Genetic Factors

The observation that 10% to 20% of patients have at least one other affected family member lends support to the role of genetic factors in the development of UC. The strongest evidence of a genetic influence is derived from three European studies wherein 6% to 16% of monozygotic twin pairs had concordant UC, compared with 0% to 5% of dizygotic twin pairs. The lifetime risk of developing disease is higher among first-degree relatives of a patient of Jewish descent and among relatives of patients with early-onset disease.

A wide array of genes are responsible for conferring genetic susceptibility, disease specificity, and phenotype in patients with UC. Linkage analyses have demonstrated that chromosomes 1, 2, 3, 5, 6, 7, 10, 12, and 17 harbor susceptibility genes for UC. Specifically, the IBD2 locus on chromosome 12 has a strong association among families with UC. Additionally, the C3435T polymorphism of the human multidrug resistance 1 ( MDR1 ) gene is also linked to susceptibility to UC.

Besides susceptibility genes, human leukocyte antigen (HLA) alleles also influence disease behavior in UC. A significantly increased frequency of HLA-A11 and HLA-A7 has been observed to occur in patients with UC. Specifically, HLA-DR1 ( DRB1*0103 ) has been associated with severe colitis. HLA-DR2 ( DRB1*1502 ) has been associated with UC in Japanese and Jewish populations.

Environmental Factors

It is now widely accepted that continuous antigenic stimulation by commensal bacteria, fungi, or viruses leads to chronic inflammation in individuals who have defects in immunoregulation, mucosal barrier function, and microbial killing. The distal terminal ileum and colon contain the highest concentrations of bacteria (almost 10 ¹² organisms per gram of luminal content), and they are a source of constant antigenic stimulus to the host immune system. Animal studies have shown rapid development of colitis when germ-free HLA-B27 transgenic rats and interleukin 10 (IL10)-deficient mice are populated with normal specific pathogen-free bacteria. Administration of antibiotics effectively prevents and reduces the severity of colitis in these animal models. There are several postulated mechanisms by which gut flora may initiate, or contribute to, the development of colitis (see Immune Factors ). By virtue of their ability to adhere to or invade the surface epithelium or to produce enterotoxins, microbial organisms stimulate production of inflammatory cytokines. Alteration of the balance between protective and harmful bacteria (e.g., Bacteroides species) reduces the concentration of short-chain fatty acids, which provide nourishment to colonocytes. An impaired mucosal barrier and inability to kill microbes because of impaired host defense mechanisms also contribute to hyperresponsiveness and production of high levels of inflammatory cytokines. Abnormal antigen processing, loss of tolerance, autoimmunity, and an abnormally excessive T-cell response are some other mechanisms that influence the severity of inflammation.

A T-cell α-chain receptor knockout mouse model of colitis has demonstrated lack of development of inflammation after appendectomy in animals at 3 to 5 weeks of age. Subsequent case-control studies on humans have also suggested that appendectomy may have a beneficial effect on the disease course. However, there have been no prospective studies confirming a possible protective effect.

The best-characterized environmental factor associated with UC is cigarette smoking. UC is more common among nonsmokers than current smokers. In fact, the second incidence peak in middle-aged men may, in part, be linked to patients who have stopped smoking later in life. A recent prospective study of a cohort of 229,111 women who were followed over a period of 32 years (Nurses Health I and II cohort) showed that the risk of UC is highest during the first 2 to 5 years after cessation of smoking but remains elevated for more than 20 years. The postulated mechanisms for the protective effect of smoking include modulation of cellular and humoral immunity, increased generation of oxygen free radicals, and alteration of cytokine levels.

Immune Factors

Both humoral and cell-mediated immunologic mechanisms play major roles in the pathogenesis of UC. UC is associated with an increase in the synthesis of IgG, notably the IgG1 and IgG3 subclasses. Most patients have circulating antibodies to a variety of dietary, bacterial, and self-antigens that are of the IgG1 subclass, and these are polyclonal in nature. Because serum antibody titers usually do not correlate with disease activity or course, it has been postulated that cross-reactivity between antibodies to bacterial antigens and colonocyte epithelial epitopes may help trigger an immunologic response that leads to mucosal inflammation.

UC is associated with several autoimmune diseases such as diabetes mellitus, pernicious anemia, and thyroid disease. The possibility that UC is an autoimmune disease is supported by the fact that patients with UC have serum antibodies directed against lymphocytes, ribonucleic acid, smooth muscle, gastric parietal cells, and thyroid tissue. Patients also have antibodies to epithelial cell–associated components, notably an autoantibody against a 40-kDa epithelial antigen found in normal colonic epithelium. This IgG autoantibody was eluted specifically from colonic mucosa of patients with UC and was not found in patients with CD or other colonic inflammatory conditions. This antigen also shares epitopes with antigens found in the bile ducts, skin, eyes, and joints, sites that are commonly associated with extraintestinal manifestations of UC. The other autoantibody associated with UC is pANCA. It is found in 60% to 80% of UC patients and belongs to the IgG3 subclass. The exact antigen to which pANCA is directed is unknown. There is some evidence that the antigen is a 50-kDa nuclear envelope protein that is specific to myeloid cells. The pathogenic relevance of pANCA is unclear. It appears to be associated with an aggressive disease course and development of pouchitis.

Bacterial antigens also trigger innate immunity by activation of pattern-recognition receptors, which include Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Activation of TLRs and NLRs results in downstream activation of nuclear factor κB, which further stimulates production of various proinflammatory cytokines and chemokines. Defects in any of these pathways can result in abnormal bacterial processing and possibly IBD.

Colonic epithelial cells express class II major histocompatibility complex (MHC) antigens and can initiate an inflammatory response by acting as antigen-presenting cells. Increased turnover of colonic epithelium, reduced metabolism of short-chain fatty acids, abnormal membrane permeability, and altered composition of mucus layers contribute to the pathogenesis of UC. Animal models of colitis produced by disruption of colonic epithelium further support the role of epithelial cells in the pathogenesis of IBD.

Release of various cytokines from the T-cell inflammatory pathways may also lead to increased epithelial cell permeability and alteration of the endothelium, contributing to diarrhea and localized ischemia, respectively.

Gross Features

In untreated cases, the extent of colonic involvement depends on the clinical severity of disease. UC classically involves the rectum with variable, but continuous, involvement of the colon more proximally ( Fig. 17.7 ). According to the Montreal classification, the extent of UC is divided into ulcerative proctitis (involvement limited to the rectum), left-sided or distal UC (involvement limited to a portion of the colorectum distal to the splenic flexure), and extensive UC or pancolitis (involvement of the colon proximal to the splenic flexure). At the initial onset of disease, pancolitis occurs in approximately 20% of patients, left-sided colitis in 50% to 60%, and proctitis or rectosigmoiditis in approximately 45% of patients. Skip lesions, in the form of appendiceal, periappendiceal, or ascending colon/cecal involvement, have been observed in as many as 80% of patients with subtotal UC (see Unusual Morphologic Variants of Ulcerative Colitis ). Based on a long-term follow-up study by Farmer and colleagues, pancolitis eventually develops in almost half (46%) of patients with proctitis or rectosigmoiditis and in more than 70% of those with left-sided colitis.

A gross specimen of subtotal ulcerative colitis showing diffuse continuous disease starting from the distal rectum and continuing up to the midportion of the ascending colon.

In the active phase of disease, the mucosa usually appears diffusely congested, granular, and edematous. Ulcers, when present, are usually small and oriented longitudinally in relation to the teniae coli. They often appear to undermine adjacent areas of mucosa, which leads to the formation of polypoid mucosal folds or inflammatory pseudopolyps. In such cases, the mucosa may have a cobblestone appearance, similar to that observed in CD. Rarely, an exaggerated form of pseudopolyp formation, known as filiform polyposis, may be present ( Fig. 17.8 ). It is characterized by the presence of elongated, slender, villiform, worm like, polypoid mucosal projections and usually spares the rectum. In severe cases, ulcers may be extensive, involve large segments of bowel, and lead to near-total or total mucosal loss.

A gross specimen of ulcerative colitis showing numerous filiform polypoid mucosal projections that represent an exaggerated form of inflammatory pseudopolyp formation (filiform polyposis).

In cases of toxic megacolon, the bowel wall appears extremely thin, dilated, and congested. The serosal surface usually demonstrates fibrinous or fibrinopurulent exudate. Rarely, there is evidence of perforation. The mucosal surface in these cases is extensively denuded, hemorrhagic, ulcerated, and, often, covered with purulent exudates.

In the quiescent (inactive) phase of UC, the mucosa may appear completely normal, or it may show diffuse granularity, either with or without inflammatory pseudopolyps. In some cases of long-standing UC, the bowel wall is thickened and contracted (“colonic foreshortening”), and the mucosal surface may appear atrophic.

In treated UC, especially when patients have been given steroid enemas, the rectal mucosa may show minimal or no abnormalities on gross examination. Similarly, in patients who have received medical treatment before surgical resection, there may be focal, diffuse, or even widespread areas of grossly normal-appearing bowel between areas of affected bowel.

Microscopic Findings

Depending on the phase of disease and the degree of inflammatory activity, UC-related colitis is categorized as chronic inactive , chronic active , or active (without features of chronicity) for the purpose of sign-out. Chronic colitis (regardless of “activity”) is defined by the presence of histologic features of chronicity ( Box 17.1 ), such as crypt architectural distortion, crypt atrophy, diffuse mixed lamina propria inflammation, basal plasmacytosis, basally located lymphoid aggregates, and Paneth cell metaplasia (in the left colon). Other changes of chronicity include lamina propria fibrosis, pyloric gland metaplasia, and Paneth cell hyperplasia in the right colon. Common changes of “activity” include neutrophilic or eosinophilic cryptitis, crypt abscesses, regenerative or degenerative epithelial changes, hemorrhage, necrosis, erosions, and ulceration. The degree of activity is graded as mild if less than 50% of the mucosa shows evidence of activity, moderate if more than 50% shows these features, and severe if surface erosion or ulceration is present.

Ascending Colon, Cecum, and Appendiceal Involvement as Skip Lesions in Ulcerative Colitis

Some patients with either subtotal or left-sided colitis show patchy, mild, chronic, or active inflammation in the cecum or ascending colon that may be falsely interpreted as CD because of the impression of segmental involvement. As many as 65% of patients with UC have limited left-sided involvement initially, but eventual extension to more proximal portions of the colon occurs in 29% to 58% of such patients. In one study by D’Haens and colleagues of 20 patients with established left-sided UC, 6 showed a sharp demarcation between affected and unaffected portions of colon, whereas 14 showed a more gradual transition. The area of transition in such cases may appear somewhat patchy, giving a false impression of skip lesions. Seventy-five percent of this latter group of patients showed an area of inflammation in the cecum, primarily in the periappendiceal mucosa, that was separate from the distal inflamed segment. In a study by Mutinga and co-workers, 14 patients with both left-sided UC and pathologically confirmed patchy right-sided chronic inflammation were compared with 35 control patients who had limited left-sided UC only. The two groups had similar demographic features, extraintestinal manifestations, severity of disease, prevalence of extension to pancolitis, and natural history, which suggests that patchy right-sided inflammation in patients with left-sided colitis has little clinical significance. This fact should be recognized by pathologists so that a false diagnosis of CD can be prevented.

In a prospective study of 271 patients with UC, including 63 with inactive left-sided or subtotal colitis, skip areas of periappendiceal cecal mucosal involvement were identified in 32% of patients. Similarly, since the original description by Davison and Dixon in 1990 of “discontinuous involvement” wherein the appendix was found to be inflamed in 21% of 62 cases of distal UC, several other studies have shown that the appendix may be involved as a “skip lesion” in this disease, although at least one other study failed to confirm this finding. In another study by Groisman and colleagues, ulcerative appendicitis was present in 86% and 87% of patients with “nonuniversal” and “universal” UC, respectively. Their study included two cases with limited left-sided involvement combined with appendiceal involvement. Overall, the role of the appendix in UC is poorly understood. Patients with prior appendectomy have been shown to have a lower risk for UC. In one study, the severity of appendiceal inflammation (ulceration) in patients with UC was a strong predictor of the development of pouchitis after a total proctocolectomy and ileoanal pouch procedure. In summary, involvement of both the appendix and the cecal or ascending colon can occur in patients with subtotal colitis. This phenomenon should be recognized by pathologists as an acceptable potential skip lesion in UC.

Initial Presentation of Ulcerative Colitis in Pediatric Patients

Several recent studies have shown that pediatric patients with untreated UC at presentation may show evidence of relative, or even complete, rectal sparing or patchy colonic disease. Markowitz and co-workers reported on 12 pediatric patients with untreated UC, 5 (42%) of whom showed patchy, mild active inflammation and mild crypt changes in rectal, compared with proximal, colonic biopsy specimens. One patient had a completely normal rectal biopsy specimen. A study by Glickman and associates compared the rectal mucosal biopsy appearance of 70 pediatric patients who had UC with that of 44 adult patients, all at initial presentation before treatment. Compared with adults, pediatric patients showed significantly fewer cases of chronic active disease and a greater number of patients with microscopic skip areas and relative rectal sparing. Two of the 70 pediatric patients had completely normal rectal biopsy specimens at initial presentation, in contrast to none of the adult patients. Therefore, an absence of features of chronicity or the presence of mild active disease and microscopic skip areas at initial presentation in pediatric patients does not exclude a diagnosis of UC. In adults, relative (but not absolute) rectal sparing (i.e., less severe inflammation in the rectum compared with the proximal colon) may be seen, rarely, at initial presentation before treatment. In one study, a 31% prevalence rate of relative rectal sparing was noted in a series of 46 adult patients with UC at initial presentation, but even in those cases, histologic features of chronicity were almost always present in rectal mucosa at the time of initial diagnosis.

Ileitis in Ulcerative Colitis

Patients with severe pancolitis, including involvement of the cecum and ileocecal valve, may show a mild degree of active inflammation in the distal few centimeters of terminal ileum; this is presumably related to inflammation-induced incompetence of the ileocecal valve and subsequent reflux of colonic contents, termed backwash ileitis . Pathologic criteria for backwash ileitis were defined in 2005. Haskell and colleagues reviewed 200 UC resection specimens and found active ileitis in 17%, confined in most cases to the distal 1 cm of ileum. Ninety percent of the cases consisted of mild, patchy neutrophilic inflammation in the lamina propria, focal cryptitis or crypt abscesses, and patchy villous atrophy and regenerative changes ( Fig. 17.18, A ). In rare instances, surface ulceration or even pyloric (mucous gland) metaplasia was present (see Fig 17.18, B ). In their study, a backwash mechanism for ileitis in UC was questioned in some cases that showed lack of cecal involvement (or only mild inflammation in the cecum) and patchy or discontinuous ileal involvement. These cases may have resulted from a drug effect or bowel preparation effect. Nevertheless, ileal findings such as crypt architectural distortion, fissuring ulceration, submucosal inflammation, granulomas, or greater lengths of ileal involvement (>5 cm) should raise a strong suspicion for CD, particularly if the patient does not have severe disease up to and involving the proximal cecum and ileocecal valve. More recently, in a large case-control study, Arrossi and associates evaluated pouch outcome in patients with UC and IBD of indeterminate type and reported that the presence of backwash ileitis was not a significant risk factor for the development of pouchitis.

Backwash ileitis. A, The small bowel mucosa shows expansion of the lamina propria by neutrophils, eosinophils, and plasma cells. There is mild villous blunting. In some cases, pyloric gland metaplasia ( B ) may be present.

Rarely, premalignant dysplastic changes and even adenocarcinoma have been shown to develop in the setting of backwash ileitis. Heuschen and colleagues found a strong association between backwash ileitis and the development of colorectal cancer in patients with UC who had undergone proctocolectomy. However, discrete pathologic criteria for backwash ileitis were not defined, and it is likely that most of the patients in whom cancer developed had CD. Neither Haskell’s nor Arrossi’s group found an increased risk for dysplasia or cancer in patients who had UC with ileitis, compared with those without ileitis.

Other factors may also lead to the development of active inflammation in the distal ileum (active ileitis) in UC, including infections, drugs (e.g., nonsteroidal antiinflammatory drugs [NSAIDs]), and, most commonly, the effects of certain bowel preparatory agents. It has been speculated that the ileum may be involved by UC in some cases, but this is controversial. In a study consisting of 50 patients with active UC, 16% of patients had ileal inflammation but without involvement of the cecum, indicating that backwash was not the cause of the ileitis (“non-backwash ileitis”). These patients had higher levels of ileal inflammatory cytokines (IL6, IL8, and tumor necrosis factor-α [TNF-α]) and, more commonly, had extraintestinal manifestations of UC (e.g., arthritis, pyoderma gangrenosum) at presentation. This condition should not be confused with CD of the terminal ileum. In CD, the distal ileum typically shows longer lengths of involvement (often >5 cm) and is associated with histologic features of chronicity, such as pyloric gland metaplasia, ulceration, and established radiologic abnormalities.

Upper GI Involvement in Ulcerative Colitis

Gastric or duodenal involvement, or both, has been rarely reported in association with clinically and pathologically confirmed UC. A study by Valdez and co-workers described four patients with chronic active inflammation in the duodenum similar in appearance to the patients’ colonic disease. In another study, five patients had chronic active gastritis and four had chronic active duodenitis; in these cases, the upper GI findings resolved after colectomy. Several similar cases have been reported in the Japanese literature. In a recent study by Lin and colleagues, esophageal, gastric, and duodenal biopsies from 69 patients with proven UC were compared with those of 97 control subjects. The most common pattern of inflammation in the upper GI tract was “focal gastritis,” followed by mixed inflammation in the basal aspect of gastric mucosa and superficial plasmacytosis. Diffuse chronic duodenitis was observed in 10% of UC patients, even after colectomy. The authors did not find specific mucosal changes in esophageal biopsy specimens from patients with UC. Until such cases have been followed for longer periods, it is difficult to know whether upper GI involvement in UC represents a manifestation of the primary inflammatory disorder or simply an unidentified, but unrelated, inflammatory disorder. Precise characterization of these cases with long-term follow-up is needed to help establish specific criteria for upper GI involvement in patients with UC.

Crohn’s-Like Aphthous Ulcers in Ulcerative Colitis

Although aphthous ulcers are characteristic of CD, they may occur in other types of colitides and even in UC. They have been reported in infectious colitis, diverticular disease, and diversion colitis, among other conditions. In one study, aphthous-type ulcers were present in 17% of UC resection specimens. In that study, manifestations of CD did not develop in any of the patients, nor was the presence of aphthous ulcers associated with the subsequent development of pouchitis.

Granulomas in Ulcerative Colitis

Some cases of active UC may show granulomas in association with ruptured crypts (see Fig. 17.13 ). This finding may be prominent and may involve many crypts at the base of the mucosa. Granulomas may also develop in UC from unrelated causes, such as degenerated collagen, particulate matter, superimposed infections, or as a result of drug reaction. In equivocal cases, mucin granulomas related to ruptured crypts may be distinguished from granulomas in CD by use of histochemical stains or evaluation of multiple deep tissue sections. In general, granulomas present in the superficial mucosa (and certainly in the submucosa) are more likely to be CD related than basal mucosal granulomas, which are often crypt related.

Genetic Factors

The relative risk of development of IBD among first-degree relatives of patients with CD is 14 to 15 times higher than in the general population. Ethnicity also appears to play a significant role. Eastern European (Ashkenazi) Jews have a twofold to fourfold higher risk for CD than non-Jews from the same geographic location. Further support for a genetic predisposition is provided by data on monozygotic and dizygotic twins. The concordance rate for CD is 67% among monozygotic twins and 8% among dizygotic twins, suggesting a strong genetic influence. Although results are inconsistent and vary with the population being studied, numerous studies have found both positive and negative associations between HLA antigens and the development of CD.

Genome-wide association studies and computerized meta-analyses have identified 71 susceptibility loci for CD on 17 chromosomes thus far. Three important pathways have been highlighted by these studies. The first susceptibility locus was identified in 2001 as nucleotide-binding oligodimerization domain 2 ( NOD2 ) or caspase-recruitment domain 15 ( CARD15 ). A homozygous carrier of disease-specific allelic variants has a 17.1-fold increased risk for CD, whereas the odds ratio for a heterozygous carrier is 2.5. Genetic polymorphisms in NOD2/CARD15 are present in 20% to 30% of patients with CD, and the abnormalities correlate with younger age at onset, ileal location of disease, and an increased likelihood of stricture formation. NOD2/CARD15 mutations are more common in white patients with CD but are rare in Asians and Africans. The NOD2/CARD15 gene product binds to muramyl dipeptide, a component of bacterial peptidoglycan found in both gram-positive and gram-negative bacteria. NOD2/CARD1 is expressed in Paneth cells that produce endogenous antimicrobial peptides known as defensins. NOD2/CARD15 gene variants interfere with binding to muramyl peptide, resulting in decreased antibacterial defense.

The second important pathway implicated in CD pathogenesis is related to autophagy, a unique process by which cytoplasmic constituents are isolated within a membrane-bound vesicle and then delivered to lysosomes for elimination. Misfolded or misaggregated proteins are eliminated via this pathway without inciting an inflammatory or autoimmune response. Variants in at least two autophagy-related genes have been associated with CD—namely, autophagy-related 16-like 1 ( ATG16L1 ) and immunity-related guanosine triphosphatase family member M ( IRGM ) gene on chromosome 5.

The third pathway associated with CD is related to IL23. IL23 is a cytokine produced by dendritic cells and macrophages in response to various antigenic signals. In response to IL-6 and transforming growth factor-β (TGF-β), naïve CD4+ T cells upregulate IL23 receptor (IL23R), which results in autocrine generation of effector T cells that produce IL17. Although most common single nucleotide polymorphisms (SNPs) in the IL23R gene are associated with an increased risk for CD and UC, rare variants appear to be protective against the development of CD.

Environmental Factors

The gradually rising incidence of CD has also been attributed to a variety of environmental factors. Higher socioeconomic status, use of oral contraceptives, NSAIDs use, increased intake of refined sugars, and decreased intake of dietary fiber have all been implicated as risk factors for CD. Zinc deficiency is associated with immunologic dysfunction in patients with CD, and some data suggest that an elemental diet may improve CD by reducing intestinal permeability.

In contrast to UC, CD is more prevalent among smokers. Smoking is an independent risk factor for clinical, surgical, and endoscopic recurrences in CD and also appears to influence disease activity after surgery. Although the pathogenesis is unclear, it is believed that smoking causes alteration of intestinal permeability, induces cytokine production, and promotes production of microvascular thrombi.

Immune Factors

Interaction of effector T cells and antigen-presenting cells is vital to the pathogenesis of CD. Processing of luminal antigens by dendritic cells located within the lamina propria and the subsequent interaction between MHC class II molecules and T-cell receptors leads to activation and differentiation of T cells. The helper T-cell Th1 and Th17 responses that characterize CD are influenced by cytokines IL23, IL6, and TGF-β. Within mononuclear cells, NF-κB plays a key role in regulating transcription of IL1, IL6, IL8, TNF, and other peptides that generate an inflammatory response. TNF is not only essential in formation of granulomas but also causes neutrophil activation and, along with interferon-γ, induces expression of MHC class II on intestinal epithelial cells.

TNF and other proinflammatory cytokines also promote expression of adhesion molecules on endothelial cells, which leads to trafficking of inflammatory cells into mucosa. Integrins α ₄ β ₇ and α _E β ₇ have ligands (mucosal addressin cellular adhesion molecule and E-cadherin, respectively) that are specific to the intestinal environment. Antibodies to the α ₄ subunit of integrin have a therapeutic role in the management of CD.

Tissue destruction (especially penetrating ulcers, fistulas, and sinuses) ultimately results when proinflammatory substances such as prostaglandins and matrix metalloproteinases are elaborated by mononuclear cells and granulocytes. Mural fibrosis, another characteristic finding of CD, is a result of TGF-β that is released in the presence of inflammation. It stimulates production of type III collagen, which not only promotes healing of ulcers but also contributes to the formation of strictures. Fat wrapping (“creeping fat”) is an indicator of transmural disease that is often identified intraoperatively. It results from upregulation of peroxisome proliferator–activated receptor-γ (PPAR-γ), which regulates homeostasis of adipose tissue. Histologically, the finding of pyloric gland metaplasia in the lower GI tract indicates chronic mucosal injury. Pyloric glands are a form of ulcer-associated cell lineage (UACL); they represent bud-like glandular structures that develop from the base of intestinal crypts at sites of chronic ulceration. The UACL expresses a variety of peptides implicated in the repair of damaged GI mucosa, notably epidermal growth factor and members of the trefoil peptide family, which restores epithelium in areas of mucosal ulceration.

The pathophysiology of diarrhea in CD is related to multiple factors. Increased mucosal permeability because of inflammation and production of prostaglandins, biogenic amines, neuropeptides, and reactive oxygen metabolites results in exudation of proteins and fluids. Bacterial overgrowth and altered colonic mobility in areas of strictured bowel also contribute to diarrhea.

Gross Features

CD is characterized by segmental involvement of the affected areas of bowel, although pancolitis may occur in a small proportion of cases ( Fig. 17.19, A ). The serosal surface often appears congested and may be covered with a fibrinous exudate. Fat wrapping (creeping fat) along the antimesenteric border is a common finding in CD. In contrast to UC, the bowel wall in CD is typically thickened. It does not lie flat on opening. Mucosal aphthous ulcers overlying lymphoid aggregates are an early feature of CD. A zone of hyperemia often surrounds larger ulcers. As the disease progresses, ulcers enlarge to form discontinuous, serpiginous, or bearclaw-type longitudinal furrows (see Fig. 17.19, B ). Areas of edematous, mildly inflamed, or even normal mucosa are located between areas of longitudinal ulcers; this results in the development of a cobblestone appearance of the mucosa. Inflammatory pseudopolyps are most commonly encountered in the transverse colon and splenic flexure. In segments of bowel involved by disease, the wall of the bowel is usually thick and fibrotic. Fissures, sinus and fistulous tracts, and mural or pericolonic abscesses may be present in complicated cases.

A, Gross specimen of Crohn’s colitis showing segmental (patchy) distribution of disease in the right colon. B, The affected segment shows deep longitudinal ulcers with a cobblestone appearance of the mucosa.

Strictures are more common with long-standing disease. Depending on the degree of obstruction, the bowel wall proximal to the stricture may be secondarily dilated and congested ( Fig. 17.20 ). Perforations are uncommon in CD, occurring only in 1% to 3% of cases. They occur as a result of superimposed ischemia or infection or as a complication of fissures, sinus tracts, or fistulas. Fibrous adhesions may seal off sites of perforation, so they may not be visible upon gross examination of the bowel.

Gross specimen of Crohn’s colitis showing stricture formation with dilatation of the proximal colonic segment ( left aspect of specimen).

Microscopic Features

Mucosal Changes.

Similar to UC, and depending on the phase of disease, the mucosa may show a wide spectrum of changes ranging from completely normal to diffuse and severe chronic active inflammation with ulceration. In biopsies, mucosal disease is categorized similar to UC: chronic inactive, chronic active, or active (see earlier discussion). Histologic features of chronicity include crypt architectural distortion, crypt atrophy, diffuse mixed lamina propria inflammation, basal plasmacytosis, basally located lymphoid aggregates, pyloric gland metaplasia, and Paneth cell metaplasia (in the left colon). Other changes of chronicity include lamina propria fibrosis and Paneth cell hyperplasia in the right colon. “Activity” is characterized by the presence of neutrophilic or eosinophilic cryptitis, crypt abscesses, regenerative or degenerative epithelial changes, necrosis, erosions, and ulceration. The degree of activity is graded as mild if less than 50% of the mucosa shows evidence of activity, moderate if more than 50% of the mucosa shows these features, and severe if surface erosion or ulceration is present.

In active CD, the disease may be patchy, with foci of injured and inflamed crypts situated adjacent to completely normal crypts. Two types of ulcers are characteristic of active CD—aphthous and fissuring ulcers. Aphthous ulcers arise in focal, mildly active CD. They are well-delineated, small, and superficial lesions that overlie lymphoid aggregates. They usually involve a length of mucosa occupied by two to four crypts. The earliest stage is a mild neutrophilic infiltrate in the superficial half of the lymphoid aggregate. Neutrophils infiltrate the crypts and form small basilar crypt abscesses, producing epithelial necrosis and an intraluminal exudate ( Fig. 17.21 ). Concomitant neutrophilic infiltration and erosion of the superficial epithelium develops into a small microabscess that covers the lymphoid aggregate as the ulcer expands. Irregularly shaped crypts with regenerative epithelial changes are typically found at the edges of older (healing) ulcers. Aphthous ulcers can continue to expand and connect to form serpiginous or longitudinally oriented ulcers.

Aphthous ulcer in Crohn’s colitis. Neutrophilic inflammation involves the epithelium overlying lymphoid aggregates, which leads to ulceration ( arrow ).

Crypt disarray is a feature of mucosal involvement in CD, similar to UC. There is significant variation in the size and shape of crypts. Features such as crypt branching and shortening are most easily appreciated at medium or low magnification ( Fig. 17.22 ). Heterogeneity in the density and distribution of lymphoplasmacytic inflammation within the lamina propria is a common finding in CD, as it is in UC. Well-circumscribed, focal collections of lymphocytes that surround several crypts (lymphoid aggregates) simulate normal lymphoid follicles. However, lymphoid aggregates in CD may reveal crypts within their center, whereas in normal lymphoid follicles, the crypts are pushed toward the periphery.

Active Crohn’s colitis with diffuse mixed inflammation, crypt architectural distortion, prominent mucosal and submucosal lymphoid aggregates, thickened muscularis mucosae, fibrosis, and perivascular lymphoid aggregates.

Although non-necrotizing epithelioid granulomas are characteristic of CD, they are neither specific nor sensitive for this diagnosis. The prevalence of granulomas in endoscopic biopsy samples ranges from 13% to 50%; in resections, it ranges from 40% to 60%. Granulomas are more frequently encountered early in the course of disease. They are typically sarcoid-like, composed of aggregates of epithelioid histiocytes admixed with lymphocytes and neutrophils ( Fig. 17.23 ). Occasionally, giant cells are present. In some cases, they may be very sparse and poorly formed, consisting only of small, pericryptal collections of closely arranged histiocytes, referred to as pericryptal microgranulomas . Serial step sections enhance the likelihood of detecting pericryptal microgranulomas. They may be present in involved as well as in uninvolved segments of colon. They may be present in any layer of the bowel wall or within pericolonic lymph nodes ( Fig. 17.24 ).

Crohn’s colitis with a well-formed epithelioid granuloma in the lamina propria, not associated with a ruptured crypt.

Crohn’s colitis with granulomas within pericolonic lymph nodes.

Granulomas in CD should be distinguished from mucin granulomas that form around ruptured crypts, which is common in UC. Macrophages within mucin granulomas usually have a greater amount of bubbly or clear cytoplasm, which is caused by phagocytosis of mucin and crypt contents. Foreign body giant cells usually are not a component of CD-related granulomas, but they may be found in mucin granulomas. Mucin stains are not helpful, because a small amount of mucin may also be present in the cytoplasm of macrophages in CD-related granulomas. Thick-walled capillaries, pericryptal fibroblastic sheaths, and tangential sections of germinal centers may mimic the well-formed granulomas of CD. The presence of necrotizing granulomas or a large number of granulomas should prompt a work-up for an infectious etiology such as tuberculosis, histoplasmosis, yersiniosis, or sarcoidosis.

Pyloric gland metaplasia is far more common in CD than in UC, and it is frequently present in the small bowel. In colonic CD, pyloric gland metaplasia is more common in the cecum and right colon ( Fig. 17.25 ).

Chronic Crohn’s colitis with pyloric gland metaplasia.

Mural Changes.

Among the common mural changes of CD are knife like fissuring ulcers and sinus tracts, which typically occur at right angles to the longitudinal axis of the bowel. They may extend through the bowel wall and may develop into a fistula or result in pericolonic abscess formation ( Fig. 17.26 ). They are usually lined by acute inflammatory cells, necrotic and granulation tissue, and loose aggregates of epithelioid histiocytes resembling early granulomas. Multinucleate giant cells may be present as well. Dense lymphoid aggregates, with or without germinal centers, are usually found at the mucosal-submucosal junction. However, transmural lymphoid aggregates that are located in the deeper aspects of the bowel wall, including the subserosal adipose tissue (“Crohn’s rosary”), are characteristic of CD ( Figs. 17.27 and 17.28 ). These are defined as collections of predominantly small, mature-appearing lymphocytes of variable size that are distributed throughout the bowel wall. Some cases of CD show prominent perivascular lymphoid aggregates, which may or may not be associated with granulomas, particularly in the submucosa. This feature has led some authorities to postulate that CD may represent a vascular disorder.

Crohn’s colitis with deep fissuring ulcers.

Chronic active Crohn’s colitis associated with abundant transmural lymphoid aggregates.

Crohn’s colitis associated with serosal-based lymphoid aggregates. Deep lymphoid aggregates located at the junction of the muscularis propria and subserosal adipose tissue give rise to a characteristic serosal “beading” pattern, also known as “Crohn’s rosary.”

Abnormalities in the smooth muscle, such as splaying and hypertrophy of muscularis mucosae and distortion (and hypertrophy) of the muscularis propria, are common in long-standing CD. Proliferation of smooth muscle that obliterates the submucosa (“muscularization of submucosa”) occurs more commonly in stricturing CD. CD also affects the neural tissue. There is both hypertrophy of nerve trunks and an increase in the number of ganglion cells. Large, abnormal fusiform nerve bundles may be seen throughout the affected bowel wall. Additionally, the myenteric plexuses may show infiltration by lymphocytes (“myenteric plexitis”) ( Fig. 17.29 ). Some studies have shown that myenteric plexitis in the proximal margins of an ileocolonic resection is more likely to be present in resection specimens of patients with a previous surgery for CD and of those with a shorter duration of disease before surgery. The severity of inflammation also appears to correlate with severity of endoscopic recurrence.

Crohn’s colitis with neural hyperplasia. Lymphocytes and plasma cells also infiltrate the myenteric plexuses (myenteric plexitis).

Some studies suggest that colonic CD less frequently shows major pathologic features than does ileal CD. A recent study by Soucy and colleagues showed that patients with isolated CD had significantly fewer major pathologic features of CD, such as strictures/stenosis, pericolonic adhesions, segmental disease, the finding of proximal disease worse than distal disease, perivascular lymphoid aggregates, and pyloric gland metaplasia, compared with those with ileal CD. A small proportion of patients from both groups showed inflammatory changes limited to the mucosa, similar to what is seen in UC (see later discussion).

Resection Specimens

UC characteristically involves the mucosa in a diffuse and continuous manner. It almost always affects the rectum. The terminal ileum may be affected to a lesser degree and exclusively in patients with pancolitis (i.e., backwash ileitis). Infections, drug or medication-related injury (e.g., NSAIDs), and bowel preparation agents can also result in inflammation of the terminal ileum. In contrast, CD shows segmental or patchy involvement of the bowel and often affects longer lengths of terminal ileum, both actively as well as chronically. In a resection specimen, a diagnosis of UC is usually established by the presence of diffuse chronic active colitis or chronic inactive colitis involving the mucosa in the absence of mural changes typical of CD, such as fissuring ulcers, transmural lymphoid aggregates, non–mucin-related granulomas, mural fibrosis, and fistulas or sinus tracts. Neural hyperplasia, hyperplasia of muscularis mucosae, and submucosal fibrosis are also less common in UC than in CD. In addition, involvement of other regions of the GI tract, especially perianal disease, is a sign of CD. Upper GI involvement in UC has been described, but it is unclear whether these changes are specific to UC or represent a nonspecific systemic immune response to a generalized inflammatory condition. A summary of the classic microscopic features of UC and CD is provided in Table 17.2 .

Because most resections are performed for medically refractory disease or disease-related complications and therefore have been treated medically, both UC and CD may show patchy, or segmental, histologic changes. One may also see a reduction in the amount of transmural inflammation in CD. Granulomas are also far less common after treatment.

Biopsy Specimens—Untreated

UC and CD demonstrate considerable overlap in morphologic features in biopsy samples with chronic and/or active disease. Furthermore, because the characteristic features of CD are typically found deeper in the bowel wall, it is difficult or impossible to distinguish UC from CD based solely on analysis of mucosal biopsy specimens. However, in untreated cases, features in favor of CD are granulomas not associated with crypt rupture, longer segments of small bowel involvement, upper GI involvement, rectal sparing, fistulas, and perianal disease.

Biopsy Specimens—Treated

After therapy, uneven healing and therapeutic effects of drugs used for the disease cause the histologic features of UC to become patchy, mimicking CD (see Unusual Morphologic Variants of Ulcerative Colitis ). In this setting, one cannot consider patchiness of disease or rectal sparing as a feature indicative of CD. In treated patients, unless there is evidence of anal or perianal IBD, granulomas unrelated to ruptured crypts, or definite chronic active ileal or upper GI involvement confirmed radiologically, it is almost impossible to distinguish UC from CD.

Morphologic Types of Dysplasia

Morphologic subtypes of dysplasia include intestinal (“adenomatous”), hypermucinous/villous, and serrated dysplasia. Some patients show a mixture of subtypes in the same patient (“mixed”). In one study of IBD cancers, 52% of dysplastic lesions were villous, 29% were serrated, 5% were tubular (adenomatous), and 13% showed mixed features. Only the intestinal type of dysplasia has been well characterized both histologically and clinically, however, and the following discussion applies mainly to that type.

Grading of Dysplasia

According to the grading system proposed by Riddell and colleagues in 1983, dysplastic changes in UC and CD are separated into three distinct categories: negative for dysplasia, indefinite for dysplasia, and positive for dysplasia (low and high grade). The Vienna grading system, which denotes five diagnostic categories, is used by many pathologists in Japan and Europe. A comparison of the two systems is outlined in Table 17.3 . Both adenoma-like and non–adenoma-like lesions are graded in the same manner as flat dysplasia.

Grade of dysplasia is determined by evaluating a combination of cytologic and architectural alterations of the epithelium. A diagnosis of “negative” is reserved for nondysplastic, regenerating epithelium ( Fig. 17.34 ).

A, Chronic inactive colitis showing colonic mucosa with complete surface maturation, considered negative for dysplasia. B, An area of marked active inflammation with erosion and a monolayer of epithelial cells show regenerative changes. The stromal cells can also show cytologic atypia. “Bizarre” (reactive) stromal cells should not be mistaken for sarcoma. C, Regenerating epithelium can also show nuclear stratification and hyperchromasia that may be mistaken for dysplasia.

Cases are considered indefinite for dysplasia when cytologic features of atypical epithelium approach or meet the criteria for low-grade dysplasia but, because of other factors such as inflammation, ulceration, or technical artifacts, that diagnosis cannot be established with certainty ( Fig. 17.35 ). Inflammation and ulceration make interpretation of atypical changes difficult (i.e., reactive versus neoplastic). Regenerating epithelium often shows enlarged and variably sized nuclei, nuclear stratification, prominent nucleoli, and mitoses. These changes overlap with those observed in true dysplasia. In some cases, tangential sectioning of the tissue or severe cautery or processing artifact may render an atypical focus difficult to interpret. In general, surface maturation is usually indicative of a regenerative process. This feature should evoke caution in diagnosing dysplasia ( Table 17.4 ).

Ulcerative colitis graded indefinite for dysplasia. A, Colonic biopsy specimen shows crypts lined by cells with enlarged, hyperchromatic nuclei. However, the lack of surface epithelium in this fragment precludes evaluation of surface maturation. Therefore, the case is best classified as indefinite for dysplasia. B, The colonic epithelium in this biopsy specimen shows nuclear hyperchromasia and stratification at the surface. However, these changes are associated with surface erosion on one part of the sample and prominent active inflammation. The latter finding indicates the possibility of reepithelialization of the mucosa, and therefore the case is best categorized as indefinite for dysplasia. C, Another example of a case considered indefinite for dysplasia. Villiform mucosal architecture, stratification, and nuclear hyperchromasia and enlargement are present. However, these changes are adjacent to an erosion, and there is at least partial surface maturation in some of the crypts.

In low-grade dysplasia, crypts show a tubular and/or villous configuration and may also demonstrate mild crypt budding and crowding. Cytologically, dysplastic crypts are lined by cells that show nuclear enlargement, elongation (“pencillate”), increased nucleus–to-cytoplasm (N : C) ratio, hyperchromasia, stratification, clumped chromatin pattern, single or multiple nucleoli, and hypereosinophilic, mucin-depleted cytoplasm ( Fig. 17.36 ). Dysplastic epithelium normally involves both the crypt and surface epithelium, but early cases may show involvement of crypts only (“crypt dysplasia”; see later discussion). Mitotic figures are often plentiful, but atypical mitotic figures are less common. In low-grade dysplasia, the nuclei are usually limited to the basal half of the cell cytoplasm, and there are no significant architectural abnormalities such as glandular crowding, cribriforming, or a back-to-back pattern. Other, less common features of low-grade dysplasia include dystrophic goblet cells and endocrine and Paneth cell metaplasia.

Low-grade dysplasia ( A, low-magnification; B, high-magnification). The crypts are lined by cells that demonstrate nuclear hyperchromasia, stratification, and enlargement. Increased mitoses are observed, and there is a distinct lack of surface maturation.

With progression from low-grade to high-grade dysplasia, the cells acquire more cytologic atypia, characterized by markedly enlarged, pleomorphic, hyperchromatic nuclei and loss of nuclear polarity ( Fig. 17.37 ). The nuclei typically show a more “open” chromatin pattern with prominent nucleoli. Full-thickness nuclear stratification is usually present. Architecturally, back-to-back glands or cribriforming may be present. Mitotic figures, both typical and atypical, are more frequent and are usually present in both the upper and lower portions of the crypts and in the surface epithelium. In general, the features of the most atypical portion of dysplastic mucosa determine the overall grade of dysplasia in any particular biopsy sample. However, there is no uniform agreement regarding the proportion of high-grade dysplastic crypts that is necessary to upgrade a biopsy from low to high grade. A simple rule of thumb is that there should be more than one or two (i.e., more than rare) high-grade crypts to designate a biopsy as high grade, but this number varies among expert pathologists.

High-grade dysplasia. A, At low power, the dysplastic crypts show irregular budding and a back-to-back glandular arrangement. B, The cytologic features of high-grade dysplasia include marked nuclear enlargement and hyperchromasia, full-thickness stratification of nuclei (not seen in this case), increased pleomorphism, and a loss of cell polarity. There is no evidence of surface maturation. C, Ulceration in an area of high-grade dysplasia. D, Another example of high-grade dysplasia shows full-thickness nuclear stratification with cytologic atypia. The dysplastic crypts are crowded and show glandular budding.

Intramucosal carcinoma is defined by the presence of cells or glands that have penetrated into but not beyond the lamina propria or muscularis mucosae. Common patterns of early invasion include single-cell or small-gland infiltration, glands with irregular jagged contours, and extensive cribriforming with pushing borders. Desmoplasia is absent when the carcinoma is limited to the mucosa, and it’s presence is diagnostic of submucosal invasion ( Fig. 17.38 ).

Invasive adenocarcinoma in a biopsy specimen from a patient with long-standing ulcerative colitis. The infiltrating neoplastic glands are surrounded by desmoplastic stroma.

Nonintestinal Types of Dysplasia

Mucinous Dysplasia.

Rarely, IBD-associated dysplasia shows predominantly mucinous epithelium that may be difficult to recognize as unequivocally neoplastic. This type of dysplasia often exhibits a villiform growth pattern. The epithelium shows small, hyperchromatic, basally oriented nuclei with little cytologic atypia. This form of dysplasia has been referred to by a variety of names, such as “villous dysplasia,” or “villous hypermucinous mucosa,” and it may be associated with either UC or CD ( Fig. 17.39 ). Purely mucinous epithelium is rare in UC or CD. Therefore, the presence of mucinous epithelium, particularly if it is villiform in contour, should raise a strong suspicion for dysplasia. The natural history and biologic characteristics of mucinous dysplasia are currently unknown.

Mucinous dysplasia. A, The mucosa shows prominent villiform architecture. B, Higher magnification shows that the individual cells contain small, hyperchromatic, basally located nuclei with minimal cytologic atypia.

Serrated Dysplasia and Other Serrated Lesions.

In some studies of UC, serrated dysplasia has represented the most common type of dysplasia. It is characterized by the presence of epithelium with a serrated or saw-toothed appearance. It usually shows a predominance of nongoblet cells. The epithelial cells show nuclear enlargement, stratification, irregular nuclear membranes, hypereosinophilic cytoplasm, and prominent nucleoli. The cytologic and architectural features are reminiscent of traditional serrated adenomas or, in some cases, a sessile serrated adenoma/polyp (SSA/P) ( Figs. 17.40 and 17.41 ). High-grade cytologic changes are uncommon in this type of dysplasia.

Serrated dysplasia in ulcerative colitis. The crypts show a serrated architecture and are lined by cells with eosinophilic cytoplasm and slightly enlarged nuclei.

Mixed serrated and conventional (intestinal-type) dysplasia in ulcerative colitis. The left half of the mucosa in this image shows serrated dysplasia characterized by crypts with serrated architecture. The epithelial cells show hypereosinophilic cytoplasm with mild nuclear enlargement and hyperchromasia. In contrast, the right half of the mucosa shows features of low-grade intestinal-type dysplasia with enlarged, hyperchromatic, and pseudostratified nuclei.

A spectrum of serrated lesions develops in the colon in some patients, ranging from conventional hyperplastic polyps ( Fig. 17.42, A ) to SSA/Ps (see Fig. 17.42, B ) and traditional serrated adenomas (TSAs). The morphologic features of these lesions in IBD are similar to those that occur in non-IBD patients (see Chapter 22 for details).

Hyperplastic polyp in a patient with ulcerative colitis. A, Sessile serrated adenoma/polyp in a patient with ulcerative colitis. B, The crypts show serrated architecture, basal dilatation, and abnormal growth (“boot” or “anchor”-shaped crypts). They are lined by cells with slight nuclear stratification and hypereosinophilic cytoplasm.

Little is known regarding the biologic characteristics and natural history of serrated lesions in IBD. In a large clinicopathologic and outcome study published in abstract form, 188 polyps from 161 IBD patients with at least one serrated polyp were analyzed. Most were hyperplastic polyps (97%) that were detected microscopically, not endoscopically. Adenocarcinoma, adenoma, or flat or elevated dysplasia did not develop in any of the patients, but additional hyperplastic or inflammatory polyps developed in 33% of the patients. In a retrospective study consisting of 94 patients with hyperplastic polyp-like changes in biopsies of flat mucosa obtained during routine surveillance (“flat serrated change”), the authors found that although 12.8% of these patients had subsequent dysplasia (DALM, low-grade dysplasia, or high-grade dysplasia) on follow-up, a multivariate analysis did not show a statistically significant difference in the risk between patients with and without these lesions. Based on these results, the authors suggested that there should be no change in routine surveillance protocols for patients with flat serrated change. One recent study, published only in abstract form, evaluated serrated lesions in 56 UC and 19 CD patients and classified them as SSA/P-like (negative for dysplasia), TSA-like (positive for low-grade dysplasia), and cytologically atypical hyperplasia-like (indefinite for dysplasia). The authors found that SSA/P-like polyps in IBD occurred preferentially in females and in the right colon, similar to sporadic polyps. However, they were not associated with synchronous or metachronous neoplasia over a follow-up period of 91 months. In contrast, TSA-like and cytologically atypical hyperplasia-like polyps were significantly associated with synchronous or metachronous neoplasia (low-grade dysplasia in 21, high-grade dysplasia in 7, and invasive adenocarcinoma in 5).

Finally, IBD patients may rarely show a spectrum of hyperplastic and serrated lesions in their colon, reminiscent of serrated polyposis syndrome. In one study by Srivastava and colleagues, three patients with IBD (UC in 2, CD in 1) developed a spectrum of serrated lesions ranging from hyperplastic polyps to sessile serrated adenomas/polyps and TSAs in large numbers throughout the colon. Two of the three patients had adenocarcinoma. These findings suggest that the presence of multiple, large, serrated lesions in a patient with IBD should prompt close surveillance for synchronous or metachronous carcinoma.

Crypt Dysplasia.

Although better characterized in patient with Barrett’s esophagus, rarely patients with IBD may develop early dysplastic changes limited to the bases of the crypts without involvement of the surface epithelium (i.e., surface maturation is present). This is known as crypt dysplasia ( Fig. 17.43 ). In our experience, most patients with crypt dysplasia reveal conventional dysplasia (involving both crypt and surface epithelium) elsewhere in the colon at the time of discovery of crypt dysplasia. Because crypt regeneration also shows surface maturation, a diagnosis of crypt dysplasia should not be made in biopsy specimens exhibiting inflammation or ulceration, nor in those that are not well oriented. At this time, the biologic characteristics and natural history of crypt dysplasia in IBD are unknown.

Crypt dysplasia in a patient with Crohn’s colitis. Colonic mucosa shows nuclear hyperchromasia, stratification, and enlargement involving the basal crypts ( A ); however, there is no involvement of the surface epithelium (i.e., surface maturation is present) ( B ).

Campylobacter jenuni

C. jejuni is one of the most frequently isolated stool pathogens in patients with ASLC. In immunocompromised patients, Campylobacter fetus is more frequently isolated. The incidence of C. jejuni –related diarrhea is 4% to 11% in the United States. Bacterial transmission usually occurs via contaminated food. In developing countries, the infection is hyperendemic in children younger than 2 years of age. The most common presenting symptoms are diarrhea (90%), fever (90%), and abdominal pain (70%). These may be accompanied by headache, myalgia, and vomiting. Stool examination typically reveals red blood cells and leukocytes. Campylobacter DNA may be isolated in as many as 19% of affected patients with acute-onset diarrhea.

Salmonella Species

At least 2000 serotypes of non- typhoid Salmonella species have been identified as potential causative agents of gastroenteritis (nontyphoid salmonellosis). Almost 45,000 cases of salmonella gastroenteritis are reported annually. In the United States, Salmonella enteritidis and Salmonella typhimurium are the most commonly isolated species. Infection is most likely to develop in children younger than 1 year of age. In addition, patients with achlorhydria, hemolytic anemia, immunosuppression, or malignancy (e.g., disseminated carcinoma, hematolymphoid malignancies) are predisposed to Salmonella infection. Gastroenteritis develops in 75% of patients infected with this organism. Patients usually present with nausea, vomiting, fever, and bloody diarrhea.

Shigella Species

Shigella infection is the most common cause of bacillary dysentery. The first documentation of shigellosis-related GI illness dates back to the American Civil War period. Currently, the incidence of shigellosis worldwide is reported to be 10% to 20% of infectious diarrhea. Although it is more common in tropical countries and temperate zones, its prevalence in the United States and Europe is increasing. In fact, the incidence of Shigella sonnei (which is more common in the United States than Shigella flexneri ) is 60% to 80% in patients with diarrhea. The infection is common in children aged 6 months to 5 years. Microbiology laboratory workers are also at risk. The clinical presentation consists of lower abdominal pain, rectal burning, bloody diarrhea, and fever. A biphasic illness is characteristic. The initial phase of infection is characterized by fever, abdominal pain, and watery diarrhea, which, after 3 to 5 days, is usually followed by tenesmus and small-volume bloody diarrhea. Very rarely, patients have an acute abdomen secondary to perforation. Presence of red blood cells and leukocytes in stool is a common finding. Stool cultures are often positive during the first few days of infection.

Escherichia coli

Although six major strains of E. coli have been implicated in human diarrheal disease, only two specific strains, enteroinvasive E. coli (EIEC) and enterohemorrhagic E. coli (EHEC), invade the colonic tissue and cause ASLC. In the United States, EHEC O157:H7 is the pathogenic strain most commonly isolated from stools of patients with bloody diarrhea. Consumption of infected hamburger meat is a common mode of disease transmission. The disease is most common in Northern climates such as Minnesota, Massachusetts, and the U.S. Pacific Northwest. Clinical symptoms for both EIEC and EHEC begin with watery diarrhea and fever, which is usually followed by 3 to 8 days of bloody diarrhea. Stool examination shows red and white blood cells. Peripheral blood examination often reveals leukocytosis with an increased number of immature white blood cells. Radiologic examination during the first week of illness may reveal a thumbprinting sign, which is the result of subepithelial edema and hemorrhage. Stool cultures are very helpful in establishing a definite diagnosis. Occasionally, polymerase chain reaction (PCR) and EIA testing for Shiga-like toxins may be necessary to confirm the diagnosis.

Yersinia enterocolitica

Y. enterocolitica causes a spectrum of clinical illnesses that range from mild gastroenteritis to invasive ileitis and colitis. In comparison to the United States, Y. enterocolitica gastroenteritis is far more common in Scandinavian and European countries. The serotypes prevalent in these countries also differ. Strain O:8 is more common in the United States, whereas O:3 and O:9 are more prevalent in Scandinavian and European countries. Almost two thirds of infections involve both the small bowel and colon (enterocolitis). Children younger than 5 years of age are commonly affected. Clinical symptoms last for 1 to 3 weeks and include fever, abdominal pain, and bloody diarrhea. As with other causes of ASLC, stool analysis often reveals the presence of blood and leukocytes. Stool culture and serologic studies may be helpful to establish a diagnosis. Radiologic findings in cases of mild gastroenteritis are nonspecific. In severe cases, the radiologic changes may mimic CD.

Tissue-Invasive Organisms

C. jejuni , Salmonella and Shigella species , E. coli, and Y. enterocolitica are organisms that invade the tissue and cause epithelial injury and death. Tissue invasion also results in the production of inflammatory cytokines that trigger an acute inflammatory reaction. In addition to tissue invasion, Shigella species undergo intracellular multiplication that allows for transmission of the infection into adjacent epithelial cells. In cases of Salmonella or Y. enterocolitica infection, organisms invade the lamina propria and submucosa and disseminate to extraintestinal sites via the bloodstream. Increased intracellular calcium and release of prostaglandin and leukotriene metabolites, serotonin, substance P, and reactive oxygen metabolites contribute to increased fluid output from epithelial cells.

Toxigenic Organisms

Enterotoxins are polypeptides secreted by bacteria that alter the transport of electrolytes and water through colonocytes without causing cellular injury. Shigella , enterotoxigenic E. coli (ETEC), Staphylococcus aureus , Clostridium perfringens, and Vibrio cholera are most associated with toxin production. Binding of enterotoxins to specific mucosal receptors causes decreased influx of sodium and chloride ions into the cells and active secretion of chloride ions from cells into the intestinal lumen. Thus, enterotoxins are responsible for the acute phase of illness. Clinical symptoms are a result of fluid and electrolyte disturbances.

Cytotoxins are polypeptides that cause tissue injury by inhibiting protein synthesis, disrupting actin and tight junction integrity, damaging mitochondria, and depleting adenosine triphosphate (ATP) within cells. Organisms that elaborate cytotoxins include C. difficile , enteropathogenic E. coli (EPEC), EHEC, and Shigella . In addition, EHEC also produces an enterohemolysin that causes endothelial damage. Endothelial injury results in initiation of the coagulation cascade that ultimately leads to an ischemic colitis–pattern of tissue injury.

Gross Findings

Grossly, the colonic mucosa may show minimal changes such as patchy edema, erythema, loss of the normal vascular pattern, and superficial erosions or ulcers. In severe cases, large segments of colon may show mucosal friability and ulceration. Some organisms reveal characteristic endoscopic findings. For instance, C. jejuni can affect any part of the colon; typically, the mucosa shows numerous, superficial ulcers that range from 2 mm to 1 cm in size. Salmonella species may produce hemorrhagic mucosa with granularity, friability, and ulceration; very rarely, toxic megacolon may develop. The colon is the major site of involvement in cases of Shigella infection; in most cases, the colonic mucosa shows patchy involvement by small, ragged ulcers with normal intervening mucosa. Aphthous ulcers may also be present. If only the rectosigmoid region is involved, mucosal involvement is usually continuous and consists of diffuse areas of ulceration and granularity. EHEC O157:H7 infection is usually segmental; infection results in friable, erythematous, and edematous mucosa with superficial ulcers. The right colon is more commonly involved than the transverse or the left colon. Pseudomembranes may develop in severe cases ( Fig. 17.45 ). Y. enterocolitica tends to affect the proximal more that the distal colon. The mucosa may appear edematous with patchy or diffuse areas of superficial erosions. Pseudomembranes and perforation are uncommon in the early phase of infection.

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