Pediatric Crohn Disease: Practice Essentials, Background, Pathophysiology (original) (raw)

Practice Essentials

Crohn disease, a chronic inflammatory bowel disease (see the image below) that was once considered rare in the pediatric population, is currently recognized as one of the most important chronic diseases that affect children and adolescents. Approximately 20-30% of all patients with Crohn disease present when they are younger than 20 years. In addition to the common GI symptoms (diarrhea, rectal bleeding, and abdominal pain), children with Crohn disease often experience growth failure, malnutrition, pubertal delay, and bone demineralization.

Colonoscopic image of large ulcer and inflammation of descending colon in 12-year-old boy with Crohn disease.

Signs and symptoms

The clinical presentation is primarily determined by the location and extent of the patient’s disease. With upper GI tract involvement, nausea, vomiting, and abdominal pain dominate as presenting symptoms.

Children with Crohn disease of the small intestine usually present with evidence of malabsorption, including the following:

• Diarrhea
• Abdominal pain
• Growth deceleration
• Weight loss
• Anorexia

Initially, manifestations of malabsorption may be quite subtle. The onset of growth failure is usually insidious and may precede GI symptoms by years.

Colonic Crohn disease may be clinically indistinguishable from ulcerative colitis (UC), with manifestations that include the following:

• Bloody mucopurulent diarrhea
• Cramping abdominal pain
• Urgency to defecate

Perianal involvement in Crohn disease may produce the following:

• Simple skin tags, fissures, abscesses, and fistulae
• Painful defecation
• Bright-red rectal bleeding
• Perirectal pain, erythema, or discharge

Physical examination findings

• Vital signs are usually normal, although tachycardia may be present in anemic patients
• Chronic intermittent fever is a common presenting sign
• Body weight and height may reveal weight loss and growth delay
• The most sensitive indicator of growth abnormalities is a decrease in growth velocity, which may be observed before the major percentile lines on standard growth curves are crossed
• Abdominal findings may vary from normal to those of an acute abdomen; diffuse abdominal tenderness is common; fullness or a discrete mass may be palpable, typically in the right lower quadrant
• Perianal disease (eg, skin tags, abscesses, fistulae, fissures) is present in approximately 45% of patients
• Tanner staging may indicate pubertal delay, which may precede the onset of intestinal symptoms
• The most common cutaneous manifestations are erythema nodosum and pyoderma gangrenosum
• Skin examination may also reveal pallor in patients with anemia or jaundice in those with concomitant liver disease
• The most common ocular findings are episcleritis and anterior uveitis
• The most common extraintestinal manifestations of Crohn disease are arthritis and arthralgia, typically involving the large joints (eg, hips, knees, ankles)

See Clinical Presentation for more detail.

Diagnosis

Laboratory data for Crohn disease are nonspecific, as follows:

• The CBC may show hypochromic microcytic anemia, from iron deficiency due to GI blood loss, or normocytic anemia of chronic disease
• levels of acute-phase reactants (ESR and CRP) are often elevated in patients with Crohn disease but may be normal
• Hypoalbuminemia is common
• Additional common deficiencies include iron and micronutrients (eg, folic acid, vitamin B-12, serum iron, total iron binding capacity, calcium, and magnesium)
• Stool studies should be obtained to rule out bacterial or parasitic infection
• Excretion of fecal calprotectin is increased with colorectal inflammation [1] ; on ELISA, the cutoff level is 50 µg/g feces.

Imaging studies

• A single-contrast upper GI radiologic series with small-bowel follow-through (SBFT) can be used to evaluate the small intestine, which cannot be reached during endoscopy
• Magnetic resonance enterography (MRE) [2] and computed tomography enterography (CTE) are as sensitive and specific as SBFT for detection of small bowel inflammation and may be more accurate for detection of extraenteric complications, including fistulae and abscesses [3]
• MRI is especially useful in the evaluation of pelvic and perianal disease
• Abdominal ultrasonography (US) can be used to investigate intestinal disease and to rule out gallbladder and kidney stones

Endoscopy

• Colonoscopy with several colonic and terminal ileal biopsies is considered a standard diagnostic procedure
• Upper endoscopy, or esophagogastroduodenoscopy (EGD), should be part of the first-line investigation
• Video capsule endoscopy is increasingly being used to evaluate for small-bowel Crohn disease in children [4]

See Workup for more detail.

Management

The general goals of treatment for children with Crohn disease are as follows:

• To achieve the best possible clinical, laboratory, and histologic control of the inflammatory disease with the least adverse effects from medication
• To promote growth with adequate nutrition
• To permit the patient to function as normally as possible (eg, in terms of school attendance and participation in activities)

Step-up approach

• Patients with mild disease are treated with preparations of 5-aminosalicylic acid (5-ASA), antibiotics, and nutritional therapy
• If no response occurs or if the disease is more severe than was initially thought, corticosteroid and immunomodulatory therapy with 6-mercaptopurine (6-MP) or methotrexate (MTX) is attempted
• Infliximab is effective in patients who have an inadequate response to conventional therapy and in patients who have fistulizing Crohn disease [5]
• Adalimumab is a safe and effective substitute for patients who are allergic to infliximab or develop high titers of human antichimeric antibodies (HACA) [6]
• Surgery is considered when medical therapy fails [7]

Surgical care

Indications for surgery include the following:

• Intractable disease with growth failure
• Obstruction or severe stenosis
• Abscess requiring drainage
• Perianal fistulae
• Intractable hemorrhage
• Perforation

Features of surgery are as follows:

• Recurrence of disease at the anastomotic site is common after resection
• Surgical treatment for Crohn disease is not curative
• Laparoscopic techniques are becoming the standard of care [8]

See Treatment and Medication for more detail.

Patient education

Education of patients and their families is encouraged and extremely important in the treatment process. Useful education materials can be obtained by contacting the Crohn’s and Colitis Foundation of America.

Background

Crohn disease is a chronic inflammatory bowel disease. Once considered rare in the pediatric population, it is recognized with increasing frequency among children of all ages. Approximately 20-30% of all patients with Crohn disease present when they are younger than 20 years. With its increasing recognition, Crohn disease has become one of the most important chronic diseases that affect children and adolescents.

In addition to the common gastrointestinal (GI) symptoms (diarrhea, rectal bleeding, and abdominal pain), children often experience growth failure, malnutrition, pubertal delay, and bone demineralization. Other problems unique to the pediatric population include the paucity of controlled clinical trials and the psychological issues that occur in children and adolescents with Crohn disease. These problems necessitate a medical approach that promotes clinical improvement and reverses growth failure with minimal toxicity.

Pathophysiology

The pathogenesis of Crohn disease is multifactorial. After a triggering event occurs in a genetically susceptible individual, an altered immune response leads to chronic inflammation of the intestine. Although the etiology of the precipitating event is unknown, luminal bacteria or specific antigens are thought to be involved.

Chronic inflammation from T-cell activation leading to tissue injury is implicated. After activation by antigen presentation, unrestrained responses of helper lymphocytes type 1 (Th1) predominate because of defective regulation. Th1 cytokines (eg, interleukin [IL]–12 and tumor necrosis factor [TNF]-α) stimulate the inflammatory response. Inflammatory cells recruited by these cytokines release nonspecific inflammatory substances (eg, arachidonic acid metabolites, proteases, platelet activating factor, and free radicals), which directly injure the intestine.

The macroscopic findings at the time of endoscopy or colonoscopy or surgery include various degrees of edema, erythema, ulceration, friability, thickening of the bowel wall and mesentery, and extension of fat over the serosal surface of the intestine (see the image below).

Skipped areas of inflammation anywhere in the upper or lower GI tract are characteristic of Crohn disease, in contrast to the continuous diffuse colonic inflammation found with ulcerative colitis (UC). Microscopic findings on intestinal mucosal biopsy consist of chronic inflammation with architectural distortion. Granulomas are sometimes noted on biopsy findings in Crohn disease but never in UC; their presence can be useful in distinguishing between these 2 entities.

Etiology

The etiology of Crohn disease is multifactorial. An interaction between the predisposing genetic factors, environmental factors, host factors, and triggering event is necessary for the disease to develop.

A high rate of concordance for Crohn disease between monozygotic twins (44.4%) compared with dizygotic twins (3.8%) was reported in a Swedish study of an unselected twin registry. [9] Because monozygotic twins share identical genomic material and yet may be discordant for Crohn disease, the genetic component is necessary but not sufficient, as in all multifactorial diseases.

About 30% of patients whose disease is diagnosed when they are younger than 20 years have a positive family history. The percentage decreases to 18% for patients whose disease is diagnosed at age 20-39 years and to 13% after age 40 years.

The first and best-described disease-associated mutations for Crohn disease were found on the NOD2/CARD15 gene, which is found on chromosome 16 and regulates intracellular immune response to bacterial products. [10] Stricturing disease necessitating early surgery, ileal involvement, and younger age at diagnosis are phenotypic characteristics that have been associated with recognized CARD15 mutations. Approximately 25% of white children have a CARD15 mutation, compared with only 2% of black and Hispanic children. [11]

Additional genes associated with Crohn disease have been discovered. An association between mutations in the IL23R gene and inflammatory bowel disease (IBD) has been confirmed, suggesting a major protective effect on susceptibility to Crohn disease. A predisposition to Crohn disease, specifically with ileal involvement, has been associated with a single-nucleotide polymorphism (SNP) in the ATG16L1 gene, which is involved in autophagocytosis, an essential component of the innate immune response targeted towards pathogen-derived proteins.

Epidemiology

United States statistics

Over the past few decades, the incidence of IBD (Crohn disease in particular) has greatly increased. The age-specific rate in North America for children aged 10-19 years is estimated to be approximately 3.5 cases per 100,000 population. The only prospective pediatric epidemiologic study from North America showed that the rate of Crohn disease in Wisconsin was 4.56 cases per 100,000 population, or twice that of UC. [12]

International statistics

The rate of Crohn disease in Europe and Canada is 2.1-3.7 cases per 100,000 population, and rates are somewhat higher in northern regions than southern regions. Crohn disease is rare in Africa, Asia, and South America.

Age-, sex-, and race-related demographics

The rate of Crohn disease reaches its first peak in the second and third decade of life. The second, smaller peak occurs in adults aged 60-80 years. Approximately 25% of all cases of IBD are diagnosed before age 20 years.

The rate of Crohn disease in women is 1.1-1.8 times higher than that in men. There is a reverse pattern with pediatric IBD, which occurs at a higher rate in boys than in girls. In the United States, the pediatric male-to-female ratio in 2003 was 1.6:1.

Crohn disease is more common in Whites than in Blacks and is rare in Asian and Hispanic children. Rates are higher in people of Jewish descent, particularly Ashkenazi Jews and Jews of middle European origin compared with Sephardic or eastern European Jews.

Prognosis

Although Crohn disease may have a sizable effect on the life of a child or adolescent, with appropriate treatment and support, the prognosis is good, and the risk of a fatal outcome is extremely low.

Death from Crohn disease is extremely rare in children and adolescents. Severe and complicated Crohn disease may result in prolonged hospitalizations, multiple surgical procedures, growth failure, malnutrition, pubertal delay, and poor quality of life.

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Author

Andrew B Grossman, MD Associate Professor of Clinical Pediatrics, Co-Director, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania

Andrew B Grossman, MD is a member of the following medical societies: American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Crohn's and Colitis Foundation of America

Disclosure: Nothing to disclose.

Coauthor(s)

Petar Mamula, MD Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine

Petar Mamula, MD is a member of the following medical societies: American Academy of Pediatrics, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Chief Editor

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Royal College of Physicians and Surgeons of Canada

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers' bureau.

Acknowledgements

Robert Baldassano, MD Director, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, Associate Professor, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania

Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Stefano Guandalini, MD Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital

Stefano Guandalini, MD is a member of the following medical societies: American Gastroenterological Association, European Society for Paediatric Gastroenterology, Hepatology & Nutrition, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.