Overview of Diagnosis and Medical Treatment of Inflammatory Bowel Diseases

Genetic Susceptibility

Numerous studies have confirmed that genetic factors contribute to the pathogenesis of IBD. Studies found that the first-degree relatives of patients with IBD are approximately 3–20 times more likely to develop the disease than general population. The Ashkenazi Jews have 3–4 times higher risk of disease than non-Jewish population. The concordance rate for CD in monozygotic twins was as high as 50%, further suggesting the heritable risk of IBD.

The genome-wide association studies (GWAS) have identified more than 160 susceptibility loci for IBD, the majority associated with both UC and CD. The nucleotide-binding oligomerization domain 2 (NOD2) was the first susceptibility gene identified to be associated with CD. The wild-type NOD2 gene actives nuclear factor κB in response to the muramyl dipeptide, a fragment of bacterial peptidoglycan; this process is deficient in CD patients with mutant forms of NOD2. The discovery of other IBD susceptibility genes associated with autophagy-modulating innate immune (ATG16L1, IRGM, and LRRK), genes related to Th17/IL-23 pathway (IL23R, IL12B, STAT3, JAK2, TNFSF15, and TYK2), and genes regulating epithelial function (OCTN2, ECM1, CDH1, HNF4A, and GNA12) suggest the key role of epithelial barrier dysfunction in the inflammation of IBD. The genetic assessment of IBD for the diagnostic purpose, however, is not recommended in routine clinical practice, as only 13.1% of the disease heritability can be explained by genetic variations. This may be due to the fact that IBD is a spectrum of polygenic disorders. On the other hand, it should be pointed out that IBD or IBD-like conditions can be monogenic disorders (such as IL-10 and IL-10R mutations), especially in infant and pediatric onset IBD.

Microbiota

Multiple layers of evidences suggest that gut microbiota or microbiome plays a crucial role in the pathogenesis of IBD. Rodent models of IBD found that the animals of developed colitis in the presence of normal microflora, but not in germ-free conditions. Studies in patients with CD showed that CD would not recur at the neoterminal ileum after ileocolonic resection in the presence of ileostomy or fecal diversion.

The intestinal microbiota is acquired at birth and then remains fairly stable over time. However, fluctuations in quality, quantity, and composition of microbiota may occur in response to environmental and developmental factors, as well as disease conditions. The alterations in both diversity and density of microbes, that is, dysbiosis, have been observed in patients with IBD. Although no specific bacteria has been found to have consistent association with IBD, some dominant bacterial species have been implicated in the intestinal inflammation of the disease. In CD, an increase in Escherichia coli and a decrease in Firmicutes were reported. Decreased biodiversity, with a lower proportion of Firmicutes and an increased proportion of Proteobacteria and Enterobacteriaceae , was reported in patients with UC.

Immune Dysregulation

Most previous studies have focused on the role of abnormal adaptive immune responses of IBD. Earlier evidence suggests that UC is a modified T-helper-2 (Th2) disease, whereas CD is Th1 driven. Present studies showed that there are many other subtypes of CD4-positive T-helper cells, including regulatory T cells, Th17, Tfh, and Th9 cells, in addition to Th1 and Th2. All these subtypes of CD4-positive T-helper cells play a central role in the immune-mediated inflammation of IBD. Humoral immunity also plays an important part in the pathogenesis of IBD, as evidenced by alterations in production of immunoglobulin subclasses.

The innate immune also contributes to inflammatory process in IBD. At healthy state, intestinal epithelium, mucus layer, and IgA work in concert and separate luminal microflora from the mucosal immune system. IBD is initiated by the breach of mucosal barrier, which allows for luminal microflora to trigger a sustained and uninhibited inflammatory response. The innate immune response is mediated by various cells including epithelial cells, neutrophils, dendritic cells, monocytes, macrophages, Paneth cells, and natural killer cells. The innate immune dysregulation found in IBD includes an increased intestinal permeability, abnormal mucin production, deficiency in antimicrobial peptides, dysfunctioned epithelial cells, Paneth cells, dendritic cells, neutrophils, monocytes/macrophages, along with excessive immune cell recruitment and activation, and an increased production of inflammatory cytokines and other proinflammatory mediators.

Environmental Factors

Although the pathogenesis of IBD remains not entirely clear, epidemiological studies has identified a number of risk factors that may be associated with the development of IBD, including smoking, appendectomy, diet, and the use antibiotics, oral contraceptives or nonsteroidal antiinflammatory drugs (NSAIDs). Smoking and appendectomy have different effects on UC and CD. Smoking increases the risk for CD, in contrast, it may be a protective factor for UC. The risk of CD increases significantly after appendectomy, which may be due to the misdiagnosis in patients with incipient CD. In contrast, appendectomy has been shown to be protective for the development of UC. Other risk factors include the Western diet (processed, fried, sugary, and fatty foods).

Endoscopic Evaluation

The endoscopy plays an important role in the diagnosis of UC and CD. A proper colonoscopy for the diagnosis and differential diagnosis in IBD should include intubation of the terminal ileum, photo documentation and tissue biopsy of each segment of the terminal ileum and large bowel. We should emphasize the importance of photo documentation and biopsy in the index colonoscopy for the diagnosis and differential diagnosis of UC and CD.

On colonoscopy, UC typically involves the rectum and extends proximally in a continuous pattern. In mild UC, endoscopy may show granular, erythematous mucosa with a loss of vascular pattern. In moderate UC, erosions or microulceration may emerge. In severe UC, shallow or deep ulceration with spontaneous bleeding may be evident. Pseudopolyps, mucosal bridge, and mucosal scars may be present in patients with UC due to recurrent episodes of relapse and remission. The right colon including the ileocecum area is generally normal in patients with proctitis or left-sided UC. However, occasionally a small area of inflammation surrounding the appendiceal orifice (i.e., the cecal patch) can be found in some patients with proctitis or left-sided UC, particularly in pediatric patients. The terminal ileum of patients with UC is typically normal, but a limited segment of distal ileum may be involved in some with pancolitis, a condition known as backwash ileitis. Diffuse colitis with backwash ileitis is often seen in patients with concurrent primary sclerosing cholangitis (PSC). We believe that nontreated UC always involves the rectum and always have diffuse pattern of inflammation in the involved portion of the large bowel on the index colonoscopy. Medical treatment, topical or systemic, can result in rectal sparing or segmental disease distribution in UC, which may be confused with CD.

Colonoscopy with biopsy is an the important modality for the diagnosis of CD. Any parts of GI tract, from the oral cavity to anus, can be affected by CD, the most common being the terminal ileum and colon. The disease process of CD is typically segmental and asymmetrical. The patients with CD may present with small or aphthous ulcers in early stage. The typical endoscopic findings of CD include longitudinal ulcerations (predominantly along the mesentery side) and cobblestoning lesions. An upper endoscopy is recommended in children suspected of CD or in adults with CD having upper GI symptoms. Push enteroscopy or balloon-assisted enteroscopy can be used to evaluate and biopsy the lesions of small bowel of patients with suspected CD. Video capsule endoscopy (VCE) has been used in the diagnosis and differential diagnosis of CD. Although VCE is a sensitive modality for the assessment of inflammation and ulcers in the small bowel, there have been concerns in its lower specificity, inability of obtaining tissue sample, and the risk for capsule retention.

Histologic Evaluation

Histologic evaluation is essential in patients with IBD to establish the chronicity of inflammation and to rule out other causes of colitis. Pathology is not everything, but without pathology, there is no IBD diagnosis. Both UC and CD share a number of histologic features of chronic, structural alterations, including crypt architecture distortion, crypt abscess, mucus depletion, lamina propria mononuclear cell infiltration, basal lymphoplasmacytosis, and pyloric gland metaplasia or Paneth cell metaplasia. Although none of these features are specific, the presence of two or more these features is highly suggestive of IBD.

Histologic findings are helpful to differentiate CD from UC. Microscopically, inflammation of UC is typically superficial, diffuse and continuous, involving mucosa, lamina propria, muscularis mucosae, and even to the level of superficial submucosa, which is different from multifocal, discontinuous, and transmural lesions of CD. The histologic hallmarks of CD is the presence of are non-caseating granulomas and transmural inflammation. However, granulomas are seen in only 30%–40% of cases with CD on mucosal biopsy.

Abdominal Imaging

Abdominal imaging is not recommended as the primary modality in the initial diagnosis of UC because of its low diagnostic sensitivity for early disease. Changes at early stage of UC, including edema, hyperemia, and abnormal mucin production, are beyond the spatial resolution of computed tomography (CT). With disease progression, mural stratification and bowel wall thickening can be visualized on CT in patients with UC. These CT findings are not specific since they can be seen in CD and other forms of colitis. The imaging features on magnetic resonance imaging (MRI) in UC is similar to those of CT.

Cross-sectional abdominal imaging, such as CT or MRI, has been useful in the evaluation of CD, to diagnose and monitor bowel inflammation, perianal disease and complications (for example, stricture, fistula, and abscess). The imaging features of CD include ulcerations, enhancement, mural stratification (enhancement of only the inner layer of bowel wall), bowel wall thickening (generally > 3 mm), increased mesenteric fat density (fibrofatty proliferation), mural edema, and engorged vasa recta (the “comb” sign). The MRI is less commonly performed than CT for evaluating CD in clinical practice, due to its high cost, technical difficulties, limited availability, and a greater interobserver variability in interpreting images. However, MRI with a special protocol is more accurate in assessing fistula and abscess than CT.

Laboratory Evaluation

A complete blood count, liver enzymes, urea, creatinine, electrolytes and iron panel, and C-reactive protein (CRP) should be periodically obtained in patients with IBD. Patients with severe disease may have anemia, low albumin, and electrolyte abnormalities due to diarrhea, dehydration, or malnutrition.

Fecal or serological markers are helpful in assessing and monitoring disease activity. The most commonly used serological markers for the measurement of disease activity are erythrocyte sedimentation rate (ESR) and CRP. Fecal markers such as calprotectin, lactoferrin, and S100A12 are able to identify active disease or bowel inflammation, distinguishing it from functional disorders, such as irritable bowel syndrome (IBS). A number of antibodies have been detected in patients with IBD. Anti- Saccharomyces cerevisiae antibody (ASCA) and perinuclear antineutrophil cytoplasmic antibody (pANCA) may be useful in differentiating UC from CD. A high ASCA level was reported to be associated with CD, with a high specificity level of 96%–100%, whereas an increased level of pANCA was shown to be more common among patients with UC. Other reported serological markers for the diagnosis, differential diagnosis, and prognosis include E. coli outer membrane porin C antibody (anti-OmpC), CBir1 flagellin antibody, anti- Pseudomonas fluorescens (anti-I2), and anti-glycan antibodies (e.g., anti-laminaribioside carbohydrate antibody, anti-chitobioside carbohydrate antibody, anti-mannobioside carbohydrate antibody).

In case of severe or refractory disease or disease flare-up, stool testing for enteric pathogens are recommended for example, cytomegalovirus (CMV), Clostridium difficile , Campylobacter species, and E. coli 0157:H7.

Irritable Bowel Syndrome

IBS is considered as a part of functional bowel disease spectrum. Symptomatology of IBS and IBD may overlap, including chronic abdominal pain, diarrhea, and bloating. In fact, some patients with IBD may report IBS-like symptoms long before being diagnosed as having IBD. However, patients with IBS typically do not have the “red flags”, such as weight loss, anemia, incontinence, nocturnal seepage, and tenesmus. Colonoscopy with biopsy typically suffices the distinction between IBS and IBD or microscopic colitis.

Microscopic Colitis

Microscopic colitis consists of two forms, lymphocytic colitis and collagenous colitis. The main histologic feature of both forms of microscopic colitis is the presence of intraepithelial lymphocytosis. Thickened submucosal collagen band is an additional feature for collagenous colitis. The main symptoms of patients with microscopic colitis are diarrhea and abdominal cramps. Some patients may also have endoscopic inflammation with erythema and even aphthous ulcers. Interestingly, a few patients with microscopic colitis may “progress” into IBD, whereas IBD patients may have concurrent intraepithelial lymphocytosis and even thickened submucosal collagen band. Therefore, microscopic colitis may be considered as a part of IBD or IBD-like disease spectrum (see Chapter 2 ).