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Gluten sensitive enteropathy and other causes of small intestinal lymphocytosis.

Recent studies on gluten sensitive enteropathy (GSE) have heightened the pathologist's awareness of intraepithelial lymphocytes in duodenal biopsies. Mild histologic forms of GSE are now recognized with increased IELs as the only histologic change. In this review, both the classic morphology and "minimal deviation" GSE are discussed in detail, with special emphasis on the differential diagnosis and how to avoid overdiagnosing this condition. The Marsh-Oberhuber classification is described and contrasted with a more practical diagnostic terminology that is recommended for use in pathology reports. Other important conditions associated with duodenal lymphocytosis, such as refractory sprue, autoimmune enteropathy, and Helicobacter pylori-associated duodenitis, are also presented.

Biopsy↗

A stable isotope study of zinc kinetics in Irish setters with gluten-sensitive enteropathy.

The short-term kinetics of Zn turnover were studied in Irish setters with gluten-sensitive enteropathy and control dogs following intravenous injection of 0.25 mg 96.5% enriched 70ZnCl2. The 70Zn enrichment of serum was found closely to obey two-compartment kinetics and the derived two-compartment decay equation was used to calculate the size and turnover of the two initial rapidly exchanging pools of body Zn. In normal Irish setters isotopic Zn initially equilibrates with a pool (a) of size 1.27 (SD 0.46) mumol/kg and then with a second pool (b) of size 6.83 (SD 1.72) mumol/kg. The fractional turnover of pool (b) was approximately one eighth that of pool (a). Enteropathic dogs showed no reduction in the size of either rapidly exchangeable Zn pool, reduction in serum Zn concentration or abnormality in Zn balance and hence these results do not support the possibility of an underlying Zn deficiency in this disorder.

Animals↗

Major histocompatibility complex susceptibility genes for dermatitis herpetiformis compared with those for gluten-sensitive enteropathy.

Dermatitis herpetiformis (DH) shares some clinical features and major histocompatibility complex (MHC) markers with gluten-sensitive enteropathy (GSE). We compared MHC haplotypes in 27 patients with DH, 35 patients with GSE, and normal controls. As in GSE, the frequencies of two extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were increased in patients with DH. Distributions of fragments of extended haplotypes, consisting of some but not all of the elements of complete extended haplotypes, were analyzed to attempt to localize a susceptibility gene. Besides complete extended susceptibility haplotypes, (DR3, DQ2) and (DR7, DQ2) fragments were most common in GSE. In contrast, DH showed only a few such fragments but many instances of the fragment (SC01). The differences in distribution of these fragments in the two diseases were highly significant (P < 0.002). HLA-DQ2 and DR3 had the highest odds ratios for GSE, but the highest odds ratio for DH was for the complotype SC01. These findings suggest that the MHC susceptibility gene for DH is between class II and complotype regions, closest to the complotype, whereas that for GSE is in the class II region.

Celiac Disease↗

Satiating effect of proteins in healthy subjects: a comparison of egg albumin, casein, gelatin, soy protein, pea protein, and wheat gluten.

The influence of six dietary protein types (egg albumin, casein, gelatin, soy protein, pea protein, and wheat gluten) on satiety and food intake was investigated. Twelve healthy subjects ingested six protein-manipulated lunches (approximately 5.2 MJ, 22% of energy as protein) according to a within-subjects design. Test meals were controlled for energy, macronutrients, fiber, and palatability. Nearly 65% of total protein varied between sessions. After lunch, satiety was assessed for 8 h and energy and macronutrients intakes were measured for 24 h. Blood was collected for determination of postprandial plasma glucose and insulin responses. Results showed no effect of the type of protein on satiety, on 24-h energy or macronutrient intakes, or on postprandial plasma glucose and insulin concentrations. These findings differ in part from those obtained previously in humans, which suggested that proteins may be differentiated in terms of their satiating capacities. We conclude that varying the protein source in a mixed meal does not affect food behavior in healthy humans, probably because coingestion of carbohydrate and fat with protein buffers the kinetics of the physiologic mechanisms implicated in postprandial satiety after a protein load.

Adult↗

Longitudinal changes in bone metabolism and bone mineral content in children with celiac disease during consumption of a gluten-free diet.

BACKGROUND: A gluten-free diet (GFD) rapidly corrects the bone mineral deficit of children with untreated celiac disease. The mechanisms underlying such changes are still poorly understood. OBJECTIVE: In a longitudinal study, we monitored changes in bone metabolism during consumption of a GFD. DESIGN: We studied 22 white patients with celiac disease (11 girls) aged 10.5 +/- 1.0 y at the time of diagnosis. We compared bone metabolism and bone mass values in these patients with those in 428 healthy white children aged 11.3 +/- 0.2 y. Bone-specific alkaline phosphatase (a bone formation index) and N-terminal telopeptide of type I collagen (NTx; a bone resorption marker) were measured at the time of diagnosis and after 2, 6, and 12 mo of the GFD. Bone mineral content was measured at the lumbar spine and for the whole skeleton. RESULTS: The bone mineral content of patients was significantly lower than that of control subjects at the time of diagnosis but not after 1 y of the GFD. Serum bone-specific alkaline phosphatase concentrations of patients were significantly lower than those of control subjects at the time of diagnosis (P = 0.0064) and increased gradually and significantly during the GFD (ANOVA F = 4.71; P = 0.024). Conversely, patients with untreated disease had significantly higher urinary concentrations of NTx than did healthy control subjects (P < 0.0001). Urinary concentrations of NTx were not significantly affected by treatment (P = 0.37). CONCLUSIONS: The rate of bone metabolism is altered in children with untreated celiac disease, and these alterations may be the cause of osteopathy. Remarkable changes occur after the initiation of a GFD, and they result in a more balanced equilibrium.

Alkaline Phosphatase↗

Early postmolt performance of laying hens fed a low-protein corn molt diet supplemented with corn gluten meal, feather meal, methionine, and lysine.

Commercial White Leghorn hens (65, 63, or 70 wk of age in Experiments 1, 2, and 3, respectively) were induced molted by feed withdrawal until approximately 28% body weight was lost. All hens were then weighed, and seven replicate groups of 12 hens each were fed molt diets. In Experiment 1, three diets consisted of a corn basal diet (7.9% CP) or this diet supplemented with corn gluten meal (CGM) and Lys or feather meal (FM), Met, and Lys. In Experiments 2 and 3, varying levels of FM and FM with Met and Lys were evaluated. A 16% CP corn-soybean meal diet was used as a positive control in all experiments. The molt diets were fed for 17, 15, and 17 d in Experiments 1, 2, and 3, respectively, and production performance was measured for 8 wk from the beginning of feeding the layer diet. In all experiments, hens fed the 16% CP corn-soybean meal molt diet returned to egg production and regained body weight at a faster rate than did hens fed any of the other diets. In Experiment 1, early egg production of hens fed the corn basal diet supplemented with CGM and Lys or supplementation with FM, Met, and Lys was greater (P < 0.05) than that of hens fed the basal diet alone. In Experiment 2, very early egg production (Week 1) and body weight gain were lower (P < 0.05) for hens fed the corn basal diet than for hens fed the basal supplemented with FM, Met, and Lys. The addition of 5.75 or 8.5% FM or 5.75% FM plus Met and Lys generally increased (P < 0.05) early egg production and postmolt body weight gain compared to the corn basal diet in Experiment 3. The present study thus indicated that improved early postmolt performance may be achieved by supplementation of a low-protein corn molt diet with various combinations of CGM, FM, Met, and Lys.

Animal Feed↗

Role of lymphocytic immunophenotyping in the diagnosis of gluten-sensitive enteropathy with preserved villous architecture.

Clinically significant gluten-sensitive enteropathy (GSE) can be associated with architecturally normal small bowel villi and evenly distributed increased intraepithelial T lymphocytes (IELs). This distribution pattern of IELs has been shown to be a sensitive feature of GSE but to be of relatively low specificity, thus limiting its usage as a diagnostic marker. We demonstrate herein the potential diagnostic role of IEL immunophenotyping. We show that a top-heavy distribution pattern of CD3+ IELs is a sensitive diagnostic feature of GSE. Despite overlap between GSE and non-GSE patients, the difference is underscored when using a tip-to-base ratio. Of the GSE patients, 87.5% showed a tip-to-base ratio >1.7 compared with only 12.5% of non-GSE patients and none in controls. This pattern was retained in 50% of treated GSE patients, although the CD3+ tip-IEL scores were significantly smaller. Conversely, CD8 immunostaining appears of limited diagnostic value. The discrepancy in distribution of CD3+ and CD8+ IELs between GSE and non-GSE patients can be explained by the presence of CD4- CD8- TCR-gamma delta+ IELs which, have been reported in GSE. Since the immunophenotyping of T- IELs is feasible with readily available antibodies, and given the clinical benefits for patients with 'latent' GSE, we advocate using CD3 immunostaining to triage patients with normal villi and increased IELs.

Adolescent↗

Immunohistologic parameters in minimal morphologic change duodenal biopsies from patients with clinically suspected gluten-sensitive enteropathy.

Subclinical or latent cases of gluten-sensitive enteropathy (GSE) are difficult to diagnose, and serology-positive, histology-negative (minimal morphologic change) and serology-negative, histology-positive patients have been identified. Both, particularly the histology-negative group, require the correct diagnosis for proper management, especially because the concept of minimal histologic change GSE has escaped attention in standard textbooks. We assessed the numbers and distribution of intraepithelial T cells and their subsets with CD3, CD8, and CD4 immunostaining and examined for crypt hyperplasia with mitotic and Ki-67 proliferative indices with the aim of refining the criteria for the diagnosis of minimal change GSE. Duodenal biopsies from 46 clinically suspected cases of GSE tested for antigliadin, antiendomysium, and antitissue transglutaminase antibodies were divided into four groups: serology-positive, histology-positive (S+H+, n = 20); serology-positive, histology-negative (S+H-, n = 22), representing the minimal morphologic change group; serology-negative, histology-positive (S-H+, n = 4); and serology-negative, histology-negative (S-H-, n = 28), controls with histologically normal duodenal biopsies obtained for unrelated reasons. The numbers of CD3+ and CD8+ intraepithelial T cells (IETCs) were significantly higher in histology-positive biopsies with (mean, 40.3/100 and 39.3/100 enterocytes, respectively) and without positive serology (mean, 33.3/100 and 35/100 enterocytes, respectively) compared with all other groups (S+H-, mean, 26.5/100 and 24.3/100 enterocytes, respectively; S-H-, mean, 23.3/100 and 17.9/100 enterocytes, respectively). Values for Ki-67 index in crypt enterocytes were also significantly different between histology-positive and histology-negative groups (P = 0.000). The distribution of CD3+ and CD8+ IETCs was mostly even along the surface enterocytes in histology-positive cases compared with the controls, which showed an uneven distribution. The 2 parameters that significantly discriminated between minimal morphologic change GSE (S+H-) and controls (S-H-) were Ki-67 index (P = 0.007) and the distribution pattern of CD8+ IETCs (P = 0.049). CD4 IETC counts were generally low, with no significant difference between all groups. The few S-H+ cases seen most likely represented false-negative serology, because the assessed parameters of this group and S+H+ cases were indistinguishable.

Adolescent↗

Epilepsy and celiac disease: favorable outcome with a gluten-free diet in a patient refractory to antiepileptic drugs.

BACKGROUND: There is a well-documented relationship between epilepsy and celiac disease, including a syndrome characterized by epilepsy, occipital calcifications, and celiac disease. REVIEW SUMMARY: We report the case of a 23-year-old woman with an 11-year history of refractory epileptic seizures and newly diagnosed biopsy-proven celiac disease with increased antiendomysium immunoglobulin A antibodies. The patient showed a dramatic improvement after starting a gluten-free diet. CONCLUSION: This case emphasizes the need to include celiac disease in the differential diagnosis when investigating the etiology of epilepsy in refractory patients.

Adult↗

A patient with osteomalacia as single presenting symptom of gluten-sensitive enteropathy.

A 59-year-old male patient presented with invalidating osteomalacia of 2.5 years' duration. The osteomalacia was caused by severe malabsorption due to gluten-sensitive enteropathy (GSE). There were no other signs or symptoms of GSE in this patient. Clinical presentation with monosymptomatic osteomalacia is very unusual. It seems that patients with GSE who undergo little exposure to the sun are at particular risk of developing overt osteomalacia. Unrecognized GSE should always be considered in the differential diagnosis of osteomalacia.

Celiac Disease↗

Use of HLA marker associations and HLA haplotype linkage to estimate disease risks in families with gluten-sensitive enteropathy.

Based on a two-locus, double recessive model, we derive formulas for the risks that relatives of individuals with gluten-sensitive enteropathy (GSE) will also develop the disease. The calculations take advantage of: the linkage between the HLA locus and one of the two proposed GSE loci, and the preferential association of the HLA-DR3 and DR7 alleles with the GSE disease allele that occupies the HLA-linked locus. We use Bayes' rule to quantitate the strength of the association between the GSE disease allele and the HLA marker allele. This method predicts that siblings of the proband have an overall 10% risk for GSE, which is consistent with observed family data. This predicted risk rises to 30% when siblings are HLA-identical to the proband (also consistent with observed data) or when the sibling has the DR3 allele in the HLA haplotypes not shared with the proband. In those populations where DR7 also is associated with GSE, siblings of probands have a 10% predicted risk for GSE when only one HLA haplotype is shared with the proband and DR7 is included in the unshared haplotype. Other DR alleles are associated with much lower disease risks. By separating individuals into high and low risk groups, HLA typing identifies those individuals who would benefit from further diagnostic procedures. This general strategy should be applicable to other multilocus, marker-associated diseases.

Alleles↗

Coeliac disease in children with Type 1 diabetes mellitus: the effect of the gluten-free diet.

PATIENTS AND METHODS: We assessed the frequency of coeliac disease in 281 children with Type 1 diabetes and the effect of gluten-free diet (GFD) in newly diagnosed cases. Serological screening was performed using anti-gliadin and anti-endomysium antibodies. Data were obtained about clinical symptoms, height and weight-for-height. RESULTS: A small intestinal biopsy was recommended to 18 patients (6.4%) with positive serological results and 12 children agreed. Nine of them had coeliac disease. Three out of nine coeliac children complained about gastrointestinal symptoms. On a GFD, the symptoms disappeared in two patients. Iron-deficiency anaemia was present in four subjects and disappeared in the three patients who accepted the GFD. In three patients (33%), coeliac disease was asymptomatic. Height and weight-for-height were in the normal range for all patients. For well-complying patients, there was a significant increase in height standard deviation at diagnosis and on follow-up (-0.28 vs. +0.35) (P = 0.03). Changes in weight-for-height were not significant (-4.0% vs. +1.4%) (P = 0.28). There was a trend to an improvement in HbA(1c) (8.0 vs. 7.3%) (P = 0.05). CONCLUSIONS: Serological screening is effective. There is a therapeutic benefit for some screening-detected patients, but confirmatory studies are needed.

Adolescent↗

Erythema elevatum diutinum associated with celiac disease: response to a gluten-free diet.

An 11-year-old girl with a history of insulin-dependent diabetes mellitus had erythema elevatum diutinum (EED) associated with a celiac disease related to a possible kidney disease. Dapsone did not improve the skin manifestations. However, the lesions disappeared after a gluten-free diet was begun. To our knowledge, this report describes the first case of EED in a patient with celiac disease.

Celiac Disease↗

Variability of histologic lesions in relation to biopsy site in gluten-sensitive enteropathy.

OBJECTIVES: It is generally believed that in gluten-sensitive enteropathy or celiac disease (CD), mucosal lesions may have a patchy distribution. We wanted to verify this concept and establish whether one or more biopsy samples are needed in order to make a correct diagnosis of CD. METHODS: One hundred and twelve consecutive children with positive antiendomysium (EMA) or antitissue transglutaminase (tTGA) antibodies, referred to us for suspected CD, were enrolled in a prospective fashion. During upper GI endoscopy four to five biopsies were taken from Treitz and/or distal duodenum (D3), intermediate duodenum (D2), proximal duodenum (D1), and duodenal bulb (B). Histologic lesions were classified according to Marsh criteria modified by Oberhuber. RESULTS: A total of 110 patients, all HLA-DQ2 or DQ8 positive, had a final diagnosis of CD (59 classic, 28 atypical, and 23 silent): 102/110 (92.7%) had type 3 lesion-(a) mild, (b) moderate, or (c) severe-in at least one site and 94/110 (85.4%) had villous atrophy (VA) of some degree in all sites. VA of identical degree was present in all biopsy sites in 55/110 (50%) patients. Total VA (type 3c) was present in at least one site in 85/110 (75%), in all sites in 50/110 (45.4%), and significantly increased in aborad direction ((chi(2) > 26.22 with (= 0.01 and d.f. (degrees of freedom) = 12). Eight out of 110 (7.2%) CD patients had exclusively type 1 or 2 lesions, no patient had lesion variability >1 degree and none had normal biopsies. There was no correlation between type or distribution of histologic lesions and clinical presentation of CD. CONCLUSIONS: Mucosal atrophy is present in 85% of patients with CD and total VA is significantly more frequent in distal duodenum or proximal jejunum. Fifty percent of patients have identical VA throughout the duodenum and no duodenal areas are histologically normal. In genetically susceptible children with positive serology, a diagnosis of CD can reliably be made even if biopsies are not taken from the distal duodenum or jejunum.

Adolescent↗

Coeliac disease and malignancy of the duodenum: diagnosis by endoscopy, successful treatment of the malignancy, and response to a gluten free diet.

A patient presented with subtotal villous atrophy and a malignant duodenal tumour of uncertain histogenesis. He was successfully treated by resection and chemotherapy and the small bowel mucosa recovered on a gluten free diet. The tumour was diagnosed at upper gastrointestinal endoscopy when barium studies and abdominal computed tomography were normal, thus making this one of the earliest coeliac malignancies diagnosed.

Antineoplastic Combined Chemotherapy Protocols↗

IgA anti-tissue transglutaminase as a diagnostic marker of gluten sensitive enteropathy.

AIMS: To compare and contrast the sensitivity, specificity, and positive predictive values of IgA antibodies to guinea pig tissue transglutaminase (ELISA), endomysium, and reticulin (immunofluorescence), and gliadin (ELISA), and IgG antibodies to gliadin and tissue transglutaminase. METHODS: Sera from 27 newly diagnosed patients with coeliac disease, 65 biopsied gastrointestinal disease controls, and 50 consecutive blood donors were tested. All cases were adults. RESULTS: IgA anti-tissue transglutaminase showed a sensitivity of 85% (23/27 coeliac disease cases seropositive), specificity 97% (2/65 controls and one blood donor showing low titre positivity), and a positive predictive value of 92%. High titre anti-tissue transglutaminase was only seen in coeliac disease. Disease controls with mucosal damage unrelated to gluten enteropathy were IgA anti-tissue transglutaminase negative. Sensitivity, specificity, and positive predictive values for IgA anti-endomysial antibody (monkey oesophagus) were 100%, 100%, and 100%, respectively, and for IgA anti-gliadin, 93%, 95%, and 89%, respectively. CONCLUSIONS: Tissue transglutaminase is a major autoantigen in coeliac disease. IgA (but not IgG) anti-tissue transglutaminase, especially when in high titre, is closely associated with coeliac disease, but low titres may not be disease specific. In this small pilot study, the established IgA anti-endomysial assay was the superior test.

Adult↗