Chapter IX.11. Inflammatory Bowel Disease
Mikayla L. Sonnleitner
September 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Alan Ikeda. This current third edition chapter is a revision and update of the original author’s work.


This is a 16 year old female who presents with fever and diarrhea. Further questioning finds that she has had similar episodes in the past few years, but none as severe as the current episode. She does not weigh herself regularly so weight loss could not be confirmed. However, she does admit that her clothes feel somewhat looser than last year. Her menstrual periods are regular. Her last menstrual period began two weeks ago.

Exam: VS T 37.0, P 85, RR 18, BP 100/65, oxygen saturation 100% in room air. Height is at the 50th percentile. Weight is at the 5th percentile. She is a thin appearing female in no acute distress. HEENT exam is significant for slightly tacky oral mucous membranes. Her eyes are not sunken. Neck is supple without lymphadenopathy. Her heart has a regular rhythm, but slight tachycardia with no murmurs. Her lungs are clear with good aeration. Her abdomen appears scaphoid. There are mildly hyperactive bowel sounds with diffuse vague abdominal pain without any point tenderness. No masses or organomegaly are noted. Her extremities are cool at the distal limbs, but warm and dry otherwise. Her pulses are good with brisk capillary refill. No rashes are noted. Her breasts and genitalia are Tanner stage 3-4. Rectal exam demonstrates non-specific discomfort without masses or severe tenderness. Her anus is normal externally. Her stool is guaiac positive.

A CBC shows mild microcytic, hypochromic anemia and thrombocytopenia. Wright's stain of the stool for fecal leukocytes is positive for WBCs, but no eosinophils. Stool, blood and urine cultures are obtained.


Inflammatory bowel disease (IBD) is a term that is used to describe Crohn’s disease and ulcerative colitis, which are chronic inflammatory diseases of the gastrointestinal tract. Crohn's disease (CD) is also known as regional enteritis. The disease is described as discontinuous (regional) areas of transmural inflammation that affect any part of the GI tract (mouth to anus). Ulcerative colitis (UC) is described as a process that results in continuous (diffuse) superficial colonic ulceration.

Although there are some discrepancies over previous misdiagnoses of IBD as infectious gastroenteritis, most experts agree that the incidence of UC has increased over the first half of the 1900s. Since then, the prevalence of UC has plateaued, while Crohn's disease has increased during the 1950s to 1980s, with a 30% increased incidence of pediatric-onset CD since 1983. The incidence of UC and CD are similar worldwide. Both have an increased prevalence in the Northern regions of the world. The two diseases are prevalent in North America, northwestern Europe, and in the United Kingdom. This is in comparison to the relatively decreased rates in Southern Europe, South Africa, and Australia. IBD is rare in Asia, Africa, and South America, although the incidence of IBD is increasing worldwide (2).

UC and CD are both diseases of late adolescence and early adulthood. However, there have been documented cases of IBD diagnosed in infancy and childhood. The incidence of UC is roughly equal in the male and female gender. Caucasians, especially Ashkenazi Jewish, have a greater risk than other ethnicities (2).

Although the precise mechanism of IBD is still unknown, the general consensus is that it is multifactorial. There is currently no known infectious agent that has been identified/isolated which reproducibly causes IBD. Still, infection may be a triggering event for an acute episode of IBD. Viruses and Mycobacterium avium paratuberculosis are some of the organisms that have been studied in relation to CD development (1).

Genetics is a likely contributor in the pathogenesis of IBD. Monozygotic twins have a concordance rate of 30% in CD. UC has less of a genetic preponderance as monozygotic twins have a concordance rate of 15%. Dizygotic twins have a concordance rate of 4% in both CD and UC (8). There are multiple studies attempting to isolate the gene(s) involved in this disease that are beyond the scope of this chapter.

Dietary components have also been studied. No toxin or antigen has been isolated. There is no direct evidence of a cause-and-effect relationship between IBD development and specific dietary antigens. Some interesting modulating factors are the protective effects of breastfeeding against CD and appendectomy against UC. Cigarette smoking increases the risk for CD while it decreases the risk for UC. The hygiene hypothesis has also been suggested as the cause of increasing chronic inflammatory disease prevalence. Less exposure to microbes in infancy and early childhood leads to a weaker and more poorly-adapted immune system, causing an ineffective immune response (2).

The big picture is that multiple events have an additive effect on disrupting homeostasis, resulting in an abnormal mucosal immune response, which leads to intestinal inflammation. If this inflammatory response is not well regulated, then chronic IBD develops.

Table 1. Common Comparative Aspects of CD and UC:
Crohn’s Disease
Ulcerative Colitis
Location
Mouth to anus
50% ileocolic
30% small intestine
Colon only
Abdominal Mass
Common
Rare
Perianal Disease
Common
Rare
Strictures
Common
Unusual
Fistula
Common
Unusual
Risk of Cancer
Increased slightly
Increased slightly
Gross Pathology
Transmural inflammation
Skip lesions
Aphthoid lesions
Fissuring ulceration
Granuloma
Fibrosis
Mucosal inflammation
Diffuse involvement
Crypt abscesses
Crypt distortion
Histopathology
Edema, increased mononuclear cells in lamina propria
Hallmark: transmural extension into bowel wall and adventitia
Active UC:
Neutrophils in mucosa
Goblet cell mucus depletion
Clumps of neutrophils in crypt lumens
Clinical Presentation
Abdominal pain
Anemia
Weight loss
Falling off growth curve
Delayed puberty
Perianal lesions
Finger clubbing
Bloody, mucusy diarrhea
Lower abdominal cramps (less common)
Abdominal tenderness
Vomiting
Fever
Weight loss

Crohn's Disease commonly presents with crampy abdominal pain, recurrent fever, weight loss, and diarrhea. Abdominal pain is diffuse and more severe than in UC and often worse in the lower right quadrant. Rectal bleeding is seen in 80% to 85% of the cases. Weight loss, anorexia, and delayed growth occur in 58%, 25%, and 4% of cases, respectively (9). This growth abnormality may present as short stature and/or delay in sexual maturation. Perianal disease may be the presenting complaint. Further examination may show a fistula, perianal fissures, skin tags, or recurrent abscesses.

Ulcerative colitis presents with bloody stools, abdominal pain, and tenesmus. 100% of cases present with bloody mucousy stool. Mild disease is defined as fewer than 6 stools per day, no fever, no anemia, and no hypoalbuminemia. Moderate disease is described as more than 6 stools per day, fever, anemia, and hypoalbuminemia. 90% of cases present with mild to moderate disease. Severe disease exhibits high fever, abdominal tenderness and distention, tachycardia, leukocytosis, hemorrhage, severe anemia, and more than eight stools per day. Extensive disease is described as inflammation extending proximal to the splenic flexure, while left-sided disease is inflammation extending proximal to the rectum but not the splenic flexure. Proctitis is described as inflammation limited to the rectum (5). Rare complications that may arise include toxic megacolon and intestinal perforation.

Extraintestinal complications of IBD may involve the joints (arthralgias are more common than arthritis), integument (erythema nodosum and pyoderma gangrenosum), eyes (episcleritis, uveitis, and rarely, orbital myositis), hepatobiliary system (sclerosing cholangitis, chronic active hepatitis), pancreas (pancreatitis), renal system (nephrolithiasis, hydronephrosis), coagulation system (hypercoagulability), and bone (decreased bone density).

The diagnosis is based on clinical presentation, radiologic findings, endoscopy with mucosal biopsy, and exclusion of other causes. Since corticosteroids will likely be used for treatment, stool cultures are done to rule out infectious causes. The stool may need to be evaluated for tuberculosis and schistosomiasis. Double-contrast barium enema may show diminished colonic haustrations in UC (lead pipe sign). In CD, it may identify nodularity, skip areas, a string sign (where the lumen is very narrow), and fistula formation. Colonoscopy is superior to evaluate the large bowel because of its increased sensitivity and biopsy capability for histologic assessment.

Fecal calprotectin is a non-invasive marker of intestinal inflammation. It is abnormal in patients with some bacterial infections, in patients with inflammatory bowel disease (IBD), and other inflammatory conditions. It can be useful when the differential must distinguish IBD from non-inflammatory conditions such as irritable bowel syndrome. In patients with IBD, it can also be used to assess disease activity and severity (6,7).

Hematologic findings may exhibit anemia and thrombocytopenia. Further studies may show specific nutritional deficiencies including iron deficiency, hypoalbuminemia, and elevated transaminases. There have been recent advances in serologic testing, which in addition to screening for IBD, can differentiate between CD and UC. Anti-neutrophil cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) are laboratory tests that are used to serve this purpose. ANCAs are immunoglobulin IgG antibodies that are directed against neutrophil cytoplasmic components. Initially ANCAs had been studied in Wegener's granulomatosis and necrotizing vasculitis. By utilizing immunofluorescence studies, UC can be identified as it demonstrates perinuclear staining (pANCA). The test is specific in separating IBD from infectious colitis and other GI disorders. While the specificity is 91% (3), the sensitivity is only 55% to 65%. ASCAs are IgG and IgA antibodies that bind to mannose sequences in the cell wall of S. cerevisiae strain Su1. The specificity and sensitivity of this test is also suboptimal. It is positive in 50% to 70% of people with CD, 10% to 15% of people with UC, and 5% to 10% of those with other GI disorders (6). Its low sensitivity and specificity have kept these studies from replacing definitive radiologic and endoscopic studies. The tests are also limited in the cases where they are most needed. In CD limited to the colon, the pANCA may also be positive. ASCA is also less likely to be positive in CD limited to the colon. Thus, the dilemma remains in which the clinician attempts to distinguish UC from CD involving the colon only.

Mesalamine or balsalazide (diazo-bonded 5-ASA) is the usual treatment for mild to moderate UC, while sulfasalazine is the usual treatment for Crohn's disease with colonic involvement (5). Sulfasalazine, the previously indicated initial treatment for UC, is more poorly tolerated than the currently recommended treatments. In moderate to severe UC and Crohn's disease of the small bowel, corticosteroids are used. Care must be taken to rule out bacterial causes of diarrhea prior to starting systemic corticosteroid therapy. Severe UC is treated with hyperalimentation, high dose corticosteroids, cyclosporine, and surgery (7). Corticosteroids may result in growth retardation. Antibiotics (metronidazole, ciprofloxacin, levofloxacin) are used to reduce fistula symptoms in patients with CD. Azathioprine and 6-mercaptopurine are immunomodulating drugs which are used to reduce inflammation of the intestines, so that the corticosteroid doses can be reduced. Anti-TNF-alpha is a newer intervention that may be beneficial in Crohn’s disease. Azathioprine monotherapy has been compared with various combination therapies with TNF-alpha inhibitors to assess effectiveness in maintaining remission. There is moderate evidence that combination therapy with azathioprine and infliximab has better remission induction rates compared to infliximab monotherapy (4). Other treatments beyond the scope of this chapter include risankizumab-rzaa, ozanimod, and tofacitinib.

Surgical resection is indicated when there are, intestinal complications, intra-abdominal abscesses, bowel-bladder fistula, perforation, hemorrhage, and/or intractable symptoms despite medical therapy. Surgical resection does not necessarily result in a cure. In some patients, elective colectomy is performed to reduce or eliminate the risk of colon cancer.

Crohn's disease may be subdivided into 3 categories: 1) The fistulizing type may form fistulas that are entero-enteric (between bowel segments), bowel-bladder, enterocutaneous (bowel to skin), perianal fistulas, and/or intra-abdominal abscess. 2) Patients with fibrostenosing disease have persistent abdominal pain and radiologic findings consistent with stenoses of the small or large intestine. 3) The inflammatory category includes patients who do not fit either of the two diseases or had been in one category and now fit in another. As listed above, growth impairment may occur either secondary to the illness or to therapy.

Death in CD is rare in children. Adults with Crohn's colitis may have the same risk for cancer as do patients with UC. The overall risk for colorectal cancer is 8% after twenty years of disease (6). This risk is increased in those affected by perianal disease. Most patients undergo resection of the affected segment within 20 years, which decreases the overall incidence of carcinoma.

Ulcerative colitis is also divided into 3 categories, which include mild, moderate and severe disease. One large study noted 70% of children entering remission by three months despite their initial severity level. The greater the severity of the disease, the greater the likelihood of undergoing a colectomy. Of those with moderate to severe disease, 9% and 25% underwent colectomy by 1 and 5 years, respectively (7).

After 10 years, the mortality of patients with Crohn’s Disease increases due to various gastrointestinal causes, including cancer (6). After 20 years, the risk of CD patients developing colon cancer is 8%, which is similar to those with UC (6).


Questions
1. What portion(s) of the GI tract are affected by CD versus UC?

2. Which IBD has a greater association with cancer?

3. What are the common histologic findings in CD and UC?

4. Name three extraintestinal findings in IBD?

5. Describe the three types of CD and UC.


References
1. Cardinale CJ, Hakonarson H. Chapter 1. Genetics of Inflammatory Bowel Diseases. In: Mamula P, Grossman AB, Baldassano RN, Markowitz, JE (eds). Pediatric Inflammatory Bowel Diseases, 3rd edition, 2017. Springer, New York, NY. pp:3-5.
2. Saeed SA, Kugathasan S. Chapter 6. Epidemiology of Pediatric Inflammatory Bowel Disease. In: Mamula P, Grossman AB, Baldassano RN, Markowitz, JE (eds). Pediatric Inflammatory Bowel Diseases, 3rd edition. 2017. Springer, New York, NY. pp:3-5.
3. Pang Y, Ruan H, Wu D, et al. Assessment of clinical activity and severity using serum ANCA and ASCA antibodies in patients with ulcerative colitis. Allergy Asthma Clin Immunol 2020;16(1):37. doi:10.1186/s13223-020-00433-1
4. Chande N, Patton PH, Tsoulis DJ, et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2015(10):CD000067. doi:10.1002/14651858.CD000067
5. Ko CW, Singh S, Feuerstein JD, Falck-Ytter C, et al. AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology 2019;156(3):748–764. doi: 10.1053/j.gastro.2018.12.009
6. Griffiths AM, Van Limbergen J. Chapter 20.4a. Crohn’s Disease. In: Kleinman RE, Goulet OJ, Mieli-Vergani G, et al (eds). Walker’s Pediatric Gastrointestinal Disease, 6th edition. 2018. People’s Medical Publishing House, Raleigh, NC. pp:2040-2144.
7. Croft NM. Chapter 20.4b. Ulcerative and Indeterminate Colitis (Including Inflammatory Bowel Disease Unclassified). In: Kleinman RE, Goulet OJ, Mieli-Vergani G, et al (eds). Walker’s Pediatric Gastrointestinal Disease, 6th edition. 2018. People’s Medical Publishing House, Raleigh, NC. pp:2145-2202.
8. Brant SR. Update on the heritability of inflammatory bowel disease: the importance of twin studies. Inflamm Bowel Dis 2011;17:1-5. doi: 10.1002/ibd.21385
9. Goyal A. Chapter 16. The History and Physical Exam. In: Mamula P, Grossman AB, Baldassano RN, Markowitz, JE (eds). Pediatric Inflammatory Bowel Diseases, 3rd edition, 2017. Springer, New York, NY. pp:195-198.


Answers to questions
1. CD affects the gut anywhere between the mouth to the anus, while UC affects the colon only.
2. Although UC is sometimes cited as having a greater risk for cancer, many studies have demonstrated similar cancer risks in UC and CD. Both have high cancer risk.
3. CD: Transmural inflammation, skip areas, aphthoid lesions, fissuring ulceration, granuloma, fibrosis. UC: Mucosal inflammation, diffuse involvement, crypt abscesses, crypt distortion.
4. Joints: arthralgias are more common than arthritis. Integument: erythema nodosum and pyoderma gangrenosum. Eyes: episcleritis, uveitis, and rarely, orbital myositis. Hepatobiliary system: sclerosing cholangitis, chronic active hepatitis. Pancreas: pancreatitis. Renal system: nephrolithiasis, hydronephrosis. Coagulation system: hypercoagulability. Bone: decreased bone density.
5. Crohn's disease may be subdivided into 3 categories: 1) The fistulizing type, 2) Patients with fibrostenosing disease, and 3) The inflammatory category. Ulcerative colitis is divided into three categories: mild, moderate, severe.


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