Nemoci a infekce tenkého střeva prof. Gerhard Rogler – Gastro Update Europe 2019, Budapest

Celiac disease is thought to affect 1% of the western population. Human leukocyte antigen haplotypes DQ2 and DQ8 are present in over 90% of the celiac patients compared to approx. 40% in the general population. Celiac disease may be associated with other autoimmune diseases. In addition to intestinal symptoms, celiac disease may be complicated by vitamin and trace mineral deficiences, bone disease and malignancy. Non-celiac gluten intolerance/sensitivity and seronegative celiac disease have recently been described. Perhaps enterovirus infection may increase the risk of developing celiac disease. Monthly stool samples from Norwegian DQ2/DQ8 positive children were checked starting from age month 3 to 36 for enterovirus and adenovirus using real-time reverse transcriptase polymerase chain reaction. After a mean of 10 years, celiac disease was diagnosed in 25 of 220 children. Enterovirus was found in 17% of the stool samples and was significantly more frequent in samples collected before development of celiac disease antibodies. Such data are quite intriguing and ask for more information to fully understand the way early viral infection leads to celiac enteropathy in predisposed individuals.

A meticulously followed gluten-free diet is so far the only treatment to antagonize the chronic inflammatory tissue destruction. An important recent study revealed that chronic inflammation permanently reconfigures the tissue-resident lymphocytic compartment. Normally there is a stable tissue-resident lymphocyte population which plays a key role in immune surveillance. In celiac disease, gluten-induced inflammation triggers a depletion of such naturally occurring intraepithelial lymphocytes. Exclusion of dietary gluten appears insufficient to reconstitute this important subset of intraepithelial lymphocytes. Clinicians should be aware of the extensive differential diagnosis in celiac-like mucosal abnormalities; conditions accompanied by enhanced intraepithelial lymphocytosis include: non-steroidal anti-inflammatory drugs or proton pump inhibitor consumption, Giardia or Cryptosporidium infection, immunodeficiency disorders, bacterial overgrowth, irritable bowel syndrome etc; conditions accompanied by villus atrophy with or without intraepithelial lymphocytosis include: angiotensin receptor blocker-associated enteropathy (olmesartan etc), mycophenolate mofetil, autoimmune enteropathy, immunodeficiency disorders, eosinophilic disorders, chemoradiation etc. Olmesartan-associated enteropathy is an under-diagnosed cause of diarrhea, weight loss and pan-malabsorption.

Lifelong strict gluten-free diet therapy is demanding, which explains the many strategies for non-dietary treatment which are currently being explored as exemplified in the Fig. 1 (figures are available only on the website www.csgh.info).

Hopefully some results of the many ongoing trials will lead to clinically useful application in the future. The American Gastroenterology Association recently published a clinical practice update on diagnosis and monitoring of celiac disease. What follows is a selection of the recommendations. High tissue transglutaminase-imunoglobulin (tTG-IgA) levels are reliable for diagnosing active disease. When celiac disease is suspected but biopsies are negative, positive tTG-IgA should lead to repeat biopsy sometime in the future. When patients have already started a gluten-free diet before a proper diagnosis was made, it is suggested that the patient goes back to a normal diet with three slices of wheat bread daily for 1–3 months before repeat determination of tTG-IgA. A biopsy-avoiding diagnostic pathway was schematically suggested (Fig. 2 – figures are available only on the website www.csgh.info).

There is a rising interest for „point of care“ testing for several diseases, also for celiac disease with Simtomax, which detects IgA and IgG antibodies against deamidated gliadin peptides. This test was prospectively evaluated in over 1,000 German patients, of whom 4.1% had celiac disease. Simtomax’ sensitivity and specificity were 79 and 94% respectively, and positive and negative predictive value 37 and 99%, therefore unsuitable as a screening test in routineclinical practice.

Non-celiac gluten sensitivity, detected by controlled gluten challenge, may be present in a minority of all those avoiding gluten containing food (the gluten hype). Avoiding wheat products in such patients not only lowers the gluten intake but also the amount of FODMAPs, which may contribute to the symptom improvement. Yet a mild gluten-triggered immune reaction may also be ongoing in those sensitive individuals as suggested by higher numbers of intraepithelial CD3+ T-cells and lamina propria CD45+ cells and eosinophils in duodenal mucosa. More detailed studies are necessary before we understand the pathophysiological differences between celiac disease and gluten/wheat sensitivity.

Campylobacter jejuni is the leading cause of foodborne bacterial enteritis in humans. As shown in a large German study, consumption of chicken meat (74%) and eating out were the most important factors for campylobacter infection. Problematic is the rising antimicrobial resistance. In Japan, the ciprofloxacin resistance rose in approx. 10 years from 35 to 42%. Also in a Turkish cohort, Campylobacter isolates were found to be resistant to ciprofloxacin (74%), tetracyclin (25%) and erythromycin (6%). In a French cohort, quinolone resistance rose from 48 to 55%. These are alarming figures making erythromycin or azithromycin now the treatment of choice. Prevention is crucial and only possible by meticulous avoiding of food contamination via raw chicken meat during food preparation.

Also non-typhoidal Salmonella bacteremia is increasing especially in the elderly, as shown in a recent British study. Note that 34% of the bacteremia isolates were resistant to a 1^st line antibiotic regimen, frequently quinolone. Death occurred in 12% of the (most often) elderly patients. Other studies also pointed to the steady rise of plasmid-mediated quinolone resistance in human non-typhoidal Salmonella infections.

The frequency of Clostridioides difficile (a gram-positive, spore-forming anaerobic bacterium) is increasing worldwide. The infection may lead to severe life-threathening (pseudomembranous) colitis. The most important risk factors include antibiotic therapy, old age and hospital stay. Diagnosis is based on toxin detection in stool. Toxin A is an enterotoxin damaging the mucosal barrier function and stimulating intestinal secretion, and toxin B is a cytotoxin-driving inflammation. Antibiotic therapy of choice is based on vancomycin, fidaxomicin and, less so, metronidazole. In severe or recurrent or refactory patients, fecal microbiota transplantation may be successful in > 90%. In successfully treated patients, a rapid and sustained stool enrichment was seen with microorganisms producing a bile salt hydrolase. This hydrolase converts taurocholic acid, a potent trigger for C. difficile germination, to cholic acid and deoxycholic acid, potent inhibitors of C. difficile growth. New British Society of Gastroenterology guidelines include the following statements:

• sterile 0.9% saline should be considered as an appropriate diluent for fecal transplant production and cryoprotectant, such as glycerol should be added for frozen preparations;
• > 50 g stool, should be used per transplant preparation;
• stool should be mixed 1: 5 with diluent to make the emulsion;
• homogenisation and filtration of the preparation should be undertaken in a closed disposable system.

More than 30 million individuals worldwide are yearly affected by traveller’s diarrhea. For prophylaxis, bismuth subsalicylate may be considered for any traveler, and rifaximin (but not fluoroquinolones) when antibiotic prophylaxis is indicated. The illustration below summerizes recent overall recommendations for traveller’s diarrhea (Fig. 3 – figures are available only on the website www.csgh.info).

For moderate disease, both azithromycin (preferably a single dose) and rifaximin may be considered. Rifamysin SV-MMX is a novel poorby absorbed broad spectrum antibiotic, active against an-/aerobic, gram-pos/neg pathogens and shown to be as effective as ciprofloxacin, without substantial induction of extended-spectrum beta-lactamase-producing Escherichia coli.

The Gastro Update Europe 2020 will be held on June 5–6, 2020 in Bratislava, Slovakia. For more information visit www.gastro-update-europe.eu.

Prof. Guido Tytgat, MD, PhD

Department of Gastroenterology and

Hepatology

Academic Medical Center

Meibergdreef 9

1105 AZ Amsterdam

The Netherlands

 g.n.tytgat@amc.uva.nl

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