Gluten-Related Disorders: Diagnostic Approaches, Treatment Pathways, and Future Perspectives

Gluten-related disorders are prevalent worldwide, especially in developing countries. These diseases have similar clinical manifestations. Although they are characterized by a specific pathophysiological response to ingestion of gluten, differential diagnosis of these disorders is very challenging. Failure to diagnose and treat these disorders at an early stage, can lead to irreparable health and cost damages. Gluten-Related Disorders: Diagnostic Approaches, Treatment Pathways, and Future Perspectives solves this problem by reporting up-to-date scientific findings that allow for faster, more accurate diagnosis of gluten-related disorders as well as guidance on treatment options. By identifying the distinctive features of each of the gluten-related disorders, the chapters lead readers to optimal diagnosis and treatment options as well as better research designs for future research studies on the pathogenesis of these disorders. This reference provided by experts in the field is perfect for researchers, scientists, and medical practitioners who are involved in addressing gluten-related disorders.

• Provides a comprehensive overview on all aspects of gluten-related disorders, incorporating many up-to-date scientific findings
• Highlights the differences and overlaps in clinical presentations of gluten-related disorders in order to aid differential diagnosis
• Presents the current understanding of the pathogenesis of gluten-related disorders, which can be used to inform future research endeavors

• Language: English
• Publisher: Academic Press
• Release date: Sep 19, 2021
• ISBN: 9780128218587

Book preview

Chapter 1

Introduction

Mohammad Rostami-Nejad,    Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Gluten is a complex of structure-building proteins founds in certain cereal grains including wheat, barley, and rye. Gluten-containing grains play an important role in food technology and have become the most widely consumed dietary components worldwide. The gluten content of wheat varieties has gradually increased over time, leading to a significant spread of gluten-related disorders (GRDs). Celiac disease (CeD), dermatitis herpetiformis (DH), gluten ataxia (GA) as autoimmune, wheat allergy (WA) as allergic and non-celiac gluten sensitivity (NCGS) as non-autoimmune-allergic diseases are the five main categories of GRDs. Each GRD occurs following specific pathophysiological responses to gluten, and recent advances have been made in unraveling each of these disorders’ pathogenic pathways. GRDs present with typical and atypical manifestations. Similar presentations of GRDs make their final diagnosis challenging. A long-life gluten-free diet (GFD) is the mainstay of GRDs treatment, warranting good health in the majority of patients. Regular monitoring and follow-up strategies include evaluating symptoms, assessing GFD adherence, and looking for disease complications are necessary for proper handling of GRDs.

Keywords

Gluten-related disorders; pathophysiological responses; autoimmune diseases; allergic diseases; nonautoimmune-allergic diseases

Chapter Outline

Outline

References 3

Gluten is a complex of structure-building proteins founds in certain cereal grains, including wheat, barley, and rye and contributes to the appearance and elasticity of baked products. Gluten-containing grains play an important role in food technology and have become the most widely consumed dietary components worldwide. The glutamine- and proline-rich structure of gluten makes this protein resistant to human digestive proteases and gives it the ability to trigger inappropriate immune responses in genetically susceptible individuals. The cultivation of gluten-containing grains, which started in the Middle East about 10,000 years ago, along with the growth of civilizations, has led to a broad spectrum of gluten-related disorders (GRDs). The gluten content of wheat varieties has gradually increased over time, leading to a significant spread of GRDs. Although gluten is known to be the main triggering factor of GRDs, recent studies proposed that other components of wheat like fructans, α-amylase/trypsin inhibitors, lectins, and fermentable oligo-, di-, and monosaccharides and polyols may contribute to these disorders presentations.

Gluten is a complex of structure-building proteins founds in certain cereal grains, including wheat, barley, and rye and contributes to the appearance and elasticity of baked products [1]. Gluten-containing grains play an important role in food technology and have become the most widely consumed dietary components worldwide [2–4]. The glutamine- and proline-rich structure of gluten makes this protein resistant to human digestive proteases and gives it the ability to trigger inappropriate immune responses in genetically susceptible individuals [5,6]. The cultivation of gluten-containing grains, which started in the Middle East about 10,000 years ago, along with the growth of civilizations, has led to a broad spectrum of gluten-related disorders (GRDs) [7–9]. The gluten content of wheat varieties has gradually increased over time, leading to a significant spread of GRDs [10,11]. Although gluten is known to be the main triggering factor of GRDs, recent studies proposed that other components of wheat like fructans, α-amylase/trypsin inhibitor, lectins, and fermentable oligo-, di-, and monosaccharides and polyols may contribute to these disorders presentations [5].

Celiac disease (CeD), dermatitis herpetiformis (DH), gluten ataxia (GA) as autoimmune; wheat allergy (WA) as allergic; and nonceliac gluten sensitivity (NCGS) as nonautoimmune-allergic diseases are the five main categories of GRDs [2,12,13] (Fig. 1.1). CeD is the most common, multiorgan, chronic gluten-sensitive enteropathy [14,15]. DH is the typical gluten ingestion-related dermatopathy with a chronic-relapsing course [16,17]. GA, a gluten-induced cerebellar ataxia, is the commonest neurological disturbance of GRDs [12,18]. WA is one of the most common food allergies caused by adverse immune system reactions to wheat and related grains which is classified into two main categories: IgE-mediated and non-IgE-mediated [19,20]. NCGS refers to another adverse immune reaction to gluten that is different from CeD and WA [21–23].

Figure 1.1 Gluten-related disorders.

GRDs have gradually become epidemiologically relevant disorders and their estimated global prevalence range from 0.6% to 13% of the general population [13]. The most common GRDs are CeD and NCGS that have attracted the attention of the scientific community [5,24–26].

Along with gluten as the main environmental factor, genetic background and immunological responses may also play an essential role in the onset of GRDs [27,28].

Each GRD occurs following specific pathophysiological responses to gluten, and recent advances have been made in unraveling each of these disorders’ pathogenic pathways [5,29]. In CeD, innate and adaptive immune responses formed against dietary gluten cause small intestine mucosal lesions, intestinal villi atrophy, and nutrient malabsorption [27,30]. DH is characterized by deposition of IgA antitransglutaminase antibodies, produced in response to gluten exposure, in the superficial papillary dermis areas, which cause a bullous skin disease [17,31]. GA is accompanied by damage to Purkinje cells and cerebellar injury due to the cross-reaction of gluten-related antibodies with Purkinje cells antigenic epitopes [32,33]. In WA, allergic responses are induced by cross-linking of IgE antibodies with gluten peptides and the release of chemical mediators [5,34]. NCGS is caused by adverse innate immune responses against gluten, which is different from the CeD T-cell-mediated immunologic or WA allergic responses [21,35].

GRDs present with typical and atypical manifestations [2]. Digestive symptoms including diarrhea, steatorrhea, and weight loss are more common in CeD patients; however, these patients may have extraintestinal symptoms such as fatigue, osteoporosis, and mouth ulcers, or even be entirely asymptomatic [36,37]. DH is characterized by vesiculobullous, pruritic, and localized lesions distributed on the extensor surfaces such as elbows, knees, buttocks, and shoulders. It can also rarely be accompanied by gastrointestinal complications [31,38]. GA like other ataxias is associated with different neurological manifestations including gaze-evoked nystagmus, dysarthria, and gait ataxia [39]. WA presents with typical allergic manifestations include gastrointestinal, dermal, respiratory, circulatory, and cerebral symptoms [40]. NCGS has a wide range of intestinal and extraintestinal symptoms with similarity to other GRDs manifestations [21,41].

Similar presentations of GRDs make their final diagnosis challenging [42]. Histopathological assessment of duodenal biopsies is the gold standard for CeD diagnosis and plays a relevant role in differentiating CeD from other GRDs [43]. Accordingly, a critical first step in assessing nonresponsive and refractory CeD patients is to ensure the correctness of the initial diagnosis of celiac disease by biopsy evaluation [44,45]. Moreover, skin biopsy assessment using direct immunofluorescence is useful in DH diagnosis [46]. However, histology alone is not specific for GRDs correct differential diagnosis and the distinction of these globally significant conditions is based on a combination of clinical evaluation and specific tests [42]. Diagnostic tests for GRDs include serological and duodenal biopsy evaluations along with human leukocyte antigen-typing for CeD [47], skin biopsy assessment for DH (confirmatory serologic tests can be considered in some cases), skin patch testing, and serum IgE evaluation for WA [2,20,46]. As the optimal diagnostic approach to evaluate patients with suspected GA remains uncertain, its diagnosis is supported by the presence of some autoantibodies in serum [48,49]. Besides, there is no specific NCGS diagnostic biomarker and the diagnosis of NCGS is dependent on the exclusion of WA and CeD [50].

A long-life gluten-free diet (GFD) is the mainstay of GRDs treatment, warranting good health in the majority of patients [5,51]. Currently, due to the better description of GRDs pathomechanisms, alternative or complementary therapeutic approaches for GRDs have been proposed through different strategies [5,33,52,53].

Patients with one autoimmune disorder have an increased tendency to acquiring others [54]. There are numerous genetic, autoimmune, or neurological disorders associated with different types of GRDs. For instance, there is an increased prevalence of type 1 diabetes mellitus and thyroid abnormalities in CeD and DH patients [2,55].

Regular monitoring and follow-up strategies include evaluating symptoms, assessing GFD adherence, and looking for disease complications are necessary for proper handling of GRDs. These assessments should be performed at regular intervals and highlight the change in the patient’s health status [51,56].

A small subgroup of CeD patients is primarily or secondarily refractory to a GFD and has persistent or recurrent malabsorptive symptoms and CeD-related intestinal tissue damages [57]. Refractory CeD (RCD) is subdivided into two types: RCD-I and RCD-II [58]. While RCD-II has poor prognosis and usually progresses to overt enteropathy-associated T-cell lymphoma, type I generally has a more benign course [59,60].

While numerous studies concerning different aspects of GRDs have been published, a comprehensive integrating book that brings together all this clinical information was lacking. We have the honor to present this new book, which brings together all five categories of GRDs in different areas of knowledge, to integrate necessary and wide apart information. This book will be interesting to the researchers and clinicians, immunologists and pathologists, medical students, student nurses, students of dietetics, patients with GRDs, food and diagnostic companies, nutritional medicine, analytical laboratories, and research centers.

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Chapter 2

Gluten-related disorders: an evolving story*

Geoffrey K.T. Holmes,    Gastroenterology, Royal Derby Hospital, Derby, United Kingdom

Abstract

When Gee described coeliac disease in 1888 and Dicke introduced the gluten-free diet in 1950, neither could have known the implications of what they had launched. Coeliac disease has moved from being an uncommon illness confined to children of European descent to one of the most common chronic disorders encountered in the western world that can occur at any age and in many other countries. Gluten-related disorders now include not only coeliac disease and dermatitis herpetiformis but also non-coeliac gluten sensitivity, wheat allergy and gluten ataxia (neuropathy). This chapter traces the early recognition of gluten-related disorders to the present time, highlighting some of the more important developments.

Keywords

History; coeliac disease; dermatitis herpetiformis; non-coeliac gluten sensitivity; wheat allergy; gluten ataxia

Chapter Outline

Outline

Introduction 7

Early history of sprue 7

The modern era of coeliac disease 11

Discovery of abnormalities in upper small bowel mucosa 11

Introduction of per oral small bowel biopsy 12

Exploration of mucosal morphology 13

Upper small bowel mucosal lesions 13

Introduction of the gluten-free diet 14

Search for toxic components of gluten 16

Definitions of coeliac disease 16

Serum antibodies 17

Epidemiology 18

Clinical considerations 19

Treatment 20

Aetiology 20

Dermatitis herpetiformis 22

Non-coeliac gluten sensitivity 22

Wheat allergy 24

Allergy, hypersensitivity and immunity 24

Gluten ataxia 24

Conclusion 25

References 25

Introduction

When Gee described coeliac disease in 1888 and Dicke introduced the gluten-free diet in 1950, neither could have known the implications of what they had launched. Coeliac disease has moved from being an uncommon illness confined to children of European descent to one of the most common chronic disorders encountered in the western world that can occur at any age and in many other countries. Gluten-related disorders now include not only coeliac disease and dermatitis herpetiformis but also non-coeliac gluten sensitivity, wheat allergy and gluten ataxia (neuropathy). This chapter traces the early recognition of gluten-related disorders to the present time, highlighting some of the more important developments.

Early history of sprue

The first description of sprue is attributed to Aretaeus the Cappadocian, a prominent Greek physician (Fig. 2.1), who flourished during the first or second centuries CE. His writings were translated and edited in 1856 by Francis Adams and printed in London for the Sydenham Society under the title, The Extant Works of Aretaeus the Cappadocian. Book two, On the Causes and Symptoms of Chronic Diseases, contains chapter seven entitled, On the Coeliac Affection. It makes fascinating reading. Aretaeus considered coeliac disease to be a chronic, relapsing and remitting illness occurring in adults, mainly women, with little chance of cure. He identified symptoms including pallor, lethargy, emaciation, muscle weakness, abdominal pain and rumblings and pale, offensive stools [1]. He also described a continued diarrhoea in children but considered it had a different mechanism from that responsible for causing the coeliac affection in adults. Also in book two, On the Therapeutics of Chronic Diseases, he even attempted a definition [2]. If the stomach be irretentive of the food, and if it pass through undigested, unchanged and crude, so that nothing ascends into the body, we call such persons coeliacs. He suggested treatments such as reducing food intake, emetics, cupping, scarifying, application of leeches and various dietary manoeuvres and exercise might help. It is not clear how effective these measures were or what the outlook for patients was because at this point the record is incomplete.

Figure 2.1 Aretaeus the Cappadocian. From the Wellcombe Collection.

A fascinating case report published by Gasbarrini and colleagues in 2010 proposed that a young women who died in Italy during the first century CE might have had coeliac disease based on observations of her remains [3]. It was possible to extract DNA from bone and a tooth and she was found to carry the haplotype HLA-DQ 2.5 that is strongly associated with coeliac disease [4].

Vincent Ketelaer, a Dutch physician born in 1627, is remembered for his book, De aphthis nostratibus, seu Belgarium sprouw, first published in 1669 [5]. It is often said that he described tropical or non-tropical sprue but this has been challenged because he was using the word sprouw to mean only stomatitis and not a bowel disorder as was the practice at that time [6]. Only later would tropical or non-tropical malabsorptive disease be referred to as sprue. The first description of tropical sprue is usually attributed to William Hillary, an English Physician, whose best known work, Observations on the changes of the air and the concomitant epidemical diseases of the Island of Barbados, was published in London in 1759 [7].

Matthew Baillie (1761–1823) an eminent British physician described features of a particular species of purging that included, malnutrition, abdominal distention, offensive, pale and frothy stools in people some of whom had never left Britain [8]. The illness relapsed and remitted but was progressive and death resulted from exhaustion. However, Baillie commented intriguingly that, some patients have appeared to derive considerable advantage from living almost entirely on rice. It is tempting to think this an early description of coeliac disease [9].

In 1888 Samuel Gee (Fig. 2.2) having drawn attention to the disorder in a lecture delivered on October 5 1887, at the Hospital for Sick Children, Great Ormond Street, London, produced his landmark paper, On the coeliac affection. Gee was familiar with the writings of Aretaeus and not only mentioned him in his paper but also gave it the same title as that used by Aretaeus 1800 years earlier probably as a mark of his admiration for the work of this ancient author [10]. Gee regarded the coeliac affection as, a kind of chronic indigestion which is met with in persons of all ages, yet especially apt to affect children between one and five years old. He described the clinical features with remarkable accuracy and prophetically suggested that, if the patient can be cured at all, it must be by means of diet. He was unable to identify the presence of any pathological changes, Whether atrophy of the glandular crypts of the intestines be ever or always present I cannot tell. He might well have hit on the value of a gluten-free diet without knowing it for he wrote, A child, who was fed upon a quart of the best Dutch mussels daily, throve wonderfully, but relapsed when the season for mussels was over: next season he could not be prevailed upon to take them. This is an experiment which I have not yet been able to repeat. He also wrote Sometimes from India Englishmen return sick with the coeliac affection, implying that he considered sprue, although he does not use the term and the coeliac affection were one and the same disorder. Parsons, Professor of diseases of children in the University of Birmingham, UK, paid tribute to this paper, Certainly it is true that whenever people believe that they have discovered some new fact in coeliac disease, a reference to this classic cameo has a chastening effect, for time after time, they will find that their discovery has been forestalled [11].

Figure 2.2 Samuel Gee (1839–1911). Reproduced with permission from the Royal College of Physicians of London.

Gibbons was introduced to the coeliac disorder by Gee and reported four cases, all children in 1889 [12]. Three made a partial recovery on non-specific treatment while a fourth, after an initial remission of symptoms, died of acute haemorrhagic purpura; the post-mortem findings had already been published [13]. Gibbons, like Gee, noted no distinctive pathological changes, Examination of the bowel after death has led to the discovery of nothing. He considered the signs and symptoms were clear cut, different from dysentery and drew particular attention to loss of muscle power and an unwillingness of children to climb stairs. In common with Gee, he thought that manipulation of the diet was the only useful form of treatment and considered the prognosis to be very poor.

In 1902 Bramwell presented a case of infantilism to the Medico-Chirurgical Society of Edinburgh [14]. In a publication in 1915, he again reported on this patient and documented others that he was aware of [15]. At the end of this paper, he referred to two other cases who he considered were examples of patients described by Herter and labelled these gastrointestinal infantilism.

In 1903 Cheadle produced his paper on acholia which he defined as the absence of bile in the stools, but without jaundice, or signs of obstruction to the biliary outflow into the upper bowel [16]. He classified the cases of Gee and Gibbons as examples of acholia and described five cases in children and one in an adult. For the first time, fat in the stools of some of the patients was estimated chemically. One fatal case came to post-mortem but no distinctive changes were observed. He agreed with Gibbons that the clinical features could be attributed to a nervous disturbance that alters hepatic function and considered that teething or a chill might be triggering mechanisms. In 1905 the term acholia disappeared from the literature.

Herter seems to have rediscovered the coeliac affection, for he appeared unfamiliar with the writings of Gee, Gibbons and Cheadle. His book, published in 1908, Infantilism from chronic intestinal infection, became widely known [17]. He described children with chronic fatty diarrhoea and infantilism. He demonstrated that they had virtually no positive calcium balance and the greater part of the fat in the faeces was in the form of fatty acids and contended therefore, that the loss was due to malabsorption of fat and not due to fat splitting. He attributed the malabsorption to an enteritis caused by overgrowth of gram positive bacteria, particularly Bifidobacterium bifidum. These cases were regarded as examples of Gee’s disease by authorities at that time [18,19].

In 1914 Poynton and colleagues [20] presented in detail the case histories of nine children with chronic recurrent diarrhoea and considered that these were cases of coeliac disease as described by Gee. Nevertheless, Armstrong an author of the original paper, in a letter to the Lancet wrote that the term coeliac had been purposefully avoided because it was felt that the alterations in gut function might have resulted from diarrhoea rather than the other way round [21]. Still [18] accepted the cases as examples of Gee’s disease as did Miller [19] apart from the fatal case which he thought more likely to be chronic dysentery of the asylum type. The principle importance of the paper centres on the post-mortem findings in the only fatal case encountered. The autopsy was carried out 24 hours after death. A photomicrograph of a section through the mucosa and the submucosa of the jejunum is intriguing. It was commented that the jejunum showed marked round cell infiltration but the villi were cut eccentrically. Villi are absent and the crypts do appear elongated. Was this unrecognised villous atrophy? Although the diagnosis in this particular case was in doubt and post-mortem findings of little value, a systematic attempt had been made, probably for the first time, to relate clinical and pathological findings in coeliac disease. It is evident that around this time coeliac disease was being referred to by a variety of terms; Gee’s disease, acholia, Gee-Herter disease, intestinal infantilism and chronic recurrent diarrhoea in childhood but coeliac disease was soon retained as the accepted one and employed by Still in his three influential Lumleian lectures presented to the Royal College of Physicians, London, in 1918 [22].

Coeliac disease was now being diagnosed more frequently so that researchers could accrue small series of patients for analysis. In his first lecture, Still [18] reviewed the symptoms of coeliac disease, drawing on his experience of 41 children. He commented on the plethora of features encountered and the slow and tedious progress of the disorder. At least six children had died although some seemed to make a recovery, partial or complete as they grew older. The second lecture was concerned with the pathology of coeliac disease. He was aware of only two autopsy reports neither of which was particularly informative [23]. In the final lecture treatment was considered, the most important aspect of which was manipulation of the diet. Still advised a diet of reduced fat especially from cow’s milk, lentils, rice, potatoes and grape juice, the latter to offset scurvy [24]. On this regime, he commented it was nearly always possible to obtain a marked improvement in health.

Beginning in 1920 Miller [25] published a series of papers on coeliac disease and wrote on many aspects including anaemia, fatty stools, enlargement of the abdomen, retardation of growth and development, anorexia, fever, convulsions, megacolon and late rickets. He was aware that patients usually entered remission in late childhood and could tolerate a normal diet. In his experience the disorder was seldom fatal [25–28]. He recognised that fat absorption might be abnormal even in the absence of symptoms while adults could remain well on a full normal diet and commented on a non-diarrhoeic form of the disease. He continued to advance his theory that coeliac disease was a digestive fault, probably an abnormality of bile salt secretion and not an organic disorder because an autopsy had not revealed any relevant pathology for he stated, no chronic enteritis or other organic cause for the chronic fatty diarrhoea could be found [27]. He reported in 1924 that he had never seen a case of coeliac disease originating in adult life [28].

Parsons in 1932 [11] reviewed aspects of coeliac disease in 94 children of whom 73 were observed at the Children’s Hospital Birmingham, UK and 21 at the Boston Children’s Hospital, USA. He recognised the disorder was not seen in infants still being breast fed, it could occur in one or both homologous twins and also in more than one instance in sisters and cousins. Girls were more frequently affected than boys. Based on his experience Parsons reported that the disease tends to remit in puberty and rarely persists into adult life. Ten children (10%) were known to have died. He presented some autopsy findings, but was only able to conclude that, There is no morbid anatomy of coeliac disease. Unsurprisingly, he had nothing to offer on causation and endorsed Howland’s [29] three-stage dietary treatment regime, emphasising the value of a high protein diet with a very low fat content and no carbohydrates until considerable clinical improvement occurred. He commented, I think there can be no doubt that coeliac disease is more common than these statistics represent and that the number of cases particularly of the less severe varieties, will increase with dissemination of knowledge regarding it. He believed that sprue and coeliac disease were different entities.

Tropical sprue and coeliac disease were discussed in a meeting held at the Royal Society of Medicine, London, in 1924 [28]. It was argued by some discussants (Miller and Powell) that these were probably separate entities based on clinical features. Scheel in 1905 [30] described a 35-year-old woman who had never left Holland, who developed a disorder resembling tropical sprue. Likewise, Wood in 1925 [31] was aware of a syndrome like tropical sprue occurring in patients who had never left the northern states of America. He thought that the diagnosis was most likely pernicious anaemia writing, One feels that the diagnosis was largely a matter of geography. In the tropics it would be called tropical sprue, while out of the tropics it would be called pernicious anaemia, but made no mention of non-tropical sprue as a separate condition. Similar cases were reported by others [32]. Holmes and Starr in 1929 [33] used the term non-tropical sprue to denote a nutritional disturbance in adults resembling coeliac disease in five patients. The diagnosis of tropical sprue was discounted. They considered that the patients could equally have been classified as having adult coeliac disease. This new term, non-tropical sprue, was readily adopted. In 1932 Thaysen produced his influential monograph, Non-tropical sprue. A study of idiopathic steatorrhoea, which was widely referred to but was only an incomplete review of the subject to that date [34]. He identified 34 patients with non-tropical sprue from the literature who formed the basis for a clinical study of the disorder reported in his monograph. He took the view, as did many others [35–37] that tropical sprue, non-tropical sprue and coeliac disease were identical or nearly identical conditions and grouped them under the heading of idiopathic