Table 1 shows the differential diagnosis of inflammatory and lymphoproliferative disorders.
Chronic non‐specific duodenitis induced by H pylori
Duodenal inflammation can be secondary to various causes, and different pathological mechanisms may cause the same morphological appearance. Thus, duodenal inflammation can be divided into two main groups according to the aetiology: duodenitis secondary to H pylori
infection (associated with chronic active gastritis and ulcer disease), also called chronic active duodenitis or chronic non‐specific duodenitis or Hpylori
bulbitis and duodenitis due to other causes such as GSE, Crohn's disease, drugs, Whipple's disease, parasitic infections or ulcerative colitis.40
Non‐specific duodenitis or peptic duodenitis is a condition associated with acid injury.
infection has a role in the pathogenesis of the DGM and inflammation of the duodenal bulb.37
The prevalence of H pylori
infection increases progressively with age, reaching a plateau after the fourth decade of life.41
Endoscopy shows DGM or chronic duodenal bulb inflammation to be associated with H pylori
‐positive chronic gastritis, villous atrophy of the distal duodenal mucosa (ie, GSE), duodenal ulcer and duodenal bulb deformity and scarring.37
DGM and duodenitis are not age related and are independent of the use of NSAIDs.37
DGM and H pylori
are both usually found in the proximal duodenum. H pylori
colonises the duodenal mucosa only in areas of gastric metaplasia and such colonisation leads to a chronic active duodenitis.21,42,43
Madsen et al42
showed chronic active duodenitis to be associated with H pylori
in 94.1% cases.
colonisation of the duodenal bulb may affect the pathogenesis of duodenal ulcer.43,44
A much higher prevalence and extent of DGM and H pylori
in the duodenal bulb in patients with duodenal ulcer than in those with gastric ulcer or chronic gastritis supports this hypothesis.44H pylori
is associated with duodenal ulcer: 90% of the patients with duodenal ulcer are infected by H pylori
Only a small percentage of cases of duodenitis are associated with the use of NSAIDs. Clearly, however, patients with duodenal ulcers of unknown aetiology may be more common than previously believed. H pylori
‐negative duodenal ulcers are associated with older age, pre‐existing malignancy, recent surgery, underlying sepsis and NSAID usage. Only 13% of patients with H pylori
‐negative duodenal ulcers, however, had a history of NSAIDs, suggesting that other risk factors, such as stress secondary to surgery or to sepsis, may have a key role in the development of ulcer.45
Gastric metaplasia of intestinal crypts is well recorded in chronic ulceration of the small intestine from any cause such as Crohn's disease or ingestion of potassium tablets.21
Histological features of chronic non‐specific duodenitis
Mononuclear cells such as lymphocytes and plasma cells are normally present in the lamina propria of the duodenum. Thus, their presence is not considered to be diagnostic for chronic duodenal inflammation.37
The diagnosis of duodenitis is made when there is infiltration by inflammatory cells with changes in villous architecture and surface and crypt epithelium. Duodenitis can be graded according to the amount of neutrophilic and plasma cell infiltration, villous height, Brunner's gland hyperplasia with prolapse into the lamina propria and gastric metaplasia46
(fig 3). Duodenitis can show a spectrum of mucosal changes. Mild duodenitis is characterised by a small increase in the number of chronic inflammatory cells in the lamina propria, associated with slight widening and flattening of villi, whereas severe duodenitis shows an intense, mixed acute and chronic inflammatory cell infiltrate of the lamina propria and infiltration of polymorphonuclear neutrophils into the surface epithelium, together with changes in the mucosal architecture: DGM and increasing flattening of the villi.21
Moderate duodenitis is defined by a severity that is between mild and severe.39
The activity of duodenitis is dependent on the neutrophilic infiltration.39,46
Heavy polymorphonuclear invasion is associated with epithelial degeneration, with cytoplasmic vacuolisation, intercellular oedema, and frequent microerosions and true erosions. H pylori
is often, but not always, present in this degenerated epithelium.39
DGM and inflammation of the duodenal bulb may be associated with villous atrophy of the mucosa of the distal duodenum.37
DGM can also be found in 13%48
to 42% of children infected with H pylori
Duodenitis seems to be the only feature associated with DGM development and is not a consequence of H pylori
A high prevalence of DGM and duodenitis is found in children infected with H pylori
, but duodenal ulceration does not seem to be related to the presence of DGM and duodenitis.48
Histological assessment for duodenal H pylori
seems to be less reliable than culture.49
Differential diagnosis of chronic non‐specific duodenitis
The differential diagnosis of duodenitis includes mainly GSE. In peptic duodenitis, prominent foci of polymorphonuclear leucocytes and villous atrophy may be difficult to distinguish from the changes seen in GSE.21
In addition, typical features of GSE may coexist with infiltration of the polymorphonuclear leucocytes in the lamina propria, in the crypts and extending focally into the surface epithelium, and with focal DGM.21
Features useful in distinguishing peptic duodenitis from GSE include the relative lack of architectural changes in non‐specific duodenitis, the scanty polymorphonuclear leucocyte infiltrate and the absence or focal presence of gastric metaplasia in GSE.21
Severe inflammation, however, may be very difficult to distinguish from GSE and some assessment of IEL, together with the clinicopathological correlation, is the best way to distinguish between the two different causes of inflammation in the duodenum.21
Active duodenitis is less common in patients taking NSAIDs, but is strongly associated with gastric metaplasia, H pylori
‐positive gastritis and duodenal ulceration.46
Eosinophilic gastroenteritis is manifested by eosinophilic infiltration of the gastrointestinal tract and peripheral eosinophilia. Three main diagnostic criteria are used: (1) the presence of gastrointestinal symptoms; (2) biopsy specimens showing eosinophilic infiltration of one or more areas of the gastrointestinal tract; and (3) no evidence of parasitic, intestinal or extraintestinal disease. The aetiology remains unclear, although an association with various allergic diseases such as asthma, food sensitivities and eczema has been reported. The age of the patients is variable and the disease is diagnosed in children as well as in adults. An increase in the eosinophil count may occur secondarily in inflammatory bowel disease, autoimmune diseases, as a reaction to drugs, infections, hypereosinophilia syndrome and after solid‐organ transplantation.
Eosinophils are normally present in the lamina propria. The precise histological criteria required to diagnose eosinophilic gastroenteritis are ambiguous.
Eosinophilic gastroenteritis may have a patchy disease distribution or the mucosa is spared altogether, as in muscular and serosal types of eosinophilic gastroenteritis. Degranulated eosinophils and eosinophil cationic protein in the intestinal mucosa are seen along with histological damage in eosinophilic gastroenteritis.
The duodenum may be affected with other segments of the gastriontestinal tract.
Histological features of eosinophilic duodenitis
The architecture is variably perturbed and numerous eosinophils are seen in the lamina propria, forming clusters and infiltrating crypts and the surface epithelium. Many of them may also be degranulated. Intermixed neutrophils, plasma cells and lymphocytes are also seen. Eosinophilic microabscesses are rarely seen.
An increase in the eosinophil count may also be found in other conditions such as GSE and food allergy.50
GSE or coeliac disease is considered to be an autoimmune enteropathy in susceptible people, triggered by the ingestion of gluten‐containing grains.52
It has a genetic background, being associated with HLA‐DQ2 and HLA‐DQ8. The pathogenesis entails a T cell‐mediated immune response and autoreactive B lymphocytes that produce autoantibodies directed against tissue transglutaminase or endomysium.52
Because of the protean nature of the disease, the exact prevalence of GSE is still underestimated and the correct diagnosis is directly related to the criteria used.52
The prevalence is variable in different countries, ranging from 1 in 70 to 1 in 550 people, with an estimated worldwide prevalence of 1 in 266.52
The clinical presentation varies with the age of the patient, the duration and extent of the disease and the presence of extraintestinal disease.52
Three forms of GSE are described. The classic form, characterised by gastrointestinal symptoms such as diarrhoea, abdominal distension and malabsorption, is diagnosed in patients aged 6–8 months, after the introduction of weaning foods in the diet.52
Pathological changes are mainly found in the duodenal mucosa and in the upper jejunum, but in some cases the entire small intestine may be affected. The histological spectrum of the lesions ranges from a slight villous flattening to a decreased V:C ratio, crypt hyperplasia, variably increased plasma cell and lymphocyte infiltration in the lamina propria and a marked increase in the IEL count.
The atypical form of GSE is characterised by extraintestinal symptoms such as dermatitis herpetiformis, iron‐deficiency anaemia, short stature, dental enamel hypoplasia, arthritis and arthralgia, chronic hepatitis and hypertransaminasaemia, osteoporosis, idiopathic cerebellar ataxia, delayed puberty, recurrent miscarriages and reduced fertility.
The asymptomatic or silent form is characterised by the presence of changes in the mucosa, probably limited to the upper tract of the small intestine. Careful clinical investigation can, however, disclose subtle symptoms.52
The potential or latent form shows isolated positivity of coeliac serology at first testing and the typical intestinal damage later in life.53
Patients with GSE who do not comply with a GFD have persistent mucosal damage and may develop complications such as gastrointestinal malignancies, principally lymphoma.
The diagnostic protocol is based on the following:
- History and clinical presentation
- Serological screening (tTGA, EMA and anti‐gliadin antibodies)
- Histological findings
- Obvious clinical and serological response to a GFD
- Age >2 years
- Exclusion of other clinical conditions mimicking GSE.52
A single duodenal biopsy, followed by a favourable response to the GFD, is sufficient to confirm the diagnosis.52
A recent study on a paediatric population proposed a duodenal biopsy for conclusive diagnosis in children with a tTGA titre <100 U (results of <20 U or between 20 and 100 U) and negative IgA. Patients with a tTGA titre >100 U should be considered to be positive for GSE, without evaluating a duodenal biopsy specimen. However, a biopsy specimen should be taken if patients do not experience any improvement in symptoms with the GFD. Patients with a normal tTGA titre (<20 U) with highly suggestive symptoms or predisposition to GSE should also undergo biopsies.54
On the other hand, antibody titres may be normal in up to 5% of all patients with GSE, in 20–30% of those with early mucosal changes22
and in 20–50% of patients, mostly adults, who do not present with obvious symptoms of malabsorption. In these instances, duodenal and jejunal biopsies are an essential diagnostic tool.22
GSE has a wide spectrum of histological abnormalities, ranging from normal villous architecture to total villous atrophy.
The biopsy can also confirm the diagnosis or suggest it in patients with atypical presentation or when the serology does not support the diagnosis. Once the diagnosis is established, the biopsy is a useful tool to follow up adherence to a GFD in patients with unsatisfactory clinical response, and also to detect compliance.22
Pathogenesis of the small intestine damage can be divided into three phases: (1) an infiltrative phase characterised by an increase in the IEL count; (2) a hyperplastic phase characterised by crypt hyperplasia; and (3) a destructive phase, characterised by progressive villous atrophy, leading to a flattened mucosa.
The current histopathological diagnosis is made using the Marsh Classification28
and consists of a four‐stage grading system with 40 IELs per 100 epithelial cells as the normal upper limit:
- Type I: infiltrative lesion, characterised by intraepithelial lymphocytosis and a normal villous architecture of the duodenal mucosa
- Type II: hyperplastic lesion, characterised by intraepithelial lymphocytosis and crypt hyperplasia, with a normal villous architecture
- Type III: destructive lesion, characterised by intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy
- Type IV: hypoplastic lesion, characterised by a normal IEL count, normal crypt length and villous atrophy (fig 4).
Figure 4Diagrammatic representation and comparison of the different classification proposed in gluten‐sensitive enteropathy. V:C, villous to crypt ratio.
Oberhuber et al7
modified this classification by splitting the type III lesions in three substages: (A) mild villous atrophy, (B) marked villous atrophy and (C) completely flat mucosa (fig 4). This modification, however, has reproducibility problems. Recently, a new classification with three grades was proposed by Corazza and Villanacci.55
Marsh–Oberhuber's type I infiltrative lesion is maintained; the normal upper limit of IELs is 25 IELs per 100 epithelial cells and CD3 immunostaining is carried out on biopsy samples lacking villous abnormalities (grade A). The type II hyperplastic lesion is rarely seen and regression from villous atrophy to isolated crypt hyperplasia has never been shown after treatment. Oberhuber stage IIIA and IIIB are grouped into a single stage and considered to be a single diagnostic category (grade B1). In fact, grading the villous atrophy into mild or marked can result in considerable interobserver and intraobserver variation. Stage IIIC, often seen and considered to be the diagnostic feature of GSE, is maintained in the revised classification as grade B2.
Marsh–Oberhuber's type‐IV hypoplastic lesion in virtually never seen and was made obsolete by the recent finding of an aberrant IEL clone that is characteristic of refractory sprue, ulcerative jejunoileitis and enteropathy‐type intestinal T cell lymphoma. Thus, this classification divides lesions seen in GSE into non‐atrophic (grade A) and atrophic (grade B); grade B is further split into grade B1 when the V:C ratio <3:1 and grade B2 when the mucosa is flat and no villi are present55
The validity, reproducibility and accuracy of this classification, however, are yet to be proved.
In patients with GSE, the response to a GFD is characterised by an improvement in clinical symptoms and mucosal damage. The clinical improvement may occur in days, whereas the mucosal damage may take up to 2 years. The healing of the mucosa occurs more rapidly in the distal part of the small bowel and is characterised by an increase in villous size, reduction in crypt hyperplasia and reduction in the IEL count with raised γδ T cells. A reduction in the IEL count and an improvement in the V:C ratio are observed, although they may not normalise, indicate a favourable response to the GFD. An abnormal histopathological appearance may persist in many patients who are on a GFD.19
Refractory GSE (refractory sprue, unclassified sprue)
The term refractory sprue is often used generically and ambiguously to define a pathological condition affecting the small bowel, which histologically resembles GSE.
It is correctly defined as symptomatic severe small‐intestinal villous atrophy mimicking GSE, not responding to at least 6 months of a strict GFD.56
The diagnosis of refractory sprue is rare and should be made in patients with GSE after unresponsiveness to a strict GFD and after exclusion of any other disorder mimicking GSE.35
Refractory sprue can be divided into primary and secondary. An initial resistance to the GFD characterises primary refractory sprue, whereas secondary refractory sprue is defined by an initial response to the GFD followed by a relapse.56
Thus, primary refractory sprue may erroneously include many different pathological conditions lacking any relationship to GSE.
A strict GFD for 12 months is considered to be a reasonable period of waiting for mucosal improvement before making a diagnosis of refractory sprue.
The prevalence of refractory sprue has been estimated to be around 7–8%.57
The male to female ratio is 1:3.2 and the mean age of patients is 51 years.56
Patients present with diarrhoea, abdominal pain, weight loss and microcytic anaemia.35,56
An initial diagnosis of GSE may be made because of the villous atrophy with an increased IEL count. Anti‐gliadin or EMA are often found before the GFD, but disappear during the diet. The association with HLA‐DQ2 phenotype suggests that refractory sprue is related to GSE.56
Associated conditions are collagenous sprue, ulcerative jejunitis, hyposplenism, mesenteric lymph node cavitation, lymphocytic colitis, collagenous colitis and dermatitis herpetiformis.56
Histological features of refractory sprue
Architectural changes in the duodenal biopsy specimen range from partial to total (grade IV) villous atrophy.35
The mucosa contains a diffuse and dense mononuclear infiltrate of mainly plasma cells in the lamina propria and a massive increase in the IEL count. The IELs and lymphocytes in the lamina propria are normal to medium in size, with a normal cytological appearance.35
In refractory sprue, most IELs have an abnormal phenotype, characterised by intracytoplasmic CD3ε and CD103, but a loss of expression of TCR, CD3, CD4 or CD8 on their cell surface in 52–98% of cases56
and they show a restricted rearrangement of the TCRγ gene.35
Clonal TCRγ gene rearrangement is expressed in as many as 75% of patients with refractory sprue. The lamina propria CD3+ T cell population is a mixture of CD4 and CD8 cells.58
On the other hand, in specimens from untreated patients with active GSE, the number of IELs that express CD103, CD7, CD3, TCRαβ and CD8 is markedly increased compared with those of controls, but most IELs express TCRαβ or TCRγδ and CD8 or CD4,35
and there is no TCRγ gene clonal rearrangement.56
A simple immunohistochemical method using anti‐CD3 and anti‐CD8 antibodies on paraffin wax sections has been suggested to distinguish between GSE and refractory sprue. Its utility in clinical practice, however, is yet to be proved.59
CD30 expression by IELs of patients with refractory sprue indicates a poor prognosis, and it has been associated with the presence of overt enteropathy‐associated T cell lymphoma60
or enteropathy‐type intestinal T cell lymphoma (EITCL), which is the preferred term for this condition.61,62
Immunohistochemical negativity for several antigens that are normally found on IELs, such as CD8 or the TCRβ chain, in combination with clonal T cell populations by polymerase chain reaction may help in identifying refractory sprue with malignant transformation.63
Although a morphologically identifiable tumour is absent, the presence of an abnormal T cell population is now diagnosed as crypt EITCL, an early intraepithelial form of EITCL.56,62,64
Enteropathy‐type intestinal T cell lymphoma
Lymphomas of the small intestine are usually of T cell origin and tend to be a complication of long‐standing GSE.65
In 50% of cases, the patient presents with an EITCL, whereas the underlying GSE is still dormant.65
The annual incidence rate is 0.5–1 per million people in Western countries. This is a rare form of malignancy, accounting for around 35% of all small‐bowel lymphomas.66
Patients in their fifth or sixth decade present with abdominal pain, diarrhoea and weight loss secondary to malabsorption, signs of obstruction or even (spontaneous) perforation or haemorrhage.58,65
A palpable tumour may be found.
Macroscopic observation showed EITCL to be often multifocal, with ulcerative lesions, with a high perforation rate at presentation or during chemotherapy.65
The T cell lymphomas of the small bowel are roughly divided into those with enteropathy and those without.65
Histological features of EITCL
The architecture is distorted, with villous atrophy and ulcerations. An atypical population of neoplastic lymphocytes infiltrates the mucosa. Lymphoma cells may consist of pleomorphic medium to large cells that are CD3+, CD4− and CD8−, or of small and monomorphic cells that are CD3+, CD4−, CD8+ and CD56+. The neoplastic cells also contain T‐cell Intracellular Antigen 1 cytotoxic granules.58,65
The adjacent intact mucosa shows the histological features of GSE, a variable grade of villous atrophy with marked increase in IEL count,58,65
where the percentage of CD4− and CD8− IELs ranges from 48% to 86% and from 7% to 18% in pleomorphic and monomorphic lymphomas, respectively. In monomorphic lymphomas, most CD3+ IELs express both CD8 and CD56.58
The tumour cells of EITCL virtually always express CD30. CD30+ IELs are present in the tissue adjacent to or merging with overt lymphoma and are scattered in villi a long way away from such tumours and even in jejunal biopsy specimens.60
This marker has been associated with a poor outcome.60
The immunophenotype is not absolutely specific, however; CD3 may be lacking, CD8 may be positive and CD30 may be negative.65
The same monoclonal T cell population is present in intact mucosa, benign‐appearing ulcers and overt lymphomas. The multifocality of the monoclonal IELs suggests that crypt EITCL affects the entire length of the small intestine.
Little is known about T cell lymphomas of the small intestine without enteropathy.
Immunoproliferative small‐intestinal disease
Immunoproliferative small‐intestinal disease (IPSID) is a mucosa‐associated lymphoid‐tissue lymphoma, characterised by infiltration of the bowel wall with a plasma cell population that secretes a monotypic, truncated immunoglobulin αheavy chain lacking an associated light chain.67,68,69
The so‐called non‐secretory IPSID variant is characterised morphologically by the proliferation of small centrocyte‐like lymphoid cells lacking the extreme plasmacytic differentiation.70
IPSID principally affects young adults with approximately equal incidence in both sexes, predominantly affects the duodenum and jejunum and tends to be associated with chronic diarrhoea and abdominal pain.70
Most cases reported are from the Middle East, North and South Africa and the Far East. Sporadic cases are reported in other regions, usually in immigrants from high‐prevalence regions.70
Patients usually present with intermittent diarrhoea and abdominal pain and symptoms related to malabsorption. Obstruction and abdominal masses are typical of the advanced stage. The final diagnosis is usually established by endoscopic biopsies or laparotomy.
In early disease, the duodenal mucosa may appear normal. Thickening, erythema and nodularity of the mucosal folds may be seen in the duodenum and upper jejunum.70
The stomach is rarely affected.70
Histological features of IPSID
The spectrum of the histopathological lesions ranges from apparently benign lymphoid infiltration to malignant, diffuse, large B cell lymphoma.71
The duodenal and jejunal biopsy specimens show a dense infiltrate of dysmorphic plasma cells and centrocyte‐like lymphocytes in the lamina propria, with villous blunting or villous atrophy.70,71
The overlying epithelium is usually intact and crypts are spared. Lymphoepithelial lesions caused by centrocyte‐like lymphocytes are, however, present. Immunohistochemical studies show that the plasma cells are CD20−, whereas the centrocyte‐like lymphocytes are CD20+. The cytoplasm of both types of cells shows intense staining for immunoglobulin αheavy chain, with no detectable expression of light chains or surface immunoglobulin.71
Low‐grade IPSID may progress to higher‐grade large‐cell lymphoplasmacytic and immunoblastic lymphoma. This is characterised by an increment in the atypia of plasma cells arranged in aggregates, and later by sheets of dysmorphic plasma cells and immunoblasts invading into the submucosa and the muscularis propria.70
Autoimmune enteropathy is a condition characterised by villous atrophy, indistinguishable from that of GSE but unresponsive to a GFD. The classic criteria for the diagnosis are histological evidence of enteropathy, a lack of any triggering food protein, presence of anti‐enterocyte antibodies, persistent diarrhoea after prolonged fasting and presence of organ‐specific autoantibodies.74
Anti‐gliadin antibodies may be present.76
HLA‐DQ2 may be found, being generally associated with autoimmune diseases.76
Under this name, however, we can group different conditions that are characterised by the presence of autoantibodies against various cellular components in the small bowel.
These autoimmune conditions usually occur in children75
and rarely in adults.76,77
Clinically, patients present with chronic diarrhoea and malabsorption. This condition may also be associated with colitis.77
In adults, a possible association between the autoimmune enteropathy and a hepatitis C virus infection, believed to be a trigger for autoimmune diseases, has been reported.77
Patients have a family history of autoimmune diseases.77
A recessively inherited defect of the small intestine is characterised by intractable infantile diarrhoea, family history of sibling death from chronic diarrhoea, opportunist infections (of the respiratory tract) associated with a defective T cell activation and autoantibodies, anti‐enterocytes and anti‐goblet cells.78
Serum autoantibodies can be directed against enterocytes or goblet cells and different immunological changes (either a T cell abnormality or immunoglobulin deficiency) may favour the appearance of gut epithelial cell autoantibodies.79,80,81,82,83
Histological features of autoimmune enteropathy
The duodenal biopsy specimen is characterised by varying degrees of architectural changes, ranging from normal to mild, patchy, villous blunting to partial or total villous atrophy.77,83
Crypts may be normal or hyperplastic.83
The histological findings in the jejunal biopsy specimen show villous blunting with normal crypts and a dense mucosal inflammatory infiltrate. When autoantibodies against goblet cells are present, the small bowel and the colon are strikingly characterised by goblet cell depletion.78
Immunohistochemically, the mucosal inflammatory infiltrate has CD2, CD3, CD4 and CD8 lymphocytes. The IEL count may be normal or increased76,77
and is predominantly represented by CD8.78
The number of γδ+ lymphocytes in the lamina propria or epithelial compartment is normal,78
which helps in distinguishing autoimmune enteropathy from GSE.
The differential diagnosis is GSE with food intolerance or allergy enteropathy.
Food allergy may produce a wide variety of patchy or diffuse mucosal lesions in any part of the gastrointestinal tract. The mucosal pathology may manifest as oesophagitis, gastritis, mild villous atrophy or colitis.81
Lymphonodular hyperplasia of the duodenal bulb is found in people with untreated food allergy and in people on an elimination diet.84
The lesion tends to be most prominent on the duodenal bulb just after the pylorus and spreads to the distal duodenum in only a few patients.84
Villous atrophy, even partial villous atrophy, is not found in patients with food allergy, although crypt hyperplasia and an increase in the eosinophil count may be observed in the lamina propria in both untreated and treated patients. These features are non‐specific, however, and are also found in patients with GSE.84
A considerable increase in the density of γδ+ IELs of the duodenal mucosa may be present in children even beyond infancy and characterises the active and untreated phase of food allergy.