Overview of Diagnosis and Medical Treatment of Inflammatory Bowel Diseases





List of Abbreviations


6MP


6-mercaptopurine


ADA


Adalimumab


ASCA


Anti- Saccharomyces cerevisiae antibody


AZA


Azathioprine


CD


Crohn’s disease


CDAI


The Crohn’s Disease Activity Index


CDEIS


Crohn’s Disease Endoscopic Index of Severity


CMV


Cytomegalovirus


CRP


C-reactive protein


CT


Computed tomography


DAI


Disease Activity Index


EIM


Extra-intestinal manifestations


ESR


Erythrocyte sedimentation rate


GI


Gastrointestinal


GWAS


Genome-wide association studies


IBD


Inflammatory bowel disease


IBS


Irritable bowel syndrome


IFX


Infliximab


ITB


Intestinal tuberculosis


MMX


Multimatrix


MRI


Magnetic resonance imaging


MTX


Methotrexate


NOD2


Nucleotide-binding oligomerization domain 2


NSAID


Nonsteroidal antiinflammatory drugs


OmpC


Outer membrane porin


pANCA


Perinuclear antineutrophil cytoplasmic antibody


PML


Progressive multifocal leukoencephalopathy


PSC


Primary sclerosing cholangitis


RCT


Randomized controlled trial


SES-CD


Simple Endoscopic Score for Crohn’s Disease


TNF


Tumor necrosis factor


TPMT


Thiopurine S-methyltransferase


UC


Ulcerative colitis


VCE


Video capsule endoscopy




Introduction


Inflammatory bowel disease (IBD) is an idiopathic chronic gut inflammatory condition. It comprises two major entities: ulcerative colitis (UC) and Crohn’s disease (CD). UC is characterized by chronic inflammation limited to mucosal and superficial submucosal layers of the large bowel, whereas CD is segmental and transmural bowel inflammation that may involve any parts of the entire gastrointestinal (GI) tract. One of the hallmarks of CD is the presence of non-caseating granulomas on histology.




Epidemiology


The annual incidence of IBD varies significantly all over the world. The highest incidence rates of UC and CD have been reported in Europe (24.3 per 100,000 person-years) and Australia (29.3 per 100,000 per person-years). The lowest incidence rates of UC and CD were both found in Asia, with 0.36 per 100,000 person-years for UC in Thailand and 0.24 per 100,000 person-years for CD in Malaysia. The highest reported prevalence for IBD was in Europe (UC, 505 per 100,000 persons-years; CD, 322 per 100,000 persons-years) and North America (UC, 249 per 100,000 persons-years; CD, 319 per 100,000 persons-years).


The incidence and prevalence of IBD have shown evident geographic variations. There is a North–South disease gradient within European countries, such as Scandinavian countries, France, Italy, Spain, and Portugal. The incidence of IBD was found to be higher in the northern than southern latitude. The same trend was also observed in the United States. In contrast, another study demonstrated an East–West disease gradient in Canada.


There is a bimodal age distribution of IBD with the initial peak being in the second to third decade and the second peak being in the sixth decade. The median age of onset of CD was slightly younger than that of UC. There was an equal gender distribution for UC. In contrast, there is gender-specific distribution in CD. Studies from the West showed a slight female predominance in CD, although a male predominance is present in low-incidence areas.




Etiology and Pathogenesis


The pathogenesis of IBD is not entirely clear. It is a reason why some investigators have used the term idiopathic inflammatory bowel disease . The IBD is believed to result from a dysregulated immune response to the intestinal microbiota on the background of genetic susceptibility.


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).




Diagnosis


There are no standard diagnostic criteria for IBD. The diagnosis of IBD is usually established by a combined assessment of clinical presentation and endoscopic, histopathological, radiographic, and laboratory findings. A definitive diagnosis of IBD can not be made without detailed endoscopic and histologic evaluation.


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.




Differential Diagnosis


The IBD is a lifelong disease and the establishment of a firm diagnosis is meant a lifelong commitment from both patient’s and clinician’s perspective. There is a long list of diseases that can mimic IBD, including IBS, microscopic colitis, celiac disease, infectious colitis, radiation colitis, ischemic colitis, and medication-associated colitis.


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 ).


Celiac Disease


Diarrhea, abdominal pain, weight loss, and anemia are common presentation of celiac disease and CD. Serology tests for celiac disease, small bowel biopsy, and proper response to gluten free diet are critical for the differential diagnosis.


Acute Infectious Colitis


At the time of presentation, acute infectious colitis should be excluded before making a diagnosis of IBD. The information in recent traveling, antibiotic use, and GI infection should be sought. In patients having diarrhea for more than 4 weeks, a suspicion of IBD or IBS should be raised. A positive stool testing for specific enteric pathogens can help to identify the infectious etiology. However, a negative stool examination does not necessarily imply a diagnosis of IBD. Under this circumstance, histopathological evaluation is needed. The presence of histologic features of chronicity, such as mononuclear cell infiltration in the lamina propria, crypt architecture distortion, basal lymphoplasmacytosis, and pyloric gland or Paneth cell metaplasia, favors the diagnosis of IBD. Pseudomembranous colitis and “erupting volcano” lesion on histology are characteristic features of Clostridium difficile infection.


Differentiating IBD from acute infectious colitis is usually not difficult. Proper follow-up and close observation of clinical course over time may be the best approach. Of note, infectious colitis may occur on top of IBD. Therefore, the presence of one of these pathogens can’t exclude a diagnosis of IBD. In addition, IBD can be triggered by an enteric infection. Therefore, stool testing for these specific pathogens should be performed at the time of the initial presentation and at the time of disease flare-up.


Chronic Infectious Colitis


The distinction between IBD and chronic infectious colitis from intracellular bacteria, such as intestinal tuberculosis (ITB), Samonella , and Yersinia could be challenging.


For patients from developing countries, such as India and China, ITB is the most important one for the differential diagnosis, as the treatment of IBD and ITB is completely different. ITB at the terminal ileum and cecum can mimic CD. The presence of caseating granulomas, typically large in number and size, and positive finding for acid-fast bacilli are diagnostic features of tuberculosis. Grouped or circumferential ulcers (vs. longitudinal ulcers in CD), nodules, and deformed ileocecal valve are the features favoring ITB. Patients with Yersinia or Salmonella infection may present aphthoid ulcers at the terminal ileum, which may resemble CD. Special microbiological work up for Yersinia includes cold culture of stool specimens.


Radiation Colitis


Radiation can cause mucosal inflammation that mimic UC. Radiation colitis may develop weeks to years after abdominal or pelvic irradiation. Although being nonspecific, histologic findings suggestive of radiation colitis include eosinophilia infiltrates, epithelial atypia, fibrosis, capillary telangiectasia, and vasculopathy. Radiation therapy is occasionally used in patients with underlying IBD for IBD-associated or non-IBD-associated neoplasia. Radiation injury to gut mucosa in patients with underlying IBD has been a challenge for the diagnosis and management.


Ischemic Colitis


Ischemia can cause intestinal inflammation which mimics both UC and CD. Differential diagnosis between ischemic colitis and late-onset CD can be difficult. Their endoscopic features may overlap to a great degree. Patients with atherosclerotic disease, congestive heart failure, or recent hypotensive events have an increased risk of developing ischemic colitis. Patients with ischemic colitis present with abdominal pain and bleeding. The common locations of ischemic colitis are splenic flexure, rectal sigmoid junction, and proximal ascending colon. Acute ischemic colitis has intramucosal hemorrhage, and chronic ischemic colitis can have intramucosal fibrosis and crypt drop out, which are not common in patients with IBD. Basal lymphoplasmocytosis, a common histologic feature of UC and CD, is rare in ischemic colitis.


Diversion Colitis


Patients with diversion colitis have a clear history of surgically excluded bowel and prominent lymphoid hyperplasia on histology. Although clinical history can make differential diagnosis between diversion colitis and IBD, it has been difficult to identify the dominant histopathological component in IBD patients with diverting ostomies. The treatment of diversion colitis and that of IBD do not entirely overlap.


Diverticulitis


Patients with diverticulitis may have a known history of diverticulosis and present with acute or recurrent left-lower-quadrant pain or painless bleeding. Detection of diverticula and localized inflammation at and around diverticula on colonoscopy or cross-sectional imaging favors the diagnosis of diverticulitis.


Diverticular colitis is considered as a disease phenotype related to mucosal prolapse and/or ischemia, which is easily confused with diverticulitis and Crohn’s colitis with or without diverticulosis, as both have a segmental distribution. Mucosa around mouth of diverticulum, not diverticulum itself, is normally inflamed in diverticular colitis, which is different from diverticulitis. Mucosal biopsy of inflamed mucosa near the diverticulum typically shows prolapse or ischemic changes.


Medication-Associated Colitis


Nonsteroidal antiinflammatory drugs can also cause chronic diarrhea and ulcers and inflammation along the GI track. However, patients with NSAID-associated colitis usually have a clear history of medication use and may not show basal lymphoplasmacytosis on histology. Some medications, such as check-point immune therapy drugs, may cause IBD or IBD-like conditions ( Chapter 2 ).


Solitary Rectal Ulcer Syndrome


Patients with solitary rectal ulcer syndrome and UC or Crohn’s colitis may have overlapping clinical presentation and endoscopic features. Histologic findings of architectural distortion, fibrosis, and muscle-cell hyperplasia can be helpful in differentiating solitary rectal ulcer syndrome from UC or Crohn’s colitis. The endoscopic and histologic abnormalities of solitary rectal ulcer syndrome are prominently at the anterior wall of the rectum, in contrast to the diffuse involvement of UC. In addition, barium defecography and anorectal manometry may reveal rectal prolapse, rectocele, and dyssynergic defecation pattern.


Behcet Syndrome


Behcet disease has many overlapping features with CD, although the former is predominantly vasculitis in nature, with ulcer lesions in oral and perianal, and genital area ( Chapter 2 ).




Classification of UC


An accurate diagnosis of UC should involve defining the extent and severity of inflammation. Various instruments for evaluating disease extent or severity were developed. The most commonly used modalities among them are the Montreal Classification, the Truelove and Witts’ severity index, and the Mayo Score.


The Montreal Classification


The Montreal consensus panel proposed a classification system of disease extent and severity for UC based on the anatomic extent, frequency and severity of diarrhea, the presence of systemic symptoms, and laboratory abnormalities ( Table 1.1 ). An accurate classification of disease extent for UC is important as it provides the information for selecting the appropriate pharmaceutical agents and baseline for monitoring disease extension. For example, patient with distal disease responds well to suppositories (in E1 disease) or enemas (in E2 disease). In contrast, those with extensive colitis or previously called pancolitis, oral agents may be the first choice. The Montreal Classification stratifies UC severity into mild, moderate, and severe. A periodic assessment of the disease severity of UC can help clinicians to make the therapeutic decision, therefore improving the short- and long-term outcomes.



Table 1.1

The Montreal Classification of Ulcerative Colitis








































Item Montreal Classification Definition
Disease Extent
Ulcerative proctitis E1 Only involves rectum
Left-sided ulcerative proctitis E2 Extending to the splenic flexure
Extensive ulcerative proctitis E3 Extending proximal to the splenic flexure
Disease Severity
Clinical remission S0 Asymptomatic
Mild S1 ≤4 stools per day (with or without blood),absence of systemic disease, normal inflammatory markers (erythrocyte sedimentation rate)
Moderate S2 >4 stools per day, but with minimal signs of systemic toxicity
Severe S3 ≥6 bloody stools daily, pulse rate ≥ 90 beats/min, temperature >37.5°C, hemoglobin <10.5 g/dL, and erythrocyte sedimentation rate ≥30 mm/h


Truelove and Witts’ Severity Index


In 1955, Truelove and Witts described an instrument to measure disease activity in a clinical trial of oral cortisone for active UC. The Truelove and Witts’ severity index composed of eight variables: bowel frequency, blood in stool, temperature, pulse, hemoglobin, physical signs, ESR, and X-ray. Subsequently an instrument with simplified version of Truelove and Witts’ severity index was developed, which excluded variables of X-ray and physical signs ( Table 1.2 ). Although the Truelove and Witts’ severity index is helpful to broadly classify patients and used extensively in clinical trials, it is too complicated to be used in daily clinical practice.


Dec 30, 2019 | Posted by in GASTROENTEROLOGY | Comments Off on Overview of Diagnosis and Medical Treatment of Inflammatory Bowel Diseases
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