CROHN'S DISEASE in pediatric

Crohn's disease is An inflammatory disease primarily of the terminal ileum characterized by transmural inflammation resulting in abdominal pain, diarrhea, and weight loss.

EPIDEMIOLOGY:

• incidence: 5-11/100,000
• age of onset:
• peak age of onset in 2nd and 3rd decades
• less than 5% present before 5 years of age
• risk factors:
• M = F
• whites > blacks
• Jews

PATHOGENESIS:

1. Etiology

expression of the disease seems to be dependent upon a susceptible host being exposed to specific triggers:

1. Genetic Predisposition (Susceptible Host)

• likelihood of finding inflammatory bowel disease in a 1st degree relative of the patient is 5-25%
• siblings and parents of patients are 17-35x and 35-70x, respectively, more likely to develop Crohn's Disease than the general population
• high concordance in monozygotic twins

2. Specific Triggers

neither exogenous (infectious, drugs, toxins) or endogenous (immune) triggers have been identified thus far
there is no convincing evidence to implicate a particular bacteria, myobacteria, virus, or protozoan
a defininte immunogenic etiology has not been established, i.e., autoimmune, defect in antigen processing, or immunoregulation

2. Anatomic Gastrointestinal Involvement

Areas (%)

• terminal ileum + variable segments of the colon (particularly the ascending colon) - 50-60%
• small bowel involvement only (most in terminal ileum) - 30-35%
• large bowel only - 10-15%
• the esophagus, stomach, or duodenum is involved in 30-40% of patients

CLINICAL FEATURES:

1. Gastrointestinal Manifestations

• abdominal pain (75%)
• diarrhea (65%)
• weight loss (65%)
• fever (50%)
• growth retardation (25%)
• nausea/vomiting (25%)
• rectal bleeding (20%)
• perirectal disease (15%)
• extraintestinal manifestations (25%)

1. Abdominal Pain

• position of pain reflects site of bowel involvement:
• right lower quadrant (RLQ) - terminal ileum or cecal
• periumbilical - colonic or diffuse small bowel
• epigastric - gastroduodenal
• odynphagia & dysphagia - esophageal
• pain is persistent, severe, and can awaken patient from sleep
• worse with eating and, if colon involved, with defecation
• RLQ pain may be associated with tenderness, and a fullness or distinct mass on palpation
• pain is the result of transmural inflammation resulting in irritation of the serosa, gut dysmotility, and/or distension

2. Diarrhea

• ranges from 2-10 loose movements/day +/- nocturnal defecation
• bloody diarrhea often with colonic involvement or small bowel disease with ulceration

3. Weight Loss

• multifactoral etiology for malnutrition -> weight loss:
• sub-optimal intake (anorexia)
• malabsorption of fats, proteins, carbohydrates, with deficiencies of iron, folic acid, calcium, magnesium, zinc, vitamins D, K, B12
• increased energy requirements associated with inflammation
• increased stooling

4. Fever

• low grade or spiking (to 40 C)
• may persist for long periods

5. Growth Retardation

• due to chronic undernutrition or high-dose steroids
• may precede the clinical illness by months or years
• may continue during states of remission

6. Perirectal Disease

• perirectal inflammation with fissures, fistulas, tags, or adhesions

2. Gastrointestinal Complications

1. Hemorrhage

• massive acute GI bleed (in 1% of patients) due to ulceration into a large blood vessel

2. Obstruction

• due to severe bowel wall inflammation/edema, stricture formation, adhesions, and/or abscesses
• usually partial rather than complete
• chronic partial obstruction may lead to a bacterial overgrowth +/- malabsorption

3. Perforation

• rare complication
• if occurs, usually involves the terminal ileum
• results in free air in the abdominal cavity +/- peritonitis

4. Abscess

• due to transmural bowel inflammation with fistulization and perforation
• may be enteroperitoneal, interloop, intramesenteric, retroperitoneal-ileopsoas, hepatic, splenic, or subdiaphragmatic

5. Fistula Formation

• common complication
• perianal and perirectal fistulization most common
• other types: enteroenteric (ileal-sigmoid colon most common), enterovesical, enterovaginal, enterocutaneous

6. Others

• toxic megacolon (3.7%) - increases to 11% if disease confined to colon
• carcinoma - 20x greater risk than in general population

3. Extraintestinal Manifestations

1. Hepatobiliary

1. Hepatic

• chronic hepatitis
• fatty liver
• cirrhosis
• hepatic abscess
• hepatic granuloma
• hepatic steatosis

2. Biliary

• cholecystitis (acalculous, granulomatous)
• cholelithiasis
• pericholangitis
• sclerosing cholangitis

2. Renal

• enterovesical fistulas
• nephrolithiasis
• perinephric abscess
• perivesical infection
• ureteral obstruction & hydronephrosis +/- hypertension
• amyloidosis (associated with renal failure)

3. Rheumatoid

1. Arthralgias and Arthritis (in 15% of patients)

• may be present several years before the onset of gastrointestinal symptoms
• large joints of the legs more commonly affected
• arthritis is non-deforming, transient, asymmetric and more common with colonic involvement
• activity of joint disease often parallels the activity of the bowel disease

2. Ankylosing Spondylitis

• in 2-6% of patients
• course tends to be independent of the bowel disease

3. Clubbing

• particularly with small bowel disease

4. Musculoskeletal

• myalgias
• granulomatous myositis and myopathy

5. Cutaneous

• erythema nodosum
• pyoderma gangrenosum
• epidermolysis bullosa acquisita
• canker sores
• polyarteritis nodosa
• granulomatous dermatitis ("metastatic" Crohn's)

6. Ocular

• episcleritis
• iritis
• orbital pseudotumor
• posterior subcapsular cataracts (steroid therapy)
• uveitis

7. Vascular

• thrombocytosis with vascular complications:
• deep vein thrombosis
• pulmonary embolism
• neurovascular disease (seizures, encephalopathy)
• vasculitis (involving the aorta & subclavian artery)

INVESTIGATIONS:

1. Endoscopy/Colonoscopy

1. Macroscopic

• focal or segmental inflammation with skip areas of normal mucosa
• complications of inflammation:
• cobblestone pattern (ulceration with regeneration and hyperplasia)
• wall thickening with stricture formation
• fissures, sinues, ulcerations, fistulas, phlegmon (inflammatory masses)
• matted adjacent loops of bowel

2. Microscopic

1. Early Changes

superfical aphtoid lesions of mucosa overlying lymphoid follicles; granulomas

2. Later changes

1. Transmural Enterocolitis

• diagnostic with histopathology of intestinal lesions showing extensive infiltration with inflammatory cells
• lymphocytes, histiocytes, plasma cells found throughout the bowel wall but extensively in the submucosa
• collagen deposition within the submucosa leading to strictures +/- obstruction
• deep fissuring ulceration into the muscularis propria
• crypt abscesses and goblet cell depletion

2. Granulomas

may be absent in 60-70% of biopsies

2. Imaging Studies

1. Barium Enema

1. Single Contrast

• to identify colonic fissures
• contraindicated in suspected cases of severe colitis

2. Double Contrast (Air-Barium)

to define mucosal defects - narrowing, stenotic areas, cobblestoning, filling defects

2. Upper GI Series with Small Bowel Followthrough

• particularly to visualize the terminal ileum:
• cobblestone
• deep ulcers
• fistula
• nodularity
• stenotic areas (string sign)
• thickened bowel loops

3. Abdominal Ultrasound/CT

• bowel wall thickening
• abscesses

3. Serum

• elevated ESR (80%)
• anemia (70%)
• hypoalbuminemia (60%)
• thrombocytosis (60%)
• normal WBC
• normal or low zinc, magnesium, calcium, phosphorus
• anemia is usually microcytic (with low serum iron and ferritin) but can be macrocytic with folate or B12 deficiencies

4. Stools

• guaiac-positive in 35% of cases
• negative for pathogens

5. For Malabsorption

1. Fat

elevated 72 hour fecal fat excretion

2. Carbohydrate

positive Breath Hydrogen Test

3. Protein

elevated fecal clearance of serum alpha-1 antitrypsin in 90% of cases

MANAGEMENT:

1. Diagnosis

Laboratory - microscopic examination of lesions showing transmural inflammation with skip lesions

2. Education

diagnosis, definition, epidemiology, prognosis, treatment options (multidisciplinary approach with Paediatrics, Gastroenterologists, Dieticians, Psychologists, Surgery, etc.)

3. Treatment Options

treatment of acute exacerbations

4. Goals of Therapy

• therapy (pharmacolgic, nutritional, or surgery) is not curative
• no prophylactic role of therapy
• goal is to control symptoms, prevent complications, improve growth, and to induce remission during an acute episode by either pharmacologic, nutritional and/or surgical strategies
• a Paediatric Crohn's Disease Activity Index (PCDAI) has been devised to moniter the progress of the disease (J. Ped. Gastroent. Nut. 10:439 [1991])

5. Management Strategies

1. Pharmalogical

1. Prednisone

• 1-2 mg/kg/day po od or bid (maximum 40-60 mg/d) an anti-inflammatory agent role is to induce remission in those with small or large bowel disease
• once in remission, decrease dose by 5 mg/week
• may require parenteral therapy if active disease is serious
• long-term, low-dose daily therapy does not prevent relapses or decrease the disease progression
• contraindicated if intra-abdominal sepsis
• side effects: growth suppression, posterior subcapsular cataracts, glaucoma, aseptic necrosis of the femoral head, vertebral collapse, hypertension, depression, acne, hirsutism, striae (may be minimized by alternate day low dose therapy)

2. Sulfasalazine

• 30-50 mg/kg/day po bid-tid
• an anti-inflammatory agent by decreasing prostaglandin and leukotriene synthesis
• role is to induce remission in those with large bowel disease
• sustained-release aminosalicylic acid (5-ASA) may be superior to placebo in treating ileitis
• side effects: nausea, vomiting, abdominal pain, headaches for up to 2 weeks after onset; hypersensitivity rash, bone marrow suppression, pancreatitis, reversible male infertility

3. Antibiotics

1. Broad-Spectrum

• Ampicillin/Gentamicin/Flagyl, for febrile patients even in the absence of sepsis (to cover for microfistulization and localized infection)
• Metronidazole, 15-20 mg/kg/day po bid-tid acts as an antibiotic and to suppress cell-mediated immunity, indicated for perirectal or colonic disease,75% have recurrence if medication discontinued. Sside effects: peripheral neuropathy - 85% develop a sensory peripheral neuropathy or reduced nerve conduction velocity; paresthesia (all reversible on decreasing or stopping medication)

4. Immunosuppressive Therapy

• azathiprine, 6-mercaptopurine
• may decrease steroid doses in those patients with severe disease on high steroid dosages and improve disease symptoms after 3-4 months of therapy

2. Nutritional Therapy

1. Elemental Diet

• use during acute exacerbations
• as effective as TPN + complete bowel rest in inducing remission
• may act to decrease inflammation of the bowel by decreasing antigenic stimulation of the gut
• less effective in inducing remission in patients with colonic involvement, fistulas, and perianal disease
• may administer by nocturnal tube feeds

2. Total Parenteral Nutrition (TPN)

indications:

• severe acute exacerbations
• severe disease + malnutrition
• extensive bowel resection leading to a short gut syndrome
• reverse growth retardation
• usually used as adjunctive therapy to medications

3. Others

mineral and/or vitamin deficiencies with specific therapy

3. Surgery

1. Bowel Resection

50-70% of children require surgery within 10-15 years after diagnosis
indications:

• failure of pharmacologic/nutritional therapy
• steroid toxicity
• others - obstruction, hemorrhage, perforation, fistula
• procedure is not curable but to put the disease into remission with the risk of recurrence dependent upon the extent and severity of the disease

2. Strictures

surgical resection or strictureplasty for localized strictures

3. Severe Perirectal Disease

may treat conservatively (abscess drainage, anal fistulotomy, partial internal sphincterectomy, and/or proctectomy) or by fecal diversion with an ileostomy or colostomy

4. Supportive (Psychiatric)

• individual and/or family counselling
• age-appropriate support groups
• depression due to having a chronic incurable disease

6. Prognosis

Crohn's Disease at this time is a chronic incurable disease of the bowel marked by periods of exacerbation and remission (99% suffer at least one relapse)
triggers of acute exacerbations are unknown but viral illnesses (EBV, adenovirus) may play a role
unable to predict the extent and severity of the disease over time (except those with ileocolitis have greater morbidity)
thus while morbidity is very high, mortality is essentially zero