Correlation between IgA antiendomysial antibodies and subtotal villous atrophy in dermatitis herpetiformis.

Serum IgA antiendomysial antibodies (EmA) were present in 20 (64.5%) of 31 patients with dermatitis herpetiformis (DH) on a normal diet. A significant correlation was found between these antibodies and the severity of gluten-induced jejunum damage. IgA EmA were positive in 19 (86%) of the 22 DH patients with subtotal villous atrophy, in comparison with the positivity of only one (11%) of the nine DH patients with less severe intestinal involvement (partial villous atrophy or mild abnormalities). The specificity of this test for gluten-sensitive enteropathy was 100%, these antibodies being consistently negative in biopsied disease controls showing a normal jejunal mucosa. Moreover, IgA EmA proved to be useful in monitoring the response to gluten withdrawal in DH patients, as these antibodies always disappeared in all the DH cases studied after 1 year of gluten-free diet together with the regrowth of jejunal villi. The strict relationship between IgA EmA and subtotal villous atrophy is more helpful still since the enteropathy present in DH is usually symptomless and therefore difficult to suspect.     

Small intestinal function and dietary status in dermatitis herpetiformis.

Small intestinal morphology and function were assessed in 82 patients with dermatitis herpetiformis, 51 of whom were taking a normal diet and 31 a gluten free diet. Methods used were histopathological evaluation of jejunal mucosal biopsy specimens, quantitation of intraepithelial lymphocytes, cellobiose/mannitol permeability test, tissue disaccharidase values, serum antigliadin antibodies, and formal assessment of dietary gluten content by a dietician. There was no correlation between dietary gluten intake and the degree of enteropathy in the 51 patients taking a normal diet, whereas biopsy specimens were normal in 24 of the 31 patients on a gluten free diet, all previously having been abnormal. Eighteen patients on gluten containing diets had normal jejunal histology and in seven of these all tests of small intestinal morphology and function were entirely normal. Intestinal permeability was abnormal and serum antigliadin antibodies were present in most patients with enteropathy. Studies of acid secretion in seven patients showed that hypochlorhydria or achlorhydria did not lead to abnormal permeability in the absence of enteropathy. This study shows that a combination of objective tests of small intestinal architecture and function will detect abnormalities in most dermatitis herpetiformis patients, including some with histologically normal jejunal biopsy specimens. Nevertheless there is a small group in whom all conventional intestinal investigations are entirely normal.     

Linear IgA bullous dermatosis responsive to a gluten-free diet

Dermatitis herpetiformis is associated with a gluten-sensitive enteropathy in >85% of cases. Both the skin lesions and the enteropathy respond to gluten restriction. Linear IgA bullous dermatosis has a much lower prevalence of histological small bowel abnormalities, and lesions are not known to respond to gluten restriction. We report a patient with linear IgA bullous dermatosis and gluten-sensitive enteropathy. This report addresses the issue of whether linear IgA bullous dermatosis can be associated with gluten-sensitive enteropathy. We evaluated the response to gluten restriction and normal diet by following the status of the patient's jejunal biopsies and skin lesions. The patient responded to gluten restriction, as shown by resolution of jejunal abnormalities and skin lesions and subsequently by recurrence of jejunal abnormalities and skin lesions with reinstitution of a gluten-containing diet. This report demonstrates that linear IgA bullous dermatosis can respond to gluten restriction if an underlying gluten-sensitive enteropathy is present.     

Effect of antibiotic therapy on gluten-sensitive enteropathy

Summary In 2 cases of gluten-sensitive enteropathy, clinical recovery, partial in one and complete in the other, followed the administration of a gluten-free diet. When challenged with gluten both patients had a pronounced relapse. After the prolonged administration of tetracycline both patients have resumed a normal diet and show no effect when challenged with gluten. If these results can be confirmed in other patients, there must be a factor other than gluten in the so-called gluten-sensitive enteropathy.Supported in part by Grants AM-5093-08 and M01-FR30 from the National Institutes of Health, U. S. Public Health Service.     

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.     

Gluten challenge in children with dermatitis herpetiformis: a clinical, morphological and immunohistological study.

Twenty one children with dermatitis herpetiformis were studied in an attempt to evaluate the response in the skin, in jejunal morphology, and in jejunal immunoglobulin containing cell counts to gluten elimination and subsequent gluten challenge. In all of the 15 patients whose jejunal biopsy was studied after the eventual gluten challenge the jejunal lesion had returned in 2.4 to 28 months. The numbers of IgA- and IgM-containing cells were similarly raised in primary and postchallenge biopsies. In the 13 patients whose skin improved during a gluten free diet and who were challenged with gluten the rash worsened and the dapsone/sulphapyridine requirement increased. The jejunal deterioration was equally marked in the six patients whose gluten challenge was stopped because of an intractable rash as it was in those who completed the preplanned challenge. The specimens of the former, however, had significantly more IgA-containing cells than specimens of the latter. The number of intraepithelial lymphocytes clearly reflected the degree of intestinal damage. IgA-containing cells proved to be the most sensitive indicator of an immune reaction taking place in the gut of these patients. Even in the two children with initially normal or nearly normal jejunal mucosa, the IgA cell counts in the jejunal lamina propria were markedly raised.     

IgA antibodies to jejunum

Serum IgA antibodies to jejunum (JAB) were found in 78 (96%) of 81 adults and children with untreated celiac disease. Not only did IgA JAB display a significant higher prevalence than IgA antigliadin antibodies (AGA) (72%) in untreated gluten-sensitive enteropathy, but they also allowed us to identify another three celiacs in addition to those detected by IgA antiendomysial antibodies (EmA). Like IgA EmA, IgA JAB persisted at low titer in seven (14%) of 50 celiacs tested after 12 months of gluten-free diet (GFD) despite the regrowth of jejunal villi, whereas IgA AGA disappeared in all these patients consistently with the normalization of intestinal mucosa. IgA JAB and EmA reappearance was close to 100% in the 13 celiacs studied after six months of gluten challenge, while IgA AGA reached the highest prevalence (about 70%) after one month of gluten ingestion without any increase in the following months. All disease and healthy controls were always negative for the three IgA antibodies. Our results prove that IgA JAB and EmA are the best screening tests for active (untreated and on gluten challenge) celiac disease, whereas IgA AGA should be used for monitoring the response to gluten withdrawal. IgA JAB are an expression of a specific immunity directed against the target organ of gluten-sensitive enteropathy, but, before ascribing them a role in the pathogenesis of celiac disease, it should be ascertained whether their production is a primary event leading to jejunal lesions or whether it is a secondary phenomenon due to antigen release from a previously damaged jejunal mucosa.     

Abnormal permeability precedes the development of a gluten sensitive enteropathy in Irish setter dogs.

Intestinal permeability to 51Cr-EDTA was examined during the development of gluten sensitive enteropathy in dogs bred from affected Irish setters and reared on a normal wheat containing diet. Comparisons were made with litter mates reared on a gluten free diet and with a control group of age matched, clinically healthy Irish setters reared on the normal diet. Studies at 4, 6, 8, and 12 months of age were correlated with morphometric and biochemical examinations of peroral jejunal biopsy specimens. Permeability was increased at all ages in the group fed gluten free diet compared with control dogs, although there were no differences in villus height, intraepithelial lymphocyte density, and alkaline phosphatase activity. At four months, permeability in the normal diet group was greater than in controls, although comparable with that in the gluten free diet group. Permeability in the normal diet group increased further in conjunction with the development of partial villus atrophy and reduced alkaline phosphatase activity, and by 12 months permeability was significantly greater than in their gluten free diet litter mates and the control dogs. The findings suggest that an underlying permeability abnormality may be involved in the pathogenesis of gluten sensitive enteropathy in Irish setter dogs.     

Prostanoids in jejunal biopsy specimens of celiac children with active disease and on challenge diet. Radioimmunologic evaluation

Prostanoid generation (prostaglandin E2 and thromboxane B2) in jejunal biopsy specimens from celiac patients was evaluated, comparing celiac patients with celiac patients on challenge diet and controls. Generation of prostaglandin E2 in jejunal specimens from 14 children with active celiac disease was significantly higher (341.8 +/- 82.3 ng/g; mean +/- SEM) than that from 7 celiac patients on gluten challenge diet (69.4 +/- 13.2 ng/g) or 8 normal children (92 +/- 23 ng/g) (p less than 0.05). In contrast, thromboxane B2 generation in jejunal specimens from all three groups did not show any statistically significant variation. Our results indicate that prostaglandin E2 generation is not merely related to the activity of clinical symptoms, since patients receiving gluten challenge had prostaglandin E2 levels that did not differ from those of controls.     

Dietary modulation of gluten sensitivity in a naturally occurring enteropathy of Irish setter dogs.

Gluten sensitivity in a naturally occurring enteropathy of Irish setter dogs, and the effects of excluding dietary cereal from birth on the subsequent response to gluten challenge were investigated. Peroral jejunal biopsy specimens were obtained at 1 year of age for morphometric and biochemical examinations, and intestinal permeability was assessed using 51Cr-ethylenediaminetetraacetic acid. Affected setters, reared on a normal wheat containing diet, exhibited partial villus atrophy, intraepithelial lymphocyte infiltration, reduced brush border alkaline phosphatase activity, and increased intestinal permeability. Gluten sensitivity was shown by introduction of a gluten free diet, which resulted in resolution of morphological and biochemical abnormalities and decreased intestinal permeability, and subsequent gluten challenge, which resulted in relapse. In contrast, littermates reared exclusively on a cereal free diet showed minimal changes when challenged with gluten, apart from intraepithelial lymphocyte infiltration. These findings document a gluten sensitive enteropathy in Irish setters and indicate that exclusion of dietary cereal from birth may modify subsequent expression of the disease.     

Small-bowel involvement in dermatitis herpetiformis and in linear-IgA bullous dermatosis

In 23 patients with dermatitis herpetiformis (DH) and five patients with linear-IgA bullous dermatosis (BD), we evaluated the occurrence of histologic jejunal changes and small-bowel function abnormalities. None of the patients showed clinical signs or symptoms of malabsorption. Morphological jejunal changes consistent with gluten-sensitive enteropathy were found in 82% of DH patients and in 60% of BD patients. However, BD patients showed only mild jejunal histologic abnormalities, whereas more severe jejunal lesions were found in most patients with DH. Functional tests showed a rough correlation with the severity of the jejunal lesions, being almost completely normal in BD patients and DH patients with mild intestinal damage, whereas most of DH patients with subtotal or total villous atrophy showed abnormal d-xylose tests and folic acid assays. Lactose tolerance tests (H2 breath test and blood glucose after oral lactose load) showed no correlation with the degree of jejunal damage.     

Selective immunoglobulin a deficiency, ulcerative colitis, and gluten-sensitive enteropathy--a unique association.

A patient with selective immunoglobulin A deficiency, severe ulcerative colitis, and malabsorption had a flat jejunal mucosa demonstrated by peroral biopsy. Treatment at different times with a gluten-free diet for the jejunal lesion and corticosteroids for the ulcerative colitis, led to improvement of the malabsorption. A repeat jejunal biopsy demonstrated histological improvement of the jejunal mucosa, even though the colitis remained active. The occurrence of immunoglobulin A deficiency in a patient with ulcerative colitis and gluten-sensitive enteropathy is uncommon.     

Intestinal antibody pattern of coeliac disease: association with gamma/delta T cell receptor expression by intraepithelial lymphocytes, and other indices of potential coeliac disease.

Patients with coeliac disease have IgM antibodies and IgA anti-gliadin antibody in gut secretions, and also high counts of intraepithelial lymphocytes (IEL) that express the gamma/delta T cell receptor. These features of intestinal immunity may be markers of latent coeliac disease. Their occurrence was examined in 77 patients referred for jejunal biopsy, in whom biopsy histology was normal, to establish the extent to which these, and other candidate markers (high total IEL count, serum IgA anti-gliadin antibody (AGA), and increased permeability) coexist in the same patient. Twelve patients had high serum anti-gliadin antibody titres and nine increased permeability. The gamma/delta IEL count was high (> 5.5 per mm villus epithelium) in nine patients, the intestinal antibody pattern was positive in 21, and the total IEL count was high (> 40 per 100 enterocytes) in 13. Overall, 31 patients had positive indices, but in 19 only a single test was abnormal. High gamma/delta IEL counts were found in six of 21 intestinal antibody positive patients, but in only two of 56 who were intestinal antibody negative (p < 0.001); there were no other significant associations. Clinical tests of gluten sensitivity will be required to establish the prevalence of latent gluten sensitive enteropathy in the 40% of patients referred for jejunal biopsy in whom one or more of the immunological indices of potential coeliac disease is present.     

The effect on jejunal mucosa of withdrawing and adding dietary gluten in cases of idiopathic steatorrhoea

Biopsy studies of the jejunal mucosa in patients with idiopathic steatorrhoea after periods on a gluten-free diet showed that the epithelium improved quickly in respect of surface cell height, mucosal thickness, and mitosis count, and more slowly in respect of villous height and width. In no case was recovery complete in every particular. Appearances seen through the dissecting microscope improved slowly and incompletely.Gluten loading after a period on a gluten-free diet partially reversed some of these mucosal changes in as short a time as five to seven days.Measuring such changes may help to hasten the diagnosis in some patients with suspected gluten-sensitive enteropathy in whom there is otherwise difficulty in assessing the clinical response to a gluten-free diet. The histological response of the jejunum to a gluten-free diet and to subsequent gluten loading may help to clarify the aetiological relationship between carcinoma and jejunal mucosal atrophy.     

HLA-DR expression, natural killer cells and IgE containing cells in the jejunal mucosa of coeliac children.

The expression of HLA-DR by surface and crypt epithelium and the numbers of cells of natural killer (NK) phenotype and of IgE containing cells were studied with monoclonal antisera using the peroxidase technique. We examined 48 jejunal biopsy specimens taken from 35 coeliac children before treatment (11), during gluten free diet (20) and after gluten challenge (17), and 13 control specimens. The luminal surface of the epithelial cells stained with HLA-DR antiserum in all specimens, but the cytoplasm of the surface epithelial cells took up the stain more frequently in the specimens from the controls (5/13) than those from the coeliacs (2/48) (p less than 0.01). In 21/28 specimens taken from coeliacs when on a gluten containing diet the crypt epithelium showed strong HLA-DR expression, while only 4/20 (p less than 0.01) specimens of coeliacs on a gluten free diet and 1/13 specimens of controls had similar staining. Among the intraepithelial lymphocytes no cells of NK phenotype were found in specimens from patients or controls. As compared with control specimens biopsy specimens from untreated coeliac patients showed smaller numbers of NK cells in the lamina propria. No difference was found in the numbers of IgE containing cells between the patients and controls. The strong expression of HLA-DR by the crypt epithelial cells in coeliac children on a normal diet suggest that these cells are involved in the presentation of the antigen.     

Dermatitis herpetiformis: diagnosis, diet and demography

We describe a long term study of 76 patients with dermatitis herpetiformis. Unlike patients with coeliac disease, where the peak incidence was during the first and fourth decades, no dermatitis herpetiformis patients presented in the first decade; also, there was a male preponderance in dermatitis herpetiformis which contrasts with the excess of females in coeliac disease. The apparent prevalence of dermatitis herpetiformis was 11 per 100 000 in our population; approximately one fifth of that of coeliac disease. Jejunal villous atrophy was present in 78% of our dermatitis herpetiformis patients, and a single jejunal biopsy was as effective at detecting this as the multiple biopsy technique. A majority of patients were able to stop, or radically reduce their dapsone or sulphapyridine treatment after the institution of a gluten free diet. Spontaneous remission of the skin lesion occurred in only two patients not receiving a gluten free diet. Gastric parietal or thyroid antibodies were detected in 38% of patients, and three cases of thyroid disease and two cases of pernicious anaemia were detected. Lymphoma developed in two patients, one being intestinal in origin. We conclude that a gluten free diet is of therapeutic benefit in dermatitis herpetiformis and that spontaneous remission is uncommon in those not on a diet. Despite patchiness of the enteropathy, a single jejunal biopsy is quite adequate to diagnose the presence of upper intestinal villous atrophy.     

Gluten Challenge in Patients with Celiac Disease: Evaluation of α1-Antitrypsin Clearance

Our aim in this study was to monitor changes of the intestinal structure by alpha 1-antitrypsin clearance (alpha 1-ATCL) in order to offer an alternative to the gluten challenge biopsy. In addition, we evaluated the possibility of reducing the time of gluten challenge. Twelve patients had a presumptive diagnosis of celiac disease based on clinical and histological grounds. They were studied when the jejunal histology was normal after gluten-free diet and an alpha 1-ATCL was normal. The gluten was introduced by returning to a normal diet. The challenge lasted 4 wk. We measured alpha 1-ATCL at the end of the 1st and 4th wk, and a new jejunal biopsy was obtained at the end of the 4th wk. By wk 1, alpha 1-ATCL was abnormal in 11 patients but normal in one. By wk 4, alpha 1-ATCL was abnormal in 10 patients and still normal in one. The post-challenge biopsies showed atrophy in 11 and was normal only in the patient with normal alpha 1-ATCL at wk 1 and 4. One patient with abnormal alpha 1-ATCL had to stop the challenge at the first week. The patient with normal clearance at wk 1 and 4 and normal biopsy at wk 4 had abnormal results at 6 months. These data support our hypothesis that alpha 1-ATCL can be used as evidence of gluten toxicity after gluten challenge, and that this test can be abnormal as early as 1 wk after gluten is reintroduced.     

Response of the skin in dermatitis herpetiformis to a gluten free diet, with reference to jejunal morphology.

Twenty-one patients with dermatitis herpetiformis have been on a gluten free diet regularly followed up for at least one year (mean four years). Eighteen patients had a 'flat' mucosal appearance (grade III), one patient had moderately severe mucosal abnormality (grade II), one patient had mild mucosal abnormality (grade I), and one patient had a normal mucosal appearance (grade O). On the diet, 10 patients had no skin rash and took no dapsone, seven patients controlled the skin rash on a lower dose of dapsone, and four noticed no improvement. There was no correlation between pre-diet jejunal morphology and response of the skin. A repeat jejunal biopsy, on the gluten free diet, was possible in 15 patients. While all those with skin improvement showed some improvement in jejunal morphology, there was no association between the degree of skin improvement and the degree of recovery of the jejunal mucosa.     

Gluten-sensitive enteropathy: Synthesis of antigliadin antibody in vitro

The intestinal mucosa of patients with gluten-sensitive enteropathy responds to gluten challenge in vivo with a striking increase in IgA and IgM synthesis. Whether this increase in immunoglobulin synthesis is due in some part to the production of antigliadin antibodies is examined. Using an affinity chromatography technique it has been demonstrated that in six of seven patients with gluten-sensitive enteropathy approximately half of the net increase in IgA and IgM synthesis occurring after gluten challenge can be attributed to the synthesis of antigliadin antibody. These data strengthen the hypothesis that immunological phenomena are related to the pathogenesis of glutensensitive enteropathy.