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Epidemiology, Pathogenesis, and Diagnosis of Inflammatory Bowel Diseases
IBD comprises conditions characterized by chronic or relapsing immune activation and inflammation within the GI tract. Crohn disease (CD) and UC are the 2 major forms of IBD; less common, but increasingly recognized, are the microscopic colitides, primarily collagenous colitis and lymphocytic colitis (see Chapter 128 ). Other chronic inflammatory conditions of the intestine share some features of presentation and pathogenesis with IBD, but they have identifiable etiologies; examples of these disorders include diversion colitis, infection (e.g., intestinal TB), radiation colitis, and drug-induced colitis (see Chapter 128 ).
The 2 major forms of IBD share many clinical and epidemiologic characteristics, suggesting that underlying causes may be similar. In approximately 10% of cases, CD cannot be distinguished from UC on clinical grounds (see “IBD-U” discussed later), although the 2 diseases are most often considered distinct syndromes with divergent treatments and prognoses.
CD is a chronic inflammatory disorder that may involve any part of the alimentary tract from the mouth to the anus, but with a propensity for the distal small intestine and proximal colon. In contrast, UC only affects the colon and rectum. Inflammation in CD often is discontinuous along the longitudinal axis of the intestine and may involve all bowel layers from mucosa to serosa, whereas in UC, inflammation starts in the rectum, is continuous, and is superficial, only affecting the epithelial layer of the mucosa. Affected persons with CD usually experience diarrhea and abdominal pain, frequently accompanied by weight loss. Patients with UC will often experience bloody diarrhea with urgency. CD, in distinction to UC, may manifest unique complications such as strictures and fistulas, which often necessitate surgery. Numerous extraintestinal manifestations also may be present in patients with IBD, regardless of whether CD or UC. The etiology of IBD is incompletely understood, but is generally believed to be related to immune dysregulation triggered by the intestinal microbiota influenced by environmental exposures in genetically susceptible individuals. Medical therapy for IBD is aimed at control of inflammation and improvement of symptoms, but is not curative.
Epidemiology
The first reports of IBD predominantly occurred following the Industrial Revolution in the Western world. Sir Samuel Wilks described IBD in 1859 when he wrote about “idiopathic colitis” and recognized it as distinct from the then much more common bacillary dysentery; he also reported the pathologic finding of a dilated and thinned colon with severe pancolonic inflammation which today we recognize as toxic megacolon. In 1875, Dr. Wilks introduced the term “UC” into the medical vernacular. A disease that was not recognized a generation earlier now was emerging in epidemic proportions. By 1909, the Royal Society of Medicine held a symposium to review hundreds of cases of UC hospitalized in London, England. Sir William Allchin addressed the symposium, stating, “UC is a provisional title and its future retention or rejection will be determined by a clearing up of certain points in connexion with the natural history of the disease.” The incidence of UC rose rapidly in North America and Europe throughout the first few decades of the 1900s. In the early 20th century, inflammation of the ileum challenged the notion of isolated colonic involvement in UC. In 1913 T. K. Dalziel published a case series of patients with inflammation in their small bowel that preceded the Burrill Crohn, Leon Ginzburg, and Gordon Oppenheimer landmark study in 1932 describing granulomatous inflammation of the terminal ileum that they named regional ileitis, and which was subsequently called “Crohn disease.”
Following the 1950s, the incidence of IBD accelerated rapidly in portions of the Western world (North America, Europe and Australia). A systematic review of over 200 population-based studies performed during the 20th century revealed that ¾ of studies on CD and two-thirds of studies on UC demonstrated statistically significant increasing incidence. Initially, UC was more commonly diagnosed than CD, however, in the latter half of the 20th century, the diagnosis of CD caught up to, and in several regions surpassed, the diagnosis of UC in the Western world. An updated systematic review showed a dramatic change in the incidence of IBD at the turn of the 21st century in the Western world: over three-fourth of studies showed that the incidence of IBD in the Western world had stabilized, and in some regions was decreasing. From 1990 to 2015, most studies in the Western world reported that the incidence of both CD and UC were in a range between 5 and 15 per 100,000. Although some countries reported higher incidence rates, the ceiling for both the incidences of CD and UC was between 20 and 30 per 100,000 ( Fig. 115.1 ).
The decades of rising incidence of IBD in the Western world during the 20th century resulted in a steady increase in the prevalence of IBD. This is because of the medically incurable nature of IBD primarily diagnosed in young individuals, and the fact that the incidence of new cases outpaces mortality. For example, Olmsted County, Minnesota, in the USA has tracked the prevalence of IBD for more than 5 decades, during which time the prevalence of CD rose from 28 per 100,000 in 1965 to 246.7 per 100,000 in 2011. In the 21st century, the prevalence of IBD exceeds 0.3% in North America, Western Europe, and Australia. Canada and Scandinavia have the highest reported prevalence. A national Canadian study demonstrated that the prevalence of IBD was 0.5% in 2008, and forecasting models predicted that the prevalence to be 0.75% in 2020, and approaching 1.0% of the national population by 2030. The rising prevalence of IBD will be a major challenge for the health infrastructure of the Western world.
IBD can be diagnosed at any age, although the most common ages of diagnosis are in adolescence and early adulthood. Whereas the incidence of IBD is stabilizing in many Western regions, the incidence of IBD in children has shown different patterns. For unexplained reasons, the incidence of IBD in children under 10 years of age, and particularly under 6 years of age (very early onset IBD), is increasing in certain regions of the Western world. Moreover, seniors with IBD are a rapidly growing population, due to a combination of new diagnoses of IBD in older adults and the advancing age of patients with IBD who were diagnosed earlier in adulthood. Over the next decade, GI clinics in the Western world will face a juxtaposition of diagnosing young individuals with IBD while caring for an older IBD population.
Population-based data on the incidence or prevalence of IBD during the 20th century were sparse from regions outside the Western world. Limited data from Asia, Africa, and Latin America suggested that during the 20th century the occurrence of IBD was low in countries outside the Western world. Although IBD was primarily diagnosed in Caucasians, individuals of all ethnicities were susceptible to IBD. Immigration studies demonstrated that individuals moving from low-prevalence regions (e.g., Southeast Asia) to high-prevalence regions were at increased risk of developing IBD. The risk was particularly pronounced in first and second generation offspring of immigrants. At the turn of the 21st century, the evolution of IBD had manifest global spread, with newly industrialized countries in Asia, Africa, and Latin America reporting rapidly rising incidences. For example, in Seoul, Latin Korea, the incidence of CD and UC rose from 1991 to 2005 by 14% and 10%, respectively. The explanation for the dramatic rise in the incidence of IBD outside the Western world is multifactorial and includes increased awareness of IBD, advances in health care infrastructure, improved access to health care, development of disease surveillance systems to track the incidence of IBD, and presumably exposure to environmental risk factors for IBD that are associated with westernization of a newly industrialized society. IBD is a global disease today.
Etiology and Pathogenesis
The etiology of IBD is currently unknown but appears to be multifactorial. The current hypothesis is that CD and UC result from overly aggressive T-cell mediated immune responses to specific components of the intestinal microbiota in genetically susceptible individuals, and that disease expression is triggered by additional environmental factors. Dysregulation or constitutive activation of the enteric immune response leads to the development of acute and chronic inflammation and the pathologic features of mucosal damage. The specific inciting antigens for the inflammatory process have yet to be identified, but several sources have been suggested including pathogenic and commensal microorganisms ( Fig. 115.2 ).
Genetics
Family History
Familial aggregation of IBD was first reported in the 1930s. The relative risk among first-degree relatives of subjects with IBD is 8 to 10 times higher than that of the general population. Roughly 1 in 5 patients with CD report having at least one affected relative. Many families have more than one affected member, and although there is a tendency within families for either CD or UC to be present exclusively, mixed kindreds also occur.
Ethnicity also plays a role. Eastern European (Ashkenazi) Jews are at a 2- to 4-fold higher risk of developing IBD than non-Jewish Caucasians of the same geographic location, and they also are at greater risk of having multiple affected family members. Studies of monozygotic and dizygotic twins suggest that genetic composition is a more powerful determinant for CD than for UC. The concordance rate among monozygotic twins is as high as 67% for CD but only 13% to 20% for UC ; in one study, a lower rate of concordance for CD has been reported among monozygotic twins. In 3 large European twin pair studies, approximately 6% to 16% of monozygotic twin pairs had concordant UC compared with 0% to 5% of dizygotic twin pairs. Most studies have described concordance of disease location and disease behavior, supporting the supposition that there is a genetic component to these characteristics of the diseases.
Susceptibility Genes
The inheritance of CD and UC cannot be described by a simple Mendelian genetics model. Multiple genes are involved and different genes confer susceptibility, disease specificity, and phenotype. A landmark study combining data from more than 75,000 cases of CD and UC, controls, and results from 15 genome-wide association (GWA) studies reported a total of 163 loci that may confer increased risk for the development of IBD. Thirty of these loci are specific to CD and 23 to UC. These loci are thought to account for 13.6% of the disease variance of CD and 7.5% of the disease variance of UC. Interestingly, 113 of the 163 loci are associated with other immune diseases, most strongly with psoriasis and ankylosing spondylitis. Susceptibility loci for IBD are also shared with primary immunodeficiencies and mycobacterial infections. These results suggest that rather than being separate diseases, CD and UC are part of the same spectrum of disease. They also suggest that many immune diseases and even susceptibility to certain infections may be part of a disease continuum that reflects immune response to environmental triggers.
Due to genetic associations related to disease location, a genotype-phenotype association study proposed that IBD be considered as 3 conditions rather than 2: ileal CD, colonic CD, and UC. In addition, genome-wide genetic correlation between PSC and UC was significantly greater than that between PSC and CD.
GWA studies have identified genes associated with susceptibility to mycobacterial infections, such as leprosy and tuberculosis. Mycobacterium tuberculosis susceptibility genes include VDR , which encodes the vitamin D receptor, providing a possible link with epidemiologic data that negatively associate risk of CD with sunlight and vitamin D exposure.
The findings of GWA studies in CD and IBD generally support a connection between disease susceptibility and host interactions with microbes. This is exemplified in the first described susceptibility locus for CD. The NOD2 ( N ucleotide-binding O ligomerization D omain containing 2) gene, also known as CARD15 ( CA spase- R ecruitment D omain 15) was identified in 2001. The allelic variants most commonly associated with CD in European and American populations include one frameshift insertion leading to early truncation of the protein (Leu1007fsinsC) and 2 missense mutations (Arg702Trp, Gly908Arg). Carriage of disease-associated allelic variants on both chromosomes confers an odds ratio for CD of 17.1 (95% confidence interval [CI], 10.7 to 27.2), whereas heterozygotes have an odds ratio of 2.5 (95% CI, 2.0 to 2.9) for the disease. Genetic polymorphisms of NOD2/CARD15 have been associated with younger onset, ileal location of disease, and increased likelihood of stricture formation. It has been estimated that as many as 20% to 30% of patients with CD have abnormal NOD2/CARD15 . Nevertheless, penetrance of NOD2/CARD15 is not more than 5% of individuals bearing 2 copies of disease-associated polymorphisms, and roughly 0.5% in heterozygous persons, indicating that disease-related allelic variants of the gene may be found in a large number of people who do not have CD.
The discovery of the association of NOD2/CARD15 with CD has opened a remarkable window into our understanding of the pathogenesis of CD. The gene product of NOD2/CARD15 is a cytosolic protein that functions as an intracellular sensor of bacteria. Specifically, this protein binds to muramyl dipeptide (MDP; MurNAc-L-Ala-D-isoGln), a component of bacterial peptidoglycan, found in gram-positive and gram-negative bacteria. The NOD2/CARD15 protein is expressed in a wide diversity of cells, including macrophages, lymphocytes, fibroblasts, and intestinal epithelial cells, specifically Paneth cells, which lie within the crypts and produce endogenous antimicrobial peptides called defensins. The NOD2/CARD15 gene consists of 2 CARD domains, a nucleotide binding domain, and 10 leucine-rich repeats (LRR). NOD2/CARD15 variants associated with CD lie within the LRR and interfere with binding to MDP. In mononuclear cells, mutations in NOD2 result in decreased activation of nuclear factor (NF)-κB, whereas an excess of NF-κB expression is observed in tissue inflamed by CD. This apparent paradox has yet to be unraveled completely, but it is clear that defects in NOD2 impair antibacterial responses, particularly to oral exposure to pathogens. Notably, Paneth cell-production of β-defensins is defective in CD patients with variant NOD2 . These findings strongly implicate defects in innate immunity—the immediate and nonspecific immune responses to microbial infection—in a subset of patients with CD, with subsequent chronic activation of adaptive immunity, the antigen-specific responses mediated by APCs and T cells.
Beyond NOD2 , multiple genetic defects in the autophagy pathway also provide a link to defective host-microbe interactions and have been implicated in CD. Autophagy is an ancient cellular process, highly conserved in evolution, by which segments of cytoplasm are isolated within a membrane and delivered to lysosomes (or “inflammasomes”) by mechanisms that do not involve transport through endocytic or vacuolar sorting pathways. This unique process plays a role in cellular homeostasis by clearing proteins that are long-lived, misfolded, or aggregated, and by clearing apoptotic bodies, which might otherwise trigger inflammation and autoimmunity. Autophagy has been shown to contribute directly to innate immunity through direct killing of pathogens; activation of Toll-like and NOD-like receptors, which are pattern recognition receptors that activate the innate immune response; and elaboration of immunomodulatory cytokines such as interferon (IFN)-γ. Autophagy also stands at the interface of innate and adaptive immune responses, delivering antigen to HLA class II molecules in APCs for antigen-specific binding.
GWA studies have identified variants that predispose to CD in at least 2 autophagy-related genes. The first, the autophagy-related 16-like 1 ( ATG16L1 ) gene, was noted as having a disease-associated single nucleotide polymorphism (SNP) that encodes an amino acid substitution in exon 8, resulting in a change from alanine to threonine ; this minor allele is protective against CD. ATG16L1 is expressed by intestinal epithelial cells, APCs, and various subsets of human T cells. The second autophagy gene associated with CD is the IRGM (immunity-related GTPase [guanosine triphosphatase] family member M) gene on chromosome 5q33.1. It has been suggested that the disease-associated variants of this gene do not affect the amino acid sequence of its product, but they more likely alter its expression. IRGM appears to be important in resistance to intracellular pathogens such as mycobacteria, Listeria monocytogenes , and Toxoplasma gondii .
A third pathway associated with CD is IL-23 and the gene products associated with this protein. IL-23 is a heterodimeric cytokine comprising 2 linked subunits (p19 and p40). IL-23 is produced by many cell types, including dendritic cells and macrophages, in response to diverse microbial signals. Naïve CD4 + T cells up-regulate IL-23 receptor when exposed to IL-6 and transforming growth factor (TGF)-β, completing an autocrine loop in the generation of Th17 T cells, effector T cells that produce IL-17. A rare variant of the IL23R gene leading to a glutamine at position 381 rather than an arginine is strongly protective for CD; other, more common SNPs are associated with increased risk for CD and UC. In the same pathway, variants of the IL12B gene, encoding the p40 subunit common to IL-12 and IL-23, and of the JAK2 and STAT3 genes, with roles in IL23R signaling, as well as in Th17 differentiation in the case of STAT3 , also have been associated with CD susceptibility. Together, these findings support the pivotal role of this pathway in maintaining mucosal homeostasis in the normal intestine.
In UC, specific loci have been identified on chromosomes 1-7, 11, 15-17, 19, and 20. The NOD2 / CARD15 gene mutations located on chromosome 16 associated with CD have not been associated with UC, although UC patients from families with a history of CD and UC may possess NOD2 variants, which might suggest that their diagnosis of UC should be reconsidered. Further, patients with UC undergoing colectomy with ileal pouch-anal anastomosis who carried the NOD2insC polymorphism were more likely to be diagnosed with chronic pouchitis or a CD-like phenotype than those carrying the wildtype NOD2 gene. ATG16L1 is not seen in patients with UC, whereas another autophagy gene, IRGM is shared between diseases; both of these genes are involved in bacterial processing and the protection of cells from various bacterial pathogens and their toxins (i.e., autophagy). A number of CD loci or genes (or both) have been identified in UC, however, and include IL-23R on chromosome 1p31, which encodes the interleukin (IL)-23 receptor; chromosome 3p21, which encodes MST1 and other potential genes of interest; IL-12β on chromosome 5q33, which encodes the IL-12 receptor β1 subunit (also known as p40) that constitutes part of both the IL-23 and IL-12 receptors; NKX2-3 on chromosome 10q24, which encodes NK2 transcription factor related, locus 3; and chromosome 17q21, which encodes STAT3 and other potential genes of interest. With respect to the gene encoding IL-23R, several polymorphisms of this gene have been identified, most notably the Arg381Gln polymorphism. Heterozygous carriage of the glutamine allele is associated with a 3-fold decreased risk of CD and a more modest reduction in the risk of UC in non-Jewish populations; this reduction is not seen in UC within the Jewish population. IL-23R is important because it plays a key role in the differentiation of a subset of T cells called Th17 cells .
In a trans-ancestry genetic association study of IBD in 86,640 Europeans and 9846 individuals of East Asian, Indian or Iranian descent, 38 risk loci were identified, increasing the number of known IBD risk loci to 200. The majority of these loci are shared across diverse ancestry groups, with only a handful demonstrating population-specific effects driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM) (see Fig. 115.2 ).
Very early onset IBD (VEOIBD) refers to children diagnosed with IBD before the age of 6 years. VEOIBD has been increasingly recognized with rising incidence. The heritability of VEOIBD is believed to be higher than in adolescents and adults diagnosed with IBD. Several monogenic mutations have been attributed to VEOIBD, including the interleukin 10 (IL10) and IL10 receptor genes and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex genes, such as neutrophil cytosolic factor 2 (NCF2). Table 115.1 provides a list of monogenic defects that have been associated with clinical manifestations of IBD. The diagnosis of monogenic disorders should be suspected when IBD is diagnosed at an early age (e.g., infancy), is associated with a strong family history–in particular consanguinity, is resistant to conventional therapies, has severe presentations such as perianal fistula, and associated conditions of autoimmunity. Diagnosing a monogenic disorder in VEOIBD includes functional screening with genetic confirmation. Several research groups have suggested specialist genetic testing in VEOIBD using contemporary methods of next generation sequencing with targeted gene panel or whole exome sequencing. An algorithmic approach to monogenic diagnosis is presented in Figure 115.3 .
TABLE 115.1
Monogenic Diseases Associated With IBD-Like Clinical Manifestations Stratified by Mechanism
IPEX, Immunodysregulation, Polyendocrinopathy, and enteropathy, X-linked; MASP, Mannon-binding Lectin Serine Protease
| Mechanism | Syndrome or Disorder | Genes |
|---|---|---|
| Defects in immune inhibitory mechanisms or immunoregulation | Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome | FOXP3 |
| IPEX-like | IL2RA, STAT1 | |
| IL-10 signaling defects | IL10RA, IL10RB, IL10 | |
| Disruption of epithelial barrier or epithelial response | Dystrophic bullosa | COL7A1 |
| Kindler syndrome | FERMT1 | |
| X-linked ectodermal immunodeficiency | IKBKG | |
| TTC7A deficiency | TTC7A | |
| ADAM17 deficiency | ADAM17 | |
| Familial diarrhea | GUCY2C | |
| Disrupted T- and B-cell selection and activation | Combined variable immunodeficiency 1 | ICOS |
| Combined variable immunodeficiency 8 | LRBA | |
| IL-21 deficiency | IL21 | |
| Agammaglobulinemia | BTK, PIK3R1 | |
| Hyper IgM syndrome | CD40LG, AICDA | |
| Wiskott–Aldrich syndrome | WAS | |
| Omenn syndrome | DCLRE1C | |
| Severe combined immunodeficiency | IL2RG, LIG4, ADA, CD3ϒ, | |
| Hoyeraal-Hreidarsson syndrome | DKC1, RTEL1 | |
| Hyper IgE syndrome | DOCK8 | |
| Hyperinflammatory and autoinflammatory disorders | Mevalonate kinase deficiency | MVK |
| Phospholipase C-γ2 defects | PLCG2 | |
| Familial Mediterranean fever | MEFV | |
| Familial hemophagocytic lymphohistiocytosis type 5 | STXBP2 | |
| X-linked lymphoproliferative syndrome 2 (XLP2) | XIAP | |
| X-linked lymphoproliferative syndrome 1 (XLP1) | SH2D1A | |
| Hermansky-Pudlak 1 | HPS1 | |
| Hermansky-Pudlak 4 | HPS4 | |
| Hermansky-Pudlak 6 | HPS6 | |
| Reduced clearance of bacteria by phagocyte defects | Chronic granulomatous disease | CYBB, CYBA, NCF1, NCF2, NCF4 |
| Glycogen storage disease type 1b | SLC37A4 | |
| Congenital neutropenia | G6PC3 | |
| Leukocyte adhesion deficiency 1 | ITGB2 | |
| Others | MASP deficiency | MASP2 |
| Trichohepatoenteric syndrome | SKIV2L, TTC37 |
Uhlig HH, Schwerd T, Loletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 2014; 147(5):990–1007.
Environmental Factors
Even with notable progress in GWA studies, identified genetic risk factors account at best for 25% of the estimated heritability for IBD in the European ancestry populations. More rare genetic variants of new or already identified loci may yet be discovered, but it is clear that environmental factors also are important. As noted earlier, the rising incidence of CD and UC over many decades, and in developing countries, strongly suggests an environmental contribution to the expression of disease.
The Hygiene Hypothesis may explain the emergence of IBD. Children raised with limited exposure to microbes in relatively sterile environments do not adequately prime their immune system for processing microorganisms. Consequently, later in life, their immune response inappropriately attacks their organs following exposure to pathogenic microorganisms. The Hygiene Hypothesis is supported by indirect evidence including studies demonstrating that CD and UC are less likely to occur in persons living in rural areas or on a farm, raised in large families, exposed to pets in childhood, and who drink unpasteurized milk. Further, individuals who experience a GI infection are more likely to develop IBD later in life; this is particularly true among children diagnosed with IBD. With a greater appreciation of the role of the microbiome in the pathogenesis of IBD, the Hygiene Hypothesis is being re-evaluated in the context of early-life exposures that influence the composition and diversity of the microbiome in children. Research supporting this context have shown that IBD is more likely to occur among infants who are prescribed antibiotics in the first year of life and who are predominantly bottle-fed. In Asia, where the incidence of IBD has accelerated since the turn of the 21st century, breastfeeding was highly protective against the development of IBD. Collectively, these studies are demonstrating the intricate relationship between environmental exposures, the intestinal microbiome, and the onset of IBD.
Several other environmental risk factors have been associated with CD and UC of which the most extensively studied is smoking. Numerous studies conducted in the Western world have consistently demonstrated that individuals who smoke are more likely to be diagnosed with CD, and those who quit smoking are at increased risk of developing UC. Moreover, adults with CD who continue to smoke are more likely to require intestinal resections and smoking cessation is a well-recognized therapeutic intervention for CD. In contrast, smoking was not a risk factor for the development of CD when evaluated in multiple countries across Asia, a finding highlighting the heterogeneity of environmental risk factors in different regions of the world. Oral contraceptive pills have also been implicated with the development of CD, particularly among smokers. In addition, NSAIDs have been associated with the development of IBD, and may trigger flares. Children and adolescents experiencing appendicitis are less likely to be diagnosed with UC. IBD occurs more commonly in countries of northern latitudes, which has been postulated to be related to vitamin D deficiency from less sun exposure.
Western diets composed of low fiber, and higher consumption of red meat, fats and refined sugars and reduced consumption of dietary fiber are associated with the development of IBD, presumably by influencing the composition and diversity of the intestinal microbiome. Animal studies suggest that food additives such as sweeteners and emulsifiers also may incite inflammation in the bowel. The association between fast food consumption and IBD may result from exposure to fatty foods or food additives, or indirectly through reduced levels of physical activity in the population that consumes fast foods ( Fig. 115.4 ).
A growing body of literature has evaluated an association between psychiatric illness and the development and worsening of prognosis of IBD. A systematic review concluded that patients with IBD are more likely to suffer from depression and anxiety compared with healthy controls. Depression is the most commonly associated psychologic condition, although cohort studies suggest associations with anxiety and bipolar disorders. However, controversies in the literature exist; for example, the Nurses’ Health Study observed a relationship between depression and CD, but not UC. Also, a large Danish study did not observe an increased risk of IBD among parents who experienced the loss of a child. Moreover, a recent cohort study suggests that treating depressed patients with antidepressants may mitigate the risk of developing IBD. In a population-based registry of individuals with known IBD, there was a strong relationship between perceived stress and GI symptoms in both patients with CD and UC, but the perceived stress was not related to concurrent intestinal inflammation based on measurement of fecal calprotectin.
Immunobiology
Intestinal Microbiota
In light of the nature of the pathologic findings in CD and UC, it has long been clear that IBD represents a state of sustained immune response. The question arises as to whether this is an appropriate response to an unrecognized pathogen or an inappropriate response to an innocuous stimulus. Many infectious agents have been proposed as the cause of CD, including Mycobacterium paratuberculosis , chlamydia, Listeria monocytogenes , cell-wall-deficient Pseudomonas species, reovirus, and many others. A proposed association between early measles vaccination and CD has been disproved. Another suggestion has been that the commensal flora, although normal in speciation, possess more subtle virulence factors, such as enteroadherence, that may cause or contribute to the onset of IBD.
Among the most enduring hypotheses is that Mycobacterium avium subspecies paratuberculosis (MAP) has been implicated as an etiologic agent in CD. This notion dates to Dalziel’s observation in 1913 that idiopathic granulomatous enterocolitis in humans is similar to Johne disease, a granulomatous bowel disease of ruminants caused by M. paratubercu. Most investigation in this area, to date, has been inconclusive, providing insufficient evidence to prove or reject the hypothesis. A randomized controlled trial comparing combination antibiotics (e.g., clarithromycin, rifabutin, and clofazimine) that are believed to target MAP to placebo was negative.
Numerous clinical and experimental observations have suggested involvement of the intestinal bacterial microbiota in the pathogenesis of IBD. The most obvious observation is that CD and UC preferentially occur in regions of the bowel that contain the highest concentration of bacteria, namely, the terminal ileum and the colon, where bacterial concentrations approach 10 12 organisms per gram of lumenal contents. Interestingly, diverting the fecal stream in patients with CD can treat and even prevent disease, whereas reinfusion of ileostomy contents leads to new inflammatory changes within only one week. Other human data have shown that antibiotics are useful in the treatment or postoperative prevention of CD and pouchitis. Finally, probiotics have been shown to have efficacy in the primary and secondary prevention of pouchitis. The most glaring evidence of the necessary role of bacteria in the pathogenesis of IBD derives from rodent data showing that genetically susceptible mice or rats in a gnotobiotic (germ-free) environment do not have intestinal inflammation; however, these same rodents rapidly develop intestinal inflammation after bacterial colonization. Just as in humans, rodent intestinal inflammation can be treated and prevented with antibiotics and probiotics.
Intestinal microbiome dysbiosis has been consistently described in patients with IBD. Dysbiosis can be a cause as well as an outcome of IBD. Specific characteristic alterations in IBD include decreased bacterial diversity, with expansion of putative aggressive groups (e.g., Proteobacteria, Fusobacterium species, and Ruminococcus gnavus ), accompanied by decreases in protective groups (e.g., Lachnospiraceae, Bifidobacterium species, Roseburia, and Sutterella) (see Figs. 115.2 and 115.4 ). This dysbiosis is present at early stages of disease, even before patients have been treated. Primarily, there is a notable reduction in Firmicutes. One bacterium in particular, Faecalibacterium prausnitzii , a member of the Firmicutes phylum and Clostridia class of organisms has been shown to be depleted in the ileocolonic mucosa of patients with CD. Adherent-invasive Escherichia coli (AIEC), which can adhere to intestinal epithelial cells via FimH and cell adhesion molecule and escape autophagy when inside macrophages, also has been implicated in the pathogenesis of CD. More recently, Proteus species (Phylum, Proteobacteria; Enterobacteriaceae family) have been identified as potential pathogen in CD recurrence after intestinal resection. Proteus species possess many virulence factors potentially relevant to GI pathogenicity, including motility; adherence; the production of urease, hemolysins, and IgA proteases; and the ability to acquire antibiotic resistance. Apart from dysbiosis of the intestinal bacteria, emerging evidence suggest that viruses and fungi also can contribute to the development of CD and UC. Patients with IBD harbor an expansion of fecal caudovirales viruses, alterations in mucosa virobiota with functional distortion and dysbiosis in the fungome communities.
In light of the diversity of substances and bacteria within the intestinal lumen, it is remarkable that the intestine is not perpetually inflamed. The presence of low-level physiologic inflammation within the healthy intestinal mucosa represents a state of preparedness to deal with potentially harmful agents. A more vigorous response would not be appropriate if directed toward the innocuous commensal flora of the intestine. Experiments in animal models of IBD suggest that in a genetically susceptible host, a classic pathogen is not necessary to cause IBD, but rather commensal enteric flora are sufficient to induce an inappropriate chronic inflammatory response. In diverse models, animals raised under germ-free conditions show diminished or delayed expression of the IBD phenotype. Such models suggest that a diversity of genetic alterations, including those that affect intestinal barrier function and regulation of mucosal immunity, can result in intestinal inflammation. As in the animal models of IBD, evidence in patients with CD also points to an over-responsiveness of mucosal T cells to the enteric flora, manifest in part by the presence of antibodies against an array of bacterial antigens. Patients with CD who have disease-associated polymorphisms of the NOD2 gene and their unaffected relatives have increased levels of antibodies against bacterial antigens such as E. coli outer membrane porin C (OmpC) and flagellin (see Figs. 115.2 and 115.4 ).
Intestinal Immune System
In IBD, breaches in a well-regulated mucosal immune system lead to chronic, uncontrolled mucosal inflammation. Lumenal antigens gain access to the underlying intestinal tissue via a “leaky” gut. Innate and adaptive immune cells express a number of molecular pattern-recognition receptors. Microbial antigens from commensal organisms trigger and maintain an inflammatory response through several different pathways leading to a change in their functional status from immune tolerance to activation and inflammation with differentiation of naive T cells into effector T cells (Th1, Th17, and Th2) and natural killer T cells. Intestinal epithelial cells also express co-stimulatory molecules which enable them to function as APCs and further contributes to the effector T-cell response in IBD (see Fig. 115.2 ).
Epithelial Barrier
Intestinal epithelial cells are the first line of defense of the mucosal immune system. Colonocytes express class II MHC antigens and can function as APCs. In addition, they also express cytokine receptors, secrete various cytokines and chemokines, and express leukocyte adhesion molecules. Thus abnormalities in colonic epithelial cells may contribute to the development of IBD. Patients with UC have an increased turnover rate of colonic epithelium and other abnormalities of epithelial cells including reduced metabolism of short-chain fatty acids, especially butyrate; abnormal membrane permeability ; and altered composition of glycoprotein mucus produced by the colonic epithelium. Specifically, the mucus layer in UC appears to be thinner than normal. In patients with UC, these and other abnormalities can lead to finding increased numbers of adherent bacteria, in both the mucus layer and even at the epithelial surface. The role of epithelial cells in the pathogenesis of IBD is further supported by animal models of colitis produced by disruption of colonic epithelium. The small intestine also contains specialized epithelial cells known as Paneth cells that play an important role in innate intestinal defenses as regulators of microbial density and in protecting nearby stem cells by production of antimicrobial proteins, such as defensins, which have broad activities in-vitro against Gram-positive and Gram-negative bacteria in CD. Disruption of the mucus layer by emulsifiers, which are ubiquitous in western and now global diets, or by mutations in the MUC2 gene, might promote bacterial translocation and has been associated with IBD (see Fig. 115.2 ).
Antigen Recognition and Immunoregulation
The interaction between effector T cells and APCs is critical to the pathogenesis of IBD (see Fig. 115.2 ). The antigens that perpetuate the inflammatory response are taken up by APCs. Degradation of antigen within proteasomes results in presentation of an epitope in the context of MHC class II. Interaction between MHC class II and the T-cell receptor (CD3) results in antigen-specific interaction between the macrophage and the CD4 + T cell. This event is necessary but not sufficient to activate the T cell. A second co-stimulatory signal is needed as well, because binding of CD3 to MHC class II without a co-stimulatory signal can result in anergy or apoptosis. Important co-stimulatory signals include binding of TNF to TNF receptor, CD40 to CD40 ligand, and B7 to CD28.
Inflammation normally is kept in check through an active process termed immune tolerance. The nature of the co-stimulatory signal, the type of APC, and the cytokine milieu influence the differentiation of T cells into populations of effector T cells, which are involved in harmful immune responses, and regulatory T cells, which ameliorate the immune response. Dendritic cells in the lamina propria actively sample the lumenal contents and play a particularly vital role as key APCs capable of shaping the immune response.
As noted earlier, the p40 subunit is common to IL-12 and IL-23, each of which, in turn, is critical in shaping the Th1 and Th17 responses that characterize CD. In addition to IL-23, the presence of TGF-β and IL-6 facilitate differentiation of naïve T cells into pathogenic Th17 cells. Activated APCs further shape and amplify the immune response by producing the T-cell growth factor IL-2 and the proinflammatory cytokines IL-1 and TNF. Within mononuclear cells, the key nuclear transcription factor is NF-κB, which regulates the transcription of IL-1, IL-6, IL-8, TNF, and other peptides central to the inflammatory response.
In addition to being essential to the formation of granulomas, TNF causes neutrophil activation and, along with IFN-γ, induces the expression of MHC class II on intestinal epithelial cells. Moreover, TNF and other proinflammatory cytokines contribute to the expression of adhesion molecules on the endothelial cells of the intestinal vasculature (see Fig. 115.2 ).
Immune Cell Homing to the Intestinal Mucosa
Expression of adhesion molecules is critical to amplify the immune response. Adhesion molecules on the leukocyte surface and their ligands on the endothelium of venules in the lamina propria interact in a coordinated multistep process that permits trafficking of inflammatory cells into the mucosa. First, a weak interaction between selectins on the leukocyte surface and the endothelium leads to rolling of the leukocytes along the endothelium. Second, in the presence of chemokines, such as IL-8, activation occurs and integrins are expressed on the leukocyte surface. Third, interactions between leukocyte integrins and immunoglobulin-like cellular adhesion molecules (CAMs) on the endothelial surface lead to spreading of the cell and diapedesis. Specificity is conferred by the presence of tissue-specific CAMs. The integrins α 4 β 7 and αEβ 7 are of special importance in IBD, because the corresponding ligands—mucosal addressin CAM and E-cadherin—are intestine specific. Mucosal addressin CAM is expressed constitutively on the endothelium of venules in the lamina propria, whereas binding of αEβ 7 on intestinal lymphocytes to E-cadherin on the intestinal epithelium permits localization of intraepithelial lymphocytes. Specifically, lymphocytes are imprinted with a trafficking program during activation by dendritic cells. Dendritic cells residing in Peyer patches or small bowel-draining lymph nodes can metabolize vitamin A to produce retinoic acid and induce the expression of α4β7 integrin and CCR9 on T and B lymphocytes. Antibodies to either MAdCAM-1 or its ligand α4β7 (e.g., vedolizumab) and to the β7 subunit of this heterodimeric integrin (e.g., etrolizumab) prevent lymphocyte recruitment, reduce the severity of colonic inflammation, and have been shown to be effective in clinical studies of IBD (see Chapter 116 ; see Fig. 115.2 ).
Pathologic Features
Crohn Disase
Focal intestinal inflammation is the hallmark pathologic finding in CD. This tendency for inflammation to be focal is evident in focal crypt inflammation, focal areas of marked chronic inflammation, the presence of aphthae and ulcers on a background of little or no chronic inflammation, and the interspersing of segments of involved bowel with segments of uninvolved bowel. Even within a single biopsy specimen, one can see a pronounced variability in the degree of inflammation.
Aphthae
The earliest characteristic lesion of CD is the aphthous erosion. These superficial breaks in the mucosa are minute, range in size from barely visible to 3 mm, and are surrounded by a halo of erythema. In the small intestine, aphthae arise most often over lymphoid aggregates, with destruction of the overlying M cells. CD aphthae typically occur in normal mucosa, although villus blunting may be seen in the surrounding small intestinal mucosa. Aphthae represent focal areas of immune activation. The M cells and underlying lymphoid aggregates are primary locations for antigen sampling and presentation, and HLA-DR is strongly expressed on the follicle-associated epithelium of the aphthous ulcer. Contact with lumenal contents is a key factor in the development of aphthous erosions in CD. Aphthae heal in bowel that has been excluded from the fecal stream by ileostomy, whereas reestablishing intestinal continuity leads to their recurrence ; these observations provide strong evidence for the role of lumenal factors in the early pathogenesis of CD.
Granulomas
The presence of granulomas ( Fig. 115.5 ), while highly characteristic of CD, is neither unique to CD, nor universally identified in patients who have other features of CD. Noncaseating granulomas, like aphthae are believed to be an early finding. Estimates of the prevalence of granulomas in CD have varied greatly, ranging from 9% to 66%. Whether granulomas are found appears to be, in part, a matter of how hard one looks and how much tissue is available for examination; the more tissue sampled, the larger the specimen, and the more levels taken for histopathology, the more likely granulomas will be found.
Granulomas may be discovered in involved and uninvolved bowel, in any layer of the intestine, and in mesenteric lymph nodes. Granulomas also may be found outside the GI tract (e.g., in skin, eye, and liver), although extraintestinal granulomas are rare; occasionally, they may be recognized as millet seed-like nodules on the serosal surface of the bowel at laparotomy. The granulomas of CD are sarcoid-like, consisting of collections of epithelioid histiocytes and a mixture of other inflammatory cells, including lymphocytes and eosinophils; giant cells occasionally are seen. The granulomas usually are sparse, scattered, and not well-formed. In contrast to the granulomas of TB, there is little or no central necrosis, and acid-fast stains and mycobacterial cultures are negative. It also is important to distinguish the granulomas of CD from those that can occur in association with a ruptured crypt, which typically is found at the base of the crypt and represents a response to mucin released from injured goblet cells; these may be found in UC and other conditions.
Later Pathologic Findings
Resected specimens of intestine may show localized foci of architectural distortion unaccompanied by chronic inflammation, an observation that suggests early superficial lesions such as aphthae may be transient and reversible. When the disease becomes chronic, however, aphthae can coalesce into larger ulcers with a stellate appearance. Linear or serpiginous ulcers can form when multiple ulcers fuse in a longitudinal direction. The classic cobblestoned appearance of CD results when linear and transverse ulcers intersect and networks of ulcers surround areas of relatively normal mucosa with prominent submucosal edema. Ulcers also can extend down to the muscularis propria.
A prevailing generalization is that intestinal inflammation in CD is a transmural process, in contrast to the more superficial inflammation of UC. The transmural nature of the inflammation, however, cannot be appreciated on superficial endoscopic biopsy specimens, and in resected specimens it tends to be focal. Transmural involvement is observed less commonly than is disease of the mucosa and submucosa, but to the extent that transmural disease is noted, it is highly consistent with a diagnosis of CD. Dense lymphoid aggregates can enlarge the submucosa. At times, lymphoid aggregates also may be seen just outside the muscularis propria. The presence of lymphoid aggregates in the submucosa and external to the muscularis propria is a reliable sign of CD even when granulomas are not seen. Lymphoid aggregates occasionally may be seen within the muscularis propria, most often adjacent to the myenteric plexus.
Large ulcers, sinus tracts, fistulae, and strictures are late features of CD. Sinuses and fistulas represent extensions of fissures; sinus tracts end blindly, and fistulas enter epithelial-lined organs such as bowel, skin, bladder, or vagina. Intramural sinus tracts are recognized easily on barium studies. With penetration of inflammation to the serosa, serositis can occur, resulting in adhesion of bowel to loops of small intestine, colon, or other adjacent organs. As a result of the chronicity of the inflammatory process and adhesions, free perforation is much less common than walled-off or contained intra-abdominal abscesses. Fissures and fistulas are lined by neutrophils and surrounded by histiocytes and a mononuclear cell infiltrate; partial epithelialization also is often observed, perhaps reflecting incomplete healing.
Fibrosis is another transmural aspect of CD. Fibrosis may be evident grossly as irregular thickening of the bowel wall and, along with hypertrophy of the muscularis mucosa, can contribute to the development of strictures. TGF-β is released locally in the presence of inflammation and is a cytokine that is critical for restitution and healing. In CD, however, TGF-β may act as a double-edged sword. Fibroblasts isolated from the lamina propria produce primarily type III collagen in response to TGF-β1 and, in the inflamed tissues of CD, significantly greater amounts of type III collagen are produced in response to this cytokine. Thus a cytokine considered essential to the healing process also is implicated in the fibrogenesis of CD.
Other Findings
At the anatomic level, one of the most characteristic findings of CD is the presence of fat wrapping or creeping fat , a term that refers to the edging of mesenteric fat onto the serosal surface of the bowel. Surgeons have long taken fat wrapping as a reliable indicator of the presence of diseased tissue. Mesenteric adipose tissue hypertrophy and fat wrapping are recognized early in the course of disease at laparotomy or laparoscopy. Locally, fat wrapping correlates with the presence of underlying acute and chronic inflammation, as well as transmural inflammation in the form of lymphoid aggregates. It is intriguing that patients with an increased ratio of visceral to subcutaneous fat are at significantly increased risk for complicated disease behavior. Expression of peroxisome proliferator-activated receptor (PPAR)γ, a pivotal mediator in the regulation of adipose tissue homeostasis, is increased greatly in the tissues of patients with CD. In turn, adipocytes may participate in the inflammatory process of CD by producing TNF and other inflammatory mediators.
At the microscopic level, the finding of pyloric metaplasia in the terminal ileum, normally a response to peptic ulcer disease when found in the duodenum, suggests a diagnosis of CD. Careful descriptive immunopathology of areas of pyloric metaplasia reveals the presence of an ulcer-associated cell lineage. Bud-like glandular structures arise adjacent to areas of ulceration and are distinguished by the production of epidermal growth factor (EGF) in acinar cells of the nascent gland and by trefoil proteins in the more superficial cells lining the tract. EGF and trefoil proteins, in turn, can promote restitution of the epithelium in adjacent mucosal ulceration.
UC
Macroscopically, the mucosa in UC appears hyperemic, edematous, and granular in mild disease. As disease progresses, the mucosa becomes hemorrhagic, with visible punctate ulcers. These ulcers can enlarge and extend into the lamina propria. They are often irregular in shape with overhanging edges or may be linear along the line of the teniae coli. Epithelial regeneration with recurrent attacks results in the formation of pseudopolyps, which is typical of long-standing UC but which also may develop rapidly in acute disease ( Fig. 115.6 ). Another characteristic appearance of long-standing UC is atrophic and featureless colonic mucosa, which is associated with shortening and narrowing of the colon. Patients with severe disease can develop acute dilatation of the colon, also characterized by thin bowel wall and grossly ulcerated mucosa with only small fragments or islands of mucosa remaining. With perforation of the colon, a fibrinopurulent exudate may be seen on the serosal surface of the bowel.
Microscopically, the early stage of UC is marked by edema of the lamina propria and congestion of capillaries and venules, often with extravasation of red blood cells. These findings are followed by an acute inflammatory cell infiltrate of neutrophils, lymphocytes, plasma cells, and macrophages, often accompanied by increased numbers of eosinophils and mast cells. Neutrophilic infiltration of colonic crypts gives rise to cryptitis and ultimately to crypt abscesses with neutrophilic accumulations in the crypt lumens. This migration of neutrophils from the circulation into the lamina propria occurs in response to a variety of chemoattractants, including chemotactic peptides of colonic bacteria, IL-8, activated complement, platelet-activating factor, and leukotriene B 4 . Cryptitis is associated with discharge of mucus from goblet cells and increased epithelial cell turnover. Thus the acute inflammatory infiltration results in the characteristic histopathology of goblet cell mucin depletion, formation of exudates, and epithelial cell necrosis. None of these histologic findings, however, are specific for UC.
Inflammation in UC characteristically is confined to the mucosa, in contrast to the transmural involvement of CD. The inflammatory changes typically end at the lumenal aspect of the muscularis mucosa. With increasing inflammation, however, the surface epithelial cells become flattened, eventually ulcerate, and can become undermined if the ulcers are deep. At this stage of the disease, some inflammation and vascular congestion may be present in the submucosa, and ulceration can extend into the muscularis mucosa. This deeper involvement allows confusion with CD, but usually it presents diffusely rather than with the segmental fissuring pattern of transmural inflammation that characterizes CD.
During the healing phase of UC, the inflammatory infiltrate subsides and epithelial regeneration takes place. Epithelial cells undergoing regenerative changes become cuboidal with eccentric, large nuclei, and prominent nucleoli; these features may be confused with dysplasia. Thus the diagnosis of dysplasia in UC should be made with caution in the presence of acute inflammation. Accordingly, surveillance colonoscopy should be performed, when possible, during a period of remission.
A classic histologic feature of chronic quiescent UC is crypt architectural distortion or actual dropout of glands ( Fig. 115.7 ). Architectural changes include branching or bifurcated (bifid) glands, wide separation among glands, and shortened glands that do not extend down to the muscularis mucosa. Architectural alteration is a prominent feature of chronic quiescent UC, but histologic abnormalities can revert to normal early in the course of disease once mild flares resolve. Another characteristic feature of chronic quiescent UC is Paneth cell metaplasia, with Paneth cells being located distal to the hepatic flexure, where they normally are absent. Other nonspecific chronic changes seen in UC include neuronal hypertrophy and fibromuscular hyperplasia of the muscularis mucosa. Varying degrees of acute or chronic inflammation of the lamina propria may be present in chronic quiescent disease.
Most of the pathologic findings described above are not specific for UC. Features that reflect chronicity and thus argue against a diagnosis of infectious or acute self-limited colitis include distorted crypt architecture, crypt atrophy, increased intercryptal spacing to fewer than 6 crypts per millimeter, an irregular mucosal surface, basal lymphoid aggregates, and a chronic inflammatory infiltrate. The histologic severity of inflammation does not necessarily correlate with clinical disease activity in patients with UC, and patients may be relatively symptom free although histology reveals significant inflammation.
Clinical Features
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