Inflammatory Bowel Disease - IBD

Diagnosis

Indications for Testing 

• Diarrhea, bloody stools

Laboratory Testing

• Initial testing
  • CBC – microcytic anemia and thrombocytosis most common abnormalities
  • Sedimentation rate (ESR) or C-reactive protein (CRP)
    • Elevated ESR or CRP differentiates IBD from irritable bowel syndrome (IBS)
  • Albumin – may be decreased
  • Stool evaluation – rule out infectious etiologies
    • Clostridium difficile by PCR – if risk factors present
    • Ova and parasite stool culture – only if appropriate history
• Serologic testing for specific antibodies may be useful in supporting a diagnosis and classification of IBD, especially in indeterminate colitis; however, marker testing is not recommended as the sole means of definite diagnosis of IBD
  • >20 serologic markers currently identified for IBD with variable diagnostic performance
  • Classic markers that are widely available include the following 
    • Saccharomyces cerevisiae antibodies (ASCA) IgG and IgA antibodies
      • CD 60-70%; UC 10-15%
    • Atypical anti-neutrophilic cytoplasmic antibodies (atypical ANCA)
      • CD 5-15%; UC 60-80%
    • Anti-glycan antibodies (Crohn’s diagnostic panel) may also be useful in predicting risk for abdominal surgery in disease confirmed cases
  • Outer membrane protein complex (OMP) IgA antibodies
    • CD 50%; UC <10%
    • May detect ASCA seronegative CD patients
  • Others include anti-Iz IgA, CBir1 flagellin, anti-glycan antibodies
• Fecal calprotectin and lactoferrin
  • Not specific or sensitive in diagnosis of IBD
  • May assist in differentiating IBD from functional disorders of the intestinal tract, such as irritable bowel syndrome
    • Use of fecal lactoferrin may avert unnecessary endoscopies
    • Negative result and low pretest probability of disease may be sufficient to rule out a diagnosis of IBD
    • Positive result warrants further testing to definitely diagnose IBD

Histology

• Gold standard for diagnosis (American College of Gastroenterologists, 2011)
• CD – presence of sarcoid-like granulomas, lymphoid hyperplasia, ileal inflammation
• UC – cryptitis, crypt abscesses, mucin depletion, crypt atrophy, Paneth cell metaplasias

Imaging Studies

• CT/MRI scan
• Double-contrast barium enema – use only when endoscopy is not available
  • CD – ileum, terminal ileum, ileocecal valve and cecum
  • UC – ileum usually spared

Other Testing

• Endoscopy – gold standard when combined with histology
  • Wireless capsule endoscopy for detecting small bowel lesions
    • May be most helpful in patients with continued symptoms after surgery for UC

Prognosis

• Use any available panel that includes S. cerevisiae, laminar bioside carbohydrate, mannobioside carbohydrate, and chitobioside carbohydrate antibodies
• Positive result for ≥2 markers is associated with poor prognosis in CD

Differential Diagnosis

• IBS
• Colorectal cancer
• Ischemic colitis
• Infectious diarrhea – viral, bacterial, parasitic (Tropheryma whippleii)
• Celiac disease
• Diverticulitis
• Collagenous colitis
• Drug-induced enteropathy
• Eosinophilic gastroenteritis
• Pancreatic neuroendocrine tumor
  • Gastrinoma
  • VIPoma
  • Somatostatinoma

Screening

Monitoring

Pharmacogenetics and Therapeutic Drug Monitoring

• Thiopurine S-methyltransferase (TPMT)
  • Thiopurine prodrugs are metabolized via TPMT enzymatic activity
  • Deficiency of TPMT predicts hematopoietic toxicity after thiopurine treatment
  • Testing to determine activity level may be helpful in dosing thiopurine drugs and help avert bone marrow suppression
    • For deficient activity, dose reduction of 80-90% may be required
    • For intermediate activity, dose reduction of 20-50% may be required
• Infliximab – serum concentration testing for drug monitoring

Clinical Background

Inflammatory bowel disease (IBD) represents a spectrum of chronic disorders affecting the gastrointestinal tract, with Crohn disease (CD) and ulcerative colitis (UC) as the major disorders. When a definite diagnosis of CD or UC cannot be made following colectomy, disease is referred to as indeterminate colitis (IC). The term inflammatory bowel disease unclassified (IBDU) can be used to reflect clinical and endoscopic evidence of IBD with no small bowel involvement, no histological evidence in favor of CD or UC, and no infection.

Epidemiology

• Incidence
  • CD – 7-8/100,000
  • UC – 11/100,000
• Age
  • Initial and most common peak – 15-30 years
  • Second, smaller peak at >60 years
• Sex
  • CD – M>F, 1.8:1
  • UC – M:F, equal
• Ethnicity – incidence highest in Ashkenazi Jews and lowest in African Americans and Hispanics

Risk Factors

• Genetics
  • CD – first-degree relatives have 4- to 20fold increased risk   

Pathophysiology

• Inappropriate and persistent activation of the immune system against normal intestinal flora
  • CD
    • Typically involves ileum 
    • May affect any part of digestive tract
    • Extends deep into affected tissues
    • Asymmetrical and segmental with areas of both healthy and diseased tissue
  • UC
    • Ulcers and inflammation in top layers of colon and rectal lining
    • Symmetrical
    • Uninterrupted inflammation from the rectum proximally

Clinical Presentation

• CD – ileocolitis, abdominal pain, fever
• UC – diarrhea, rectal bleeding, abdominal pain
• Extraintestinal manifestations – up to 35% of IBD cases
  • Dermatologic
    • Erythema nodosum – 15% CD and 10% UC
    • Pyoderma gangrenosum – <1% CD and 5-10% UC
    • Sweet syndrome – acute febrile neutrophilic dermatosis
  • Musculoskeletal
    • Arthritis – 10-15% of all IBD patients; large joints, often asymmetric
    • Ankylosing spondylitis – 10% of all IBD patients
  • Ophthalmologic
    • Uveitis/iritis – 10% of all IBD patients
    • Episcleritis
  • Gastrointestinal
    • Hepatic steatosis – 50% of all IBD patients
    • Primary sclerosing cholangitis (PSC) – 1-5% of all IBD patients
      • 50-75% of all PSC patients have IBD
    • Cholelithiasis
  • Genitourinary
    • Ureteral obstruction and fistulae – <5% of all patients
    • Nephrolithiasis – 10-20% CD
    • Metabolic bone disease
• Complications
  • CD – fistulas, abscesses
  • UC – massive hemorrhage, toxic megacolon, marked increase in incidence of colon cancer

Treatment

• Early treatment may delay complications
• Goal of treatment is remission

Pediatrics

Clinical Background

Epidemiology

• Prevalence – 10-25% of IBD cases diagnosed in childhood
  • Steady increase in incidence over past four decades
• Sex
  • M>F – less so than in adult-onset disease

Clinical Presentation

• Childhood-onset disease typically has more severe phenotype characterized by extensive intestinal involvement with rapid, early progression
• Most patients present before adolescence
  • <5 years – isolated colonic disease common
  • 6-17 years – small bowel disease and extensive disease more common
• Crohn disease (CD) more common than ulcerative colitis (UC)

Treatment

• Immunomodulatory treatment needed much more often

Diagnosis

Indications for Testing

• Diarrhea, bloody stools

Laboratory Testing

• Initial testing
  • CBC – microcytic anemia and thrombocytosis most common abnormalities
  • Sedimentation rate (ESR) or C-reactive protein (CRP)
    • 25% of children with mild IBD have normal CRP, ESR
  • Albumin – may be decreased
  • Stool evaluation – rule out infectious etiologies
    • Clostridium difficile toxin B gene (tcdB) by PCR – if risk factors present
    • Ova and parasite stool culture – based on patient history
  • Normal test results for CBC, albumin, stool examination and antimicrobial drug intake should not prevent a full workup of IBD, if clinical suspicion for disease is strong
• Serologic testing – not recommended as sole means of diagnosis
  • Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) may be useful adjunct diagnostic tools
  • Fewer studies in children
  • Negative results do not rule out IBD – assays have low sensitivities for UC and CD
  • Crohn disease (CD) prognostic panel
    • May be useful in predicting disease phenotype in confirmed CD patients
    • Panel is made up of 4 glycan antibody tests
      • Saccharomyces cerevisiae antibody (gASCA) IgG
      • Laminaribioside carbohydrate antibody (ALCA), IgG
      • Mannobioside carbohydrate antibody (AMCA), IgG
      • Chitobioside carbohydrate antibody (ACCA), IgA
    • Presence of two or more markers has a specificity of  ≥95% for CD with a 1.7 elevated relative risk for abdominal surgery compared to seronegative patients with CD
• Fecal lactoferrin and calprotectin may assist in differentiating IBD from functional disorders of the intestinal tract, such as irritable bowel syndrome
  • May avert unnecessary endoscopies
  • For pediatric patients with GI symptoms and a low pretest probability of disease, a positive result helps justify further invasive testing

Histology 

• Gold standard for diagnosis (American College of Gastoenterologists, 2011)

Other Testing

•  Endoscopy – gold standard when combined with histology

Monitoring

• Fecal lactoferrin and calprotectin
  • Most useful in monitoring disease severity
  • Cannot be used to differentiate IBD from irritable bowel syndrome

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Saccharomyces cerevisiae Antibodies, IgG & IgA 0050564 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Use S. cerevisiae antibodies along with pANCA and OMP IgA to differentiate CD from UC in patients with suspected IBD Results should be used in conjunction with clinical history, imaging and/or histological studies Results may serve as adjunct diagnostic tools for CD
Anti-Neutrophil Cytoplasmic Antibody, IgG 0050811 Method: Semi-Quantitative Indirect Fluorescent Antibody	Detection of atypical pANCA pattern in the absence of ASCA IgG and IgA antibodies is associated with UC Results should be used in conjunction with clinical history, imaging and/or histological studies Results may serve as adjunct diagnostic tools in differentiating UC from CD If ANCA screen detects antibodies ≥1:20 dilution, titer to end point is added
Ankylosing Spondylitis (HLA-B27) Genotyping 0050392 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Most useful in patients with suspicion for ankylosing spondylitis