Gluten, major histocompatibility complex, and the small intestine: A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’)

Background Celiac disease (CD) is an immune-mediated enteropathic condition triggered in genetically susceptible individuals by the ingestion of gluten. Although common in Europe, CD is thought to be rare in the United States, where there are no large epidemiologic studies of its prevalence. The aim of this study was to determine the prevalence of CD in at-risk and not-at-risk groups in the United States. Methods Serum antigliadin antibodies and anti–endomysial antibodies (EMA) were measured. In EMA-positive subjects, human tissue transglutaminase IgA antibodies and CD-associated human leukocyte antigen DQ2/DQ8 haplotypes were determined. Intestinal biopsy was recommended and performed whenever possible for all EMA-positive subjects. A total of 13 145 subjects were screened: 4508 first-degree and 1275 second-degree relatives of patients with biopsy-proven CD, 3236 symptomatic patients (with either gastrointestinal symptoms or a disorder associated with CD), and 4126 not-at-risk individuals. Results In at-risk groups, the prevalence of CD was 1:22 in first-degree relatives, 1:39 in second-degree relatives, and 1:56 in symptomatic patients. The overall prevalence of CD in not-at-risk groups was 1:133. All the EMA-positive subjects who underwent intestinal biopsy had lesions consistent with CD. Conclusions Our results suggest that CD occurs frequently not only in patients with gastrointestinal symptoms, but also in first- and second-degree relatives and patients with numerous common disorders even in the absence of gastrointestinal symptoms. The prevalence of CD in symptomatic patients and not-at-risk subjects was similar to that reported in Europe. Celiac disease appears to be a more common but neglected disorder than has generally been recognized in the United States.

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/215079/ioi20641.pdf

Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study

A BSTRACT Background Radiographic contrast agents can cause a reduction in renal function that may be due to reactive oxygen species. Whether the reduction can be prevented by the administration of antioxidants is unknown. Methods We prospectively studied 83 patients with chronic renal insufficiency (mean [±SD] serum creatinine concentration, 2.4±1.3 mg per deciliter [216± 116 µmol per liter]) who were undergoing computed tomography with iopromide, a nonionic, low-osmolality contrast agent. Patients were randomly assigned either to receive the antioxidant acetylcysteine (600 mg orally twice daily) and 0.45 percent saline intravenously, before and after administration of the contrast agent, or to receive placebo and saline. Results Ten of the 83 patients (12 percent) had an increase of at least 0.5 mg per deciliter (44 µmol per liter) in the serum creatinine concentration 48 hours after administration of the contrast agent: 1 of the 41 patients in the acetylcysteine group (2 percent) and 9 of the 42 patients in the control group (21 percent; P=0.01; relative risk, 0.1; 95 percent confidence interval, 0.02 to 0.9). In the acetylcysteine group, the mean serum creatinine concentration decreased significantly (P<0.001), from 2.5±1.3 to 2.1±1.3 mg per deciliter (220±118 to 186±112 µmol per liter) 48 hours after the administration of the contrast medium, whereas in the control group, the mean serum creatinine concentration increased nonsignificantly (P=0.18), from 2.4±1.3 to 2.6±1.5 mg per deciliter (212±114 to 226± 133 µmol per liter) (P<0.001 for the comparison between groups). Conclusions Prophylactic oral administration of the antioxidant acetylcysteine, along with hydration, prevents the reduction in renal function induced by iopromide, a nonionic, low-osmolality contrast agent, in patients with chronic renal insufficiency. (N Engl J Med 2000;343:180-4.)

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Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine.

Ulcerative colitis (UC) and Crohn’s disease (CD) (collectively termed inflammatory bowel disease (IBD)) are complex disorders reflected by wide variation in clinical practice. These guidelines, commissioned by the Clinical Services’ Committee of the British Society of Gastroenterology (BSG) for clinicians and allied professionals caring for patients with IBD in the United Kingdom, provide an evidence based document describing good clinical practice for investigation and treatment. The guidelines are intended to bring consistency, but should not necessarily be regarded as the standard of care for all patients. Individual cases must be managed on the basis of all clinical data available for that case. Patient preferences should be sought and decisions jointly made between patient and health professional.

### 1.1 Development of guidelines

A comprehensive literature search was performed using electronic databases (Medline, PubMed, and Ovid; keywords: “inflammatory bowel disease”, “ulcerative colitis”, and “Crohn’s disease”) by Dr Carter. A preliminary document was drafted by Dr Carter, Dr Lobo, and contributing authors. This was summarised by Dr Travis and revised after circulation first to the committee and then to members of the IBD section of the BSG, before submission to the Clinical Services’ Committee.

### 1.2 Grading of recommendations1

The guidelines conform to the North of England evidence based guidelines development project. The grading of each recommendation is dependent on the category of evidence supporting it:





### 1.3 Scheduled review of guidelines

The content and evidence base …

https://gut.bmj.com/content/gutjnl/53/suppl_5/v1.full.pdf

Guidelines for the management of inflammatory bowel disease in adults

Tremendous progress has been made in our understanding of food-based allergic disorders over the past 5 years. Recent epidemiologic studies suggest that nearly 4% of Americans are afflicted with food allergies, a prevalence much higher than appreciated in the past. In addition, the prevalence of peanut allergy was found to have doubled in American children less than 5 years of age in the past 5 years. Many food allergens have been characterized at the molecular level, which has contributed to our increased understanding of the immunopathogenesis of many allergic disorders and might soon lead to novel diagnostic and immunotherapeutic approaches. The management of food allergies continues to consist of educating patients on how to avoid relevant allergens, to recognize early symptoms of an allergic reaction in case of an accidental ingestion, and to initiate the appropriate emergency therapy. However, the recent successful clinical trial of anti-IgE therapy in patients with peanut allergy and the number of immunomodulatory therapies in the pipeline provide real hope that we will soon be able to treat patients with food allergy.

https://www.jacionline.org/article/S0091-6749(04)01145-5/pdf

Update on food allergy

https://www.gastrojournal.org/article/S0016-5085(98)70007-1/pdf

Autoantibodies to tissue transglutaminase as predictors of celiac disease

Currently recognised forms of gluten sensitive enteropathy Within the framework of the current definition (a permanent gluten sensitive enteropathy), clinical, pathological, epidemiological, and immunological approaches are revealing several forms of coeliac disease. In so called active coeliac disease, malabsorption, and nutritional deficiencies range from profound to minimal; clinically silent coeliac disease is being increasingly recognised for example, in family studies. Pathologically there is also a degree of heterogeneity. Descriptive terms such as 'flat mucosa', or 'subtotal villus atrophy', are the pathologist's shorthand for a cluster of features (villus, crypt sizes, epithelial cell damage, intraepithelial and lamina propria lymphoid cell infiltrates) which together characterise the enteropathy of coeliac disease. Quantitative histology and computerised image analysis have shown that these features occur in a continuum, with the flat lesion at one end of the spectrum and a mucosa with normal villus and crypt architecture, but an abnormally high density or count of villus intraepithelial lymphocytes, at the other. 2 The latter would be reported as normal by most clinical pathologists. This fact is important when the evidence for the existence of latent coeliac disease is reviewed. This term should only be applied to patients who fulfil the following conditions: (i) have a normal jejunal biopsy while taking a normal diet; (ii) at some other time, before or since, have had a flat jejunal biopsy which recovers on a gluten free diet. The suggestion that there might be a 'precoeliac' state was first made by Weinstein who described two patients with dermatitis herpetiformis and normal jejunal biopsies in whom typical coeliac like enteropathy developed some weeks after 20 g gluten was added to their already gluten containing diet.3 Two studies from the United Kingdom have confirmed this observation45 and the concept is supported by

https://gut.bmj.com/content/gutjnl/34/2/150.full.pdf

Clinical and pathological spectrum of coeliac disease--active, silent, latent, potential.

Low bone mineral density in Crohn's disease, but not in ulcerative colitis, at diagnosis

Background—Polyethylene glycol (PEG) 3350 is a non-absorbable, nonmetabolised osmotic agent used in lavage solutions for gut cleansing. Aims—To compare the eYcacy of PEG and lactulose in chronic constipation. Methods—A total of 115 patients with chronic constipation entered a multicentre, randomised, comparative trial. They initially received two sachets containing either PEG (13 g/sachet) or lactulose (10 g/sachet) and were given an option to change the dose to one or three sachets/ day, depending on response. Results—Ninety nine patients completed the trial. After four weeks, patients in the PEG group (n=50) had a higher number of stools and a lower median daily score for straining at stool than patients in the lactulose group (n=49). Overall improvement was greater in the PEG group. Clinical tolerance was similar in the two groups, but flatus was less frequently reported in the PEG group. The mean number of liquid stools was higher in the PEG group but the diVerence was significant only for the first two weeks. There were no serious adverse events and no significant change in laboratory tests in either group. At the end of the study, the number of sachets used by the patients was 1.6 (0.7)/day in the PEG group and 2.1 (0.7)/day in the lactulose group. Sixty one patients completed a further two months open study of one to three sachets PEG daily; there was no loss of eYcacy and no serious toxicity. Conclusion—Low dose PEG 3350 was more eVective than lactulose and better tolerated. (Gut 1999;44:226‐230)

https://gut.bmj.com/content/gutjnl/44/2/226.full.pdf

Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation

Summary: The normal effect of feeding an antigen, such as ovalbumin (hens' egg albumin), to adult animals is the induction of a state of specific nonreactivity of the lymphoid tissues when the same antigen is presented again (oral tolerance). We have carried out feeding experiments in neonatal mice to investigate subsequent immune responses after physiologic antigen exposure and to examine the role of the neonatal intestine. We demonstrate for the first time that feeding a weight related dose of ovalbumin within the first week of life results in priming for both humoral and cell-mediated immune responses, despite the profound tolerance found in adult animals when treated in the same way. When the time scale of antigen exposure was extended into the prenatal period, the enhancement of the immune response was even more pronounced. These effects are long lasting and effects on cell-mediated immune responses are still demonstrable 14 wk after the initial priming feed. We postulate that after an antigen feed in the neonatal period, immunologic and digestive immaturity lead to a net gain in T help which prevents the induction of systemic hyporesponsiveness (oral tolerance).

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Anne Ferguson

Papers

Autoantibodies to tissue transglutaminase as predictors of celiac disease

Clinical and pathological spectrum of coeliac disease--active, silent, latent, potential.

Low bone mineral density in Crohn's disease, but not in ulcerative colitis, at diagnosis

Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation

Immune responses to fed protein antigens in mice. 3. Systemic tolerance or priming is related to age at which antigen is first encountered.