Pepsin and Its Importance for Functional Dyspepsia: Relic, Regulator or Remedy?

BACKGROUND: Functional dyspepsia is a heterogeneous disorder lacking an established therapeutic strategy. Historical treatment attempts with pepsin products were shrugged off, as a simple calculation shows that quantitative substitution is pointless. However, such attempts might have been right for the wrong reason. SUMMARY: Today, the role of pepsins is primarily seen in the provision of signalling amino acids (especially phenylalanine and tryptophan) and peptides, which initiate processes promoting digestion. Proteolysis benefits from pepsin variants showing, contrary to common belief, activities of up to a pH value of 5.0. Non-clinical and clinical studies support the view that liberated amino acids produce a variety of direct and indirect effects. Signal chains stimulated by (mostly aromatic) amino acids lead to secretion of gastrin and cholecystokinin (CCK), mediated, respectively, by CCK2 (gastrin) and Ca2+-sensing receptors in the parietal cell, and Ca2+-sensing receptors in the antral and duodenal mucosa. Thus, CCK effects such as secretion of pancreatic enzymes and promotion of gastric accommodation are (also) consequential to peptic liberation of amino acids. Key Message: As functional dyspepsia represents a heterogeneous disorder, it may be intriguing to view pepsin as a potential (although still to be proven) treatment modality, distinguished by a diversity of pro-digestive effects.

Nitric oxide synthase gene polymorphisms in functional dyspepsia.

OBJECTIVE: Nitrinergic control is important in meal-induced satiety. The aim of this study was to assess functional polymorphisms in nitric oxide synthase (NOS) genes in the susceptibility to functional dyspepsia (FD). METHODS: Genomic DNA from 89 patients with FD and 180 healthy subjects matched for age and gender were typed for the gene of neuronal NOS (nNOS, rs2682826), inducible NOS (iNOS, rs2297518) and a variable number tandem repeat in intron 4 of endothelial NOS (eNOS). Patients ingested 500 mL of Ensure(®) during a 20 min period and dyspeptic symptoms were scored. RESULTS: Genotype frequencies of eNOS and iNOS were not significantly different between FD patients and controls. The frequency of the T allele in nNOS was significantly higher in FD patients compared to the controls (49 vs. 16 %; odds ratio 5.01; 95 % confidence interval 2.83-9.01; p < 0.05). Patients with the T allele in the nNOS polymorphism reported a higher satiation score than those with the CC genotype during the nutrition drink test (median 179 vs. 117; p < 0.05). CONCLUSION: The nNOS gene polymorphism is associated with susceptibility to FD and influences satiation in FD patients. Our data support the importance of NOS gene polymorphisms in the pathogenesis of FD.

H+ /K+ ATPase expression in human parietal cells and gastric acid secretion in elderly individuals.

OBJECTIVE: To investigate whether the ultrastructure and hydrogen potassium adenosine triphosphate (H+ /K+ ATPase) expression of human parietal cells were associated with aging. METHODS: In all, 50 participants who underwent gastroscopy due to dyspepsia were divided into two age groups, with 19 in the younger group (YG, aged 20-59 years) and 31 in the elder group (EG, aged ≥60 years). The ultrastructure of their parietal cell was determined by electron microscopy (EM), and the expressions of H+ /K+ ATPase α-subunit mRNA and ß-unit protein were detected. Furthermore, 24-h esophageal pH monitoring was performed in the two groups. RESULTS: EM images showed no distinct difference in the morphology and distribution of parietal cells or the acid secretion-related organelle between the two groups. There were no differences between YG and EG in the proportion of mitochondria and the tubulovesicular system area. The expressions of H+ /K+ ATPase α-subunit mRNA and ß-subunit protein showed no age-related alteration between YG and EG. The expression of H+ /K+ ATPase α-subunit mRNA in EG was higher than that in YG, whereas the expression of ß-subunit protein was significantly higher in those aged ≥80 years than in the YG. No significant difference was found in the 24-h esophageal pH monitoring between YG and EG. CONCLUSION: Acid secretion-related organelles in parietal cells do not degenerate with aging, the expression of H+ /K+ ATPase even shows a trend to increase, indicating the existence of intact molecular biological basis for acid secretion in healthy elderly individuals.

Examination of serum pepsinogen in functional dyspepsia.

BACKGROUND/AIMS: Although serum pepsinogen (PG) is considered as a marker of gastric atrophy, it also reflects gastric acid secretion, which closely influences dyspeptic symptoms. We investigated serum PG levels and PGI/PGII ratios in dyspeptic patients, in relation to various different subtypes of symptoms including Rome III classifications. METHODOLOGY: Serum PGs were measured in 75 subjects with dyspeptic symptoms and 42 asymptomatic healthy subjects. RESULTS: PG II level was significantly higher (p=0.0001) and PG I/II ratio was significantly lower (p<0.0001) in subjects with H. pylori infection than those without, while no associations were found between PG levels and usage of H2 receptor antagonists or proton-pump inhibitors. In all subjects with pain in stomach, abdominal bloating and PDS-like symptoms according to Rome III criteria, presented significantly higher levels of PGI, compared to subjects without symptoms (p=0.043, 0.015 and 0.037, respectively). In addition, burning sensation and abdominal pain presented significantly higher PGI/II ratios (p=0.0005 and 0.003, respectively), and higher PGI/II ratio was also positively correlated with a number of symptoms (p=0.04). When subjects were divided according to H. pylori infection status, higher PGI/II ratio was significantly associated with abdominal pain in H. pylori negative subjects (p=0.03), while higher PGI level was significantly associated with functional esophageal disorders (FEG) according to Rome III criteria, and higher number of dyspeptic symptoms in H. pylori positive subjects (p=0.016). CONCLUSIONS: Our data suggest that subjects with higher PGI level, and PG I/II ratio are more likely to develop several dyspeptic symptoms.

[Role of matrix metalloproteinases and their tissue inhibitor in the morphogenesis of chronic Helicobacter pylori-associated gastritis in children].

The authors examined gastric biopsy specimens in 40 children aged 7 to 15 years: 30 children with the clinical diagnosis of chronic Helicobacter pylori (HP)-associated chronic gastritis (CG) and 10 children with functional dyspepsia (FD). In HP-associated CG, the gastric mucosa (GM) showed higher levels of matrix metalloproteinases (MMP) and their tissue inhibitor in the antral and fundal stomach than those in FD. There was an increased exposure of the markers MMP-9 and MMP-2, which was most evident in the fundal GM and correlated with the activity of inflammation. The significant elevation of TIMP-1 suggests that compensatory reactions are tense and may cause GM remodeling with enhanced collagen generation. The increased synthesis and activation of MMP-9 and MMP-2 can stimulate the realization of ulcerogenic properties of these metalloproteinases. The findings revealed the points of application of target drugs to some links of the pathogenesis of HP-associated CG in children.

Comparison of endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, and fecal elastase 1 in chronic pancreatitis and clinical correlation.

OBJECTIVES: In this study, we prospectively compared the use of endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasonography (EUS), and fecal elastase 1 in patients with chronic pancreatitis and searched for correlation with symptoms, clinical findings, and elastase 1 levels. METHODS: Twenty-four consecutive patients (19 were male, and 5 were female) with chronic pancreatitis who had already undergone ERCP within the last 2 years and 19 healthy control subjects (10 were male, and 9 were female) are studied prospectively. Clinical and laboratory parameters of the patients were recorded, and all underwent EUS and fecal elastase 1 testing. Fecal elastase 1 was measured in healthy control subjects. RESULTS: The ERCP and EUS severity scores were 1 in 0 to 2 patients, 2 in 6 to 8 patients, and 3 in 18 to 14 patients. Sensitivity and specificity of fecal elastase for chronic pancreatitis were 75% and 100%, respectively. There was a negative correlation between disease duration and fecal elastase 1 levels. Patients with dyspepsia or those who use pancreatic enzyme preparations had significantly lower fecal elastase 1 levels than others. CONCLUSIONS: Endoscopic retrograde cholangiopancreatography and EUS are nearly equal in staging chronic pancreatitis. Fecal elastase 1 correlates well with these tests. Fecal elastase 1 also correlates well with some clinical symptoms such as dyspepsia and disease history.

Helicobacter pylori infection upregulates endothelial nitric oxide synthase expression and induces angiogenesis in gastric mucosa of dyspeptic patients.

BACKGROUND: Helicobacter pylori (H. pylori) infection induces nitric acid (NO) overproduction through inducible NO synthase (NOS) expression, subsequent DNA damage and enhanced antiapoptosis signal transduction sequence in the human gastric mucosa, whereas its possible effect on endothelial nitric oxide synthase (eNOS) expression has not as yet been investigated. The aim of this study was to evaluate the effect of H. pylori infection in the expression of eNOS in gastric mucosa. PATIENTS AND METHODS: We prospectively studied 30 nonsmoking dyspeptic patients (12 men, 18 women, mean age 54.26+/-12.89 years). The diagnosis of H. pylori infection was based mainly on histology. The histological grading of H. pylori infection was evaluated according to the modified Sydney classification. Histological grading of eNOS expression and microvessel density as estimated by CD34 expression were determined by immunohistochemistry (degree 0-3) and correlated with H. pylori infection and histological degree of gastritis. RESULTS: Twelve patients were H. pylori-positive and 18 patients were H. pylori-negative. The two groups were matched for age (P=0.139), sex (P=0.342) and similar degree of gastritis. Intensity of eNOS and CD34 expression in the corpus and antrum were significantly correlated (P<0.001). eNOS expression was correlated with H. pylori infection in the mucosa of the body and antrum (P=0.013 and 0.037, respectively) but not with gastric inflammation and activity (P=0.848 and 0.871, respectively, for the corpus and P=0.565 and 0.793, respectively, for the antrum). H. pylori-positive patients showed higher expression of CD34-positive blood vessels in the mucosa of the antrum (P=0.048). CD34 expression was correlated with gastric inflammation and activity (P=0.03 and 0.044, respectively) in the mucosa of the antrum of H. pylori-positive patients. CONCLUSION: H. pylori infection upregulates eNOS, and induces angiogenesis, contributing to H. pylori-associated pathophysiology in gastric mucosa.

Molecular mechanisms in therapy of acid-related diseases.

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.

[Intensity of lipids peroxidation and state of antioxidant protective system in calves, which have had dyspepsia]. / Intensyvnist' lipoperoksydatsiï i stan antyoksydantnoï systemy zakhystu v teliat, perekhvorivshykh na dyspepsiiu.

The intensive development of lipids peroxidation with simultaneous deficit of antioxidant protective factors in organism of calves, which have had neonathal enteropathology was shown. The effectiveness of phospolipid preparation FLP-MD, which makes antioxidant protective mechanisms stronger during this pathological state, and may be recommended as a drug for reparation therapy in complex scheme of dyspepsia medical treatment and proves a necessity of the antioxidant preparations application.

Pepsinogen A, pepsinogen C, and gastrin as markers of atrophic chronic gastritis in European dyspeptics.

Serum levels of pepsinogen and gastrin are parameters that can be used as biomarkers for gastric mucosa. The aim of this study was to validate these serum biomarkers, that is pepsinogen A (PGA), pepsinogen C (PGC), PGA/PGC ratio, and gastrin, as screening tests for precancerous lesions: atrophic chronic gastritis (ACG) or Helicobacter pylori-related corpus-predominant or multifocal atrophy. The study population was comprised of a subsample of 284 patients from the 451 included in the Eurohepygast cohort, between 1995 and 1997. The concentrations of PGA, PGC, and gastrin were measured by radioimmunoassays. Histological diagnosis was the gold standard. Cut-off points were calculated using receiving operator characteristics (ROC) curves. Factors linked to variation of biomarkers were identified using multivariate linear regression. The mean of each biomarker in the sample was: PGA, 77.4 microg x l(-1); PGC, 13.2 microg x l(-1); PGA/PGC, 6.7; and gastrin, 62.4 ng x l(-1). For ACG patients, the areas under the PGA, PGC, PGA/PGC, and gastrin ROC curves were 0.55, 0.62, 0.73, and 0.58, respectively. The best cut-off point for PGA/PGC was 5.6, with sensitivity 65% and specificity 77.9%. For H. pylori-related corpus-predominant or multifocal atrophy, the areas under the respective ROC curves were 0.57, 0.67, 0.84, and 0.69. The best cut-off point for PGA/PGC was 4.7, with sensitivity 77.1% and specificity 87.4%. The results suggested that only the PGA/PGC ratio can be considered as a biomarker for precancerous lesions of the stomach, and may be useful as a screening test.

Examination of small bowel enzymes in chronic diarrhea.

BACKGROUND: In Indonesia, the proportion of daily carbohydrate intake is approximately 60-80%. A number of small bowel disorders can result in the impairment of absorption and enzyme deficiency. Chronic diarrhea is common in Indonesia. METHODS: Thirty-four functional dyspeptic patients with an endoscopically normal small bowel as a control group, and 17 chronic diarrhea patients from the Division of Gastroenterology, University of Indonesia/Cipto Mangunkusumo Hospital were included in this study. All patients underwent a gastroduodenojejunoscopy and an ileocolonoscopy examination. Biopsies were taken from the jejunum (two specimens) and the biopsy specimens were examined for enzyme analysis (lactase, maltase, sucrase). The data were analyzed by using the Kruskal-Wallis or anova. RESULTS: The lactase level of the chronic diarrhea group was significantly lower compared with that of the control group (1.941 +/- 1.621 vs 2.502 +/- 2.098 micro mol/min mg protein; P < 0.001). The maltase level of the chronic diarrhea group was significantly lower compared with that of the control group (280.942 +/- 148.173 vs 371.920 +/- 250.177 micro mol/min mg protein; P < 0.001). The sucrase level of the chronic diarrhea group was significantly lower compared with that of the control group (48.474 +/- 28.553 vs 66.727 +/- 49.685 micro mol/min mg protein; P < 0.001). CONCLUSION: The enzyme activity concentrations (lactase, maltase, sucrase) were much lower in chronic diarrhea cases compared with the controls.

Disaccharidase activities in dyspeptic children: biochemical and molecular investigations of maltase-glucoamylase activity.

BACKGROUND: Maltase-glucoamylase enzyme plays an important role in starch digestion. Glucoamylase deficiency is reported to cause chronic diarrhea in infants, but its role in dyspeptic children is unknown. METHODS: Glucoamylase and other disaccharidase specific activities were assayed from duodenal biopsy specimens in 44 children aged 0.5-18 years (mean, 10 +/- 5 years) undergoing endoscopy to evaluate dyspeptic symptoms. All subjects had normal duodenal histology. Intestinal organ culture was used to evaluate synthesis and processing of maltase-glucoamylase. Sequencing of the maltase-glucoamylase coding region was performed in subjects with low activity or variation of isoform in organ culture. RESULTS: Twenty-two of the dyspeptic children had one or more disaccharidases with low specific activity. Twelve subjects (28%) had low activity of glucoamylase. Eight subjects had low activities of glucoamylase, sucrase, and lactase. Low glucoamylase activity was not correlated with the isoform phenotype of maltase-glucoamylase as described by metabolic labeling and sodium dodecyl sulfate electrophoresis. Novel nucleotide changes were not detected in one subject with low glucoamylase activity or in two subjects with variant isoforms of maltase-glucoamylase peptides. CONCLUSION: Twelve of 44 dyspeptic children had low specific activity of duodenal maltase-glucoamylase. Eight of these children had low specific activity of all measured disaccharidases.

Helicobacter pylori non-cytotoxic genotype enhances mucosal gastrin and mast cell tryptase.

AIMS: To determine the association, if any, between H pylori genotype and the gastric mucosal variations in the levels of gastrin, somatostatin, tryptase, and histamine. METHODS: 49 patients affected by duodenal ulcer and 48 by non-ulcer dyspepsia were studied. To identify the H pylori genotype, the presence of the cagA gene and vacA alleles m1, m2, s1, and s2 were analysed by polymerase chain reaction. Gastrin, somatostatin, tryptase, and histamine were measured in antral mucosal biopsies. RESULTS: 57 patients were infected with H pylori (30 with duodenal ulcer and 27 with non-ulcer dyspepsia). Gastrin and tryptase were increased in patients with H pylori infection, although the variations were statistically significant only for gastrin; somatostatin and histamine were not influenced by H pylori infection. In patients with non-ulcer dyspepsia the absence of the cagA gene and the presence of vacA alleles s2 and m2 were associated with higher values of tryptase and to a lesser extent of gastrin. These associations were not found in patients with duodenal ulcer. CONCLUSIONS: The cagA negative s2m2 strain of H pylori may be less dangerous for the gastric mucosa than other H pylori strains since it enhances tryptase production by gastric mucosal mast cells; this enzyme is thought to stimulate tissue turnover and favour wound healing.

Helicobacter pylori and the null genotype of glutathione-S-transferase-mu in patients with gastric adenocarcinoma.

BACKGROUND: Chronic Helicobacter pylori infection now is recognized as an important causative agent for gastric carcinoma. However, only a small minority of infected individuals develop the malignancy, even in areas with a high prevalence of gastric carcinoma. It has been postulated that the absence of glutathione-S-transferase-mu (GST-mu), which impairs detoxification of exogenous carcinogens, might predispose some infected individuals to the development of gastric carcinoma. METHODS: Patients with histologically confirmed adenocarcinoma of the stomach were tested for H. pylori infection and the GST-mu genotype. Prevalence of GST-mu gene deletion was compared with the H. pylori status of the patients. A group of gender- and age-matched control subjects with known H. pylori-related nonulcer dyspepsia also were tested for the GST-mu genotype and compared with patients with H. pylori positive carcinoma. RESULTS: Fifty-one patients with gastric adenocarcinoma were enrolled into the study. Thirty-five were found to have H. pylori in the resected specimens. The null genotype of GST-mu was significantly more common among those patients with H. pylori positive carcinoma compared with the H. pylori negative group (65.7% vs. 31.3%; P < 0.05). Homozygous deletion of GST-mu was significantly higher in the H. pylori positive carcinoma patients than in the H. pylori-infected, nonmalignant control group (65.7% vs. 37.1%; P < 0.05). CONCLUSIONS: The null genotype for GST-mu is found more commonly in gastric carcinoma associated with H. pylori infection. The absence of the GST-mu enzyme may increase the risk of the development of gastric carcinoma in these patients.

Lack of evidence for sialidase activity in Helicobacter pylori.

The role of sialic acid for the adhesion of Helicobacter pylori to gastric mucosa cells and/or to the mucin layer is still under debate. Several but not all H. pylori strains express a sialic acid-binding adhesin, specific for terminal alpha-2,3-sialic acid residues. Recently, the production of sialidase by H. pylori was reported [Dwarakanath, A.D. et al. (1995) FEMS Immunol. Med. Microbiol. 12,213 216]. We analysed several strains isolated from gastric biopsies cultivated both in liquid media and on agar plates for sialidase. Activity of this enzyme was first assayed using the fluorigenic substrate 4-methylumbelliferyl-alpha-D-N-acetylneuraminic acid. Since the fluorimetric assay can give false-positive results caused by non-specific interactions with umbelliferyl-tagged substances, we used also the more sensitive and specific assay with sialyl-[3H]lactitol as a substrate. No evidence for sialidase activity of H. pylori strains, cultivated under both inducible and non-inducible conditions, was obtained.

Unusual association of macroamylasemia and hyperlipasemia: report of two cases.

OBJECTIVE: To describe two cases of macroamylasemia associated with hyperlipasemia. METHODS AND RESULTS: The patients were a young male soccer player who had sustained a kick in the groin during a match and a woman with a specific dyspeptic complaints. In both the macroamylasemia had been previously undetected; when admitted with the above complaints, serum pancreatic isoamylase levels, as determined by the inhibitor method, were markedly increased, as were serum lipase levels. In both cases these findings led to the erroneous diagnosis of pancreatitis and consequent multiple diagnostic and therapeutic procedures. The cause of the hyperlipasemia was not clear in either case, although the possibility that it was due to the presence of macrolipase cannot be excluded. CONCLUSION: The possibility of macroamylasemia associated with hyperlipasemia should be kept in mind to avoid unnecessary diagnostic and therapeutic efforts.

Effect of pancreatic enzymes in non-ulcer dyspepsia. A pilot study.

The symptomatic effect of pancreatic enzymes was examined in 37 patients with non-ulcer dyspepsia (NUD) recruited from general practice by means of a 24-day multicrossover model (MCOM) including six treatment periods and five regular interchanges between pancreatic enzymes and placebo. The evaluation was based on a comparison of the enzyme- and placebo-associated symptoms and on the number of times pancreatic enzymes were associated with less symptoms than the preceding or following placebo period in individual patients. No evidence of a short-term effect of pancreatic enzymes in NUD was found.

Enzyme activities in biopsy specimens from human gastric mucosa.

The distribution of a series of marker enzymes in the gastric mucosa was studied by analysis of homogenized biopsy specimens from the lesser and greater curvature of the body and antrum, respectively, obtained from 11 control patients. The activities varied significantly between the regions for the membrane enzymes lactase (p less than 0.0001), neutral-alpha-glucosidase (p less than 0.005), alkaline phosphatase (p less than 0.01), leucyl-beta-naphthylamidase (p less than 0.005), and 5'-nucleotidase (p less than 0.0001) and the lysosomal enzymes N-acetyl-beta-D-glucosaminidase (p less than 0.0001) and acid beta-glucuronidase (p less than 0.0001), using analysis of variance modified for repeated measurements. When paired comparisons between regions were evaluated, the enzyme activities of the antral regions were significantly higher than those of the body stomach. The activities of gamma-glutamyltransferase, acid phosphatase, and the mitochondrial enzyme monoamine oxidase did not alter between regions, nor did the protein to DNA ratio. The demonstrated biochemical distinction between antrum and body of the stomach may be explained by different physiological and histological properties of the two parts.

Elevated gastric juice enzymes--a marker for increased gastric cancer risk?

Measurement of beta-glucuronidase and lactic dehydrogenase in the fasting gastric juice of dyspeptic patients is a useful test for gastric cancer, but about 10% of patients tested have positive results without a demonstrable carcinoma. We have compared the histological features of multiple endoscopic gastric biopsies from 17 such patients with apparently false positive enzyme tests with gastric biopsies from 17 age and sex matched patients with negative enzyme tests. Epithelial dysplasia, a precancerous lesion, was found in 3 patients with positive enzyme tests but was not found in those with negative enzyme tests. Sulphomucin-containing intestinal metaplasia, another lesion which is associated with carcinoma of the stomach, was found in 8 patients with a positive enzyme test (including all 3 with dysplasia) but in only one patient with a negative enzyme test. These findings suggest that patients with positive gastric juice enzyme tests who do not have an established carcinoma form a group who are at increased risk of developing gastric cancer in the future and who may be worthy of long-term follow-up.