Chapter 15 – Coeliac Disease




Abstract




Coeliac disease (CD) is a chronic, immune-mediated condition caused by exposure to dietary gluten in genetically susceptible individuals. The prevalence of CD in the general population is estimated at 1%. A gluten-free diet (GFD) is an effective treatment for the vast majority of individuals with CD. Despite advances in serological testing, the duodenal biopsy remains essential for the diagnosis of CD. The morphological features of established CD have been well described. However, early changes in the duodenum, e.g. an increase in intraepithelial lymphocytes, are not specific for CD. Architectural changes in the duodenal biopsy are more specific for CD, but the pathologist should be aware of other conditions that can cause villous atrophy. Some patients with CD do not respond to a GFD, and may have refractory CD (RCD), a condition believed to represent a cryptic form of the most common malignancy in CD: enteropathy-associated T-cell lymphoma. Early detection of RCD is essential in guiding more aggressive management. The aims of this chapter are to describe the histological features of CD and its variations and complications, and to discuss the key differential diagnoses, with particular emphasis on features that help to distinguish CD from other conditions.





Chapter 15 Coeliac Disease


Colan M. Ho-Yen and Fuju Chang



Introduction


Coeliac disease (CD), also known as coeliac sprue or gluten-sensitive enteropathy, is a chronic, immune-mediated condition caused by exposure to dietary gluten in genetically susceptible individuals.1,2 The prevalence of CD in the general population is estimated at 1%.3


Following consumption of wheat, barley, or rye, gluten peptides can gain access to the lamina propria via transcellular or paracellular routes.4 Gliadin can induce the release of zonulin, a modulator of intestinal permeability.5 This results in cytoskeletal reorganisation and the opening of tight junctions, thereby enhancing paracellular transport of gliadin.4 Once in the lamina propria, the ubiquitous enzyme tissue transglutaminase (tTG) deamidates glutamine residues on gliadin peptides, increasing the binding affinity of these peptides to antigen-presenting cells (APCs) bearing the HLA-DQ2/DQ8 molecules.4,6 The recognition of these APCs by gluten-reactive CD4+ T cells forms the basis of the adaptive immune response, and the subsequent T cell-mediated inflammatory cascade that causes mucosal changes that are characteristic of CD.7


Gluten-derived peptides can also initiate an innate immune response, in a process orchestrated by interleukin-15 (IL-15).8 IL-15 induces the expression of MICA, a stress molecule on enterocytes.9 The resultant interaction between MICA and NKG2D receptors on intraepithelial lymphocytes (IELs) is thought to contribute to epithelial cytotoxicity.9


CD presents with diarrhoea and symptoms of malabsorption, such as weight loss, steatorrhoea, and anaemia.1 Other signs and symptoms include abdominal pain, glossitis, constipation, oral aphthous ulcers, dermatitis herpetiformis, osteoporosis, psychiatric disturbances (including schizophrenia), and, in children, failure to thrive.1,10


Conventional treatment for CD is a gluten-free diet (GFD) which, in most patients, results in a marked improvement in symptoms within weeks.1 Current recommendations advise a gluten intake of less than 10 mg per day.11 A GFD is also protective against some of the complications of CD, including adverse foetal outcome and lymphoma.11 Strict adherence to a GFD can be a challenge, and clinical trials of alternative therapies are currently underway.12,13 These alternative therapies include compounds that reduce the immunogenicity of gluten, regulate intestinal permeability, and/or modulate the immune/inflammatory response.12,13 While these new potential therapies have some promise, none is currently recommended outside the clinical trial setting.11



Diagnosis


The diagnosis of CD is based on clinical, serological, and histopathological findings.14



Serological and Genetic Testing in Coeliac Disease


Serological testing is often an initial step in the assessment of a patient for possible CD.12 Recent developments have led to a selection of highly sensitive and specific antibody tests, which are more reliable than the older anti-gliadin antibody tests used previously in the diagnosis of CD.12 These newer antibodies, which include IgA-tTG antibody, IgA-endomysial antibody (EMA), and IgA/IgG de-amidated gliadin peptide antibody (DPG), have a reported specificity and sensitivity in excess of 90%.12 Currently, the American College of Gastroenterology clinical guidelines recommend tTG for detecting CD in patients over 2 years of age.15


In patients with an IgA deficiency, IgG-DPG testing is appropriate.15 IgA-EMA testing remains the most sensitive serological test but requires immunofluorescence. Therefore, it is subject to interobserver variation.12,16


More than 98% of CD patients express the HLA-DQ2 or HLA-DQ8.17 Therefore, HLA typing can be of help to exclude the diagnosis, particularly in those patients who are already on a GFD or have had equivocal serological/histological results.11,17 However, it cannot confirm the diagnosis.



Histopathology


Despite the advances in serological testing, the duodenal biopsy remains essential for the diagnosis of CD.10,11 It is worthwhile considering several points before undertaking a thorough morphological assessment of the duodenal biopsy.


Ideally, the patient is on a gluten-containing diet at the time of biopsy. Unfortunately, patients commonly present after a variable amount of time on a GFD.10 In this circumstance, there may be a degree of mucosal healing, and the histology report should consider this possibility. Mucosal injury in CD tends to be more severe in the proximal small intestine and may be patchy. Therefore, guidelines usually recommend multiple biopsies (four to six).11,18


While biopsies from the duodenal bulb may show features related to peptic injury, and while prominent Brunner’s glands can affect the interpretation of the villous architecture, biopsies from this site are nevertheless important because the duodenal bulb may be particularly sensitive to gluten-induced injury.18 Good orientation of the biopsies is crucial in permitting accurate assessment of the villous architecture. As a minimum, the pathologist should look for at least three or four adjacent, well-visualised crypt-villous units.18


The main histological features of CD are villous atrophy, crypt hyperplasia, increased chronic inflammatory cells IELs and mononuclear cells in the lamina propria) and morphological changes in the enterocytes (Fact Sheet 15.1).10




Fact Sheet 15.1 Histological Features of Coeliac Disease


Increased IELs




  • May be the only histological abnormality



  • >30 per 100 enterocytes is abnormal



  • May show an even distribution along villi (contrasting with the normal decrescendo pattern from base to tip)



  • CD3 immunostaining may highlight lymphocytes but is not a routine investigation


Crypt hyperplasia




  • Increased mitotic figures


Villous atrophy




  • Crypt to villous height ratio decreased (normal ratio is 3:1 to 5:1)



  • Graded as mild atrophy, moderate (subtotal) atrophy, or absent villi (total atrophy)


Lamina propria inflammation




  • Mostly plasma cells and T lymphocytes



  • Smaller numbers of neutrophils, eosinophils and mast cells


Changes in the surface enterocytes




  • Loss of cell height (cuboidalisation)



  • Cytoplasmic basophilia



  • Cytoplasmic vacuolation


Mild thickening of the subepithelial collagen band


Based on refs. 1, 2, 19, 20, 22, 23.

Increased IELs are a non-specific finding but may be the only histological manifestation of CD19,20 (Figure 15.1). In recent years, several groups have addressed the question of exactly what constitutes raised IELs, partly because of the replacement of capsule biopsies of the jejunum with the duodenal biopsies that are now standard in CD diagnosis.2022 These studies suggested a cut-off of 20–25 lymphocytes per 100 enterocytes as the upper limit for normal duodenal mucosa.2022 Immunohistochemistry for CD3 may be helpful in giving a more accurate IEL count20,22 (Figure 15.2). However, this is a subject of controversy and indeed some experts advise strongly against the use of CD3 staining. CD3 immunostaining is not necessary routinely but may be useful when the IEL count is close to the cut-off for abnormality. IEL counts between 25 and 29 on CD3-immunostained sections are usually regarded as ‘borderline’, with counts above 30 considered as ‘pathological intraepithelial lymphocytosis’.20,22





Figure 15.1 Intraepithelial lymphocytosis with normal villous architecture in a duodenal biopsy. Note that the intraepithelial lymphocytes (IELs) are present along the entire villus and over its tip. The normal villous IEL decrescendo pattern is lost. Marsh-Oberhuber type 1 change.





Figure 15.2 Intraepithelial lymphocytes (IELs) are positive for CD3. These cells are easier to identify with CD3 immunostaining than with H&E staining. CD3 immunostaining can help to give a more accurate IEL count in difficult or borderline cases.


Well-orientated villi are optimal for the IEL count, which should include at least 300 enterocytes. The final IEL count should be a mean number per 100 enterocytes.20,22 The count should avoid the villi close to lymphocytic aggregates, as IEL counts are always higher in these areas. Only those lymphocytes residing above the basement membrane should be included in the IEL count.22


In addition to the IEL count, the distribution of the IELs is worth examining when considering a diagnosis of CD.23 In normal small intestinal mucosal biopsies obtained from the distal duodenum (Figure 15.3), the density of IELs decreases from the middle to the distal (upper) third of the villi, resulting in a ‘decrescendo pattern’.23 In a study of 78 patients, Goldstein et al. found that a loss of this ‘decrescendo pattern’, leading to an even distribution of IELs along the sides and tips of the villi, was more common in patients with gluten sensitivity (Figure 15.4).23





Figure 15.3 Normal duodenal mucosa. Occasional intraepithelial lymphocytes (IELs) are present and their density is greatest along the lower and middle thirds and sharply decreases along the upper third of the villus.





Figure 15.4 Immunohistochemistry for CD3 highlights increased intraepithelial lymphocytes along the sides and tips of the villi and loss of the normal ‘decrescendo’ pattern.


The majority of IELs in CD are positive for CD3 and most IELs express CD8 (70%), with a smaller number (5%–10%) expressing CD4, in keeping with the helper/inducer phenotype.1 A fifth of IELs are negative for both CD4 and CD8.1 The relative proportions are probably similar in CD and in normal mucosa.


Together with IELs, villous atrophy and crypt hyperplasia are the key parameters in the classification schemes (see later) that some pathologists use to stage CD (Figure 15.5).2426 Villous atrophy / crypt hyperplasia is detectable in well-orientated sections, when there is a reduction in the normal villous height to crypt depth ratio of between 5:1 and 3:1.1 The presence of increased mitotic figures (normally seen only in the lower third of the crypt) is another feature of CD, and may indicate the presence of crypt hyperplasia, even in suboptimally orientated biopsies.1,19





Figure 15.5 Together with increased intraepithelial lymphocytes, villous atrophy and crypt hyperplasia are the key parameters used to assess the duodenal damage caused by gluten sensitivity. Biopsy from a non-responsive coeliac disease patient showing subtotal villous atrophy with intraepithelial lymphocytosis and a chronic inflammatory infiltrate in the lamina propria (Marsh-Oberhuber type 3b change).


The lamina propria may be expanded by a mixed inflammatory cell infiltrate.19 Plasma cells and T lymphocytes are the predominant cell types, but smaller numbers of neutrophils, eosinophils and mast cells can also be present.19 In a study of 150 newly diagnosed CD patients, Brown et al. observed at least focal neutrophilic infiltration of the lamina propria in more than 56% of the cohort.2 Furthermore, eosinophils, with a density of 20 per high-power field or more, were present in almost a quarter of cases.2 Raised eosinophils and an increased neutrophil count were both associated with a more advanced stage of disease.2


Several morphological alterations in the surface enterocytes occur in CD.1,2,19 These changes, which tend to be more prominent when associated with villous atrophy, include cuboidalisation and a loss of enterocyte height (resulting in an increased nuclear/cytoplasmic ratio), cytoplasmic basophilia, and cytoplasmic vacuolation (Figure 15.6).1,2,19 Another mucosal change that can occur is mild thickening of the basement membrane. Up to 45% of CD biopsies may have at least focal thickening (i.e.>1.5 µm) of the subepithelial collagen band (see later).2





Figure 15.6 Duodenal biopsy from a patient with untreated coeliac disease showing surface epithelial cytoplasmic vacuolation.


In practice, identification of otherwise unexplained intraepithelial lymphocytosis, even if villous architecture is normal or minimally disturbed, raises the possibility of CD. A count of more than 30 per 100 epithelial cells can be regarded as abnormal, and a count of 25 to 29 as borderline and probably abnormal. The pathology report should advise the clinical team to exclude CD by reviewing the clinical findings and, in particular, by performing serological tests. The report should also state that there are other causes of intraepithelial lymphocytosis, particularly drugs and infection (Fact Sheet 15.2). Identification of unexplained villous atrophy without intraepithelial lymphocytosis may also be difficult to interpret. The pathologist should initially consider the possibility of artefactual changes, e.g. biopsy malorientation, trauma, etc., and of proximal (D1) origin, as they can mimic atrophy. In addition, there are many causes other than CD of genuine villous atrophy, including infection, drugs, and non-specific (peptic) duodenitis. As is the case for intraepithelial lymphocytosis, clinical and serological exclusion of CD may be appropriate if there is villous atrophy, while also bearing in mind the differential diagnosis. If both intraepithelial lymphocytosis and villous atrophy are present and are otherwise unexplained, the recommendation to exclude CD should be stronger because there are few other causes of this histological picture.




Fact Sheet 15.2 Causes of an Increase in Intraepithelial Lymphocyte Numbers




  • Coeliac disease



  • Infections (e.g. Helicobacter pylori, giardiasis, Campylobacter)



  • Drugs (e.g. non-steroidal anti-inflammatory drugs)



  • Small intestinal bacterial overgrowth



  • Autoimmune disease (e.g. autoimmune enteropathy, connective tissue disorders, thyroiditis)



  • Inflammatory bowel disease



  • Sarcoidosis



  • Food protein intolerance



  • Common variable immune deficiency



  • Microscopic colitis



  • Tropical sprue



  • Idiopathic


Based on refs. 69, 83.


Variants / Special Types of Coeliac Disease



Collagenous Sprue


Collagenous sprue (CS) is a malabsorptive disorder that commonly presents with diarrhoea, abdominal pain, weight loss, and/or anaemia.27 CS mainly involves the proximal small intestine, although it can also affect the jejunum.27,28 The disease may be diffuse or patchy, and show variation in severity of the mucosal lesions.27,28


The histological changes seen in CS include subtotal and total villous atrophy, increased IELs, cytoplasmic vacuolation, detachment of the epithelium, lamina propria inflammation, and neutrophilic infiltration.29 As the name suggests, the hallmark of CS is thickening of the subepithelial collagen plate (Figure 15.7), associated with entrapped capillaries and other cellular elements of the lamina propria.27,29 There is no precise definition of what constitutes a thickened subepithelial collagen plate. Based on the observation that 60% of biopsies from CD patients showed minimal subepithelial fibrosis, with an average thickness of 3 µm, Vakiani et al. used a cut-off of>5 µm to identify CS.29





Figure 15.7 Duodenal biopsy showing subepithelial collagen formation (collagenous sprue) from a patient with known coeliac disease. There is subtotal villous atrophy, mild intraepithelial lymphocytosis, and focal gastric metaplasia.


The relationship between CD and CS is also unclear. Most commentators acknowledge a possible association between the two conditions, based in part on the clinical, serological, and pathological overlap, and some authors suggest that CS can evolve from pre-existing CD.27,29 Others claim that CS is a distinct entity and that positive CD serology does not occur in ‘true’ CS.30 A further complication is the finding that biopsies from CD patients who do not respond to a GFD (refractory CD, see later) may also show a thickened collagen band.31


In one report, collagenous enteritis (affecting the duodenum or the ileum or occasionally both) was associated with advanced patient age at presentation, an absence of coeliac antibodies, and possibly with several drugs including olmesartan, non-steroidal anti-inflammatory drugs, proton pump inhibitors, and statins. Despite similar HLA profiles, the authors concluded that collagenous enteritis is not a form of CD.32


From a practical point of view, any significant thickening of the collagen plate (particularly if>5 µm) should be noted in the text of the pathology report and reference made to the possibility of CS. These patients may require close follow-up, as they may be less responsive than those with CD to a GFD, necessitating alternative treatment such as steroids.30,33



Involvement of Other Parts of the Gastrointestinal Tract by Coeliac Disease


CD may also be associated with gastrointestinal (GI) inflammation outside the small intestine.2,34,35 Lynch et al. found that 4 of 18 patients with current lymphocytic gastritis (LG, defined as an IEL count more than 25/100 gastric epithelial cells,35 had duodenal or jejunal villous atrophy and were seropositive for IgA EMA.34 Moreover, two patients started a GFD and showed clinical improvement; the one patient who underwent repeat endoscopy showed a non-significant reduction in the number of antral/body mucosal IELs.34


In a study of 70 CD patients, Feeley et al. found that seven (10%) also had LG, and that the risk of LG was unrelated to the presence or absence of Helicobacter pylori infection.35 A more recent study identified LG in more than 30% of CD patients and found that its presence was associated with the intensity of inflammation in the concurrent duodenal material.2 Interestingly, these workers also noted lymphocytic colitis (Figure 15.8) in 31% and lymphocytic ileitis in 17% of CD patients, although only a limited number of biopsies were available from these sites.2





Figure 15.8 Colonic biopsy showing microscopic lymphocytic colitis: diffuse increase in inflammatory cells in the lamina propria with intraepithelial lymphocytosis (left, H&E staining). The IELs are positive for CD3 (right).


The association between CD and LG has prompted some to speculate that, when superimposed on a background of CD, LG may be a reflection of a diffuse enteropathy that primarily involves the small intestine rather than a distinct entity.34,35



Classification Schemes


There are two main systems for classifying the mucosal lesions in CD: the Marsh–Oberhuber classification and the more recent Corazza classification (Table 15.1).2426 In the original Marsh classification, five lesions were recognised: pre-infiltrative lesions (type 0) were essentially normal; the type 1 lesion (referred to as infiltrative) was characterised by increased IELs only (Figures 15.1 and 15.2); type 2 lesions (hyperplastic) showed crypt hyperplasia in addition to increased IELs; and type 3 lesions (destructive) showed flattening of the villi (Figure 15.5).24 The fifth category (type 4 lesions) was defined as atrophic or hypoplastic lesions, indicative of chronic/end-stage disease.24




Table 15.1 Classification schemes for coeliac disease






























Marsh Marsh–Oberhuber Corazza-Villanacci
Type 0 lesion: Normal Type 0 lesion: Normal


  • Grade A lesion: Non-atrophic



  • Increased IELs



  • +/− crypt



  • hyperplasia

Type 1 lesion: Increased IELs Type 1 lesion: Increased IELs



  • Type 2 lesion: Increased IELs



  • Crypt hyperplasia




  • Type 2 lesion: Increased IELs



  • Crypt hyperplasia




  • Type 3 lesion: Increased IELs



  • Crypt hyperplasia



  • Villous atrophy




  • Type 3a lesion: Increased IELs


    Crypt hyperplasia


    Mild villous atrophy



  • Type 3b lesion: Increased IELs


    Crypt hyperplasia


    Moderate villous atrophy



  • Type 3c lesion: Increased IELs


    Crypt hyperplasia


    Absent villi




  • Grade B1 lesion: Atrophic


    Mild/marked


    villous atrophy



  • Grade B2 lesion: Atrophic


    No detectable villi

Type 4 lesion: Atrophic/hyperplastic mucosa (rare) Type 4 lesion: Atrophic/hyperplastic mucosa (rare)


Based on refs. 2426.

IELs, intraepithelial lymphocytes.

In the Oberhuber modification, the type 3 category was subdivided into 3a (Figure 15.9), 3b (Figures 15.5 and 15.10), and 3c (Figure 15.11), corresponding to mild villous atrophy, marked villous atrophy, and absent villi (flat mucosa) respectively.25 The goal of this subdivision was to increase diagnostic precision and to allow comparisons of sequential biopsies following treatment to be more accurate.25





Figure 15.9 Duodenal biopsy showing mild partial villous atrophy, intraepithelial lymphocytosis, crypt hyperplasia, and chronic inflammation in the lamina propria. Marsh–Oberhuber type 3a change.





Figure 15.10 Moderate partial villous atrophy with marked intraepithelial lymphocytosis is seen in this duodenal biopsy (Marsh–Oberhuber type 3b change).





Figure 15.11 Duodenal biopsy from a patient with coeliac disease showing total villous atrophy, marked intraepithelial lymphocytosis, crypt hyperplasia, and dense inflammatory infiltration of the lamina propria (Marsh–Oberhuber type 3c change).


More recently, Corazza and Villanacci proposed a new classification in which the type 1 and type 2 lesions were combined to form ‘Grade A’ lesions; type 3a and 3b lesions were merged into a ‘Grade B1’ category, and ‘Grade B2’ lesions replaced the type 3c lesions of the Marsh–Oberhuber system.26 The authors argued that this simplified classification system, where lesions were split into non-atrophic (Grade A) and atrophic (Grade B) lesions, with fewer categories of villous atrophy, would lead to more uniform reporting among pathologists.26 A subsequent study showed that there was better interobserver agreement with this system compared with the Marsh–Oberhuber approach, with mean kappa values of 0.55 and 0.35, respectively.36


Disadvantages of these schemes include extra time, interobserver variability, and an uncertain contribution to diagnosis and management. Assessment and categorisation of crypt hyperplasia and villous atrophy are inevitably subjective. Counting of lymphocytes, though also vulnerable to interobserver variation, is more objective. In practice, use of these classification schemes is not universal. It may be more common in units that have research activity. A simple description of the degree of villous atrophy and a record of the IEL count may be sufficient in most settings, depending on other factors and on clinicians’ requirements.




Practice Points 15.1 Approach to the Interpretation of Biopsies Taken for Coeliac Disease


Coeliac Disease Diagnosis




  • Relies on clinical picture, serology, and histology



  • Histology is not diagnostic in isolation



  • Sometimes the features are not typical, e.g. negative serology, absence of symptoms, normal villous architecture, or combinations of these



  • In difficult cases, repeat biopsies after introduction of a gluten-free diet and possibly again after a gluten challenge are an option


Intraepithelial Lymphocyte Counts




  • Recorded per 100 enterocytes



  • Assessed in at least 300 enterocytes in well-oriented villi



  • Only lymphocytes above the basement membrane are included



  • Villi close to lymphocytic aggregates are unsuitable for assessment



  • >30 per 100 is abnormal



  • 25–29 is borderline, probably abnormal


Intraepithelial Lymphocytosis with Normal Villi or Minimal Villous Changes




  • Advise exclusion of CD clinically and serologically



  • State that there are other causes such as drugs and infection (see Fact Sheet 15.2 and Table 15.3)


Villous Atrophy without Intraepithelial Lymphocytosis




  • Exclude artefactual change, e.g. biopsy malorientation, trauma



  • Exclude proximal duodenal (D1) origin (where villi are shorter)



  • Advise clinical and serological exclusion of CD if atrophy is otherwise unexplained (although some authors require intraepithelial lymphocytosis before supporting a histological diagnosis of CD)



  • State that there are other possible causes, e.g. infection, drugs, ‘peptic’ duodenitis (see Table 15.3)


Intraepithelial Lymphocytosis Combined with Villous Atrophy




  • Strongly recommend clinical consideration of CD


Marsh/Marsh–Oberhuber Classifications and Similar Schemes




  • Used in some centres



  • Value in clinical practice is uncertain



Complications of Coeliac Disease


Patients with CD are at an increased risk of developing malignant complications, including lymphoma and carcinoma (Table 15.2).37 Enteropathy-associated T-cell lymphoma (EATL) is a subtype of non-Hodgkin’s lymphoma (NHL) which is specifically associated with CD.38 In addition, some CD patients may not show a sustained response to a GFD, and are suffering from refractory coeliac disease (RCD).39,40 Immunophenotypic and molecular studies suggest that a proportion of RCD patients have an early or cryptic form of EATL.41




Table 15.2 Complications of coeliac disease












































Condition Morphological features Immunohistochemical features Clonality studies
RCD1


  • Increased IELs



  • Lamina propria chronic inflammation



  • Villous atrophy



  • Subepithelial collagen band (sometimes)

IELs express surface CD3, CD8, and TCRβ Polyclonal TCR
RCD2 As above IELs express cytoplasmic CD3; negative reactivity for surface CD3, CD4, CD8, and TCR Clonal TCR
Ulcerative jejunitis


  • Ulceration



  • Increased IELs



  • Lamina propria chronic inflammation



  • Villous atrophy

IELs express CD3; negative reactivity for CD4/8 Clonal TCR
EATL type 1


  • Medium-sized lymphoid cells with prominent nucleoli and moderate cytoplasm



  • Occasional pleomorphic cells may be present




  • Lymphoid cells positive for TIA, CD3, and CD7



  • Negative for CD4, CD8, CD5, CD56



  • CD30 may be expressed in pleomorphic cells

Clonal TCR
EATL type 2 Monomorphic population of medium-sized lymphoid cells with hyperchromatic nuclei and minimal cytoplasm


  • Lymphoid cells positive for TIA, CD3, CD8, CD56



  • Negative for CD4

Clonal TCR
Small intestinal adenocarcinoma Similar to adenocarcinoma arising in large intestine N/A N/A


Based on refs. 31, 41, 43, 45, 48, 52, 54, 56, 57, 6063.

EATL, enteropathy associated T-cell lymphoma; IELs, intraepithelial lymphocytes; RCD, refractory CD; TCR, T-cell receptor; TIA, T-cell intracellular antigen; N/A, not applicable.


Refractory Coeliac Disease


RCD is diagnosed when a CD patient continues to experience symptoms despite adhering to a strict GFD for more than 12 months, and after excluding other causes of villous atrophy.42 The reported prevalence of RCD is variable and may be as high as 9%.39 A more recent Dutch study found a cumulative incidence of 0.04 over a 6-year period.42


RCD has two subtypes: type 1 RCD (RCD1) shows an essentially normal IEL population, whereas type 2 RCD (RCD2) is characterised by an aberrant, clonal IEL phenotype.43



RCD1

Symptoms of RCD1 include fatigue, weight loss, diarrhoea (sometimes alternating with constipation), steatorrhoea, nausea, and abdominal pain.31 Patients may also develop other autoimmune conditions, and infection and thrombo-embolic events may complicate the picture.44


Although the morphological changes that occur in RCD may not necessarily be more severe than those in CD, biopsies from most RCD1 patients show at least partial villous atrophy, in keeping with Marsh–Oberhuber type 3 lesions.31,43 The IELs in RCD1 have a normal cytological appearance, and the lamina propria shows a moderately dense infiltrate of lymphocytes and plasma cells.45 In a study of 10 RCD1 patients, Olaussen et al. also identified subepithelial collagenous bands in four patients, similar to that observed in CS.31 Another study of RCD patients (no distinction was made between types 1 and 2) found that relative thinning of the mucosa and subcryptal chronic inflammation (inflammatory infiltrates between the crypt base and muscularis mucosae) was more common in the RCD group than in controls.46 Other, non-specific findings in RCD patients were concomitant collagenous/lymphocytic colitis, LG, acute inflammation, and gastric metaplasia.46


The immunophenotype of IELs in RCD1 is similar to that seen in uncomplicated CD, with surface expression of CD3, CD8, and TCRβ (Figure 15.12).31,43 Some authors assert that the proportion of CD8/TCRβ-positive IELs should be greater than 50% in RCD1, and that a lower percentage raises the possibility of RCD2.43 In TCR (T-cell receptor) gene re-arrangement studies, most cases of RCD1 show polyclonal IELs, although clonal expansions are detectable in a minority.31,47


Figure 15.12



(A) Refractory coeliac disease type 1 (RCD1) immunophenotype. Intraepithelial lymphocyte (IEL) phenotyping on duodenal biopsies. The IELs are CD3 positive





(B) CD8 positive.



RCD2

The majority of RCD2 patients present with diarrhoea, abdominal pain, weight loss, and malabsorption.43 Patients may also develop skin lesions reminiscent of pyoderma gangrenosum, or ulceration of the limbs and face; there may be a history of long-standing chest/sinusoidal infections or an unexplained fever.43 As with RCD1, most small intestinal biopsies show Marsh–Oberhuber type 3 lesions, with a variable degree of villous atrophy.47


The key feature that differentiates RCD2 from RDC1 is the emergence of a dominant population of morphologically normal but immunophenotypically aberrant IELs that demonstrate clonal rearrangements of the TCR gene48 (Figure 15.13). The abnormal IELs in RCD2 show cytoplasmic expression of CD3 (Figure 15.14), but have lost expression of surface CD3, CD4, CD8 (Figure 15.14), and TCR.48 The identification of aberrant IELs in the stomach and large intestine of RCD2 patients suggests that, like CD, RCD2 may diffusely involve the GI tract.49





Figure 15.13 Radiolabelled polymerase chain reaction (PCR)-single strand conformational polymorphism (SSCP) analysis of TCR Vc gene rearrangements. DNA was isolated from formalin-fixed duodenal biopsy specimens from two patients (labelled 1 and 2) with refractory coeliac disease type 2 (RCD2) and peripheral blood lymphocyte DNA from a healthy control (labelled 3). Each PCR amplicon is run on the SSCP gel in a native (N) and denatured form (D). Dominant clonal populations (discrete bands) are demonstrated in both RCD2 samples (1 and 2), whereas there is a polyclonal pattern (smear) in the healthy control DNA (3).


Sep 2, 2020 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 15 – Coeliac Disease
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