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
  • 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
        • ASCA IgG antibodies – found in 60-70% of CD and 10-15% of UC patients
        • ASCA IgA antibodies – found in 35% of CD and <1% of UC patients
        • Detection of ASCA IgG and IgA antibodies in the same serum specimen is highly specific for CD
      • 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
    • No role for HLA-B27 testing in IBD – test is most useful in patients symptomatic for ankylosing spondylitis
  • Fecal calprotectin
    • Precision of test higher in children
    • May assist in differentiating IBD from functional disorders of the intestinal tract, such as irritable bowel syndrome
      • May avert unnecessary endoscopies (van Rheenen, 2010)
      • Negative result and low pretest probability of disease may be sufficient to rule out a diagnosis of IBD (Yang, 2014)
      • Positive result warrants further testing to definitely diagnose IBD
      • Superior to CRP, ESR, ASCA, and p-ANCA (von Roon, 2007; Henderson, 2012)

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

Screening

  • Colorectal cancer screening is highly recommended for UC patients because of an increased risk of colon cancer

Monitoring

  • Fecal lactoferrin
    • Released from polymorphonuclear leukocyte granules during active mucosal inflammation
    • May be useful as a marker in UC for monitoring disease severity
    • May be used for monitoring IBD activity and predicting relapse
    • Correlates with disease activity
  • Fecal calprotectin
    • Released from neutrophils during active inflammatory episodes
    • Concentration is proportionately related to degree of inflammation; however, GI bleeding does not proportionally increase calprotectin
    • May be useful in monitoring disease severity and in predicting relapse

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 activity and neutralizing antibody
    • Infliximab is a TNF-a inhibitor drug used for the treatment of patients with inflammatory diseases such as Crohn disease and ulcerative colitis
    • Up to 30% of patients receiving the recommended dosage of infliximab have primary response failure
      • This necessitates increased infliximab dosage or shortening of the dosage interval
    • Secondary response failure therapy is seen in up to 50% of patients treated with infliximab due to rise of anti-infliximab antibodies
      • This requires changing to a different TNF-a inhibitor drug

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
  • 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
    • 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 calprotectin may assist in differentiating IBD from functional disorders of the intestinal tract, such as irritable bowel syndrome
    • May avert unnecessary endoscopies (van Rheenen, 2010)
    • For pediatric patients with GI symptoms and a low pretest probability of disease, a positive result helps justify further invasive testing (Yang, 2014)

Histology 

  • Gold standard for diagnosis (American College of Gastroenterologists, 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
Test Name and Number Recommended Use Limitations Follow Up
Inflammatory Bowel Disease Differentiation Profile 0050567
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Use to distinguish Crohn disease (CD) from ulcerative colitis (UC) in patients with suspected IBD

Panel includes Saccharomyces cerevisiae antibody, IgG; Saccharomyces cerevisiae antibody IgA; anti-neutrophil cytoplasmic antibody, atypical pattern

Results should be used in conjunction with clinical history, imaging and/or histological studies

Limited usefulness of serology alone in predicting CD or UC

Detection of both Saccharomyces IgG and IgA antibodies in the same serum specimen is highly specific for CD

Crohn Disease Prognostic Panel 2001613
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Prognosticator for CD

Components include S. cerevisiae antibody, IgG; laminaribioside carbohydrate antibody IgG; mannobioside carbohydrate antibody IgG; and chitobioside carbohydrate antibody, IgA

If only one of the 4 markers is positive, clinical specificity is ≥85%

Results alone are not diagnostic or prognostic

Positive results may indicate an aggressive disease; however, negative results do not rule out aggressive disease

If all 4 markers are negative and IBD is suspected, recommend testing for ANCA by IFA to confirm/exclude possibility of UC

Calprotectin, Fecal 0092303
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Aid in differentiation of IBD from functional disorders of the gastrointestinal (GI) system (eg, irritable bowel syndrome [IBS])

Aid in monitoring of IBD and prediction of relapse

Clinical sensitivity – 95%

Clinical specificity – 91%

Test is not specific nor diagnostic for IBD

Presence of infections, inflammatory disorders, GI bleeding, and colorectal cancer may elevate levels of calprotectin

Does not differentiate UC from CD

False negatives are more common in children and teenagers than adults

 
Lactoferrin, Fecal by ELISA 0061164
Method: Qualitative Enzyme-Linked Immunosorbent Assay

May be used for monitoring IBD activity and predicting relapse

May assist in differentiating IBD from functional disorders of the intestinal tract, such as IBS

Positive results suggest the presence of the inflammatory bowel pathologies; however, other intestinal ailments, including GI infections and colorectal cancer, can result in elevated lactoferrin

 
Thiopurine Methyltransferase, RBC 0092066
Method: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Detect risk for severe myelosuppression with standard dosing of thiopurine drugs

Individualize dosing of thiopurine drugs

Does not replace clinical monitoring

Genotype cannot be inferred from TPMT activity (phenotype)

TPMT inhibitors may contribute to false-low test results

TPMT activity should be assessed prior to treatment with thiopurine drugs

Blood transfusion within 30 days will reflect donor status

 
TPMT Genotype 2002573
Method: Qualitative Polymerase Chain Reaction

Consider genotyping if RBC level is not normal

   
Infliximab Activity and Neutralizing Antibody 2008320
Method: Cell Culture/ Cell function assay involving cell stimulation /Quantitative Chemiluminescent Immunoassay/ Semi-Quantitative Chemiluminescent Immunoassay

Evaluate response failure to infliximab therapy

Help determine and adjust dosage or identify the need to change to another anti-TNF-α inhibitor

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Rule out infectious process; check for microcytic anemia and thrombocytosis

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Differentiate IBD from IBS

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Differentiate IBD from IBS

Clostridium difficile toxin B gene (tcdB) by PCR 2002838
Method: Qualitative Polymerase Chain Reaction

Consider in hospitalized patients with appropriate risk factors

Ova and Parasite Exam, Body Fluid or Urine 2002277
Method: Qualitative Concentration/Microscopy

Help rule out parasitic cause in patients with appropriate travel or exposure history or in immunocompromised patients

Stool antigen testing is recommended to rule out Giardia duodenalis(synonyms Giardia lamblia, Giardia intestinalis), Cryptosporidium or Entamoeba histolytica

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