Hannu Nuutinen

Crohn's Disease Activity Assessed by Fecal Calprotectin and Lactoferrin : Correlation with Crohn's Disease Activity Index and Endoscopic Findings

Background: Correlation of endoscopic Crohns disease activity with fecal calprotectin and lactoferrin is insufficiently studied. We evaluated the clinical significance of these neutrofil‐derived proteins in assessment of Crohns disease activity by comparing them with endoscopic disease activity and with Crohns disease activity index (CDAI) and serum CRP. Methods: A total of 77 CD patients underwent one or more ileocolonoscopies (n = 106) with scoring of Crohns disease index of severity (CDEIS). Patients provided stool samples for calprotectin and lactoferrin measurements and blood samples for CRP. Clinical activity was based on the CDAI. Results: Both fecal calprotectin and lactoferrin correlated significantly with CDEIS (Spearmans r 0.729 and 0.773, P < 0.001). With a cutoff level of 200 &mgr;g/g for a raised fecal calprotectin concentration, sensitivity was 70%, specificity 92%, positive predictive value (PPV) 94%, and negative predictive value (NPV) 61% in predicting endoscopically active disease (CDEIS ≥ 3). A fecal lactoferrin concentration of 10 &mgr;g/g as the cutoff value gave a sensitivity, specificity, PPV, and NPV of 66%, 92%, 94%, and 59%. Sensitivity of CDAI ≥ 150 to detect endoscopically active disease was only 27%, specificity 94%, PPV 91%, and NPV 40%. A raised serum CRP (> 5 mg/l) gave a sensitivity, specificity, PPV, and NPV of 48%, 91%, 91%, and 48%. Conclusions: For evaluation of Crohns disease activity, based on endoscopic findings, more sensitive surrogate markers than is CDAI or CRP are fecal calprotectin and lactoferrin. These prove to be useful tools for estimation of disease activity in Crohns disease.

Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn's disease and histological findings

Background  Faecal calprotectin and lactoferrin increasingly serve as surrogate markers of disease activity in IBD. Data on the correlation of these markers with simple endoscopic score for Crohn’s disease (SES‐CD) and with histological findings are as yet limited.

Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti‐TNF‐alpha therapy for Crohn's disease

Background: Fecal calprotectin and lactoferrin are promising noninvasive biomarkers for intestinal inflammation. In Crohns disease (CD), during anti‐TNF‐alpha (TNF‐&agr;) treatment, the clinical significance of these markers has, however, been insufficiently explored. Methods: Among CD patients receiving anti‐TNF‐&agr; therapy we assessed the role of fecal calprotectin and lactoferrin as surrogate markers for mucosal healing. Before and 3 months after the beginning of anti‐TNF‐&agr; induction, 15 patients underwent ileocolonoscopy with scoring of the Crohns Disease Index of Severity (CDEIS). Fecal samples for calprotectin and for lactoferrin measurements were collected and the Crohns Disease Activity Index (CDAI) was calculated at the time of the endoscopies and 2 and 8 weeks after the first treatment. Results: The median CDEIS fell from 13.0 to 4.8 (P = 0.002) and CDAI from 158 to 68 (P = 0.005). Accordingly, the median fecal calprotectin concentration fell from 1173 &mgr;g/g to 130 &mgr;g/g (P = 0.001) and fecal lactoferrin from 105.0 &mgr;g/g to 2.7 &mgr;g/g (P = 0.001). Of the 15 patients, 11 (73%) showed an endoscopic response to treatment and 5 of these achieved endoscopic remission (CDEIS < 3). In those 5 patients the fecal calprotectin concentration declined from 1891 &mgr;g/g (range 813–2434) to 27 &mgr;g/g (13–130) and lactoferrin from 92.4 &mgr;g/g (35.5–235.6) to 1.9 &mgr;g/g (0.0–2.1). Conclusions: Compared to pretreatment values, concentrations of fecal calprotectin and lactoferrin after the anti‐TNF‐&agr; treatment were significantly lower. During anti‐TNF‐&agr; therapy these fecal neutrophil‐derived proteins may thus be useful surrogate markers for mucosal healing.

Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: A three‐year randomized trial

Ursodeoxycholic acid (UDCA) is a safe medical therapy for primary biliary cirrhosis (PBC), but its effect on liver histology remains uncertain. Budesonide is a glucocorticoid with high receptor activity and high first‐pass metabolism in liver. We evaluated the combination of budesonide and UDCA on liver histology and compared this with UDCA alone in a 3‐year prospective, randomized, open multicenter study. Patients with PBC (n = 77), at stages I to III, were randomized into 2 treatment arms, A (n = 41): budesonide 6 mg/d and UDCA 15 mg/kg/d and B (n = 36): UDCA 15mg/kg/d. Liver histology was assessed at the beginning and at the end of the study. Liver function tests and glucose and cortisol values were determined every 4 months. Paired liver biopsy specimens were available from 69 patients (A = 37 and B = 32). Stage improved 22% in group A but deteriorated 20% in group B (P = .009). Fibrosis decreased 25% in group A but increased 70% in group B (P = .0009). S‐PIIINP decreased significantly in group A. Inflammation decreased in both groups, 34% in group A (P = .02), but only 10% in group B (P = NS). Serum liver enzymes decreased significantly in both treatment arms. Bilirubin values rose in group B but stayed stable in group A (A/B P = .002). A mild systemic glucocorticoid effect from budesonide was evident after 2 years. In conclusion, budesonide combined with UDCA improved liver histology, whereas the effect of UDCA alone was mainly on laboratory values. Studies with longer follow‐up using a combination of budesonide and UDCA are warranted to confirm safety and effects. (HEPATOLOGY 2005.)

Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: A randomized placebo‐controlled trial

No effective medical therapy is currently available for primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA) improves liver enzymes, but its effect on liver histology is controversial. Metronidazole (MTZ) prevents PSC‐like liver damage in animal models and reduces intestinal permeability. We recruited 80 patients with PSC into a randomized placebo‐controlled study to evaluate the effect of UDCA and MTZ (UDCA/MTZ) compared with UDCA/placebo on the progression of PSC. Patients (41 UDCA/placebo and 39 UDCA/MTZ) were followed every third month. Assessment of liver function test, histological stage and grade, and cholangiography (via ERCP) at baseline showed no differences between the groups. After 36 months, serum aminotransferases γ‐glutamyltransferase, and alkaline phosphatase (ALP) decreased markedly in both groups, serum ALP more significantly in the UDCA/MTZ group (−337 ± 54 U/L, P < .05) compared with the UDCA/placebo group. The New Mayo Risk Score decreased markedly only in the UDCA/MTZ group (−0.50 ± 0.13, P < .01). The number of patients with improvement of stage (P < .05) and grade (P < .05) was higher in the combination group. ERCP findings showed no progression or improvement in 77% and 68% of patients on UDCA/MTZ and UDCA/placebo, respectively. In conclusion, combining MTZ with UDCA in PSC improved serum ALP levels and New Mayo Risk Score, but no statistically significant effect on disease progression as assessed via liver histology or ERCP was seen. Long‐term studies using a higher dose of UDCA combined with MTZ in larger patient populations are indicated. (HEPATOLOGY 2004;40:1379–1386.)

Faecal calprotectin and lactoferrin are reliable surrogate markers of endoscopic response during Crohn's disease treatment

Abstract Objective. Serial monitoring data for faecal calprotectin and lactoferrin during Crohns disease (CD) therapy are scarce. The aim of this research was to study the behaviour of faecal biomarkers during CD therapy. Material and methods. Adult CD patients (n = 19) needing therapy enhancement were prospectively recruited. The simple endoscopic score for Crohns disease (SES-CD) was administered before and 4–6 months after therapy. At baseline and at 2–3 and 4–6 months, patients provided faecal samples for measurements of calprotectin and lactoferrin. Results. Of 19 patients, seven were endoscopic responders, three were partial responders and nine were non-responders. During therapy, both faecal-biomarker concentrations decreased significantly in responders: median calprotectin from 1282 μg/g (range 156–2277 μg/g) to 73 μg/g (range 7–2222; P = 0.005) and lactoferrin from 233 μg/g (range 2.8–802 μg/g) to 0.0 μg/g (range 0.0–420 μg/g; P = 0.005), and these changes correlated significantly with changes in the SES-CD. In non-responders, changes in faecal biomarkers were non-significant: calprotectin decreased from 1017 μg/g (range 53–3928 μg/g) to 223 μg/g (range 35–15 330 μg/g; P = 0.594) and lactoferrin from 22.5 μg/g (range 2.1–629 μg/g) to 13.0 μg/g (range 3.5–1259 μg/g; P = 0.515). Conclusions. The faecal neutrophil-derived proteins calprotectin and lactoferrin are reliable surrogate markers of mucosal improvement. Endoscopic responders achieved normalization of faecal biomarkers, whereas in the majority of endoscopic non-responders these markers remained abnormal.

Endoscopic evaluation of Crohn's disease activity: Comparison of the CDEIS and the SES‐CD

Background: Few data exist of prospective parallel scoring of the validated endoscopic scores in Crohns disease (CD), Crohns Disease Index of Severity (CDEIS), and Simple Endoscopic Score for Crohns Disease (SES‐CD). Methods: Both the CDEIS and the SES‐D were scored immediately after each endoscopy of 86 CD patients referred for ileocolonoscopy in a cross‐sectional study. Furthermore, after CD therapy, 32 CD patients underwent a follow‐up endoscopy with scoring of the CDEIS and SES‐CD. Endoscopic scorings were graded as inactive, mild, moderate, or severe. Clinical activity was assessed with the Crohns Disease Activity Index (CDAI) and serum C‐reactive protein (CRP) was measured. Results: The SES‐CD correlated with the CDEIS significantly (Spearmans r = 0.938, P < 0.0001). Weaker correlations were detected between the SES‐CD and the CDAI (r = 0.473) or CRP (r = 0.525, both P < 0.0001). Grading of SES‐CD from inactive to severe correlated significantly with grading of the CDEIS (r = 0.859, P < 0.0001). Changes between baseline and follow‐up endoscopy scores correlated significantly (r = 0.828 between delta‐CDEIS and delta‐SES‐CD, P < 0.001), but failed to correlate with delta‐CDAI or delta‐CRP (all P > 0.05). Conclusions: Both validated endoscopic scores, the CDEIS and SES‐CD, and their changes during CD therapy demonstrated a close correlation. For scoring of endoscopic activity in clinical routine, the SES‐CD could replace the CDEIS. Inflamm Bowel Dis 2010

Fecal calprotectin and S100A12 have low utility in prediction of small bowel Crohn's disease detected by wireless capsule endoscopy

Abstract Objective. Data on fecal calprotectin and S100A12 in predicting wireless capsule endoscopy (WCE) findings in suspicion of Crohns disease (CD) are scarce. Our aim was to study the role of calprotectin and S100A12 in predicting inflammatory lesions of small bowel in patients undergoing WCE. Material and methods. 84 patients undergoing WCE (77 for suspicion of CD and 7 CD patients for evaluation of disease extent) were prospectively recruited. WCE findings were scored. Patients provided a stool sample for measurements of biomarkers. Patients underwent an esophagogastroduodenoscopy and ileocolonoscopy before WCE. Results. WCE was abnormal in 35 (42%) of 84 patients: 14 patients with CD, 8 with NSAID enteropathies, 8 with angioectasias, 4 with polyps or tumors, and 1 with ischemic stricture. Median calprotectin concentration in the study population was 22 μg/g (range 2–342) and S100A12 concentration 0.048 μg/g (range 0.003–1.215). Fecal calprotectin was significantly higher in CD patients (median 91, range 2–312) compared with those with normal WCE or other abnormalities (p = 0.008), whereas fecal S100A12 (0.087 μg/g, range 0.008–0.896) did not differ between the groups (p = 0.166). In detecting inflammatory small bowel lesions, sensitivity, specificity, positive predictive value, and negative predictive value for fecal calprotectin (cutoff 50 μg/g) were 59%, 71%, 42%, and 83%, and for S100A12 (cutoff 0.06 μg/g) these were 59%, 66%, 38%, and 82%. Conclusions. In predicting small bowel inflammatory changes, fecal biomarkers calprotectin and S100A12 have moderate specificity, but low sensitivity. Neither fecal calprotectin nor S100A12 can be used for screening or excluding small bowel CD.

Ethanol-derived Microbial Production of Carcinogenic Acetaldehyde in Achlorhydric Atrophic Gastritis

Background: Acetaldehyde is a local carcinogen in the digestive tract in humans. Atrophic gastritis leads to microbial colonization of the stomach, which could enhance microbial production of acetaldehyde from ethanol. The aim of the study was to study microbial ethanol metabolism and acetaldehyde production in the stomach of achlorhydric atrophic gastritis patients. Methods: For the in vivo study, glucose or ethanol was infused via a nasogastric tube to the stomach of seven achlorhydric atrophic gastritis patients and five healthy controls. Gastric juice samples for ethanol and acetaldehyde determinations and microbial analysis were obtained at 30 and 60 min after the infusions. For the in vitro study, gastric juice samples from 14 atrophic gastritis patients and 16 controls were obtained during gastroscopy, whereafter the samples were incubated for 2 h with 1% ethanol at 37 °C and acetaldehyde was determined. Results: Minor endogenous ethanol and acetaldehyde concentrations were detected after glucose infusion in the gastric juice of four atrophic gastritis patients. After ethanol infusion, the mean intragastric acetaldehyde level of the atrophic gastritis patients was 4.5-fold at 30 min and 6.5-fold at 60 min compared to controls. In vitro, the difference between the study groups was even higher, 7.6-fold. A vast selection of oral bacterial species and some Enterobacteriaceae and yeasts were presented in the gastric juice of atrophic gastritis patients. Conclusions: Microbial ethanol metabolism leads to high intragastric acetaldehyde levels after ethanol drinking in achlorhydric atrophic gastritis patients. This could be one of the factors responsible for enhanced gastric cancer risk among atrophic gastritis patients.

Long term metabolic consequences of ileal pouch–anal anastomosis for ulcerative colitis

OBJECTIVES:Chronic inflammation in the ileal pouch is the most significant late complication after ileal pouch–anal anastomosis (IPAA). It leads to changes in mucosal morphology, with consequent decreased vitamin B12, bile acid and cholesterol absorption documented. The aims of this study were to evaluate long term metabolic consequences at least 5 yr after IPAA and the influence of pouchitis on pouch histology and on bile acid, lipid, and vitamin B12, A, E, and D metabolism.METHODS:A total of 104 patients with a J-pouch who were operated on between 1985 and 1994, as well as 21 ulcerative colitis patients with a conventional ileostomy were enrolled for the study. Routine blood tests, vitamin status, vitamin B12 levels, and bile acid absorption were determined, as well as endoscopy with biopsies. The pouchitis disease activity index (PDAI) was calculated. On the basis of histology, IPAA patients were divided into three subgroups: 1) those with no villous atrophy, 2) those with partial villous atrophy, and 3) those with subtotal or total villous atrophy.RESULTS:Incidence of pouchitis was 42.3%, and was strongly associated with villous atrophy. In IPAA patients with subtotal or total villous atrophy (32.7%), serum levels of albumin, calcium, total cholesterol, triglycerides, and vitamin E were significantly reduced (p < 0.05). The lowest bile acid and vitamin B12 absorption rates were seen in patients with inflammation in the proximal limb. Vitamin D deficiency was seen in 10.6%, and vitamin A and B12 deficiency in approximately 5% of IPAA patients.CONCLUSIONS:Metabolic consequences after IPAA are associated with pouchitis, grade of villous atrophy, and extent of inflammation in the remaining ileum. Patients with active chronic inflammation need long term follow-up.