Chronic bowel diseases. Chronic diseases of small and large intestine

 

 

I. Chronic diseases of small intestine: (Crohn’s disease:

aetiology, diagnosis, differential diagnosis, treatment, complications).

 

Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by chronic inflammation at various sites in the GI tract. Both cause di­arrhea, which may be profuse and bloody. Certain differences in disease patterns jus­tify a distinction between Crohn’s disease and ulcerative colitis, although groupings and subgroupings are somewhat artificial. Some cases are difficult, if not impossible, to classify.

The term colitis applies only to inflamma­tory disease of the colon (eg, ulcerative, granulomatous, ischemic, radiation, or infec­tious colitis). Spastic or mucous colitis is a misnomer often applied to a functional dis­order that is more properly described as ir­ritable bowel syndrome.

 

CROHN’S DISEASE –

A nonspecific chronic transmural inflam­matory disease that most commonly af­fects the distal ileum and colon but may occur in any part of the GI tract.

Etiology and Epidemiology

The exact cause of Crohn disease remains unknown. Genetic, microbial, immunologic, environmental, dietary, vascular, and psychosocial factors have been implicated, as have smoking and use of oral contraceptives and nonsteroidal anti-inflammatory agents (NSAIDs). Patients may inherit susceptibility for an aberrant immunologic response to 1 or more of these provoking factors. Interaction between the predisposing genetic factors, environmental factors, host factors, and triggering event is likely necessary for the disease to develop.

Studies have found compelling evidence for an inheritable risk for the development of Crohn disease. However, classic mendelian inheritance is not seen. Most of the genes thought to be involved in the development of the disease play a role in mucosal immunity, and their products are found on the mucosal barrier epithelium.

When the genetics of Crohn disease were first investigated, a strong association was found with chromosome 16 (IBD1 gene), which led to the identification of 3 single nucleotide polymorphisms (SNPs), 2 missense and 1 frameshift, in the NOD2 gene (now called CARD15), the first gene clearly identified as a susceptibility gene for Crohn disease.

NOD2/CARD15 is a polymorphic gene involved in the innate immune system. Of its more than 60 variations, 3 play a role in 27% of patients with Crohn disease, primarily in those with ileal disease. Subsequent studies suggest that CARD15 genotype is associated not only with the onset of disease but also with its natural history. A study in a German and Norwegian cohort showed that patients with 1 of the 3 identified risk alleles for CARD15 were more likely to have either ileal or right-colon disease.

Another early genome-wide association study (GWAS) looked at Jewish and non-Jewish case-control cohorts and identified 2 SNPs in the IL23R gene, which encodes 1 subunit of the IL-23 receptor protein. Interestingly, this study also described the promising nature of certain therapies that block the function of IL-23. Further research suggested that one particular polymorphism in the IL23R gene showed the strongest association in a German population.

However, another study found that the Arg381Gln substitution is associated with childhood onset of IBD in Scotland. Numerous other loci have been identified as conferring susceptibility to Crohn disease. Several large studies found multiple susceptibility loci and confirmed earlier findings.

In a meta-analysis of 3 GWASs, 526 SNPs from 74 distinct genomic loci were found. In addition to loci that have been previously discussed, 21 new loci were found that were associated with an increased risk of developing Crohn disease. Among the new loci were some very interesting implications, including the genes CCR6, IL12B, STAT3, JAK2, LRRK2, CDKAL1, and PTPN22.Most of these genes are involved in signal transduction in certain immune function, as well as genes involved more directly with immune function.

The interlectin gene (ITLN1) is expressed in the small bowel and colon and is involved in recognition of certain microorganisms in the intestine. Other GWASs found associations between susceptibility to Crohn disease and polymorphisms in genes associated with the intestinal milieu. One study, involving nearly 20,000 SNPs in 735 individuals with Crohn disease, found an association in the ATG16L1 gene, which encodes the autophagy-related 16-like protein involved in the autophagosome pathway that processes intracellular bacteria.

SNPs in other autophagy genes have also been associated with susceptibility to Crohn disease, as in one study examining at 2 polymorphisms that flanked the IRGM gene and that may be in the regulatory material for the gene.Subsequently, various other loci have been implicated in the autophagy pathway as being associated with Crohn disease, with mounting evidence that the autophagosome pathway is very important in the pathogenesis of the disease.

Studies have also provided strong support for IBD susceptibility genes on chromosome 5p13.1, which is a gene desert but does modulate expression of the PTGER4 gene. A murine PTGER4 knockout model has been studied and found to exhibit significant susceptibility to severe colitis.

A large genomic study of multiple diseases confirmed many of the findings found in earlier studies and identified several additional loci of interest for Crohn disease. A locus at 3p21 is located within the BSN gene, which encodes a brain-specific scaffold protein involved ieurotransmitter release. However, the MST1 gene is located nearby and encodes a macrophage stimulation gene, and the authors felt that this represented a more plausible explanation for the association.

A locus at 10q24.2 is located near the NKX2-3 gene, which is a homeodomain-containing transcription factor.

Disruption of the homologous gene in a murine model resulted in defective development of the intestine. The investigators hypothesized that changes to expression of this gene could alter the migration of lymphocytes in the intestine and change its inflammatory response. The last locus discussed in this model is immediately upstream of the PTPN2 on chromosome 18p11 and encodes a T cell protein tyrosine phosphatase, which is a negative regulator of inflammation.

 Infectious agents such as Mycobacterium paratuberculosis, Pseudomonas species, and Listeria species have all been implicated in the pathogenesis of Crohn disease, suggesting that the inflammation seen with the disease is the result of a dysfunctional, but appropriate, response to an infectious source.

Interleukins and TNF-α have also been implicated in the disease process. Crohn disease is characterized by a Th1 cellular immune response pattern that leads to production of IL-12, TNF-α, and interferon gamma. TNF-α has been shown to play a critical role in the inflammation in this disease. Increased production of TNF-α by macrophages in patients with Crohn disease results in increased concentrations of TNF-α in the stool, blood, and mucosa.

Environmental influences such as tobacco use seem to have an effect on Crohn disease. Smoking has been shown to double the risk of Crohn disease, whereas the risk of developing ulcerative colitis  is lower in people who smoke than in those who have never smoked or in those who stopped smoking before their diagnosis.

It has been suggested that a diet high in fatty foods may increase the risk of Crohn disease.Concerns about the measles vaccine and the development of the disease have proved to be unfounded. Although appendectomy has been suggested to be protective in ulcerative colitis, it is not a protective factor in Crohn disease.

In 1998, the prevalence of Crohn disease in the United States was estimated on the basis of data from Olmstead County, Minnesota, and was approximated at 8 cases per 100,000 population.A subsequent analysis of a geographically diverse health insurance claims database estimated the prevalence of Crohn disease among US children and adults in 2003-2004 to be closer to 201 cases per 100,000 persons among adults and 43 per 100,000 among children.

Urban areas may have a higher prevalence of IBD than rural areas do.Upper socioeconomic classes are thought to have a higher prevalence than lower socioeconomic classes, a difference that is likely influenced by increased access to health care, though genetic and environmental factors may also play a role.

Within Europe and North America, a north-to-south gradient in the frequency of IBD in populations is present. This difference in incidence correlates with the highest frequency of IBD in temperate climates and more industrialized parts of the world, such as Western Europe and North America. As new regions assume Western cultural practices, an increased prevalence of ulcerative colitis is usually found approximately 1 decade before the observed increase in Crohn disease.

The overall incidence of Crohn disease in Europe is about 5.6 per 100,000 inhabitants (7.0 per 100,000 person-years iorthern centers vs 3.9 in southern centers)  In most Western European countries, the incidence has stabilized or slightly increased. Increases are reported from some high-incidence areas (eg, Denmark and Sweden). Earlier studies from the 1980s reported an incidence of 4.1 per 100,000 person-years, whereas data for 2003-2005 indicate an incidence of 8.6 per 100,000 person-years.

Incidence figures in Asia range from 0.5 to 4.2 cases per 100,000 persons. The lowest recorded rates of new cases appear to be in South Africa (0.3-2.6 cases per 100,000 persons) and Latin America (0-0.03 cases per 100,000 persons).

A systematic review revealed that the highest prevalence for Crohn disease in North America was 319 per 100,000 persons, compared with 322 per 100,000 persons in Europe.The highest annual incidence figures were 20.2 per 100,000 person-years in North America, 12.7 per 100,000 person-years in Europe, and 5.0 per 100,000 person-years in Asia and the Middle East. In time-trend analyses, 75% of the epidemiologic studies showed statistically significant increases in the incidence of Crohn disease over time.

Age,sex and rase-related demographics

The age of onset of Crohn disease has a bimodal distribution. The first peak occurs between the ages of 15 and 30 years (late adolescence and early adulthood), and the second occurs mainly in women between the ages of 60 and 70 years. However, most cases begin before age 30 years, and approximately 20-30% of all patients with Crohn disease are diagnosed before age 20 years. A greater proportion of colonic and distal Crohn disease has been diagnosed in older patients, whereas younger patients have predominantly ileal disease

In general, the frequency of IBD is similar in males and females, with some studies showing a very slight female predominance. The rate of Crohn disease is 1.1-1.8 times higher in women than in men.This pattern is reversed with pediatric IBD, which has a higher incidence in boys than in girls (pediatric male-to-female ratio, ~1.6:1).

Crohn disease is reported to be more common in white patients than in black patients and rare in Asian and Hispanic children. Approximately 20% of all IBD patients are of black descent. Rates are higher in people of Jewish descent, particularly in Ashkenazi Jews and Jews of middle European origin as compared with Sephardic or eastern European Jews.

Prognosis

Crohn disease is a chronic inflammatory condition with an indolent course. Appropriate medical and surgical therapy helps patients to have a reasonable quality of life, with an overall good prognosis and an extremely low risk of a fatal outcome.

 Several earlier studies estimated a slight decrease in life expectancy associated with certain prognostic indicators, such as female sex, long disease duration, and disease location. The increased mortality was related to pulmonary malignancies, genitourinary tract diseases, and GI, liver, and biliary diseases.

In contrast, other studies have reported normal survival in patients with Crohn disease. With the advent of new medical therapies, population-based studies have shown that overall survival for North American patients with IBD is similar to that expected in the US white population. Individuals with Crohn disease were at increased risk of death from complications of GI disease, GI malignancy, and chronic obstructive pulmonary disease (COPD).

In a Danish study that evaluated trends in mortality from 1982 to 2010, investigators observed a 50% higher mortality in patients with Crohn disease relative to the general population; this percentage did not change over time.

Crohn disease is typically characterized by periods of remission and relapse. In the first year after diagnosis, the relapse rate approaches 50%, with 10% of patients having a chronic relapsing course. Most patients develop complications that require surgery, and postoperative clinical relapse occurs in a significant proportion. The risk of surgery at 5-year intervals after diagnosis is as follows:

• 5 years after diagnosis – The cumulative probability of having only 1 surgical procedure is 37%; 2 or more surgical procedures, 12%; and no surgical procedures, 51%

• 10 years after diagnosis – The cumulative probability of having only 1 surgical procedure is 39%; 2 or more surgical procedures, 23%; and no surgical procedures, 39%

• 15 years after diagnosis – The cumulative probability of having only 1 surgical procedure is 34%; 2 or more surgical procedures, 36%; and no surgical procedures, 30%

Patients with proximal small bowel disease have a higher risk of mortality than those who have ileal or ileocecal disease. The excess mortality may be ascribed to complications of Crohn disease.

Acute Crohn disease of the terminal ileum is often discovered during laparotomy for suspected appendicitis and has an excellent prognosis. The acute episode is usually treated conservatively, and as many as two thirds of patients may show no subsequent evidence of regional enteritis.

 Discussion of the diagnosis, management, and surveillance of colorectal cancer in patients with IBD is beyond the scope of this article. Current data suggest that with the advent of improved therapies for patients with IBD, there is a trend toward decreasing risk of colorectal cancer. For more information, see the following 2 guidelines:

• AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. 2010. Available at:

• Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn disease or adenomas. London, UK: National Institute for Health and Clinical Excellence (NICE); 2011.

Genetic studies are yielding evidence associating particular variants of the CARD15 gene with the prognosis of Crohn disease

Specific CARD15 mutations have been linked with the intestinal site of the disease (eg, ileal site), and certain variants have been found to be associated with the propensity for developing strictures and with an early onset of disease. In the future, these variants may be helpful in predicting the course of the disease in affected individuals.

Pathology

The earliest mucosal lesion of Crohn’s dis­ease is crypt injury in the form of inflamma­tion (cryptitis) and crypt abscesses, which progress to tiny focal aphthoid ulcers, usu­ally located over nodules of lymphoid tissue. In some cases, these lesions regress; in others, the inflammatory process evolves with influx and proliferation of macrophages and other inflammatory cells, occasionally forming noncaseating granulomas with multinu­cleated giant cells.

Transmural spread of inflammation leads to lymphedema and bowel wall thickening, which may eventually result in extensive fibrosis. Development of patchy mucosal ul­cers and longitudinal and transverse ulcers with intervening mucosal edema frequently creates a characteristic cobblestoned ap­pearance. The attached mesentery is thick­ened and lymphedematous; mesenteric fat typically extends onto the serosal surface of the bowel. Mesenteric lymph nodes often enlarge. Transmural inflammation, deep ulceration, edema, muscular proliferation, and fibrosis cause deep sinus tracts and fis­tulas, mesenteric abscesses, and obstruction, which are the major local complica­tions. Granulomas can occur in lymph nodes, peritoneum, the liver, and all layers of the rowel wall and are occasionally seen at laparotomy or laparoscopy as miliary nodules. Although pathognomonic, granulomas are absent in up to 50 % of patients and are there­fore not essential to diagnose Crohn’s dis­ease. They appear to have no definitive bearing on the clinical course.

Segments of diseased bowel are charac­teristically sharply demarcated from adja­cent normal bowel (“skip areas”)—thus the name regional enteritis. Of all cases of Crohn’s disease, about 33% involve the ileum ileitis); about 45% involve the ileum and co­lon (ileocolitis), with a predilection for the right side of the colon; and about 15 % involve the colon alone (granulomatous colitis). Occasionally, the entire small bowel is involved jejunoileitis), and rarely, the stomach, duodenum, or esophagus. The perianal region is also affected in 1/4 to 1/3 of cases.

VIDEO 1 (normal intestine)

 

         The spectrum of Crohn disease presentations includes (a) gastroduodenitis (7% of patients), (b, c) jejunoileitis and ileitis (33% of patients), (d) ileocolitis (45% of patients), and (e) colitis (15% of patients).

CROHN’S DISEASE: MACROSCOPIC       FEATURES

 

 

 

CD can affect any part ofthe gastrointestinal tract from the mouth to the anus. CD is segmental, with skip areas in the midst of diseased intestine. Perirectal fistulas, fissures, abscesses, and anal stenosis are present in one-third of patients with CD, particularly those with colonic involvement. CD may also involve the liver and the pancreas.

Unlike UC, CD is a transmural process. Endoscopically, aphthous or small superficial ulcerations characterize mild disease; in more active disease, stellate ulcerations fuse longitudinally and transversely to demarcate islands of mucosa that frequently are histologically normal. This “cobblestone” appearance is characteristic of CD, both endoscopically and by barium radiography. As in UC, pseudopolyps can form in CD.

Active CD is characterized by focal inflammation and formation of fistula tracts, which resolve by fibrosis and stricturing of the bowel. The bowel wall thickens and becomes narrowed and fibrotic, leading to chronic, recurrent bowel obstructions. Projections of thickened mesentery encase the bowel (“creeping fat”) and serosal and mesenteric inflammation promote adhesions and fistula formation.

CROHN’S DISEASE: MICROSCOPIC FEATURES

The earliest lesions are aphthoid ulcerations and focal crypt abscesses with loose aggregations of macrophages, which form noncaseating granulomas in all layers of the bowel wall from mucosa to serosa. Granulomas can be seen in lymph nodes, mesentery, peritoneum, liver, and pancreas. Although granulomas are a pathognomonic feature of CD, only half of cases reveal granulomas on surgical or endoscopic biopsy specimens. Other histologic features of CD include submucosal or subserosal lymphoid aggregates, particularly away from areas of ulceration, gross and microscopic skip areas, and transmural inflammation that is accompanied by fissures that penetrate deeply into the bowel wall and sometimes form fistulous tracts or local abscesses.

CLINICAL PRESENTATION. CROHN’S DISEASE. Signs and Symptoms  Although CD usually presents as acute or chronic bowel inflammation, the inflammatory process evolves toward one of two patterns of disease: a fibrostenotic-obstructing pattern or a penetrating-fistulous pattern, each with different treatments and prognoses. The site of disease influences the clinical manifestations.

Ileocolitis  Because the most common site of inflammation is the terminal ileum, the usual presentation of ileocolitis is a chronic history of recurrent episodes of right lower quadrant pain and diarrhea. Sometimes the initial presentation mimics acute appendicitis with pronounced right lower quadrant pain, a palpable mass, fever, and leukocytosis. Only at laparotomy, when the appendix is found to be normal, is the ileitis discovered. Pain is usually colicky; it precedes and is relieved by defecation. A low-grade fever is usually noted. High-spiking fever suggests intraabdominal abscess formation. Weight loss is commonѕtypically 10 to 20% of body weight-and develops as a consequence of diarrhea, anorexia, and fear of eating.

 

 

An inflammatory mass may be palpated in the right lower quadrant of the abdomen. The mass is composed of inflamed bowel, adherent and indurated mesentery, and enlarged abdominal lymph nodes. Extension of the mass can cause obstruction of the right ureter or bladder inflammation, manifested by dysuria and fever. Edema, bowel wall thickening, and fibrosis of the bowel wall within the mass account for the radiographic “string sign” of a narrowed intestinal lumen.

 

 

 

Bowel obstruction may take several forms. In the early stages of the disease, bowel wall edema and spasm produce intermittent obstructive manifestations and increasing symptoms of postprandial pain. Over several years, this persistent inflammation gradually progresses to fibrostenotic narrowing and stricture. Diarrhea will decrease and eventually lead to chronic bowel obstruction and obstipation. Acute episodes of obstruction occur as well, precipitated by bowel inflammation and spasm or sometimes by impaction of undigested food. These episodes usually resolve with intravenous fluids and gastric decompression.

Severe inflammation of the ileocecal region may lead to localized wall thinning, with microperforation and fistula formation to the adjacent bowel, the skin, the urinary bladder, or to an abscess cavity in the mesentery. Enterovesical fistulas typically present as dysuria or recurrent bladder infections or less commonly as pneumaturia or fecaluria. Enterocutaneous fistulas follow tissue planes of least resistance, usually draining through abdominal surgical scars. Enterovaginal fistulas are rare and present as dyspareunia or as a feculent or foul-smelling, often painful vaginal discharge. They are unlikely to develop without a prior hysterectomy.

Diarrhea is characteristic of active disease; its causes include: (1) bacterial overgrowth in obstructive stasis or fistulization, (2) bile-acid malabsorption due to a diseased or resected terminal ileum, (3) intestinal inflammation with decreased water absorption and increased secretion of electrolytes.

Colitis and Perianal Disease  Patients with colitis present with low-grade fevers, malaise, diarrhea, crampy abdominal pain, and sometimes hematochezia. Gross bleeding due to deep colonic ulceration is not as common as in UC and appears in about half of patients with exclusively colonic disease. Only 1 to 2% bleed massively. Pain is caused by passage of fecal material through narrowed and inflamed segments of large bowel. Decreased rectal compliance is another cause for diarrhea in Crohn’s colitis patients. Toxic megacolon has been associated with severe inflammation and short-duration disease.

Perianal disease affects about one-third of patients with Crohn’s colitis and is manifested by incontinence, large hemorrhoidal tags, anal strictures, anorectal fistulae, and perirectal abscesses. Not all patients with perianal fistula will have endoscopic evidence of colonic inflammation.

Gastroduodenal Disease  Symptoms and signs of upper gastrointestinal tract disease include nausea, vomiting, and epigastric pain. Patients usually have a H. pylori-negative gastritis..

Laboratory, Endoscopic, and Radiographic Features  Laboratory abnormalities include elevated sedimentation rate and C-reactive protein. In more severe disease, findings include hypoalbuminemia, anemia, and leukocytosis.

Endoscopic features of CD include rectal sparing, aphthous ulcerations, fistulas, and skip lesions. Endoscopy is useful for biopsy of mass lesions or strictures, or for visualization of filling defects seen on barium enema. Colonoscopy allows examination and biopsy of the terminal ileum, and upper endoscopy is useful in diagnosing gastroduodenal involvement in patients with upper tract symptoms. Ileal or colonic strictures may be dilated with balloons introduced through the colonoscope. Endoscopic appearance correlates poorly with clinical remission; thus, repeated endoscopy is not used to monitor the inflammation.

In CD early radiographic findings in the small bowel include thickened folds and aphthous ulcerations. “Cobblestoning” from longitudinal and transverse ulcerations most frequently involves the small bowel. In more advanced disease, strictures, fistulas, inflammatory masses, and abscesses may be detected. The earliest macroscopic findings of colonic CD are aphthous ulcers. These small ulcers are often multiple and separated by normal intervening mucosa. As more severe disease develops, aphthous ulcers become enlarged, deeper, and occasionally connected to one another, forming longitudinal stellate, serpiginous, and linear ulcers.

CT findings include mural thickening >2 cm, homogeneous wall density, mural thickening of small bowel, mesenteric fat stranding, perianal disease, and adenopathy. CT scanning can help identify abscesses, fistulas, and sinus tracts. Magnetic resonance imaging (MRI) may prove superior for demonstrating pelvic lesions such as ischiorectal abscesses.

 

The most common patterns of Crohn’s dis­ease pathology are (1) inflammation char­acterized by right lower quadrant abdominal pain and tenderness; (2) recurrent partial ob­struction caused by intestinal stenosis and leading to severe colic, abdominal disten­tion, constipation, and vomiting; (3) diffuse jejunoileitis, with inflammation and obstruc­tion resulting in malnutrition and chronic debility; and (4) abdominal fistulas and ab­scesses, usually late developments, often causing fever, painful abdominal masses, and generalized wasting.

Enterocutaneous fistulae in Chrohn’s disease

 

Obstruction; development of enteroenteric, enterovesical, retroperitoneal, or enterocutaneous fistulas; and abscess formation are common complications of inflamma­tion. Intestinal bleeding, perforation, and small-bowel cancer develop rarely. When the colon alone is affected, the clinical picture may be indistinguishable from that of ulcer­ative colitis.

 

         Endoscopic spectrum of Crohn disease includes (a) aphthous ulcerations amid normal colonic mucosal vasculature; (b) deeper, punched-out ulcers in ileal mucosa; (c) a single colonic linear ulcer; and (d) deep colonic ulcerations forming a stricture.

Extraintestinal manifestations are cat­egorized as:

Complications that usually parallel the ac­tivity of the intestinal disease and possibly represent acute immunologic or microbi­ologic concomitants of the bowel inflam­mation: peripheral arthritis, episcleritis, aphthous stomatitis, erythema nodosum, and pyoderma gangrenosum. These mani­festations may be reported by > 1/3 of patients hospitalized with inflammatory bowel disease. They are twice as common when colitis is present as when disease is confined to the small bowel. When extraintestinal manifestations  occur, they are multiple in about 1/3 of patients. Disorders associated with inflammatory bowel disease but running an  independent course: ankylosing spondylitis, sacroiliitis, uveitis, and primary sclerosing cholangi­tis. The genetic association of these syndromes and of Crohn’s disease (and ulcerative colitis) with the HLA antigen B27 is discussed under the extracolonic complications of ulcerative colitis, below. Complications that relate directly to dis­rupted bowel physiology: kidney stones from disorders of uric acid metabolism, impaired urinary dilution and alkalinization, and excessive dietary oxalate absorp­tion; urinary tract infections, especially with fistulization into the urinary tract; and hydroureter and hy­dronephrosis from ureteral compression by retroperitoneal extension of the intes­tinal inflammatory process. Other bowel-related complications include malabsorp­tion, especially in the face of extensive ileal resection or bacterial overgrowth from chronic small-bowel obstruction or fistulization; gallstones, related to im­paired ileal reabsorption of bile salts; and amyloidosis, secondary to long-standing inflammatory and suppurative disease. Thromboembolic complications may oc­cur, usually with severe disease activity, as a result of hypercoagulability associated with altered levels of clotting factors and platelet abnormalities.

Diagnosis

Crohn’s disease should be suspected in a patient with the inflammatory or obstructive symptoms described above and in a patient without prominent GI symptoms but with perianal fistulas or abscesses or with other­wise unexplained arthritis, erythema no­dosum, fever, anemia, or stunted growth (in a child).

Laboratory findings are nonspecific and may include anemia, leukocytosis, hypoalbuminemia, and increased levels of acute-phase reactants reflected in elevated ESR, C-reactive protein, or orosomucoids. Elevated alkaline phosphatase and γ-glutamyltranspeptidase accompanying colonic disease often reflect primary sclerosing chol­angitis.

Definitive diagnosis is usually made by x-ray. Barium enema x-ray may show reflux of barium into the terminal ileum with irregu­larity, nodularity, stiffness, wall thickening, and a narrowed lumen.

              X-ray showing abnormal terminal ileum in Crohn’s disease

 A small-bowel series with spot x-rays of the terminal ileum usually most clearly shows the nature and extent of the lesion. An upper GI series without small-bowel follow-through usually misses the di­agnosis.

In advanced cases, the string sign may be seen with marked ileal strictures and sepa­ration of bowel loops. In earlier cases, x-ray diagnosis may sometimes be difficult, but air double-contrast barium enema and enteroclysis may show superficial aphthous and lin­ear ulcers. In questionable cases, colonos­copy and biopsy may help confirm the diagnosis of Crohn’s colitis and allow direct visualization and biopsy of the terminal ileum. Upper GI endoscopy may identify gastroduodenal involvement in Crohn’s disease patients with upper GI symptoms. Although CT can detect extramural complications (eg, fistulas, abscesses, masses), it is not rou­tinely needed for initial diagnosis. Ultra­sound may help delineate gynecologic pa­thology in women with lower abdominal and pelvic pain.

Differential Diagnosis

Differentiation from ulcerative colitis may be difficult in the 20% of cases in which Crohn’s disease is confined to the colon (Crohn’s colitis). The principal differential diagnoses are acute infectious (self-limited) colitis and ulcerative colitis. Acute infec­tious colitis is best established by stool cul­ture, rectal biopsy, and watchful waiting. Dif­ferentiating ulcerative colitis is detailed in Table 1. Although perinuclear antineutrophil cytoplasmic antibodies are present in 60 to 70% of ulcerative colitis patients and in only 5 to 20% of Crohn’s disease patients, and anli-Saccharomyces cerevisiae antibodies are relatively specific for Crohn’s disease, these tests are not sufficiently refined in routine clinical application as to reliably separate the two diseases.

Crohn’s disease of the small bowel (ileitis) requires differentiation from other inflam­matory, infectious, and neoplastic disorders in the right lower quadrant. If in the acute presentation a prior history of chronic bowel symptoms has not been elicited, ileitis may be first diagnosed during surgical explora­tion for suspected acute appendicitis. Peri­appendiceal abscess may produce more chronic symptoms and thus be more difficult to diagnose clinically.

Pelvic inflammatory disease, ectopic preg­nancy, and ovarian cysts and tumors also produce right lower quadrant inflammatory signs and must be ruled out when consider­ing Crohn’s disease in women. Cancer of the cecum, ileal carcinoid, lymphosarcoma, sys­temic vasculitis, radiation enteritis, ileocecal TB, and ameboma may mimic the x-ray find­ings of Crohn’s disease. AIDS-related oppor­tunistic infections (eg, Mycobacterium avium-intracellulare, cytomegalovirus) must also be considered as causes of localized il­eitis. Yersinia enterocolitica enteritis must be excluded if an inflamed, edematous terminal ileum and associated mesenteric adenitis are seen during surgery for acute right lower quadrant pain. Although Yersinia enteritis is self-limited without chronic intestinal se­quelae, the initial clinical picture may be in­distinguishable from Crohn’s disease, so ap­propriate serologic and bacteriologic studies are necessary. In questionable cases, a 3-mo follow-up x-ray of the terminal ileum is val­uable, because Yersinia enteritis will usu­ally resolve completely by this time but Crohn’s disease will not.

Nongranulomatous ulcerative jejunoileitis has features of both Crohn’s disease and sprue, with malabsorption, small-bowel ul­ceration, and villous atrophy, but it lacks granulomatous pathology, fistulization, and extraintestinal manifestations of Crohn’s disease. Eosinophilic gastroenteritis gener­ally has prominent gastric involvement (rare in Crohn’s disease) and is often associated with peripheral eosinophilia, which is the clue to diagnosis.

Differentiation between ulcerative colitis and Crohn disease is critical to developing a treatment plan. In addition, prolonged use of cathartics, especially cascara, over many years may lead to a condition known as cathartic colon. Other problems to be considered include collagenous colitis and lymphocytic colitis (rarely requires surgery, low risk for malignancy), infectious colitis, ischemic colitis in elderly patients, and  radiation colitis

Radiologic findings in cases of acute infective enterocolitis from infection caused by Entamoeba histolytica (amebiasis), cytomegaloviral colitis, and Isospora, Salmonella, Shigella, or Yersinia may be similar to the findings seen in cases of ulcerative colitis; this is especially true with CT scans.

Ulcerative colitis versus Crohn disease

Grossly, Crohn disease is characteristically noncontiguous, with intervening, or skipped, areas of normal mucosa. The ulcerations in Crohn disease tend to be linear and often lead to the classic cobblestone appearance of the mucosa. Crohn disease may involve the entire GI tract, whereas ulcerative colitis involves only the large bowel.

Microscopically, the inflammation in ulcerative colitis and Crohn disease can appear the same, but noncaseating granulomas are present only in Crohn disease. Granulomas are present in 60% of Crohn disease specimens but are never present in ulcerative colitis specimens; therefore, their presence is specific for Crohn disease. The inflammation of Crohn disease may be transmural, whereas it is confined to the mucosa and submucosa in ulcerative colitis. Unfortunately, the differentiation is not always possible preoperatively. All large series of proctocolectomies include a subset of patients (approximately 10%) who were preoperatively thought to have ulcerative colitis but were subsequently diagnosed with Crohn disease.

The traditional idea that ulcerative colitis involves only the large bowel has been challenged. Significant gastroduodenal inflammation in children with ulcerative colitis has been reported. However, aphthous ulceration is considered unique to Crohn disease.In addition, patchiness of the colonic mucosa suggestive of skip lesions may occur during the treatment phase of ulcerative colitis, leading one to question the diagnosis. These patchy areas may be seen endoscopically in as many as 38% of patients with ulcerative colitis who undergo medical therapy. Rectal sparing may also occur at some point during medical treatment of ulcerative colitis in as many as 44% of cases. Proximal disease may be seen even after proctocolectomy. Capsule endoscopy has demonstrated patchy inflammation in the proximal bowel in patients with chronic pouchitis following proctocolectomy with ileal pouch reconstruction. Distinguishing ulcerative colitis from Crohn disease is important. See the table below.

Table 1. Distinguishing Ulcerative Colitis from Crohn Disease

Ulcerative Colitis	Crohn Disease
Only colon involved	Panintestinal
Continuous inflammation extending proximally from rectum	Skip-lesions with intervening normal mucosa
Inflammation in mucosa and submucosa only	Transmural inflammation
No granulomas	Noncaseating granulomas
Perinuclear ANCA (pANCA) positive	ASCA positive
Bleeding (common)	Bleeding (uncommon)
Fistulae (rare)	Fistulae (common)

Cathartic colon

The radiologic appearance of cathartic colon is similar to that of ulcerative colitis. In cathartic colon, the changes are more marked in the right hemicolon than in the left. The bowel is distensible, and there are inconstant areas of bowel narrowing and loss of haustra.

Other diagnostic considerations

In addition to excluding Crohn disease, guidelines from the World Gastroenterology Organization recommend ruling out the following in the differential diagnosis of ulcerative colitis:

• Chronic schistosomiasis

• Amebiasis

• Intestinal tuberculosis

• Ischemic colitis

• Radiation colitis

 

 

Prognosis

Although spontaneous remission or med­ical therapy may result in a prolonged asymptomatic interval, established Crohn’s disease is rarely cured but instead is char­acterized by intermittent exacerbations. In the absence of surgical intervention, the dis­ease never extends into new areas of small bowel beyond its initial distribution at first diagnosis. With judicious medical and, where appropriate, surgical therapy, most patients with Crohn’s disease function well and adapt successfully. Disease-related mor­tality is very low and continues to decrease.

GI cancer, including cancer of the colon and small bowel, is the leading cause of Crohn’s disease-related death. Patients with long-standing Crohn’s disease of the small bowel are at increased risk of small-bowel cancer, with bowel in continuity as well as in bypassed loops. Furthermore, patients with Crohn’s disease of the colon have a long-term risk of colorectal cancer equal to that of ulcerative colitis, given the same ex­tent and duration of disease.

Approximately 70% of Crohn’s disease pa­tients ultimately require surgery. Further­more, Crohn’s disease is likely to recur even after resection of all clinically apparent dis­ease.

 

TABLE 1.   DIFFERENTIATING BETWEEN CROHN’S DISEASE AND ULCERATIVE COLITIS

 

 

 

 

Treatment

No cure is known. Cramps and diarrhea may be relieved by oral administration up to 4 times a day (ideally before meals) of anticholiner­gics, diphenoxylate 2.5 to 5 mg, loperamide 2 to 4 mg, deodorized opium tincture 0.5 to 0.75 mL (10 to 15 drops), or codeine 15 to 30 mg. Such symptomatic treatments are safe, except in cases of severe, acute Crohn’s co­litis, which may progress to toxic megacolon as in ulcerative colitis. Hydrophilic mucilloids (eg, methylcellulose or psyllium prep­arations) sometimes help prevent anal irri­tation by increasing stool firmness.

Sulfasalazine primarily benefits patients with mild to moderate colitis and ileocolitis but has some efficacy in ileitis as well. It may also maintain remission, although it has not been proven to prevent recurrence after sur­gery. (For details of sulfasalazine therapy, see Treatment under Ulcerative Colitis.)

Mesalamine (5-aminosalicylic acid), the active moiety of sulfasalazine, is available in several oral formulations designed to release in various segments of the small bowel and colon. It is especially useful in patients who are intolerant of sulfasalazine. In doses of up to 4 g/day, mesalamine is effective for induc­ing and maintaining remission and is show­ing considerable promise for inhibiting post­operative recurrence.

Corticosteroid therapy treats the acute stages of Crohn’s disease by dramatically re­ducing fever and diarrhea, relieving abdom­inal pain and tenderness, and improving the appetite and sense of well-being. Large doses of oral prednisone, 40 to 60 mg/day, should be given initially. The equivalent dose of hy­drocortisone (200 to 300 mg) may be given by continuous IV drip to hospitalized pa­tients with severe disease. The daily dose of prednisone is gradually reduced after a sat­isfactory response so that, after 1 or 2 mg, it is ≤ 10 mg.

Although as little as 5 or 10 mg/day of pred­nisone may help control symptoms in some patients, long-term therapy often does more harm than good. Corticosteroids should be avoided when obvious infections (eg, fistulas, abscesses) are present. In uncertain cases (eg, those with a tender, inflammatory mass), antibiotics should be given concurrently.

The new topically active corticosteroid budesonide can be given orally or as an en­ema and has low systemic bioavailability and thus  reduced  adrenal  suppression.   Controlled-release budesonide given orally induces remissions with somewhat fewer side effects than prednisolone, but it is not as effective as the conventional corticosteroid and seems no better than placebo in preventing relapses beyond 6 monthes.

Broad-spectrum antibiotics that are active against enteric gram-negative and anaerobic flora may help reduce disease activity in many patients but are most consistently effective for suppurative complications (eg, infected; fistula, abscess). Metronidazole 1 to 1.5 g/day is beneficial, especially in Crohn’s colitis, and is particularly useful for treating perianal lesions. Neuropathy manifested chiefly by paresthesias is a common, potentially serious side effect of long-term use; it is usually reversible when the drug is stopped. There is a high incidence of relapse after discontinuing the drug. Among other broad-spectrum anti­biotics, ciprofloxacin has shown particular promise, but the results of multidrug antituberculous regimens have been mixed.

Immunomodulating drugs, particularly the antimetabolites azathioprine and 6-mercaptopurine, are effective as long-term therару. Azathioprine 2.0 to 3.5 mg/kg/day or 6- mercaptopurine 1.5 to 2.5 mg/kg/day orally significantly improves overall clinical status, decreases    corticosteroid requirements, heals fistulas, and maintains remission for many years. However, these drugs often do not produce clinical benefits for 3 to 6 monthes and side effects of allergy, pancreatitis, and leukopenia must be watched for.

Methotrexate 25 mg IM or subcutaneously once/week benefits some patients with severe corticosteroid-refractory disease, even those who have failed to respond to azathioprine or 6-mercaptopurine. High-dose cyclosporine has demonstrated benefits in inflammatory and fistulous disease, but its long-term use is contraindicated by multiple toxicities. Inflix­imab, a monoclonal antibody that inhibits tumor necrosis factor, can be given I/V for mod­erate to severe Crohn’s disease (especially fistulous disease) refractory to other treat­ments; long-term efficacy and side effect remain to be determined. Other potential immunoregulatory treatments include inter-leukin-1 blockers, antibody to interleukin-12, anti-CD4 antibodies, adhesion molecule inhibitors, and down-regulatory cytokines These many experimental treatment ap­proaches attest to the inadequacy of current: drug therapy for Crohn’s disease. Some patients with intestinal obstruction or fistulas have improved with elemental diets or hyperalimentation, at least over a short term, and children often achieve increased rates of growth. Thus, these mea­sures may serve as preoperative or adjunc-tive therapy and may even be valuable as primary therapy.

Surgery.

 Surgery is usually necessary for recurrent intestinal obstruction or intractable fistulas oг abscesses. Resection of the grossly in­volved bowel may ameliorate symptoms in­definitely but does not cure the disease. Sul­fasalazine has not been shown to prevent postoperative recurrence, but mesalamine > 2 g/day may be effective. The recurrence rate, defined by endoscopic lesions at the anastomotic site, is > 70% at 1 year and > 85% at 3 years; defined by clinical symptoms, it is about 25 to 30% at 3 years and 40 to 50% at 5 years. Ultimately, further surgery is required in nearly 50% of cases. However, recurrence rates appear to be reduced by early postop­erative prophylaxis with mesalamine, met­ronidazole, or possibly 6-mercaptopurine. Moreover, when surgery has been performed for specific complications or failure of med­ical therapy, most patients experience an improved quality of life.

 

II. Chronic diseases of large intestine: irritable bowel syndrome (aetiology, diagnosis, differential diagnosis, treatment, complications).

EPIDEMIOLOGY

         The symptoms associated with irritable bowel syndrome (IBS) are experienced by up to 20% of the population in the West. Although most sufferers will not consult a doctor, the condition still represents 50% of referrals to gastroenterologists. It is a transcultural condition and and is recognised in Africa, India and China. It is more common in urban populations, and is twice as prevalent in women. Symptoms tend to begin in the teens and twenties and decrease with age but the condition may be lifelong.

CLINICAL FEATURES (Fig. 1)

There is a host of symptoms that are associated with IBS but the following are the most important.

 

Fig. 1 Clinical features of IBS.

Abdominal pain

         This is the central feature and is usually described as colicky or constant, particularly in the lower abdomen or left iliac fossa. However, the pain may take on a variety of qualities and may be located anywhere within the abdomen. The intensity of the pain varies from intermittently, mildly annoying to extremely severe. It may be present at any time of day or night but it is unlikely to awaken sufferers from their sleep. It is frequently worsened by eating and relieved by defaecation.

Altered bowel habit.

It is worth remembering that the range of normality for defaecation is between once every 3 days and three times a day. The bowel habit in IBS is most often alternating in that sufferers describe periods of infrequent, hard often ‘pellet-like’ motions interspersed with increased frequency of looser stools. It is usually possible to determine a diarrhoea-or constipation- predominant IBS type, which has implications for treatment strategies. There is often urgency, a feeling of incomplete evacuation and passage of mucus associated with defaecation. Rectal bleeding, steatorrhoea and nocturnal defaecation are not features of IBS and warrant further investigation. Passage of mucus is often described as being increased by sufferers but a mechanism for this has not been found nor has it been reliably documented.

Bloating.

A sensation of abdominal distension is often described although it is quite difficult to demonstrate this consistently in IBS sufferers. Younger women report that they feel as if they are 9 months pregnant. This symptom may be the result of increased intestinal gas, which is probably swallowed air, but may also reflect altered intestinal motility.

Non-colonic gastrointestinal symptoms.

Frequent associated symptoms are of heartburn, nausea, postprandial fullness and pain which may be attributable to the gallbladder or biliary tree. This may be due to a generalized smooth muscle abnormality.

Extra-intestinal symptoms.

These include urinary frequency and dysuria. Dyspareunia may be present if specifically enquired about, and there may be features of fibromyalgia or chronic fatigue syndrome. Psychological factors may be relevant as there does appear to be an increased incidence of depressive illness and neuroticism amongst sufferers. In order to try to standardise the diagnosis, first Manning in 1978 described a series of symptoms which positively discriminated for IBS and subsequently in Rome these symptoms were refined (Table 1). However, these symptoms commonly occur in other organic gut conditions.

PATHOPHYSIOLOGY

                   Table 1 Rome criteria for the diagnosis of IBS

 

 

 

Perhaps because of the heterogeneous nature of the condition and lack of a definitive diagnostic test, elucidating the cause or causes of symptoms has been unsuccessful. Although no single, consistent feature has been identified, abnormalities have been detected in:

• gastrointestinal motility – there are shorter transit times and hypomotility in diarrhoea-predominant IBS, and reduced, high  amplitude, peristaltic contractions in constipation-predominant IBS. The observed motility changes, however, do not correlate well with clinical features.

 

• altered visceral sensation – increased sensitivity to inflated balloons in both small and large bowel has been demonstrated and increased rectal sensitivity is a common finding.

• psychological abnormalities – both sufferers and doctors recognise the effect of psychological stress on the symptoms, but quantifying this is difficult. Psychological symptoms are more prevalent in IBS sufferers, particularly in those referred to hospital and up to 60% may fulfil diagnostic criteria for mental disorders such as depression and anxiety. Disease phobia and bodily preoccupation are also more common. Some patients describe the onset of their symptoms following an episode of gastroenteritis and there does not appear to be a major psychological component to their condition.

• endocrine changes – many women recognise that the symptoms of IBS are more marked during menstruation. No obvious hormonal correlations have been made but there are increased levels of prostaglandin E2 and F2 around this time and this may be important. Symptoms often worsen following hysterectomy which is presumably not explained by hormonal changes but may be due to damage to pelvic nerves at the time of surgery. Unfortunately, some patients undergo hysterectomy when the pain is actually caused by IBS which persists after the operation – a problem that needs to be recognised by gynaecologists.

MANAGEMENT

A thorough history is of prime importance because of the lack of a diagnostic test and broad differential diagnosis that the symptoms of IBS create. It was formerly taught that the diagnosis should be made positively and not by excluding other conditions, but some diagnoses are excluded by the history and examination and others excluded by simple tests. During the history-taking, special attention should be  given to ensure that sinister symptoms such as marked weight loss, rectal bleeding, steatorrhoea, nocturnal diarrhoea, and associated skin or joint symptoms are not present. In addition to a general examination, sigmoidoscopy should be carried out and a rectal biopsy taken, particularly in diarrhoea-predominant IBS. Blood investigations should include full blood count, biochemistry, liver function tests, and the inflammatory markers: erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). With a good history and a normal result from the above investigations, a positive diagnosis of IBS can be made, particularly in the younger age group (<40 years). It is prudent to include further colonic examination such as barium enema studies in the older age group to exclude colonic neoplasia. Over-investigation may simply serve to convince sufferers that the physician is not sureof the diagnosis and is best avoided. Occasionally, factors will confound the diagnosis such as a slightly raised CRP which will usually warrant further GI investigations but may be due to many non-GI  conditions.

TREATMENT

Successful treatment of sufferers with IBS takes considerable skill on the part of the physician. The approach taken at the time of diagnosis will have long-term effects on how patients view their condition. Careful discussion of possible mechanisms of the causes of pain and relevant trigger factors such as diet and anxiety and the universal nature of the condition will often serve to reassure sufferers.

THERAPEUTIC OPTIONS

Dietary manipulation An increase in dietary fibre has been favoured advice for years but makes as many sufferers worse as it does better. It is most useful in constipation-predominant IBS but may worsen bloating. Exclusion diets whereby various food types are removed then subsequently reintroduced into the diet until triggers are found may be beneficial in some cases but are a protracted and rather arduous treatment. Lactose intolerance may affect 10% of the population and contribute to symptoms of diarrhoea and bloating. Exclusion of dairy products from the diet is probably the easiest way to confirm this although a lactose breath test can also be used. Patients will often experiment with their diet themselves and may try unsubstantiated protocols such as low yeast diets which will usually do no harm.

Drugs

         Anticholinergics such as dicyclomine and hyoscine may help pain and diarrhoea but can have side-effects with urinary retention and effects on intraocular pressures. Antispasmodics such as mebeverine and peppermint-based products (particularly for constipation-dominant IBS) may help pain and bloating and are widely used as they do not have anticholinergic side-effects. Antidepressants have long been used in patients with severe IBS and it may be most appropriate to consider a tricyclic for diarrhoea-predominant IBS and a selective serotonin reuptake inhibitor for constipation-predominant IBS. Prokinetics may help post-prandial fullness, bloating and constipation but worsen diarrhoea-predominant IBS. If constipation does not respond to adequate bulking of the stool or an osmotic laxative then a stimulant laxative may be required. Likewise, only if diarrhoea is intractable and troublesome should constipating agents such as loperamide be used.

Complementary therapies

Hypnotherapy, stress management, psychotherapy and acupuncture have all been used and may help some sufferers.

 

III. Chronic diseases of large intestine: Ulcerative colitis

 (aetiology, diagnosis, differential diagnosis, treatment, complications).

ULCERATIVE COLITIS –

A chronic, inflammatory, and ulcerative disease arising in the colonic mucosa, characterized most often by bloody diar­rhea.

Etiology and Epidemiology.

The exact etiology of ulcerative colitis is unknown, but certain factors have been found to be associated with the disease, and some hypotheses have been presented. Etiologic factors potentially contributing to ulcerative colitis include genetic factors, immune system reactions, environmental factors, nonsteroidal anti-inflammatory drug (NSAID) use, low levels of antioxidants, psychological stress factors, a smoking history, and consumption of milk products.

Genetics

The current hypothesis is that genetically susceptible individuals have abnormalities of humoral and cell-mediated immunity and/or generalized enhanced reactivity against commensal intestinal bacteria and that this dysregulated mucosal immune response predisposes to colonic inflammation.

A family history of ulcerative colitis (observed in 1 in 6 relatives) is associated with a higher risk for developing the disease. Disease concordance has been documented in monozygotic twins. Genetic association studies have identified multiple loci, including some that are associated with both ulcerative colitis and Crohn disease; one recently identified locus is also associated with susceptibility to colorectal cancer

Chromosomes are thought to be less stable in patients with ulcerative colitis, as measured with telomeric associations in peripheral leukocytes^.This phenomenon may also contribute to the increased cancer risk. Whether these abnormalities are the cause or the result of the intense systemic inflammatory response in ulcerative colitis is unresolved.

Immune reactions

Immune reactions that compromise the integrity of the intestinal epithelial barrier may contribute to ulcerative colitis. Serum and mucosal autoantibodies against intestinal epithelial cells may be involved. The presence of antineutrophil cytoplasmic antibodies (ANCA) and anti– Saccharomyces cerevisiae antibodies (ASCA) is a well-known feature of inflammatory bowel disease

In addition, an immune modulatory abnormality has been assumed to be responsible for the lower incidence of ulcerative colitis in patients who have undergone previous appendectomy. The incidence of previous appendectomy is lower in patients with ulcerative colitis (4.5%) than in control subjects (19%), and a further protective effect is observed if the appendectomy was performed before the patient was 20 years of age. Also, patients in whom appendectomy was performed for inflammatory disorders (eg, or mesenteric adenitis) seem to have a lower incidence of ulcerative colitis than patients who undergo appendectomy for other disorders such as nonspecific abdominal pain.

Environmental factors

Environmental factors also play a role. For example, sulfate-reducing bacteria, which produce sulfides, are found in large numbers in patients with ulcerative colitis, and sulfide production is higher in patients with ulcerative colitis than in other people. Sulfide production is even higher in patients with active ulcerative colitis than in patients in remission. The bacterial microflora is altered in patients with active diseaseA decrease in Klebsiella species is seen in the ileum of patients relative to controls. This difference disappears after proctocolectomy.

Nonsteroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drug (NSAID) use is higher in patients with ulcerative colitis than in control subjects, and one third of patients with an exacerbation of ulcerative colitis report recent NSAID use. This finding leads some to recommend avoidance of NSAID use in patients with ulcerative colitis.

Other factors

Other factors that may be associated with ulcerative colitis include the following:

• Vitamins A and E, both considered antioxidants, are found in low levels in as many as 16% of children with ulcerative colitis exacerbation.

• Psychological and psychosocial stress factors can play a role in the presentation of ulcerative colitis and can precipitate exacerbations.

• Smoking is negatively associated with ulcerative colitis. This relationship is reversed in Crohn disease.

• Milk consumption may exacerbate the disease.

Pathology.

Pathologic changes begin with degenera­tion of the reticulin fibers beneath the mu­cosal epithelium, occlusion of the subepithe­lial capillaries, and progressive infiltration of the lamina propria with plasma cells, eosin­ophils, lymphocytes, mast cells, and polymorphonuclear leukocytes. Crypt abscesses, epithelial necrosis, and mu­cosal ulceration ultimately develop. The dis­ease usually begins in the rectosigmoid and may extend proximally, eventually involving the entire colon, or it may involve most of the large bowel at once. Ulcerative proctitis, which is localized to the rectum, is a very common and more benign form of ulcerative colitis. It is often refractory to treatment and undergoes late proximal spread in about 20 to 30% of cases.

ULCERATIVE COLITIS: MACROSCOPIC FEATURES

UC is a mucosal disease that usually involves the rectum and extends proximally to involve all or part of the colon. Approximately 40 to 50% of patients have disease limited to the rectum and rectosigmoid, 30 to 40% have disease extending beyond the sigmoid but not involving the whole colon, and 20% have a total colitis. Proximal spread occurs in continuity without areas of uninvolved mucosa. When the whole colon is involved, the inflammation extends 1 to 2 cm into the terminal ileum in 10 to 20% of patients. This is called backwash ileitis and has little clinical significance. Although variations in macroscopic activity may suggest skip areas, biopsies from normal-appearing mucosa are usually abnormal. Thus, it is important to obtain multiple biopsies from apparently uninvolved mucosa, whether proximal or distal, during endoscopy.

With mild inflammation, the mucosa is erythematous and has a fine granular surface that looks like sandpaper. In more severe disease, the mucosa is hemorrhagic, edematous, and ulcerated. In long-standing disease, inflammatory polyps (pseudopolyps) may be present as a result of epithelial regeneration. The mucosa may appear normal in remission but in patients with many years of disease it appears atrophic and featureless and the entire colon becomes narrowed and foreshortened. Patients with fulminant disease can develop a toxic colitis or a toxic megacolon where the bowel wall becomes very thin and the mucosa is severely ulcerated, which may lead to perforation.

 

 

ULCERATIVE COLITIS: MICROSCOPIC FEATURES

Histologic findings correlate well with the endoscopic appearance and clinical course of UC. The process is limited to the mucosa and superficial submucosa with deeper layers unaffected except in fulminant disease. In UC, two major histologic features are indicative of chronicity and help distinguish it from infectious or acute self-limited colitis. First, the crypt architecture of the colon is distorted; crypts may be bifid and reduced iumber, often with a gap between the crypt bases and the muscularis mucosae. Second, some patients have basal plasma cells and multiple basal lymphoid aggregates. Mucosal vascular congestion with edema and focal hemorrhage, and an inflammatory cell infiltrate of neutrophils, lymphocytes, plasma cells, and macrophages may be present. The neutrophils invade the epithelium, usually in the crypts, and give rise to cryptitis and, ultimately, to crypt abscesses. The cryptitis is associated with mucus discharge from goblet cells and increased epithelial cell turnover. Histologically, this results in goblet cell depletion. Other chronic changes that are sometimes seen are neuronal hypertrophy and fibromuscular hyperplasia of the muscularis mucosae.

 

Chronic Ulcerative Colitis

 

These photos are from a total colectomy done for clinically severe, intractable chronic ulcerative colitis (CUC). The photo above shows a veritable shag carpet of inflammatory pseudopolyps. Yes, this does look an awful lot like a case of familial adenomatous polyposis, but microscopically there was no adenomatous or otherwise dysplastic change anywhere in the whole colon.

The photo below may look like bacon frying in a cast iron skillet, but it’s actually a closeup of three longitudinal sections through the colon wall. For each section, the serosa/adventitial connective tissue is shown as bright yellow lumps on the bottom. Right above is the ribbon-like muscularis propria, unbesmirched and indifferent to the devastation that has made an inflammatory ruin of the mucosa and submucosa above it.