Introduction to Coeliac Disease

Learning objectives

By the end of this chapter, participants will be able to:

1. Describe coeliac disease (CD), potential signs and symptoms
2. Understand the complications and prognosis associated with CD
3. Recognise common misinterpretations and other intestinal diseases with which CD may be misdiagnosed

A brief introduction to coeliac disease

• • CD is a chronic, multi-organ autoimmune disease that is triggered by exposure to dietary gluten in genetically predisposed individuals.^1,2
  • Gluten is a protein component of wheat, rye, and barley; it is poorly digested in the human intestine, regardless of the presence of CD. Oats contain a gluten-related protein that is not harmful.²
  • For individuals with CD, gluten exposure leads to a highly variable degree of intestinal damage and CD is characterised by a chronic inflammation of the intestines.²

• CD may also be referred to as gluten-sensitive enteropathy, coeliac or non-tropical sprue,³ but this terminology is not ²

Epidemiology and prevalence

• CD prevalence has substantially increased over the last 50 years, largely due to improved diagnostic tools and increased screening of high-risk individuals.¹ However, the majority of patients with CD remain undetected.^1,3
• Until the 1980s, CD was considered a rare disease that primarily affected paediatric patients.⁴ We now understand that it affects all age groups, including the elderly, and primarily affects females.⁴
• CD affects approximately 1% of individuals worldwide, but there are significant variations between different countries, ranging from 0.33% in Ireland to 2% in Finland.³
• Evidence suggests that there may remain an average of 4 undiagnosed cases for every diagnosed case of CD.^5,6

Aetiology

• CD develops due to lack of immune tolerance to peptide antigens derived from gluten proteins called prolamins.
• Prolamins are partially resistant to breakdown human proteases. Fragments of them remain intact in the small intestinal lumen, where they trigger immune activation leading to intestinal damage.⁷
• Gluten or its derivatives provoke an autoimmune response to a self-protein known as tissue transglutaminase or type-2 transglutaminase (TG2), which is present in the gut and other organs. TG2 autoantibodies are a marker for the diagnosis and the follow-up of CD, as their production is gluten dependent.⁸
• CD appears to be multifactorial. Human leukocyte antigen (HLA) risk alleles must be present but are not sole markers for CD indication.³ The majority of CD patients have the variant HLA-DQ2 allele or the HLA-DQ8 allele.²
• Additional non-HLA genes contribute to genetic susceptibility.³
• The presence of gluten in the diet is necessary for CD pathogenesis. Gluten induces several changes in intestinal permeability, HLA recognition and immune responses to both gluten and TG2, all of which contribute to the development of CD.⁹
• The disease does not develop in the absence of gluten, even in the presence of a genetic predisposition.³

Clinical presentation

• • The clinical presentation of CD varies widely, and the onset of symptoms may occur at any time in life when gluten is in the diet.⁴
  • Common signs and symptoms include:⁷
    1. gastrointestinal (GI) symptoms, usually mild, such as diarrhoea and abdominal distention
    2. Iron deficiency (with or without anaemia)
    3. Chronic fatigue
    4. Reduced bone mineral density
  • Rare forms of CD include dermatitis herpetiformis (a specific cutaneous manifestation of CD) and gluten ataxia (an idiopathic sporadic form of ataxia with positive serologic markers for gluten sensitisation). Other extra-intestinal manifestations may also occur.^3,9
  • CD may also present with ataxia without a comorbid enteropathy. In these cases, diagnosis is complicated and usually requires referral to a specialist centre, as well as close clinical and serological monitoring.¹⁰
  • Depending on clinical, immunological, and histopathological features, CD may be classified as symptomatic/asymptomatic, classical/non-classical, subclinical, or refractory CD.²
  • Three histological classifications have been mainly used for CD:
    1. Marsh classification was the first to associate the evolution of mucosal damage with a progressive gluten intake in CD patients, which is illustrated below.^2,11

*Later studies suggested the best cut-off for normality of intraepithelial lymphocytes was 18/100 enterocytes

• 2. Marsh-Oberhuber classification subcategorised stage 3 into stages 3A, 3B and 3C depending on the degree of villous flattening. The Marsh-Oberhuber classification is currently used by most pathologists, even though Marsh himself was against the additional subclassification.^1,12
     • There is now a move away from grading severity towards measuring villous height/crypt depth ratio by morphometry.¹³
  3. Corazza classification attempts to simplify the grading system, aiming to minimise the controversy of the former classifications and to facilitate the comparison between follow-up biopsies.¹

• While these classifications represent the historical common practice of categorising mucosal architecture, there is a general movement away from the classic grading categories towards classification by morphometry. Serology can be used, with or without biopsy, to diagnose CD in people who meet serological and genetic criteria, although guidelines still recommend biopsy confirmation in adults.^1,14,15

Causes and predisposing factors

• Onset of CD can occur at any time after gluten introduction, but the trigger is not always gluten alone.
• The onset of symptoms may be much later than onset of the disease itself. Although the clinical presentation of CD can include typical symptoms of malabsorption, there are oligosymptomatic and even asymptomatic cases – these tend to be diagnosed during screening of high-risk groups.¹⁶
• Environmental trigger factors can include gastrointestinal infections, medications, α-interferon, and surgery.¹
• Viral infections by reoviruses have been proposed to trigger pathways leading to the development of CD.¹⁷
• Several genetic risk factors have been identified, most of which are associated with immunological functions and B-cell and T-cell functions.⁴ The highest risk is associated with the HLA risk alleles (HLA-DQ2 or HLA-DQ8).¹
• CD4 gluten-reactive T cells (T-cell receptor α/β expressing) are indicators of CD and are not found in people without the disease.⁴
• A family history of CD increases the risk of CD. Risk is greater in first-degree relatives (especially monozygotic twins) compared with second-degree relatives, but both are at increased risk of CD compared with the general population.^1,4 There is a 5-10% risk of CD in a child with a first-degree relative with CD.^1,7
• The presence of certain autoimmune diseases and genetic syndromes are associated with an increased prevalence of CD. These include: type 1 diabetes mellitus, autoimmune thyroid or liver diseases, Down syndrome, Turner syndrome, Williams syndrome and selective humoral IgA deficiency.^1,3

Signs and symptoms

• Classic CD is associated with malabsorption dominated by diarrhoea, steatorrhoea, weight loss or failure to thrive.²
• Non-classical CD may have no distinct malabsorptive symptoms but rather presents with iron-deficiency anemia.⁴
• CD can also be asymptomatic, with patients only identified by mass testing.² Some patients are asymptomatic but demonstrate clinical or laboratory signs and are classified as having subclinical CD.²
• It is increasingly understood that signs and symptoms of CD vary and may include anaemia, vague abdominal symptoms, bone and reproductive issues, neuropathy, ataxia, and depression. (Figure 1)³
• Symptoms may vary with age, with children notably demonstrating malnutrition, growth delays, and pubertal delays.¹⁶

Figure 1: CD has a wide spectrum of signs and symptoms, which may vary significantly between patients.^3,7,10,16,18

• Patients with CD can be classified into common subgroups, based on their clinical presentation and the response to a gluten-free diet (GFD). The different subgroups are presented below (note: this is not an official classification of CD).^2,7

Coeliac disease complications

• Bones: Patients with CD have a greater risk of osteopenia and bone fracture, as well as of an early onset of osteoporosis and osteomalacia. Patients with severe CD have very low serum calcium and elevated parathyroid hormone levels.¹
• Cancer: Patients with CD are at high risk of developing malignancies, such as enteropathy-associated T-cell lymphomas or lymphoproliferative diseases.¹
• Skin: Dermatitis herpetiformis is characterised as the specific cutaneous manifestation of CD and shares the same HLA haplotypes with CD. Other adverse skin conditions induced by CD may include psoriasis and non-specific dermatological issues (such as dry skin, easy bruising, brittle nails, and thinning hair).¹
• Oral: If CD is developed before the age of 7, abnormalities in the development of permanent teeth and the structure of the dental enamel (both hypoplasia and hypomineralisation) can occur.¹
• Neurological: Gluten ataxia is the most common neurological disorder in CD, followed by idiopathic peripheral neuropathy, gluten encephalopathy and epilepsy. Psychiatric complications associated with CD include anxiety, depression, learning difficulties, sleep disturbances and eating disorders.¹
• Cardiovascular: Cardiomyopathy or myocarditis may lead to chronic or acute cardiac failure.¹⁸
• Reproductive disorders: There is evidence that the fertile life span narrows with CD due to a delayed menarche or early menopause, while the incidence of secondary amenorrhoea is increased. It has also been proven that CD is associated with a higher risk of pregnancy complications and a short breastfeeding period.¹⁹ Clinically severe CD symptoms may occur post-partum.¹

Coeliac disease comorbidities

• Common disorders associated with CD include thyroid disease, type 1 diabetes, Sjögren’s syndrome and multiple sclerosis.^{4, 20}
• Comorbidities may not always preventable as genetics can be a primary cause in addition to environmental factors.
  • Certain HLA alleles are overrepresented in patients with CD and increase the risk for type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.²⁰
  • CD also increases the susceptibility to other autoimmune disorders, such as Addison’s disease, arthritis, and autoimmune hepatitis.²¹
• There is an increased risk of developing certain types of cancers although the risk appears to decrease for some cancers if a strict GFD is maintained.²¹

Differential diagnoses

• Although CD is the most common cause of enteropathy (intestinal villous atrophy with crypt hyperplasia) in the Western world, other diseases may cause small intestinal inflammation but do not qualify as CD.²
• Wheat allergy is an immunologic reaction to wheat proteins which can be classified into four categories based on the route of allergen exposure and the underlying immunological mechanisms:³
  • Classic food allergy (skin, gastrointestinal and respiratory symptoms)
  • Exercise-induced anaphylaxis
  • Occupational asthma (baker’s asthma) and rhinitis
  • Contact urticaria
• Non-coeliac gluten sensitivity (NCGS) is a condition characterised by irritable bowel syndrome-like symptoms and extra-intestinal manifestations, when CD and IgE-mediated wheat allergy have been excluded.^1,3
• Clinical and pathogenic differences among CD, wheat allergy and NCGS are presented below:

Summary

• CD is a chronic, multi-organ autoimmune disease that is triggered by exposure to dietary gluten in genetically predisposed individuals.^1,2
• Gluten induces several changes in intestinal permeability, HLA recognition and immune responses to both gluten and the self-protein transglutaminase 2 (TG2), all of which contribute to the development of CD.⁹
• CD prevalence has substantially increased over the last 50 years, mainly due to increased screening and diagnosis among high-risk individuals.¹ Serology plays an important role in screening and diagnosis (generally with biopsy confirmation). Nevertheless, many patients with CD remain undetected.^1,3,6
• Clinical presentation of CD varies widely. Common signs and symptoms include:⁷
  • Gastrointestinal (GI) symptoms, usually mild, such as diarrhoea and abdominal distention
  • Iron deficiency (with or without anaemia)
  • Chronic fatigue
  • Reduced bone mineral density
• Onset of CD can occur at any time after gluten introduction, but the trigger is not always gluten alone. Other trigger factors can include gastrointestinal infections, medications, α-interferon, and surgery.¹ The onset of symptoms may be much later than the onset of the disease itself, and not all individuals with CD experience symptoms.
• Other CD symptoms can include complications affecting teeth and bones, skin and mucosa, central nervous system, reproductive system, heart, and general mental and physical wellbeing.^1,4,19
• Differential diagnoses for CD include non-coeliac gluten sensitivity and wheat allergy.⁹

References

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2. Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013;62:43–52.
3. World Gastroenterology Organisation Global Guidelines. Celiac disease. 2016; Long Version: 1–35.
4. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63:1210–1228.
5. Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? Gastroenterology. 2015;128(4 Suppl 1):S47–51.
6. Mustalahti K, Catassi C, Reunanen A, Fabiani E, Heier M, McMillan S, Murray L, Metzger MH, Gasparin M, Bravi E, Mäki M; Coeliac EU Cluster, Project Epidemiology. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann Med. 2010 Dec;42(8):587-95
7. BMJ Best Practice: Coeliac Disease. 2018. Available at: https://bestpractice.bmj.com/topics/en-gb/636 [last accessed November 2020].
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10. Hadjivassiliou M, Sanders DS, Grünewald RA, et al. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010;9:318–330.
11. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992;102:330–354.
12. Marsh NM, Johnson WM, Rostami K. Mucosal histopathology in celiac disease: a rebuttal of Oberhuber’s sub-division of Marsh III. Gastroenterol Hepatol Bed Bench. 2015;8(2):99–109.
13. Husby S, Koletzko S, Korponay-Szabó I, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70:141–157.
14. Taavela J, Koskinen O, Huhtala H, et al. Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. PLoS One 2013;8(10):e76163
15. Fuchs V, Kurppa K, Huhtala H et al. Serology‐based criteria for adult coeliac disease have excellent accuracy across the range of pre‐test probabilities. Aliment Pharmacol Ther. 2019;49:277–284.
16. Vivas S, Vaquero L, Rodrigues-Martin L, Caminero A. Age-related differences in celiac disease: Specific characteristics of adult presentation. World J Gastrointest Pharmacol Ther. 2015;6(4):207–212.
17. Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, Mayassi T, Meisel M, Kim SM, Discepolo V, Pruijssers AJ, Ernest JD, Iskarpatyoti JA, Costes LM, Lawrence I, Palanski BA, Varma M, Zurenski MA, Khomandiak S, McAllister N, Aravamudhan P, Boehme KW, Hu F, Samsom JN, Reinecker HC, Kupfer SS, Guandalini S, Semrad CE, Abadie V, Khosla C, Barreiro LB, Xavier RJ, Ng A, Dermody TS, Jabri B. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science. 2017 Apr 7;356(6333):44-50.
18. Menezes TM, Motta ME. Celiac disease prevalence in children and adolescents with myocarditis and dilated cardiomyopathy. J Pediatr (Rio J). 2012;88(5):439–442.
19. Tersigni C, Castellani R, de Waure C, et al. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update. 2014;20(4):582–593.
20. Ludvigsson JF, Card T, Ciclitira PJ, et al. Support for patients with celiac disease: A literature review. United European Gastroenterol J. 2015;3(2):146–159.
21. Celiac Disease Foundation. Autoimmune Disorders. Available at: https://celiac.org/about-celiac-disease/related-conditions/autoimmune-disorders/ [last accessed November 2020].