I. Biemond

Serum chromogranin A as a screening test for gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy.

Background Serum chromogranin A (CgA), a marker of neuroendocrine neoplasia, increases during profound gastric acid inhibition, possibly reflecting the trophic effect of gastrin on the enterochromaffin‐like (ECL) cells.

Serum gastrin and chromogranin A during medium‐ and long‐term acid suppressive therapy: a case‐control study

Serum chromogranin A (CgA) is regarded as a reliable marker of neuroendocrine proliferation. We previously described increased serum CgA levels during short‐term profound gastric acid inhibition.

Peptic Ulcer, Non-Ulcer Dyspepsia and Irritable Bowel Syndrome in the Netherlands and Japan

To study the prevalence of peptic ulcer, non-ulcer dyspepsia and irritable bowel syndrome (IBS) in the Dutch and Japanese working population, a structured history using a questionnaire on gastrointestinal symptoms during the preceding 3 months was obtained from persons undergoing a periodic medical examination. Principal components factor analysis of questionnaire responses was conducted to examine interrelationships of symptoms. In Holland, 427 men and 73 women participated (mean age 48.0 years), while in Japan 196 men and 35 women took part (mean age 48.8 years). In both the Japanese and the Dutch population, factor analysis yielded clusters of symptoms consistent with previously defined clinical syndromes: dyspepsia, diarrhoea-predominant IBS and constipation-predominant IBS. The prevalences of verified peptic ulcer history were 19% and 17% (95% confidence intervals (CI): 14-26% and 7-34%) in Japanese men and women in contrast to 5% and 0% (95% CI: 3-8% and 0-5%) in Dutch men and women respectively. The ratio of duodenal to gastric ulcer was 4.5: 1 in Holland and 1.5:1 in Japan. The 3-month period prevalence of non-ulcer dyspepsia was 13% in both the Japanese and the Dutch population and was twice as high in women as in men (p < 0.01). There was considerable overlap between dyspepsia subgroups. IBS was present in 25% of the Japanese and in 9% of the Dutch (p < 0.001) and occurred twice as often in women as in men (p < 0.01). In conclusion, factor analysis supported the existence of dyspepsia and IBS as distinct syndromes in both countries.(ABSTRACT TRUNCATED AT 250 WORDS)

Blimp1 regulates the transition of neonatal to adult intestinal epithelium.

In many mammalian species, the intestinal epithelium undergoes major changes that allow a dietary transition from mothers milk to the adult diet at the end of the suckling period. These complex developmental changes are the result of a genetic programme intrinsic to the gut tube, but its regulators have not been identified. Here we show that transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1) is highly expressed in the developing and postnatal intestinal epithelium until the suckling to weaning transition. Intestine-specific deletion of Blimp1 results in growth retardation and excessive neonatal mortality. Mutant mice lack all of the typical epithelial features of the suckling period and are born with features of an adult-like intestine. We conclude that the suckling to weaning transition is regulated by a single transcriptional repressor that delays epithelial maturation.

Cholecystokinin receptors in human pancreas and gallbladder muscle: A comparative study

Abstract BACKGROUND & AIMS: Cholecystokinin (CCK) receptors mediate pancreatic secretion and gallbladder contraction. Hitherto, little information on characteristics of CCK receptors in the human pancreas was available. This study identifies CCK receptors in the human pancreas and compares their characteristics with the CCK receptors in the human gallbladder. METHODS: Visualization and quantification of 125I-Bolton-Hunter sulfated CCK octapeptide (125I-BH-CCK-8) binding to tissue sections of the human pancreas and gallbladder were performed by storage phosphor autoradiography. RESULTS: Specific bindings for CCK were visualized in pancreatic tissue and the smooth muscle layer of the gallbladder. Binding of 125I-BH-CCK-8 to the pancreas was inhibited by agonists with the affinities (dissociation constant) of CCK (0.11 nmol/L) approximately gastrin (0.15 nmol/L) and by antagonists with the affinities of CCK-B receptor antagonist (L365,260, 0.18 nmol/L) > CCK-A receptor antagonist (lorglumide, 8.1 nmol/L). In contrast to the pancreas, binding of 125I-BH-CCK-8 to the gallbladder muscle was inhibited with high affinity by CCK-8 and lorglumide but was replaced to a small degree by gastrin and L365,260. CONCLUSIONS: The sub-types of receptors for CCK in the human pancreas and gallbladder are different. The human pancreas predominantly expresses CCK-B receptors, whereas only CCK-A receptors were localized in the human gallbladder muscle. (Gastroenterology 1996 Dec;111(6):1621-6)

Loss of Indian hedgehog activates multiple aspects of a wound healing response in the mouse intestine

BACKGROUND & AIMS Indian Hedgehog (Ihh) is expressed by the differentiated epithelial cells of the small intestine and signals to the mesenchyme where it induces unidentified factors that negatively regulate intestinal epithelial precursor cell fate. Recently, genetic variants in the Hh pathway have been linked to the development of inflammatory bowel disease. METHODS We deleted Ihh from the small intestinal epithelium in adult mice using Cyp1a1-CreIhh(fl/fl) conditional Ihh mutant mice. Intestines were examined by immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction. RESULTS Deletion of Ihh from the intestinal epithelium initially resulted in a proliferative response of the intestinal epithelium with lengthening and fissioning of crypts and increased Wnt signaling. The epithelial proliferative response was associated with loss of bone morphogenetic protein and Activin signaling from the epithelium of the villus and crypts, respectively. At the same stage we observed a substantial influx of fibroblasts and macrophages into the villus core with increased mesenchymal transforming growth factor-β signaling and deposition of extracellular matrix proteins. Prolonged loss of Ihh resulted in progressive leukocyte infiltration of the crypt area, blunting and loss of villi, and the development of intestinal fibrosis. CONCLUSIONS Loss of Ihh initiates several events that are characteristic of an intestinal wound repair response. Prolonged loss resulted in progressive inflammation, mucosal damage, and the development of intestinal fibrosis. Ihh is a signal derived from the superficial epithelial cells that may act as a critical indicator of epithelial integrity.

The serological gastric biopsy: a non-endoscopical diagnostic approach in management of the dyspeptic patient: significance for primary care based on a survey of the literature.

Background : Measurement of the serum concentration of the secretory products of the gastric mucosa, pepsinogen A (PgA), pepsinogen C (PgC) and gastrin is called the serological gastric biopsy. Additional measurement of Helicobacter pylori antibodies and antibodies to parietal cells and intrinsic factor supports the non-invasive diagnostic value of the serum markers. In many clinical studies, the diagnostic potential of the serum markers in predicting the topography and severity of gastric mucosal disorders has been established. The aim was to assess the diagnostic value of the serological gastric biopsy for primary care. Method : Survey of the literature. Results : The cell-physiological background of the serological gastric biopsy , the interpretation of the outcome of serum markers and the relation of these parameters to various gastric mucosal disorders are described. Measurement of PgA is a reliable way to discriminate between mucosal gastritis and functional dyspepsia. PgA is raised in duodenal, gastric and pyloric ulcer even though gastrin is normal. Both PgA and gastrin are raised in renal insufficiency and the Zollinger-Ellison syndrome. A low PgA is indicative of mucosal atrophy and a good indicator for gastric hypoacidity. An additional low PgA:C ratio is indicative of atrophic gastritis or extensive intestinal metaplasia of the stomach. A hypopepsinogenaemia can also be an alarm symptom for gastric cancer. A low PgA and a high gastrin is indicative of corpus atrophy. Conclusion : In primary care, the serological gastric biopsy might be a feasible and appropriate diagnostic method for management of the dyspeptic patient. Further research in general practice has to be done to validate the predictive value of the serological gastric biopsy and to define a diagnostic strategy.

Seroepidemiology of gastritis in Japanese and Dutch working populations: evidence for the development of atrophic gastritis that is not related to Helicobacter pylori.

Serological markers of gastritis, like pepsinogen A, pepsinogen C, gastrin, and Helicobacter pylori antibodies, can be used to explore the state of the gastric mucosa in populations with contrasting cancer risks. A decreasing pepsinogen A:C ratio and an increasing serum gastrin are known to reflect an increasing severity of atrophic corpus gastritis, which is a precursor of gastric cancer. In 723 subjects (without gastroduodenal surgery) from Japanese (n = 225) and Dutch (n = 498) working populations, which had a similar composition of age (mean 48 years), sex (male to female ratio 6:1), and type of occupation, fasting serum samples were analysed for IgG antibodies to H pylori, pepsinogen A, pepsinogen C, and gastrin in the same laboratory. H pylori infection was significantly more prevalent in the Japanese than in the Dutch (74.7% and 31.3%); as was a very low pepsinogen A, indicative of severe mucosal atrophy (4.4% and 1.6%). Among subjects with and without severe mucosal atrophy the H pylori seropositivity rate was similar. Between the Japanese and the Dutch there were significant differences in mean gastrin (31.8 and 13.4 pmol/l) and pepsinogen A:C ratio (1.7 and 2.9). These intercountry differences were as great for H pylori negative subjects (gastrin: 23.7 and 10.3 pmol/l, pepsinogen A:C ratio: 2.4 and 3.2) as for H pylori positive subjects (gastrin: 34.6 and 20.1 pmol/l, pepsinogen A:C ratio: 1.5 and 2.5). The intercountry difference in gastrin nearly disappeared after stratification into categories of pepsinogen A:C ratio. In conclusion, the intercountry differences in pepsinogen A:C ratio and gastrin reflect a higher prevalence of mild and severe mucosal atrophy of the corpus in the Japanese than in the Dutch, both among H pylori positive and negative subjects. Thus, these findings suggest that in the Japanese the development of atrophic gastritis is in part unrelated to H pylori.

Rage signalling promotes intestinal tumourigenesis

Development of colon cancer is a multistep process that is regulated by intrinsic and extrinsic cellular signals. Extrinsic factors include molecular patterns that are derived from either pathogens (PAMPs) or cellular damage (DAMPs). These molecules can promote tumourigenesis by activation of the innate immune system, but the individual contribution of ligands and their receptors remains elusive. The receptor for advanced glycation end products (Rage) is a pattern recognition receptor that binds multiple ligands derived from a damaged cell environment such as Hmgb1 and S100 protein. Here we show that Rage signalling has a critical role in sporadic development of intestinal adenomas, as ApcMin/+ Rage−/− mice are protected against tumourigenesis.

Faecal Parameters in the Assessment of Activity in Inflammatory Bowel Disease

BACKGROUND Determination of inflammatory activity is helpful when assessing the efficacy of drugs in therapeutic trials and in facilitating management of individual patients with inflammatory bowel disease (IBD). Faecal parameters have been hypothesized to be more specific than non-faecal measurements in the assessment of intestinal inflammation. METHODS Review of the literature on faecal measurements in IBD. RESULTS AND CONCLUSIONS Leakage of various proteins and leukocyte products into the intestinal lumen can be assessed and quantified in stool specimens and serve as a measurement of inflammatory activity. Several of these faecal parameters are raised in patients with IBD. There is a considerable overlap between patients with active and those with inactive disease, however, and the correlation of the faecal parameters with disease activity indices is often low. The value of alpha1-antitrypsin measurement in faeces in the assessment of intestinal inflammation has been well established. Further studies in patients with IBD are needed to determine whether other faecal parameters, such as lactoferrin, tumour necrosis factor alpha, PMN-elastase, lysozyme, leucocyte esterase, immunoglobulin A, among others, are more accurate or cost-effective than measurement of alpha1-antitrypsin in the stools of such patients.