Inflammatory Bowel Disease - IBD

  • Diagnosis
  • Screening
  • Monitoring
  • Pharmacogenetics
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Diarrhea, bloody stools

Laboratory Testing

  • Nonspecific initial testing
    • CBC – microcytic anemia and thrombocytosis most common abnormalities
    • C-reactive protein (CRP)
      •  Preferred test to differentiate between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) (Choosing Wisely: 5 Things Physicians and Patients Should Question, 2015; American Society for Clinical Pathology)
        • Elevated CRP differentiates IBD from IBS
        • Normal CRP does not rule out IBD
          • Low specificity for IBD
          • Sensitivity is variable and dependent on disease (ulcerative colitis [UC] versus Crohn disease [CD])
        • If CRP not available, order erythrocyte sedimentation rate (ESR)
    • Fecal calprotectin – marker of gut inflammation with good sensitivity (Langhorst, 2008)
    • Albumin – may be decreased
    • Stool evaluation – rule out infectious etiologies
      • Clostridium difficile toxin B gene (tcdB) by polymerase chain reaction (PCR) – if risk factors are present
      • Parasitic analysis (PCR testing recommended) – only if appropriate history
    • Normal test results for CBC, albumin, stool examination, and antimicrobial drug intake should not prevent a full evaluation for IBD, if clinical suspicion for disease is strong
  • Serologic testing for specific antibodies
    • May be useful in supporting a diagnosis and classification of IBD, especially in indeterminate colitis
    • Marker testing cannot be used as the sole means of definitive diagnosis of IBD – lacks sensitivity, specificity (ACG, 2009)
    • >20 serologic markers are currently identified for IBD, with variable diagnostic performance
    • Classic markers that are widely available include the following
      • Anti-Saccharomyces cerevisiae antibodies (ASCA)
        • 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 (ANCA)
        • CD – 5-15%
        • UC – 60-80%
      • Anti-glycan antibodies (Crohn diagnostic panel)
        • May be useful in predicting disease phenotype in confirmed CD patients
        • Panel consists of 4 glycan antibody tests
          • Saccharomyces cerevisiae antibody (ASCA) IgG
          • Laminaribioside carbohydrate antibody (ALCA), IgG
          • Mannobioside carbohydrate antibody (AMCA), IgG
          • Chitobioside carbohydrate antibody (ACCA), IgA
        • Presence of ≥2 markers has a specificity of  ≥95% for CD with a 1.7 elevated relative risk for abdominal surgery compared to seronegative patients with CD
    • Other markers – anti-I2 IgA, anti-flagellin (Cbir1)
    • No role for HLA-B27 testing in IBD – most useful in patients symptomatic for ankylosing spondylitis
  • Fecal calprotectin
    • May assist in differentiating IBD from functional disorders of the intestinal tract, such as IBS (Langhorst, 2008)
    • May avoid 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 definitively diagnose IBD
    • Superior to CRP, ESR, ASCA, and perinuclear ANCA tests (von Roon, 2007; Henderson, 2012)

Histology

  • Gold standard for diagnosis (American College of Gastroenterologists, 2011; European Consensus, 2012)
    • CD – presence of sarcoid-like granulomas, lymphoid hyperplasia, ileal inflammation
    • UC – cryptitis, crypt abscesses, mucin depletion, crypt atrophy, Paneth cell metaplasias

Imaging Studies

  • MRI or CT enetrography/enteroclysis
  • Double-contrast barium enema – use only when endoscopy is unavailable
    • CD – ileum, terminal ileum, ileocecal valve, and cecum
    • UC – ileum is usually spared

Other Testing

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

Prognosis

  • Use any available panel that includes ASCA, ALCA, AMCA, ACCA
  • Positive result for ≥2 markers is associated with poor prognosis in CD

Differential Diagnosis

  • Colorectal cancer (CRC) screening – highly recommended for patients with ulcerative colitis because of an increased risk for CRC
  • Fecal lactoferrin
    • Released from polymorphonuclear leukocyte granules during active mucosal inflammation
    • May be useful as a marker in IBD for monitoring disease severity
      • Correlates with disease activity
    • May be used for monitoring inflammatory bowel disease activity and predicting relapse
      • Sensitivity and specificity higher in CD
  • Fecal calprotectin
    • Released from neutrophils during active inflammatory episodes
    • Concentration is proportionately related to degree of inflammation
      • Gastrointestinal bleeding does not proportionally increase calprotectin, but will increase values if >100 mL/day of bleeding
    • May be useful in monitoring disease severity and in predicting relapse (Stragier, 2013)
      • Better for UC than CD (Stragier, 2013)
  • CRP
    • Decreased values correlate with improvement in disease (Stragier, 2013)
  • Thiopurine drugs – may be used in treating IBD
    • Thiopurine prodrugs are metabolized via thiopurine methyltransferase (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 may 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
    • Genotype for the TPMT gene cannot be inferred from TPMT activity (phenotype)
    • TPMT phenotype testing does not replace need for clinical monitoring of patients treated with thiopurine drugs
      • Phenotype testing should not be requested for patients currently treated with thiopurine drugs; results will be falsely low
      • Current TPMT phenotype may not reflect future TPMT phenotype, particularly in patients who received blood transfusions within 30-60 days of testing
  • Infliximab activity and neutralizing antibody
    • Infliximab is a tumor necrosis factor (TNF)-α inhibitor drug used for the treatment of patients with inflammatory bowel diseases, such as Crohn disease and ulcerative colitis
    • Up to 30% of patients receiving the recommended dosage of infliximab have primary response failure
      • Necessitates increased infliximab dosage or shortening of the dosage interval
    • Up to 50% of patients treated with infliximab have secondary response failure due to anti-infliximab antibodies
      • Necessitates change to a different TNF-alpha inhibitor drug
    • Antibody testing may aid in therapy decision-making process

Inflammatory bowel disease (IBD) represents a spectrum of chronic disorders affecting the gastrointestinal tract; Crohn disease (CD) and ulcerative colitis (UC) are the major disorders. When a definite diagnosis of CD or UC cannot be made following colectomy, the 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 (CDC, 2014)
    • CD – 3-15/100,000
    • UC – 2-14/100,000
  • Age
    • Initial and most common peak – 15-30 years
    • Second, smaller peak – >60 years
  • Sex
    • CD – M<F
    • UC – M:F, equal
  • Ethnicity
    • Highest in Caucasians and Ashkenazi Jews
    • Lowest in African Americans, Asians, and Hispanics

Risk Factors

  • Increased risk
    • Medications (eg, NSAIDs)
    • Infections (eg, Salmonella typhi, Campylobacter jejuni)
  • Genetics
    • CD – first-degree relatives have 10-15-fold increased risk (Laass, 2014)

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 (so-called “strip” lesions)
  • 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, diarrhea (less prominent than in UC)
  • UC – bloody diarrhea, rectal bleeding, abdominal pain
  • Extraintestinal manifestations – up to 35% of IBD cases
    • Dermatologic
      • Erythema nodosum
      • Pyoderma gangrenosum
      • Sweet syndrome – acute febrile neutrophilic dermatosis
    • Musculoskeletal
      • Arthritis – large joints, often asymmetric
      • Ankylosing spondylitis, sacroiliitis
    • Ophthalmologic
      • Uveitis/iritis
      • Episcleritis
      • Optic neuritis
    • Gastrointestinal
    • Genitourinary
  • Complications
    • CD – fistulas, abscesses
    • UC – massive hemorrhage, toxic megacolon, marked increase in incidence of colon cancer

Clinical Background

Epidemiology

  • Prevalence – 10-25% of inflammatory bowel disease (IBD) cases diagnosed during childhood
    • Steady increase in incidence over past four decades
  • Sex
    • M>F (male predominance is less 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)
  • Often nonspecific initial presentation – anemia, fever, growth failure

Diagnosis

Indications for Testing

  • Diarrhea, bloody stools

Laboratory Testing

  • Nonspecific initial testing
    • CBC – microcytic anemia and thrombocytosis most common abnormalities
    • C-reactive protein (CRP)
      • 25% of children with mild IBD have normal CRP
    • Albumin – may be decreased
    • Stool evaluation – rule out infectious etiologies
      • Clostridium difficile toxin B gene (tcdB) by polymerase chain reaction (PCR) – if risk factors are present
      • Parasitic analysis (PCR testing recommended) – only if appropriate history
    • Normal test results for CBC, albumin, stool examination, and antimicrobial drug intake should not prevent a full evaluation for IBD, if clinical suspicion for disease is strong
  • Serologic testing
    • May be useful in supporting a diagnosis and classification of IBD, especially in indeterminate colitis; however, marker testing cannot be used as the sole means of definitive diagnosis of IBD
    • Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) may be useful adjunct diagnostic tools
    • Fewer studies in children
    • Negative results do not rule out IBD – tests have low sensitivities for ulcerative colitis (UC) and Crohn disease (CD)
    • Anti-glycan antibodies (Crohn diagnostic panel)
      • May be useful in predicting disease phenotype in confirmed CD patients
      • Panel consists of 4 glycan antibody tests
        • Saccharomyces cerevisiae antibody (ASCA) IgG
        • Laminaribioside carbohydrate antibody (ALCA), IgG
        • Mannobioside carbohydrate antibody (AMCA), IgG
        • Chitobioside carbohydrate antibody (ACCA), IgA
      • Presence of ≥2 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
    • Sensitivity/specificity – higher in children
    • May assist in differentiating IBD from functional disorders of the intestinal tract, such as IBS (Langhorst, 2008)
    • May avoid 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

  • Refer to Diagnosis section

Other Testing

  •  Endoscopy – gold standard when combined with histology

Monitoring

  • Refer to Monitoring section
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.

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

Limitations 

Test is not specific or diagnostic for IBD

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

Does not differentiate UC from CD

Results may fluctuate as disease activity fluctuates; GI bleeding results in increased CALPRO

False negatives are more common in children and teenagers than adults

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

Limitations 

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

Inflammatory Bowel Disease Differentiation Panel 2013270
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

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

Limitations 

Results alone are not diagnostic or prognostic

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

Follow-up 

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

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

Limitations 

Does not replace clinical monitoring

TPMT inhibitors may contribute to false-low test results

TPMT activity should be assessed prior to treatment with thiopurine drugs

TPMT testing – blood transfusion within 30 days will reflect donor status

Thiopurine Drug Metabolites 2011134
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Limitations 

Limit of quantification (LOQ)

  • LOQ – 12.5 pmol/8 x 108 RBC (6-TGN)
  • LOQ – 325 pmol/ 8 x 108 RBC (6-methyl mercaptopurine nucleotide [6-MMPN])

Thiopurine Methyltransferase (TPMT) Genotyping, 4 Variants 2012233
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Only targeted TPMT allele variants will be detected by this panel

Diagnostic errors can occur due to rare sequence variations

Genotyping in patients who have received allogenic stem cell/bone marrow transplant will reflect donor status

Genotyping cannot distinguish the *1/*3A genotype from the *3B/*3C genotype

Thiopurine drug metabolism and risk for toxicity may be affected by genetic and nongenetic factors that are not evaluated by this test

Test does not assess for TPMT allele variants associated with ultra-high enzyme activity

Genotyping does not replace the need for therapeutic drug monitoring or clinical observation

Infliximab Activity and Neutralizing Antibody 2008320
Method: Cell Culture/Quantitative Chemiluminescent Immunoassay/ Semi-Quantitative Chemiluminescent Immunoassay

Guidelines

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010; 105(3): 501-23; quiz 524. PubMed

North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Colitis Foundation of America, Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, Kirschner BS, Kugathasan S, Baldassano RN, Russo PA. Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr. 2007; 44(5): 653-74. PubMed

General References

Beniwal P, Harrell L. The status of diagnostic markers for inflammatory bowel disease. Curr Gastroenterol Rep. 2010; 12(6): 479-84. PubMed

Bossuyt X. Serologic markers in inflammatory bowel disease. Clin Chem. 2006; 52(2): 171-81. PubMed

Dotan I. New serologic markers for inflammatory bowel disease diagnosis. Dig Dis. 2010; 28(3): 418-23. PubMed

Feuerstein JD, Cheifetz AS. Ulcerative colitis: epidemiology, diagnosis, and management. Mayo Clin Proc. 2014; 89(11): 1553-63. PubMed

Glick SR, Carvalho RS. Inflammatory bowel disease. Pediatr Rev. 2011; 32(1): 14-24; quiz 25. PubMed

Henderson P, Casey A, Lawrence SJ, Kennedy NA, Kingstone K, Rogers P, Gillett PM, Wilson DC. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease. Am J Gastroenterol. 2012; 107(6): 941-9. PubMed

Jellema P, van Tulder MW, van der Horst HE, Florie J, Mulder CJ, van der Windt DA. Inflammatory bowel disease: a systematic review on the value of diagnostic testing in primary care. Colorectal Dis. 2011; 13(3): 239-54. PubMed

Jones J, Loftus EV, Panaccione R, Chen L, Peterson S, McConnell J, Baudhuin L, Hanson K, Feagan BG, Harmsen SW, Zinsmeister AR, Helou E, Sandborn WJ. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn's disease. Clin Gastroenterol Hepatol. 2008; 6(11): 1218-24. PubMed

Laass MW, Roggenbuck D, Conrad K. Diagnosis and classification of Crohn's disease. Autoimmun Rev. 2014; 13(4-5): 467-71. PubMed

Langhorst J, Elsenbruch S, Koelzer J, Rueffer A, Michalsen A, Dobos GJ. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol. 2008; 103(1): 162-9. PubMed

Lewis JD. The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. Gastroenterology. 2011; 140(6): 1817-1826.e2. PubMed

Lichtenstein GR, Hanauer SB, Sandborn WJ, Practice Parameters Committee of American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol. 2009; 104(2): 465-83; quiz 464, 484. PubMed

Loddenkemper C. Diagnostic standards in the pathology of inflammatory bowel disease. Dig Dis. 2009; 27(4): 576-83. PubMed

Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. 2007; 133(5): 1670-89. PubMed

Prideaux L, De Cruz P, Ng SC, Kamm MA. Serological antibodies in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis. 2012; 18(7): 1340-55. PubMed

Satsangi J, Silverberg MS, Vermeire S, Colombel J. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006; 55(6): 749-53. PubMed

Sellin JH, Shah RR. The promise and pitfalls of serologic testing in inflammatory bowel disease. Gastroenterol Clin North Am. 2012; 41(2): 463-82. PubMed

Sipponen T, Savilahti E, Kolho K, Nuutinen H, Turunen U, Färkkilä M. Crohn's disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn's disease activity index and endoscopic findings. Inflamm Bowel Dis. 2008; 14(1): 40-6. PubMed

Stragier E, Van Assche G. The use of fecal calprotectin and lactoferrin in patients with IBD. Review. Acta Gastroenterol Belg. 2013; 76(3): 322-8. PubMed

van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ. 2010; 341: c3369. PubMed

von Roon AC, Karamountzos L, Purkayastha S, Reese GE, Darzi AW, Teare JP, Paraskeva P, Tekkis PP. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol. 2007; 102(4): 803-13. PubMed

Wilkins T, Jarvis K, Patel J. Diagnosis and management of Crohn's disease. Am Fam Physician. 2011; 84(12): 1365-75. PubMed

Yang Z, Clark N, Park KT. Effectiveness and cost-effectiveness of measuring fecal calprotectin in diagnosis of inflammatory bowel disease in adults and children. Clin Gastroenterol Hepatol. 2014; 12(2): 253-62.e2. PubMed

Zisman TL, Rubin DT. Novel diagnostic and prognostic modalities in inflammatory bowel disease. Gastroenterol Clin North Am. 2009; 38(4): 729-52. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Jaskowski TD, Litwin CM, Hill HR. Analysis of serum antibodies in patients suspected of having inflammatory bowel disease. Clin Vaccine Immunol. 2006; 13(6): 655-60. PubMed

Lin J, Welker NC, Zhao Z, Li Y, Zhang J, Reuss SA, Zhang X, Lee H, Liu Y, Bronner MP. Novel specific microRNA biomarkers in idiopathic inflammatory bowel disease unrelated to disease activity. Mod Pathol. 2014; 27(4): 602-8. PubMed

Salk JJ, Bansal A, Lai LA, Crispin DA, Ussakli CH, Horwitz MS, Bronner MP, Brentnall TA, Loeb LA, Rabinovitch PS, Risques RA. Clonal expansions and short telomeres are associated with neoplasia in early-onset, but not late-onset, ulcerative colitis. Inflamm Bowel Dis. 2013; 19(12): 2593-602. PubMed

Shirts B, von Roon AC, Tebo AE. The entire predictive value of the prometheus IBD sgi diagnostic product may be due to the three least expensive and most available components. Am J Gastroenterol. 2012; 107(11): 1760-1. PubMed

Medical Reviewers

Last Update: August 2016