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New tests in gastroenterology

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  • 1. New Tests in Gastroenterology Stephen Bridger ACB Meeting 10/11/2005
  • 2. Gastroenterology
    • Too Busy
      • Too Many patients
        • IBS 14 - 24% of adult population, + 28% of referrals to GI clinics
      • Too Many Investigations
        • Doubling of endoscopy workload in last 10 yrs
    • Non Specific nature of GI symptoms
        • Even alarm symptoms such as rectal bleeding common (1 in 7 adults/week) + poorly predictive of significant GI pathology
    • Unable to predict which of our chronic patients will relapse and when.
  • 3.
    • “ Would you mind very much if I went in before you? You’ve only a sore throat and I’ve diarrhoea”
  • 4.  
  • 5. Lundberg JO et al . (2005) Technology Insight: calprotectin, lactoferrin and nitric oxide as novel markers of inflammatory bowel disease Nat Clin Pract Gastroenterol Hepatol 2: 96 – 102 doi:10.1038/ ncpgasthep0094
  • 6. Calprotectin
    • 35 KDa Calcium and Zinc binding protein found in neutrophils, monocytes, and macrophages
    • Up to 60% of the total cytosolic protein content of neutrophils
    • First Described in 1980
    • Initially called L1 protein
    • Antimicrobial and Anti-tumour activity
    • reduces local zinc concentrations, and inhibits zinc dependent metalloproteinases
  • 7. Clinical Use
    • Resists metabolic degradation
    • measured in stool, plasma, CSF, sputum, amniotic fluid
    • Stool samples can be sent by post, then frozen and batch analysed
    • Approx £10 per test
    • Upper limit of normal in stool is 10mg/l
    • As little as 5gm stool sample required
  • 8. Clinical Uses
    • extensively validated, showing consistent abnormalities in patients with IBD, colorectal carcinoma, and nonsteroidal enteropathy
    • Proposed as a useful outpatient screening test for organic small bowel or colorectal pathology. May be particularly useful in children.
    • Proposed as an IBD monitoring test, can predict steroid refractory disease, or which “well patients” are likely to relapse. Potential for monitoring the efficacy of new therapeutic regimes.
  • 9. General Background
    • Levels relatively unaffected by GI bleeding
    • need > 100mls of blood per day to increase calprotectin level by 6mg/l
    • In active Crohn’s disease, levels of calprotectin up to 40,000 mg/l reported
  • 10. Guidelines for the investigation of chronic diarrhoea, Gut 2003
    • “ Stool markers of gastrointestinal inflammation such as lactoferrin and, more recently, calprotectin , are of considerable research interest but, as yet, these have not been introduced into clinical practice.”
  • 11. A simple method for assessing intestinal inflammation in Crohn's disease Tibble et al Gut 2000
    • 22 patients: fecal calprotectin compared with 4 day 111 Indium White Cells
      • Good correlation (r = 0.8 , P<0.0001)
    • 116 patients with known Crohn’s disease, calprotectin was compared with healthy controls
    • 220 consecutive patients attending a GI clinic, 31 newly diagnosed Crohn’s disease, 159 patients with IBS...
  • 12. Calprotectin: Crohn’s versus Controls
  • 13. Calprotectin compared with CRP
  • 14. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease Tibble et al Gastroenterology 2002
    • Prospective study: 602 new GI referrals
    • 4 Gastroenterologists blinded to the results of calprotectin and permeability, other investigations determined by Physicians
    • 263 patients diagnosed with organic disease
  • 15. Referral Symptoms
  • 16. Calprotectin Levels in the Different Diagnostic Groups
  • 17. Sensitivity/Specificity for Organic and Non-Organic Disease
  • 18. Odds Ratios for Organic and Non-organic Disease
  • 19. Diagnostic accuracy of fecal calprotectin in distinguishing organic causes of chronic diarrhoea from IBS: A prospective study in adults and children. Carroccio et al Clin Chem Jun 2003
    • Prospective study 120 patients
    • Raised Calprotecin levels predicted pts with IBD with 100% sensitivity and 95% specificity
    • Diagnostic accuracy higher in children
    • Coeliac disease was the commonest cause of false negatives
  • 20. Fecal calprotectin - a useful screening test for inflammation of the colon in children. Fagerberg et al DDW 2003
    • 36 children : calprotectin prior to colonoscopy
    • 22 of the children had colitis on Hxpath + endoscopic criteria:
      • Mean calprotectin 349 (15.4 - 1860 mg/L)
    • Sensitivity & Positive predictive value 95%
    • Specificity of 93%
  • 21. Fecal Calprotectin as an aid to Diagnosis in intestinal inflammation Dolwani et al DDW 2003
    • 65 patients with abdo pain + diarrhoea
    • All referred for Barium follow through
    • 15 false negatives: 6 IBD, 4 IBS, 5 uncertain
  • 22. Fecal Calprotectin in steroid dependent Colitis. An indicator of clinical response Atkinson DDW 2003
    • 27 patients with steroid dependent colitis in remission
    • Calprotectin checked at 0, 8 and 16 weeks
    • steroids reduced at 2 weekly intervals until relapse or cessation
    • Mean Calprotectin at Time Zero was 6 x higher in those patients who Relapsed (P = 0.0009)
    • “ CPT may differentiate between pts with merely symptomatic response and those with genuine mucosal healing- failure to lower CPT sufficiently may indicate the need for a trial of a different therapy”
  • 23. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease Gastroenterology 2000;119:15-22
  • 24. Subclinical intestinal inflammation: An inherited abnormality in Crohn’s disease relatives? Gastroenterology June 2003
  • 25.  
  • 26. Effect of Pentavac and MMR vaccination on the intestine Gut 2002 816-17
    • 109 consecutive infants attending an Iceland Vaccination clinic had fecal calpro taken 1 week prior and 2 and 4 weeks after Pentavac (12 months) and MMR (18 months)
    • No differences at any time of study
    • “ MMR very unlikely to cause ‘autistic enterocolitis’”
  • 27. Calprotectin versus FOB in Bowel Cancer
    • FOB screening in asymptomatic patients has reduced bowel ca mortality by 15-33%
    • Detection threshold about 2-4 mls of blood/100g stool but tumours bleed intermittently and polyps may not bleed at all
    • Sensitivity of FOB may be as low as 26%
  • 28. Faecal Calprotectin and FOB tests in the diagnosis of colorectal carcinoma and adenoma. Gut 2001 49(3):402-8
    • 3 FOBs and 1 stool calprotectin sample
    • Three groups
      • 96 Controls (healthy volunteers)
      • 62 consecutive patients with newly diagnosed bowel cancer
      • 233 consecutive patients referred for colonoscopy for polyp follow up, cancer surveillance, anaemia
  • 29. Calprotectin vs FOB 71 100 10.5 - 3388 132 14 D 100 86 1.5-314 62 14 C 46 88 2-3770 115 24 B 20 90 7-933 62.5 10 A +’ve by FOB +’ve by calprotectin range median n Dukes Stage
  • 30. Faecal Calprotectin in the Different Diagnostic Groups
  • 31. Fecal Calprotectin levels in a high risk population for colorectal neoplasia Kronberg et al Gut 2000 (46) 795 -800
  • 32. Calprotectin and Cancer
  • 33. Conclusions
    • Calprotectin has significant advantages over guaiac based FOB testing
      • Higher sensitivity for colorectal ca
      • More likely to detect patients with Dukes A + B
      • More likely to detect patients with rectal and right sided tumours
      • Single test rather than 3 samples
      • No dietary restrictions
  • 34. Conclusions 2
    • Sensitivity >95% for detecting patients with IBD
    • Failure to lower CPT predicts those patients with steroid refractory disease (even if the patient has had a good symptomatic response to steroids)
    • Asymptomatic patients with IBD with CPT > 50mg/l have a 90% probability of relapse in the next 12 months
    • CPT reduction in IBD treated patients appears to correlate with endoscopic mucosal healing
    • CPT levels much more clinically useful in IBD than any of the currently used systemic immune tests (CRP, ESR, Igs, Plts)
  • 35. The Future?
    • GI OPD screening
      • Organic versus non-organic
      • Investigate versus observe
    • Population based bowel cancer screening
      • Selected high risk groups
    • IBD monitoring
    • Availability ?
  • 36.