., 1977) The role of the carbohydrate perdon may be that it acts as a binding site which is concerned with the entry of gliadin peptides into the intestinal mucosa, or it may he that the carbohydrate is responsible for some of the antigenicity of gluten. The demonstration that gluten exclusion benefits schizophrenic patients who are being treated with phenothiazines, (Dohan, 1966; Singh and Kay, 1976) suggested that there is a relationship between the two conditions and ted us to study a group of schizophrenic pattents to ascertain ff there was an increased incidence of coeliac disease among the schizophrenics. No coeliac disease was found in over 9go chronic schizophrenic patients and this indicates that the favourab]e response to a gluten free diet is not due to a high incidence of coeliac disease amongst schizophrenics (Stephens et al., 1977b). An important association of coeliac disease is the association with malignant disease. It is accepted that the incidence of intraabdominal lymphoma and sarcin-
223
oma of the gastrointestinal tract is increased in patients wgh coeliac disease. This incidence may be as high as 15 per cent (Harris et al., 1967). Since 1s in Galway, we have seen three patients with coeWac disease and [ymphoma of the intestine. A ludher patient whose histology is debatable may also have had lymphoma. A further coeliac patient had a jejunal adenocarcinoma. A fifth patient died outside hoSpital with iaundice and a large abdominal mass. A sixth died in hospital with general inanition and was known to have a monoclonal gammepathy for a year prior to death. A post mortem was not carried out. Her son had eoeliac disease. None of these patients had been treated for coe[iac disease for longer than three years but we felt that the evidence that they were coeliaes was considerable although the criteria of improvement of the mucesa with subsequent deterioration on reintroduction of gliadin could not be fulfilled. It remains to be conclusively decided whether or not a gluten free diet reduces the incidence of malignancy. Initial reports (Stokes et al., 1973) suggested protection but a more recent report from the same group (Holmes et al., I976} indicates that this may not be so. NeverthelesS, the rarity of reports of childhood coeliacs, treated with a gluten free diet, who later develop lymphoma is striking. Presumably as a gluten free diet was only introduced in the 1950's another 10 or 15 years must elapse before these patients reach the age group where they are most likely to develop lymphoma. It is striking that those patients with malignancy may give a history consistent with coeliac disease going back to childhood but a history of long treatment of coeliac disease is much rarer. The four, possibly six coeliaes with malignancy, seen over a seven year period, come from a total of 69 adult coeliacs diagnosed during this same period of time. Interestingly, one patient with an ilea~ lymphoma was seen who did not have coeliac disease, but his
224 brother had disease.
IRrSH JOURNAL OF MEDICAL SCIENCE well
documented
ooeliac
To establish t h e effect of t r e a t m e n t on the i n c i d e n c e of f y m p h o m a w o u l d a p p e a r to be possible in Ireland if a long t e r m register for c o e l i a c s is established. T h e h i g h i n c i d e n c e of t h e disease a n d t h e relatively stable population favour this t y p e of study, T h e e s t a b l i s h m e n t of a register of c o e l i a c p a t i e n t s is one of t h e a r e a s of r e s e a r c h at present b e i n g c o n sidered by t h e E,E.C. C o e l i a c d i s e a s e is also a r e i e v a n t p u b l i c health c o n s i d e r a t i o n . T h e r e a r e 1 0 - 1 5 , 0 0 0 c o e l i a c s in t h i s c o u n t r y a n d it w o u l d be of g r e a t a s s i s t a n c e to t h e m if m a n u f a c t u r e r s of food p r o d u c t s c l e a r l y i n d i c a t e d if g l u t e n is a b s e n t f r o m t h e i r products. O c c a s i o n a l l y t h e s m a l l intestinal m u c osa itself w a n d e r s a n d is to be f o u n d s o m e w h a t in i s o l a t i o n in t h e s t o m a c h . Biochemically this intestinal metaplasia is like t h e s m a l l i n t e s t i n e end s i m i l a r e n z y m e s a r e to be f o u n d (Little et of., 1977). Intestinal m e t a p l a s i a in t h e stomach accompanies gastric carcinoma a n d m a y p l a y an a e t i o l o g i c a l role. Professor D o n e g a n h a s s h o w n p a r t i c u l a r interest in t h e s e l a t e r studies and I h o p e w i l l c o n t i n u e to do so for m a n y years. would like to express my gratitude to my coJleagges for their cooperation and expertise over the years. Their names are documented in the list of references. The Western Health Goard, The Medical Research CounciJ of Ireland and the WeJIcome Trust have financed many of the studies, ReferenGe~
Barry, R. E. and Read, A. E. 1972. Two types of coeriac disease. Gut, 13, 846 e~cke, W. K. 1950. Coeliakie. Doctoral theis, University of Utrecht. Dohan, F. C, 1966. Cereals and schizophrenia, data and hypothesFs. Acta Psychiatr. Scand. 42, 125. Gee, S. On the ceeliae affection, St. Bert's HOSpitat Eeports, 1888, 24, 17. Harris,, O. D., Cooke, W. T., Thompson, W. T. and Waterhouse, g, A. H. 1967. Malignancy in adult coeliae disease and idiopathic steatorr hoea, Am. J, Med. 42, 699.
Hekkens, W., Haex, A. J. C. and WJllighagen, R, G. 1970. Some aspects of gli~din fractionation and testing by a biochemicaf method. In "Coeliac Disease", Ed, C. C. Booth and n H. Dowling, Edinburgh, Livingstone, p. 11. Hoimes, G. K. T., Stokes, P L., Sorah~n, T. M., Prior, P., Waterbouse, J. A. Ifl. and Cooke, W T. 1976. CoeliaG disease, gluten free diet and marignancy. Gut, 17, 612. Liltle, M. P. G.r McCarthy, C. F,, Mooney, P. A and Waiters, J. M. 1977. Intestinal metaprasia : biochemical aspects. J. Physiol. 263, 279. McCarthy, C. F., Borland, J. L., Lynch, H. J., Owen, E. E and Tyorr M. P. 1964. Defective uptake o1 basic amino acids and L-cystine by intestinal mucosa of patents with cystinuria. J. Clin. Invest. 43, 1518. McCarthy,, C& F. and Ty0r, M. P. 1964. RelaLion of fatty acid esterdicati0n by intestinal mucosa of several species to variations in mucosaJ anatomy, Gastroenterology, 46, 691. McCarthy, C, F, Beriand, d L., Kurtz, S. M. and Ruffin, J. M, 1964. The value o1 dissecting microscope in the diagnosis of non-tropical sprue, Am. J, Path. 44, 585, McNicholl, e., Egan-Mitchell, B. and Fottrelh P. F 1974. Varying gluten susceptibility in coeliac disease. In "Coeliac Disease", Ed. W, Th. J. M, Hekkens and A, S. Pena, p. 413, Mann, D. L., Katz, S. I., Nelson, D. L., Abelson, L. G. and Strober, W. 1976 Specific B-ceil antigens associated with gluten-sensitive enter0pathy and dermatitis herpetiformis Lancet i, ~10. Milne, M. D., Asatoer, A, M., Edwards, D, G. an~ Loughbridge, L. W. 1961, The intestinaJ absorption defect in cyst[~uria. Gut, 2, 323, Mylotte, M., Egan-MitchelJ, B., Fottrell, P. P,, McNicholJ, B and McCarthy, C, F. 1974. Family studies in eoeJiac disease. Quart. J, Mad. 43, 359. O'ReiJly, D., Murphy, J,, McLeughlin, J,, Brad. shaw, J. and Dean, G. 1974. The prevalence of coel~ae disease and cystic fibrosis in Ireland, Scotland, England and Wales. fnt. J Epidem. 3, 247. PauJley, J. W. 1954, Observations on the aet~ology cf idiopathic steatorrhoea, Brit. Med. J. iL 1318. Photon, J. J., FottrelJ, P, F., Stevens, F M,, McNicholl, B. and McCarthy, C, F. 1974. The nature of gliadin toxicity in coel[ac disease. A New Concept, [n "Coeliar Disease". Ed. W. Th. J, M. Hekkens and A. S. Pone, p. 60. Phelan, J. J., StevenSr F. M,, McNichorl, B., Fottrell, P, F. and McCarthy, C. F. 1977. Coeliac disease: the abold[on of gliadin toxicity in enzymes from Aspergillus niger J. Clin, So. and Med. ~iol. (in press). singh, M. M and Kay S. I~. 1976 Wheat gluten as a pathogenic factor in schizophrenia. Science, 191, 40~.
WANDERINGS IN THE SMALL INTESTINE Stevens, F M, Phelan, J. J., Comerford, F.R., Fottrell, P. F. and McNicholl, B. 1977. Effect of glutenin an coeHac small intestine, Ir. J. Med. SC (in press) Stevens, F M., Lloyd, R. S,, Geraghty, S. M.J., Reynolds M. T G, SarMield, M. H.~ McNicholl, B,, FoBrell, P. F., Wright, R. and McCarthy, C. F. 1977 Schizophrenia and coeliac disease~ the nature of the relationship. J. Psychok Med. (in pressl. Stevens, F. M., Watt, D., Baker, S., Egan-Mitche[L B., McNicholl, B, and McCarthy, C. F. (in proparation).
225
Stokes, P. S. and Holmes, G. N. T. 1974: Malignancy in coeiiac disease. Clinics in Gastroenterolegy, 3, 159. Stokes, P. L., Asquith, P., Holmes, G. K. T., McKenzie, P. end Cooke, W. T. 1972. Histocompatibility (HL-A) antigens associated with adult coeliac disease. Lancet ~i, 152. Townley, R. R. W., Cornell, H. J., Bhattal, P. S. and Mitchell, J. D. 1973. Toxicity of wheat gliad~n fractions in coeliac disease. Lancet i, 1363. Weinstein, W. M. Piercey, J. R. A. and Dessetor, J. B, I974. Dermatitis herpet~formis arid ~ e l i a c sprue. In "Coeliac Disease", Ed. W. Th. J. M. Hekkens and A. S, Pone. p. 361.
Department of Medicine at~d Gastroenterology, University College and Regional Hospital, Galway. T HE small intestine is a fascinating = o r g a n through which to wander. It combines digestive, absorptive, metabolic and endocrine functions. Areas that are morphologically similar are functfonally quite different for example, bile acids and vitamin B,= are selectively absorbed in the terminal few feet of the ileum, but not from the structurally similar mid-ileum. To review the funcbons of the small intestine [s not the purpose of this article, but some concentra6on on aspects of work on the small intestine of particular interest to the group working on disorders of this organ in University Colrege, Galway is attempted. The clinical effects of cys5nuria are due to the formation of renal calculi because of a defective renal tubular reabsorption of cystine. Ornithine, lysine and arginine are also poorly re-absorbed in the renal tubules. Milne et al. (1961) first demonstrated that malabsorption of some of these amino acids was present in cystinurir patients. In 1964 it was possible to demonstrate that the active transport system of these amine acids in the small intestine of two cystinuric patients was absent (McCarthy et al., 1984). Multiple intestinal biopsies from these patients were incubated with dilute solutions of amino acids and at the end of a period of incubation the level of the amino acids in the intestinal tissue water was no higher than that in the incubation fluid. No histological abnormality was present ~n the cystinuric mucosa Intestinal tissue from non-cystinuric patients concentrated the amino acids six to eight times. Major structural differences do not exist between the proximal and distal parts of the small intestine, but
minor differences are apparent and in some instances correlate with functional dissimilarities. The villi of the proximal small intestine of the golden hamster are long and slender compared to the shorter villi of the distal intestine, and the proximal intestine is more effective to the esterification of fat. Comparison of fatty acid esterification by villi of different shape in the hamster, rat, guinea pig and pigeon also show this correlation of function and structure (McCarthy and Tyor, 1964). Coeliac disease is a common disorder of the small intestine. Described by Gee in 1585, it was not until more than 60 years later that Paulley (1954) demonstrated that the malabsorption in the disease is due to gross damage to the mucosa. This description was some years after Dicke's (1950) major breakthrough on the role of gluten in the disease. For the practical management of patients, this disorder may be described as a condition in which the small intestinar rnucosa is significantly abnormal and in which improvement occurs when gluten is excluded from the diet. Difficulties occur when this definition is applied to indNidual patients. A patient with an initial response to a gluten free diet and a return towards normal of the intestinal mucosal morphology will certainly be considered as having classical coeliac disease. When such patient is given gluten with resultant deterioration in mucosal morphology, and who then fails to improve again when g~uten is removed from the diet is difficult to classify. Initially classification as a coe[iac is certainly correct but what of later on ? What
221
222
IRISHJOURNALOF MEDICALSCIENCE
of the patient with abnormal mucosawho improves clinically, but whose jejunal histology does not ? Changes in the intestinal mueosa in eoeliac disease are most marked in the upper small intestine (McCarthy et al., 1964) and presumably improvement occurs in the less damaged ileum before, or at least, more completely than in the proximal intestine. Therefore, apparent failure to improve, as judged by a feiunal biopsy, does not exclude histological improvement ir~ the ileum. Patients are occasionally seen in whom coeliac disease bas been diagnosed years previously without a jejunal biopsy and who have improved on a gluten free diet A jeiunal biopsy after this period of time on a gluten free diet iS norma~ but then d{fficuRy exists as to the cerlainty of diagnosis Challenge with glulen is carried out but when should the next intestinal biopsy be done - - how long does it take for deterioration to occur? In many challenge experiments eight to 48 hours is suggested but yet in the studies by McNichog et aL (1974) many months elapsed before rnueoeal change was noted. Is coetiac disease a single disease or a group of entities which have yet to be separated from each other? Where do lhe patients with reduced intestinal ceh lular turnover, described by Barry and Read (1974) fit in ? All of these questions are of particular relevance in Ireland where the disease is common. Our studJes in Galway indicate that the incidence of the disorder is between one in 300 and one in 500 of the population (MyJotte et al., 1973). The studies of O'Reilty et el. (1974) suggest that the disease is equally common in the rest of the country. The reason for this high incidence or prevalence of the disorder is not clear. It appears that the genetic make-up which predisposes to coeliac disease may be more common in Ireland than elsewhere, Histocompatibility antigen B.8 occurs in 80 per cent of patients with coeliac disease and in most studies of the non-eoeliac population the inr
once is 18-30 per cent (Stokes et el., 1972). Studies in the Galway area indicate a much higher level in the population, probably greater than 40 per cent (Stevens et al., 1977). It is probable that studies of the B-lymphocyte marker described by Mann et el. (1976) in a very high percentage of eoeliac patients will throw further light on the genetic background of the disorder. The genetic factors in coeliac disease are such that when a diagnosis of cooliac disease is made the first degree relatives should be studied. Unfortunately, the only test which excJudes coeliac disease is a duodenal or jejunal biopsy and whether this needs to 6e done in all families depends on the individual circumstances. In our family studies {Mylette et al., 1974), 12 per cent of first degree re[alives who had intesinal biopsies done also had the disorder. We find that only 4 or 5 per cent of coeliacs do not have either HLA1, 8 er 12 (Stevens et al., 1977). The delermination, therefore, of these tissue antigens is useful as a preliminary screening test but can not allow confident exclusion of the disease. It may be that the B-lymphocyte coeliac marker will be of greater help. Even if it is not possible to actively exclude coeliac disease in the f~rst degree relatives, interview and examination and simple investigations such as haemoglobin estimation and serum iron will enable 50 per cent at least of coeliacs to be detected. Studies on the intake of gluten in Ireland have not been available but it is unlikely that the gluten intake is unduly high. That patients with coeliac disease may show a varied response to increasing amounts of gluten is suggested by the studies of WeinsteJn et ~1. (1974) who found that the normal mucosa in some patients with dermatitis herpetitformis became abnormal when large amounts of gluten were fed. Since Bicke's indication that gluten is harmful to coegac patients, subsequent investigations have indJceted that pepsin, tryp-
WANDERING8 iN THE SMALLINTESTINE sin and pancreatic enzymes do not destroy the toxicity of gluten to ooeliac patients although degradation of gluten to its constituent amino acids removes toxicity. Fractionation of gliadin peptides has produced various factions that are toxic to coeliac patients (Hekkens et aL, 1970; Townley et al., 1973). Phelan et at. (1974 and 1977) have suggested a differenl approach to the toxic constituent of gliadin. This approach is based on the fact that the toxicity of gliadin is greatly reduced or abolished by the reaction with carbohydrase enzyme from Aspergillus niger. From this experiment it is suggested that the molecules responsible for the toxicity, probably a carbohydrate, are widely distributed throughout the gliadin molecule. Glutenin has been considered to be non-toxic to coeliae patients. Glutenin contains the same carbohydrate as giladin and recently it was shown that glutenin is toxlc to coeliac patients (Stevens et al., 1977) The role of the carbohydrate perdon may be that it acts as a binding site which is concerned with the entry of gliadin peptides into the intestinal mucosa, or it may he that the carbohydrate is responsible for some of the antigenicity of gluten. The demonstration that gluten exclusion benefits schizophrenic patients who are being treated with phenothiazines, (Dohan, 1966; Singh and Kay, 1976) suggested that there is a relationship between the two conditions and ted us to study a group of schizophrenic pattents to ascertain ff there was an increased incidence of coeliac disease among the schizophrenics. No coeliac disease was found in over 9go chronic schizophrenic patients and this indicates that the favourab]e response to a gluten free diet is not due to a high incidence of coeliac disease amongst schizophrenics (Stephens et al., 1977b). An important association of coeliac disease is the association with malignant disease. It is accepted that the incidence of intraabdominal lymphoma and sarcin-
223
oma of the gastrointestinal tract is increased in patients wgh coeliac disease. This incidence may be as high as 15 per cent (Harris et al., 1967). Since 1s in Galway, we have seen three patients with coeWac disease and [ymphoma of the intestine. A ludher patient whose histology is debatable may also have had lymphoma. A further coeliac patient had a jejunal adenocarcinoma. A fifth patient died outside hoSpital with iaundice and a large abdominal mass. A sixth died in hospital with general inanition and was known to have a monoclonal gammepathy for a year prior to death. A post mortem was not carried out. Her son had eoeliac disease. None of these patients had been treated for coe[iac disease for longer than three years but we felt that the evidence that they were coeliaes was considerable although the criteria of improvement of the mucesa with subsequent deterioration on reintroduction of gliadin could not be fulfilled. It remains to be conclusively decided whether or not a gluten free diet reduces the incidence of malignancy. Initial reports (Stokes et al., 1973) suggested protection but a more recent report from the same group (Holmes et al., I976} indicates that this may not be so. NeverthelesS, the rarity of reports of childhood coeliacs, treated with a gluten free diet, who later develop lymphoma is striking. Presumably as a gluten free diet was only introduced in the 1950's another 10 or 15 years must elapse before these patients reach the age group where they are most likely to develop lymphoma. It is striking that those patients with malignancy may give a history consistent with coeliac disease going back to childhood but a history of long treatment of coeliac disease is much rarer. The four, possibly six coeliaes with malignancy, seen over a seven year period, come from a total of 69 adult coeliacs diagnosed during this same period of time. Interestingly, one patient with an ilea~ lymphoma was seen who did not have coeliac disease, but his
224 brother had disease.
IRrSH JOURNAL OF MEDICAL SCIENCE well
documented
ooeliac
To establish t h e effect of t r e a t m e n t on the i n c i d e n c e of f y m p h o m a w o u l d a p p e a r to be possible in Ireland if a long t e r m register for c o e l i a c s is established. T h e h i g h i n c i d e n c e of t h e disease a n d t h e relatively stable population favour this t y p e of study, T h e e s t a b l i s h m e n t of a register of c o e l i a c p a t i e n t s is one of t h e a r e a s of r e s e a r c h at present b e i n g c o n sidered by t h e E,E.C. C o e l i a c d i s e a s e is also a r e i e v a n t p u b l i c health c o n s i d e r a t i o n . T h e r e a r e 1 0 - 1 5 , 0 0 0 c o e l i a c s in t h i s c o u n t r y a n d it w o u l d be of g r e a t a s s i s t a n c e to t h e m if m a n u f a c t u r e r s of food p r o d u c t s c l e a r l y i n d i c a t e d if g l u t e n is a b s e n t f r o m t h e i r products. O c c a s i o n a l l y t h e s m a l l intestinal m u c osa itself w a n d e r s a n d is to be f o u n d s o m e w h a t in i s o l a t i o n in t h e s t o m a c h . Biochemically this intestinal metaplasia is like t h e s m a l l i n t e s t i n e end s i m i l a r e n z y m e s a r e to be f o u n d (Little et of., 1977). Intestinal m e t a p l a s i a in t h e stomach accompanies gastric carcinoma a n d m a y p l a y an a e t i o l o g i c a l role. Professor D o n e g a n h a s s h o w n p a r t i c u l a r interest in t h e s e l a t e r studies and I h o p e w i l l c o n t i n u e to do so for m a n y years. would like to express my gratitude to my coJleagges for their cooperation and expertise over the years. Their names are documented in the list of references. The Western Health Goard, The Medical Research CounciJ of Ireland and the WeJIcome Trust have financed many of the studies, ReferenGe~
Barry, R. E. and Read, A. E. 1972. Two types of coeriac disease. Gut, 13, 846 e~cke, W. K. 1950. Coeliakie. Doctoral theis, University of Utrecht. Dohan, F. C, 1966. Cereals and schizophrenia, data and hypothesFs. Acta Psychiatr. Scand. 42, 125. Gee, S. On the ceeliae affection, St. Bert's HOSpitat Eeports, 1888, 24, 17. Harris,, O. D., Cooke, W. T., Thompson, W. T. and Waterhouse, g, A. H. 1967. Malignancy in adult coeliae disease and idiopathic steatorr hoea, Am. J, Med. 42, 699.
Hekkens, W., Haex, A. J. C. and WJllighagen, R, G. 1970. Some aspects of gli~din fractionation and testing by a biochemicaf method. In "Coeliac Disease", Ed, C. C. Booth and n H. Dowling, Edinburgh, Livingstone, p. 11. Hoimes, G. K. T., Stokes, P L., Sorah~n, T. M., Prior, P., Waterbouse, J. A. Ifl. and Cooke, W T. 1976. CoeliaG disease, gluten free diet and marignancy. Gut, 17, 612. Liltle, M. P. G.r McCarthy, C. F,, Mooney, P. A and Waiters, J. M. 1977. Intestinal metaprasia : biochemical aspects. J. Physiol. 263, 279. McCarthy, C. F., Borland, J. L., Lynch, H. J., Owen, E. E and Tyorr M. P. 1964. Defective uptake o1 basic amino acids and L-cystine by intestinal mucosa of patents with cystinuria. J. Clin. Invest. 43, 1518. McCarthy,, C& F. and Ty0r, M. P. 1964. RelaLion of fatty acid esterdicati0n by intestinal mucosa of several species to variations in mucosaJ anatomy, Gastroenterology, 46, 691. McCarthy, C, F, Beriand, d L., Kurtz, S. M. and Ruffin, J. M, 1964. The value o1 dissecting microscope in the diagnosis of non-tropical sprue, Am. J, Path. 44, 585, McNicholl, e., Egan-Mitchell, B. and Fottrelh P. F 1974. Varying gluten susceptibility in coeliac disease. In "Coeliac Disease", Ed. W, Th. J. M, Hekkens and A, S. Pena, p. 413, Mann, D. L., Katz, S. I., Nelson, D. L., Abelson, L. G. and Strober, W. 1976 Specific B-ceil antigens associated with gluten-sensitive enter0pathy and dermatitis herpetiformis Lancet i, ~10. Milne, M. D., Asatoer, A, M., Edwards, D, G. an~ Loughbridge, L. W. 1961, The intestinaJ absorption defect in cyst[~uria. Gut, 2, 323, Mylotte, M., Egan-MitchelJ, B., Fottrell, P. P,, McNicholJ, B and McCarthy, C, F. 1974. Family studies in eoeJiac disease. Quart. J, Mad. 43, 359. O'ReiJly, D., Murphy, J,, McLeughlin, J,, Brad. shaw, J. and Dean, G. 1974. The prevalence of coel~ae disease and cystic fibrosis in Ireland, Scotland, England and Wales. fnt. J Epidem. 3, 247. PauJley, J. W. 1954, Observations on the aet~ology cf idiopathic steatorrhoea, Brit. Med. J. iL 1318. Photon, J. J., FottrelJ, P, F., Stevens, F M,, McNicholl, B. and McCarthy, C, F. 1974. The nature of gliadin toxicity in coel[ac disease. A New Concept, [n "Coeliar Disease". Ed. W. Th. J, M. Hekkens and A. S. Pone, p. 60. Phelan, J. J., StevenSr F. M,, McNichorl, B., Fottrell, P, F. and McCarthy, C. F. 1977. Coeliac disease: the abold[on of gliadin toxicity in enzymes from Aspergillus niger J. Clin, So. and Med. ~iol. (in press). singh, M. M and Kay S. I~. 1976 Wheat gluten as a pathogenic factor in schizophrenia. Science, 191, 40~.
WANDERINGS IN THE SMALL INTESTINE Stevens, F M, Phelan, J. J., Comerford, F.R., Fottrell, P. F. and McNicholl, B. 1977. Effect of glutenin an coeHac small intestine, Ir. J. Med. SC (in press) Stevens, F M., Lloyd, R. S,, Geraghty, S. M.J., Reynolds M. T G, SarMield, M. H.~ McNicholl, B,, FoBrell, P. F., Wright, R. and McCarthy, C. F. 1977 Schizophrenia and coeliac disease~ the nature of the relationship. J. Psychok Med. (in pressl. Stevens, F. M., Watt, D., Baker, S., Egan-Mitche[L B., McNicholl, B, and McCarthy, C. F. (in proparation).
225
Stokes, P. S. and Holmes, G. N. T. 1974: Malignancy in coeiiac disease. Clinics in Gastroenterolegy, 3, 159. Stokes, P. L., Asquith, P., Holmes, G. K. T., McKenzie, P. end Cooke, W. T. 1972. Histocompatibility (HL-A) antigens associated with adult coeliac disease. Lancet ~i, 152. Townley, R. R. W., Cornell, H. J., Bhattal, P. S. and Mitchell, J. D. 1973. Toxicity of wheat gliad~n fractions in coeliac disease. Lancet i, 1363. Weinstein, W. M. Piercey, J. R. A. and Dessetor, J. B, I974. Dermatitis herpet~formis arid ~ e l i a c sprue. In "Coeliac Disease", Ed. W. Th. J. M. Hekkens and A. S, Pone. p. 361.
