A 12-year-old Girl with Bloody Diarrhea

Pediatric Pathways

A 12-year-old Girl with Bloody Diarrhea

After reading this article and answering the review questions the reader will be able to:

  1. Recognize the signs and symptoms suggestive of Inflammatory Bowel Disease (IBD)
  2. Describe an appropriate IBD diagnostic workup
  3. Differentiate Crohn’s disease from Ulcerative colitis
  4. List available treatment options for IBD

Case

Sarah, a 12-year-old female, comes to your office with a history of bloody diarrhea. Sarah was well until two weeks ago when she started having diffused abdominal pain, nausea, and loose stools up to five times daily. Her stools became bloody, more frequent and began waking her up during the night. She developed severe urgency and pain with defecation. She also complained of low degree fevers, poor appetite, and fatigue. She denies recent travel or sick contacts.

Her past medical history is negative for any chronic disorders. She has never been hospitalized nor had surgeries in the past. She does not take any medications or herbal supplements. She is not allergic to any medication. Her parents and siblings are healthy, but her maternal grandmother had celiac disease.

Physical examination: WT 32 kg (3%), HT 155cm (50%-75%), BMI 13 (≤ 3%). She appears pale and tired, but in no acute distress. Her sclera is not icteric and conjunctiva and oropharynx are not hyperemic. She has a small, rounded ulcer on her lower lip. Her neck is without masses or lymphadenopathy. Her lungs are clear to auscultation. Cardiac examination reveals sinus tachycardia without murmurs. Abdomen is soft, not distended, but tender in right lower quadrant. Her liver and spleen are not enlarged. There are no intraabdominal masses palpable. She has audible bowel sounds. Perianal examination reveals a small skin tag at 9 o’clock. Her skin is well perfused with painful nodules noted on her right shin (Figure 1).

Figure 1: Painful nodules on lower extremity

Pediatric Pathways: Painful nodules on lower extremity

Laboratory workup: WBC 5.0 (ref: 4.0-10.5 K/ul), Hemoglobin 9.0 (ref: 12.0-15.0 g/dl), Hematocrit 28 (ref: 35%-45%), and Platelets 384 (ref: 160-370 K/ul) with the following differential 38% neutrophils, 48% lymphocytes, 7% monocytes, 1% basophils. Total protein 7.0 (ref:6.0-8.0 g/dl), albumin 3.0 (ref: 3.3-4.7 g/dl), calcium 8.4 mg/dl (ref: 8.5-10.2 mg/dl), ESR 40 (ref:0-20 mm/hr), CRP 4.0 (ref:0-1 mg/dl), 25-OH vitamin D 20 (ref:30-80 ng/ml), and vitamin B 12 150 (ref: 210-911 pg/ml).

Stool studies for Salmonella, Shigella, Campylobacter, Yersenia, and Clostridium difficile are negative. You see Sarah in your office for follow up in one week. Her symptoms are perisitent and you decide to send her to the pediatric gastroenterologist for an IBD work up. An upper endoscopy and colonoscopy are performed (Figures 2 and 3).

Figure 2: Upper endoscopy and colonoscopy demonstrating a.) erythema and focal erosions in the antrum, b.) aphthous, focal ulcers in the second portion of the duodenum, c.) cobblestoning and deep ulcerations in the sigmoid colon, and d.) loss of architecture, pseudo polyps, deep ulceration and diffused inflammatory exudates in the transverse colon.

Figure 2a

Upper endoscopy and colonoscopy demonstrating erythema and focal erosions in the antrum

Figure 2b

Upper endoscopy and colonoscopy demonstrating aphthous, focal ulcers in the second portion of the duodenum

Figure 2c

Upper endoscopy and colonoscopy demonstrating loss of architecture, pseudo polyps, deep ulceration and diffused inflammatory exudates in the transverse colon

Figure 2d

Upper endoscopy and colonoscopy demonstrating cobblestoning and deep ulcerations in the sigmoid colon

Figure 3. Pathology demonstrating a.) chronic, active colitis with submucosal granulomas and crypt distortion, and b.) a well-organized granuloma in the lamina.

Pathology demonstrating a.) chronic, active colitis with submucosal granulomas and crypt distortion, and b.) a well-organized granuloma in the lamina.

Final diagnosis: Based on the clinical presentation, laboratory studies, and histopathology findings, the patient was diagnosed with Crohn’s disease of the small bowel and colon.

Overview of Inflammatory Bowel Disease(IBD)

Inflammatory bowel disease (IBD) is a general term encompassing a range of diseases that cause chronic inflammation in the gastrointestinal tract and are not due to infection or other identifiable causes.1 The two main types of IBD are Crohn’s disease (CD) and Ulcerative colitis (UC). The Crohn’s and Colitis Foundation of America estimates that as many as one million Americans have either CD or UC.2 Of these individuals, approximately 20% are diagnosed in their childhood.3 The incidence and prevalence of CD and UC are comparable.2 Most pediatric epidemiologic studies shown an increased incidence of CD compared to UC; however, in children aged 3-5 years, UC is more common than CD.3,4

While pediatric CD and UC represent two unique idiopathic inflammatory disorders, their signs and symptoms are similar. CD is a transmural inflammatory condition that can affect any part of the gastrointestinal tract, but most commonly involves the terminal ileum, ascending colon, and perianal area.1,5 In contrast, inflammation in classic UC is limited to the mucosal layer of the colon. In a subset of patients with IBD involving the colon, clinicians may have difficulty categorizing the illness as either CD or UC, so the term “indeterminate colitis” may sometimes be used. Endoscopic features differentiating CD from UC are listed in Table 1.

Table 1. Endoscopic features and histology differentiating CD from UC.

 

CD

UC

Endoscopic findings

  • Deep, aphthous or linear ulcers
  • Cobblestoning
  • Skip lesions
  • Strictures
  • Fistula
  • Perianal lesions
  • Segmental distribution
  • Superficial ulcers
  • Erythema
  • Loss of vascular patterns and granularity
  • Friability
  • Pseudopolyps
  • Continuous changes ascending from rectum

Histology

  • Submucosal or transmural involvement
  • Crypt distortion
  • Crypt abscess
  • Granulomas (noncaseating)
  • Focal changes and patchy distribution
  • Mucosal involvement
  • Crypt distortion
  • Crypt abscess
  • Crypt drop outs
  • Goblet cell depletion
  • Continuous distribution
 

The pathogenesis of IBD is likely a result of complex interactions of genetic, environmental, and immune factors. IBD is familial; up to 25% of patients may have a close relative with either CD or UC.2 If a patient has a first-degree relative with the disease, his or her risk of developing IBD is about ten times greater than that of general population. If that relative happens to be a sibling, the risk is 30 times greater. Many genes may play a role in determining risk of developing IBD. These genes include the NOD2/CARD 15 gene (which was the first gene shown to increase risk of developing IBD), the interleukin-23-receptor gene, and the ATG1 6L1 gene. Several other genes (IBD5, DLG5, IBD3, MDR1) have been identified as factors in the pathogenesis of IBD and these, along with the role of intestinal flora, are currently been investigated.6,7 Environmental factors such as diets, occupation, education, breastfeeding, climate, stress, NSAID exposure have been investigated; however, no specific environmental agents have been proven to be etiologic factors for IBD.6 Interestingly, while IBD can occur in any country, countries in northern climates that are more developed (United States, Canada, northern Europe) have a higher prevalence of IBD.2

Evaluation

The evaluation of a child with suspected IBD involves history taking, physical examination, laboratory investigation, endoscopy with biopsies, and radiology. Table 2 lists the important elements during the history, physical exam and laboratory workup that may differentiate IBD from other diagnoses.

Table 2. Important elements during the interview, physical exam, and laboratory workup

Interview

  • Recent infections
  • Travel history
  • Medication use (especially antibiotics or NSAIDs)
  • Family history (history of IBD, celiac, other autoimmune disorders)
  • Extraintestinal manifestations (mouth, skin, eyes, and joints)

Physical exam

 

  • General well-being
  • Weight, height, BMI , growth percentile
  • Mouth (ulcers)
  • Skin (rashes such as erythema nodosum)
  • Joints (arthritis)
  • Abdomen (tenderness, distension, masses)
  • Perianal disease including abscess and fissure

Laboratory findings

 

  • Microcytic, hypochromic anemia
  • Low total protein, albumin
  • Elevated inflammatory markers

Children with IBD often display symptoms of chronic illness that may help clinicians suspect IBD early in the course of evaluation. These symptoms include abdominal pain, chronic diarrhea (either with or without blood), perianal lesions, growth failure, and weight loss. Growth failure is present at diagnosis in 10 to 40% of children with IBD. Weight loss is present in 85% of pediatric CD patients and 65% of pediatric UC patients. Compared with adults, children with new onset IBD are more likely to present with pancolitis (entire colon is involved); therefore, systemic symptoms such as anemia and fatigue may be more common.

Treatment

Pediatric IBD treatment is directed to the individual needs of each child and requires clinicians to weigh the risks and benefits of therapeutic agents. Treatment has increasingly focused on anti-inflammatory and steroid-sparing strategies because children’s growth and development can be negatively affected by persistent inflammation and/or corticosteroid dependency.

5-ASA agents. The 5-aminosalicylates (ASA) are anti-inflammatory agents, such as sulfasalazine and mesalamine, that treat mild cases of UC and CD, especially when there is colonic involvement.8 As a class, 5-ASA agents are generally well-tolerated; however, the sulfa moiety of sulfasalazine is a potential allergen in some patients. Adverse effects of sulfasalazine, such as headache, nausea, photosensitivity, severe skin rashes, pancreatitis, leukopenia, and hepatitis, have been reported in approximately 20% of pediatric patients.8 There have also been rare reports of pericarditis and pneumonitis. The sulfa moiety also decreases folate absorption, so patients treated with sulfasalazine should receive daily folate supplement. Newer formulations use alternative mechanisms to deliver mesalamine to the affected site, but also have side effects and appear to be somewhat less effective without sulfa.

Corticosteriods. Corticosteroids should only be used as induction agents, and then patients are weaned as a maintenance drug is initiated. For mild-to-moderate ileocolonic CD in patients who can swallow capsules, budesonide should be used preferentially because of less systemic steroid exposure. In a study of children being treated for CD with either budesonide or prednisone, adverse events were noted in 32% of the budesonide group and 71% of the prednisone group. The risk of growth impairment is of particular concern for children with CD.9 Growth failure has been estimated to affect anywhere from 10 to 40% of all children with IBD, and is 3 times more likely to be permanent in children with CD than in those with UC.10 Molecular mechanisms that are proposed to impair growth in IBD include inflammatory cytokines, altered hormones and sex-steroid levels, and insufficient nutrition.9 The risk of growth impairment in children with IBD can be compounded by further growth impairment due to corticosteroid therapy itself. Other common adverse events associated with corticosteroids include bone loss, elevated blood pressure, elevated blood sugar, acne, hirsutism, facial swelling, weight gain, and increased risk of infection.

Immunomodulators. The immunomodulators 6-mercaptopurine (6-MP) and azathioprine are widely used in CD and UC to reduce steroid exposure and maintain remission. These drugs may take up to 3 to 6 months to achieve maximal effect. In general, when used, therapeutic doses are usually 1 to 1.5 mg/kg/day for 6-MP and 2 to 3 mg/kg/day for azathioprine.8

Methotrexate. Methotrexate has been commonly used in pediatric Crohn’s disease. Its role in ulcerative colitis has been still investigated. In a small, open-label study of children with CD resistant to 6-MP, the response rate to methotrexate was 50%. Methotrexate has been used for induction and maintenance of the remission in pediatric CD. It is typically started in children subcutaneously or orally at 15 mg/m2 per week up to 25 mg per week. Adverse effects include myelosuppression, oral ulcers, and increased risk of infections, pneumonitis, hepatitis and hepatic fibrosis.

Antibiotics. Although there are no controlled data available that show that antibiotics are efficacious, antibiotics are commonly used in IBD management in clinical practice. They have a limited role in treating intestinal inflammation and should be used primarily to treat complications such as abdominal or perianal abscesses. Ciprofloxacin and metronidazole are the two most commonly used antibiotics in IBD.

Biologic agents. Several biologic agents are approved for treatment of moderate-to-severe CD in adult patients. One of these, infliximab, has also been approved for use in pediatric patients with CD and severe UC. Adverse events most often experienced by IBD patients using these agents include infusion reactions, symptoms due to immune response directed against anti–TNF-α agents, opportunistic infections, and malignancy.8

Nutritional therapy has been used in pediatric IBD in one of three ways: (1) primary therapy to induce remission in small bowel CD, (2) supplemental therapy to improve weight gain and growth, and (3) to replenish micronutrient deficiencies. Primary therapy requires that 90% of the patient’s caloric needs are met by giving elemental or polymeric formulas as a whole source of nutrition. Although it can be taken by mouth, formula is often provided by nasogastric or gastrostomy tube because of its poor palatability. Supplemental nutritional therapy is used when a patient cannot take the recommended daily allowance for energy.

Indications for operative intervention in CD include complications of the disease such as bowel obstruction from intestinal stricture, intestinal perforation with or without abscess, fistulas, or hemorrhage. Additionally, individuals with segmental CD refractory to optimal medical management or causing substantial nutritional or growth failure may require surgical intervention.

Conclusion

IBD is a chronic inflammatory condition of the GI tract, marked by periods of exacerbation and remission. Children with ileocolitis generally have poorer response to medications and a greater need for surgery than those with small bowel disease alone. Younger age (less than age 25) appears to be associated with a greater risk for relapse.1,2 The risk of colorectal cancer appears to be similar in ulcerative colitis and Crohn’s colitis, and is affected by disease duration and severity. Chronic 5-ASA administration may decrease the risk of colorectal cance.13,14 Yearly screening colonoscopy for patients with colonic inflammation of greater than 8-10 years is indicated. Adenocarcinoma of the small bowel is rare, but occurs more frequently than in the general population. Affected patients often have disease for more than 20 years at the time of cancer development, tend to be male, have fistulizing disease, and previous surgical bowel resection.14,15 Death from IBD is extremely rare in the pediatric population.

Education of both the patient and family is essential in the management of IBD. Demystification of the disease course and thorough explanation for rationale of therapy and its complication often relieve unjustified fears.

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References

  1. Inflammatory bowel disease in children and adolescents. Children’s Digestive Health and Nutrition Foundation
  2. About Crohn’s disease. Crohn’s and Colitis Foundation of America; info@ccfa.org
  3. Kugathasan S, Judd RH, Hoffman RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a state population based study. J Pediatr. 2003;143: 525-531.
  4. Bousvaros A, Sylvester F, Kugathasan S, et al. Challenges in pediatric inflammatory bowel disease. Inflammatory Bowel Dis. 2006;12:885-913.
  5. Bousvaros A, Antonioli DA, Colleti RB, et al. Differentiating ulcerative colitis form Crohn’s disease: report of the working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America. J Pediatr Gastrenterol Nutr. 2007;44:653-674.
  6. Hugot J-P, Bellaiche M. Inflammatory bowel disease: the pediatric gastroenterologist perspective. Pediatr Radiol. 2007;37:1065-1070.
  7. Kugathasan S, Baldassano RN, Bradfield J, et al. Loci on 20q13 and 21q22 are associated with pediatric onset inflammatory bowel disease. Nat Genet. 2008;40: 1211-1215.
  8. Rufo PA, Bousvaros A. Current therapy of inflammatory bowel disease in children. Pediatric Drugs. 2006;8:279-302.
  9. Walters TD, Griffiths A. Mechanism of growth impairment in pediatric Crohn’s disease. Nat Rev Gastroenterol Hepatol. 2009;6:513-523.
  10. Hait E, Bousvaros A, Grand R. Pediatric inflammatory bowel disease: what children can teach adult. Inflamm Bowel Dis. 2005;11:519-527.
  11. Boot AM, Bouquet J, Krenning EP, et al. Bone mineral density and nutritional status in children with chronic inflammatory bowel disease. Gut 1998;42:188-194.
  12. Irving PM, Gearry RB, Sparrow MP,et at. Review article: Appropriate use of corticosteroids in Crohn’s disease. Aliment Pharmacol Ther. 2007;26:313-329.
  13. Munkholm P,. Incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 2003;18(Suppl 2):1-5
  14. Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn’s disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 1994;35:950-954.
  15. Van Hogezand RA, Eichhorn RF, Choudry A, et al. Malignancies in inflammatory bowel disease: fact or fiction? Scan J Gastroenterol Suppl. 2002;236:48-53.
  16. Loftus EV Jr, Tremaine WJ, Habermann TM, et al. Risk of lymphoma in inflammatory bowel disease. Am J Gastroenterol 2000;95:2308-2312.

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