Inflammatory bowel disease (IBD) consists of two classic forms: Crohn’s disease (CD) and ulcerative colitis (UC). CD and UC have distinctive clinicopathological features. Clinically, the diagnosis of IBD is made based on a combined assessment of clinical, endoscopic, imaging, and histologic features. Classic CD is characterized by transmural, granulomatous, and skip lesions at any part of the gastrointestinal (GI) tract, whereas classic UC is featured with diffuse mucosal inflammation starting from the rectum, in some patients, extending proximally.

The scope of IBD is beyond the two classic disease entities, CD and UC. IBD represents a disease spectrum with ranging and overlapping etiology, pathogenesis, clinical phenotype, disease course, and prognosis. Even between CD and UC, there is a histopathologically defined disease category of indeterminate colitis (IC) in which transmural inflammation from severe or fulminant colitis defies a clear diagnosis of CD or UC. There are clinical situations that show both features of CD and UC, such as UC with duodenitis, recurrent complex perianal fistula without luminal disease. They are labeled as IBD-unclassified (IBD-U) ( Fig. 1.1 ).

Range of inflammatory bowel disease (IBD) from the rectum to the upper GI tract. CD , Crohn’s disease; GI , gastrointestinal; ICV , ileocecal valve; UC , ulcerative colitis.

Modified from S. Chang, B. Shen, Classification and reclassification of inflammatory bowel diseases: from clinical perspective, in: B. Shen (Ed.), Interventional Inflammatory Bowel: Endoscopic Management of Complications Elsevier, Cambridge, MA, 2018, pp. 17–34.

In a broader sense, microscopic colitis, consisting of lymphocytic colitis and collagenous colitis, and immune checkpoint inhibitor-associated enterocolitis can be considered variants of IBD. In addition, patients with IBD may have concurrent extraintestinal manifestations (EIM), involving joints (such as ankylosing spondylitis [AS] and sacral iliitis), liver (such as primary sclerosing cholangitis [PSC]), skin (such as pyoderma gangrenosum [PG], and erythema nodosum [EN]), eyes (such as uveitis and iritis), lungs (such as bronchiectasis), and other organs. On the contrary, immune-mediated disorders, other than IBD, can also affect the gut. Autoimmune (such as autoimmune hepatitis, systemic lupus erythematosus, and Hashimoto thyroiditis) and autoinflammatory diseases (such as familial Mediterranean fever and Blau syndrome) can occur concomitantly with IBD. To complicate the picture even further, chronic infectious diseases of the gut, such as intestinal tuberculosis (ITB) and chronic Salmonella and Yersinia enterocolitis, can mimic CD ( Fig. 1.2 ). There is a spectrum of disease phenotypes based on the depth of the involved gut ( Fig. 1.3 ).

Range of overlap syndrome from isolated gut disorder to multiorgan involvement of immune-mediated disorders. CD , Crohn’s disease; GI , gastrointestinal; IBD , inflammatory bowel disease; ITB , intestinal tuberculosis; UC , ulcerative colitis.

Modified from S. Chang, B. Shen, Classification and reclassification of inflammatory bowel diseases: from clinical perspective, in: B. Shen (Ed.), Interventional Inflammatory Bowel: Endoscopic Management of Complications, Elsevier, Cambridge, MA, 2018, pp. 17–34.

Depth of inflammation in various forms of immune-mediated chronic inflammatory bowel disease.

Modified from S. Chang, B. Shen, Classification and reclassification of inflammatory bowel diseases: from clinical perspective, in: B. Shen (Ed.), Interventional Inflammatory Bowel: Endoscopic Management of Complications. Elsevier, Cambridge, MA, 2018, pp. 17–34.

The current theory holds that IBD results from abnormal interactions of environmental and microbiological factors and immune systems in genetically susceptible hosts. Microbiota, host immune system, and genetic factors play key roles in the pathogenesis of IBD. However, various degrees of contribution and interactions of these factors result in a wide spectrum of disease phenotypes in patients at different ages of onset, different stages of the disease, and different ethnic groups. For example, some adult-onset CD may be considered a polygenetic disorder , while very-early onset CD often represents a monogenic disorder . Furthermore, the presence of IBD simply reflects an epiphenomenon of GI involvement by immune-mediated systemic diseases.

Classification based on the location of the disease

A spectrum of disease phenotypes of IBD exists according to the location, ranging from isolated perianal CD (without luminal disease), ulcerative proctitis to CD of the upper GI tract, regardless of the depth of bowel wall involvement ( Fig. 1.1 ). In clinical practice, this author also notice a unique form of the CD that only involves the ileocecal valve (ICV). It is likely that thick musculature at ICV plays a role in the disease course of CD at this location. The natural history of isolated CD at ICV is characterized by the initial stage of inflammation and stricture formation with neuronal hyperplasia, transmural fibrosis, and muscular hypertrophy, leading to the development of ileocecal, ileo-ileal, or ileo-sigmoid fistula. The appearance of hypertrophic or strictured ICV reminds the features of achalasia. Endoscopic valvectomy for ileocecal fistula with ICV stricture may offer a “cure,” similar to myotomy for achalasia ( Fig. 1.4 , Table 1.3 ) . Isolated CD at ICV may represent a unique phenotype that was not classified in the Montreal classification.

Isolated Crohn’s disease at the ileocecal valve. (A) Ulcerated stricture at the ileocecal valve; (B) normal terminal ileum except for a mild fecal stasis-associated mucosal change with excessive exudates.

Table 1.3

Proposed classification of inflammatory bowel diseases .

Criteria	Class	Description		Examples
Disease location, extent, and depth±granulomas	Ulcerative colitis			Classic UC
	Crohn’s disease			Classic CD
	Indeterminate colitis
Age of onset	Very early onset		Age 0	IL-10/IL-10 R mutations
	Early onset	Age 0–10 years
			Age 10–17 years
	Regular onset		Age 17–40 years
	Late onset		Age>50 years
Phenotype	Inflammatory			Inflammatory CD; classic UC
	Stricturing			Stricturing CD; UC with strictures
	Penetrating			Fistulizing CD
Locations	Oral
	Upper GI
	Jejunum
	Ileum
	Ileocecal valve
	Colon
	Rectum
	Perianal
	Extraintestinal			Metastatic CD of the skin, lung, and liver
Concurrent or immune-mediated disorders	IBD			Isolated UC or CD of the gut
	IBD-V	IBD +	IBD + classic extraintestinal manifestations	UC with concurrent PSC
		IBD ++	IBD + autoimmune and/or autoinflammatory disorders±classic extraintestinal manifestations	IBD with concurrent microscopic colitis, celiac disease, and hidradenitis suppurativa
		IBD ±	Diseases sharing clinical features and possible etiopathogenetic pathways with classic IBD±classic extraintestinal manifestations of IBD, autoimmune or autoinflammatory disorders	Lymphocytic colitis, collagenous colitis; Behcet disease, cryptogenic multifocal ulcerous stenosing enteritis, ulcerative jejunitis
Etiology of IBD	Primary or idiopathic	Monogenic	IL-10, IL-10Ra, IL-10Rb mutations
				Very-early onset IBD
		Polygenic		Classic UC; classic CD
	Secondary	Identifiable pathogens	Mycobacterial paratuberculosis
			Medication-induced	Mycophenolate-associated colitis; Ipilimumab-associated colitis
			Organ transplantation-induced	Postsolid organ transplant IBD-like conditions, cord colitis syndrome
			Surgery-induced	Pouchitis, Crohn’s disease-like conditions of the pouch, postcolectomy panenteritis, bariatric surgery-associated IBD
Genetic etiology	Monogenic			IL-10/IL-10R mutations, very-early onset IBD, familial Mediterranean fever
	Polygenic			Classic early or late-onset CD and classic UC
Disease spread process	Intrinsic (“inside-out”)		Starting from the mesentery with vascular, lymphatic, or enteric neural system, spreading to the wall and mucosa of the gut	Subset of obese CD patients; subset of patients with sclerosing mesenteritis or lymphangitis
	Extrinsic (“outside-in”)		External triggers (e.g., bacteria and breach of mucosal barrier) leading to mucosal inflammation	Fulminant UC: from mucosal disease to transmural inflammation

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