Crohn’s Disease

CD is classified based on the age of onset (A1–A3), location of involvement (L1–L4), phenotypes (B1–B3), and the presence or absence of perianal disease ( Table 1.1 ). Clinical presentation of CD is largely dependent on the disease location (small bowel vs. large bowel vs. small and large bowel) and phenotype (inflammatory [ Fig. 1.1 ] vs. fibrostenotic [ Fig. 1.2 ] vs. penetrating [ Fig. 1.3 ]). The majority of patients with CD at the time of presentation had an inflammatory phenotype. As the disease progresses, a majority of patients develop structural complications, such as stricture, fistulas, and abscesses, after 5 years of diagnosis. Common presentations of CD are abdominal pain, diarrhea, bloating, low-grade fever, weight loss, and failure to thrive. Patients may present with anemia or iron deficiency, chronic disease, or vitamin B12 deficiency. A combined assessment of clinical, endoscopic, histologic, radiographic, and laboratory features is necessary for the diagnosis, phenotyping, disease monitoring, response to therapy, and surveillance of neoplasia. Endoscopy, including ileocolonoscopy, ileoscopy via stoma, pouchoscopy, and upper GI endoscopy, plays a key role in the diagnosis, differential diagnosis, disease monitoring, and dysplasia surveillance. The documentation of histopathological features of noncaseating granulomas, acute inflammation, chronic structural changes, and transmural inflammation is important for diagnosis and differential diagnosis. Commonly used abdominal imaging modalities are computed tomography (CT), CT enterography (CTE), magnetic resonance imaging (MRI), MR enterography (MRE), and contrasted enteroclysis or enemas. Laboratory tests are used to identify concurrent infectious etiology (e.g., GI pathogens including Clostridium difficile in the stool and cytomegalovirus [CMV] in the blood), monitor disease activity, assess treatment response (e.g., hemoglobin, iron profile, erythrocyte sedimentation rate, C-reactive protein, and fecal calprotectin), and to measure the level of drugs, antidrug antibodies, and metabolites.

Crohn’s ileitis with longitudinal ulcers along the mesentery edge.

Crohn’s disease with stricture at the ileocecal valve.

Crohn’s disease with ileosigmoid fistula with characteristic “clover leaves”-like configuration on computed tomography enterography.

All patients with CD require medical therapy to control the disease activity, prevent disease progression and disease-associated structural complications, and reduce the risk of hospitalization, surgery, and colitis-associated neoplasia (CAN). Medical therapy consists of induction and maintenance. Systemic corticosteroids and budesonide are used for induction therapy in ileal or ileocolonic CD. Immunomodulators, such as 6-mercaptopurine (6MP) and azathioprine (AZA), are used for maintenance therapy. Anti-tumor necrosis factor (TNF) (e.g., infliximab, adalimumab, certolizumab pegol), ^, antiintegrin (e.g., vedolizumab), and antiinterleukin (e.g., ustekinumab and risankinumab) biologics and small-molecule agents (such as tofacitinib, upadacitinib) are used for both induction and maintenance therapy. A combination of biologics and immunomodulators is used to facilitate efficacy and reduce the development of antidrug antibodies.

Endoscopic therapy plays a growing role in the management of structural complications from CD or CD surgery. Currently, the main indications for endoscopic therapy in IBD are the treatment of stricture (with endoscopic balloon dilation [EBD], endoscopic stricturotomy [ESt], ^, and endoscopic strictureplasty [ESTx] ), fistula and abscess (with endoscopic incision and drainage, and endoscopic fistulotomy), acute and chronic anastomotic leaks (with endoscopic closure and endoscopic sinusotomy), and polyps or dysplasia (with endoscopic polypectomy, endoscopic mucosal resection [EMR], and endoscopic submucosal dissection [ESD] ). Endoscopic therapy bridges medical and surgical therapy by enhancing medical therapy, deferring or avoiding surgery, managing postoperative complications, and monitoring postoperative disease recurrence.

Despite medical and endoscopic therapy, most patients with CD eventually require surgery. Commonly performed surgical procedures for CD are ileocolonic resection (ICR) with ileocolonic anastomosis (ICA) or ileorectal anastomosis (IRA), ileal resection with ileoileal anastomosis and surgical strictureplasty (e.g., Heineke-Mikulicz strictureplasty for stricture <10 cm, Finney strictureplasty for stricture 10–20 cm, and side-to-side isoperistaltic strictureplasty or Michelassi strictureplasty for strictures >20 cm). Fecal diversion with the construction of a temporary or permanent ileostomy or colostomy is also performed in patients with refractory CD in the downstream bowel, perianal disease, or anastomosis.

Ulcerative Colitis

Ulcerative colitis is classified based on disease extent (proctitis vs. left-side colitis vs. extensive colitis) ( Figs. 1.4 and 1.5 ) and severity (mild vs. moderate vs. severe; fulminant or megacolon) ( Table 1.2 ). UC is characterized by diffuse, continuous inflammation from the anal verge to the above bowel with a sharp demarcation between the affected and nonaffected bowel. Colonoscopy with biopsy is essential for diagnosis, differential diagnosis, disease monitoring, assessment of treatment response, and dysplasia surveillance. All patients with UC have involvement in the rectum before the initiation of medical therapy. Patchiness of disease distribution may occur after patients receive medical therapy. Histopathological documentation of chronicity with structural distortions (e.g., basal lymphoplasmacytosis, crypt distortion, and Paneth cell metaplasia) is a prerequisite for the diagnosis. Colonoscopic biopsy with immunohistoc hemistry is valuable to evaluate CMV infection. Endoscopic mucosal healing is a frequently used outcome measure for clinical practice and research protocol.

Ulcerative proctitis with sharp demarcation between the inflamed and noninflamed bowel.

Ulcerative colitis with diffuse large bowel wall thickening on computed tomography.

Classic clinical presentations of UC are urgency, tenesmus, abdominal pain, incontinence, and rectal bleeding. The assessment of the fecal GI pathogen panel (including C. difficile ) is indicated for any UC flare-up. Office-based flexible sigmoidoscopy may be used to assess mild to moderate flare. Patients with fulminant UC or megacolon present with distention, fever, and tachycardia. Imaging with abdominal series or CT may be used to assess the wall thickness of inflamed bowel and dilated bowel. Long-standing UC predisposes the patient to the development of CAN. In patients with left-side colitis or extensive colitis for more than 8–10 years, regular (e.g., yearly) surveillance colonoscopy is recommended. ^, Patients with concurrent UC and primary sclerosing cholangitis (PSC) should undergo yearly surveillance colonoscopy.

Medical treatment options are slightly more for UC than for CD. Oral and topical mesalamines are widely used for induction and maintenance therapy for mild-to-moderate UC. Systemic corticosteroids and budesonide are used for induction therapy. Immunomodulators, such as 6MP, AZA, and methotrexate, have been used for maintenance therapy. Anti-TNF (e.g., infliximab, golimumab, adalimumab), ^, antiintegrin (e.g., vedolizumab), and antiinterleukin (e.g., ustekinumab) biologics are used for both induction and maintenance therapy. Combined anti-TNF and immunomodulator therapy are used for the treatment of UC in clinical practice. A battery of small molecule agents has been studied and some of them have been approved by the Food and Drug Administration for induction and maintenance therapy. These agents include sphingosine-1-phosphate receptor modulator (ozanimod), Janus kinase inhibitor (tofacitinib), and Janus kinase 1 inhibitor (e.g., upadacitinib and filgotinib ).

Endoscopic therapy in patients with UC is currently limited to ESD in selected patients with CAN. However, endoscopic therapy, such as EBD, ESt, endoscopic sinusotomy, and endoscopic fistulotomy, has been extensively used in patients with complications of ileal pouch–anal anastomosis (IPAA).

Approximately 15–20% of patients with UC eventually require colectomy for medically refractory disease, poor tolerance of medications, or the development of CAN. Restorative proctocolectomy (RPC) with IPAA is the preferred surgical treatment modality. Some patients may elect to have colectomy with ileorectal anastomosis, or total proctocolectomy and permanent Brooke ileostomy, while others choose to have a continent ileostomy (e.g., Kock pouch or Barnett continent intestinal reservoir [BCIR]). While RPC and IPAA or continent ileostomy greatly improve patients’ quality of life, structural, inflammatory, functional, neoplastic, and metabolic complications can occur.

Diverticular Bleeding

Colonic diverticular bleeding is the most common cause of lower GI tract bleeding, which is usually diagnosed with colonoscopy ( Fig. 1.6 ). A population-based retrospective study showed that the mean cumulative incidence of diverticular bleeding was 14 per 100,000 inhabitants per year. Diverticular bleeding results from an atrial source either at the dome or the neck of the diverticulum. Typical clinical presentations are acute and painless hematochezia. On colonoscopy, it was estimated that 60% of cases of diverticular bleeding were observed in the left colon. In contrast, on an angiogram, the bleeding diverticulum is more often observed in the right colon. ^,

Diverticulosis. (A) Active bleeding; (B) bleeding treated with endoclip.

Most patients with diverticular bleeding can be managed conservatively without endoscopic, radiographic, or surgical intervention. In a retrospective study of 142 patients with diverticular bleeding, 137 (96.5%) were managed conservatively with bleeding spontaneously stopped. However, approximately one-fourth to one-third of patients experienced rebleeding. A systemic analysis showed only 16% (range: 7.6–100%) of patients with colonic diverticular bleeding needed an interventional treatment, including therapeutic colonoscopy or interventional radiology. Colonoscopic therapy is the most commonly performed initial approach for unremitting bleeding, comprising 66% of all treated patients. Commonly used endoscopic treatment modalities include band ligation, clipping ( Fig. 1.6B ), injection, hemostatic powder, and cauterization. Transcatheter arterial embolization was performed in about 10% (range: 3.3–100%) of all diverticular bleedings. Emergent colectomy was required in 25% (range: 2.2–30.4%).

Diverticulitis

Fewer than 5% of patients with diverticulosis develop diverticulitis ( Fig. 1.7 ). About 12% of patients with diverticulitis have complicated diverticulitis ( Fig. 1.8 ). It is noted that approximately 20% of patients with the initial episode of diverticulitis had a second episode at 10 years, of whom 20% had a third episode within 1 year. Approximately 20% of patients with incident diverticulitis have at least one recurrence. The risk of recurrence is higher in patients with a history of complicated diverticulitis successfully treated without surgery than those with a history of uncomplicated diverticulitis. Uncomplicated diverticulitis involves thickening of the colon wall and pericolonic inflammatory changes. Complicated diverticulitis is defined as diverticulitis with abscess ( Fig. 1.8 ), perforation, stricture, obstruction, and/or fistula. About 4% of uncomplicated diverticulitis may, later on, develop into complicated diverticulitis.

Diverticulitis on flexible sigmoidoscopy.

Diverticulitis with abscesses marked with a green bar on computed tomography.

Reported risk factors for diverticulitis include Western diets, red meat consumption, obesity, smoking, lack of physical activity, use of nonsteroidal antiinflammatory drugs (NSAIDs), low vitamin D, and use of corticosteroids. Diverticulitis likely results from a complex interaction of genetics, gut microbiota, diet and lifestyle factors, and medications.

Classic clinical presentations of diverticulitis are abdominal pain, fever, tenderness of the abdomen, leukocytosis, and bandemia. Patients with complicated diverticulitis may have tachycardia, hypotension, abdominal mass, or fistula. Rarely, patients with ischemic colitis, colon malignancy, or CD can have similar clinical presentations. Diagnosis and differential diagnosis of diverticulitis usually require CT. According to the expert review from the American Gastroenterological Association (AGA), the decision on the diagnostic colonoscopy after an episode depends on the patient’s history, most recent colonoscopy, and disease severity and course. In those with a history of diverticulitis and chronic symptoms, alternative diagnoses should be excluded with both imaging and colonoscopy. Occasionally, MRI and contrasted enemas are performed to illustrate strictures and fistulas.

Oral or intravenous antibiotics are used for the treatment of acute episodes of diverticulitis. According to the AGA expert review, antibiotic treatment is used selectively, rather than routinely, in immunocompetent patients with mild acute uncomplicated diverticulitis. However, antibiotic therapy is strongly advised in immunocompromised patients.

Segmental colectomy is more a definitive therapy than a medical therapy. However, segmental colectomy does not necessarily eradicate the risk of recurrence. Segmental colectomy with or without fecal diversion may be performed in an emergent or elective setting. The decision on elective segmental colectomy is determined by multiple factors, including the patient’s comorbidities (especially immune status), severity or complications of diverticulitis, patient preferences, operative risks and benefits, and available local surgical expertise.

Diverticular Colitis

It is estimated that the prevalence of diverticular colitis or SCAD is approximately 1.3–3.8%. Endoscopic incidence of SCAD is expected in every 300–400 colonoscopies of symptomatic patients. SCAD occurs primarily in the elderly, which coincides with the second peak of the incidence of IBD. SCAD is characterized by microscopic and macroscopic mucosal inflammation in the descending or sigmoid colon with relative sparing of the rectum and proximal colon. In contrast to diverticulitis, the mucosal inflammation in SCAD appears to spare the mouth of the diverticulum or diverticulum cavity ( Fig. 1.9 ). The etiology and pathogenesis of SCAD are not clear. Purported contributing factors include ischemia, mucosal prolapse, dysbiosis, and IBD-like conditions.

Diverticular colitis. (A) Inflammation in the mucosa around the mouth of a diverticulum; (B) gastrografin enema showed sigmoid diverticuli.

Patients with SCAD often present with left lower quadrant pain, dyschezia, constipation, diarrhea, and hematochezia. Some patients may have a low-grade fever. Colonoscopy with biopsy is the diagnostic modality of choice for SCAD. The pattern of SCAD on histology is divided into four categories: (1) type A, acute, and chronic inflammation without architectural changes of the crypts. There might be intraepithelial microabscess; (2) type B, pattern resembling active chronic UC with most patients showing active inflammation with crypt architectural changes, and diffuse intraepithelial abscesses; (3) type C, a wide spectrum of inflammatory infiltration with transmucosal lymphoid follicles, and microfissures; and (4) type D, mimicking active severe chronic UC with massive active inflammation, architectural changes of crypts, diffuse cryptitis, crypt abscesses, and goblet cell depletion. This author found that patients with SCAD often have sigmoid dyskinesia with redundant sigmoid colon or sigmoidocele, as demonstrated by barium defecography or MRI defecography.

Most patients with SCAD treated with mesalamine or topical corticosteroids have favorable responses. Few patients may require therapy with immunosuppressive agents, such as anti-TNF biologics. Rarely, the patient may need segmental colectomy.

Pathogenetic Pathways

Most CRC evolves from a polyp. There are two major distinct precursor lesion pathways: (1) the traditional adenoma-carcinoma pathway (i.e., the chromosomal instability sequence with genomic events initiated by an APC mutation, followed by RAS activation or function loss of p53); and (2) the serrated neoplasia pathway (i.e., RAS and RAF mutations, and epigenetic instability, characterized by the CpG island methylation phenotype leading to microsatellite stable and unstable cancer).

Lynch syndrome or MUTYH-associated polyposis is the most common cause of inherited CRC. Lynch syndrome results from a germline mutation in one of the DNA mismatch repair (MMR) genes (MutL homolog 1 [ MLH1 ], MSH2, MSH6 , postmeiotic segregation 2 [ PMS2 ]) or the EPCAM gene. Therefore, tumors in Lynch syndrome typically have high microsatellite instability (MSI-H) and loss of expression of MMR protein.

Screening

Screening colonoscopy with polypectomy has been shown to reduce the risk of CRC. Stool blood (e.g., guaiac-based fecal occult blood quantitative and fecal immunochemical tests) or molecular markers (e.g., multitarget stool DNA tests) have also been used for screening. The stool tests have been used in combination with colonoscopy or flexible sigmoidoscopy. The majority of studies of the screening demonstrated the reduction of CRC-associated modality. ^, CT colonography is used as a complementary method for the diagnosis of polyps and CRC in those who may not tolerate colonoscopy.

Patients with Lynch syndrome are at increased risk of synchronous and metachronous CRC. CRC in Lynch syndrome is seen more often in the right colon than the left colon seen in sporadic CRCs. While most Lynch-associated CRCs evolve from adenomas, the adenomas in this syndrome tend to be flatter and bigger with a higher frequency of high-grade dysplasia and/or villous features than sporadic adenomas. The adenoma-carcinoma sequence may also progress more rapidly in Lynch syndrome as compared with sporadic CRC (35 months vs. 10–15 years). Adenoma development may also be bypassed altogether, with cancers developing directly from microscopic colonic mucosal crypts.

Diagnosis and Staging

For staging CRC, the tumor, node, metastasis (TNM) staging system of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) is preferred ( Table 1.3 ). Diagnosis of CRC should be confirmed by a full colonoscopy and biopsy. During the colonoscopy, any lesions suspected of CRC should be biopsied and marked with ink ( Figs. 1.10 and 1.11 ). Synchronous colon cancer has been reported to be present in 4% of patients with sporadic colon cancer. Synchronous polyps should be removed ( Fig. 1.10 ). Colonoscopy for decompression of colonic obstruction with EBD or stent placement is occasionally performed in an emergent setting to allow for tumor staging and optimization of patient status.

Table 1.3

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