Epidemiology and Clinical Features

Gluten-sensitive enteropathy (GSE), or celiac disease, is an autoimmune-mediated disorder that results in damage to the small-intestinal mucosa and leads to malabsorption of nutrients. Although this disease was described more than a century ago, only in the past 60 years has the role of dietary gluten in its pathogenesis been recognized. GSE has a worldwide distribution but is most common in countries with populations of European descent (Europe, North and South America, and Australia), where the prevalence is approximately 1%. Although it is less common in Asia and Africa, GSE is expected to become more prevalent in these countries as wheat consumption increases. A recent change in the gluten reaction landscape is the emergence of “gluten sensitivity” as a separate, poorly understood, and possibly immune- (not autoimmune-) mediated condition, which along with wheat allergy and GSE, forms a spectrum of gluten-related disorders. The discussion here is limited to GSE.

GSE may appear at any time in life, from early childhood to late adulthood. It is presumed that patients who are diagnosed in adulthood have had a mild form of disease for a long period. Classic symptoms include abdominal discomfort, diarrhea, and steatorrhea. Some patients do not have diarrhea but instead exhibit other signs and symptoms, including short stature, infertility, neurologic disorders, recurrent aphthous stomatitis, or dermatitis herpetiformis. In adults with occult GSE, complaints of fatigue often uncover the presence of iron deficiency anemia, which ultimately leads to the correct diagnosis. Some patients are entirely asymptomatic and initially have only histologic changes on biopsy analysis. The term latent celiac disease has been used to describe patients with this presentation (see later discussion). Factors governing the type of clinical presentation and the expression of symptoms are poorly understood. It was once thought that the development and severity of symptoms were related to the length of intestine involved rather than the severity of mucosal pathology in a single biopsy specimen; however, recent studies appear to refute that theory. Attention is now being focused on the action of gluten-sensitized lymphocytes to increase mucosal cytokine levels as a determiner of clinical symptoms, regardless of severity or length of mucosa showing villous blunting.

Pathogenesis

GSE is an immunologic disorder that occurs in genetically susceptible hosts. Environmental influences are important as well. The familial nature of the disease was originally established in a study of 17 probands and their families, who underwent biopsies of the small bowel. An increased incidence of GSE was found in first-degree relatives of symptomatic patients. Studies have documented that 10% to 20% of asymptomatic first-degree relatives have mild histologic changes, such as increased intraepithelial lymphocytes (IELs) without villous blunting, or have mild mucosal lesions. In such a setting, the decision to institute a gluten-free diet depends on a variety of factors.

Genetic studies have established the strong association with major histocompatibility complex class II, with as many as 95% of patients carrying either the human leukocyte antigen HLA-DQ2 allele (the majority) or the HLA-DQ8 allele. However, these genetic phenotypes do not explain the pathogenesis entirely, because 30% of the normal population carry the DQ2 haplotype without disease, and not all patients with GSE carry this specific phenotype. Studies have identified at least seven non-HLA genes associated with an increased risk of GSE, including CCR3 , and the interleukin locus IL2 / IL21 . Some of the identified genes are also common in type 1 diabetes and rheumatoid arthritis, suggesting that they impart a generalized increased risk of autoimmunity. The reader is referred to several reviews on the genetics of GSE.

In the proper genetic environment, exposure to the prolamin fractions of gluten found in wheat, rye, and barley (gliadin, secalin, and hordein, respectively), results in a local immune response. Additional environmental components may be related to previous infections. For example, the E1b protein of adenovirus 12 has been shown to contain amino acid sequence homology with α-gliadin antibodies, and T cells that recognize these viral proteins cross-react with gliadin. The crucial role of intestinal tissue transglutaminase has also been elucidated. Tissue transglutaminase (tTG), a ubiquitous enzyme in human tissues, catalyzes the formation of cross-links between glutamine and lysine residues in substrate proteins. tTG is believed to stabilize extracellular matrix molecules in the setting of mucosal injury and granulation tissue. In 1997, Dieterich and colleagues demonstrated that dietary gliadin, which is rich in the amino acid glutamine, serves as a substrate for tTG. It is thought that the resulting cross-linked molecules (gliadin-gliadin or gliadin-tTG) become antigenic epitopes for a subsequent immune response. Of the more than 50 T cell–stimulating epitopes in gluten proteins, a 33-mer peptide that may be the primary initiator of the inflammatory response in GSE has been identified. Investigations into the role of tTG in GSE have led to improved diagnostic tests (described later).

The immune response to dietary gluten involves both antibody- and cell-mediated injury. Antibody-induced injury may occur via antigen-antibody complex deposition with complement activation and also by the induction of cell-mediated cytotoxicity. Activated mucosal T cells have been shown to cause epithelial injury, probably through the release of cytokines, including IL15.

The clinical diagnosis of GSE depends on detection of the appropriate combination of symptoms, laboratory evidence of malabsorption, and the presence of serum autoantibodies. New and increasingly accurate serologic tests continue to be added to the “diagnostic tool kit” for GSE. These include the enzyme-linked immunosorbent assay for immunoglobulin A (IgA) anti-tTG antibodies, which has a high degree of sensitivity (77% to 100%) and specificity (91% to 100%). tTG antibody determination has become the serologic test of choice for GSE, largely replacing antigliadin and antiendomysial antibody tests. The antiendomysial antibody (EMA) test is as sensitive and specific as the anti-tTG test with human recombinant protein, but the immunofluorescence EMA test is labor intensive and relies on a more subjective interpretation than the anti-tTG determination does. Today, the EMA is often used as a confirmatory test when tTG test results or clinical or biopsy findings are ambiguous.

Traditional antigliadin antibody testing no longer has a place in GSE diagnosis because of its lack of specificity. However, a new generation of antigliadin antibodies, known as deamidated gliadin peptides (DGP), are being used in a promising IgG-based test that has shown high concordance with both tTG and EMA tests, with possibly greater sensitivity in children and in early disease. This test also has the advantage of detecting GSE in IgA-deficient patients.

HLA testing to detect susceptible HLA phenotypes (DQ2 and DQ8) has an increasing role in the diagnostic workup of GSE because the absence of DQ2 or DQ8 virtually excludes the diagnosis. Finally, transglutaminase-specific IgA deposits can be found by immunofluorescence in frozen sections of biopsy specimens obtained from small-intestinal mucosa in patients with GSE, even those with normal to near-normal histology. Although this technique is not currently in widespread use, it could become more prevalent in the future, especially in confirming histologically mild disease. For a more detailed discussion of the current approach to clinical diagnosis and management of GSE, several excellent reviews are available.

Pathologic Features

Gross Pathology

In a landmark study, Rubin and associates described the appearance of normal duodenal mucosa on biopsy samples with the use of a hand lens and showed that the mucosa is characterized by numerous slender villi with a delicate capillary network that floats in formalin like “the tentacles of a sea anemone.” In contrast, mucosa specimens from patients with GSE have a barren, stubby surface, without normal villi, containing widely spaced, irregular capillaries ( Fig. 16.1 ). However, endoscopic findings in patients with GSE are subtle and often unreliable. A flat, scalloped appearance of the duodenal mucosa, most likely reflecting loss of villi, may be seen. One endoscopic study found that a reduction of folds, scalloping, mosaic pattern, and nodular mucosa were sensitive but not specific endoscopic findings in GSE, because they were also seen in some dyspeptic patients without GSE. A meta-analysis of studies testing the diagnostic sensitivity and specificity of video capsule endoscopy in GSE reported that the images seen were sufficient to correctly diagnose the condition. However, there are insufficient data on the performance of this tool in the mild histologic forms that are commonly at issue today. Confocal laser microscopy shows promise as an endoscopic technique that can recognize villous irregularity and blunting, with the caveats that interobserver variability is high and the technique is not yet widely available.

A, Normal small bowel mucosa viewed with a dissecting microscope (zirconium arc lighting). The villi are slender and translucent, allowing visualization of the underlying delicate capillary network (unstained). B, Small bowel mucosa from a patient with celiac disease. The surface is irregular and devoid of villi (unstained).

(From Rubin CE, Brandborg LL, Phelps PC, et al. Studies of celiac disease: I. The apparent identical and specific nature of the duodenal and proximal jejunal lesion in celiac disease and idiopathic sprue. Gastroenterology. 1960;38:28-49.)

Histology of Untreated Disease

In normal small bowel mucosa, the ratio of villus height to crypt depth is between 3 : 1 and 5 : 1, depending on the anatomic location ( Fig. 16.2 ). Epithelial cells lining the villi contain basally located nuclei with abundant mature cytoplasm and a preponderance of absorptive cells admixed with goblet cells. A faint density, representing the microvillus brush border, can be appreciated on hematoxylin and eosin (H&E)-stained tissue sections. Studies have confirmed that there are approximately 20 lymphocytes per 100 epithelial cells in healthy people, with minor variations. The lamina propria normally contains a mixture of plasma cells, lymphocytes, and occasional eosinophils. Each of the three mucosal components (i.e., architecture, epithelium, and lamina propria) should be carefully examined in cases of suspected GSE.

A, Normal duodenal bulb. The duodenal bulb is a transition zone that is normally subjected to physiologic peptic injury. Brunner glands ( asterisk ) and increased mononuclear inflammation are frequently present in the mucosa, resulting in broader and shorter villi. B, Normal second duodenum and proximal jejunum. The villus-to-crypt ratio is between 3 : 1 and 5 : 1. There are, on average, two intraepithelial lymphocytes per 10 enterocytes ( inset ).

The pathology of GSE is described here in conjunction with a grading scheme that can be used in pathology reports ( Table 16.1 ). At the time of this writing, the Marsh-Oberhuber classification is being used regularly in Europe but has not gained wide acceptance in the United States for routine use in pathology reports. Inclusion of the Marsh-Oberhuber subtype requires prior knowledge (e.g., by serology) that the patient has GSE, and biopsy requisition forms often do not provide that information. In addition, differences between types 0, 1, and 2 in the Marsh scheme are subtle, so there is a high degree of inter-observer variability among pathologists. To avoid these issues, it is reasonable to use the term mucosal lesion or villous blunting , as detailed in the following discussion, with a modifier (i.e., mild, moderate, or severe) to reflect the degree of villous blunting.

Table 16.1

Diagnostic Terminology for Reports

Histology	Pathology Report *
	A, Duodenal mucosa with normal villous architecture and increased intraepithelial lymphocytes, see note. Note: Increased intraepithelial lymphocytes may be seen in a variety of conditions, including mild forms of GSE. If suspicion for GSE exists, correlation with serologic tests is necessary. Helicobacter pylori gastritis, peptic injury, and NSAID injury should also be considered.
	B, Mild mucosal lesion (or mild villous blunting), see note. Note: The findings are nonspecific but may represent GSE in the proper clinical setting. Correlation with serologic studies is indicated. (Include differential diagnosis as appropriate.)
	C, Moderate mucosal lesion, see note. Note: The findings are characteristic of GSE in the proper clinical setting. Correlation with serologic studies is indicated. (Include differential diagnosis as appropriate.)
	D, Severe mucosal lesion, see note. Note: The findings are characteristic of GSE in the proper clinical setting. Correlation with serologic studies is indicated. (Include differential diagnosis as appropriate.)

 

GSE , Gluten-sensitive enteropathy; NSAID , nonsteroidal anti-inflammatory drug.

* The content of the note will depend on the clinical information provided and findings in gastric and other biopsies. For ease of reading and clarity, do not include an exhaustive list of all causes of small bowel inflammation. Rather, tailor the report to fit the clinical situation.

Nonetheless, it is important from both a research and a clinical perspective to be aware of the Marsh-Oberhuber classification scheme ( Table 16.2 ). This system describes five histologic lesions associated with GSE, termed preinfiltrative (type 0), infiltrative (type 1), infiltrative-hyperplastic (type 2), flat-destructive (type 3), and atrophic-hypoplastic (type 4). Two modifications to this scheme have been proposed in an attempt to simplify the diagnosis for pathologists and clinicians. Neither has been universally accepted at the time of this writing, but they are included for the sake of completeness in Table 16.3 .

Biopsies without Villous Blunting

Preinfiltrative lesions (type 0) exhibit normal mucosa and are seen predominantly in patients who have dermatitis herpetiformis without evidence of malabsorption.

Infiltrative lesions (type 1) have an increased number of IELs with preserved villous architecture, whereas infiltrative-hyperplastic lesions (type 2) show the additional feature of elongated crypts. Both of these patterns of injury are seen in patients with GSE (with or without symptoms), in first-degree relatives of patients with GSE, and in patients with dermatitis herpetiformis. Phenotypic analyses have shown that the increase in IELs is the result of increased numbers of γ/δ T cells. Biopsy specimens with these subtle changes are challenging to interpret; clinical correlation with serology is required to confirm a diagnosis of GSE, because similar histology is seen in other conditions. By definition, the villus height and the villus-to-crypt ratio is normal or near-normal ( Fig. 16.3 ). The diagnosis relies on the detection of increased IELs, assessment of which is now a routine part of small bowel biopsy interpretation (see later discussion). The proportion of patients with these minimal histologic changes in whom severe histologic lesions and symptoms eventually develop is unknown. One small study found that 4 (33%) of 12 patients with mild changes on duodenal biopsies progressed to GSE with flat mucosa at follow-up. However, in a larger study with 8 to 25 years of follow-up, GSE eventually developed in only 5 (2.1%) of 236 patients with increased IELs or a slight reduction in villus-to-crypt ratio. These data are complicated by the newer knowledge that patchy histologic findings are more common in GSE than once appreciated. Therefore, sampling error in these studies cannot be excluded.

Untreated celiac disease. This duodenal biopsy was taken from an asymptomatic patient who was discovered to have antitissue transglutaminase antibodies. Normal villi are present, but there is a marked increase in the number of intraepithelial lymphocytes ( arrows ).

Counting Intraepithelial Lymphocytes

Numerous studies have shed light on appropriate methods to count IELs ( Table 16.4 ). Reassessment of the normal range of IELs in the second portion of the duodenum has been performed by several investigators by using H&E-stained sections and sections stained for CD3 antigen, establishing an upper limit of 20 lymphocytes per 100 epithelial cells in normal mucosa in the duodenum. Careful analysis by using CD3 and γ or δ T-cell stains have shown that IEL counts of greater than 25 per 100 epithelial cells (or a ratio of greater than 1 : 4) merit suspicion for potential celiac disease, whereas counts greater than 29 per 100 epithelial cells are found almost exclusively in patients with GSE. However, this kind of analysis is impractical for routine use.

Table 16.4

Methods of Counting IELs in Architecturally Normal Duodenal Biopsies *

Interpretation	Counts	Stain
Diagnosis by Counting IELs per 100 Enterocytes (300-500 Cells Counted)
Upper limit of normal	20/100 25/100	H&E CD3
Borderline increased	25-29/100	H&E or CD3
Definitely increased	>29/100	H&E or CD3
Diagnosis by Villous Tip Method (5 Villi, 20 Enterocytes per Villous Tip, Mean Count)
Upper limit of normal	5/20	H&E or CD3
Definitely increased	≥6/20	H&E or CD3

 

H&E , Hematoxylin and eosin; IELs , intraepithelial lymphocytes.

* Avoid all lymphoglandular complexes. Average the sum of at least five villi.

A more practical approach, the villous tip counting method, has been validated in at least four studies. In H&E- or CD3-stained sections, averaging the number of IELs per 20 epithelial cells in at least five villous tips is done to obtain a rapid and comparable assessment of IEL counts. With this approach, lymphocyte counts of 6 to 12 IELs per 20 epithelial cells in the tips of villi in architecturally normal mucosa are found in patients with serologic or other evidence of GSE. The IEL counts are lower than in untreated flat GSE and higher than in normal controls. Although CD3 stains were used for cell counting in one study, equivalent results were obtained by using H&E stains in two others. The counts obtained by using the villus tip method correlate well with previously cited studies reporting that greater than 29 IELs per 100 epithelial cells is abnormal. A slightly different counting approach was taken in a landmark prospective study that compared IEL counts with serology in a random adult population. IELs were counted in a total of 50 enterocytes (in groups of 10) along the sides and tops of villi. In this study, counts of greater than 25 IELs per 100 epithelial cells detected GSE, whereas higher cutoffs missed 50% of cases. Importantly, this study found equally elevated IEL numbers in 3.8% of non-GSE controls, most of whom had Helicobacter pylori gastritis. The term lymphocytic enteropathy (or duodenal lymphocytosis ) has emerged to describe the spectrum of patients with increased IELs and normal villous architecture. The term lymphocytic duodenosis has been proposed to refer to the subset of this group that are proved serologically to not have GSE.

Numerous conditions other than GSE are associated with the presence of increased IELs in architecturally normal duodenal biopsies. These include H. pylori gastritis ( Fig. 16.4 ), injury caused by use of nonsteroidal antiinflammatory drugs (NSAIDs), viral gastroenteritis ( Fig. 16.5 ), tropical sprue, cow’s milk protein sensitivity, bacterial overgrowth, and some immune conditions.

Helicobacter pylori –associated duodenitis. An increase in intraepithelial lymphocytes in the first and second portions of the duodenum is not uncommon in the setting of H. pylori gastritis. Gluten-sensitive enteropathy is not suggested in this setting unless clinical evidence supports that diagnosis.

Viral gastroenteritis. This biopsy specimen from the second duodenum reveals mild villous blunting and a marked increase in the number of intraepithelial lymphocytes ( arrow in inset ). Viral studies revealed acute infection with rotavirus in this patient, who recovered spontaneously.

In summary, the following approach is recommended for biopsies in patients who have normal or near-normal villous architecture and a perceived increase in IELs or who have the clinical potential for a diagnosis of GSE (i.e., positive tTG serology). First, perform a low-power scan of villi and villus tips, looking for either a diffuse or a patchy increase in IELs. Avoid areas of lymphoglandular complexes, because they lead to falsely elevated IEL counts. If a striking increase in IELs is detected, there is no need to perform an IEL cell count. The number of IELs can be evaluated by the villus tip method for subtle cases, if desired, without the need for a CD3 stain. Because correlation with serology is required in all cases, use of excessive time or expense counting IELs in the diagnostic setting is not recommended. Pathology reports should contain a descriptive diagnosis, such as “duodenal mucosa with preserved villous architecture and increased intraepithelial lymphocytes,” with a note recommending correlation with clinical or serologic evidence of GSE (see Table 16.1 ), because many disorders can lead to an increase in IELs in the small intestine. Some of these disorders are listed in Table 16.5 .

Table 16.5

Disorders Showing Histologic Overlap with Gluten-Sensitive Enteropathy

Conditions Associated with Increased Intraepithelial Lymphocytes *	Conditions Associated with Villous Blunting
Helicobacter pylori gastritis Viral gastroenteritis Autoimmune enteropathy Tropical sprue Refractory sprue Protein intolerance Bacterial overgrowth	Common variable immunodeficiency Microvillus inclusion disease Autoimmune enteropathy Tropical sprue Refractory sprue Protein intolerance Bacterial overgrowth Radiation or chemotherapy Nutritional deficiencies Eosinophilic gastroenteritis Crohn’s disease

 

* Not all conditions associated with increased intraepithelial lymphocytes also show villous blunting.

Biopsies with Blunted Villi

The flat-destructive pattern (Marsh type 3) is the classic mucosal lesion associated with symptomatic GSE. Duodenal biopsy specimens reveal loss of normal small-intestinal architecture resulting from a decrease in the height of the villi (villous blunting) accompanied by crypt hyperplasia. Type 3 was further subdivided by Oberhuber into types 3a (mild blunting), 3b (moderate blunting), and 3c (severe blunting). These types correspond to mild , moderate , and severe mucosal lesions (or villous blunting).

It is suggested that pathology reports be accompanied by a note, the content of which depends on the degree of clinical information available at the time of sign-out (see Table 16.1 ). If clinical information is not provided, the note might read, “These histologic findings are consistent with GSE in the appropriate clinical setting.” In contrast, if a prior history of GSE is known or positive tTG antibodies have been identified, the note could read, “The histologic findings support a clinical diagnosis of GSE.” The terms mucosal lesion and villous blunting are nonspecific and useful to help convey that an architectural abnormality exists but the cause is unknown at the time of sign-out. It also reminds pathologists that villous blunting is a nonspecific finding that may be seen in a variety of conditions.

The histology of GSE with villous blunting is characteristic but variable. Biopsy specimens from the duodenum reveal loss of normal architecture caused by a decrease in the height of villi. In many cases, the mucosa appears completely flat. In others, the villi may be broad and only mildly to moderately shortened, or they may be irregular. In clinical practice, histologic overlap between mild, moderate, and severe blunting is often observed in single biopsy specimens ( Fig. 16.6 ). Loss of villus height is usually matched by crypt elongation or hyperplasia, so the overall width of the mucosa usually remains unchanged. The degree of injury observed in surface and crypt epithelia can vary widely and does not always reflect the degree of villous blunting or the severity of symptoms. When the condition is severe, the surface epithelium shows loss of its columnar shape, mucin depletion, vacuolization, and enlargement of cell nuclei (see Fig. 16.6, A ). Cells may show loss of polarity with stratification, pyknosis, and fragmentation of nuclei. IELs are increased, especially in the tips of villi. The epithelium situated along the length of blunted villi may appear entirely normal, despite its proximity to severely affected cells at the surface. Hyperplastic crypts often show a variable degree of nuclear enlargement and increased mitoses, most likely reflecting an increase in proliferative activity.

Celiac disease. A, Severe lesion. The surface epithelium shows loss of its columnar shape and mucin depletion. There is a marked increase in the number of intraepithelial lymphocytes (IELs) ( arrows ). The elongated crypts show increased mitotic activity and enlarged nuclei. The lamina propria is expanded by plasma cells and lymphocytes. B, Moderate lesion. In many cases of untreated celiac disease, only mild to moderate villous blunting is present. In this duodenal biopsy specimen with moderate villous blunting, all the other hallmarks of the disease, including increased number of IELs and crypt hyperplasia, are present. C , Treated celiac disease. Duodenal biopsy specimens obtained from patients consuming a gluten-free diet may reveal persistent mild abnormalities. In this example, the villous architecture is almost normal, but a slightly increased number of IELs and mild reactive changes are present.

The lamina propria in GSE typically shows a variable increase in plasma cells. Neutrophils and crypt abscesses are uncommon but may be present focally. However, the finding of diffuse, or marked, acute inflammation should prompt consideration of other diagnoses, such as peptic duodenitis, Crohn’s disease, and refractory sprue.

Atrophic-hypoplastic lesions (type 4) are rare and are similar to the lesions described in biopsy samples from patients with refractory, or unclassified, sprue (discussed later). The finding of atrophic mucosa may correlate with lack of response to a gluten-free diet.

Histology of Treated Disease (Response to a Gluten-Free Diet)

Small bowel biopsy specimens obtained as soon as 1 week to even several months after complete exclusion of dietary gluten may show only a modest improvement in villous architecture and persistently elevated numbers of IELs despite an excellent clinical response. However, in most cases, these features return to normal or near-normal states (i.e., a mild mucosal lesion) within 2 to 3 months after institution of a gluten-free diet (see Fig. 16.6, C ). Some patients show persistence of moderate or even severe lesions despite marked clinical improvement. Repeat biopsies are not required if the clinical response to a gluten-free diet is positive; they are indicated only if the clinical response is poor and other disorders (e.g., refractory sprue, lymphoma, infection) need to be excluded.

Malignancy in Gluten-Sensitive Enteropathy

An association between GSE and an increased incidence of lymphoma and carcinoma has been reported. Although some studies have suggested a relative risk of approximately 30-fold, recent population-based studies suggest that the increased risk may be lower. In two large population-based studies of patients with latent celiac disease, defined as positive serology with normal biopsy, there was no increase in mortality or lymphoma risk on follow-up. The role of adherence to a gluten-free diet in decreasing the risk of malignancy in patients with GSE is controversial. A number of studies have confirmed that strict dietary compliance, especially beginning in childhood, probably confers protection from malignant complications. Intestinal lymphoma in GSE, first documented in 1937, has occurred in 5% to 10% of patients in some series. Lymphomas that arise in this setting have been variably categorized and were originally classified as reticulum cell sarcomas or malignant histiocytosis. In some reports, the term ulcerative jejunitis (now understood to be synonymous with lymphoma) has been used to describe tumors that develop in the setting of malabsorption. The term enteropathy-associated T-cell lymphoma has also been applied. In 1985, Isaacson and colleagues characterized these tumors as T-cell lymphomas. However, B-cell lymphomas may rarely develop in association with refractory sprue as well.

Lymphoma may manifest as solitary or multiple tumors and may involve any portion of the small bowel, with or without involvement of the mesenteric lymph nodes. Clinically, the onset of lymphoma is frequently associated with relapse of malabsorption in previously gluten-responsive patients.

Whereas older studies cite an increased frequency of carcinomas, especially those arising in the GI tract, in patients with GSE, recent population studies in Sweden and the United Kingdom suggest no increase in the incidence of solid tumors in GSE. They do, however, confirm an increase in lymphoproliferative disorders.

Other Complications in Gluten-Sensitive Enteropathy

A variety of intestinal and extraintestinal pathologic con­ditions occur in patients with GSE. These include lym­phocytic gastritis, collagenous gastritis, lymphocytic colitis, collagenous colitis, dermatitis herpetiformis, nonspecific intestinal ulceration, and other associations.

Differential Diagnosis

As with mild infiltrative lesions, the flat appearance of type 3 lesions is not specific for GSE (see Box 16.1 ). Flattening of small-intestinal villi can be seen in several conditions, such as tropical sprue, bacterial overgrowth, unclassified sprue, specific food allergies, and common variable hypogammaglobulinemia (see Table 16.5 ). It is also observed in infants and young children with viral gastroenteritis or cow’s milk intolerance. Small bowel Crohn’s disease and eosinophilic gastroenteritis may rarely result in villous blunting. Distinction of these entities from GSE rests primarily on clinical, not pathologic, data. However, in the rare instance of a flat mucosal biopsy in common variable hypogammaglobulinemia, lack of lamina propria plasma cells and concurrent infection with Giardia are clues to the correct diagnosis. Biopsy specimens in tropical sprue only rarely show completely flat mucosa, and a history of residence in tropical climates allows distinction from GSE. Above all, serum antibody tests and response to a gluten-free diet are of paramount importance in distinguishing GSE from these other conditions.

Epidemiology and Clinical Features

Tropical sprue is a chronic malabsorptive syndrome, often associated with folate and vitamin B ₁₂ deficiency, that occurs in residents of or visitors to the Indian subcontinent and parts of Southeast Asia, Central America, and the Caribbean. Notable exceptions are Jamaica and sub-Saharan Africa, where the disease is rare. In tropical populations, adults are more severely affected than children. The disease occurs in both endemic and epidemic forms. Patients experience chronic nonbloody diarrhea, weight loss, bloating, and abdominal cramps. In severe cases, secondary vitamin deficiencies can lead to complications of nutritional deficiencies (such as subacute combined degeneration of the spinal cord caused by B ₁₂ deficiency).

The cause of tropical sprue remains unknown, although the preponderance of evidence supports an infectious origin. The illness probably begins with an acute infection of the small or large intestine that may be bacterial, viral, or parasitic in origin. Subsequently, a chronic infection, with colonization of the small bowel by aerobic enterotoxigenic bacteria, is believed to occur, and this probably results in ongoing injury to enterocytes. Bacteria isolated from patients with tropical sprue include Klebsiella pneumoniae, Escherichia coli , and Enterobacter cloacae. However, a consistent and specific causal agent has not been identified. An environment conducive to bacterial overgrowth may result from the release of enteroglucagon, a potent inhibitor of peristalsis, during the acute infectious phase of the disease. A study from India documented contamination of the small bowel with aerobic bacteria and prolonged orocecal transit time in patients with tropical sprue; both abnormalities reversed after prolonged antibiotic treatment. The theory of bacterial overgrowth is strongly supported by the response of some patients to broad-spectrum antibiotics, such as tetracycline, along with folic acid. In addition, studies have shown an increased frequency of HLA antigens Aw19 and Aw13 in some patients with tropical sprue. However, the role of HLA antigens in the pathogenesis of this disease remains poorly understood.

The entire small bowel is usually affected, including the ileum, and this leads to vitamin B ₁₂ and folate deficiency in most symptomatic patients. Vitamin deficiencies may lead to proliferative injury (e.g., megaloblastic change) to the intestinal crypts and other epithelia. Megaloblastic change, or macrocytosis, refers to the nuclear and cyto­plasmic enlargement of epithelial cells that occurs in the setting of interrupted DNA synthesis and cell division (see Chapter 6 ).

Pathologic Features

Asymptomatic native populations susceptible to tropical sprue often harbor pathologic changes that include villous shortening and increased inflammation. The degree of abnormality in asymptomatic people is usually minor but is occasionally pronounced. Evidence of malabsorption is also frequently found in asymptomatic native residents.

As stated earlier, the entire small bowel, including the ileum, is usually affected in tropical sprue. This is in contrast to GSE, in which pathologic lesions are present in the duodenum and jejunum and only rarely extend into the ileum. The patterns of distribution of these two diseases are consistent with their pathogenesis. Tropical sprue is caused by colonization of the bowel by bacteria, whereas GSE is a response to a dietary antigen that is present in highest concentration in the proximal gut.

Gross Pathology

In early studies of small bowel mucosa (with a dissecting microscope) biopsy specimens from symptomatic patients and from some asymptomatic patients in endemic areas revealed an abnormal villous pattern characterized by fusing and broadening of the villi. The jejunum is usually more severely affected than the ileum, which may appear normal under the dissecting microscope despite being abnormal histologically.

Microscopic Pathology

There is significant overlap between the histologic features of tropical sprue and those of GSE. Small bowel biopsies in tropical sprue reveal varying degrees of villous blunting, crypt hyperplasia, and increased mitotic activity ( Fig. 16.8 ). Increased lamina propria lymphocytes, plasma cells, and eosinophils, as well as IELs, are also seen. In tropical sprue, IELs are more numerous in the crypts than in the surface cells—unlike GSE, in which the reverse situation occurs. In severe cases, decreased mitotic activity is combined with a lack of surface epithelial cell maturation. The cells acquire a cuboidal shape, become mucin depleted, and accumulate cytoplasmic fat droplets. As previously mentioned, concomitant folate and B ₁₂ deficiency may lead to mucosal atrophy, manifested by crypts lined by cells with markedly enlarged (megaloblastic) nuclei. Completely flat mucosa, common in GSE, is almost never seen in tropical sprue.

Tropical sprue. A variable degree of villous blunting is seen in tropical sprue. In this duodenal biopsy specimen, only mild villous blunting is present. A marked increase in the number of intraepithelial lymphocytes, and this is more prevalent in the crypts than in the surface epithelium. The lamina propria is expanded with mononuclear cells.

(Courtesy of Raymond Yesner, MD, Yale University.)

Electron microscopic studies of small bowel biopsy specimens in tropical sprue have revealed irregularities of microvilli, increased lysosomes, accumulation of fat in surface epithelium, and the presence of dense material beneath the basal lamina.

Differential Diagnosis

The histologic changes in tropical sprue are nonspecific and can be seen in a variety of conditions (see Fig. 16.8 ). A clinical history of residence in, or prolonged visits to, endemic areas is critical in establishing a correct diagnosis. Parasitic and other specific infections must be excluded before a diagnosis of tropical sprue can be made confidently. Biopsy specimens that show completely flat mucosa should arouse suspicion for other diseases such as GSE. However, mild to moderate mucosal lesions may be seen in both GSE and tropical sprue. Clinical improvement after treatment with broad-spectrum antibiotics further supports a diagnosis of tropical sprue.

Pathogenesis

Bacterial overgrowth by coliform bacteria in the small intestine occurs in a variety of conditions, all of which predispose the individual to decreased intestinal motility and stasis. These include motor and neural disorders such as scleroderma, diabetes mellitus, pseudo-obstruction, and amyloidosis; structural defects such as diverticulosis and strictures; genetic conditions such as pancreatic deficiency resulting from cystic fibrosis; and surgical manipulations that lead to isolated bowel segments, such as Billroth II gastrojejunal anastomosis or short bowel syndrome. Immune deficiency states, such as AIDS and common variable immune deficiency, may also result in bacterial overgrowth and may contribute to the diarrheal illness that frequently occurs in these conditions. Clinically significant bacterial overgrowth also occurs in older adult patients without any other predisposing features, especially those with disabilities. Several studies have documented bacterial overgrowth in patients with irritable bowel syndrome, although this remains controversial.

Clinical Features

Regardless of the underlying cause, this syndrome is characterized by overgrowth of anaerobic bacteria (normally confined to the colon) within the small intestine. Patients with this condition typically have diarrhea and steatorrhea, although malabsorption of vitamin B ₁₂ , carbohydrates, and other nutrients can occur as well. Proposed theories of pathogenesis include deconjugation of bile salts by anaerobic bacteria, which leads to fat malabsorption. In addition, certain nutrients, such as vitamin B ₁₂ , may be depleted by luminal bacteria. Ultrastructural studies of this condition also have revealed evidence of damage to surface epithelium and the brush border, with some evidence of defective fat transport and absorption.

Several methods of diagnosis have been used to detect bacterial overgrowth. The traditional gold standard is small-intestinal aspirate culture showing growth of at least 10 ⁵ colony-forming units of bacteria per milliliter of small bowel fluid (normal small bowel has <10 ⁴ colonies per milliliter). Typically, multiple organisms are identified and include species of bacteroides, enterococcus, and lactobacillus. Other diagnostic tests include the C-labeled d -xylose and hydrogen breath tests. When bacterial overgrowth is suspected or proven, antibiotic therapy results in marked improvement.

Pathologic Features

Small bowel biopsy specimens from patients with bacterial overgrowth may be histologically normal despite clinical evidence of malabsorption. When abnormal, they typically reveal mild to moderate villous blunting with increased chronic inflammation in the lamina propria and epithelium, as well as crypt hyperplasia ( Fig. 16.9 ). Vacuolated epithelial cells, probably containing lipid, may also be seen. One study found that villous blunting, defined as a villus to crypt ratio less than 3 : 1, was the most common abnormality in small bowel biopsy specimens from patients with bacterial overgrowth versus controls. However, in the same study, more than half of the specimens from patients with bacterial overgrowth were scored as histologically unremarkable. When present, histologic changes tend to be patchy and vary from segment to segment, so that biopsies taken during the same procedure from different sites may show different degrees of abnormality. This pattern of involvement helps to distinguish bacterial overgrowth from GSE.

Bacterial overgrowth. This medium-power image was obtained from a resection specimen of a patient with bacterial overgrowth. The appearance of the mucosa can vary, and this example shows increased numbers of intraepithelial lymphocytes and lamina propria plasma cells. Villous architecture is largely preserved. The histology is nonspecific and shows overlap with many other conditions, as described in the text.

(Courtesy of Joel Greenson, MD, University of Michigan.)

As in other conditions characterized by villous blunting, the histologic features are entirely nonspecific and do not correlate with severity of clinical symptoms.

Clinical Features

Symptoms of eosinophilic gastroenteritis vary depending on the layer of the bowel wall that is involved. The mucosal form most frequently manifests with GI hemorrhage, nausea, vomiting, and diarrhea. Protein-losing enteropathy and other forms of malabsorption may also occur in this type. Patients with primarily mural disease usually have abdominal pain and symptoms of small bowel obstruction, such as nausea and vomiting. The serosal form often manifests with ascites, as well as abdominal pain, nausea, and vomiting.

Once the condition has been accurately diagnosed, treatment consists of steroids. Surgical resection of obstructed segments of small bowel is frequently performed before diagnosis, because it is difficult to establish a diagnosis by biopsy if the mucosa is not involved or cannot be sampled. Although some diagnostic importance is given to the finding of peripheral eosinophilia, it may be absent in as many as 25% of patients. The natural history of eosinophilic gastroenteritis remains largely unknown. In a recent study, three different courses of disease were identified: single flare, recurring disease, and continuous course. In the same study, approximately 40% of patients demonstrated spontaneous remission, while the remainder were treated and showed greater than 95% response to steroids.

Pathogenesis

The pathogenesis of eosinophilic gastroenteritis remains unknown but may be different for the three types described (mucosal, mural, and serosal). Familial cases do occur, but no specific genetic abnormalities or inheritance patterns have been identified. In some patients with mucosal disease, eosinophilic gastroenteritis appears to be related to food allergy. IgE is elevated in some patients. On the other hand, several studies have shown that the degree of tissue injury and the severity of symptoms are related to the degree of eosinophilic infiltration and to eosinophilic activation and degranulation. Extracellular major basic protein and eosinophil cationic protein are present at increased levels in affected mucosa. Experimental models with electron microscopy have demonstrated neuronal damage secondary to eosinophil infiltration and degranulation. Eotaxin 1, a highly selective eosinophil chemokine, is important for the migration of eosinophils into the GI tract in health and disease. IL5 may work synergistically with eotaxin 1 in eosinophil migration. The triggers for chemokine activation in eosinophilic gastroenteritis are unknown but are presumably related to altered immune responses to environmental antigens in susceptible hosts.

Pathologic Features

Eosinophils are a normal constituent of the gastrointestinal lamina propria, to varying degrees depending on the site; they serve a protective role against infections, particularly parasitic infestations. However, when eosinophil numbers are increased, the diagnosis of eosinophilic gastroenteritis should be considered. The pathologic changes in eosinophilic gastroenteritis depend on the anatomic location of disease. Because mucosal biopsies are frequently normal in the mural and serosal forms of disease, the finding of normal mucosa in biopsy specimens from patients with suspected eosinophilic gastroenteritis does not exclude the diagnosis. In the mucosal type, an increase in both intact and degranulated eosinophils is seen in the lamina propria and infiltrating the epithelium ( Fig. 16.10 ). Some specimens may show eosinophilic crypt abscesses, surface erosion, or ulceration. The infiltrate may be severe and diffuse or mild and patchy. Biopsies from multiple sites are often needed to detect the presence of mucosal disease. In the small intestine, the mucosal architecture is usually normal, or it may show mild villous blunting. However, severe mucosal lesions (flat mucosa) have also been reported in rare instances. In addition to the lamina propria, eosinophils may accumulate in the muscularis mucosae and the superficial submucosa. The density of eosinophils is often greatest in the deepest portion of the mucosa.

Eosinophilic gastroenteritis. The epithelium may not show significant injury. In other cases, the epithelium may be infiltrated by eosinophils, with the formation of crypt abscesses and ulceration.

The pathology of the mural form of eosinophilic gastroenteritis is characteristic ( Fig. 16.11 ). Resection specimens show thickening and induration of the intestinal wall on gross examination. Ulceration may be present. Microscopically, prominent edema and a marked eosinophilic infiltrate are the hallmarks of mural eosinophilic gastroenteritis. Submucosal edema is frequently prominent and may also extend into the muscle layer. As in mucosal biopsies, eosinophilic infiltration is usually of a severe degree, but it can also be patchy. Dense eosinophilic infiltrates may extend into the subserosa. In serosal eosinophilic gastroenteritis, edema and eosinophils are limited to the subserosal layers. In this setting, the diagnosis can usually be made by ascitic fluid cytology.

Eosinophilic gastroenteritis. In the mural form, edema and eosinophils extend into the submucosa and muscularis propria.

Differential Diagnosis

The diagnosis of eosinophilic gastroenteritis in resection specimens is usually straightforward. The differential diagnosis includes many other conditions that can lead to elevated tissue eosinophil levels, such as parasitic infections, vasculitis, and Crohn’s disease. Parasites must be excluded by careful examination of tissue sections and by stool examination. In vasculitis, the inflammation tends to be centered in and around blood vessels, and ischemic changes may be present. Although clinical and radiologic confusion with Crohn’s disease often occurs, the distinction from Crohn’s disease is relatively simple in histologic sections. The differential diagnosis in mucosal biopsies is more difficult, especially if the stomach is not involved and the degree of eosinophilic infiltration is patchy. However, certain features of Crohn’s disease, such as focally enhanced neutrophilic exudates and granulomas, are never seen in eosinophilic gastroenteritis. Occasionally, cases of GSE can be associated with increased mucosal eosinophils. However, clinical correlation with serum autoantibodies and attention to the other characteristic features of GSE usually make distinguishing it from eosinophilic gastroenteritis straightforward. The concurrent or subsequent development of GSE and dermatitis herpetiformis has been reported in patients with eosinophilic gastroenteritis.

Pathologic Features

Peptic duodenitis is characterized by the presence of three main pathologic features, all of which may vary in severity: increased plasma cell infiltration, neutrophils in the lamina propria or epithelium (or both), and reactive epithelial changes, including villous blunting. Gastric surface metaplasia is not always used as an absolute criterion for peptic duodenitis, because it may be found in cases without inflammation and therefore may simply represent an adaptive response to chronic acid exposure. However, most cases of peptic duodenitis show extensive gastric surface metaplasia, which can be highlighted with a periodic acid–Schiff (PAS) stain ( Fig. 16.13 ). The distribution of changes is often patchy and can be missed as a result of sampling error.

Peptic duodenitis secondary to heterotopia. Both gastric mucous cells and oxyntic glands are present.

In mild cases, near-normal mucosa can be seen with only a borderline increase in plasma cells and subtle reactive epithelial changes. These changes are not usually associated with symptoms and therefore may be physiologic. In moderately active peptic duodenitis, the epithelium is infiltrated by neutrophils and shows mucin depletion, a syncytial growth pattern, and more marked reactive epithelial changes, such as nuclear hyperchromasia and increased mitoses. Surface cells containing abundant PAS-positive mucin (gastric surface metaplasia) are usually easily identifiable. Brunner glands are hyperplastic and, as a result, may be prominent in the mucosa above the level of the muscularis mucosae. Severe cases show erosion or ulceration. If the ulcer is caused by peptic injury, concomitant H. pylori gastritis is frequently present.

Differential Diagnosis

Pathologic changes in peptic duodenitis are nonspecific. NSAID injury, Crohn’s disease, celiac disease, and infections may have a similar histologic appearance. Clinical correlation and stains for organisms (including H. pylori ) should be performed to help differentiate among these conditions. However, the degree of gastric surface metaplasia, combined with prominent Brunner glands, especially in a patient with documented H. pylori gastritis, often helps in establishing a diagnosis of peptic duodenitis.

Clinical Features

GI toxicity resulting from NSAID use is increasingly common, causing as many as 100,000 hospital admissions annually in the United States and many more worldwide. Ulceration of the stomach and proximal duodenum resulting from NSAIDs has long been recognized. However, numerous studies have documented ulceration leading to significant hemorrhage, perforation, or obstruction also occurring in the distal small bowel and colon as a result of NSAID use. The term NSAID enteropathy has been used to describe this condition. Patients may have persistent iron deficiency anemia despite the absence of gastroduodenal involvement. The incidence of small bowel inflammation and ulceration has been reported to be as high as 46% to 70% among long-term NSAID users. A more modest increase was found in an autopsy series, wherein 8.4% of patients previously taking NSAIDs had jejunal or ileal ulcers, compared with 0.6% of controls.

Pathogenesis

The cause of NSAID enteropathy is most likely multifactorial, involving a sequence of events. Local topical irritation, enterohepatic recirculation, and increased mucosal permeability secondary to cellular injury and loss of tight junction function, as well as microcirculatory events, all play a role. These events may allow infiltration of luminal antigens, bile, and bacterial products, which in turn incite an inflammatory response. Newer types of NSAIDs, known as selective cyclooxygenase-2 (COX-2) inhibitors, are associated with a significantly lower incidence of intestinal side effects, but they still carry a risk of ulceration and hemorrhage, especially in long-term users.

Pathologic Features

A wide spectrum of histologic changes may occur in the small bowel as a result of NSAID injury. Mild lesions consist of superficial erosions with nonspecific neutrophilic and plasmacytic infiltrates ( Fig. 16.14 ). Erosions are frequently multiple and can progress to form deep ulcers, which may cause severe hemorrhage. In one surgical study of 11 patients who underwent emergent small bowel resection for NSAID-induced ulceration, ulcers were observed the ileum in eight and in the jejunum in four, and they were multiple in 50% of cases. The ability to obtain jejunal biopsies during push enteroscopy has led to the documentation of more subtle changes, including mild villous blunting in some cases. However, severe, diffuse villous blunting has not been reported in NSAID injury.

Nonsteroidal antiinflammatory drug injury. In this biopsy specimen of the terminal ileum, marked expansion of the lamina propria is seen, with occasional crypts containing neutrophils.

A rare but more distinctive form of NSAID enteropathy is referred to as diaphragm disease ( Fig. 16.15 ). This condition involves numerous thin, weblike mucosal septa that project into the lumen and cause significant narrowing and obstruction. The middle small intestine and the ileum are the preferred sites of involvement. The mucosal diaphragms consist of mucosa with reactive epithelial changes, with or without surface erosions, and prominent submucosal fibrosis. The bands of fibrous tissue are characteristically oriented perpendicular to the surface of the mucosa. Mild chronic inflammation is usually present. The fibrosis is thought to result from recurrent ulceration and scarring. These diaphragms are fairly specific for NSAID injury.

Nonsteroidal antiinflammatory drug (NSAID) injury. A, Low-power view of NSAID-induced diaphragm disease. This cross section is through one of the thin fibrous septa that form the luminal diaphragm. Submucosal fibrosis is prominent. B, High-power view shows a slightly disorganized mucosa with reactive changes and submucosal fibrosis.

(Courtesy of Robert Odze, MD, Brigham and Womens Hospital.)

Differential Diagnosis

The differential diagnosis of the common ulcerating form of NSAID injury includes peptic and H. pylori –induced duodenitis, Crohn’s disease, and, rarely, infections such as Giardia . The lack of specificity of the histologic changes seen in some of the previously discussed entities can cause diagnostic dilemmas, especially in biopsies of the terminal ileum, where the distinction between NSAID injury and Crohn’s disease has significant clinical implications. Aphthous lesions may occur in both diseases, but significant plasma cell infiltrates, crypt distortion, and pseudopyloric metaplasia are much less common in NSAID injury. In the upper GI tract, gastric biopsies help distinguish H. pylori –related injury from NSAID-induced injury to the proximal duodenum. In addition, peptic duodenitis, which is frequently associated with marked gastric surface metaplasia in the duodenum, is not specifically associated with NSAID injury. Appropriate clinical information is important to differentiate between these disorders. The differential diagnosis for NSAID-induced diaphragm disease includes radiation or chemotherapy injury, chronic ischemia, Crohn’s disease, and the rare entity CMUSE (cryptogenic multifocal ulcerating stenosing enteritis; see later discussion).

Radiation Injury

The GI tract is exquisitely sensitive to radiation. The small intestine is the most sensitive portion of the gut, followed by the stomach, colon, and esophagus. Radiation injury related to therapy is subdivided into acute and chronic forms.

Acute Radiation Injury

In the acute stage, clinical symptoms related to small-intestinal involvement include diarrhea, abdominal pain, and bloating. The severity of toxicity is related to the radiation dose and to the volume of intestine exposed. This syndrome, frequently called radiation enteritis , occurs in 20% to 70% of exposed patients and can appear within hours after exposure. However, biopsies are not usually obtained at this stage unless the clinical features suggest that other conditions, such as opportunistic infections, may be present. The earliest histologic changes occur in the surface and crypt epithelia, which show mitotic arrest, nuclear enlargement, and hyperchromasia as well as flattening and separation of cells. Increased numbers of apoptotic bodies in the crypts are typical. Ultrastructurally, loss of microvilli, vacuolization of endoplasmic reticulum, and other changes have also been reported.

After 7 or more days of therapy, the area of the epithelial surface is reduced by approximately 40%, and the mucosa is notable for villous blunting, crypt hypoplasia, and a marked decrease in the number of lymphocytes in the lamina propria. Ulceration can occur at this stage and may be widespread if exposure is persistent. In addition to epithelial changes, endothelial cells are similarly damaged, resulting in increased vascular permeability and submucosal edema. The acute syndrome is transient; symptoms and histologic changes usually resolve within several weeks after cessation of radiation.

The most important differential diagnosis in the setting of acute radiation therapy is opportunistic infection. Special stains and cultures should be used to exclude infections in these as in all other immunocompromised patients. Acute radiation injury may also mimic the early phase of ischemic injury. In addition, the degree of epithelial atypia often present in acute radiation injury may occasionally be mistaken for dysplasia, particularly if the clinical history is unknown.

A unique and novel form of radiation brachytherapy is selective internal radiation therapy using biocompatible resin-based yttrium 90 ( ⁹⁰ Y)-labeled microspheres that are delivered via arterial catheters to selectively target inoperable tumors, such as metastatic lesions of the liver. If delivery of the spheres is imperfect, the spheres can travel to the gastrointestinal tract, leading to mucosal damage, including ulcerations, days to months after exposure.

Chronic Radiation Injury

Chronic radiation injury develops years after radiation exposure, regardless of the presence or severity of previous acute radiation injury. The reported incidence of chronic radiation injury after radiotherapy has ranged from 1% to 36%. With the use of current radiotherapy regimens and protective measures, the incidence is now reported to range from 5% to 10%. The incidence and severity of chronic radiation injury has been shown to be related to the overall dosage and to the volume of small bowel irradiated.

Clinical symptoms are variable but usually reflect chronic ulceration (pain, hemorrhage), stricture formation (obstruction), or perforation. The symptoms are related to long-term, irreversible pathologic changes in mesenchymal tissue that ultimately lead to vascular insufficiency. Most likely, these changes occur secondary to sustained overexpression of inflammatory and fibrogenic cytokines. Although epithelial and villous architectural changes usually return to normal after acute radiation injury, stromal cells, especially fibroblasts, and endothelial cells undergo a variety of persistent changes. Enlargement of fibroblasts, with expansion and vacuolization of their cytoplasm, an increase in nuclear size, and hyperchromasia are common. Although the cells increase in size, the nucleus-to-cytoplasm ratio typically stays within the normal range. Submucosal fibrosis and, occasionally, fibrosis of the muscularis propria may be present as well ( Fig. 16.16, A and B ). Intimal proliferation of small and medium-sized arteries, with partial or total occlusion of the vascular lumen, is a frequent finding in surgical specimens removed because of stricture formation (see Fig. 16.16, C ). Ischemic changes in the overlying mucosa are often present ( Fig. 16.16, D ). Mucosal biopsies obtained from strictured segments may show ulceration, mucosal fibrosis, crypt branching, and inflammation. Although these findings are nonspecific, they are compatible with chronic radiation injury in the proper clinical setting.

Chronic radiation injury. A, This segment of small intestine contains a symptomatic stricture. On low power, the mucosa appears intact, but there is extensive submucosal fibrosis. Ectatic, thin-walled blood vessels are noted at the junction of the mucosa and submucosa ( arrows ). B, Fibrosis of the muscularis propria ( MP ) can also occur in severe cases. C, The mesenteric vessels ( arrows ) within the subserosa frequently show severe intimal proliferation ( bar ), thrombosis, and occlusion of the vessel lumen. D, Mucosal biopsies may show ischemic-type surface erosions. E, Ectatic vessels are present in the mucosa and submucosa. Radiation-induced telangiectases are often associated with bleeding. Mild architectural distortion of the crypt epithelium can be seen.

Mucosal telangiectases and vascular proliferations may also develop as a long-term sequela of radiation therapy (see Fig. 16.16, E ). They may be missed on histologic examination because thin-walled vessels frequently collapse after biopsy.

Chemotherapy Injury

Chemotherapy agents frequently cause acute enteritis that may be debilitating. The pattern of injury reflects four phases of disease: (1) an influx of inflammatory cells into the lamina propria, demonstrated in animal models; (2) loss of epithelial cells and mucosal structure; (3) disruption of large areas of epithelial lining; and (4) recovery with regrowth of epithelium and a return to normal structure and function. In fact, the histologic changes seen in small-intestinal biopsies after chemotherapy are similar to those seen in acute radiation injury. Biopsies obtained shortly after chemotherapy show reactive nuclear and cytologic atypia and macrocytosis ( Fig. 16.17 ). These changes reflect an arrest of maturation, which occurs within hours after administration of the drug. Mitotic figures are usually decreased in number, and an increase in apoptotic bodies is observed in epithelial crypts, along with villous blunting, which may be severe. Cytotoxic chemotherapy is associated with an increase in a variety of pro-apoptotic proteins, including TP53, caspase 3, and Bax and Bak in small-intestinal crypt cells. Necrosis of crypt epithelium may follow, with the development of surface erosions. These changes are transient, and the mucosa usually returns to normal within a few weeks after cessation of treatment.

Chemotherapy injury. Small bowel biopsy specimens obtained shortly after chemotherapy often reveal villous blunting, nuclear enlargement, and cytoplasmic basophilia. A decrease in mitotic activity is seen, caused by an arrest of cell proliferation. No significant inflammation is observed.