Inflammatory Bowel Disease

Introduction

Inflammatory bowel disease (IBD) is a multifactorial disease characterized by chronic inflammation with periods of remission and exacerbation of the GI tract. IBD is classically categorized as either Crohn’s disease (CD) or Ulcerative Colitis (UC). The two disorders have many common elements, however there are some characteristics used to differentiate the two. Crohn's disease is characterized by transmural inflammation and skip lesions, while Ulcerative Colitis is typically characterized by mucosal inflammation only and contiguous involvement of the GI tract which includes the rectal mucosa. Further differences between the two is outlined in Table 1.  

Incidence

• Current incidence is estimated 5-11/100,000 in the US
• 20-25% of new IBD cases are diagnosed in children
• There is acceleration in incidence in recent years with the most significant increases occurring in children < 9yrs.
• M:F is 1.5:1 for pediatric CD vs 1:1 in adult CD
• M:F is 1:1 for pediatric UC, similar to adult UC
• The ratio of CD:UC is 2.8:1 compared to a ratio of 0.85:1 in adults.
• Whites and Eastern European Jews have a higher incidence

Etiology

The precise cause is unknown, though several theories exist. 

• The hygiene hypothesis- low microbial exposure early in life leads to less capable immune system later in life, unable to eliminate offending agents causing chronic inflammation
• Heritable disease- family history is a very strong risk factor for disease
• Infectious cause- limited evidence, but an entero-adhesive/ invasive strain of E.Coli has been associated with ileal CD.
• Impaired interaction with gut flora- there is enhanced reactivity against gut bacterial antigens in those with IBD, and some gene mutations associated with IBD code bacterial-sensing proteins

Clinical Features of IBD

• Intestinal symptoms: characterized by variable and overlapping symptoms

• The classic triad for UC is abdominal pain, diarrhea and rectal bleeding
• The classic triad for CD is abdominal pain (often localized to the RLQ), diarrhea and weight loss.
• Other symptoms especially for UC include-

• hematochezia
• fecal urgency
• low grade/intermittent fevers
• anorexia
• anemia,
• hypoalbuminemia

• Other symptoms for CD include-
  • growth failure
  • non-bloody to melanotic stool to frank blood in stool
  • recurrent apthous-stomatitis
  • anal disease including tags, fissures, fistulas or abscess
• Growth Failure- more frequent in CD>UC, often precedes diagnosis
• Other-
  • nausea/vomiting,
  • pain with defecation,
  • fever without localization
  • clubbing

• Extra-intestinal manifestations:
  • Joint inflammation- peripheral joints or axial joints (ankylosing spondylitis and sacroiliitis)
  • Cutaneous manifestations- erythema nodusum and pyoderma gangrenosum
  • Ocular disease- episleritis and uveitis- more frequent in CD
  • Osteoporosis
  • Oral apthous stomatitis
  • Primary sclerosing cholangitis- in UC patients
  • Renal stones- classically oxalate stones
  • Pancreatitis
  • Neurologic symptoms include neuropathies, myelopathies, and myasthenia gravis
  • Clubbing

Differentiating Crohn's and Ulcerative Colitis

Table 1. Classic Findings

Diagnosis

• Lab studies: CBC with diff, ESR, CRP, LFTs
• Exclude infectious etiology with screening stool studies: culture for Salmonella, Shigella, E.coli, Campylobacter, Yersinia; examination for Giardia and Cryptosporidium; assay for C. diff; if history applicable check for Entamoeba histolytica.
• Fecal calprotectin (CP) and lactoferrin (FL)- noninvasive markers for gut inflammation
• Serology- not recommended for screening or isolated diagnostic tool. Most useful to differentiate UC vs CD in children with indeterminate colitis. Includes:
• ASCA (anti-Saccharomyces cerevisiae antibody)
• Immunoglobin A and G
• ANCA (anti-neutrophil cytoplasmic antibody)
• Histamine protein 1
• DNAase-specific
• Anti Omp C (outer membrane protein of E. coli) (see Table 1)
• Imaging- endoscopy both esophagogastroduodenoscopy and colonoscopy with biopsy sampling is the gold standard: differences seen in imaging and pathology are outlined in Table 1.

Treatment

• Steroids- used for induction of remission with a taper given over 2 mo.; budesonide which has significant first pass metabolism is delivered more to distal ileum and proximal colon and has less efficacy in CD and little efficacy for UC compared to other conventional steroids.
• Nutritional therapy- uses specific elemental or polymeric formulas as primary treatment to induce remission. Has been shown to produce short term remission in 80% of children with CD. May be considered as first line agent in pediatric population with CD, but difficult adherence.
• 5-Aminosalicylates- well tolerated in children with few side effects, but possibly little efficacy compared to placebo in CD for induction of remission. Mild to moderate effect for remission and maintenance in UC.
• 6-MP and azathioprine (AZA)- slow onset of action (3-6mo), used for maintenance of remission in both UC and CD.
• Methotrexate- often used for induction and maintenance in CD, especially if refractive to 6-MP class or steroids. May be helpful for maintenance in UC if steroid dependent or refractory to other treatments. Subcutaneous injections are more efficacious than oral medication.
• Cyclosporine- only used as a rescue therapy in severe, refractory UC.
• Biologics- Infliximab is the first TNF-alpha blocker to be approved for pediatric IBD. It is a chimeric monoclonal IgG antibody that binds TNF-alpha. It shows efficacy for induction and maintenance in both CD and UC, often use is reserved for moderate-severe disease. There have been cases of hepatosplenic T-cell lymphoma often in young males patients taking both infliximab and 6-MP/AZA. Therefore infliximab is not currently used in conjunction with immunomodulators.
• Antibiotics- metronidazole and ciprofloxacin are often used for fistula or pouchitis treatment.
• Surgery- indications include fulminant colitis, perforation, stricture, absess, fistula, toxic megacolon, failure of medical therapy or steroid dependency, dysplasia, pediatric growth failure or pubertal delay

References:

1. Mamula, Petar, et al. Inflammatory bowel disease in children 5 years of age and younger. The American journal of gastroenterology 97.8 (2002): 2005-2010.
2. Shikhare G and Kugathasan S. Inflammatory bowel disease in children: current trends. J Gastroenterol. 2010; 45:673-82.
3. Sauer C and Kugathasan S. Pediatric Inflammatory bowel disease: highlighting pediatric differences in IBD. Gastroenterol Clin N Am. 2009; 38:611-28.
4. Crandall, Wallace V., et al. Improved outcomes in a quality improvement collaborative for pediatric inflammatory bowel disease. Pediatrics 129.4 (2012): e1030-e1041.
5. Podolsky D.K. Inflammatory Bowel Disease. NEJM Vol. 347 No. 6 August 8, 2002
6. Galbraith S., Drolet B, et al. Asymptomatic Inflammatory Bowel Disease Presenting With Mucocutaneous Findings. Pediatrics 2005. 116: e439-e444
7. Hyams J. Inflammatory Bowel Disease Pediatrics in Review September 2005 12.
8. Colombo J et al. Getting current on the treatment of inflammatory bowel disease.  Contemporary Pediatrics Oct 2006
9. Mack et al. Laboratory Values for Children with Newly Diagnosis Inflammatory Bowel Disease. Pediatrics June 2007
10. Glick S, and Caravalho R.  Inflammatory Bowel Disease.  Pediatrics in Review January 2011