REVIEW
Histopathological diagnosis of gluten-sensitive enteropathy

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Summary

As the prevalence rate of gluten-sensitive enteropathy (GSE) may reach 1:99–1:133 in both Europe and North America, there is an increased recognition of ‘silent’ GSE in patients complaining of fatigue alone, presenting with mild anaemia or subtle delays in growth in children. Small bowel biopsies can either confirm or suggest the diagnosis when the presentation is atypical. Microscopic evaluation of the mucosa is also important to monitor adherence to the gluten-free diet and detect complications, especially gastrointestinal neoplasms such as intestinal T-cell lymphoma.

Introduction

Gluten-sensitive enteropathy (GSE) (coeliac disease, coeliac sprue) is a chronic but reversible enteropathy related to a gluten-containing diet and characterized by malabsorption.1 This genetically determined condition is a polygenic disorder associated with HLA-DQ2 or HLA DQ8.2, 3 In predisposed subjects, ingestion of wheat gliadin or similar prolamins from rye, barley and possibly oats leads to inflammatory injury of the small intestinal mucosa.2, 4 Once considered to be relatively uncommon, recent studies demonstrate that the prevalence rate may reach 1:99–1:133 in both Europe and North America.2 Consequent to the diagnosis, a life-long gluten-free diet is recommended to prevent complications including osteoporosis and gastrointestinal neoplasms, especially intestinal T-cell lymphoma.5

Serological tests useful to detect GSE include IgA antitissue transglutaminase antibodies, IgA anti-endomysial antibodies, IgA and IgG antigliadin antibodies and IgA antireticulin antibodies. Of these, the former two have optimal sensitivity and specificity as well as a high positive predictive value.6, 7 However, antibody titres can be normal in up to 5% of all GSE patients and in 20–30% of those with early mucosal changes.8, 9, 10, 11, 12

Combined with the fact that between 20% and 50% of patients, mostly adults, fail to present with frank malabsorptive symptoms,13, 14, 15 duodenal and jejunal biopsies remain the diagnostic gold standard frequently necessary for the diagnosis of GSE.

Small bowel biopsies can either confirm the diagnosis when serological data and clinical impressions are suggestive of this disorder, or suggest it when the patients have a subclinical and/or atypical presentation, or the serological evaluation fails to support the diagnosis. Once the diagnosis is established, the histological evaluation remains important to monitor adherence to a gluten-free diet when the clinical response is not satisfactory, as well as to detect gastrointestinal complications that may arise.2, 16

We will review herein the diagnostic criteria of GSE and pitfalls associated with the evaluation of biopsies from patients either suspected or diagnosed with GSE, and focus on the form frustre with relatively preserved villous architecture.

Section snippets

Normal histology of the small bowel

The small bowel mucosa is characterized by tall, evenly distributed villi that are underlined by crypts with a normal villous:crypt length ratio of about 3:1–5:1.17

However, in practice, villi are not always straight and tall, but tend to bend in different directions and vary in shape from slender, finger-like to plumper, leaf-like structures.18 In addition, villi over-riding or adjacent to lymphoid aggregates are often shortened, broadened or sometimes even absent. To overcome these challenges,

Histological features of GSE

Various alterations can be seen, ranging from increased IEL counts without significant architectural changes to villous atrophy and crypt hyperplasia. As a rule of thumb, five histological features should be evaluated when considering a diagnosis of GSE. These include an increase in the number of IELs, an increased inflammatory infiltration of the lamina propria, alteration of the enterocytes, villous atrophy and crypt hyperplasia.20, 21 Other features that may be seen are an increased number

Staging

A modified Marsh classification recognizing seven types and based on the number of IELs, crypt hyperplasia and villous atrophy is favoured by most (Table 1).16 Notably, type 4 is a hypoplastic lesion, characterized by a flat mucosa with normal crypt height, a normal IEL count, and deposition of collagen in the mucosa and submucosa. It is seen in patients who are unresponsive to a gluten-free diet and/or who have developed unfavourable complications. It is rarely encountered in practice.43

Clinicopathological correlation and sampling

Although we are all familiar with the classical presentation with abdominal distention and diarrhoea, there has recently been an increased recognition of ‘silent’ GSE in patients complaining fatigue alone or presenting with mild anaemia. In the paediatric population, subtle delays in growth can be the only alarming feature leading to further investigation.

In years past, biopsies were obtained using suction capsules, and jejunal mucosa was the representative site for diagnosing GSE. However, the

Evaluation of patients on a gluten-free diet

While patients on a gluten-free diet may report a marked symptomatic improvement within days, mucosal improvement may be slow and incomplete, particularly in adults.45 Improvement, which may continue for up to 2 years, is characterized by reduction of villous atrophy and crypt hyperplasia, while the number of IELs decreases concurrently. Notably, the histological improvement is usually more rapid in the distal small bowel. However, in some cases, the mucosa may not regain a completely normal

Differential diagnosis of GSE

A wide differential diagnosis, somewhat different depending on the patient's age or whether the biopsies reveal flattened mucosa or normal villi with increased IELs, should be entertained. In addition, appropriate clinicopathological (and serological) correlation and response to a gluten-free diet are important to confirm the diagnosis.

Complications in GSE

A wide realm of complications including malignancies (T-cell lymphoma, small intestinal adenocarcinoma, oropharyngeal and oesophageal cancers) and numeral diseases including auto-immune diseases are associated with GSE.45 We will limit our comments to cryptic intestinal T-cell lymphoma associated with refractory sprue, since the changes are subtle with architecturally preserved villi.

Refractory sprue is defined as severe symptomatic villous atrophy with no initial or secondary response to a

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