New Tests in Gastroenterology Stephen Bridger ACB Meeting 10/11/2005
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.
“Would you mind very much if I went in before you? You’ve only a sore throat and I’ve diarrhoea”
Lundberg JO et al. (2005) Technology Insight: calprotectin, lactoferrin and nitric oxide as novel markers of inflammatory bowel disease Nat Clin Pract Gastroenterol Hepatol2:96–102 doi:10.1038/ncpgasthep0094
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
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
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.
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
Guidelines for the investigation of chronic diarrhoea,Gut 2003 • “Stool markers of gastrointestinal inflammationsuch as lactoferrin and, more recently,calprotectin, areof considerable research interest but, as yet, these have notbeen introduced into clinical practice.”
A simple method for assessing intestinal inflammation in Crohn's diseaseTibble et al Gut 2000 • 22 patients: fecal calprotectin compared with 4 day 111Indium 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...
Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal diseaseTibble 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
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
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%
Fecal Calprotectin as an aid to Diagnosis in intestinal inflammationDolwani 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
Fecal Calprotectin in steroid dependent Colitis. An indicator of clinical responseAtkinson 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”
Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease Gastroenterology 2000;119:15-22
Subclinical intestinal inflammation: An inherited abnormality in Crohn’s disease relatives?Gastroenterology June 2003
Effect of Pentavac and MMR vaccination on the intestineGut 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’”
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%
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
Fecal Calprotectin levels in a high risk population for colorectal neoplasia Kronberg et al Gut 2000 (46) 795 -800
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
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)
The Future? • GI OPD screening • Organic versus non-organic • Investigate versus observe • Population based bowel cancer screening • Selected high risk groups • IBD monitoring • Availability ?