Inflammatory Bowel Disease

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

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

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

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

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

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

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count and Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count/Differential

Use:

Rule out infectious process; check for microcytic anemia and thrombocytosis

Test name: Sedimentation Rate, Westergren (ESR)

ARUP #: 0040325

Methodology: Visual Identification

Use:

Differentiate IBD from irritable bowel syndrome (IBS)

Test name: C-Reactive Protein

ARUP #: 0050180

Methodology: Quantitative Immunoturbidimetry

Use:

Differentiate IBD from IBS

Test name: Inflammatory Bowel Disease Differentiation Profile

ARUP #: 0050567

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Use:

Use to distinguish CD from UC in patients with suspected IBD

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

Limitations:

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

Limited usefulness of serology alone in predicting CD or UC

Follow-up:

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

Test name: Crohn Disease Prognostic Panel

ARUP #: 2001613

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Prognosticator for Crohn disease

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 greater than or equal to 85%

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

Test name: Calprotectin, Fecal

ARUP #: 0092303

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Use:

May be used to monitor IBD activity and predict relapse

May help differentiate IBD from functional disorders of the intestinal tract such as IBS

Limitations:

Test is not specific for IBD

Presence of GI infections and colorectal cancer may also elevate levels of calprotectin

Does not differentiate among inflammatory bowel pathologies

False negatives are more common in children and teenagers than adults

Test name: Lactoferrin, Fecal by ELISA

ARUP #: 0061164

Methodology: Qualitative Enzyme-Linked Immunosorbent Assay

Use:

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

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

Test name: Clostridium difficile toxin B gene (tcdB) by PCR

ARUP #: 2002838

Methodology: Qualitative Polymerase Chain Reaction

Use:

Consider in hospitalized patients with appropriate risk factors

Test name: Ova and Parasite Exam, Body Fluid or Urine

ARUP #: 2002277

Methodology: Qualitative Concentration/Microscopy

Use:

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

Limitations:

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

Test name: Thiopurine Methyltransferase, RBC

ARUP #: 0092066

Methodology: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Use:

Perform TPMT testing in patients who will receive thiopurine drugs; measures enzymatic levels to determine risk of toxicity

Limitations:

Does not measure concentration of parent drug (6-thioguanine, azathioprine, or 6-mercaptopurine) or metabolites

Does not replace need for clinical monitoring of patients treated with thiopurine drugs

Genotype for TPMT cannot be inferred from TPMT activity in red blood cells

Phenotype testing should not be requested for patients currently treated with thiopurine drugs because results will be falsely low

TPMT enzyme activity can be inhibited by naproxen (Aleve^®), ibuprofen (Advil^®, Motrin^®), ketoprofen (Orudis^®), furosemide (Lasix^®), sulfasalazine (Azulfidine^®), mesalamine (Asacol^®), olsalazine (Dipentum^®), mefenamic acid (Ponstel^®), thiazide diuretics, and benzoic acid inhibitors

Test name: TPMT Genotype

ARUP #: 2002573

Methodology: Qualitative Polymerase Chain Reaction

Use:

Consider genotyping if RBC level is not normal

Additional Tests Available

Test name: Saccharomyces cerevisiae Antibodies, IgG & IgA

ARUP #: 0050564

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

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