The small intestine in diabetes mellitus. Correlation of clinical phenomena to histomorphometric findings in peroral biopsy material

Summary Biopsy material obtained from the first portion of the jejunum of 56 unselected diabetics and 21 normal controls was examined under the electron microscope (in 8 cases) or with a method of stereologic morphometry. Controls were found to have a villous volume (VVi) of 50.19±10.1%. All values below 40% were interpreted as an expression of deterioration of the mucous membrane. Altogether 12.5% of the diabetics showed total atrophy, and 20% had significant reduction of VVi. These changes did not correlate with intestinal disorders or other signs of diabetes. In total atrophy histochemical changes could be demonstrated. Microangiopathy was not observed in the intestinal mucosa.     

Effect of difluoromethyl ornithine (DFMO) on small intestine of adult and weanling rats

Oral feeding ofdl-difluoromethyl ornithine (DFMO) (2% in waterad libitum) for 14 days has no detectable effect on the small intestine of adult rats.Similar feeding of DFMO to weanling rat pups caused diarrhea in three to four days accompanied by a decrease in food consumption and body weight compared to age-matched controls. Significant decreases in small intestinal mucosal weight, total protein, DNA, enterokinase, leucine amino peptidase, sucrase, and maltase contents were observed in the DFMO-treated group four days after treatment. Extending the treatment to seven days led to a more severe reduction in these parameters. Villous atrophy of the mucosa was demonstrable by light microscopy and morphometric measurements. The mucosa of the DFMO-treated rat pups showed a reduction in total thickness and villous height but no change in crypt depth. A significant reduction in villus-crypt ratio was also seen.Changes in small intestinal mucosal parameters were not due to a decrease in food intake since pair-fed, agematched rat pups showed no biochemical changes compared to control pups. DFMO-treated weanling rats showed less than 5% of ornithine decarboxylase (ODC) activity when compared to age-matched control animals. The effects observed on the small intestinal mucosa are presumably due to inhibition of ornithine decarboxylase activities by DFMO which prevents the proliferation, regeneration, and maturation of epithelial cells. The relative insensitivity of the adult rat small intestine to DFMO treatment suggests a lesser dependence of its intestinal mucosa to ODC activities.     

Intestinal lymphoma and sprue: A systematic approach

Intestinal lymphoma is frequently associated with sprue-like bowel patterns. A standardized approach to the problem is suggested.Intestinal lymphoma has been subdivided into four groups, depending on the extent of involvement of the anatomical region. Only cases with specific lesions are accepted as primary lymphoma.The villous pattern in 179 cases at necropsy with suitably preserved mucosa was determined to form a normal baseline for comparison with the uninvolved portions of the lymphomatous small bowel. Only 15% of all small bowel of this random material of children more than 1 year old and adults showed a flattened mucosa.The non-lymphomatous mucosa of 20 cases with definitely primary intestinal reticulum or lymphosarcoma showed severe sprue-like atrophy in 18 (90%). Two cases of intestinal Hodgkin's disease and four cases of gastric lymphoma were associated with regular mucosal patterns.It is concluded that sprue-like villous atrophy of the small bowel is definitely a triggering factor for the development of primary intestinal reticulum cell or lymphosarcoma. A hypothesis for the possible aetiological relationship of these two conditions is discussed.     

Mucosal biotransformation rates in the small intestine of children.

Biotransformation of ingested xenobiotics is known to take place in the gastrointestinal mucosa of laboratory animals and adult humans as well as in the liver. We studied the activities of aryl hydrocarbon hydroxylase, epoxide hydrolase, and glutathione peroxidase in 242 peroral small intestinal biopsy samples of children aged eight months to 18 years: 201 with normal histology, 21 with partial villous atrophy, and 20 with severe villous atrophy. All these enzymes were detectable even in the youngest children. The aryl hydrocarbon hydroxylase activity was age dependent, while the other measured enzyme activities were not related to the age of the patients. The aryl hydrocarbon hydroxylase activity was not related to the mucosal histology, but the epoxide hydrolase and glutathione peroxidase activities were diminished in samples with severe villous atrophy as compared with normal mucosa. This suggests that small intestinal mucosa with villous atrophy may produce oxidated, reactive metabolites, but further metabolism into detoxication products is decreased. This may expose persons with mucosal atrophy to possible harmful effects of environmental xenobiotics entering the body even at low doses.     

Small-bowel metaplasia arising in the remnant esophagus after esophagojejunostomy--a [corrected] prospective study in patients with a history of total gastrectomy

OBJECTIVES: The pathogenesis of Barrett's mucosa is incompletely understood. Acidic gastro-esophageal reflux is considered an essential causative factor. The aim of this study was to detect esophageal columnar metaplasia after total gastrectomy with esophagojejunostomy, a condition of enteric, but nonacidic reflux. METHODS: In a prospective study, patients with a history of total gastrectomy and esophagojejunostomy were investigated for the presence of columnar metaplasia in the remnant esophagus. Patients with such history, who were now referred for esophagogastroduodenoscopy, were included during a 2-yr period. Biopsies for histopathology were taken from the anastomosis and any columnar metaplasia of the esophagus. RESULTS: In 8 of 25 patients (32%) with a history of gastrectomy, columnar metaplasia was found in the remnant esophagus, mostly in shape of tongues, partly associated with erosive reflux esophagitis. Histopathology showed a typical small-bowel mucosa, but with some villous atrophy. In a resection specimen, a double-layered muscularis mucosa was present, which proved the metaplastic nature of the intestinal mucosa. Length of the columnar metaplasia correlated with the time interval since surgery. CONCLUSIONS: Esophageal mucosa, if exposed long term to an enteric, but nongastric refluxate, can evolve into a highly differentiated intestinal metaplasia, which resembles small-bowel mucosa. This proves that complete-type intestinal metaplasia may arise not only in the stomach, but also in the esophagus. Esophageal intestinalization seems to reflect adaptation to enteric reflux.     

JEJUNAL BIOPSY IN MALIGNANT DISEASE

The appearance of the small bowel mucosa and mucosal measurements are described in 45 patients with various malignant conditions and compared with the findings in 25 control subjects. The mean villous height and mean total mucosal thickness were significantly reduced in the patients with malignant disease. The mucosa in malignant disease was normal in 38%, and showed simple atrophy in 31%, partial villous atrophy in 29% and subtotal villous atrophy in 2% of cases. The mucosal changes were related to the duration of illness and the degree of loss of weight. They were less frequently detected in patients with bronchial carcinoma. The presence of metastases, the treatment given, the interval before death and the presence of steatorrh?a were not related to the abnormal mucosa. Steatorrh?a was detected in one-third of the patients, but it was usually slight. Steatorrh?a did not account for weight loss and abnormalities in the small bowel mucosa appeared to be unrelated to the steatorrh?a.     

Intestinal villous atrophy in chronic active hepatitis

Three out of 16 patients with chronic active hepatitis (CAH) had total or subtotal villous atrophy in a suction biopsy taken from the upper jejunum. One of the three patients had a history of intestinal dysfunction. The patients with abnormal intestinal mucosa had lower levels of serum albumin and higher levels of IgG than patients without intestinal mucosal changes. The occurrence of intestinal villous atrophy in CAH may be due to a genetically determined disposition to CAH and coeliac disease associated with HLA-B8, which was carried by all three patients. The present findings have led to trials with gluten-free diet in CAH associated with intestinal villous atrophy.     

T lymphocyte populations of the intestinal mucosa in celiac disease in children. Immunohistochemical study

In order to study the distribution of lymphocyte subpopulations in a pathologic intestinal mucosa, the authors, instead of using the classic method by counting the number of lymphocytes, present an original method permitting the exploitation of quantified data from labelled surface cells by texture analyser coupled with a computerized system. We investigated 25 children presenting with chronic diarrhea and villous atrophy and 5 control subjects. Fifteen of the 25 children had celiac disease (10 active with total villous atrophy and 5, celiac disease in remission with healing mucosa), 5 cow's milk protein intolerance with total or partial villous atrophy and 5, chronic diarrhea with partial villous atrophy. Immunohistochemical study with monoclonal antibodies was carried out on frozen sections using a three-step immunoperoxidase technique. Compared with the 5 controls, patients with food intolerance (celiac disease and cow's milk protein intolerance) showed a significant increase of T suppressor lymphocytes (p less than 0.01 and p less than 0.05) in the epithelium, whereas there were more T helper lymphocytes in the lamina propria (p less than 0.05 and p less than 0.01). Non-treated celiac disease was distinguished from treated celiac disease by a marked increase in intra-epithelial T cytotoxic-suppressors. These results suggest that T cytotoxic-suppressors may be the mediators of the lesions observed in celiac disease.     

Combined impact of mucosal damage and of cystic fibrosis on the small intestinal brush border enzyme activities

In 61 cystic fibrosis (CF) patients, the small intestinal mucosa was studied at the time of diagnosis before starting therapy. In 19 out of 61 patients, partial villous atrophy on light microscopy and shortened villi on stereomicroscopic examination were seen. On the biopsy specimens, maltase, sucrase, lactase and alkaline phosphatase activities were studied. Comparison of the enzymatic activities in CF patients having damaged mucosa and a group of patients having similar mucosal lesions of unspecified origin (UTID), reveals a significantly more pronounced decrease of the alkaline phosphatase activity (p < 0.005) in the CF patients. This is in agreement with previous reported results in CF patients with normal mucosa. The abnormal mucosal findings could be due to the decreased neutralization of the gastric content delivered into the duodenum, the early inflammatory reaction present in the CF mucosa and/or to the impaired synthesis of membrane glycoproteins and enzymes secondary to the CFTR mutation.     

IgA anti-actin antibodies ELISA in coeliac disease: A multicentre study

BACKGROUND: Previous studies have demonstrated that serum anti-actin antibodies are a reliable marker of intestinal damage severity in coeliac disease. AIMS: To validate in a multicentre study the clinical usefulness of serum IgA anti-actin antibody ELISA and its possible use in monitoring intestinal mucosa lesions during gluten-free diet. PATIENTS AND METHODS: Four centres recruited 205 newly diagnosed coeliac disease patients with villous atrophy, 80 healthy controls and 81 "disease" controls. Twelve coeliac disease patients on gluten-free diet but with persistent symptoms underwent serum IgA anti-actin antibody assay and intestinal histology evaluation. IgA anti-actin antibody ELISA was performed with a commercial kit. All coeliac disease patients underwent intestinal histology study. RESULTS: IgA anti-actin antibodies showed a sensitivity of 80% and a specificity of 85% in the diagnosis of coeliac disease patients with villous atrophy. The area under the receiving operator curve for anti-actin antibodies was 0.873 [95% C.I. 0.805-0.899]. Serum anti-actin antibodies values were significantly higher in coeliac disease patients than in healthy or "disease" controls (P<0.0001). Serum anti-actin antibodies were positive in 41 of the 60 coeliac disease patients with mild intestinal histology lesions (69%) and in 123 of the 145 with severe lesions (85.3%) (P<0.05). There was a significant inverse correlation between anti-actin antibody values and the villi/crypts ratio (r=-0.423; P<0.0001). In the 12 coeliac disease patients on gluten-free diet who underwent re-evaluation as they were persistently symptomatic, intestinal histology showed three cases with persistent villous atrophy: all of these were positive for serum anti-actin antibodies ELISA, whereas both serum anti-tTG and EmAs were negative. The other nine patients showed normal intestinal villi and were negative for serum anti-actin antibodies. CONCLUSIONS: Anti-actin antibodies are a reliable marker of severe intestinal mucosa damage in coeliac disease patients and a simple ELISA technique offers an accurate method for their determination. These antibodies seem to be a very reliable marker of persistent intestinal damage in coeliac disease patients.     

嗜酸乳杆菌合生元对抗生素相关腹泻大鼠肠道菌群和肠黏膜损伤的作用

背景：抗生素相关腹泻（AAD）是抗生素治疗最常见的不良反应。随着抗生素应用的日益广泛,AAD病例逐年增多。目的：探讨嗜酸乳杆菌与低聚异麦芽糖（IMO）组成的合生元对AAD大鼠肠道菌群和肠黏膜损伤的作用。方法：50只大鼠随机分为5组。四组模型组以盐酸林可霉素灌胃6d诱导AAD,之后其中一组予0.9%NaCl溶液灌胃7d作为自然恢复组,另三组分别予低、中、高剂量合生元灌胃7d。正常对照组仅予0.9%NaCl溶液灌胃7d。行肠道菌群分析后处死各组大鼠,行肠黏膜形态学观察和图像分析。结果：AAD模型大鼠肠道菌群失调,小肠黏膜水肿、糜烂、萎缩、坏死、脱落,绒毛排列紊乱、稀疏。不同剂量合生元组肠道菌群失调均有所改善,与正常对照组相比无明显差异;小肠黏膜病变均轻于自然恢复组,尤其是中、高剂量合生元组,小肠黏膜厚度、绒毛高度和隐窝深度较自然恢复组显著增加（P〈0.01）。结论：嗜酸乳杆菌合生元对AAD大鼠肠道菌群失调和肠黏膜损伤有一定治疗作用。     

Coeliac disease: changing views on gluten-sensitive enteropathy

BACKGROUND: The continuing flow of scientific development in coeliac disease in the past decade points to the need for the formulation of a new concept of pathophysiology and clinical approach to the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6; immunological research has led to the concept of a T-cell-driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies; and our understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten-sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs, and it may present with less severe symptoms of malabsorption. Screening studies suggest an overall prevalence of up to 1 in 200-300. METHODS: Update on histopathology concentrating on the work of our research group. RESULTS: We specifically describe the work of our group in Arnhem concerning the identification and validation of the spectrum of intestinal histopathology in gluten-sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypt hyperplasia (Marsh II lesion), and villous atrophy, subdivided into partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of 'refractory coeliacs', including the identification of (pre-)malignant aberrant T cells in the intestinal mucosa of these patients. CONCLUSION: New data on immunogenetics, epidemiology, histopathology and patient characteristics point to a significant change of view on coeliac disease.     

Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study.

This study aimed to investigate the effects of chronic ingestion of small amounts of gliadin on children with coeliac disease. A four week challenge was performed on 20 children who had been on a gluten free diet for mean (SD) 14 (3) months. They were given a daily dose of either 100 mg (group A, n = 10, mean age 4 (2) years) or 500 mg of gliadin (group B, mean age 5 (3) years). The effects of the gliadin were monitored by morphometric study of the jejunal mucosa, intestinal permeability test with cellobiose/mannitol, and serum antigliadin antibody test. After the challenge, group A patients showed a significant increase in the mean intraepithelial lymphocyte count (before challenge 11 (3), afterwards 19 (6)) and a decrease in the villous height/crypt depth ratio (beforehand 1.5 (0.1), afterwards 1.3 (0.2)), while the intestinal permeability test remained normal and the IgA-antigliadin antibody increased in four of 10 children. After the challenge group B showed more pronounced histological changes, an increase in the mean urinary cellobiose/mannitol % (beforehand 0.028 (0.020), afterwards 0.058 (0.028)), and IgA-antigliadin antibody positivity in six of eight subjects. The discriminant analysis function showed that the pretreatment group, group A after challenge, and group B after challenge were correctly classified in 90% of cases by functions based on the individual intraepithelial lymphocyte count and the villous height/crypt depth ratio. This study shows that chronic ingestion of small amounts of gluten causes dose-dependent damage to the small intestinal mucosa in children with coeliac disease. The predictive value of laboratory tests, such as the antigliadin antibody test and the intestinal permeability test seems to be lower in treated patients than in those with active coeliac disease.     

Role of the "immersion technique" in diagnosing celiac disease with villous atrophy limited to the duodenal bulb

GOALS: To investigate if the so-called immersion technique during upper endoscopy may be helpful to predict patterns of villous atrophy restricted to the duodenal bulb. BACKGROUND: Patients with celiac disease may have a patchy distribution of duodenal villous atrophy. In some cases, mucosa of duodenal bulb may be the only intestinal area involved. The immersion technique is a novel procedure that allows visualizing duodenal villi directly during endoscopy. STUDY: With this prospective study, the immersion duodenoscopy was performed in 67 celiac subjects to investigate their duodenal villous pattern. Villi were evaluated both in the first and in the second duodenal segment and judged as present or absent (flat mucosa). Results were compared with histology as reference. RESULTS: Among celiac subjects, 49 were newly diagnosed and 18 previously diagnosed celiac patients. Four (8%) newly diagnosed and 7 (39%) previously diagnosed celiac subjects had an extension of the villous atrophy (flat mucosa) limited to the duodenal bulb. The sensitivity, specificity, and positive and negative predictive values of the immersion-based duodenal investigation in predicting areas of duodenal villous atrophy was always 100%. CONCLUSIONS: Immersion technique may be useful for directing duodenal biopsies in celiac subjects with a patchy distribution of villous atrophy. This procedure can avoid blinded sampling of the duodenal mucosa and enhance the diagnostic yield.     

Coeliac disease: more than villous atrophy

A continuing flow of new scientific developments concerning coeliac disease in the last decade asks for the formulation of a new concept of pathophysiology and clinical approach of the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6. Immunological research has led to the concept of a T-cell driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies, and in addition the understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs and the disease may present with less severe symptoms of malabsorption while screening studies suggest an overall prevalence of up to 1 in 200-300. In the present paper (an update on histopathology) we specifically describe the work of our group in Arnhem, concerning the identification and validation of the spectrum of intestinal histopathology in gluten sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypthyperplasia (Marsh II lesion), and villous atrophy, subdivided in partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of "refractory coeliacs", including the identification of (pre-) malignant aberrant T-cells in the intestinal mucosa of these patients. The new data on immunogenetics, epidemiology, histo-pathology and patient characteristics point to a significant change of views on coeliac disease.     

Carnosinase activity of human gastrointestinal mucosa.

Carnosinase, the dipeptidase which hydrolyses carnosine and other histidine-containing dipeptides, was assayed in mucosal tissues of the human and of the rat gut. Kinetic properties of the intestinal enzyme were found to be similar to carnosinase of other animal tissues. Little or no activity was detected in human gastric or colonic mucosa, and the levels were lower in duodenal than jejunal mucosa. The distribution of carnosinase is similar to that of the disaccharidases. Mean carnosinase activity was 8-8 units/g weight in 15 patients with histologically normal mucosa compared with 5-7 units in five with villous atrophy. The enzyme levels increased with histological improvement of the mucosa in patients with coeliac disease on a gluten-free diet. Tolerance curves for carnosine and its constitutent amino acids showed malabsorption of the dipeptide in a patient with carnosinase deficiency. It is concluded that the intestinal mucosa has much less hydrolase activity for carnosine than for glycylglycine and other dipeptidases, and the relatively slow hydrolysis appears to be the rate-limiting step in the total absorptive process.     

Gluten challenge in borderline gluten-sensitive enteropathy

OBJECTIVES: In patients with signs and symptoms of malabsorption, suggestive of gluten-sensitive enteropathy, small intestinal biopsies sometimes only reveal infiltration of lymphocytes into the mucosal epithelium. This infiltrative lesion (Marsh I) is not a definite proof for gluten-sensitive enteropathy. However, in the present study, we aimed to show that a subgroup of these patients could ultimately be identified as being gluten sensitive. METHODS: A total of 38 patients with a Marsh I lesion were subjected to a gluten challenge comprising 30 g of gluten added daily to a normal gluten-containing diet for 8 wk. Before and after the challenge, small intestinal biopsies were taken, and symptoms and signs of malabsorption were scored. RESULTS: In 12 patients we demonstrated a significant change in mucosal histopathology, i.e., subtotal villous atrophy (Marsh IIIB, n = 1), partial villous atrophy (Marsh 3A, n = 6) or infiltrative-crypthyperplastic lesions (Marsh II, n = 5). In the other 26 patients, the small intestinal mucosa remained unchanged. After initiation of a gluten-free diet, follow-up small intestinal biopsies in 12 patients who initially had progressive mucosal pathology after gluten challenge showed normalization of mucosal pathology in seven cases, regression to a Marsh I lesion in four, and to a Marsh II lesion in one. Symptom relief was seen in all 12 patients. Ten of 26 patients without histological response to the gluten challenge were motivated to adhere to a gluten-free diet. Follow-up biopsies revealed unchanged Marsh I lesions in eight patients and normalization (Marsh 0) in two patients. Three patients had follow-up biopsies while on a normal diet. All had unchanged Marsh I lesions. CONCLUSIONS: In the present study we demonstrated that a gluten challenge might be useful in identifying patients as being sensitive to gluten if initial small intestinal biopsies reveal only minor abnormalities.     

Duodenal disaccharidase activities in the follow-up of villous atrophy in coeliac disease

BACKGROUND: In active coeliac disease, mucosal atrophy is associated with a marked decrease in intestinal disaccharidase enzyme activities. We investigated the value of duodenal mucosal disaccharidases to predict the severity of mucosal villous atrophy and its recovery in 50 patients with coeliac disease. METHODS: Duodenal mucosal histology and disaccharidase activities were studied at least twice with a mean interval of 9 months. Histology of specimens from all patients was examined by the same pathologist blinded to the data on disaccharidase activities. Mucosal damage was scored into four groups as follows: Grade 0 = normal mucosa; grade I = slight villous atrophy, that is, cryptic component 30%-50%; grade 2 = moderate villous atrophy, that is, cryptic component 50%-90%; grade 3 = severe villous atrophy, that is, cryptic component >90%. The enzyme activities of the disaccharidases were determined as U/g protein. RESULTS: Duodenal mucosal disaccharidase activities were good predictors of the grade of mucosal villous atrophy. Positive predictive values for moderate or severe villous atrophy were 90% for maltase (maltase activity <150 U/g protein), 86% for sucrase (<40 U/g protein) and 71% for lactase (<20 U/g protein). Accordingly, negative predictive values, that is, none or only minimal villous atrophy (grades 0 or 1) with normal disaccharidase activities, were 71% for maltase, 70% for sucrase and 63% for lactase. CONCLUSIONS: The increase in duodenal disaccharidase activities correlated with recovery of the mucosa based on histology. Besides the histological examination, measurement of disaccharidase activities offers an additional tool to evaluate response to a gluten-free diet in patients with coeliac disease.     

Morphometric studies of the small intestine following jejuno-ileal shunt operation.

In five patients in whom a jejuno-ileal by-pass had been previously performed for massive obesity, a relaparotomy was performed because of subjective complaints or unsatisfactory weight reduction. At the reoperation morphometric studies were made of the functioning segments and the by-passed intestine. Length and circumferential measurements were taken, and the villous height and mucosal thickness were measured from histological biopsies. The results were compared with the findings in a control group. After shunt operation adoptive hypertrophy in the functioning remnant, a considerable length growth and dilatation of the gut, as well as a marked increase in villous height and total mucosal thickness, were demonstrated. These adaptive changes seem to be more marked in the distal part of the small intestine. No atrophy of the mucosa could be demonstrated in the excluded intestinal loop.     

Cellobiose/mannitol sugar permeability test complements biopsy histopathology in clinical investigation of the jejunum

Intestinal permeability to probe molecules has been shown to correlate closely with the presence or absence of villous atrophy in a jejunal biopsy. The purpose of this study was to establish if there exist groups of patients with functional derangement of intestinal permeability but normal histopathology of the small bowel mucosa. In 135 patients a cellobiose/mannitol permeability test was performed at the same time as jejunal biopsy. Diagnosis included coeliac disease, Crohn's disease, irritable bowel syndrome, idiopathic diarrhoea, self diagnosed food allergy, atopic eczema and postinfectious malabsorption. The value of the cellobiose/mannitol test in identifying patients with abnormal jejunal biopsy histopathology was confirmed. The permeability test was abnormal in all 28 patients with partial or subtotal villous atrophy, and also in all 10 in whom there was a high intraepithelial lymphocyte count despite normal villi and crypts. Functional abnormality of the small intestine has not previously been reported in patients with this jejunal biopsy abnormality. Abnormalities of permeability were also found in patients with idiopathic diarrhoea, folate deficiency, postinfectious or traveller's diarrhoea, small bowel Crohn's disease, and atopic eczema. These results show that sugar permeability tests have more potential in clinical investigation than merely serving as screening tests before jejunal biopsy. There are groups of patients without morphological changes in the small bowel in whom intestinal permeability is abnormal.