INFLAMMATORY BOWEL DISEASE.

Although the etiology and pathogenesis of IBD remains largely unknown, recent research indicated that the individual's genetic susceptibility, external environment, intestinal microbial flora, and immune responses are all involved and functionally integrated in the pathogenesis of IBD. It appears that IBD is a disease of

cleanliness. The "hygiene hypothesis" for IBD postulates that multiple childhood exposures to enteric pathogens protect an individual from developing IBD later in life, while individuals raised in a more sanitary environment are more likely to develop IBD. In common with diseases such as asthma, multiple sclerosis, and rheumatoid arthritis, it demonstrates an inverse relationship with the degree of sanitation: poor sanitation appears to protect against IBD.

ULCERATIVE COLITIS. 1. Patterns of distribution. Ulcerative colitis is characterized by recurring episodes of inflammation limited to

the mucosal layer of the colon. It commonly involves the rectum and may extend in a proximal and continuous fashion to involve other parts of the colon. Skip lesions are not seen. Proctitis upon presentation is found in 36-60% of patients, involvement of the descending colon occurs in 16-45%, and involvement of the entire colon (pancolitis) occurs in 14-35% of cases. The small intestine is normal.

A large number of environmental factors are considered risk factors for IBD, including smoking, diet, drugs, geography, social stress, and psychological element. Among them,

smoking remains the most widely studied and replicated environmental prompter for IBD. Smoking affects both UC and CD but with opposite effects: smoking protects against UC, while has a detrimental effect on CD. Psychological stress acts as a promoting or relapsing factor for IBD. Studies have reported an increasing incidence of anxiety or depression in IBD patients. Stress can damage the intestinal barrier function and disturb gut microbiota and immune function.

IRRITABLE BOWEL SYNDROME.

1. Definition. Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by chronic, relapsing abdominal pain, bloating, and changes in bowel habits. The estimated prevalence of IBS in North America is 10-15%. The peak prevalence from 20 to 39 years of age. Women are 2-3 times more likely to develop IBS than men. 2. Clinical presentation. Patients present with recurrent and episodic abdominal pain, altered bowel habits (constipation, diarrhea, or mixed), urgency, mucus discharge with stools. Many patients also report fibromyalgia or other chronic pain disorders. Patients are often labeled as 'neurotic' and told that symptoms are all in their mind. 3. Laboratory studies. IBS is considered a diagnosis of "exclusion" and laboratory studies are ordered to rule out other gut disorders. Abdominal x-ray and colonoscopy are negative.

DIVERSION COLITIS. Surgical treatment of rectosigmoid cancer or complicated diverticulitis sometimes requires creation of a temporary colostomy

(Hartmann procedure). The Hartmann procedure involves resection of the rectosigmoid colon with creation of a colostomy. Diversion colitis refers to non-specific inflammation that occurs in segments of the colon and rectum that are diverted from the fecal stream by surgery. • Clinical manifestations consist of anorectal pain, mucous discharge, and rectal bleeding. Grossly, the rectal stump shows erythema, diffuse granularity, mucosal friability, and superficial ulcerations. • Microscopically, increased mucosal chronic inflammation, lymphoid follicular hyperplasia, crypt abscesses are noted. The mechanisms responsible for diversion colitis are unknown, but changes in the luminal microbiota and diversion of the fecal stream that provides nutrients to colonic epithelial cells have been proposed. • Diversion colitis resolves after anastomosis and restoration of fecal flow.

Population-based studies have provided compelling evidence that genetic factors contribute to the pathogenesis of IBD; an 8- to 10-fold greater risk of IBD among relatives of UC and CD probands has been demonstrated. In particular, twin and family studies for IBD have shown that a child has a

26-fold increased risk for developing CD when another sibling already has it, and the risk is increased 9-fold in the case of UC.

Crohns Clinical presentation.

Abdominal pain, prolonged diarrhea (with or without gross bleeding), fatigue, and weight loss are the cardinal symptoms of CD. Periods of active disease are alternated by asymptomatic periods that last for weeks to many months. • Distal ilium involvement is associated with right lower quadrant pain. The pain most often reflects the episodes of small bowel obstruction by strictures. • Intermittent diarrhea without gross blood is characteristic for CD. • Perianal fistula occurs in up to 40% of cases and presents with perianal pain and drainage

SEROLOGIC MARKERS IN IBD.

Anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are the best studied serological markers. The ASCA+/pANCA- phenotype is characteristic of CD, while the ASCA-/pANCA+ phenotype is found in UC

Genome-wide association studies (GWAS) have identified 163 susceptibility loci for IBD of which 110 are associated with both diseases, 30 CD specific and 23 UC specific. NOD2 is an important susceptibility gene in

Crohn disease. The protein product codes by NOD2 gene is an intracellular receptor that recognizes the structural motifs of cell wall constituents of both Gram-positive and Gram-negative bacteria. NOD2 activation in normal individuals leads to the generation of an immunosuppressive response in the form of increased regulatory T cell activity. The healthy organism is immunologically tolerant to gut bacteria. NOD2 mutations trigger the production of inflammatory cytokines followed by development of inflammatory intestinal disease. Intestinal mucosa harboring NOD2 loss-of-function mutations loses tolerance to its bacterial neighbors.

Microscopic findings ulcerative colitis.

Crypt architectural distortion and increased mucosal chronic inflammation are the two characteristic histologic findings. The chronic inflammatory cells consist of variable numbers of plasma cells, eosinophils, and lymphocytes, which expand the lamina propria and extend into the muscularis mucosae. • Neutrophils, the hallmark of active disease, are located within crypt epithelium (cryptitis) and crypt lumens (crypt abscesses). • Granulomas are not found in patients with UC. Fistulas and abscesses do not occur. • In severe cases, extensive mucosal destruction may be accompanied by ulcers that extend more deeply into the submucosa, but the muscularis propria is rarely involved. • Paneth cell metaplasia is often present but pyloric gland metaplasia is infrequent.

INDETERMINATE COLITIS.

There is extensive pathologic and clinical overlap between UC and CD; definitive diagnosis is not possible in 10% of IBD patients. These cases are termed indeterminate colitis (IC). Patients with IC show only colon involvement, with rectal sparing, segmentary lesions, transmural inflammation, fissuring-type ulcerations, no epithelioid granuloma, and onset after initiating use of cigarettes. Only serologic studies are helpful in categorizing IC.

LABORATORY STUDIES IN IBD.

Laboratory study results are nonspecific. CBC is useful for detecting anemia, which may be due to chronic blood loss, and malabsorption of vitamin B12 or folate. Leukocytosis and thrombocytosis may be due to chronic inflammation. Hypoalbuminemia is commonly seen due to malabsorption, associated with hypergammaglobulinemia. Elevated C-reactive protein (CRP) level or erythrocyte sedimentation rate (ESR), correlate with disease activity. Electrolyte abnormalities are due to diarrhea and dehydration.

Crohns Microscopic findings.

The inflammation is transmural. Lymphocytes and plasma cells infiltrate the bowel wall from mucosa to serosa. During the active phase of CD, numerous neutrophils infiltrate crypt epithelium (cryptitis) or accumulate in the crypt lumen (crypt abscess). There is associated crypt destruction with ulceration. • Non-caseating epithelioid granulomas are one of the diagnostic hallmarks of Crohn disease. They have been found in 40-60% of cases; therefore, absence of granulomas does not exclude Crohn disease. They are composed of aggregates of epithelioid cells admixed with lymphocytes and neutrophils. Occasionally, giant cells are present. • Epithelial metaplasia, another consequence of chronic relapsing injury, often takes the form of gastric antral appearing glands, and is called pseudopyloric metaplasia

Inflammatory bowel disease (IBD) is

a chronic condition caused by a dysregulated immune response to host intestinal microflora. IBD comprise two types of chronic relapsing intestinal disorders: Crohn disease (CD) and ulcerative colitis (UC). CD can cause transmural inflammation and affect any part of the gastrointestinal tract (most commonly, the terminal ileum or the perianal region) in a non-continuous type. In contrast, UC is typified by mucosal inflammation and limited to the mucosal layer of the colon.

Immunological factors. IBD is characterized by an

aberrant intestinal inflammatory response that results from dysfunctional innate and adaptive immune pathways. CD is driven by a Th1 response and UC is associated with a Th2 response. The newly described Th17 cells are also involved in the gut inflammatory response in IBD. Intestinal mucosa harboring NOD2 loss-of-function mutations loses tolerance to its bacterial neighbors, leading to activation of inflammatory pathways.

3. Clinical presentation ulcerative colitis. Patients with UC predominantly complain of

attacks of bloody diarrhea with mucous discharge from the rectum. Associated symptoms include colicky abdominal pain, urgency, tenesmus, and incontinence. The onset of symptoms is usually gradual, and symptoms are progressive over several weeks. The severity of symptoms may range from mild disease with ≤4 stools per day to severe disease with >10 stools per day. Patients may have systemic symptoms including fever, hypotension, tachycardia, pallor, and fatigue.

MICROSCOPIC COLITIS. 1. Definition. Microscopic colitis (MC) is a chronic inflammatory condition characterized by

chronic diarrhea, normal endoscopic findings and presence of distinct microscopic abnormalities in the colon. MC is subdivided into 2 primary types: collagenous colitis and lymphocytic colitis, determined by histologic appearance. MC is not related to CD or UC, which are more severe forms of inflammatory bowel disease. 2. Epidemiology. The reported prevalence rates of collagenous colitis and lymphocytic colitis are 42 and 69 per 100,000 persons, respectively. The median age at diagnosis of MC is 65 years. The male-to-female ratio is 1:2.4 for MC. 3. Pathology. Endoscopic examination shows a normal colon, the mucosa is not grossly inflamed. • The key histological feature of lymphocytic colitis is increased intraepithelial lymphocytes in colonic biopsies with an otherwise normal appearance and architecture of the colon. Chronic inflammatory cells are present in lamina propria of the mucosa. The inflammation mainly consists of lymphocytes and plasma cells, but eosinophils and neutrophils may also be observed. The subepithelial collagen is unremarkable (< 10 μm thick). • The key histological feature of collagenous colitis is a thickened collagen band immediately beneath the surface epithelial cells. The collagen band is usually 15-30 μm thick. The surface epithelium may show intraepithelial lymphocytosis and areas of epithelial denudation. The lamina propria is diffusely infiltrated by a lymphocytic inflammatory infiltrate.

Pathology Ulcerative Colitis. (A) Gross findings. Gross examination of a resection specimen in UC classically shows a

diffuse and continuous chronic inflammation which involves the rectum and spreads proximally with gradually decreasing severity of inflammation. The transition between the involved and the normal mucosa is sharp. The serosa is typically unremarkable. • The bowel wall is of normal thickness, reflecting the absence of transmural inflammation. • The mucosa is flat and bloody, has a friable granular appearance and shows superficial ulcers, or may be granular with numerous pseudopolyps. Ulcers are superficial, they do not cross muscularis mucosae and do not replicate with deep, fissuring serpentine ulcerations of CD. Pseudopolyps are islands of regenerating colonic mucosa surrounded by ulcerations that bulge into the lumen. • Strictures, fistulas, abscesses, and creeping fat are not seen in the colonic resected specimen.

Defective epithelial barrier. IBD patients have generalized

tight junction alterations associated with increased intestinal permeability. Epithelial tight junctions are the key structures that maintain the intestinal barrier. Ultrastructural studies have shown a decrease in numbers and in the complexity of tight junctions of the epithelial cells, which increase basal permeability. Loss of epithelial barrier allows the permeation of microorganisms into the lamina propria, resulting in the activation of the mucosal immune system and the inflammatory lesions characteristic for IBD.

COLITIS-ASSOCIATED COLORECTAL CANCER. Colon cancer develops in 5-13% of all patients with UC and 0.4-0.8% of patients with CD. Risk increases sharply 8 to 10 years after disease onset. • Colitis-associated colorectal cancer (CAC) is a

tumor that develops in the context of chronic inflammation, differs from sporadic colorectal cancer, and is considered the most serious complication of IBD. CAC has a greater malignant potential than sporadic CRC. Colonic epithelium is damaged by free oxygen radicals produced in the context of the inflammatory milieu. Failure to remove or repair free radical-initiated damage can be mutagenic to epithelium. • CAC begins as dysplasia, which, just as in Barrett esophagus and chronic gastritis, represents in situ transformation. The progression of dysplasia to carcinoma is generally accompanied by an accumulation of the genetic mutations.

EXTRAINTESTINAL MANIFESTATIONS OF IBD. Between 25-40% of IBD patients experience extraintestinal manifestations, which develop years after the diagnosis of IBD.

• Arthritis. Arthritis is the most common extraintestinal manifestation (20% of patients). Nondestructive arthritis can affect the large or small peripheral joints or the spine (sacroiliitis, or ankylosing spondylitis). • Eye involvement. Ocular disease occurs in 5% of patients and include uveitis, scleritis, and episcleritis. • Skin involvement. Skin lesions occur in 10% of patients and include erythema nodosum and pyoderma gangrenosum. • Hepatobiliary involvement. Primary sclerosing cholangitis occurs in 8% of UC and 3% of CD patients. About 70% of patients with PSC have underlying IBD, most frequently UC in over 75% of cases. • Renal stones. About 12-28% of IBD patients develop renal stones. Calcium oxalate and uric acid kidney stones can result from diarrhea, dehydration and metabolic acidosis.

Pathology. Crohns is not continuous but shows segmental distribution of lesions with skip areas. There is sharp demarcation between affected and unaffected foci. (A) Gross findings.

The bowel involvement begins with shallow aphthous ulcers, which coalesce to form long, serpentine or linear ulcers along the length of the bowel. The longitudinal ulcers are connected by short transverse ulcers giving the bowel a cobblestone appearance. • Inflammatory polyps occur in one third of patients. They consist of compact, non-epithelialized granulation tissue, representing a dense mixture of lymphocytes, plasma cells and neutrophils infiltrating the lamina proper lamina of ulcerated epithelium. • A pseudopolyp is another type of growth composed of surviving islets of mucosa between zones of ulceration undergoing hyperplasia. • Fistulas. Deep vertical fissures develop between mucosal folds leading to perforation or formation of fistulas or sinus tracts to other bowel loops, skin, bladder, or vagina. • Fat wrapping (creeping fat phenomenon). The adipose tissue expands from the mesentery towards the intestine. In normal individuals, the mesenteric fat stops before it gets to 50% of the circumference. In CD, the subserosal adipose tissue surrounds almost 100% of the bowel circumference. This "creeping fat" phenomenon is caused by adipocyte hyperplasia. • Rubbery intestinal wall. The intestinal wall is thickened and rubbery as a consequence of transmural edema, inflammation, submucosal fibrosis, and hypertrophy of the muscularis propria. • Strictures. Segmental areas of luminal narrowing of ileum develop at sites of transmural inflammation

Microbial factors. The whole human gut microbiome consists of approximately 160 species. The gut microbiome has a mutual symbiotic relationship with the human host. There is a significant difference in the gut microbiome of healthy individuals and IBD patients in terms of load and diversity. The pattern of dysbiosis most associated with IBD patients is a

decrease in commensal bacteria diversity, particularly in Firmicutes and Bacteroides, and a relative increase of bacterial species belonging to Enterobacteriaceae.

CROHN DISEASE. 1. Patterns of distribution. CD is characterized by involvement of the

distal small and proximal large intestine: 80% of patients have small bowel involvement, usually in the distal ileum; 20% have disease limited to the colon; 50% have involvement of both the ileum and colon; and one-third of patients have perianal disease.

Intestinal complications Crohns. These complications of CD are due to the transmural nature of the disease.

• Sinus tracts (7% of patients) precede intestinal fistulas. They are incomplete fistulas ending in a "cul de sac", and are located within stenotic, severely thickened bowel segments. They may progress to abscess and fistula formation. • Abscesses are found in up to 10-28% of CD patients. They most commonly occur in the abdominal wall, rectus sheath, or iliopsoas muscle. • Fistulas form in up to 50% of patients during their disease course. Fistulas are found perianal in the majority of cases, followed by enteroenteric, enterovaginal, enterovesical, or entero-cutaneous. They feature a central fissure that penetrates through the lamina propria and muscularis mucosa into deeper layers of the underlying gut wall. In general, fistulae are lined by granulation tissue. • Free bowel perforation (2% of cases) with the free flow of intestinal contents into the general peritoneal cavity is one of the most serious complications of CD and is associated with symptoms of classic peritonitis. Perforation sites are ileum and jejunum. • Strictures occur because of longstanding inflammation and lead to bowel obstruction. The terminal ileum is the most common site for stricture formation