The small intestine has three structural parts: duodenum, jejunum and ileum. The jejunum and ileum are about 2.5 m long and 3 m long respectively in adults and form the majority of the small intestine, which has a total mucosal surface area of approximately 30 square metres. The small intestine was long regarded as a place where little happens, essentially because visualisation was imprecise or inaccurate. With the development of flexible endoscopy, it was possible first to reach the ileum because of ileocolonoscopy, and later to reach the jejunum because of enteroscopy. As a result of these developments, biopsies from the ileum and jejunum are now part of routine histopathological practice. The pathology may include neoplastic and inflammatory diseases. This chapter on jejunitis and ileitis focuses mainly on the inflammatory conditions. These can be limited to the small intestine, jejunum, and/or terminal ileum, or may also involve the upper gastrointestinal tract and/or colon and rectum. The text includes a description of both acute, usually infectious, diseases, and chronic inflammatory diseases. There are many chronic diseases, affecting in particular the terminal ileum. Clinically, Crohn’s disease is often a consideration. Drug-induced lesions, infections, endometriosis, ulcerative colitis, lymphoma, and lymphoid hyperplasia can mimic Crohn’s disease of the terminal ileum. Biopsies can help to solve the differential diagnosis and orient the clinical team towards proper management of the patient.
The small intestine is a tubular organ that extends from the pyloric sphincter to the ileocaecal valve. It consists of three portions: the duodenum, the jejunum, and the ileum. While overall the anatomy and histology are quite similar, at the level of the mucosa there are some important differences between the three portions.
The duodenum is the proximal, shortest, and most fixed portion of the small intestine, lying posterior to the parietal peritoneum. After the duodenum crosses the aorta, it ascends and curves anteriorly to join the jejunum at a sharp turn known as the duodenojejunal flexure. The jejunum constitutes about two-fifths of the small intestine and the ileum about three-fifths. There is no clear external demarcation between them, although there are some differences. The ileum has a thinner wall and a narrower lumen than the jejunum. Mesenteric fat is more abundant in the mesentery of the ileum than in that of the jejunum, and the vasculature in the mesentery is slightly different. The ileum has more vascular loops than the jejunum, and the vasa recta (straight arteries) are shorter.
Overall, the mucosa of the small intestine is a complex micro-world, populated by various types of cells forming an organised and dynamic community that is well equipped for many functions, including secretion, absorption, and defence. ‘Organised community’ means that the cell types are structurally present in different compartments, including epithelial cells lining the surface and the crypts, lamina propria cells with lymphocytes, cells of the monocyte/macrophage lineage, eosinophils, mast cells, connective tissue cells, vascular structures, and nerve endings. Neutrophils are normally not present. ‘Dynamic community’ means that there is continuous cell renewal for most cell types.
The Mucosa of the Ileum, and a Comparison with the Mucosa of the Duodenum and Jejunum
Compared to the proximal small bowel, the mucosa of the ileum displays several distinctive features, including the presence of more epithelial goblet cells on the surface, shorter villi, and the presence of Peyer’s patches. These features should be considered when examining biopsies of the ileum. The ileum and jejunum, unlike the duodenum, do not have Brunner’s glands in the submucosa. The ileum has Peyer’s patches in the mucosa, but the duodenum and jejunum do not.
In the ileum, villi are typically shorter than the villi at more proximal sites in the small intestine. A gradual further loss of villi occurs with transition towards the colon. Therefore, the architecture of terminal ileum biopsies is different from that of other parts of the small intestine.
Peyer’s patches are lymphoid structures located in the mucosa (Figure 19.1). They are concentrated in the distal 25 cm of the ileum but extend proximally for 200 cm. They are most numerous in the terminal 10–15 cm, where they form a lymphoid ring. The more proximal patches are oval, antimesenteric, and irregularly spaced. Peyer’s patches are a major component of the gut-associated lymphoid tissue (GALT), acting as immune-inductive sites. Each patch consists of a cluster of lymphoid nodules ranging from 5 to more than 900, which bulge upward towards the lumen and downward across the muscularis mucosae. Granular brown-black pigment is common in the deep portions of Peyer’s patches or in the lamina propria of the ileum, especially in adults. The pigment can accumulate within macrophages and probably originates from atmospheric or dietary sources. The lymphoid tissue of Peyer’s patches may displace villi and crypts.
Figure 19.1 Peyer’s patch. The lymphoid aggregate is covered by cuboidal cells constituting the follicle-associated epithelium.
Structurally, four distinct compartments are distinguishable: follicle, dome, interfollicular region, and follicle-associated epithelium.1
Lymphoid follicles within Peyer’s patches contain germinal centres populated by B cells with occasional CD4+ T cells and macrophages, surrounded by a mantle zone. The dome is the area between the follicle and the overlying epithelium. The follicle-associated epithelium of Peyer’s patches comprises specialised low cuboidal (follicle-associated epithelial [FAE]) cells and flattened enterocytes, the so-called M cells (M = membrane or microfold). They facilitate interaction between antigens and lymphocytes. Luminal antigens, after removal from the lumen by the M cells, are incorporated into cytoplasmic pinocytotic vacuoles. Indeed, M cells express the protease cathepsin E that other antigen-presenting cells express and can act accordingly. After selective endocytosis of antigens, M cells transport the antigens to intraepithelial macrophages and lymphocytes, which then migrate to lymph nodes. Initiation of the immune reaction occurs in the lymph nodes, and the immune effector cells formed in this process then migrate towards and infiltrate the surface epithelium of the small intestine over its whole length, forming the intraepithelial lymphocytes (IELs). In physiological conditions, there are up to four lymphocytes per 100 IELs in the ileum. Peyer’s patches normally are more prominent during infancy and childhood than they are in adulthood.
The epithelial lining in the ileum differs from the lining in other portions not only by the presence of the M cells, but also by the fact that there are proportionately more goblet cells in the surface layer of the ileum than in the more proximal sections of the small intestine (Figure 19.2). Furthermore, ileal epithelial cells may express special molecules such as ileal bile acid transporter (IBAT) protein, which are not apparent on routine microscopy.2
Figure19.2 Normal ileal mucosa.
The small intestinal epithelium is normally composed of five epithelial cell types: columnar enterocytes, goblet cells, neuroendocrine cells, Paneth cells, and stem cells. The most abundant cells are the columnar enterocytes. Their main functions are terminal digestion of food substances in the proximal duodenum, and the absorption of nutrients by apical microvilli in the duodenum and jejunum.
Goblet cells produce and secrete mucins in order to form a protective luminal mucus layer. This becomes more important in the distal small intestine. Goblet cells have a turnaround time similar to that of the columnar enterocytes. Accordingly, loss of goblet cells in an ileal biopsy suggests recent epithelial injury.
Neuroendocrine cells release hormones in an endocrine and paracrine fashion. Among these, the 5-hydroxytryptamine-containing cells predominate. However, substance P, serotonin, vasoactive intestinal polypeptide, and somatostatin D–secreting cells are also present. The hormones released by these cells help in the regulation of ileal secretion, absorption, motility, and mucosal cell proliferation.
The Paneth cells, located in the crypt base, secrete defensins and other antimicrobial peptides such as cryptidins and lysozyme to keep the crypts sterile and to protect enterocytes and stem cells.3, 4 The formation of these cells is regulated by stem cells.
Stem cells have been identified by the Wnt target gene leucine-rich-repeat-containing G-protein coupled receptor 5 (LGR5).5 This receptor is expressed by self-renewing and pluripotent cells at the crypt base. Irreversible labelling of these cells revealed that all four other epithelial cell types (columnar cells, goblet cells, Paneth cells, and neuroendocrine cells) arise from these cells. Olfactomedin 4 (also known as OLFM4, hGC1, or GW112), is another specific marker for the LGR5 stem cells. Adult ileal mucosal stem cells might be different from stem cells in other areas, for instance by inducing bile acid uptake and expressing the IBAT protein.6
The Value of Biopsies of the Jejunum and Ileum
The major indication for biopsies of the jejunum (during enteroscopy) and terminal ileum (during ileocolonoscopy) is the presence of lesions observed either with endoscopy or with other imaging techniques. The diagnostic yield of biopsies obtained from normal-appearing mucosa is low. For a long time, the small intestine was regarded as a place where little happens. Endoscopy with biopsy initially focused mainly on the duodenum and upper jejunum for the diagnosis of peptic ulcer disease, coeliac disease, and infections such as giardiasis.
Endoscopic evaluation of the jejunum eventually became possible with the advent of capsule endoscopy. This technology and its visualisation of lesions created the need for deep enteroscopy systems to allow biopsy and non-surgical treatment of small bowel pathology. Indications for push enteroscopy and intraoperative enteroscopy with biopsy include malabsorption and unexplained diarrhoea, exploration of radiographic abnormalities of the proximal small bowel, and small bowel tumours.7
Double-balloon enteroscopy appears to be a safe and effective method to access small bowel strictures, with direct visualisation and tissue sampling or for therapeutic balloon dilation. In a retrospective study of 71 consecutive patients with small bowel stricture, surgical pathology reported the possible aetiology as non-steroidal anti-inflammatory drugs (32%), non-specific (21%), Crohn’s disease (21%), radiation-induced (9%), tumour (10%), anastomotic (4%), coeliac disease (1%), and surgical adhesions (1%).8
Enteroscopy is not yet widespread. In contrast, ileocolonoscopy has become a major diagnostic tool for patients presenting with abdominal pain and diarrhoea or changes in bowel habit. The ileum is now one of the most common sites of the intestine to undergo endoscopic biopsy. However, indications require careful consideration. The prevalence of diarrhoea in the population in Western Europe is about 5%, making it a major cause of disability. Approximately 1% of patients needs specialised investigations, including endoscopy and/or hospitalisation.
The differential diagnosis for diarrhoea originating in the lower gastrointestinal (GI) tract includes irritable bowel syndrome and a variety of inflammatory disorders that can affect the ileum and colon such as infections, idiopathic inflammatory bowel disease (IBD) (including ulcerative colitis [UC] and Crohn’s disease), lymphocytic and collagenous colitis, ischaemic colitis, and drug-induced colitis. For therapeutic reasons, it is important to distinguish inflammatory and non-inflammatory causes and to identify patients with IBD. The final diagnosis is normally the result of a combination of clinical data, laboratory values, microbiological examinations, radiology, endoscopy, and histology, any of which may strongly suggest the diagnosis. In practice, gastroenterologists rely heavily on endoscopy and histology. However, biopsies may not always present a solution.
Overall, ileal biopsies can provide a definite diagnosis in approximately 18% of the cases presenting with diarrhoea. In a retrospective study of 414 consecutive patients, the authors examined all terminal ileum biopsies received in a two-year period and recorded the indications for ileoscopy and the endoscopic findings. They also noted the number of biopsies taken during each procedure. No patient had more than one set of biopsies. Indications comprised known or strongly suspected IBD (38%) (Crohn’s disease 20%, UC 16%, and inflammatory bowel disease, unclassified 1.4%), followed by diarrhoea (33%), anaemia/haematochezia (15%), abdominal pain (6%), and abnormal imaging (5%). The terminal ileum was endoscopically normal in 81% and histologically normal in 82%. The diagnostic yield of the biopsies varied with the indication, being highest for known or suspected Crohn’s disease (40%) and lower for UC (17.6%), diarrhoea (10.4%), and abdominal pain (4.3%). Histological lesions were particularly likely to be present in samples from endoscopic ileitis (84%) or ulcers/erosions (69%).9 Overall, the figure of 18% positivity is low for a diagnostic test which is costly and time-consuming. Also, the study took place in an academic tertiary care medical centre that may not be representative of all centres. Other studies have shown that macroscopic and/or microscopic abnormalities are present in the ileum in 1.8%–7.4% of unselected patients.10, 11 In these studies also, ileal histology is positive in 19% of patients with IBD. Therefore, it seems that the diagnostic yield of histology of terminal ileum biopsies is highest in patients with inflammatory bloody diarrhoea (Practice Points 19.1).
Limited value in chronic non-bloody diarrhoea + normal ileoscopy
Highest yield in inflammatory bloody diarrhoea
Diagnostic yield of ileal biopsies:9
Known or suspected Crohn’s disease: 40%
Ulcerative colitis: 17.6%
Abdominal pain: 4.3%
Endoscopic ileitis: 84%
Endoscopic ulcers or erosions: 69%
Based on the available data, biopsies of the terminal ileum are indicated in patients in whom Crohn’s disease is suspected because of clinical symptoms, a family history, abdominal complaints, and/or abnormal imaging. A normal biopsy in a patient with a radiological diagnosis of inflammatory disease of the terminal ileum and normal endoscopy helps to reject suspicion of Crohn’s disease.12 Biopsy of the terminal ileum is also especially useful in specific clinical settings, including left-sided colitis, and in patients with severe inflammatory activity where the clinical differential diagnosis may be difficult. Additional indications are diarrhoea in young children, the initial onset of an inflammatory disease, and immunocompromised patients. In patients with active pancolitis, biopsy of the terminal ileum may help to distinguish between Crohn’s disease and the ‘backwash’ ileitis of UC.13, 14
For patients presenting with non-bloody, non-inflammatory diarrhoea, the situation is different. In a series of 508 examples, there were abnormal endoscopic findings in 26 (5%). Ileoscopic abnormality was the sole abnormality of the examination in 13 of these 26 cases. There was no clinically significant histological abnormality in 158 patients with a normal ileoscopic examination. Other studies confirm this observation, reporting diagnostic histopathology in 0.6% patients with chronic diarrhoea and normal ileoscopy. Therefore, routine biopsy of the terminal ileum is of limited value in patients with chronic non-bloody diarrhoea and normal ileoscopy, except for selected patients with additional symptoms such as anaemia and abdominal pain.15–17
A normal ileal biopsy in a patient with a radiological diagnosis of inflammatory disease of the terminal ileum and normal endoscopy helps to reject suspicion of Crohn’s disease.
Histological Features of Ileitis and Jejunitis
The changes can range from mild (alteration of enterocytes, shortening of microvilli) to severe (ulcerations, villous atrophy, increase in IELs, and active inflammation). They can affect the jejunum and ileum separately or in combination with duodenal involvement. Jejunitis and ileitis are multifactorial inflammatory conditions with several aetiological triggers such as infections, medications, and systemic inflammatory processes.18 Several of these aetiologies can induce other morphological changes that are sometimes more prominent.
A diagnosis of the aetiology or the type of enteritis or ileitis depends on a combination of different microscopic features, including changes in the epithelial and lamina propria cell compartments. Alterations of the epithelial cells include changes of surface epithelial cells, crypt and surface architectural changes, and metaplasia.
The changes occurring in the lamina propria do not develop from a zero baseline of leucocytes. Essentially, these changes comprise an increase in total cellularity, a more prominent or less prominent redistribution of the infiltrating cells so that the infiltrate may or may not have a similar density throughout the lamina propria, and changes in composition. Ideally, changes in both cellularity and distribution should be present.
Epithelial cell modifications include changes in cell type, changes in shape and size of surface epithelial cells, and loss of cells that can result in erosions and ulceration (Figure 19.3). As indicated earlier, the mucosa of the ileum is characterised by a relatively high proportion of goblet cells within the epithelium covering the villi. The precise number of goblet cells compared to columnar enterocytes is uncertain, but available data indicate counts ranging from 37 (+/−5) to 50 goblet cells per 100 epithelial cells. An increase beyond 50%, sometimes called hypercrinia (goblet cell hyperplasia), occurs in Crohn’s disease but can also occur in other conditions (Figure 19.4). Goblet cell hyperplasia occurs in experimental infections as well as in infections in animals and has been linked to a Th2 type response.19 In contrast, some authors have also described a decrease in goblet cells, which they called jejunalisation. The appearance of cuboidal and/or flattened cells points to a phenomenon of ‘restitution’. This is a process capable of restoring the continuity of the epithelial surface. Cells next to the damaged area, usually in the upper part of the crypts, may reorganise their cytoskeletons, create specialised structures known as pseudopodia, and loosen their linkage to the underlying matrix. This enables them to migrate and spread over the damaged area. This process can occur within hours following damage. Damage that is more severe will result in erosions or ulcerations.
Figure 19.3 Erosion of the ileum. Villi are partially lost. The surface on the right is covered by flattened cells starting abruptly on the edge of necrotic material. In the underlying lamina propria the cellular infiltrate is increased.
Figure 19.4 The villi are lined almost entirely by mucus secreting cells indicating ‘hypercrinia’.
In jejunitis and ileitis, crypts may show reactive changes. These include a small increase in mitotic figures and a relative increase in the proliferative compartment. The cells in the lower crypt become elongated and contain an enlarged, basal nucleus. These changes indicate ‘re-epithelialisation’ and recovery. Apoptosis of crypt epithelial cells may be noted. Furthermore, the distribution of Paneth cells may become irregular.16
Architectural changes in the small intestinal mucosa include variability in size and shape of villi, such as shortening, broadening (drumstick appearance), irregularity, and loss (Figure 19.5). Crypts may appear branching and shortened, and the distance between the crypts can become irregular. The distortion of the crypt architecture or loss of ‘test tube rack appearance’ is a major feature of chronic ileitis.20
Figure 19.5 Active ileal Crohn’s disease: the villi are irregular and thickened; the surface epithelium is flattened and partially lost; the lamina propria cellular infiltrate is increased in density and mixed in composition; lymphatics are dilated; and a microgranuloma is present in the top of one of the villi (fourth from the right arrow).
Two types of metaplastic changes may occur in the ileum: gastric surface (foveolar) metaplasia, as in the duodenum (see Chapters 9 and 14 and Figures 9.22 and 14.1) and pseudopyloric or pyloric gland metaplasia (PGM) (Fact Sheet 19.1). PGM, also called pseudopyloric mucous glands, mucoid metaplasia, or ulcer-associated cell lineage, is characterised by the presence of small round glands in the deep mucosa, usually near ulcers. Histologically the glands resemble mucinous gastric antral glands. The phenomenon is likely to be the result of a healing process. It is associated with increased secretion of antimicrobial peptides such as lysozyme.3, 4 PGM is not pathognomonic for Crohn’s disease and can occur in other intestinal inflammatory conditions (Figure 19.6). Spasmolytic polypeptide-expressing metaplasia is a similar phenomenon that typically occurs in the stomach.
Pseudopyloric or pyloric gland metaplasia
Pseudopyloric mucous glands
Ulcer-associated cell lineage
Spasmolytic polypeptide-expressing metaplasia (occurs in stomach rather than small bowel)
Small round glands similar to mucinous gastric antral glands in the deep mucosa
Usually near an ulcer
The result of a healing process
Characteristic but not pathognomonic of Crohn’s disease
Gastric (foveolar) surface metaplasia
Changes in the lamina propria include an increased density of lymphocytes and plasma cells, associated with higher numbers of histiocytes and eosinophils. Eosinophils are sometimes part of the increased density of the cellular infiltrate, and in other cases the increase in eosinophils can be overwhelming, with infiltration of epithelial cells by eosinophils. Changes in composition of the infiltrate, and particularly the appearance of neutrophils in the lamina propria and in surface and crypt epithelial cells, indicate active inflammation.
Mild microscopic changes of the small bowel (alterations of enterocytes with microvillus changes and an altered number of intraepithelial lymphocytes), not limited to the jejunum or ileum, in the absence of macroscopic changes, have been called ‘microscopic enteritis’ (Fact Sheet 19.2). However, such a diagnosis is inadequate in itself and implies a need for further investigations, including a careful history and comprehensive clinical and biochemical evaluation, in order to determine the aetiology. 18
Affects duodenum, jejunum, and/or ileum
Micronutrient deficiencies may occur
Not a specific diagnosis
Requires further investigation
Mild, e.g. alteration of enterocytes, shortening of microvilli
Severe, e.g. ulceration, active inflammation, villous atrophy, increased intraepithelial lymphocytes
Systemic inflammatory processes
Changes in lamina propria monocyte/macrophage cells can lead to the formation of granulomas, defined as collections of large monocytes with abundant pale eosinophilic cytoplasm and a large oval nucleus together with other inflammatory cells. They form clusters. Granulomas may occur in a wide variety of diseases, including bacterial infections (mycobacteria, Yersinia, leprosy, syphilis) parasitic infections (Schistosoma mansoni), fungal infections (Candida), and several conditions of unknown or poorly understood aetiology such as sarcoidosis and Crohn’s disease. Drugs are another cause. Granulomas in histological sections are a key feature of Crohn’s disease in many countries, but tuberculosis remains a major differential diagnosis in many areas of Africa and South-East Asia (Figure 19.7). Central necrosis and caseation should raise the suspicion of tuberculosis. However, caseation of tuberculous granulomas is a rare finding in the bowel, and intestinal tuberculosis is more commonly characterised by the presence of multiple and confluent non-necrotising granulomas. Our policy is to do a Ziehl–Neelsen stain whenever multiple granulomas are present, even though it is rarely positive. In countries where tuberculosis is still common, this diagnosis should be the first suspect.
Figure 19.7 Ileal biopsy: the villi are thickened, and in the lamina propria on the right the cellular infiltrate is increased in density and a granuloma is present (arrow). The sample was obtained from a patient in Cambodia. In this context, tuberculosis is the most likely diagnosis.
Stromal changes of ileitis include thickening of the basement membrane underlying the surface epithelium, fibrosis, irregular thickening of the muscularis mucosae, and dilatation of the lymphatic channels in the fibrovascular core of the villi.
Features in favour of chronic (relapsing) inflammatory disease are architectural changes of the villi and crypts, PGM, hypercrinia, gastric metaplasia of surface epithelial cells, and an increase in density of the cellular infiltrate with associated changes in distribution (Practice Points 19.2). A diagnosis of ‘active’ disease depends on the presence of neutrophils. Activity can be subdivided into mild, moderate, or severe, or into stage II and III.21
Villous architectural changes
Crypt architectural changes
Hypercrinia (goblet cell hyperplasia)
Gastric metaplasia of the surface epithelium
Increased cellularity of lamina propria accompanied by changes in cell distribution
Jejunitis and Ileitis: Causes
The most common causes of enteritis are infections, chemicals, medications, Crohn’s disease, so-called ‘backwash ileitis’ in UC, ileitis associated with spondylo-arthropathies, and ileitis associated with microscopic colitis. Eosinophilic enteritis, ischaemic enteritis, enteritis due to vasculitis, ileitis in association with endometriosis, infiltrative ileitis due to systemic mastocytosis, radiation enteritis, and ileitis in graft-versus-host disease are less common.
Infections are viral (especially in children), bacterial, and, less commonly, fungal or parasitic. Contaminated food or water is the major causative factor. Viral infections affect the upper small intestine more often, while bacterial infection involves the colon and ileum more often. Chemicals include non-steroidal anti-inflammatory drugs (NSAIDs) but also recreational and illegal drugs such as cocaine. Some cases remain idiopathic.22 The major causes of ileitis are summarised in Table 19.1.
NSAID, non-steroidal anti-inflammatory drug.
Acute enteritis is usually infectious. It may affect only the small intestine, but often involves the stomach and upper small intestine, including the duodenum and jejunum, or the colon and ileum. Histology is usually not necessary and not helpful for the diagnosis. Most enteric infections are limited in time, with a history of watery or bloody diarrhoea for one week. However, chronic diarrhoea with three or more loose stools for more than 30 days can be the result of viral infections (rotavirus, cytomegalovirus [CMV], adenovirus) and bacterial infections (Campylobacter, Clostridioides difficile, Aeromonas, Escherichia coli, Salmonella, Yersinia) (Fact Sheet 19.3).
Three or more loose stools for more than 30 days
Hyperplasia of Peyer’s patches
Lymphoid tissue infiltrated by large deeply staining macrophages containing intracellular organisms (typhoid cells or Mallory’s cells)
Four stages: lymphoid hyperplasia, histiocytic hyperplasia, epithelioid granuloma formation, and central granuloma necrosis
Viral gastroenteritis (Fact Sheet 19.4) affects the paediatric age group most commonly. Infections due to rotavirus and noroviruses are most often localised to the small bowel. Rotavirus infects virtually all children before they reach two to three years of age. Symptomatic episodes occur mainly between 7 and 15 months. Children up to the age of two years suffer more severe symptoms, while neonates and adults are relatively immune and usually have only mild disease. Noroviruses are particularly associated with outbreaks of diarrhoea in hospitals and in residential facilities for the elderly. Adenoviruses and astroviruses cause diarrhoea that affects young children most often but can also affect older children and adults. In adults, symptoms are usually mild. Enteroviruses can cause severe gastroenteritis in immunocompromised patients but can also be present in asymptomatic carriers.
Children ≫ adults
Histology not specific
Changes often patchy
Variable shortening of villi
Elongation of crypts
Moderate chronic inflammation of lamina propria
Denser towards the lumen
Supranuclear cytoplasmic vacuolation
Shedding of enterocytes from the apical portion of the villi
Resembles abetalipoproteinaemia, but less continuous
Mild mixed mucosal inflammation
Slight increase in crypt epithelial cell apoptosis
Loss of polarity of surface epithelial cells
Dystrophic goblet cells
Inclusions in epithelial cell nuclei demonstrable by immunohistochemistry
Broadening, blunting, and irregularity of villi
Vacuolation and disarray of surface enterocytes
Surface and crypt epithelial cell apoptosis increased
Intraepithelial lymphocytes increased (up to 60 per 100 enterocytes)
Lamina propria polymorphonuclear and mononuclear cells increased
Coronavirus: May be associated with necrotising enterocolitis in infants
Cytomegalovirus: Primary infection rare in immunocompetent individuals
Most cases of viral gastroenteritis last only a few days, and therefore affected persons do not commonly seek or need medical attention and biopsies are rarely necessary. The pathology is not specific and histology is not a good method for making the diagnosis. However, it is good to know the major features because, with the widespread use of endoscopy, pathologists may encounter biopsies from children with an acute disease. Various lesions may develop.
Rotavirus is a lytic virus that causes diarrhoea primarily by the reduction of enzymes of the brush-border of enterocytes (disaccharidases, lactase, etc.) and destruction of intestinal villous epithelial cells. It can enter the cells by receptor-mediated endocytosis, and then replicates in the gut. Acute rotavirus (type A) enteritis may be associated with variable shortening of the villi, a moderate round cell infiltrate in the lamina propria, and elongation of crypts. Early in the infection, supranuclear cytoplasmic vacuolation and shedding of enterocytes from the apical portion of the villi may be apparent on routine staining (Figure 19.8). The microscopic picture in single cells is similar to the appearances seen in abetalipoproteinaemia (and occasionally in juvenile nutritional megaloblastic anaemia) but the distribution of the affected cells in viral infection is more discontinuous. The lamina propria infiltrate looks ‘top heavy’ or denser towards the lumen. Lesions are often patchy. Virus particles, demonstrable by electron microscopy, are present in the villi and crypts.
Figure 19.8 Surface epithelial cells showing supranuclear vacuolisation. This can be the result of a viral infection (or drug-induced damage).
Adenovirus infection is associated with mild mixed mucosal inflammation and a slight increase in crypt cell apoptosis. Loss of polarity of surface epithelial cells with dystrophic goblet cells may suggest the infection. Inclusions within the nucleus of the surface epithelial or crypt epithelial cells are readily demonstrable by immunohistochemical techniques.
Histological changes observed in norovirus infection include broadening, blunting, and irregularity of villi and vacuolation of the surface enterocytes. The villous changes induce a reduction of the surface area by nearly 50%. In addition, reactive disarray of surface epithelial cells may be apparent. There are increases in surface and glandular epithelial cell apoptosis and proliferation of glandular cells. Crypt epithelial cell apoptosis is a feature shared with rejection. Therefore, infections in intestinal transplants show features that overlap with allograft rejection. There is a reduction of expression of tight junctional proteins occludin, claudin-4, and claudin-5. There is an increase in intraepithelial lymphocyte numbers (up to 60 per 100 enterocytes). In the lamina propria, polymorphonuclear and mononuclear cells are increased in association with symptomatic illness.
Primary CMV infection of the small intestine in immunocompetent individuals is rare. It is usually asymptomatic, but it can produce non-specific symptoms similar to many acute viral illnesses or more serious lesions such as GI bleeding and even perforation (probably due to ischaemia).25
The bacterial pathogens most often identifiable are Shigella, Salmonella, Campylobacter, Clostridioides difficile, Yersinia, Escherichia coli, and Klebsiella oxytoca. Several bacteria such as Yersinia pseudotuberculosis, Campylobacter jejuni, and Salmonella species will induce infections of both the small and large intestine. Some bacteria, such as Salmonella and Yersinia, are located preferentially in the ileum, appendix, and right colon. Shigella, Salmonella typhi, and Yersinia, for instance, invade through the M cells in the ileum. Both Y. enterocolitica and Y. pseudotuberculosis cause a terminal ileitis and localised mesenteric adenitis, with thickening of the terminal ileum and enlargement of local lymph nodes (Figure 19.9) while involvement of the appendix is less common. Clinical evidence suggests that the site of Campylobacter infection is usually the ileum and jejunum rather than the large intestine.26