Emanuel Burri

The use of fecal calprotectin as a biomarker in gastrointestinal disease

Abdominal discomfort including pain, bloating and diarrhea is common. It often arises from functional gastrointestinal disorders but may indicate inflammatory bowel disease (IBD). Calprotectin is an abundant neutrophil protein that is released during inflammation. When measured in feces, it can be used to differentiate between non-organic and inflammatory intestinal disorders, especially to identify IBD. Fecal calprotectin might also be useful to monitor patients with IBD under treatment and to predict the risk of recurrence of active disease prior to clinical relapse. The use of fecal calprotectin has been investigated in a number of gastrointestinal disorders other than IBD, for example, as screening test for colorectal cancer but the available data are limited. This article summarizes the current literature on the use of fecal calprotectin in clinical practice.

Faecal calprotectin - a useful tool in the management of inflammatory bowel disease

Inflammatory bowel disease (IBD) should be suspected in any patient presenting with chronic or recurrent abdominal pain and diarrhoea. Current guidelines suggest performing invasive endoscopy with histological sampling for further diagnosis. Measuring calprotectin, a neutrophilic protein, in faeces has been proposed as a surrogate marker of intestinal inflammation. Calprotectin values have been shown to reliably differentiate between IBD and non-organic disease in symptomatic patients and, when elevated, warrant early endoscopic investigation to rule out IBD and other organic pathologies. Endoscopy with histological sampling is also used to evaluate disease activity and here, too, faecal calprotectin values seem to correlate well. In a number of studies, faecal calprotectin values have consistently shown to better assess mucosal inflammation than clinical indices and serum markers. Calprotectins advantage of non-invasive monitoring of disease activity is especially beneficial when considering the dynamics of repeated measurements. Mucosal healing (MH) has been associated with sustained clinical remission, reduced rates of hospitalisation and of surgical resection, both in Crohns disease and ulcerative colitis patients. Elevated faecal calprotectin levels in patients in clinical remission are associated with increased risk of disease relapse within 12 months follow-up. In most clinically quiescent IBD, residual mucosal inflammation is still present; it appears that faecal calprotectin can detect subclinical mucosal inflammation and thus might identify patients at risk for relapse. In summary, measuring faecal calprotectin can be highly useful in the diagnosis and disease management of patients with IBD and could help predict disease course.

Serum Protein Electrophoresis: An Underused but Very Useful Test

Serum protein electrophoresis is used in clinical practice to identify patients with multiple myeloma and other serum protein disorders. It is an inexpensive and easy-to-perform screening procedure. Electrophoresis separates serum proteins based on their physical properties and identifies morphologic patterns in response to acute and chronic inflammation, various malignancies, liver or renal failure, and hereditary protein disorders. For gastroenterologists, the use of serum protein electrophoresis may be helpful in the diagnosis of both common diseases with unusual presentations and rare disorders with typical presentations. Therefore, it represents an ideal screening tool.

Mechanisms of postprandial abdominal bloating and distension in functional dyspepsia

Objective Patients with irritable bowel syndrome and abdominal bloating exhibit abnormal responses of the abdominal wall to colonic gas loads. We hypothesised that in patients with postprandial bloating, ingestion of a meal triggers comparable abdominal wall dyssynergia. Our aim was to characterise abdominal accommodation to a meal in patients with postprandial bloating. Design A test meal (0.8 kcal/ml nutrients plus 27 g/litre polyethylenglycol 4000) was administered at 50 ml/min as long as tolerated in 10 patients with postprandial bloating (fulfilling Rome III criteria for postprandial distress syndrome) and 12 healthy subjects, while electromyographic (EMG) responses of the anterior wall (upper and lower rectus, external and internal oblique via bipolar surface electrodes) and the diaphragm (via six ring electrodes over an oesophageal tube in the hiatus) were measured. Means +/− SD were calculated. Results Healthy subjects tolerated a meal volume of 913±308 ml; normal abdominal wall accommodation to the meal consisted of diaphragmatic relaxation (EMG activity decreased by 15±6%) and a compensatory contraction (25±9% increase) of the upper abdominal wall muscles (upper rectus and external oblique), with no changes in the lower anterior muscles (lower rectus and internal oblique). Patients tolerated lower volume loads (604±310 ml; p=0.030 vs healthy subjects) and developed a paradoxical response, that is, diaphragmatic contraction (14±3% EMG increment; p<0.01 vs healthy subjects) and upper anterior wall relaxation (9±4% inhibition; p<0.01 vs healthy subjects). Conclusions In functional dyspepsia, postprandial abdominal distension is produced by an abnormal viscerosomatic response to meal ingestion that alters normal abdominal accommodation.

Abdomino-Phrenic Dyssynergia in Patients With Abdominal Bloating and Distension

OBJECTIVES:The abdomen normally accommodates intra-abdominal volume increments. Patients complaining of abdominal distension exhibit abnormal accommodation of colonic gas loads (defective contraction and excessive protrusion of the anterior wall). However, abdominal imaging demonstrated diaphragmatic descent during spontaneous episodes of bloating in patients with functional gut disorders. We aimed to establish the role of the diaphragm in abdominal distension.METHODS:In 20 patients complaining of abdominal bloating and 15 healthy subjects, we increased the volume of the abdominal cavity with a colonic gas load, while measuring abdominal girth and electromyographic activity of the anterior abdominal muscles and of the diaphragm.RESULTS:In healthy subjects, the colonic gas load increased girth, relaxed the diaphragm, and increased anterior wall tone. With the same gas load, patients developed significantly more abdominal distension; this was associated with paradoxical contraction of the diaphragm and relaxation of the internal oblique muscle.CONCLUSIONS:In this experimental provocation model, abnormal accommodation of the diaphragm is involved in abdominal distension.

Abdominothoracic Mechanisms of Functional Abdominal Distension and Correction by Biofeedback

BACKGROUND & AIMS In patients with functional gut disorders, abdominal distension has been associated with descent of the diaphragm and protrusion of the anterior abdominal wall. We investigated mechanisms of abdominal distension in these patients. METHODS We performed a prospective study of 45 patients (42 women, 24-71 years old) with functional intestinal disorders (27 with irritable bowel syndrome with constipation, 15 with functional bloating, and 3 with irritable bowel syndrome with alternating bowel habits) and discrete episodes of visible abdominal distension. Subjects were assessed by abdominothoracic computed tomography (n = 39) and electromyography (EMG) of the abdominothoracic wall (n = 32) during basal conditions (without abdominal distension) and during episodes of severe abdominal distension. Fifteen patients received a median of 2 sessions (range, 1-3 sessions) of EMG-guided, respiratory-targeted biofeedback treatment; 11 received 1 control session before treatment. RESULTS Episodes of abdominal distension were associated with diaphragm contraction (19% ± 3% increase in EMG score and 12 ± 2 mm descent; P < .001 vs basal values) and intercostal contraction (14% ± 3% increase in EMG scores and 6 ± 1 mm increase in thoracic antero-posterior diameter; P < .001 vs basal values). They were also associated with increases in lung volume (501 ± 93 mL; P < .001 vs basal value) and anterior abdominal wall protrusion (32 ± 3 mm increase in girth; P < .001 vs basal). Biofeedback treatment, but not control sessions, reduced the activity of the intercostal muscles (by 19% ± 2%) and the diaphragm (by 18% ± 4%), activated the internal oblique muscles (by 52% ± 13%), and reduced girth (by 25 ± 3 mm) (P ≤ .009 vs pretreatment for all). CONCLUSIONS In patients with functional gut disorders, abdominal distension is a behavioral response that involves activity of the abdominothoracic wall. This distension can be reduced with EMG-guided, respiratory-targeted biofeedback therapy.

Accommodation of the abdomen to its content: integrated abdomino-thoracic response

Background  We previously showed that changes in intra‐abdominal content induce a volume‐dependent muscular response of the anterior abdominal wall and the diaphragm. We aimed to determine the contribution of the thorax to abdominal accommodation and the influence of the intra‐abdominal expansion rate.

Measurement of calprotectin in ascitic fluid to identify elevated polymorphonuclear cell count

AIM To evaluate the diagnostic capability of calprotectin in ascitic fluid for detecting a polymorphonuclear (PMN) cell count > 250/μL ascites. METHODS In this prospective observational study, a total of 130 ascites samples were analysed from 71 consecutive patients referred for paracentesis. Total and differential leukocyte cell counts were determined manually with a Neubauer chamber and gentian-violet stain. Calprotectin was measured in 1 mL ascetic fluid by enzyme-linked immunosorbent assay (ELISA) and a point-of-care (POC) lateral flow assay with the Quantum Blue(®) Reader (Bühlmann Laboratories). All measurements were carried out in a central laboratory by senior personnel blinded to patient history. A PMN count > 250/μL was the primary endpoint of the study. The diagnostic value of ascitic calprotectin measurement was assessed by comparing to the final diagnosis of each patient that had been adjudicated by investigators blinded to calprotectin values. RESULTS The PMN count was > 250/μL in 19 samples (14.6%) from 15 patients (21.1%) and varied widely among the study population (range 10-19 800/mL and 1-17 820/mL, respectively). Spontaneous bacterial peritonitis (SBP) was the final diagnosis in four patients (5.6%). All patients with PMN ≤ 250/μL had negative bacterial culture. PMN count was elevated in five patients with peritoneal carcinomatosis, three with lymphoma, one with neuroendocrine carcinoma, and two with secondary peritonitis due to abdominal perforation. PMN cell counts correlated with ascitic calprotectin values (Spearmans rho; r = 0.457 for ELISA, r = 0.473 for POC). A considerable range of ascitic calprotectin concentrations was detected by ELISA [median 0.43 μg/mL, interquartile range (IQR) 0.23-1.23 (range 0.10-14.93)] and POC [median 0.38 μg/mL, IQR 0.38-0.56 (range 0.38-13.31)]. Ascitic calprotectin levels were higher in samples with PMN > 250/μL, by both ELISA [median (IQR) 2.48 μg/mL (1.61-3.65) vs 0.10 μg/mL (0.10-0.36), P < 0.001] and POC [2.78 μg/mL (2.05-5.37) vs 0.38 μg/mL (0.38-0.41), P < 0.001]. The area under the receiver operating characteristics curve for identifying an elevated PMN count was 0.977 (95%CI: 0.933 to 0.995) for ELISA and 0.982 (95%CI: 0.942 to 0.997) for POC (P = 0.246 vs ELISA). Using the optimal cut-off value for ELISA (0.63 μg/mL), ascitic calprotectin had 94.8% sensitivity, 89.2% specificity, positive and negative likelihood ratios of 8.76 and 0.06 respectively, positive and negative predictive values of 60.0% and 99.0% respectively, and 90.0% overall accuracy. Using the optimal cut-off value for POC (0.51 μg/mL), the respective values were 100.0%, 84.7%, 6.53, 0.00, 52.8%, 100% and 87.7%. Correlation between ELISA and POC was excellent (r = 0.873, P < 0.001). The mean ± SD of the difference was -0.11 ± 0.48 μg/mL with limits of agreement of + 0.8 μg/mL (95%CI: 0.69 to 0.98) and -1.1 μg/mL (95%CI: -1.19 to -0.91). CONCLUSION Ascitic calprotectin reliably predicts PMN count > 250/μL, which may prove useful in the diagnosis of SBP, especially with a readily available bedside testing device.

Abdominal accommodation induced by meal ingestion: differential responses to gastric and colonic volume loads

Background  Using an experimental model of colonic gas infusion, we previously showed that the abdominal walls adapt to its content by an active phenomenon of abdominal accommodation. We now hypothesized that abdominal accommodation is a physiological phenomenon, and aimed to confirm that it can be induced by ingestion of a meal; a secondary aim was to determine whether the response to gut filling is region‐specific.

Faecal calprotectin in the diagnosis of inflammatory bowel disease.

Suspicion of inflammatory bowel disease should be raised in any patient with chronic or recurrent abdominal pain and diarrhoea. However, symptoms of inflammatory bowel disease (IBD) overlap with functional gastrointestinal disorders and those patients may not need endoscopy. Currently, colonoscopy with multiple biopsies is considered the gold standard to establish the diagnosis of IBD. Unfortunately, patient selection for endoscopy based on symptoms is not reliable. The use of guidelines of appropriateness for endoscopy yields significantly more significant findings but the selection criteria suffer from low specificity. Calprotectin is a calcium binding protein of neutrophil granulocytes that correlates well with neutrophil infiltration of the intestinal mucosa when measured in faeces. In the last decade, a large body of evidence on the diagnostic value of faecal calprotectin has accumulated and measurement of calprotectin in faeces has been suggested as a surrogate marker of intestinal inflammation. Testing of faecal calprotectin has been highly useful to distinguish organic from functional intestinal disorders in patients with abdominal complaints. Additionally, faecal calprotectin has reliably identified colonic inflammation in patients with suspected IBD. The use of this inexpensive and widely available test in the evaluation and risk stratification in patients with abdominal complaints is likely to increase in the future.