CD SKILLS Coeliac disease in the spotlight CD SKILLS (DTP 571) project is co-funded by the Interreg Danube Transnational Programme. CIP - Kataložni zapis o publikaciji Univerzitetna knjižnica Maribor Editors: Petra Rižnik, Jasmina Dolinšek, Jernej Dolinšek 616.34-008.1(075)(0.034.2) Authors: Ida Čarnohorski, Jasmina Dolinšek, Jernej Dolinšek, COELIAC disease in the spotlight Nataša Dragutinovič, Judit Gyimesi, Almuthe Christina Hauer, [Elektronski vir] / [editors Petra Rižnik, Martina Klemenak, Sibylle Koletzko, Ilma Rita Korponay-Szabo, Jasmina Dolinšek, Jernej Dolinšek Tomaž Krenčnik, Dušanka Mičetić-Turk, Zrinjka Mišak, Rouzha Pancheva, ; authors Ida Čarnohorski ... et al.]. - Vesna Pavkov, Manuel Prevedel, Tatiana Raba, Petra Rižnik, E-knjiga. - Maribor : University Medical Alina Stanescu Popp, Peter Szitanyi, Katharina Julia Werkstetter Centre, 2022 Proofreading: Dianne Jones Način dostopa (URL): https:/ www.interreg-danube.eu/ Publisher: University Medical Centre Maribor, 2022 approved-projects/cd-skills/outputs ISBN 978-961-7039-87-0 (PDF) COBISS.SI-ID 149184771 Design: Studio 8 d.o.o. Coeliac disease in the spotlight 3 Coeliac disease in the spotlight Table of contents 1 Introduction ..................................................................................................................................................................... 5 2 History of coeliac disease ....................................................................................................................................... 6 3 Epidemiology .................................................................................................................................................................. 8 4 Aetiology ........................................................................................................................................................................... 10 5 Clinical presentation ................................................................................................................................................ 14 6 Diagnostics ..................................................................................................................................................................... 19 7 Risk groups .................................................................................................................................................................... 24 8 Treatment ....................................................................................................................................................................... 26 9 Follow-up ......................................................................................................................................................................... 29 10 Complications ................................................................................................................................................................ 31 11 Quality of life of coeliac disease patients .................................................................................................. 33 12 Clinical cases ................................................................................................................................................................. 34 13 Quiz results ..................................................................................................................................................................... 35 14 Answers for clinical cases .................................................................................................................................... 36 4 Coeliac disease in the spotlight 1 Introduction Coeliac disease? Coeliac disease Coeliac disease affects more than 1% of the population and it is therefore very likely that every physician, regardless of his/ her specialisation, will frequently face a patient with this condition. For this reason, it is very important to know the principles of management of the disease including its pathophysiology, epidemiology, clinical presentation, diagnostic procedures, treatment and long-term management options. The information presented by the authors of this study material, together with case studies provides the most recent knowledge about coeliac disease required to optimise the quality of care for these patients, which is still often sub-optimal. We sincerely hope that you will enjoy reading this study material and that it will serve you as a useful reference in your future practice. Editorial Board. 5 Coeliac disease in the spotlight 2 History of coeliac disease 2 History of coeliac disease OBJECTIVES: • To learn about the history of the development of coeliac disease. • To learn about the trend in the development of diagnostic methods for coeliac disease. Ancient history (rice), but his publication went unnoticed. ease, knowledge about specific changes A long, long time ago, there was no coe- In 1888, an English physician, Dr Samuel in the intestinal mucosa, and the possi- liac disease on planet Earth. This was not Gee, a leading paediatrician of that time, bility of performing a biopsy of the small the result of poor awareness and poor published a description of the clinical pic-intestine with an instrument. diagnostic possibilities or the fact that ture of coeliac disease in London, and his humans had different genes. This was a publication became the basis of the mo- Recent history result of the fact that, at that time, there dern description of the disease. Gee, like The 2nd meeting of the European Society was no gluten in their diet. Baillie, believed that “If a patient is cured for Paediatric Gastroenterology, Hepatol- at all, it must be by the means of a diet.” ogy and Nutrition (ESPGHAN) in Interlak- Man was a hunter and a gatherer, eating In 1908, the American paediatrician Her- en in 1969 opened a new chapter in the fruits, nuts, tubers and occasionally the ter published a book on coeliac disease, history of coeliac disease. There, the first meat of hunted animals. This diet lasted which is why the disease was later often criteria for establishing a diagnosis were for a very long time, from the beginning called Gee-Herter’s disease. His greatest established: evidence of abnormal mor- of humankind (approx. 2.5 million years contribution was the finding that chil- phology of the small intestinal mucosa, its ago) and remained unchanged until dren with coeliac disease could tolerate normalisation after the elimination of glu-10,000 years ago. It was only after the end fats better than carbohydrates. In 1920, ten from the diet, and relapse after inten-of the last Ice Age, with the onset of ma- Sidney Haas introduced a very successful tional gluten exposure – gluten challenge. jor climate changes, that men started to banana diet in the treatment of children Based on the characteristic changes in grow food. The agricultural revolution in with coeliac disease. His publication was the small intestinal mucosa that occur as the Neolithic period thus forever changed a great success, and for several decades, a result of gluten consumption, coeliac the way people live. In South-East Asia be- the “banana diet” was very popular. The disease has been called gluten enterop- tween today’s southern Turkey and Iraq, diet completely excluded bread and athy. people began to cultivate wild cereals at grains and was, in principle, a form of a the end of the Ice Age. These first types gluten-free diet. However, it was only after The first criteria of the ESPGHAN for di- of wheat, barley and rye did not contain World War II in 1950, that a Dutch paedi- agnosing coeliac disease in 1970 (the so- much gluten. It is known that the culti- atrician, W. K. Dicke, made a fundamen- called “classic criteria”) were therefore vation of cereals relates to the spread of tal discovery by observing that the caus- based on changes in the intestinal muco- agricultural populations across the Med- ative factor for the disease was a protein sa, which are today most often described iterranean and the Pannonian plain into called gluten from the wheat grain. In according to the Marsh/Oberhuber classi-Europe. As the population grew, so did his doctoral dissertation, he demonstrat- fication (Chapter 6). In the 1980s, after the need for food and increased food pro- ed a dramatic improvement in clinical the discovery of coeliac disease-specific duction. As a result, new types of cereals symptoms of the disease when wheat, antibodies, the first critical comments on appeared, which enabled a larger yield of rye and oats were excluded from the diet. the criteria appeared, hence modified cri- crops with higher content of gluten and He later discovered that the toxic compo- teria were adopted at the 22nd ESPGHAN other proteins in the grain. Bread gradu- nent in wheat flour was alcohol-soluble meeting in Budapest in 1989. The basic ally became a basic everyday food. In the gliadin. At the time of Dicke’s discovery, change was to abandon the mandatory 16th century, the production of pasta and other research enabled the identification gluten challenge, a so-called diagnostic other flour products spread from south- of the pathological substrate of coeliac procedure with three biopsies, and the ern Italy throughout Europe. The gluten disease. Post-mortem reports of patients importance of serological tests was em- content in the daily diet of the European with tropical sprue described morpho- phasised. population has only increased significant- logical changes in the small intestine, ly in the last three centuries. A significant although these were initially believed to Since 1990, coeliac disease has been increas- percentage of the population never de- be artefacts of autolysis. Paulley was the ingly described as an autoimmune disease veloped a tolerance to this new protein, first researcher to demonstrate with cer- associated with a specific HLA-haplotype gluten, and coeliac disease developed. tainty that mucosal changes in the small DQ2 or DQ8. The missing autoantigen, tis- intestine are characteristic of coeliac dis- sue transglutaminase, was discovered in History ease. This was later confirmed by the in- 1997 in Germany, thus it was unanimously Clinical symptoms of malabsorption were troduction of a peroral biopsy of the small accepted that coeliac disease is an auto- described from around the 6th century intestine. A major breakthrough in the immune condition, the trigger of which BC in India. In ancient Greece, in the 1st field of diagnostics occurred in the late is gluten, and that the autoantigen is tis- century BC, the physician Areteus from 1950s when Margot Shiner described a sue transglutaminase (Chapter 4). Along Cappadocia clearly described the clinical new intestinal biopsy device with which with the changes in the understanding picture of the disease (the classic, gastro- she successfully performed a biopsy of of the pathogenesis of coeliac disease, intestinal form) naming it koiliakos. The the distal duodenum. This, together with knowledge of the clinical presentation of adjective “coeliac” is the Latin version of the development of a simple capsule the disease also changed. The perspective the Greek word “koilia”, which means ab-by Crosby, allowed the identification of that coeliac disease is a childhood disease domen. Subsequent descriptions of the characteristic changes in the mucosa of of the white population, mostly with a disease can be traced back to the 17th and the proximal gastrointestinal tract – i.e., characteristic phenotype (i.e., blue-eyed, 18th centuries. Dr Mathew Baillie, unaware mucosal atrophy. In the 1960s, three very and light-haired children), changed in of Areteus, described chronic diarrhoea important new fundamentals of coeliac the 1980s. Coeliac disease was also found in adults characterised by a large, disten- disease emerged: the knowledge that to be increasingly associated with other ded abdomen, for which he advised a diet gluten is the triggering factor for the dis- diseases (Chapter 7). It has become clear 6 2 History of coeliac disease Coeliac disease in the spotlight that the presentation of coeliac disease is read in 5-10 minutes (Chapter 6). The de- agnosis, the determination of specific changing, with a decreasing number of velopment of genetics also played a key coeliac disease antibodies is most impor- gastrointestinal symptoms and signs and role in the understanding and diagnostics tant, and for the first time, the possibility an increasing number of various extrain- of coeliac disease. Family and twin studies of establishing a diagnosis without intes- testinal complications (Chapter 5). These have shown that the disease has an im- tinal biopsy under certain specific con- facts probably contributed to the increas- portant genetic background. Most studies ditions was introduced. The latest 2020 ing attention and in-depth research on focused on the correlation with HLA (hu- guidelines for diagnosing coeliac disease coeliac disease with significant changes man leukocyte antigen) alleles encoded in children and adolescents further rein- in the epidemiology of the disease (Chap- on the sixth chromosome (6p21.3). In par- force the no-biopsy approach and elimi- ter 3). ticular, the discovery of antibodies against nate the need for genetic testing in the transglutaminase, which are autoanti- diagnostic process (Chapter 6). Progress and innovations in bodies in coeliac disease, and the discov- the field of coeliac disease ery of a genetic predisposition character- diagnostics istic of coeliac disease, provided insight Although the development of medi- At first, antigliadin antibodies (AGA) were into the basic pathogenetic mechanisms cine dictates changing the diagnos- used in clinical practice, followed by an- that lead to the development of the dis- tic criteria based on the evidence ti-endomysial antibodies (EMA), which ease. Today, we know that coeliac disease and although, in the case of coeliac were first described in patients with coe- is not only a disease of childhood and that disease, we no longer talk about glu- liac disease in 1984 and were quickly in- it not only presents with gastrointestinal troduced into routine use. EMA have long complaints. Recent data even show that ten enteropathy but rather about a been the gold serological standard for the frequency of coeliac disease in the el-systemic immune disease caused by diagnosing coeliac disease. Antibo dies derly is higher than in children. gluten, one fact remains unchanged against tissue transglutaminase (TGA) in the story. With the unpreceden- were introduced at the turn of the mi- Due to the active approach to pa- ted development that we have wit- llennium. Antibodies against deamidated tient-finding, there was a constant in- nessed in the field of diagnosis and gliadin peptide are also used for diagnos- crease in the frequency of the disease understanding of coeliac disease, it tic purposes, but they have no advantage in Europe and the USA at the end of the is quite unusual that there has not over TGA and EMA in diagnosing coeliac last century. Today, coeliac disease is one been anything new in the treatment disease. In 2005, for the first time, the data of the most common chronic diseases of coeliac disease for more than 70 on a rapid test that enables the detection (Chapter 3). years. A strict lifelong gluten-free diet of antibodies against tissue transglutami- is still considered the only acceptable nase was published. This method utilises At the present time treatment. Perhaps it is here where tissue transglutaminase in erythrocytes The ESPGHAN diagnostic criteria pub-there is more room for future re- to detect TGA in a capillary blood sam- lished in 2012 brought an important search and progress, which is already ple. Rapid tests can be performed at the change in the approach to patients with underway (Chapter 8). patient’s bedside, and the results can be coeliac disease. When establishing a di- QUIZ 1. Why was there no coeliac disease in the distant past? 2. What discovery led to the first major breakthrough in diagnosing coeliac disease? REFERENCES 1. Colledge S, Conolly J, Shennan S. 11. Shiner M. Duodenal biopsy. celiac disease patients not carrying the Archeobotanical evidence for the spread Lancet.1956;1:17-9. DQA1*05-DQB1*02 (DQ2) heterodimer: of farming in the eastern Mediterranean. 12. Meeuwisse GW. Diagnostic criteria in results from the European Genetics Curr Antropo.2004;45:S35-9. coeliac disease. Acta Paediatr Scand.1970; Cluster on Celiac Disease. Hum 2. Greco L. Evolution of coeliac disease. 59:461-3. Immunol.2003;64:469-77. In: Changing features of coeliac 13. Marsh MN. Gluten, major 19. Vilppula A, Kaukinen K, Luostarinen disease.1998;80-2. histocompatibility complex, and L, Krekelä I, Patrikainen H, Valve R, et 3. Baker SJ, Mathan VI. Syndrome of the small intestine. A molecular and al. Increasing prevalence and high tropical sprue in South India. Am J Clin immunobiologic approach to the incidence of celiac disease in elderly Nutr.1968;21:984-93. spectrum of gluten sensitivity (‘celiac people: a population-based study. BMC 4. Dowd B, Walker-Smith J. Samuel Gee, sprue’). Gastroenterology.1992;102:330-54. Gastroenterol.2009;9:49. Aretaeus, and the coeliac affection. Br 14. Revised criteria for diagnosis of coeliac 20. Korponay-Szabo IR, Raivio T, Laurila K, Med J.1974;2(5909): 45-7. disease. Report of Working Group Opre J, Kiraly R, Kovacs JB, et al. Coeliac 5. Baillie M. Observations on a particular of European Society of Paediatric disease case finding and the diet species of purging. Med Trans R Coll Gastroenterology and Nutrition. Arch Dis monitoring by point-of-care testing. Phys.1815;5:166 Child.1990;65:909-11. Aliment Pharmacol Ther.2005;22:729-37. 6. Gee SJ. On the celiac affection. St. 15. Dietrich W, Ehnis T, Bauer M, Donner 21. Husby S, Koletzko S, Korponay-Szabo Bartholomew’s Hosp Rep.1888;24:17-20. P, Volta U, Riecken EO, Schuppan D. IR, Mearin ML, Phillips A, Shamir R, 7. Herter CA. On infantilism from chronic Identification of tissue transglutaminase et al. European Society for Pediatric intestinal infection. New York: McMillan; as the autoantigen of coeliac disease. Nat Gastroenterology, Hepatology, and 1908. Med.1997; 3:797-801. Nutrition Guidelines for the Diagnosis of Coeliac Disease. J Pediatr Gastroenterol 8. Haas SV. The value of the banana in the 16. Savilahti E, Viander M, Perkkio M, Vaino Nutr.2012;54:136–60. treatment of celiac disease. Am J Dis E, Kalimi K, Reunala T. IgA antigliadin Child.1924;28:421-37. antibodies. A marker of mucosal 22. Husby S, Koletzko S, Korponay-Szabó I, Kurppa K, Mearin ML, Ribes-Koninckx 9. Dicke WK. Coeliakie. Een onderzoek damage in childhood coeliac disease. C, et al. European Society for Paediatric naar de nadelige invloed van sommige Lancet.1983;1:320-2. Gastroenterology, Hepatology and graansoorten op de lijder aan coeliakie. 17. Chan KN, Phillips AD, Mirakion R, Walker Nutrition Guidelines for Diagnosing MD Thesis.Utrecht; 1950. Smith JA. Endomysial antibody screening Coeliac Disease 2020. J Pediatr 10. Paulley JW. Observations on the aetiology in children. J Pediatr Gastroenterol Gastroenterol Nutr. 2020;70(1):141-156. of idiopathic steatorrhoea. Jejunal and Nutr.1994;18:316-20. lymph-node biopsies. Br Med J.1954;4:1318- 18. Karell K, Louka AS, Moodie SJ, Ascher 21. H, Clot F, Greco L, et al. HLA types in 7 Coeliac disease in the spotlight 3 Epidemiology 3 Epidemiology OBJECTIVES: • To learn about the incidence and prevalence of coeliac disease. • To learn about the trends in diagnosed coeliac disease across Europe. • To learn about the prevalence of undiagnosed coeliac disease. coeliac disease through the diagnostic have longstanding symptoms attributed procedure has been facilitated by the in-to some other diagnoses (such as irritable REMEMBER: troduction of non-invasive and accurate bowel syndrome) without being tested Incidence is the number of newly serological testing, especially EMA after for coeliac disease. diagnosed cases per unit of popula- 1990 and TGA after 2000. tion during a stated period of time. The prevalence of undiagnosed coeliac Over time, there have been widespread disease identified from paediatric screen- Prevalence is the total number increases in the reported incidence of di- ing surveys in Europe ranged from 0.10% of cases of a disease existing in a agnosed coeliac disease (Scotland 27.7% across Northern Ireland to 3.03% in Spain. population divided by the total average annual increase, Norway 23.3%, population. Sweden 17.9%, Spain 13.3%), with two ex- As shown by meta-analysis, the preva- ceptions (Wales and England). In Sweden, lence of paediatric coeliac disease is With a prevalence of 1% in the general a sharp increase in the incidence of paedi- significantly higher in Northern Europe population, coeliac disease (CD) is one atric coeliac disease (the so-called “Swed- (1.82%; 95% CI=1.70-1.95) than in other Eu- of the most prevalent immune-mediat- ish epidemic”) was observed until the ropean regions, Eastern (0.98%; 0.69-1.35), ed gastrointestinal disorders. However, mid-1990s. The incidence rose to a peak Southern (0.69%; 0.62-0.77) and Western many studies and several systematic of almost 100 per 100,000 person-years in (0.60%; 0.43-0.81). For individual countries reviews on the incidence* and preva- children aged under 5 years and almost since 2000, the prevalence in Sweden lence** of CD have shown large varia- 200 per 100,000 in infants. This increase (1.93%; 1.80-2.07) has been found in multi- tions not only across different regions was linked to the introduction of large ple studies to be significantly higher than but also within the same countries. This amounts of gluten into infants’ diets soon in all other countries, followed by Spain is partly due to different study methodo- after the cessation of breastfeeding, as (1.15%; 0.95-1.38), Italy (0.84%; 0.72-0.97) logies, but it also reflects disparities in well as to improvements over time in case and Turkey (0.49%; 0.40-0.59). These high the awareness of CD, and variations in detection. However, after this “epidemic,” rates may reflect greater awareness and healthcare resources and diagnostic pro- childhood-onset coeliac disease stabi- better-developed case detection strate- tocols used to detect CD. lised in Sweden in the period from 2003 gies, but they also indicate genuinely to 2009. Other regions also reported sta- high rates of coeliac disease. Incidence and trends in bilisation or even a decrease in incidence. diagnosed coeliac disease In Finland, the adult incidence decreased Other recent meta-analyses have esti- The highest incidence of diagnosed CD by 3.4% annually from 2005 to 2014 and mated the prevalence of coeliac disease in children in Europe has been reported the childhood incidence stabilised from to be 0.7% in the United States, 0.6% in in Norway, Sweden, Finland, and Spain, 2008 to 2013. As these regions represent Asia, 0.5% in Africa, and 0.4% in South with rates of more than 50 per 100,000 areas with some of the highest inciden- America. person-years in children. The lowest in- ces of coeliac disease, coeliac disease may cidence has been reported in Estonia have reached its peak incidence in these The incidence of coeliac disease was re- (3.1 per 100,000), and Switzerland (5 per nations. However, it should be noted that ported to be higher in women than men 100,000). due to the lack of national registries, data (17.0 vs 7.8 per 100,000 person-years in a on the incidence of paediatric coeliac pooled analysis), although a meta-analy-Meta-analyses have shown that the dise ase at a national level are not availa-sis of screening studies found only a slight pooled incidence of paediatric CD (after ble for the majority of countries (in Europe increase in seropositivity among female the year 2000) was 21.3 per 100,000 per- less than 25% of countries have provided participants. son-years compared with 12.9 in adults, data on a national level). with a pooled child-to-adult incidence Some racial and ethnic differences in rate ratio of 1.7. Prevalence of undiagnosed the prevalence of coeliac disease have coeliac disease from screening also been reported, independent of dif- As shown across Europe, the median surveys ferences in testing rates. In the United age at diagnosis in children has risen While in the past CD was considered a States, coeliac disease is less common in sharply: from the study periods before rare condition, more recent studies have non-Hispanic black (seroprevalence 0.2%) 1990 when the median age at diagnosis shown that it is one of the most common and Hispanic (0.3%) vs white individuals was 1.9 years, in the 1990s, when the me- life-long disorders. (1.0%). Likewise, the prevalence of coeliac dian age increased to 3.1 years, and then disease can vary widely between coun- to 7.6 years for study periods since 2000 Screening studies worldwide have re- tries despite geographical proximity and (p<0.001). This is reflected in the higher in- vealed that the prevalence of CD is much even within the same country. It has been crease in incidence in the older paediatric higher than the reported incidence of shown that 1.4% of individuals in Finland age groups than in infants and children diagnosed patients, implying that de- were found by screening to have coeliac younger than 5 years. This is, at least part- spite greater awareness, a substantial disease compared to only 0.6% in the ad-ly, related to greater awareness, better proportion of individuals with coeliac jacent Russian Karelia, although there are recognition and more active case-finding disease remain undiagnosed. According no significant differences in compatible strategies, thus milder, non-classical and to cross-sectional screening studies, up HLA haplotypes. Differences have been extraintestinal forms of coeliac disease to 80 to 90% of CD cases are not recog-found even within the same countries, as well as asymptomatic cases are being nised. There are several reasons for this: for example in India, although, the preva- diagnosed. At the same time, the whole some patients are minimally sympto- lence did not vary by urban vs rural areas process from a suspected diagnosis of matic or asymptomatic, and others may or with socioeconomic status. The reasons 8 3 Epidemiology Coeliac disease in the spotlight for these regional and ethnic differences are unknown, but it is assumed that more than one factor is involved. When compa- KEEP IN MIND ring different screening studies, it should - Coeliac disease is one of the most prevalent immune-mediated gastrointestinal also be kept in mind that studies may vary disorders. in methodology, including the study peri- od, in the age groups of subjects studied, - Both the incidence and prevalence of coeliac disease in the paediatric population diagnostic tests used and their sensitivity have risen across Europe. and specificity, in the way the final diag- - The prevalence of previously undiagnosed coeliac disease from screening surveys nosis is made, and the proportion of sus-ranges from 0.10% to 3.03% (median = 0.70%). pected cases confirmed by biopsy. QUIZ 1. How prevalent is coeliac disease in the general population in Europe? 2. What might be the cause of the differences in the prevalence of coeliac disease in different regions? REFERENCES 1. Ashtari S, Pourhoseingholi MA, Rostami 11. Singh P, Arora S, Singh A, Strand TA, K, Aghdaei HA, Rostami-Nejad M, Makharia GK. Prevalence of celiac Busani L, et al. Prevalence of gluten- disease in Asia: A systematic review and related disorders in Asia-Pacific region: a meta-analysis. J Gastroenterol Hepatol systematic review. J Gastrointestin Liver 2016;31(6):1095-101. Dis 2019;28(1): 95-105. 12. Tapsas D, Hollen E, Stenhammar L, Falth- 2. Ivarsson A. The Swedish epidemic Magnusson K. Unusually High Incidence of coeliac disease explored using an of Paediatric Coeliac Disease in Sweden epidemiological approach--some during the Period 1973 - 2013. PLoS One lessons to be learnt. Best Pract Res Clin 2015; 10(12):e0144346. Gastroenterol 2005;19(3): 425-40. 13. Tjon JM, van Bergen J, Koning F. Celiac 3. Jansson-Knodell CL, Hujoel IA, West CP, disease: how complicated can it get? Taneja V, Prokop LJ, Rubio-Tapia A, et Immunogenetics. 2010;62(10):641-51. al. Sex Difference in Celiac Disease in Undiagnosed Populations: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019; 17(10): 1954-68 e13. 4. King JA, Jeong J, Underwood FE, Quan J, Panaccione N, Windsor JW, et al. Incidence of Celiac Disease Is Increasing Over Time: A Systematic Review and Meta-analysis. Am J Gastroenterol. 2020;115(4):507-525. 5. Kivela L, Kaukinen K, Lahdeaho ML, Huhtala H, Ashorn M, Ruuska T, et al. Presentation of Celiac Disease in Finnish Children Is No Longer Changing: A 50- Year Perspective. J Pediatr 2015;167(5):1109- 15 e1. 6. Laass MW, Schmitz R, Uhlig HH, Zimmer KP, Thamm M, Koletzko S. The prevalence of celiac disease in children and adolescents in Germany. Dtsch Arztebl Int. 2015;112(33-34):553-60. 7. Lebwohl B, Rubio-Tapia A. Epidemiology, Presentation, and Diagnosis of Celiac Disease. Gastroenterology. 2021;160(1):63- 75. 8. Megiorni F, Pizzuti A. HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: practical implications of the HLA molecular typing. J Biomed Sci.2012;19(1):88. 9. Roberts SE, Morrison-Rees S, Thapar N, Benninga MA, Borrelli O, Broekaert I, et al. Systematic review and meta-analysis: the incidence and prevalence of paediatric coeliac disease across Europe. Aliment Pharmacol Ther.2021;54(2):109-128. 10. Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018;16(6):823-36 e2. 9 Coeliac disease in the spotlight 4 Aetiology 4 Aetiology OBJECTIVES: • To understand the pathogenesis of coeliac disease. • To learn about gluten and its role in the development of coeliac disease. • To understand the role of genetics in the development of coeliac disease. • To identify possible environmental factors involved in the development of coeliac disease. Coeliac disease is a lifelong systemic au- toimmune disorder elicited by gluten and related prolamins in genetically suscepti- ble individuals, but various environmental factors also influence the development of the disease. Pathogenesis of coeliac disease Both the innate and acquired immune systems are involved in the pathogene- sis of CD. After ingesting gluten, digested peptides in the small intestine pass to the lamina propria where they are deamidat- ed and recognised by antigen-presenting cells via their class II HLA (human leuco- cyte antigen) molecules, triggering an abnormal CD4+ T-cell immune response. The formation of a peptide-HLA mole- cule complex on the surface of the anti- gen-presenting cells is responsible for the transcription, configuration and signal- ling of the events involved in the develop- ment of the disease, thus representing an important step in the pathogenesis of CD. Gluten The most important factor in the devel- opment of CD is gluten, which accounts for 85-90% of the proteins in wheat grain. Gluten (meaning glue in Latin) is the Figure 1. Factors that may cause coeliac disease. common name for a protein complex that is composed of two groups of pro- teins divided according to their solubility. The major group are alcohol-soluble pro- lamins (wheat - gliadins), and the second is acid-soluble glutelins (wheat - gluten- ins). The term gluten, therefore, indicates a broad group of prolamins found in wheat. Other prolamins showing similar immunogenic peptides are also found in rye (secalins), barley (hordeins), and other closely related grains. The major prolamins of the more distantly related maize (zeins) seem to have evolved inde- pendently and show no harmful effects in CD patients. The same is also true of rice (oryzins). Oats (avenins), in their pure form, are not harmful either, but they are often contaminated with wheat or other cereals. In vitro studies have shown that the immunogenicity of oats depends on the cultivar, making their use in patients with CD questionable. Studies have shown that different gluten peptides act directly against the intestinal mucosa or trigger an immune response. So far, the highest toxicity has been attri- Figure 2. Classification of cereal proteins from grains that are buted to α-gliadin, which contains the not tolerated in coeliac disease. 10 4 Aetiology Coeliac disease in the spotlight most immunogenic peptides. Gluten is often used in the food and cos- metics industries because of its charac- teristics, which give viscosity, elasticity, and better structure to the final product. It is especially utilised in bread production giving the bread a greater volume and its typical structure. Genetic factors Coeliac disease is a multifactorial disease with a strong genetic background. The most studied association of CD is with the HLA-DQ2 and HLA-DQ8 haplotypes. HLA molecules are members of the major his- Figure 3. HLA-DQ2/-DQ8 and its role in the development of coeliac tocompatibility complex, composed of α- disease in the gut. and β-chains encoded by specific variants of the HLA-DQA1 and HLA-DQB1 genes. The HLA-DQ2 haplotype is encoded by the DQA1*0501 and DQB1*0201 alleles. It is expressed in about 90% of patients with CD, and the HLA-DQ8 haplotype, en- coded by the DQA1*0301 and DQB1*0302 alleles, is expressed in another 5% of pa- tients. Almost all of the other 5% of pa- tients have at least one of the two alleles encoding DQ2 (DQA1*0501 or DQB1*0201). In the general population, the frequency of genotypes associated with CD is 30- 40%, but only about 1-3% of gene carriers develop the disease. A negative test result for DQ2/DQ8 is likely to exclude CD, but a positive result has a lower diagnostic value. In the last decade, genome-wide association studies have found that the HLA locus is the major genetic factor, al- though at least 39 non-HLA genes have also been associated with an increased risk of developing the disease. Immunological factors The primary mechanism involved in the development of CD is an inappropriate immune response to peptides that form gluten, especially prolamins (wheat - gli- adin, rye - secalin, barley - hordein). Since Figure 4. Mechanisms of mucosal damage in coeliac disease (Di Sabatino et al. these proteins contain large amounts of Lancet. 2009). proline and glutamine, their degradation in the gastrointestinal tract is incomplete. Therefore, some peptides can pass undi- gested from the intestinal lumen using the transcellular or paracellular pathways. In some individuals, the passage of these gluten peptides across the lamina propria results in the deamidation of gliadin pep- tide by the enzyme tissue transglutami- nase, which increases its immunogenici- ty and facilitates its binding to HLA-DQ2 and HLA-DQ8 molecules on antigen-pre- senting cells. Gliadin peptides are then presented to the CD4+ T- cells, which consequently produce large amounts of proinflammatory cytokines, including in- terferon-gamma, inducing Th1 cells and increasing the formation of tumour ne- crosis factor-alpha, which plays an impor- tant role in intestinal mucosal damage. To a lesser extent, cytokines also induce Th2 cells, which induce clonal expansion of B-lymphocytes and their differenti- ation into plasma cells, which secrete antigliadin antibodies, anti-endomysial antibo dies (EMA) and antibodies against tissue transglutaminase (TGA). Some gli- adin peptides that are not recognised by T-lymphocytes activate antigen-presenting Figure 5. Coeliac disease pathogenesis (Cenit MC et al. Nutrients. 2015). cells, intestinal epithelial cells and especially 11 Coeliac disease in the spotlight 4 Aetiology CD8+ T-lymphocytes. The latter are also hyperplasia, and an increased number of velop CD. This suggests that additional stimulated by interleukin-15, leading to intraepithelial lymphocytes. environmental factors play a role in the an increase in the number of receptors development of the disease. The effects for natural killer cells, thereby promoting Environmental factors of the type of delivery, feeding methods cell death and increasing intestinal wall Although the HLA genotype and gluten after delivery, the use of antibiotics to- permeability. This inflammatory response consumption are common in the gen- gether with the influence of early infec- results in matrix degradation, mucosal re- eral population, only a small proportion tions and the gut microbiota, have been modelling, intestinal villous atrophy, crypt of genetically susceptible individuals de- studied. Environmental factor Association with CD Type of delivery None Feeding methods, Neither the time of gluten introduction nor the duration of breastfeeding affects the overall risk of amount and timing of developing the disease. gluten introduction. Recommendation: The introduction of gluten into an infant’s diet anytime from 4 to 12 months of age. In children at increased risk of developing CD, early introduction of gluten is associated with an earlier onset of CD, but the cumulative incidence in later childhood is similar in both groups. Recommendation: Large amounts of gluten should be avoided in the first weeks after gluten introduction and in early childhood. Use of antibiotics or The use of antibiotics in pregnancy was not associated with the development of CD in the offspring. other drugs The use of proton pump inhibitors was associated with an increased risk of developing CD, probably due to changes in the gastrointestinal microbiome. Early infections Gastrointestinal infections, rotavirus in children, Campylobacter infections in adults, and reovirus infections have been suggested as risk factors for developing CD, and rotavirus vaccination has been shown to have a protective effect. An increased total number of infections (> 10 vs <4 in the first 18 months of life) was indicative of an increased risk of CD. Colonisation with Helicobacter pylori may reduce the risk of CD. A higher number of respiratory infections in the first 18 months suggested an increased risk of developing the disease later in childhood. Gut microbiota Patients with CD have an altered gut microbiota that does not completely normalise even after the introduction of a gluten-free diet. The Bifidobacterium bifidum concentration was found to be significantly higher in untreated patients with CD than in healthy individuals. In children with CD, a higher incidence of duodenal Gram-negative and potentially pro-inflammatory bacteria was found at confirmation of the diagnosis compared to healthy controls. QUIZ 1. Which of the following best describes coeliac disease? a) Coeliac disease is an autoimmune disease that affects only the small intestine. b) Coeliac disease is a systemic immune-mediated disease that affects genetically predisposed people. c) Coeliac disease is an allergic disease that affects mostly people from atopic families. d) Coeliac disease is a food intolerance restricted to wheat and wheat-containing products affecting the small intestine. e) Coeliac disease is an enzyme deficiency disorder affecting the breakdown of wheat and other gluten-containing foods. 2. Which HLA haplotypes are related to coeliac disease? 3. What is the frequency of genotypes associated with CD in the general population? 4. Which statement is correct? (multiple answers possible) a) Gluten is a protein that comprises a minor part of the wheat grain. b) Avenins are noxious for CD patients. c) TGA antibodies are secreted due to Th2 stimulation by cytokines. d) Gut microbiota might have a role in the development of CD. e) Early introduction of gluten is associated with earlier development of CD in at-risk children. 12 4 Aetiology Coeliac disease in the spotlight REFERENCES 1. Husby S, Koletzko S, Korponay-Szabó I, 18. Kemppainen KM, Lynch KF, Liu E, Kurppa K, Mearin ML, Ribes-Koninckx Lönnrot M, Simell V, Briese T, et al. Factors C, et al. European Society for Paediatric That Increase Risk of Celiac Disease Gastroenterology, Hepatology and Autoimmunity After a Gastrointestinal Nutrition Guidelines for Diagnosing Infection in Early Life. Clin Gastroenterol Coeliac Disease 2020. J Pediatr Hepatol. 2017; 15(5): p. 694-702. Gastroenterol Nutr. 2020; 70(1): p. 141 56. 19. Mårild K, Kahrs CR, Tapia G, Stene LC, 2. Serena G, Lima R, Fasano A. Genetic and Størdal K. Infections and Risk of Celiac Environmental Contributors for Celiac Disease in Childhood: A Prospective Disease. Curr Allergy Asthma Rep. 2019; Nationwide Cohort Study. Am J 19(9): p. 1-10. Gastroenterol. 2015; 110(10): p. 1475-84. 3. McAllister BP, Williams E, Clarke K. A 20. Mårild K, Ye W, Lebwohl B, Green Comprehensive Review of Celiac Disease/ PHR, Blaser MJ, Card T, et al. Antibiotic Gluten-Sensitive Enteropathies. Clinic Rev Exposure and the Development of Coeliac Allerg Immunol. 2019; 57(2): p. 226-43. Disease: A Nationwide Case-Control Study. 4. Biesiekierski JR. What is gluten? J BMC Gastroenterol. 2013; 13: p. 109. Gastroenterol Hepatol. 2017; 32(1): p. 78-81. 21. Mårild K, Ludvigsson J, Sanz J, F LJ. 5. Lebwohl B, Sanders DS, Green PHR. Antibiotic Exposure in Pregnancy and Risk Coeliac disease. Lancet. 2018; 391(10115): p. of Coeliac Disease in Offspring: A Cohort 70-81. Study. BMC Gastroenterol. 2014; 14: p. 75. 6. Silano M, Vincentinin O, De Vincenzi M. 22. Mårild K, Kahrs CR, Tapia G, Stene LC, Toxic, immunostimulatory and antagonist Størdal K. Maternal Infections, Antibiotics, gluten peptides in celiac disease. Curr and Paracetamol in Pregnancy and Med Chem. 2009; 16(12): p. 1489-98. Offspring Celiac Disease: A Cohort Study. 7. Di Sabatino A, Corazza GR. Coeliac disease. J Pediatr Gastroenterol Nutr. 2017; 64(5): p. Lancet. 2009 Apr 25;373(9673):1480-93. doi: 730-36. 10.1016/S0140-6736(09)60254-3. 23. Lebwohl B, Spechler SJ, Wang TC, Green 8. Spector Cohen I, Day AS, Shaoul R. Gluten PHR, F LJ. Use of Proton Pump Inhibitors in Celiac disease - More or Less. Rambam and Subsequent Risk of Celiac Disease. Maimonides Med J. 2019; 10(1): p. e0007. Dig Liver Dis. 2014; 46(1): p. 36-40. 9. Parzanese I, Qehajaj D, Patrinicola F, 24. Freedberg DE, Lebwohl B, Abrams JA. The Aralica M, Chiriva-Internati M, Stifter S, et Impact of Proton Pump Inhibitors on the al. Celiac disease: From pathophysiology Human Gastrointestinal Microbiome. Clin to treatment. World J Gastrointest Lab Med. 2014; 34(4): p. 771-85. Pathophysiol. 2017; 8(2): p. 27-38. 25. Brown JJ, Short SP, Stencel-Baerenwald 10. Lindfors K, Ciacci C, Kurppa K, Lundin J, Urbanek K, Pruijssers AJ, McAllister N, KEA, Makharia G, Mearin ML, et al. Coeliac et al. Reovirus-Induced Apoptosis in the disease. Nat Rev Dis Primers. 2019; 5(1): p. Intestine Limits Establishment of Enteric 1-18. Infection. J Virol. 2018; 92(10): p. e02062-17. 11. Liu E, Lee H, Aronsson C, Hagopian 26. Verdu EF, Galipeau HJ, Jabri B. Novel W, Koletzko S, Rewers M, et al. Risk of players in coeliac disease pathogenesis: pediatric celiac disease according to HLA role of the gut microbiota. Nat Rev haplotype and country. N Engl J Med. Gastroenterol Hepatol. 2015; 12(9): p. 497- 2014; 371(1): p. 42-9. 506. 12. Koletzko S, Lee HS, Beyerlein A, Aronsson 27. Cenit MC, Olivares M, Codoñer-Franch P, CA, Hummel M, Liu E, et al. Cesarean Sanz Y. Intestinal Microbiota and Celiac Section on the Risk of Celiac Disease in Disease: Cause, Consequence or Co- the Offspring: The Teddy Study. J Pediatr Evolution? Nutrients. 2015; 7(8): p. 6900-23. Gastroenterol Nutr. 2018; 66(3): p. 417-24. 28. Nistal E, Caminero A, Vivas S, Ruiz de 13. Aronsson CA, Lee HS, Liu E, Uusitalo U, Morales JM, Sáenz de Miera LE, Rodríguez- Hummel S, Yang J, et al. Age at gluten Aparicio LB, et al. Differences in faecal introduction and risk of celiac disease. bacteria populations and faecal bacteria Pediatrics. 2015; 135(2): p. 239-45. metabolism in healthy adults and celiac 14. Vriezinga SL, Auricchio R, Bravi E, Castillejo disease patients. Biochimie. 2012; 94(8): p. G, Chmielewska A, Crespo Escobar P, et 1724-9 al. Randomized feeding intervention in 29. Nadal I, Donat E, Ribes-Koninckx C, infants at high risk for celiac disease. N Calabuig M, Sanz Y. Imbalance in the Engl J Med. 2014; 371(14): p. 1304-15. composition of the duodenal microbiota 15. Lionetti E, Castellaneta S, Francavilla R, of children with coeliac disease. J Med Pulvirenti A, Tonutti E, Amarri S, et al. Microbiol. 2007; 56(12): p. 1669-74. Introduction of gluten, HLA status, and 30. Wessels M, Auricchio R, Dolinsek J, Donat the risk of celiac disease in children. N Eng E, Gillett P, Mårild K, Meijer C, Popp A, J Med. 2014; 371(14): p. 1295-303. Mearin ML. Review on pediatric coeliac 16. Szajewska H, Shamir R, Mearin L, Ribes- disease from a clinical perspective. Eur J Koninckx C, Catassi C, Domellof M, et Pediatr. 2022 May;181(5):1785-1795. al. Gluten Introduction and the Risk of Coeliac Disease: A Position Paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2016; 62(3): p. 507-13. 17. Vaarala O, Jokinen J, Lahdenkari M, Leino T. Rotavirus Vaccination and the Risk of Celiac Disease or Type 1 Diabetes in Finnish Children at Early Life. Pediatr Infect Dis J. 2017; 36(7): p. 674-5. 13 Coeliac disease in the spotlight 5 Clinical presentation 5 Clinical presentation OBJECTIVES: • To understand the diverse clinical presentation of coeliac disease. • To recognise symptoms and signs that could be associated with coeliac disease. • To differentiate between different forms of coeliac disease. The symptoms of CD can be attributed and signs or it can even be asympto- labsorption are more common than to a combination of inflammation, nu- matic. Extraintestinal manifestations in older children and adolescents, in trient deficiency caused by malabsorp-of the disease can affect almost every whom the most common symptom is tion, and the autoimmune response to organ, including the nervous system, abdominal pain. In adults, the disease the enzyme tissue transglutaminase. liver, skin, reproductive system, cardio-often does not present with character- In the past, CD was known as an illness vascular system, and musculoskeletal istic signs and symptoms, but with ex-of childhood, with a characteristic clin- system, and are usually associated with traintestinal manifestations or serious ical presentation of diarrhoea with ma- a more serious clinical and histological complications of the disease, which labsorption syndrome. Nowadays, we picture. Some of these manifestations can, in rare cases, also be seen in child-know that CD is a systemic disease that can present in early childhood, whereas hood. There are vulnerable periods of life can occur at any age. Although it caus- others do not appear until adulthood or when high nutrient demands may lead es impairment of intestinal absorption, advanced age. to severe symptoms faster or more of- gastrointestinal symptoms occur in only ten. These are early childhood (1-4 years about half of the patients since the dis- It has been shown that the clinical pres- of age) and puberty, both characterised ease is not limited to the digestive tract entation can vary according to the pa- by a rapid growth spurt, and the lacta- but can manifest itself by many intesti- tient’s age. In very young children (<3 tion period after giving birth in women. nal as well as extraintestinal symptoms years), the signs and symptoms of ma- OSLO Classification of coeliac disease Classical CD Symptoms and signs of malabsorption: diarrhoea, steatorrhoea, bloating, growth retardation or weight loss, anaemia, neurological disorders due to vitamin B deficiency, osteopenia due to vitamin D and calcium deficiency. Symptomatic CD Intestinal symptoms without signs of malabsorption: recurrent abdominal pain, vomiting, constipation. Extraintestinal symptoms: fatigue, poor concentration, headaches, migraine, ataxia, dental enamel defects, infertility. Subclinical CD No clinical symptoms, only abnormal laboratory levels of certain parameters such as elevated liver transaminases or iron deficiency. Asymptomatic CD CD-specific laboratory changes in patients who appear to be symptom-free. Refractory CD Despite a long (>12 months) gluten-free diet, the symptoms and signs of malabsorption and villous atrophy persist. The disease is resistant to treatment. While refractory CD has not been reported in children and adolescents with CD, probably around 1% of adult patients are affected, most of whom are over 50 years of age. The following symptoms in a patient with CD keeping a strict gluten-free diet warrant extensive diagnostic work-up: chronic diarrhoea, unintended weight loss, fever, fatigue, and night sweats for unclear reasons. Based on the number and characteristics of certain immune cells (intraepithelial lymphocytes, IEL) in the mucosa, refractory CD is subdivided into type I (RCD1): Marsh 3 lesions with normal types of intraepithelial lymphocytes and type II (RCD2): Marsh 3 lesions with an increased number (>20%) of aberrant intraepithelial lymphocytes (CD3 and CD8 negative) with pre-malignant characteristics and T-cell receptor clonality. Patients with RCD should be diagnosed, treated, and monitored in specialist units. If the diagnosis is confirmed, medical therapy (in addition to a gluten-free diet) and close monitoring are needed due to the increased risk of malignancy in the small intestine (enteropathy-associated T-cell lymphoma, EATL) in patients with type II RCD. Potential CD The symptoms are non-specific or absent, CD-specific antibodies are positive and the duodenal mucosa appears normal (Marsh 0 or 1). 14 5 Clinical presentation Coeliac disease in the spotlight Figure 6. The coeliac iceberg. Some cases of coeliac disease are above the surface and are easi-er to diagnose, while others are below the surface and therefore more difficult to identify. Gastrointestinal symptoms Diarrhoea, fatty, pale, foul-smelling stools or an increase in the stool volume, bloating, flatulence, lac-and signs tose and other carbohydrate intolerances, abdominal pain, recurrent vomiting, constipation. Mouth and teeth: mouth ulcers, dental enamel defects. Liver, spleen, and pancreatic Elevated levels of liver enzymes, autoimmune hepatitis, autoimmune biliary disease, severe liver fail-disorders ure, spleen function disorder (hyposplenism), pancreatic insufficiency. Haematological and Anaemia (iron deficiency, folate deficiency, vitamin B12 deficiency), bruising or prolonged bleeding bleeding disorders time (vitamin K deficiency), malignant disorders of immune cells (lymphoma). Growth, development, and Low body weight or slow weight gain, weight loss, fatigue, general weakness, lack of concentration, general health growth retardation, delayed puberty, moodiness. Skin disorders Dermatitis herpetiformis (Duhring's disease): a cutaneous manifestation of CD, characterised by itch-ing and a blistering rash typically localised on the elbows, knees, shoulders, back, and buttocks or other extensor surfaces, with extremities symmetrically affected. Gastrointestinal symptoms are rare. Skin biopsy shows the pathognomonic granular deposits of immunoglobulin A in the papillary dermis. Damage to the intestinal mucosa can also be found. Patients with severe skin symptoms may need special medications in addition to a gluten-free diet. Cardiovascular disorders Dilatative heart disease, heart failure. Pulmonary disorders Restrictive pulmonary disease (pneumonitis or alveolitis), frequent airway infections. Kidney disorders Proteinuria, haematuria. Musculoskeletal system Swollen legs, muscular cramps, or pain (myalgia), muscular weakness and decreased muscular tone, joint pain and inflammation, osteoporosis and osteopenia, rickets. Neurological problems Headache, mood and behavioural disorders, hyperactivity, concentration problems, tiredness, foggy mind, depression, sensory or gait problems, ataxia, epilepsy. Reproductive system Infertility and miscarriages, lower birth weight of children. Nutrient deficiencies Calcium, vitamin D, vitamin B12, iron. Coeliac crisis a) acute abdomen with intense pain, distension, and poor general condition. b) severe disbalance of body fluids as a consequence of intense diarrhoea, loss of potassium, sodium, chloride, calcium, and other minerals causing general weakness and cardiac problems. 15 Coeliac disease in the spotlight 5 Clinical presentation SYMPTOMS diarrhoea apathy constipation headache vomiting joint pain abdominal pain hyperactivity bloating CHILDREN dyspepsia bone pain loose stools infertility/ miscarriage abdominal pain depression irritable bowel ataxia tiredness premature constipation ADULTS menopause Figure 7. Possible symptoms of coeliac disease. SIGNS malnutrition aphthae failure to thrive delayed puberty abdominal distension oedema short stature rickets anaemia arthritis dental enamel defects hypertransaminasaemia CHILDREN malnutrition, weight loss peripheral neuropathy abdominal distension brittle nails short stature myopathy iron deficiency anaemia hypertransaminasaemia osteopenia/osteoporosis aphthae oedema hair loss ADULTS bone fracture Figure 8. Possible signs of coeliac disease. 16 5 Clinical presentation Coeliac disease in the spotlight CASE STUDIES A 15-year-old boy was referred to the outpatient clinic be-An 18-month-old girl was admitted to hospital because of cause of microcytic anaemia. His mother explained that dehydration due to diarrhoea. The complaints had started the boy had been treated unsuccessfully for anaemia with 2 weeks previously when she presented with signs of acute iron supplements for more than two years. He has had fre-gastroenteritis with vomiting and diarrhoea. She stopped quent migraine attacks, occasional mild abdominal discom-vomiting 4 days prior to admission, but she still had liq-fort and has been very tired most of the time. He defecates uid stools with mucus but no blood, 6 to 10 times per day. twice a day, and the stool is of normal colour and consisten-Her appetite was bad, she was tired, pale and apathetic. At cy. From time to time, he has had mouth ulcers but current-home, they had already tried a lactose-free diet, racecadotril ly has none. On physical examination, he was slightly pale, and probiotics, but the frequency and form of the stools had with no other obvious abnormalities. Serological tests for not changed. She has had no fever and has not complained coeliac disease were highly positive. of abdominal pain. At admission, she was mildly dehydrated, with a prominent distended abdomen. Laboratory results showed hypoalbuminaemia, with mild electrolyte imbal-ance, and inflammatory markers were low. Stool cultures A 16-year-old girl was referred to the outpatient clinic be-were negative. Coeliac disease POCT was immediately posi-cause of suspected lactose intolerance. She explained that tive, and serological markers for CD were very high. she has been avoiding milk for the last 6 years, since she felt nauseous after drinking it or eating dairy products, except cheese. She observed similar problems when eating crois-sants. In the past few years, she noticed that when eating A 72-year-old woman came to the coeliac disease outpa-pizza, she felt early satiety and could only tolerate one piece. tient clinic after many years of searching for the cause of She has had no abdominal pain and her defecation and apher health problems. At the age of 67, the symptoms that petite were also normal. She had been treated for microcytic had occasionally occurred in previous years became more anaemia with iron supplements for a year. Her haemoglobin pronounced. An extremely uncomfortable feeling in her levels were normal at the last check-up. Serology for coeliac body, which the patient described as “feeling creepy in my disease was highly positive. own body”, accompanied by the symptoms of diagnosed gastritis, forced the patient to self-initiate a gastritis diet to eliminate foods that she suspected were causing the feeling of discomfort. As the new diet regimen and drugs pre-An 8-year-old girl was referred to the outpatient clinic be-scribed for gastritis did not produce the desired results, and cause of abdominal distention and frequent flatulence. Her she became very weak and malnourished, the family doctor mother explained that the girl has had a slightly distend-referred her to a psychiatrist for suspected eating disorders. ed abdomen and frequently passed wind since the age She was then diagnosed with anxiety disorder and depres-of 2 years. From time to time, she has complained of mild sion, but her complaints continued despite the medication abdominal pain, and sometimes her stools were soft and she received. At the last visit to the gastroenterologist, se-sticky. Her parents had a feeling that her complaints were rological tests for CD were ordered and TGA were positive. more frequent if she ate very starchy food. For the last three Gastroscopy with biopsy confirmed damage to the small months, she has had no complaints except frequent wind, intestinal villi (Marsh stage 3). which was not related to the type of food she had eaten. Her appetite was good, she defecated once per day, and her stool consistency and colour were normal. Coeliac disease serology was highly positive. QUIZ 1. Which of the following is/are correct? (multiple answers possible) a) Coeliac disease always presents with gastrointestinal symptoms. b) Coeliac disease can present with gastrointestinal symptoms. c) Coeliac disease never presents with gastrointestinal symptoms. d) Coeliac disease can present without gastrointestinal symptoms. e) Coeliac disease can be asymptomatic. 2. How does the clinical presentation of CD differ between small children and adults? 3. Which are the vulnerable periods when the clinical presentation of CD can be more severe? 4. What are the characteristics of classical CD? 5. What is the common skin manifestation of CD? How is it diagnosed and treated? 6. In which patients would coeliac disease be among the most likely diagnoses? (multiple answers possible) a) A 14-year-old boy with microcytic anaemia. b) A 6-year-old boy with fever and haematuria. c) A 13-year-old girl with recurrent abdominal pain. d) A 3-month-old girl with chronic diarrhoea and abdominal distention. 17 Coeliac disease in the spotlight 5 Clinical presentation REFERENCES 1. Green PH, Krishnareddy S, Lebwohl B. Clinical manifestations of celiac disease. Dig Dis. 2015; 33(2): p. 137-40. 1. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013; 62(1): p. 43-52. 2. Kivelä L, Kaukinen K, Lähdeaho ML, Huhtala H, Ashorn M, Ruuska T, et al. Presentation of Celiac Disease in Finnish Children Is No Longer Changing: A 50-Year Perspective. J Pediatr. 2015; 167(5): p. 1109-15. 3. Roma E, Panayiotou J, Karantana H, Constantinidou C, Siakavellas SI, Krini M, et al. Changing pattern in the clinical presentation of pediatric celiac disease: a 30-year study. Digestion. 2009; 80(3): p. 185-91. 4. Visakorpi JK, Mäki M. Changing clinical features of coeliac disease. Acta Paediatr Suppl. 1994; 83(395): p. 10-3. 5. Gokce S, Arslantas E. Changing face and clinical features of celiac disease in children. Pediatr Int. 2015; 57(1): p. 107-12. 6. Tajuddin T, Razif S, Dhar R, Thorne J, Murray FE. Clinical presentation of adult coeliac disease. Ir Med J. 2011; 104(1): p. 20-2. 7. Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, Absan H, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol. 2001; 96(1): p. 126-31. 8. Agardh D, Lee H, Kurppa K, Simell V, Aronsson C, Jörneus O, et al. Clinical features of celiac disease: a prospective birth cohort. Pediatrics. 2015; 135(4): p. 627-34. 9. Laurikka P, Nurminen S, Kivelä L, Kurppa K. Extraintestinal Manifestations of Celiac Disease: Early Detection for Better Long-Term Outcomes. Nutrients. 2018; 10(8): p. 1015. 10. Pogačar MŠ, Vlaisavljević V, Turk E, Mičetić-Turk D. Reproductive complications in celiac disease patients in Slovenia. Eur J Obstet Gynecol Reprod Biol. 2019; 238: p. 90-4. 11. Riznik P, De Leo L, Dolinsek J, Gyimesi J, Klemenak M, Koletzko B, Koletzko S, Korponay- Szabó IR, Krencnik T, Not T, Palcevski G, Sblattero D, Werkstetter KJ, Dolinsek J. Clinical Presentation in Children with Coeliac Disease in Central Europe. J Pediatr Gastroenterol Nutr. 2021 Apr 1;72(4):546-551. 12. Persechino F, Galli G, Persechino S, Valitutti F, Zenzeri L, Mauro A, Corleto VD, Parisi P, Ziparo C, Evangelisti M, Quatrale G, Di Nardo G. Skin Manifestations and Coeliac Disease in Paediatric Population. Nutrients. 2021 Oct 15;13(10):3611. 13. Sahin Y. Celiac disease in children: A review of the literature. World J Clin Pediatr. 2021 Jul 9;10(4):53-71. 14. Rowinski SA, Christensen E. Epidemiologic and therapeutic aspects of refractory coeliac disease - a systematic review. Dan Med J. 2016 Dec;63(12):A5307. 18 6 Diagnostics Coeliac disease in the spotlight 6 Diagnostics OBJECTIVES: • To understand the diagnostic possibilities for the diagnosis of coeliac disease. • To understand the importance of a regular diet before testing for coeliac disease. • To understand the role of POCT tests in diagnosing coeliac disease. • To be able to explain the requirements of a no-biopsy approach for diagnosing coeliac disease. • To understand the role of genetic testing in the diagnosis of coeliac disease. • To learn what tests should be done at the primary-care facility when suspecting coeliac disease. The diagnosis of CD is guided by the cussed with a clinician. Exclusion of glu- taken from the first part of the duode- clinical presentation, but the definitive ten from the diet based solely on these num (bulbus) and at least four samples diagnosis is based on the presence of a tests can seriously influence the perfor- from the distal part of the duodenum. specific immune response and charac- mance and interpretation of laboratory teristic histological changes in the small blood tests that are more reliable and intestinal mucosa. need to be performed to confirm the diagnosis. Blood tests – serological tests The initial step in diagnosing coeliac disease is the determination of the presence of specific antibodies in the blood. In coeliac disease, it is possible to detect antibodies against the en- zyme tissue transglutaminase (TGA), found in many human tissues. These antibodies are produced only when gluten is consumed and are very rarely found in individuals without the dis- ease. They usually fall to normal levels Figure 11. Endoscope. within a couple of months after a pa- tient with coeliac disease starts a strict gluten-free diet. The same is also true Upper endoscopy with biopsies from for anti-endomysial antibodies (EMA), the duodenum enables the patholo- which are as reliable as TGA, although gists to determine the changes typical the test is more difficult to perform of coeliac disease: and is, therefore, more expensive. Thus, clinicians use it as a second-line 1. Increased number of intraepithe- test to confirm a previously positive lial lymphocytes (IEL) (normal <25 TGA test. The current ESPGHAN (Eu- IEL/100 enterocytes). ropean Society for Paediatric Gastro- 2. Shortening of the mucosal villi - Vil- enterology, Hepatology and Nutrition) lous atrophy (normal villous height to guidelines for the diagnosis of coeliac Figure 9. Coeliac disease point-of-care crypt depth ratio is 3:1 to 5:1). disease in children allow clinicians to test demonstration. 3. Elongation of the crypts - Crypt hy- diagnose the disease in certain cases perplasia. without upper endoscopy and intesti- nal biopsy. This approach can be used The histopathological findings in CD in children and adolescents who have are commonly classified according very high levels of TGA and a positive to the Marsh-Oberhuber classifica- confirmatory EMA test in a second tion, which defines four subtypes of blood sample. Since both tests typi- mucosal changes. Type Marsh 0 rep- cally determine only the presence of resents normal intestinal mucosa, IgA class antibodies, the total immu- Marsh 1 is the infiltration phase with noglobulin A (total IgA) concentration lymphocytes infiltrating the epitheli- also needs to be determined. If low to- um of the intestinal villi, Marsh 2 is the Figure 10. Coeliac disease point-of-care tal IgA is found, tests determining IgG infiltrative-hyperplastic phase with test (positive). antibodies should be used. crypt hypertrophy and hyperplasia, and lymphocytes markedly infiltrating Point-of-care testing Intestinal biopsy the epithelium. Marsh 3 is the destruc- Point-of-care tests for determining If the initial autoantibody test is suggestive phase, which is the most common autoantibodies in capillary blood (fin- tive of coeliac disease, further investiga- finding in patients with CD. There are ger-prick blood) are widely available tions are always needed to confirm the no villi, the crypts are severely hyper-in many regions. However, these tests diagnosis. In some cases, it is necessary plastic and hypertrophic, and the infil- are not sufficient to diagnose coeliac to perform an intestinal biopsy. It is rec-tration of the epithelium with lympho- disease and the results need to be dis- ommended that at least one sample is cytes is very pronounced. 19 Coeliac disease in the spotlight 6 Diagnostics The histology report alone indicating coeliac disease without positive autoantibodies is not sufficient to diagnose coeliac Figure 12. Marsh-Oberhuber classification of mucosal changes in coeliac disease. disease! munological marker of CD. Detection of disease and further tests are not nec- intestinal TGA can therefore assist in the essary. Genetic risk markers specific diagnosis in cases of doubtful histology to the disease, i.e., HLA-DQ2 and HLA- results. DQ8, can be found in approximately one-third of the general population. HLA testing According to the ESPGHAN guidelines, Genetic testing is especially helpful in genetic testing is not mandatory for excluding coeliac disease. Individuals confirmation of the diagnosis in chil-who are negative for HLA-DQ2 or HLA- dren and adolescents. DQ8 have no risk of developing the Figure 13. Normal small intestinal mucosa. Figure 15. Impact of biopsy orientation. Biopsy 1a and 2a (left side) both show ap-parently normal villi, but only cross-sections of the crypts are visible, which indicates wrong orientation and cutting, which does not allow any reading. However, pathologists have interpreted 1a and 2a as normal (Marsh 0 to 1). In pictures 1b and 2b (right side), the same biopsies are shown, but they have been tilted and re-cut in Figure 14. Mucosal changes in coeliac the correct orientation (perpendicular cutting). Now it is obvious that both 1b and disease - Marsh 3C. 2b show villous atrophy and crypt hyperplasia and the same pathologists reported Marsh 3B to 3C for these biopsies. Both biopsies clearly support a diagnosis of CD in combination with positive serology, but misclassification can easily happen if the Despite being a gold standard for diag-pathologist does not consider the correct orientation and cutting! Source: FocusIN-nosing CD, several pitfalls in the inter- CD with histology slides from Taavela et al. 2013. pretation of duodenal biopsies must also be considered. Histological analy- sis has been reported to lack diagnos- tic accuracy owing to the high interob- server variability, differences between routine and more specialised pathology laboratories, low rates of the correct orientation of biopsy samples, and the low number of samples taken. These factors can lead to an inadequate inter- pretation of mucosal changes. There- fore, new methods for the detection of intestinal TGA are being developed to supplement histological findings in di- agnosing CD. Due to greater awareness of CD, there is an increasing number of symptomat- ic patients with positive CD antibodies despite histologically normal intestinal mucosa and more patients with nega- tive or fluctuating serum antibodies and normal intestinal mucosa. In these two conditions (potential, pre-potential CD), it has been observed that the presence of intestinal TGA is the only mucosal im- Figure 16. Intestinal TGA deposits detected (yellow colour - TGA IgA antibodies). 20 6 Diagnostics Coeliac disease in the spotlight Diagnosing coeliac disease without intestinal biopsy However, according to the current guidelines, upper Based on the current ESPGHAN guide-endoscopy must be performed to confirm the diagnosis of lines, when all specific criteria have coeliac disease in adults. been met, the diagnosis of coeliac dis- ease in children and adolescents can safely be made without the need for upper endoscopy and intestinal biopsy. WHAT TO DO IN THE PRIMARY CARE FACILITIES 1. The TGA-IgA levels must be very high, WHEN CD IS SUSPECTED: i.e., more than 10 times the upper lim- 1. Determine the IgA antibody level: it of the cut-off value. a. If IgA is normal, determine IgA TGA; 2. Auto-antibodies against EMA must b. if IgA is undetectable, perform IgG TGA or if unable, refer to a be positive in a second blood sample. (paediatric) gastroenterologist; 3. A paediatric gastroenterologist should be involved in the process 2.) If IgA TGA is positive – refer to a (paediatric) gastroenterologist. and should explain the no-biopsy ap- 3.) Do not advise starting a gluten-free diet! proach to parents and patients. ESPGHAN 2020 guidelines for diagnosing coeliac disease in children and adolescents: A. CD serology positive Clinical suspicion CD risk group for any reason1 of CD Initial stage Measure serum TGA-IgA and total IgA TGA-IgA negative TGA-IgA and total IgA See B TGA-IgA positive Refer to paediatric GI (specialist in CD) B. TGA IgA negative Initial stage Review initial total IgA Total IgA low5 Total IgA Total IgA normal Consider risk of false negative serology: • low or short duration of gluten intake • immunosuppressive medication • extraintestinal manifestations6 Risk for false seronegativity Risk for false seronegativity Consult paediatric GI (specialist in CD) No risk No CD Figure 17. Diagnostic approach in children and adolescents with CD – initial care (A, B). 21 Coeliac disease in the spotlight 6 Diagnostics A. Review the results of the initial TGA-IgA antibodies2 Discuss diagnostic pathways with the family3 Specialist care Discrepant serology TGA-IgA See B TGA-IgA positive TGA-IgA <10xULN4 Consider TGA-IgA conc. (ULN) TGA-IgA ≥10xULN Biopsy – See C Test for EMA (separate blood sample) EMA-IgA negative EMA-IgA EMA-IgA positive CD confirmed B. Risk for false negative serology? Total IgA low Specialist care Consider HLA determination Perform IgG test (TGA, EMA, DGP) EMA-IgA positive lgG TGA, EMA or DGP HLA-DQ2/DQ8 Risk possible lgG tests negative Biopsy – See C HLA negative HLA-DQ2/8 positive Consider risk of false negative serology CD unlikely, Follow and retest consider on a normal gluten Risk of false seronegativity other diagnosis intake, consider biopsy No risk No CD C. Specialist care Oesophagogastroduodenoscopy Revise quality & orientation of the biopsy ≥4 biopsies from distal duodenum Consult experienced pathologist and ≥1 from bulb Marsh 0-1 Revise histopathology Histopathology7 Marsh 0-1 Marsh 2-3 Marsh 0 (normal) or marsh 1 (only increased IEL) confirmed and positive serology. CD confirmed Options • Consider consultation with a CD expert center • Consider false positive TGA result and test for EMA (if positive = potential CD) • Consider additional tests (HLA, TGA deposits, etc.) • Follow and retest on a normal gluten intake • Consider relevance of symptoms Footnotes 1. Other than TGA-IgA, including point-of-care tests (POCT) and DGP. 2. Check the value also in relation to the cut-off and repeat the test if questionable or borderline. No need to retest if done with validated assay with calibration curve. Test with conventional TGA-IgA test if positive POCT and TGA has not been measured quantitatively. 3. Convey the message that the diagnosis of coeliac disease with or without biopsy confirms the need for a lifelong gluten-free diet and that re-evaluation after introduction of the diet would need prolonged re-exposure to gluten with a series of further investigations. 4. If TGA-IgA is only borderline positive confirm sufficient gluten intake and considerer retesting of TGA-IgA and EMA. 5. Low for age or <0.2 g/l above the age of 3 years. 6. For example, dermatitis herpetiformis, in which serology is frequently negative. 7. The cut-off for normal numbers of IEL is >25 cells/100 enterocytes. Figure 18. Diagnostic approach in children and adolescents with CD – specialist care (A, B, C). 22 6 Diagnostics Coeliac disease in the spotlight QUIZ 1. Based on which test/s would you confirm CD? (multiple answers possible) a) Faecal inflammation markers (e.g., calprotectin). b) Coeliac disease-specific antibodies stool test. c) Coeliac disease-specific serology tests. d) Upper endoscopy with biopsy. e) Colonoscopy with biopsy. 2. Which of the following serological tests is used as the first-line test for the diagnosis of coeliac disease? a) EMA (anti-endomysial antibodies) b) AGA (anti-gliadin antibodies) c) TGA (tissue transglutaminase antibodies) d) d-GP Ab (deamidated gliadin antibodies) 3. A patient with symptoms and signs suggestive of coeliac disease tests negative for IgA TGA antibodies while consuming normal amounts of gluten. What is recommended? (multiple answers possible) a) Consider other diseases. b) Determine total IgA and perform IgG t-TG Ab test if IgA deficient. c) Perform EMA IgA. d) Perform endoscopy with duodenal biopsy. e) Repeat the TGA IgA Ab test. 4. Which conditions need to be fulfilled to consider diagnosing coeliac disease without intestinal biopsy? 5. Which classification is used for histological evaluation of biopsy specimens in CD? 6. Based on which test results would you be able to confirm coeliac disease? (Normal TGA <16) a) Microcytic anaemia, normal biochemistry, TGA 67. b) 14.10.2022 TGA >200, 24.10.2022 EMA positive. c) Elevated liver enzymes, TGA 50, Marsh 2. d) TGA 12, Marsh 3, EMA negative REFERENCES 1. Husby S, Koletzko S, Korponay-Szabó I, 8. Dickson BC, Streutker CJ, Chetty R. Coeliac I, Vogrincic M, Werkstetter KJ, Dolinsek Kurppa K, Mearin ML, Ribes-Koninckx disease: an update for pathologists. J Clin J. The Use of Biopsy and “No-Biopsy” C, et al. European Society for Paediatric Pathol. 2006; 59(10): p. 1008-16. Approach for Diagnosing Paediatric Gastroenterology, Hepatology and 9. Oberhuber G, Granditsch G, Vogelsang Coeliac Disease in the Central European Nutrition Guidelines for Diagnosing Coeliac H. The histopathology of coeliac disease: Region. Gastroenterol Res Pract. 2019 Nov Disease 2020. J Pediatr Gastroenterol Nutr. time for a standardized report scheme for 15;2019:9370397. 2020; 70(1): p. 141 56. pathologists. Eur J Gastroenterol Hepatol. 16. Meijer CR, Schweizer JJ, Peeters A, Putter 2. Koletzko S, Auricchio R, Dolinsek J, Gillett 1999; 11(10): p. 1185-94. H, Mearin ML. Efficient implementation P, Korponay-Szabo I, Kurppa K, et al. No 10. Marsh NM, Johnson WM, Rostami K. of the ‘non-biopsy approach’ for the Need for Routine Endoscopy in Children Mucosal histopathology in celiac disease: diagnosis of childhood celiac disease in with Celiac Disease on a Gluten-free Diet. a rebuttal of Oberhuber’s sub-division the Netherlands: a national prospective J Pediatr Gastroenterol Nutr. 2017; 65(3): p. of Marsh III. Gastroenterol Hepatol Bed evaluation 2010-2013. Eur J Pediatr. 2021 267-9. Bench. 2015; 8(2): p. 99-109. Aug;180(8):2485-2492. doi: 10.1007/s00431- 3. Kowalski K, Mulak A, Jasinska M, 11. Marsh MN. Patterns of Gluten-Induced 021-04068-1. Epub 2021 Apr 15. Paradowski L. Diagnostic challenges in Mucosal Change. In Feighery C, ÒFarrelly 17. Al-Toma A, Volta U, Auricchio R, Castillejo G, celiac disease. Adv Clin Exp Med. 2017; C. Gastrointestinal Immunology and Sanders D, Cellier C, et al. European Society 26(4): p. 729-37. Gluten-Sensitive Disease. Dublin: Oak Tree for the Study of Coeliac Disease (ESsCD) 4. Dieterich W, Ehnis T, Bauer M, Donner Press; 1992. p. 147-57. guideline for coeliac disease and other P, Volta U, Riecken E, et al. Identification 12. Reilly NR, Husby S, Sanders DS, Green PHR. gluten-related disorders. United European of Tissue Transglutaminase as the Coeliac disease: to biopsy or not? Nat Rev Gastroenterol J. 2019; 7(5): p. 583-613. Autoantigen of Celiac Disease. Nat Med. Gastroenterol Hepatol. 2018; 15(1): p. 60-6. 18. Losurdo G, Di Leo M, Santamato E, Arena 1997; 3(7): p. 797-801. 13. Wolf J, Petroff D, Richter T, Auth M, Uhlig H, M, Rendina M, Luigiano C, Ierardi E, Di Leo 5. Husby S, Murray JA. Diagnosing coeliac Laass M, et al. Validation of Antibody-Based A. Serologic diagnosis of celiac disease: disease and the potential for serological Strategies for Diagnosis of Pediatric Celiac May it be suitable for adults? World J markers. Nat Rev Gastroenterol Hepatol. Disease Without Biopsy. Gastroenterology. Gastroenterol. 2021 Nov 14;27(42):7233-7239. 2014; 11(11): p. 655-63. 2017; 153(2): p. 410-9. 19. Baykan AR, Cerrah S, Ciftel S, Vural MK, 6. Costa S, Astarita L, Ben-Hariz M, Currò G, 14. Werkstetter KJ, Korponay-Szabó IR, Popp Kasap E. A No-Biopsy Approach for the Dolinsek J, Kansu A, et al. A point-of-care A, Villanacci V, Salemme M, Heilig G, et al. Diagnosis of Celiac Disease in Adults: Can It test for facing the burden of undiagnosed Accuracy in Diagnosis of Celiac Disease Be Real? Cureus. 2022 Jul 3;14(7):e26521. doi: celiac disease in the Mediterranean Without Biopsies in Clinical Practice. 10.7759/cureus.26521. area: a pragmatic design study. BMC Gastroenterology. 2017; 153(4): p. 924-35. 20. De Leo L, Bramuzzo M, Ziberna F, Gastroenterol. 2014; 14: p. 219. 15. Riznik P, Balogh M, Bódi P, De Leo L, Villanacci V, Martelossi S, Di Leo G, et al. 7. Walker MM, Ludvigsson JF, Sanders DS. Dolinsek J, Guthy I, Gyimesi J, Horváth Á, Diagnostic Accuracy and Applicability of Coeliac disease: review of diagnosis and Kis I, Klemenak M, Koletzko B, Koletzko Intestinal Auto-Antibodies in the Wide management. Med J Aust. 2017; 207(4): p. S, Korponay-Szabó IR, Krencnik T, Not T, Clinical Spectrum of Coeliac Disease. 173-8. Palcevski G, Pollák É, Sblattero D, Tokodi EBioMedicine. 2020; 51: p. 102567. 23 Coeliac disease in the spotlight 7 Risk groups 7 Risk groups OBJECTIVES: • To identify coeliac disease risk groups. • To understand the purpose of risk group screening. Although coeliac disease is common, there Risk group Risk gr % CD are certain groups of people with a high- er risk of developing the disease. It is very First-degree relatives 10-20% important to actively search for the disease Other autoimmune disorders Type-1 diabetes mellitus 3-12% in these groups. The initial step can be ge- netic testing for HLA-DQ2 or DQ8, and if the Autoimmune thyroid 2-7% genetic risk is confirmed, these individuals disease need to be further tested with serological tests. Since coeliac disease can occur at any Autoimmune liver disorders 12-13% age, individuals with positive HLA-DQ2 or DQ8 haplotypes should be followed regu- Immunoglobulin A deficiency 2-8% larly to detect delayed-onset disease. How- Chromosomal abnormalities Down syndrome 5-12% ever, current guidelines for diagnosing CD in children and adolescents propose per- Turner syndrome 2-5% forming TGA IgA as an initial test in risk- group children. Williams syndrome up to 9% CASE STUDIES An 18-year- old boy was referred to the coeliac disease out-A 12-year-old boy has been followed in the coeliac disease patient clinic for family screening since his sister had been outpatient clinic for the past 5 years because of a family his-diagnosed with coeliac disease 1 month previously. He ex-tory of coeliac disease (his mother, aunt and cousin have plained that he had no specific complaints, except for prob-coeliac disease). He missed the last two appointments for lems with atopic dermatitis for many years. He had no ab-CD screening because of COVID restrictions and since he dominal pain, he defecated twice a day, and the stool was was feeling well all the time, his parents were not worried. A usually of normal consistency. His appetite was good and year ago, while playing football, he fell and suffered a com-overall, he felt well. Serology for coeliac disease was highly pression fracture of Th9 and five months after that, he suf-positive. fered a Th10 fracture when he fell from a standing position. His bone mineral density was found to be low; osteoporosis was confirmed, and the endocrinologist started treatment with bisphosphonates. At that time, repeat CD serology, A 4.5-year-old girl with Down’s syndrome had been followed showed elevated levels of TGA and positive EMA. at the paediatric gastroenterology department since the age of 2 years. When she was first seen, she was in excellent general condition, thriving well and had regular and normal stools. Since Down’s syndrome is associated with coeliac disease, coeliac serology was performed at the age of 2 and was A 4-year-old girl was referred to our paediatric gastroenter-negative. In addition, HLA DQ typing showed a positive ge-ology outpatient clinic because she was passing 3-4 watery netic predisposition for coeliac disease (DQ 2.5). Screening stools per day. Prior to the first visit, the primary-care paedi-for coeliac disease was repeated at the age of 3 and 3.5 years atrician performed anti-tissue transglutaminase antibodies, and again was negative. All that time, she ate gluten with which were negative. At the examination in our clinic, the no restrictions. At the age of 4.5 years, the patient was still in patient had abdominal distension, but otherwise, she was good clinical condition, gaining weight, with regular stools, in a good condition, thriving well, with no signs of anaemia. and not complaining of abdominal pain. However, coeliac As her IgA status was unknown, total IgA was ordered along disease antibodies were ≥10 times the upper limit of normal with IgG class antibodies to deamidated gliadin peptide and with positive endomysial antibodies from the second (DGP). The results showed IgA deficiency and highly positive blood sample, coeliac disease was diagnosed with a no bi-IgG DGP antibodies. A duodenal biopsy showed Marsh IIIb opsy approach, according to the ESPGHAN 2020 guidelines. and the diagnosis of coeliac disease was confirmed. A 38-year-old woman visited her general practitioner because her daughter had been recently diagnosed with CD. She told the doctor that she has had abdominal pain for many years and that she had tried several diets, with no effect. When her daughter was diagnosed with coeliac disease, she was told that family members are an important risk group, so she requested testing for CD. Her GP ordered CD serological tests that were positive, and she was therefore referred to the gastroenterology outpatient clinic for further diagnostic procedures. 24 7 Risk groups Coeliac disease in the spotlight QUIZ 1. Which risk group has »the most risk« of developing CD? 2. What tests are usually performed when a risk group patient is referred to a paediatric gastroenterologist for the first time? 3. How often does the CD patient’s brother (HLA-DQ3/HLA-DQ7) have to be screened for CD? 4. A person whose sister is coeliac is asymptomatic while consuming normal amounts of gluten. Previous genetic tests showed a genetic predisposition for coeliac disease. TGA antibodies are negative, total IgA is within the normal range. What would you recommend? a) Coeliac disease is not present at the given time. Continue normal diet, and schedule follow-up visit for repeated testing, especially if symptoms appear. b) Start a gluten-free diet. Coeliac disease is very likely. c) Tests are unclear. Perform a biopsy to confirm the diagnosis. d) Tests are unclear. Perform other serological tests (EMA or DGP Ab). REFERENCES 1. Ludvigsson JF, Card TR, Kaukinen K, Bai J, 10. Bonamico M, Pasquino AM, Mariani P, Zingone F, Sanders DS, et al. Screening for Danesi HM, Culasso F, Mazzanti L, et celiac disease in the general population al. Prevalence and clinical picture of and in high-risk groups. United European celiac disease in Turner syndrome. J Clin Gastroenterol J. 2015; 3(2): p. 106-20. Endocrinol Metab. 2002; 87(12): p. 5495-8. 2. Ch’ng CL, Jones MK, Kingham JG. Celiac 11. Liu E, Wolter-Warmerdam K, Marmolejo disease and autoimmune thyroid disease. J, Daniels D, Prince G, Hickey F. Routine Clin Med Res. 2007; 5(3): p. 184-92. Screening for Celiac Disease in Children 3. Mustalahti K, Sulkanen S, Holopainen with Down Syndrome Improves Case P, Laurila K, Collin P, Partanen J, et al. Finding. J Pediatr Gastroenterol Nutr. Coeliac disease among healthy members 2020. of multiple case coeliac disease families. 12. Mårild K, Størdal K, Hagman A, Ludvigsson Scand J Gastroenterol. 2002; 37(2): p. 161-5. JF. Turner Syndrome and Celiac Disease: A 4. Bibbò S, Pes GM, Usai-Satta P, Salis R, Case-Control Study. Pediatrics. 2016; 137(2): Soro S, Quarta Colosso BM, et al. Chronic p. e20152232. autoimmune disorders are increased 13. Lundin KE, Wijmenga C. Coeliac in coeliac disease: A case-control study. Disease and Autoimmune Disease- Medicine (Baltimore). 2017; 96(47): p. Genetic Overlap and Screening. Nat Rev e8562. Gastroenterol Hepatol. 2015; 12(9): p. 507-15. 5. Hagopian W, Lee HS, Liu E, Rewers M, 14. Husby S, Koletzko S, Korponay-Szabo She JX, Ziegler AG, et al. Co-occurrence IR, Mearin ML, Phillips A, Shamir R, of Type 1 Diabetes and Celiac Disease et al. European Society for Pediatric Autoimmunity. Pediatrics. 2017; 140(5): p. Gastroenterology, Hepatology, and e20171305. Nutrition Guidelines for the Diagnosis of 6. Mıhçı E, Nur BG, Berker-Karaüzüm Coeliac Disease. J Pediat Gastroent Nutr. S, Yılmaz A, Artan R. Celiac disease in 2012; 54(1): p. 136-60. patients with Williams-Beuren syndrome. Turk J Pediatr. 2015; 57(6): p. 599-604. 7. Meini A, Pillan NM, Villanacci V, Monafo V, Ugazio AG, Plebani A. Prevalence and diagnosis of celiac disease in IgA-deficient children. Ann Allergy Asthma Immunol. 1996; 77(4): p. 333-6. 8. Mårild K, Stephansson O, Grahnquist L, Cnattingius S, Söderman G, Ludvigsson JF. Down syndrome is associated with elevated risk of celiac disease: a nationwide case-control study. J Pediatr. 2013; 163(1): p. 237-42. 9. Singh P, Arora S, Lal S, Strand TA, Makharia GK. Risk of Celiac Disease in the First- and Second-Degree Relatives of Patients With Celiac Disease: A Systematic Review and Meta-Analysis. Am J Gastroenterol. 2015; 110(11): p. 1539-48. 25 Coeliac disease in the spotlight 8 Treatment 8 Treatment OBJECTIVES: • To learn how coeliac disease can be treated. • To recognise gluten-free and gluten-containing cereals. • To be able to identify hidden sources of gluten. • To recognise the safe amount of gluten in gluten-free products. The only available treatment for CD is a lifelong strict gluten-free diet, which can be started only after firm confirmation of the diagnosis by a specialist. Patients have to avoid all gluten-containing prod- ucts. These include products from wheat and wheat cultivars, rye, barley, Khorasan wheat, triticale and bulgur. Due to the high likelihood of cross-contamination, it is also recommended that oats be avoid- ed in many regions. It has been shown, however, that consumption of uncon- taminated oats is safe and may improve the patient’s quality of life. CD patients can safely consume naturally gluten-free foods and food that is produced specially for CD patients. There are many more nat- urally gluten-free foods than gluten-con- taining foods. Some are not related to grains at all, e.g., fruits, vegetables, ani- mal products (meat, milk, and eggs), po- tatoes and roots. In addition, gluten-free cereals are naturally available, such as rice and corn. Of course, gluten-free cereals can be successfully used to substitute gluten-containing cereals. However, glu- ten can be found in many foods where it would not be expected (cheese, sweets, sauces, spices, some meat products, and many dairy products). These products may contain gluten in the form of a food additive that is supposed to enhance the properties of the food. It is extremely difficult to maintain a strict gluten-free diet since gluten contami- nation is very common. “Hidden” gluten can be found in sausages, soups, sauces, ice cream and even non-food products, mainly medications, cosmetics, and toys. In addition, products that are made espe- cially for CD patients can contain traces of gluten due to the cross-contamination of grains during grinding, storage, and the use of grains. Unintentional cross-con- tamination can be an important problem for patients and might lead to tissue dam- age, especially in the long term. Although a well-informed and compliant patient will manage to avoid 99.99% of gluten, it is Figure 19. Comparison in the amount of gluten between regular gluten-containing bread (left) and gluten-free labelled bread (right). 26 8 Treatment Coeliac disease in the spotlight impossible to maintain a diet 100% free of plaints may persist. The most common strictive. Therefore, efforts are being made gluten. Therefore, the term “gluten-free” cause of persistent symptoms is ongo- to explore alternative therapies. These are refers to an extremely low gluten intake ing gluten ingestion (inadvertent or vol- classified by their mechanisms of action: that is below the threshold of what is con- untary). However, in some patients, mild modification of gluten, intraluminal ther- sidered harmful to coeliac patients. It has abdominal discomfort may remain even apy, immunomodulation, intestinal per- been found that a daily intake of up to 10 on a strict gluten-free diet, although the meability, and modulation of the adaptive mg of pure gluten is very unlikely to cause CD-specific antibodies have normalised. response. The immunogenic content of any signs or symptoms in most patients. In a very small proportion of patients, re- gluten could be decreased, for example, It is now widely accepted that the maxi- fractory CD causes persistent signs and by using genetically modified wheat or by mum level of gluten in foods may not ex- symptoms. intraintestinal gluten digestion using glu- ceed 20 ppm (parts per million; mg/kg). tenases (peptidases). Using binder drugs, However, modern gluten-free products For most patients, the following clinical the gluten in the gut lumen could be se-rarely contain more than 5 ppm of gluten. effects and improvements will occur: questered before it is digested into immu- nogenic peptides and absorbed. Another When shopping, only pseudo-cereals • Normalisation of antibody levels and possible approach would be to prevent or processed foods labelled with the regeneration of the intestinal mucosa. the uptake of digested gluten through crossed-grain symbol and ID number • Decreased risk of long-term health intestinal epithelial tight junctions using should be chosen, if available. This la-complications (osteoporosis/osteope- a zonulin antagonist or to prevent the bel guarantees that a food contains less nia, lymphoproliferative disorders, au- enhancement of the immunogenicity of than 20mg/kg gluten. The crossed-grain toimmune conditions). digested gluten by the intestinal tissue symbol is a registered trademark that is • Weight normalisation if underweight. transglutaminase using tissue transglu- protected in many countries and is pro- • In children: catch-up growth and nor- taminase inhibitors. There has also been moted by coeliac disease organisations mal physical development. research into how to prevent downstream worldwide. The AOECS (Association of Eu- • In women: improved pregnancy out- immune activation after the uptake of ropean Coeliac Societies) provides a regu- comes. gluten immunogenic peptides through larly updated list of certified products by the intestinal mucosal epithelial layer, member associations from different Eu- Although a GFD requires a thorough for example, by using HLA-DQ2 blockers, ropean countries. lifestyle change, patients should keep in which prevent the presentation of glu- mind that there are no side effects. Un- ten-derived antigens. However, all these On a strict GFD, the coeliac disease-as- dertaking it carefully, under the supervi- therapies have several important limita- sociated antibody levels gradually nor- sion of a clinician and/or dietitian, the diet tions due to complications or the lack of malise, and affected tissues usually will benefit the overall health of coeliac a complete response, hence most are still fully recover. However, this may take sev- disease patients. in the pre-clinical phases. eral months, whereas symptoms may im- prove much faster, particularly in children. Other possible therapies Although symptoms may also completely A gluten-free diet, as the only treatment resolve in adults, gastrointestinal com- option for CD, is very challenging and re- Figure 20. Possible new therapies for coeliac disease (Yoosuf S, Makharia GK. Front Pediatr.2019). 27 Coeliac disease in the spotlight 8 Treatment QUIZ 1. What kind of gluten-free diet is recommended for patients with coeliac disease to prevent serious complications of the disease? a) Diet with reduced gluten intake. b) Strict gluten-free diet for a short period (a few months) and then reduced gluten intake. c) Strict gluten-free diet for a short period and then a normal diet d) Strict gluten-free diet for a longer period (several years) and then reduced gluten intake. e) Strict gluten-free diet for a longer period and then a normal diet. f) Strict lifelong gluten-free diet. 2. Should you start a gluten-free diet after positive CD-specific antibody tests but before the diagnosis is confirmed (by confirmatory antibody testing or intestinal biopsy)? 3. How much gluten can gluten-free products contain? 4. Which of the following grains do you think should be excluded by patients with CD because they contain gluten? Please, underline them. WHEAT, BUCKWHEAT, RICE, BARLEY, MILLET, OATS, TRITICALE, RYE, KAMUT, SPELT, MAIZE, BULGUR, SOY. 5. Are there other treatment possibilities besides a gluten-free diet? REFERENCES 1. Theethira TG, Dennis M. Celiac disease and the gluten-free diet: consequences and recommendations for improvement. Dig Dis. 2015; 33(2): p. 175-82. 2. Aaltonen K, Laurikka P, Huhtala H, Mäki M, Kaukinen K, Kurppa K. The Long-Term Consumption of Oats in Celiac Disease Patients Is Safe: A Large Cross-Sectional Study. Nutrients. 2017; 9(6): p. 611. 3. Catassi C, Fabiani E, Iacono G, D’Agate C, Francavilla R, Biagi F, et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007; 85(1): p. 160-6. 4. Catassi C, Rossini M, Rätsch IM, Bearzi I, Santinelli A, Castagnani R, et al. Dose Dependent Effects of Protracted Ingestion of Small Amounts of Gliadin in Coeliac Disease Children: A Clinical and Jejunal Morphometric Study. Gut. 1993; 34(11): p. 1515-9. 5. Vaquero L, Bernardo D, León F, Rodríguez-Martín L, Alvarez-Cuenllas B, Vivas S. Challenges to drug discovery for celiac disease and approaches to overcome them. Expert Opin Drug Discov. 2019; 14(10): p. 957-68. 6. Yoosuf S, Makharia GK. Evolving Therapy for Celiac Disease. Front Pediatr. 2019; 7: p. 193. 7. Serena G, Kelly C, Fasano A. Nondietary Therapies for Celiac Disease. 2019. ; 48(1): p. 145-63. 8. Chamani E, Sargolzaei J, Tavakoli T, Rezaei Z. microRNAs: Novel Markers in Diagnostics and Therapeutics of Celiac Disease. DNA Cell Biol. 2019; 38(7): p. 708-17. 28 9 Follow-up Coeliac disease in the spotlight 9 Follow-up OBJECTIVES: • To learn how coeliac disease patients should be followed. • To understand which investigations need to be performed during follow-up visits. • To learn how the transition to adult care should be organised. After the diagnosis of coeliac disease is with complete blood cell count, micronu- cific clinical grounds, for example, if there established, patients must follow a strict tritional status (haemoglobin, iron, vita- are doubts about the original diagnosis gluten-free diet, so consultation with a min B12, and vitamin D levels) and liver en-or suspicion of the occurrence of an ad- dietitian is advisable. Dietary counselling zyme measurements if found abnormal ditional condition, for example, other pos- may be the best instrument not only for at diagnosis. Any abnormality should be sible concomitant enteropathies, such as maintaining patient adherence, but also followed, and deficiencies corrected until Crohn’s disease, autoimmune enterop- to evaluate the patient’s nutritional sta- normalisation. If abnormalities persist, ad- athy, small-bowel bacterial overgrowth, tus, to optimise and nutritionally balance ditional diagnoses should be considered cow’s milk protein allergy and pancreatic the gluten-free diet and to offer support and appropriately investigated. Screening insufficiency. to families facing many challenges of the for thyroid disease with TSH and thyroxine new dietary lifestyle. (and autoantibodies if indicated) may be For better adjustment to the life changes considered during follow-up after clinical associated with the presence of chronic The first follow-up visit with the paediatric evaluation. Routine bone-density screen- disease, some patients will also benefit gastroenterologist should be performed ing is not recommended. Bone mineral from psychological counselling. 3-6 months after diagnosis. Subsequent density should be measured at least once visits should be every 6 months until after initiation of the gluten-free diet if Transition to adult care normalisation of TGA levels, and every one of the following applies: An adolescent with CD is usually trans-12–24 months thereafter. The effective- ferred to adult care at the age of 18 years. ness of treatment is assessed by the im- • CD was diagnosed during adulthood The transfer should be structured and, provement in symptoms and signs and (BMD measurement to be scheduled at a minimum, include a transition letter normalisation of CD-specific antibodies, about one year after starting a GFD) or “coeliac passport” providing data on which might take several months. The ti- • Other risk factors for osteoporosis are the diagnosis, follow-up, anthropometric tres of TGA IgA antibodies can be expect- present (e.g., corticosteroid therapy for data, possible comorbidities, and dietary ed to fall below the cut-off of the normal other co-morbidities) adherence level. values within 12 months after starting a • The adherence to the strict gluten-free strict gluten-free diet. In many patients, diet is poor. they may normalise much earlier. It is im- portant to assess adherence to the glu- The lack of decreasing IgA-TGA levels af- ten-free diet. ter 6–12 months on a GFD or persisting positive IgA-TGA levels should be as- During the follow-up visit, patients should sessed by carefully reviewing dietary be evaluated for gastrointestinal and ex- compliance and testing IgA-TGA using traintestinal signs and symptoms and an- the same test from the same manufac- thropometric measurements. Special at- turer. Routine assessment of mucosal tention must be paid to children’s growth healing by small-bowel biopsies is not and development (physical, psychosocial, recommended in children with CD fol- and pubertal development). The level of lowing a GFD. Re-biopsy is considered TGA IgA should be measured together only in selected CD cases, based on spe-QUIZ 1. When should the first follow-up visit be performed? 2. How often should patients with coeliac disease be followed when stable? 3. 10 years after the diagnosis of coeliac disease was confirmed by serology and biopsy, the patient is still without symptoms since he is on a strict gluten-free diet. Serological tests are negative. What is recommended? a) Coeliac disease is no longer present. Diet is no longer needed. b) The clinical picture and serological tests suggest good disease control. Continue the diet. c) A control biopsy is needed to confirm intestinal healing and if so, gluten can be re-introduced stepwise into the patient’s diet. d) A gluten challenge for six months is recommended, and serological tests should be repeated after this period. 4. Are repeated intestinal biopsies required after diagnosing coeliac disease to follow patients’ responses? 29 Coeliac disease in the spotlight 9 Follow-up REFERENCES 1. Mearin ML, Agardh D, Antunes H, Al- Toma A, Auricchio R, Castillejo G, et. al. ESPGHAN Special Interest Group on Celiac Disease. ESPGHAN Position Paper on Management and Follow-up of Children and Adolescents with Celiac Disease. J Pediatr Gastroenterol Nutr. 2022 Sep 1;75(3):369-386. 2. Wessels M, Auricchio R, Dolinsek J, Donat E, Gillett P, Mårild K, et. al. Review on pediatric coeliac disease from a clinical perspective. Eur J Pediatr. 2022 May;181(5):1785-1795. 3. Wessels M, Dolinsek J, Castillejo G, Donat E, Riznik P, Roca M, et. al. Follow-up practices for children and adolescents with celiac disease: results of an international survey. Eur J Pediatr. 2022 Mar;181(3):1213-1220. 4. Cohen ME, Jaffe A, Strauch CB, Lewis SK, Lebwohl B, Green PHR. Determinants of Follow-up Care for Patients With Celiac Disease. J Clin Gastroenterol. 2018; 52(9): p. 784-8. 5. Pinto-Sanchez MI, Bai JC. Toward New Paradigms in the Follow Up of Adult Patients with Celiac Disease on a Gluten- Free Diet. Front Nutr. 2019; 6: p. 153. 6. Husby S, Bai JC. Follow-up of Celiac Disease. Gastroenterol Clin North Am. 2019; 48(1): p. 127-46. 7. Myléus A, Reilly NR, Green PHR. Rate, Risk Factors, and Outcomes of Nonadherence in Pediatric Patients With Celiac Disease: A Systematic Review. Clin Gastroenterol Hepatol. 2020; 18(3): p. 562-73. 8. Mustalahti K, Lohiniemi S, Collin P, Vuolteenaho N, Laippala P, Mäki M. Gluten-free diet and quality of life in patients with screen-detected celiac disease. Eff Clin Pract. 2002; 5(3): p. 105-13. 9. Husby S, Murray JA, Katzka DA. AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease: Changing Utility of Serology and Histologic Measures: Expert Review. Gastroenterology. 2019; 156(4): p. 885-9. 10. Vriezinga SL, Schweizer JJ, Koning F, Mearin L. Coeliac disease and gluten- related disorders in childhood. Nat Rev Gastroenterol Hepatol. 2015; 12(9): p. 527- 36. 11. Deora V, Aylward N, Sokoro A, El-Matary W. Serum Vitamins and Minerals at Diagnosis and Follow-up in Children with Celiac Disease. J Pediatr Gastroenterol Nutr. 2017; 65(2): p. 185-9. 12. Wessels MMS, van Veen II, Vriezinga SL, Putter H, Rings EH, Mearin ML. Complementary Serologic Investigations in Children with Celiac Disease Is Unnecessary during Follow Up. J Pediatr. 2016; 169: p. 55-60. 30 10 Complications Coeliac disease in the spotlight 10 Complications OBJECTIVES: • To be able to identify possible complications of coeliac disease. • To understand the importance of the timely diagnosis of coeliac disease. When a patient is diagnosed with coeliac dis- ease and maintains a strict gluten-free diet, Depression usually all symptoms resolve. However, if the Loss of quality of life gluten-free diet is not adhered to strictly or if the disease is diagnosed in adults or with substantial delay, the risk of complications in- creases. Among the most dangerous compli- Irritable Bowel Syndrome cations is malignant lymphoma of the small Pancreatic insufficiency intestine, although complications can also Refractory CeD affect various organ systems, such as the re- malignancy (short-bowel lymphoma) productive, neurological, cardiovascular, and haematological systems. Psychiatric disorders can also occur. Low bone mineral density can Infertility result in bone fractures. These complications, Abortion which rarely present in children, can be irre- versible and the introduction of a strict glu- Pre-term birth ten-free diet might not bring complete reso- Low birth weight lution of the damage already present. Therefore, the development of the long-term complications of undiagnosed and/or untreat- Osteoporosis ed coeliac disease is another important factor that calls for early detection (and appropriate treatment) of the disease in all symptomatic patients as well as in patients that belong to the so-called risk groups for coeliac disease. Figure 21. Possible complications of untreated coeliac disease. PATIENT STORIES A boy who was operated for Hirschsprung’s disease as A 43-year-old man was referred to the emergency room due to an infant was admitted to the surgical department at vomiting and weight loss. He explained that he had been feel-the age of 3 years due to severe abdominal distension, ing unwell for the past six months, had no appetite, and had failure to thrive and anaemia. Obstruction was suspect-lost 15 kg. He had been vomiting a lot and he also had frequent ed and surgical revision was undertaken. Afterwards, the abdominal pain. Twenty-five years previously, he had been di-anaemia was corrected, and he started to gain weight, al-agnosed with coeliac disease, but he had not been very com-though his weight gain was still not satisfactory. This was pliant with the diet. During the examination, he complained attributed to the socially deprived conditions in which he of abdominal pain, and he looked undernourished. Labora-lived. A few months later, he was again seen by the sur-tory blood tests showed hypoalbuminaemia with electrolyte geon for an uncomplicated arm fracture that occurred disturbances. Serological tests for coeliac disease were highly after a mild trauma. His arm was placed in a cast, and the positive. An oesophagogastroduodenoscopy was performed, bone healed well. However, at the age of 4 years, he was which showed active coeliac disease, and a subtotal stenosis of readmitted to hospital for a broken leg requiring surgery. the distal part of the duodenum was found on X-ray passage. Blood tests revealed anaemia and given the patient’s A deep duodenoscopy showed tumour formation. Histology history, coeliac serology was ordered, which came back revealed an adenocarcinoma, most likely as a complication of highly positive. untreated coeliac disease. Surgical resection was performed. 31 Coeliac disease in the spotlight 10 Complications QUIZ 1. Which of the following may be a complication of untreated (or undiagnosed) coeliac disease? (multiple answers possible) a) Anaemia b) Osteoporosis c) Intestinal lymphoma d) Colon cancer e) Cardiac problems f) Renal insufficiency g) Inflammatory bowel disease h) Infertility 2. Which complication of CD can be resolved with a gluten-free diet? a) Microcytic anaemia b) Osteopenia c) Intestinal lymphoma d) Epilepsy 3. Which patients’ growth retardation/small stature can still be resolved with a gluten-free diet? a) A 4-year-old girl b) A 19-year-old boy c) A 34-year-old man d) A 15-year-old girl REFERENCES 1. Goddard CJR, Gillett HR. Complications of coeliac disease: are all patients at risk? Postgrad Med J. 2006; 82(973): p. 705-12. 2. Biagi F, Schiepatti A, Maiorano G, Fraternale G, Agazzi S, Zingone F, et al. Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentation. Dig Liver Dis. 2018; 50(6): p. 549-52. 3. Walker MM, Ludvigsson JF, Sanders DS. Coeliac disease: review of diagnosis and management. Med J Aust. 2017; 207(4): p. 173-8. 4. Laurikka P, Nurminen S, Kivelä L, Kurppa K. Extraintestinal Manifestations of Celiac Disease: Early Detection for Better Long-Term Outcomes. Nutrients. 2018; 10(8): p. 1015. 5. Pengiran Tengah DS, Wills AJ, Holmes GK. Neurological complications of coeliac disease. Postgrad Med J. 2002 Jul;78(921):393-8. doi: 10.1136/pmj.78.921.393. PMID: 12151653; PMCID: PMC1742420. 6. Bommu VJL, Mirza L. Osteoporosis Can Be the Sole Presentation in Celiac Disease. Cureus. 2021 Dec 22;13(12):e20602. doi: 10.7759/ cureus.20602. 7. Brousse N, Meijer JW. Malignant complications of coeliac disease. Best Pract Res Clin Gastroenterol. 2005 Jun;19(3):401-12. 32 11 Quality of life of coeliac disease patients Coeliac disease in the spotlight 11 Quality of life of coeliac disease patients For some patients, the time from the first symptoms to getting a coeliac diagnosis can be a long and hard journey, but for all of them, the real challenge starts after the diagnosis. Answers to the questions What is gluten and how can I avoid it? What can I eat? Where can I eat? How can I prepare gluten-free food? How can I ensure a safe environment in school or kindergarten? What are my rights? can be found on the web and social media, but one has to be aware that those sources can some- times be unreliable. Coeliac societies are organisations where pa- tients can find answers to their questions, as well as practical help and support while living with coeliac disease. From the patient’s perspective, key features relevant to adherence to gluten-free diets are: • Accepting the disease and the “loss” of some aspects of normal life, due to the re- strictions of a gluten-free diet. • Understanding the basics of coeliac dis- ease. • Understanding what a gluten-free diet is and what a nutritionally balanced diet is. • Knowing what (industrial) products can be used in gluten-free diets and the availabili- ty of those products. • The affordable price of gluten-free prod- ucts. • Knowing what the critical points are in pre- paring gluten-free meals. • Having key skills to prepare homemade gluten-free products (bread, cakes, pastry, etc.) and meals generally. • Having the option to eat safely outside the house, especially in educational institutions (kindergartens, schools), hospitals, homes for the elderly, etc. • Accepting the fact that a person/child with coeliac disease is different because of his/ her special dietary needs and that he/she also has special educational needs. • Having a supporting/inclusive environ- ment where one feels safe, accepted, and equal to others. That especially refers to kindergartens and schools because chil- dren are a vulnerable population. School programmes and curriculums, as well as materials and methods used, should be adjusted to CD patients. Children and edu- cational workers should also be sensitive to the needs of children with CD. All these features have to be considered in comprehensive and multidisciplinary health- care for CD patients. Various stakeholders must be included to provide help and support and protect the mental and physical health of coeliac patients and enable them to live nor- mal functional lives, which will, in the end, re- sult in a decrease in public health issues and high costs related to nonadherence to a glu- ten-free diet. 33 Coeliac disease in the spotlight 12 Clinical cases 12 Clinical cases 1. A primary-care paediatrician calls the paediatric gastroenterology outpatient clinic asking for consultation. He presents a case of an 11-year-old boy on a regular diet, with abdominal pain that occurs 2-3 times a month. CD serological tests were performed one week previously. The results are as follows: total IgA – normal; TGA 19 (upper level of normal 16). What would you recommend? 2. A mother and her 4-year-old girl come to the outpatient clinic because of the girl’s diarrhoea. She tells you, that the girl defecates 3 times per day, and the stool is soft, but not entirely liquid. She has already tried a gluten-free diet at home and ever since the girl has been on the diet, she defecates once per day. What would you recommend? 3. The mother of a newly diagnosed CD patient comes to the coeliac disease outpatient clinic for family screening of her 13-month-old son. Her older daughter had been diagnosed with CD 5 months previously. What investigations would you perform and what instructions will you give to the mother? 4. A 17- year- old boy was admitted to the hospital for planned upper endoscopy because of suspicion of H. pylori infection (positive stool test). An endoscopy revealed nodular gastritis. The histology re- sults confirm H. pylori infection. Marsh 3a changes were observed in duodenal biopsies. You schedule a follow-up visit to test for coeliac disease. TGA and EMA were both found to be negative. What would your decision be? 5. A 10- year- old girl was referred to the outpatient clinic because of weight loss and growth retardation. Her mother tells you that the girl has always been the smallest in her class, and despite eating well, she has not gained weight appropriately. She has never complained of abdominal pain, but sometimes she has felt a bit nauseous after lunch, regardless of what she has eaten. She is also very tired all the time and sometimes a bit restless. Laboratory results showed TGA 200 (upper level of normal 16), and EMA is positive. What would you suggest to the girl and her mother? 6. A 4-year-old girl was referred to the outpatient clinic because of abdominal pain and constipation. Her mother explained that the girl has frequently complained of abdominal pain, es- pecially in the evening during the week. The ab- dominal pain persists for a few minutes and is usually self-limiting. She defecates once every three days and the stools are usually hard in the form of small bobs. She has already tried a diet without cow’s milk proteins, but no obvious changes were observed. The mother then explains that she had been reading about a gluten-free diet and had decided to give it a try. When you ask what the girl usually eats, her mother tells you that she usually eats cornbread or spelt pasta. They have stopped eating white bread at home. Since they excluded white bread, the girl has been doing better, so the mother would like to have a certificate that her daughter has coeliac disease so she can receive gluten-free food in kindergarten. What would you tell the mother? 34 13 Quiz results Coeliac disease in the spotlight 13 Quiz results 2. HISTORY OF COELIAC DISEASE 6. DIAGNOSIS 1) A long time ago, there was no gluten in the human diet. Man 1) c, d was a hunter and a gatherer, so he ate fruits, nuts, tubers and 2) c occasionally the meat of hunted animals. It was only after the 3) a, b, c, d, e end of the last ice age that he started growing food and the 4) No-biopsy approach: TGA-IgA > 10 times the upper limit of first types of cereals appeared. normal, EMA positive in a second blood sample, a paediatric 2) The invention of the jejunal biopsy device, with which a bi-gastroenterologist is involved in the process. opsy of the distal duodenum was successfully performed for 5) Marsh – Oberhuber the first time. 6) b, c 3. EPIDEMIOLOGY 7. RISK GROUPS 1) 1%. 1) First-degree family members of CD patients. 2) The disparities in the awareness of CD, variations in health-2) TGA IgA. Genetic testing can also be considered. care resources and diagnostic protocols used to detect CD. 3) Screening is not necessary since he has no genetic predisposition to the development of CD. 4) a 4. AETIOLOGY: 1) b 2) HLA DQ2/DQ8 8. TREATMENT 3) 30-40% 1) f 4) c, d, e 2) No, the diet can be initiated when the diagnosis is confirmed. 3) Below 20 ppm. 4) Grains that need to be excluded: WHEAT, BARLEY, TRITICALE, 5. CLINICAL PRESENTATION RYE, KAMUT, SPELT, BULGUR. 1) b, d, e 5) No. 2) In very young children, signs and symptoms of malabsorption are more common than in older children and adolescents, in whom abdominal pain is the most common symptom. In 9. FOLLOW-UP adults, the disease often does not present with characteristic 1) 3-6 months after diagnosis. signs and symptoms, but with extraintestinal manifestations 2) Once every 12-24 months. or serious complications. 3) b 3) Early childhood (1-4 years of age), puberty, and the period of 4) No. lactation after giving birth in women. 4) Classical CD presents with symptoms and signs of malabsorption: diarrhoea, steatorrhoea, bloating, growth retarda-10. COMPLICATIONS tion or weight loss, anaemia, neurological disorders due to 1) a, b, c, e, h vitamin B deficiency, osteopenia due to vitamin D and calci-2) a, b um deficiency. 3) a 5) Dermatitis herpetiformis. Diagnosis: skin biopsy, showing pathognomonic granular deposits of immunoglobulin A in the papillary dermis. Damage to the intestinal mucosa can also be found. Patients with severe skin symptoms may need special medications in addition to a gluten-free diet. 6) a, c 35 Coeliac disease in the spotlight Clinical cases results 14 Clinical cases results 1. Test again in approx. 3-6 months and if TGA positive, perform upper en- doscopy if needed (according to the antibody level). Advise a normal, glu- ten-containing diet until the end of the diagnostic process. 2. To confirm the diagnosis of CD, glu- ten in sufficient quantity (10-15g/ day) must be reintroduced into the diet for at least three months. Then, repeat the tests and proceed accord- ing to the guidelines. Gluten reintro- duction can be safely done only at a specific age to prevent the harmful effect of gluten on a child’s growth. 3. TGA IgA should be performed along- side total IgA determination, and you may also consider genetic testing. You need to explain to the mother that there is a risk of her younger son developing CD, so if the genetic tests are positive, he will be screened approximately annually, or sooner if symptoms/signs suggestive of CD appear. The boy should not be on a gluten-free diet in the meantime. 4. You prescribe eradication therapy for H. pylori infection. CD serology tests should be performed again in six months (TGA IgA) and repeated upper endoscopy should be consid- ered after that (unless eligible for the no-biopsy approach). Until these tests, the boy should eat a regular, gluten-containing diet. 5. The girl probably has coeliac disease. You explain the disease and the diag- nostic process. Due to the very high levels of TGA, she is eligible for the no-biopsy approach, and you sched- ule her for the second blood with- drawal for EMA testing. 6. You can safely perform CD serologi- cal testing since the girl was not re- ally on a gluten-free diet. If the tests are positive, proceed according to the diagnostic algorithm. You advise about treatment for constipation. 36 List of used abbreviations Coeliac disease in the spotlight List of used abbreviations AOECS Association of European Coeliac Societies AGA Anti-gliadin antibodies DGP Deamidated gliadin peptide DGP Ab Deamidated gliadin peptide antibodies EMA Anti-endomysial antibodies ESPGHAN European Society for Paediatric Gastroenterology, Hepatology and Nutrition HLA Human leukocyte antigen IEL Intraepithelial lymphocytes IgA Immunoglobulin A IgE Immunoglobulin E IgG Immunoglobulin G IgM Immunoglobulin M POCT Point-of-care-testing ppm Parts per million RC Refractory celiac disease TGA Tissue transglutaminase antibodies TSH Thyroid-stimulating hormone 37 Coeliac disease in the spotlight E-learning course for healthcare professionals and patients Within the CD SKILLS (Interreg Danube Transnational Programme) project two innovative e-learning tools have been implemented, one for healthcare professionals and the other for patients. The e-learning tools are an upgrade CD SKILLS of the existing tools developed within the Focus IN CD project (Interreg Central Europe Programme) and updated in Understandable ✔ accordance with the new ESPGHAN (European Society of Interactive ✔ Paediatric Gastroenterology, Hepatology and Nutrition) Free of costs ✔ guidelines for the management of coeliac disease published in 2020. The e-learning tools, which are available in Detailed ✔ English, German, Slovenian, Hungarian and Croatian, have been updated, and versions have been added in Romanian and Czech. E-tools are available at : www.celiacfacts.eu. Don’t worry! ALL INFORMATION ABOUT CD SKILLS E-TOOLS IS AVAILABLE HERE: Celiac disease?!? www.celiacfacts.eu CD Skills Razglednica A5 DEC 2022.indd 1 29/11/2022 11:33 The postcard promoting coeliac disease e-learning tools for patients and healthcare professionals. CD SKILLS transnational information exchange network for healthcare professionals CD SKILLS transnational information exchange network - an open-access web-based platform designed for healthcare professionals, was established within the project. The aim of the platform is to exchange knowledge and information, discuss challenging cases and share problems in the field of coeliac disease with other members of the network. Each month, an interesting and instructional clinical case is presented as a “case-of-the-month “ presentation. The second part of the platform is dedicated to “cases for discussion“ where partners and other healthcare professionals can present and discuss challenging coeliac disease cases, ask questions and share problems. Visit the platform at: https://cdskills.eu/. Exchange platform to share the challenges of coeliac disease. CD SKILLS publications During the two and a half years of the CD SKILLS project, four publications aimed at coeliac patients, healthcare professionals, caterers and medical students have CD SKILLS been prepared to raise knowledge, increase compe- tences and foster uniformity in the management of coeliac disease (CD). All brochures are available in the languages of the partners on the project website: Hand in https://www.interreg-danube.eu/approved-projects/ cd-skills (Library). hand with Coeliac Disease Brochure for healthcare professionals “Hand in hand with celiac disease” 38