Olof Sandström

Celiac disease revealed in 3% of Swedish 12-year-olds born during an epidemic

Objective: Sweden experienced a marked epidemic of celiac disease between 1984 and 1996 in children younger than 2 years of age, partly explained by changes in infant feeding. The objective of this study was to determine the prevalence of celiac disease in 12-year-olds born during the epidemic (1993), including both symptomatic and screening detected cases. Patients and Methods: All sixth-grade children in participating schools were invited (n = 10,041). Symptomatic and, therefore, previously diagnosed celiac disease cases were ascertained through the National Swedish Childhood Celiac Disease Register and/or medical records. All serum samples were analyzed for antihuman tissue transglutaminase (tTG)-IgA (Celikey), and serum-IgA, and some for tTG-IgG and endomysial antibodies. A small intestinal biopsy was recommended for all children with suspected undiagnosed celiac disease. Results: Participation was accepted by 7567 families (75%). Previously diagnosed celiac disease was found in 67 children; 8.9/1000 (95% confidence interval [CI] 6.7–11). In another 192 children, a small intestinal biopsy was recommended and was performed in 180. Celiac disease was verified in 145 children, 20/1000 (95% CI 17–23). The total prevalence was 29/1000 (95% CI 25–33). Conclusions: The celiac disease prevalence of 29/1000 (3%)—with two thirds of cases undiagnosed before screening—is 3-fold higher than the usually suggested prevalence of 1%. When these 12-year-olds were infants, the prevailing feeding practice was to introduce gluten abruptly, often without ongoing breast-feeding, which might have contributed to this unexpectedly high prevalence.

Prevalence of Childhood Celiac Disease and Changes in Infant Feeding

OBJECTIVES: Between 1984 and 1996, Sweden experienced an “epidemic” of clinical celiac disease in children <2 years of age, attributed partly to changes in infant feeding. Whether infant feeding affects disease occurrence and/or the clinical presentation remains unknown. We investigated and compared the total prevalence of celiac disease in 2 birth cohorts of 12-year-olds and related the findings to each cohort’s ascertained infant feeding. METHODS: A 2-phase cross-sectional screening study was performed in which 13 279 children from 2 birth cohorts participated: children born during the epidemic (1993) and children born after the epidemic (1997). Previously diagnosed cases were reported and confirmed. Blood samples were analyzed for serological markers and children with positive values were referred for small intestinal biopsy. Infant feeding practices in the cohorts were ascertained via questionnaires. Prevalence comparisons were expressed as prevalence ratios. RESULTS: The total prevalence of celiac disease was 29 in 1000 and 22 in 1000 for the 1993 and 1997 cohorts, respectively. Children born in 1997 had a significantly lower risk of having celiac disease compared with those born in 1993 (prevalence ratio: 0.75; 95% confidence interval: 0.60–0.93; P = .01). The cohorts differed in infant feeding (specifically, in the proportion of infants introduced to dietary gluten in small amounts during ongoing breastfeeding). CONCLUSIONS: A significantly reduced prevalence of celiac disease in 12-year-olds indicates an option for disease prevention. Our findings suggest that the present infant feeding recommendation to gradually introduce gluten-containing foods from 4 months of age, preferably during ongoing breastfeeding, is favorable.

Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease

OBJECTIVES:Alterations in the composition of the microbiota in the intestine may promote development of celiac disease (CD). Using scanning electron microscopy (SEM) we previously demonstrated that rod-shaped bacteria were present on the epithelium of proximal small intestine in children with CD but not in controls. In this study we characterize the microbiota of proximal small intestine in children with CD and controls and identify CD-associated rod-shaped bacteria.METHODS:Proximal small intestine biopsies from 45 children with CD and 18 clinical controls were studied. Bacteria were identified by 16S rDNA sequencing in DNA extracted from biopsies washed with buffer containing dithiothreitol to enrich bacteria adhering to the epithelial lining, by culture-based methods and by SEM and transmission electron microscopy.RESULTS:The normal, mucosa-associated microbiota of proximal small intestine was limited. It was dominated by the genera Streptococcus and Neisseria, and also contained Veillonella, Gemella, Actinomyces, Rothia, and Haemophilus. The proximal small intestine microbiota in biopsies from CD patients collected during 2004–2007 differed only marginally from that of controls, and only one biopsy (4%) had rod-shaped bacteria by SEM (SEM+). In nine frozen SEM+ CD biopsies from the previous study, microbiotas were significantly enriched in Clostridium, Prevotella, and Actinomyces compared with SEM− biopsies. Bacteria of all three genera were isolated from children born during the Swedish CD epidemic. New Clostridium and Prevotella species and Actinomyces graevenitzii were tentatively identified.CONCLUSIONS:Rod-shaped bacteria, probably of the indicated species, constituted a significant fraction of the proximal small intestine microbiota in children born during the Swedish CD epidemic and may have been an important risk factor for CD contributing to the fourfold increase in disease incidence in children below 2 years of age during that time.Am J Gastroenterol advance online publication, 15 September 2009; doi:10.1038/ajg.2009.524

Delay to celiac disease diagnosis and its implications for health-related quality of life

BackgroundTo determine how the delay in diagnosing celiac disease (CD) has developed during recent decades and how this affects the burden of disease in terms of health-related quality of life (HRQoL), and also to consider differences with respect to sex and age.MethodsIn collaboration with the Swedish Society for Coeliacs, a questionnaire was sent to 1,560 randomly selected members, divided in equal-sized age- and sex strata, and 1,031 (66%) responded. HRQoL was measured with the EQ-5D descriptive system and was then translated to quality-adjusted life year (QALY) scores. A general population survey was used as comparison.ResultsThe mean delay to diagnosis from the first symptoms was 9.7 years, and from the first doctor visit it was 5.8 years. The delay has been reduced over time for some age groups, but is still quite long. The mean QALY score during the year prior to initiated treatment was 0.66; it improved after diagnosis and treatment to 0.86, and was then better than that of a general population (0.79).ConclusionsThe delay from first symptoms to CD diagnosis is unacceptably long for many persons. Untreated CD results in poor HRQoL, which improves to the level of the general population if diagnosed and treated. By shortening the diagnostic delay it is possible to reduce this unnecessary burden of disease. Increased awareness of CD as a common health problem is needed, and active case finding should be intensified. Mass screening for CD might be an option in the future.

Age-induced changes in the enteric nervous system in the mouse.

The enteric nervous system of the murine gut was investigated by immunocytochemistry in 1-, 3-, 12- and 24-month-old mice, using protein gene product 9.5, a general marker for nerve elements. Myenteric and submucosal plexi were quantified by computerized image analysis. In antrum, there were significantly fewer neurones per ganglion in both myenteric and submucosal ganglia of 12- and 24-month-old mice than in 3-month-old animals. The same was true of duodenum and colon. The relative volume density of nerve fibres in antral muscularis propria was significantly greater in the 1-, 12- and 24-month-old mice than in the 3-month-old mice. In colon, there were fewer submucosal ganglia per millimetre baseline in 1-month-old mice than in 3-month-old mice. The colonic myenteric ganglion in 1-, 12- and 24-month-old mice was smaller than in 3-month-old mice. There was no statistical difference between females and males regarding the number of ganglia per millimetre baseline, ganglionic area, number of neurones per ganglion or the relative volume density of nerve fibres in either the myenteric or submucosal plexi. As the enteric nervous system is responsible for coordinating and integrating the motility of the gut, the ageing-related changes reported here may well be of some relevance for the increased gastrointestinal motility dysfunction in the elderly persons.

Ageing and endocrine cells of human duodenum

Motility and secretory disorders of the gastrointestinal tract and associated glands increase with ageing. The duodenum contains several peptide/amine producing cells that play an important role in regulating gastrointestinal motility and secretion. The present study was performed to elucidate changes in these cells that may have arisen as a result of ageing. A total of four age groups of subjects, aged 1-2, 20-29, 40-49 and 60-69 years were studied. The various endocrine cell types were identified by immunohistochemistry and quantified by computerized image analysis, and two parameters were determined; the number of cells/mm3 epithelial cells and the cell secretory index (CSI), which indicates the immunoreactive secretory granule content of the endocrine cells. Chromogranin A- and serotonin-immunoreactive (IR) cells were fewer in 1-2-year-olds than in 20-29-year-olds. Gastrin/CCK-IR cells were significantly more numerous in 1-2-year-olds and 60-69 years-olds than in 20-29-year-olds. Somatostatin-IR cells were more numerous in the 40-49-year-olds than in the 20-29 years-olds. The CSI was higher in chromogranin A-, gastric inhibitory polypeptide (GIP)-, somatostatin- and gastrin/CCK-IR cells in 1-2-year-olds than in 20-29-year-olds. There was no significant sex difference regarding the numbers and CSI of other endocrine cell types. This study established the absence of sex-related differences in all endocrine cell types investigated, regarding numbers and physiological activity. Age, on the other hand, was shown to be associated with changes in the numbers of CCK-, somatostatin- and serotonin-IR, which may have some bearing on the gastrointestinal disorders of the elderly.

Selective feeding by baltic herring

The selective nature of feeding by baltic herring (Clupea harengus, L.) in the Bothnian bay was studied by comparison of the food intake and the abundance of potential zooplankton prey. Simultaneous sampling of zooplankton and capture of fish revealed that:1.The largest food items available are selected.2.When copepods are eaten, adults and late copepodids are preferred.3.Compared to males Eurytemora spp. females are overrepresented in the stomachs although they are less abundant in plankton. The fact that they carry conspicuous egg sacs is thought to be the cause for this.

Usefulness of Symptoms to Screen for Celiac Disease

OBJECTIVE: To describe the frequency of symptoms and associated conditions among screening-detected celiac disease (CD) cases and non-CD children and to evaluate questionnaire-based case-finding targeting the general population. METHODS: In a population-based CD screening of 12-year-olds, children and their parents completed questionnaires on CD-associated symptoms and conditions before knowledge of CD status. Questionnaire data for those who had their CD detected in the screening (n = 153) were compared with those of children with normal levels of CD markers (n = 7016). Hypothetical case-finding strategies were also evaluated. Questionnaires were returned by 7054 (98%) of the children and by 6294 (88%) of their parents. RESULTS: Symptoms were as common among screening-detected CD cases as among non-CD children. The frequency of children with screening-detected CD was similar when comparing the groups with and without any CD-related symptoms (2.1% vs 2.1%; P = .930) or CD-associated conditions (3.6% vs 2.1%; P = .07). Case-finding by asking for CD-associated symptoms and/or conditions would have identified 52 cases (38% of all cases) at a cost of analyzing blood samples for 2282 children (37%) in the study population. CONCLUSIONS: The current recommended guidelines for finding undiagnosed CD cases, so-called active case-finding, fail to identify the majority of previously undiagnosed cases if applied in the general population of Swedish 12-year-olds. Our results warrant further studies on the effectiveness of CD case-finding in the pediatric population, both at the clinical and population-based levels.

Intestinal T-cell responses in celiac disease : impact of celiac disease associated bacteria

A hallmark of active celiac disease (CD), an inflammatory small-bowel enteropathy caused by permanent intolerance to gluten, is cytokine production by intestinal T lymphocytes. Prerequisites for contracting CD are that the individual carries the MHC class II alleles HLA-DQ2 and/or HLA-DQ8 and is exposed to gluten in the diet. Dysbiosis in the resident microbiota has been suggested to be another risk factor for CD. In fact, rod shaped bacteria adhering to the small intestinal mucosa were frequently seen in patients with CD during the “Swedish CD epidemic” and bacterial candidates could later be isolated from patients born during the epidemic suggesting long-lasting changes in the gut microbiota. Interleukin-17A (IL-17A) plays a role in both inflammation and anti-bacterial responses. In active CD IL-17A was produced by both CD8+ T cells (Tc17) and CD4+ T cells (Th17), with intraepithelial Tc17 cells being the dominant producers. Gluten peptides as well as CD associated bacteria induced IL-17A responses in ex vivo challenged biopsies from patients with inactive CD. The IL-17A response was suppressed in patients born during the epidemic when a mixture of CD associated bacteria was added to gluten, while the reverse was the case in patients born after the epidemic. Under these conditions Th17 cells were the dominant producers. Thus Tc17 and Th17 responses to gluten and bacteria seem to pave the way for the chronic disease with interferon-γ-production by intraepithelial Tc1 cells and lamina propria Th1 cells. The CD associated bacteria and the dysbiosis they might cause in the resident microbiota may be a risk factor for CD either by directly influencing the immune responses in the mucosa or by enhancing inflammatory responses to gluten.

How Age Changes the Content of Neuroendocrine Peptides in the Murine Gastrointestinal Tract

Background: Motility disorders in the gastrointestinal tract increase with ageing, and colorectal carcinoma is a tumor of the middle-aged and elderly. Gastrointestinal secretion, absorption, motility, cell proliferation, local immune defense and blood flow are all regulated by the neuroendocrine peptides. It is conceivable that gastrointestinal disorders at an advanced age may be accompanied by changes in this regulatory system. Objective: To ascertain possible age-related changes in neuroendocrine peptides in a rodent animal model. Methods: The concentrations of various neuroendocrine peptides were determined by radioimmunoassays in tissue extracts from the antrum, duodenum and colon of mice in four different age groups: 1, 3, 12 and 24 months. The neuroendocrine peptides investigated were: secretin, gastric inhibitory polypeptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, vasoactive intestinal polypeptide (VIP), substance P, neuropeptide Y (NPY), galanin and neurotensin. Results: Antrum: Concentrations of somatostatin, VIP and substance P decreased significantly in 1-month-old mice (but that of neurotensin increased) compared with 3-month-old mice. In 12-month-old and 24-month-old mice, concentrations of gastrin, somatostatin, VIP, substance P, NPY, galanin and neurotensin all decreased vis-à-vis 3-month-old mice. Duodenum: Whereas the levels of secretin, GIP and neurotensin increased, those of gastrin, motilin, somatostatin, VIP, substance P, NPY and galanin decreased in 1-month-old mice vis-à-vis 3-month-old mice. In both 12-month-old and 24-month-old mice, the concentrations of secretin and GIP increased, compared with those of 3-month-old mice. The levels of gastrin, motilin, somatostatin, VIP, NPY and galanin decreased in both 12-month-old and 24-month-old mice vis-à-vis 3-month-old mice. Substance P and neurotensin concentrations decreased in 12-month-old mice, but not in 24-month-old mice. Colon: In 1-month-old mice the levels of PYY, somatostatin, VIP, substance P and galanin decreased vis-à-vis 3-month-old mice. In 12-month-old mice, the concentrations of PYY, somatostatin, VIP, NPY, galanin and neurotensin decreased compared with those in 3-month-old mice. In 24-month-old mice, the VIP level decreased, whereas the substance P level increased. Conclusion: The changes in neuroendocrine peptides observed in the gastrointestinal tract of this murine animal model could be of some relevance for the increased gastrointestinal dysfunction in the elderly human. They may also be involved in the development of colorectal cancer.