Chris J. Mulder

Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice

OBJECTIVE:We have undertaken a study to assess the efficiency of serological tests in the diagnosis of celiac disease (CD) during the period January 1, 1994 to January 7, 1997. Our aim was to evaluate the sensitivity of IgA antiendomysium (EMA) and IgA antigliadin (AGA) with regard to the degree of histological abnormality in biopsy specimens of small intestine in untreated celiac disease patients and first-degree relatives.METHODS:The study population comprised 101 cases: 85 untreated celiac patients and 16 first-degree relatives with a mean age of 42 yr (range, 2–76 yrs). Sixteen of 85 were excluded from study because they did not satisfy the study or diagnostic criteria of CD. EMA and AGA have been compared with the degree of villous atrophy (VA) in 69 celiac patients and 16 relatives according to the Marsh criteria of 1992. We divided the Marsh III histology into three subgroups as follows: Marsh IIIa (partial VA), Marsh IIIb (subtotal VA), and Marsh IIIc (total villous atrophy).RESULTS:The specificity and positive predictive value of EMA for CD was excellent, because all EMA-positive patients (n = 42) were diagnosed with CD. The sensitivity of EMA, however, differed between CD subgroups; in patients with total VA, the sensitivity of EMA was 100% (17/17). However, in patients with partial VA (Marsh IIIa), the sensitivity of EMA was disappointing, only 9/29 (31%). Three of 72 celiacs with Marsh IIIb and Marsh IIIc had IgA deficiency and were excluded from the study. Elevated AGA has been detected in the sera of 39 of 69 (62%) patients. A combination of EMA and AGA tests showed a sensitivity of 76% (53/69). None of 16 first-degree relatives with Marsh I-II had positive EMA.CONCLUSIONS:Interpretation of negative serology needs great awareness. Although EMA sensitivity in total villous atrophy is excellent, in partial villous atrophy the sensitivity of EMA appears to be disappointing. Our experience shows that EMA and AGA have only limited value in screening programs for CD.

Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial

BACKGROUND Both single-dose brachytherapy and self-expanding metal stent placement are commonly used for palliation of oesophageal obstruction due to inoperable cancer, but their relative merits are unknown. We undertook a randomised trial to compare the outcomes of brachytherapy and stent placement in patients with oesophageal cancer. METHODS Nine hospitals in the Netherlands participated in our study. Between December, 1999, and June, 2002, 209 patients with dysphagia from inoperable carcinoma of the oesophagus or oesophagogastric junction were randomly assigned to stent placement (n=108) or single-dose (12 Gy) brachytherapy (n=101), and were followed up after treatment. Primary outcome was relief of dysphagia during follow-up, and secondary outcomes were complications, treatment for persistent or recurrent dysphagia, health-related quality of life, and costs. Analysis was by intention to treat. FINDINGS Nine patients (six [brachytherapy] vs three [stent placement]) did not receive their allocated treatments. None was lost to follow-up. Dysphagia improved more rapidly after stent placement than after brachytherapy, but long-term relief of dysphagia was better after brachytherapy. Stent placement had more complications than brachytherapy (36 [33%] of 108 vs 21 [21%] of 101; p=0.02), which was mainly due to an increased incidence of late haemorrhage (14 [13%] of 108 vs five [5%] of 101; p=0.05). Groups did not differ for persistent or recurrent dysphagia (p=0.81), or for median survival (p=0.23). Quality-of-life scores were in favour of brachytherapy compared with stent placement. Total medical costs were also much the same for stent placement (8215) and brachytherapy (8135). INTERPRETATION Despite slow improvement, single-dose brachytherapy gave better long-term relief of dysphagia than metal stent placement. Since brachytherapy was also associated with fewer complications than stent placement, we recommend it as the primary treatment for palliation of dysphagia from oesophageal cancer.

A Prospective Study Comparing Video Capsule Endoscopy with Double-Balloon Enteroscopy in Patients with Obscure Gastrointestinal Bleeding

OBJECTIVE:Obscure gastrointestinal bleeding from jejunal and ileal lesions remains undiagnosed using traditional imaging techniques (radiologic, endoscopic). This prospective study compares the diagnostic detection rate of small-bowel lesions using wireless video capsule endoscopy (VCE) with the detection rate using double-balloon enteroscopy (DBE) in patients with obscure gastrointestinal bleeding (OGIB). Tolerance, adverse events, endoscopic interventions, and prognosis were described as secondary aims.METHODS:Thirty-five consecutive patients with obscure gastrointestinal bleeding were evaluated (22 males and 13 females; mean age 63.2 yr; range, 19–86 yr). The detection rates of the Given M2A wireless VCE and DBE were compared.RESULTS:Small-bowel abnormalities were detected using VCE in 28 (80%) of the 35 patients with OGIB, compared with 21 (60%) of the 35 patients using DBE (P = 0.01). Both examinations were well tolerated, but VCE was more acceptable to patients. No major adverse event occurred after either examination. Biopsies (n = 27), argon plasma coagulation (n = 19), tattoo injection (n = 8), and polypectomy (n = 2) were feasible with DBE when indicated in 27 of the 35 patients (77%). During a median (range) follow-up period of 5 (2–12) months, 26 (74%) patients remained clinically stable and did not require blood transfusions after DBE procedures. Eighteen (51%) of those who remained clinically stable had received APC therapy.CONCLUSIONS:High detection rates of the causes of OGIB are feasible with VCE and DBE. Although the detection rate of VCE was superior, our results indicate that the procedures are complementary; an initial diagnostic imaging employing VCE might be followed by therapeutic and interventional DBE.

Histologic Follow-up of People With Celiac Disease on a Gluten-Free Diet Slow and Incomplete Recovery

To assess histologic recovery in response to gluten withdrawal in celiac disease, 158 patients seen in our hospital during a 15-year period underwent follow-up small intestine biopsies (SIBs) within 2 years after starting a gluten-free diet; further SIBs were done if villous atrophy was present. A modified Marsh classification was used (IIIA, partial villous atrophy; IIIB, subtotal villous atrophy; IIIC, total villous atrophy). Of patients with Marsh IIIA, IIIB, or IIIC lesions, histologic remission was seen in 65.0% within 2 years, 85.3% within 5 years, and 89.9% in long-term follow-up. Eleven patients (7.0%) with persisting (partial) villous atrophy had symptoms and signs of malabsorption and were considered to have refractory celiac disease; 5 of them developed an enteropathy-associated T-cell lymphoma. Children recovered up to 95% within 2 years and 100% in the long-term. Histologic recovery in celiac disease after starting a gluten-free diet takes time and is incomplete or absent in a substantial subgroup of patients (10.1% villous atrophy after 5 years). Systematic follow-up of patients with celiac disease and the malabsorption syndrome and secondary complications is needed.

Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 × 10−6) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 × 10−5). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.

The spectrum of celiac disease: epidemiology, clinical aspects and treatment

Celiac disease is a gluten-sensitive enteropathy that affects people of all ages worldwide. This disease has emerged as a major health-care problem, as advances in diagnostic and screening methods have revealed its global prevalence. Environmental factors such as gluten introduction at childhood, infectious agents and socioeconomic features, as well as the presence of HLA-DQ2 and/or HLA-DQ8 haplotypes or genetic variations in several non-HLA genes contribute to the development of celiac disease. Growing insight into the variable clinical and histopathological presentation features of this disease has opened new perspectives for future research. A strict life-long gluten-free diet is the only safe and efficient available treatment, yet it results in a social burden. Alternative treatment modalities focus on modification of dietary components, enzymatic degradation of gluten, inhibition of intestinal permeability and modulation of the immune response. A small group of patients with celiac disease (2–5%), however, fail to improve clinically and histologically upon elimination of dietary gluten. This complication is referred to as refractory celiac disease, and imposes a serious risk of developing a virtually lethal enteropathy-associated T-cell lymphoma.

Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study.

Objective To investigate the value of serum antitissue transglutaminase IgA antibodies (IgA-TTG) and IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of coeliac disease in cohorts from different geographical areas in Europe. The setting allowed a further comparison between the antibody results and the conventional small-intestinal histology. Methods A total of 144 cases with coeliac disease [median age 19.5 years (range 0.9-81.4)], and 127 disease controls [median age 29.2 years (range 0.5-79.0)], were recruited, on the basis of biopsy, from 13 centres in nine countries. All biopsy specimens were re-evaluated and classified blindly a second time by two investigators. IgA-TTG were determined by ELISA with human recombinant antigen and IgA-EMA by an immunofluorescence test with human umbilical cord as antigen. Results The quality of the biopsy specimens was not acceptable in 29 (10.7%) of 271 cases and a reliable judgement could not be made, mainly due to poor orientation of the samples. The primary clinical diagnosis and the second classification of the biopsy specimens were divergent in nine cases, and one patient was initially enrolled in the wrong group. Thus, 126 coeliac patients and 106 controls, verified by biopsy, remained for final analysis. The sensitivity of IgA-TTG was 94% and IgA-EMA 89%, the specificity was 99% and 98%, respectively. Conclusions Serum IgA-TTG measurement is effective and at least as good as IgA-EMA in the identification of coeliac disease. Due to a high percentage of poor histological specimens, the diagnosis of coeliac disease should not depend only on biopsy, but in addition the clinical picture and serology should be considered.

A major non-HLA locus in celiac disease maps to chromosome 19

BACKGROUND AND AIMS The pathogenesis of celiac disease is still unknown despite its well-known association with human leukocyte antigen (HLA)-DQ2 and DQ8. It is clear that non-HLA genes contribute to celiac disease development as well, but none of the previous genome-wide screens in celiac disease have resulted in identification of these genes. METHODS We, therefore, performed a 2-stage, genome-wide screen in 101 affected sibpairs from 82 Dutch families who met strict diagnostic criteria. The small intestinal biopsy samples, on which the original celiac disease diagnoses had been based, showed a Marsh III lesion in all patients on reevaluation by 1 pathologist. For association analysis of markers in regions linked to celiac disease, 216 independent MIII patients and 216 age- and sex-matched controls were available. RESULTS As expected, highly significant linkage to the HLA-region was detected (multipoint maximum lod score [MMLS] = 8.14). More importantly, significant linkage was also present at 19p13.1 (MMLS = 4.31), with the peak at marker D19S899. Moreover, this marker was also significantly associated with celiac disease in the case-control study (corrected P = 0.016). Furthermore, we identified suggestive linkage to 6q21-22, which is approximately 70 cM downstream from the HLA region (MMLS = 3.10). CONCLUSIONS Significant linkage of celiac disease to chromosome region 19p13.1 was detected in our genome-wide screen. These results were confirmed by the association of D19S899 to celiac disease in an independent case-control cohort. Furthermore, we identified a possible second celiac disease locus on chromosome region 6q21-22.

Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease.

The functional integrity of the small bowel is impaired in coeliac disease. Intestinal permeability, as measured by the sugar absorption test probably reflects this phenomenon. In the sugar absorption test a solution of lactulose and mannitol was given to the fasting patient and the lactulose/mannitol ratio measured in urine collected over a period of five hours. The sugar absorption test was performed in nine patients with coeliac disease with an abnormal jejunum on histological examination, 10 relatives of patients with coeliac disease with aspecific symptoms but no villous atrophy, six patients with aspecific gastrointestinal symptoms but no villous atrophy, and 22 healthy controls to determine whether functional integrity is different in these groups. The lactulose/mannitol ratio (mean (SEM) is significantly higher in both coeliac disease (0.243 (0.034), p < 0.0001)) and relatives of patients with coeliac disease (0.158 (0.040), p < 0.005)) v both healthy controls (0.043 (0.006)) and patients with aspecific gastrointestinal symptoms (0.040 (0.011)). The lactulose/mannitol ratio in relatives of coeliac disease patients was significantly lower than in the coeliac disease patient group (p = 0.04). The lactulose/mannitol ratio was the same in healthy controls and patients with aspecific gastrointestinal symptoms. It is concluded that the sugar absorption test is a sensitive test that distinguishes between patients with coeliac disease and healthy controls. The explanation for the increased permeability in relatives of patients with coeliac disease is uncertain. Increased intestinal permeability may be related to constitutional factors in people susceptible to coeliac disease and may detect latent coeliac disease. The sugar absorption test may therefore be helpful in family studies of coeliac disease.

Value of symptoms and additional diagnostic tests for colorectal cancer in primary care: systematic review and meta-analysis.

Objective To summarise available evidence on diagnostic tests that might help primary care physicians to identify patients with an increased risk for colorectal cancer among those consulting for non-acute lower abdominal symptoms. Data sources PubMed, Embase, and reference screening. Study eligibility criteria Studies were selected if the design was a diagnostic study; the patients were adults consulting because of non-acute lower abdominal symptoms; tests included signs, symptoms, blood tests, or faecal tests. Study appraisal and synthesis methods Two reviewers independently assessed quality with a modified version of the QUADAS tool and extracted data. We present diagnostic two by two tables and pooled estimates of sensitivity and specificity. We refrained from pooling when there was considerable clinical or statistical heterogeneity. Results 47 primary diagnostic studies were included. Sensitivity was consistently high for age ≥50 (range 0.81-0.96, median 0.91), a referral guideline (0.80-0.94, 0.92), and immunochemical faeces tests (0.70-1.00, 0.95). Of these, only specificity of the faeces tests was good. Specificity was consistently high for family history (0.75-0.98, 0.91), weight loss (0.72-0.96, 0.89), and iron deficiency anaemia (0.83-0.95, 0.92), but all tests lacked sensitivity. None of these six tests was (sufficiently) studied in primary care. Conclusions Although combinations of symptom and results of immunochemical faeces tests showed good diagnostic performance for colorectal cancer, evidence from primary care is lacking. High quality studies on their role in the diagnostic investigation of colorectal cancer in primary care are urgently needed.