Marlou Adriaanse

Serum I-FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies

Enterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I‐FABP) is a sensitive marker to study enterocyte damage.

Additional value of serum I-FABP levels for evaluating celiac disease activity in children

Abstract Objectives. Addition of a non-invasive marker for intestinal damage to the currently used parameters for celiac disease activity (symptoms, serologic tests and biopsy) might further improve clinical management of celiac disease (CD). Intestinal fatty acid binding protein (I-FABP) is a cytosolic enterocyte protein and sensitive marker for enterocyte damage in the small intestine. We investigated whether serum I-FABP levels can reliably identify villous atrophy in children with a positive CD antibody screening. Moreover, the recovery of I-FABP levels after gluten free diet (GFD) was studied. Methods. I-FABP levels were analyzed retrospectively in 49 children with biopsy proven CD and in 19 patients with a positive screening but without histological confirmation of CD. Blood was collected before biopsy and repeatedly after the onset of GFD. Results. Initial I-FABP concentrations in CD (median 458 pg/ml) were significantly (p < 0.001) elevated compared to controls (median 20 pg/ml). In the control group, only two of 19 children were found to have elevated I-FABP levels, of which one was subsequently diagnosed with CD after gluten challenge. I-FABP concentrations correlated with severity of villous atrophy. In all CD patients, I-FABP levels decreased quickly after GFD and normalized in 80% of patients within 12 weeks. Conclusions. Elevated I-FABP levels accurately predict villous atrophy in children with a positive serologic test for CD (positive predictive value 98%). In addition, measurement of I-FABP enables monitoring the response to GFD.

Serum I-FABP Detects Gluten Responsiveness in Adult Celiac Disease Patients on a Short-Term Gluten Challenge

Objectives:Response to gluten challenge (GC) is a key feature in diagnostic algorithms and research trials in celiac disease (CD). Currently, autoantibody titers, late responders to GC, and invasive duodenal biopsies are used to evaluate gluten responsiveness. This study investigated the accuracy of serum intestinal-fatty acid binding protein (I-FABP), a marker for intestinal epithelial damage, to predict intestinal damage during GC in patients with CD.Methods:Twenty adult CD patients in remission underwent a two-week GC with 3 or 7.5 g of gluten daily. Study visits occurred at day −14, 0, 3, 7, 14, and 28. Serum I-FABP, antibodies to tissue transglutaminase (tTG-IgA), deamidated gliadin peptides (IgA-DGP), and anti-actin (AAA-IgA) were assessed at each visit. Villous-height to crypt-depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) count were evaluated at day −14, 3, and 14. Forty-three CD-serology negative individuals were included to compare serum I-FABP levels in CD patients on a gluten-free diet (GFD) with those in healthy subjects.Results:Serum I-FABP levels increased significantly during a two-week GC. In contrast, the most pronounced autoantibody increase was found at day 28, when patients had already returned to a GFD for two weeks. IgA-AAA titers were only significantly elevated at day 28. I-FABP levels and IEL count correlated at baseline (r=0.458, P=0.042) and at day 14 (r=0.654, P=0.002) of GC. Neither gluten dose nor time on a GFD influenced I-FABP change during GC.Conclusions:Serum I-FABP levels increased significantly during a two-week GC in adult CD patients and correlated with IEL count. The data suggest that serum I-FABP is an early marker of gluten-induced enteropathy in celiac patients and may be of use in both clinical and research settings.

Plasma Cathepsin D Levels: A Novel Tool to Predict Pediatric Hepatic Inflammation

OBJECTIVES:Nonalcoholic steatohepatitis (NASH) is the most severe form of a hepatic condition known as nonalcoholic fatty liver disease (NAFLD). NASH is histologically characterized by hepatic fat accumulation, inflammation, and ballooning, and eventually coupled with fibrosis that, in turn, may progress to end-stage liver disease even in young individuals. Hence, there is a critical need for specific noninvasive markers to predict hepatic inflammation at an early age. We investigated whether plasma levels of cathepsin D (CatD), a lysosomal protease, correlated with the severity of liver inflammation in pediatric NAFLD.METHODS:Liver biopsies from children (n=96) with NAFLD were histologically evaluated according to the criteria of Kleiner (NAFLD activity score) and the Brunt’s criteria. At the time of liver biopsy, blood was taken and levels of CatD, alanine aminotransferase (ALT), and cytokeratin-18 (CK-18) were measured in plasma.RESULTS:Plasma CatD levels were significantly lower in subjects with liver inflammation compared with steatotic subjects. Furthermore, we found that CatD levels were gradually reduced and corresponded with increasing severity of liver inflammation, steatosis, hepatocellular ballooning, and NAFLD activity score. CatD levels correlated with pediatric NAFLD disease progression better than ALT and CK-18. In particular, CatD showed a high diagnostic accuracy (area under receiver operating characteristic curve (ROC-AUC): 0.94) for the differentiation between steatosis and hepatic inflammation, and reached almost the maximum accuracy (ROC-AUC: 0.998) upon the addition of CK-18.CONCLUSIONS:Plasma CatD holds a high diagnostic value to distinguish pediatric patients with hepatic inflammation from children with steatosis.

Evidence for a Cystic Fibrosis Enteropathy.

Background Previous studies have suggested the existence of enteropathy in cystic fibrosis (CF), which may contribute to intestinal function impairment, a poor nutritional status and decline in lung function. This study evaluated enterocyte damage and intestinal inflammation in CF and studied its associations with nutritional status, CF-related morbidities such as impaired lung function and diabetes, and medication use. Methods Sixty-eight CF patients and 107 controls were studied. Levels of serum intestinal-fatty acid binding protein (I-FABP), a specific marker for enterocyte damage, were retrospectively determined. The faecal intestinal inflammation marker calprotectin was prospectively studied. Nutritional status, lung function (FEV1), exocrine pancreatic insufficiency (EPI), CF-related diabetes (CFRD) and use of proton pump inhibitors (PPI) were obtained from the medical charts. Results Serum I-FABP levels were elevated in CF patients as compared with controls (p<0.001), and correlated negatively with FEV1 predicted value in children (r-.734, p<0.05). Faecal calprotectin level was elevated in 93% of CF patients, and correlated negatively with FEV1 predicted value in adults (r-.484, p<0.05). No correlation was found between calprotectin levels in faeces and sputum. Faecal calprotectin level was significantly associated with the presence of CFRD, EPI, and PPI use. Conclusion This study demonstrated enterocyte damage and intestinal inflammation in CF patients, and provides evidence for an inverse correlation between enteropathy and lung function. The presented associations of enteropathy with important CF-related morbidities further emphasize the clinical relevance.

Serum Markers in the Clinical Management of Celiac Disease

The advent of highly reliable noninvasive celiac diagnostic tests has transformed the field of celiac disease, from diagnosis, to evaluation of epidemiology, to clinical and translational research. Serologic tests in their modern forms are highly sensitive and specific for diagnosis, allowing for consideration of avoidance of diagnostic intestinal biopsy in some settings. On the other hand, as predictors of intestinal damage and for use in monitoring disease activity, currently available noninvasive tests have been disappointing. Serologic tests, while a measure of disease activity, do not correlate well with histology or symptomatology, and it is unclear if they predict long-term risk. Additionally, while the many clinically available tests have improved accessibility, they can have widely different cutoff levels and overall performance, making the comparison of levels in individual patients over time and across populations quite difficult. In the future, we can expect to see improvement in the currently available serologic tests including tissue transglutaminase and deamidated gliadin peptide with expansion of the dynamic range of the tests, and the celiac care community should push for a standardization of assays that would simplify research and patient care. Additionally, current serologic tests are measures of the adaptive immune response in celiac disease but do not directly measure intestinal inflammation. Promising work on intestinal fatty acid-binding protein and other assays which directly measure intestinal damage may complement traditional serologic tests and further improve our ability to noninvasively diagnose and monitor celiac disease. The coming years hold promise for the continuing evolution of serum-based tests in celiac disease with the possibility of substantial improvement of patient care and clinical research.

Progress towards non-invasive diagnosis and follow-up of celiac disease in children : a prospective multicentre study to the usefulness of plasma I-FABP

This prospective study investigates whether measurement of plasma intestinal-fatty acid binding protein (I-FABP), a sensitive marker for small intestinal epithelial damage, improves non-invasive diagnosing of celiac disease (CD), and whether I-FABP levels are useful to evaluate mucosal healing in patients on a gluten-free diet (GFD). Ninety children with elevated tTG-IgA titres and HLA-DQ2/DQ8 positivity were included (study group). Duodenal biopsies were taken, except in those fulfilling the ESPGHAN criteria. Plasma I-FABP levels and tTG-IgA titres were assessed sequentially during six months of follow-up. Eighty children with normal tTG-IgA titres served as control group. In 61/90 (67.8%) of the children in the study group an increased I-FABP level was found; in all these children CD diagnosis was confirmed. Interestingly, in 14/30 (46.7%) children with slightly elevated tTG-IgA titres (<10x upper limit of normal), an increased I-FABP level was found. In all these children the diagnosis of CD was confirmed histologically. After gluten elimination for six weeks I-FABP levels had decreased towards levels in the control group. Measurement of plasma I-FABP, in addition to tTG-IgA, EMA-IgA and HLAtyping, enables non-invasive diagnosing of CD in a substantial number of children, and might therefore be of value in the diagnostic approach of CD.

Human leukocyte antigen typing using buccal swabs as accurate and non-invasive substitute for venipuncture in children at risk for celiac disease.

Human leukocyte antigen (HLA) typing is an important step in the diagnostic algorithm for celiac disease (CD) and is also used for screening purposes. Collection of blood is invasive and accompanied with emotional impact especially in children. Genetic technological progress now enables HLA typing from buccal cell samples. This study evaluated the reliability and feasibility of HLA typing for CD‐associated HLA polymorphisms using buccal swabs as routine test in high‐risk individuals.

Hla typing using buccal swabs as accurate and non-invasive substitute for venipuncture in children at risk for celiac disease.

Human leukocyte antigen (HLA) typing is an important step in the diagnostic algorithm for celiac disease (CD) and is also used for screening purposes. Collection of blood is invasive and accompanied with emotional impact especially in children. Genetic technological progress now enables HLA typing from buccal cell samples. This study evaluated the reliability and feasibility of HLA typing for CD‐associated HLA polymorphisms using buccal swabs as routine test in high‐risk individuals.

Letter: serum I-FABP as marker for enterocyte damage in first-degree relatives of patients with coeliac disease - authors' reply

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