Laboratory markers in IBD - Free Webs
Laboratory markers in IBD
• In IBD physicians apply a combination of symptoms, clinical examination, laboratory indices, radiology, and endoscopy with histology to make the diagnosis, to assess severity, and to predict the outcome of disease.
• Clinical indices give only indirect measurement of disease activity and may not accurately predict inflammatory activity found by endoscopic and histological examination.
• Endoscopy is accurate but is invasive and expensive.
• Hence, there has been a search for biological markers in IBD for:
o Diagnostic and differential diagnostic purposes.
o Assessment of disease activity and risk of complications.
o Prediction of relapse.
o Monitoring the effect of therapy.
o Avoid invasive (endoscopic) procedures.
Characters of an ideal marker
|Table 1 Performance and qualities of an ideal marker |
|Performance |Qualities |
|Simple |Be disease specific: identify individuals at risk for IBD and differentiate IBD from non-IBD |
|Easy to perform |Able to objectively measure disease activity |
|Not or minimally invasive |Able to predict the disease course (relapse or recurrence) |
|Cheap |Able to monitor the effect of treatment |
|Rapid |Have a prognostic value in assessing morbidity/mortality |
|Reproducible between labs and individuals | |
Biomarkers that may be Used to Determine Activity in Inflammatory Bowel Disease
THE ACUTE PHASE RESPONSE AND IBD
• The presence of active gut inflammation in patients with IBD ( acute phase reaction ( migration of leucocytes to the gut ( production of several proteins ( detected in serum or stools.
|Acute phase reactants |ESR |
| |C-reactive protein |
| |Orosomucoid |
| |Thrombopoietin |
| |Platelet count |
| |Fibrinogen |
| |Lactoferrin |
| |Serum amyloid A |
| |α1-antitrypsin |
C REACTIVE PROTEIN
• Under normal circumstances: produced by hepatocytes in low quantities (200–250 mg/l.
• Characters:
• Short half life (19 hours):Rise early after the onset of inflammation and rapidly decrease after resolution of the inflammation.
• Function:
• Binds to phosphocholine containing microorganisms or particles ( complement activation.
• Plays a role in the Opsonization of infectious agents and damaged cells.
• CRP and IBD
|UC |CD |
|Diagnose and to predict the activity |Correlate with disease activity |
|Lower |Higher |
|Correlate with severe clinical activity and active disease at |CD activity index, radioactive-labelled faecal granulocyte |
|colonoscopy but not with histological inflammation |excretion and faecal calprotectin. May be low in ileitis. |
• There is remarkable heterogeneity in the CRP response between CD and UC.
o CD is associated with a strong CRP response.
o UC has only a modest to absent CRP response.
• Proposed explanation for this heterogeneity
o Serum IL-6 concentrations were significantly increased in patients with CD compared with UC.
o In UC the inflammation is confined to the mucosa whereas in CD it is transmural.
o Polymorphisms in the CRP gene, located on the long arm of chromosome 1, account for inter individual differences in baseline CRP production in humans.
ERYTHROCYTE SEDIMENTATION RATE
• Definition: rate at which erythrocytes migrate through the plasma.
• Not specific for IBD
• Depend on the plasma concentration and on the number and size of the erythrocytes.
• Peak much less rapidly and may also take several days to decrease
• May vary with age.
|UC |CD |
|Correlate with disease activity |Less accurate measure of disease activity |
|Normal in proctitis and proctosigmoiditis |Correlates more with colonic disease and does not reflect the |
| |disease activity of small bowel |
Other serum Markers
• White blood cell count.
o Increase as part of the acute phase response.
o Not specific for IBD.
▪ Seen in other inflammatory conditions.
▪ Influenced by some treatments used in IBD.
• Glucocorticoids ( increased.
• Azathioprine ( decreased.
• Platelets.
o Platelet count correlates with disease activity in IBD.
o Non specific.
• Albumin ( not specific.
• Neopterin ( synthesized and released from monocytes/macrophages upon non-specific stimulation.
o The level of neopterin in urine and serum has been shown to correlate with disease activity of UC and CD but this is not IBD specific.
|Others |Elastase |
| |Myeloperoxidase |
| |Leucocyte esterase |
| |Serum tenascin C |
| |B2-microglobulin |
| |Neutrophil elastase |
| |Soluble adhesion molecules |
| |Angiogenic proteins |
Cytokines
• The expression of proinflammatory cytokines is markedly increased in the intestinal mucosa in patients with active IBD, although not always accompanied by increased concentration of cytokines in the serum.
TNF-α and TNF-α Receptor
• Tumor necrosis factor-α is produced by activated macrophages and monocytes.
• Serum concentration of TNF-α is often not consistently elevated in IBD and are thus of limited utility as markers of disease activity.
• The same conclusion applies to the measurement of TNF-α concentration in stool.
• TNF receptors ( more studies required.
Interleukins, Interleukin Receptors and Interleukin Receptor Antagonists
|Interleukin |Action |Value in IBD |
|IL receptor antagonists (IL-1RA) |Anti-proinflammatory effects |Increased in patients with active IBD |
|IL-1RA/IL-1 ratio | |Decreases with increasing IBD activity |
|Interleukin-2 receptor (IL-R) |Shed by activated T cells into circulation |Correlates with disease activity in both UC and CD. |
| |along with IL-2. | |
|Interleukin-6 |Anti-inflammatory and proinflammatory effects |Elevated serum IL-6 concentrations are found in active CD but|
| | |not always in UC |
|Interleukin-8 |Important for neutrophil chemotaxis. |Elevated in patients with active UC but not sensitive. |
| | |Not elevated in patients with active CD. |
|Interleukin-10 |Anti-inflammatory cytokines |Elevated in active UC and CD. |
| | |May correlate with endoscopic and disease activity. |
Adhesion Molecules
• Leucocytes do not readily adhere to vascular endothelium in an unstimulated state.
• Inflammatory signals ( induce expression of proteins on the endothelial cell surface ( promote the adhesion and extravasation of activated immune cells from the circulation ( underlying tissues.
• These proteins are known as cell adhesion molecules and they are expressed by immune cell, endothelial cell and epithelial cells.
• They can be in soluble form or leucocyte-bound form.
|L-, P- and E-selectin |
|Cell adhesion molecules |Mucosal adressin-cell adhesion molecule (MAdCAM-1) |
| |Intercellular adhesion molecule-1 (sICAM-1) |
| |Vascular cell adhesion molecule-1 (sVCAM-1) |
• No support to the routine use of soluble adhesion molecules as disease activity markers in IBD.
Serum tenascin C
• Multifunctional matrix protein present in connective tissue and is induced in inflammation and repair.
• Tenascins modulates cell adhesion.
• Not specific of IBD.
Serum levels of B2-microglobulin
• Useful to assess the disease activity in CD but not in UC.
Plasma levels of neutrophil elastases
• Independent parameter for assessment of disease activity and may be more useful than other markers such as ESR and CRP in identifying the patients in remission.
Serum immune markers
• Deoxyribonuclease (DNase I) sensitive perinuclear antineutrophil cytoplasmic autoantibody (pANCA) associated with IBD. The IBD associated pANCA defines an antibody to a nuclear antigen which is sensitive to DNase I.
• ASCA (Anti-Saccharomyces cervisiae antibody). This antibody is present in the serum of up to 70 percent of Crohn's disease patients.
• Pancreatic antibody This antibody is observed in approximately 30 percent of Crohn's disease patients.
• Anti-OmpC (outer membrane porin from E. coli). An IgA response to OmpC is seen in 55 percent of Crohn's disease patients.
Genetic markers
• A significant role for genetic factors in IBD was established.
• NOD2 gene
• Nucleotide-binding oligomerization domain (NOD) proteins are cytosolic proteins that include principal regulators of apoptosis.
• There is association of Nod2 (CARD15) polymorphisms with CD.
• Mutations in the leucine-rich region of the NOD2 gene have been identified as susceptibility factors for CD
• NOD2/CARD15 genotyping is helpful in differentiating indeterminate colitis patients.
• TPMT gene
• Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of azathioprine, 6-mercaptopurine and thioguanine.
• Correlations between mutations in the TPMT gene with susceptibility to leukopenia from azathioprine therapy can help select candidates for this therapy.
FAECAL MARKERS
|Faecal |Faecal excretion of 111Indium-labelled white cells |
| |Leucocytes products |
| |Serum proteins |
| |Calprotectin |
| |Lactoferrin |
• Advantages of faecal markers:
o Stools are easy accessible in IBD patients.
o Serum markers may be increased by various conditions other than gut inflammation.
o Higher specificity for IBD in the absence of gastrointestinal infection.
o Representative of mucosal inflammation in the bowel.
Calprotectin
• 36 kDa calcium and zinc binding protein
• Released from cells during cell activation or death.
• Very sensitive marker for detection of inflammation in the gastrointestinal tract.
• It is stable in faeces for several days after excretion.
• Easily measured in stool by ELISA.
• Faecal calprotectin level is 2-10 mg/L in healthy individuals.
|UC |CD |
|Correlate with endoscopic and histological activity |Correlate with endoscopic and histological activity |
|Stronger predictor of relapse |Less |
Faecal Lactoferrin
• Nature: a glycoprotein found in many body fluids as well as in granules of neutrophil granulocytes.
• Faecal lactoferrin levels quickly increase after influx of neutrophils into intestinal lumen during inflammation.
• Measured by ELISA on a single stool sample.
• Normal value is 1.45 ± 0.4 μg/g of faecal weight.
• Value in IBD:
o Increased in patients with active IBD (specificity between 85% and 90%).
o Rise significantly prior to a clinically evident relapse and may be a good marker to predict subsequent IBD flares.
o Correlates with histological inflammation.
Other Faecal Markers
|Other |Faecal α1-antitrypsin. |
| |Myeloperoxidase. |
| |Leucocyte esterase. |
| |TNF-α. |
| |111Indium-labelled white cells scan |
| |Intestinal permeability test |
| |Whole gut lavage fluid for immunoglobulin and albumin |
Intestinal Permeability
• Intestinal permeability using differential 5 h urinary excretion ratio (ratio of lactulose and l-rhamnose) and CrEDTA.
• Limited value in assessing the disease activity.
• Can predict relapse, as less than 20% of patients who have normal intestinal permeability relapse in 6 months.
White Cell Scan and 4-Day Faecal Excretion Test
• Abdominal scanning with 111-Indium white cell technique
o Visualizes segments of inflamed bowel and
o Quantitates the degree of intestinal inflammatory activity.
• When combined with 4-day faecal excretion of labelled white cells, the inflammatory activity can be quantified accurately and can be used to document the response to treatment.
• Has a good correlation with colitis but not ileitis and poor correlation with the CD activity index.
• Expensive and more technically demanding.
Whole Gut Lavage
• Gut lavage fluid proteins have been studied as marker of disease activity in IBD.
• Gut lavage IgG was found to be a more specific disease marker than albumin in the lavage fluid.
Use of laboratory markers in the diagnosis and differential diagnosis of IBD
• CRP is the most sensitive marker in detecting IBD, values range between:
o 50% and 60% for UC.
o 70% and 100% for CD.
• Faecal calprotectin has been shown to enable diagnosis of IBD.
• A cut off of 30 µg/g had 100% sensitivity in discriminating active CD from IBS.
• Increased faecal calprotectin has been described in healthy first degree relatives of patients with CD.
Use of laboratory markers to monitor disease activity in IBD
• Laboratory markers ESR, serum albumin, [pic]1 proteinase inhibitor, cholinesterase, CRP, and haematocrit have been shown to correlate with endoscopic activity.
• There is a good correlation between ESR and clinical activity, however dependent on disease location.
• ESR correlated less well with UC restricted to the rectum and with CD restricted to the upper small bowel.
• The correlation of laboratory markers with disease activity has been shown to be much stronger for CD than for UC.
• Faecal calprotectin also correlates well with endoscopic and histological activity in patients with UC and in CD, and increased calprotectin levels normalize once the inflammation is resolved.
• Good correlation exists between ß2 microglobulin and disease activity.
Role of laboratory markers for monitoring the effect of treatment
• A decrease in CRP in response to therapy is objective evidence that the drug has a beneficial effect on gut inflammation.
• Persistently raised CRP indicates failure of the therapy to control mucosal inflammation.
Role of laboratory markers in prediction of Relapse
• If relapse can be predicted in IBD, it is likely to change the approach to treatment.
A Laboratory Index for Predicting Relapse in Asymptomatic Patients with Crohn's Disease
• A prognostic index was formulated based on ESR, α2-globulin and α1-glycoprotein.
−3.5 + (ESR × 0.03) + (acid α1-glycoprotein × 0.013) + (α2-globulin × 2)
• A value more than +0.35 suggests likelihood of relapse (sensitivity 71%, specificity and positive predictive value 100%).
• Patients with CRP > 20 mg/L and an ESR > 15 mm/first hour had an eightfold increased risk of relapse in the next 6 weeks in CD.
• Serum levels of IL-6 useful to predict relapse in steroid-induced remission in patients with CD.
• High serum level of soluble IL-2 receptors in patients with CD was highly predictive of relapse.
• A significant role of faecal calprotectin and lactoferrin in prediction of relapse in IBD.
• Faecal markers and rectal mucosal IL-8 are promising biomarkers for prediction of relapse in patients with UC.
• Small intestinal permeability has sensitivity and specificity of 84% and 61%, respectively, to predict the relapse in patients with small intestinal CD.
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